Publications by authors named "Edouard Hirsch"

106 Publications

Three Different FDG Patterns in Periventricular Nodular Heterotopia Correlated to Video Stereoelectroencephalography.

Clin Nucl Med 2021 Mar 4. Epub 2021 Mar 4.

From the Service de Médecine Nucléaire et d'Imagerie Moléculaire, Institut de Cancérologie Strasbourg Europe (ICANS) ICube, Université de Strasbourg/CNRS (UMR 7357) Service de Neurologie, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourgand Service de Neurochirurgie, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.

Abstract: A 40-year-old woman with a drug-resistant focal epilepsy underwent cerebral FDG PET in phase 1 presurgical epilepsy study. MRI essentially showed multiple periventricular nodular heterotopias. The stereoelectroencephalography coupled to MRI and FDG PET helped to define the anatomofunctional correlation of the epileptogenic zone network. This procedure brought to light 3 distinct patterns of FDG consumption, corresponding to different anatomoelectroclinical features. This pattern was already found in a previous FDG PET reflecting a "stable" permanent intralesional intercritical stereoelectroencephalography activity, an electrical "signature" of the lesion. Finally, functional imaging improved thermocoagulation in this patient and emphasized the use of FDG in drug-resistant epilepsy.
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http://dx.doi.org/10.1097/RLU.0000000000003573DOI Listing
March 2021

Exome sequencing in 57 patients with self-limited focal epilepsies of childhood with typical or atypical presentations suggests novel candidate genes.

Eur J Paediatr Neurol 2020 Jul 29;27:104-110. Epub 2020 May 29.

Department of Medical Genetics, Member of the ERN EpiCARE, University Hospital of Lyon, Lyon, France; Institut NeuroMyoGène, CNRS UMR 5310 - INSERM U1217, Lyon, France; Université de Lyon - Université Claude Bernard Lyon 1, Lyon, France. Electronic address:

Objective: Self-limited focal epilepsies of childhood (SFEC) are amongst the best defined and most frequent epilepsy syndromes affecting children with usually normal developmental milestones. They include core syndromes such as Rolandic epilepsy or "Benign" epilepsy with Centro-Temporal Spikes and the benign occipital epilepsies, the early onset Panayiotopoulos syndrome and the late-onset Gastaut type. Atypical forms exist for all of them. Atypical Rolandic epilepsies are conceptualized as belonging to a continuum reaching from the "benign" RE to the severe end of the Landau-Kleffner (LKS) and Continuous Spike-Waves during Sleep syndromes (CSWS). GRIN2A has been shown to cause the epilepsy-aphasia continuum that includes some patients with atypical Rolandic epilepsy with frequent speech disorders, LKS and CSWS. In the present study, we searched novel genes causing SFEC with typical or atypical presentations.

Methods: Exome sequencing was performed in 57 trios. Patients presented with typical or atypical SFEC, negative for GRIN2A pathogenic variant.

Results: We found rare candidate variants in 20 patients. Thirteen had occurred de novo and were mostly associated to atypical Rolandic Epilepsy. Two of them could be considered as disease related: a null variant in GRIN2B and a missense variant in CAMK2A. Others were considered good candidates, including a substitution affecting a splice site in CACNG2 and missense variants in genes encoding enzymes involved in chromatin remodeling.

Significance: Our results further illustrate the fact that atypical SFEC are more likely to have Mendelian inheritance than typical SFEC.
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http://dx.doi.org/10.1016/j.ejpn.2020.05.003DOI Listing
July 2020

Focal epilepsy in SCN1A-mutation carrying patients: is there a role for epilepsy surgery?

Dev Med Child Neurol 2020 11 15;62(11):1331-1335. Epub 2020 Jun 15.

Department of Developmental Neurosciences, UCL NIHR BRC Great Ormond Street Institute of Child Health, London, UK.

Variants in the gene SCN1A are a common genetic cause for a wide range of epilepsy phenotypes ranging from febrile seizures to Dravet syndrome. Focal onset seizures and structural lesions can be present in these patients and the question arises whether epilepsy surgery should be considered. We report eight patients (mean age 13y 11mo [SD 8y 1mo], range 3-26y; four females, four males) with SCN1A variants, who underwent epilepsy surgery. Outcomes were variable and seemed to be directly related to the patient's anatomo-electroclinical epilepsy phenotype. Patients with Dravet syndrome had unfavourable outcomes, whilst patients with focal epilepsy, proven to arise from a single structural lesion, had good results. We conclude that the value of epilepsy surgery in patients with an SCN1A variant rests on two issues: understanding whether the variant is pathogenic and the patient's anatomo-electroclinical phenotype. Careful evaluation of epilepsy phenotype integrated with understanding the significance of genetic variants is essential in determining a patient's suitability for epilepsy surgery. Patients with focal onset epilepsy may benefit from epilepsy surgery, whereas those with Dravet syndrome do not. WHAT THIS PAPER ADDS: Patients should not automatically be excluded from epilepsy surgery evaluation if they carry an SCN1A variant. Patients with focal epilepsy may benefit from epilepsy surgery; those with Dravet syndrome do not.
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http://dx.doi.org/10.1111/dmcn.14588DOI Listing
November 2020

Biallelic PDE2A variants: a new cause of syndromic paroxysmal dyskinesia.

Eur J Hum Genet 2020 10 28;28(10):1403-1413. Epub 2020 May 28.

Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS U7104, INSERM U1258, 67400, Illkirch, France.

