Management of seizures in patients with primary mitochondrial diseases: consensus statement from the InterERNs Mitochondrial Working Group

Michelangelo Mancuso¹, Maria T Papadopoulou², Yi Shiau Ng^{3

4}, Anna Ardissone⁵, Marcello Bellusci⁶, Enrico Bertini⁷, Lidia Di Vito⁸, Teresinha Evangelista⁹, Carmen Fons¹⁰, Omar Hikmat¹¹, Rita Horvath¹², Thomas Klopstock^{13

14

15}, Cornelia Kornblum¹⁶, Costanza Lamperti⁵, Laura Licchetta⁸, Maria Judit Molnar¹⁷, Kristin N Varhaug¹⁸, Mar O'Callaghan¹⁰, Ronit M Pressler^{19

20}, Manuel Schiff^{21

22}, Serenella Servidei^{23

24}, Nora Szabo²⁵, Gráinne S Gorman^{3

4}, J Helen Cross^{19

20}, Shamima Rahman^{19

20}

Affiliations

¹ Department of Clinical and Experimental Medicine, Neurological Institute, University of Pisa, Pisa, Italy.
² Department of Pediatric Clinical Epileptology, Sleep Disorders and Functional Neurology, University Hospital of Lyon, Member of the ERN EpiCARE, Lyon, France.
³ Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute AND National Institute for Health and Care Research (NIHR) Newcastle Biomedical Research Centre (BRC), Newcastle University, Newcastle upon Tyne, UK.
⁴ NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
⁵ Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
⁶ Reference Center for Inherited Metabolic Disorders MetabERN, Mitochondrial Disorders Research Group (imas12), '12 de Octubre' University Hospital, Madrid, Spain.
⁷ Research Unit of Neuromuscular Disease, Translational Pediatrics and Clinical Genetics, Bambino Gesu' Children's Research Hospital, IRCCS, Rome, Italy.
⁸ IRCCS Istituto delle Scienze Neurologiche di Bologna, Full Member of the European Reference Network for Rare and Complex Epilepsies (EpiCARE), Bologna, Italy.
⁹ Department of Neuropathology, Functional Unit of Neuromuscular pathology and Department of Neuromyology, Institute of Myology, EURO-NMD coordination, Pitié-Salpêtrière Hospital, APHP Sorbonne University, Paris, France.
¹⁰ Epilepsy and Neurometabolics Units, Pediatric Neurology Department, Hospital Sant Joan de Déu, Institut de Recerca Sant Joan de Déu, Barcelona, Spain.
¹¹ Department of Paediatrics and Adolescent Medicine, Haukeland University Hospital, Bergen and Department of Clinical Medicine (K1), University of Bergen, Bergen, Norway.
¹² Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
¹³ Department of Neurology, Friedrich-Baur-Institute, LMU University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.
¹⁴ German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
¹⁵ Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
¹⁶ Department of Neurology, Section of Neuromuscular Diseases, University Hospital Bonn, Bonn, Germany.
¹⁷ Institute of Genomic Medicine and Rare Disorders, Semmelweis University, Budapest, Hungary.
¹⁸ Department of Neurology, Haukeland University Hospital, Bergen, Norway.
¹⁹ UCL Great Ormond Street Institute of Child Health, London, UK.
²⁰ Great Ormond Street Hospital for Children, London, UK.
²¹ Reference Center for Mitochondrial Disorders (CARAMMEL) and Reference Center for Inborn Errors of Metabolism, Department of Pediatrics, Necker-Enfants-Malades Hospital, Assistance Publique-Hôpitaux de Paris, University of Paris-Cité, MetabERN, Paris, France.
²² INSERM UMRS_1163, Imagine Institute, Paris, France.
²³ Dipartimento di Neuroscienze, Organi di Senso e Torace, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy.
²⁴ Dipartimento Di Neuroscienze, Università Cattolica del Sacro Cuore, Rome, Italy.
²⁵ Saint John's Hospital, Child Epilepsy Centre, Budapest, Hungary.

PMID: 38576261
PMCID: PMC11235721
DOI: 10.1111/ene.16275

Management of seizures in patients with primary mitochondrial diseases: consensus statement from the InterERNs Mitochondrial Working Group

Michelangelo Mancuso et al. Eur J Neurol. 2024 Jul.

. 2024 Jul;31(7):e16275.

doi: 10.1111/ene.16275. Epub 2024 Apr 4.

