Sex-specific disease modifiers in juvenile myoclonic epilepsy

Shakeshaft, Amy; Panjwani, Naim; Collingwood, Amber; Crudgington, Holly; Hall, Anna; Andrade, Danielle M.; Beier, Christoph P.; Fong, Choong Yi; Gardella, Elena; Gesche, Joanna; Greenberg, David A.; Hamandi, Khalid; Koht, Jeanette; Lim, Kheng Seang; Møller, Rikke S.; Ng, Ching Ching; Orsini, Alessandro; Rees, Mark; Rubboli, Guido; Selmer, Kaja K.; Striano, Pasquale; Syvertsen, Marte; Thomas, Rhys H.; Zarubova, Jana; Richardson, Mark P.; Strug, Lisa J.; Pal, Deb K.

doi:10.1038/s41598-022-06324-2

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Sex-specific disease modifiers in juvenile myoclonic epilepsy

Amy Shakeshaft, Naim Panjwani, Amber Collingwood, Holly Crudgington, Anna Hall, Danielle M. Andrade, Christoph P. Beier, Choong Yi Fong, Elena Gardella, Joanna Gesche, David A. Greenberg, Khalid Hamandi, Jeanette Koht, Kheng Seang Lim, Rikke S. Møller, Ching Ching Ng, Alessandro Orsini, Mark Rees, Guido Rubboli, Kaja K. Selmer, Pasquale Striano, Marte Syvertsen, Rhys H. Thomas, Jana Zarubova, Mark P. Richardson, Lisa J. Strug, Deb K. Pal

Scientific Reports, Volume: 12, Issue: 1

Swansea University Author: Mark Rees

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DOI (Published version): 10.1038/s41598-022-06324-2

Abstract

Juvenile myoclonic epilepsy (JME) is a common idiopathic generalised epilepsy with variable seizure prognosis and sex differences in disease presentation. Here, we investigate the combined epidemiology of sex, seizure types and precipitants, and their influence on prognosis in JME, through cross-sec...