Cause of complex dyskinesia remains elusive in some patients. A homozygous missense variant leading to drastic decrease of PDE2A enzymatic activity was reported in one patient with childhood-onset choreodystonia preceded by paroxysmal dyskinesia and associated with cognitive impairment and interictal EEG abnormalities. Here, we report three new cases with biallelic PDE2A variants identified by trio whole-exome sequencing. Mitochondria network was analyzed after Mitotracker™ Red staining in control and mutated primary fibroblasts. Analysis of retrospective video of patients' movement disorder and refinement of phenotype was carried out. We identified a homozygous gain of stop codon variant c.1180C>T; p.(Gln394*) in PDE2A in siblings and compound heterozygous variants in young adult: a missense c.446C>T; p.(Pro149Leu) and splice-site variant c.1922+5G>A predicted and shown to produce an out of frame transcript lacking exon 22. All three patients had cognitive impairment or developmental delay. The phenotype of the two oldest patients, aged 9 and 26, was characterized by childhood-onset refractory paroxysmal dyskinesia initially misdiagnosed as epilepsy due to interictal EEG abnormalities. The youngest patient showed a proven epilepsy at the age of 4 months and no paroxysmal dyskinesia at 15 months. Interestingly, analysis of the fibroblasts with the biallelic variants in PDE2A variants revealed mitochondria network morphology changes. Together with previously reported case, our three patients confirm that biallelic PDE2A variants are a cause of childhood-onset refractory paroxysmal dyskinesia with cognitive impairment, sometimes associated with choreodystonia and interictal baseline EEG abnormalities or epilepsy.
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http://dx.doi.org/10.1038/s41431-020-0641-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608189PMC
October 2020

EEG in fitness to drive evaluations in people with epilepsy - Considerable variations across Europe.

Seizure 2020 Jul 30;79:56-60. Epub 2020 Apr 30.

Division of Clinical Neuroscience, National Centre for Epilepsy, Oslo University Hospital, Norway.

Purpose: Epilepsy patients consider driving issues to be one of their most serious concerns. Ideally, decisions regarding fitness to drive should be based upon thorough evaluations by specialists in epilepsy care. In 2009, an EU directive was published aiming to harmonize evaluation practices within European countries, but, despite these recommendations, whether all epileptologists use the same criteria is unclear. We therefore conducted this study to investigate routine practices on how epileptologists at European epilepsy centers evaluate fitness to drive.

Methods: A questionnaire was sent to 63 contact persons identified through the European Epi-Care and the E-pilepsy network. The questionnaire addressed how fitness-to-drive evaluations were conducted, the involvement of different professionals, the use and interpretation of EEG, and opinions on existing regulations and guidelines.

Results: The questionnaire was completed by 35 participants (56 % response rate). Results showed considerable variation regarding test routines and the emphasis placed on the occurrence and extent of epileptiform discharges revealed by EEG. 82 % of the responders agreed that there was a need for more research on how to better evaluate fitness-to-drive in people with epilepsy, and 89 % agreed that regulations on fitness to drive evaluations should be internationally coordinated.

Conclusion: Our survey showed considerable variations among European epileptologists regarding use of EEG and how findings of EEG pathology should be assessed in fitness-to-drive evaluations. There is a clear need for more research on this issue and international guidelines on how such evaluations should be carried out would be of value.
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http://dx.doi.org/10.1016/j.seizure.2020.04.013DOI Listing
July 2020

Unstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3.

Nat Commun 2019 10 29;10(1):4919. Epub 2019 Oct 29.

Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, Hufelandstraße 55, 45147, Essen, Germany.

Familial Adult Myoclonic Epilepsy (FAME) is a genetically heterogeneous disorder characterized by cortical tremor and seizures. Intronic TTTTA/TTTCA repeat expansions in SAMD12 (FAME1) are the main cause of FAME in Asia. Using genome sequencing and repeat-primed PCR, we identify another site of this repeat expansion, in MARCH6 (FAME3) in four European families. Analysis of single DNA molecules with nanopore sequencing and molecular combing show that expansions range from 3.3 to 14 kb on average. However, we observe considerable variability in expansion length and structure, supporting the existence of multiple expansion configurations in blood cells and fibroblasts of the same individual. Moreover, the largest expansions are associated with micro-rearrangements occurring near the expansion in 20% of cells. This study provides further evidence that FAME is caused by intronic TTTTA/TTTCA expansions in distinct genes and reveals that expansions exhibit an unexpectedly high somatic instability that can ultimately result in genomic rearrangements.
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http://dx.doi.org/10.1038/s41467-019-12763-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820781PMC
October 2019

Intronic ATTTC repeat expansions in STARD7 in familial adult myoclonic epilepsy linked to chromosome 2.

Nat Commun 2019 10 29;10(1):4920. Epub 2019 Oct 29.

Adelaide Medical School and Robinson Research Institute, University of Adelaide, Adelaide, 5005, SA, Australia.

Familial Adult Myoclonic Epilepsy (FAME) is characterised by cortical myoclonic tremor usually from the second decade of life and overt myoclonic or generalised tonic-clonic seizures. Four independent loci have been implicated in FAME on chromosomes (chr) 2, 3, 5 and 8. Using whole genome sequencing and repeat primed PCR, we provide evidence that chr2-linked FAME (FAME2) is caused by an expansion of an ATTTC pentamer within the first intron of STARD7. The ATTTC expansions segregate in 158/158 individuals typically affected by FAME from 22 pedigrees including 16 previously reported families recruited worldwide. RNA sequencing from patient derived fibroblasts shows no accumulation of the AUUUU or AUUUC repeat sequences and STARD7 gene expression is not affected. These data, in combination with other genes bearing similar mutations that have been implicated in FAME, suggest ATTTC expansions may cause this disorder, irrespective of the genomic locus involved.
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http://dx.doi.org/10.1038/s41467-019-12671-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820779PMC
October 2019

KCNT1 epilepsy with migrating focal seizures shows a temporal sequence with poor outcome, high mortality and SUDEP.

