GluK2 Is a Target for Gene Therapy in Drug-Resistant Temporal Lobe Epilepsy.

OBJECTIVE: Temporal lobe epilepsy (TLE) is characterized by recurrent seizures generated in the limbic system, particularly in the hippocampus. In TLE, recurrent mossy fiber sprouting from dentate gyrus granule cells (DGCs) crea an aberrant epileptogenic network between DGCs which operates via ectopically expressed GluK2/GluK5-containing kainate receptors (KARs). TLE patients are often resistant to anti-seizure medications and suffer significant comorbidities; hence, there is an urgent need for novel therapies. Previously, we have shown that GluK2 knockout mice are protected from seizures. This study aims at providing evidence that downregulating KARs in the hippocampus using gene therapy reduces chronic epileptic discharges in TLE. METHODS: We combined molecular biology and electrophysiology in rodent models of TLE and in hippocampal slices surgically resected from patients with drug-resistant TLE. RESULTS: Here, we confirmed the translational potential of KAR suppression using a non-selective KAR antagonist that markedly attenuated interictal-like epileptiform discharges (IEDs) in TLE patient-derived hippocampal slices. An adeno-associated virus (AAV) serotype-9 vector expressing anti-grik2 miRNA was engineered to specifically downregulate GluK2 expression. Direct delivery of AAV9-anti grik2 miRNA into the hippocampus of TLE mice led to a marked reduction in seizure activity. Transduction of TLE patient hippocampal slices reduced levels of GluK2 protein and, most importantly, significantly reduced IEDs. INTERPRETATION: Our gene silencing strategy to knock down aberrant GluK2 expression demonstrates inhibition of chronic seizure in a mouse TLE model and IEDs in cultured slices derived from TLE patients. These results provide proof-of-concept for a gene therapy approach targeting GluK2 KARs for drug-resistant TLE patients. ANN NEUROL 2023;94:745-761.

Modification of brain conductivity in human focal epilepsy: A model-based estimation from stereoelectroencephalography.

OBJECTIVE: We have developed a novel method for estimating brain tissue electrical conductivity using low-intensity pulse stereoelectroencephalography (SEEG) stimulation coupled with biophysical modeling. We evaluated the hypothesis that brain conductivity is correlated with the degree of epileptogenicity in patients with drug-resistant focal epilepsy. METHODS: We used bipolar low-intensity biphasic pulse stimulation (.2 mA) followed by a postprocessing pipeline for estimating brain conductivity. This processing is based on biophysical modeling of the electrical potential induced in brain tissue between the stimulated contacts in response to pulse stimulation. We estimated the degree of epileptogenicity using a semi-automatic method quantifying the dynamic of fast discharge at seizure onset: the epileptogenicity index (EI). We also investigated how the location of stimulation within specific anatomical brain regions or within lesional tissue impacts brain conductivity. RESULTS: We performed 1034 stimulations of 511 bipolar channels in 16 patients. We found that brain conductivity was lower in the epileptogenic zone (EZ; unpaired median difference = .064, p < .001) and inversely correlated with the epileptogenic index value (p < .001, Spearman rho = -.32). Conductivity values were also influenced by anatomical site, location within lesion, and delay between SEEG electrode implantation and stimulation, and had significant interpatient variability. Mixed model multivariate analysis showed that conductivity is significantly associated with EI (F = 13.45, p < .001), anatomical regions (F = 5.586, p < .001), delay since implantation (F = 14.71, p = .003), and age at SEEG (F = 6.591, p = .027), but not with the type of lesion (F = .372, p = .773) or the delay since last seizure (F = 1.592, p = .235). SIGNIFICANCE: We provide a novel model-based method for estimating brain conductivity from SEEG low-intensity pulse stimulations. The brain tissue conductivity is lower in EZ as compared to non-EZ. Conductivity also varies significantly across anatomical brain regions. Involved pathophysiological processes may include changes in the extracellular space (especially volume or tortuosity) in epileptic tissue.

Permutation entropy-derived parameters to estimate the epileptogenic zone network.

