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Focal Cortical Dysplasia
Focal Cortical Dysplasia M Thom, University College London, London, UK r 2014 Elsevier Inc. All rights reserved.
Introduction Focal cortical dysplasia (FCD) is an intriguing brain disorder that has a strong association with epilepsy. It is considered to be a developmental abnormality but its precise cause remains unknown. The epilepsy associated with this condition is usually resistant to available drug treatments. However, with advances in neuroimaging, many of the lesions are clearly visible on magnetic resonance imaging (MRI) and surgical treatment is often a successful option. It represents one of the commonest abnormalities in epilepsy surgical series. Through study of the removed tissues, neuropathologists have gained insight into the characteristics of FCD and cellular abnormalities that might indicate how it arises during development and how it becomes epileptogenic. Over the past decades with the expansion of epilepsy surgical programs, it has become apparent through more detailed neuropathology studies that a spectrum of dysplasias exists with divergent degrees of neuropathological abnormalities. It has been necessary to develop classification systems so that similar terminology is being used both between centers and across clinical disciplines, including neuroradiology and neuropathology. These classifications have evolved over the years up to the most recent system, the International League Against Epilepsy (ILAE) 2011 classification.
Definition The current best definition for FCD is a presumed developmental abnormality of the cortical plate, associated with clinical seizures, manifesting as abnormal cytoarchitecture, restricted in extent, and with preservation of the gyral pattern.
Evolution of Classification Systems Cortical dysplasia was first described as a distinct neuropathological entity in the seminal paper by Taylor and colleagues. Published in 1971 and based on observations in 10 patients from the early epilepsy surgical programs, Taylor and colleagues considered FCD to be a developmental neuropathology, a view most workers in the field still share. The term ‘cortical dysplasia,’ literally meaning abnormal formation of the cortex, became rather freely used through the 1990s for varied malformations seen on neuroimaging, ranging from abnormalities of the cortical gryal pattern such as polymicrogyria to subtler abnormalities such as microdysgenesis. Classification schemes therefore evolved, using neuropathology as the gold standard and grouping together cases with distinct features. This was necessary to facilitate clarity in clinico–radiological–pathological correlations. The first universally accepted classification scheme was the Palmini system in 2004, which in essence separated the dysplasias with
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abnormal lamination (the ‘architectural’ dysplasias) from those with abnormal cytology (‘the cytoarchitectural’ dysplasias, equivalent to Taylor’s dysplasia); these were classified as FCD types I and II, respectively. The features of microdysgenesis were also separated from the FCDs into a group called mild malformations of cortical development. The recently revised 2011 ILAE classification has taken the further step of adding a third tier, FCD type III. This is in recognition of dysplasias that are associated with a second epileptogenic pathology and have different patho-etiological and clinical features from the ‘isolated’ dysplasias types I and II (Table 1). The necessity of revising classifications is to integrate new pathological information and to provide clear definitions that are reproducible following testing, scientifically valid, and can be consistently applied between centers, in order to allow meaningful clinical outcome data to emerge for future surgical planning and patient management.
Pathology Features Macroscopic Features The majority of FCD cases are diagnosed in surgical resection specimens and there are relatively few reports of postmortem examples. Following fixation and slicing of the tissue sample, the dysplastic region may be (but not always) visible to the naked eye, FCD type II being more readily identified macroscopically (Figures 1(a) and (b)). The gyral pattern appears normal but the region of dysplasia may appear firmer (due to local gliosis) with poorer definition between the gray and white matter as compared to the adjacent normal cortex. As noted in Taylor’s original paper, there is a tendency for FCD type II to be centered on the bottom of a sulcus (Figures 1(c)–(f)), although in some cases the abnormality can extend over several adjacent gyri or rarely it can be multifocal. In terms of lobar involvement, distribution around the central sulcus, frontal, and temporal lobes is more common in surgical series.
