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1. Clinical Management of Drug Resistant Epilepsy: A Review on Current Strategies

Author

Guery D and Rheims S

Subjects
drug resistant epilepsy, epilepsy surgery, antiseizure drugs, comprehensive care, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract

Deborah Guery,1 Sylvain Rheims1– 3 1Department of Functional Neurology and Epileptology, Hospices Civils De Lyon and University of Lyon, Lyon, France; 2Lyon’s Neuroscience Research Center, INSERM U1028/CNRS UMR 5292, Lyon, France; 3Epilepsy Institute, Lyon, FranceCorrespondence: Sylvain RheimsDepartment of Functional Neurology and Epileptology, Hospices Civils De Lyon and University of Lyon, 59 Boulevard Pinel, Bron Cedex, 69677, FranceTel +33 4 72 35 79 00Email sylvain.rheims@chu-lyon.frAbstract: Drug resistant epilepsy (DRE) is defined as the persistence of seizures despite at least two syndrome-adapted antiseizure drugs (ASD) used at efficacious daily dose. Despite the increasing number of available ASD, about a third of patients with epilepsy still suffer from drug resistance. Several factors are associated with the risk of evolution to DRE in patients with newly diagnosed epilepsy, including epilepsy onset in the infancy, intellectual disability, symptomatic epilepsy and abnormal neurological exam. Pharmacological management often consists in ASD polytherapy. However, because quality of life is driven by several factors in patients with DRE, including the tolerability of the treatment, ASD management should try to optimize efficacy while anticipating the risks of drug-related adverse events. All patients with DRE should be evaluated at least once in a tertiary epilepsy center, especially to discuss eligibility for non-pharmacological therapies. This is of paramount importance in patients with drug resistant focal epilepsy in whom epilepsy surgery can result in long-term seizure freedom. Vagus nerve stimulation, deep brain stimulation or cortical stimulation can also improve seizure control. Lastly, considering the effect of DRE on psychologic status and social integration, comprehensive care adaptations are always needed in order to improve patients’ quality of life.Keywords: drug resistant epilepsy, epilepsy surgery, antiseizure drugs, comprehensive care

Published
2021

2. Profile of perampanel and its potential in the treatment of partial onset seizures

Author

Rheims S and Ryvlin P

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract

Sylvain Rheims,1,2 Philippe Ryvlin1,21Department of Functional Neurology and Epileptology and Institute for Children and Adolescent with Epilepsy, Hospices Civils de Lyon, Lyon, France; 2Lyon Neuroscience Research Center, INSERM U1028 / CNRS UMR 5292 Translational and Integrative Group in Epilepsy Research, Lyon, FranceAbstract: Perampanel (PER) is a novel antiepileptic compound that decreases neuronal excitability by modulating glutamatergic transmission through selective noncompetitive blockade of AMPA receptors. PER has been evaluated in three pivotal placebo-controlled randomized trials as adjunctive therapy in adult drug-resistant partial epilepsy. In comparison to placebo, adjunctive PER effectively reduces seizure frequency. The relative risk of the responder rate (95% confidence interval [CI]) was thus 1.60 (1.08–2.36), 1.79 (1.42–2.25) and 1.66 (1.24–2.23) for once-daily PER 4 mg/day, 8 mg/day and 12 mg/day, respectively. The most common adverse events associated with PER were nonspecific central nervous system side effects. Some concerns have been raised about risk of clinically significant weight gain and of psychiatric adverse events. Long-term open-label extensions of the three pivotal trials are underway. PER has recently been approved both in Europe and in the USA for the adjunctive treatment of partial onset seizures in patients aged 12 years and above. However, in the absence of a direct comparison between PER and other licensed antiepileptic drugs’ efficacy and tolerability, the clinical advantages of PER over the other drugs in intractable partial epilepsy remains to be determined.Keywords: perampanel, epilepsy, antiepileptic drug, partial seizures

