Safety and effectiveness of perampanel monotherapy after adjunctive therapy through retention rate in subjects with focal-onset seizures with or without focal to bilateral tonic-clonic seizures: A multicenter retrospective study in Korea.

OBJECTIVE: To assess the effectiveness and tolerability of perampanel monotherapy following conversion from adjunctive therapy. METHODS: This was a multicenter, retrospective, non-interventional study of Korean patients aged ≥12 years with focal-onset seizures (FOS) with or without focal to bilateral tonic-clonic seizures. Data were extracted from electronic medical records of perampanel-treated patients from 1 February 2016 to 31 October 2020. Kaplan-Meier estimated retention rates, effectiveness, and safety were recorded. RESULTS: Subjects (n = 66, mean age 46.2 years) were mostly male (68.2%) with focal to bilateral tonic-clonic seizure (71.2%). Mean duration of illness was 86.3 months. Retention rates after conversion to perampanel monotherapy at 3, 6, and 12 months (primary outcome) were 96.0%, 96.0%, and 75.6%, respectively. Overall retention rates in patients receiving perampanel as adjunctive or monotherapy at 3, 6, 12, 18, and 24 months after perampanel add-on were 100%, 98.3%, 95.9%, 92.6%, and 92.6%, respectively. Mean retention duration was 41.2 months (overall perampanel administration) and 21.4 months (monotherapy). Mean seizure frequency/28 days in the Full Analysis Set (n = 61) was comparable for adjunctive and monotherapy (0.2 ± 0.79 vs 0.2 ± 0.64; change between adjunctive and monotherapy periods: 0.0 ± 0.59; p = 0.498). Perampanel was well tolerated and no new safety signals were identified. Dizziness (4.6%), only reported during adjunctive therapy, was the most common treatment-emergent adverse event. CONCLUSIONS: Conversion to perampanel monotherapy from adjunctive therapy showed promising results in subjects with FOS with/without focal to bilateral tonic-clonic seizures; further studies in a larger population are needed to confirm these encouraging data.

Lateralizing Characteristics of Morphometric Changes to Hippocampus and Amygdala in Unilateral Temporal Lobe Epilepsy with Hippocampal Sclerosis.

Background andObjective: In the present study, a detailed investigation of substructural volume change in the hippocampus (HC) and amygdala (AMG) was performed and the association with clinical features in patients with mesial temporal lobe epilepsy with hippocampal sclerosis (TLE-HS) determined. Methods: The present study included 22 patients with left-sided TLE-HS (LTLE-HS) and 26 patients with right-sided TLE-HS (RTLE-HS). In addition, 28 healthy controls underwent high-resolution T2-weighted image (T2WI) and T1-weighted image (T1WI) MRI scanning. Subfield analysis of HC and AMG was performed using FreeSurfer version 6.0. Results: Patients with TLE-HS showed a decrease in the volume of substructures in both HC and AMG, and this change was observed on the contralateral side and the ipsilateral side with HS. The volume reduction pattern of substructures showed laterality-dependent characteristics. Patients with LTLE-HS had smaller volumes of the ipsilateral subiculum (SUB), contralateral SUB, and ipsilateral cortical nucleus of AMG than patients with RTLE-HS. Patients with RTLE-HS had reduced ipsilateral cornu ammonis (CA) 2/3 and contralateral cortico-amygdaloid transition area (CAT) volumes. The relationship between clinical variables and subregions was different based on the lateralization of the seizure focus. Focal to bilateral tonic-clonic seizures (FTBTCS) was associated with contralateral and ipsilateral side subregions only in LTLE-HS. The abdominal FAS was associated with the volume reduction of AMG subregions only in LTLE-HS, but the volume reduction was less than in patients without FAS. Conclusions: The results indicate that unilateral TLE-HS is a bilateral disease that shows different laterality-dependent characteristics based on the subfield analysis of HC and AMG. Subfield volumes of HC and AMG were associated with clinical variables, and the more damaged substructures depended on laterality in TLE-HS. These findings support the evidence that LTLE-HS and RTLE-HS are disparate epilepsy entities rather than simply identical syndromes harboring a mesial temporal lesion. In addition, the presence of FAS supports good localization value, and abdominal FAS has a high localization value, especially in patients with LTLE-HS.

