How should etiology change the classification of the epilepsies? Report from the ILAE 2021–2025 Terminology Commission
Nicola Specchio, Stéphane Auvin, Francesca Bisulli, Scott Demarest, Elena Gardella, Angelina Kakooza Mwesige, Rima Nabbout, Alshimaa S. Othman, Kollencheri Puthenveettil Vinayan, Robyn Whitney, Elaine Wirrell, Hideo Yamanouchi, Ji Yeoun Yoo, Sameer M. Zuberi, J. Helen Cross, Ingrid E. SchefferAbstract
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.