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Objective: Attention-deficit/hyperactivity disorder (ADHD) is commonly observed in children with epilepsy. However, factors associated with the development of ADHD and which might help to guide its therapeutic management, remain an issue of debate., Methods: We conducted a multicenter prospective observational study that included children, aged 6-16 years, with both epilepsy and ADHD according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria. After inclusion, patients entered a 12-16 week follow-up period during which they were either treated with methylphenidate or they did not receive specific ADHD treatment. ADHD was evaluated with the ADHD Rating Scale-IV., Results: One hundred sixty-seven patients were included, of which 91 were seizure-free during the preinclusion baseline period. At inclusion, the ADHD Rating Scale-IV total score was 30.4 ± (standard deviation) 9.2, the inattentive subscore was 17.3 ± 4.4, and the hyperactive subscore was 13.2 ± 6.6. We did not detect any difference of ADHD Rating Scale-IV scores across patients' age or gender, age at epilepsy onset, epilepsy syndrome, seizure frequency, or number of ongoing antiepileptic drugs. Methylphenidate was initiated in 61 patients, including 55 in whom a follow-up evaluation was available. At the last follow-up, 41 patients (75%) treated with methylphenidate and 39 (42%) of those who did not received ADHD therapy demonstrated ≥25% decrease of ADHD Rating Scale-IV total score (p < 0.001). Response to methylphenidate was greater in girls but was not influenced by any epilepsy-related variables., Significance: We did not detect any epilepsy-related factor associated with the severity of ADHD. Twenty-five percent of patients did not respond to methylphenidate. A better understanding of the pathologic process that underlies ADHD development in childhood epilepsy might be required to improve therapeutic strategies., (Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.)

Purpose: The European Union-funded E-PILEPSY network aims to improve awareness of, and accessibility to, epilepsy surgery across Europe. In this study we assessed current clinical practices in epilepsy monitoring units (EMUs) in the participating centers., Method: A 60-item web-based survey was distributed to 25 centers (27 EMUs) of the E-PILEPSY network across 22 European countries. The questionnaire was designed to evaluate the characteristics of EMUs, including organizational aspects, admission, and observation of patients, procedures performed, safety issues, cost, and reimbursement., Results: Complete responses were received from all (100%) EMUs surveyed. Continuous observation of patients was performed in 22 (81%) EMUs during regular working hours, and in 17 EMUs (63%) outside of regular working hours. Fifteen (56%) EMUs requested a signed informed consent before admission. All EMUs performed tapering/withdrawal of antiepileptic drugs, 14 (52%) prior to admission to an EMU. Specific protocols on antiepileptic drugs (AED) tapering were available in four (15%) EMUs. Standardized Operating Procedures (SOP) for the treatment of seizure clusters and status epilepticus were available in 16 (59%). Safety measures implemented by EMUs were: alarm seizure buttons in 21 (78%), restricted patient's ambulation in 19 (70%), guard rails in 16 (59%), and specially designated bathrooms in 7 (26%). Average costs for one inpatient day in EMU ranged between 100 and 2200 Euros., Conclusion: This study shows a considerable diversity in the organization and practice patterns across European epilepsy monitoring units. The collected data may contribute to the development and implementation of evidence-based recommended practices in LTM services across Europe., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Attention deficit hyperactivity disorder (ADHD) is a well-known comorbidity in children with epilepsy. In English-speaking countries, the scores of the original ADHD-rating scale IV are currently used as main outcomes in various clinical trials in children with epilepsy. In French-speaking countries, several French versions are in use though none has been fully validated yet. We sought here for a partial validation of a French version of the ADHD-RS IV regarding construct validity, internal consistency (i.e., scale reliability), item reliability, and responsiveness in a group of French children with ADHD and epilepsy., Method: The study involved 167 children aged 6-15years in 10 French neuropediatric units. The factorial structure and item reliability were assessed with a confirmatory factorial analysis for ordered categorical variables. The dimensions' internal consistency was assessed with Guttman's lambda 6 coefficient. The responsiveness was assessed by the change in score under methylphenidate and in comparison with a control group., Results: The results confirmed the original two-dimensional factorial structure (inattention, hyperactivity/impulsivity) and showed a satisfactory reliability of most items, a good dimension internal consistency, and a good responsiveness of the total score and the two subscores., Conclusion: The studied French version of the ADHD-RS IV is thus validated regarding construct validity, reliability, and responsiveness. It can now be used in French-speaking countries in clinical trials of treatments involving children with ADHD and epilepsy. The full validation requires further investigations., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose of Review: This review summarizes recent evidence on the seizure, safety, cognitive and psychosocial outcomes of epilepsy surgery and their predictors., Recent Findings: Risks of serious surgical complications have dramatically decreased over years to drop below 1% for temporal lobe resections. Although chances of postoperative seizure freedom largely vary between recent series, some data suggest that long-term seizure control might be achieved in over 80% of patients with mesial temporal lobe epilepsy or neocortical epilepsy associated with type 2 focal cortical dysplasia, and in up to two-thirds of patients with extratemporal lobe epilepsy. In the same conditions, some recent series challenge the classic view that a normal MRI is associated with worse outcome, an important finding given the greater proportion of MRI-negative patients now considered for epilepsy surgery., Summary: These provocative findings appear to partly reflect the advances in the optimal use or postprocessing of neuroimaging data, as well as the identification of temporal plus epilepsy. This latter condition, which is characterized by normal MRI in half of patients and very poor outcome following anterior temporal lobectomy, was found to represent the main predictor of temporal lobe epilepsy surgery failures. Postoperative cognitive and quality-of-life outcomes, which partly depend on seizure control, are also influenced by antiepileptic drugs and psychiatric comorbidities.