Brain 2019 10;142(10):2996-3008

Reference Centre for Rare Epilepsies, Department of Pediatric Neurology, Necker Enfants Malades Hospital, Paris Descartes University, Paris, France.

Epilepsy of infancy with migrating focal seizures was first described in 1995. Fifteen years later, KCNT1 gene mutations were identified as the major disease-causing gene of this disease. Currently, the data on epilepsy of infancy with migrating focal seizures associated with KCNT1 mutations are heterogeneous and many questions remain unanswered including the prognosis and the long-term outcome especially regarding epilepsy, neurological and developmental status and the presence of microcephaly. The aim of this study was to assess data from patients with epilepsy in infancy with migrating focal seizures with KCNT1 mutations to refine the phenotype spectrum and the outcome. We used mind maps based on medical reports of children followed in the network of the French reference centre for rare epilepsies and we developed family surveys to assess the long-term outcome. Seventeen patients were included [age: median (25th-75th percentile): 4 (2-15) years, sex ratio: 1.4, length of follow-up: 4 (2-15) years]. Seventy-one per cent started at 6 (1-52) days with sporadic motor seizures (n = 12), increasing up to a stormy phase with long lasting migrating seizures at 57 (30-89) days. The others entered this stormy phase directly at 1 (1-23) day. Ten patients entered a consecutive phase at 1.3 (1-2.8) years where seizures persisted at least daily (n = 8), but presented different semiology: brief and hypertonic with a nocturnal (n = 6) and clustered (n = 6) aspects. Suppression interictal patterns were identified on the EEG in 71% of patients (n = 12) sometimes from the first EEG (n = 6). Three patients received quinidine without reported efficacy. Long-term outcome was poor with neurological sequelae and active epilepsy except for one patient who had an early and long-lasting seizure-free period. Extracerebral symptoms probably linked with KCNT1 mutation were present, including arteriovenous fistula, dilated cardiomyopathy and precocious puberty. Eight patients (47%) had died at 3 (1.5-15.4) years including three from suspected sudden unexpected death in epilepsy. Refining the electro-clinical characteristics and the temporal sequence of epilepsy in infancy with migrating focal seizures should help diagnosis of this epilepsy. A better knowledge of the outcome allows one to advise families and to define the appropriate follow-up and therapies. Extracerebral involvement should be investigated, in particular the cardiac system, as it may be involved in the high prevalence of sudden unexpected death in epilepsy in these cases.
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http://dx.doi.org/10.1093/brain/awz240DOI Listing
October 2019

Update on the genetics of the epilepsy-aphasia spectrum and role of GRIN2A mutations.

Epileptic Disord 2019 Jun;21(S1):41-47

Aix-Marseille University, INSERM UMR1249, INMED, Marseille, France.

Formerly idiopathic, focal epilepsies (IFE) are self-limiting, "age-related" diseases that mainly occur during critical developmental periods. Childhood epilepsy with centrotemporal spikes, or Rolandic epilepsy (RE), is the most frequent form of IFE. Together with the Landau-Kleffner syndrome and the epileptic Encephalopathy related to Status Epilepticus during slow Sleep syndrome (ESES), RE is part of a single and continuous spectrum of childhood epilepsies and epileptic encephalopathies with acquired cognitive, behavioral and speech and/or language impairment, known as the epilepsy-aphasia spectrum (EAS). The pathophysiology has long been attributed to an elusive and complex interplay between brain development and maturation processes on the one hand, and susceptibility genes on the other hand. Studies based on the variable combination of molecular cytogenetics, Sanger and next-generation sequencing tools, and functional assays have led to the identification and validation of genetic mutations in the GRIN2A gene that can directly cause various types of EAS disorders. The recent identification of GRIN2A defects in EAS represents a first and major break-through in our understanding of the underlying pathophysiological mechanisms. In this review, we describe the current knowledge on the genetic architecture of IFE.
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http://dx.doi.org/10.1684/epd.2019.1056DOI Listing
June 2019

Encephalopathy related to Status Epilepticus during slow Sleep: from concepts to terminology.

Epileptic Disord 2019 Jun;21(S1):5-12

Paediatric Neurosciences Research Group, Royal Hospital for Children & University of Glasgow, Member of the European Reference Network EpiCARE, Glasgow, UK.

Five pediatric and adult neurologists with clinical and research interests in Encephalopathy related to Status Epilepticus during slow Sleep (ESES) express their opinions on definition, diagnostic assessment and terminology that may be considered for this condition. The aim of this "debate" is to identify aspects in which there is a shared opinion and areas where there are still controversies in the classification and suggest areas which demand further studies and research.
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http://dx.doi.org/10.1684/epd.2019.1051DOI Listing
June 2019

Comparison of Functional Deficit Zone Defined by FDG PET to the Epileptogenic Zones Described in Stereo-Electroencephalograph in Drug-Resistant Epileptic Patients Treated by Surgery.

Clin Nucl Med 2019 Jul;44(7):526-531

Unité Médico-chirurgicale de l'Epilepsie, and.

