Neuropathological Insights into Unexpected Cognitive Decline in Epilepsy

Abstract

Objective Some patients unexpectedly display an unfavorable cognitive course after epilepsy surgery subsequent to any direct cognitive sequelae of the surgical treatment. Therefore, we conducted in‐depth neuropathological examinations of resective specimens from corresponding patients to provide insights as to the underlying disease processes. Methods In this study, cases with significant cognitive deterioration following a previous postoperative assessment were extracted from the neuropsychological database of a longstanding epilepsy surgical program. An extensive reanalysis of available specimens was performed using current, state‐of‐the‐art neuropathological examinations. Patients without cognitive deterioration but matched in regard to basic pathologies served as controls. Results Among the 355 operated patients who had undergone more than one postoperative neuropsychological examination, 30 (8%) showed significant cognitive decline in the period after surgery. Of the 24 patients with available specimens, 71% displayed further neuropathological changes in addition to the typical spectrum (ie, hippocampal sclerosis, focal cortical dysplasias, vascular lesions, and low‐grade tumors), indicating (1) a secondary, putatively epilepsy‐independent neurodegenerative disease process; (2) limbic inflammation; or (3) the enigmatic pathology pattern of "hippocampal gliosis" without segmental neurodegeneration. In the controls, the matched individual principal epilepsy‐associated pathologies were not found in combination with the secondary pathology patterns of the study group. Interpretation Our findings indicate that patients who unexpectedly displayed unfavorable cognitive development beyond any direct surgical effects show rare and very particular pathogenetic causes or parallel, presumably independent, neurodegenerative alterations. A multicenter collection of such cases would be appreciated to discern presurgical biomarkers that help with surgical decision‐making. ANN NEUROL 2023;93:536–550

The multifactorial etiology of cognitive deficits in epilepsy and the neuropathology of mesial temporal lobe epilepsy beyond hyperphosphorylated tau

“…We recently re-analyzed resective specimens of a rare subsample of patients who presented with unexpected cognitive decline (subsequent to any direct cognitive sequelae of epilepsy surgery in the past) and found secondary pathologies indicating limbic inflammation or the enigmatic pathology pattern of "hippocampal gliosis" without segmental neurodegeneration or signs of a neurodegenerative disease process. 5 Regarding the latter subgroup, p-tau was detected in three temporal specimens in combination with the primary pathologies of HS (n = 2) and a ganglioglioma. In the control specimens of patients with stable or even recovered cognitive functions, we did not find p-tau or any other secondary pathology.…”

“…4 However, this does not preclude the existence of small subgroups of patients with epilepsy who show cognitive decline over time due to an underlying neurodegenerative disease. 5 Nowadays the multifactorial etiology of cognitive deficits in epilepsy is well established and accepted. 6 It considers the active epilepsy (epileptic seizures and interictal epileptic discharges), the underlying pathology, the pharmacological treatment, psychiatric comorbidities as well as compensatory mechanisms (reserve capacities, plasticity) and neurodevelopmental aspects (developmental hindrance, senescence).…”