Reasons for failed temporal lobe epilepsy surgery remain unclear. Temporal plus epilepsy, characterized by a primary temporal lobe epileptogenic zone extending to neighboured regions, might account for a yet unknown proportion of these failures. In this study all patients from two epilepsy surgery programmes who fulfilled the following criteria were included: (i) operated from an anterior temporal lobectomy or disconnection between January 1990 and December 2001; (ii) magnetic resonance imaging normal or showing signs of hippocampal sclerosis; and (iii) postoperative follow-up ≥ 24 months for seizure-free patients. Patients were classified as suffering from unilateral temporal lobe epilepsy, bitemporal epilepsy or temporal plus epilepsy based on available presurgical data. Kaplan-Meier survival analysis was used to calculate the probability of seizure freedom over time. Predictors of seizure recurrence were investigated using Cox proportional hazards model. Of 168 patients included, 108 (63.7%) underwent stereoelectroencephalography, 131 (78%) had hippocampal sclerosis, 149 suffered from unilateral temporal lobe epilepsy (88.7%), one from bitemporal epilepsy (0.6%) and 18 (10.7%) from temporal plus epilepsy. The probability of Engel class I outcome at 10 years of follow-up was 67.3% (95% CI: 63.4-71.2) for the entire cohort, 74.5% (95% CI: 70.6-78.4) for unilateral temporal lobe epilepsy, and 14.8% (95% CI: 5.9-23.7) for temporal plus epilepsy. Multivariate analyses demonstrated four predictors of seizure relapse: temporal plus epilepsy (P < 0.001), postoperative hippocampal remnant (P = 0.001), past history of traumatic or infectious brain insult (P = 0.022), and secondary generalized tonic-clonic seizures (P = 0.023). Risk of temporal lobe surgery failure was 5.06 (95% CI: 2.36-10.382) greater in patients with temporal plus epilepsy than in those with unilateral temporal lobe epilepsy. Temporal plus epilepsy represents a hitherto unrecognized prominent cause of temporal lobe surgery failures. In patients with temporal plus epilepsy, anterior temporal lobectomy appears very unlikely to control seizures and should not be advised. Whether larger resection of temporal plus epileptogenic zones offers greater chance of seizure freedom remains to be investigated., (© The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: To identify the clinical determinants of occurrence of postictal generalized EEG suppression (PGES) after generalized convulsive seizures (GCS)., Methods: We reviewed the video-EEG recordings of 417 patients included in the REPO2MSE study, a multicenter prospective cohort study of patients with drug-resistant focal epilepsy. According to ictal semiology, we classified GCS into 3 types: tonic-clonic GCS with bilateral and symmetric tonic arm extension (type 1), clonic GCS without tonic arm extension or flexion (type 2), and GCS with unilateral or asymmetric tonic arm extension or flexion (type 3). Association between PGES and person-specific or seizure-specific variables was analyzed after correction for individual effects and the varying number of seizures., Results: A total of 99 GCS in 69 patients were included. Occurrence of PGES was independently associated with GCS type (p < 0.001) and lack of early administration of oxygen (p < 0.001). Odds ratio (OR) for GCS type 1 in comparison with GCS type 2 was 66.0 (95% confidence interval [CI 5.4-801.6]). In GCS type 1, risk of PGES was significantly increased when the seizure occurred during sleep (OR 5.0, 95% CI 1.2-20.9) and when oxygen was not administered early (OR 13.4, 95% CI 3.2-55.9)., Conclusion: The risk of PGES dramatically varied as a function of GCS semiologic characteristics. Whatever the type of GCS, occurrence of PGES was prevented by early administration of oxygen., (© 2015 American Academy of Neurology.)

Ictal anxiety is a frequent epileptic symptom; it is usually brief, associated with objective clinical signs, and is not positively influenced by external factors, in contrast to psychiatric disorders. These criteria can, however, be misleading, especially in patients with psychiatric comorbidities. We report two patients with a history of drug-resistant right temporal lobe epilepsy, who developed long-lasting psychiatric symptoms, suggestive of exacerbation of their comorbid anxiety disorder. However, intracranial EEG data and [(18)F] FDG-PET suggested that these symptoms were related to seizure activity, highlighting the difficulties in differentiating ictal symptoms from psychiatric episodes in some patients with epilepsy and comorbid psychiatric disorders. [Published with video sequence].

Objectives: We examined whether IV administration of cyclosporine in combination with thrombolysis might reduce cerebral infarct size., Methods: Patients aged 18 to 85 years, presenting with an anterior-circulation stroke and eligible for thrombolytic therapy, were enrolled in this multicenter, single-blinded, controlled trial. Fifteen minutes after randomization, patients received either an IV bolus injection of 2.0 mg/kg cyclosporine (Sandimmune, Novartis) or placebo. The primary endpoint was infarct volume on MRI at 30 days. Secondary endpoints included infarct volume according to the site (proximal/distal) of arterial occlusion and recanalization after thrombolysis., Results: From October 2009 to July 2013, 127 patients were enrolled. The primary endpoint was assessed in 110 of 127 patients. The reduction of infarct volume in the cyclosporine compared with the control group was overall not significant (21.8 mL [interquartile range, IQR 5.1, 69.2 mL] vs 28.8 mL [IQR 7.7, 95.0 mL], respectively; p = 0.18). However, in patients with proximal occlusion and effective recanalization, infarct volume was significantly reduced in the cyclosporine compared with the control group (14.9 mL [IQR 1.3, 23.2 mL] vs 48.3 mL [IQR 34.5, 118.2 mL], respectively; p = 0.009)., Conclusions: Cyclosporine was generally not effective in reducing infarct size. However, a smaller infarct size was observed in patients with proximal cerebral artery occlusion and efficient recanalization., Classification of Evidence: This study provides Class I evidence that in patients with an acute anterior-circulation stroke, thrombolysis plus IV cyclosporine does not significantly decrease 30-day MRI infarct volume compared with thrombolysis alone., (© 2015 American Academy of Neurology.)

A 40-year-old hypertensive woman experienced a left hemispheric stroke revealing an acute pituitary apoplexy and a dissection limited to the lacerum segment of the left internal carotid artery. The relationship between pituitary apoplexy and arterial dissection is discussed., (Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Epilepsy surgery is the most effective way to control seizures in patients with drug-resistant focal epilepsy, often leading to improvements in cognition, behaviour, and quality of life. Risks of serious adverse events and deterioration of clinical status can be minimised in carefully selected patients. Accordingly, guidelines recommend earlier and more systematic assessment of patients' eligibility for surgery than is seen at present. The effectiveness of surgical treatment depends on epilepsy type, underlying pathology, and accurate localisation of the epileptogenic brain region by various clinical, neuroimaging, and neurophysiological investigations. Substantial progress has been made in the methods of presurgical assessment, particularly in patients with normal features on MRI, but evidence is scarce for the indication and effect of most presurgical investigations, with no biomarker precisely delineating the epileptogenic zone. A priority for the development of epilepsy surgery is the generation of high-level evidence to promote the harmonisation and dissemination of best practices., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Objectives: Secondary generalized tonic-clonic seizures (SGTCS) are among the most severe forms of seizures, and the main risk factor for sudden unexpected death in epilepsy (SUDEP). Whether some antiepileptic drugs (AEDs) might be more efficacious than others on SGTCS in patients with drug-resistant focal epilepsy thus represents an important clinical issue for which no data are currently available., Methods: We performed a meta-analysis of randomized controlled trials of adjunctive AED in which information on efficacy outcomes (i.e., responder rate and/or frequency per 28 days relative to baseline) were available both for all seizure types and for SGTCS. The primary analysis evaluated the efficacy of AEDs on all types of seizure and on SGTCS by comparing the responder rates for AED and for placebo., Results: Responder rate was available both for all seizure types and for SGTCS in 13 of the 72 eligible trials, evaluating 7 AEDs. Only three AEDs--lacosamide, perampanel and topiramate--showed greater efficacy than placebo. However, confidence intervals of relative risks overlapped for all AEDs but pregabalin, which demonstrated significantly lower efficacy than lacosamide, perampanel, and topiramate. Moreover, there was a nonsignificant trend toward a lower relative risk of responder rate for SGTCS than for all seizure types, which appeared related to a greater response to placebo for this outcome., Significance: Indirect comparison of AEDs using randomized placebo-controlled add-on trials does not support robust differences between AEDs to prevent SGTCS. Alternative designs for evaluation of therapeutic interventions in patients at risk for SGTCS-related complications are required., (Wiley Periodicals, Inc. © 2014 International League Against Epilepsy.)

