Treatment compliance, treatment patterns, and healthcare utilization in epilepsy patients with first add-on antiepileptic drugs: A nationwide cohort study.

Objective: This study aimed to assess the treatment compliance, patterns, healthcare resource utilization (HCRU), and costs of anti-epilepsy drugs (AEDs) as the first add-on therapy in patients with epilepsy. Methods: We conducted a retrospective population-based cohort study using Korean National Health Insurance claims data from 2016 to 2020. Patients with epilepsy who newly received AED add-on therapy were identified and followed for up to 12 months to evaluate persistence, adherence, treatment patterns, HCRU, and costs. Results: Among 6,746 patients who initiated AED add-on therapy, 65.5% were persistent on their index AED add-on from the index date until the end of the follow-up period, and the mean persistent time on the index add-on was 307.3 ± 92.3 days. A total of 76.8% patients were adherent, with a medication possession ratio (MPR) ≥80%, and the mean MPR was 88.9 ± 25.4%. Persistence and adherence to the index AED add-on were relatively higher among patients prescribed lamotrigine, levetiracetam, oxcarbazepine, and perampanel than those prescribed carbamazepine, topiramate, or valproate. A total of 41.0% of the patients changed their index AED add-on during the follow-up period. The carbamazepine, topiramate, and valproate groups had higher rates of change than the other AED groups. HCRU and costs tended to be lower in the lamotrigine, levetiracetam, oxcarbazepine, and perampanel groups. Furthermore, perampanel showed the lowest HCRU and costs for all-cause cases as well as the lowest length of stay and outpatient visits for epilepsy-related cases. Conclusion: In this population-based study, the use of lamotrigine, levetiracetam, oxcarbazepine, or perampanel as the first add-on therapy in patients with epilepsy contributed to better treatment compliance and lower HCRU and costs than that of carbamazepine, topiramate, or valproate.

Chronic social stress in early life can predispose mice to antisocial maltreating behavior.

Purpose: In our previous study, we developed an assay system to evaluate antisocial maltreating behavior of conspecific mice using a perpetrator-victim paradigm. We also generated a mouse model for the maltreating behavior by mimicking child maltreatment or abuse. Here, we further investigate the antisocial behavior using anti-aggressive and antipsychotic drugs. Methods: Model mice sequentially subjected to maternal separation (MS), social defeat (SD), and social isolation (SI) in that order (MS/SD/SI model) were subjected to a maltreating behavioral task. The MS/SD/SI mice were treated with oxytocin (OXY), clozapine (CLZ), haloperidol (HAL), and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). Western blotting and enzyme-linked immunosorbent assay were used for protein analysis. Results: A substantial portion of the MS/SD/SI model mice (46% of males and 40% of females) showed a higher number of nose pokes than the control. OXY or 8-OH-DPAT treatment reduced the high number of nose pokes by the MS/SD/SI mice, whereas HAL increased it. CLZ did not affect the number of nose pokes by the MS/SD/SI mice. Interestingly, although the OXY level in the MS/SD/SI mice was similar to that in the control, the amount of OXY receptor was lower in the MS/SD/SI mice. The amount of 5-HT1A receptor was also decreased in the MS/SD/SI mice. Conclusion: Chronic social stress in childhood might predispose a mouse to antisocial behavior. Our maltreating behavior assay system, including the MS/SD/SI model, is a good animal system for research on and drug screening for brain disorders associated with antisocial or psychotic behavior.

Gut microbiome diversity in a febrile seizure mouse model.

Purpose: Febrile seizures at a young age can provoke late-onset temporal lobe epilepsy. Since recent evidence has suggested that the gut microbiome affects central nervous system pathology across the blood-brain barrier, we hypothesized that febrile seizures alter the composition of the gut microbiome to provoke epilepsy. Methods: Third-generation C57BL/6 mice were separated into two groups (n = 5 each), and hot air was applied to only one group to cause febrile seizures. After two weeks of heat challenge, the fecal pellets acquired from each group were analyzed. Results: The gut microbiota of fecal pellets from each group revealed five taxa at the genus level and eight taxa at the species level that were significantly different in proportion between the groups. Conclusion: Although there was no significant difference in the overall diversity of the gut microbiota between the two groups, the identified heterogeneity may imply the pathognomonic causative relevance of febrile seizures and the development of epilepsy.

