Safety, tolerability, and efficacy of brivaracetam as adjunctive therapy in patients with focal seizures, generalized onset seizures, or Unverricht-Lundborg disease: An open-label, long-term follow-up trial.

This long-term open-label extension (OLE) trial was conducted to evaluate the long-term safety and tolerability of brivaracetam (BRV) at individualized doses in patients with epilepsy and focal (partial-onset) or generalized onset seizures, or Unverricht-Lundborg disease (ULD). A secondary objective was to evaluate efficacy of BRV in the subgroups of patients with focal or generalized onset seizures. Patients with epilepsy were eligible to enroll in this OLE (N01125; NCT00175916) and were analyzed if they had completed a previous double-blind BRV trial (N01114 [NCT00175929], N01252 [NCT00490035], N01254 [NCT00504881], N01187 [NCT00357669], and N01236 [NCT00368251]), and were expected to obtain a reasonable benefit from long-term BRV treatment. Patients entered the OLE at the BRV dose recommended at the end of the previous trial, with dose adjustments of BRV and concomitant antiseizure medications permitted. Safety variables included treatment-emergent adverse events (TEAEs). Efficacy variables in patients with focal seizures were percent reduction in focal seizure frequency, 50 % responder rates, and 6- and 12-month seizure-freedom. Eight hundred and fifty-three patients (729 [85.5 %] with focal seizures, 30 [3.5 %] with generalized onset seizures, and 94 [11.0 %] with ULD) were enrolled and included in the Safety Set. Overall, 619 (72.6 %) patients discontinued the trial, mainly due to lack of efficacy (354 [41.5 %]), adverse events (100 [11.7 %]), and patient choice (98 [11.5 %]). During the OLE, 588 (68.9 %) patients received BRV for ≥12 months, 403 (47.2 %) for ≥36 months, and 223 (26.1 %) for ≥96 months. The most common modal dose of BRV was 150 mg/day (415 [48.7 %] patients). In the ULD subgroup, the most common modal BRV dose was 100 mg/day (44/94 [46.8 %] patients), and 37/94 (39.4 %) patients had ≥96 months of BRV exposure. Overall, 720/853 (84.4 %) patients reported TEAEs, 451 (52.9 %) had a drug-related TEAE, and 95 (11.1 %) discontinued BRV due to a TEAE. In the ULD subgroup, 87/94 (92.6 %) patients reported TEAEs, 60 (63.8 %) had a drug-related TEAE, and 16 (17.0 %) discontinued due to a TEAE. In patients with focal seizures, the median reduction in focal seizure frequency from Baseline was 43.1 % (n = 728), the 50 % responder rate was 43.6 % (n = 729), and 6- and 12-month seizure freedom rates were 22.2 % and 15.8 %, respectively (n = 595). Overall, BRV was well-tolerated as long-term adjunctive therapy in patients with focal seizures, generalized onset seizures, or Unverricht-Lundborg disease, with improvements in focal seizure frequency maintained over time.

Understanding the challenge of comparative effectiveness research in focal epilepsy: A review of network meta-analyses and real-world evidence on antiepileptic drugs.

OBJECTIVE: Head-to-head randomized controlled trials (RCTs) are the gold standard for assessing comparative treatment effects. In the absence of direct comparisons between all possible antiepileptic drugs (AEDs), however, clinical decision-making in focal (partial onset) epilepsy relies on alternative evidence borne from indirect comparisons including network meta-analyses (NMAs) and from real-world evidence (RWE) studies. We review NMAs and observational RWE studies comparing AEDs in the adjunctive setting to compare the robustness of these methods and to formulate recommendations for future evidence development. METHODS: A literature review identified NMAs and RWE studies comparing AEDs for the adjunctive treatment of focal seizures published between January 2008 and October 2018. NMAs were evaluated for robustness using a framework based on guidelines from the National Institute for Health and Care Excellence Decision Support Unit and the International Society for Pharmacoeconomics and Outcomes Research. RWE studies were evaluated using the GRACE checklist. RESULTS: From a total of 1993 records, 11 NMAs and six RWE studies were eligible. Key limitations identified in the NMAs include nonsystematic selection of RCTs, unexplored heterogeneity between included RCTs in terms of study and patient characteristics, and selection of AEDs and AED doses or dosing strategies that are not reflective of clinical practice. The main limitations of RWE studies concern sample size, design, and analysis methods. Approximately 90% of comparisons between individual AEDs were nonsignificant in the NMAs. None of the RWE studies adjusted for baseline differences between comparator groups; therefore, they lack the validity to make comparative conclusions. SIGNIFICANCE: Current NMAs and RWE studies provide only nominal comparative evidence for AED treatments in focal epilepsy, and should be used with caution for decision-making due to their methodological limitations. To overcome these hurdles, adherence to methodological guidelines and concerted efforts to collect relevant outcome data in the real world are needed.