Objectives: The aim of our study was to explore the functional connectivity between the insula and other cortical regions, in human, using cortico-cortical evoked potentials (CCEPs), Experimental Design: We performed intra-cerebral electrical stimulation in eleven patients with refractory epilepsy investigated with depth electrodes, including 39 targeting the insula. Electrical stimulation consisted of two series of 20 pulses of 1-ms duration, 0.2-Hz frequency, and 1-mA intensity delivered at each of the 39 insular bipoles. Rates of connectivity were reported whenever a noninsular cortical region was tested by at least ten stimulating/recording electrode pairs in three or more patients, Results: Significant CCEPs were elicited in 193 of the 578 (33%) tested connections, with an average latency of 33 ± 5 ms. The highest connectivity rates were observed with the nearby perisylvian structures (59%), followed by the pericentral cortex (38%), the temporal neocortex (28%), the lateral parietal cortex (26%), the orbitofrontal cortex (25%), the mesial temporal structures (24%), the dorsolateral frontal cortex (15%), the temporal pole (14%), and the mesial parietal cortex (11%). No connectivity was detected in the mesial frontal cortex or cingulate gyrus. The pattern of connectivity also differed between the five insular gyri, with greater connectivity rate for the posterior short gyrus (49%), than for the middle short (29%), and two long gyri (28 and 33%), Conclusion: The human insula is characterized by a rich and complex connectivity that varies as a function of the insular gyrus and appears to partly differ from the efferences described in nonhuman primates., (Copyright © 2014 Wiley Periodicals, Inc.)

Background: Dysembryoplastic neuroepithelial tumors (DNTs) represent a prevalent cause of epileptogenic brain tumors, the natural evolution of which is much more benign than that of most gliomas. Previous studies have suggested that [(11)C]methionine positron emission tomography (MET-PET) could help to distinguish DNTs from other epileptogenic brain tumors, and hence optimize the management of patients. Here, we reassessed the diagnostic accuracy of MET-PET for the differentiation between DNT and other epileptogenic brain neoplasms in a larger population., Methods: We conducted a retrospective study of 77 patients with focal epilepsy related to a nonrapidly progressing brain tumor on MRI who underwent MET-PET, including 52 with a definite histopathology. MET-PET data were assessed by a structured visual analysis that distinguished normal, moderately abnormal, and markedly abnormal tumor methionine uptake and by semiquantitative ratio measurements., Results: Pathology showed 21 DNTs (40%), 10 gangliogliomas (19%), 19 low-grade gliomas (37%), and 2 high-grade gliomas (4%). MET-PET visual findings significantly differed among the various tumor types (P < .001), as confirmed by semiquantitative analyses (P < .001 for all calculated ratios), regardless of gadolinium enhancement on MRI. All gliomas and gangliogliomas were associated with moderately or markedly increased tumor methionine uptake, whereas 9/21 DNTs had normal methionine uptake. Receiver operating characteristics analysis of the semiquantitative ratios showed an optimal cutoff threshold that distinguished DNTs from other tumor types with 90% specificity and 89% sensitivity., Conclusions: Normal MET-PET findings in patients with an epileptogenic nonrapidly progressing brain tumor are highly suggestive of DNT, whereas a markedly increased tumor methionine uptake makes this diagnosis unlikely., (© The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Occurrence of generalized tonic-clonic seizures (GTCS) is one of the most important risk factors of seizure-related complications and comorbidities in patients with epilepsy. Their prevention is therefore an important aspect of therapeutic management both in idiopathic generalized epilepsies and in focal epilepsies., Areas Covered: It has been shown that the efficacy of antiepileptic drugs (AEDs) varies across epilepsy syndromes, with some AEDs efficacious against focal seizures with secondary GTCS (sGTCS) but aggravating primary GTCS (pGTCS). In patients with pGTCS, evidence-based data support the preferential use of valproic acid, lamotrigine, levetiracetam and topiramate. In patients with sGTCS, all AEDs approved in the treatment of focal epilepsies might be used., Expert Opinion: Both in pGTCS and sGTCS, additional data are required, specifically to inform about the relative efficacy of AEDs in relation to each other. Although valproic acid might be the most efficacious drug in idiopathic generalized epilepsies, it should be avoided in women of childbearing age due to its safety profile. In patients with sGTCS, AEDs for which the impact on this seizure type has been formally evaluated and which have demonstrated greater efficacy than placebo might preferentially be used, such as lacosamide, perampanel and topiramate.

Objectives: The anatomical organization of the insular cortex is characterized by its rich and heterogeneous cytoarchitecture and its wide network of connections. However, only limited knowledge is available regarding the intrainsular connections subserving the complex integrative role of the insular cortex. The aim of this study was to analyze the functional connectivity within- and across-insular subregions, at both gyral and functional levels., Experimental Design: We performed intracerebral electrical stimulation in 10 patients with refractory epilepsy investigated with depth electrodes, 38 of which were inserted in the insula. Bipolar electrical stimulation, consisting of two series of 20 pulses of 1-ms duration, 0.2-Hz frequency, and 1-mA intensity, was delivered at each insular contact. For each stimulated insular anatomical region, we calculated a rate of connectivity, reflecting the proportion of other insular contacts, showing significant evoked potentials., Results: Statistically significant evoked potentials were recorded in 74% of tested connections, with an average latency of 26 ± 3 ms. All insular gyri were interconnected, except the anterior and posterior short gyri. Most connections were reciprocal, showing no clear anterior to posterior directionality. No connection was observed between the right and the left insula., Conclusions: These findings point to specific features of human insula connectivity as compared to non-Human primates, and remain consistent with the complex integration role devoted to the human insula in many cognitive domains. Periodicals, Inc., (Copyright © 2013 Wiley Periodicals, Inc.)

Purpose of Review: Long-term video-electroencephalography monitoring (LTM) in epilepsy monitoring units (EMUs) exposes patients to a variety of serious adverse events (SAEs) and safety issues, which have recently caught attention and are summarized in this review., Recent Findings: SAEs observed during LTM affect about 10% of patients and include secondary generalized tonic-clonic seizures, seizure clusters and status epilepticus, unusual for the patient; seizure-related falls, injuries, fractures, and aspiration; postictal psychosis; and cardiorespiratory distress, including sudden unexpected death in epilepsy (SUDEP) and near-SUDEP, which were encountered by more than 10% of European and Australian EMUs. Accordingly, 3% of US-based EMUs suffer a death within a 1-year duration census. Many of these SAEs might be promoted by antiepileptic drugs (AEDs) withdrawal, for which no specific guideline is currently available. Current recommendations regarding optimal organization of EMUs, and in particular continuous supervision by a dedicated staff, are not followed by respectively 20 and 26% of European and US-based EMUs., Summary: SAEs during LTM are a significant concern and might be aggravated by suboptimal EMU organization and staff education. Lack of high-level evidence stands out as the main limiting factor to the development and dissemination of appropriate guidelines.

