Hippocampe et épilepsie : données issues des tissus humains

International audienceSurgical removal of the epileptogenic zone provides an effective therapy for several focal epileptic syndromes. This surgery offers the opportunity to study pathological activity in living human tissue for pharmacoresistant partial epilepsy syndromes including temporal lobe epilepsies with hippocampal sclerosis, cortical dysplasias, epilepsies associated with tumors and developmental malformations. Slices of tissue from patients with these syndromes retain functional neuronal networks and may generate epileptic activities. The properties of cells in this tissue may not be greatly changed, but excitatory synaptic transmission is often 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 the 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, which projects to the entorhinal cortex. Interictal events seem to be triggered by GABAergic cells, which paradoxically excite about 20% of subicular pyramidal cells while simultaneously inhibiting the majority. Interictal discharges thus depend on both GABAergic and glutamatergic signaling. The depolarizing effects of GABA depend on a pathological elevation in levels of chloride in some subicular cells, similar to those of developmentally immature cells. Such defect is caused by a perturbed expression of the cotransporters regulating intracellular chloride concentration, the importer NKCC1 and the extruder KCC2. Blockade of NKCC1 actions by the diuretic bumetanide restores intracellular chloride and thus hyperpolarizing GABAergic actions and consequently suppressing interictal activity.La résection chirurgicale de la zone épileptogène est la procédure thérapeutique de choix de multiples épilepsies focales. Elle permet d’étudier les activités pathologiques dans du tissu humain maintenu en vie in vitro pour divers syndromes épileptiques pharmacorésistantes dont les épilepsies temporales avec sclérose hippocampique, dysplasies corticales, autres malformations développementales ou tumeurs. In vitro, dans des tranches de tissu issues de pièces opératoires, le réseau épileptique est conservé et des activités épileptiques sont produites. À l’échelle neuronale, les propriétés intrinsèques semblent peu modifiées, certaines composantes synaptiques excitatrices glutamatergiques apparaissent renforcées et l’inhibition GABAergique est maintenue. Dans le néocortex, qu’il soit dysplasique ou non, une activité synchrone épileptiforme n’est généralement pas enregistrée spontanément mais doit être induite pharmacologiquement. L’initiation des décharges ictales implique alors la signalisation GABAergique et une augmentation de la concentration extracellulaire en potassium. Au sein de tissus provenant de patients souffrant d’épilepsies mésio-temporales associées à une sclérose hippocampique, une activité épileptiforme est recueillie spontanément. Il s’agit de bouffées interictales générées non pas dans l’hippocampe mais dans le subiculum, sa région de sortie interfacée avec le cortex entorhinal. Cette activité est initiée par la décharge d’interneurones qui excitent paradoxalement par le GABA libéré environ 1/5 des cellules pyramidales, hyperpolarisant les autres. Les décharges sont donc sous-tendues tant par la signalisation GABAergique que glutamatergique. L’origine des réponses dépolarisantes au GABA est une perturbation de l’homéostasie du chlore, secondaire à une modification de l’expression des co-transporteurs régulant sa concentration intracellulaire, NKCC1 et KCC2, évoquant un retour à un phénotype neuronal immature. La restauration d’une concentration normale en chlore en bloquant NKCC1 par le diurétique bumétanide permet ainsi de supprimer les activités interictales

: Seizure onset zone imaging

International audienceStereo-electroencephalography is used to localize the seizure onset zone and connected neuronal networks in surgical candidates suffering from intractable focal epilepsy. The concept of an epileptogenicity index has been proposed recently to represent the likelihood of various regions being part of the seizure onset zone. It quantifies low-voltage fast activity, the electrophysiological signature of seizure onset usually assessed visually by neurologists. Here, we revisit epileptogenicity in light of neuroimaging tools such as those provided in statistical parametric mapping software. Our goal is to propose a robust approach, allowing easy exploration of patients' brains in time and space. The procedure is based upon statistical parametric mapping, which is an established framework for comparing multi-dimensional image data that allows one to correct for inherent multiple comparisons. Statistics can also be performed at the group level, between seizures in the same patient or between patients suffering from the same type of epilepsy using normalization of brains to a common anatomic atlas. Results are obtained from three case studies (insular reflex epilepsy, cryptogenic frontal epilepsy and lesional occipital epilepsy) where tailored resection was performed, and from a group of 10 patients suffering from mesial temporal lobe epilepsy. They illustrate the basics of the technique and demonstrate its very good reproducibility and specificity. Most importantly, the proposed approach to the quantification of the seizure onset zone allows one to summarize complex signals in terms of a time-series of statistical parametric maps that can support clinical decisions. Quantitative neuroimaging of stereo-electroencephalographic features of seizures might thus help to provide better pre-surgical assessment of patients undergoing resective surgery

Laser interstitial thermal therapy is effective and safe for the treatment of brain tumors in NF1 patients after cerebral revascularization for moyamoya angiopathy: a report on two cases