Loss-of-Function Mutations in NR4A2 Cause Dopa-Responsive Dystonia Parkinsonism.

BACKGROUND: The group of dystonia genes is expanding, and mutations of these genes have been associated with various combined dystonia syndromes. Among the latter, the cause of some dystonia parkinsonism cases remains unknown. OBJECTIVE: To report patients with early-onset dystonia parkinsonism as a result of loss-of-function mutations in nuclear receptor subfamily 4 group A member 2. METHODS: Phenotypic characterization and exome sequencing were carried out in 2 families. RESULTS: The 2 patients reported here both had a history of mild intellectual disability in childhood and subsequently developed dystonia parkinsonism in early adulthood. Brain magnetic resonance imaging was normal, and DATscan suggested bilateral dopaminergic denervation. Two frameshift mutations in NR4A2 were identified: a de novo insertion (NM_006186.3; c.326dupA) in the first case and another small insertion (NM_006186.3; c.881dupA) in the second. CONCLUSIONS: NR4A2 haploinsufficiency mutations have been recently reported in neurodevelopmental phenotypes. Our findings indicate that dystonia and/or parkinsonism may appear years after initial symptoms. Mutations in NR4A2 should be considered in patients with unexplained dystonia parkinsonism. © 2020 International Parkinson and Movement Disorder Society.

Conscious and unconscious expectancy effects: A behavioral, scalp and intracranial electroencephalography study.

OBJECTIVE: The scope of unconscious cognition stretched its limits dramatically during the last 40 years, yet most unconscious processes and representations that have been described so far are fleeting and very short-lived, whereas conscious representations can be actively maintained in working memory for a virtually unlimited period. In the present work we aimed at exploring conscious and unconscious lasting (>1 second) expectancy effects. METHODS: In a series of four experiments we engaged participants in the foreperiod paradigm while using both unmasked and masked cues that were informative about the presence/absence of an upcoming target. We recorded behavioral responses, high-density scalp EEG (Exp. 2a), and intra-cranial EEG (Exp. 2b). RESULTS: While conscious expectancy was associated with a large behavioral effect (~150 ms), unconscious expectancy effect was significant but much smaller (4 ms). Both conscious and unconscious expectancy Contingent Negative Variations (CNVs) originated from temporal cortices, but only the late component of conscious CNV originated from an additional source located in the vicinity of mesio-frontal areas and supplementary motor areas. Finally, only conscious expectancy was accessible to introspection. CONCLUSIONS: Both unmasked and masked cues had an impact on response times and on brain activity. SIGNIFICANCE: These results support a two-stage model of the underlying mechanisms of expectancy.

How can transition to adult care be best orchestrated for adolescents with epilepsy?

Objective evidence is limited for the value of transition programs for youth with chronic illness moving from pediatric to adult care; however, such programs intuitively "make sense". We describe the strengths and weaknesses of a variety of transition programs from around the world for adolescents with epilepsy. Consequences of poorly organized transition beyond suboptimal seizure control may include an increased risk of sudden unexpected death in epilepsy (SUDEP), poor psychological and social outcome, and inadequate management of comorbidities. The content of transition programs for those with normal intelligence differs from those with intellectual disability, but both groups may benefit from an emphasis on sporting activities. Concerns that may interfere with optimal transition include lack of nursing or social work services, limited numbers of adult neurologists/epileptologists confident in the treatment of complex pediatric epilepsy problems, institutional financial support, and time constraints for pediatric and adult physicians who treat epilepsy and the provision of multidisciplinary care. Successful programs eventually need to rely on a several adult physicians, nurses, and other key healthcare providers and use novel approaches to complex care. More research is needed to document the value and effectiveness of transition programs for youth with epilepsy to persuade institutions and healthcare professionals to support these ventures.

Microglial phenotypes in the human epileptic temporal lobe.

