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In Vivo Gamma-Aminobutyric Acid Increase as a Biomarker of the Epileptogenic Zone: An Unbiased Metabolomics Approach Hamelin S, Stupar V, Maziere L, et al. Epilepsia. 2021;62(1):163-175.Objective:Following surgery, focal seizures relapse in 20% to 50% of cases due to the difficulty of delimiting the epileptogenic zone (EZ) by current imaging or electrophysiological techniques. Here, we evaluate an unbiased metabolomics approach based on ex vivo and in vivo nuclear magnetic resonance spectroscopy (MRS) methods to discriminate the EZ in a mouse model of mesiotemporal lobe epilepsy (MTLE).Methods:Four weeks after unilateral injection of kainic acid (KA) into the dorsal hippocampus of mice (KA-MTLE model), we analyzed hippocampal and cortical samples with high-resolution magic angle spinning (HRMAS) MRS. Using advanced multivariate statistics, we identified the metabolites that best discriminate the injected dorsal hippocampus (EZ) and developed an in vivo MEGAPRESS MRS method to focus on the detection of these metabolites in the same mouse model.Results:Multivariate analysis of HRMAS data provided evidence that γ-aminobutyric acid (GABA) is largely increased in the EZ of KA-MTLE mice and is the metabolite that best discriminates the EZ when compared with sham and, more importantly, when compared with adjacent brain regions. These results were confirmed by capillary electrophoresis analysis and were not reversed by a chronic exposition to an antiepileptic drug (carbamazepine). Then, using in vivo noninvasive GABA-edited MRS, we confirmed that a high GABA increase is specific to the injected hippocampus of KA-MTLE mice.Significance:Our strategy using ex vivo MRS-based untargeted metabolomics to select the most discriminant metabolite(s), followed by in vivo MRS-based targeted metabolomics, is an unbiased approach to accurately define the EZ in a mouse model of focal epilepsy. Results suggest that GABA is a specific biomarker of the EZ in MTLE.

Simple febrile seizures last for less than 10 minutes and resolve spontaneously, in the context of a febrile illness, without focal features or recurrence during the subsequent 24 hours. We report the case of fortuitous video-EEG recording of a FS, clinically classified as “simple”, which demonstrated a focal, temporal onset. This clinical finding is in agreement with animal model studies demonstrating focal onset. [Published with video sequences]

Summary Objective To obtain perspective on epilepsy in patients referred to tertiary centers in France, and describe etiology, epilepsy syndromes, and identify factors of drug resistance and comorbidities. Methods We performed a cross-sectional analysis of the characteristics of 5,794 pediatric and adult patients with epilepsy included in a collaborative database in France between 2007 and 2013. Comparisons between groups used Student's t-test or Fisher's exact test for binary or categorical variables. Factors associated with drug resistance and intellectual disability were evaluated in multi-adjusted logistic regression models. Results Mean age at inclusion was 17.9 years; children accounted for 67%. Epilepsy was unclassified in 20% of patients, and etiology was unknown in 65%, including those with idiopathic epilepsies. Etiologies differed significantly in adult- when compared to pediatric-onset epilepsy; however, among focal structural epilepsies, mesial temporal lobe epilepsy with hippocampal sclerosis began as often in the pediatric as in adult age range. Drug resistance concerned 53% of 4,210 patients evaluable for seizure control and was highest in progressive myoclonic epilepsy (89%), metabolic diseases (84%), focal cortical dysplasia (70%), other cortical malformations (69%), and mesial temporal lobe epilepsy with hippocampal sclerosis (67%). Fifty-nine percent of patients with focal structural epilepsy and 69% with epileptic encephalopathies were drug resistant; however, 40–50% of patients with West syndrome and epileptic encephalopathy with continuous spike-and-waves during sleep were seizure-free. Ages at onset in infancy and in young adults shared the highest risk of drug resistance. Epilepsy onset in infancy comprised the highest risk of intellectual disability, whereas specific cognitive impairment affected 36% of children with idiopathic focal epilepsy. Significance Our study provides a snapshot on epilepsy in patients referred to tertiary centers and discloses needs for diagnosis and treatment. Large databases help identify patients with rare conditions that could benefit from specific prospective studies.

