Lacosamide and sodium channel-blocking antiepileptic drug cross-titration against levetiracetam background therapy.

OBJECTIVE: To assess prospectively the effectiveness of lacosamide (LCM) added to levetiracetam (LEV) after down-titration of a concomitant sodium channel blocker (SCB) among patients with focal epilepsy not adequately controlled on LEV and SCB. METHODS: In this open-label trial, LCM was initiated at 100 mg/day and up-titrated to 200-600 mg/day over 9 weeks; SCB down-titration started when LCM dose reached 200 mg/day. Patients remained on stable LCM/LEV doses for 12 weeks' maintenance (21-week treatment period). The primary outcome was retention rate on LCM. RESULTS: Due to recruitment challenges, fewer than the planned 300 patients participated in the trial, resulting in the trial being underpowered. Overall, 120 patients (mean age 39.7 years) started and 93 completed the trial. The most frequently used SCBs were lamotrigine (39.2%), carbamazepine (30.8%) and oxcarbazepine (27.5%). Eighty-four patients adhered to protocol and discontinued their SCB after cross-titration, but there was insufficient evidence for 36 patients. Retention rate was 73.3% (88/120) for all patients and 83.3% (70/84) for those with evidence of SCB discontinuation. Seizure freedom for patients completing maintenance was 14.0% (13/93). Discontinuation due to adverse events (6.7%) and lack of efficacy (3.3%) occurred primarily during cross-titration. Most frequently reported adverse events during treatment were dizziness (23.3%), headache (15.0%) and fatigue (8.3%). CONCLUSIONS: In patients with uncontrolled seizures on LEV/SCB, the LCM/LEV combination appeared to be effective and well tolerated. A cross-titration schedule-flexible LCM up-titration, concomitant SCB down-titration and stable background LEV-could present a feasible and practical approach to initiating LCM while minimizing pharmacodynamic interactions with a SCB.

Are auras a reliable clinical indicator in medial temporal lobe epilepsy with hippocampal sclerosis?

BACKGROUND AND PURPOSE: Medial temporal lobe epilepsy with unilateral hippocampal sclerosis (MTLE-HS) is the most frequent form of surgical temporal lobe epilepsy. In this study, it was aimed to determine whether different types of aura represent a cardinal and characteristic feature of MTLE-HS and might provide a diagnostic complement to help identify patients who will be seizure-free after surgery. METHODS: All types of auras and associations of auras reported by 400 MTLE-HS patients referred for surgery were retrospectively collected and their statistical correlation with the postoperative outcome was examined in a subgroup of 305 patients who underwent surgery. RESULTS: A total of 876 auras were collected, classified into 12 categories. Globally, MTLE-HS patients reported widely variable auras and groupings of auras. Most common were autonomic and abdominal visceral auras, followed by psychoaffective and experiential auras; less common, but seen in 10%-15% of patients, were non-specific auras, somatosensory auras and visual auras, and least common, reported by less than 10% of patients, were auditory, gustatory, vestibular, olfactory and intellectual auras. No auras were reported in 10% of patients. 65% of patients experienced more than one type of aura (two to seven). No specific groupings of aura type were apparent. No evidence was found for correlation between postoperative outcome and (i) any category of aura, (ii) the number of categories of aura per patient and (iii) any association of categories of auras. CONCLUSION: Auras and association of auras vary widely in MTLE-HS and provide no useful insight into surgical outcome.

Lateralizing value of semiology in medial temporal lobe epilepsy.

OBJECTIVES: Analysing the clinical characteristics of seizures constitutes a fundamental aspect of the presurgical evaluation of patients with medial temporal lobe epilepsy and unilateral hippocampal sclerosis (MTLE-HS), the most frequent form of focal epilepsy accessible to surgery. We sought to retrospectively determine whether objective manifestations could have a reliable lateralizing value in a large population of MTLE-HS patients and if their presence could help to identify those patients who would be seizure free after surgery. MATERIAL AND METHODS: We analysed the frequency and predictive lateralizing value of objective ictal and postictal signs in 391 patients with MTLE-HS (183 left/208 right). Data were derived from chart review and not from blinded videoEEG analysis. Correlation between the presence of reliable lateralizing signs and postoperative outcome was performed in a subgroup of 302 patients who underwent surgery. RESULTS: Contralateral dystonic posturing was the most frequent and reliable lateralizing sign that correctly lateralized the focus in 96% of patients. Unilateral head/eye deviation was noted in 42% of the patients and predicted unilateral focus in 67%. Ipsilateral postictal nose wiping, contralateral clonus and hypokinesia correctly lateralized the focus in 75%, 81%, respectively, and 100 of patients but were less frequently depicted. Postictal aphasia was a strong lateralizing sign for left MLE-HS. The presence of reliable lateralizing signs was not a predictor of seizure freedom. CONCLUSION: Seizure semiology is a simple tool that may permit reliable lateralization of the seizure focus in MTLE-HS. The presence of reliable lateralizing signs is not associated with a better postoperative outcome.