Microglia, the immune cells of the brain, are highly plastic and possess multiple functional phenotypes. Differences in phenotype in different regions and different states of epileptic human brain have been little studied. Here we use transcriptomics, anatomy, imaging of living cells and ELISA measurements of cytokine release to examine microglia from patients with temporal lobe epilepsies. Two distinct microglial phenotypes were explored. First we asked how microglial phenotype differs between regions of high and low neuronal loss in the same brain. Second, we asked how microglial phenotype is changed by a recent seizure. In sclerotic areas with few neurons, microglia have an amoeboid rather than ramified shape, express activation markers and respond faster to purinergic stimuli. The repairing interleukin, IL-10, regulates the basal phenotype of microglia in the CA1 and CA3 regions with neuronal loss and gliosis. To understand changes in phenotype induced by a seizure, we estimated the delay from the last seizure until tissue collection from changes in reads for immediate early gene transcripts. Pseudotime ordering of these data was validated by comparison with results from kainate-treated mice. It revealed a local and transient phenotype in which microglia secrete the human interleukin CXCL8, IL-1B and other cytokines. This secretory response is mediated in part via the NRLP3 inflammasome.

Making a 'JUMP' from paediatric to adult healthcare: A transitional program for young adults with chronic neurological disease.

BACKGROUND: "JUMP" is a multidisciplinary program based at the Pitie-Salpêtrière Hospital Paris that transitions young adults with chronic neurological conditions from paediatric to adult healthcare. Transitional care programs have been shown to improve medical, educational and psychosocial outcomes for adolescent patients. METHODS: Demographic details and health-related variables of all patients referred to the JUMP program were collected. Satisfaction outcome measures were the 18-item On Your Own Feet Transfer Experience Scale (OYOF-TES) and a visual analogue scale, which assessed overall satisfaction with the transfer process. Scales were sent to JUMP patients attending the JUMP day hospital (n = 94) and their parents (n = 94). RESULTS: Since its inception, 111 patients have been seen in the JUMP program. Nine neurological clinical syndromes and four main underlying etiologies were identified. Approximately half of all questionnaires and scales (86/188) sent to patients and parents were returned. Eighty-nine percent of patients and 91% of parents were very satisfied with their transfer experience. There was a strong, positive correlation between patient and parent satisfaction [r = 0.910; p < 0.0001]. CONCLUSION: The JUMP program which is rooted in a multidisciplinary and coordinated approach to transitional care encompasses a broad range of neuro-pathologies. Overall, satisfaction levels were high amongst patients within the program, and their parents. The key role played by the coordination nurse specialists throughout the transfer process is a likely key determinant in satisfaction levels.

[Family caregivers of young patients suffering from chronic neurological diseases during the transition from neuropediatrics to adult neurology: An observational study of the burden felt by the primary family caregiver.] / Les aidants familiaux de jeunes patients atteints de maladies neurologiques chroniques lors de la transition entre secteur pédiatrique et prise en charge en milieu adulte : étude observationnelle de l?aidant familial principal.

Introduction / Context: The transition of young patients from pediatric to adult departments is a critical period with high risks of interruption of the care circuits, thus justifying the implementation of transition programs. This period is also difficult for caregivers, more particularly the main family caregiver. This study addresses the impact of this transition upon the family caregivers of young adults suffering from chronic neurological diseases. OBJECTIVES: To identify the main family caregivers, their profile, and to evaluate their implication and feelings in terms of burden at the time of the transition. METHODS: A questionnaire, which included a modified version of the Zarit Burden Interview, was sent to the families of young patients who had recently moved to the adult neurology department. RESULTS: Twenty-nine of the forty families contacted replied: the main caregiver is usually the mother (86.6%), the mean age is 51.8, 65% had kept their professional occupation, and 21% had quit. The burden scale showed that 65.5% felt little or no burden. DISCUSSION AND CONCLUSION: This limited feeling of burden may be explained by the fact that the majority of patients did not have a motor/intellectual disability. The burden scale we used was originally created for caregivers of elderly patients (often their children), and may not be suitable for assessing children's parents. More specific scales should be considered.

Rapid eye movement sleep behavior disorder or epileptic seizure during sleep? A video analysis of motor events.

