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1. Supporting patients with heart failure with digital therapeutics—A pilot study in Germany

Author: S. Reif, S. Schubert, J. Stiefel, F. Husri, T. Fischlein, M. Pauschinger, and J. Klucken
Subjects: Computer applications to medicine. Medical informatics, R858-859.7
Abstract: Objective Continuous monitoring and targeted behavioral interventions have been shown to improve health status and quality of life for heart failure patients. Digital therapeutics offer the possibility to make more frequent monitoring and targeted behavioral interventions available for more people. Methods We conduct a pilot study with 71 patients who were given a smartphone app and wearables for a 3-month period. Clinical indicators as well as patient-reported outcomes were collected at entry and exit examinations. Results The New York Heart Association class remained stable or improved. Most quantitative outcome measures improved (6-minute walk test distance + 21 m, Kansas City Cardiomyopathy Questionnaire summary score + 6.0 points, European Heard Failure Self-care Behavior Scale summary score + 6.6 points, correct answers in the Atlanta Heart Failure Knowledge Test + 2.1), although the changes were mainly not significantly different from zero. There was no change in EQ-5D weight and 9-item Shared Decision-Making Questionnaire summary score. Conclusions This before–after comparison shows that an app-based intervention can work as a digital therapeutic for heart failure patients.
Published: 2022
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2. The phenotypic and genotypic spectrum of epilepsy and intellectual disability in adults: Implications for genetic testing

Author: Sophie vonBrauchitsch, Denise Haslinger, Silvia Lindlar, Holger Thiele, Natalie Bernsen, Felix Zahnert, Philipp S. Reif, Yunus Balcik, Ping Yee Billie Au, Colin B. Josephson, Janine Altmüller, Adam Strzelczyk, Susanne Knake, Felix Rosenow, Andreas Chiocchetti, and Karl Martin Klein
Subjects: adults, developmental and epileptic encephalopathy, epilepsy, genetic testing, genetics, intellectual disability, Neurology. Diseases of the nervous system, RC346-429
Abstract: Abstract Objective The phenotypic and genotypic spectrum of adult patients with epilepsy and intellectual disability (ID) is less clear than in children. We investigated an adult patient cohort to further elucidate this and inform the genetic testing approach. Methods Fifty‐two adult patients (30 male, 22 female) with epilepsy, at least mild ID and no known genetic or acquired cause were included and phenotyped. Variants identified through exome sequencing were evaluated using ACMG criteria. Identified variants were compared with commercially available gene panels. Cluster analysis of two features, age at seizure onset and age at ascertainment of cognitive deficits, was performed. Results Median age was 27 years (range 20‐57 years) with median seizure onset at 3 years and median ascertainment of cognitive deficits at 1 year. Likely pathogenic/pathogenic variants were identified in 16/52 patients (31%) including 14 (27%) single nucleotide variants and 2 (4%) copy number variants. Simulated yield of commercial gene panels varied between 13% in small (≤144 genes) and 27% in large panels (≥1478 genes). Cluster analysis (optimal number 3 clusters) identified a cluster with early seizure onset and early developmental delay (developmental and epileptic encephalopathy, n = 26), a cluster with early developmental delay but late seizure onset (ID with epilepsy, n = 16) and a third cluster with late ascertainment of cognitive deficits and variable seizure onset (n = 7). The smaller gene panels particularly missed the genes identified in the cluster with early ascertainment of cognitive deficits and later onset of epilepsy (0/4) as opposed to the cluster with developmental and epileptic encephalopathy (7/10). Significance Our data indicates that adult patients with epilepsy and ID represent a heterogeneous cohort that includes grown‐up patients with DEE but also patients with primary ID and later onset of epilepsy. To maximize diagnostic yield in this cohort either large gene panels or exome sequencing should be used.
Published: 2023
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3. The phenotypic and genotypic spectrum of epilepsy and intellectual disability in adults: Implications for genetic testing

Author: Sophie von Brauchitsch, Denise Haslinger, Silvia Lindlar, Holger Thiele, Natalie Bernsen, Felix Zahnert, Philipp S. Reif, Yunus Balcik, Ping Yee Billie Au, Colin B. Josephson, Janine Altmüller, Adam Strzelczyk, Susanne Knake, Felix Rosenow, Andreas Chiocchetti, and Karl Martin Klein
Subjects: Neurology, Neurology (clinical), Technology Platforms
Abstract: OBJECTIVE: The phenotypic and genotypic spectrum of adult patients with epilepsy and intellectual disability (ID) is less clear than in children. We investigated an adult patient cohort to further elucidate this and inform the genetic testing approach. METHODS: Fifty-two adult patients (30 male, 22 female) with epilepsy, at least mild ID and no known genetic or acquired cause were included and phenotyped. Variants identified through exome sequencing were evaluated using ACMG criteria. Identified variants were compared with commercially available gene panels. Cluster analysis of two features, age at seizure onset and age at ascertainment of cognitive deficits, was performed. RESULTS: Median age was 27 years (range 20-57 years) with median seizure onset at 3 years and median ascertainment of cognitive deficits at 1 year. Likely pathogenic/pathogenic variants were identified in 16/52 patients (31%) including 14 (27%) single nucleotide variants and 2 (4%) copy number variants. Simulated yield of commercial gene panels varied between 13% in small (≤144 genes) and 27% in large panels (≥1478 genes). Cluster analysis (optimal number 3 clusters) identified a cluster with early seizure onset and early developmental delay (developmental and epileptic encephalopathy, n=26), a cluster with early developmental delay but late seizure onset (ID with epilepsy, n=16) and a third cluster with late ascertainment of cognitive deficits and variable seizure onset (n=7). The smaller gene panels particularly missed the genes identified in the cluster with early ascertainment of cognitive deficits and later onset of epilepsy (0/4) as opposed to the cluster with developmental and epileptic encephalopathy (7/10). SIGNIFICANCE: Our data indicates that adult patients with epilepsy and ID represent a heterogeneous cohort that includes grown-up patients with DEE but also patients with primary ID and later onset of epilepsy. To maximize diagnostic yield in this cohort either large gene panels or exome sequencing should be used.
Published: 2023

4. Ictal conduction aphasia and ictal angular gyrus syndrome as rare manifestations of epilepsy: The importance of ictal testing during video-EEG monitoring

Author: Johann Philipp Zöllner, Anja Haag, Anke Hermsen, Sebastian Bauer, Friederike Stahl, Karina Wulf, Katja Menzler, Philipp S. Reif, Marlies Wagner, Axel Pagenstecher, Ulrich Sure, Susanne Knake, Felix Rosenow, and Adam Strzelczyk
Subjects: Seizure, Gerstmann's syndrome, Semiology, Acalculia, Left–right disorientation, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: The aim of these two case reports is to demonstrate that a predefined, structured, multimodal clinical bed-side testing during seizures in a long-term video-EEG monitoring setting facilitates diagnosis of complex neuropsychological syndromes. To the best of our knowledge, we present the first case of conduction aphasia as the sole ictal semiology, and a patient with focal seizures producing an angular gyrus syndrome in the speech dominant hemisphere. The relevance of diagnosing ictal aphasic and angular gyrus syndromes and localizing the symptomatogenic zone is discussed. Current pathophysiological concepts are presented regarding conduction aphasia and Gerstmann's syndrome.
Published: 2017
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5. Cutaneous Granulomas in Dolphins Caused by Novel Uncultivated Paracoccidioides brasiliensis

Author: Raquel Vilela, Gregory D. Bossart, Judy A. St. Leger, Leslie M. Dalton, John S. Reif, Adam M. Schaefer, Peter J. McCarthy, Patricia A. Fair, and Leonel Mendoza
Subjects: lacaziosis, lobomycosis, cutaneous granulomas, Lacazia loboi, Paracoccidioides brasiliensis, P. lutzii, Medicine, Infectious and parasitic diseases, RC109-216
Abstract: Cutaneous granulomas in dolphins were believed to be caused by Lacazia loboi, which also causes a similar disease in humans. This hypothesis was recently challenged by reports that fungal DNA sequences from dolphins grouped this pathogen with Paracoccidioides brasiliensis. We conducted phylogenetic analysis of fungi from 6 bottlenose dolphins (Tursiops truncatus) with cutaneous granulomas and chains of yeast cells in infected tissues. Kex gene sequences of P. brasiliensis from dolphins showed 100% homology with sequences from cultivated P. brasiliensis, 73% with those of L. loboi, and 93% with those of P. lutzii. Parsimony analysis placed DNA sequences from dolphins within a cluster with human P. brasiliensis strains. This cluster was the sister taxon to P. lutzii and L. loboi. Our molecular data support previous findings and suggest that a novel uncultivated strain of P. brasiliensis restricted to cutaneous lesions in dolphins is probably the cause of lacaziosis/lobomycosis, herein referred to as paracoccidioidomycosis ceti.
Published: 2016
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6. Drug-Resistant Juvenile Myoclonic Epilepsy: Misdiagnosis of Progressive Myoclonus Epilepsy

Author: Sarah Martin, Adam Strzelczyk, Silvia Lindlar, Kristina Krause, Philipp S. Reif, Katja Menzler, Andreas G. Chiocchetti, Felix Rosenow, Susanne Knake, and Karl Martin Klein
Subjects: epilepsy, genetics, Lafora disease, progressive myoclonus epilepsy, juvenile myoclonic epilepsy, pharmacoresistance, Neurology. Diseases of the nervous system, RC346-429
Abstract: Juvenile myoclonic epilepsy (JME) is a common epilepsy syndrome characterized by bilateral myoclonic and tonic-clonic seizures typically starting in adolescence and responding well to medication. Misdiagnosis of a more severe progressive myoclonus epilepsy (PME) as JME has been suggested as a cause of drug-resistance. Medical records of the Epilepsy Center Hessen-Marburg between 2005 and 2014 were automatically selected using keywords and manually reviewed regarding the presence of a JME diagnosis at any timepoint. The identified patients were evaluated regarding seizure outcome and drug resistance according to ILAE criteria. 87/168 identified JME patients were seizure-free at last follow-up including 61 drug-responsive patients (group NDR). Seventy-eight patients were not seizure-free including 26 drug-resistant patients (group DR). Valproate was the most efficacious AED. The JME diagnosis was revised in 7 patients of group DR including 6 in whom the diagnosis had already been questioned or revised during clinical follow-up. One of these was finally diagnosed with PME (genetically confirmed Lafora disease) based on genetic testing. She was initially reviewed at age 29 yrs and considered to be inconsistent with PME. Intellectual disability (p = 0.025), cognitive impairment (p < 0.001), febrile seizures in first-degree relatives (p = 0.023) and prominent dialeptic seizures (p = 0.009) where significantly more frequent in group DR. Individuals with PME are rarely found among drug-resistant alleged JME patients in a tertiary epilepsy center. Even a very detailed review by experienced epileptologists may not identify the presence of PME before the typical features evolve underpinning the need for early genetic testing in drug-resistant JME patients.
Published: 2019
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7. Comparative Innate and Adaptive Immune Responses in Atlantic Bottlenose Dolphins (Tursiops truncatus) With Viral, Bacterial, and Fungal Infections

Author: Gregory D. Bossart, Tracy A. Romano, Margie M. Peden-Adams, Adam M. Schaefer, Charles D. Rice, Patricia A. Fair, and John S. Reif
Subjects: bottlenose dolphin, Tursiops truncatus, innate immune response, adaptive immune response, infectious disease, Immunologic diseases. Allergy, RC581-607
Abstract: Free-ranging Atlantic bottlenose dolphins (n = 360) from two southeastern U.S. estuarine sites were given comprehensive health examinations between 2003 and 2015 as part of a multi-disciplinary research project focused on individual and population health. The study sites (and sample sizes) included the Indian River Lagoon (IRL), Florida, USA (n = 246) and Charleston harbor and associated rivers (CHS), South Carolina, USA (n = 114). Results of a suite of clinicoimmunopathologic tests revealed that both populations have a high prevalence of infectious and neoplastic disease and a variety of abnormalities of their innate and adaptive immune systems. Subclinical infections with cetacean morbillivirus and Chlamydiaceae were detected serologically. Clinical evidence of orogenital papillomatosis was supported by the detection of a new strain of dolphin papillomavirus and herpesvirus by molecular pathology. Dolphins with cutaneous lobomycosis/lacaziasis were subsequently shown to be infected with a novel, uncultivated strain of Paracoccidioides brasiliensis, now established as the etiologic agent of this enigmatic disease in dolphins. In this review, innate and adaptive immunologic responses are compared between healthy dolphins and those with clinical and/or immunopathologic evidence of infection with these specific viral, bacterial, and fungal pathogens. A wide range of immunologic host responses was associated with each pathogen, reflecting the dynamic and complex interplay between the innate, humoral, and cell-mediated immune systems in the dolphin. Collectively, these studies document the comparative innate and adaptive immune responses to various types of infectious diseases in free-ranging Atlantic bottlenose dolphins. Evaluation of the type, pattern, and degree of immunologic response to these pathogens provides novel insight on disease immunopathogenesis in this species and as a comparative model. Importantly, the data suggest that in some cases infection may be associated with subclinical immunopathologic perturbations that could impact overall individual and population health.
Published: 2019
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8. Endomyometritis caused by HSV-2 in an immunocompromised woman

Author: S Reif, L-C Horn, C Pietsch, A von Braun, B Wolf, B Aktas, and N Dornhöfer
Published: 2022
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9. The environment as a driver of immune and endocrine responses in dolphins (Tursiops truncatus).

Author: Patricia A Fair, Adam M Schaefer, Dorian S Houser, Gregory D Bossart, Tracy A Romano, Cory D Champagne, Jeffrey L Stott, Charles D Rice, Natasha White, and John S Reif
Subjects: Medicine, Science
Abstract: Immune and endocrine responses play a critical role in allowing animals to adjust to environmental perturbations. We measured immune and endocrine related markers in multiple samples from individuals from two managed-care care dolphin groups (n = 82 samples from 17 dolphins and single samples collected from two wild dolphin populations: Indian River Lagoon, (IRL) FL (n = 26); and Charleston, (CHS) SC (n = 19). The immune systems of wild dolphins were more upregulated than those of managed-care-dolphins as shown by higher concentrations of IgG and increases in lysozyme, NK cell function, pathogen antibody titers and leukocyte cytokine transcript levels. Collectively, managed-care care dolphins had significantly lower levels of transcripts encoding pro-inflammatory cytokine TNF, anti-viral MX1 and INFα and regulatory IL-10. IL-2Rα and CD69, markers of lymphocyte activation, were both lower in managed-care care dolphins. IL-4, a cytokine associated with TH2 activity, was lower in managed-care care dolphins compared to the free-ranging dolphins. Differences in immune parameters appear to reflect the environmental conditions under which these four dolphin populations live which vary widely in temperature, nutrition, veterinary care, pathogen/contaminant exposures, etc. Many of the differences found were consistent with reduced pathogenic antigenic stimulation in managed-care care dolphins compared to wild dolphins. Managed-care care dolphins had relatively low TH2 lymphocyte activity and fewer circulating eosinophils compared to wild dolphins. Both of these immunologic parameters are associated with exposure to helminth parasites which is uncommon in managed-care care dolphins. Less consistent trends were observed in a suite of hormones but significant differences were found for cortisol, ACTH, total T4, free T3, and epinephrine. While the underlying mechanisms are likely multiple and complex, the marked differences observed in the immune and endocrine systems of wild and managed-care care dolphins appear to be shaped by their environment.
Published: 2017
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10. Physical fitness and plasma leptin in women with recent gestational diabetes.