MTLE with hippocampal sclerosis in adult as a syndrome.

Mesial temporal lobe epilepsy with hippocampal sclerosis, (MTLE-HS) is a well characterized disorder which associates electroclinical features suggestive of seizure onset in the mesial or limbic structures of the temporal lobe, and hippocampal sclerosis. This underlying pathology differentiates MTLE-HS from MTLE due to other pathological substrates. Typically, when MTLE-HS is diagnosed, a typical course of the disease can be retrospectively recognized, including early prolonged febrile seizures, a latent period, onset in mid-to-late childhood, auras that may initially occur in isolation, periods of seizure remission during adolescence or early adulthood. Then the condition progresses, associating elaborated seizures, progressive drug-resistance and cognitive, mainly memory, disorders of variable intensity. The seizures have a relatively gradual onset/offset, developing over 1-2minutes, with partial awareness at the onset, and lasting for 2 to 10minutes. Auras are common, with visceral, autonomic, psycho-affective, experiential components, presenting less frequently diverse sensory or sensorial symptoms. Awareness is generally preserved at onset, but then loss of consciousness occurs, with initial motionless stare, and automatisms, which typically are oro-alimentary, vocal or gestural, accompanied by motor signs such as contralateral dystonic posturing. A dysphasia is frequent when the focus is in the dominant hemisphere, often prolonged by a post-ictal dysphasia and confusion. Interictal EEG shows anterior or mid-temporal spikes/sharp ipsilaterally to the focus, in combination with non-epileptiform regional slowing. These changes may be bilateral but usually predominates ipsilaterally. Ictal EEG changes are marked by rhythmic temporal alpha or theta activity within 30seconds of clinical onset. The hallmark is the presence of hippocampal sclerosis, demonstrable on coronal MRI sequences by unilateral (or asymmetrical) decrease in hippocampal volume and increase in signal on T2-weighted sequences. The diagnosis of MTLE is crucial because of its frequent poor prognosis under antiepileptic drugs, and of the possibility of excellent results after resective surgery. PET scanning shows a typical antero-mesial hypometabolism extending to the pole and lateral aspects of the temporal lobe. Presurgical investigations may also include depth-electrode recordings in case of doubt about more extensive or bilateral onsets. They demonstrate and lateralize the amygdalo-hippocampal discharges, some of them remaining apparently asymptomatic in the absence of extrahippocampal spreading. These interactions between hippocampal and extrahippocampal networks confer its specificity to MTLE-HS, together with its remarkable natural course. This entity is diagnostically essential, whether it should be regarded as an epileptic syndrome, disease or a distinctive constellation.

[Evolution of ideas and techniques, and future prospects in epilepsy surgery]. / Évolution des idées et des techniques, et perspectives d'avenir en chirurgie de l'épilepsie.

INTRODUCTION: The aim of this article was to review and evaluate the published literature related to the outcome of epilepsy surgery, while placing it in an historical perspective, and to describe the future prospects in this field. STATE OF ART: Temporal lobe surgery achieves seizure freedom in about 70% of cases. Seizure outcome is similar in the pediatric population. Extratemporal resections impart good results to 40% to 60% of patients, with a better prognosis in the case of frontal lobe surgery. Pediatric hemispherotomy leads to seizure control in about 80% of children. Radiosurgery used as a treatment for temporal mesial epilepsy has an outcome quite similar to that obtained with surgical resection, but provides a neuropsychological advantage. Radiosurgery is also effective in 60% of children treated for seizures related to hypothalamic hamartoma. Regarding palliative surgery, callosotomy and multiple subpial transections show satisfactory outcomes in over 60% of cases. Neuromodulation techniques (vagus nerve stimulation and bilateral stimulation of the anterior nucleus of the thalamus) allow a 50% reduction of seizures in half of patients. PERSPECTIVES: Transcranial magnetic stimulation combined with electroencephalography seems a promising technique because of its diagnostic, prognostic and therapeutic applications. Transcranial ultrasound stimulation, which can reversibly control neuronal activity, is also under consideration. Concerning neuromodulation, trigeminal nerve stimulation may become an alternative to vagus nerve stimulation; while other targets of deep brain stimulation are being evaluated. Also, the possibility of coupling SEEG seizure focus detection with concomitant laser or radiofrequency focus destruction is under development. CONCLUSIONS: Constant evolution of epilepsy surgery has improved patient outcomes over time. Current research and development axes suggest the continuation of this trend and a reduction of the invasiveness of surgical procedures.