Published
2013

21. Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals

Author

Motelow, JE, Povysil, G, Dhindsa, RS, Stanley, KE, Allen, AS, Feng, Y-CA, Howrigan, DP, Abbott, LE, Tashman, K, Cerrato, F, Cusick, C, Singh, T, Heyne, H, Byrnes, AE, Churchhouse, C, Watts, N, Solomonson, M, Lal, D, Gupta, N, Neale, BM, Cavalleri, GL, Cossette, P, Cotsapas, C, De Jonghe, P, Dixon-Salazar, T, Guerrini, R, Hakonarson, H, Heinzen, EL, Helbig, I, Kwan, P, Marson, AG, Petrovski, S, Kamalakaran, S, Sisodiya, SM, Stewart, R, Weckhuysen, S, Depondt, C, Dlugos, DJ, Scheffer, IE, Striano, P, Freyer, C, Krause, R, May, P, McKenna, K, Regan, BM, Bennett, CA, Leu, C, Leech, SL, O'Brien, TJ, Todaro, M, Stamberger, H, Andrade, DM, Ali, QZ, Sadoway, TR, Krestel, H, Schaller, A, Papacostas, SS, Kousiappa, I, Tanteles, GA, Christou, Y, Sterbova, K, Vlckova, M, Sedlackova, L, Lassuthova, P, Klein, KM, Rosenow, F, Reif, PS, Knake, S, Neubauer, BA, Zimprich, F, Feucht, M, Reinthaler, EM, Kunz, WS, Zsurka, G, Surges, R, Baumgartner, T, von Wrede, R, Pendziwiat, M, Muhle, H, Rademacher, A, van Baalen, A, von Spiczak, S, Stephani, U, Afawi, Z, Korczyn, AD, Kanaan, M, Canavati, C, Kurlemann, G, Muller-Schluter, K, Kluger, G, Haeusler, M, Blatt, I, Lemke, JR, Krey, I, Weber, YG, Wolking, S, Becker, F, Lauxmann, S, Bosselmann, C, Kegele, J, Hengsbach, C, Rau, S, Steinhoff, BJ, Schulze-Bonhage, A, Borggraefe, I, Schankin, CJ, Schubert-Bast, S, Schreiber, H, Mayer, T, Korinthenberg, R, Brockmann, K, Wolff, M, Dennig, D, Madeleyn, R, Kalviainen, R, Saarela, A, Timonen, O, Linnankivi, T, Lehesjoki, A-E, Rheims, S, Lesca, G, Ryvlin, P, Maillard, L, Valton, L, Derambure, P, Bartolomei, F, Hirsch, E, Michel, V, Chassoux, F, Rees, M, Chung, S-K, Pickrell, WO, Powell, R, Baker, MD, Fonferko-Shadrach, B, Lawthom, C, Anderson, J, Schneider, N, Balestrini, S, Zagaglia, S, Braatz, V, Johnson, MR, Auce, P, Sills, GJ, Baum, LW, Sham, PC, Cherny, SS, Lui, CHT, Delanty, N, Doherty, CP, Shukralla, A, El-Naggar, H, Widdess-Walsh, P, Barisi, N, Canafoglia, L, Franceschetti, S, Castellotti, B, Granata, T, Ragona, F, Zara, F, Iacomino, M, Riva, A, Madia, F, Vari, MS, Salpietro, V, Scala, M, Mancardi, MM, Nobili, L, Amadori, E, Giacomini, T, Bisulli, F, Pippucci, T, Licchetta, L, Minardi, R, Tinuper, P, Muccioli, L, Mostacci, B, Gambardella, A, Labate, A, Annesi, G, Manna, L, Gagliardi, M, Parrini, E, Mei, D, Vetro, A, Bianchini, C, Montomoli, M, Doccini, V, Barba, C, Hirose, S, Ishii, A, Suzuki, T, Inoue, Y, Yamakawa, K, Beydoun, A, Nasreddine, W, Zgheib, NK, Tumiene, B, Utkus, A, Sadleir, LG, King, C, Caglayan, SH, Arslan, M, Yapici, Z, Topaloglu, P, Kara, B, Yis, U, Turkdogan, D, Gundogdu-Eken, A, Bebek, N, Tsai, M-H, Ho, C-J, Lin, C-H, Lin, K-L, Chou, I-J, Poduri, A, Shiedley, BR, Shain, C, Noebels, JL, Goldman, A, Busch, RM, Jehi, L, Najm, IM, Ferguson, L, Khoury, J, Glauser, TA, Clark, PO, Buono, RJ, Ferraro, TN, Sperling, MR, Lo, W, Privitera, M, French, JA, Schachter, S, Kuzniecky, R, Devinsky, O, Hegde, M, Greenberg, DA, Ellis, CA, Goldberg, E, Helbig, KL, Cosico, M, Vaidiswaran, P, Fitch, E, Berkovic, SF, Lerche, H, Lowenstein, DH, Goldstein, DB, Motelow, JE, Povysil, G, Dhindsa, RS, Stanley, KE, Allen, AS, Feng, Y-CA, Howrigan, DP, Abbott, LE, Tashman, K, Cerrato, F, Cusick, C, Singh, T, Heyne, H, Byrnes, AE, Churchhouse, C, Watts, N, Solomonson, M, Lal, D, Gupta, N, Neale, BM, Cavalleri, GL, Cossette, P, Cotsapas, C, De Jonghe, P, Dixon-Salazar, T, Guerrini, R, Hakonarson, H, Heinzen, EL, Helbig, I, Kwan, P, Marson, AG, Petrovski, S, Kamalakaran, S, Sisodiya, SM, Stewart, R, Weckhuysen, S, Depondt, C, Dlugos, DJ, Scheffer, IE, Striano, P, Freyer, C, Krause, R, May, P, McKenna, K, Regan, BM, Bennett, CA, Leu, C, Leech, SL, O'Brien, TJ, Todaro, M, Stamberger, H, Andrade, DM, Ali, QZ, Sadoway, TR, Krestel, H, Schaller, A, Papacostas, SS, Kousiappa, I, Tanteles, GA, Christou, Y, Sterbova, K, Vlckova, M, Sedlackova, L, Lassuthova, P, Klein, KM, Rosenow, F, Reif, PS, Knake, S, Neubauer, BA, Zimprich, F, Feucht, M, Reinthaler, EM, Kunz, WS, Zsurka, G, Surges, R, Baumgartner, T, von Wrede, R, Pendziwiat, M, Muhle, H, Rademacher, A, van Baalen, A, von Spiczak, S, Stephani, U, Afawi, Z, Korczyn, AD, Kanaan, M, Canavati, C, Kurlemann, G, Muller-Schluter, K, Kluger, G, Haeusler, M, Blatt, I, Lemke, JR, Krey, I, Weber, YG, Wolking, S, Becker, F, Lauxmann, S, Bosselmann, C, Kegele, J, Hengsbach, C, Rau, S, Steinhoff, BJ, Schulze-Bonhage, A, Borggraefe, I, Schankin, CJ, Schubert-Bast, S, Schreiber, H, Mayer, T, Korinthenberg, R, Brockmann, K, Wolff, M, Dennig, D, Madeleyn, R, Kalviainen, R, Saarela, A, Timonen, O, Linnankivi, T, Lehesjoki, A-E, Rheims, S, Lesca, G, Ryvlin, P, Maillard, L, Valton, L, Derambure, P, Bartolomei, F, Hirsch, E, Michel, V, Chassoux, F, Rees, M, Chung, S-K, Pickrell, WO, Powell, R, Baker, MD, Fonferko-Shadrach, B, Lawthom, C, Anderson, J, Schneider, N, Balestrini, S, Zagaglia, S, Braatz, V, Johnson, MR, Auce, P, Sills, GJ, Baum, LW, Sham, PC, Cherny, SS, Lui, CHT, Delanty, N, Doherty, CP, Shukralla, A, El-Naggar, H, Widdess-Walsh, P, Barisi, N, Canafoglia, L, Franceschetti, S, Castellotti, B, Granata, T, Ragona, F, Zara, F, Iacomino, M, Riva, A, Madia, F, Vari, MS, Salpietro, V, Scala, M, Mancardi, MM, Nobili, L, Amadori, E, Giacomini, T, Bisulli, F, Pippucci, T, Licchetta, L, Minardi, R, Tinuper, P, Muccioli, L, Mostacci, B, Gambardella, A, Labate, A, Annesi, G, Manna, L, Gagliardi, M, Parrini, E, Mei, D, Vetro, A, Bianchini, C, Montomoli, M, Doccini, V, Barba, C, Hirose, S, Ishii, A, Suzuki, T, Inoue, Y, Yamakawa, K, Beydoun, A, Nasreddine, W, Zgheib, NK, Tumiene, B, Utkus, A, Sadleir, LG, King, C, Caglayan, SH, Arslan, M, Yapici, Z, Topaloglu, P, Kara, B, Yis, U, Turkdogan, D, Gundogdu-Eken, A, Bebek, N, Tsai, M-H, Ho, C-J, Lin, C-H, Lin, K-L, Chou, I-J, Poduri, A, Shiedley, BR, Shain, C, Noebels, JL, Goldman, A, Busch, RM, Jehi, L, Najm, IM, Ferguson, L, Khoury, J, Glauser, TA, Clark, PO, Buono, RJ, Ferraro, TN, Sperling, MR, Lo, W, Privitera, M, French, JA, Schachter, S, Kuzniecky, R, Devinsky, O, Hegde, M, Greenberg, DA, Ellis, CA, Goldberg, E, Helbig, KL, Cosico, M, Vaidiswaran, P, Fitch, E, Berkovic, SF, Lerche, H, Lowenstein, DH, and Goldstein, DB

Abstract

Both mild and severe epilepsies are influenced by variants in the same genes, yet an explanation for the resulting phenotypic variation is unknown. As part of the ongoing Epi25 Collaboration, we performed a whole-exome sequencing analysis of 13,487 epilepsy-affected individuals and 15,678 control individuals. While prior Epi25 studies focused on gene-based collapsing analyses, we asked how the pattern of variation within genes differs by epilepsy type. Specifically, we compared the genetic architectures of severe developmental and epileptic encephalopathies (DEEs) and two generally less severe epilepsies, genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). Our gene-based rare variant collapsing analysis used geographic ancestry-based clustering that included broader ancestries than previously possible and revealed novel associations. Using the missense intolerance ratio (MTR), we found that variants in DEE-affected individuals are in significantly more intolerant genic sub-regions than those in NAFE-affected individuals. Only previously reported pathogenic variants absent in available genomic datasets showed a significant burden in epilepsy-affected individuals compared with control individuals, and the ultra-rare pathogenic variants associated with DEE were located in more intolerant genic sub-regions than variants associated with non-DEE epilepsies. MTR filtering improved the yield of ultra-rare pathogenic variants in affected individuals compared with control individuals. Finally, analysis of variants in genes without a disease association revealed a significant burden of loss-of-function variants in the genes most intolerant to such variation, indicating additional epilepsy-risk genes yet to be discovered. Taken together, our study suggests that genic and sub-genic intolerance are critical characteristics for interpreting the effects of variation in genes that influence epilepsy.

