Neuropathologic and clinical features of human medial temporal lobe epilepsy

Abstract

Background and purpose: There is recent evidence of various types of morphological changes in the hippocampus of a rodent model of medial temporal lobe epilepsy (mTLE). However, little is known about such changes in humans. We examined the histological changes [i.e., neuronal loss, cell genesis, and granule cell dispersion (GCD)] in surgical hippocampal specimens taken from patients with mTLE.

Methods: Nissl staining, and nestin and Prox1 immunohistochemistry were performed on human hippocampal specimens obtained from patients with medically intractable mTLE, thus allowing the analysis of neuronal loss, cell genesis, and GCD, respectively. We also assessed the correlations between clinical parameters and the histopathologic findings.

Results: The degree of cell genesis in the granule cell layer was significantly correlated with the severity of GCD, history of childhood febrile seizures, and frequent generalized seizures. Cell genesis was not correlated with cell death, age at seizure onset, duration of epilepsy, or the mean frequency of all seizures.

Conclusions: Our results indicate that cell genesis in the dentate gyrus of patients with mTLE is associated with GCD and is influenced by the presence of febrile seizures during childhood and the frequency of episodes of generalized seizures.

Keywords: dentate gyrus; epilepsy; hippocampus; pathology; temporal lobe.

Fig. 1

Histopathological results of the semiquantitative scoring system. Nissl staining (for neuronal loss) shows (A) grade 1, 20% of neurons lost, (B) grade 2, 20-50% of neurons lost, and (C) grade 3>50% of neurons lost. Nestin immunostaining (for cell genesis) shows (D) grade 1, few positive cells present (<3 cells/HPF), (E) grade 2, a few positive cells present (3-10 cells/HPF), (F) grade 3, a moderate number of positive cells present (10-100 cells/HPF), and (G) grade 4, a high number of positive cells present (>100 cells/HPF). Prox1 immunostaining (for GCD) shows (H) grade 2, granule cell bodies dispersed into the molecular layer forming an irregular outer border, (I) grade 3, double-layer granule cell bodies organized in two layers, and (J) grade 4, granule cell death prevails. Scale bar=100 µm. GCD: granule cell dispersion.

Fig. 2

The distribution of (A) patients with or without a history of FS and (B) with frequent or rare generalized seizures, relative to the degree of nestin positivity (cell genesis). A mild degree of cell genesis was classified as the pathological grading score of nestin of 1 or 2, and a moderate-to-severe degree of cell genesis was classified as grade 3 or 4. Cell genesis was significantly higher in patients with a history of FS (p=0.030) and with frequent generalized seizures (p=0.026). FS: febrile seizures.