OBJECTIVE: Quantification of the epileptogenic zone network (EZN) most frequently implies analysis of seizure onset. However, important information can also be obtained from the postictal period, characterized by prominent changes in the EZN. We used permutation entropy (PE), a measure of signal complexity, to analyze the peri-ictal stereoelectroencephalography (SEEG) signal changes with emphasis on the postictal state. We sought to determine the best PE-derived parameter (PEDP) for identifying the EZN. METHODS: Several PEDPs were computed retrospectively on SEEG-recorded seizures of 86 patients operated on for drug-resistant epilepsy: mean baseline preictal entropy, minimum ictal entropy, maximum postictal entropy, the ratio between the maximum postictal and the minimum ictal entropy, and the ratio between the maximum postictal and the baseline preictal entropy. The performance of each biomarker was assessed by comparing the identified epileptogenic contacts or brain regions against the EZN defined by clinical analysis incorporating the Epileptogenicity Index and the connectivity epileptogenicity index methods (EZNc), using the receiver-operating characteristic and precision-recall. RESULTS: The ratio between the maximum postictal and the minimum ictal entropy (defined as the Permutation Entropy Index [PEI]) proved to be the best-performing PEDP to identify the EZNC . It demonstrated the highest area under the curve (AUC) and F1 score at the contact level (AUC 0.72; F1 0.39) and at the region level (AUC 0.78; F1 0.47). PEI values gradually decreased between the EZN, the propagation network, and the non-involved regions. PEI showed higher performance in patients with slow seizure-onset patterns than in those with fast seizure-onset patterns. The percentage of resected epileptogenic regions defined by PEI was significantly correlated with surgical outcome. SIGNIFICANCE: PEI is a promising tool to improve the delineation of the EZN. PEI combines ease and robustness in a routine clinical setting with high sensitivity for seizures without fast activity at seizure onset.

Takotsubo syndrome linked to paroxysmal sympathetic hyperactivity as a postoperative complication after brain tumor removal: a case report and literature review.

Paroxysmal sympathetic hyperactivity (PSH) is a relatively common syndrome typically observed following traumatic brain injury (TBI). It manifests through a combination of non-specific symptoms that collectively define its presentation. Linked to sympathetic hyperactivity, takotsubo syndrome is a cardiomyopathy marked by left ventricular dysfunction and may coincide with PSH. While various factors can lead to the simultaneous occurrence of these syndromes, a notably rare scenario involves their manifestation after brain tumor removal. The nonspecific nature of PSH symptoms and of the cardiac dysfunction in takotsubo syndrome pose challenges in accurately diagnosing these conditions in an intensive care unit (ICU) setting. They often overlap with more prevalent diagnoses like sepsis, pulmonary embolism, and acute heart failure. Thus, it is crucial for clinicians dealing with these patients to be aware that symptoms indicating sympathetic activity surge and left heart failure might prompt consideration of takotsubo syndrome and PSH. This study presents the case of an 8-year-old girl who developed takotsubo syndrome associated with sympathetic hyperactivity following the surgical removal of a bulbar tumor. To the best of our knowledge, this is the tenth case of PSH following brain tumor removal in a pediatric patient and the first reported case of occurrence of takotsubo linked to PSH after brain tumor removal. We offer a detailed account of the patient's clinical journey in the ICU, accompanied by a comprehensive review of relevant literature to identify similar cases. The significance of this case study lies in emphasizing the potential occurrence of takotsubo syndrome due to PSH and underscores the importance of early diagnosis and management due to their association with unfavorable clinical outcomes.

The effect of selective dorsal rhizotomy on the improvement of the quality of life of children with stage GMFCS IV and V cerebral palsy: Pain, nursing, positioning, and dressing.

