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mTOR pathway has been demonstrated through prevention of seizures in conditional knockout
TSC1 animal models that show some of the pathological features of TSC, by treatment with
rapamycin, an mTOR inhibitor. Early clinical trials of mTOR inhibitors in the treatment of TSC
are also encouraging, with reduction in lesion size. A recent study detected human papilloma
virus in balloon cells in FCD IIB but not in TS lesions91 but this finding has not been replicated92.
Mutations in DEPDC5, PTEN and PIK3CA have been reported in FCD93,94.

Epilepsy is clearly associated with FCD lesions. Single cell recordings from dysplastic neurons
have demonstrated abnormal intrinsic membrane properties and ion channel functions81 although
no spontaneous epileptiform depolarisations have been shown, suggesting they are unlikely to
operate as ‘pacemaker’ neurons95. Immature balloon cells do not display spontaneous synaptic
current or action potentials81 and lack synaptic contacts suggesting they are inert bystanders.
Studies of glutamate transporters propose that balloon cells might exhibit a protective effect
against local ictal activity, through increased glutamate clearance mechanisms86. Altered
assembly of NMDA and AMPA receptors has been shown in neurones in FCD and alteration of
the GABAergic system is also evident in FCD II with reduction of interneurons and cytomegalic
cells reported95. Abnormal expression of cationic-chloride co-transporters that regulate
intracellular chloride and influence the capacity of GABA to generate hyperpolarising inhibitory
potentials, have been shown in FCD. Studies of gap junction proteins, including Cx43 have also
shown abnormal aggregates around balloon cells in FCD IIB, which could be of functional
significance in the formation of abnormal local networks. Additionally, increased and altered
distribution of Aquaporin 4 in relation to the dysplastic neurones has been shown in FCD II which
may influence local fluid homeostasis and modify neuronal function. Finally, increasing interest
has been directed at the contribution of pro-inflammatory mechanisms in FCD II in
epileptogenesis.

Mild malformations of cortical development (MCD)
Mild MCD in epilepsy encompass more subtle cortical abnormalities previously referred to as
microdysgenesis or ‘architectural dysplasias’. Mild MCD are divided into two categories: Type
I with ectopic neurones placed in or adjacent to layer I; and type II with microscopic single
neuronal heterotopia outside layer I including the white matter. The precise aetiology of these
subtle abnormalities, their relevance in epilepsy and significance in terms of predicting outcome
following surgery remains less certain, compared to for example FCD IIB96.

FCD type III
FCD type IIIa refers to a variety of alterations in cortical architectural organisation observed in
patients with HS. The aetiology and pathogenesis of FCD Type IIIa remains to be determined,
but is likely an associated process to MTS. One common type of FCD IIIa, also called temporal
lobe sclerosis, clusters of neurons are observed in the outer part of layer II62. It is accompanied
by severe neuronal cell loss in layer II and III with associated laminar gliosis (see Figure below).
It is observed in around 10% of patients with HS in the context of TLE and may have been
acquired early in life following a precipitating injury, such as a febrile seizure. Horizontal bundles
of myelinated axons can be observed to a variable degree in all cases. FCD type IIIb refers to
dysplasias observed adjacent to glioneuronal tumours and FCD IIIc and FCD IIId to those
observed in the context of underlying vascular malformation and early vascular/inflammatory
disease processes respectively.