Cytoarchitectural Abnormalities in Hippocampal Sclerosis

Abstract

Hippocampal sclerosis (HS) is the most common pathological substrate for temporal lobe epilepsy with a characteristic pattern of loss of principle neurons primarily in CA1 and hilar subfields. Other cytoarchitectural abnormalities have been identified in human HS specimens, including dispersion of dentate granule cells and cytoskeletal abnormalities in residual hilar cells. The incidence of these features, their relationship to the severity of HS and potential indication of underlying hippocampal maldevelopment is unverified. In a series of 183 hippocampectomies we identified classical HS (grades 3 and 4) in 90% of specimens, granule cell disorganization or severe dispersion in 40% of cases with a bilaminar pattern in 10%, and cytoskeletal abnormalities in hilar cells in 55% of cases. The severity of granule cell disorganization correlated closely with the degree of hippocampal neuronal loss but not with the age at first seizure or a history of a precipitating event for epilepsy such as prolonged febrile seizures. These findings suggest that granule cell disorganization is closely linked with the progression of HS rather than a hallmark of impaired hippocampal maturation. Furthermore, stereological quantitation of granule cells showed evidence of cell loss but greater numbers in regions of maximal dispersion, which may indicate enhanced neurogenesis of these cells. Quantitation of reelin-and calretinin-positive Cajal-Retzius cells in the dentate gyrus molecular layer in 26 cases showed no correlation between the number of these cells and the severity of granule cell dispersion, but increased numbers of these cells were present in HS with respect to control groups. Although a role for Cajal-Retzius cells is therefore not implicated in the mechanism of granule cell disorganization, their excess number may be indicative of underlying hippocampal maldevelopment in HS.

Temporal lobe epilepsy with mesial temporal sclerosis: hippocampal neuronal loss as a predictor of surgical outcome

“…A possible disadvantage of our methodology is the fact that only a single section of hippocampus was analyzed. This section is thought to be representative of all hippocampal pathology, but patterns of HS could vary along the anteroposterior axis of hippocampus in some patients 19 , suggesting a possible pathological bias.…”

Molecular abnormalities of the hippocampus in severe psychiatric illness: postmortem findings from the Stanley Neuropathology Consortium

“…Secretion of reelin by Cajal-Retzius interneurons in the marginal zone of the developing cortex is thought to act as a stop signal for migrating neurons. Reduced reelin RNA levels in the dentate gyrus from patients with temporal lobe epilepsy may be related to the degree of granule cell dispersion in this disorder 29,30 and reeler mice have significant disruptions in the architecture of dentate granule cells. 31 Although gross disarray of dentate granule cell architecture has not been reported in severe mental illness, a subtler defect than that seen in epilepsy may be present in schizophrenia, bipolar disorder, and major depression.…”

Compensatory Neurogenesis in the Injured Adult Brain

“…In contrast, following seizure activity BrdU+ cells were found extensively in the dentate hilus and/or dentate molecular layer of the hippocampus, indicating aberrant migration of dividing cells in response to seizure-induced cell loss (Parent, et al, 1997, Scharfman, et al, 2000, Scharfman, et al, 2002, Parent, et al, 2006. Similarly, displaced granule cells have been observed in hippocampal tissues obtained from patients with TLE (Houser, 1990, Thom, et al, 2002, Liu, et al, 2008. This suggests that acute seizure-induced dentate gyrus neurogenesis promotes aberrant circuitry development, which likely contributes to the evolution of initial seizure-induced hippocampal injury into chronic epilepsy (Kuruba, et al, 2009).…”