Comparing Ictal Cardiac Autonomic Changes in Patients with Frontal Lobe Epilepsy and Temporal Lobe Epilepsy by Ultra-Short-Term Heart Rate Variability Analysis.

Background and Objectives: Abnormal epileptic discharges in the brain can affect the central brain regions that regulate autonomic activity and produce cardiac symptoms, either at onset or during propagation of a seizure. These autonomic alterations are related to cardiorespiratory disturbances, such as sudden unexpected death in epilepsy. This study aims to investigate the differences in cardiac autonomic function between patients with temporal lobe epilepsy (TLE) and frontal lobe epilepsy (FLE) using ultra-short-term heart rate variability (HRV) analysis around seizures. Materials and Methods: We analyzed electrocardiogram (ECG) data recorded during 309 seizures in 58 patients with epilepsy. Twelve patients with FLE and 46 patients with TLE were included in this study. We extracted the HRV parameters from the ECG signal before, during and after the ictal interval with ultra-short-term HRV analysis. We statistically compared the HRV parameters using an independent t-test in each interval to compare the differences between groups, and repeated measures analysis of variance was used to test the group differences in longitudinal changes in the HRV parameters. We performed the Tukey-Kramer multiple comparisons procedure as the post hoc test. Results: Among the HRV parameters, the mean interval between heartbeats (RRi), normalized low-frequency band power (LF) and LF/HF ratio were statistically different between the interval and epilepsy types in the t-test. Repeated measures ANOVA showed that the mean RRi and RMSSD were significantly different by epilepsy type, and the normalized LF and LF/HF ratio significantly interacted with the epilepsy type and interval. Conclusions: During the pre-ictal interval, TLE patients showed an elevation in sympathetic activity, while the FLE patients showed an apparent increase and decrease in sympathetic activity when entering and ending the ictal period, respectively. The TLE patients showed a maintained elevation of sympathetic and vagal activity in the pos-ictal interval. These differences in autonomic cardiac characteristics between FLE and TLE might be relevant to the ictal symptoms which eventually result in SUDEP.

The Role of Anterior Thalamic Deep Brain Stimulation as an Alternative Therapy in Patients with Previously Failed Vagus Nerve Stimulation for Refractory Epilepsy.

Deep brain stimulation (DBS) has provided new treatment options for refractory epilepsy; however, treatment outcomes of DBS in refractory epilepsy patients previously treated with vagus nerve stimulation (VNS) have not been clarified. Herein, treatment outcomes of DBS of the anterior nucleus of the thalamus (ANT-DBS) in patients who had previously experienced VNS failure are reported. Seven patients who had previously experienced VNS failure underwent ANT-DBS device implantation. VNS was turned off before DBS device implantation. Monthly seizure counts starting from baseline to 12-18 months after DBS were analyzed. Five (71.3%) of the 7 patients experienced a >50% reduction of seizure counts after DBS; 1 responder reached a seizure-free status after DBS therapy. Of the 2 nonresponders, 1 subject showed improvement in seizure strength and duration, which lessened the impact of the seizures on the patient's quality of life. This is the first study in which favorable outcomes of ANT-DBS surgery were observed in individual patients with refractory epilepsy who had not responded to prior VNS. Further studies with a larger number of subjects and longer follow-up period are needed to confirm the feasibility of ANT-DBS in patients who have previously experienced VNS failure.

SPECT perfusion changes during ictal automatisms with preserved responsiveness in patients with right temporal lobe epilepsy.