Author: C Gar, M Rottenkolber, H Grallert, F Banning, I Freibothe, V Sacco, C Wichmann, S Reif, A Potzel, V Dauber, C Schendell, N N Sommer, B Wolfarth, J Seissler, A Lechner, and U Ferrari
Subjects: Medicine, Science
Abstract: Low physical fitness (PF) is a risk factor for type 2 diabetes mellitus (T2D). Women with a history of gestational diabetes (GDM) are at risk for T2D at a young age, but the role of PF in this population is not clear. PF has also been found to correlate inversely with plasma leptin in previous studies. Here, we examine whether women who had GDM have lower PF than women after a normoglycemic pregnancy and, second, whether PF is associated with plasma leptin, independently of body fat mass.Cross-sectional analysis of 236 participants in the PPSDiab Study (cohort study of women 3-16 months after delivery, 152 after gestational diabetes (pGDM), 84 after normoglycemic pregnancy (control subjects); consecutively recruited 2011-16); medical history, physical examination with bioelectrical impedance analysis (BIA), whole body magnetic resonance imaging (MRI) (n = 154), 5-point oral glucose tolerance test, cardiopulmonary exercise testing, clinical chemistry including fasting plasma leptin; statistical analysis with Mann-Whitney U and t -test, Spearman correlation coefficient, multiple linear regression.Women pGDM had lower maximally achieved oxygen uptake (VO2peak/kg: 25.7(21.3-29.9) vs. 30.0(26.6-34.1)ml/min/kg; total VO2peak: 1733(1552-2005) vs. 1970(1767-2238)ml/min; p
Published: 2017
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11. Natural History Study of STXBP1-Developmental and Epileptic Encephalopathy into Adulthood

Author: Hannah Stamberger, David Crosiers, Ganna Balagura, Claudia M. Bonardi, Anna Basu, Gaetano Cantalupo, Valentina Chiesa, Jakob Christensen, Bernardo Dalla Bernardina, Colin A. Ellis, Francesca Furia, Fiona Gardiner, Camille Giron, Renzo Guerrini, Karl Martin Klein, Christian Korff, Hana Krijtova, Melanie Leffler, Holger Lerche, Gaetan Lesca, David Lewis-Smith, Carla Marini, Dragan Marjanovic, Laure Mazzola, Sarah McKeown Ruggiero, Fanny Mochel, Francis Ramond, Philipp S. Reif, Aurélie Richard-Mornas, Felix Rosenow, Christian Schropp, Rhys H. Thomas, Aglaia Vignoli, Yvonne Weber, Elizabeth Palmer, Ingo Helbig, Ingrid E. Scheffer, Pasquale Striano, Rikke S. Møller, Elena Gardella, and Sarah Weckhuysen
Subjects: Adult, Epilepsy, Movement Disorders, Adolescent, Infant, Electroencephalography, Middle Aged, Young Adult, Munc18 Proteins, Seizures, Activities of Daily Living, Mutation, Humans, Human medicine, Neurology (clinical)
Abstract: Neurology 99(3), e221-e233 (2022). doi:10.1212/WNL.0000000000200715, Published by Wolters Kluwer, Philadelphia, Pa.
Published: 2022
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12. NEXMIF encephalopathy: an X-linked disorder with male and female phenotypic patterns

Author: Zaid Afawi, Shekeeb S. Mohammad, Geoffrey Wallace, Ayelet Zerem, Amy L Schneider, Kyra E. Stuurman, Deepak Gill, Alison M. Muir, Russell C. Dale, Gali Heimer, Martino Montomoli, Elena Gardella, Emmanuelle Ranza, Simone Mandelstam, Peter Procopis, Øyvind L. Busk, Christian Korff, Arjan Bouman, Boudewijn Gunning, Connie T.R.M. Stumpel, Yunus Balcik, Christa de Geus, Philipp S. Reif, Yue-Hua Zhang, Sameer M. Zuberi, Volodymyr Kharytonov, Sébastien Küry, Patrick Edery, Sebastien Moutton, Trine Bjørg Hammer, Hannah Stamberger, Joseph D. Symonds, Gaetan Lesca, Samuel F. Berkovic, Massimiliano Rossi, Danique R.M. Vlaskamp, Eric W. Klee, Mark T Mackay, Felix Rosenow, Erica L. Macke, Chirag Patel, Jacob Bie Granild-Jensen, Helenius J. Schelhaas, Danielle M. Andrade, Lynette G. Sadleir, Iris M de Lange, Roseline Caumes, Eva Morava, Frédéric Tran Mau-Them, Anita Cairns, Keren Yosovich, Jing Zhang, Bruria Ben Zeev, Nicolas Chatron, Dorit Lev, Laura Reed, Pauline Monin, Eva H. Brilstra, Birgitte Bertelsen, Georgie Hollingsworth, Nienke E. Verbeek, Heather C Mefford, Rikke S. Møller, Johan R. Helle, Christina Fenger, Meriel McEntagart, Thomas Smol, Mark F. Bennett, Yuri A. Zarate, Renzo Guerrini, Elena Parrini, Candace T. Myers, Judith S. Verhoeven, Bertrand Isidor, Ruth Shalev, David A. Koolen, Ingrid E. Scheffer, Bobby P. C. Koeleman, Lauren Gunderson, Michael S. Hildebrand, Tara Sadoway, Richard J. Leventer, Sanjay M. Sisodiya, Krati Shah, Edith P. Almanza Fuerte, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Polikliniek (9), Klinische Genetica, and Clinical Genetics
Subjects: Male, Pediatrics, medicine.medical_specialty, INTELLECTUAL DISABILITY, Autism Spectrum Disorder, Encephalopathy, Nerve Tissue Proteins, ILAE COMMISSION, MOSAICISM, Epilepsy/genetics, CLASSIFICATION, Epilepsy, Brain Diseases/genetics, Genes, X-Linked, Seizures, Intellectual disability, Genotype, medicine, Humans, developmental and epileptic encephalopathy, MYOCLONIA, Atonic seizure, Genetics (clinical), Brain Diseases, ddc:618, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], KIAA2022, business.industry, MUTATIONS, medicine.disease, Phenotype, Autism Spectrum Disorder/genetics, Genes, X-Linked/genetics, Autism spectrum disorder, intellectual disability, NEXMIF, Autism, epilepsy, Female, INACTIVATION, Human medicine, Seizures/genetics, business, POSITION PAPER
Abstract: Contains fulltext : 231688.pdf (Publisher’s version ) (Closed access) PURPOSE: Pathogenic variants in the X-linked gene NEXMIF (previously KIAA2022) are associated with intellectual disability (ID), autism spectrum disorder, and epilepsy. We aimed to delineate the female and male phenotypic spectrum of NEXMIF encephalopathy. METHODS: Through an international collaboration, we analyzed the phenotypes and genotypes of 87 patients with NEXMIF encephalopathy. RESULTS: Sixty-three females and 24 males (46 new patients) with NEXMIF encephalopathy were studied, with 30 novel variants. Phenotypic features included developmental delay/ID in 86/87 (99%), seizures in 71/86 (83%) and multiple comorbidities. Generalized seizures predominated including myoclonic seizures and absence seizures (both 46/70, 66%), absence with eyelid myoclonia (17/70, 24%), and atonic seizures (30/70, 43%). Males had more severe developmental impairment; females had epilepsy more frequently, and varied from unaffected to severely affected. All NEXMIF pathogenic variants led to a premature stop codon or were deleterious structural variants. Most arose de novo, although X-linked segregation occurred for both sexes. Somatic mosaicism occurred in two males and a family with suspected parental mosaicism. CONCLUSION: NEXMIF encephalopathy is an X-linked, generalized developmental and epileptic encephalopathy characterized by myoclonic-atonic epilepsy overlapping with eyelid myoclonia with absence. Some patients have developmental encephalopathy without epilepsy. Males have more severe developmental impairment. NEXMIF encephalopathy arises due to loss-of-function variants.
Published: 2021
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13. Algal Bloom–Related Illness: Improving Health Outcomes in Primary Care

Author: Nancy Harris, John S. Reif, Kathi Voege Harvey, Adam M. Schaefer, Diane Esposito, Pamela Alderman, and Shirley C. Gordon
Subjects: Advanced and Specialized Nursing, medicine.medical_specialty, medicine.diagnostic_test, business.industry, fungi, Blue green algae, Physical examination, Primary care, 030204 cardiovascular system & hematology, Health outcomes, Algal bloom, 03 medical and health sciences, Human health, 0302 clinical medicine, medicine, Medical history, 030212 general & internal medicine, Intensive care medicine, business
Abstract: Blue-green algal blooms can be found in fresh and salt waters across the United States as well as globally. Despite growing concern about the impact of cyanotoxins produced by these harmful algae blooms on human health, potential health outcomes are unknown, and there are no clear diagnostic or clinical guidelines for blue-green algal bloom–related illness. Therefore, when patients present with systemic manifestations of exposure, it is critical that clinicians identify the level of contact and systematically document health effects through a thorough patient history and physical examination to elucidate acute and long-term health outcomes. Current knowledge for assessment, treatment, clinical management, and prevention of blue-green algal bloom–related illness is outlined. Interdisciplinary teams of researchers are needed to better understand the health outcomes to improve diagnostics and treatment for providers in primary care.
Published: 2020
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14. Could the 2017 ILAE and the four-dimensional epilepsy classifications be merged to a new 'Integrated Epilepsy Classification'?

Author: André Palmini, Jonathan P. Miller, Giorgio LoRusso, Milan Brázdil, Asim Shahid, Rebecca O'Dwyer, Hajo M. Hamer, Bernhard J. Steinhoff, Kiyohito Terada, Hans Holthausen, Nuria Lacuey, Shi Hui Lim, Américo Ceiki Sakamoto, Hans O. Lüders, Antonio Gil-Nagel, Walter van Emde Boas, Michael Devereaux, Gerhard Kurlemann, Thomas Bast, K Krakow, Susanne Schubert-Bast, Selim R. Benbadis, Susanne Knake, Adriana Bermeo-Ovalle, Stefan Beyenburg, Günter Krämer, Patrick Landazuri, Norman Delanty, Soheyl Noachtar, Jayanti Mani, Luisa V. Londoño, Bettina Schmitz, Andres M. Kanner, Felix Rosenow, Naoki Akamatsu, Jan Rémi, Sebastian Bauer, Christoph Baumgartner, Matthew C. Walker, Alireza Bozorgi, Lauren Ghanma, Stefano Francione, Mar Carreño, John S. Duncan, Naiara García Losarcos, Philippe Kahane, Manuel Toledo, Guadalupe Fernandez-Baca Vaca, Shirin Jamal Omidi, Jun T. Park, Philipp S. Reif, Riki Matsumoto, Stjepana Kovac, Adam Strzelczyk, Peter Widdess-Walsh, Stephan Schuele, C. Ákos Szabó, Giri Kalamangalam, Andrew Bleasel, and Nitin Tandon
Subjects: Epilepsy, Concordance, Headline, General Medicine, medicine.disease, Patient preference, Terminology, 03 medical and health sciences, 0302 clinical medicine, Neurology, Practice Guidelines as Topic, Epilepsy syndromes, medicine, Etiology, Humans, Ictal, Neurology (clinical), Psychology, Societies, Medical, 030217 neurology & neurosurgery, Cognitive psychology
Abstract: Over the last few decades the ILAE classifications for seizures and epilepsies (ILAE-EC) have been updated repeatedly to reflect the substantial progress that has been made in diagnosis and understanding of the etiology of epilepsies and seizures and to correct some of the shortcomings of the terminology used by the original taxonomy from the 1980s. However, these proposals have not been universally accepted or used in routine clinical practice. During the same period, a separate classification known as the "Four-dimensional epilepsy classification" (4D-EC) was developed which includes a seizure classification based exclusively on ictal symptomatology, which has been tested and adapted over the years. The extensive arguments for and against these two classification systems made in the past have mainly focused on the shortcomings of each system, presuming that they are incompatible. As a further more detailed discussion of the differences seemed relatively unproductive, we here review and assess the concordance between these two approaches that has evolved over time, to consider whether a classification incorporating the best aspects of the two approaches is feasible. To facilitate further discussion in this direction we outline a concrete proposal showing how such a compromise could be accomplished, the "Integrated Epilepsy Classification". This consists of five categories derived to different degrees from both of the classification systems: 1) a "Headline" summarizing localization and etiology for the less specialized users, 2) "Seizure type(s)", 3) "Epilepsy type" (focal, generalized or unknown allowing to add the epilepsy syndrome if available), 4) "Etiology", and 5) "Comorbidities & patient preferences".
Published: 2020
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15. Linear skin markings in common bottlenose dolphins ( <scp> Tursiops truncatus </scp> ) from the Indian River Lagoon, Florida

Author: Jessie Stevens, Brandy Nelson, Elizabeth Murdoch Titcomb, Anne Sleeman, Gregory D. Bossart, John S. Reif, Adam M. Schaefer, Luke Yrastorza, and Marilyn Mazzoil
Subjects: Fishery, Geography, Photo identification, Aquatic Science, Ecology, Evolution, Behavior and Systematics
Published: 2020
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16. Assessment of Serum Amyloid A, Haptoglobin, and Protein Electrophoresis in Clinically Healthy and Abnormal Bottlenose Dolphins (Tursiops truncatus)

Author: Sarah Miller, Kevin Roberts, Adam M. Schaefer, Carolyn Cray, Gregory D. Bossart, and John S. Reif
Subjects: Pathology, medicine.medical_specialty, biology, business.industry, Haptoglobin, biology.protein, medicine, Animal Science and Zoology, Serum amyloid A, Aquatic Science, Gel electrophoresis of proteins, business, Nature and Landscape Conservation
Published: 2020
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17. From theory to practice: Critical points in the 2017 ILAE classification of epileptic seizures and epilepsies

