Focal Cortical Dysplasia in Childhood

Epilepsy
Tarek Shaker, MSc,1 Anne Bernier, MD,1 and Lionel Carmant, MD, FRCP (C)*

Focal cortical dysplasia is a common cause of medication resistant epilepsy. A better

understanding of its presentation, pathophysiology and consequences have helped us
improved its treatment and outcome. This paper reviews the most recent classification,
pathophysiology and imaging findings in clinical research as well as the knowledge gained
from studying genetic and lesional animal models of focal cortical dysplasia. This review of this
recently gained knowledge will most likely help develop new research models and new
therapeutic targets for patients with epilepsy associated with focal cortical dysplasia.
Semin Pediatr Neurol 23:108-119 C 2016 Elsevier Inc. All rights reserved.

Introduction classification systems for FCD have been proposed. The

currently accepted one was established in 2011 by a task force

M alformations of cortical development comprise a spec-

trum of brain abnormalities caused by defects in brain
development, failing to elaborate a functional laminated cortex.
of the International League Against Epilepsy, and divides FCD
into 3 groups based mainly on histological findings4 (Table).

Focal cortical dysplasias (FCD) are a subgroup of malforma-

tions of cortical development characterized by aberrant cortical
architecture in a localized area of the brain, and have been
reported as the most frequent structural brain lesion encoun-
tered in children submitted to surgery for medication resistant
epilepsy.1,2 Increasing efforts have been made in the last
decade to better define the different types of FCD and
understand their pathophysiology, hoping this could help
identify new therapeutic targets. In this article, we review the
classification, pathology, and recent advances in the patho-
physiology of FCD derived from human and animal studies.
Pathological Findings of FCD
FCD Type I
FCD type I consist of isolated areas of dyslamination without
any cytologic abnormality. Radial dyslamination (FCD type Ia)
is characterized by organization of the cortex in microcolumns,
defined by the presence of more than 8 neurons aligned in a
vertical orientation. Tangential dyslamination (FCD type 1b),
on the other hand, constitutes a failure to establish the 6-
layered horizontal composition of the neocortex. The combi-
nation of abnormal cortical architecture in both radial and
tangential direction characterizes FCD type Ic.

FCD Types and Classification

The term FCD was first introduced by Taylor et al in 1971,
to describe microscopic abnormalities identified in a series
of 10 patients who underwent epilepsy surgery.3 Different
From the *Division of Neurology, Department of Pediatrics and Neuros-
ciences, CHU Sainte-Justine, University of Montreal, Montreal, Quebec,
Canada.
1
These authors contributed equally to the work.
Address reprint requests to Lionel Carmant, MD, Division of Neurology,
Department of Pediatrics and Neurosciences, CHU Sainte-Justine, Uni-
versity of Montreal, Montreal, Quebec, Canada, H3T 1C5. E-mail: lionel.
carmant@umontreal.ca
FCD Type II
FCD type II consist of areas of cortical dyslamination with
specific cytologic abnormalities: dysmorphic neurons are
present in both FCD types IIa and IIb, whereas balloon cells
are observed exclusively in type IIb. Dysmorphic neurons can
be recognized by their enlarged cell body and nucleus,
abnormally distributed Nissl substance and cytoplasmic accu-
mulation of neurofilament proteins. Balloon cells have an
enlarged cell body with opalescent glassy eosinophilic cyto-
plasm, no Nissl substance, and can be indistinguishable from
giant cells found in cortical tubers of tuberous sclerosis
complex (TSC).