The management of epilepsy is an essential clinical issue in many patients with brain tumors. Tumoral epilepsy is often drug resistant and is associated with poor quality of life. Surgery represents a key therapeutic option in the management of patients with refractory tumoral epilepsy, with high rates of postoperative seizure freedom, especially when gross total resection can be performed. The selection of surgical candidates first requires extrapolation of the presumed underlying pathology and its potential for malignant transformation from clinical and imaging data, especially MRI characteristics. These data determine the decision for surgery, as well as its timing and technical aspects in relation to the risk of postoperative deficit. In glioneuronal tumors, where seizures are often drug-resistant and risk of malignant transformation is very low, epilepsy surgery is usually recommended to alleviate disabling seizures and side effects of antiepileptic drugs. However, the risk of postoperative deficit may outweigh potential benefits of surgery in tumors located within eloquent cortex. This issue is particularly relevant for glioneuronal tumors located within the dominant mesial temporal structures in patients in whom seizure control might require additional hippocampectomy, associated with a high risk of memory decline. In contrast, in patients with low-grade gliomas or aggressive brain neoplasms, both the decision to perform surgery and selection of the best surgical approach primarily rely on the oncologic imperative rather than epileptologic considerations. In these patients, the extent of tumor resection correlates with improved survival, progression-free survival, as well as with the chances of postoperative seizure control., (Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.)

Despite major advances in neuroimaging, no lesion is visualized on MRI in up to a quarter of patients with drug-resistant focal epilepsy presenting for presurgical evaluation. These patients demonstrate poorer surgical outcomes than those with lesion seen on MRI. Accurate localization of the seizure onset zone (SOZ) is more difficult in MRI-negative patients and often requires invasive EEG recordings. Positron emission tomography (PET) and magnetoencephalography (MEG) have been proposed as clinically relevant tools to localize the SOZ prior to intracranial EEG recordings. However, there is no consensus regarding the optimal gold standard that should be used for assessing the performance of these presurgical investigations. Here, we review the current knowledge concerning the usefulness of PET and MEG for presurgical assessment of MRI-negative epilepsy. Beyond the individual diagnostic performance of MEG and of different PET tracers, including [(18)F]-fluorodeoxyglucose, [(11)C]flumazenil, and markers of 5-HT1A receptors, recent data suggest that the combination of PET and MEG might provide greater sensitivity and specificity than that of each of the two individual tests in patients with normal MRI.

Background: Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in people with chronic refractory epilepsy. Very rarely, SUDEP occurs in epilepsy monitoring units, providing highly informative data for its still elusive pathophysiology. The MORTEMUS study expanded these data through comprehensive evaluation of cardiorespiratory arrests encountered in epilepsy monitoring units worldwide., Methods: Between Jan 1, 2008, and Dec 29, 2009, we did a systematic retrospective survey of epilepsy monitoring units located in Europe, Israel, Australia, and New Zealand, to retrieve data for all cardiorespiratory arrests recorded in these units and estimate their incidence. Epilepsy monitoring units from other regions were invited to report similar cases to further explore the mechanisms. An expert panel reviewed data, including video electroencephalogram (VEEG) and electrocardiogram material at the time of cardiorespiratory arrests whenever available., Findings: 147 (92%) of 160 units responded to the survey. 29 cardiorespiratory arrests, including 16 SUDEP (14 at night), nine near SUDEP, and four deaths from other causes, were reported. Cardiorespiratory data, available for ten cases of SUDEP, showed a consistent and previously unrecognised pattern whereby rapid breathing (18-50 breaths per min) developed after secondary generalised tonic-clonic seizure, followed within 3 min by transient or terminal cardiorespiratory dysfunction. Where transient, this dysfunction later recurred with terminal apnoea occurring within 11 min of the end of the seizure, followed by cardiac arrest. SUDEP incidence in adult epilepsy monitoring units was 5·1 (95% CI 2·6-9·2) per 1000 patient-years, with a risk of 1·2 (0·6-2·1) per 10,000 VEEG monitorings, probably aggravated by suboptimum supervision and possibly by antiepileptic drug withdrawal., Interpretation: SUDEP in epilepsy monitoring units primarily follows an early postictal, centrally mediated, severe alteration of respiratory and cardiac function induced by generalised tonic-clonic seizure, leading to immediate death or a short period of partly restored cardiorespiratory function followed by terminal apnoea then cardiac arrest. Improved supervision is warranted in epilepsy monitoring units, in particular during night time., Funding: Commission of European Affairs of the International League Against Epilepsy., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Four patients with refractory epilepsy and hypermotor seizures (HMS) benefited from an intracerebral investigation after a presurgical evaluation and demonstrated an ictal onset zone primarily involving the posterior cortex, specifically the posterior cingulate gyrus in two patients. At seizure onset, these two patients reported a falling sensation, followed by HMSs characterized by swinging movements of the trunk with intense grasping of the bed railing. The two other patients with lateral parietal seizure onset reported blurred vision and dizziness, followed by a mixed pattern of the previously described type 1 and 2 HMSs. Three patients have been operated on, including two class I of Engel after 36 and 52months of follow-up. One patient developed a postoperative infection and continues to suffer seizures. Pathological findings disclosed a type IIa focal cortical dysplasia in all the patients. The last patient is awaiting surgery. Posterior cortex epilepsies, including those originating from the posterior cingulate cortex, can be responsible for HMSs., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The greater reliability of randomised controlled trials (RCTs) over non-randomised studies to objectively assess efficacy and/or safety of new therapeutic interventions is one of the main paradigms which sustains the evidence-based decision process in clinical practice. This assumption is primarily based on the hypothesis that randomisation, and particularly blinding procedure, drastically reduces the potential bias related to the preferences of patients and physicians. However, from non-randomised studies to double-blind, placebo-controlled RCTs, the preferences of patients and physicians can impact the evaluation of treatment effectiveness. Both internal validity and external validity of RCTs are impacted by various biases related to patient and physician preferences. Thus, influence of patient and physician expectations on trial outcomes might be much less trivial than expected, both in open-label and double-blind, placebo-controlled, randomised trials. Accordingly, it might be interesting to systematically collect information about patient preferences before randomisation, using dedicated questionnaires, in order to be able to evaluate the impact of non-preferred allocation on trial results.

Ezogabine/retigabine (RTG) is a novel antiepileptic compound that activates a voltage-sensitive neuronal-specific outward potassium current that decreases neuronal excitability. RTG has been evaluated in three pivotal placebo-controlled randomized trials as adjunctive therapy in adult drug-resistant partial epilepsy. In comparison to placebo, adjunctive RTG effectively reduces seizure frequency. The relative risk of the responder rate (95% CI) was thus 1.71 (1.24-2.35), 2.18 (1.61-2.96) and 2.35 (1.72-3.22) for RTG 600, 900 and 1200 mg/day, respectively. The most common adverse events associated with RTG were nonspecific CNS side effects. No major effect on cardiac rhythm or conduction has been reported so far. Long-term open-label extensions of these three pivotal trials are underway. RTG has recently been approved both in Europe and in the USA for the adjunctive treatment of partial-onset seizures in adults aged 18 years and above.