AIM: The objective of this study is to evaluate the benefit of selective dorsal rhizotomy on the quality of life of patients with severe spasticity with significant impairment of gross motor functions (GMFCS stages IV and V) according to 4 items: pain, nursing care, positioning, and dressing. MATERIALS AND METHODS: We conducted a monocentric retrospective cohort study including patients who underwent selective dorsal rhizotomy between March 2008 and May 2022 at the University Hospital of Marseille. RESULTS: Seventy percent of patients showed an improvement in quality of life criteria: dressing, nursing, positioning, and pain at the last follow-up. A small proportion of patients still showed a worsening between the first 2 follow-ups and the last follow-up. Postoperatively, 27.3% of patients were free of joint spasticity treatment, and we have shown that there was a significant decrease in the number of children who received botulinum toxin postoperatively. However, there was no significant reduction in the number of drug treatments or orthopaedic procedures following RDS. For the CPCHILD© scores, an overall gain is reported for GMFCS IV and V patients in postoperative care. The gain of points is more important for GMFCS IV patients. Improvement was mainly observed in 2 domains, "comfort and emotions" and "hygiene and dressing". For the "quality of life" item, only 3 parents out of the 8 noted a positive change. CONCLUSION: Our study shows an improvement in nursing care, positioning, and dressing which are associated with a reduction in pain in children with a major polyhandicap GMFCS IV and V who have benefited from a selective dorsal rhizotomy.

Low-grade epilepsy-associated neuroepithelial tumours with a prominent oligodendroglioma-like component: The diagnostic challenges.

AIMS: We searched for recurrent pathological features and molecular alterations in a retrospective series of 72 low-grade epilepsy-associated neuroepithelial tumours (LEATs) with a prominent oligodendroglioma-like component, in order to classify them according to the 2021 World Health Organization (WHO) classification of central nervous system (CNS) tumours. METHODS: Centralised pathological examination was performed as well as targeted molecular analysis of v-Raf murine sarcoma viral oncogene homologue B (BRAF) and fibroblast growth factor receptor 1 (FGFR1) by multiplexed digital polymerase chain reaction (mdPCR). DNA methylation profiling was performed in cases with sufficient DNA. In cases with no genetic alteration by mdPCR and sufficient material, RNA sequencing was done. RESULTS: We first reclassified our cohort into three groups: ganglioglioma (GG, n = 14), dysembryoplastic neuroepithelial tumours (DNTs, n = 19) and glioneuronal tumours/paediatric-type low-grade glioma (LGG) not otherwise specified (GNT/PLGG NOS, n = 39). mdPCR found an alteration in 38/72 cases. Subsequent RNA sequencing revealed a fusion transcript involving BRAF, FGFR1/2/3 or neurotrophic tyrosine kinase receptor type 2 [NTRK2] in 9/25 cases. DNA methylation profiling found 12/46 cases with a calibrated score ≥0.9. Unsupervised hierarchical clustering revealed two clusters: Cluster 1 was enriched with cases classified as DNT at histology, belonging to the LGG-DNT methylation class (MC), with haematopoietic progenitor cell antigen (CD34) negativity and FGRF1 alterations; Cluster 2 was enriched with cases classified at histology as GG, belonging to the LGG-GG MC MC, with BRAF V600E mutation and CD34 positivity. The tumours reclassified as GNT/PLGG NOS were equally distributed across both clusters. Interestingly, all polymorphous low-grade neuroepithelial tumour of the young belonged to Cluster 2, whereas diffuse LGG mitogen-activated protein kinase (MAPK) pathway-altered were equally distributed among the two clusters. This led us to build an algorithm to classify LEATs with a prominent oligodendroglioma-like component. CONCLUSIONS: Integrated histomolecular diagnosis of LEATs with a prominent oligodendroglioma-like component remains challenging. Because these tumours can be split into two major clusters of biological significance, the clinicopathological relevance of the four types recognised by the WHO CNS5 within this spectrum of tumours is questionable.

Changes in epileptogenicity biomarkers after stereotactic thermocoagulation.