Microscopic Features Focal cortical dysplasia type I FCD type I is characterized by the presence of abnormal radial and/or tangential alignment of neurons but without significant abnormalities of neuronal morphology. Care has to be taken in the differentiation of FCD type I from normal regional variations in cortical cytoarchitecture. In fact some studies have demonstrated that the intra- and interobserver reproducibility for the diagnosis of FCD type I is much less than for FCD type II and the diagnosis open to subjective lower interpretation. There is a need for molecular or immunohistochemical diagnostic markers that can discriminate FCD type I from normal cortex as well as other dysplasias. For
Encyclopedia of the Neurological Sciences, Volume 2
doi:10.1016/B978-0-12-385157-4.00590-X
Focal Cortical Dysplasia
Table 1
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The International League Against Epilepsy (2011) classification scheme for focal cortical dysplasia
Dysplasia type
Pathological features
FCD type I (isolated)
Focal cortical dysplasia with abnormal radial cortical lamination (FCD type Ia)
FCD type II (isolated)
Focal cortical dysplasia with dysmorphic neurons (FCD type IIa)
FCD type III (associated with principal lesion)
Cortical lamination Cortical lamination Cortical lamination Cortical lamination abnormalities in the abnormalities adjacent abnormalities abnormalities adjacent to any other lesion acquired temporal lobe to a glial or adjacent to glioneuronal tumor vascular during early life, for associated with (FCD type IIIb) malformation example, trauma, ischemic hippocampal sclerosis (FCD type (FCD type IIIc) injury, encpehalitis (FCD type IIId) IIIa) FCD III (not otherwise specified (NOS)): if a clinically/radiologically suspected principal lesion is not available for microscopic examination Rare association of FCD type II with hippocampal sclerosis, tumors, or vascular malformation should not be classified as FCD type III
Focal cortical dysplasia with abnormal tangential cortical lamination (FCD type Ib)
Focal cortical dysplasia with abnormal radial and tangential cortical lamination (FCD type Ic)
Focal cortical dysplasia with dysmorphic neurons and balloon cells (FCD type IIb)
Source: Adapted from Blumcke I, Thom M, Aronica E, et al. (2011) The clinicopathologic spectrum of focal cortical dysplasias: A consensus classification proposed by an ad hoc Task Force of the ILAE Diagnostic Methods Commission. Epilepsia 52: 158–174.
example, there is no activation of the mammalian target of rapamycin complex 1 (mTORC1) in FCD type I and absent expression of progenitor cell markers as observed in FCD type II (see next section). In another study of FCD type I from young patients utilizing cortical layer markers, abnormal expression of Otx1 and Tbr1 was noted in small immature neurons at the junction of layers I and II; similar cells were also positive for doublecortin, attesting to their immaturity, and these were not noted in other FCD types or in normal controls.
Focal cortical dysplasia type II This dysplasia subtype is characterized by the identification of dysmorphic neurons. These are large, abnormally shaped, and orientated neurons that may reside in any of the cortical laminae (and often present throughout the cortical thickness) except layer I. These neurons do not respect laminar or tangential ordering of the normal cortex, which gives rise to a haphazard arrangement at low magnification (Figures 1(c) and (d), and Figures 2(c) and (d)). Dysmorphic cells have a ‘tigroid’ pattern on hematoxylin and eosin (H&E) and cresyl violet stain (Figure 3(a)). Dysmorphic neurons are also present in the white matter beneath the dysplasia where they may be orientated in a more horizontal direction. In some cases neurons in the superficial cortical layers retain a more pyramidal morphology whereas dysmorphic neurons in deeper layers are more globoid in shape. In between dysmorphic neurons more normal cortical pyramidal and smaller neurons are visible. The abnormal area merges with normal cortex at the margins and often isolated dysmorphic neurons may be identified at some distance away from the main focus of dysplasia. In pediatric FCD type II cases there is an impression of a greater packing density of neurons as verified by quantitative data. The second prominent cell component that is observed in FCD type IIb is the balloon cell (Figure 3(a)). These are large, round cells with ‘frosted glass’ cytoplasm on H&E and an eccentrically placed nucleus. Multinucleated balloon cells may be present. They may be present in groups or clusters, and