Published
2021

29. Reversible acute postpartum cerebral angiopathy

Author

Rheims, S., Nighoghossian, N., Hermier, M., Formaglio, M., Cakmak, S., Derex, L., Trouillas, P., Centre de Recherche et d'Application en Traitement de l'Image et du Signal (CREATIS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-École Supérieure Chimie Physique Électronique de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
[SPI.ACOU]Engineering Sciences [physics]/Acoustics [physics.class-ph], [INFO.INFO-TS]Computer Science [cs]/Signal and Image Processing, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, [INFO.INFO-TI]Computer Science [cs]/Image Processing [eess.IV], [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, [PHYS.PHYS.PHYS-MED-PH]Physics [physics]/Physics [physics]/Medical Physics [physics.med-ph], [SDV.IB]Life Sciences [q-bio]/Bioengineering, [SDV.IB.MN]Life Sciences [q-bio]/Bioengineering/Nuclear medicine, [SPI.SIGNAL]Engineering Sciences [physics]/Signal and Image processing, [PHYS.MECA.ACOU]Physics [physics]/Mechanics [physics]/Acoustics [physics.class-ph]
Abstract

article

Published
2006

32. Comité de rédaction

Author

Béjot, Y., Créange, A., Defebvre, L., Mazighi, M., Alamowitch, S., Anheim, M., Arnulf, I., Attal, N., Azulay, P., Behin, A., Bourdillon, P., Bourgin, P., Brochet, B., Calvière, L., Ceccaldi, M., Clavelou, P., Corcia, P., Cordonnier, C., Debouverie, M., Delorme, T., Denier, C., Detante, O., de Sèze, J., Ducros, A., Dumurgier, J., Eusebio, A., Félician, O., Froment, C., Grabli, D., Hoang-Xuan, K., Jonas, J., Krystkowiak, P., Laforêt, P., Lamirel, C., Lannuzel, A., Laplaud, D., Lavallée, P., Lebouvier, T., Lévy, R., Magy, L., Maillard, L., Maltête, D., Martinaud, O., Meissner, W., Moreau, C., Moreau, T., Nicolas, G., Nizard, J., Olivot, J.-M., Peter-Derex, L., Pico, F., Pouget, J., Proust, F., Rheims, S., Ricard, D., Ruppert, E., Sharshar, T., Sibon, I., Thobois, S., Timsit, S., Touzé, E., Tranchant, C., Turc, G., Tyvaert, L., Verny, C., Viala, F., Vidailhet, M., Vighetto, A., Vukusic, S., Wolff, V., Zephir, H., Zuber, M., Camdessanché, J.-P., Flamand-Roze, E., Labauge, P., Moro, E., and Nasr, N.

Published
2021
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36. Peri-ictal pseudoprogression in patients with brain tumor

Author

Rheims, S., primary, Ricard, D., additional, van den Bent, M., additional, Taillandier, L., additional, Bourg, V., additional, Desestret, V., additional, Cartalat-Carel, S., additional, Hermier, M., additional, Monjour, A., additional, Delattre, J.-Y., additional, Sanson, M., additional, Honnorat, J., additional, and Ducray, F., additional

Published
2011
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37. High-purified cannabidiol efficacy and safety in a cohort of adult patients with various types of drug-resistant epilepsies

Author

Perriguey, M., El Succar, M., Clément, A., Lagarde, S., Ribes, O., Dode, X., Rheims, S., and Bartolomei, F.

Abstract

About 30% of patients with epilepsy are drug resistant. Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS) and tuberous sclerosis complex (TSC) are diseases for which high-purified-cannabidiol (CBD) known as Epidiolex® (GW pharma) can be prescribed in add-on of other medications in case of drug-resistance. Currently, there are only a few recent data in the literature about the efficacy and safety of CBD in other forms of refractory epilepsies especially focal epilepsies in adults. We report retrospectively the experience of high-purified-CBD use in two French reference medical centers for epilepsy in various forms of drug-resistant epilepsy. We distinguished two groups of patients: group A with epileptic encephalopathies and group B with focal or multifocal epilepsy. Safety and efficacy (% of responder patients) were evaluated. Finally, 73 patients (51 in group A and 22 in group B) used high-purified CBD as an add-on treatment for their drug-resistant epilepsy. Patients in group A were significantly younger (p = 0.0155), with a longer exposition of treatment (p = 0.0497) than group B and with higher doses (p = 0.0300). Respectively, 15 patients (29.4%) and five patients (22.7%) were responders during the follow-up period (p = 0.552). The association with clobazam was more frequent in responders than in non-responder patients (16 patients (80%) versus four (20%)). The most frequent side effect was somnolence. At the end of follow-up, 15 patients in group A (29.4%) and nine patients in group B (40.1%) had stopped the high-purified-CBD treatment due to aggravation of seizure, absence of positive effects, or adverse events. This study showed no significant difference regarding the type of drug-resistant epilepsy and suggests that this treatment may be of interest for all types of drug-resistant epilepsy.

Published
2023
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40. Aphemia Related to a Premotor Cortex Infarction.

Author

Rheims, S., Nighoghossian, N., Hermier, M., Formaglio, M., Cakmak, S., Derex, L., and Trouillas, P.

Subjects
*LETTERS to the editor, *SPEECH disorders
Abstract

A letter to the editor is presented outlining a case of a woman with aphemia associated with an initial mutism linked to a lateral premotor cortex infarction.

Published
2006
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41. A survey of the European Reference Network EpiCARE on clinical practice for selected rare epilepsies

Author

Baumgartner, Tobias, Carreño, Mar, Rocamora, Rodrigo, Bisulli, Francesca, Boni, Antonella, Brázdil, Milan, Horak, Ondrej, Craiu, Dana, Pereira, Cristina, Guerrini, Renzo, San Antonio‐Arce, Victoria, Schulze‐Bonhage, Andreas, Zuberi, Sameer M., Hallböök, Tove, Kalviainen, Reetta, Lagae, Lieven, Nguyen, Sylvie, Quintas, Sofia, Franco, Ana, Cross, J. Helen, Walker, Matthew, Arzimanoglou, Alexis, Rheims, Sylvain, Granata, Tiziana, Canafoglia, Laura, Johannessen Landmark, Cecilie, Sen, Arjune, Rattihalli, Rohini, Nabbout, Rima, Tartara, Elena, Santos, Manuela, Rangel, Rui, Krsek, Pavel, Marusic, Petr, Specchio, Nicola, Braun, Kees P. J., Smeyers, Patricia, Villanueva, Vicente, Kotulska, Katarzyna, Surges, Rainer, Tinuper, Paolo, Licchetta, Laura, Michelucci, Roberto, Toulouse, Joseph, Panagiotakaki, Eleni, Ostrowsky‐Coste, Karine, Lesca, Gaetan, de Curtis, Marco, Elisak, Martin, Domańska‐Pakiea, Dorota, Sadowski, Krzysztof, Baumgartner T., Carreno M., Rocamora R., Bisulli F., Boni A., Brazdil M., Horak O., Craiu D., Pereira C., Guerrini R., San Antonio-Arce V., Schulze-Bonhage A., Zuberi S.M., Hallbook T., Kalviainen R., Lagae L., Nguyen S., Quintas S., Franco A., Cross J.H., Walker M., Arzimanoglou A., Rheims S., Granata T., Canafoglia L., Johannessen Landmark C., Sen A., Rattihalli R., Nabbout R., Tartara E., Santos M., Rangel R., Krsek P., Marusic P., Specchio N., Braun K.P.J., Smeyers P., Villanueva V., Kotulska K., Surges R., Tinuper P., Licchetta L., Michelucci R., Toulouse J., Panagiotakaki E., Ostrowsky-Coste K., Lesca G., de Curtis M., Elisak M., Domanska-Pakiea D., and Sadowski K.