Resume Introduction Un protocole d’hypothermie corporelle globale (HCG) dans le traitement de l’encephalopathie anoxo-ischemique (EAI) du nouveau-ne a terme est applique dans notre reseau depuis mai 2004. L’objectif principal de notre etude etait d’evaluer sa faisabilite ; l’objectif secondaire etant d’apprecier son influence sur l’evolution des nouveau-nes. Methodes Etude retrospective monocentrique des nouveau-nes admis pour EAI depuis mai 2004. La faisabilite du protocole a ete appreciee par son observance lors des 72 premieres heures d’hospitalisation. L’organisation du suivi ainsi que le devenir apres l’âge de 1 an, juge par le taux combine de deces et de sequelles neurologiques, ont ete analyses en comparant notre population a un groupe temoin historique. Resultats Vingt-cinq enfants ont ete inclus. Le protocole n’avait pas ete correctement applique pour 8 enfants soit parce que le degre d’HCG demande n’etait pas atteint, soit du fait d’une admission tardive, soit en raison d’une mauvaise appreciation de la gravite de l’EAI. Pour les 17 enfants traites, l’HCG avait ete obtenue a 6,4 h de vie. Aucun enfant n’avait ete perdu de vue apres mai 2004. Quarante pour cent des enfants avec EAI ont eu une evolution neurologique defavorable apres l’instauration du protocole versus 87 % avant (p Conclusion Le principal facteur limitant a la mise en place de l’HCG est la necessite d’une admission precoce du nouveau-ne, impliquant son transfert rapide. Le protocole s’est accompagne d’une amelioration du suivi et de l’evolution a 1 an.

Summary Purpose: Nonconvulsive status epilepticus (NCSE) is clinically difficult to diagnose, especially in old patients without epilepsy, and requires electroencephalography (EEG) for diagnosis. Its incidence among elderly patients with confusion of unknown origin (CUO) remains undetermined. Methods: A 1-year prospective study was conducted in patients aged 60 years or older, for whom EEG was requested because of confusion considered to be of unknown origin after initial clinical, biologic, and imaging investigations. Diagnosis criteria included a validated clinical assessment scale to confirm confusion. Results: Of 44 patients with confirmed CUO, 7 presented with de novo NCSE. NCSE population had a mean age of 76 years (range, 60–97 years). No statistically significant differences were found between NCSE patients and others for age, drugs, presence of myoclonia, eyelid myoclonia, tachycardia, or agitation. In contrast, an acute onset (

International audience; OBJECTIVE: To determine the prognostic value of early electroencephalograms (EEG) in full-term neonates suffering from hypoxic ischemic encephalopathy (HIE) exposed to whole-body hypothermia (cooled group), compared to neonates treated conventionally (control group). METHODS: The study included all term neonates born at Grenoble Hospital between 2000 and 2006 with symptoms of HIE. The first two EEGs were reviewed retrospectively and classified according to current electrophysiological criteria. In the cooled group, EEGs were recorded with a mean body temperature of 33°C. Neurological outcome was correlated with EEG pattern. RESULTS: An EEG inactive or paroxysmal pattern was associated with death in 60% of the controls, while all survivors had neurological sequels. In the cooled group, this EEG pattern was only predictive of death in 40% while survivors had normal examination at 1 year of age. Mild abnormalities on the first EEG correlated with a good prognosis in both groups. The second EEG had a high predictive value, particularly in the cooled group. Persistence of inactivity at 3 days after birth was always associated with death. CONCLUSIONS: After HIE, the first two EEGs are good prognostic indicators, also in the cooled group. Strong discontinuity in the EEG observed on the first hours after hypothermia induction can be associated with a good outcome. SIGNIFICANCE: Early Stage 4 EEGs recorded during the hypothermia may not always indicate a poor prognosis in HIE.