Author: André Palmini, Sebastian Bauer, John S. Duncan, Kiyohito Terada, Shirin Jamal Omidi, Nuria Lacuey, Philippe Kahane, Andres M. Kanner, J. Bernhard Steinhoff, Guadalupe Fernandez-Baca Vaca, Stjepana Kovac, Thomas Bast, Naiara García Losarcos, Américo Ceiki Sakamoto, Jayanti Mani, Mar Carreño, Antonio Gil-Nagel, Walter van Emde Boas, Patrick Landazuri, Gerhard Kurlemann, Naoki Akamatsu, Giri Kalamangalam, Andrew Bleasel, Shih-Hui Lim, Norman Delanty, Susanne Knake, Soheyl Noachtar, Hans Holthausen, Hajo M. Hamer, Hans O. Lüders, Selim R. Benbadis, Jan Rémi, Felix Rosenow, Alireza Bozorgi, Jonathan P. Miller, Rebecca O'Dwyer, Giorgio LoRusso, Matthew C. Walker, Adriana Bermeo-Ovalle, Asim Shahid, Adam Strzelczyk, Michael Devereaux, Riki Matsumoto, Lauren Ghanma, Philipp S. Reif, Jun T. Park, Susanne Schubert-Bast, Christoph Baumgartner, Stefan Beyenburg, Peter Widdess-Walsh, Milan Brázdil, Manuel Toledo, Stephan Schuele, C. Ákos Szabó, Guenter Kraemer, and Nitin Tandon
Subjects: medicine.medical_specialty, Epilepsy, MEDLINE, Theory to practice, 16. Peace & justice, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, Neurology, Seizures, 030225 pediatrics, medicine, Humans, Neurology (clinical), Psychology, Psychiatry, International league against epilepsy, 030217 neurology & neurosurgery
Abstract: Dr Fisher and colleagues have recently provided a commentary on our critique of the 2017 International League Against Epilepsy (ILAE) classification of epileptic seizures and epilepsies. The commentary was disappointing in that it did not depart from their original views and suggests a lack of engagement to consider an alternative framework that might improve the ILAE classifications of epileptic seizures and the epilepsies. Epileptologists actively dealing with people with epilepsy must provide feedback and express their views on any official ILAE position, as the latter would only be valid if it succeeds in striking a balance between the perspectives of any ILAE commission and that of the practitioners. It is evident that thoughtful critiques of ILAE position papers can only be forwarded once a text is published and their directions put into use, which is what we did in our critique, in an effort to achieve the best synthesis of accumulated knowledge that could result in a practical, useful, and forward-looking classification of epileptic seizures and the epilepsies.
Published: 2020
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18. Prospective evaluation of interrater agreement between EEG technologists and neurophysiologists

Author: Isabelle Beuchat, Senubia Alloussi, Philipp S. Reif, Nora Sterlepper, Felix Rosenow, and Adam Strzelczyk
Subjects: Adult, Male, Adolescent, Consciousness, Science, Neurophysiology, Medical Overuse, Encephalopathy, Sensitivity and Specificity, Article, Young Adult, Seizures, Medical Laboratory Personnel, Humans, Prospective Studies, ddc:610, Aged, Aged, 80 and over, Observer Variation, Epilepsy, Electroencephalography, Middle Aged, Medicine, Female
Abstract: We aim to prospectively investigate, in a large and heterogeneous population, the electroencephalogram (EEG)-reading performances of EEG technologists. A total of 8 EEG technologists and 5 certified neurophysiologists independently analyzed 20-min EEG recordings. Interrater agreement (IRA) for predefined EEG pattern identification between EEG technologists and neurophysiologits was assessed using percentage of agreement (PA) and Gwet-AC1. Among 1528 EEG recordings, the PA [95% confidence interval] and interrater agreement (IRA, AC1) values were as follows: status epilepticus (SE) and seizures, 97% [96–98%], AC1 kappa = 0.97; interictal epileptiform discharges, 78% [76–80%], AC1 = 0.63; and conclusion dichotomized as “normal” versus “pathological”, 83.6% [82–86%], AC1 = 0.71. EEG technologists identified SE and seizures with 99% [98–99%] negative predictive value, whereas the positive predictive values (PPVs) were 48% [34–62%] and 35% [20–53%], respectively. The PPV for normal EEGs was 72% [68–76%]. SE and seizure detection were impaired in poorly cooperating patients (SE and seizures; p
Published: 2021

19. Fractures in Parkinson’s Disease: injury patterns, hospitalization, and therapeutic aspects

Author: Nils Mühlenfeld, Martin Pieper, Laurent M. Willems, René D. Verboket, Esther Paule, Ingo Marzi, Nicolas Söhling, Adam Strzelczyk, and Philipp S. Reif
Subjects: 030222 orthopedics, medicine.medical_specialty, Sports medicine, business.industry, Osteoporosis, Poison control, 030208 emergency & critical care medicine, Critical Care and Intensive Care Medicine, medicine.disease, Femoral Neck Fractures, Trunk, 03 medical and health sciences, 0302 clinical medicine, Quality of life, Internal medicine, Cohort, Emergency Medicine, Medicine, Orthopedics and Sports Medicine, Surgery, business, Complication
Abstract: The primary aim of this study was to analyze the frequency and characteristic patterns of fall-related fractures as well as consecutive hospitalization and management relating to such fractures. In addition, important pathognomonic and therapeutic aspects are discussed. This retrospective mono-center study was conducted at the University Hospital Frankfurt am Main, Germany. Between 2007 and 2017, a total of 145 PD patients with fall-related fractures were identified via a retrospective systematic query in the hospital information system using the ICD-10 German modification codes G20.0–G20.9. Patients with unclear or falsely coded PD were strictly excluded. The mean age of the cohort was 77.7 years (± 7.5, median 77.) and 57.9% of the cohort were females (n = 84). A total number of 151 fractures were reported, with 140 patients (96.6%) suffering from one, four patients from two (2.8%), and one patient from three fractures (0.6%) at a time. For 43.9% (n = 65) of the cohort, fractures concerned lower extremities (LE) followed by trunk (38.1%, n = 58) and upper extremities (UE, 17.9%, n = 27). Most common fracture types in LE were femoral neck fractures (52.3%, n = 34). Mean length of hospital stay (LOS) was 13.6 days (95% CI 12.4–14.7). In 43.4% (n = 63) of cases, an interim admission to an intensive-care unit (ICU) was necessary. Mean ICU LOS was 2.3 days (95% CI 1.5–3.0), and mean LOS for normal care unit was 10.5 days (95% CI 10.3–12.4). Surgical treatment was necessary in 75.9% of the cases (n = 110). Patients undergoing surgical treatment showed significantly longer LOS compared to conservatively treated patients (p
Published: 2019
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20. Unstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3

Author: Rahel T. Florian, Florian Kraft, Elsa Leitão, Sabine Kaya, Stephan Klebe, Eloi Magnin, Anne-Fleur van Rootselaar, Julien Buratti, Theresa Kühnel, Christopher Schröder, Sebastian Giesselmann, Nikolai Tschernoster, Janine Altmueller, Anaide Lamiral, Boris Keren, Caroline Nava, Delphine Bouteiller, Sylvie Forlani, Ludmila Jornea, Regina Kubica, Tao Ye, Damien Plassard, Bernard Jost, Vincent Meyer, Jean-François Deleuze, Yannick Delpu, Mario D. M. Avarello, Lisanne S. Vijfhuizen, Gabrielle Rudolf, Edouard Hirsch, Thessa Kroes, Philipp S. Reif, Felix Rosenow, Christos Ganos, Marie Vidailhet, Lionel Thivard, Alexandre Mathieu, Thomas Bourgeron, Ingo Kurth, Haloom Rafehi, Laura Steenpass, Bernhard Horsthemke, FAME consortium, Eric LeGuern, Karl Martin Klein, Pierre Labauge, Mark F. Bennett, Melanie Bahlo, Jozef Gecz, Mark A. Corbett, Marina A. J. Tijssen, Arn M. J. M. van den Maagdenberg, and Christel Depienne
Subjects: Science, lcsh:Q, lcsh:Science
Abstract: Familial cortical myoclonic tremor with epilepsy (FAME) is a slowly progressing cortical tremor mapping to various genomic loci, including intronic expansions in SAMD12 for FAME1. Here, Florian et al. describe mixed intronic TTTTA/TTTCA expansions of various lengths in the first intron of MARCH6 as a cause of FAME3.
Published: 2019
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21. Temporal Changes in Antibiotic Resistance Among Bacteria Isolated from Common Bottlenose Dolphins (Tursiops truncatus) in the Indian River Lagoon, Florida, 2003-2015

Author: Tyler Harrington, Patricia A. Fair, Gregory D. Bossart, Peter J. McCarthy, John S. Reif, and Adam M. Schaefer
Subjects: Antibiotic resistance, Zoology, Animal Science and Zoology, Aquatic Science, Biology, biology.organism_classification, Bacteria, Nature and Landscape Conservation
Published: 2019
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22. Seizure management and prescription patterns of anticonvulsants in Dravet syndrome: A multicenter cohort study from Germany and review of literature

Author: Joe Carroll, Arne Herting, Adelheid Wiemer-Kruel, Malin Kalski, Susanne Schubert-Bast, Ulrich Bettendorf, Felix Rosenow, Gerhard Kluger, Matthias Kieslich, Daniel Macdonald, Sarah von Spiczak, Gerhard Kurlemann, Markus Wolff, Bernd A. Neubauer, Philipp S. Reif, Clive Pritchard, Thomas U. Mayer, Adam Strzelczyk, Thomas Bast, Tilman Polster, Karl Martin Klein, Lara Kay, Regina Trollmann, and John Irwin
Subjects: Male, Topiramate, Pediatrics, medicine.medical_specialty, Clobazam, Epilepsies, Myoclonic, Drug Prescriptions, Cohort Studies, 03 medical and health sciences, Behavioral Neuroscience, Epilepsy, 0302 clinical medicine, Dravet syndrome, Seizures, Germany, medicine, Stiripentol, Humans, 030212 general & internal medicine, Medical prescription, business.industry, Valproic Acid, medicine.disease, Neurology, Midazolam, Anticonvulsants, Drug Therapy, Combination, Female, Neurology (clinical), business, 030217 neurology & neurosurgery, medicine.drug, Cohort study
Abstract: Objective The aim of this study was to describe the treatment pattern of patients with Dravet syndrome (DS) in Germany with routine antiepileptic drugs (AEDs) and emergency medication, and to review the literature of real-world evidence on medicine utilization of patients with DS in Europe. Methods Patient use of routine AEDs and emergency medications over 3–6 months was analyzed from a 2018 multicenter survey of 93 caregivers of patients with DS throughout Germany. Results were contextualized in a review of real-world evidence on medicine utilization of patients with DS in Europe. Results The variety of medications and the most frequent combinations routinely used by patients with DS (AEDs and others) are described. Patients use a large number of pharmaceutical treatments to manage seizures. The five most commonly used AEDs were sodium valproate (66% of the patients; mean daily dose: 660 mg; 24.5 mg per kg bodyweight), bromide (44%; 1462 mg; 51.2 mg per kg), clobazam (41%; 10.4 mg; 0.32 mg per kg), stiripentol (35%; 797 mg; 27.6 mg per kg), and topiramate (24%; 107 mg; 3.5 mg per kg). Ninety percent had reported using emergency medications in the last 3 months;, with the most common medications being Buccolam (40%, an oromucosal form of midazolam) and diazepam (20%, mostly rectal application). No discernable relationships between current medication and age or seizure frequency were observed. Significance This is the first comprehensive report of routine AEDs and emergency medication use in a large sample of patients with DS in Germany over a period of 3–6 months and shows that despite the most common AED combinations being in line with clinical guidelines/best practice, there is no discernable impact of best treatment on seizure frequency. We find a higher use of bromide in Germany compared with other real-world evidence in Europe.
Published: 2019
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23. The role of mTOR inhibitors in preventing epileptogenesis in patients with TSC: Current evidence and future perspectives

Author: Matthias Kieslich, Felix Rosenow, Adam Strzelczyk, Karl Martin Klein, Philipp S. Reif, and Susanne Schubert-Bast
Subjects: congenital, hereditary, and neonatal diseases and abnormalities, Epileptogenesis, 03 medical and health sciences, Behavioral Neuroscience, Tuberous sclerosis, Epilepsy, 0302 clinical medicine, Tuberous Sclerosis, 030225 pediatrics, Animals, Humans, Medicine, Mechanistic target of rapamycin, PI3K/AKT/mTOR pathway, Sirolimus, biology, business.industry, TOR Serine-Threonine Kinases, medicine.disease, Discovery and development of mTOR inhibitors, nervous system diseases, Treatment Outcome, medicine.anatomical_structure, Neurology, biology.protein, Anticonvulsants, Neurology (clinical), TSC1, TSC2, business, Neuroscience, 030217 neurology & neurosurgery, Forecasting
Abstract: Tuberous sclerosis complex (TSC) is one of the most common genetic causes of epilepsy. Mutations in the TSC1 or TSC2 genes lead to the dysregulation of the mechanistic target of rapamycin (mTOR) pathway. This mTOR pathway hyperactivation is associated with several processes resulting in epileptic conditions. The occurrence of seizures and their treatment outcomes seem to play a crucial role in cognitive and behavioral developments in patients with TSC. Mechanistic target of rapamycin inhibitors have been proven to be effective in epilepsy treatment in individuals with TSC. Specifically, because of their disease-modifying mechanism of action, they have the capability to prevent epileptogenesis in patients with TSC. This article will provide an overview of the current evidence of and delineate future perspectives for mTOR inhibitors and their role in preventing epileptogenesis.
Published: 2019
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24. Genomic sequencing of a virus representing a novel type within the species Dyopipapillomavirus 1 in an Indian River Lagoon bottlenose dolphin

Author: Kuttichantran Subramaniam, Stephen D. McCulloch, James F. X. Wellehan, Eric Delwart, John S. Reif, Adam M. Schaefer, Thomas B. Waltzek, Terry Fei Fan Ng, Patricia A. Fair, Juli D. Goldstein, Gregory D. Bossart, and Galaxia Cortés-Hinojosa
Subjects: Phocoena, Genomics, Genome, Viral Proteins, 03 medical and health sciences, Rivers, Virology, medicine, Animals, Papillomaviridae, Phylogeny, 030304 developmental biology, Genomic organization, Whole genome sequencing, 0303 health sciences, biology, Contig, 030306 microbiology, General Medicine, biology.organism_classification, Bottlenose dolphin, medicine.disease, Bottle-Nosed Dolphin, Tumor Virus Infections, Florida, Papilloma, Female
Abstract: Fecal samples collected from free-ranging Atlantic bottlenose dolphins (BDs) in the Indian River Lagoon of Florida were processed for viral discovery using a next-generation sequencing (NGS) approach. A 693-bp contig identified in the NGS data was nearly identical to the partial L1 gene sequence of a papillomavirus (PV) previously found in a penile papilloma in a killer whale (Orcinus orca). Based on this partial bottlenose dolphin papillomavirus (BDPV) sequence, a nested inverse PCR and primer-walking strategy was employed to generate the complete genome sequence. The full BDPV genome consisted of 7299 bp and displayed a typical PV genome organization. The BDPV E6 protein contained a PDZ-binding motif, which has been shown to be involved in carcinogenic transformation involving high-risk genital human PVs. Screening of 12 individual fecal samples using a specific endpoint PCR assay revealed that the feces from a single female BD displaying a genital papilloma was positive for the BDPV. Genetic analysis indicated that this BDPV (Tursiops truncatus papillomavirus 8; TtPV8) is a new type of Dyopipapillomavirus 1, previously sequenced from an isolate obtained from a penile papilloma in a harbor porpoise (Phocoena phocoena). Although only a partial L1 sequence has been determined for a PV detected in a killer whale genital papilloma, our finding of a nearly identical sequence in an Atlantic BD may indicate that members of this viral species are capable of host jumping. Future work is needed to determine if this virus is a high-risk PV that is capable of inducing carcinogenic transformation and whether it poses a significant health risk to wild delphinid populations.
Published: 2019
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25. Spitzes Graphoelement: epilepsietypisch oder Normvariante?