Topiramate dosage optimization for effective antiseizure management via population pharmacokinetic modeling.

OBJECTIVE: Despite the suggested topiramate serum level of 5-20 mg/L, numerous institutions have observed substantial drug response at lower levels. We aim to investigate the correlation between topiramate serum levels, drug responsiveness, and adverse events to establish a more accurate and tailored therapeutic range. METHODS: We retrospectively analyzed clinical data collected between January 2017 and January 2022 at Seoul National University Hospital. Drug responses to topiramate were categorized as "insufficient" or "sufficient" by reduction in seizure frequency ≥ 50%. A population pharmacokinetic model estimated serum levels from spot measurements. ROC curve analysis determined the optimal cutoff values. RESULTS: A total of 389 epilepsy patients were reviewed having a mean dose of 178.4 ± 117.9 mg/day and the serum level, 3.9 ± 2.8 mg/L. Only 5.6% samples exhibited insufficient response, with a mean serum level of 3.6 ± 2.5 mg/L while 94.4% demonstrated sufficient response, with a mean 4.0 ± 2.8 mg/L, having no statistical significance. Among the 69 reported adverse events, logistic regression analysis identified a significant association between ataxia and serum concentration (p = 0.04), with an optimal cutoff value of 6.5 mg/L. INTERPRETATION: This study proposed an optimal therapeutic concentration for topiramate based on patients' responsiveness to the drug and the incidence of adverse effects. We recommended serum levels below 6.5 mg/L to mitigate the risk of ataxia-related side effects while dose elevation was found unnecessary for suboptimal responders, as the drug's effectiveness plateaus at minimal doses.

Long-term efficacy and safety of adjunctive perampanel in patients from the Asia-Pacific region with refractory focal-onset seizures in Study 335 open-label extension.

OBJECTIVE: To evaluate the long-term efficacy, safety, and tolerability of adjunctive perampanel for the treatment of patients with refractory focal-onset seizures (FOS), with or without focal to bilateral tonic-clonic seizures (FBTCS), from the Asia-Pacific region. METHODS: Study 335 (NCT01618695) was a randomized, double-blind, placebo-controlled, Phase III study. Patients aged ≥12 years with refractory FOS who completed the Core Study could enter an open-label extension (OLEx) Phase (6-week Conversion and ≥46-week Maintenance Period). Endpoints included median percent reduction in seizure frequency per 28 days, 50% responder and seizure-freedom rates, and treatment-emergent adverse events (TEAEs). RESULTS: The Intent-to-Treat Analysis Set included 704 patients (529 received perampanel and 175 received placebo during the Core Study; all patients received perampanel during OLEx). The median percent reduction in seizure frequency and 50% responder rates in patients who received perampanel during the Core Study were maintained throughout the OLEx Phase (Week 64-75: 55.9% and 54.3%, respectively). Seizure freedom for ≥12 consecutive months at any time during perampanel treatment was achieved by 4.1% of patients with FOS and 14.2% of patients with FBTCS. Among patients treated with perampanel 4 mg/day (n = 83), median reduction in seizure frequency was lower in those who received concomitant enzyme-inducing anti-seizure medications (EIASMs) than those who received non-EIASMs. The most common TEAE was dizziness (n = 318; 46.8%); 141 (20.8%) patients had TEAEs that led to study/drug withdrawal. SIGNIFICANCE: Overall, long-term seizure control was achieved with adjunctive perampanel in patients with refractory FOS, with or without FBTCS, in an Asia-Pacific population.

Teratoma pathology and genomics in anti-NMDA receptor encephalitis.