BackgroundThe co-occurrence of moyamoya vasculopathy and extra-optic pathway tumors is rare in neurofibromatosis type 1 (NF1), with only four cases described in the literature. Brain surgery in these patients may be challenging because of the risk of brain infarction after skin and dural incision. Given its percutaneous and minimally invasive nature, laser interstitial thermal therapy (LITT) is an ideal option for the treatment of brain tumors in these patients. Here, we report on two patients with NF1 and moyamoya syndrome (MMS) treated for a brain glioma with LITT, after cerebral revascularization.CasesThe first patient, with familial NF1, underwent bilateral indirect revascularization with multiple burr holes (MBH) for symptomatic MMS. Two years later, she was diagnosed with a left temporal tumor, with evidence of radiologic progression over 10 months. The second patient, also with familial NF1, developed unilateral MMS when he was 6 years old and was treated with MBH. At the age of 15 years, MRI showed a right cingular lesion, growing on serial MRIs. Both patients underwent LITT with no perioperative complications; they are progression free at 10 and 12 months, respectively, and the tumors have decreased in volume.DiscussionWhile the association of extra-optic neoplasm and moyamoya angiopathy is seldom reported in NF1, tumor treatment is challenging in terms of both avoiding stroke and achieving oncological control. Here, we show in 2 cases, that LITT could be a safe and effective option in these rare conditions

Probabilistic functional tractography of the human cortex revisited

In patients with pharmaco-resistant focal epilepsies investigated with intracranial electroencephalography (iEEG), direct electrical stimulations of a cortical region induce cortico-cortical evoked potentials (CCEP) in distant cerebral cortex, which properties can be used to infer large scale brain connectivity. In 2013, we proposed a new probabilistic functional tractography methodology to study human brain connectivity. We have now been revisiting this method in the F-TRACT project (f-tract.eu) by developing a large multicenter CCEP database of several thousand stimulation runs performed in several hundred patients, and associated processing tools to create a probabilistic atlas of human cortico-cortical connections. Here, we wish to present a snapshot of the methods and data of F-TRACT using a pool of 213 epilepsy patients, all studied by stereo-encephalography with intracerebral depth electrodes. The CCEPs were processed using an automated pipeline with the following consecutive steps: detection of each stimulation run from stimulation artifacts in raw intracranial EEG (iEEG) files, bad channels detection with a machine learning approach, model-based stimulation artifact correction, robust averaging over stimulation pulses. Effective connectivity between the stimulated and recording areas is then inferred from the properties of the first CCEP component, i.e. onset and peak latency, amplitude, duration and integral of the significant part. Finally, group statistics of CCEP features are implemented for each brain parcel explored by iEEG electrodes. The localization (coordinates, white/gray matter relative positioning) of electrode contacts were obtained from imaging data (anatomical MRI or CT scans before and after electrodes implantation). The iEEG contacts were repositioned in different brain parcellations from the segmentation of patients' anatomical MRI or from templates in the MNI coordinate system. The F-TRACT database using the first pool of 213 patients provided connectivity probability values for 95% of possible intrahemispheric and 56% of interhemispheric connections and CCEP features for 78% of intrahemisheric and 14% of interhemispheric connections. In this report, we show some examples of anatomo-functional connectivity matrices, and associated directional maps. We also indicate how CCEP features, especially latencies, are related to spatial distances, and allow estimating the velocity distribution of neuronal signals at a large scale. Finally, we describe the impact on the estimated connectivity of the stimulation charge and of the contact localization according to the white or gray matter. The most relevant maps for the scientific community are available for download on f-tract. eu (David et al., 2017) and will be regularly updated during the following months with the addition of more data in the F-TRACT database. This will provide an unprecedented knowledge on the dynamical properties of large fiber tracts in human.Peer reviewe

Focal cortical dysplasia in children : in vivo localization with perfusion imaging, and in vitro characterization of epileptic activities

