Late-Onset Epilepsy With Unknown Etiology: A Pilot Study on Neuropsychological Profile, Cerebrospinal Fluid Biomarkers, and Quantitative EEG Characteristics

Abstract

Introduction: Despite the fact that epilepsy has been associated with cognitive decline, neuropsychological, neurobiological, and neurophysiological features in patients with late-onset epilepsy of unknown etiology (LOEU) are still unknown. This cross-sectional study aims to investigate the neuropsychological profile, cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD), and resting-state quantitative electroencephalographic (qEEG) cortical rhythms in LOEU patients with mild cognitive impairment (LOEU-MCI) and with normal cognition (LOEU-CN), compared to non-epileptic MCI (NE-MCI) and cognitively normal (CN) controls. Methods: Consecutive patients in two clinical Units diagnosed with LOEU-CN (19), LOEU-MCI (27), and NE-MCI (21) were enrolled, and compared to age and sex-matched cognitively normal subjects CN (11). Patients underwent standardized comprehensive neuropsychological evaluation and CSF core AD biomarkers assessment (i.e., CSF Aβ42, phospho-tau and total tau, classified through A/T/(N) system). Recordings of resting-state eyes-closed electroencephalographic (EEG) rhythms were collected and cortical source estimation of delta (<4 Hz) to gamma (>30 Hz) bands with exact Low Resolution Electromagnetic Tomography (eLORETA) was performed. Results: Most LOEU patients had an MCI status at seizure onset (59%). Patients with LOEU-MCI performed significantly worse on measures of global cognition, visuo-spatial abilities, and executive functions compared to NE-MCI patients (p < 0.05). Regarding MCI subtypes, multiple-domain MCI was 3-fold more frequent in LOEU-MCI than in NE-MCI patients (OR 3.14, 95%CI 0.93-10.58, p = 0.06). CSF Aβ42 levels were lower in the LOEU-MCI compared with the LOEU-CN group. Finally, parietal and occipital sources of alpha (8-12 Hz) rhythms were less active in the LOEU-MCI than in the NE-MCI and CN groups, while the opposite was true for frontal and temporal cortical delta sources. Nardi Cesarini et al. LOEU: Cognitive, CSF, qEEG Profile Discussion: MCI status was relatively frequent in LOEU patients, involved multiple cognitive domains, and might have been driven by amyloidosis according to CSF biomarkers. LOEU-MCI status was associated with abnormalities in cortical sources of EEG rhythms related to quiet vigilance. Future longitudinal studies should cross-validate our findings and test the predictive value of CSF and EEG variables.

Diagnosing cognitive disorders in older adults with epilepsy

“…Of interest, in our cohort, a great proportion of patients with late‐onset TLE met criteria for MCI. Recent studies have documented the presence of cognitive deficits around the time of diagnosis in patients with late‐onset epilepsy that eventually follows a progressive course 8,30 . Thus the “second hit” hypothesis may also explain why patients with a new epilepsy diagnosis late in life may experience cognitive decline.…”

Diagnosing Cognitive Disorders in Older Adults with Temporal Lobe Epilepsy

“…Critically, the prevalence of clinical diagnoses associated with abnormal cognitive aging (e.g., MCI, dementia) remains unknown. A small number of empirical studies have compared the average cognitive profiles of older patients with epilepsy to healthy controls and have reported worse cognitive performance in epilepsy patients 8,9,[23][24][25] . However, these studies have included heterogeneous groups of patients with a wide range of epilepsy syndromes and have not applied uniform diagnostic criteria.…”

“…By applying widely used empirically-derived diagnostic criteria for MCI, we were able to identify the presence of a cognitive disorder in 63% of patients with long-standing TLE and 56% of those with a more recent epilepsy diagnosis. There are studies suggesting progressive cognitive decline in patients with long-standing TLE 21 , as well as studies documenting the presence of cognitive deficits around the time of diagnosis in patients with late onset epilepsy that eventually follow a progressive course 8, 26 . Thus, a diagnostic approach such as the one employed in our study offers the ability to identify patients that may be at risk for further cognitive decline and/or dementia and may benefit from early intervention (e.g., control of CVRFs) and close monitoring of their cognitive functioning.…”

“…This bi-directional relationship has been linked to the presence of tau pathology 29 , amyloid-B precursor protein 30 , and senile plaques 31, 32 in TLE, all of which are pathological hallmarks of AD. Nardi Cesarini et al 8 , reported that patients with late-onset epilepsy of unknown origin who met criteria for MCI, had similar AD-like cerebrospinal fluid profiles to patients with MCI without seizures. However, AD-related biomarkers have also been identified in resected tissue of young to middle-aged TLE patients with chronic epilepsy.…”

“…Furthermore, the prevalence of cognitive disorders in older patients with TLE is unknown. In a subset of epilepsy patients at risk for accelerated aging, cognitive impairments have been described as similar to those in classic mild cognitive impairment (cMCI) 8, 9 , the preclinical phase of Alzheimer’s disease (AD), including prominent deficits in memory. However, these studies included small samples, a wide range of epilepsy syndromes, or only compared the average cognitive profiles across groups.…”