INTRODUCTION: Ovarian teratoma is a common occurrence in patients with anti-NMDA receptor encephalitis (NMDARe), and its removal is crucial for a favorable prognosis. However, the initial pathogenesis of autoimmunity in the encephalitic teratoma remains unclear. In this study, we aimed to investigate the genomic landscape and microscopic findings by comparing NMDARe-associated teratomas and non-encephalitic control teratomas. MATERIALS AND METHODS: A prospective consecutive cohort of 84 patients with NMDARe was recruited from January 2014 to April 2020, and among them, patients who received teratoma removal surgery at Seoul National University Hospital were enrolled. We conducted a comparison of whole-exome sequencing data and pathologic findings between NMDARe-associated teratomas and control teratomas. RESULTS: We found 18 NMDARe-associated teratomas from 15 patients and compared them with 17 non-encephalitic control teratomas. Interestingly, the genomic analysis revealed no significant differences in mutations between encephalitic and non-encephalitic teratomas. Pathologic analysis showed no discrepancies in terms of the presence of neuronal tissue and lymphocytic infiltration between the encephalitic teratomas (n = 14) and non-encephalitic teratomas (n = 18). However, rituximab-naïve encephalitic teratomas exhibited a higher frequency of germinal center formation compared to non-encephalitic teratomas (80% vs. 16.7%, P = 0.017). Additionally, rituximab-treated encephalitic teratomas demonstrated a reduced number of CD20+ cells and germinal centers in comparison to rituximab-naïve encephalitic teratomas (P = 0.048 and 0.023, respectively). DISCUSSION: These results suggest that the initiation of immunopathogenesis in NMDARe-associated teratoma is not primarily attributed to intrinsic tumor mutations, but rather to immune factors present in the encephalitic patient group, ultimately leading to germinal center formation within the teratoma.

Using spectral and temporal filters with EEG signal to predict the temporal lobe epilepsy outcome after antiseizure medication via machine learning.

Epilepsy is a neurological disorder in which the brain is transiently altered. Predicting outcomes in epilepsy is essential for providing feedback that can foster improved outcomes in the future. This study aimed to investigate whether applying spectral and temporal filters to resting-state electroencephalography (EEG) signals could improve the prediction of outcomes for patients taking antiseizure medication to treat temporal lobe epilepsy (TLE). We collected EEG data from a total of 46 patients (divided into a seizure-free group (SF, n = 22) and a non-seizure-free group (NSF, n = 24)) with TLE and retrospectively reviewed their clinical data. We segmented spectral and temporal ranges with various time-domain features (Hjorth parameters, statistical parameters, energy, zero-crossing rate, inter-channel correlation, inter-channel phase locking value and spectral information derived from Fourier transform, Stockwell transform, and wavelet transform) and compared their performance by applying an optimal frequency strategy, an optimal duration strategy, and a combination strategy. For all time-domain features, the optimal frequency and time combination strategy showed the highest performance in distinguishing SF patients from NSF patients (area under the curve (AUC) = 0.790 ± 0.159). Furthermore, optimal performance was achieved by utilizing a feature vector derived from statistical parameters within the 39- to 41-Hz frequency band with a window length of 210 s, as evidenced by an AUC of 0.748. By identifying the optimal parameters, we improved the performance of the prediction model. These parameters can serve as standard parameters for predicting outcomes based on resting-state EEG signals.

Identification of bacterial pathogens in brain abscesses by metagenomic approach using nanopore 16S amplicon sequencing.

Brain abscess is medically challenging. In this study, we applied nanopore sequencing for 16S rRNA analysis and investigated its efficacy and diagnostic value for patients with brain abscesses. Genomic DNA was extracted from the pus samples (n = 27) of brain abscess, and 16S rRNA genes were amplified by PCR. Sequencing libraries were generated using a rapid barcoding kit, and the generated reads were analyzed using the EPI2ME16S workflow. A conventional culture study was performed. More sensitive identification of pathogens was made by 16S sequencing, faster than the culture study. The proportion of anaerobic bacteria identified by 16S sequencing was higher (75%) than that obtained by culturing (32%). Polymicrobial infections were identified in 10 cases (40%) by 16S sequencing, while the culture study identified multiple bacteria in only 2 cases (8%). 16S sequencing was useful for identifying the composition of polymicrobial infections, including rare pathogens, and for the initial diagnosis of space-occupying lesions.