Introduction: The purpose of presurgical assessment is to delimit the epileptogenic zone and the functional deficit zone with a brain MRI, an electroencephalograph or even a stereo-electroencephalograph (SEEG), neuropsychological evaluation, and a cerebral FDG PET. Several studies concur that the hypometabolism of FDG PET seems to be consistent with epileptogenic zones. We compared the functional deficit zone defined by FDG PET with the results of the SEEG, for each cluster electrode contact (CEC) located in the gray matter.

Methods: The electrode diagram of the 15 patients (486 CECs) operated on for drug-resistant epilepsy was merged with MRI and FDG PET. The metabolisms of FDG PET and SEEG were compared using a logistic regression test.

Results: The presence of hypometabolism resulted in a significantly higher risk of being in the seizure onset zone and the irritative zone, particularly when it was intense. Of the deeply hypometabolic CECs, 47% were in the seizure onset zone and 76% in the irritative zone. Normal metabolism resulted in a significantly higher probability of being in the healthy zone.

Conclusions: This study demonstrated an association between the presence of normal metabolism and the location of CECs in the healthy zone, and between the presence of pathological metabolism and the location of CECs in the seizure onset zone and the irritative zone, with metabolism abnormalities progressively more present and more intense near the seizure onset zone.
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http://dx.doi.org/10.1097/RLU.0000000000002615DOI Listing
July 2019

Can histologically normal epileptogenic zone share common electrophysiological phenotypes with focal cortical dysplasia? SEEG-based study in MRI-negative epileptic patients.

J Neurol 2019 Aug 4;266(8):1907-1918. Epub 2019 May 4.

Epileptology Department, Timone Hospital, Inst Neurosci Syst, Service d'Epileptologie, Aix Marseille University, APHM, INSERM, INS, 264 Rue St Pierre, 13005, Marseille, France.

Objective: We aimed to assess stereoelectroencephalography (SEEG) seizure-onset and interictal patterns associated with MRI-negative epilepsy and investigate their possible links with histology, extent of the epileptogenic zone (EZ) and surgical outcome.

Methods: We retrospectively analysed a cohort of 59 consecutive MRI-negative surgical candidates, who underwent SEEG recordings followed by cortectomy between 2000 and 2016.

Results: Most of the eight distinct seizure-onset patterns could be encountered both in confirmed focal cortical dysplasia (FCD) and in histologically non-specific or normal cases. We found strong correlation (p = 0.008) between seizure-onset pattern and histology for: (1) slow-wave/DC-shift prior to low voltage fast activity (LVFA), associated with normal/non-specific histology, and (2) bursts of polyspikes prior to LVFA, exclusively observed in FCD. Three interictal patterns were identified: periodic slow-wave/gamma burst, sub-continuous rhythmic spiking and irregular spikes. Both "periodic" patterns were more frequent in but not specific to FCD. Surgical outcome depended on the EZ complete removal, regardless electrophysiological features.

Conclusions: Histologically normal and FCD-associated epileptogenic zones share distinct interictal and ictal electrophysiological phenotypes, with common patterns between FCD subtypes and between dysplastic and apparently normal brain.

Significance: Some specific seizure-onset patterns seem to be predictive of the underlying histology and may help to detect an MRI-invisible FCD.
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http://dx.doi.org/10.1007/s00415-019-09339-4DOI Listing
August 2019

Illusory own body perceptions mapped in the cingulate cortex-An intracranial stimulation study.

Hum Brain Mapp 2019 06 13;40(9):2813-2826. Epub 2019 Mar 13.

Neurology Department, University Emergency Hospital Bucharest, Bucharest, Romania.

Body awareness is the result of sensory integration in the posterior parietal cortex; however, other brain structures are part of this process. Our goal is to determine how the cingulate cortex is involved in the representation of our body. We retrospectively selected patients with drug-resistant epilepsy, explored by stereo-electroencephalography, that had the cingulate cortex sampled outside the epileptogenic zone. The clinical effects of high-frequency electrical stimulation were reviewed and only those sites that elicited changes related to body perception were included. Connectivity of the cingulate cortex and other cortical structures was assessed using the h coefficient, following a nonlinear regression analysis of the broadband EEG signal. Poststimulation changes in connectivity were compared between two sets of stimulations eliciting or not eliciting symptoms related to body awareness (interest and control groups). We included 17 stimulations from 12 patients that reported different types of body perception changes such as sensation of being pushed toward right/left/up, one limb becoming heavier/lighter, illusory sensation of movement, sensation of pressure, sensation of floating or detachment of one hemi-body. High-frequency stimulation in the cingulate cortex (1 anterior, 15 middle, 1 posterior part) elicits body perception changes, associated with a decreased connectivity of the dominant posterior insula and increased coupling between other structures, located particularly in the nondominant hemisphere.
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http://dx.doi.org/10.1002/hbm.24563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6865384PMC
June 2019

Mild malformations of cortical development in sleep-related hypermotor epilepsy due to mutations.

Ann Clin Transl Neurol 2019 02 25;6(2):386-391. Epub 2018 Dec 25.

Danish Epilepsy Centre, Filadelfia Dianalund Denmark.

Mutations in the sodium-activated potassium channel gene have been associated with nonlesional sleep-related hypermotor epilepsy (SHE). We report the co-occurrence of mild malformation of cortical development (mMCD) and mutations in four patients with SHE. Focal cortical dysplasia type I was neuropathologically diagnosed after epilepsy surgery in three unrelated MRI-negative patients, periventricular nodular heterotopia was detected in one patient by MRI. Our findings suggest that epileptogenicity may result not only from dysregulated excitability by controlling Na+K+ transport, but also from mMCD. Therefore, pathogenic variants in may encompass both lesional and nonlesional epilepsies.
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http://dx.doi.org/10.1002/acn3.708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6389734PMC
February 2019

High-frequency oscillations and spikes running down after SEEG-guided thermocoagulations in the epileptogenic network of periventricular nodular heterotopia.

