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Amygdala: Neuropathology studies have reported gliosis and neuronal loss in the lateral nucleus
in resections of amygdala from patients with temporal lobe epilepsy, in particular the ventro-
medial aspects are more severely affected55. In addition, the basal nuclei, particularly the
parvicellular division, may be involved56. In cases with severe neuronal loss and gliosis the term
‘amygdala sclerosis’ may be applied but there is no strict definition for the extent and severity of
neuronal loss for this diagnosis42. As a result, reports on the incidence of amygdala sclerosis
varies between institutions from 3576%55. Greater amygdala neuronal loss has been shown in
patients with hippocampal sclerosis, although amygdala sclerosis has also been reported in
isolation42. Amygdala enlargement has been reported in TLE but the underlying pathology
substrate is variable and includes tumours and malformation.

Entorhinal cortex (EC) in HS: There is also evidence that characteristic pathological changes
are present in the entorhinal cortex (EC) in patients with hippocampal sclerosis and that this
region may have importance in the initiation of mesial temporal lobe seizures or development of
HS. The EC at the junction between hippocampus and neocortex acts as a conduit for incoming
afferent information and reciprocal efferent signals. It also contributes to local signal processing
and modulation, and intracortical networks between the deep and superficial cortical regions have
been shown. The EC has reciprocal connections with the hippocampus. Neurones from
superficial layers (mainly layers II and III) send glutamatergic afferents, via the perforant
pathway, to the dentate granule cells and CA1 neurones; subicular and CA1 pyramidal neurones
have feedback connections to the deeper layers of the EC. Neuroimaging studies have reported
volume reduction of parahippocampal gyral structures in TLE, mainly ipsilateral to the
seizures[57] and abnormal epileptiform activity has been recorded in the EC region58, which may
sustain seizures. In pathological studies of animal models of TLE, and post-status, selective
vulnerability of layer III neurones was shown59,60. Quantitative studies of this region in patients
with hippocampal sclerosis undergoing surgery have suggested more subtle and variable patterns
of gliosis and neuronal loss, with destruction of an entire lamina being relatively uncommon55,61.

Neocortex: In the neocortex, loss of neurones, when present, is most apparent in mid-cortical
layers with associated gliosis. Subcortical white matter gliosis, atrophy, Chaslin’s superficial
cortical gliosis and increased deposits of corpora amylacea may also be prominent. Mild, focal
leptomeningeal chronic inflammatory infiltrates may follow a seizure. When extensive in the
temporal lobe the pattern of temporal lobe sclerosis may be accompanied by reorganisational
dysplasia, now termed FCD type IIIa (see section below for dysplasia) (for review of temporal
lobe sclerosis see Thom et al 200962). Quantitative post mortem studies of patients with
hippocampal sclerosis also support more widespread neocortical pathology63.

Thalamus: Volume reduction of the thalamus has been observed with MRI studies64, as well as
in post mortem65 and experimental studies66 of epilepsy, and is more closely linked with
hippocampal and amygdala atrophy and TLE. Neuronal loss and gliosis may be widespread but
with some evidence for greater involvement of dorsomedial nuclei67. Thalamic atrophy is more
often unilateral and associated atrophy of the fornix and mamillary bodies may also be seen.
Proposed pathomechanisms for injury include direct effects of seizures or transneuronal
degeneration via connecting pathways.

Cerebellum: In neuropathological studies of patients with a history of epilepsy, macroscopic
atrophy of the cerebellum has long been identified6, present in 25% of cases in one post mortem
series65. It is generally regarded that cerebellar atrophy is likely to be acquired during the course
of the epilepsy rather than a predisposing factor for seizures. MRI volumetric studies, for
example, have shown increased atrophy in established epilepsy compared to newly-diagnosed