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Published in:	Scientific Reports
ISSN:	2045-2322
Published:	Springer Science and Business Media LLC 2022
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Here, we investigate the combined epidemiology of sex, seizure types and precipitants, and their influence on prognosis in JME, through cross-sectional data collected by The Biology of Juvenile Myoclonic Epilepsy (BIOJUME) consortium. 765 individuals met strict inclusion criteria for JME (female:male, 1.8:1). 59% of females and 50% of males reported triggered seizures, and in females only, this was associated with experiencing absence seizures (OR = 2.0, p < 0.001). Absence seizures significantly predicted drug resistance in both males (OR = 3.0, p = 0.001) and females (OR = 3.0, p < 0.001) in univariate analysis. In multivariable analysis in females, catamenial seizures (OR = 14.7, p = 0.001), absence seizures (OR = 6.0, p < 0.001) and stress-precipitated seizures (OR = 5.3, p = 0.02) were associated with drug resistance, while a photoparoxysmal response predicted seizure freedom (OR = 0.47, p = 0.03). Females with both absence seizures and stress-related precipitants constitute the prognostic subgroup in JME with the highest prevalence of drug resistance (49%) compared to females with neither (15%) and males (29%), highlighting the unmet need for effective, targeted interventions for this subgroup. We propose a new prognostic stratification for JME and suggest a role for circuit-based risk of seizure control as an avenue for further investigation.</abstract><type>Journal Article</type><journal>Scientific Reports</journal><volume>12</volume><journalNumber>1</journalNumber><paginationStart/><paginationEnd/><publisher>Springer Science and Business Media LLC</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint/><issnElectronic>2045-2322</issnElectronic><keywords/><publishedDay>21</publishedDay><publishedMonth>2</publishedMonth><publishedYear>2022</publishedYear><publishedDate>2022-02-21</publishedDate><doi>10.1038/s41598-022-06324-2</doi><url/><notes/><college>COLLEGE NANME</college><department>Biomedical Sciences</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>BMS</DepartmentCode><institution>Swansea University</institution><apcterm/><funders>This work was supported by the Canadian Institutes of Health Research: Biology of Juvenile Myoclonic Epilepsy 201503MOP‐342469 (DKP, LJS) and 201809FDN-407295 (LJS); UK Medical Research Council, Centre for Neurodevelopmental Disorders MR/N026063/1 (DKP, MPR); UK Medical Research Council, Programme Grant MR/K013998/1, (MPR); PhD stipend from UK Medical Research Council and the Sackler Institute for Translational Neurodevelopment (AS); NIHR Specialist Biomedical Research Centre for Mental Health of South London and Maudsley National Health Service Foundation Trust (DKP, MPR); UK Engineering and Physical Sciences Research Council, Centre for Predictive Modelling in Healthcare (EP/N014391/1 (MPR)); DINOGMI Department of Excellence of MIUR 2018–2022 (legge 232 del 2016 (PS)); Wales BRAIN Unit and Research Delivery Staff funded by Welsh Government through Health and Care Research Wales (KH); Biomarin srl, ENECTA srl, GW Pharmaceuticals, Kolfarma srl. and Eisai (PS); South-Eastern Regional Health Authority, Norway (Project Number 2016129) (JK); The Research Council of Norway (Project Number 299266 (MS)); Epilepsy Research UK (RT, MR); Health & Care Research Wales (MR), Wales Gene Park (MR), Abertawe Bro Morgannwg University NHS R&D (MR); UCB (GR); Nationwide Children’s Hospital (DAG); Odense University Hospital (JG); University of Southern Denmark (17/18517 (CPB)).</funders><projectreference/><lastEdited>2022-08-25T13:46:35.2945529</lastEdited><Created>2022-08-05T12:54:09.5152975</Created><path><level id="1">Faculty of Medicine, Health and Life Sciences</level><level id="2">Swansea University Medical School - Medicine</level></path><authors><author><firstname>Amy</firstname><surname>Shakeshaft</surname><order>1</order></author><author><firstname>Naim</firstname><surname>Panjwani</surname><order>2</order></author><author><firstname>Amber</firstname><surname>Collingwood</surname><order>3</order></author><author><firstname>Holly</firstname><surname>Crudgington</surname><order>4</order></author><author><firstname>Anna</firstname><surname>Hall</surname><order>5</order></author><author><firstname>Danielle M.</firstname><surname>Andrade</surname><order>6</order></author><author><firstname>Christoph P.</firstname><surname>Beier</surname><order>7</order></author><author><firstname>Choong Yi</firstname><surname>Fong</surname><order>8</order></author><author><firstname>Elena</firstname><surname>Gardella</surname><order>9</order></author><author><firstname>Joanna</firstname><surname>Gesche</surname><order>10</order></author><author><firstname>David A.