Subjects
Adult, Male, Consensus, Epilepsies, Myoclonic, tuberous sclerosis complex, Dravet syndrome, autoimmune encephalitis, orphan disease, progressive myoclonic epilepsy, targeted therapies, tuberous sclerosis complex, Cohort Studies, progressive myoclonic epilepsy, Rare Diseases, Tuberous Sclerosis, Surveys and Questionnaires, targeted therapie, Humans, Everolimus, orphan disease, Epilepsy, Infant, Middle Aged, autoimmune encephalitis, targeted therapies, Dravet syndrome, Europe, Full‐length Original Research, Encephalitis, Anticonvulsants, Female, autoimmune encephaliti, Spasms, Infantile
Abstract

Objective Clinical care of rare and complex epilepsies is challenging, because evidence‐based treatment guidelines are scarce, the experience of many physicians is limited, and interdisciplinary treatment of comorbidities is required. The pathomechanisms of rare epilepsies are, however, increasingly understood, which potentially fosters novel targeted therapies. The objectives of our survey were to obtain an overview of the clinical practice in European tertiary epilepsy centers treating patients with 5 arbitrarily selected rare epilepsies and to get an estimate of potentially available patients for future studies. Methods Members of the European Reference Network for rare and complex epilepsies (EpiCARE) were invited to participate in a web‐based survey on clinical practice of patients with Dravet syndrome, tuberous sclerosis complex (TSC), autoimmune encephalitis, and progressive myoclonic epilepsies including Unverricht Lundborg and Unverricht‐like diseases. A consensus‐based questionnaire was generated for each disease. Results Twenty‐six of 30 invited epilepsy centers participated. Cohorts were present in most responding centers for TSC (87%), Dravet syndrome (85%), and autoimmune encephalitis (71%). Patients with TSC and Dravet syndrome represented the largest cohorts in these centers. The antiseizure drug treatments were rather consistent across the centers especially with regard to Dravet syndrome, infantile spasms in TSC, and Unverricht Lundborg / Unverricht‐like disease. Available, widely used targeted therapies included everolimus in TSC and immunosuppressive therapies in autoimmune encephalitis. Screening for comorbidities was routinely done, but specific treatment protocols were lacking in most centers. Significance The survey summarizes the current clinical practice for selected rare epilepsies in tertiary European epilepsy centers and demonstrates consistency as well as heterogeneity in the treatment, underscoring the need for controlled trials and recommendations. The survey also provides estimates for potential participants of clinical trials recruited via EpiCARE, emphasizing the great potential of Reference Networks for future studies to evaluate new targeted therapies and to identify novel biomarkers.