Ictal automatism with preserved responsiveness (APR) has been reported, particularly in nondominant temporal lobe epilepsy (TLE), but its pathophysiology remains poorly understood. This study sought to investigate the relationship between APRs and increased cerebral blood flow (CBF) using ictal single photon emission computed tomography (SPECT) in TLE. Forty-seven subjects with right mesial TLE (15 with and 32 without APR) were enrolled. Patients with APR (APR+) were subdivided into four groups according to degree of responsiveness during seizures. Cerebral blood flow changes during these seizures were semiquantitatively assessed by subtraction ictal SPECT coregistered to MRI (SISCOM). Hyperperfusion in temporal regions did not vary significantly between the APR+ and APR- groups. Cerebral blood flow changes in the frontal area, insula, cingulum, and occipital area were also nonsignificant. However, hyperperfusion in the ipsilateral parietal areas was more frequent in the APR- group than in the APR+ group. Furthermore, hyperperfusion of the contralateral basal ganglia showed an inclination to be more common in the APR- group, but without statistical significance. The study suggested that the involvement of the parietal association cortex during seizure may play an important role in ictal loss of consciousness in TLE. Further studies will be needed to elucidate the pathophysiology of changes in consciousness during temporal lobe seizures.

Correlation between headaches and affective symptoms in patients with epilepsy.

Headaches are a neglected entity in patients with epilepsy (PWE), although PWE have a high chance of suffering from seizure-related as well as seizure-unrelated headaches. We aimed to identify the prevalence and characteristics of headaches and investigate the correlation between headaches and affective symptoms in PWE. Consecutive PWE who visited our tertiary outpatient clinic were interviewed about headaches and epilepsy. Affective symptoms were evaluated using the Korean version of the Beck Depression Inventory-II (BDI-II), Beck Anxiety Inventory (BAI), and suicidality portion of the Mini-International Neuropsychiatric Interview. We classified headaches as interictal or seizure-related headaches (SRHs; pre- and postictal). Tension-type headache and migraine were defined based on International Classification of Headache Disorders criteria. From the initial cohort of 177 patients (92 men, mean age: 37.1years), 73 (41.2%) reported suffering from interictal (N=34, 19.2%), preictal (N=3, 1.7%), and postictal (N=48, 27.1%) headaches. Univariate analysis revealed significantly higher BDI and BAI scores in the headache group. Tension-type headaches were the most frequent, and half of the interictal headaches and most of the SRHs were untreated. Spearman's partial correlation analyses showed that headaches overall were significantly related with depression and anxiety. Interictal headaches were correlated with depression only, and postictal headaches were correlated with depression as well as suicidality, separately. These results show that investigating and controlling headaches may relieve affective symptoms and ultimately improve the quality of life of PWE.

Can an exercise bicycle be safely used in the epilepsy monitoring unit?: An exercise method to provoke epileptic seizures and the related safety issues.

BACKGROUND AND PURPOSE: Long-term videoelectroencephalogram (video-EEG) monitoring is performed to diagnose an epileptic seizure and to investigate the differential diagnosis of paroxysmal events. To provoke an epileptic seizure, an exercise method is performed in some cases during long-term video-EEG recording in the epilepsy monitoring unit (EMU). The purpose of this study was two-fold: to assess the frequency and severity of adverse events associated with the use of an exercise bicycle and to find a way to safely use it in the EMU. METHODS: A retrospective survey was performed on all epileptic seizure videos recorded in the EMU from January 2012 to December 2013. Three hundred and fifty patients were included in this study. RESULTS: Eleven patients experienced an epileptic seizure while riding the exercise bicycle in the EMU. One patient's foot got stuck between the cycling pedal and its strap, and one patient fell off the exercise bicycle during the epileptic seizure. However, there were no serious adverse events over two years. CONCLUSION: Epileptic seizures were not frequent while riding the exercise bicycle, and serious injuries did not occur. But, there is a need to improve the safety in the EMU to control the potentially dangerous factors associated with the use of the exercise bicycle and to continuously monitor the patients with help from the staff.

Therapeutic Drug Monitoring of 6 New-Generation Antiseizure Medications Using a Mass Spectrometry Method: Analysis of 2-Year Experience in a Large Cohort of Korean Epilepsy Patients.