Five-Year Retention of Perampanel and Polytherapy Patterns: 328 Patients From a Single Center in South Korea.

BACKGROUND AND PURPOSE: Perampanel (PER) is an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid antagonist used to treat focal and generalized epilepsy. Comprehensive data from real-world settings with long-term follow-ups are still scarce. This study aimed to determine the factors related to PER retention and the polytherapy pattern with PER. METHODS: We reviewed all patients with epilepsy with a history of PER prescription during 2008-2017 and over a follow-up of >3 years. PER usage patterns and associated factors were analyzed. RESULTS: Among the 2,655 patients in the cohort, 328 (150 females, 178 males) were enrolled. The ages at onset and diagnosis were 21.1±14.7 years and 25.6±16.1 years (mean±standard deviation), respectively. The age at the first visit to our center was 31.8±13.8 years. Seizure types were focal, generalized, and unknown onset in 83.8%, 15.9%, and 0.3% of patients, respectively. The most common etiology was structural (n=109, 33.2%). The maintenance duration of PER was 22.6±19.2 months (range=1-66 months). The initial number of concomitant antiseizure medications was 2.4±1.4 (range=0-9). The most common regimen was PER plus levetiracetam (n=41, 12.5%). The median number of 1-year seizures before PER usage was 8 (range=0-1,400). A seizure reduction of >50% was recorded in 34.7% of patients (52.0% and 29.2% in generalized and focal seizures, respectively). The 1-, 2-, 3-, 4-, and 5-year retention rates for PER were 65.3%, 50.4%, 40.4%, 35.3%, and 21.5%, respectively. A multivariate analysis indicated that lower age at onset was associated with longer retention (p=0.01). CONCLUSIONS: PER was safely used in patients with diverse characteristics and was maintained for a long time in a real-world setting, especially in patients with a lower age at onset.

Myelin oligodendrocyte glycoprotein antibody-associated encephalitis after severe acute respiratory syndrome coronavirus 2 infection: a case report and retrospective case reviews.

Several cases of myelin oligodendrocyte glycoprotein (MOG) antibody-associated encephalitis have been reported after coronavirus disease 2019 (COVID-19). In this case, the patient presented with focal status epilepticus with impaired awareness, auditory hallucinations, and incoherent speech after COVID-19. Brain magnetic resonance imaging revealed no specific findings. Cerebrospinal fluid results showed pleocytosis and MOG antibody testing confirmed anti-MOG antibody with live cell-based fluorescence-activated cell sorting assay. The patient was diagnosed with MOG antibody-associated autoimmune encephalitis and treated with intravenous immunoglobulin, rituximab, and tocilizumab. This case occurred presumably due to auto-antibody production following COVID-19.

Lesion Detection Through MRI Postprocessing in Pathology-Proven Focal Cortical Dysplasia: Experience at a Single Institution in the Republic of Korea.

BACKGROUND AND PURPOSE: Focal cortical dysplasia (FCD) is one of the most common causes of drug-resistant epilepsy, and necessitates a multimodal evaluation to ensure optimal surgical treatment. This study aimed to determine the supportive value of the morphometric analysis program (MAP) in detecting FCD using data from a single institution in Korea. METHODS: To develop a standard reference for the MAP, normal-looking MRIs by two scanners that are frequently used in this center were chosen. Patients with drug-resistant epilepsy and FCD after surgery were candidates for the analysis. The three-dimensional T1-weighted MRI scans of the patients were analyzed as test cases using the MAP. RESULTS: The MRI scans of 87 patients were included in the analysis. The radiologist detected abnormal findings correlated with FCD (RAD positive [RAD(+)]) in 34 cases (39.1%), while the MAP could detect FCD in 25.3% of cases. A combination of the MAP (MAP[+] cases) with interpretations by the radiologist increased the detection to 42.5% (37 cases). The lesion detection rate was not different according to the type of reference scanners except in one case. MAP(+)/RAD(-) presented in three cases, all of which had FCD type IIa. The detection rate was slightly higher using the same kind of scanner as a reference, but not significantly (35.0% vs. 22.4% p=0.26). CONCLUSIONS: The results of postprocessing in the MAP for detecting FCD did not depend on the type of reference scanner, and the MAP was the strongest in detecting FCD IIa. We suggested that the MAP could be widely utilized without developing institutional standards and could become an effective tool for detecting FCD lesions.