108 http://dx.doi.org/10.1016/j.spen.2016.06.007
1071-9091/16/& 2016 Elsevier Inc. All rights reserved.
FCD in children
Table ILAE Classification of Focal Cortical Dysplasias
Focal cortical dysplasia type I (isolated dyslamination)
FCD type Ia: abnormal radial (vertical) cortical lamination.
FCD type Ib: abnormal tangential (horizontal) cortical
lamination.
FCD type Ic: abnormal radial and tangential cortical
lamination.
Focal cortical dysplasia type II (dyslamination with dysmorphic
neurons)
FCD type IIa: with dysmorphic neurons.
FCD type IIb: with dysmorphic neurons and balloon cells.
Focal cortical dysplasia type III (associated with principal
lesion)
FCD type IIIa: cortical lamination abnormalities in the
temporal lobe associated with hippocampal sclerosis.
FCD type IIIb: cortical lamination abnormalities adjacent to a
glial or neuroglial tumor.
FCD type IIIc: cortical lamination abnormalities adjacent to a
vascular malformation.
FCD type IIId: cortical lamination abnormalities adjacent to
any lesion acquired during early life (eg, trauma, ischemic
injury, and encephalitis).
ILAE, International League Against Epilepsy.
FCD Type III
FCD type III refer to alterations in cortical lamination or
cytoarchitectural composition associated with hippocampal
atrophy (type IIIa), glial or glioneuronal tumors (type IIIb),
vascular malformations (type IIIc), or other epileptogenic
lesions like encephalitis, ischemic injury, and trauma (type
IIId). To be considered FCD type III rather than “dual
pathology,” the area of dyslamination must be adjacent to
the lesion or affecting the same lobe.
Neuroimaging and
Electrophysiological Findings in
FCD
The major predictor for a favorable surgical outcome in
children with FCD is the removal of the entire dysplastic
cortex.5-7 Therefore, a complete presurgical evaluation to
define the extent of FCD with neuroimaging and electro-
physiology is crucial.
Magnetic Resonance Imaging
The diagnosis of FCD by magnetic resonance imaging (MRI)
can be challenging, and requires specific protocols looking at
cortical thickness, gray or white matter signal and junction, and
sulcal or gyral patterns.8 Even with experienced neuroradiolo-
gists, 37% of the patients with FCD type I and 15% of those
with FCD type II are considered to have a normal MRI.6
Abnormalities are often subtle in FCD type I, with moderate
increases in the white matter signal on T2 weighted image
(T2WI) and fluid attenuation inversion recovery (FLAIR), mild
109
blurring of the gray or white matter and volume loss of
the subcortical white matter leading to lobar atrophy or
hypoplasia.5 Characteristics suggestive of FCD type II tend to
be more easily identified, with cortical thickness abnormalities,
hyperintensities of the cortex and subcortical white matter in
T2WI and FLAIR, blurring of the gray or white matter and sulcal
or gyral abnormalities.5,9-12 The transmantle sign, a T2WI white
matter signal hyperintensity tapering toward the ventricle,
reported to be specific of FCD type II, is found in approximately
30% of the patients.5,9,13 Although FCD type I and II can be
present in any lobe, FCD type I has been reported more
frequently in the temporal lobe, whereas FCD type II seems to
have a predilection for the frontal lobe14,15 (Fig. 1). Finally, no
specific sign is reported for FCD type III, but the diagnosis is
usually made in the periphery of the principal lesion.
Technological advances have improved the yield of presur-
gical imaging. The latest high-field MRIs (7.0 T) has shown
abnormalities in 20% of patients with focal epilepsy and
previously normal MRIs.16 Moreover, detection of cortical
thickening, gray or white matter blurring and cortical signal
abnormalities is improved by voxel-based analysis of T1WI
and FLAIR scans.17,18
Diffusion Tensor Imaging
Diffusion tensor imaging (DTI), by enabling the measurement
of diffusion of free water molecules, permits the assessment of
the cerebral microstructure and fiber tracking. Therefore, it can
be used to better evaluate the extent of the lesion, which is
often larger on DTI than on MRI.19
Functional Imaging
18-Fluorodeoxyglucose positron emission tomography is
highly sensitive (60%-92%) in the detection of FCD.5,20
Single-photon emission computed tomography can also be used
to locate the epileptogenic dysplastic zone. However, the area
localized by fluorodeoxyglucose positron emission tomography
and single-photon emission computed tomography can repre-
sent, due to technical issues, not only the primary epileptogenic
zone but also the area of propagation of epileptic activity.20,21
Correlation with other modalities is therefore required.
Electroencephalography and Other
Electrophysiological Evaluations
While the electroencephalogram (EEG) of FCD type I is often
normal or nonspecific, the patients with FCD type II have been
reported to have rhythmic interictal epileptiform discharges
correlating spatially with the anatomical extent of their
lesion22,23 (Fig. 2).
Electrocorticography shows patterns of repetitive spikes,
spike-and-waves, polyspikes, or bursts of fasts rhythms
interspaced with quiescient periods.14 These abnormalities
tend to increase during drowsiness and during nonrapid eye
movement sleep.12,22,23 The ictal pattern usually shows
intensification of the interictal activity, with the appearance
of low-voltage fast-activity.12,14,23 Magnetoencephalography,
110 T. Shaker et al.