</firstname><surname>Greenberg</surname><order>11</order></author><author><firstname>Khalid</firstname><surname>Hamandi</surname><order>12</order></author><author><firstname>Jeanette</firstname><surname>Koht</surname><order>13</order></author><author><firstname>Kheng Seang</firstname><surname>Lim</surname><order>14</order></author><author><firstname>Rikke S.</firstname><surname>Møller</surname><order>15</order></author><author><firstname>Ching Ching</firstname><surname>Ng</surname><order>16</order></author><author><firstname>Alessandro</firstname><surname>Orsini</surname><order>17</order></author><author><firstname>Mark</firstname><surname>Rees</surname><orcid/><order>18</order></author><author><firstname>Guido</firstname><surname>Rubboli</surname><order>19</order></author><author><firstname>Kaja K.</firstname><surname>Selmer</surname><order>20</order></author><author><firstname>Pasquale</firstname><surname>Striano</surname><order>21</order></author><author><firstname>Marte</firstname><surname>Syvertsen</surname><order>22</order></author><author><firstname>Rhys H.</firstname><surname>Thomas</surname><order>23</order></author><author><firstname>Jana</firstname><surname>Zarubova</surname><order>24</order></author><author><firstname>Mark P.</firstname><surname>Richardson</surname><order>25</order></author><author><firstname>Lisa J.</firstname><surname>Strug</surname><order>26</order></author><author><firstname>Deb K.</firstname><surname>Pal</surname><order>27</order></author></authors><documents><document><filename>60751__24872__a3d72f86d5004fc0b2573a71c3fea969.pdf</filename><originalFilename>60751.pdf</originalFilename><uploaded>2022-08-05T12:56:21.4030726</uploaded><type>Output</type><contentLength>1974484</contentLength><contentType>application/pdf</contentType><version>Version of Record</version><cronfaStatus>true</cronfaStatus><documentNotes>This article is licensed under a Creative Commons Attribution 4.0 International License</documentNotes><copyrightCorrect>true</copyrightCorrect><language>eng</language><licence>http://creativecommons.org/licenses/by/4.0/</licence></document></documents><OutputDurs/></rfc1807>
spelling	2022-08-25T13:46:35.2945529 v2 60751 2022-08-05 Sex-specific disease modifiers in juvenile myoclonic epilepsy 10f39a4e9c2ee00d453cd84c10667ac8 Mark Rees Mark Rees true false 2022-08-05 BMS Juvenile myoclonic epilepsy (JME) is a common idiopathic generalised epilepsy with variable seizure prognosis and sex differences in disease presentation. Here, we investigate the combined epidemiology of sex, seizure types and precipitants, and their influence on prognosis in JME, through cross-sectional data collected by The Biology of Juvenile Myoclonic Epilepsy (BIOJUME) consortium. 765 individuals met strict inclusion criteria for JME (female:male, 1.8:1). 59% of females and 50% of males reported triggered seizures, and in females only, this was associated with experiencing absence seizures (OR = 2.0, p < 0.001). Absence seizures significantly predicted drug resistance in both males (OR = 3.0, p = 0.001) and females (OR = 3.0, p < 0.001) in univariate analysis. In multivariable analysis in females, catamenial seizures (OR = 14.7, p = 0.001), absence seizures (OR = 6.0, p < 0.001) and stress-precipitated seizures (OR = 5.3, p = 0.02) were associated with drug resistance, while a photoparoxysmal response predicted seizure freedom (OR = 0.47, p = 0.03). Females with both absence seizures and stress-related precipitants constitute the prognostic subgroup in JME with the highest prevalence of drug resistance (49%) compared to females with neither (15%) and males (29%), highlighting the unmet need for effective, targeted interventions for this subgroup. We propose a new prognostic stratification for JME and suggest a role for circuit-based risk of seizure control as an avenue for further investigation. Journal Article Scientific Reports 12 1 Springer Science and Business Media LLC 2045-2322 21 2 2022 2022-02-21 10.1038/s41598-022-06324-2 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University This work was supported by the Canadian Institutes of Health Research: Biology of Juvenile Myoclonic Epilepsy 201503MOP‐342469 (DKP, LJS) and 201809FDN-407295 (LJS); UK Medical Research Council, Centre for Neurodevelopmental Disorders MR/N026063/1 (DKP, MPR); UK Medical Research Council, Programme Grant MR/K013998/1, (MPR); PhD stipend from UK Medical Research Council and the Sackler Institute for Translational Neurodevelopment (AS); NIHR Specialist Biomedical Research Centre for Mental Health of South London and Maudsley National Health Service Foundation Trust (DKP, MPR); UK Engineering and Physical Sciences Research Council, Centre for Predictive Modelling in Healthcare (EP/N014391/1 (MPR)); DINOGMI Department of Excellence of MIUR 2018–2022 (legge 232 del 2016 (PS)); Wales BRAIN Unit and Research Delivery Staff funded by Welsh Government through Health and Care Research Wales (KH); Biomarin srl, ENECTA srl, GW Pharmaceuticals, Kolfarma srl. and Eisai (PS); South-Eastern Regional Health Authority, Norway (Project Number 2016129) (JK); The Research Council of Norway (Project Number 299266 (MS)); Epilepsy Research UK (RT, MR); Health & Care Research Wales (MR), Wales Gene Park (MR), Abertawe Bro Morgannwg University NHS R&D (MR); UCB (GR); Nationwide Children’s Hospital (DAG); Odense University Hospital (JG); University of Southern Denmark (17/18517 (CPB)). 