Epilepsy Res 2019 02 15;150:27-31. Epub 2018 Dec 15.

Aix Marseille University, Institut de Neurosciences des Systèmes, Inserm, U1106, Marseille, France; Aix Marseille University, Service de Neurophysiologie Clinique, Hôpital Timone, Marseille, France. Electronic address:

Objective: Epilepsy associated with periventricular nodular heterotopia (PNH) is characterized by complex relationships between the heterotopic and the normotopic cortex during the interictal state and at seizure onset. High-frequency oscillations (HFO) have been proposed as a marker of epileptogenicity that might reflect disease activity. The effects of thermocoagulations on epileptogenicity in this context remain unknown. We aimed to investigate the interictal HFO- and spike profiles of different cortical structures before and after two consecutive SEEG-guided thermocoagulations, in correlation with seizure outcome, in a patient with PNH-related drug-resistant epilepsy.

Methods: The epileptogenic zone (EZ) was defined by SEEG analysis based on the Epileptogenicity Index. Interictal spikes, ripples (80-250 Hz) and fast ripples (FR, 250-330 Hz) were analyzed within the heterotopia, the temporal neocortex and the hippocampus.

Results: The SEEG recordings revealed a distributed EZ involving the heterotopia and the posterior temporal neocortex. Both structures were targeted by thermocoagulations. Background spikes, ripples and FR-rates were significantly higher in PNH compared to the normotopic cortex. A drastic reduction of spikes (by over 80%) and absence of FR were demonstrated both in the PNH and in the neocortex during the second SEEG exploration 6 months after the first thermocoagulation, whereas no significant difference was observed in the posterior hippocampus. Ripples were significantly reduced by the first and suppressed by the second thermocoagulation within the three structures. Seizures relapsed after two months but decreased in frequency after the first thermocoagulation. Sustained seizure-freedom was achieved only after the second procedure.

Conclusions: Our data demonstrate the running down of interictal HFO and spikes within the epileptogenic network following thermocoagulations of heterotopic and normotopic sites involved at seizure onset. This dynamics was in good correlation with significantly improved seizure control.

Significance: Combination of ictal and different interictal markers of epileptogenicity, including HFO and spike analysis, is important to get the full picture of the epileptogenic zone and could help to evaluate the disease activity.
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http://dx.doi.org/10.1016/j.eplepsyres.2018.12.006DOI Listing
February 2019

Hypoxemia following generalized convulsive seizures: Risk factors and effect of oxygen therapy.

Neurology 2019 01 19;92(3):e183-e193. Epub 2018 Dec 19.

From the Department of Functional Neurology and Epileptology (S.R., B.M.A., V.A.), Hospices Civils de Lyon and University of Lyon; Lyon's Neuroscience Research Center (S.R., B.M.A., V.A., L.B., P.R.), INSERM U1028/CNRS UMR 5292, France; Hospital of Clinics of Ribeirão Preto (V.A.), University of São Paulo, Brazil; Department of Neurology (J.C., L.V.), University Hospital of Toulouse; Neurology Department (L.M.), University Hospital of Nancy; Clinical Neurophysiology and Epileptology Department (F.B.), Timone Hospital, Marseille; Department of Clinical Neurophysiology (P.D.), Lille University Medical Center, EA 1046, University of Lille2; Department of Neurology (E.H.), University Hospital of Strasbourg; Department of Neurology (V.M.), Hôpital Pellegrin, Bordeaux; Epilepsy Unit, Department of Neurosurgery (F.C.), Centre Hospitalier Sainte-Anne, University Paris Descartes; La Teppe Epilepsy Center (D.T.), Tain l'Hermitage,; Epilepsy Unit (A.C.), Montpellier; Department of Neurology (A.B.), University Hospital of Rennes; Epileptology Unit (V.N.), Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière and Brain and Spine Institute (ICM; INSERM UMRS1127, CNRS UMR7225, UPMC University Paris 06); Department of Neurology (P.K.), Grenoble-Alpes University Hospital, GIN, INSERM U1216, and Grenoble Alpes University; Department of Clinical Neurophysiology (B.D.T.), INSERM U930, University Hospital of Tours; Department of Neurology (P.T.), University Hospital of Nice; Department of Neurology (S.R.), University Hospital of Clermont-Ferrand, France; Department of Clinical Neurosciences (S.R., P.R.), Centre Hospitalo-Universitaire Vaudois, Lausanne, Switzerland; and Epilepsy Institute (E.H., L.B., P.R.), Lyon, France.

Objective: To analyze the factors that determine the occurrence or severity of postictal hypoxemia in the immediate aftermath of a generalized convulsive seizure (GCS).

Methods: We reviewed the video-EEG recordings of 1,006 patients with drug-resistant focal epilepsy included in the REPOMSE study to identify those with ≥1 GCS and pulse oximetry (SpO) measurement. Factors determining recovery of SpO ≥ 90% were investigated using Cox proportional hazards models. Association between SpO nadir and person- or seizure-specific variables was analyzed after correction for individual effects and the varying number of seizures.

Results: A total of 107 GCS in 73 patients were analyzed. A transient hypoxemia was observed in 92 GCS (86%). Rate of GCS with SpO <70% dropped from 40% to 21% when oxygen was administered early ( = 0.046). Early recovery of SpO ≥90% was associated with early administration of oxygen ( = 0.004), absence of postictal generalized EEG suppression (PGES) ( = 0.014), and extratemporal lobe epilepsy ( = 0.001). Lack of early administration of O ( = 0.003), occurrence of PGES ( = 0.018), and occurrence of ictal hypoxemia during the focal phase ( = 0.022) were associated with lower SpO nadir.

