Epilepsy prevalence and incidence may increase with age among adults with Down syndrome, with the age-related increases largely driven by symptomatic Alzheimer's disease, according to a prospective, multicenter observational study.
Investigators pooled harmonized data from 7 clinical cohorts in Spain, Germany, Ireland, and France, with an aggregate observation period from October 2012 to July 2025. They included 4,804 adults with Down syndrome who received structured follow-up at specialist clinics. Cognitive status was determined by clinical consensus at each visit. Active epilepsy required an epilepsy diagnosis plus ongoing antiseizure drug use or at least 1 unprovoked seizure during the previous 5 years. Patients with childhood-onset epilepsy could contribute to prevalence analyses but were excluded from analyses of new adult-onset epilepsy.
At the last visit, 67% (n = 3,238) patients were cognitively stable, 6% (n = 267) had uncertain or nonneurodegenerative cognitive decline, 7% (n = 321) had prodromal Alzheimer's disease, and 20% (n = 978) had Alzheimer's disease dementia. At the last visit, active epilepsy was identified in 15% (n = 699) of the patients. Prevalence increased from 39 per 1,000 patients aged 18 to 24 years to 390 per 1,000 among those aged 60 years or older. Among patients aged 60 years or older, the prevalence was 121 per 1,000 in asymptomatic patients vs. 459 per 1,000 in those with symptomatic Alzheimer's disease.
The investigators operationalized late-onset myoclonic epilepsy in Down syndrome (LOMEDS) as active epilepsy beginning from 1 year prior to recorded Alzheimer's disease diagnosis onward, without age or seizure-semiology restrictions. A change-point analysis placed the acceleration in first-seizure incidence at about 1 year prior to the recorded diagnosis, supporting use of that interval for the study definition.
After accounting for mortality as a competing event, cumulative LOMEDS incidence increased from 10% at Alzheimer's disease diagnosis to 57% at 9 years following diagnosis. Myoclonic and generalized tonic-clonic seizures were the most frequently observed seizure types.
The complete-case multivariable model identified associations between LOMEDS and longer time since Alzheimer's disease diagnosis, severe or profound intellectual disability, and APOE epsilon 4 carrier status. LOMEDS was associated with about twice the mortality risk.
Among 360 patients with longitudinal Cambridge Cognitive Examination for Older Adults with Down Syndrome assessments, patients with symptomatic Alzheimer's disease without LOMEDS had a decline of 3.6 points per year. Following seizure onset, scores showed an immediate 7.1-point decrease, and the modeled rate of decline subsequently totaled 7.8 points per year.
Electroencephalographic measures showed limited diagnostic performance for epilepsy. The investigators cited incomplete biomarker data, variable timing and short duration of electroencephalography, caregiver-reported seizure timing and semiology, possible ascertainment bias, possible misclassification of nonepileptic myoclonus, and limited generalizability beyond the predominantly White study population.
“Cognitive trajectories also decline more steeply after seizure onset, with rates of deterioration roughly twice those seen in symptomatic Alzheimer's disease without epilepsy,” wrote lead study authors Lucía Maure-Blesa, MD, and María Carmona-Iragui, MD, PhD, of the Sant Pau Memory Unit at the Universitat Autònoma de Barcelona , and colleagues.
The study received support from the German Research Foundation under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology and from the Bundesministerium für Bildung und Forschung project CLINSPECT-M. Full disclosures of the study authors can be found in the study.
Source:The Lancet