OBJECTIVE: Stereo-electroencephalography (SEEG)-guided radiofrequency thermocoagulation (RF-TC) aims at modifying epileptogenic networks to reduce seizure frequency. High-frequency oscillations (HFOs), spikes, and cross-rate are quantifiable epileptogenic biomarkers. In this study, we sought to evaluate, using SEEG signals recorded before and after thermocoagulation, whether a variation in these markers is related to the therapeutic effect of this procedure and to the outcome of surgery. METHODS: Interictal segments of SEEG signals were analyzed in 38 patients during presurgical evaluation. We used an automatized method to quantify the rate of spikes, rate of HFOs, and cross-rate (a measure combining spikes and HFOs) before and after thermocoagulation. We analyzed the differences both at an individual level with a surrogate approach and at a group level with analysis of variance. We then evaluated the correlation between these variations and the clinical response to RF-TC and to subsequent resective surgery. RESULTS: After thermocoagulation, 19 patients showed a clinical improvement. At the individual level, clinically improved patients more frequently had a reduction in spikes and cross-rate in the epileptogenic zone than patients without clinical improvement (p = .002, p = .02). At a group level, there was a greater decrease of HFOs in epileptogenic and thermocoagulated zones in patients with clinical improvement (p < .05) compared to those with no clinical benefit. Eventually, a significant decrease of all the markers after RF-TC was found in patients with a favorable outcome of resective surgery (spikes, p = .026; HFOs, p = .03; cross-rate, p = .03). SIGNIFICANCE: Quantified changes in the rate of spikes, rate of HFOs, and cross-rate can be observed after thermocoagulation, and the reduction of these markers correlates with a favorable clinical outcome after RF-TC and with successful resective surgery. This may suggest that interictal biomarker modifications after RF-TC can be clinically used to predict the effectiveness of the thermocoagulation procedure and the outcome of resective surgery.

Metronomic Maintenance With Weekly Vinblastine After Induction With Bevacizumab-Irinotecan in Children With Low-grade Glioma Prevents Early Relapse.

BACKGROUND: Pediatric low-grade glioma (pLGG) represents the most common brain tumor in childhood. Previous studies have reported that a therapeutic strategy on the basis of the association of bevacizumab alone (B) or in combination with irinotecan (BI) could produce rapid tumor response and clinical improvement in children with pLGG. Nevertheless, a majority of patients relapses shortly (median, 5 mo) after stopping B or BI treatment. We proposed metronomic maintenance with weekly vinblastine added after a 6 months induction of B/BI to prevent early relapse. PATIENTS AND METHODS: Monocentric retrospective analysis of a patient with pLGG treated with B or BI for 6 months followed by a 12-month maintenance with weekly vinblastine (6 mg/m²) from October 2012 to September 2019 in a single institution. RESULTS: In total, 18 patients (7 males and 11 females) were identified. Because of progression during the B or BI induction 2/18 children were excluded. In total, 16 patients were analyzed with a median age of 10 years (range, 4 to 16 y). A total of 13 patients received BI and 3 patients received B alone. The mean duration of induction was 6.2 months (range, 2 to 12 mo). After induction 5/16 patients had a partial radiologic response, 11/16 patients had stable disease. All patients started maintenance (median duration, 12 mo; range, 3 to 12 mo). With a median follow-up of 3.9 years after the end of B or BI (range, 11 mo to 7.2 y), 15/16 patients were alive and 9/16 patients were progression-free. Seven of 16 children progressed with a median time to progression of 23 months (ranges, 5 to 39 mo). Three of 16 (18%) children progressed during vinblastine maintenance and 4/16 (25%) patients after the end of maintenance. After the total duration of treatment, clinical improvement was noted in 4 patients, 9 patients had stable symptoms, and only 3 patients progressed. One and 2-year event-free survival were, respectively, 81.2% and 56.2%. Two-year overall survival was 93.7%. CONCLUSIONS: We report here, the potential benefit and the improvement of progression-free survival by adding metronomic maintenance with weekly vinblastine after initial induction with B or BI in children with low-grade glioma.

Description of a giant hypothalamic hamartoma associated with an immature ruptured giant sacrococcygeal teratoma: a case report.

Giant hypothalamic hamartomas (GHH) are rare neonatal intracerebral congenital malformations responsible for gelastic epilepsy and/or endocrine disturbances. Sacrococcygeal teratomas (SCT) are fetal neoplasms associated with perinatal morbidity and mortality, especially hemorrhagic complications in giant examples (GSCT). Here, we describe an immature ruptured GSCT complicated by hemorrhagic shock at 32-week gestation boy requiring an emergency delivery, followed immediately by urgent surgical removal. A brain lesion resembling a GHH was also present on the antenatal MRI. In order to exclude metastatic immature teratoma or glioma, a biopsy was performed by a retro-sigmoidal approach, which confirmed the nature of the hamartoma. Here, we describe for the first time the association of a ruptured immature GSCT associated with a GHH.

Impact of the Craniofacial Surgery Simulation in Anterior Plagiocephaly on Orbits and Oculomotor Muscles: Biomechanical Analysis With a Finite Element Model.

