Defining clinico-neuropathological subtypes of mesial temporal lobe epilepsy with hippocampal sclerosis

Abstract

Hippocampal sclerosis (HS) is the most frequent cause of drug-resistant focal epilepsies (ie, mesial temporal lobe epilepsy with hippocampal sclerosis; mTLE-HS), and presents a broad spectrum of electroclinical, structural and molecular pathology patterns. Many patients become drug resistant during the course of the disease, and surgical treatment was proven helpful to achieve seizure control. Hence, up to 40% of patients suffer from early or late surgical failures. Different patterns of hippocampal cell loss, involvement of other mesial temporal structures, as well as temporal neocortex including focal cortical dysplasia, may contribute to the extent of the epileptogenic network and will be discussed. An international consensus is mandatory to clarify terminology use and to reliably distinguish mTLE-HS subtypes. High-resolution imaging with confirmed histopathologic diagnosis, as well as advanced neurophysiologic and molecular genetic measures, will be a powerful tool in the future to address these issues and help to predict each patient's probability to control their epilepsy in mTLE-HS conditions.

Figure 1

Neuropathological subtypes of hippocampal sclerosis. A. Classic hippocampal sclerosis with pronounced neuronal cell loss in CA4 and CA1. Note severe cell loss also in the internal limb of the dentate gyrus (DGi), compared to the mid portion or DGe area. Experimental data has shown that this patterns correlates with the patient's impairment to store and recall memory [WADA‐testing of the isolated hemisphere; (23)]. B. Severe hippocampal sclerosis is characterized by abundant neuronal cell loss in hippocampal CA4, CA3 and CA1 sectors. C. CA1 Sclerosis is a rare and atypical HS pattern characterized by predominated cell loss in CA1. Semiquantitative measurements reveal pyramidal cell loss in other sectors as well, but at a lower extent that is not really visible by visual inspection (<30%; Table 1). Please also note the different patterns of granule cell loss in this patient (higher magnifications shown in E–I). Granule cell loss is evident at the external limb (black arrow). Granule cell dispersion visible at the mid portion (green arrow). Bilaminar architecture at the internal limb (red arrow). D. A patient with limbic encephalitis and late onset of her MTLE. The surgical specimen showed restricted cell loss within the CA4 region. This rare pattern is classified as atypical CA4 sclerosis (Table 1). E. Higher magnification of a normal human dentate gyrus with densely packed granule cells and sharp borders to subgranular and molecular layers. F. Granule cell pathology with significant granule cell loss indicated by layer thinning. G. granule cell dispersion with spreading of granule cell clusters into the molecular layer, as described by (44). H. Aberrant bilaminar architecture of the granule cell layer is visible. I: Granule cell dispersion with spreading of granule cells into the molecular layer. NeuN immunohistochemistry with hematoxylin counterstaining (4 µm thin paraffin‐embedded section; applies to all Figure 1 images). GCL = granule cell layer; ML = molecular layer. Scale bar in D (applies also to A–C) = 1000 µm; scale bar in I (applies also to E–H) = 100 µm.

Figure 2

Temporal lobe sclerosis (FCD type IIIa according to 2011 ILAE classification system). A.“Temporal lobe sclerosis”(98) can be identified in approx. 10% of mTLE‐HS patients and is characterized by an abnormal supragranular cell layer (arrow). This pattern should be specified as associated FCD (type IIIa) according to the 2011 consensus classification system for focal cortical dysplasias (9). B. Serial section to A identifies laminar astrogliosis below the aberrant supragranular cell layer (arrow), indicating severe neuronal cell loss in layers 2/3. Glial fibrillary acidic protein immunoreactivity. C. In the same patient, severe HS was evident following microscopic inspection at the midbody level of a NeuN stained and en bloc resected hippocampus. I–III = cortical layers; DGe/DGi = external and internal limbs of the dentate gyrus. Scale bar in A (applies also to B) = 100 µm; scale bar in C = 1000 µm.