CONTEXT.­: New-generation antiseizure medications (ASMs) are increasingly prescribed, and therapeutic drug monitoring (TDM) has been proposed to improve clinical outcome. However, clinical TDM data on new-generation ASMs are scarce. OBJECTIVE.­: To develop and validate a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for therapeutic drug monitoring (TDM) of 6 new-generation ASMs in serum and analyze the clinical TDM data from a large cohort of Korean patients with epilepsy. DESIGN.­: Stable isotope-labeled internal standards were added to protein precipitations of serum. One microliter of sample was separated on Agilent Poroshell EC-C18 column, and lacosamide, perampanel, gabapentin, pregabalin, vigabatrin, and rufinamide were simultaneously quantified by Agilent 6460 triple-quad mass spectrometer in multiple-reaction monitoring mode. Linearity, sensitivity, precision, accuracy, specificity, carryover, extraction recovery, and matrix effect were evaluated. TDM data of 458 samples from 363 Korean epilepsy patients were analyzed. RESULTS.­: The method was linear with limit of detection less than 0.05 µg/mL in all analytes. Intraassay and interassay imprecisions were less than 5% coefficient of variation. Accuracy was within ±15% bias. Extraction recovery ranged from 85.9% to 98.8%. A total of 88% (403 of 458) were on polypharmacy, with 29% (118 of 403) using concomitant enzyme inducers. Only 38% (175 of 458) of the concentrations were therapeutic, with 53% (244 of 458) being subtherapeutic. Drug concentration and concentration-to-dose ratio were highly variable among individuals in all 6 ASMs. CONCLUSIONS.­: A simple and rapid LC-MS/MS method for TDM of 6 ASMs was developed and successfully applied to clinical practice. This large-scale TDM data could help establish an effective monitoring strategy for these drugs.

Ocular motor characteristics of different subtypes of spinocerebellar ataxia: distinguishing features.

Because of frequent involvement of the cerebellum and brainstem, ocular motor abnormalities are key features of spinocerebellar ataxias and may aid in differential diagnosis. Our objective for this study was to distinguish the subtypes by ophthalmologic features after head-shaking and positional maneuvers, which are not yet recognized as differential diagnostic tools in most common forms of spinocerebellar ataxias. Of the 302 patients with a diagnosis of cerebellar ataxia in 3 Korean University Hospitals from June 2011 to June 2012, 48 patients with spinocerebellar ataxia types 1, 2, 3, 6, 7, or 8 or with undetermined spinocerebellar ataxias were enrolled. All patients underwent a video-oculographic recording of fixation abnormalities, gaze-evoked nystagmus, positional and head-shaking nystagmus, and dysmetric saccades. Logistic regression analysis controlling for disease duration revealed that spontaneous and positional downbeat nystagmus and perverted head-shaking nystagmus were strong predictors for spinocerebellar ataxia 6, whereas saccadic intrusions and oscillations were identified as positive indicators of spinocerebellar ataxia 3. In contrast, the presence of gaze-evoked nystagmus and dysmetric saccades was a negative predictor of spinocerebellar ataxia 2. Positional maneuvers and horizontal head shaking occasionally induced or augmented saccadic intrusions/oscillations in patients with spinocerebellar ataxia types 1, 2, and 3 and undetermined spinocerebellar ataxia. The results indicated that perverted head-shaking nystagmus may be the most sensitive parameter for SCA6, whereas saccadic intrusions/oscillations are the most sensitive for spinocerebellar ataxia 3. In contrast, a paucity of gaze-evoked nystagmus and dysmetric saccades is more indicative of spinocerebellar ataxia 2. Head-shaking and positional maneuvers aid in defining ocular motor characteristics in spinocerebellar ataxias. © 2013 Movement Disorder Society.

Factors influencing serum topiramate concentrations in routine therapeutic drug monitoring in Korean adult patients with epilepsy.