L R

L R

FLAIR (3 mm slices)

Figure 1 (A) MRI of a patient with medication resistant frontal lobe epilepsy that was read as normal despite a suspected
bottom of the sulcus focal cortical dysplasia (crossing of the lines). Texture analysis showed not only blurring of the affected
sulcus (upper arrow) but also the characteristic transmantle sign (lower arrow). (B) Cortical thickness analysis further
confirmed the suspected lesion (arrow). After removal of the lesion, the patient has remained seizure free for the past 8 years
and is now off medications and attending university. (Color version of figure is available online.)
FCD in children 111

Figure 2 (A) EEG of a patient with focal seizures postinfantile spasms demonstrating continuous focal spikes in right
occipital region with focal slowing (arrows). Review of the MRI demonstrated asymmetrical myelination and blurring of the
gray-white matter in the corresponding area (arrow). This patient also underwent successful epilepsy surgery and has
remained seizure free over the past 16 months but remains on monotherapy antiepileptic drug. (Color version of figure is
available online.)
112
by allowing measurements of the brain’s magnetic fields, can
be used for mapping the epileptogenic zone in MRI negative
epilepsy and has been shown to improve mapping of the
epileptogenic zone.24
Hypotheses of FCD Formation
The exact mechanism that leads to the development of FCD
remains to be elucidated, but a few hypotheses have been
advanced. Since FCD is most likely a heterogeneous condition,
both genetic and acquired causes could be involved.
Genetic Causes
Disturbances in the proteins involved in the Wnt/Notch
pathway, implicated in cortical development, have been found
in FCD type IIb.25 However, it is unlikely that mutations in
genes of this pathway could cause FCD, since they are usually
lethal in the embryo.26 Owing to pathological similarities
between the tubers of TSC and FCD type IIb, many experts
have advanced that a link could exist between these two
entities. This hypothesis has been confirmed over the last
decade, with increasing evidence showing that FCD type IIb is
associated with an abnormal activation of the mammalian
target of rapamycin (mTOR) pathway.27 However, the cause of
this aberrant activation is not known. Polymorphisms in TSC1
and TSC2 genes have been studied with conflicting results:
some found increased polymorphisms in TSC1 gene in surgical
samples of patients with FCD type IIb when compared with
controls,28 whereas others did not.29
Recent evidences suggest defects elsewhere in the mTOR
pathway for other subtypes of FCD. Families with focal
epilepsy and FCD type IIa have been shown to share germline,
germline mosaic and brain somatic mutations in DEPDC5.30,31
Moreover, upregulation of AKT3 was found in a patient with
FCD type Ib and infantile spasms,32 and brain somatic mTOR
mutations were found in patients with FCD type II.33,34
Acquired Causes
Viral infections transmitted by transplacental route have been
hypothesized to be responsible for the development of some
FCD. Evidence of human papillomavirus 16 has been found in
FCD type IIb by 2 independent teams,35,36 which is interesting
because human papillomavirus 16 oncoprotein E6 is known to
be a potent activator of mTOR signaling.37 One of these teams
also found evidence of cytomegalovirus and human herpes
virus type 6 in FCD type IIb.36 However, others did not find
any proof of its presence.38,39
Evidences of an implication of immune and inflammatory
processes in FCD are also increasingly found.40 In fact, the
presence of activated microglia, astrocytic proliferation, and
proinflammatory cytokines in the dysplastic cortex of
patients with FCD supports the role of the inflammatory
response in the clinical behavior of FCD.41,42 Interestingly,
increased levels of P2X7R, a purinergic receptor presumed
to induce microglial activation, have recently been found in
dysplastic tissue from patients with FCD, and correlated
T. Shaker et al.
with increased levels of the cytokine IL-1ß, an important
regulator of neuroinflammation.43 Studies suggest that the
inflammatory response is more prominent in FCD type II
than type I,44 and seems to be in direct correlation with
seizure frequency.42
Other causes of FCD are included in the subtypes of FCD
type III.4 However, whether the FCD is acquired or not in
those situations is a matter of debate, particularly for hippo-
campal sclerosis (HS) and Rasmussen encephalitis. It has in fact
been suggested that FCD could be causal in those conditions,
creating a predisposing epileptogenic environment that trig-