Background: Sudden unexpected death in epilepsy (SUDEP) represents the main cause of death in patients with refractory epilepsy. No evidence-based intervention to prevent SUDEP exists. We postulated that pooling data from randomised placebo-controlled trials in patients with refractory epilepsy might show a lower incidence of SUDEP in patients receiving antiepileptic drugs (AEDs) at efficacious doses than in those receiving placebo., Methods: We searched Medline and the Cochrane Library for randomised trials investigating any AED in the add-on treatment of drug-resistant epilepsy in adults. We extracted the number and causes of death in patients allocated to AEDs at doses that were more efficacious than placebo against seizures, AEDs at non-efficacious doses, and placebo. In our primary analysis, we compared the occurrence of definite or probable SUDEP between patients given efficacious AED doses and those given placebo using the Mantel-Haenszel method, with exclusion of trials with no event., Findings: Data of 33 deaths, including 20 deemed as SUDEP, were extracted from 112 eligible randomised trials. 18 deaths were classified as definite or probable SUDEP and two as possible SUDEP. Definite or probable SUDEP, all SUDEP, and all causes of death were significantly less frequent in the efficacious AED group than in the placebo group, with odds ratios of 0·17 (95% CI 0·05-0·57, p=0·0046), 0·17 (0·05-0·57, p=0·0046), and 0·37 (0·17-0·81, p=0·0131), respectively. Rates of definite or probable SUDEP per 1000 person-years were 0·9 (95% CI 0·2-2·7) in patients who received efficacious AED doses and 6·9 (3·8-11·6) in those allocated to placebo., Interpretation: Treatment with adjunctive AEDs at efficacious doses may have reduced the incidence of definite or probable SUDEP by more than seven times compared with placebo in patients with previously uncontrolled seizures. This result provides evidence in favour of active treatment revision for patients with refractory epilepsy., Funding: None., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Purpose: Although gamma-knife radiosurgery (GKS) has proved efficacious in temporal lobe epilepsy (TLE), its antiepileptic mechanism of action remains elusive. Human and experimental data suggest that subnecrotic radiation-induced tissue changes might contribute to the antiepileptic effect of GKS. However, there are no data regarding the evolution of electroencephalography (EEG) activity within GKS-treated hippocampus, information that aid in better understanding both the mechanism of action and the reason for failure of GKS treatment., Methods: Two patients with disabling seizures 4 and 6 years after mesial temporal GKS with a marginal dose of 24 Gy were investigated with stereotactic intracerebral EEG recordings. Both patients had right TLE with hippocampal atrophy, but with past history of Coxsackie virus meningoencephalitis and congenital toxoplasmosis, respectively. Ten to 12 electrodes were implanted, including seven to eight electrodes within the epileptic temporal lobe., Key Findings: In both patients, depths electrodes placed within the irradiated mesial temporal structures disclosed a remarkable pattern of subcontinuous spiking activity intermingled with asymptomatic rhythmic discharges up to 1 min in duration. This activity differed from the abnormalities usually captured in mesial TLE (mTLE) and suggested radiosurgery-induced brain changes. Both patients underwent anterior temporal lobectomy and achieved a class I outcome after a follow-up of 18 and 40 months, respectively. Pathologic examination of the surgical specimens showed variable degrees of radiation-effect changes., Significance: Our study shows that mesial temporal structures previously treated with GKS can demonstrate a persistent high degree of epileptiform activity in patients who failed to respond to that treatment. Although this persistent EEG activity appears likely to reflect GKS-induced brain changes, its relation to GKS seizure outcome remains unclear., (Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.)

Purpose: Because of the lack of head-to-head adjunctive-therapy trials of antiepileptic drugs (AEDs) in refractory partial epilepsy, meta-analyses of placebo-controlled randomized controlled trials (RCTs) represent a potentially important source of evidence to guide treatment decisions. However, such indirect comparisons raise various methodologic issues that may hamper their relevance., Methods: All RCTs in adult refractory partial epilepsy were analyzed to assess whether efficacy outcomes are influenced by: characteristics of patients and trials ; use of last observation carried forward (LOCF) analysis; evaluation period (entire period versus maintenance period); and year of publication. A meta-analysis of these AEDs was then performed taking these factors into consideration., Key Findings: Sixty-three RCTs evaluating 20 AEDs were included. The following variables influenced efficacy estimates: (1) responder rates correlated positively with duration of the entire treatment period (p = 0.038); (2) response to placebo was significantly greater in the maintenance period than in the entire treatment period (p = 0.005); (3) responder rates increased over the years both for AEDs (p < 0.001) and for placebo (p = 0.001); (4) LOCF analysis overestimated responder rates for AEDs (p < 0.001) and for placebo (p = 0.001) compared with completer-based analysis, and the overestimation correlated positively with withdrawal rates (p < 0.001). A meta-analysis of available data showed large differences in efficacy ranking in relation to dose selection and type of analysis, but these were mostly nonsignificant due to statistical power limitations., Significance: Several methodologic issues hamper the relevance of indirect comparisons of AEDs in the adjunctive-therapy of refractory partial epilepsy. Some of these issues could be overcome by improved standardization in the reporting of efficacy outcomes., (Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.)

GABA depolarizes immature neurons because of a high [Cl(-)](i) and orchestrates giant depolarizing potential (GDP) generation. Zilberter and coworkers (Rheims et al., 2009; Holmgren et al., 2010) showed recently that the ketone body metabolite DL-3-hydroxybutyrate (DL-BHB) (4 mM), lactate (4 mM), or pyruvate (5 mM) shifted GABA actions to hyperpolarizing, suggesting that the depolarizing effects of GABA are attributable to inadequate energy supply when glucose is the sole energy source. We now report that, in rat pups (postnatal days 4-7), plasma D-BHB, lactate, and pyruvate levels are 0.9, 1.5, and 0.12 mM, respectively. Then, we show that DL-BHB (4 mM) and pyruvate (200 μM) do not affect (i) the driving force for GABA(A) receptor-mediated currents (DF(GABA)) in cell-attached single-channel recordings, (2) the resting membrane potential and reversal potential of synaptic GABA(A) receptor-mediated responses in perforated patch recordings, (3) the action potentials triggered by focal GABA applications, or (4) the GDPs determined with electrophysiological recordings and dynamic two-photon calcium imaging. Only very high nonphysiological concentrations of pyruvate (5 mM) reduced DF(GABA) and blocked GDPs. Therefore, DL-BHB does not alter GABA signals even at the high concentrations used by Zilberter and colleagues, whereas pyruvate requires exceedingly high nonphysiological concentrations to exert an effect. There is no need to alter conventional glucose enriched artificial CSF to investigate GABA signals in the developing brain.