PURPOSE: Topiramate (TPM) is a broad-spectrum anticonvulsant used both as an adjunctive treatment and as monotherapy. In this study, the results from a routine therapeutic drug monitoring (TDM) service for TPM are summarized. In addition, factors influencing the variability in serum concentration of TPM and the effects of comedication on serum TPM concentration were investigated. METHODS: Serum measurements of TPM from a routine TDM database were analyzed retrospectively. Concentration-to-dose ratio (CDR) was calculated to assess pharmacokinetic variability. We compared CDRs for patients receiving TPM monotherapy and patients receiving TPM with other antiepileptic drugs, together with the effects of each comedication on TPM concentration were studied. RESULTS: There were 510 samples from 476 adult patients. Serum TPM was below 2.0 mg/L or above 10.0 mg/L in 28.2% and 5.9% of samples, respectively. Although serum TPM was broadly related to prescribed dose, there was wide variation. Most patients using TPM were treated in combination with other anticonvulsants (90.8%). TPM-CDR in patients receiving TPM monotherapy was not significantly different from those receiving TPM in combination with nonenzyme inducers, but TPM-CDR was lower in patients who were taking inducers (P < 0.0001, Kruskal-Wallis test, Dunnett method). CONCLUSIONS: A large interindividual variability in TPM serum concentrations was observed in this cohort of patients. TDM of TPM is useful in selected patients such as those suspected of poor compliance/absorption and those who may experience pharmacokinetic changes because of comedication or physiological changes.

Intraoperative neurophysiologic monitoring: basic principles and recent update.

The recent developments of new devices and advances in anesthesiology have greatly improved the utility and accuracy of intraoperative neurophysiological monitoring (IOM). Herein, we review the basic principles of the electrophysiological methods employed under IOM in the operating room. These include motor evoked potentials, somatosensory evoked potentials, electroencephalography, electromyography, brainstem auditory evoked potentials, and visual evoked potentials. Most of these techniques have certain limitations and their utility is still being debated. In this review, we also discuss the optimal stimulation/recording method for each of these modalities during individual surgeries as well as the diverse criteria for alarm signs.

Exploring Autonomic Alterations during Seizures in Temporal Lobe Epilepsy: Insights from a Heart-Rate Variability Analysis.

Epilepsy's impact on cardiovascular function and autonomic regulation, including heart-rate variability, is complex and may contribute to sudden unexpected death in epilepsy (SUDEP). Lateralization of autonomic control in the brain remains the subject of debate; nevertheless, ultra-short-term heart-rate variability (HRV) analysis is a useful tool for understanding the pathophysiology of autonomic dysfunction in epilepsy patients. A retrospective study reviewed medical records of patients with temporal lobe epilepsy who underwent presurgical evaluations. Data from 75 patients were analyzed and HRV indices were extracted from electrocardiogram recordings of preictal, ictal, and postictal intervals. Various HRV indices were calculated, including time domain, frequency domain, and nonlinear indices, to assess autonomic function during different seizure intervals. The study found significant differences in HRV indices based on hemispheric laterality, language dominancy, hippocampal atrophy, amygdala enlargement, sustained theta activity, and seizure frequency. HRV indices such as the root mean square of successive differences between heartbeats, pNN50, normalized low-frequency, normalized high-frequency, and the low-frequency/high-frequency ratio exhibited significant differences during the ictal period. Language dominancy, hippocampal atrophy, amygdala enlargement, and sustained theta activity were also found to affect HRV. Seizure frequency was correlated with HRV indices, suggesting a potential relationship with the risk of SUDEP.

Identifying important factors for successful surgery in patients with lateral temporal lobe epilepsy.