Surgical treatment for mesial temporal lobe epilepsy associated with hippocampal sclerosis.

INTRODUCTION: Hippocampal sclerosis is the most common cause of pharmacoresistant epilepsy amenable for surgical treatment and seizure control. The aim of this article is to review and evaluate the published literature related to the outcome of the surgical treatment of mesial temporal lobe epilepsy (MTLE) associated with hippocampal sclerosis (HS) and to describe the future prospects in this field. STATE OF ART: Surgery of MTLE associated with HS achieves long-term seizure freedom in about 70% (62-83%) of cases. Seizure outcome is similar in the pediatric population. Mortality following temporal resection is very rare (<1%) and the rate of definitive neurological complication is low (1%). Gamma knife stereotactic radiosurgery used as a treatment for MTLE would have a slightly worse outcome to that of surgical resection, but would provide neuropsychological advantage. However, the average latency before reducing or stopping seizures is at least 9 months with radiosurgery. Regarding palliative surgery, amygdalohippocampal stimulation has been demonstrated to improve the control of epilepsy in carefully selected patients with intractable MTLE who are not candidates for resective surgery. PERSPECTIVES: Recent progress in the field of imaging and image-guidance should allow to elaborate tailored surgical strategies for each patient in order to achieve seizure freedom. Concerning therapeutics, closed-loop stimulation strategies allow early seizure detection and responsive stimulation. It may be less toxic and more effective than intermittent and continuous neurostimulation. Moreover, stereotactic radiofrequency amygdalohippocampectomy is a recent approach leading to hopeful results. Closed-loop stimulation and stereotactic radiofrequency amygdalohippocampectomy may provide a new treatment option for patients with pharmacoresistant MTLE. CONCLUSIONS: Mesial temporal lobe surgery has been widely evaluated and has become the standard treatment for MTLE associated with HS. Alternative surgical procedures like gamma knife stereotactic radiosurgery and amygdalohippocampal stimulation are currently under assessment, with promising results.

First genetic evidence of GABA(A) receptor dysfunction in epilepsy: a mutation in the gamma2-subunit gene.

Major advances in the identification of genes implicated in idiopathic epilepsy have been made. Generalized epilepsy with febrile seizures plus (GEFS+), benign familial neonatal convulsions and nocturnal frontal lobe epilepsy, three autosomal dominant idiopathic epilepsies, result from mutations affecting voltage-gated sodium and potassium channels, and nicotinic acetylcholine receptors, respectively. Disruption of GABAergic neurotransmission mediated by gamma-aminobutyric acid (GABA) has been implicated in epilepsy for many decades. We now report a K289M mutation in the GABA(A) receptor gamma2-subunit gene (GABRG2) that segregates in a family with a phenotype closely related to GEFS+ (ref. 8), an autosomal dominant disorder associating febrile seizures and generalized epilepsy previously linked to mutations in sodium channel genes. The K289M mutation affects a highly conserved residue located in the extracellular loop between transmembrane segments M2 and M3. Analysis of the mutated and wild-type alleles in Xenopus laevis oocytes confirmed the predicted effect of the mutation, a decrease in the amplitude of GABA-activated currents. We thus provide the first genetic evidence that a GABA(A) receptor is directly involved in human idiopathic epilepsy.

Epileptic seizures can be anticipated by non-linear analysis.

Epileptic seizures are a principal brain dysfunction with important public health implications, as they affect 0.8% of humans. Many of these patients (20%) are resistant to treatment with drugs. The ability to anticipate the onset of seizures in such cases would permit clinical interventions. The view of chronic focal epilepsy now is that abnormally discharging neurons act as pacemakers to recruit and entrain other normal neurons by loss of inhibition and synchronization into a critical mass. Thus, preictal changes should be detectable during the stages of recruitment. Traditional signal analyses, such as the count of focal spike density, the frequency coherence or spectral analyses are not reliable predictors. Non-linear indicators may undergo consistent changes around seizure onset. Our objective was to follow the transition into seizure by reconstructing intracranial recordings in implanted patients as trajectories in a phase space and then introduce non-linear indicators to characterize them. These indicators take into account the extended spatio-temporal nature of the epileptic recruitment processes and the corresponding physiological events governed by short-term causalities in the time series. We demonstrate that in most cases (17 of 19), seizure onset could be anticipated well in advance (between 2-6 minutes beforehand), and that all subjects seemed to share a similar 'route' towards seizure.