PURPOSE: The aim of this study was to show the displacements and strain induced by the supraorbital band advancement during a craniofacial surgery for an anterior plagiocephaly on the orbital bones and the orbital content thanks to a numerical surgical simulation using the finite element method. METHODS: A three-dimensional (3D) finite element model of a child with an anterior plagiocephaly was entirely created from a tomodensitometry of a patient followed by our Craniofacial Pediatric team. Data of the tomodensitometry were computed with Slicer 3D to re-create the orbit geometry. Mesh production, properties of the model, and simulations of the fronto-orbital advancement were conducted on Hyperworks software (Altair Engineering, Inc., Detroit, MI, USA). RESULTS: The resulting 3D Finite Element Model was used to perform the supraorbital advancement simulation. Displacement and strain patterns were studied for orbital bones, oculomotor muscles, and eyeballs. Relative high strain in the both trochlear area and excycloration of the right orbit are among the most interesting results as torsional strabismus as V-pattern strabismus are often described in children with an anterior plagiocephaly. CONCLUSIONS: This pediatric Finite-Element Model of both orbits of a child with an anterior plagiocephaly showed the impact of the fronto-orbital advancement on the oculomotor system. This model described the relationship between the craniofacial surgery and the strabismus in the unilateral coronal synostosis. The advantages of this model are the many opportunities for improvement, including postoperative period and additional surgical procedures.

[Low grade glioma with MYBL1 alteration: Case report of an uncommon pediatric neoplasm]. / Gliome de bas grade avec altération de MYBL1 : observation d'une nouvelle entité tumorale pédiatrique.

Diffuse gliomas with MYB or MYBL1 alterations are rare tumours mostly affecting children or young adults with long-term epilepsy. This category of glioma includes two morphological subtypes. The angiocentric subtype is characterized by an angiocentric pattern of growth and a frequent MYB:QKI fusion. The isomorphic subtype corresponds to a highly differentiated astrocytic glioma with low cellularity, low proliferation and no specific microscopic features. The diagnosis is based on the imaging, demonstrating a supratentorial tumor, associated with the confirmation of a MYB or MYBL1 rearrangement. Here, we report the case of a 7-year-old child who presented a right frontal brain lesion corresponding to an isomorphic diffuse glioma with MYBL1 alteration.

Electrical stimulation for seizure induction during SEEG exploration: a useful predictor of postoperative seizure recurrence?

OBJECTIVE: Direct electrical stimulations of cerebral cortex are a traditional part of stereoelectroencephalography (SEEG) practice, but their value as a predictive factor for seizure outcome has never been carefully investigated. PATIENTS AND METHOD: We retrospectively analysed a cohort of 346 patients operated on for drug-resistant focal epilepsy after SEEG exploration. As potential predictors we included: aetiology, MRI data, age of onset, duration of epilepsy, age at surgery, topography of surgery and whether a seizure was induced by either low frequency electrical stimulation (LFS) or high frequency electrical stimulation. RESULTS: Of 346 patients, 63.6% had good outcome (no seizure recurrence, Engel I). Univariate analysis demonstrated significant correlation with favourable outcome (Engel I) for: aetiology, positive MRI and seizure induced by stimulation. At multivariate analysis, informative MRI, type II focal cortical dysplasia and tumour reduced the risk of seizure recurrence (SR) by 47%, 58% and 81%, respectively. Compared with the absence of induced seizures, the occurrence of ictal events after LFS significantly predicts a favourable outcome on seizures, with only 44% chance of disabling SR at last follow-up. CONCLUSION: Among the already known predictors outcome, seizure induction by LFS therefore represents a positive predictive factor for seizure outcome after surgery.

Relationship between PET metabolism and SEEG epileptogenicity in focal lesional epilepsy.

