Inhibition of epileptiform activity by neuropeptide Y in brain tissue from drug-resistant temporal lobe epilepsy patients.

In epilepsy patients, drug-resistant seizures often originate in one of the temporal lobes. In selected cases, when certain requirements are met, this area is surgically resected for therapeutic reasons. We kept the resected tissue slices alive in vitro for 48 h to create a platform for testing a novel treatment strategy based on neuropeptide Y (NPY) against drug-resistant epilepsy. We demonstrate that NPY exerts a significant inhibitory effect on epileptiform activity, recorded with whole-cell patch-clamp, in human hippocampal dentate gyrus. Application of NPY reduced overall number of paroxysmal depolarising shifts and action potentials. This effect was mediated by Y2 receptors, since application of selective Y2-receptor antagonist blocked the effect of NPY. This proof-of-concept finding is an important translational milestone for validating NPY-based gene therapy for targeting focal drug-resistant epilepsies, and increasing the prospects for positive outcome in potential clinical trials.

The inhibitory effect of functional lesions on eloquent brain areas: from research bench to operating bed.

Objectives: Functioning, but injured cerebral connections are hypothesized to inhibit cortical plasticity. Study of neural networks can validate this hypothesis, and provide further practical clues for clinical and surgical options to restore function in eloquent brain areas. Material and methods: Cortical lesions in eloquent areas were simulated by means of artificial neural networks. Next, functional restoration of these networks after lesional bypass was studied. Results: The accuracy of network outputs was reduced from 92% to 72% (P-value < 0.001) when logical temporal connections with dysfunctional lesions were established. Restoration of function was almost totally achieved by bypassing the lesion, without any significant changes in network nodal weights. Estimated remaining functional fraction errors were trivial (0.0044%-1.4%). Discussion: Examples of functional decline due to disturbing signals are Todd's paralysis and Landau-Kleffner syndrome. Functional restoration after lesionectomy in eloquent areas of the brain is also practiced. Likewise, injured connections provide routes of influence for disturbing impulses. Conclusion: Herein, the proposed evidences provide theoretical clues to formulate new avenues in restorative functional neurosurgery. They may help to identify suitable lesions and suitable techniques for functional restoration including dissection of disturbing connections, bridging and bypassing lesions that can be corroborated by simulation.

Outcome following multiple subpial transection in Landau-Kleffner syndrome and related regression.

OBJECTIVE: To determine whether multiple subpial transection in the posterior temporal lobe has an impact on long-term outcome in children who have drug-resistant Landau-Kleffner syndrome (LKS) or other "electrical status epilepticus during sleep" (ESES)-related regression. Given the wide variability in outcomes reported in the literature, a secondary aim was to explore predictors of outcome. METHODS: The current study includes a surgery group (n = 14) comprising patients who underwent multiple subpial transection of the posterior temporal lobe and a nonsurgery comparison group (n = 21) comprising patients who underwent presurgical investigations for the procedure, but who did not undergo surgery. Outcomes were assessed utilizing clinical note review as well as direct assessment and questionnaires. RESULTS: The distribution of nonclassical cases was comparable between groups. There were some differences between the surgery and nonsurgery groups at presurgical investigation including laterality of discharges, level of language impairment, and age; therefore, follow-up analyses focused on change over time and predictors of outcome. There were no statistically significant differences between the groups in language, nonverbal ability, adaptive behavior, or quality of life at follow-up. There was no difference in the proportion of patients showing improvement or deterioration in language category over time for either group. Continuing seizures and an earlier age of onset were most predictive of poorer quality of life at long-term follow-up (F2,23 = 26.2, p = <0.001, R(2) = 0.714). SIGNIFICANCE: Both surgery and nonsurgery groups had similar proportions of classic LKS and ESES-related regression. Because no significant differences were found in the changes observed from baseline to follow-up between the two groups, it is argued that there is insufficient evidence to suggest that multiple subpial transection provides additional benefits over and above the mixed recovery often seen in LKS and related regressive epilepsies.

A review of the relationships between Landau-Kleffner syndrome, electrical status epilepticus during sleep, and continuous spike-waves during sleep.

The goal of this report is to review the relationships between Landau-Kleffner syndrome (LKS), electrical status epilepticus during sleep (ESES), and continuous spike-waves during sleep (CSWS). LKS is a clinical syndrome involving mainly acquired aphasia and sometimes seizures. Other clinical findings include cognitive impairments and global regression of behavior. The EEG may evolve from more benign conditions into ESES (or CSWS), seen in 50% of patients with LKS, or may also show focal findings. Seizures include atypical absence, generalized tonic-clonic, atonic, and partial motor attacks. Effective medications are discussed. The EEG patterns CSWS and ESES are likely equivalent terms. CSWS is used by some authors, and ESES by others. Patients with these patterns usually show mental retardation, seizures, and global regression. More benign EEG patterns, like focal discharges, may develop into these more severe generalized patterns, which are associated with atypical absences, negative myoclonus, and cognitive disturbances. Memory disorders are common, because the nearly continuous generalized discharges in sleep do not allow for the memory consolidation that also occurs during sleep. Medications and possible etiologies are discussed.