[Seizure prediction: from myth to reality]. / Prédiction des crises d'épilepsie: du mythe à la réalité.

INTRODUCTION: Clinical, metabolic and electrophysiologic studies suggest the existence of a preictal state, a transition between the interictal state and seizure. STATE OF THE ART: Analysis of the intracranial EEG by mathematical methods shows changes of the brain dynamics several minutes before the occurrence of partial seizures. These modifications can be widespread and not restricted to the epileptogenic focus, which would explain why they can also be detected from scalp EEG. Several scenarios could underlie the preictal state: a progressive recruitment of neurons or a facilitating state with a high probability of seizure occurrence. Because of the high rate of false predictions, no satisfactory method for seizure prediction has been currently proposed. PERSPECTIVES: A European multicenter study (Evolving platform for improving living expectation of patients suffering from IctAl events [EPILEPSIAE]) is currently evaluating a combination of 44 methods applied for EEG and ECG analysis on long-term recordings obtained from a large multicenter database (www.epilepsiae.eu). CONCLUSION: Combining analyses of multi-level signals including intracranial EEG and microelectrodes, scalp EEG and in vitro electrophysiological studies of post-operative tissues should help clarify brain dynamics during the pre-ictal state.

Different spatial memory systems are involved in small- and large-scale environments: evidence from patients with temporal lobe epilepsy.

Recent reports show that humans and animals do not acquire information about routes and object locations in the same way. In spatial memory, a specific sub-system is hypothesized to be involved in encoding, storing and recalling navigational information, and it is segregated from the sub-system devoted to small-scale environment. We assessed this hypothesis in a sample of patients treated surgically for intractable temporal lobe epilepsy. We found double dissociations between learning and recall of spatial positions in large space versus small space. These results strongly support the hypothesis that two segregate systems process navigational memory for large-scale environments and spatial memory in small-scale environments.

The effects of railway noise on sleep medication intake: results from the ALPNAP-study.

In the 1980s/90s, a number of socio-acoustic surveys and laboratory studies on railway noise effects have observed less reported disturbance/interference with sleep at the same exposure level compared with other modes of transportation. This lower grade of disturbance has received the label "railway bonus", was implemented in noise legislation in a number of European countries and was applied in planning and environmental impact assessments. However, majority of the studies investigating physiological outcomes did not find the bespoke difference. In a telephone survey (N=1643) we investigated the relationship between railway noise and sleep medication intake and the impact of railway noise events on motility parameters during night was assessed with contact-free high resolution actimetry devices. Multiple logistic regression analysis with cubic splines was applied to assess the probability of sleep medication use based on railway sound level and nine covariates. The non-linear exposure-response curve showed a statistically significant leveling off around 60 dB (A), Lden. Age, health status and trauma history were the most important covariates. The results were supported also by a similar analysis based on the indicator "night time noise annoyance". No railway bonus could be observed above 55 dB(A), Lden. In the actimetry study, the slope of rise of train noise events proved to be almost as important a predictor for motility reactions as was the maximum sound pressure level - an observation which confirms similar findings from laboratory experiments and field studies on aircraft noise and sleep disturbance. Legislation using a railway bonus will underestimate the noise impact by about 10 dB (A), Lden under the conditions comparable with those in the survey study. The choice of the noise calculation method may influence the threshold for guideline setting.

Distinct visual perspective-taking strategies involve the left and right medial temporal lobe structures differently.

This study assesses the role of the human medial temporal lobe (MTL) structures in the coordination of spatial information across perspective change and, in particular, in visual perspective taking--namely the capacity to know what another individual is seeing on the visual scene. Fourteen patients with unilateral temporal lobe resection and 21 control subjects performed two tasks, called 'object location memory' and 'viewpoint recognition', respectively. In the object location memory task, subjects had to memorize the position of a target object in the environment from an initial viewpoint. They were then shown the same environment from a new viewpoint and had to indicate whether or not the target object had moved. In the viewpoint recognition task, subjects had to imagine the perspective of an avatar from the initial viewpoint and then decide whether or not the new viewpoint was that of the avatar. The results showed a double dissociation, with left MTL patients being impaired in the object location memory task but not in the viewpoint recognition task and right MTL patients being impaired in the viewpoint recognition task but not in the object location memory task. Furthermore, based on multiple regression analyses between performance and the volumes of the different MTL structures, we discuss the specific involvement of the left temporopolar cortex and of the right hippocampus in different kinds of visual perspective taking.