2022-08-25T13:46:35.2945529 2022-08-05T12:54:09.5152975 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Amy Shakeshaft 1 Naim Panjwani 2 Amber Collingwood 3 Holly Crudgington 4 Anna Hall 5 Danielle M. Andrade 6 Christoph P. Beier 7 Choong Yi Fong 8 Elena Gardella 9 Joanna Gesche 10 David A. Greenberg 11 Khalid Hamandi 12 Jeanette Koht 13 Kheng Seang Lim 14 Rikke S. Møller 15 Ching Ching Ng 16 Alessandro Orsini 17 Mark Rees 18 Guido Rubboli 19 Kaja K. Selmer 20 Pasquale Striano 21 Marte Syvertsen 22 Rhys H. Thomas 23 Jana Zarubova 24 Mark P. Richardson 25 Lisa J. Strug 26 Deb K. Pal 27 60751__24872__a3d72f86d5004fc0b2573a71c3fea969.pdf 60751.pdf 2022-08-05T12:56:21.4030726 Output 1974484 application/pdf Version of Record true This article is licensed under a Creative Commons Attribution 4.0 International License true eng http://creativecommons.org/licenses/by/4.0/
title	Sex-specific disease modifiers in juvenile myoclonic epilepsy
spellingShingle	Sex-specific disease modifiers in juvenile myoclonic epilepsy Mark Rees
title_short	Sex-specific disease modifiers in juvenile myoclonic epilepsy
title_full	Sex-specific disease modifiers in juvenile myoclonic epilepsy
title_fullStr	Sex-specific disease modifiers in juvenile myoclonic epilepsy
title_full_unstemmed	Sex-specific disease modifiers in juvenile myoclonic epilepsy
title_sort	Sex-specific disease modifiers in juvenile myoclonic epilepsy
author_id_str_mv	10f39a4e9c2ee00d453cd84c10667ac8
author_id_fullname_str_mv	10f39a4e9c2ee00d453cd84c10667ac8_***_Mark Rees
author	Mark Rees
author2	Amy Shakeshaft Naim Panjwani Amber Collingwood Holly Crudgington Anna Hall Danielle M. Andrade Christoph P. Beier Choong Yi Fong Elena Gardella Joanna Gesche David A. Greenberg Khalid Hamandi Jeanette Koht Kheng Seang Lim Rikke S. Møller Ching Ching Ng Alessandro Orsini Mark Rees Guido Rubboli Kaja K. Selmer Pasquale Striano Marte Syvertsen Rhys H. Thomas Jana Zarubova Mark P. Richardson Lisa J. Strug Deb K. Pal
format	Journal article
container_title	Scientific Reports
container_volume	12
container_issue	1
publishDate	2022
institution	Swansea University
issn	2045-2322
doi_str_mv	10.1038/s41598-022-06324-2
publisher	Springer Science and Business Media LLC
college_str	Faculty of Medicine, Health and Life Sciences
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hierarchy_top_title	Faculty of Medicine, Health and Life Sciences
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hierarchy_parent_title	Faculty of Medicine, Health and Life Sciences
department_str	Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str	1
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description	Juvenile myoclonic epilepsy (JME) is a common idiopathic generalised epilepsy with variable seizure prognosis and sex differences in disease presentation. Here, we investigate the combined epidemiology of sex, seizure types and precipitants, and their influence on prognosis in JME, through cross-sectional data collected by The Biology of Juvenile Myoclonic Epilepsy (BIOJUME) consortium. 765 individuals met strict inclusion criteria for JME (female:male, 1.8:1). 59% of females and 50% of males reported triggered seizures, and in females only, this was associated with experiencing absence seizures (OR = 2.0, p < 0.001). Absence seizures significantly predicted drug resistance in both males (OR = 3.0, p = 0.001) and females (OR = 3.0, p < 0.001) in univariate analysis. In multivariable analysis in females, catamenial seizures (OR = 14.7, p = 0.001), absence seizures (OR = 6.0, p < 0.001) and stress-precipitated seizures (OR = 5.3, p = 0.02) were associated with drug resistance, while a photoparoxysmal response predicted seizure freedom (OR = 0.47, p = 0.03). Females with both absence seizures and stress-related precipitants constitute the prognostic subgroup in JME with the highest prevalence of drug resistance (49%) compared to females with neither (15%) and males (29%), highlighting the unmet need for effective, targeted interventions for this subgroup. We propose a new prognostic stratification for JME and suggest a role for circuit-based risk of seizure control as an avenue for further investigation.
published_date	2022-02-21T04:19:07Z
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Sex-specific disease modifiers in juvenile myoclonic epilepsy

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