Author: Esther Paule, Laurent M. Willems, Philipp S. Reif, Adam Strzelczyk, and Felix Rosenow
Subjects: 03 medical and health sciences, 0302 clinical medicine, Physiology (medical), 05 social sciences, 0501 psychology and cognitive sciences, Neurology (clinical), 030217 neurology & neurosurgery, 050105 experimental psychology, Pathology and Forensic Medicine
Abstract: Zusammenfassung Trotz zunehmender Automatisierung elektrophysiologischer Diagnostikverfahren in der Medizin stutzt sich die Analyse elektroenzephalographischer Kurven in der Routinediagnostik weiterhin uberwiegend auf visuelle Mustererkennung und deren Interpretation. Besondere Schwierigkeiten konnen hierbei im Rahmen der Differenzierung steil akzentuierter Potentialmuster entstehen und deren Einteilung in Artefakte, Normvarianten oder pathologische Aktivitat, die die Grundlage einer jeden Befundung darstellt. Dieser Ubersichtartikel hat das Ziel haufige steil konfigurierte Graphoelemente darzustellen und deren jeweilige Charakteristika zu beschreiben, wobei sowohl auf physiologische Transienten, als auch auf Graphoelemente unklarer Signifikanz sowie epilepsietypische Potentiale eingegangen wird.
Published: 2018
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26. Spectrum of Phenotypic, Genetic, and Functional Characteristics in Patients With Epilepsy With

Author: Niklas, Schwarz, Simone, Seiffert, Manuela, Pendziwiat, Annika Verena, Rademacher, Tobias, Brünger, Ulrike B S, Hedrich, Paul B, Augustijn, Hartmut, Baier, Allan, Bayat, Francesca, Bisulli, Russell J, Buono, Ben Zeev, Bruria, Michael G, Doyle, Renzo, Guerrini, Gali, Heimer, Michele, Iacomino, Hugh, Kearney, Karl Martin, Klein, Ioanna, Kousiappa, Wolfram S, Kunz, Holger, Lerche, Laura, Licchetta, Ebba, Lohmann, Raffaella, Minardi, Marie, McDonald, Sarah, Montgomery, Lejla, Mulahasanovic, Renske, Oegema, Barel, Ortal, Savvas S, Papacostas, Francesca, Ragona, Tiziana, Granata, Phillip S, Reif, Felix, Rosenow, Annick, Rothschild, Paolo, Scudieri, Pasquale, Striano, Paolo, Tinuper, George A, Tanteles, Annalisa, Vetro, Felix, Zahnert, Ethan M, Goldberg, Federico, Zara, Dennis, Lal, Patrick, May, Hiltrud, Muhle, Ingo, Helbig, and Yvonne, Weber
Subjects: Epilepsy, Phenotype, Shaw Potassium Channels, Seizures, Exome Sequencing, Humans, Epilepsy, Generalized
Abstract: Individuals withWe identified novelThese findings implicate
Published: 2021

27. Heterozygous variants in KCNC2 cause a broad spectrum of epilepsy phenotypes associated with characteristic functional alterations

Author: Manuela Pendziwiat, Renske Oegema, Ioanna Kousiappa, Yvonne G. Weber, Francesca Ragona, Dennis Lal, Ulrike B. S. Hedrich, Mulahasanovic L, Gali Heimer, Kearney H, Hiltrud Muhle, Pasquale Striano, Paolo Scudieri, Annika Rademacher, Rothschild A, Michele Iacomino, Lohmann E, Augustijn Pb, Russell J. Buono, Holger Lerche, Philipp S. Reif, George A. Tanteles, Karl Martin Klein, Bayat A, Francesca Bisulli, Wolfram S. Kunz, Montgomery S, Bruria Bz, Papacostas Ss, Renzo Guerrini, Laura Licchetta, Ingo Helbig, Bruenger T, Federico Zara, Zahnert F, Marie T. McDonald, Hartmut Baier, Patrick May, Niklas Schwarz, Doyle Mg, Simone Seiffert, Vetro A, Paolo Tinuper, Ortal B, Tiziana Granata, Felix Rosenow, and Raffaella Minardi
Subjects: Genetics, Valproic Acid, Broad spectrum, Epilepsy, biology, Xenopus, medicine, Causative gene, biology.organism_classification, medicine.disease, Phenotype, Exome sequencing, medicine.drug
Abstract: BackgroundKCNC2 encodes a member of the shaw-related voltage-gated potassium channel family (KV3.2), which are important for sustained high-frequency firing and optimized energy efficiency of action potentials in the brain.MethodsIndividuals with KCNC2 variants detected by exome sequencing were selected for clinical, further genetic and functional analysis. The cases were referred through clinical and research collaborations in our study. Four de novo variants were examined electrophysiologically in Xenopus laevis oocytes.ResultsWe identified novel KCNC2 variants in 27 patients with various forms of epilepsy. Functional analysis demonstrated gain-of-function in severe and loss-of-function in milder phenotypes as the underlying pathomechanisms with specific response to valproic acid.ConclusionThese findings implicate KCNC2 as a novel causative gene for epilepsy emphasizing the critical role of KV3.2 in the regulation of brain excitability with an interesting genotype-phenotype correlation and a potential concept for precision medicine.
Published: 2021
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28. Distinct gene-set burden patterns underlie common generalized and focal epilepsies

Author: Mahmoud Koko, Roland Krause, Thomas Sander, Dheeraj Reddy Bobbili, Michael Nothnagel, Patrick May, Holger Lerche, Yen-Chen Anne Feng, Daniel P Howrigan, Liam E Abbott, Katherine Tashman, Felecia Cerrato, Tarjinder Singh, Henrike Heyne, Andrea Byrnes, Claire Churchhouse, Nick Watts, Matthew Solomonson, Dennis Lal, Erin L Heinzen, Ryan S Dhindsa, Kate E Stanley, Gianpiero L Cavalleri, Hakon Hakonarson, Ingo Helbig, Sarah Weckhuysen, Slavé Petrovski, Sitharthan Kamalakaran, Sanjay M Sisodiya, Patrick Cossette, Chris Cotsapas, Peter DeJonghe, Tracy Dixon-Salazar, Renzo Guerrini, Patrick Kwan, Anthony G Marson, Randy Stewart, Chantal Depondt, Dennis J Dlugos, Ingrid E Scheffer, Pasquale Striano, Catharine Freyer, Kevin McKenna, Brigid M Regan, Susannah T Bellows, Costin Leu, Caitlin A Bennett, Esther M C Johns, Alexandra Macdonald, Hannah Shilling, Rosemary Burgess, Dorien Weckhuysen, Melanie Bahlo, Terence J O'Brien, Marian Todaro, Hannah Stamberger, Danielle M Andrade, Tara R Sadoway, Kelly Mo, Heinz Krestel, Sabina Gallati, Savvas S Papacostas, Ioanna Kousiappa, George A Tanteles, Katalin Štěrbová, Markéta Vlčková, Lucie Sedláčková, Petra Laššuthová, Karl Martin Klein, Felix Rosenow, Philipp S Reif, Susanne Knake, Wolfram S Kunz, Gábor Zsurka, Christian E Elger, Jürgen Bauer, Michael Rademacher, Manuela Pendziwiat, Hiltrud Muhle, Annika Rademacher, Andreas vanBaalen, Sarah vonSpiczak, Ulrich Stephani, Zaid Afawi, Amos D Korczyn, Moien Kanaan, Christina Canavati, Gerhard Kurlemann, Karen Müller-Schlüter, Gerhard Kluger, Martin Häusler, Ilan Blatt, Johannes R Lemke, Ilona Krey, Yvonne G Weber, Stefan Wolking, Felicitas Becker, Christian Hengsbach, Sarah Rau, Ana F Maisch, Bernhard J Steinhoff, Andreas Schulze-Bonhage, Susanne Schubert-Bast, Herbert Schreiber, Ingo Borggräfe, Christoph J Schankin, Thomas Mayer, Rudolf Korinthenberg, Knut Brockmann, Dieter Dennig, Rene Madeleyn, Reetta Kälviäinen, Pia Auvinen, Anni Saarela, Tarja Linnankivi, Anna-Elina Lehesjoki, Mark I Rees, Seo-Kyung Chung, William O Pickrell, Robert Powell, 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, Nina Barišić, Norman Delanty, Colin P Doherty, Arif Shukralla, Mark McCormack, Hany El-Naggar, Laura Canafoglia, Silvana Franceschetti, Barbara Castellotti, Tiziana Granata, Federico Zara, Michele Iacomino, Francesca Madia, Maria Stella Vari, Maria Margherita Mancardi, Vincenzo Salpietro, Francesca Bisulli, Paolo Tinuper, Laura Licchetta, Tommaso Pippucci, Carlotta Stipa, Raffaella Minardi, Antonio Gambardella, Angelo Labate, Grazia Annesi, Lorella Manna, Monica Gagliardi, Elena Parrini, Davide Mei, Annalisa Vetro, Claudia Bianchini, Martino Montomoli, Viola Doccini, Carla Marini, Toshimitsu Suzuki, Yushi Inoue, Kazuhiro Yamakawa, Birute Tumiene, Lynette G Sadleir, Chontelle King, Emily Mountier, Hande S Caglayan, Mutluay Arslan, Zuhal Yapıcı, Uluc Yis, Pınar Topaloglu, Bulent Kara, Dilsad Turkdogan, Aslı Gundogdu-Eken, Nerses Bebek, Sibel Uğur-İşeri, Betül Baykan, Barış Salman, Garen Haryanyan, Emrah Yücesan, Yeşim Kesim, Çiğdem Özkara, Annapurna Poduri, Beth R Shiedley, Catherine Shain, Russell J Buono, Thomas N Ferraro, Michael R Sperling, Warren Lo, Michael Privitera, Jacqueline A French, Steven Schachter, Ruben I Kuzniecky, Orrin Devinsky, Manu Hegde, Pouya Khankhanian, Katherine L Helbig, Colin A Ellis, Gianfranco Spalletta, Fabrizio Piras, Federica Piras, Tommaso Gili, Valentina Ciullo, Andreas Reif, Andrew McQuillin, Nick Bass, Andrew McIntosh, Douglas Blackwood, Mandy Johnstone, Aarno Palotie, Michele T Pato, Carlos N Pato, Evelyn J Bromet, Celia Barreto Carvalho, Eric D Achtyes, Maria Helena Azevedo, Roman Kotov, Douglas S Lehrer, Dolores Malaspina, Stephen R Marder, Helena Medeiros, Christopher P Morley, Diana O Perkins, Janet L Sobell, Peter F Buckley, Fabio Macciardi, Mark H Rapaport, James A Knowles, Genomic Psychiatry Cohort, Ayman H Fanous, Steven A McCarroll, Namrata Gupta, Stacey B Gabriel, Mark J Daly, Eric S Lander, Daniel H Lowenstein, David B Goldstein, Samuel F Berkovic, Benjamin M Neale, Epi25 Collaborative, Koko M., Krause R., Sander T., Bobbili D.R., Nothnagel M., May P., Lerche H., Bisulli F., Tinuper P., Pippucci T., Abbott, Liam E., Hengsbach, Christian, Rau, Sarah, Maisch, Ana F., Steinhoff, Bernhard J., Schulze-Bonhage, Andreas, Schubert-Bast, Susanne, Schreiber, Herbert, Borggräfe, Ingo, Schankin, Christoph J., Mayer, Thomas, Tashman, Katherine, Korinthenberg, Rudolf, Brockmann, Knut, Kurlemann, Gerhard, Dennig, Dieter, Madeleyn, Rene, Kälviäinen, Reetta, Auvinen, Pia, Saarela, Anni, Linnankivi, Tarja, Lehesjoki, Anna-Elina, Cerrato, Felecia, Rees, Mark I., Chung, Seo-Kyung, Pickrell, William O., Powell, Robert, Schneider, Natascha, Balestrini, Simona, Zagaglia, Sara, Braatz, Vera, Johnson, Michael R., Auce, Pauls, Singh, Tarjinder, Sills, Graeme J., Baum, Larry W., Sham, Pak C., Cherny, Stacey S., Lui, Colin H. T., Barišic, Nina, Delanty, Norman, Doherty, Colin P., Shukralla, Arif, McCormack, Mark, Heyne, Henrike, El-Naggar, Hany, Canafoglia, Laura, Franceschetti, Silvana, Castellotti, Barbara, Granata, Tiziana, Zara, Federico, Iacomino, Michele, Madia, Francesca, Vari, Maria Stella, Mancardi, Maria Margherita, Byrnes, Andrea, Salpietro, Vincenzo, Bisulli, Francesca, Tinuper, Paolo, Licchetta, Laura, Pippucci, Tommaso, Stipa, Carlotta, Minardi, Raffaella, Gambardella, Antonio, Labate, Angelo, Annesi, Grazia, Churchhouse, Claire, Manna, Lorella, Gagliardi, Monica, Parrini, Elena, Mei, Davide, Vetro, Annalisa, Bianchini, Claudia, Montomoli, Martino, Doccini, Viola, Marini, Carla, Suzuki, Toshimitsu, Watts, Nick, Inoue, Yushi, Yamakawa, Kazuhiro, Tumiene, Birute, Sadleir, Lynette G., King, Chontelle, Mountier, Emily, Caglayan, Hande S., Arslan, Mutluay, Yapici, Zuhal, Yis, Uluc, Solomonson, Matthew, Topaloglu, Pinar, Kara, Bulent, Turkdogan, Dilsad, Gundogdu-Eken, Asli, Bebek, Nerses, Ugur-Iseri, Sibel, Baykan, Betül, Salman, Baris, Haryanyan, Garen, Yücesan, Emrah, Lal, Dennis, Kesim, Yesim, Özkara, Çigdem, Poduri, Annapurna, Shiedley, Beth R., Shain, Catherine, Buono, Russell J., Ferraro, Thomas N., Sperling, Michael R., Lo, Warren, Privitera, Michael, Heinzen, Erin L., French, Jacqueline A., Schachter, Steven, Kuzniecky, Ruben I., Devinsky, Orrin, Hegde, Manu, Khankhanian, Pouya, Helbig, Katherine L., Ellis, Colin A., Spalletta, Gianfranco, Piras, Fabrizio, Dhindsa, Ryan S., Piras, Federica, Gili, Tommaso, Ciullo, Valentina, Reif, Andreas, McQuillin, Andrew, Bass, Nick, McIntosh, Andrew, Blackwood, Douglas, Johnstone, Mandy, Palotie, Aarno, Stanley, Kate E., Pato, Michele T., Pato, Carlos N., Bromet, Evelyn J., Carvalho, Celia Barreto, Achtyes, Eric D., Azevedo, Maria Helena, Kotov, Roman, Lehrer, Douglas S., Malaspina, Dolores, Marder, Stephen R., Cavalleri, Gianpiero L., Medeiros, Helena, Morley, Christopher P., Perkins, Diana O., Sobell, Janet L., Buckley, Peter F., Macciardi, Fabio, Rapaport, Mark H., Knowles, James A., Cohort, Genomic Psychiatry, Fanous, Ayman H., Hakonarson, Hakon, McCarroll, Steven A., Gupta, Namrata, Gabriel, Stacey B., Daly, Mark J., Lander, Eric S., Lowenstein, Daniel H., Goldstein, David B., Lerche, Holger, Berkovic, Samuel F., Neale, Benjamin M., Helbig, Ingo, Krause, Roland, May, Patrick, Weckhuysen, Sarah, Petrovski, Slavé, Kamalakaran, Sitharthan, Sisodiya, Sanjay M., Cossette, Patrick, Cotsapas, Chris, DeJonghe, Peter, Dixon-Salazar, Tracy, Guerrini, Renzo, Kwan, Patrick, Marson, Anthony G., Stewart, Randy, Depondt, Chantal, Dlugos, Dennis J., Scheffer, Ingrid E., Striano, Pasquale, Freyer, Catharine, McKenna, Kevin, Regan, Brigid M., Bellows, Susannah T., Leu, Costin, Bennett, Caitlin A., Johns, Esther M. C., Macdonald, Alexandra, Shilling, Hannah, Burgess, Rosemary, Weckhuysen, Dorien, Bahlo, Melanie, O'Brien, Terence J., Todaro, Marian, Stamberger, Hannah, Andrade, Danielle M., Sadoway, Tara R., Mo, Kelly, Krestel, Heinz, Gallati, Sabina, Papacostas, Savvas S., Kousiappa, Ioanna, Tanteles, George A., Šterbová, Katalin, Vlcková, Markéta, Sedlácková, Lucie, Laššuthová, Petra, Klein, Karl Martin, Rosenow, Felix, Reif, Philipp S., Knake, Susanne, Kunz, Wolfram S., Zsurka, Gábor, Elger, Christian E., Bauer, Jürgen, Rademacher, Michael, Feng, Yen-Chen Anne, Pendziwiat, Manuela, Muhle, Hiltrud, Rademacher, Annika, van Baalen, Andreas, von Spiczak, Sarah, Stephani, Ulrich, Afawi, Zaid, Korczyn, Amos D., Kanaan, Moien, Canavati, Christina, Howrigan, Daniel P., Müller-Schlüter, Karen, Kluger, Gerhard, Häusler, Martin, Blatt, Ilan, Lemke, Johannes R., Krey, Ilona, Weber, Yvonne G., Wolking, Stefan, Becker, Felicitas, DFG Research Unit FOR-2715 (Germany), FNR (Luxembourg), NHGRI (US), NHLBI (US), DAAD (Germany). [sponsor], and Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center]
Subjects: Exome sequencing, Male, Medicine (General), Neurology [D14] [Human health sciences], Gene-set, Genome-wide association study, Disease, Biology, Epileptogenesis, General Biochemistry, Genetics and Molecular Biology, Whole Exome Sequencing, Epilepsy, R5-920, medicine, Missense mutation, Humans, Exome, Genetic Predisposition to Disease, Gene, Genetic association, Ultra-rare variant, Genetics, Neurologie [D14] [Sciences de la santé humaine], Burden analysis, Genetic Variation, General Medicine, medicine.disease, Ultra-rare variants, Gene-sets, Case-Control Studies, Medicine, epilepsy, Epilepsy, Generalized, Female, Genetics & genetic processes [F10] [Life sciences], Epilepsies, Partial, Human medicine, Burden analysi, Génétique & processus génétiques [F10] [Sciences du vivant], Case-Control Studie, Research Paper, Genome-Wide Association Study, Human
Abstract: EBioMedicine 72, 103588 (2021). doi:10.1016/j.ebiom.2021.103588, Published by Elsevier, Amsterdam [u.a.]
Published: 2021
Full Text: View/download PDF