Objective: The mechanisms of epileptogenesis in Sturge-Weber syndrome (SWS) are unknown. We explored the properties of neurons from human pediatric SWS cortex in vitro and tested in particular whether gamma-aminobutyric acid (GABA) excites neurons in SWS cortex, as has been suggested for various types of epilepsies., Methods: Patch-clamp and field potential recordings and dynamic biphoton imaging were used to analyze cortical tissue samples obtained from four 6- to 14-month-old pediatric SWS patients during surgery., Results: Neurons in SWS cortex were characterized by a relatively depolarized resting membrane potential, as was estimated from cell-attached recordings of N-methyl-D-aspartate channels. Many cells spontaneously fired action potentials at a rate proportional to the level of neuronal depolarization. The reversal potential for GABA-activated currents, assessed by cell-attached single channel recordings, was close to the resting membrane potential. All spontaneously firing neurons recorded in cell-attached mode or imaged with biphoton microscopy were inhibited by GABA. Spontaneous epileptiform activity in the form of recurrent population bursts was suppressed by glutamate receptor antagonists, the GABA(A) receptor agonist isoguvacine, and the positive allosteric GABA(A) modulator diazepam. Blockade of GABA(A) receptors aggravated spontaneous epileptiform activity. The NKCC1 antagonist bumetanide had little effect on epileptiform activity., Interpretation: SWS cortical neurons have a relatively depolarized resting membrane potential and spontaneously fire action potentials that may contribute to increased network excitability. In contrast to previous data depicting excitatory and proconvulsive actions of GABA in certain pediatric and adult epilepsies, GABA plays mainly an inhibitory and anticonvulsive role in SWS pediatric cortex.

In the early postnatal period, energy metabolism in the suckling rodent brain relies to a large extent on metabolic pathways alternate to glucose such as the utilization of ketone bodies (KBs). However, how KBs affect neuronal excitability is not known. Using recordings of single NMDA and GABA-activated channels in neocortical pyramidal cells we studied the effects of KBs on the resting membrane potential (E(m)) and reversal potential of GABA-induced anionic currents (E(GABA)), respectively. We show that during postnatal development (P3-P19) if neocortical brain slices are adequately supplied with KBs, E(m) and E(GABA) are both maintained at negative levels of about -83 and -80 mV, respectively. Conversely, a KB deficiency causes a significant depolarization of both E(m) (>5 mV) and E(GABA) (>15 mV). The KB-mediated shift in E(GABA) is largely determined by the interaction of the NKCC1 cotransporter and Cl(-)/HCO3 transporter(s). Therefore, by inducing a hyperpolarizing shift in E(m) and modulating GABA signaling mode, KBs can efficiently control the excitability of neonatal cortical neurons.

Alzheimer's disease is associated with an increased risk of unprovoked seizures. However, the underlying mechanisms of seizure induction remain elusive. Here, we performed video-EEG recordings in mice carrying mutant human APPswe and PS1dE9 genes (APdE9 mice) and their wild-type littermates to determine the prevalence of unprovoked seizures. In two recording episodes at the onset of amyloid beta (Abeta) pathogenesis (3 and 4.5 months of age), at least one unprovoked seizure was detected in 65% of APdE9 mice, of which 46% had multiple seizures and 38% had a generalized seizure. None of the wild-type mice had seizures. In a subset of APdE9 mice, seizure phenotype was associated with a loss of calbindin-D28k immunoreactivity in dentate granular cells and ectopic expression of neuropeptide Y in mossy fibers. In APdE9 mice, persistently decreased resting membrane potential in neocortical layer 2/3 pyramidal cells and dentate granule cells underpinned increased network excitability as identified by patch-clamp electrophysiology. At stimulus strengths evoking single-component EPSPs in wild-type littermates, APdE9 mice exhibited decreased action potential threshold and burst firing of pyramidal cells. Bath application (1 h) of Abeta1-42 or Abeta25-35 (proto-)fibrils but not oligomers induced significant membrane depolarization of pyramidal cells and increased the activity of excitatory cell populations as measured by extracellular field recordings in the juvenile rodent brain, confirming the pathogenic significance of bath-applied Abeta (proto-)fibrils. Overall, these data identify fibrillar Abeta as a pathogenic entity powerfully altering neuronal membrane properties such that hyperexcitability of pyramidal cells culminates in epileptiform activity.

In order to improve patient compliance and decrease toxicity of antiepileptic drugs (AEDs), the recent strategy for epilepsy management has been to expand the use of extended-release (XR) formulations. Lamotrigine (LTG), an AED with broad efficacy, is available as a twice-daily immediate-release formulation. A once-daily XR formulation of LTG (LTG-XR) is currently being developed. LTG-XR tablets contain a modified-release eroding matrix formulation designed to control the dissolution rate of LTG. The bioavailability of LTG-XR is similar to that of LTG-IR, except in patients taking enzyme-inducing AEDs in whom the bioavailability of LTG-XR is 21% lower. In adult drug-resistant partial epilepsy, adjunctive LTG-XR effectively reduces the seizure frequency and is well tolerated. Trials in an elderly population with partial epilepsy as well as in adults with refractory primary tonic-clonic seizures are underway. Once-daily LTG-XR may represent a future option for patients with poor compliance to twice-daily immediate-release LTG.

Background: Hypermotor seizures (HMS) are characterized by complex movements involving the proximal segment of the limbs and trunk. Although they are primarily reported in mesial frontal or orbitofrontal epilepsies, they have also been described in patients with temporal or insular epilepsies, questioning the localizing value of HMS in patients contemplating epilepsy surgery. Furthermore, HMS can include different forms of HM behaviors. Whether these clinical variations may be systematized and may reflect different locations of the epileptogenic zone (EZ) has not been evaluated yet., Methods: We have retrospectively analyzed ictal signs and intracerebral EEG data in 11 patients presenting with HMS who became seizure free following epilepsy surgery with a minimum follow-up of 24 months. Clinical phenomena were reviewed blinded to seizure onset zone., Results: Two types of HMS could be distinguished in this population: HMS1, observed in six patients, mainly consisted of marked agitation that either included body rocking, kicking, or boxing, associated with a facial expression of fear. HMS2, observed in the five other patients, mainly consisted of mild agitation that included either horizontal movements or rotation of trunk and pelvis while lying on the bed, usually associated with tonic/dystonic posturing. SEEG findings showed that the EZ associated with HMS1 was mainly centered on the ventromesial frontal cortex. Conversely, HMS2 was primarily associated with an EZ localized within the mesial premotor cortex., Conclusions: Although these findings remain to be confirmed by larger studies, they may help optimize the placement of intracerebral electrodes in patients contemplating epilepsy surgery.

Pregabalin is one of the latest antiepileptic drugs introduced for the treatment of partial epilepsy. Its efficacy and safety as adjunctive therapy in refractory partial epilepsy have been established in four double-blind placebo-controlled trials (n = 1396) and 4 long-term open-label studies (n = 1480). In 3 fixed-dose trials, the proportion of patients with a >/=50% reduction in seizure frequency across the effective dose-range (150-600 mg/day) ranged between 14% and 51%, with a clear dose-response relationship. Suppression of seizure activity could be demonstrated as early as day 2. The most frequently reported CNS-related adverse events included dizziness, somnolence, ataxia and fatigue, were usually mild or moderate, and tended to be dose related. In long-term studies, weight gain was reported as an adverse event by 24% of patients. When pregabalin dose was individualized to according to response within the 150 to 600 mg/day dose range, tolerability was considerably improved compared with use of a high-dose, fixed-dose regimen (600 mg/day) without titration. In long-term studies up to 4 years, no evidence of loss efficacy was identified. During the last year on pregabalin, 3.7% of patients were seizure-free. Pregabalin appears to be a useful addition to the therapeutic armamentariun for the management of refractory partial epilepsy.