gered by certain events (“double-hit hypothesis”), could cause
a cascade of events leading to HS or Rasmussen encephali-
tis.45,46 However, results of our animal model of the double-hit
hypothesis for HS cannot be extrapolated for FCD type IIId,
since our model is one of dual pathology.45
FCD and Epileptogenesis
The understanding of how a FCD induces epileptogenesis
could lead to new therapeutic targets and is therefore an
important area of research.47 The intrinsic epileptogenicity of
FCD has clearly been demonstrated,48,49 suggesting impaired
balance between excitation and inhibition. One hypothesis is
that dysplastic tissue could recapitulate or maintain immature
properties, including a paradoxical excitatory effect of GABA.
Indeed, depolarizing GABA activity has been documented in
dysplastic tissue resected from patients with FCDs.50 However,
reduced GABAergic inhibition has also been demonstrated,
with abnormal organization of GABAergic interneurons.51 On
the molecular level, expression of GABAA receptor is decreased
in areas of FCD, whereas expression of glutamate receptors
(GluR) and N-methyl-D-aspartate [NMDA] receptors is
increased.52,53 Moreover, the increased expression of NMDA
receptors is more pronounced in highly epileptogenic dys-
plastic tissue when compared with less epileptogenic lesions.54
Nevertheless, the nature of human studies limits the possibility
to know if these changes are causative, adaptative or are only
markers of epileptic activity.
Models of FCD
Animal Models
To better understand the mechanisms of epileptogenicity in
FCD, a number of animal models have been developed. These
models can be generally categorized into either genetic or
acquired. In genetic models, genes involved in neuronal
proliferation, differentiation as well as migration in the central
nervous system (CNS) have been targeted to create transgenic
animals harboring cortical malformations, whereas acquired
models are based on inducing cortical defects using chemical,
like methylazoxymethanol (MAM), or physical injury, like
freeze-lesion and in utero irradiation, within a developmental
time window, that is, during the late stages of neuronal
migration. To date, none of the models available has succeeded
to fully replicate all the defining features of FCD in humans,
FCD in children
but all do mimic certain aspects of the disorder. On the one
hand, dysmorphic neurons and giant cells reminiscent of
balloon cells are observed in genetic models, however,
dyslamination and neuronal disorientation extend beyond
the cortex into other brain regions.55-59 On the other hand,
despite the ability of injury-inducing models to produce
aberrant architecture and neuronal positioning more specific
to the cortical structures, these models lack, for the most part,
the presence of cells with pronounced morphological abnor-
malities.60-62
Nonetheless, a high incidence of spontaneous seizures has
been reported in a number of transgenic mouse lines where
genes suppressing the mTOR pathway, primarily Tsc1/2, have
been inactivated.55,56,58,59,63 Furthermore, animals with
acquired FCDs exhibit a heightened susceptibility to seizure
development,64-68 and in some models resulted in sponta-
neous epileptiform activity in vivo.69-73 In agreement with
the molecular changes noticed in human epilepsy, upregula-
tion or potentiation of NMDA and GABA receptors were also
identified in multiple animal FCD models.71,74-76 Thus, FCD
models are valuable tools to study how putative structural,
molecular and functional changes in the cortex contribute to
epileptogenesis.
Genetic Models
TSC1/2 Models
Different types of transgenic animals have been developed in
attempt to model FCD. Given the strong association between
mutations in the mTOR pathway and cortical malformations,
inactivation of the upstream mTOR signaling regulators TSC1/
2 has been the main experimental approach in recent years to
explore FCD genetic etiologies.
Conventional Tsc1/2 homozygous knockout was embryonic
lethal,77,78 and heterozygous Tsc1/2 mutation did not manifest
any pathological abnormalities or spontaneous seizures.79,80
More recently, using the Cre-lox recombination system in mice
to create Tsc1 conditional knockout (cKo) in neurons, that is,
Cre-mediated excision of the Tsc1 gene driven by the neuron-
specific promoter Synapsin, resulted in severe developmental
neuropathologies, namely enlarged dysplastic neurons.55 Sim-
ilarly, abnormal cortical lamination and neuronal dispersion
were respectively detected in astrocyte-specific (Gfap pro-
moter-driven)56,59 and neural progenitor-specific (Emx1 and
Gfap2 promoter-driven)57,58,63 Tsc1/2 cKo mice. Furthermore,