Conclusion: Postictal hypoxemia was observed in the immediate aftermath of nearly all GCS but administration of oxygen had a strong preventive effect. Severity of postictal hypoxemia was greater in temporal lobe epilepsy and when hypoxemia was already observed before the onset of secondary GCS.
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http://dx.doi.org/10.1212/WNL.0000000000006777DOI Listing
January 2019

GRIN2A-related disorders: genotype and functional consequence predict phenotype.

Brain 2019 01;142(1):80-92

Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany.

Alterations of the N-methyl-d-aspartate receptor (NMDAR) subunit GluN2A, encoded by GRIN2A, have been associated with a spectrum of neurodevelopmental disorders with prominent speech-related features, and epilepsy. We performed a comprehensive assessment of phenotypes with a standardized questionnaire in 92 previously unreported individuals with GRIN2A-related disorders. Applying the criteria of the American College of Medical Genetics and Genomics to all published variants yielded 156 additional cases with pathogenic or likely pathogenic variants in GRIN2A, resulting in a total of 248 individuals. The phenotypic spectrum ranged from normal or near-normal development with mild epilepsy and speech delay/apraxia to severe developmental and epileptic encephalopathy, often within the epilepsy-aphasia spectrum. We found that pathogenic missense variants in transmembrane and linker domains (misTMD+Linker) were associated with severe developmental phenotypes, whereas missense variants within amino terminal or ligand-binding domains (misATD+LBD) and null variants led to less severe developmental phenotypes, which we confirmed in a discovery (P = 10-6) as well as validation cohort (P = 0.0003). Other phenotypes such as MRI abnormalities and epilepsy types were also significantly different between the two groups. Notably, this was paralleled by electrophysiology data, where misTMD+Linker predominantly led to NMDAR gain-of-function, while misATD+LBD exclusively caused NMDAR loss-of-function. With respect to null variants, we show that Grin2a+/- cortical rat neurons also had reduced NMDAR function and there was no evidence of previously postulated compensatory overexpression of GluN2B. We demonstrate that null variants and misATD+LBD of GRIN2A do not only share the same clinical spectrum (i.e. milder phenotypes), but also result in similar electrophysiological consequences (loss-of-function) opposing those of misTMD+Linker (severe phenotypes; predominantly gain-of-function). This new pathomechanistic model may ultimately help in predicting phenotype severity as well as eligibility for potential precision medicine approaches in GRIN2A-related disorders.
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http://dx.doi.org/10.1093/brain/awy304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6308310PMC
January 2019

Quantitative analysis and EEG markers of KCNT1 epilepsy of infancy with migrating focal seizures.

Epilepsia 2019 01 7;60(1):20-32. Epub 2018 Dec 7.

INSERM Unit U1129 Infantile Epilepsies and Brain Plasticity, University Paris Descartes, Sorbonne Paris Cité, Paris, France.

Objective: We aimed to characterize epilepsy of infancy with migrating focal seizures (EIMFS), a rare, severe early onset developmental epilepsy related to KCNT1 mutation, and to define specific electroencephalography (EEG) markers using EEG quantitative analysis. The ultimate goal would be to improve early diagnosis and to better understand seizure onset and propagation of EIMFS as compared to other early onset developmental epilepsy.

Methods: EEG of 7 EIMFS patients with KCNT1 mutations (115 seizures) and 17 patients with other early onset epilepsies (30 seizures) was included in this study. After detection of seizure onset and termination, spatiotemporal characteristics were quantified. Seizure propagation dynamics were analyzed using chronograms and phase coherence.

Results: In patients with EIMFS, seizures started and were localized predominantly in temporal and occipital areas, and evolved with a stable frequency (4-10 Hz). Inter- and intrahemispheric migrations were present in 60% of EIMFS seizures with high intraindividual reproducibility of temporospatial dynamics. Interhemispheric migrating seizures spread in 71% from temporal or occipital channels to the homologous contralateral ones, whereas intrahemispheric seizures involved mainly frontotemporal, temporal, and occipital channels. Causality links were present between ictal activities detected under different channels during migrating seizures. Finally, time delay index (based on delays between the different ictal onsets) and phase correlation index (based on coherence of ictal activities) allowed discrimination of EIMFS and non-EIMFS seizures with a specificity of 91.2% and a sensitivity of 84.4%.

Significance: We showed that the migrating pattern in EIMFS is not a random process, as suggested previously, and that it is a particular propagation pattern that follows the classical propagation pathways. It is notable that this study reveals specific EEG markers (time delay and phase correlation) accessible to visual evaluation, which will improve EIMFS diagnosis.
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http://dx.doi.org/10.1111/epi.14605DOI Listing
January 2019

Correction: The landscape of epilepsy-related GATOR1 variants.

Genet Med 2019 Aug;21(8):1896

Sorbonne Université, UPMC Univ Paris 06, UMR S 1127, F-75013 Paris, France.

The original version of this article contained an error in the spelling of the author Erik H. Niks, which was incorrectly given as Erik Niks. This has now been corrected in both the PDF and HTML versions of the article.
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http://dx.doi.org/10.1038/s41436-018-0325-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608233PMC
August 2019

[Epilepsy, medical and nursing news].

Rev Infirm 2018 Aug - Sep;67(243):17-19

Institut des épilepsies IDEE, Lyon, 59, boulevard Pinel, 69500 Bron, France; Centre hospitalier universitaire (CHU) de Strasbourg, 1, place de l'Hôpital, 67091 Strasbourg, France.