Background: Despite guidelines establishing the need to perform comprehensive paediatric drug development programs, pivotal trials in children with epilepsy have been completed mostly in Phase IV as a postapproval replication of adult data. However, it has been shown that the treatment response in children can differ from that in adults. It has not been investigated whether differences in drug effect between adults and children might occur in the treatment of drug-resistant partial epilepsy, although such differences may have a substantial impact on the design and results of paediatric randomised controlled trials (RCTs)., Methods and Findings: Three electronic databases were searched for RCTs investigating any antiepileptic drug (AED) in the add-on treatment of drug-resistant partial epilepsy in both children and adults. The treatment effect was compared between the two age groups using the ratio of the relative risk (RR) of the 50% responder rate between active AEDs treatment and placebo groups, as well as meta-regression. Differences in the response to placebo and to active treatment were searched using logistic regression. A comparable approach was used for analysing secondary endpoints, including seizure-free rate, total and adverse events-related withdrawal rates, and withdrawal rate for seizure aggravation. Five AEDs were evaluated in both adults and children with drug-resistant partial epilepsy in 32 RCTs. The treatment effect was significantly lower in children than in adults (RR ratio: 0.67 [95% confidence interval (CI) 0.51-0.89]; p = 0.02 by meta-regression). This difference was related to an age-dependent variation in the response to placebo, with a higher rate in children than in adults (19% versus 9.9%, p < 0.001), whereas no significant difference was observed in the response to active treatment (37.2% versus 30.4%, p = 0.364). The relative risk of the total withdrawal rate was also significantly lower in children than in adults (RR ratio: 0.65 [95% CI 0.43-0.98], p = 0.004 by metaregression), due to higher withdrawal rate for seizure aggravation in children (5.6%) than in adults (0.7%) receiving placebo (p < 0.001). Finally, there was no significant difference in the seizure-free rate between adult and paediatric studies., Conclusions: Children with drug-resistant partial epilepsy receiving placebo in double-blind RCTs demonstrated significantly greater 50% responder rate than adults, probably reflecting increased placebo and regression to the mean effects. Paediatric clinical trial designs should account for these age-dependent variations of the response to placebo to reduce the risk of an underestimated sample size that could result in falsely negative trials.

The neonatal period is critical for seizure susceptibility, and neocortical networks are central in infantile epilepsies. We report that application of 4-aminopyridine (4-AP) to immature (P6-P9) neocortical slices generates layer-specific interictal seizures (IISs) that transform after recurrent seizures to ictal seizures (ISs). During IISs, cell-attached recordings show action potentials in interneurons and pyramidal cells in L5/6 and interneurons but not pyramidal neurons in L2/3. However, L2/3 pyramidal neurons also fire during ISs. Using single N-methyl-d-aspartate (NMDA) channel recordings for measuring the cell resting potential (Em), we show that transition from IISs to ISs is associated with a gradual Em depolarization of L2/3 and L5/6 pyramidal neurons that enhances their excitability. Bumetanide, a NKCC1 co-transporter antagonist, inhibits generation of IISs and prevents their transformation to ISs, indicating the role excitatory GABA in epilepsies. Therefore deep layer neurons are more susceptible to seizures than superficial ones. The initiating phase of seizures is characterized by IISs generated in L5/6 and supported by activation of both L5/6 interneurons and pyramidal cells. IISs propagate to L2/3 via activation of L2/3 interneurons but not pyramidal cells, which are mostly quiescent at this phase. In superficial layers, a persistent increase in excitability of pyramidal neurons caused by Em depolarization is associated with a transition from largely confined GABAergic IIS to ictal events that entrain the entire neocortex.

GABA depolarizes immature cortical neurons. However, whether GABA excites immature neocortical neurons and drives network oscillations as in other brain structures remains controversial. Excitatory actions of GABA depend on three fundamental parameters: the resting membrane potential (Em), reversal potential of GABA (E(GABA)), and threshold of action potential generation (Vthr). We have shown recently that conventional invasive recording techniques provide an erroneous estimation of these parameters in immature neurons. In this study, we used noninvasive single N-methyl-d-aspartate and GABA channel recordings in rodent brain slices to measure both Em and E(GABA) in the same neuron. We show that GABA strongly depolarizes pyramidal neurons and interneurons in both deep and superficial layers of the immature neocortex (P2-P10). However, GABA generates action potentials in layer 5/6 (L5/6) but not L2/3 pyramidal cells, since L5/6 pyramidal cells have more depolarized resting potentials and more hyperpolarized Vthr. The excitatory GABA transiently drives oscillations generated by L5/6 pyramidal cells and interneurons during development (P5-P12). The NKCC1 co-transporter antagonist bumetanide strongly reduces [Cl(-)]i, GABA-induced depolarization, and network oscillations, confirming the importance of GABA signaling. Thus a strong GABA excitatory drive coupled with high intrinsic excitability of L5/6 pyramidal neurons and interneurons provide a powerful mechanism of synapse-driven oscillatory activity in the rodent neocortex in vitro. In the companion paper, we show that the excitatory GABA drives layer-specific seizures in the immature neocortex.

Purpose: Indication of gamma-knife surgery (GKS) in temporal lobe epilepsy (TLE) remains a matter of debate. Either positive or negative results have been reported in studies with a maximum follow-up of 24 months. No long-term data have been published yet., Methods: We collected data from 15 TLE patients who underwent GKS and whose follow-up was longer than 24 months. Localisation and extension of the epileptogenic zone (EZ) were assessed by SEEG in eight patients. Ten patients were presenting with mesial TLE (mTLE) while in the other five SEEG showed that the EZ was extending beyond mesio-temporal structures. GKS procedure was targeted to the EZ at a dose of 21.1+/-2.6Gy at the margin., Results: The mean duration of the follow-up was 60+/-22.3 months. At last follow-up, seven patients (46.7%) were free of disabling seizure. The last seizure following GKS occurred on average after a delay of 19.75+/-20.62 months. No patient suffered recurrent seizures after a long period free of disabling seizures. No significant prognostic predictor could be individualized in this population. However, 6 of the 10 patients with mTLE (60%) were seizure free whereas only 1 of the 5 (20%) whose EZ was more extended exhibited the same seizure outcome., Conclusion: When a positive outcome is achieved, the risk of seizure recurrence remains low at long term. In patients with typical mTLE, long-term GKS results may be closed to those observed after conventional surgery. Conversely, this procedure should not be proposed to patients in whom SEEG results suggest that the EZ is not restricted to mesial temporal structures.

