New clinicopathological associations and histoprognostic markers in ILAE types of hippocampal sclerosis

Abstract

Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) is a heterogeneous syndrome. Surgery results in seizure freedom for most pharmacoresistant patients, but the epileptic and cognitive prognosis remains variable. The 2013 International League Against Epilepsy (ILAE) histopathological classification of hippocampal sclerosis (HS) has fostered research to understand MTLE-HS heterogeneity. We investigated the associations between histopathological features (ILAE types, hypertrophic CA4 neurons, granule cell layer alterations, CD34 immunopositive cells) and clinical features (presurgical history, postsurgical outcome) in a monocentric series of 247 MTLE-HS patients treated by surgery. NeuN, GFAP and CD34 immunostainings and a double independent pathological examination were performed. 186 samples were type 1, 47 type 2, 7 type 3 and 7 samples were gliosis only but no neuronal loss (noHS). In the type 1, hypertrophic CA4 neurons were associated with a worse postsurgical outcome and granule cell layer duplication was associated with generalized seizures and episodes of status epilepticus. In the type 2, granule cell layer duplication was associated with generalized seizures. CD34+ stellate cells were more frequent in the type 2, type 3 and in noHS. These cells had a Nestin and SOX2 positive, immature neural immunophenotype. Patients with nodules of CD34+ cells had more frequent dysmnesic auras. CD34+ stellate cells in scarce pattern were associated with higher ratio of normal MRI and of stereo-electroencephalographic studies. CD34+ cells were associated with a trend for a better postsurgical outcome. Among CD34+ cases, we proposed a new entity of BRAF V600E positive HS and we described three hippocampal multinodular and vacuolating neuronal tumors. To conclude, our data identified new clinicopathological associations with ILAE types. They showed the prognostic value of CA4 hypertrophic neurons. They highlighted CD34+ stellate cells and BRAF V600E as biomarkers to further decipher MTLE-HS heterogeneity.

Locally Reducing KCC2 Activity in the Hippocampus is Sufficient to Induce Temporal Lobe Epilepsy

“…In addition to spontaneous seizures, mTLE is characterized by profound hippocampal changes which include increased gliosis and decreased neuronal number [ 3 , 34 ]. Therefore, we assessed if reducing KCC2 activity in the hippocampus has any effects on these parameters.…”

Hippocampal morphometry in sudden and unexpected death in epilepsy (SUDEP)

“…Granule cell dispersion is commonly associated with HS in TLE, noted in 76% of surgical specimens in a recent series 17 . In the context of HS, seizure-induced loss of reelinsynthesising interneurons has been shown to initiate neo-migration of mature granule cells 18 .…”

Bcl‐2/Bax ratio increase does not prevent apoptosis of glia and granular neurons in patients with temporal lobe epilepsy

“…The dentate gyrus was also evaluated using a semiquantitative examination: 0 = normal granular cell layer, 1 = generalized or focal dispersion of granular cell layer, 2 = generalized or severe granular cell loss. When samples presented both dispersion and duplication, they were classified in the duplication subgroup . Two blinded observers performed the HS classification using a multi‐head microscope.…”

“…Patients with HS type 1 present earlier seizure onset than patients with HS types 2 or 3, but HS type 1 is related with better postoperative outcome . Recently, studies have shown association between neuronal loss and/or gliosis in the hippocampus with cognitive deficits, electrophysiological and magnetic resonance imaging (MRI) findings and psychiatric comorbidities in patients with TLE …”