Clinicoradiologic data of familial cerebral cavernous malformation with age-related disease burden.

OBJECTIVE: Familial cerebral cavernous malformation (FCCM) is an autosomal dominant disease induced by loss-of-function mutations in three CCM genes, KRIT1, CCM2, and PDCD10. However, previous studies paid little attention to analyzing the radiologic features and age-related disease burden according to the genes. Therefore, we retrospectively reviewed the genetic tests of our center's clinical FCCM patients. METHOD: This study investigated clinical FCCM patients with multiple lesions or a family history of CCMs who underwent the FCCM gene (KRTI1, CCM2, and PDCD10) panel test. The clinical, genetic, and radiologic features were analyzed. RESULT: Among the patients (n = 34) undergoing the FCCM gene test, twenty-seven patients had CCM confirmed by brain MRI, and twenty-one patients were considered to have FCCM (cohort 1). In cohort 1, thirteen patients had mutations in the FCCM gene, but eight did not. Cohort 2 comprised cohort 1 and four family members with the same mutation as the probands. Six novel variants in CCM genes were detected (KRIT1 c.22_26del, c.815dup, c.1094_1098del, c.1147-2A>G, c.2124dup, and PDCD10 c.150 + 1dup). Cohort 1 demonstrated that brainstem lesions were mostly associated with the mutation detection in CCM genes (brainstem, lateral temporal, and parietal lesions vs. lateral temporal and parietal lesions, AUC 0.928 vs. 0.779, P = 0.0389). The radiologic severity worsened according to age in the KRIT1 group compared with the Mutation not detected group (correlation coefficient 0.75 (P < 0.001) versus 0.53 (P = 0.004)). CONCLUSION: The brainstem lesion could be the radiologic marker for FCCM with the mutation detected. The age-related disease burden regarding FCCM according to genetic information was demonstrated.

MOG antibody-associated encephalitis in adult: clinical phenotypes and outcomes.

BACKGROUND: We investigated the clinical characteristics and outcomes of myelin oligodendrocyte glycoprotein (MOG) antibody-associated autoimmune encephalitis (MOGAE) in adult patients. METHODS: From an institutional cohort, we analysed adult patients with MOGAE followed-up for more than 1 year. Disease severity was assessed using the modified Rankin scale (mRS) and Clinical Assessment Scale in Autoimmune Encephalitis scores. Immunotherapy profiles, outcomes and disease relapses were evaluated along with serial brain MRI data. RESULTS: A total of 40 patients were enrolled and categorised into cortical encephalitis (18 patients), limbic encephalitis (LE, 5 patients) and acute disseminated encephalomyelitis (ADEM, 17 patients). 80.0% of patients achieved good clinical outcomes (mRS 0‒2) and 40.0% relapsed. The LE subtype was associated with an older onset age (p=0.004) and poor clinical outcomes (p=0.014) than the other subtypes but with a low rate of relapse (0.0%). 21/25 (84.0%) relapse attacks were associated with an absence or short (≤6 months) immunotherapy maintenance. On MRI, the development of either diffuse cerebral or medial temporal atrophy within the first 6 month was correlated with poor outcomes. MOG-antibody (MOG-Ab) was copresent with anti-N-methyl-D-aspartate receptor (NMDAR)-antibody in 13 patients, in whom atypical clinical presentation (cortical encephalitis or ADEM, p<0.001) and disease relapse (46.2% vs 0.0%, p<0.001) were more frequent compared with conventional NMDAR encephalitis without MOG-Ab. CONCLUSIONS: Outcomes are different according to the three phenotypes in MOGAE. Short immunotherapy maintenance is associated with relapse, and brain atrophy was associated with poor outcomes. Patients with dual antibodies of NMDAR and MOG have a high relapse rate.