29. 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
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30. Real-life survey of pitfalls and successes of precision medicine in genetic epilepsies

Author: Susanne Schubert-Bast, Yvonne G. Weber, Simona Balestrini, Sanjay M. Sisodiya, Cheryl Hemingway, Ingo Borggraefe, Antonietta Coppola, Anna Rosati, Martino Montomoli, Philipp S. Reif, Pasquale Striano, Rikke S. Møller, Felix Rosenow, Katri Silvennoinen, Davide Mei, Serena Troisi, Clinda Puvirajasinghe, Renzo Guerrini, Carla Marini, Antonella Riva, Karl Martin Klein, Holger Lerche, Maria Gogou, Daniela Chiarello, Wendy D Jones, Federico Zara, J. Helen Cross, Balestrini, S, Chiarello, D, Gogou, M, Silvennoinen, K, Puvirajasinghe, C, Jones, Wd, Reif, P, Klein, Km, Rosenow, F, Weber, Yg, Lerche, H, Schubert-Bast, S, Borggraefe, I, Coppola, A, Troisi, S, Møller, R, Riva, A, Striano, P, Zara, F, Hemingway, C, Marini, C, Rosati, A, Mei, D, Montomoli, M, Guerrini, R, Cross, Jh, and Sisodiya, Sm.
Subjects: Adult, Male, medicine.medical_specialty, Adolescent, High variability, MEDLINE, Disease, 03 medical and health sciences, Epilepsy, Young Adult, 0302 clinical medicine, medicine, Humans, ddc:610, Precision Medicine, Intensive care medicine, Child, 030304 developmental biology, Genetic testing, Aged, Retrospective Studies, 0303 health sciences, medicine.diagnostic_test, business.industry, Infant, Middle Aged, medicine.disease, Precision medicine, 3. Good health, Psychiatry and Mental health, Molecular Diagnostic Techniques, Child, Preschool, Cohort, Surgery, Observational study, Female, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract: Journal of neurology, neurosurgery, and psychiatry 92(10), 1044-1052 (2021). doi:10.1136/jnnp-2020-325932, Published by BMJ Publishing Group, London
Published: 2020
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31. DIagnostic Subdural EEG electrodes And Subdural hEmatoma (DISEASE): a study protocol for a prospective nonrandomized controlled trial

Author: Felix Rosenow, Eva Herrmann, Volker Seifert, Elke Hattingen, Juergen Konczalla, Adam Strzelczyk, Philipp S. Reif, Sae-Yeon Won, Thomas M. Freiman, and Daniel Dubinski
Subjects: medicine.medical_specialty, Neurology, Clinical Trial Protocol, Status epilepticus, Electroencephalography, lcsh:RC346-429, lcsh:RC321-571, law.invention, 03 medical and health sciences, Subdural hematoma, 0302 clinical medicine, Invasive EEG monitoring, Randomized controlled trial, Modified Rankin Scale, law, medicine, 030212 general & internal medicine, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, lcsh:Neurology. Diseases of the nervous system, Outcome, medicine.diagnostic_test, business.industry, Glasgow Outcome Scale, Seizure, Clinical trial, Anesthesia, Subdural strip electrode, Neurosurgery, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: Background Epileptic seizures are common clinical features in patients with acute subdural hematoma (aSDH); however, diagnostic feasibility and therapeutic monitoring remain limited. Surface electroencephalography (EEG) is the major diagnostic tool for the detection of seizures but it might be not sensitive enough to detect all subclinical or nonconvulsive seizures or status epilepticus. Therefore, we have planned a clinical trial to evaluate a novel treatment modality by perioperatively implanting subdural EEG electrodes to diagnose seizures; we will then treat the seizures under therapeutic monitoring and analyze the clinical benefit. Methods In a prospective nonrandomized trial, we aim to include 110 patients with aSDH. Only patients undergoing surgical removal of aSDH will be included; one arm will be treated according to the guidelines of the Brain Trauma Foundation, while the other arm will additionally receive a subdural grid electrode. The study’s primary outcome is the comparison of incidence of seizures and time-to-seizure between the interventional and control arms. Invasive therapeutic monitoring will guide treatment with antiseizure drugs (ASDs). The secondary outcome will be the functional outcome for both groups as assessed via the Glasgow Outcome Scale and modified Rankin Scale both at discharge and during 6 months of follow-up. The tertiary outcome will be the evaluation of chronic epilepsy within 2–4 years of follow-up. Discussion The implantation of a subdural EEG grid electrode in patients with aSDH is expected to be effective in diagnosing seizures in a timely manner, facilitating treatment with ASDs and monitoring of treatment success. Moreover, the occurrence of epileptiform discharges prior to the manifestation of seizure patterns could be evaluated in order to identify high-risk patients who might benefit from prophylactic treatment with ASDs. Trial registration ClinicalTrials.gov identifier no. NCT04211233.
Published: 2020

32. Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies

Author: Christian E. Elger, Wolfgang Lieb, Claudia B. Catarino, Pasquale Striano, Andreja Avbersek, Daniel H. Lowenstein, Philip E. M. Smith, G. Neil Thomas, Dick Lindhout, Erin L. Heinzen, Sanjay M. Sisodiya, Orrin Devinsky, Alexander R. H. Smith, Rainer Surges, Stefan Wolking, Patrick Cossette, Annapurna Poduri, Eric B. Geller, Stacey S. Cherny, Maria Stella Vari, Peter De Jonghe, Kevin Haas, Andres Ingason, Reetta Kälviäinen, Krishna Chinthapalli, Dennis Lal, Graeme J. Sills, Martina Moerzinger, Jonathan P. Bradfield, Mark R Newton, Federico Zara, Sheryl R. Haut, Warren D. Lo, Holger Lerche, Felix Rosenow, Robert C. Knowlton, Mark McCormack, Sarah Rau, Felicitas Becker, Andre Franke, Heidi E. Kirsch, Patrick Kwan, Remi Stevelink, Rodney A. Radtke, Michele Iacomino, Faith Pangilinan, Ulrich Stephani, David F. Smith, Eva M. Reinthaler, Chantal Depondt, Hiltrud Muhle, Russell J. Buono, Alison J. Coffey, Ellen Campbell, Marvin Johnson, Bernhard J. Steinhoff, Sarah von Spiczak, Yvonne G. Weber, Ping-Wing Ng, Kerstin Hallmann, Philipp S. Reif, David Goldstein, Bettina Schmitz, Antonietta Coppola, Jerry J. Shih, Karen Oliver, Anne-Mari Kantanen, Rossana Tozzi, Markus Wolff, Albert J. Becker, Anne M. Molloy, Lisa Slattery, James L. Mills, Judith L.Z. Weisenberg, Jacqueline A. French, Lawrence C. Brody, Int League Against Epilepsy Conso, Peter Widdess-Walsh, Helle Hjalgrim, Christian Hengsbach, Christoph J. Schankin, Johan G. Eriksson, Tracy A. Glauser, Yu-Lung Lau, Larry Baum, Anna-Elina Lehesjoki, Nicole M. Walley, Josemir W. Sander, Markus M. Noethen, Simon Glynn, Jennifer Jamnadas-Khoda, Thomas Bast, Susanne Schoch, Iscia Lopes-Cendes, Doug Speed, Anja C M Sonsma, John Craig, Ingo Helbig, Marian Todaro, Gregory D. Cascino, Steven C. Schachter, Fritz Zimprich, Samuel F. Berkovic, Michael Privitera, Ben Francis, Martin Krenn, Rikke S. Møller, Eileen P.G. Vining, Martha Feucht, Bobby P. C. Koeleman, Ruben Kuzniecky, Christian Gieger, K. Meng Tan, Dalia Kasperaviciute, Pauls Auce, Gianpiero L. Cavalleri, Melanie Bahlo, Zhi Wei, Nasir Mirza, David J. Balding, Mike Smith, Liu Lin Thio, Alastair Compston, Katja E. Boysen, Gerrit-Jan de Haan, Hongsheng Gui, Hakon Hakonarson, Christopher D. Whelan, Colin P. Doherty, Youling Guo, Aarno Palotie, Wolfram S. Kunz, Slavé Petrovski, Thomas Sander, Frank Visscher, Bianca Berghuis, Costin Leu, Verena Gaus, Dennis J. Dlugos, Ingrid E. Scheffer, Alberto Malovini, Konstantin Strauch, Wanling Yang, Saskia Freytag, H. Stroink, Pak C. Sham, Norman Delanty, Terence J. O'Brien, Carolien G.F. de Kovel, Thomas U. Mayer, Anthony G Marson, Bassel Abou-Khalil, Thomas N. Ferraro, Dorothée G.A. Kasteleijn-Nolst Trenité, Roland Krause, Sarah Peter, Peter Nuernberg, Theresa Scattergood, Michael R. Sperling, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Clinicum, Department of Medical and Clinical Genetics, Medicum, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, Int League Against Epilepsy Conso, Abou-Khalil, Bassel, Auce, Paul, Avbersek, Andreja, Bahlo, Melanie, J Balding, David, Bast, Thoma, Baum, Larry, J Becker, Albert, Becker, Felicita, Berghuis, Bianca, F Berkovic, Samuel, E Boysen, Katja, P Bradfield, Jonathan, C Brody, Lawrence, J Buono, Russell, Campbell, Ellen, D Cascino, Gregory, B Catarino, Claudia, L Cavalleri, Gianpiero, S Cherny, Stacey, Chinthapalli, Krishna, J Coffey, Alison, Compston, Alastair, Coppola, Antonietta, Cossette, Patrick, J Craig, John, de Haan, Gerrit-Jan, De Jonghe, Peter, F de Kovel, Carolien G, Delanty, Norman, Depondt, Chantal, Devinsky, Orrin, J Dlugos, Denni, P Doherty, Colin, E Elger, Christian, G Eriksson, Johan, N Ferraro, Thoma, Feucht, Martha, Francis, Ben, Franke, Andre, A French, Jacqueline, Freytag, Saskia, Gaus, Verena, B Geller, Eric, Gieger, Christian, Glauser, Tracy, Glynn, Simon, B Goldstein, David, Gui, Hongsheng, Guo, Youling, F Haas, Kevin, Hakonarson, Hakon, Hallmann, Kerstin, Haut, Sheryl, L Heinzen, Erin, Helbig, Ingo, Hengsbach, Christian, Hjalgrim, Helle, Iacomino, Michele, Ingason, André, Jamnadas-Khoda, Jennifer, R Johnson, Michael, Kälviäinen, Reetta, Kantanen, Anne-Mari, Kasperavičiūte, Dalia, Kasteleijn-Nolst Trenite, Dorothee, E Kirsch, Heidi, C Knowlton, Robert, C Koeleman, Bobby P, Krause, Roland, Krenn, Martin, S Kunz, Wolfram, Kuzniecky, Ruben, Kwan, Patrick, Lal, Denni, Lau, Yu-Lung, Lehesjoki, Anna-Elina, Lerche, Holger, Leu, Costin, Lieb, Wolfgang, Lindhout, Dick, D Lo, Warren, Lopes-Cendes, Iscia, H Lowenstein, Daniel, Malovini, Alberto, G Marson, Anthony, Mayer, Thoma, Mccormack, Mark, L Mills, Jame, Mirza, Nasir, Moerzinger, Martina, S Møller, Rikke, M Molloy, Anne, Muhle, Hiltrud, Newton, Mark, Ng, Ping-Wing, M Nöthen, Marku, Nürnberg, Peter, J O'Brien, Terence, L Oliver, Karen, Palotie, Aarno, Pangilinan, Faith, Peter, Sarah, Petrovski, Slavé, Poduri, Annapurna, Privitera, Michael, Radtke, Rodney, Rau, Sarah, S Reif, Philipp, M Reinthaler, Eva, Rosenow, Felix, W Sander, Josemir, Sander, Thoma, Scattergood, Theresa, C Schachter, Steven, J Schankin, Christoph, E Scheffer, Ingrid, Schmitz, Bettina, Schoch, Susanne, C Sham, Pak, J Shih, Jerry, J Sills, Graeme, M Sisodiya, Sanjay, Slattery, Lisa, Smith, Alexander, F Smith, David, C Smith, Michael, E Smith, Philip, M Sonsma, Anja C, Speed, Doug, R Sperling, Michael, J Steinhoff, Bernhard, Stephani, Ulrich, Stevelink, Remi, Strauch, Konstantin, Striano, Pasquale, Stroink, Han, Surges, Rainer, Meng Tan, K, Lin Thio, Liu, Neil Thomas, G, Todaro, Marian, Tozzi, Rossana, S Vari, Maria, G Vining, Eileen P, Visscher, Frank, von Spiczak, Sarah, M Walley, Nicole, G Weber, Yvonne, Wei, Zhi, Weisenberg, Judith, D Whelan, Christopher, Widdess-Walsh, Peter, Wolff, Marku, Wolking, Stefan, Yang, Wanling, Zara, Federico, Zimprich, Fritz, Wellcome Trust, GlaxoSmithKline Services Unlimited, Commission of the European Communities, Medical Research Council (MRC), and Imperial College Healthcare NHS Trust- BRC Funding
Subjects: 0301 basic medicine, Linkage disequilibrium, LD SCORE REGRESSION, Neurology [D14] [Human health sciences], General Physics and Astronomy, Genome-wide association study, ILAE COMMISSION, Neurodegenerative, Genome, Linkage Disequilibrium, Epilepsy, Gene Frequency, Missing heritability problem, 2.1 Biological and endogenous factors, Aetiology, lcsh:Science, International League Against Epilepsy Consortium on Complex Epilepsies, Multidisciplinary, Genetic Predisposition to Disease/genetics, Chromosome Mapping, ASSOCIATION, Epilepsy/classification, Single Nucleotide, ABSENCE, 3. Good health, Technologie de l'environnement, contrôle de la pollution, SNP HERITABILITY, Neurological, Genome-Wide Association Study/methods, Case-Control Studie, Engineering sciences. Technology, Human, Biotechnology, EXPRESSION, SUSCEPTIBILITY LOCI, Genotype, Science, Quantitative Trait Loci, 610 Medicine & health, Computational biology, Biology, Quantitative trait locus, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Article, GENETIC ARCHITECTURE, 03 medical and health sciences, MD Multidisciplinary, medicine, Genetics, SNP, Chimie, FRONTAL-LOBE, Humans, Genetic Predisposition to Disease, Polymorphism, METAANALYSIS, Neurologie [D14] [Sciences de la santé humaine], Physique, Human Genome, Neurosciences, General Chemistry, Astronomie, medicine.disease, Genetic architecture, Brain Disorders, 030104 developmental biology, Gene Expression Regulation, Case-Control Studies, epilepsy, lcsh:Q, 3111 Biomedicine, Quantitative Trait Loci/genetics, Genome-Wide Association Study
Abstract: The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 individuals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel. Using various prioritization criteria, we pinpoint the 21 most likely epilepsy genes at these loci, with the majority in genetic generalized epilepsies. These genes have diverse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin-B6 metabolism enzyme. Converging evidence shows that the common variants associated with epilepsy play a role in epigenetic regulation of gene expression in the brain. The results show an enrichment for monogenic epilepsy genes as well as known targets of antiepileptic drugs. Using SNP-based heritability analyses we disentangle both the unique and overlapping genetic basis to seven different epilepsy subtypes. Together, these findings provide leads for epilepsy therapies based on underlying pathophysiology., SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2018
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33. Telecritical Care Clinical and Operational Strategies in Response to COVID-19