adult mice in all the earlier-mentioned cKo models displayed
epileptogenesis, which was dependent on mTOR activation,
demonstrated by the ability of the mTOR inhibitors, mainly
rapamycin, to suppress seizures.56-59,63 Although the pathol-
ogy of these mice lacked FCD key features, including (1) the
phenotype was diffuse as opposed to focal lesions in tubers,
and (2) lesions were not confined to the cortex. Also, in the
case of neuron- and neural progenitor-specific cKo, hypomye-
lination was reported,55,57,58,63 hence, marking mutation-
induced molecular mechanisms that are not specific to FCD.
Surprisingly, inducible neuron-specific Tsc1Nestin cKo, where
Tsc1 was timely deleted in adult mice, developed epileptogenic
113
discharges within 2-9 days of gene deletion, despite lack of
discernible histological abnormalities.81 This suggests that the
molecular mechanisms downstream of TSC1/2, which con-
tribute to epileptogenesis are potentially disjoint from the ones
inducing lesion formation.
In order to restrict Cre recombination to the cortex,
Feliciano et al82 elegantly developed a localized TSC1 inacti-
vation model by taking advantage of the in utero electro-
poration technique.82 They stereotaxically delivered Cre-
containing plasmids to cortical cells of E15/16 transgenic
mouse embryos that have the Tsc1 allele flanked by LoxP
sites, leading to discrete focal lesions confined to the cortex.82
The lesions showed some tuber hallmarks, including dyslami-
nation and ectopic hypertrophic neurons, but were devoid of
balloon cells or increased GFAP immunoreactivity, which is a
marker of enhanced gliosis. However, the model failed to
induce spontaneous seizures.
Injury-Induced Models
Chemical Injury Model
Administration of antiproliferative compounds, such as MAM
and 1,3-bis (2-chloroethyl)-N-nitrosourea (or Carmustine), to
rodents during embryogenesis interferes with CNS develop-
ment by inhibiting cell division of neural progenitors in the
brain, thus ultimately disrupting layer formation.60,83 When
compared with other antimitotic agents, MAM effects are
highly selective to the CNS,60 and therefore are considered to
be a suitable neurotoxin to induce cortical lesions. Although
the MAM model has been extensively examined, MAM-
induced in vivo spontaneous seizures were only reported in
one study.73 Yet, hyperexcitability and seizure susceptibility
were common observations in the bulk of the literature on this
FCD model.84
The model is generated in rats by in utero injection of MAM
at E15/E16, resulting in selective ablation of layers II-IV, while
other cortical layers are spared.85 In addition, MAM treatment
causes ectopic neuronal migration ultimately leading to
heterotopic neuronal clusters. However, the effect of MAM is
widespread to other areas beside the cortex, mainly the
hippocampus and to a lesser extent the striatum, thalamus,
and hypothalamus.85 The most consistent characteristics of the
MAM model are cortical thinning, along with heterotopia
within the neocortex, in the periventricular white matter and
CA1-CA2 regions of the hippocampus.60,83,85,86 Of note, there
is evidence suggesting that hippocampal heterotopic neurons
are dysplastic cells of cortical lineage.86,87
Imaging and tracing experiments demonstrated ectopic
mossy fiber innervations outside of heterotopia in the hippo-
campus88 as well as excessive synaptic connectivity between
heterotopic cortex and other brain regions.89 Electrophysio-
logical recordings and c-fos activity marker assay confirmed
functional activity between these synapses.90,91 Interestingly,
when the long-term effect of prenatal MAM treatment was
investigated in adult rats (P70 and P160) via immunohisto-
chemistry, neuronal density in the CA1-CA3 and dentate
gyrus, and mossy fiber synaptogenesis were similar to control
114
rats. In addition, no signs of gliosis were detected in adult rats
of either group,92 which suggests that some of MAM cellular
and histological effects on the hippocampus are short-term.
Ex vivo electrophysiological recordings in the CA1 of P25-
P35 MAM-treated rats indicated that extracellular potassium
concentrations ([Kþ]o) above physiological levels, led to
spontaneous epileptiform-like bursts upon fiber stimulation,
a phenomenon that was not detected in control slices under
the same conditions.93 In a separate study, patch-clamp
recordings revealed augmented hyperexcitability caused by
loss of potassium channel-mediated A-type current, specifi-
cally Kv4.2 channel subunit, in heterotopic pyramidal-like cells
in the CA1, whereas other intrinsic electrophysiological
properties were not changed.87 These findings were corrobo-