OBJECTIVE: Lateral temporal lobe epilepsy (LTLE) has been diagnosed in only a small number of patients; therefore, its surgical outcome is not as well-known as that of mesial temporal lobe epilepsy. We aimed to evaluate the long-term (5 years) and short-term (2 years) surgical outcomes and identify possible prognostic factors in patients with LTLE. METHODS: This retrospective cohort study was conducted between January 1995 and December 2018 among patients who underwent resective surgery in a university-affiliated hospital. Patients were classified as LTLE if ictal onset zone was in lateral temporal area. Surgical outcomes were evaluated at 2 and 5 years. We subdivided based on outcomes and compared clinical and neuroimaging data including cortical thickness between two groups. RESULTS: Sixty-four patients were included in the study. The mean follow-up duration after the surgery was 8.4 years. Five years after surgery, 45 of the 63 (71.4%) patients achieved seizure freedom. Clinically and statistically significant prognostic factors for postsurgical outcomes were the duration of epilepsy before surgery and focal cortical dysplasia on postoperative histopathology at the 5-year follow-up. Optimal cut-off point for epilepsy duration was eight years after the seizure onset (odds ratio 4.375, p-value = 0.0214). Furthermore, we propose a model for predicting seizure outcomes 5 years after surgery using the receiver operating characteristic curve and nomogram (area under the curve = 0.733; 95% confidence interval, 0.588-0.879). Cortical thinning was observed in ipsilateral cingulate gyrus and contralateral parietal lobe in poor surgical group compared to good surgical group (p-value < 0.01, uncorrected). CONCLUSIONS: The identified predictors of unfavorable surgical outcomes may help in selecting optimal candidates and identifying the optimal timing for surgery among patients with LTLE. Additionally, cortical thinning was more extensive in the poor surgical group.

Intraoperative visual evoked potential has no association with postoperative visual outcomes in transsphenoidal surgery.

OBJECTIVE: The aim of this study was to elucidate the relationship between changes in the intraoperative visual evoked potential (VEP) waveform and postoperative visual functional outcomes. METHODS: Between February 2009 and December 2010, we performed endoscopic endonasal transsphenoidal surgery for sellar or perisellar lesions in 65 consecutive patients with intraoperative VEP monitoring using scalp electrodes under total venous anesthesia. Among the 65 patients, 53 patients were followed-up with postoperative visual function evaluation. VEP waveforms measured at baseline were compared with those obtained toward the end of surgery and the association between changes in VEP waveforms and visual outcomes measured preoperatively and postoperatively were assessed. RESULT: Reproducible waveforms were obtained intraoperatively in 95 of 106 eyes (89.6%). Of the 95 eyes with reproducible VEP, 64 eyes had stable VEP during the surgery, 19 eyes showed VEP improvement, and 12 eyes had VEP deterioration. Of 64 eyes with a stable VEP, 42 showed no change in visual acuity postoperatively, 13 manifested improvement, and 9 worsened. Of 19 eyes with intraoperative VEP improvement, 13 exhibited no change, 4 improved, and 2 worsened postoperatively. Among 12 eyes with VEP deterioration, just 2 eyes showed visual worsening while the other 10 did not change or improved. Postoperative visual evaluation revealed no light perception in 2 eyes whose intraoperative VEP waveforms were stable throughout the surgery. CONCLUSIONS: Intraoperative monitoring of VEP with scalp electrodes under total venous anesthesia had a reproducibility of 89.6% during transsphenoidal surgery for sellar or perisellar lesions. However, the intraoperative VEP waveforms showed no association with postoperative visual outcomes.

Semi-supervised automatic seizure detection using personalized anomaly detecting variational autoencoder with behind-the-ear EEG.

