Within the broad classification of epilepsy, mesial temporal lobe epilepsy (MTLE) is the most common location-related epilepsy. This may be lesional or non-lesional, with the great majority of non-lesional MTLE being associated pathologically with hippocampal sclerosis (HS). There remains much debate in the neurological world regarding HS as a cause or consequence of seizures. Pathological evidence has shown the presence of HS in brains of dementia patients without clinical epilepsy (19, 104) . In addition, MTLE patients with dual pathology may have HS that is: (i) a non-specific result of the primary epileptogenic lesion and not in itself epileptogenic; (ii) secondary to the primary epileptogenic lesions but also epileptogenic; or (iii) a primary HS that coexists with another epileptogenic lesions (109) . Proponents of the initiating hit theory of epilepsy argue that the progressive nature of MTLE demonstrates HS as a consequence of the seizure process. Typically a variable latent period between the initial precipitating incident and habitual unprovoked seizures is present, followed by a silent period between the first habitual unprovoked seizure and the onset of intractability. This strongly suggests that the pathology is progressive (5) . Worsening HS creates a cycle whereby increased seizure severity and frequency lead to further neuropathological changes and hence worsening clinical seizures. Several theories for the cause of HS have been proposed, with the most commonly quoted being febrile convulsions. Other theories include vascular injuries and developmental abnormalities. It is this process of progression to seizures of worsening severity with increasing frequency that is termed epileptogenesis (Figure 1 ).