Author: Nehal P. Thakkar, Michael B. Green, Scott Lindblom, Michael S. Reif, Alfred Papali, and Jaspal Singh
Subjects: Telemedicine, Surge Capacity, Critical Care, business.industry, Staffing, Intensivist, COVID-19, Health Informatics, General Medicine, Intensive Care Units, Resource (project management), Health Information Management, Software deployment, Workforce, Health care, Humans, Operations management, Business, Delivery of Health Care, Pandemics
Abstract: Background: The cororavirus disease 19 (COVID-19) pandemic has strained intensive care unit (ICU) material and human resources to global crisis levels. The risks of staffing challenges and clinician exposure are of significant concern. One resource, telecritical care (TCC), has the potential to optimize efficiency, maximize safety, and improve quality of care provided amid large-scale disruptions, but its role in pandemic situations is only loosely defined. Planning and Preparation Phase: We propose strategic initiatives by which TCC may act as a force multiplier for pandemic preparedness in response to COVID-19, utilizing a tiered approach for increasing surge capacity needs. The goals involved usage of TCC to augment ICU capacity, optimize safety, minimize personal protective equipment (PPE) use, improve efficiencies, and enhance knowledge of managing pandemic response. Implementation Phase: A phased approach utilizing TCC would involve implementing remote capabilities across the enterprise to accomplish the goals outlined. The hardware and software needed for initial expansion to cover 275 beds included $956,670 for mobile carts and $173,106 for home workstations. Team role deployment and bedside clinical care centering around TCC as critical care capacity expand beyond 275 beds. Surge capacity was not reached during early phases of the pandemic in the region, allowing refinement of TCC during subsequent pandemic phases. Conclusions: Leveraging TCC facilitated pandemic surge planning but required redefinition of typical ICU staffing models. The design was meant to workforce efficiencies, reduce PPE use, and minimize health care worker exposure risk, all while maintaining quality care standards through an intensivist-led model. As health care operations resumed and states reopened, TCC is being used to support shifts in volume and critical care personnel during the pandemic evolution. The lessons applied may help health care systems through variable phases of the pandemic.
Published: 2020

34. Analysis of shared common genetic risk between amyotrophic lateral sclerosis and epilepsy

Author: Schijven, D., Stevelink, R., Mccormack, M., van Rheenen, W., Luykx, J. J., Koeleman, B. P. C., Veldink, J. H., Aleksey, Shatunov, Mclaughlin, Russell L., van der Spek, Rick A. A., Alfredo, Iacoangeli, Kenna, Kevin P., van Eijk, Kristel R., Nicola, Ticozzi, Boris, Rogelj, Katarina, Vrabec, Metka, Ravnik-Glavač, Blaž, Koritnik, Janez, Zidar, Lea, Leonardis, Leja Dolenc Grošelj, Stéphanie, Millecamps, François, Salachas, Vincent, Meininger, Mamede de Carvalho, Susana, Pinto, Marta, Gromicho, Ana, Pronto-Laborinho, Mora, Jesus S., Ricardo, Rojas-García, Meraida, Polak, Siddharthan, Chandran, Shuna, Colville, Robert, Swingler, Morrison, Karen E., Shaw, Pamela J., John, Hardy, Orrell, Richard W., Alan, Pittman, Katie, Sidle, Pietro, Fratta, Andrea, Malaspina, Simon, Topp, Susanne, Petri, Susanna, Abdulla, Carsten, Drepper, Michael, Sendtner, Thomas, Meyer, Ophoff, Roel A., Staats, Kim A., Martina, Wiedau-Pazos, Catherine, Lomen-Hoerth, Van Deerlin, Vivianna M., Trojanowski, John Q., Lauren, Elman, Leo, Mccluskey, Nazli Basak, A., Thomas, Meitinger, Peter, Lichtner, Milena, Blagojevic-Radivojkov, Andres, Christian R., Gilbert, Bensimon, Bernhard, Landwehrmeyer, Alexis, Brice, Payan, Christine A. M., Safaa, Saker-Delye, Alexandra, Dürr, Wood, Nicholas W., Lukas, Tittmann, Wolfgang, Lieb, Andre, Franke, Marcella, Rietschel, Sven, Cichon, Nöthen, Markus M., Philippe, Amouyel, Christophe, Tzourio, Jean-François, Dartigues, Uitterlinden, Andre G., Fernando, Rivadeneira, Karol, Estrada, Albert, Hofman, Charles, Curtis, van der Kooi, Anneke J., Markus, Weber, Shaw, Christopher E., Smith, Bradley N., Daisy, Sproviero, Cristina, Cereda, Mauro, Ceroni, Luca, Diamanti, Roberto Del Bo, Stefania, Corti, Comi, Giacomo P., Sandra, D'Alfonso, Lucia, Corrado, Bertolin, Cinzia, Soraru', Gianni, Letizia, Mazzini, Viviana, Pensato, Cinzia, Gellera, Cinzia, Tiloca, Antonia, Ratti, Andrea, Calvo, Cristina, Moglia, Maura, Brunetti, Simona, Arcuti, Rosa, Capozzo, Chiara, Zecca, Christian, Lunetta, Silvana, Penco, Nilo, Riva, Alessandro, Padovani, Massimiliano, Filosto, Ian, Blair, Nicholson, Garth A., Rowe, Dominic B., Roger, Pamphlett, Kiernan, Matthew C., Julian, Grosskreutz, Witte, Otto W., Robert, Steinbach, Tino, Prell, Beatrice, Stubendorff, Ingo, Kurth, Hübner, Christian A., Nigel Leigh, P., Federico, Casale, Adriano, Chio, Ettore, Beghi, Elisabetta, Pupillo, Rosanna, Tortelli, Giancarlo, Logroscino, John, Powell, Ludolph, Albert C., Weishaupt, Jochen H., Wim, Robberecht, Philip Van Damme, Brown, Robert H., Glass, Jonathan D., Landers, John E., Orla, Hardiman, Andersen, Peter M., Philippe, Corcia, Patrick, Vourc'H, Vincenzo, Silani, van Es, Michael A., Jeroen Pasterkamp, R., Lewis, Cathryn M., Gerome, Breen, Ammar, Al-Chalabi, van den Berg, Leonard H., Veldink, Jan H., Daniela, Calini, Isabella, Fogh, Barbara, Castellotti, Franco, Taroni, Stella, Gagliardi, Giacomo, Comi, Sandra, D’Alfonso, Pegoraro, Elena, Giorgia, Querin, Francesca, Gerardi, Fabrizio, Rinaldi, Maria Sofia Cotelli, Luca, Chiveri, Maria Cristina Guaita, Patrizia, Perrone, Giancarlo, Comi, Carlo, Ferrarese, Lucio, Tremolizzo, Marialuisa, Delodovici, Giorgio, Bono, Stefania, Cammarosano, Antonio, Canosa, Dario, Cocito, Leonardo, Lopiano, Luca, Durelli, Bruno, Ferrero, Antonio, Bertolotto, Alessandro, Mauro, Luca, Pradotto, Roberto, Cantello, Enrica, Bersano, Dario, Giobbe, Maurizio, Gionco, Daniela, Leotta, Lucia, Appendino, Cavallo, Cavallo, Enrico, Odddenino, Claudio, Geda, Fabio, Poglio, Paola, Santimaria, Umberto, Massazza, Antonio, Villani, Roberto, Conti, Fabrizio, Pisano, Mario, Palermo, Franco, Vergnano, Paolo, Provera, Maria Teresa Penza, Marco, Aguggia, Nicoletta Di Vito, Piero, Meineri, Ilaria, Pastore, Paolo, Ghiglione, Danilo, Seliak, Nicola, Launaro, Giovanni, Astegiano, Bottacchi, Edo, Isabella Laura Simone, Stefano, Zoccolella, Michele, Zarrelli, Franco, Apollo, William, Camu, Jean Sebastien Hulot, Francois, Viallet, Philippe, Couratier, David, Maltete, Christine, Tranchant, Marie, Vidailhet, Bassel, Abou-Khalil, Pauls, Auce, Andreja, Avbersek, Melanie, Bahlo, David, J Balding, Thomas, Bast, Larry, Baum, Albert, J Becker, Felicitas, Becker, Bianca, Berghuis, Samuel, F Berkovic, Katja, E Boysen, Jonathan, P Bradfield, Lawrence, C Brody, Russell, J Buono, Ellen, Campbell, Gregory, D Cascino, Claudia, B Catarino, Gianpiero, L Cavalleri, Stacey, S Cherny, Krishna, Chinthapalli, Alison, J Coffey, Alastair, Compston, Antonietta, Coppola, Patrick, Cossette, John, J Craig, Gerrit-Jan de Haan, Peter De Jonghe, Carolien G, F de Kovel, Norman, Delanty, Chantal, Depondt, Orrin, Devinsky, Dennis, J Dlugos, Colin, P Doherty, Christian, E Elger, Johan, G Eriksson, Thomas, N Ferraro, Martha, Feucht, Ben, Francis, Jacqueline, A French, Saskia, Freytag, Verena, Gaus, Eric, B Geller, Christian, Gieger, Tracy, Glauser, Simon, Glynn, David, B Goldstein, Hongsheng, Gui, Youling, Guo, Kevin, F Haas, Hakon, Hakonarson, Kerstin, Hallmann, Sheryl, Haut, Erin, L Heinzen, Ingo, Helbig, Christian, Hengsbach, Helle, Hjalgrim, Michele, Iacomino, Andrés, Ingason, Michael, R Johnson, Reetta, Kälviäinen, Anne-Mari, Kantanen, Dalia, Kasperavičiūte, Dorothee Kasteleijn-Nolst Trenite, Heidi, E Kirsch, Robert, C Knowlton, Bobby P, C Koeleman, Roland, Krause, Martin, Krenn, Wolfram, S Kunz, Ruben, Kuzniecky, Patrick, Kwan, Dennis, Lal, Yu-Lung, Lau, Anna-Elina, Lehesjoki, Holger, Lerche, Costin, Leu, Dick, Lindhout, Warren, D Lo, Iscia, Lopes-Cendes, Daniel, H Lowenstein, Alberto, Malovini, Anthony, G Marson, Thomas, Mayer, Mark, Mccormack, James, L Mills, Nasir, Mirza, Martina, Moerzinger, Rikke, S Møller, Anne, M Molloy, Hiltrud, Muhle, Mark, Newton, Ping-Wing, Ng, Markus, M Nöthen, Peter, Nürnberg, Terence, J O’Brien, Karen, L Oliver, Aarno, Palotie, Faith, Pangilinan, Sarah, Peter, Slavé, Petrovski, Annapurna, Poduri, Michael, Privitera, Rodney, Radtke, Sarah, Rau, Philipp, S Reif, Eva, M Reinthaler, Felix, Rosenow, Josemir, W Sander, Thomas, Sander, Theresa, Scattergood, Steven, C Schachter, Christoph, J Schankin, Ingrid, E Scheffer, Bettina, Schmitz, Susanne, Schoch, Pak, C Sham, Jerry, J Shih, Graeme, J Sills, Sanjay, M Sisodiya, Lisa, Slattery, Alexander, Smith, David, F Smith, Michael, C Smith, Philip, E Smith, Anja C, M Sonsma, Doug, Speed, Michael, R Sperling, Bernhard, J Steinhoff, Ulrich, Stephani, Remi, Stevelink, Konstantin, Strauch, Pasquale, Striano, Hans, Stroink, Rainer, Surges, K Meng Tan, Liu Lin Thio, G Neil Thomas, Marian, Todaro, Rossana, Tozzi, Maria, S Vari, Eileen P, G Vining, Frank, Visscher, Sarah von Spiczak, Nicole, M Walley, Yvonne, G Weber, Zhi, Wei, Judith, Weisenberg, Christopher, D Whelan, Peter, Widdess-Walsh, Markus, Wolff, Stefan, Wolking, Wanling, Yang, Federico, Zara, Fritz, Zimprich, Project MinE ALS GWAS Consortium, International League Against Epilepsy Consortium on Complex Epilepsies, Department of Medical and Clinical Genetics, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, Clinicum, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, and HUS Helsinki and Uusimaa Hospital District
Subjects: Risk, 0301 basic medicine, Aging, Genetic correlation, Geriatrics & Gerontology, education, Genome-wide association study, Biology, ALS, Epilepsy, Amyotrophic Lateral Sclerosis, Gene Frequency, Humans, Genetic Variation, Genome-Wide Association Study, Negative Results, Article, 3124 Neurology and psychiatry, 03 medical and health sciences, 0302 clinical medicine, Genetic variation, medicine, Amyotrophic lateral sclerosis, Allele frequency, Genetics, Science & Technology, Mechanism (biology), General Neuroscience, 3112 Neurosciences, Neurosciences, medicine.disease, 3. Good health, Minor allele frequency, 030104 developmental biology, Neurology (clinical), Neurosciences & Neurology, Geriatrics and Gerontology, Life Sciences & Biomedicine, 030217 neurology & neurosurgery, Developmental Biology
Abstract: Because hyper-excitability has been shown to be a shared pathophysiological mechanism, we used the latest and largest genome-wide studies in amyotrophic lateral sclerosis (n = 36,052) and epilepsy (n = 38,349) to determine genetic overlap between these conditions. First, we showed no significant genetic correlation, also when binned on minor allele frequency. Second, we confirmed the absence of polygenic overlap using genomic risk score analysis. Finally, we did not identify pleiotropic variants in meta-analyses of the 2 diseases. Our findings indicate that amyotrophic lateral sclerosis and epilepsy do not share common genetic risk, showing that hyper-excitability in both disorders has distinct origins. ispartof: NEUROBIOLOGY OF AGING vol:92 ispartof: location:United States status: published
Published: 2020
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35. Prone, lateral, or supine positioning at seizure onset determines the postictal body position: A multicenter video-EEG monitoring cohort study

