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With progressive damage, neuronal ballooning with distortion of cell shape, neurofilament
accumulation, and laminar disorganisation may also be noted, reminiscent of cortical dysplasia
(FCD IIId)125 and apoptotic neurones have been identified[126]. In the later stages large areas of
pan-laminar or patchy cortical necrosis are characteristic with extensive neuronal loss, astrocytic
gliosis and cortical spongiosis and the inflammatory process is less prominent. Cortical scars may
be extensive, involving a whole gyrus or more ‘punched out’ wedge-like areas of destruction may
be observed. The topography of the inflammatory process varies within specimens with regions
of either atrophy, active inflammation alternating with stretches of uninvolved cortex. The
multifocal nature of the disease process highlights why cortical biopsies may give a false negative
result. Patchy inflammation and myelin loss in the underlying white matter and involvement of
the deep grey nuclei may also be present in RE and inflammation may extend to the hippocampus
and additional hippocampal sclerosis may be present. In cases where post mortem tissue is
available, true bilateral disease with associated inflammatory change is probably very rare127,128.

Concepts of epileptogenesis in lesional neuropathologies
The term epileptogenesis encompasses the cascade of cellular events, following which a brain
develops spontaneous seizures or epilepsy. Epileptogenesis is often divided into three stages: the
acute event (the triggering insult or initial seizure), a latent period (clinically silent), and
spontaneous seizures. In humans, the latent period can last for months or years. These processes
are most often applied to the study of ‘acquired’ or symptomatic epilepsies, estimated to represent
up to 50% of all epilepsies, but may also operate in genetic or idiopathic epilepsies129. The main
challenges in studying the processes of epileptogenesis in advanced-stage human tissues is to
distinguish underlying pre-existing abnormalities from secondary maladaptive reorganisational
changes. It is also likely that multiple epileptogenic mechanisms operate. Understanding
epileptogenesis is essential to identifying new therapeutic targets. At present, most available
drugs are ‘anti-epilepsy’ rather than ‘anti-epileptogenesis’130, but there are promising new
options, modifying cellular responses that could prevent epilepsy in the first instance131,132.
Important areas include targeting inflammatory responses in epilepsy, blood brain barrier