PURPOSE: This study aims to evaluate the performance of 18F-FDG PET for distinguishing the epileptogenic zone (EZ) from propagation and non-involved zones at brain area level, as defined using stereo-EEG (SEEG), in patients with pharmacoresistant epilepsy due to malformations of cortical development (MCD). Additionally, we seek to determine the relationship between 18F-FDG-PET data and post-surgical seizure outcome. METHODS: Thirty-eight patients with MCD were explored with 18F-FDG PET and SEEG. We compared PET metabolism of each patient to a control population of healthy subjects. Based on MRI and SEEG, we separated 4 distinct zones at individual level: lesional, epileptogenic non-lesional, propagation, and non-involved. Then, we analysed (1) difference of PET metabolism within these four distinct zones; (2) performance of PET in defining the EZ within the SEEG-sampled areas; and (3) relation between extension of PET hypometabolism and post-surgical seizure outcome. RESULTS: We found (1) a gradient of PET hypometabolism from non-involved to propagation, then to epileptogenic and lesional zones (p < 0.001); (2) good performance of PET in defining the EZ (AUC of ROC curve = 0.82); (3) poorer post-surgical prognosis associated with PET hypometabolism extension beyond SEEG sampling (p = 0.024). CONCLUSION: 18F-FDG-PET has good accuracy in determining EZ in patients with MCD even if the hypometabolism is not limited to the EZ. Furthermore, hypometabolic extension is unfavourably associated with post-surgical prognosis.

Quantitative analysis of hyperkinetic seizures and correlation with seizure onset zone.

OBJECTIVE: Hyperkinetic epileptic seizures (HKS) are difficult to characterize and localize according to semiologic features. We propose a multicriteria scale to help visual analysis and report results of cerebral localization. METHODS: We assessed seizures from 37 patients with HKS, explored with stereoelectroencephalography during presurgical evaluation. We used a multicriteria scale (hyperkinetic seizure scale [HSS]) with 10 semiologic features, scored independently by two neurologists. The item scores were used to group seizures using the k-means method. Semiologic features were correlated with the seizure onset zone (SOZ) localization (temporal, prefrontal dorsolateral, prefrontal ventromesial, parietal, insular). RESULTS: Fifty-five seizures were analyzed, and each item of the HSS was compared between the two examiners with good interrater agreement (85.3%). Dystonia, integrated behavior, and bilateral or unilateral hyperkinetic movements were statistically significant according to localization. Three clusters were identified according to the HSS and correlated with different patterns of anatomic localization of SOZ. Cluster 1 was characterized clinically by asymmetric hyperkinetic movements associated with marked dystonia and vocalization. It mainly included parietal seizures. Cluster 2 was characterized by bilateral and symmetrical stereotyped hyperkinetic movements without dystonia. It represented half of temporal seizures and one-third of prefrontal seizures (dorsolateral). Cluster 3 was characterized by seizures with strong emotionality and vocalization with bilateral and symmetrical hyperkinetic movements and integrated behavior. It involved half of temporal seizures and a majority of prefrontal (ventromesial) seizures. SIGNIFICANCE: We propose a first attempt to quantify clinical patterns of HKS. The HSS may help to predict SOZ localization according to three main groups of hyperkinetic seizures.

Prefrontal seizure classification based on stereo-EEG quantification and automatic clustering.

PURPOSE: Frontal seizures are organized according to anatomo-functional subdivisions of the frontal lobe. Prefrontal seizures have been the subject of few detailed studies to date. The objective of this study was to identify subcategories of prefrontal seizures based on seizure onset quantification and to look for semiological differences. METHODS: Consecutive patients who underwent stereoelectroencephalography (SEEG) for drug-resistant prefrontal epilepsy between 2000 and 2018 were included. The different prefrontal regions investigated in our patients were dorsolateral prefrontal cortex (DLPFC), ventrolateral prefrontal cortex (VLPFC), dorsomedial prefrontal cortex (DMPFC), ventromedial prefrontal cortex (VMPFC), and orbitofrontal cortex (OFC). The seizure onset zone (SOZ) was determined from one or two seizures in each patient, using the epileptogenicity index (EI) method. The presence or absence of 16 clinical ictal manifestations was analyzed. Classification of prefrontal networks was performed using the k-means automatic classification method. RESULTS: A total of 51 seizures from 31 patients were analyzed. The optimal clustering was 4 subgroups of prefrontal seizures: a "pure DLPF" group, a "pure VMPF" group, a "pure OFC" group, and a "global prefrontal" group. The first 3 groups showed a mean EI considered epileptogenic (>0.4) only in one predominant structure, while the fourth group showed a high mean EI in almost all prefrontal structures. The median number of epileptogenic structures per seizure (prefrontal or extrafrontal) was 5 for the "global prefrontal" group and 2 for the other groups. We found that the most common signs were altered consciousness, automatisms/stereotypies, integrated gestural motor behavior, and hyperkinetic motor behavior. We found no significant difference in the distribution of ictal signs between the different groups. CONCLUSION: Our study showed that although most prefrontal seizures manifest as a network of several anatomically distinct structures, we were able to determine a sublobar organization of prefrontal seizure onset with four groups.