[Postictal psychosis syndrome: a clinical entity to be recognized]. / Le syndrome de psychose post-ictale : une entité clinique à connaître.

INTRODUCTION: Post-ictal psychosis syndrome (PIP) belongs to the group of epileptic psychoses which, according to the most commonly used classification, is to be distinguished from ictal psychoses, on one hand, and from inter-ictal psychoses, on the other. OBJECTIVES: The present paper aims to review recent data concerning the clinical, therapeutic and pathophysiological aspects of PIP. METHODS: We report four cases of PPI, which involved four patients hospitalized at the Salpêtrière hospital between 2001 and 2005, and discuss these cases in light of the relevant literature. RESULTS: The PIP fit generally occurs in patients suffering from intractable temporal lobe epilepsy which started several years before. The psychiatric disorders suddenly take hold after a series of complex partial seizures with frequent secondarily generalized tonic clonic seizures. During the episode, EEG recordings do not show any epileptic activity. Psychiatric symptoms consist of persecutory delusive ideas, verbal and visual hallucinations, agitation, and aggressiveness. Mood disorders are variable from one patient to another and exhibit intraindividual fluctuation. In most patients given antipsychotic drugs, the short-term outcome of PIP is favorable . In the long-term, even if recurrence is the main long-term risk, progression to severe mood disorders or to poor prognosis inter-ictal psychosis is possible. Accordingly, the clinician must be aware of this syndrome in order to correctly diagnose PIP since effective treatment with antipsychotic drugs is available. CONCLUSION: The short-term prognosis of PPI is usually favorable but this syndrome can potentially develop in the long-term to more severe psychiatric disorders. It is, therefore, important to recognize PIP syndromes which respond more readily to pharmacological treatments than other types of psychoses.

Is anterior temporal lobectomy a precipitating factor for transient global amnesia?

Little is known about the pathophysiology of transient global amnesia (TGA) and how it is related to epilepsy. We report here five typical episodes of TGA, each occurring several years after surgery for epilepsy. In all cases, patients were seizure-free after a surgery consisting of anterior temporal lobectomy for refractory medial temporal lobe epilepsy associated with hippocampal sclerosis (n = 4) or linked with a dysembryoplastic neuroepithelial tumour (n = 1). Investigations, including MRI or CT scan, angio-MRI or echocardiogram or vascular echo Doppler, excluded a vascular origin. Using accepted criteria to distinguish between TGA and epileptic amnesic attacks--the typical clinical presentation, the long duration of the episode, the absence of other symptoms associated with seizures and the absence of recurrence--it is evident that these patients suffered a TGA. These studies suggest that hippocampal resection carried out therapeutically in some epileptic patients may be a precipitating factor for TGA.

K-complex-induced seizures in autosomal dominant nocturnal frontal lobe epilepsy.

OBJECTIVE: To examine in detail the relations between seizures and K-complexes in autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). METHODS: Prolonged continuous video-EEG recording and analysis of 30 seizures in an 18-year-old woman suffering from ADNFLE with a CHRNA4 gene mutation. RESULTS: Twenty-seven of 30 recorded seizures started just after a K-complex. In nine cases a sound induced a K-complex that was immediately followed by the seizure. Most seizures preceded repetitive and brief ictal restarts. CONCLUSIONS: Three new characteristics have been observed in this ADNFLE patient: a K-complex is almost invariably present at seizure onset; sounds trigger some seizures; ictal restarts occur often. SIGNIFICANCE: These new observations--the presence of K-complexes at seizure onset and occurrence of sound-triggered seizures--support the view that ADNFLE seizures may be initiated by K-complexes.

Autobiographical memory after temporal lobe resection: neuropsychological and MRI volumetric findings.