are often found in the white matter immediately beneath the abnormal cortex or aggregating in layer I, although they can be present throughout the cortex. Balloon cells often trail into the deep white matter toward the ventricle and this is often associated with a reduction of density of myelinated fibers (Figures 2(a) and (b)). Abnormalities of the cortical myeloarchitecture are also present in the region of dysplasia (Figure 2(f)). In some dysplasias, balloon cells are the dominant cell type, whereas in others they are less visible. Their identification, which may be aided by immunohistochemistry (see later), is a requisite for the classification as FCD type IIb (Table 1). Occasional cells may be observed that have cytological features intermediate between balloon cells and dysmorphic neurons (Figure 3(d)). There appears to be a decline in neuronal density in FCD with aging (Figure 2(d)). In addition, premature accumulation of neurofibrillary tangles and phosphorylated tau in dysmorphic neurons but not balloon cells have been shown, possibly implying accentuated vulnerability to aging and neurodegeneration in these abnormal cell types. Immunohistochemistry of focal cortical dysplasia type II In FCD type IIb, the contrasting morphology of dysmorphic neurons and balloon cells is supported by their distinct immunoprofiles with many markers (Table 2). The abnormal position, shape, and somato-dendritic morphology of dysmorphic neurons becomes apparent on immunohistochemistry for NeuN and both phosphorylated and nonphosphorylated neurofilament proteins (Figures 3(b) and 4(a)); balloon cells are usually negative for these markers. Dysmorphic neurons appear surrounded by synaptic proteins, particularly visible in the white matter (Figure 4(b)). They may additionally retain expression of developmentally regulated proteins such as Pax6, Otx1, doublecortin (Figure 4(e)), and nestin (Figure 4(c)). Overall dysmorphic neurons express markers supporting their origins from radially migrating neurons (Otx1, Pax6 immunopositivity) from the ventricular zone, rather than tangentially
(a)
(b)
(c)
(d)
(e)
(f)
Figure 1 Macroscopic findings in FCD. A case of surgically resected FCD type IIb. (a) Normal adjacent gyrus with good demarcation between the gray and the white matter. (b) In the region of FCD the demarcation becomes less clear with the cortex merging with the white matter (arrowhead). (c) NeuN staining of the abnormal gyrus shown in (b) shows normal laminar pattern of neurons at the crown (star) but in the depths of the sulcus the neurons become randomly spaced with loss of laminar order. Similarly, (d) in neurofilament stain (SMI32), in the normal cortex (star) the expression is mainly axonal but in the region of dysplasia single large neurons are evident at low power. (e) Myelin basic proteins also confirm alteration to the myeloarchitecture in the region of dysplasia with increased cortical myelinated fibers in the region of dysplasia (arrowhead). (f) CD34 staining at low magnification highlights aberrant expression of this stem cell protein particularly in the sulcal depths at the cortical–white matter junction.
Focal Cortical Dysplasia
Luxol fast blue/cresyl violet
Normal
FCD II
VI
WM
(a)
(b)
I
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migrating neurons from the medial ganglion eminence (Dlx1, Dlx2 immunonegativity). Their phenotype (Tbr1, Map1b, and N200 immunopositivity) supports the notion that they most closely resemble intermediate progenitor cells that give rise to mature cortical pyramidal cells. In contrast, a proportion of balloon cells label strongly with glial fibrillary acidic protein (GFAP), in support of astroglial lineage; balloon cells may also be GFAP negative (Figure 3(c)). Additional labeling with developmentally regulated intermediate filaments such as vimentin, nestin, and GFAP-delta (Figure 4(d)) supports a more immature glial phenotype. In addition, stem cell proteins such as CD133, b-integrin, and CD34 (Figures 3(e) and (f)) are often expressed in balloon cells, the latter displaying a typical peripheral labeling pattern, enhancing multipolar processes. Coexpression of neuronal markers has been demonstrated in a proportion of balloon cells in several studies, suggesting aberrant differentiation or a pluripotency with abnormal cellfate specification of these cells. Bcl-2 expression in balloon cells also raises the possibility of excessive antiapoptotic activity and abnormal postdevelopmental survival. Studies of cell cycle proteins, including mcm2, cdk4 (Figure 4(g)), and p53, confirm their ongoing proliferative capacity, but balloon cells appear arrested in the early G1 phase of the cell cycle, failing to either divide or die. Immunophenotypical characteristics, including expression of Pax6, ER81, and Otx1, lend support to the hypothesis of the derivation of balloon cells from radial glial stem cells that have failed to regress.
NeuN
Focal cortical dysplasia type III
IV
SMI94 (myelin)
(c)
(d)
VI
(e)
(f)
Figure 2 Myelo- and cytoarchitecture in FCD IIb. In the left-hand column normal cortex is compared to the region of FCD on the right and labeled with luxol fast blue (a,b), NeuN (c,d), and SMI94 (e,f). Poor demarcation is observed between layer VI and the white matter (b) with an abnormal distribution of neurons (d) and evidence of a reduction in their overall density and more horizontal orientation of deeper cortical neurons. The SMI94 stain shows normal radial bundles of myelinated fibers in (e) with an anarchic pattern of fibers in the region of dysplasia (f).
