Histopathological Evidence of Neurodegenerative Pathology in Epilepsy: A Systematic Review

Epilepsy affects > 50 million people worldwide and is associated with a disproportionate burden of cognitive impairment. Emerging evidence suggests that neurodegenerative proteinopathies, particularly hyperphosphorylated tau (p-tau) and amyloid-β (Aβ), may contribute to cognitive dysfunction in people with epilepsy (PWE), even in the absence of dementia. However, the prevalence, distribution, and clinical significance of these proteins in epilepsy remain unclear. We conducted a systematic review of neuropathological studies examining neurodegenerative pathology in PWE without primary neurodegenerative disease. The review followed PRISMA guidelines and was registered with PROSPERO (CRD42024612990). A search of PubMed/MEDLINE, Ovid MEDLINE, Ovid Embase, and the Cochrane was performed from database inception to 7/8/2024. Eligible studies included human observational studies, case series, and post-mortem or surgical pathology assessing p-tau, amyloid, TDP-43, or related proteinopathies in PWE. Two reviewers independently screened studies, extracted data, and assessed risk of bias. Forty-two studies met the inclusion criteria. Most studies involved drug-resistant temporal lobe epilepsy (TLE) with hippocampal sclerosis. P-Tau was the most consistently reported finding, identified across multiple epilepsy types with a prevalence ranging from 3%-95%. Amyloid was detected less consistently but occurred in both temporal and extratemporal epilepsies. Several studies reported associations between p-tau burden and seizure frequency, epilepsy duration, and cognitive impairment, particularly in mesial TLE, although findings were heterogeneous. Neurodegenerative pathology, especially p-tau, is frequently observed in epilepsy and may represent a biological link between seizures, hyperexcitability, and cognition. These findings suggest that epilepsy may intersect with neurodegenerative mechanisms and underscore the need for studies integrating neuropathology, biomarkers, and cognitive outcomes.