EEG latency analysis for hemispheric lateralisation in Landau-Kleffner syndrome.

OBJECTIVE: To determine the reliability of latency analysis in lateralising the origin of epileptiform discharges in pre-surgical assessment of Landau-Kleffner syndrome (LKS). METHODS: A computer aided-method was developed to identify leading regions and measure inter-hemispheric latencies before and after averaging discharges. Scalp and intracranial EEG recordings were studied from seven patients undergoing surgical treatment. The laterality suggested by latency analysis was compared with that suggested by pharmacological tests. RESULTS: Latency analysis of bilateral discharges showed a consistent leading hemisphere. The earliest low-amplitude deflections were located in temporal regions in all patients. Contralateral low-amplitude deflections, and ipsilateral and contralateral earliest large negative peaks were recorded in temporal and less frequently in parasagittal regions. Presurgical inter-hemispheric latencies ranged between 8 and 48 ms for the deflections and between 4 and 30 ms for the peaks. The leading hemisphere identified by latency analysis of the earliest low-amplitude deflections coincided with that suggested by pharmacological tests in all 7 patients, whereas latency of later components coincided in 6. CONCLUSIONS: Latency analysis appears to be a reliable method to estimate the hemisphere driving bilateral discharges in LKS. SIGNIFICANCE: It can be carried out non-invasively and could be used to confirm, and eventually replace, results from pharmacological tests.

Magnetoencephalography in Landau-Kleffner syndrome.

Magnetoencephalography (MEG) detects weak magnetic fields outside the head. Spikes generated on the perisylvian convexity are detected only by electroencephalography (EEG), whereas spikes with intrasylvian generators are selectively seen by MEG. Generators of MEG and EEG spikes are determined using equivalent current dipoles (ECDs) that represent local cortical activity in parallel pyramidal neurons. MEG localizes cortical spike generators with a 1-2-cm spatial accuracy, and with a millisecond time resolution. This allows tracking of neural activity over successive synaptic connections in the cortical network. Both EEG and MEG are necessary for comprehensive spatial and temporal description of perisylvian epileptic networks in the Landau-Kleffner syndrome (LKS). MEG studies suggest that in more than 80% of LKS patients, the bilateral epileptic discharges are generated in the auditory- and language-related perisylvian cortex. Approximately 20% of children with LKS children have a unilateral perisylvian pacemaker that triggers secondary bilateral synchrony of spikes. This 20% may regain considerable language skills after multiple subpial transections (MSTs) of the pacemaker area. Outcome data of a few surgery patients suggest an indispensable role of MEG when planning the most efficient therapy for patients with LKS.

The surgical treatment of Landau-Kleffner syndrome.

The medical management of Landau-Kleffner syndrome is usually effective for seizure control and eventual seizure remission. However, the response for language and behavior is often poor. Surgery, in the form of multiple subpial transections (MSTs) to include Wernicke's area has been suggested as a way forward if electrophysiologic lateralization can be demonstrated. Surgical series in the literature are few and outcome from surgery variable.

Multiple subpial transection in Landau-Kleffner syndrome.

We have considered multiple subpial transection (MST) as a treatment option for Landau-Kleffner syndrome (LKS) for the past 6 years. The effect of this technique on language and cognitive ability, behaviour, seizures, and EEG abnormalities is analysed here. Five children (4 males, 1 female; aged 5.5 to 10 years) underwent MST with sufficiently detailed pre- and postoperative data for analysis. Behaviour and seizure frequency improved dramatically after surgery in all children. Improvement in language also occurred in all children, although none improved to an age-appropriate level. All five had electrical status epilepticus in sleep (ESES) before surgery, which was eliminated by the procedure. One child has had an extension of his MST due to the recurrence of ESES and accompanying clinical deterioration with good effect. An attempt is made to set the effect of MST against the natural history of the condition. MST is an important treatment modality in LKS, although the timing of this intervention and its effect on final language outcome remains to be defined.

Recent advances in candidate selection for pediatric epilepsy surgery.

Many patients who were once considered inoperable are candidates for a wide variety of surgical procedures. This trend is particularly striking at pediatric centers that serve patients with diverse forms of epilepsy that compromise development. Newer diagnostic techniques, including structural and functional imaging, EEG monitoring, and surgical technology, can provide a complete representation of the etiology and expression of the epileptic focus, including accurate cortical localization. This review focuses on several forms of epilepsy that, until recently, were not regarded to be surgically amenable. The adverse seizure and neurobehavioral prognosis in patients with these disorders provides the justification to search for innovative treatments. With more sophisticated tools for preoperative evaluation and an expanding knowledge base, it is likely that the number of surgical candidates will continue to increase in the future.

Magnetoencephalography in children with Landau-Kleffner syndrome and acquired epileptic aphasia.