PURPOSE: To compare the motor semiology of sleep behavior disorder (RBD) during rapid eye movement (REM) with epileptic seizures in non-REM and REM sleep. METHODS: We analyzed the types and frequency of motor events from videos of patients with RBD (n = 15, mean age 64.8 years, 179 motor episodes) and patients with epilepsy (n = 15, mean age 34.4 years, 87 sleep-related epileptic seizures including 34 during REM sleep). RESULTS: Patients with sleep-related epileptic seizures more often woke up abruptly (28% vs. 0.3%), raised head/trunk (31% vs. 1.6%), opened their eyes (89% vs. 5%), had whole body movements (74% vs. 14%) or dystonic posturing (29% vs. 1.3%), manipulated objects in their environment (44% vs. 3.9%), as if emerging from sleep with ictal automatisms, and sniffed, coughed, or breathed differently during motor events. In contrast, RBD patients more often remained lying down with closed eyes (99% vs. 78%) as if still asleep, with non-stereotyped jerky movements (42% vs. 8%) and outward-directed behaviors (14% vs. 2%) than patients with epilepsy. There were no differences in violent behaviors and vocalizations between groups. Comparison with subgroups of REM or non-REM sleep seizures yielded many similar findings. CONCLUSION: These different motor patterns discriminate between RBD events and sleep-associated seizures, and could be used as an aid to differential diagnosis.

New clinicopathological associations and histoprognostic markers in ILAE types of hippocampal sclerosis.

Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) is a heterogeneous syndrome. Surgery results in seizure freedom for most pharmacoresistant patients, but the epileptic and cognitive prognosis remains variable. The 2013 International League Against Epilepsy (ILAE) histopathological classification of hippocampal sclerosis (HS) has fostered research to understand MTLE-HS heterogeneity. We investigated the associations between histopathological features (ILAE types, hypertrophic CA4 neurons, granule cell layer alterations, CD34 immunopositive cells) and clinical features (presurgical history, postsurgical outcome) in a monocentric series of 247 MTLE-HS patients treated by surgery. NeuN, GFAP and CD34 immunostainings and a double independent pathological examination were performed. 186 samples were type 1, 47 type 2, 7 type 3 and 7 samples were gliosis only but no neuronal loss (noHS). In the type 1, hypertrophic CA4 neurons were associated with a worse postsurgical outcome and granule cell layer duplication was associated with generalized seizures and episodes of status epilepticus. In the type 2, granule cell layer duplication was associated with generalized seizures. CD34+ stellate cells were more frequent in the type 2, type 3 and in noHS. These cells had a Nestin and SOX2 positive, immature neural immunophenotype. Patients with nodules of CD34+ cells had more frequent dysmnesic auras. CD34+ stellate cells in scarce pattern were associated with higher ratio of normal MRI and of stereo-electroencephalographic studies. CD34+ cells were associated with a trend for a better postsurgical outcome. Among CD34+ cases, we proposed a new entity of BRAF V600E positive HS and we described three hippocampal multinodular and vacuolating neuronal tumors. To conclude, our data identified new clinicopathological associations with ILAE types. They showed the prognostic value of CA4 hypertrophic neurons. They highlighted CD34+ stellate cells and BRAF V600E as biomarkers to further decipher MTLE-HS heterogeneity.

Single-unit activities during the transition to seizures in deep mesial structures.

Focal seizures are assumed to arise from a hypersynchronous activity affecting a circumscribed brain region. Using microelectrodes in seizure-generating deep mesial regions of 9 patients, we investigated the firing of hundreds of single neurons before, during, and after ictal electroencephalogram (EEG) discharges. Neuronal spiking activity at seizure initiation was highly heterogeneous and not hypersynchronous. Furthermore, groups of neurons showed significant changes in activity minutes before the seizure with no concomitant changes in the corresponding macroscopic EEG recordings. Altogether, our findings suggest that only limited subsets of neurons in epileptic depth regions initiate the seizure-onset and that ictogenic mechanisms operate in submillimeter-scale microdomains. Ann Neurol 2017 Ann Neurol 2017;82:1022-1028.

Cortical neurons and networks are dormant but fully responsive during isoelectric brain state.

