Hippocampal granule cell dispersion: a non-specific finding in pediatric patients with no history of seizures

Abstract

Chronic epilepsy has been associated with hippocampal abnormalities like neuronal loss, gliosis and granule cell dispersion. The granule cell layer of a normal human hippocampal dentate gyrus is traditionally regarded as a compact neuron-dense layer. Histopathological studies of surgically resected or autopsied hippocampal samples primarily from temporal lobe epilepsy patients, as well as animal models of epilepsy, describe variable patterns of granule cell dispersion including focal cell clusters, broader thick segments, and bilamination or "tram-tracking". Although most studies have implicated granule cell dispersion as a specific feature of chronic epilepsy, very few "non-seizure" controls were included in these published investigations. Our retrospective survey of 147 cadaveric pediatric human hippocampi identified identical morphological spectra of granule cell dispersion in both normal and seizure-affected brains. Moreover, sections across the entire antero-posterior axis of a control cadaveric hippocampus revealed repetitive occurrence of different morphologies of the granule cell layercompact, focally disaggregated and bilaminar. The results indicate that granule cell dispersion is within the spectrum of normal variation and not unique to patients with epilepsy. We speculate that sampling bias has been responsible for an erroneous dogma, which we hope to rectify with this investigation.

Heat-Shock Induces Granule Cell Dispersion and Microgliosis in Hippocampal Slice Cultures

“…They might, however, be useful as a model to interpret the role of an inflammatory state in the brain, possibly favoring the development of epilepsy. In this context, it should be noted that Roy et al (2020) , who recently reported on GCD as a non-specific finding in pediatric patients, did not observe a microglia reaction in the analyzed hippocampal tissue with no history of seizures. This finding, together with our observation of microgliosis after heat-shock, underpins the importance of microgliosis as an important parameter to distinguish pathological from non-specific granule dispersion.…”

“…On the other hand, recent retrospective studies on hippocampi of pediatric patients with or without seizure history did not show significant differences of cell loss or GCD ( Harding and Thom, 2001 ; Roy et al, 2020 ). In addition, abnormal neuronal stratification and microgliosis were also observed in the hippocampus of seizure-free individuals, suggesting that GCD cannot be considered to be pathognomonic for TLE ( Roy et al, 2020 ), much in contrast to earlier studies which had judged GCD to be a specific histopathological feature of TLE ( Lurton et al, 1997 ; Koyama et al, 2012 ; Thom, 2014 ). Febrile seizures and ectopic granule cell positioning were hyperthermia-induced in rats in vivo ( Koyama et al, 2012 ).…”

“…Since an inverse correlation was found between the number of Reelin-expressing cells in the hippocampus and the extent of GCD in TLE patients, a causal relationship between reduced Reelin availability and GCD had been suggested ( Haas et al, 2002 ; Haas and Frotscher, 2010 ; Bozzi et al, 2012 ). In turn, a recent study reported on GCD in the hippocampus of pediatric patients that did not suffer from epilepsy, indicating that GCD, at least at early age, might be within the normal variation range of dg morphology ( Roy et al, 2020 ). Thus, careful interpretation of the causes that might underlie GCD should take into account that morphological variation or apparent dispersion at early stages might reflect newborn granule cells that migrate from the tertiary proliferation zone to form a compact gcl.…”

“…Moreover, granule cell dispersion (GCD) is frequently observed in hippocampal tissue affected by TLE ( Houser, 1990 ; Lurton et al, 1997 ; Haas et al, 2002 ; Gong et al, 2007 ; Blumcke et al, 2009 ; Haas and Frotscher, 2010 ), and previous studies have shown that granule cell displacement can lead to incorrect connections of these neurons, which may favor the development of epileptic discharges ( Dashtipour et al, 2001 ; Kowalski et al, 2010 ; Cameron et al, 2011 ). In turn, GCD has also been observed in the dentate gyrus (dg) of pediatric patients that did not suffer from epilepsy, suggesting that GCD may be within the normal variation range of granule cell layer (gcl) morphology ( Roy et al, 2020 ).…”

Sudden Unexplained Death in Childhood: A Neuropathology Review

“…Observational and experimental protocols designed to evaluate GCL alterations are necessarily biased toward hippocampal sampling which might account for a trend toward increased sensitivity to over-interpret normal anatomic variants in some cases as the spectrum of normal variant anatomy during hippocampal development is poorly defined and prevalence data for the general pediatric population are lacking. A recent morphometric analysis of archived autopsy pediatric material found no correlation between GCD and seizure history (54). Thus, the significance of GCL alterations remains uncertain.…”