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Hippocampal sclerosis (HS) has been recognized as the most commonly encountered pathological substrate of mesial temporal lobe epilepsy (MTLE). The pathological condition was initially described by early neuropathologists based on postmortem material. Studies in familial MTLE are also important for better understanding of the pathogenesis of HS. HS identified by magnetic resonance imaging (MRI) has been associated with poor medical control of seizures. Neurologic examination is usually normal except for facial asymmetry and memory deficits, which are material-specific for the side of ictal onset. Interictal electroencephalogram (EEG) findings in patients with MTLE typically include unilateral or bilaterally independent mesial temporal spikes, best seen with basal derivations. Treatment should start with a first-line antiepileptic drug (AED) in monotherapy, the dose of which is increased until seizure freedom or the occurrence of side effects such as tiredness, dizziness, diploplia, or gait disturbance.