This study examined the contribution of medial temporal lobe (MTL) structures in autobiographical memory. While some investigators have reported a temporal gradient in memory performance, characterized by retrieval difficulties limited to recent periods of life [Squire and Alvarez (Retrograde amnesia and memory consolidation: a neurobiological perspective. Curr Opin Neurobiol 1995; 5: 169-77)], others have suggested that this impairment involves all life-time periods [Nadel and Moscovitch (Memory consolidation, retrograde amnesia and the hippocampal complex. Curr Opin Neurobiol 1997; 7: 217-27)]. In this study, autobiographical memory was assessed in 22 patients who had undergone a left (n = 12) or a right (n = 10) MTL resection for the relief of epileptic seizures and in 22 normal control participants. For this purpose, we used an autobiographical memory task (TEMPau, Piolino et al., 2003) across four time periods covering the subjects' entire lifespan. For each period, an overall autobiographical memory score (AM score) was obtained, from which a strictly episodic score (SE score), characterized by specificity and richness of details, was computed. For all events recalled, Remember responses justified by specificity of factual, spatial and temporal contents (jR responses) were measured using the Remember/Know paradigm. MRI volumetric analyses performed on the medial (i.e. hippocampus, temporopolar, entorhinal, perirhinal and parahippocampal cortices) and lateral temporal (i.e. superior, middle and inferior temporal gyri) lobe structures stated that the resection mainly included MTL structures. AM and SE scores were impaired in patients with right and left MTL resections as compared to normal controls across all time periods, reflecting the patients' particular difficulty in producing specific and detailed memories across all periods. This impairment was associated with poor autonoetic consciousness, revealed by the small number of jR responses across all periods. Results of correlation analysis between MRI volume measures of temporal lobe structures and autobiographical memory scores suggest that the right MTL structures are particularly responsive in reliving the encoding context regardless of remoteness. Our results support the bilateral MTL contribution to episodic autobiographical memory covering the entire lifespan, which is consistent with the multiple trace theory of MTL function [Moscovitch et al. (Functional neuroanatomy of remote episodic, semantic and spatial memory: a unified account based on multiple trace theory. J Anat 2005; 207: 35-66.)].

Autonoetic consciousness in autobiographical memories after medial temporal lobe resection.

This study aims to investigate autonoetic consciousness associated with episodic autobiographical memory in patients who had undergone unilateral medial temporal lobe resection for intractable epilepsy. Autonoetic consciousness, defined as the conscious feeling of mentally travelling back in time to relive a specific event, was assessed using the Remember/Know (R/K) paradigm across different time periods as proposed in the autobiographical memory task developed by Piolino et al. (TEMPau task). Results revealed that the two patient groups (left and right temporal resection) gave reduced sense of reliving (R) responses and more familiarity (K) responses than healthy controls. This poor autonoetic consciousness was highlighted when patients were asked to justify their Remember responses by recalling sensory-perceptive, affective or spatiotemporal specific details across all life periods. These results support the bilateral MTL contribution to episodic autobiographical memory covering the entire lifespan, which is consistent with the multiple trace theory of MTL function. This study also demonstrates the bilateral involvement of MTL structures in recalling specific details of personal events characterized by autonoetic consciousness.

[Epileptiform activities generated in vitro by human temporal lobe tissue]. / Activités épileptiques produites in vitro par le tissu temporal humain.

Drug-resistant partial epilepsies, including temporal lobe epilepsies with hippocampal sclerosis and cortical dysplasias, offer the opportunity to study human epileptic activity in vitro since the preferred therapy often consists of the surgical removal of the epileptogenic zone. Slices of this tissue retain functional neuronal networks and may generate epileptic activity. The properties of cells in this tissue do not seem to be significantly changed, but excitatory synaptic characteristics are enhanced and GABAergic inhibition is preserved. Typically, epileptic activity is not generated spontaneously by the neocortex, whether dysplastic or not, but can be induced by convulsants. The initiation of ictal discharges in neocortex depends on both GABAergic signaling and increased extracellular potassium. In contrast, a spontaneous interictal-like activity is generated by tissues from patients with temporal lobe epilepsies associated with hippocampal sclerosis. This activity is initiated not in the hippocampus but in the subiculum, an output region that projects to the entorhinal cortex. Interictal events seem to be triggered by GABAergic cells, which paradoxically excite approximately 20% of subicular pyramidal cells, while simultaneously inhibiting the majority. Interictal discharges are therefore sustained by both GABAergic and glutamatergic signaling. The atypical depolarizing effects of GABA depend on a pathological elevation in the basal levels of chloride in some subicular cells, similar to those of developmentally immature cells. This defect is caused by the perturbation of the expression of the cotransporters regulating the intracellular chloride concentration, the importer NKCC1, and the extruder KCC2. Blockade of excessive NKCC1 by the diuretic bumetanide restores intracellular chloride and thus hyperpolarizing GABAergic actions, suppressing interictal activity.