FCD type III refers to cortical laminar abnormalities associated with a principal (presumed epileptogenic) lesion; often the dysplasia is adjacent or contiguous with the main lesion. FCD type IIIa is a dysplasia of the temporal neocortex associated with hippocampal sclerosis. One of the commonest cortical abnormalities noted has been termed temporal lobe sclerosis (TLS) and is observed in approximately 11% of patients who have hippocampal sclerosis in surgical epilepsy series. It is characterized by neuronal loss from the deeper parts of layers II and III with preservation of residual neurons in the outer part of layer II (Figure 5(a)). This is associated with laminar gliosis in layer II, and hence the term ‘sclerosis’ in recognition that the neuronal loss appears ‘acquired’ in a previously mature six-layered cortex. Superimposed on this process, there appear to be reorganizational changes in the remaining neurons in layer II including clustering, abnormal orientation, and enhanced expression of neurofilament proteins. The inhibitory interneurons in the outer cortex appear unaffected. In some cases abnormal horizontal myelinated fibers run through the superficial cortex. In approximately 40% of cases this pathology preferentially affects the temporal pole. Overall, the histology supports abnormal maturation and organization of the superficial cortex, primarily involving layer II in the TLS types of FCD IIIa as representing a postmigrational, acquired dysplastic lesion, as a result of the early frequent seizures that also cause the hippocampal sclerosis. However, recent studies using cortical layer markers have suggested that some neurons in superficial layers in TLS are misplaced layer V (ER81-positive) neurons, propose that there is an underlying dyslaminar cortical dysplasia.
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Focal Cortical Dysplasia
(a)
(b)
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(d)
(e)
(f)
Figure 3 Cell types in FCD IIb. Dysmorphic neuron is shown on the left and balloon cells in the right of figure (a) stained with hematoxylin and eosin. (b) NeuN staining confirms enlarged neurons present in the cortex with interspersed more normal-sized neurons. In addition, note the negative balloon cell. (c) Glial fibrillary acidic protein (GFAP) labels a proportion of balloon cells; labeling of dysmorphic neurons or intermediated cells is not seen with GFAP. (e and f) CD34 labeling identifies a subset of balloon cells with prominent membranous and multipolar processes.
FCD type IIIb is a dysplasia associated with tumors and is more often reported in the context of low-grade glioneuronal tumors such as dysembryoplastic neuroepithelial tumors (DNT) and gangliogliomas (World Health Organization grade I). Again, similar to reporting of FCD type I, there is variability in the recognition and reporting of FCD type IIIb. For example,
in a review of all reported DNT series (624 tumors) the variability in the association of FCD type I with DNT was 8.3–82% and for FCD type II 9–69%. Care must be taken not to interpret disrupted and subtly infiltrated cortex at the margins of the tumor as dysplasia (Figures 5(b) and (c)). The etiology and pathogenesis of FCD type IIIb, where confirmed,
Focal Cortical Dysplasia
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Table 2 Immunohistochemistry profile of the main cell types in FCD type IIB in relation to the proposed lineage of the cell type, maturation, abnormal function, and proliferative status that has been supported in some studies Cell type
Balloon cells
Dysmorphic neurons
Other cell types
Mature cell lineage markers
GFAPm ork(small proportion coexpress neuronal markers)
Nonphosphorylated neurofilament (e.g., SMI31)m Phosphorylated neurofilament (e.g., SMI32)m NeuN-
Calbindin-positive neurons-k
Immature, developmentally regulated markers
Nestinm, GFAP-deltam
Otx1m, Pax6m
Doublecortinm, Doublecortinlike proteinm, vimentinm b1-integrinm, CD34m
Doublecortinm
CD133m, Pax6m, Otx1m ER81m SOX2, Oct-4m Cell functional status/ inflammatory mediators
Synaptic vesicle protein 2A (SV2A) k Adhesion molecule on glia (AMOG)m Toll-like receptor2 m
pS6 (mTOR pathway activation) and p4E-BP1m pAKt (PiK3 pathway) m IL-1bm VEGFAm Proliferation status
Parvalbumin-positive neurons -k Calretinin-positive neurons -k
Doublecortin-like proteinm, nestin-m Tbr1m, Map1bm MASH1m Synaptophysin m
HLA-DR þ microgliam
VGlut (vesicular glutamate transporter)NKCC1 (chloride channel)m, C1q and C3d (complement pathway)m, IL-1bm Toll-like receptor 4m VEGFA, B and VEGFR1 & 2m
Mcm2m Cdk4, p53m
m, increased expression compared to normal adult cortex; k, reduced or no expression ;-, expression not altered.
