A new clinico-pathological classification system for mesial temporal sclerosis

Abstract

We propose a histopathological classification system for hippocampal cell loss in patients suffering from mesial temporal lobe epilepsies (MTLE). One hundred and seventy-eight surgically resected specimens were microscopically examined with respect to neuronal cell loss in hippocampal subfields CA1-CA4 and dentate gyrus. Five distinct patterns were recognized within a consecutive cohort of anatomically well-preserved surgical specimens. The first group comprised hippocampi with neuronal cell densities not significantly different from age matched autopsy controls [no mesial temporal sclerosis (no MTS); n = 34, 19%]. A classical pattern with severe cell loss in CA1 and moderate neuronal loss in all other subfields excluding CA2 was observed in 33 cases (19%), whereas the vast majority of cases showed extensive neuronal cell loss in all hippocampal subfields (n = 94, 53%). Due to considerable similarities of neuronal cell loss patterns and clinical histories, we designated these two groups as MTS type 1a and 1b, respectively. We further distinguished two atypical variants characterized either by severe neuronal loss restricted to sector CA1 (MTS type 2; n = 10, 6%) or to the hilar region (MTS type 3, n = 7, 4%). Correlation with clinical data pointed to an early age of initial precipitating injury (IPI < 3 years) as important predictor of hippocampal pathology, i.e. MTS type 1a and 1b. In MTS type 2, IPIs were documented at a later age (mean 6 years), whereas in MTS type 3 and normal appearing hippocampus (no MTS) the first event appeared beyond the age of 13 and 16 years, respectively. In addition, postsurgical outcome was significantly worse in atypical MTS, especially MTS type 3 with only 28% of patients having seizure relief after 1-year follow-up period, compared to successful seizure control in MTS types 1a and 1b (72 and 73%). Our classification system appears suitable for stratifying the clinically heterogeneous group of MTLE patients also with respect to postsurgical outcome studies.

Fig. 1

Cluster analysis of histopathological findings in MTS. Semi-quantitative cell measurements were transformed into z-scores and revealed five distinct patterns of hippocampal pathology: no MTS = normal hippocampus with cell loss within first standard deviation compared to controls (z-score = 0); MTS type 1a = classic hippocampal sclerosis with severe loss in CA1 and moderate loss in remaining sectors; MTS type 1b = severe hippocampal sclerosis affecting all hippocampal sectors; MTS type 2 = severe loss in CA1 and only mild pathology within remaining sectors (i.e. CA1-sclerosis); MTS type 3 = end folium sclerosis with moderate cell loss in all sectors with the exception of CA1. Open circles identify individual patients, which escaped the group determining patterns. z-CA1-CA4 = z-score of CA1-CA4 field of cornu ammonis; z-DG = z-score of dentate gyrus

Fig. 2

Histopathological findings in MTS patients. a no MTS, b MTS type 3 (end folium sclerosis), c MTS type 2 (CA1-sclerosis), d MTS type 1a (classic hippocampal sclerosis) and e MTS type 1b (severe hippocampal sclerosis). Scale bars 1 mm. Asterisks index regions with predictive cell loss patterns

Fig. 3

Experience of initial precipitating injury (IPI) correlates with pathology patterns. Box plots identified an association between early onset of IPI in patients with MTS type 1a and MTS type 1b (median age 2 or 3 years, respectively). IPI occurred later in patients with atypical variants of MTS, i.e. types 2 and 3 (median age 6 years or 13 years, respectively). Patients without hippocampal cell loss experienced IPI during adolescence (median age 16 years)