Revisiting hippocampal sclerosis in mesial temporal lobe epilepsy according to the "two-hit" hypothesis

Hippocampal sclerosis (HS) is the most common neuropathological pattern observed in pharmacoresistant epilepsy and represents a critical feature in mesial temporal lobe epilepsy syndrome. However, its pathophysiological mechanisms and neuropathological consequences on seizures remain mostly unresolved. The new international classification of hippocampal sclerosis aims at standardizing its description to allow comparisons between different clinical studies. However, several aspects are not considered in this classification (granule cell dispersion, sprouting, glial modifications…). In this chapter, we discuss these different features associated with hippocampal sclerosis in perspective with the "two-hit" hypothesis and propose mechanisms that could be involved in the modulation of some specific neuropathological aspects like early life stress, hyperthermic seizures, brain lesions or hormonal modifications.