rated with a notable reduction of Kv4.2 subunit detected via
immunohistochemistry and in situ hybridization,87 thus,
implicating heterotopic neurons as a plausible source of high
[Kþ]o-induced spontaneous epileptiform activity. However,
recent data showed that epileptiform activity is triggered
independent of heterotopic neurons94 (discussed “hyperexcit-
able belt” in the next section).
CA1 hippocampal recordings in slices obtained from MAM-
treated rats also demonstrated that the NMDA component of
evoked glutamate-mediated excitatory postsynaptic currents
has amplified amplitude and slower decay time as compared
with slices derived from saline injected control animals.74
Further support for NMDA receptor impairment comes from
immunoprecipitation and Western blot analysis where cortical
and hippocampal tissue of MAM-treated rats exhibited a
significant reduction in NR2A/B subunit assembly into NMDA
receptor complex as well as NR2A/B phosphorylation, specif-
ically in postsynaptic membranes.95 Similar alterations in
postsynaptic NMDA composition and phosphorylation have
been reported in epilepsy patients diagnosed with periven-
tricular heterotopia.96 Therefore, the MAM model bears some
similarities to human cortical malformations.
Cortical Freeze-Lesion Model
In this model, physical injury is induced in newborn pups by
local cooling of the neocortical surface, usually by bringing a
liquid nitrogen-cooled probe in contact with the cranium
overlying the cortex, thus, leading to a focal necrotic lesion.61
In adult rodents, cortical freeze-lesion mimics traumatic brain
injury,97 whereas in prenatal and neonatal rats or mice (up to
P4), and while cortical cells are still in the migratory state, the
pathophysiology produced by the same experimental protocol
resembles human neuronal migration disorders,61 including
3-4 layered cortex, that is, microgyrus or cortical cleft, that is,
schizencephaly.
The model is well studied in rats, but comparable results
have been reported in mice. Focal cortical freeze-lesions in
neonatal (P0/P1) rodents, produced by 8-10 seconds contact of
probes 1-2 mm in size, have consistently proven to lead to a
localized four layered microgyrus by P10 as opposed to the
normal 6-layered cortex.62,69 Following the freezing proce-
dure, necrosis within the lesion is believed to be repaired by re-
T. Shaker et al.
routing of migrating neurons98 as well as invasion of reactive
glia99 from surrounding cortical regions to the lesion site,
culminating in layering abnormalities. Characterization of
axonal connectivity in P60 lesioned rats revealed disorganized
thalamocortical, corticothalamic, and callosal projections in the
microgyrus and surrounding cortical tissue.100,101
Structural dyslamination is restricted to the hemisphere
ipsilateral to the lesion, and the hippocampal and subcortical
structures have normal histological appearance.102 Thus,
unlike other FCD models, histological disruptions in the
freeze-lesion model are localized rather than diffuse. Never-
theless, neuropathological alterations are widespread beyond
the lesion. For example, when compared with sham-operated
rats, AMPA, and kainic acid receptor binding was significantly
enhanced not only in dysplastic neurons within the micro-
gyrus but in remote cortical regions as well.75 Also, potentia-
tion of NMDA current was reported in cortical dysplastic
neurons and CA1 hippocampal pyramidal neurons, where
upregulation of NR2B subunit was suggested to drive this
enhanced hyperexcitability.75,103-105
Furthermore, there was a global downregulation in GABAA
receptor expression and binding throughout the ipsilateral
cortex, along with reduced GABAA expression in the ipsilateral
hippocampus and restricted areas of the contralateral
cortex.75,106 Electrophysiological data confirmed functional
decrease in GABAergic currents. In contrast, GABAB down-
regulation was restricted to dysplastic neurons.75
So far no spontaneous seizures have been reported in freeze-
lesioned newborn rats (i.e., without a second insult), however,
many studies described propagating epileptiform activity in
response to presynaptic stimulation during ex vivo electro-
physiological recordings.107-109 Strikingly, epileptogenicity
was not generated within the dysplastic tissue, but rather by
cortical neurons that are in immediate vicinity of the micro-
gyrus,107-109 thus suggesting that the epileptic network lies
outside the site of the lesion. This corresponds to clinical data
where in epileptic FCD patients, ictal activity extends beyond
the anatomical lesion visible via imaging approaches.110 The