Author: Marc-Philipp Bergmann, Philipp S. Reif, Laurent M. Willems, Susanne Knake, Katharina Mahr, Lara Kay, Katja Menzler, Adam Strzelczyk, Karl Martin Klein, Leona Möller, Felix Rosenow, Johann Philipp Zöllner, and Susanne Schubert-Bast
Subjects: medicine.medical_specialty, Supine position, business.industry, General Medicine, Odds ratio, medicine.disease, Sitting, Confidence interval, 03 medical and health sciences, Epilepsy, Prone position, Position (obstetrics), 0302 clinical medicine, Neurology, Internal medicine, mental disorders, medicine, Cardiology, Neurology (clinical), business, psychological phenomena and processes, 030217 neurology & neurosurgery, Cohort study
Abstract: Most patients who die from sudden unexpected death in epilepsy (SUDEP) are found in the prone position. We evaluated whether changes in body position occur during generalized convulsive seizures (GCSs).GCSs in patients undergoing video-EEG-monitoring between 2007 and 2017 at epilepsy centers in Frankfurt and Marburg were analyzed in relation to changes in body position.A total of 494 GCSs were analyzed among 327 patients. At seizure onset, positions included supine (48.2 %), right lateral (19.0 %), left lateral (15.6 %), sitting or standing (14.0 %), and prone (3.2 %). Between seizure onset and the start of generalization, 57.5 % of participants altered body positions. During four seizures, patients adopted a prone position, while, in five seizures, patients moved from a prone position. Patients who experienced GCS onset while in a nonprone position had a 2.1 % risk of entering the prone position by the end of their seizure. In contrast, 56.2 % of those in an initial prone position remained so at the end of the GCS, with an odds ratio for maintaining that position of 60.2 (95 % confidence interval: 29.1-124.3; p0.001). The likelihood of ending up in the prone position post-GCS did not vary among patients with different nonprone starting positions (p = 0.147).Seizures in prone position occur during sleep and the highest risk for postictal prone positioning appears to be being in the prone position at GCS onset. Epilepsy patients should therefore be advised to go to sleep in a supine or lateral position to reduce their SUDEP risk.
Published: 2020

36. Genetische Epilepsien

Author: Karl Martin Klein and Philipp S. Reif
Published: 2020
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37. Genetische Diagnostik

Author: Karl Martin Klein and Philipp S. Reif
Published: 2020
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38. Detection of cortical malformations using enhanced synthetic contrast images derived from quantitative T1 maps

Author: René-Maxime Gracien, Elke Hattingen, Michelle Maiworm, Philipp S. Reif, Ulrike Nöth, Susanne Knake, Ralf Deichmann, and Marlies Wagner
Subjects: Adult, Male, media_common.quotation_subject, Contrast Media, 030218 nuclear medicine & medical imaging, White matter, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Nuclear magnetic resonance, Cortical abnormalities, medicine, Image Processing, Computer-Assisted, Contrast (vision), Humans, Radiology, Nuclear Medicine and imaging, ddc:610, Perivascular space, Gray Matter, Spectroscopy, media_common, Physics, Brain Mapping, Pixel, Cortical malformations, Middle Aged, Magnetic Resonance Imaging, White Matter, Hyperintensity, Malformations of Cortical Development, medicine.anatomical_structure, Molecular Medicine, Female, Cortical thickening, 030217 neurology & neurosurgery
Abstract: The detection of cortical malformations in conventional MR images can be challenging. Prominent examples are focal cortical dysplasias (FCD), the most common cause of drug-resistant focal epilepsy. The two main MRI hallmarks of cortical malformations are increased cortical thickness and blurring of the gray (GM) and white matter (WM) junction. The purpose of this study was to derive synthetic anatomies from quantitative T1 maps for the improved display of the above imaging characteristics in individual patients. On the basis of a T1 map, a mask comprising pixels with T1 values characteristic for GM is created from which the local cortical extent (CE) is determined. The local smoothness (SM) of the GM-WM junctions is derived from the T1 gradient. For display of cortical malformations, the resulting CE and SM maps serve to enhance local intensities in synthetic double inversion recovery (DIR) images calculated from the T1 map. The resulting CE- and/or SM-enhanced DIR images appear hyperintense at the site of cortical malformations, thus facilitating FCD detection in epilepsy patients. However, false positives may arise in areas with naturally elevated CE and/or SM, such as large GM structures and perivascular spaces. In summary, the proposed method facilitates the detection of cortical abnormalities such as cortical thickening and blurring of the GM-WM junction which are typical FCD markers. Still, subject motion artifacts, perivascular spaces, and large normal GM structures may also yield signal hyperintensity in the enhanced synthetic DIR images, requiring careful comparison with clinical MR images by an experienced neuroradiologist to exclude false positives.
Published: 2019

39. Use of Emergency Medication in Adult Patients with Epilepsy: A Multicentre Cohort Study from Germany

Author: Ilka Immisch, Katja Menzler, Sebastian Bauer, Adam Strzelczyk, Karl Martin Klein, Felix Rosenow, Susanne Knake, Anke Hermsen, Philipp S. Reif, Jeannette Kadel, and Lara Kay
Subjects: Pediatrics, medicine.medical_specialty, business.industry, Sedation, Lorazepam, Status epilepticus, medicine.disease, 03 medical and health sciences, Psychiatry and Mental health, Epilepsy, 0302 clinical medicine, medicine, Outpatient clinic, Midazolam, Pharmacology (medical), 030212 general & internal medicine, Neurology (clinical), medicine.symptom, Adverse effect, business, 030217 neurology & neurosurgery, Cohort study, medicine.drug
Abstract: Emergency treatment with benzodiazepines is indicated in prolonged seizures, seizure clusters and status epilepticus. The aim of this study was to evaluate the use of emergency medication in adult patients with epilepsy. All adult epilepsy patients attending the epilepsy outpatient clinics of the university hospitals in Frankfurt and Marburg in 2015 were asked to participate in this questionnaire-based, retrospective survey. A total of 481 patients with a mean age of 43.4 years (range 18–94 years, 54% female) participated in the study. Among them, 134 patients (27.9%) reported on the prescription of an emergency medication during the last year. Patients receiving emergency medication were younger and exhibited a lower age at epilepsy onset, a higher seizure frequency and a higher number of regularly taken antiepileptic drugs. The most frequently taken emergency drugs were oral lorazepam tablets (65.7%; n = 88 out of 134), followed by buccal midazolam (23.9%, n = 32) and rectal diazepam (17.9%, n = 24). The most common indications for administering the emergency medication were seizures continuing for several minutes (35.1%, n = 47), but almost the same number of patients (33.6%, n = 45) stated that the rescue medication was given during or after every seizure. Regarding adverse events, sedation was named as a major (18.7%, n = 25) or moderate (29.1%; n = 39) problem by a substantial number of patients. Difficulties in administration were reported by 17 (13%) patients. Two-thirds assessed the efficacy of their emergency medication as good (50.7%, n = 68) or as very good (15.7%, n = 21). For multivariate logistic regression analysis, aspects such as young age at onset, active epilepsy, structural etiology, presence of generalised tonic–clonic seizures, past medical history of status epilepticus and living with another person independently predicted prescription of emergency medication. In most cases, unsuitable benzodiazepines with slow absorption due to oral administration were prescribed, or buccal midazolam solution was used off-label in adults. Furthermore, inappropriate use of emergency medication at every seizure was reported by a substantial number of participating patients.
Published: 2018
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40. Dolphin Sightings in the Vicinity of Land/Ocean Biogeochemical Observatories: Relationships with Weather and Water Quality

Author: Mackenzie Daniel, Elizabeth Murdoch Titcomb, Dennis Hanisak, Adam M. Schaefer, Marilyn Mazzoil, Tyler Harrington, and John S. Reif
Subjects: Biogeochemical cycle, Oceanography, Environmental science, Animal Science and Zoology, Water quality, Aquatic Science, Nature and Landscape Conservation
Published: 2018
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41. Use of brivaracetam in genetic generalized epilepsies and for acute, intravenous treatment of absence status epilepticus

Author: Bernhard J. Steinhoff, Felix Rosenow, Susanne Schubert-Bast, Gerhard Kurlemann, Sebastian Bauer, Ilka Immisch, Alexander B. Kowski, Rhina Kunz, Lara Kay, Susanne Knake, Philipp S. Reif, Adam Strzelczyk, Laurent M. Willems, Lisa Langenbruch, Karl Martin Klein, Gabriel Möddel, Karen Müller-Schlüter, Isabel Steinig, and Felix von Podewils
Subjects: Adult, Male, medicine.medical_specialty, Adolescent, Status epilepticus, Brivaracetam, Cohort Studies, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Product Surveillance, Postmarketing, medicine, Humans, 030212 general & internal medicine, Child, Adverse effect, Aged, Aged, 80 and over, business.industry, Retrospective cohort study, Middle Aged, medicine.disease, Pyrrolidinones, Treatment Outcome, Neurology, Tolerability, Injections, Intravenous, Anticonvulsants, Epilepsy, Generalized, Female, Neurology (clinical), Levetiracetam, medicine.symptom, Juvenile myoclonic epilepsy, business, Myoclonus, 030217 neurology & neurosurgery, medicine.drug
Abstract: Objective The objective of this study was to evaluate effectiveness, retention, and tolerability of brivaracetam (BRV) in genetic generalized epilepsies (GGE) in clinical practice. Methods A multicenter, retrospective cohort study recruiting all patients that started BRV in 2016 and 2017. Results A total of 61 patients (mean age = 29.8, range = 9-90 years, 41 female [67%]) were treated with BRV. They were difficult to control, with 2.4 failed antiepileptic drugs (AEDs) in the past, taking 1.9 AEDs on average at baseline. The length of exposure to BRV ranged from 7 days to 24 months, with a mean retention time of 7.9 months, resulting in a total exposure time to BRV of 483 months. The retention rate was 82% at 3 months and 69% at 6 months. Efficacy at 3 months was 36% (50% responder rate), with 25% seizure-free for 3 months. Patients with juvenile myoclonic epilepsy showed a responder rate of 60%, with 40% being free of any seizures. Long-term 50% responder rate was present in 17 patients (28%; 11 seizure-free [18%]) for >6 months and in 14 patients (23%; 10 seizure-free [16%]) for >12 months. Treatment-emergent adverse events were observed in 26% of the patients, with the most common being somnolence, ataxia, and psychobehavioral adverse events. Use of intravenous BRV with bolus injection of 200-300 mg in two females with absence status epilepticus was well tolerated, but did not result in cessation of status epilepticus. Significance Use of BRV in GGE is well tolerated, and 50% responder rates are similar to those observed in the regulatory trials for focal epilepsies. An immediate switch from levetiracetam (LEV) to BRV at a ratio of 15:1 is feasible. The occurrence of psychobehavioral adverse events seems less prominent than under LEV, and a switch to BRV can be considered in patients with LEV-induced adverse events.
Published: 2018
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42. Psychogene nichtepileptische Anfälle

Author: Laurent M. Willems, Adam Strzelczyk, Philipp S. Reif, Felix Rosenow, and Karl Martin Klein
Subjects: 0301 basic medicine, medicine.medical_specialty, Pediatrics, business.industry, Video electroencephalography, Semiology, medicine.disease, 03 medical and health sciences, Epilepsy, 030104 developmental biology, 0302 clinical medicine, Physiology (medical), Psychogenic non-epileptic seizures, Medicine, Psychogenic disease, Medical diagnosis, Differential diagnosis, Cardiology and Cardiovascular Medicine, business, 030217 neurology & neurosurgery
Abstract: Psychogenic nonepileptic seizures (PNES) are to be considered in the differential diagnosis of a transient loss of consciousness. Their discrimination from syncope, epileptic seizures or vascular events can be difficult and requires profound knowledge about the semiology and clinical presentation of PNES and their differential diagnoses. Erroneous diagnoses and the resulting therapies lead to elevated morbidity, elevated costs and a poorer outcome. The aim of the present article is to provide an overview on PNES and their delineation from the clinical pictures of epilepsy and syncope.
Published: 2018
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43. Deficient testosterone levels in men above 45 years with major depressive disorder - an age-matched case control study

Author: A M Dikobe, C W van Staden, S Reif, and M Bornman
Subjects: Psychiatry, RC435-571
Abstract: Background. Symptoms of partial androgen deficiency in ageing men (PADAM) overlap considerably with those of major depressive disorder. The relationship between these conditions is complicated by the usual age-related decline in serum testosterone concentrations. Objectives. To test the hypothesis that depressed men above 45 years of age have lower serum testosterone concentrations than age-matched controls. Method. Serum testosterone fractions of 20 men above the age of 45 years suffering from a major depressive disorder were compared with those of 20 healthy men. An age-matched controlled design was used to account for the usual age-related decline in serum testosterone concentrations. Results. Testosterone concentrations of men suffering from a major depressive disorder were statistically significantly lower than those of an age-matched control group without depression. Conclusion. The role of testosterone deficiency in depressed men needs to be examined further in order for appropriate treatment options to be developed.
Published: 2007
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44. Personalized translational epilepsy research — Novel approaches and future perspectives