A continuous isoelectric electroencephalogram reflects an interruption of endogenously-generated activity in cortical networks and systematically results in a complete dissolution of conscious processes. This electro-cerebral inactivity occurs during various brain disorders, including hypothermia, drug intoxication, long-lasting anoxia and brain trauma. It can also be induced in a therapeutic context, following the administration of high doses of barbiturate-derived compounds, to interrupt a hyper-refractory status epilepticus. Although altered sensory responses can be occasionally observed on an isoelectric electroencephalogram, the electrical membrane properties and synaptic responses of individual neurons during this cerebral state remain largely unknown. The aim of the present study was to characterize the intracellular correlates of a barbiturate-induced isoelectric electroencephalogram and to analyse the sensory-evoked synaptic responses that can emerge from a brain deprived of spontaneous electrical activity. We first examined the sensory responsiveness from patients suffering from intractable status epilepticus and treated by administration of thiopental. Multimodal sensory responses could be evoked on the flat electroencephalogram, including visually-evoked potentials that were significantly amplified and delayed, with a high trial-to-trial reproducibility compared to awake healthy subjects. Using an analogous pharmacological procedure to induce prolonged electro-cerebral inactivity in the rat, we could describe its cortical and subcortical intracellular counterparts. Neocortical, hippocampal and thalamo-cortical neurons were all silent during the isoelectric state and displayed a flat membrane potential significantly hyperpolarized compared with spontaneously active control states. Nonetheless, all recorded neurons could fire action potentials in response to intracellularly injected depolarizing current pulses and their specific intrinsic electrophysiological features were preserved. Manipulations of the membrane potential and intracellular injection of chloride in neocortical neurons failed to reveal an augmented synaptic inhibition during the isoelectric condition. Consistent with the sensory responses recorded from comatose patients, large and highly reproducible somatosensory-evoked potentials could be generated on the inactive electrocorticogram in rats. Intracellular recordings revealed that the underlying neocortical pyramidal cells responded to sensory stimuli by complex synaptic potentials able to trigger action potentials. As in patients, sensory responses in the isoelectric state were delayed compared to control responses and exhibited an elevated reliability during repeated stimuli. Our findings demonstrate that during prolonged isoelectric brain state neurons and synaptic networks are dormant rather than excessively inhibited, conserving their intrinsic properties and their ability to integrate and propagate environmental stimuli.

Reducing placebo exposure in trials: Considerations from the Research Roundtable in Epilepsy.

The randomized controlled trial is the unequivocal gold standard for demonstrating clinical efficacy and safety of investigational therapies. Recently there have been concerns raised about prolonged exposure to placebo and ineffective therapy during the course of an add-on regulatory trial for new antiepileptic drug approval (typically ∼6 months in duration), due to the potential risks of continued uncontrolled epilepsy for that period. The first meeting of the Research Roundtable in Epilepsy on May 19-20, 2016, focused on "Reducing placebo exposure in epilepsy clinical trials," with a goal of considering new designs for epilepsy regulatory trials that may be added to the overall development plan to make it, as a whole, safer for participants while still providing rigorous evidence of effect. This topic was motivated in part by data from a meta-analysis showing a 3- to 5-fold increased rate of sudden unexpected death in epilepsy in participants randomized to placebo or ineffective doses of new antiepileptic drugs. The meeting agenda included rationale and discussion of different trial designs, including active-control add-on trials, placebo add-on to background therapy with adjustment, time to event designs, adaptive designs, platform trials with pooled placebo control, a pharmacokinetic/pharmacodynamic approach to reducing placebo exposure, and shorter trials when drug tolerance has been ruled out. The merits and limitations of each design were discussed and are reviewed here.

Adjunctive lacosamide for focal epilepsy: an open-label trial evaluating the impact of flexible titration and dosing on safety and seizure outcomes.

To evaluate the safety and effectiveness of lacosamide in a real-life setting with the use of a flexible dose titration schedule and individualised maintenance doses up to the maximum approved dose of 400 mg/day. Adults with a diagnosis of focal seizures, with or without secondary generalization, were enrolled in this open-label Phase IV trial (NCT01235403). Lacosamide was initiated at 100 mg/day (50 mg bid) and uptitrated over a 12-week period to 200, 300 or 400 mg/day, based on safety and seizure control. Although dose increases were to be in increments of 100 mg/day, intermediate doses were permitted at each escalation step for one week for patients known to be particularly sensitive to starting new AEDs. After receiving a stable, effective dose for three weeks, patients entered the 12-week maintenance period. Primary outcomes were incidence of treatment-emergent adverse events (TEAEs) and withdrawal due to TEAEs. Seizure outcomes, all secondary, were median focal seizure frequency, ≥50% reduction in focal seizure frequency, and seizure freedom. One hundred patients with a mean age of 44 years were enrolled and 74 completed the trial. The incidence of TEAEs was 64.0% (n=100), with the most frequently reported (≥5% of patients) being dizziness, headache, and asthenia. Fourteen patients withdrew due to TEAEs, most frequently due to dizziness (six patients; 6.0%), vomiting (two patients; 2%), and tremor (two patients; 2%). Among patients with baseline and maintenance phase seizure data (n=75), median reduction in focal seizure frequency from baseline was 69.7% and the ≥50% responder rate was 69.3%. Among 74 patients who completed the maintenance phase, 21 (28.4%) were seizure-free. Flexible lacosamide dosing in this open-label trial was associated with a favourable tolerability and safety profile; the nature of the TEAEs was consistent with that observed in previous pivotal trials. Treatment with lacosamide was also associated with effective seizure control.