Who are the Better Candidates for Epilepsy Surgery?

The resective epilepsy surgery can be the effective procedure to get seizure-free outcome in these drug resistant epilepsy (DRE) patients. Class I evidence firmly establishes the superiority of epilepsy surgery over medical treatments in both seizure control and quality of life for DRE patients. For the effective identification of optimal surgical candidates, it's essential to understand the prognostic factors of epilepsy surgery based on the surgical methods employed. Established positive prognostic indicators for temporal resection include the presence of hippocampal sclerosis on magnetic resonance imaging (MRI), focal lesions on MRI, unilateral temporal spikes, concordant ictal electroencephalography (EEG), and a history of prolonged febrile convulsion. Potential negative predictors encompass preoperative secondary generalized tonic-clonic seizures, a normal MRI, postoperative EEG spikes, and age at the time of surgery. For neocortical epilepsy, the prognostic factors identified through multivariate analysis were the presence of a discrete lesion, localized hypometabolism on Fluorodeoxyglucose positron emission tomography (FDG-PET), and localized ictal EEG. A significant correlation was found between achieving a seizure-free outcome in no visible lesion on MRI (MR-negative) epilepsy patients and having concordance in two or more presurgical evaluations, specifically in interictal EEG, ictal EEG, FDG-PET, and ictal single-photon emission computed tomography. There was a marked improvement in the seizure-free outcome in MR-negative temporal lobe epilepsy (TLE) by the application of this strategy. The better surgical candidates for epilepsy surgery are the followings: patients displaying a discrete lesion on MRI with concordant video-EEG monitoring (VEM) results, patients diagnosed with unilateral hippocampal sclerosis who have concordant VEM results, patients with unilateral hippocampal sclerosis but discordant VEM results, patients with focal cortical dysplasia and concordant VEM results, and patients diagnosed with MR-negative TLE who exhibit two or more consistent results from presurgical evaluations.

Issues of Women with Epilepsy and Suitable Antiseizure Drugs.

Seizure aggravation in women with epilepsy (WWE) tends to occur at two specific times during the menstrual cycle: the perimenstrual phase and the ovulation period. Antiseizure drugs (ASDs), especially those that induce enzymes, can accelerate the metabolism of hormones in oral contraceptives, rendering them less effective. Estrogen in contraceptive pills increases the metabolism of lamotrigine. Physiological changes during pregnancy can significantly impact the pharmacokinetics of ASDs, potentially necessitating adjustments in dosage for women with epilepsy to maintain seizure control. The use of valproate in pregnant women is associated with the highest risk of major congenital malformations among ASDs. Risks of major congenital malformations associated with lamotrigine, levetiracetam, and oxcarbazepine were within the range reported in the general population. Exposure to valproate can lead to lower IQ in offspring. Reduced folic acid levels are linked to orofacial clefts, cardiovascular malformations, and urogenital and limb anomalies in WWE. Decreased folate levels are expected with the use of enzyme-inducing ASDs. However, a high dose of folate was associated with an increased risk of cancer in children of mothers with epilepsy. Most ASDs are generally considered safe for breastfeeding and should be encouraged. However, no single ASD is considered ideal for childbearing WWE. Lamotrigine and levetiracetam are relatively more suitable options for this situation.

Exploration of shared features of B cell receptor and T cell receptor repertoires reveals distinct clonotype clusters.