Anatomoelectroclinical features of SEEG-confirmed pure insular-onset epilepsy.

PURPOSE: In this study, we aimed to improve our knowledge of insular epilepsy by studying anatomoelectroclinical correlations in pure insular-onset epilepsy and characterizing differences between anterior and posterior insular-onset seizures. METHODS: Patients in whom seizure-onset zone was confined to the insula and peri-insular sulcus were selected from 301 consecutive presurgical stereo-electroencephalography (EEG) recordings performed between years 2010 and 2017 in two epilepsy centers. Ictal-onset zone in stereo-EEG was delineated visually and quantitatively using epileptogenic index method. Seizure characteristics were reanalyzed, and anatomoelectroclinical correlations were assessed. Characteristics of posterior and anterior insular-onset seizures were compared. RESULTS: Eleven insular cases were identified, five of them with an anterior insular seizure onset and six with a posterior one. Nonpainful somatosensory symptoms and autonomic symptoms were the most common symptoms (73% of patients) followed by speech-related symptoms (55%) and ipsilateral eye blinking (45%). Six patients had seizures restricted to somatosensory or viscerosensory symptoms. In all patients, seizures progressed to motor symptoms. Somatosensory symptoms did not differentiate anterior from posterior insular seizures. However, hyperkinetic signs, speech modifications, and viscerosensory symptoms were related to an anterior insular seizure-onset zone. Pain, asymmetric tonic, focal clonic, and tonic symptoms were more frequent in patients with a posterior insular seizure onset. CONCLUSIONS: Seizure semiology is heterogeneous in pure insular-onset epilepsy. Differences between the anterior and posterior insular seizures reflect the functional organization of the insula. Particularly, the different types of motor symptoms may help to distinguish anterior from posterior insular seizure onset.

Diadenosine-Polyphosphate Analogue AppCH2ppA Suppresses Seizures by Enhancing Adenosine Signaling in the Cortex.

Epilepsy is a multifactorial disorder associated with neuronal hyperexcitability that affects more than 1% of the human population. It has long been known that adenosine can reduce seizure generation in animal models of epilepsies. However, in addition to various side effects, the instability of adenosine has precluded its use as an anticonvulsant treatment. Here we report that a stable analogue of diadenosine-tetraphosphate: AppCH2ppA effectively suppresses spontaneous epileptiform activity in vitro and in vivo in a Tuberous Sclerosis Complex (TSC) mouse model (Tsc1+/-), and in postsurgery cortical samples from TSC human patients. These effects are mediated by enhanced adenosine signaling in the cortex post local neuronal adenosine release. The released adenosine induces A1 receptor-dependent activation of potassium channels thereby reducing neuronal excitability, temporal summation, and hypersynchronicity. AppCH2ppA does not cause any disturbances of the main vital autonomous functions of Tsc1+/- mice in vivo. Therefore, we propose this compound to be a potent new candidate for adenosine-related treatment strategies to suppress intractable epilepsies.

The repertoire of seizure onset patterns in human focal epilepsies: Determinants and prognostic values.