Published
2021

42. Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals

Author

Joshua E. Motelow, Gundula Povysil, Ryan S. Dhindsa, Kate E. Stanley, Andrew S. Al- len, Yen-Chen Anne Feng, Daniel P. Howrigan, Liam E. Abbott, Ka- therine Tashman, Felecia Cerrato, Caroline Cusick, Tarjinder Singh, Henrike Heyne, Andrea E. Byrnes, Claire Churchhouse, Nick Watts, Matthew Solomonson, Dennis Lal, Namrata Gupta, Benjamin M. Neale, Gianpiero L. Cavalleri, Patrick Cossette, Chris Cotsapas, Peter De Jonghe, Tracy Dixon-Salazar, Renzo Guerrini, Hakon Hakonarson, Erin L. Heinzen, Ingo Helbig, Patrick Kwan, Anthony G. Marson, Slave ? Petrovski, Sitharthan Kamalakaran, Sanjay M. Sisodiya, Randy Stewart, Sarah Weckhuysen, Chantal Depondt, Dennis J. Dlugos, Ingrid E. Scheffer, Pasquale Striano, Catharine Freyer, Roland Krause, Patrick May, Kevin McKenna, Brigid M. Regan, Caitlin A. Bennett, Costin Leu, Stephanie L. Leech, Terence J. O'Brien, Marian Todaro, Hannah Stamberger, Danielle M. Andrade, Quratulain Zulfiqar Ali, Tara R. Sadoway, Heinz Krestel, Andre ? Schaller, Savvas S. Papacostas, Ioanna Kou- siappa, George A. Tanteles, Yiolanda Christou, Katalin Sterbova ?, Marke ? ta Vlckova ?, Lucie Sedlackova, Petra Lassuthova ?, Karl Martin Klein, Felix Rosenow, Philipp S. Reif, Susanne Knake, Bernd A. Neubauer, Friedrich Zimprich, Martha Feucht, Eva M. Reinthaler, Wolfram S. Kunz, Ga ?bor Zsurka, Rainer Surges, Tobias Baumgart- ner, Randi von Wrede, Manuela Pendziwiat, Hiltrud Muhle, An- nika Rademacher, Andreas van Baalen, Sarah von Spiczak, Ulrich Stephani, Zaid Afawi, Amos D. Korczyn, Moien Kanaan, Christina Canavati, Gerhard Kurlemann, Karen Mu ?ller-Schlu ?ter, Gerhard Kluger, Martin Ha ?usler, Ilan Blatt, Johannes R. Lemke, Ilona Krey, Yvonne G. Weber, Stefan Wolking, Felicitas Becker, Stephan Lauxmann, Christian Boßelmann, Josua Kegele, Christian Hengs- bach, Sarah Rau, Bernhard J. Steinhoff, Andreas Schulze-Bonhage, IngoBorggra ?fe, ChristophJ.Schankin, SusanneSchubert-Bast, Herbert Schreiber, Thomas Mayer, Rudolf Korinthenberg, Knut Brockmann, Markus Wolff, Dieter Dennig, Rene Madeleyn, Reetta Ka ?lvia ?inen, Anni Saarela, Oskari Timonen, Tarja Linnankivi, Anna-Elina Lehesjoki, Sylvain Rheims, Gaetan Lesca, Philippe Ryvlin, Louis Maillard, Luc Valton, Philippe Derambure, Fabrice Bartolomei, Edouard Hirsch, Ve ?ronique Michel, Francine Chas- soux, Mark I. Rees, Seo-Kyung Chung, William O. Pickrell, Robert Powell, Mark D. Baker, Beata Fonferko-Shadrach, Charlotte Law- thom, Joseph Anderson, Natascha Schneider, Simona Balestrini, Sara Zagaglia, Vera Braatz, Michael R. Johnson, Pauls Auce, Graeme J. Sills, Larry W. Baum, Pak C. Sham, Stacey S. Cherny, Colin H.T. Lui, Norman Delanty, Colin P. Doherty, Arif Shukralla, Hany El-Naggar, Peter Widdess-Walsh, Nina Barisic, Laura 12 The American Journal of Human Genetics 108, 1-18, June 3, 2021 Please cite this article in press as: Epi25 Collaborative, Sub-genic intolerance, ClinVar, the epilepsies: A whole-exome sequencing study of 29, 165 individuals, The American Journal of Human Genetics (2021), https://doi.org/10.1016/j.ajhg.2021.04.009 Canafoglia, Silvana Franceschetti, Barbara Castellotti, Tiziana Granata, Francesca Ragona, Federico Zara, Michele Iacomino, An- tonella Riva, Francesca Madia, Maria Stella Vari, Vincenzo Salpie- tro, Marcello Scala, Maria Margherita Mancardi, Lino Nobili, Elisa- betta Amadori, Thea Giacomini, Francesca Bisulli, Tommaso Pippucci, Laura Licchetta, Raffaella Minardi, Paolo Tinuper, Lor- enzo Muccioli, Barbara Mostacci, Antonio Gambardella, Angelo Labate, Grazia Annesi, Lorella Manna, Monica Gagliardi, Elena Parrini, Davide Mei, Annalisa Vetro, Claudia Bianchini, Martino Montomoli, Viola Doccini, Carmen Barba, Shinichi Hirose, At- sushi Ishii, Toshimitsu Suzuki, Yushi Inoue, Kazuhiro Yamakawa, Ahmad Beydoun, Wassim Nasreddine, Nathalie Khoueiry Zgheib, Birute Tumiene, Algirdas Utkus, Lynette G. Sadleir, Chontelle King, S. Hande Caglayan, Mutluay Arslan, Zuhal Yap?c?, P?nar To- paloglu, Bulent Kara, Uluc Yis, Dilsad Turkdogan, Asl? Gun- dogdu-Eken, Nerses Bebek, Meng-Han Tsai, Chen-Jui Ho, Chih- Hsiang Lin, Kuang-Lin Lin, I-Jun Chou, Annapurna Poduri, Beth R. Shiedley, Catherine Shain, Jeffrey L. Noebels, Alicia Goldman, Robyn M. Busch, Lara Jehi, Imad M. Najm, Lisa Ferguson, Jean Khoury, Tracy A. Glauser, Peggy O. Clark, Russell J. Buono, Thomas N. Ferraro, Michael R. Sperling, Warren Lo, Michael Privitera, Jac- queline A. French, Steven Schachter, Ruben I. Kuzniecky, Orrin Devinsky, Manu Hegde, David A. Greenberg, Colin A. Ellis, Ethan Goldberg, Katherine L. Helbig, Mahgenn Cosico, Priya Vaidis- waran, Eryn Fitch, Samuel F. Berkovic, Holger Lerche, Daniel H. Lowenstein, David B. Goldstein., Motelow J.E., Povysil G., Dhindsa R.S., Stanley K.E., Allen A.S., Feng Y.-C.A., Howrigan D.P., Abbott L.E., Tashman K., Cerrato F., Cusick C., Singh T., Heyne H., Byrnes A.E., Churchhouse C., Watts N., Solomonson M., Lal D., Gupta N., Neale B.M., Cavalleri G.L., Cossette P., Cotsapas C., De Jonghe P., Dixon-Salazar T., Guerrini R., Hakonarson H., Heinzen E.L., Helbig I., Kwan P., Marson A.G., Petrovski S., Kamalakaran S., Sisodiya S.M., Stewart R., Weckhuysen S., Depondt C., Dlugos D.J., Scheffer I.E., Striano P., Freyer C., Krause R., May P., McKenna K., Regan B.M., Bennett C.A., Leu C., Leech S.L., O'Brien T.J., Todaro M., Stamberger H., Andrade D.M., Ali Q.Z., Sadoway T.R., Krestel H., Schaller A., Papacostas S.S., Kousiappa I., Tanteles G.A., Christou Y., Sterbova K., Vlckova M., Sedlackova L., Lassuthova P., Klein K.M., Rosenow F., Reif P.S., Knake S., Neubauer B.A., Zimprich F., Feucht M., Reinthaler E.M., Kunz W.S., Zsurka G., Surges R., Baumgartner T., von Wrede R., Pendziwiat M., Muhle H., Rademacher A., van Baalen A., von Spiczak S., Stephani U., Afawi Z., Korczyn A.D., Kanaan M., Canavati C., Kurlemann G., Muller-Schluter K., Kluger G., Hausler M., Blatt I., Lemke J.R., Krey I., Weber Y.G., Wolking S., Becker F., Lauxmann S., Bosselmann C., Kegele J., Hengsbach C., Rau S., Steinhoff B.J., Schulze-Bonhage A., Borggrafe I., Schankin C.J., Schubert-Bast S., Schreiber H., Mayer T., Korinthenberg R., Brockmann K., Wolff M., Dennig D., Madeleyn R., Kalviainen R., Saarela A., Timonen O., Linnankivi T., Lehesjoki A.-E., Rheims S., Lesca G., Ryvlin P., Maillard L., Valton L., Derambure P., Bartolomei F., Hirsch E., Michel V., Chassoux F., Rees M.I., Chung S.-K., Pickrell W.O., Powell R., Baker M.D., Fonferko-Shadrach B., Lawthom C., Anderson J., Schneider N., Balestrini S., Zagaglia S., Braatz V., Johnson M.R., Auce P., Sills G.J., Baum L.W., Sham P.C., Cherny S.S., Lui C.H.T., Delanty N., Doherty C.P., Shukralla A., El-Naggar H., Widdess-Walsh P., Barisic N., Canafoglia L., Franceschetti S., Castellotti B., Granata T., Ragona F., Zara F., Iacomino M., Riva A., Madia F., Vari M.S., Salpietro V., Scala M., Mancardi M.M., Nobili L., Amadori E., Giacomini T., Bisulli F., Pippucci T., Licchetta L., Minardi R., Tinuper P., Muccioli L., Mostacci B., Gambardella A., Labate A., Annesi G., Manna L., Gagliardi M., Parrini E., Mei D., Vetro A., Bianchini C., Montomoli M., Doccini V., Barba C., Hirose S., Ishii A., Suzuki T., Inoue Y., Yamakawa K., Beydoun A., Nasreddine W., Khoueiry Zgheib N., Tumiene B., Utkus A., Sadleir L.G., King C., Caglayan S.H., Arslan M., Yapici Z., Topaloglu P., Kara B., Yis U., Turkdogan D., Gundogdu-Eken A., Bebek N., Tsai M.-H., Ho C.-J., Lin C.-H., Lin K.-L., Chou I.-J., Poduri A., Shiedley B.R., Shain C., Noebels J.L., Goldman A., Busch R.M., Jehi L., Najm I.M., Ferguson L., Khoury J., Glauser T.A., Clark P.O., Buono R.J., Ferraro T.N., Sperling M.R., Lo W., Privitera M., French J.A., Schachter S., Kuzniecky R.I., Devinsky O., Hegde M., Greenberg D.A., Ellis C.A., Goldberg E., Helbig K.L., Cosico M., Vaidiswaran P., Fitch E., Berkovic S.F., Lerche H., Lowenstein D.H., Goldstein D.B., Epi25 Collaborative, Institut de Neurosciences des Systèmes (INS), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, focal epilepsy, Whole Exome Sequencing, Cohort Studies, Epilepsy, 0302 clinical medicine, Genetic Marker, Missense mutation, Exome, whole-exome sequencing, generalized epilepsy, ComputingMilieux_MISCELLANEOUS, Genetics (clinical), Exome sequencing, seizures, Genetics, ClinVar, Phenotype, epileptic encephalopathy, Epi25, intolerance, Case-Control Studie, Human, Genetic Markers, seizure, Disease Association, Biology, Article, 03 medical and health sciences, Exome Sequencing, medicine, Humans, Genetic Predisposition to Disease, Genetic Testing, Generalized epilepsy, Gene, Louvain, [SCCO.NEUR]Cognitive science/Neuroscience, Correction, Genetic Variation, medicine.disease, epilepsy, Human genetics, 030104 developmental biology, Case-Control Studies, Human medicine, Cohort Studie, Genetic generalized epilepsy, 030217 neurology & neurosurgery
Abstract