Predictive factors of long-term outcomes of surgery for mesial temporal lobe epilepsy associated with hippocampal sclerosis.

OBJECTIVE: The reasons for failure of surgical treatment for mesial temporal lobe epilepsy (MTLE) associated with hippocampal sclerosis (HS) remain unclear. This retrospective study analyzed seizure, cognitive, and psychiatric outcomes, searching for factors associated with seizure relapse or cognitive and psychiatric deterioration after MTLE-HS surgery. METHODS: Seizure, cognitive, and psychiatric outcomes were reviewed after 389 surgeries performed between 1990 and 2015 on patients aged 15-67 years at a tertiary center. Three surgical approaches were used: anterior temporal lobectomy (ATL; n = 209), transcortical selective amygdalohippocampectomy (SAH; n = 144), and transsylvian SAH (n = 36). RESULTS: With an average follow-up of 8.7 years (range = 1.0-25.2), seizure outcome was classified as Engel I in 83.7% and Engel Ia in 57.1% of patients. The histological classification of HS was type 1 for 75.3% of patients, type 2 for 18.7%, and type 3 for 1.2%. Two factors were significantly associated with seizure recurrence: past history of status epilepticus and preoperative intracranial electroencephalographic recording. In contrast, neither HS type, the presence of a dual pathology, nor surgical approach was associated with seizure outcome. Risk of cognitive impairment was 3.12 (95% confidence interval = 1.27-7.70), greater in patients after ATL than in patients after transcortical SAH. A presurgical psychiatric history and postoperative cognitive impairment were associated with poor psychiatric outcome. SIGNIFICANCE: The SAH and ATL approaches have similar beneficial effects on seizure control, whereas transcortical SAH tends to minimize cognitive deterioration after surgery. Variation in postsurgical outcome with the class of HS should be investigated further.

Complications After Surgery for Mesial Temporal Lobe Epilepsy Associated with Hippocampal Sclerosis.

BACKGROUND: Hippocampal sclerosis is the most common cause of drug-resistant epilepsy amenable for surgical treatment and seizure control. This study aimed to analyze morbidities related to surgery of mesial temporal lobe epilepsy associated with hippocampal sclerosis and to identify possible risk factors for complications. METHODS: A retrospective analysis of postoperative complications was made for 389 operations performed between 1990 and 2015 on patients aged 15-67 years (mean 36.8). Three surgical approaches were used: anterior temporal lobectomy (ATL) (n = 209), transcortical selective amygdalohippocampectomy (SAH) (n = 144), and transsylvian SAH (n = 36). Complications were classified as minor or major if there was a neurologic impairment or if further surgical or medical treatment was necessary. RESULTS: Complications followed 15.4% of operations. They were classed as major for 4.1% of patients, but there were no mortalities. Persistent neurologic deficits occurred in 0.5% of patients. In 3 cases (0.8%) additional surgery was necessary to treat an intracranial hematoma, a delayed hydrocephalus, and a subdural empyema. Symptomatic visual field defects (VFDs) were frequent and included contralateral superior quadrantanopia (8.2%) or hemianopia (1.3%). Overall complications (P = 0.04) and symptomatic VFDs (P = 0.04) were most frequent in operations on men. Major complications occurred most often with the ATL surgical approach than with transcortical SAH (P = 0.03). CONCLUSIONS: Major complications occur rarely after mesial temporal surgery on epileptic patients. They occur more often following the ATL rather than transcortical SAH approach. Complications tend to be temporary with symptoms of limited duration for surgery performed by experienced teams on carefully selected and evaluated patients.