OBJECTIVE: In this study, we seek to analyze the determinants of the intracranial electroencephalography seizure onset pattern (SOP) and the impact of the SOP in predicting postsurgical seizure outcome. METHODS: To this end, we analyzed 820 seizures from 252 consecutive patients explored by stereo-electroencephalography (total of 2148 electrodes), including various forms of focal refractory epilepsies. We used a reproducible method combining visual and time-frequency analyses. RESULTS: We described eight SOPs: low-voltage fast activity (LVFA), preictal spiking followed by LVFA, burst of polyspikes followed by LVFA, slow wave/DC shift followed by LVFA, sharp theta/alpha waves, beta sharp waves, rhythmic spikes/spike-waves, and delta-brush. LVFA occurred in 79% of patients. The seizure onset pattern was significantly associated with (1) underlying etiology (burst of polyspikes followed by LVFA with the presence of a focal cortical dysplasia, LVFA with malformation of cortical development, postvascular and undetermined epilepsies), (2) spatial organization of the epileptogenic zone (EZ; burst of polyspikes followed by LVFA with focal organization, slow wave/DC shift followed by LVFA with network organization), and (3) postsurgical seizure outcome (better outcome when LVFA present). SIGNIFICANCE: This study demonstrates that the main determinants of the SOP are the underlying etiology and the spatial organization of the EZ. Concerning the postsurgical seizure outcome, the main determinant factor is the spatial organization of the EZ, but the SOP plays also a role, conferring better prognosis when LVFA is present.

The effect of medial pulvinar stimulation on temporal lobe seizures.

We investigated the effect of electrical stimulation of the medial pulvinar (PuM) in terms of its effect on temporal lobe seizures. Eight patients with drug-resistant temporal lobe epilepsy undergoing stereoelectroencephalographic exploration were included. All had at least one electrode exploring the PuM. High-frequency (50 Hz) stimulations of the PuM were well tolerated in the majority of them. During diagnostic stimulation to confirm the epileptogenic zone, 19 seizures were triggered by stimulating the hippocampus. During some of these seizures, ipsilateral pulvinar stimulation was applied (130 Hz, pulse width = 450 microseconds, duration = 3-7 seconds, 1-2 mA). Compared to non-PuM-stimulated seizures, five of eight patients experienced clinically less severe seizures, particularly in terms of degree of alteration of consciousness. On the electrical level, seizures were more rapidly clonic with a shorter tonic phase. This proof of concept study is the first to suggest that PuM stimulation could be a well-tolerated and effective means of therapeutic deep brain stimulation in drug-resistant epilepsies.

Interictal stereotactic-EEG functional connectivity in refractory focal epilepsies.

Drug-refractory focal epilepsies are network diseases associated with functional connectivity alterations both during ictal and interictal periods. A large majority of studies on the interictal/resting state have focused on functional MRI-based functional connectivity. Few studies have used electrophysiology, despite its high temporal capacities. In particular, stereotactic-EEG is highly suitable to study functional connectivity because it permits direct intracranial electrophysiological recordings with relative large-scale sampling. Most previous studies in stereotactic-EEG have been directed towards temporal lobe epilepsy, which does not represent the whole spectrum of drug-refractory epilepsies. The present study aims at filling this gap, investigating interictal functional connectivity alterations behind cortical epileptic organization and its association with post-surgical prognosis. To this purpose, we studied a large cohort of 59 patients with malformation of cortical development explored by stereotactic-EEG with a wide spatial sampling (76 distinct brain areas were recorded, median of 13.2 per patient). We computed functional connectivity using non-linear correlation. We focused on three zones defined by stereotactic-EEG ictal activity: the epileptogenic zone, the propagation zone and the non-involved zone. First, we compared within-zone and between-zones functional connectivity. Second, we analysed the directionality of functional connectivity between these zones. Third, we measured the associations between functional connectivity measures and clinical variables, especially post-surgical prognosis. Our study confirms that functional connectivity differs according to the zone under investigation. We found: (i) a gradual decrease of the within-zone functional connectivity with higher values for epileptogenic zone and propagation zone, and lower for non-involved zones; (ii) preferential coupling between structures of the epileptogenic zone; (iii) preferential coupling between epileptogenic zone and propagation zone; and (iv) poorer post-surgical outcome in patients with higher functional connectivity of non-involved zone (within- non-involved zone, between non-involved zone and propagation zone functional connectivity). Our work suggests that, even during the interictal state, functional connectivity is reinforced within epileptic cortices (epileptogenic zone and propagation zone) with a gradual organization. Moreover, larger functional connectivity alterations, suggesting more diffuse disease, are associated with poorer post-surgical prognosis. This is consistent with computational studies suggesting that connectivity is crucial in order to model the spatiotemporal dynamics of seizures.10.1093/brain/awy214_video1awy214media15833456182001.