Les dysplasies corticales (FCD) sont une cause fréquente d’épilepsie lésionnelle requérant un traitement chirurgical, caractérisées par l’association de troubles de l’architecture corticale et la présence de cellules neuronales et/ou gliales anormales Les FCD restent parfois difficiles à identifier / localiser et la physiopathologie des activités épileptiques qu’elles produisent reste mal connue. L’objectif de ce travail est d’optimiser la localisation anatomique et fonctionnelle des FCD chez l’enfant et d’étudier leur épileptogénicité par une double approche, in vivo en imagerie de perfusion IRM-ASL (Arterial Spin Labeling), et in vitro par enregistrements de tissus humains post-opératoires sur matrice de micro électrodes. L’intérêt de l’étude de ces dysplasies chez l’enfant est majeure à un âge où la récurrence des crises n’a pas encore modifié le réseau … Tout d’abord, nous avons montré une hypoperfusion focale des dysplasies corticales focales de type II colocalisée à l’hypo métabolisme en 18FDG-PET scan et au défect histologique. Nous avons développé une méthode d’analyse statistique du signal ASL permettant l’intégration des données objectives de l’imagerie dans une approche multimodale des anomalies interictales associant ASL et IRM fonctionnelle-EEG. Ensuite, nous avons exploré in vitro des tranches de cortex humain dysplasique post-opératoire. La présence d’activités épileptiques interictales spontanées témoignait de la persistance des caractéristiques épileptogéniques des FCD, variables selon les sous types histologiques. L’étude de la signalisation GABAergique et de la régulation du chlore a montré que le co transporteur du chlore NKCC1 chargeait excessivement les neurones en chlore alors que son concurrent KCC2, extrudant normalement ces anions, était down-régulé. La dérégulation neuronale du chlore qui en résulte est à l’origine d’effets paradoxalement dépolarisants du GABA, rendant compte non pas d’une perte d’inhibition GABAergique mais de son implication active dans les processus épileptiques. Enfin, nous avons contribué à mettre en évidence le rôle des hémicanaux Pannexines1, et de la transmission purinergique dans l’initiation et la maintenance des activités ictales, ouvrant une nouvelle piste thérapeutique chez les patients présentant ces épilepsies pharmaco résistantes.Focal cortical Dysplasias (FCD) are a frequent etiology of lesional epilepsy, requiring surgical treatment. They are defined by abnormalities of cortical architecture intermixed with the presence of abnormal neuronal or glial cells. Imaging FCD remains challenging, both to detect and map the lesion, and the pathophysiology of the epileptic discharges they produce is incompletely understood. The aim of this PhD is to improve in vivo FCD mapping in children with perfusion MRI, and to study in vitro their epileptogenicity with human postoperative cortical slices electrophysiological recordings on micro electrode arrays. First, we showed with ASL MRI (Arterial Spin Labeling) a focal hypoperfusion in type II FCD, colocalized with 18FDG-PET hypo metabolism and histological defects. We developed a statistical analysis of ASL under SPM integrated in a multimodal approach of FCD with EEG-fMRI and ASL-MRI. Second, we studied in vitro slices of human postoperative dysplastic cortex. We could record reliable spontaneous inter ictal discharges, specific of the histological subtype, showing that tissues retain epileptogenic features. We focused our study on GABAergic signaling and neuronal chloride regulation. We have identified an excessive chloride load in neurons by the co transporter NKCC1 whereas chloride extrusion was deficient because of KCC2 down regulation. The consequent chloride dysregulation resulted in paradoxical GABAergic depolarization, responsible for a loss of inhibitory processes but also a shift to excitatory effects of GABAergic signals. Third, we also contributed to a study on Pannexin hemichannels, revealing that Pannexin1 channels sustain initiation and maintenance of ictal activity though purinergic neurotransmission in human cortical slices, supporting new anti epileptic targets in human pharmaco resistant epilepsies

Role pronostique de l' implication de l' insula dans les épilepsies temporales (une étude SEEG)

Nous avons réalisé une étude rétrospective de l implication de l insula dans les crises d épilepsie temporales. Nous avons étudié 28 crises chez 15 patients, enregistrées avec des électrodes insulaires implantées dans le cerveau au cours d une procédure stéréotaxique. Nous avons analysé les facteurs influençant le mode de décharge dans l insula et l intervalle entre le début de la crise et le recrutement du cortex insulaire. Nous avons ainsi distingué la faible implication de l insula dans les crises temporo-mésiales, et son recrutement plus constant dans les crises mésio-latérales. Nous avons mis en évidence l importance du substrat anatomique pour établir un réseau épileptogène puisque le pôle temporal et l insula ont une origine commune comme péri-allocortex olfacto-centrique. Enfin, nous proposons un nouveau facteur pronostic en SEEG après lobectomie temporale : le délai normalisé de propagation insulaire des crises.PARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocSudocFranceF

Cortical stimulation of the epileptogenic zone for the treatment of focal motor seizures: an experimental study in the nonhuman primate.

International audienceBACKGROUND: Cortical stimulation is under investigation in clinical trials of drug-resistant epilepsy. Results are heterogeneous; therefore, more evidence from animal studies is required. OBJECTIVE: To investigate the therapeutic effects of parameters of direct stimulation of the cortical focus in a Macaca fascicularis presenting focal motor epilepsy. METHODS: We developed a model of motor seizures after intracortical injection of penicillin G in the primary motor cortex of a Macaca fascicularis. We performed electric epidural cortical stimulation at low, medium, and high frequency using continuous or short-term stimulation. Short-term stimulation was triggered on seizure onset, either visually or automatically with a seizure detection algorithm connected to a programmable stimulator. RESULTS: Automated detection could detect 100% of the seizures, but ensuing cortical electric stimulation failed to abort seizures. CONCLUSION: This study demonstrates the inefficacy of the stimulation of the cortical focus to prevent seizures induced by local injection of penicillin G. Because this model may be too severe to allow comparison to human epilepsies, further work is required in other monkey models of focal epilepsy

Multimodal imaging reveals the role of γ activity in eating-reflex seizures.

International audienceIn reflex epilepsies, alteration of γ oscillations may mediate transition between interictal and ictal states. Here, we explored a patient having seizures triggered by syrup intake. From intracranial electroencephalography combined with functional MRI, the overlap of the gustatory cortex and of the preictal and ictal onset zones, as defined by early gamma changes, motivated the successful resective surgery of the middle short gyrus of the right insula. This case provides a rare demonstration from human gamma activity that the route to seizure may be supported by the interplay between physiological and epileptogenic networks