Distinct clinical phenotypes of late onset and early onset epilepsies

Abstract Objective Despite representing the most common and fastest growing form of epilepsy in older adults, the clinical features of late onset epilepsy (LOE) and how it differs from early onset epilepsy (EOE) remain largely underexplored. Therefore, we evaluate the characteristics and risk factors of LOE compared to EOE. Methods In this single‐center, retrospective study, individuals with clinically diagnosed epilepsy presenting at the University of Virginia from July 1, 2024 to September 30, 2024 were included. A cohort of older adults was identified and divided into two groups: LOE if epilepsy onset occurred at ≥60 years and EOE if epilepsy onset was before 60 years. Univariable analysis was conducted using Pearson chi‐squared, Fisher exact, or Wilcoxon rank‐sum tests. Multivariable logistic regression was performed to identify risk factors associated with LOE. Results A total of 326 individuals were included (LOE: n = 97, EOE: n = 229). Overall, 173 (53%) were women. Age at epilepsy onset was higher in LOE (LOE: 67 years [interquartile range (IQR) = 63–73], EOE: 32 years [IQR = 13–50], p < .001). LOE subjects were more likely to be employed/retired than unemployed/disabled (93% vs. 59%, p < .001), to have focal epilepsy (93% vs. 78%, p = .002), and to demonstrate cognitive impairment (32% vs. 16%, p = .001). Cognitive impairment developed after epilepsy onset in the majority of individuals in both groups (LOE: 82%, EOE: 93%). Among the 284 (87%) individuals who underwent electroencephalography, epileptiform discharges or seizures were less frequent in LOE (31% vs. 53%, p < .001). On multivariable analysis, intracranial hemorrhage (odds ratio [OR] = 2.85, 95% confidence interval [CI] = 1.00–8.24, p = .049), intracranial infarction (OR = 2.93, 95% CI = 1.30–6.70, p = .010), current alcohol use (OR = 4.70, 95% CI = 2.22–10.16, p < .001), former alcohol use (OR = 2.31, 95% CI = 1.18–4.55, p = .015), higher medical comorbidity burden measured by Charlson Comorbidity Index (OR = 1.40, 95% CI = 1.21–1.63, p < .001), and lower body mass index (OR = .95, 95% CI = .90–1.00, p = .045) were independently associated with LOE. LOE also demonstrated significantly less temporal lobe involvement (26% vs. 38%, p = .034), a lower lifetime seizure burden (>10 lifetime‐seizures: 41% vs. 80%, p < .001), lower rate of drug‐resistant‐epilepsy (18% vs. 57%, p < .001), less prior exposure to antiseizure medications (ASMs; .65 ± .71 vs. 1.43 ± 1.92, p < .001), and less use of older generation and adjunctive ASMs compared with EOE. Significance EOE and LOE represent distinct clinical phenotypes. LOE is associated with greater focal epilepsy, cerebrovascular disease (stroke and hemorrhage), cognitive impairment, and overall higher medical comorbidity burden. Conversely, EOE reflects an epileptogenic disorder characterized by long‐standing temporal lobe involvement, drug resistance, and higher ASM exposure. Recognition of these distinctions may improve individualized diagnostic evaluation, cognitive screening, risk stratification, and therapeutic decision‐making.