Hippocampal Sclerosis in Dementia, Epilepsy, and Ischemic Injury: Differential Vulnerability of Hippocampal Subfields

Abstract

Severe neuronal loss in the hippocampus, that is, hippocampal sclerosis (HS), can be seen in 3 main clinical contexts: dementia (particularly frontotemporal lobar degeneration [FTLD]), temporal lobe epilepsy (TLE), and hippocampal ischemic injury (H–I). It has been suggested that shared pathogenetic mechanisms may underlie selective vulnerability of the hippocampal subfields such as the CA1 in these conditions. We determined the extent of neuronal loss in cases of HS-FTLD (n = 14), HS-TLE (n = 35), and H–I (n = 20). Immunohistochemistry for zinc transporter 3 was used to help define the CA3/CA2 border in the routinely processed human autopsy tissue samples. The subiculum was involved in 57% of HS-FTLD, 10% of H–I, and 0% of HS-TLE cases (p < 0.0001). The CA regions other than CA1 were involved in 57% of HS-TLE, 30% of H–I, and 0% of HS-FTLD cases (p= 0.0003). The distal third of CA1 was involved in 79% of HS-FTLD, 35% of H–I, and 37% of HS-TLE cases (p = 0.02). The distal third of CA1 was the only area involved in 29% of HS-FTLD, 3% of HS-TLE, and 0% of H–I cases (p = 0.019). The proximal-middle CA1 was the only area affected in 50% of H–I, 29% of HS-TLE, and 0% of HS-FTLD cases (p = 0.004). These findings support heterogeneity in the pathogenesis of HS.

Update on Hippocampal Sclerosis

“…The CA1 and to a lesser extent the CA4 sectors are especially vulnerable to hypoxia [7]. In addition, both the CA1 and prosubiculum-subiculum in particular are vulnerable to agerelated degeneration.…”

“…Since the hippocampus is particularly susceptible to hypoxic injury [7], the association between vascular risk factors and HS has been proposed by many authors [10, 31, 32•]. Both HS and vascular risk factors are more prevalent in elderly populations [22•, 31], so their potential relationship has to be analyzed with caution.…”

Rediscovering area CA2: unique properties and functions

“…Soon after it was discovered that hippocampal neurons in general are extremely vulnerable to seizure activity, ischaemic insult and trauma, it was noted that neurons of the CA2 region are relatively resistant to these processes 14,96 . Temporal lobe epilepsy (TLE), for example, is commonly associated with hippocampal sclerosis, which includes severe loss of pyramidal cells from the hippocampal structure 97,98 .…”

Hippocampal Sclerosis of Aging Can Be Segmental

“…The diagnosis of segmental HS-Aging was made primarily using H&E stain, but the “sclerotic” changes are difficult to discriminate with precision. Zinc transporter 3 immunostaining, choline acetyltransferase immunostaining, and Hirano silver staining have been used to delineate between CA3–CA2, CA2–CA1, and CA1–subiculum respectively, in HS cases (30). These stains can be used in future segmental HS-Aging studies to help determine which hippocampal regions are initially and/or most affected.…”