BACKGROUND AND OBJECTIVE: Epilepsy is one of the most common neurologic diseases worldwide, and 30% of the patients live with uncontrolled seizures. For the safety of patients with epilepsy, an automatic seizure detection algorithm for continuous seizure monitoring in daily life is important to reduce risks related to seizures, including sudden unexpected death. Previous researchers applied machine learning to detect seizures with EEG, but the epileptic EEG waveform contains subtle changes that are difficult to identify. Furthermore, the imbalance problem due to the small proportion of ictal events caused poor prediction performance in supervised learning approaches. This study aimed to present a personalized deep learning-based anomaly detection algorithm for seizure monitoring with behind-the-ear electroencephalogram (EEG) signals. METHODS: We collected behind-the-ear EEG signals from 16 patients with epilepsy in the hospital and used them to develop and evaluate seizure detection algorithms. We modified the variational autoencoder network to learn the latent representation of normal EEG signals and performed seizure detection by measuring the anomalies in EEG signals using the trained network. To personalize the algorithm, we also proposed a method to calibrate the anomaly score for each patient by comparing the representations in the latent space. RESULTS: Our proposed algorithm showed a sensitivity of 90.4% with a false alarm rate of 0.83 per hour without personal calibration. On the other hand, the one-class support vector machine only showed a sensitivity of 84.6% with a false alarm rate of 2.17 per hour. Furthermore, our proposed model with personal calibration achieved 94.2% sensitivity with a false alarm rate of 0.29 while detecting 49 of 52 ictal events. CONCLUSIONS: We proposed a novel seizure detection algorithm with behind-the-ear EEG signals via semi-supervised learning of an anomaly detecting variational autoencoder and personalization method of anomaly scoring by comparing latent representations. Our approach achieved improved seizure detection with high sensitivity and a lower false alarm rate.

Perampanel as First Add-On Therapy in Patients with Focal-Onset Seizures in the FAME Trial: Post hoc Analyses of Efficacy and Safety Related to Maintenance Dose and Background Antiepileptic Drug Therapy.

Background and Purpose: FAME (Fycompa® as first Add-on to Monotherapy in patients with Epilepsy; NCT02726074), a previously reported single-arm, phase IV study, showed that perampanel improved seizure control as first add-on to failed anti-seizure medication (ASM) monotherapy in 85 South Korean patients aged ≥12 years with focal-onset seizures (FOS) with/without focal to bilateral tonic-clonic seizures. We present results of three post hoc analyses of FAME that further assessed the efficacy and safety of perampanel. Methods: Patients were stratified by low- (4, 6 mg/day) versus high- (8, 10, 12 mg/day) dose maintenance perampanel, perampanel added to first- versus second-line ASM monotherapy, and concomitant background ASM monotherapy and perampanel dose. The primary endpoint was the proportion of patients with a ≥50% reduction in total seizure frequency during the 24-week maintenance period. Safety was assessed by the descriptive incidence of treatment-emergent adverse events (TEAEs). Results: In post hoc analyses, 50% responder rates were significantly higher for low- versus high-dose maintenance perampanel (88.6% vs. 40.0%; p<0.001) and when added to first- versus second-line ASM monotherapy (83.5% vs. 33.3%; p=0.013). By concomitant background ASM and perampanel maintenance dose, 50% responder rates were 100% for perampanel 4 mg/day added to carbamazepine, oxcarbazepine, lamotrigine, or valproic acid, and 85% when added to levetiracetam. Add-on perampanel improved 75% and seizure-free responder rates, and median percent changes from baseline seizure frequency per 28 days. Perampanel was well tolerated when added to ASM monotherapy, with dizziness being the most common TEAE. Conclusions: Post hoc analyses of FAME provide supportive data for the use of perampanel as an effective and well-tolerated first add-on treatment to a broad spectrum of ASM monotherapies in patients with FOS.

Perampanel as First Adjunctive Treatment in Patients with Focal-Onset Seizures in the FAME Study: Post hoc Analyses of Dose-Related Efficacy, Safety and Clinical Factors Associated with Response.