So far, the context of care supply does not meet all the needs of patients, especially those with chronic diseases. In epileptology in particular, the impact of the disease on patients' quality of life is serious enough that a lack of or insufficient care is added to critical risks, to those with existing multiple disabilities or the lack of specialised patient follow-up.
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http://dx.doi.org/10.1016/j.revinf.2018.07.004DOI Listing
December 2018

Correction to: The landscape of epilepsy-related GATOR1 variants.

Genet Med 2019 Jul;21(7):1671

Sorbonne Université, UPMC Univ Paris 06, UMR S 1127, F-75013, Paris, France.

The original version of this Article contained an error in the author list where the corresponding author Stéphanie Baulac was repeated twice. This has now been corrected in the HTML, the PDF was correct at the time of publication.
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http://dx.doi.org/10.1038/s41436-018-0284-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608347PMC
July 2019

The landscape of epilepsy-related GATOR1 variants.

Genet Med 2019 02 10;21(2):398-408. Epub 2018 Aug 10.

Sorbonne Université, UPMC Univ Paris 06, UMR S 1127, F-75013, Paris, France.

Purpose: To define the phenotypic and mutational spectrum of epilepsies related to DEPDC5, NPRL2 and NPRL3 genes encoding the GATOR1 complex, a negative regulator of the mTORC1 pathway METHODS: We analyzed clinical and genetic data of 73 novel probands (familial and sporadic) with epilepsy-related variants in GATOR1-encoding genes and proposed new guidelines for clinical interpretation of GATOR1 variants.

Results: The GATOR1 seizure phenotype consisted mostly in focal seizures (e.g., hypermotor or frontal lobe seizures in 50%), with a mean age at onset of 4.4 years, often sleep-related and drug-resistant (54%), and associated with focal cortical dysplasia (20%). Infantile spasms were reported in 10% of the probands. Sudden unexpected death in epilepsy (SUDEP) occurred in 10% of the families. Novel classification framework of all 140 epilepsy-related GATOR1 variants (including the variants of this study) revealed that 68% are loss-of-function pathogenic, 14% are likely pathogenic, 15% are variants of uncertain significance and 3% are likely benign.

Conclusion: Our data emphasize the increasingly important role of GATOR1 genes in the pathogenesis of focal epilepsies (>180 probands to date). The GATOR1 phenotypic spectrum ranges from sporadic early-onset epilepsies with cognitive impairment comorbidities to familial focal epilepsies, and SUDEP.
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http://dx.doi.org/10.1038/s41436-018-0060-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6292495PMC
February 2019

Probabilistic functional tractography of the human cortex revisited.

Neuroimage 2018 11 17;181:414-429. Epub 2018 Jul 17.

Inserm, U1216, Grenoble, F-38000, France; Univ. Grenoble Alpes, Grenoble Institut des Neurosciences, GIN, Grenoble, F-38000, France. Electronic address:

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.
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http://dx.doi.org/10.1016/j.neuroimage.2018.07.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6150949PMC
November 2018

Metabolomic characterization of human hippocampus from drug-resistant epilepsy with mesial temporal seizure.

Epilepsia 2018 03 17;59(3):607-616. Epub 2018 Jan 17.

Department of Biophysics and Nuclear Medicine, University Hospitals of Strasbourg, Strasbourg, France.

Objective: Within a complex systems biology perspective, we wished to assess whether hippocampi with established neuropathological features have distinct metabolome. Apparently normal hippocampi with no signs of sclerosis (noHS), were compared to hippocampal sclerosis (HS) type 1 (HS1) and/or type 2 (HS2). Hippocampus metabolome from patients with epilepsy-associated neuroepithelial tumors (EANTs), namely, gangliogliomas (GGs) and dysembryoplastic neuroepithelial tumors (DNTs), was also compared to noHS epileptiform tissue.

Methods: All patients underwent standardized temporal lobectomy. We applied H high-resolution magic angle spinning nuclear magnetic resonance (HRMAS NMR) spectroscopy to 48 resected human hippocampi. NMR spectra allowed quantification of 21 metabolites. Data were analyzed using multivariate analysis based on mutual information.

Results: Clear distinct metabolomic profiles were observed between all studied groups. Sixteen and 18 expected metabolite levels out of 21 were significantly different for HS1 and HS2, respectively, when compared to noHS. Distinct concentration variations for glutamine, glutamate, and N-acetylaspartate (NAA) were observed between HS1 and HS2. Hippocampi from GG and DNT patients showed 7 and 11 significant differences in metabolite concentrations when compared to the same group, respectively. GG and DNT had a clear distinct metabolomic profile, notably regarding choline compounds, glutamine, glutamate, aspartate, and taurine. Lactate and acetate underwent similar variations in both groups.

Significance: HRMAS NMR metabolomic analysis was able to disentangle metabolic profiles between HS, noHS, and epileptic hippocampi associated with EANT. HRMAS NMR metabolomic analysis may contribute to a better identification of abnormal biochemical processes and neuropathogenic combinations underlying mesial temporal lobe epilepsy.
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http://dx.doi.org/10.1111/epi.14000DOI Listing
March 2018

Epileptogenic networks in nodular heterotopia: A stereoelectroencephalography study.

Epilepsia 2017 12 6;58(12):2112-2123. Epub 2017 Oct 6.

Inserm, Institut de Neurosciences des Systèmes (INS), Aix Marseille Univ, Marseille, France.