Summary Both mild and severe epilepsies are influenced by variants in the same genes, yet an explanation for the resulting phenotypic variation is unknown. As part of the ongoing Epi25 Collaboration, we performed a whole-exome sequencing analysis of 13,487 epilepsy-affected individuals and 15,678 control individuals. While prior Epi25 studies focused on gene-based collapsing analyses, we asked how the pattern of variation within genes differs by epilepsy type. Specifically, we compared the genetic architectures of severe developmental and epileptic encephalopathies (DEEs) and two generally less severe epilepsies, genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). Our gene-based rare variant collapsing analysis used geographic ancestry-based clustering that included broader ancestries than previously possible and revealed novel associations. Using the missense intolerance ratio (MTR), we found that variants in DEE-affected individuals are in significantly more intolerant genic sub-regions than those in NAFE-affected individuals. Only previously reported pathogenic variants absent in available genomic datasets showed a significant burden in epilepsy-affected individuals compared with control individuals, and the ultra-rare pathogenic variants associated with DEE were located in more intolerant genic sub-regions than variants associated with non-DEE epilepsies. MTR filtering improved the yield of ultra-rare pathogenic variants in affected individuals compared with control individuals. Finally, analysis of variants in genes without a disease association revealed a significant burden of loss-of-function variants in the genes most intolerant to such variation, indicating additional epilepsy-risk genes yet to be discovered. Taken together, our study suggests that genic and sub-genic intolerance are critical characteristics for interpreting the effects of variation in genes that influence epilepsy.

Published
2021

43. Long-term outcomes in temporal lobe epilepsy with glutamate decarboxylase antibodies

Author

Véronique Rogemond, Dimitri Psimaras, Julie Haesebaert, Aude Belbezier, Jérôme Honnorat, Sylvain Rheims, Giulia Berzero, Géraldine Picard, Virginie Desestret, Bastien Joubert, François Ducray, Joubert, B., Belbezier, A., Haesebaert, J., Rheims, S., Ducray, F., Picard, G., Rogemond, V., Psimaras, D., Berzero, G., Desestret, V., and Honnorat, J.

Subjects
Male, Drug Resistant Epilepsy, Neurology, Drug-resistant epilepsy, Behavioral Symptoms, Epilepsy, 0302 clinical medicine, Cognition, Activities of Daily Living, 030212 general & internal medicine, Autoimmune encephalitis, Temporal lobe epilepsy, Child, Glutamate Decarboxylase, Middle Aged, Child, Preschool, Disease Progression, Female, medicine.symptom, Adult, medicine.medical_specialty, Anterograde amnesia, Anti-GAD65 antibodies, Adolescent, Temporal lobe, 03 medical and health sciences, Young Adult, Internal medicine, medicine, Memory impairment, Animals, Humans, Cognitive Dysfunction, Autoantibodies, Retrospective Studies, business.industry, Mood Disorders, medicine.disease, Amnesia, Anterograde, Rats, Mood disorders, Epilepsy, Temporal Lobe, Neurology (clinical), business, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract

Objective: To assess the long-term outcomes of patients with temporal lobe epilepsy and CSF anti-glutamate decarboxylase antibodies (GAD65-Abs). Methods: We retrospectively analyzed the clinical records of 35 patients with temporal lobe epilepsy and CSF GAD65-Abs, collected from January 1993 to December 2016 and assessed cognitive impairment and seizure activity at last visit. Cognitive impairment was considered significant if impacting on daily life activities. Immunohistochemistry on rat brain slices and ELISA were used for antibody detection and titration. Results: Median age was 30years (range 2–63), 32/35 (91%) patients were female, and median follow-up was 68months (range 7–232). At presentation, 20 patients had isolated temporal lobe epilepsy and 15 patients had other limbic symptoms, including anterograde amnesia (n = 10) and behavioral disturbances (n = 5). Progressive clinical deterioration over follow-up was reported in 28/35 patients (80%), including gradual increase of memory impairment (n = 25), and apparition of behavioral disturbances (n = 4) or mood disorders (n = 18). At last follow-up, 24/35 (69%) patients had cognitive disturbances with an impact on patient’s daily life activities, and 28/35 (80%) still had active seizures. Conclusion: Most patients with temporal lobe epilepsy and CSF GAD65-Abs develop a chronic disease with progressive cognitive impairment and refractory epilepsy regardless of the presence of additional limbic symptoms at onset.

Published
2020

44. Initial clinical presentation of young children with N-methyl- d -aspartate receptor encephalitis

Author

Jean-Michel Pedespan, Frédéric Villega, Jérôme Honnorat, Véronique Rogemond, Giulia Berzero, Virginie Desestret, Dimitri Psimaras, Jean-Christophe Antoine, Bastien Joubert, Laure Thomas, Marion Favier, Géraldine Picard, Marion Bailhache, Sylvain Rheims, Favier, M., Joubert, B., Picard, G., Rogemond, V., Thomas, L., Rheims, S., Bailhache, M., Villega, F., Pedespan, J. -M., Berzero, G., Psimaras, D., Antoine, J. -C., Desestret, V., and Honnorat, J.

Subjects
Male, Pediatrics, medicine.medical_specialty, Adolescent, Child Behavior Disorders, Disease, Focal seizures, 03 medical and health sciences, 0302 clinical medicine, Seizures, 030225 pediatrics, medicine, Humans, Autoimmune encephalitis, Child, Receptor, Retrospective Studies, Anti-N-Methyl-D-Aspartate Receptor Encephalitis, D aspartate, business.industry, Autoantibody, General Medicine, medicine.disease, Child, Preschool, Pediatrics, Perinatology and Child Health, Etiology, Female, N-methyl-D-aspartate receptor, Neurology (clinical), Presentation (obstetrics), business, 030217 neurology & neurosurgery, Encephalitis
Abstract

Autoimmune encephalitis with anti-N-methyl-d-aspartate receptor autoantibodies (NMDA-R-Abs) is a recently described disease affecting adult and pediatric patients. Symptoms of the disease are now perfectly described in the adult population but the clinical presentation is less known in young children. The aim of the present study was to describe the clinical presentation and the specificities of symptoms presented by young children with NMDA-R-Abs encephalitis to improve diagnosis of this disease, and to compare these to a series of previously published female adult patients. Fifty cases of children younger than twelve years of age diagnosed with NMDA-R-Abs encephalitis between January 1, 2007 and December 31, 2016 (27 females and 23 males) were retrospectively studied. The first neurological symptoms observed in young children with NMDA-R-Abs encephalitis were characterized by seizure (72%), especially focal seizure (42%), within a median of 15 days before other encephalitis symptoms; other patients mostly had behavioral disorders (26%). The seizures were frequently difficult to diagnose because of the transient unilateral dystonic or tonic posturing presentation or sudden unilateral pain in the absence of clonic movements. A post-ictal motor deficit was also frequently observed. This clinical presentation is different from that observed in adult females with NMDA-R-Abs encephalitis who initially present mainly psychiatric disorders (67%) or cognitive impairment (19%), and less frequently seizures (14%). The diagnosis of NMDA-R-Abs encephalitis should be systematically considered in young children of both sexes who present neurological symptoms suggesting recent seizures (focal or generalized) without obvious other etiology.