Although B cells and T cells are integral players of the adaptive immune system and act in co-dependent ways to orchestrate immune responses, existing methods to study the immune repertoire have largely focused on separate analyses of B cell receptor (BCR) and T cell receptor (TCR) repertoires. Based on our hypothesis that the shared history of immune exposures and the shared cellular machinery for recombination result in similarities between BCR and TCR repertoires in an individual, we examine any commonalities and interrelationships between BCR and TCR repertoires. We find that the BCR and TCR repertoires have covarying clonal architecture and diversity, and that the pattern of correlations appears to be altered in immune-mediated diseases. Furthermore, hierarchical clustering of public B and T cell clonotypes in both health and disease based on correlation of clonal proportion revealed distinct clusters of B and T cell clonotypes that exhibit increased sequence similarity, share motifs, and have distinct amino acid characteristics. Our findings point to common principles governing memory formation, recombination, and clonal expansion to antigens in B and T cells within an individual. A significant proportion of public BCR and TCR repertoire can be clustered into nonoverlapping and correlated clusters, suggesting a novel way of grouping B and T cell clonotypes.

Multidimensional Early Prediction Score for Drug-Resistant Epilepsy.

BACKGROUND AND PURPOSE: Achieving favorable postoperative outcomes in patients with drug-resistant epilepsy (DRE) requires early referrals for preoperative examinations. The purpose of this study was to investigate the possibility of a user-friendly early DRE prediction model that is easy for nonexperts to utilize. METHODS: A two-step genotype analysis was performed, by applying 1) whole-exome sequencing (WES) to the initial test set (n=243) and 2) target sequencing to the validation set (n=311). Based on a multicenter case-control study design using the WES data set, 11 genetic and 2 clinical predictors were selected to develop the DRE risk prediction model. The early prediction scores for DRE (EPS-DRE) was calculated for each group of the selected genetic predictors (EPS-DREgen), clinical predictors (EPS-DREcln), and two types of predictor mix (EPS-DREmix) in both the initial test set and the validation set. RESULTS: The multidimensional EPS-DREmix of the predictor mix group provided a better match to the outcome data than did the unidimensional EPS-DREgen or EPS-DREcln. Unlike previous studies, the EPS-DREmix model was developed using only 11 genetic and 2 clinical predictors, but it exhibited good discrimination ability in distinguishing DRE from drug-responsive epilepsy. These results were verified using an unrelated validation set. CONCLUSIONS: Our results suggest that EPS-DREmix has good performance in early DRE prediction and is a user-friendly tool that is easy to apply in real clinical trials, especially by nonexperts who do not have detailed knowledge or equipment for assessing DRE. Further studies are needed to improve the performance of the EPS-DREmix model.

Association of Nucleus Basalis of Meynert Functional Connectivity and Cognition in Idiopathic Rapid-Eye-Movement Sleep Behavior Disorder.

BACKGROUND AND PURPOSE: Cognitive impairments are common in isolated rapid-eye-movement sleep behavior disorder (iRBD), in which the cholinergic system may play an important role. This study aimed to characterize the cortical cholinergic activity using resting-state functional connectivity (FC) of the nucleus basalis of Meynert (NBM) according to the cognitive status of iRBD patients. METHODS: In this cross-sectional study, 33 patients with polysomnography-confirmed iRBD and 20 controls underwent neuropsychological evaluations and resting-state functional magnetic resonance imaging. Thirteen of the iRBD patients had mild cognitive impairment (iRBD-MCI), and the others were age-matched patients with normal cognition (iRBD-NC). The seed-to-voxel NBM-cortical FC was compared among the patients with iRBD-MCI, patients with iRBD-NC, and controls. Correlations between average values of significant clusters and cognitive function scores were calculated in the patients with iRBD. RESULTS: There were group differences in the FC of the NBM with the left lateral occipital cortex and lingual gyrus (adjusted for age, sex, and education level). The strength of FC was lower in the iRBD-MCI group than in the iRBD-NC and control groups (each post-hoc p<0.001). The average NBM-lateral occipital cortex FC was positively correlated with the memory-domain score in iRBD patients. CONCLUSIONS: The results obtained in this study support that cortical cholinergic activity is impaired in iRBD patients with MCI. FC between NBM and posterior regions may play a central role in the cognitive function of these patients.

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.