is unknown but it is considered likely to be an acquired process. In addition, there is uncertainty regarding the contribution of the adjacent cortex to seizure activity, which merits further investigation. FCD types IIIc and d refer to cortical changes adjacent to vascular malformation or early cortical injury or scar, respectively. In FCD IIId often there are striking abnormalities of the cortical myeloarchitecture, with marbling, islands of residual neurons, and intervening gliosis in early acquired lesions resulting in striking reorganizational changes to the cortex (Figures 5(d)–(f)). In the context of Rasmussen’s chronic encephalitis in epilepsy, coexisting cortical dysplasialike changes are frequently reported including dysmorphic neurons (Figures 5(g)–(i)). Rather than this representing a dual pathology (FCD type II plus encephalitis), it is more likely that these are reorganizational changes secondary to the primary inflammatory encephalitis (FCD type IIId).
Neuroradiology The majority of FCD type II are visible with conventional MRI. The typical features are blurring of the gray–white matter boundaries and abnormal signal intensity in the white matter on T2 and fluid-attenuated inversion recovery (FLAIR) sequences typically forming a funnel-shaped zone toward
the ventricle. It is estimated that approximately 20–30% of FCD type II are MRI negative, but increased detection can be achieved with morphometric analysis. In one series of FCD type IIIa (TLS associated with hippocampal sclerosis) the neocortical abnormalities were not detected on preoperative MRI or even following morphometric analysis. There are at present no reliable or consistent presurgical imaging changes for FCD type I, although some pediatric cases are associated with cortical and cerebral hypoplasia on MRI.
Outcome Following Surgery Paradoxically, the histologically more severe or abnormalappearing dysplasia of FCD type II has a better outcome following surgical resection than FCD type I. Seizure-free outcomes following resection of FCD type II are approximately 75% and between 20% and 43% for FCD type I. Completeness of resection of the cortical abnormality may improve chances of a seizure-free outcome, removal of the cortical rather than the white matter component being more critical. In one series the presence or absence of FCD type IIIa in addition to hippocampal sclerosis did not influence outcome, with similar seizure-free outcomes for patients with hippocampal sclerosis alone.
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Focal Cortical Dysplasia
Synaptophysin
SMI32
(a)
(b)
Nestin
Delta-GFAP
(c)
(d)
DCX
Calbindin
(e)
(f)
cdk4
GFAP
(g)
Figure 4 Immunostaining characteristics of FCD. (a) Neurofilament stains as SMI32 highlight the dysmoprhic neurons and their processes. (b) Synaptophysin shows a peripheral labeling pattern, (c) nestin highlights dysmorphic cell adjacent to a balloon cell. (d) Delta-glial fibrillary acidic protein (GFAP) typically shows strong labeling of balloon cells and their processes. (e) Doublecortin shows strong labeling of dysmorphic cells in FCD and calbindin (f) also highlights mulitpolar hypertrophic cells. (g) Cell cycle proteins expressed in a proportion of balloon cells suggest they are licensed for replication.