Authors

Affiliations

¹ Department of Clinical and Experimental Medicine, Neurological Institute, University of Pisa, Pisa, Italy.
² Department of Pediatric Clinical Epileptology, Sleep Disorders and Functional Neurology, University Hospital of Lyon, Member of the ERN EpiCARE, Lyon, France.
³ Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute AND National Institute for Health and Care Research (NIHR) Newcastle Biomedical Research Centre (BRC), Newcastle University, Newcastle upon Tyne, UK.
⁴ NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
⁵ Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
⁶ Reference Center for Inherited Metabolic Disorders MetabERN, Mitochondrial Disorders Research Group (imas12), '12 de Octubre' University Hospital, Madrid, Spain.
⁷ Research Unit of Neuromuscular Disease, Translational Pediatrics and Clinical Genetics, Bambino Gesu' Children's Research Hospital, IRCCS, Rome, Italy.
⁸ IRCCS Istituto delle Scienze Neurologiche di Bologna, Full Member of the European Reference Network for Rare and Complex Epilepsies (EpiCARE), Bologna, Italy.
⁹ Department of Neuropathology, Functional Unit of Neuromuscular pathology and Department of Neuromyology, Institute of Myology, EURO-NMD coordination, Pitié-Salpêtrière Hospital, APHP Sorbonne University, Paris, France.
¹⁰ Epilepsy and Neurometabolics Units, Pediatric Neurology Department, Hospital Sant Joan de Déu, Institut de Recerca Sant Joan de Déu, Barcelona, Spain.
¹¹ Department of Paediatrics and Adolescent Medicine, Haukeland University Hospital, Bergen and Department of Clinical Medicine (K1), University of Bergen, Bergen, Norway.
¹² Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
¹³ Department of Neurology, Friedrich-Baur-Institute, LMU University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.
¹⁴ German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
¹⁵ Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
¹⁶ Department of Neurology, Section of Neuromuscular Diseases, University Hospital Bonn, Bonn, Germany.
¹⁷ Institute of Genomic Medicine and Rare Disorders, Semmelweis University, Budapest, Hungary.
¹⁸ Department of Neurology, Haukeland University Hospital, Bergen, Norway.
¹⁹ UCL Great Ormond Street Institute of Child Health, London, UK.
²⁰ Great Ormond Street Hospital for Children, London, UK.
²¹ Reference Center for Mitochondrial Disorders (CARAMMEL) and Reference Center for Inborn Errors of Metabolism, Department of Pediatrics, Necker-Enfants-Malades Hospital, Assistance Publique-Hôpitaux de Paris, University of Paris-Cité, MetabERN, Paris, France.
²² INSERM UMRS_1163, Imagine Institute, Paris, France.
²³ Dipartimento di Neuroscienze, Organi di Senso e Torace, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy.
²⁴ Dipartimento Di Neuroscienze, Università Cattolica del Sacro Cuore, Rome, Italy.
²⁵ Saint John's Hospital, Child Epilepsy Centre, Budapest, Hungary.

PMID: 38576261
PMCID: PMC11235721
DOI: 10.1111/ene.16275

Abstract

Background and purpose: Primary mitochondrial diseases (PMDs) are common inborn errors of energy metabolism, with an estimated prevalence of one in 4300. These disorders typically affect tissues with high energy requirements, including heart, muscle and brain. Epilepsy may be the presenting feature of PMD, can be difficult to treat and often represents a poor prognostic feature. The aim of this study was to develop guidelines and consensus recommendations on safe medication use and seizure management in mitochondrial epilepsy.

Methods: A panel of 24 experts in mitochondrial medicine, pharmacology and epilepsy management of adults and/or children and two patient representatives from seven countries was established. Experts were members of five different European Reference Networks, known as the Mito InterERN Working Group. A Delphi technique was used to allow the panellists to consider draft recommendations on safe medication use and seizure management in mitochondrial epilepsy, using two rounds with predetermined levels of agreement.

Results: A high level of consensus was reached regarding the safety of 14 out of all 25 drugs reviewed, resulting in endorsement of National Institute for Health and Care Excellence guidelines for seizure management, with some modifications. Exceptions including valproic acid in POLG disease, vigabatrin in patients with γ-aminobutyric acid transaminase deficiency and topiramate in patients at risk for renal tubular acidosis were highlighted.

Conclusions: These consensus recommendations describe our intent to improve seizure control and reduce the risk of drug-related adverse events in individuals living with PMD-related epilepsy.

Keywords: consensus; epilepsy; management; mitochondrial diseases; recommendations.

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Conflict of interest statement

The authors declare no financial or other conflicts of interest.

Figures

**FIGURE 1**
(A) Consensus results for the management of focal seizures in adults with PMDs. (B) Consensus results for the management of focal seizures in children (>28 days) with PMDs. ASMs, antiseizure medications; PMDs, primary mitochondrial diseases.

**FIGURE 2**
(A) Consensus results for the management of generalized seizures in adults with PMDs. (B) Consensus results for the management of generalized seizures in children (>28 days) with PMDs. ASMs, antiseizure medications; PMDs, primary mitochondrial diseases.

**FIGURE 3**
(A) Consensus results for the management of myoclonic seizures in adults with PMDs. (B) Consensus results for the management of myoclonic seizures and infantile spasms in children (>28 days) with PMDs. PMDs, primary mitochondrial diseases.

**FIGURE 4**
Consensus results for the management of convulsive status epilepticus in children (>28 days) and adults. ASMs, antiseizure medications; IM, intramuscular; IV, intravenous; Mg, magnesium; PMDs, primary mitochondrial diseases.

See this image and copyright information in PMC

References

1. Ng YS, Bindoff LA, Gorman GS, et al. Mitochondrial disease in adults: recent advances and future promise. Lancet Neurol. 2021;20:573‐584. - PubMed
1. Rahman S. Mitochondrial diseases and status epilepticus. Epilepsia. 2018;59(Suppl 2):70‐77. - PubMed
1. Lopriore P, Gomes F, Montano V, Siciliano G, Mancuso M. Mitochondrial epilepsy, a challenge for neurologists. Int J Mol Sci. 2022;23:13216. - PMC - PubMed
1. Bindoff LA, Engelsen BA. Mitochondrial diseases and epilepsy. Epilepsia. 2012;53(Suppl 4):92‐97. - PubMed
1. Whittaker RG, Devine HE, Gorman GS, et al. Epilepsy in adults with mitochondrial disease: a cohort study. Ann Neurol. 2015;78:949‐957. - PMC - PubMed

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Management of seizures in patients with primary mitochondrial diseases: consensus statement from the InterERNs Mitochondrial Working Group

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Management of seizures in patients with primary mitochondrial diseases: consensus statement from the InterERNs Mitochondrial Working Group

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Conflict of interest statement

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