Objective: Defining the roles of heterotopic and normotopic cortex in the epileptogenic networks in patients with nodular heterotopia is challenging. To elucidate this issue, we compared heterotopic and normotopic cortex using quantitative signal analysis on stereoelectroencephalography (SEEG) recordings.

Methods: Clinically relevant biomarkers of epileptogenicity during ictal (epileptogenicity index; EI) and interictal recordings (high-frequency oscillation and spike) were evaluated in 19 patients undergoing SEEG. These biomarkers were then compared between heterotopic cortex and neocortical regions. Seizures were classified as normotopic, heterotopic, or normoheterotopic according to respective values of quantitative analysis (EI ≥0.3).

Results: A total of 1,246 contacts were analyzed: 259 in heterotopic tissue (heterotopic cortex), 873 in neocortex in the same lobe of the lesion (local neocortex), and 114 in neocortex distant from the lesion (distant neocortex). No significant difference in EI values, high-frequency oscillations, and spike rate was found comparing local neocortex and heterotopic cortex at a patient level, but local neocortex appears more epileptogenic (p < 0.001) than heterotopic cortex analyzing EI values at a seizure level. According to EI values, seizures were mostly normotopic (48.5%) or normoheterotopic (45.5%); only 6% were purely heterotopic. A good long-term treatment response was obtained in only two patients after thermocoagulation and surgical disconnection.

Significance: This is the first quantitative SEEG study providing insight into the mechanisms generating seizures in nodular heterotopia. We demonstrate that both the heterotopic lesion and particularly the normotopic cortex are involved in the epileptogenic network. This could open new perspectives on multitarget treatments, other than resective surgery, aimed at modifying the epileptic network.
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http://dx.doi.org/10.1111/epi.13919DOI Listing
December 2017

Atonic seizures in children with surgically remediable epilepsy: a motor system seizure phenotype?

Epileptic Disord 2017 Sep;19(3):315-326

Medical and Surgical Epilepsy Unit, Hautepierre Hospital, University of Strasbourg, Strasbourg, IDEE Epilepsy Institute, Lyon, France.

Atonic seizures are common in some epileptic syndromes beginning in infancy or early childhood but they are rarely described in epilepsy with focal seizures of structural aetiology. We aimed to characterize the electroclinical features of atonic seizures in surgically remediable paediatric patients and to study the spatiotemporal organization of the underlying epileptogenic networks. We retrospectively analysed two consecutive, longitudinally evaluated and surgically treated paediatric patients presenting with atonic seizures as a manifestation of pharmacoresistant epilepsy of structural aetiology, evidenced by scalp- and stereotactic intracerebral video-EEG-recordings. A quantitative analysis of the epileptogenic zone organization was performed using the "epileptogenicity index". Long-lasting generalized ictal atonia, occurring in infancy, was a predominant clinical feature in both patients, with some hints of focal origin present in one case. The seizure phenotype evolved at later age into subtle segmental atonia, associated with prominent positive motor signs. The epileptogenic zone was localized within the dorsolateral or mesiolateral premotor region. Its spatial organization was focal, matching the lesional cortex in one and distributed involving several lesional and non-lesional structures in the other case. The emergence of atonic semiology temporally correlated with involvement of both lateral and mesial premotor, as well as primary motor areas. We hypothesize that atonic seizures may be considered as a motor system seizure phenotype in the setting of structural epilepsy. Complete removal of the epileptogenic area provided excellent seizure control.
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http://dx.doi.org/10.1684/epd.2017.0930DOI Listing
September 2017

Hypothalamic hamartoma: Epileptogenesis beyond the lesion?

Epilepsia 2017 06;58 Suppl 2:32-40

Aix Marseille Univ, Inserm, INS, Systems Neurosciences Institute, Marseille, France.

The discovery of intrinsic epileptogenicity of the hypothalamic hamartoma (HH) marked a new area in understanding the associated clinical syndrome, often manifesting as progressive epileptic encephalopathy. However, therapeutic procedures targeting the HH proved to be inefficient to cure seizures in up to 50% of cases, whereas in cases with partial improvement, the electroclinical patterns of persisting seizures suggest an involvement of distant cortical regions. The concept of kindling-like secondary epileptogenesis has been suggested as a possible underlying mechanism. Yet the role of the hypothalamic lesion in the pathophysiology of the syndrome remains debatable. In the Strasbourg-Kork series, the best outcomes were obtained when the duration of epilepsy before endoscopic HH surgery did not exceed 10 years. In two patients with HH ablation followed at a later time by a temporal lobectomy, only this second surgical step allowed complete seizure freedom. These findings suggest the existence of an independent, third stage of secondary epileptogenesis in human. In the Grenoble series, stereotactic intracerebral recordings (stereo electroencephalography [SEEG]) of five HH cases demonstrated that gelastic/dacrystic seizures were correlated with discharges within the HH, whereas other seizure types were related to discharges affecting cortical regions, which sometimes seemed to be triggered by HH. In the Marseille series, two cases explored by SEEG provided evidence of extended epileptogenicity outside the limits of the HH, forming complex epileptogenic networks, with HH still triggering clusters of neocortical seizures in the first, but not obligatory involved in spontaneous seizures in the second case. Taken together, our data argue for the existence of dynamic ictal network organization, with possible "kindling-like" relationships between the HH and the neocortex or widespread epileptogenesis. Despite the existence of secondary epileptogenesis, the epileptogenic zone could still be limited to the hamartoma, for which early surgical treatment should be pragmatically considered as a first surgical step.
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http://dx.doi.org/10.1111/epi.13755DOI Listing
June 2017