Author: Anke Hermsen, Sebastian Bauer, Karl-Heinz Plate, Joachim P. Steinbach, Natascha van Alphen, Christine M. Freitag, Peter Jedlicka, Yvonne Reiss, Stephan W. Schwarzacher, Braxton A. Norwood, Adam Strzelczyk, Susanne Knake, Andreas Reif, Frederic von Wegner, Andreas G. Chiocchetti, Stephanie Schorge, Christian A. Kell, Stefan Liebner, Philipp S. Reif, Albert J. Becker, Thomas M. Freiman, Jochen Roeper, Johannes Gehrig, Michael W. Ronellenfitsch, Matthew C. Walker, Jochen Triesch, Dimitri M. Kullmann, Felix Rosenow, Diana Omigie, Karl Martin Klein, Thomas Deller, Marlies Wagner, Gerhard Schratt, and Ralf Deichmann
Subjects: 0301 basic medicine, medicine.diagnostic_test, business.industry, Context (language use), Translational research, Disease, Electroencephalography, Precision medicine, medicine.disease, 3. Good health, 03 medical and health sciences, Behavioral Neuroscience, Epilepsy, 030104 developmental biology, 0302 clinical medicine, Neurology, Neuroimaging, Medicine, Neurology (clinical), Personalized medicine, business, Neuroscience, 030217 neurology & neurosurgery
Abstract: Despite the availability of more than 15 new "antiepileptic drugs", the proportion of patients with pharmacoresistant epilepsy has remained constant at about 20-30%. Furthermore, no disease-modifying treatments shown to prevent the development of epilepsy following an initial precipitating brain injury or to reverse established epilepsy have been identified to date. This is likely in part due to the polyetiologic nature of epilepsy, which in turn requires personalized medicine approaches. Recent advances in imaging, pathology, genetics, and epigenetics have led to new pathophysiological concepts and the identification of monogenic causes of epilepsy. In the context of these advances, the First International Symposium on Personalized Translational Epilepsy Research (1st ISymPTER) was held in Frankfurt on September 8, 2016, to discuss novel approaches and future perspectives for personalized translational research. These included new developments and ideas in a range of experimental and clinical areas such as deep phenotyping, quantitative brain imaging, EEG/MEG-based analysis of network dysfunction, tissue-based translational studies, innate immunity mechanisms, microRNA as treatment targets, functional characterization of genetic variants in human cell models and rodent organotypic slice cultures, personalized treatment approaches for monogenic epilepsies, blood-brain barrier dysfunction, therapeutic focal tissue modification, computational modeling for target and biomarker identification, and cost analysis in (monogenic) disease and its treatment. This report on the meeting proceedings is aimed at stimulating much needed investments of time and resources in personalized translational epilepsy research. This Part II includes the experimental and translational approaches and a discussion of the future perspectives, while the diagnostic methods, EEG network analysis, biomarkers, and personalized treatment approaches were addressed in Part I [1].
Published: 2017
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45. Personalized translational epilepsy research — Novel approaches and future perspectives

Author: Andreas G. Chiocchetti, Christine M. Freitag, Adam Strzelczyk, Natascha van Alphen, Michael W. Ronellenfitsch, Andreas Reif, Christian A. Kell, Frederic von Wegner, Jochen Roeper, Philipp S. Reif, Yvonne Reiss, Albert J. Becker, Sebastian Bauer, Thomas M. Freiman, Stephan W. Schwarzacher, Susanne Knake, Diana Omigie, Thomas Deller, Matthew C. Walker, Jochen Triesch, Dimitri M. Kullmann, Karl Martin Klein, Anke Hermsen, Johannes Gehrig, Braxton A. Norwood, Karl-Heinz Plate, Joachim P. Steinbach, Marlies Wagner, Gerhard Schratt, Ralf Deichmann, Felix Rosenow, Peter Jedlicka, Stephanie Schorge, and Stefan Liebner
Subjects: 0301 basic medicine, medicine.diagnostic_test, business.industry, Translational research, Context (language use), Disease, Electroencephalography, Precision medicine, medicine.disease, 3. Good health, 03 medical and health sciences, Behavioral Neuroscience, Epilepsy, 030104 developmental biology, 0302 clinical medicine, Neurology, Neuroimaging, medicine, Neurology (clinical), Personalized medicine, business, Neuroscience, 030217 neurology & neurosurgery
Abstract: Despite the availability of more than 15 new "antiepileptic drugs", the proportion of patients with pharmacoresistant epilepsy has remained constant at about 20-30%. Furthermore, no disease-modifying treatments shown to prevent the development of epilepsy following an initial precipitating brain injury or to reverse established epilepsy have been identified to date. This is likely in part due to the polyetiologic nature of epilepsy, which in turn requires personalized medicine approaches. Recent advances in imaging, pathology, genetics and epigenetics have led to new pathophysiological concepts and the identification of monogenic causes of epilepsy. In the context of these advances, the First International Symposium on Personalized Translational Epilepsy Research (1st ISymPTER) was held in Frankfurt on September 8, 2016, to discuss novel approaches and future perspectives for personalized translational research. These included new developments and ideas in a range of experimental and clinical areas such as deep phenotyping, quantitative brain imaging, EEG/MEG-based analysis of network dysfunction, tissue-based translational studies, innate immunity mechanisms, microRNA as treatment targets, functional characterization of genetic variants in human cell models and rodent organotypic slice cultures, personalized treatment approaches for monogenic epilepsies, blood-brain barrier dysfunction, therapeutic focal tissue modification, computational modeling for target and biomarker identification, and cost analysis in (monogenic) disease and its treatment. This report on the meeting proceedings is aimed at stimulating much needed investments of time and resources in personalized translational epilepsy research. Part I includes the clinical phenotyping and diagnostic methods, EEG network-analysis, biomarkers, and personalized treatment approaches. In Part II, experimental and translational approaches will be discussed (Bauer et al., 2017) [1].
Published: 2017
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46. Treatment of refractory and super-refractory status epilepticus with brivaracetam: A cohort study from two German university hospitals

Author: Martin Voss, Christian Senft, Bernadette Gaida, Felix von Podewils, Felix Rosenow, Adam Strzelczyk, Isabel Steinig, Laurent M. Willems, and Philipp S. Reif
Subjects: Adult, Male, Drug Resistant Epilepsy, Pediatrics, medicine.medical_specialty, Adolescent, Status epilepticus, Brivaracetam, Cohort Studies, Hospitals, University, Young Adult, 03 medical and health sciences, Behavioral Neuroscience, Epilepsy, Status Epilepticus, 0302 clinical medicine, Refractory, Interquartile range, Germany, medicine, Animals, Humans, 030212 general & internal medicine, Aged, Retrospective Studies, Aged, 80 and over, business.industry, Medical record, Middle Aged, medicine.disease, Pyrrolidinones, Treatment Outcome, Neurology, Anesthesia, Anticonvulsants, Female, Neurology (clinical), Levetiracetam, medicine.symptom, business, 030217 neurology & neurosurgery, medicine.drug, Cohort study
Abstract: Purpose We aimed to ascertain the possible use of brivaracetam (BRV) as an option for treatment of status epilepticus (SE). Methods A review of medical records was carried out to detect BRV administration in SE patients treated in Frankfurt and Greifswald during the period February 2016 to January 2017. The primary outcome question concerned SE resolution after BRV initiation. Results During that period, BRV was started with eleven adult patients with SE. Five of these were female, and the median age was 64 (interquartile range [IQR] 21 years). The median SE duration before BRV initiation was 5 days (IQR 9 days); the median number of previous anticonvulsants used was 4 (IQR 5). Initial BRV doses ranged between 50 mg and 400 mg (median 100 mg), titrated to a daily dose of 100 to 400 mg (median 200 mg). There was a cessation of SE in the first 24 h of BRV in three patients (27%). While taking BRV, no serious side effects were seen. Conclusion Based on these cases and previous data from animal experiments, BRV may prove useful in SE treatment, and trials would be warranted to examine BRV's efficacy in treating SE and how this efficacy might be influenced by co-administration with levetiracetam.
Published: 2017
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47. Blood mercury concentrations in common bottlenose dolphins from the Indian River Lagoon, Florida: Patterns of social distribution

Author: Gregory D. Bossart, Elizabeth Murdoch Titcomb, Hui-Chen W. Stavros, Marilyn Mazzoil, Patricia A. Fair, John S. Reif, and Adam M. Schaefer
Subjects: 0106 biological sciences, education.field_of_study, geography, geography.geographical_feature_category, biology, Exposure Category, 010604 marine biology & hydrobiology, Population, Foraging, Estuary, Aquatic Science, Bottlenose dolphin, biology.organism_classification, 010603 evolutionary biology, 01 natural sciences, Fishery, Blood mercury, Social distribution, education, Ecology, Evolution, Behavior and Systematics
Abstract: Social network analysis has been shown to be effective in studying the social structure of cetacean populations. Common bottlenose dolphins (Tursiops truncatus) inhabiting the Indian River Lagoon (IRL), Florida, have among the highest concentrations of total mercury (THg) in blood reported worldwide. The purpose of this study was to examine the relationship between THg concentrations in IRL dolphins and their social affiliations. Whole blood samples from 98 dolphins with photo-identification sighting histories were collected between 2003–2007 and 2010–2012. Dolphins were categorized into approximate tertiles of low (mean 199.7 μg/L), medium (mean 366.8 μg/L), and high (mean 990.5 μg/L) THg exposure. Social associations between individual dolphins were defined by the proportion of sightings documented with another known individual. Social network measures of individuals and associations between dyads were examined to determine differences among THg categories. Strong social affiliations of individuals within the highest category of THg were found (P = 0.04), suggesting shared exposures among dolphins foraging in specific areas of the estuary. Network measures of strength and affinity were significantly higher in the highest exposure category. This report used social network analysis as a novel way to examine patterns of exposure to an environmental contaminant in a cetacean population.
Published: 2017
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48. Predicting outcome of epilepsy surgery in clinical practice: Prediction models vs. clinical acumen

Author: Philipp S. Reif, Sebastian Bauer, Barbara Carl, Anke Hermsen, Iris Gorny, Axel Pagenstecher, Felix Rosenow, Adam Strzelczyk, Colin B. Josephson, Susanne Knake, Anne Katharina Fassin, Karl Martin Klein, Christopher Nimsky, Leona Möller, Anja Haag, Katja Menzler, and Ulrich Sure
Subjects: Pediatrics, medicine.medical_specialty, business.industry, Medical record, Medizin, Retrospective cohort study, General Medicine, Patient counseling, medicine.disease, Outcome (game theory), Clinical Practice, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Neurology, Medicine, Postoperative outcome, Epilepsy surgery, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract: Purpose Epilepsy surgery is an evidence-based treatment for drug-refractory focal epilepsy. We aimed to evaluate how well preoperative outcome estimates of epilepsy surgery in clinical practice correlated with postoperative outcome and to compare prediction by the clinical team with available scores (m-SFS, ESN). Method Retrospective cohort study including patients with drug-refractory focal epilepsy who underwent resective epilepsy surgery at Epilepsy Center Hessen, Marburg, between 1998-2016. Patients were categorized into four groups based on their estimated chance of postoperative seizure freedom documented in preoperative medical records. Variables required for calculation of m-SFS and ESN were also extracted from presurgical medical records. Seizure outcome using Engel/ILAE classifications was extracted from postoperative medical records. Results 148 patients were included and 98 had follow-up at 5 years. 69 (70%) had Engel I and 50 (51%) ILAE 1 outcome. Observed 5-year outcome for very good candidates was 20/22 (91%) Engel I and 14/22 (64%) ILAE 1, for good candidates 29/40 (73%) Engel I and 21/40 (53%) ILAE 1, for candidates with slightly reduced chance 11/18 (61%) Engel I and 9/18 (50%) ILAE 1 and for candidates with considerably reduced chance 1/5 (20%) Engel I and 1/5 (20%) ILAE 1.There were no significant differences in discrimination or overall performance between predictions by the clinical team, ESN and m-SFS. Conclusions Preoperative outcome estimates corresponded well with observed outcome indicating adequate patient counseling.
Published: 2019

49. Seizure Management and Prescription Patterns of Anticonvulsants in Dravet Syndrome: A Multicenter Cohort Study from Germany and Review of Literature

Author: Susanne Schubert-Bast, Sarah von Spiczak, Gerhard Kurlemann, Adelheid Wiemer-Kruel, Daniel Macdonald, Philipp S. Reif, Bernd A. Neubauer, Regina Trollmann, Clive Pritchard, Thomas U. Mayer, Tilman Polster, Gerhard Kluger, Karl Mar, and Markus Wolff
Subjects: Pediatrics, medicine.medical_specialty, Dravet syndrome, business.industry, Medicine, Medical prescription, business, medicine.disease, Cohort study
Published: 2019
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50. Factorial validity of a neuropsychological test battery and its ability to discern temporal lobe epilepsy from frontal lobe epilepsy - A retrospective study

Author: Nadine Conradi, Tabitha Kannemann, Anke Hermsen, Marion Behrens, Felix Rosenow, Adam Strzelczyk, Philipp S. Reif, and Nina Merkel
Subjects: Adult, Male, medicine.medical_specialty, Adolescent, Epilepsy, Frontal Lobe, Audiology, Neuropsychological Tests, Verbal learning, Temporal lobe, Diagnosis, Differential, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Memory span, medicine, Verbal fluency test, Humans, Epilepsy surgery, Aged, Retrospective Studies, medicine.diagnostic_test, Working memory, Reproducibility of Results, General Medicine, Neuropsychological test, Middle Aged, Neurology, Epilepsy, Temporal Lobe, Female, Neurology (clinical), Verbal memory, Psychology, 030217 neurology & neurosurgery
Abstract: Purpose Firstly, to evaluate the validity of a neuropsychological test battery in epilepsy patients, i.e. whether its tests sufficiently allow the assessment of the required cognitive domains in this specific group. Secondly, to examine its ability to differentiate between cognitive profiles of different subgroups of focal epilepsy. Methods The test battery suggested by the German ILAE Chapter was performed on 207 epilepsy patients, and its factor structure was investigated by principal component analysis (PCA). To further examine its accuracy in two matched subgroups of patients with temporal lobe epilepsy (TLE, n = 35) and frontal lobe epilepsy (FLE, n = 35), a discriminant function analysis (DFA) was used. Results PCA revealed eleven interpretable factors, accounting for 69.1% of total variance: Divided Attention, Reaction Time, Verbal Learning, Verbal Memory, Contextual Memory, Short-term- and Working Memory, Visuospatial Functioning, Space Perception, Verbal Fluency, Response Monitoring and Cognitive Flexibility. DFA identified six test to be most appropriate to discern TLE from FLE: WMS-IV Logical Memory, recognition; WMS-R Digit Span, backwards; VLMT, repetitions; VOSP Silhouettes; VLMT, delayed recall; and RWT Phonemic verbal fluency. Group membership was correctly predicted for 78.6% of patients using cross-validation. Conclusions As neuropsychological assessments are central in clinical decision-making in presurgical work-up of epilepsy patients, the appropriateness of the test battery in use is essential. The majority of cognitive domains are sufficiently measurable by the test battery and it is highly sensitive to differentiate between the cognitive profiles of TLE and FLE. However, the selection of tests assessing nonverbal memory functions requires further improvement.
Published: 2019

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