Published
2018

46. Exome sequencing of 20,979 individuals with epilepsy reveals shared and distinct ultra-rare genetic risk across disorder subtypes.

Author

Chen S, Abou-Khalil BW, Afawi Z, Ali QZ, Amadori E, Anderson A, Anderson J, Andrade DM, Annesi G, Arslan M, Auce P, Bahlo M, Baker MD, Balagura G, Balestrini S, Banks E, Barba C, Barboza K, Bartolomei F, Bass N, Baum LW, Baumgartner TH, Baykan B, Bebek N, Becker F, Bennett CA, Beydoun A, Bianchini C, Bisulli F, Blackwood D, Blatt I, Borggräfe I, Bosselmann C, Braatz V, Brand H, Brockmann K, Buono RJ, Busch RM, Caglayan SH, Canafoglia L, Canavati C, Castellotti B, Cavalleri GL, Cerrato F, Chassoux F, Cherian C, Cherny SS, Cheung CL, Chou IJ, Chung SK, Churchhouse C, Ciullo V, Clark PO, Cole AJ, Cosico M, Cossette P, Cotsapas C, Cusick C, Daly MJ, Davis LK, Jonghe P, Delanty N, Dennig D, Depondt C, Derambure P, Devinsky O, Di Vito L, Dickerson F, Dlugos DJ, Doccini V, Doherty CP, El-Naggar H, Ellis CA, Epstein L, Evans M, Faucon A, Feng YA, Ferguson L, Ferraro TN, Da Silva IF, Ferri L, Feucht M, Fields MC, Fitzgerald M, Fonferko-Shadrach B, Fortunato F, Franceschetti S, French JA, Freri E, Fu JM, Gabriel S, Gagliardi M, Gambardella A, Gauthier L, Giangregorio T, Gili T, Glauser TA, Goldberg E, Goldman A, Goldstein DB, Granata T, Grant R, Greenberg DA, Guerrini R, Gundogdu-Eken A, Gupta N, Haas K, Hakonarson H, Haryanyan G, Häusler M, Hegde M, Heinzen EL, Helbig I, Hengsbach C, Heyne H, Hirose S, Hirsch E, Ho CJ, Hoeper O, Howrigan DP, Hucks D, Hung PC, Iacomino M, Inoue Y, Inuzuka LM, Ishii A, Jehi L, Johnson MR, Johnstone M, Kälviäinen R, Kanaan M, Kara B, Kariuki SM, Kegele J, Kesim Y, Khoueiry-Zgheib N, Khoury J, King C, Klein KM, Kluger G, Knake S, Kok F, Korczyn AD, Korinthenberg R, Koupparis A, Kousiappa I, Krause R, Krenn M, Krestel H, Krey I, Kunz WS, Kurlemann G, Kuzniecky RI, Kwan P, La Vega-Talbott M, Labate A, Lacey A, Lal D, Laššuthová P, Lauxmann S, Lawthom C, Leech SL, Lehesjoki AE, Lemke JR, Lerche H, Lesca G, Leu C, Lewin N, Lewis-Smith D, Li GH, Liao C, Licchetta L, Lin CH, Lin KL, Linnankivi T, Lo W, Lowenstein DH, Lowther C, Lubbers L, Lui CHT, Macedo-Souza LI, Madeleyn R, Madia F, Magri S, Maillard L, Marcuse L, Marques P, Marson AG, Matthews AG, May P, Mayer T, McArdle W, McCarroll SM, McGoldrick P, McGraw CM, McIntosh A, McQuillan A, Meador KJ, Mei D, Michel V, Millichap JJ, Minardi R, Montomoli M, Mostacci B, Muccioli L, Muhle H, Müller-Schlüter K, Najm IM, Nasreddine W, Neaves S, Neubauer BA, Newton CRJC, Noebels JL, Northstone K, Novod S, O'Brien TJ, Owusu-Agyei S, Özkara Ç, Palotie A, Papacostas SS, Parrini E, Pato C, Pato M, Pendziwiat M, Pennell PB, Petrovski S, Pickrell WO, Pinsky R, Pinto D, Pippucci T, Piras F, Piras F, Poduri A, Pondrelli F, Posthuma D, Powell RHW, Privitera M, Rademacher A, Ragona F, Ramirez-Hamouz B, Rau S, Raynes HR, Rees MI, Regan BM, Reif A, Reinthaler E, Rheims S, Ring SM, Riva A, Rojas E, Rosenow F, Ryvlin P, Saarela A, Sadleir LG, Salman B, Salmon A, Salpietro V, Sammarra I, Scala M, Schachter S, Schaller A, Schankin CJ, Scheffer IE, Schneider N, Schubert-Bast S, Schulze-Bonhage A, Scudieri P, Sedláčková L, Shain C, Sham PC, Shiedley BR, Siena SA, Sills GJ, Sisodiya SM, Smoller JW, Solomonson M, Spalletta G, Sparks KR, Sperling MR, Stamberger H, Steinhoff BJ, Stephani U, Štěrbová K, Stewart WC, Stipa C, Striano P, Strzelczyk A, Surges R, Suzuki T, Talarico M, Talkowski ME, Taneja RS, Tanteles GA, Timonen O, Timpson NJ, Tinuper P, Todaro M, Topaloglu P, Tsai MH, Tumiene B, Turkdogan D, Uğur-İşeri S, Utkus A, Vaidiswaran P, Valton L, van Baalen A, Vari MS, Vetro A, Vlčková M, von Brauchitsch S, von Spiczak S, Wagner RG, Watts N, Weber YG, Weckhuysen S, Widdess-Walsh P, Wiebe S, Wolf SM, Wolff M, Wolking S, Wong I, von Wrede R, Wu D, Yamakawa K, Yapıcı Z, Yis U, Yolken R, Yücesan E, Zagaglia S, Zahnert F, Zara F, Zimprich F, Zizovic M, Zsurka G, Neale BM, and Berkovic SF

Abstract

Identifying genetic risk factors for highly heterogeneous disorders like epilepsy remains challenging. Here, we present the largest whole-exome sequencing study of epilepsy to date, with >54,000 human exomes, comprising 20,979 deeply phenotyped patients from multiple genetic ancestry groups with diverse epilepsy subtypes and 33,444 controls, to investigate rare variants that confer disease risk. These analyses implicate seven individual genes, three gene sets, and four copy number variants at exome-wide significance. Genes encoding ion channels show strong association with multiple epilepsy subtypes, including epileptic encephalopathies, generalized and focal epilepsies, while most other gene discoveries are subtype-specific, highlighting distinct genetic contributions to different epilepsies. Combining results from rare single nucleotide/short indel-, copy number-, and common variants, we offer an expanded view of the genetic architecture of epilepsy, with growing evidence of convergence among different genetic risk loci on the same genes. Top candidate genes are enriched for roles in synaptic transmission and neuronal excitability, particularly postnatally and in the neocortex. We also identify shared rare variant risk between epilepsy and other neurodevelopmental disorders. Our data can be accessed via an interactive browser, hopefully facilitating diagnostic efforts and accelerating the development of follow-up studies., Competing Interests: Competing Interests B.M.N is a member of the scientific advisory board at Deep Genomics and Neumora. No other authors have competing interests to declare

Published
2024
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47. The role of SEEG in the presurgical decision-making process in MRI-normal mesial temporal lobe epilepsy.