paramicrogyral zone (also referred to as the hyperexcitable
belt) exhibits normal architecture, yet electophysiological data
indicated pronounced imbalance between excitatory and
inhibitory networks,75 likely to be caused by ectopic excitatory
input to these neurons.111 Moreover, paramicrogyral neurons
displayed aberrant intrinsic properties, including increased
input resistance and a hyperpolarized resting membrane
potential.112
Recently, Takase et al113 found that cortical dysplasias
elicited by freeze-lesions in prenatal rats at E18 were more
severe than those in neonatal rats, as indicated by complete loss
of local laminar organization.113 As postmitotic astrocytes do
not complete populating the cortex until P0,114 the pro-
nounced defects were attributed to a reduced repair capacity
of the embryonic cortex, caused by diminished reactive
astrocytic gliosis at that stage.113 A follow-up study by the
same group demonstrated that multiple, bilateral freeze-lesions
during embryogenesis are sufficient to provoke in vivo sponta-
neous seizures in adult rats, where 12 of 16 lesioned animals
exhibited spikes confined to the bilateral hippocampi.71
FCD in children
However, the mortality rate was relatively high (20%-30%), as
opposed to neonatal lesions (5%).
Similar to neonatal lesions,75,105 there was a notable increase
in the expression of NMDA glutamatergic subunits NR2A/2B
in the cortex and the hippocampus of epileptic animals vs
shams at P28, that is, before seizure manifestation.71 The same
NMDA upregulation was detected at P78, that is, after seizure
development, only in lesioned rats. Moreover, the glutamate
transporters Glutamate Aspartate Transporter and Glutamate
Transporter 1 along with GABAergic markers glutamic acid
carboxylase 65/67 (GAD65/67) were markedly upregulated in
the cortex at P28.71 Further investigations are necessary to
elucidate the epileptogenic mechanism in this novel model.
In Utero Irradiation Model
Initially used as a tool to investigate the effect of radiation on
brain development during ontogenesis,115 in utero gamma-
irradiation was found to elicit cortical malformations in
rodents, primarily rats, pertinent to human cortical dyspla-
sias.62 Depending on the timing and dose of radiation,
pathological structural changes vary in severity. Migratory
progenitors and precursors appear to be specifically vulnerable
to gamma rays, therefore, irradiation of rat embryos (usually
with 145-225 cGy dosage) during late developmental stages
( E17) mostly targets migrating cells destined to the last
forming layers during corticogenesis, that is, intermediate
layers II-IV, resulting in a 4-layered microgyrus after birth.116
Other cytoarchitectural defects include subcortical and
periventricular heterotopic gray matter, thinning of the cor-
tical mantle, clusters of disoriented neurons, and the pre-
sence of scattered giant pyramidal neurons.116 However, the
irradiation-induced phenotype is diffuse and not uniform
across the cortex. Also, neither dysmorphic nor balloon cells
were described in this model.
Postnatally, the total number of neurons in irradiated
animals (rP6) was comparable with control animals, how-
ever, irradiated rats displayed over 50% reduction of cortical
inhibitory interneurons, where the parvalbumin (PVþ)- and
calbindin (CBþ)-expressing interneuronal subtypes were sig-
nificantly decreased compared to controls, whereas the cell
number of calretinin (CRþ)-expressing subtype was not
changed.117 Notably, this robust reduction of CBþ and PVþ
interneurons, measured by cell density, continues throughout
adulthood.118 Furthermore, Zhou and Roper119 demonstrated
a functional impairment in surviving CBþ and somatostatin-
expressing interneurons within cortical dysplasias, mainly
marked decline in excitatory input and lower spontaneous
firing rate as opposed to controls, while CR interneuron firing
rate was not affected by radiation. More recently, dysplastic fast
spiking PVþ interneurons were found to have reduced output
synaptic efficiency onto other neurons as well as impaired local
gap junction coupling within these neuronal populations.120
Previous clinical studies described interneuron reduction
in tissue derived from epilepsy patients diagnosed with
FCD,61,121,122 thus implicating a potentially similar patho-
physiology between FCDs and the in utero irradiation model.
115
Electrophysiological data also indicated that excitation in
the dysplastic cortex is notably enhanced. Whole-cell patch-
clamp recordings of dysplastic and control neurons demon-
strated a significant increase in spontaneous excitatory post-
synaptic current amplitude and frequency, decrease in