Background and Purpose: Perampanel is approved for the adjunctive treatment of focal-onset seizures (FOS) with or without secondary generalized seizures. The FAME (Fycompa® as first Add-on to Monotherapy in patients with Epilepsy; NCT02726074) study evaluated the efficacy and safety of perampanel added to monotherapy in patients with FOS with or without secondary generalized seizures (SGS). Post hoc analyses of the FAME study assessed potential predictors of response and an in-depth evaluation of the safety and efficacy of perampanel. Methods: Efficacy was assessed by reduction of total seizure frequency by ≥50%, ≥75% or 100%, and safety by incidence of treatment-emergent adverse events (TEAEs) and TEAEs leading to discontinuation. Univariate and multivariate logistic regression analyses for treatment response were performed. Results: Most patients (82/85) received perampanel doses of 4-8 mg/day during maintenance therapy and the highest efficacy rates were achieved with 4 mg/day, irrespective of efficacy outcome. Doses of 4 or 6 mg/day in patients with FOS with SGS (n=16) produced comparable efficacy outcomes. In multivariate analysis, total perampanel dose was predictive of 50% and 75% response rates; longer total perampanel administration period with 50% response; and concomitant non-anti-seizure medication with a 100% response. Patients developed a TEAE more frequently during the 12-week titration period (60.2%) than the 24-week maintenance period (28.4%), including dizziness (45.5% vs. 9.1%), somnolence (10.2% vs. 0%), and headache (4.5% vs. 3.4%). Conclusions: Post hoc analyses show that even low doses of perampanel may be effective and TEAEs are usually self-limited or well-tolerated.

Prediction of the Responsiveness to Vagus-Nerve Stimulation in Patients with Drug-Resistant Epilepsy via Directed-Transfer-Function Analysis of Their Perioperative Scalp EEGs.

This study aims to compare directed transfer function (DTF), which is an effective connectivity analysis, derived from scalp EEGs between responder and nonresponder groups implanted with vagus-nerve stimulation (VNS). Twelve patients with drug-resistant epilepsy (six responders and six nonresponders) and ten controls were recruited. A good response to VNS was defined as a reduction of ≥50% in seizure frequency compared with the presurgical baseline. DTF was calculated in five frequency bands (delta, theta, alpha, beta, and broadband) and seven grouped electrode regions (left and right frontal, temporal, parieto-occipital, and midline) in three different states (presurgical, stimulation-on, and stimulation-off states). Responders showed presurgical nodal strength close to the control group in both inflow and outflow, whereas nonresponders exhibited increased inward and outward connectivity measures. Nonresponders also had increased inward and outward connectivity measures in the various brain regions and various frequency bands assessed compared with the control group when the stimulation was on or off. Our study demonstrated that the presurgical DTF profiles of responders were different from those of nonresponders. Moreover, a presurgical normal DTF profile may predict good responsiveness to VNS.

Levetiracetam Therapeutic Drug Monitoring in a Large Cohort of Korean Epileptic Patients.

Levetiracetam is a new antiepileptic drug (AED) used for treating and preventing partial or generalized seizures. The usefulness of levetiracetam therapeutic drug monitoring (TDM) is related to inter- or intra-individual pharmacokinetic variability, drug interactions, and patient noncompliance. We aimed to investigate the levetiracetam TDM status in Korean epilepsy patients. Serum trough levetiracetam concentrations were measured using liquid chromatography-tandem mass spectrometry in 710 samples from 550 patients. The median (range) daily and weight-adjusted levetiracetam doses were 1500 (20-5000) mg and 25.5 (3.03-133.0) mg/kg, respectively. Patients on levetiracetam monotherapy constituted only 19.5% of the population, while 30.1% were on co-medication with valproate and 56.0% with enzyme-inducing AEDs (EIAEDs). Observed levetiracetam concentrations were widely distributed, ranging 0.8-95 mg/L, with a median of 17.3 mg/L. Levetiracetam concentrations were therapeutic, supra-therapeutic, and sub-therapeutic in 58.5% (n = 393), 11.6% (n = 78), and 29.9% (n = 201) of samples, respectively. There was a strong correlation between weight-adjusted levetiracetam dosage and concentrations (ρ = 0.6896, p < 0.0001). In this large-scale clinical study, a large inter-individual difference in levetiracetam pharmacokinetics was observed, and levetiracetam concentrations were influenced by EIAEDs. For individual dose adjustments and monitoring compliance, routine levetiracetam TDM is needed in epilepsy patients.