BACKGROUND AND PURPOSE: Landau-Kleffner syndrome (LKS) is epileptiform aphasia acquired during childhood and occurring in children with previously normal language development. The epileptiform activity in these children is thought to result in a functional ablation of eloquent speech areas. The purpose of this study was to investigate the usefulness of magnetoencephalography (MEG) for localizing the source of epileptiform activity in these patients. METHODS: Nineteen patients with acquired aphasia and a suspected diagnosis of LKS were referred for MEG evaluation. Patients ranged in age from 4 to 14 years. Fourteen MEG studies were performed on a 74-channel system, four on a 148-channel whole-head system, and one on a 37-channel system. RESULTS: Thirteen of the 19 patients had perisylvian MEG spikes. In 10 of the patients, the spikes were bilateral, and in three they were unilateral. Four other patients had non-sylvian spikes, and two patients had no spikes recorded. The results of MR imaging were normal or noncontributory for all 19 patients. CONCLUSIONS: MEG can play a useful role in evaluating children with LKS and acquired epileptiform aphasia, both in diagnosis and in aiding presurgical localization of epileptiform activity when surgery is being considered.

Outcome of multiple subpial transections for autistic epileptiform regression.

Treatment options for atypical forms of Landau-Kleffner syndrome (LKS) are not well delineated. Many patients with typical LKS fail to respond to antiepileptic drug treatment, but some benefit from multiple subpial transections (MSTs). The authors report seven patients with autism or autistic epileptiform regression who responded in varying degrees to MSTs after failed medical management. These patients derived from an original cohort of 36 children (29 males, seven females, ranging from 2 years, 3 months to 11 years, 3 months, mean age = 5 years, 8 months) with a history of language delay or regression, as well as varying degrees of social and behavioral abnormalities, who were evaluated with video-electroencephalogram (EEG) monitoring over a 2-year period. Fifteen patients had clinical seizures (11 of the 19 children with autistic epileptiform regression and four of 12 autistic children). Epilepsy was refractory to medication in seven. Surgical treatment variously involved MSTs of the left neocortex in temporal, parietal, and frontal regions, often including regions within the classic perisylvian language areas. One patient also had a left temporal lobectomy. In all seven patients, seizure control or EEG improved after MSTs. Language, social, and overall behavior improved to a moderate degree, although improvements were temporary in most. Autistic epileptiform regression resembles LKS in that both may respond to MST. MST is used to treat epilepsy in eloquent regions. The responsiveness of autistic epileptiform regression to MST buttresses the argument that autistic epileptiform regression is a form of focal epilepsy.

Magnetoencephalography in presurgical evaluation of children with the Landau-Kleffner syndrome.

PURPOSE: Our aim was (a) to localize the primary epileptogenic cortex for possible multiple subpial transsection in four children with the Landau-Kleffner syndrome (LKS), and (b) to evaluate the impact of magnetoencephalography (MEG) in the localizing process. METHODS: We used EEG to detect the overall epileptiform activity and MEG for selective recording of fissural spikes. The cortical generators of MEG spikes were modeled with dipoles, and their activation order was determined. The voltage distribution, consistent with the earliest MEG sources, was then identified during the course of the patient's EEG spikes to determine the relative timing between stereotypic EEG and MEG spikes and to distinguish the earliest (primary) source area among the secondary ones. RESULTS: In all patients, the earliest spike activity originated in the intrasylvian cortex, spreading in one subject to the contralateral sylvian cortex within 20 ms. Secondary spikes occurred within 10-60 ms in ipsilateral perisylvian, temporooccipital, and parietooccipital areas. A single intrasylvian pacemaker initiated all epileptic activity in two patients, whereas the other two had independent left- and right-hemisphere circuits or focal spikes. MEG source dynamics predicted the results of the methohexital suppression test in two patients and was confirmed by surgery outcome in one patient, in whom all epileptic activity ceased after a small transsection of the sylvian pacemaker. CONCLUSIONS: (a) The intrasylvian cortex is a likely pacemaker of epileptic discharges in LKS, and (b) MEG provides useful presurgical information of the cortical spike dynamics in LKS patients.

Language outcome following multiple subpial transection for Landau-Kleffner syndrome.

Landau-Kleffner syndrome is an acquired epileptic aphasia occurring in normal children who lose previously acquired speech and language abilities. Although some children recover some of these abilities, many children with Landau-Kleffner syndrome have significant language impairments that persist. Multiple subpial transection is a surgical technique that has been proposed as an appropriate treatment for Landau-Kleffner syndrome in that it is designed to eliminate the capacity of cortical tissue to generate seizures or subclinical epileptiform activity, while preserving the cortical functions subserved by that tissue. We report on the speech and language outcome of 14 children who underwent multiple subpial transection for treatment of Landau-Kleffner syndrome. Eleven children demonstrated significant postoperative improvement on measures of receptive or expressive vocabulary. Results indicate that early diagnosis and treatment optimize outcome, and that gains in language function are most likely to be seen years, rather than months, after surgery. Since an appropriate control group was not available, and that the best predictor of postoperative improvements in language function was that of length of time since surgery, these data might best be used as a benchmark against other Landau-Kleffner syndrome outcome studies. We conclude that multiple subpial transection may be useful in allowing for a restoration of speech and language abilities in children diagnosed with Landau-Kleffner syndrome.