spontaneous IPSC amplitude, and decrease in miniature
Inhibitory Post-Synaptic Currents (IPSC) amplitude and
frequency in dysplastic neurons.123 In addition, patch-
clamp recordings combined with paired-pulse stimulation
revealed augmented presynaptic release probability in pyr-
amidal neurons.124 Extracellular field recordings in dysplastic
slices showed that hyperexcitability induced by the GABAA
receptor antagonist, bicuculline, was significantly higher in
pyramidal neurons of irradiated animals than in their control
counterparts.76 Hence, in utero irradiation creates an imbal-
ance between the excitatory and inhibitory networks in
dysplastic tissue, possibly leading to epileptogenicity. Indeed,
2 studies have reported spontaneous seizure activity in adult
animals, albeit the number of animals used in the experiments
was relatively small. The first study identified ictal activity in
4 of 7 irradiated rats via continuous in vivo EEG monitoring,
yet seizures originated from outside the frontal cortex or the
hippocampus.125 A subsequent study used EEG accompanied
by video recording, where seizures localized to the cortical or
hippocampal electrodes were detected in 3 of 5 animals.72
However, these results warrant further investigation.
The Two-Hit Model
Because most of the available FCD models are not sufficient to
trigger in vivo recurrent spontaneous seizures, it is hypothesized
that cortical lesions rather facilitate seizure development by
predisposing the brain to hyperexcitability. The findings that
cortical lesions in different models can lower seizure threshold
and enhance seizure activity support this notion. For example,
MAM-treated rats postnatally exposed to anesthetic agents,
such as flurothyl, or proconvulsant agents, like pilocarpine,
kainic acid (KA), and bicuculline, showed significantly lower
threshold for seizures than nontreated controls.64,65,67 Also, in
2 different studies, subjecting neonatal freeze-lesioned and
MAM-treated rats to prolonged hyperthermia, which is a
model for febrile seizures, led to reduced seizure latency.66,68
Therefore, if the perinatal FCD is followed by a seizure-
provoking insult, additive pathological contributions of both
insults (or two hits) can potentiate ictal discharges.
So far, seizures were reported in 2 distinct two-hit models
that combined perinatal cortical injury with an epileptogenic
stressor. The first model used in utero irradiation at E17,
followed by a single sub-convulsive dose of pentylenetetrazole
at P45, where only the rats exposed to both insults (8 of 11)
displayed chronic frequent epileptiform spikes (up to 50 days
postpentylenetetrazole injection) that arose from the bilateral
hippocampi.69 In the second model, cortical freeze-lesion at P1
was followed by hyperthermia-induced seizures at P10.70 After
a latent seizure-free period, spontaneous recurrent seizures
were recorded in adult rats around P80, whereas no seizure
activity was observed throughout adulthood in rats with the
116
lesion alone or hyperthermia alone.70 Seizures occurred in
86%-100% of male rats arising in the temporal lobe ipsilateral
to the lesion.45,70,126 Interestingly, male rats appear to be
particularly vulnerable in this model, as females that received
the same insults did not develop epilepsy.127 Analysis of
epileptic rats revealed hippocampal atrophy, neuronal loss,
and synaptic reorganization in the ipsilateral hippocampus as
compared to rats that underwent a single insult and naive
pups.45 Although the lesion enhanced the function of gluta-
matergic networks (as previously indicated in the Cortical
Freeze-Lesion Model Section), hyperthermia potentiated
GABAergic networks in hippocampal CA1 pyramidal cells,
thus, producing additive excitatory and inhibitory effects on
hippocampal circuits.105 For an overview on the lesion þ
hyperthermia two-hit model, see review.128
Conclusions
FCD represent a common cause of medication resistant
epilepsy in children. Their recognition has been improved by
modern imaging techniques and their complete removal leads
to a successful surgical outcome. However, both electro-
physiological and functional data in animal and human studies
suggest that in a number of these lesions, the epileptogenic
zone extends beyond the anatomical margins because of
modifications of both excitatory and synaptic networks.
Finally, surgical tissue studies over the next few years would
further improve our knowledge on the mechanisms leading to
FCD as somatic mutations or mosaicisms would be identified
in critical pathways involved in cortical development.
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