Diagnostic Criteria and Management of MELAS and Stroke-Like Episodes: Consensus-Based Statements.
Michelangelo Mancuso, Marcello Bellusci, Valerio Carelli, Irenaeus de Coo, Daria Diodato, Felix Distelmaier, Omar Hikmat, Michio Hirano, Rita Horvath, Amel Karaa, Thomas Klopstock, Mary Kay Koenig, Cornelia Kornblum, Chiara La Morgia, Piervito Lopriore, Mika Henrik Martikainen, Robert McFarland, Olimpia Musumeci, Robert D S Pitceathly, Guido Primiano, Shamima Rahman, Fernando Scaglia, Andrew Schaefer, Manuel Schiff, Luisa Semmler, Costanza Lamperti, Serenella Servidei
Journal: European journal of neurology
2026;33(4):e70588
PMID: 41999163
Abstract
BACKGROUND AND PURPOSE
Mitochondrial Encephalomyopathy, Lactic acidosis and Stroke-like episodes (MELAS) is a rare multisystem mitochondrial disorder with clinical heterogeneity. Diagnostic criteria and management strategies for MELAS and mitochondrial stroke-like episodes (SLE) remain inconsistent. This work provides international consensus recommendations on the definition, diagnosis, and management of MELAS and SLE in pediatric and adult populations.
METHODS
An international Delphi consensus process was conducted within the European Reference Network for Neuromuscular Diseases (ERN EURO-NMD), in collaboration with the US Mitochondrial Medicine Society, the ERN for Hereditary Metabolic Disorders (MetabERN), and patient representatives. Following a systematic literature review, 54 statements addressing diagnostic definitions and management of MELAS were evaluated. Statements not reaching consensus were revised and re-evaluated during a face-to-face meeting.
RESULTS
Consensus supported defining MELAS as a clinical syndrome characterized by one or more SLE in the context of mitochondrial dysfunction caused by a pathogenic mitochondrial DNA variant, particularly m.3243A>G in MT-TL1. The use of terms such as "MELAS-like" or "MELAS spectrum" was discouraged. The panel agreed that the efficacy of L-arginine, L-taurine, L-citrulline, coenzyme Q10, vitamins, and other supplements remains unproven and requires validation in clinical trials. Antiseizure medications should be initiated promptly when seizures are suspected during SLE, and intravenous corticosteroids may be beneficial acutely. Multidisciplinary management of neurological, neuropsychiatric, and systemic complications was endorsed.
CONCLUSIONS
This international consensus provides updated definitions and practical guidance for the diagnosis and management of MELAS and SLE, aiming to harmonize clinical practice and inform future evidence-based research.
© 2026 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.
Address:
Department of Clinical and Experimental Medicine, Neurological Institute, University of Pisa, Pisa, Italy.; CTMM - Interdepartmental Research Centre for Translational Medicine in Neuromuscular and Mitochondrial Diseases, University of Pisa, Pisa, Italy.; Azienda Ospedaliero Universitaria Pisana, Neurological Clinic, Pisa, Italy.; Reference Center for Inherited Metabolic Disorders MetabERN, Mitochondrial Disorders Research Group (imas12), '12 de Octubre' University Hospital, Madrid, Spain.; IRCCS Istituto Delle Scienze Neurologiche di Bologna, Programma di Neurogenetica, Bologna, Italy.; Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.; Mental Health and Neuroscience Research Institute, Graduate School MHeNS, Department Translational Genomics, Maastricht University, Maastricht, the Netherlands.; Unit of Muscular and Neurodegenerative Diseases, Children Hospital Bambino Gesù, Rome, Italy.; University Children's Hospital, Düsseldorf, Germany.; Department of Paediatrics and Adolescent Medicine, Haukeland University Hospital, Bergen, Norway.; Department of Clinical Science (K2), University of Bergen, Bergen, Norway.; H. Houston Merritt Neuromuscular Research Center, Department of Neurology, Columbia University Irving Medical Center, New York, USA.; Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.; Division of Genetics, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, USA.; Department of Neurology, Friedrich-Baur-Institute, LMU University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.; German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany.; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.; Department of Pediatrics, Division of Child & Adolescent Neurology, University of Texas McGovern Medical School, Houston, Texas, USA.; Department of Neuromuscular Diseases, Center for Neurology, University Hospital Bonn, Bonn, Germany.; Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.; IRCCS Istituto Delle Scienze Neurologiche di Bologna,UOC Clinica Neurologica, Bologna, Italy.; Department of Clinical and Experimental Medicine, Neurological Institute, University of Pisa, Pisa, Italy.; Scuola Superiore Sant'anna, Ph.D School in Translational Medicine, Pisa, Italy.; Research Unit of Clinical Medicine, University of Oulu, Oulu, Finland.; Neurocenter, Oulu University Hospital, Oulu, Finland.; Mitochondrial Research Group Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.; NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.; Department of Clinical and Experimental Medicine, Unit of Neurology and Neuromuscular Disorders, University of Messina, Messina, Italy.; Centre for Neuromuscular Diseases, Department of Neuromuscular Diseases, University College London Queen Square Institute of Neurology, London, UK.; NHS Highly Specialised Service for Rare Mitochondrial Disorders, the National Hospital for Neurology and Neurosurgery, London, UK.; Dipartimento di Neuroscienze, Organi di Senso e Torace, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy.; Dipartimento Di Neuroscienze, Università Cattolica del Sacro Cuore, Rome, Italy.; Mitochondrial Research Group, UCL Great Ormond Street Institute of Child Health and Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.; Department of Molecular and Human Genetics, Baylor College of Medicine/Texas Children's Hospital, Houston, Texas, USA.; Baylor Genetics, Houston, Texas, USA.; Joint BCM-CUHK Center of Medical Genetics, Prince of Wales Hospital, Hong Kong, SAR, China.; NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.; 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, Paris, France.; INSERM UMRS_1163, Imagine Institute, Paris, France.; Department of Neurology, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany.; Fondazione IRCCS Istituto Neurologico C. Besta, Milan, Italy.