Author

Catenoix H, Decaestecker K, Hermier M, Chochoi M, Guinet V, Montavont A, Isnard J, Boulogne S, Szurhaj W, Haegelen C, Reyns N, Guenot M, Derambure P, Jung J, and Rheims S

Abstract

Objectives: In patients with mesial temporal lobe epilepsy (mTLE) and normal MRI, anterior temporal lobectomy sparing the hippocampus might be considered because of the risk of post-operative memory deficit. However, it is unclear whether some patients with normal MRI and non-invasive EEG and semiological pattern highly suggestive of mesial temporal seizures demonstrate a seizure onset network sparing the hippocampus, potentially warranting surgery., Methods: A retrospective study of 17 patients with mTLE epilepsy and normal MRI who underwent SEEG. Only patients whose non-invasive presurgical data suggested an unilateral mesial temporal epileptogenic zone (EZ), as defined by combination of ictal semiology and ictal EEG during scalp video-EEG, were included. SEEG data were analyzed using both visual and quantitative approaches. Two EZ organization were defined: (i) EZ involved the hippocampus at the onset of the ictal discharge (HIP group): (ii) patients in whom a delay>1sec was observed between the seizure onset and the involvement of the hippocampus (nHIP group). Non-invasive clinical and functional imaging data, as well as post-operative outcomes, were compared across groups., Results: Eleven patients were included in HIP group and 6 in the nHIP group. In the nHIP group, the maximal epileptogenicity was in the amygdala in five patients and in the entorhinal cortex in one. The hippocampus normalized interictal spiking activity was not different between groups. None of the patients characteristics collected during the non-invasive presurgical workup was associated with the SEEG-based organization of the EZ. Twelve patients underwent a surgical resection, including temporal cortectomy sparing hippocampus in six. Seizure and neuropsychological post-operative outcomes were similar., Conclusion: In patients with MRI-normal mTLE, SEEG should be included in the surgical decision-making process because seizure organization cannot be predicted from non-invasive investigations. When hippocampus is not included in the EZ, temporal resection sparing the hippocampus can be considered., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Published
2024
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48. CB2 expression in mouse brain: from mapping to regulation in microglia under inflammatory conditions.

Author

Grabon W, Ruiz A, Gasmi N, Degletagne C, Georges B, Belmeguenai A, Bodennec J, Rheims S, Marcy G, and Bezin L

Subjects
Animals, Mice, Male, Gene Expression Regulation drug effects, Inflammation metabolism, Inflammation pathology, Neuroinflammatory Diseases metabolism, Microglia metabolism, Receptor, Cannabinoid, CB2 metabolism, Receptor, Cannabinoid, CB2 genetics, Receptor, Cannabinoid, CB2 biosynthesis, Brain metabolism, Mice, Inbred C57BL, Lipopolysaccharides pharmacology
Abstract

Since its detection in the brain, the cannabinoid receptor type 2 (CB2) has been considered a promising therapeutic target for various neurological and psychiatric disorders. However, precise brain mapping of its expression is still lacking. Using magnetic cell sorting, calibrated RT-qPCR and single-nucleus RNAseq, we show that CB2 is expressed at a low level in all brain regions studied, mainly by few microglial cells, and by neurons in an even lower proportion. Upon lipopolysaccharide stimulation, modeling neuroinflammation in non-sterile conditions, we demonstrate that the inflammatory response is associated with a transient reduction in CB2 mRNA levels in brain tissue, particularly in microglial cells. This result, confirmed in the BV2 microglial cell line, contrasts with the positive correlation observed between CB2 mRNA levels and the inflammatory response upon stimulation by interferon-gamma, modeling neuroinflammation in sterile condition. Discrete brain CB2 expression might thus be up- or down-regulated depending on the inflammatory context., (© 2024. The Author(s).)

Published
2024
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50. Serotonin 2C receptor in a rat model of temporal lobe epilepsy: From brainstem expression to pharmacological blockade in relation to ventilatory function.

Author

Kouchi H, Smith J, Georges B, Cracknell F, Bezin L, and Rheims S

Subjects
Animals, Rats, Male, Tryptophan Hydroxylase genetics, Tryptophan Hydroxylase metabolism, Serotonin Plasma Membrane Transport Proteins genetics, Serotonin Plasma Membrane Transport Proteins metabolism, Indoles pharmacology, Adenosine Deaminase genetics, Adenosine Deaminase metabolism, Rats, Sprague-Dawley, Serotonin 5-HT2 Receptor Antagonists pharmacology, Aminopyridines, Thiophenes, Receptor, Serotonin, 5-HT2C genetics, Receptor, Serotonin, 5-HT2C metabolism, Epilepsy, Temporal Lobe physiopathology, Epilepsy, Temporal Lobe metabolism, Brain Stem metabolism, Brain Stem drug effects, Disease Models, Animal
Abstract

Because of its involvement in breathing control and neuronal excitability, dysregulation of the serotonin (5-HT) 2C receptor (5-HT2C) might play a key role in sudden unexpected death in epilepsy. Seizure-induced respiratory arrest is thus prevented by a 5-HT2B/C agonist in different seizure model. However, the specific contribution of 5-HT2C in chronic epilepsy-related respiratory dysfunction remains unknown. In a rat model of temporal lobe epilepsy (EPI rats), in which we previously reported interictal respiratory dysfunctions and a reduction of brainstem 5-HT tone, quantitative reverse transcriptase polymerase chain reaction showed overexpression of TPH2 (5-HT synthesis enzyme), SERT (5-HT reuptake transporter), and 5-HT2C transcript levels in the brainstem of EPI rats, and of RNA-specific adenosine deaminase (ADAR1, ADAR2) involved in the production of 5-HT2C isoforms. Interictal ventilation was assessed with whole-body plethysmography before and 2 h after administration of SB242084 (2 mg/kg), a specific antagonist of 5-HT2C. As expected, SB242084 administration induced a progressive decrease in ventilatory parameters and an alteration of breathing stability in both control and EPI rats. However, the size of the SB242084 effect was lower in EPI rats than in controls. Increased 5-HT2C gene expression in the brainstem of EPI rats could be part of a compensatory mechanism against epilepsy-related low 5-HT tone and expression of 5-HT2C isoforms for which 5-HT affinity might be lower., (© 2024 International League Against Epilepsy.)

Published
2024
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