International audience; PURPOSE: Pyridoxine-Dependent Epilepsy (PDE) is a rare autosomal recessive disease with neonatal seizures resistant to conventional anti-epileptic drugs. This metabolic disease has to be diagnosed early and treated to improve outcome. We report on two new mutations that open new prenatal prospects and suggest a new diagnostic procedure. CASE REPORT: We describe PDE in a neonate carrying two novel mutations in the ALDH7A1 gene: c.[852_856delCTTAG] + [1230C > A]; p.[(Phe410Leu)] + p.[(Leu285CysfsX26)]. This case also illustrates that diagnosis could have been made without any pyridoxine withdrawal, thanks to the measurement of biomarkers. The patient was successfully treated with pyridoxine supplementation and currently shows normal neurological development.

International audience; PURPOSE: Fatigue represents a frequent complaint in epileptic patients (EP). This study attempted to evaluate fatigue in both conditions (inter-ictally and post-ictally) and to investigate the relative contribution of depression, sleepiness and epilepsy characteristics. METHODS: Consecutive EP were enrolled prospectively during a 3-month period, providing they were aged over 15 and able to fill auto-questionnaires. Age, gender, co-morbidities, seizure frequency, treatment, epilepsy syndrome, seizure lateralization and localization and last seizure occurrence were collected. Fatigue, depression and sleepiness were evaluated in both groups using the Fatigue Impact Scale (FIS), the Beck Depression Inventory (BDI), and the Epworth Sleepiness Scale (ESS). Furthermore, FIS was prospectively scored by patients post-ictally (within 24h after an incident seizure). RESULTS: 122 EP filled inclusion criteria (65 women, mean age 39±15). Among them, 82% presented with non-idiopathic partial epilepsy and 18% idiopathic generalized epilepsy. EP exhibit high chronic fatigue scores (62/160) irrespective of the type of epilepsy, seizure frequency, and number of antiepileptic drugs. FIS score was higher in post-ictally (79/160) than inter-ictally. FIS positively correlated with BDI and ESS. DISCUSSION: Chronic inter-ictal and post-ictal fatigue could represent a further complication of epilepsy, associated with depression. The impact of fatigue should be considered with the aim of improving quality of life and care of patients with epilepsy.

International audience; Epilepsy-associated changes of the anatomical organization of the dentate gyrus and hilus may play a critical role in the initiation and propagation of seizures in mesial temporal lobe epilepsy (MTLE). This study evaluated the role of longitudinal projections in the propagation of hippocampal paroxysmal discharges (HPD) in dorsal hippocampus by performing a selective transection in a mouse model for MTLE obtained by a single unilateral intrahippocampal injection of kainic acid (KA). Full transections of the dentate gyrus and hilus were performed in the transverse axis at 22 days after KA injection when spontaneous HPD were fully developed. They: (i) significantly reduced the occurrence of HPD; (ii) increased their duration at the KA injection site; (iii) abolished their spread along the longitudinal axis of the hippocampal formation and; (iv) limited granule cell dispersion (GCD) of the dentate gyrus posterior to the transection. These data suggest that: (i) longitudinal projections through the dentate gyrus and hilus are involved in HPD spread; (ii) distant hippocampal circuits participate in the generation and cessation of HPD and; (iii) GCD requires continuous HPD to develop, even when seizures are established. Our data reveal a critical role for longitudinal projections in the generation and spread of hippocampal seizures. © 2010 Wiley-Liss, Inc.

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We report on the case of an 86-year-old woman who rapidly became unable to stand and walk because of jerky movements, suggesting a clinical diagnosis of myoclonus. It was observed that both unexpected and expected stimuli (audiogenic, tactile, or visual) triggered the myoclonic jerks. Electrophysiological exploration, including a coupled EEG-EMG study, showed the occurrence of a patterned motor response to each stimulation (whatever the modality), consisting of eye blinking, head flexion, abduction of the upper arms, movement of the trunk, and bending of the knees. Given the absence of any relevant past history and lack of biological or neurological abnormalities including on CT scan brain imaging, the diagnosis of late-onset hyperekplexia was suggested. Substantial abatement of the clinical symptomatology was obtained after introduction of low-dose clonazepam.

Intermittent photic stimulation is performed during an EEG to evoke photoparoxysmal response. When they appear triggered by low-frequency stimulation in children, they are suggestive of rare diagnosis, that is, neuronal ceroid lipofuscinosis. Among adults, their significance is less well understood. Low-frequency (