How should etiology change the classification of the epilepsies? Report from the ILAE 2021–2025 Terminology Commission

The classification of the epilepsies has traditionally relied on clinical and electroencephalographic features. However, advancements in molecular genetics, neuroimaging, and our understanding of epilepsy pathophysiology necessitate a shift toward an etiology-based approach. Etiology-specific classification enables precision diagnosis and precision management by integrating genetic, structural, metabolic, infection, and immune-related insights. Genetic advances have identified more than 1000 epilepsy-related genes, revealing how variations in a single gene can produce diverse phenotypes and syndromes. Similarly, neuroimaging innovations, such as high-resolution magnetic resonance imaging and functional imaging, have enhanced detection of subtle structural abnormalities and epileptogenic zones. In 2022, the International League Against Epilepsy introduced the concept of etiology-specific epilepsy syndromes, emphasizing the interplay between etiology and syndrome. This paradigm shift moves beyond traditional classifications, offering tailored treatments that address seizures and comorbidities to improve prognosis and quality of life. Despite this progress, challenges persist. These include the complexity of defining genotype-phenotype functional relationships, limitations in diagnostic accessibility in resource-limited settings, and the integration of multifactorial causes. This article proposes extending the concept of etiology-specific epilepsy syndromes to encompass broader spectrums of phenotypes within each etiology, supported by detailed frameworks for analyzing clinical, imaging, genetic, and functional data. The aim is to refine the classification system to guide personalized, evidence-based care. This etiology-syndromic spectrum model underscores the importance of lifelong, multidisciplinary approaches to epilepsy management, balancing the value of syndrome-based insights with the transformative potential of precision medicine.

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Publication Details

Journal
Epilepsia
Published
2026-09-30
DOI
https://doi.org/10.1002/epi.70467
Primary Topic
Epilepsy research and treatment
Type
article
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article

How should etiology change the classification of the epilepsies? Report from the ILAE 2021–2025 Terminology Commission

Judith Helen Cross, Rima Nabbout, Francesca Bisulli, Elena Gardella et al.
Epilepsia
Epilepsy research and treatment
article

How should etiology change the classification of the epilepsies? Report from the ILAE 2021–2025 Terminology Commission

Judith Helen Cross, Rima Nabbout, Francesca Bisulli, Elena Gardella, Angelina Kakooza‐Mwesige, Robyn Whitney, Hideo Yamanouchi, Ingrid Eileen Scheffer, Sameer M. Zuberi, Ji Yeoun Yoo, Nicola Specchio, Elaine C. Wirrell, Scott Demarest, Stéphane Auvin, Alshimaa Shaban Othman, Kollencheri Puthenveettil Vinayan
article en

Abstract

The classification of the epilepsies has traditionally relied on clinical and electroencephalographic features. However, advancements in molecular genetics, neuroimaging, and our understanding of epilepsy pathophysiology necessitate a shift toward an etiology-based approach. Etiology-specific classification enables precision diagnosis and precision management by integrating genetic, structural, metabolic, infection, and immune-related insights. Genetic advances have identified more than 1000 epilepsy-related genes, revealing how variations in a single gene can produce diverse phenotypes and syndromes. Similarly, neuroimaging innovations, such as high-resolution magnetic resonance imaging and functional imaging, have enhanced detection of subtle structural abnormalities and epileptogenic zones. In 2022, the International League Against Epilepsy introduced the concept of etiology-specific epilepsy syndromes, emphasizing the interplay between etiology and syndrome. This paradigm shift moves beyond traditional classifications, offering tailored treatments that address seizures and comorbidities to improve prognosis and quality of life. Despite this progress, challenges persist. These include the complexity of defining genotype-phenotype functional relationships, limitations in diagnostic accessibility in resource-limited settings, and the integration of multifactorial causes. This article proposes extending the concept of etiology-specific epilepsy syndromes to encompass broader spectrums of phenotypes within each etiology, supported by detailed frameworks for analyzing clinical, imaging, genetic, and functional data. The aim is to refine the classification system to guide personalized, evidence-based care. This etiology-syndromic spectrum model underscores the importance of lifelong, multidisciplinary approaches to epilepsy management, balancing the value of syndrome-based insights with the transformative potential of precision medicine.

Epilepsia
Amrita Institute of Medical Sciences and Research Centre (IN), Royal Children's Hospital (AU), Mayo Clinic (US), Cairo University (EG), Inserm (FR), The University of Melbourne (AU), Délégation Paris 7 (FR), University of Southern Denmark (DK), Institut Universitaire de France (FR), University of Colorado Boulder (US), Université Paris Cité (FR), Universitair Ziekenhuis Leuven (BE), Royal Hospital for Children (GB), University of Colorado System (US), National Institute for Health and Care Research (GB), Sorbonne Paris Cité (FR), Children's Hospital Colorado (US), Assistance Publique – Hôpitaux de Paris (FR), Istituto delle Scienze Neurologiche di Bologna (IT), Bambino Gesù Children's Hospital (IT), Epilepsy Action (GB), Murdoch Children's Research Institute (AU), Austin Health (AU), NeuroDiderot (FR), University College London (GB), Makerere University (UG), University of Glasgow (GB), Saitama Medical University (JP), University of Bologna (IT), McMaster University (CA), Icahn School of Medicine at Mount Sinai (US), KU Leuven (BE)
Partnerships for the goals
Openalex Percentile: Top 11%
Epilepsy research and treatment
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