Natural history and clinical impact of epilepsy in adults with Down syndrome: a multicentre clinical study.
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Maure-Blesa Lucía, Carmona-Iragui María, Barroeta Isabel, Arranz Javier, Fernández Susana, Rodríguez-Baz Íñigo, Benejam Bessy, Videla Laura, Arriola-Infante José Enrique, Del Hoyo Soriano Laura, Pertierra Lucía, Vaqué-Alcázar Lídia, Sanjuan Aida, Bueno Ana, Aranha Mateus Rozalem, Lorente Oriol, Morcillo-Nieto Alejandra O, Ros-Castelló Victoria, Sierra-Marcos Alba, Sánchez-Moreno Beatriz, Lisgaras Christos Panagiotis, Blessing Esther, Osorio Ricardo S, Estanga Ainara, García-Sebastián Maite, Ros Naia, Stockbauer Anna Christina, Nuebling Georg, Remi Jan Martin, McCarron Mary, Lima Kálya, Dunne Pamela, Sirisi Sònia, Dols-Icardo Oriol, Belbin Olivia, Alcolea Daniel, Bejanin Alexandre, Lleó Alberto, Giménez Sandra, Montes Nuria, de Asua Diego Real, McGlinchey Eimear, Levin Johannes, Rebillat Anne-Sophie, Altuna Miren, Fortea Juan
Аннотация
METHODS: We conducted a multicentre, observational, longitudinal study across seven international cohorts with an aggregate observation window from Oct 24, 2012, to July 28, 2025. We included adults with Down syndrome aged at least 18 years and with at least one longitudinal clinical assessment. Alzheimer's disease staging was done by clinical consensus. Active epilepsy required an epilepsy diagnosis plus ongoing antiseizure medication or at least one seizure within the past 5 years. We analysed active epilepsy prevalence, incidence and cumulative incidence, its timing with respect to symptomatic Alzheimer's disease, and its effect on survival and cognitive trajectories as well as electroencephalogram (EEG) abnormalities.
FINDINGS: We included 4804 adults with Down syndrome (mean age 43 years [SD 13]): 3238 (67·4%) were cognitively stable, 267 (5·6%) had non-degenerative cognitive decline, 321 (6·7%) had prodromal Alzheimer's disease, and 978 (20·3%) had Alzheimer's disease dementia. Intellectual disability was mild in 1020 (24·6%) participants, moderate in 2352 (56·7%), and severe to profound in 779 (18·8%). Active epilepsy prevalence was 145·2 per adults with Down syndrome overall but significantly increased with age, particularly with symptomatic Alzheimer's disease, when epilepsy manifested mostly as myoclonic or tonic-clonic seizures. Cumulative incidence of epilepsy increased linearly after symptomatic Alzheimer's disease, from 9·5% (95% CI 7·8-11·3) at diagnosis to 56·9% (51·7-61·7) after 9 years. Risk of epilepsy increased with time since Alzheimer's disease diagnosis (adjusted odds ratio 1·33 per year [95% CI 1·22-1·45]; p<0·0001), severe-to-profound intellectual disability (2·14 per year [1·25-3·70]; p=0·0057), and APOE ε4 carriership (1·61 per year [1·04-2·49]; p=0·034), independent of age. LOMEDS was associated with increased mortality (hazard ratio 2·10 [95% CI 1·57-2·82]; p<0·0001), and faster cognitive decline. Interictal EEG abnormalities showed little diagnostic utility.
INTERPRETATION: Epilepsy increases sharply after symptomatic Alzheimer's disease onset in people with Down syndrome. The association of epilepsy with reduced survival and accelerated cognitive decline underscores the need for targeted preventive and therapeutic strategies against Alzheimer's disease-related epileptogenesis and hyperexcitability.
FUNDING: See Acknowledgments for funders.