Abstract
This study reports on a novel brain pathology in young patients with frontal lobe epilepsy (FLE) that is distinct from focal cortical dysplasia (FCD). Surgical specimens from 20 young adults with FLE (mean age, 30 years) were investigated with histological/immunohistochemical markers for cortical laminar architecture, mammalian target of (mTOR) pathway activation and inhibition, cellular autophagy, and synaptic vesicle-mediated trafficking as well as proteomics analysis. Findings were correlated with pre-/postoperative clinical, imaging, and electrophysiological data. Excessive lipofuscin accumulation was observed in abnormal dysmorphic neurones in 6 cases, but not in seven FCD type IIB and 7 pathology-negative cases, despite similar age and seizure histories. Abnormal dysmorphic neurones on proteomics analysis were comparable to aged human brains. The mTOR pathway was activated, as in cases with dysplasia, but the immunoreactivities of nucleoporin p62, DEP-domain containing protein 5, clathrin, and dynamin-1 were different between groups, suggesting that enhanced autophagy flux and abnormal synaptic vesicle trafficking contribute to early lipofuscin aggregation in these cases, compared to suppression of autophagy in cases with typical dysplasia. Cases with abnormal neuronal lipofuscin showed subtle magnetic resonance imaging cortical abnormalities that localized with seizure onset zone and were more likely to have a family history. We propose that excess neuronal lipofuscin accumulation in young patients with FLE represents a novel pathology underlying this epilepsy; the early accumulation of lipofuscin may be disease driven, secondary to as-yet unidentified drivers accelerating autophagic pathways, which may underpin the neuronal dysfunction in this condition. Ann Neurol 2016;80:882-895.
Highlights
Regions populated by dysmorphic neurones with excess lipofuscin (DN/L) were more extensive and readily evident on H&E-stained sections in cases E1 to E3 compared to cases E4 to E6, where changes were more subtle with scattered, less-frequent DN/L (Supplementary Table 1)
We describe a novel neuropathological finding in youngadult patients with focal epilepsy localizing to the frontal lobe, characterized by excessive lipofuscin accumulation within dysmorphic-appearing neurones
focal neuronal lipofuscin (FNL) was typically associated with more-subtle cortical MRI abnormalities compared to FCDIIB, was present in the active seizure onset site, and was associated with a family history of epilepsy in half the cases
Summary
This study reports on a novel brain pathology in young patients with frontal lobe epilepsy (FLE) that is distinct from focal cortical dysplasia (FCD). Methods: Surgical specimens from 20 young adults with FLE (mean age, 30 years) were investigated with histological/immunohistochemical markers for cortical laminar architecture, mammalian target of (mTOR) pathway activation and inhibition, cellular autophagy, and synaptic vesicle-mediated trafficking as well as proteomics analysis. Multimodal investigation integrating neuroimaging, electrophysiological, and functional studies is advocated in the surgical planning of patients with focal epilepsies, including suspected FCD.[9] classical imaging features are not always present in FLE resections. We hypothesized a primary abnormality in autophagy and compared multimodal investigations, including neuroimaging, electrophysiology, proteome, mTOR, and autophagic pathway analysis, to highlight the distinct characteristics of this pathology and determine the possible pathomechanism underlying this pathology
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