Cognitive dissonance resolution depends on episodic memory.

The notion that past choices affect preferences is one of the most influential concepts of social psychology since its first report in the 50 s, and its theorization within the cognitive dissonance framework. In the free-choice paradigm (FCP) after choosing between two similarly rated items, subjects reevaluate chosen items as more attractive and rejected items as less attractive. However the relations prevailing between episodic memory and choice-induced preference change (CIPC) remain highly debated: is this phenomenon dependent or independent from memory of past choices? We solve this theoretical debate by demonstrating that CIPC occurs exclusively for items which were correctly remembered as chosen or rejected during the choice stage. We used a combination of fMRI and intra-cranial electrophysiological recordings to reveal a modulation of left hippocampus activity, a hub of episodic memory retrieval, immediately before the occurrence of CIPC during item reevaluation. Finally, we show that contrarily to a previous influential report flawed by a statistical artifact, this phenomenon is absent in amnesic patients for forgotten items. These results demonstrate the dependence of cognitive dissonance on conscious episodic memory. This link between current preferences and previous choices suggests a homeostatic function of this regulative process, aiming at preserving subjective coherence.

Efficacy, safety, and tolerability of lacosamide monotherapy versus controlled-release carbamazepine in patients with newly diagnosed epilepsy: a phase 3, randomised, double-blind, non-inferiority trial.

BACKGROUND: Further options for monotherapy are needed to treat newly diagnosed epilepsy in adults. We assessed the efficacy, safety, and tolerability of lacosamide as a first-line monotherapy option for these patients. METHODS: In this phase 3, randomised, double-blind, non-inferiority trial, patients from 185 epilepsy or general neurology centres in Europe, North America, and the Asia Pacific region, aged 16 years or older and with newly diagnosed epilepsy were randomly assigned in a 1:1 ratio, via a computer-generated code, to receive lacosamide monotherapy or controlled-release carbamazepine (carbamazepine-CR) twice daily. Patients, investigators, and trial personnel were masked to treatment allocation. From starting doses of 100 mg/day lacosamide or 200 mg/day carbamazepine-CR, uptitration to the first target level of 200 mg/day and 400 mg/day, respectively, took place over 2 weeks. After a 1-week stabilisation period, patients entered a 6-month assessment period. If a seizure occurred, the dose was titrated to the next target level (400 or 600 mg/day for lacosamide and 800 or 1200 mg/day for carbamazepine-CR) over 2 weeks with a 1-week stabilisation period, and the 6-month assessment period began again. Patients who completed 6 months of treatment and remained seizure-free entered a 6-month maintenance period on the same dose. The primary efficacy outcome was the proportion of patients remaining free from seizures for 6 consecutive months after stabilisation at the last assessed dose. The predefined non-inferiority criteria were -12% absolute and -20% relative difference between treatment groups. This trial is registered with ClinicalTrials.gov, number NCT01243177. FINDINGS: The trial was done between April 27, 2011, and Aug 7, 2015. 888 patients were randomly assigned treatment. 444 patients taking lacosamide and 442 taking carbamazepine-CR were included in the full analysis set (took at least one dose of study treatment), and 408 and 397, respectively, were included in the per-protocol set. In the full analysis set, 327 (74%) patients in the lacosamide group and 308 (70%) in the carbamazepine-CR group completed 6 months of treatment without seizures. The proportion of patients in the full analysis set predicted by the Kaplan-Meier method to be seizure-free at 6 months was 90% taking lacosamide and 91% taking carbamazepine-CR (absolute treatment-difference: -1·3%, 95% CI -5·5 to 2·8 relative treatment difference: -6·0%). Kaplan-Meier estimates results were similar in the per-protocol set (92% and 93%; -1·3%, -5·3 to 2·7; -5·7%). Treatment-emergent adverse events were reported in 328 (74%) patients receiving lacosamide and 332 (75%) receiving carbamazepine-CR. 32 (7%) patients taking lacosamide and 43 (10%) taking carbamazepine-CR had serious treatment-emergent adverse events, and 47 (11%) and 69 (16%), respectively, had treatment-emergent adverse events that led to withdrawal. INTERPRETATION: Treatment with lacosamide met the predefined non-inferiority criteria when compared with carbamazepine-CR. Therefore, it might be useful as first-line monotherapy for adults with newly diagnosed epilepsy. FUNDING: UCB Pharma.