Focal granule cell bilamination of the dentate gyrus-its prevalence across the human age spectrum and review of the literature

Abstract

The prevalence of focal granule cell bilamination (FGCB) in the hippocampal dentate gyrus varies from 0% to 44%, depending on age and study population. FGCB is commonly thought to be a specific feature of temporal lobe epilepsy (TLE) but its prevalence in cases without TLE is unclear. Using formalin-fixed, paraffin-embedded hippocampal sections, this retrospective postmortem study evaluated the prevalence of FGCB and other granule cell pathologies in infants (1-12 months of age, n = 16), children (4-10 years, n = 6), and adults (28-91 years, n = 15) with no known history of epilepsy or seizures. We found FGCB in 6% of infants, 17% of children, and 27% of adults. We then compared our findings with those in published reports of sudden unexpected deaths in infancy (SUDI), childhood (SUDC), and epilepsy (SUDEP), and in surgical specimens from patients with TLE. The reported prevalence of FGCB in those studies was 6%-19% in infants, 0%-17% in children, and 0%-2% in adults in non-seizure-related cases and 9% in children and 3%-25% in adults with TLE. Our findings highlight the presence of FGCB in individuals with no known epilepsy/seizure-related histories in proportions similar to those reported in individuals with clinical epilepsy.

Keywords: SIDS; SUDC; SUDEP; SUDI; dentate gyrus; dispersion; duplication; hippocampus.

Figure 1.

Representative micrographs of focal granule cell bilamination (FGCB) in which it was present (1/16 infants, 1/6 children, 4/15 adults [numbers 1-4]). For adult case number 1, the bilaminar layer was located in the hilus, whereas in all other cases, it was in the molecular layer (ML). Infant section stained by immunohistochemistry (IHC) for TUNEL, child by H&E, adult number 1 IHC for ALZ50, adult number 2 in situ hybridization for N-methyl-D-aspartate receptor 1 (NR1), adult number 3 IHC for nicotinic acetylcholine receptor subunit beta 2, adult number 4 IHC for NeuN (although staining was hampered as reported in²³). Examples of the quantitative measures for FGCB thickness (green lines), gap between the layers (blue lines), and thickness of each layer (red lines), are provided for 2 cases.

Figure 2.

Child case with focal granule cell bilamination (FGCB) found in 1 out of 4 hippocampal blocks represented as A-D in the anteroposterior plane (distance between the tissue sections unknown). Block B had 2 sets of 5 serial sections; FGCB was found in 1 section of the first set in the second curvature formed at the internal limb (B1a, red equal sign). A1-D1 shows magnification of the internal limb with the main curvature having the presence of single ectopic cells (B1b, diamond). Red arrow in C points to a blood vessel that has resulted in a gap of the DG GCL. H&E staining is presented in black and white to allow for visual contrast.

Figure 3.

Adult case number 1 with bilaminar layer of the focal granule cell bilamination (FGCB) in the CA4/hilus region in 5/8 serial sections. Representative examples are indicated red equal signs in A and B. In the remaining 3 sections of this series, there are remnants at the tail end (black arrows in B and C), appearing as the possible start of the focal split. Black unequal signs indicate the end of the FGCB. Sections stained by immunohistochemistry for ALZ50, counterstained with hematoxylin, and shown in black and white to allow for visual contrast.

Figure 4.

Adult case number 2 was stained by non-radioactive in situ hybridization for NR1. At 4× magnification, focal granule cell bilamination (FGCB) is not appreciated in the boxed area (A), but only visible at ×20 (A1; red equal sign; demonstrating a row of 8 cells). It co-exists with single and clustered ectopic cells (black diamond). In subsequent sections (B1-E1), FGCB no is longer evident and is replaced by a row of ectopic cells (single and clusters). Red arrow in (A) points to a blood vessel disrupting the DG GCL on the internal limb.