Towards a clinico-pathological classification of granule cell dispersion in human mesial temporal lobe epilepsies

Abstract

The dentate gyrus (DG) plays a pivotal role in the functional and anatomical organization of the hippocampus and is involved in learning and memory formation. However, the impact of structural DG abnormalities, i.e., granule cell dispersion (GCD), for hippocampal seizure susceptibility and its association with distinct lesion patterns in epileptic disorders, such as mesial temporal sclerosis (MTS) remains enigmatic and a large spectrum of pathological changes has been recognized. Here, we propose a clinico-pathological classification of DG pathology based on the examination of 96 surgically resected hippocampal specimens obtained from patients with chronic temporal lobe epilepsy (TLE). We observed three different histological patterns. (1) A normal granule cell layer was identified in 11 patients (no-GCP; 18.7%). (2) Substantial granule cell loss was evident in 36 patients (referred to as granule cell pathology (GCP) Type 1; 37.5%). (3) Architectural abnormalities were observed in 49 specimens, including one or more of the following features: granule cell dispersion, ectopic neurons or clusters of neurons in the molecular layer, or bi-lamination (GCP Type 2; 51%). Cell loss was always encountered in this latter cohort. Seventy-eight patients of our present series suffered from MTS (81.3%). Intriguingly, all MTS patients displayed a compromised DG, 31 (40%) with significant cell loss (Type 1) and 47 (60%) with GCD (Type 2). In 18 patients without MTS (18.7%), seven displayed focally restricted DG abnormalities, either cell loss (n = 5) or GCD (n = 2). Clinical histories revealed a significant association between DG pathology patterns and higher age at epilepsy surgery (p = 0.008), longer epilepsy duration (p = 0.004), but also with learning dysfunction (p < 0.05). There was no correlation with the extent of pyramidal cell loss in adjacent hippocampal segments nor with postsurgical seizure relief. The association with long-term seizure histories and cognitive dysfunction is remarkable and may point to a compromised regenerative capacity of the DG in this cohort of TLE patients.

Seizure outcome in surgically treated drug-resistant mesial temporal lobe epilepsy based on the recent histopathological classifications

“…In particular, we correlated seizure outcome with pathological findings, identified according to the recently proposed classifications of MTS, 9,11 GCP, 10 FCD, 12 and ELGT. 1,54,55,73,74,91 …”

Pathologic Evaluation of Epilepsy Surgery

“…Subjektif olması ve HS'un klinik farklılıklarını yansıtmaması nedeniyle yeni sınıflama arayışı devam etmektedir. [20][21][22][23] Wyler HS derecelendirmesi: …”

Surgical and postmortem pathology studies: contribution for the investigation of temporal lobe epilepsy

“…It is characterized by broadening of the granule cell layer of the DG 12,36 . Criteria for determining dispersion vary from qualitative impressions of the layer width to more objective quantitative measures 37 . In addition to GCD, the DG may present a bilaminar pattern, defined as two parallel layers of granule cells, the inner band considered as remnant of the original DG and an additional ectopic outer band towards the molecular layer 37 (Fig 2).…”

“…Criteria for determining dispersion vary from qualitative impressions of the layer width to more objective quantitative measures 37 . In addition to GCD, the DG may present a bilaminar pattern, defined as two parallel layers of granule cells, the inner band considered as remnant of the original DG and an additional ectopic outer band towards the molecular layer 37 (Fig 2). Houser first described GCD in TLE patients' hippocampi, in which the border between granule cell and molecular layers was not distinct, with numerous granule cell somata extending into the molecular layer.…”

“…GCD may be a consequence of enhanced proliferation of granule cell precursors as a result of seizures 42,43 . Its clinical relevance is uncertain, as is its relation to surgical prognosis 12,33,37 . Dysmorphic neurons and interneurons may be encountered in the DG of TLE with MTS patients, along with GCD [44][45][46] .…”