During postnatal development of the rat hippocampus, gamma-aminobutyric acid (GABA) switches its action on CA3 pyramidal cells from excitatory to inhibitory. To characterize the underlying changes in the GABA reversal potential, we used somatic cell-attached recordings of GABA(A) and N-methyl-D-aspartate channels to monitor the GABA driving force and resting membrane potential, respectively. We found that the GABA driving force is strongly depolarizing during the first postnatal week. The strength of this depolarization rapidly declines with age, although GABA remains slightly depolarizing, by a few millivolts, even in adult neurons. Reduction in the depolarizing GABA driving force was due to a progressive negative shift of the reversal potential of GABA currents. Similar postnatal changes in GABA signalling were also observed using the superfused hippocampus preparation in vivo, and in the hippocampal interneurons in vitro. We also found that in adult pyramidal cells, somatic GABA reversal potential is maintained at a slightly depolarizing level by bicarbonate conductance, chloride-extrusion and chloride-loading systems. Thus, the postnatal excitatory-to-inhibitory switch in somatic GABA signalling is associated with a negative shift of the GABA reversal potential but without a hyperpolarizing switch in the polarity of GABA responses. These results also suggest that in adult CA3 pyramidal cells, somatic GABAergic inhibition takes place essentially through shunting rather than hyperpolarization. Apparent hyperpolarizing GABA responses previously reported in the soma of CA3 pyramidal cells are probably due to cell depolarization during intracellular or whole-cell recordings.

Epilepsy surgery has benefited from major advances during the last 20 years, thanks to the development of neuroimaging and long-term video-electroencephalographic (EEG) monitoring. However, it remains the case that only a small minority of potential epilepsy surgery candidates will have access to a comprehensive presurgical evaluation. Furthermore, this subset of patients are operated on after an average of 20 to 25 years of epilepsy duration. Among the various reasons that prevent many patients from benefiting from a timely presurgical evaluation, we need to emphasize the role of inaccurate information regarding eligibility criteria and lack of standardized practice. This review aims at providing an in-depth discussion of the current views regarding the definition of surgical candidates, and the role of the numerous investigations used in the presurgical evaluation of patients with drug-resistant epilepsy. The eligibility criteria required to enter a presurgical evaluation in 2008 should be relatively liberal, provided that the patient suffers from disabling seizures unrelated to an idiopathic generalized epileptic syndrome, despite appropriate antiepileptic drug treatment. However, the decision as to whether or not to perform a presurgical evaluation must be individualized, and take into account the likelihood of meeting the patient's expectations in terms of outcome. These expectations need to be balanced with the apparent severity of the epileptic condition, the chance of achieving a successful surgical treatment, and the risk of a postoperative neurological, cognitive, or psychiatric deterioration. The roles and specific features of the main types of presurgical investigations are reviewed.

Purpose: To report three patients with drug-resistant nocturnal hypermotor seizures (NHSs), no detectable brain lesion, and clinically defined nocturnal frontal lobe epilepsy (NFLE) or autosomal dominant NLFE (ADNFLE), whose intracerebral EEG ictal onset primarily involved the insula, rather than the mesial or orbital frontal cortex., Methods: Fourteen to 15 intracerebral electrodes were implanted in each patient, primarily sampling the frontal lobes with 80 to 91 recording leads covering the most likely side of seizure onset, and two to six leads placed within the ipsilateral insula. Electrical stimulation was used to test the epileptic threshold of frontal and insular brain regions at the various recording sites., Results: In all three patients, a low-voltage fast activity was recorded within the anterosuperior aspect of the insula at ictal onset, either in isolation, or extending to the nearby frontal operculum in the ADNFLE patient. The role of the insula was further supported in all three patients either by the presence of high-amplitude spikes that clearly predominated over that region (n = 2) or by triggering the patient's typical aura or seizure when applying an electrical stimulation at that site, selectively (n = 2)., Conclusions: The anterosuperior portion of the insula might play a pivotal role in generating nocturnal hypermotor seizures in some patients with nonlesional drug-resistant epilepsy suggesting NFLE or ADNFLE. Whether these patients are amenable to successful surgery remain an open issue.

Nocturnal frontal lobe epilepsy (NFLE) is a condition primarily characterized by seizures occurring exclusively or predominantly during sleep, the semiology of which suggest a frontal lobe origin and, more specifically, the involvement of the orbitofrontal or mesial frontal regions. It is usually considered as a relatively benign and homogeneous epileptic syndrome, the neuropsychological impact of which should be minimal. However, several issues complicate this view. 1. NFLE is rather a heterogeneous disorder which includes both sporadic and familial forms, various seizure types, and drug resistance in about 30% of patients. 2. The frontal origin of seizures has rarely been demonstrated, and mainly relies on the presence of ictal signs suggestive of frontal lobe epilepsy, but which might only reflect the propagation of ictal discharges of extrafrontal origin. 3. NFLE-like seizures were recently found to be associated with temporobasal cortical dysplasia, or an insular epileptogenic zone, including one patient with autosomal dominant frontal lobe epilepsy (ADNFLE). 4. No study has yet specifically evaluated the neuropsychological profile of patients with NFLE. Available data suggest that behavioral problems and mental retardation might be associated with ADNFLE, especially when it is related to a mutation of the nicotinic receptor subunits. Conversely, the majority of NFLE patients does not seem to present with gross cognitive disturbance, even though many of these patients complain of chronically disrupted sleep and daytime sleepiness. Further research is warranted in this field, keeping in mind that the neural networks underlying NFLE remain poorly known and might primarily involve extrafrontal brain regions in some patients.

Purpose: The lateralizing value of ictal head deviation (HD) in frontal lobe epilepsy (FLE) is a matter of debate. Although FLE is typically associated with tonic or clonic HD contralateral to seizure onset, ipsilateral HD has been noted in numerous reports. Whether both types of HD can be distinguished according to their clinical patterns has not yet been specifically investigated., Methods: We studied the clinical pattern and time of occurrence of HD of 129 seizures in 13 consecutive patients, who underwent successful surgery for FLE, including 12 investigated with an intracerebral stereotactic EEG procedure., Results: Ictal HD was ipsilateral to the epileptogenic zone (EZ) in four (30%) patients and 27 (20.9%) seizures and contralateral in five (38%) patients and 15 (11.6%) seizures. Ipsilateral HD was rarely tonic and never associated with clonic manifestation. Contralateral HD was always tonic, unnatural, and associated with hemifacial clonic movements in 86% of seizures. Ipsilateral HD occurred earlier than contralateral HD (p < 0.03), with a mean delay of 1 +/- 2 s after the first detectable ictal sign, as compared with a delay of 17 +/- 11 s for contralateral HD. Moreover, ipsilateral HD always occurred before contralateral HD when both signs coexisted in the same seizure. Our patients with ipsilateral HD demonstrated either an anterior or dorsolateral frontal EZ., Conclusions: Ipsilateral HD is a common ictal sign during FLE and can be distinguished from contralateral HD by its time of occurrence at or immediately after seizure onset and its lacking association with clonic movements.