Focal Cortical Dysplasia
What is the Cause of Focal Cortical Dysplasia? Most consider that FCD type II is a cortical malformation, but the precise timing and critical events causing this lesion are unclear. The ‘dysmature cerebral hypothesis of cortical
NeuN I
I
NeuN
CD34
II
III II
IV III
V
(a)
(b)
(c)
GFAP
I
II
VI (d)
(e)
(f)
CD68
(h)
Neurofilament
(g)
(i)
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dysplasia’ of Cepeda in 2006 proposes, based on histological and electrophysiological evidence, that balloon cells represent radial glia and dysmorphic neurons, subplate cells that have failed to degenerate or regress perinatally and have become integrated with normal postnatal neurons. There is anecdotal evidence that FCD type II is perhaps not a static lesion and ‘matures’ over time, supported by the observation of more frequent multilobar involvement in children compared to localized FCD lesions in adult brain. Indeed, a recent study of FCD type II in children confirmed in vitro isolation of a pathological cell with the phenotype of a progenitor cell/stem cell and the morphology of balloon cells. However, these cells may contribute to the formation of FCD lesions; unlike tumor stem cells, they do not show significant deoxyribonucleic acid synthesis or undergo cell division, suggesting a restricted capacity for proliferation. Owing to histological similarities between FCD type IIb and tuberous sclerosis (TSC), several studies have confirmed the activation of the pi3K-mTOR (mammalian target of rapamycin) signaling pathway in FCD type IIb, with evidence that this represents a primary pathogenic mechanism. mTOR normally regulates a number of physiological functions governing cell growth, metabolism, proliferation, and cell survival, and promotes protein synthesis including ribosomal S6 proteins and eIF43. The proteins tuberin and hamartin (mutated in TSC) normally inhibit the mTOR pathway and prevent excess cell growth and proliferation. Although in FCD, disease-causing mutations of TSC genes TSC1 and TSC2 have not been identified, there is evidence for dysregulation of mTOR signaling with activated ribosomal S6 and eIF43, which may indicate alternative activation pathways, possibly through insulin/Pi3K/Akt. Some efficacy with treatment of rapamycin in TSC lesions confirms the functional importance of this pathway in reversing their size. The molecular pathogenesis that distinguishes FCD types I–III has not been fully elucidated. However, there is no confirmation of mTOR pathway dysfunction in FCD type I, suggesting that FCD types I and II are both histologically and biologically distinct. A further possibility that deserves study is the contribution of normal residual progenitor cells to FCD. Seizures themselves or abnormal cellular activity early in life could result in abnormal recruitment of progenitor cells, with cortical reorganization and deranged gliogenesis and neurogenesis resulting in aberrant expression of developmentally regulated proteins. In support of this, cytoarchitectural
Figure 5 FCD type III subtypes. (a) The features of temporal lobe sclerosis, which is one subtype of FCD IIIa, show aggregation of remaining neurons in layer II and loss of neurons in deeper layer III. (b,c) The differential of FCD type IIIb includes cortical infiltration. In this section (b) NeuN staining is suggestive of architectural dysplasia; however, a corresponding section is labeled with CD34. (c) Confirms widespread infiltration by tumor cells. (d–f) FCD IIId. The cortex adjacent to a neonatal infarct shows ‘marbeling’ of the cortex with myelin bundles and nodules of neurons in the cortex as well as patchy gliosis (f). (g) Rasmussen’s encephalitis showing a region with cortical collapse and (h) microglial nodules. (i) Neurofilament stain shows scattered dysmorphic-appearing neurons at the margins of the atrophied cortex. This corresponds to FCD IIId and not additional FCD II.
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Focal Cortical Dysplasia
alterations have been reported in the context of known acquired postnatal lesions including early infarcts, traumatic lesions, chronic encephalitis, and mesial temporal sclerosis, which are now grouped under FCD type III. Plasticity of the maturing brain with possibly maladaptive changes in response to injury may contribute to the cellular pathology of such ‘reorganizational dysplasias’, as well as to their epileptogenicity.
regulate glutamate synthesis and removal as well as alteration of glutamate transporters, may play a role in local excitability.
What Makes Focal Cortical Dysplasia Epileptogenic?
Further Reading
It remains unclear whether seizures start within the lesions themselves or in the surrounding cortex in all FCD. In many cases of FCD type IIb, as removal of the lesion results in permanent seizure freedom, this would support the notion of intrinsic epileptogenicity. The abnormality promoting seizures may arise at the circuit level with a reduction of g-aminobutyric acid (GABA)ergic inhibitory cells and overbalance of excitatory connections. In support of this, in tissue resections a reduction in the ratio of inhibitory interneurons, including calretinin-, calbindin-, and parvalbumin-positive neurons, has been observed in FCD type II. Alternatively, at the single-cell level, alterations in the coassembly of glutamatergic receptors has been shown in dysmorphic neurons, including a-amino-3-hydroxy5-methyl-isoxazole-4-propionic acid (AMPA) and N-methylD-aspartate (NMDA). Additionally, abnormal expression of Na þ /K þ chloride co-transporter (NKCC1) identified, as a reflection of neuronal immaturity has been shown. Functional overexpression of NKCC1 can lead to higher intracellular chloride concentrations within dysplastic neurons, making it more difficult for GABA to generate inhibitory hyperpolarizing potentials in these neurons, or even causing GABA to become excitatory. Electrophysiological studies using single-cell recordings support that cytomegalic neurons have hyperexcitable intrinsic membrane properties whereas balloon cells in contrast appear nonexcitable. In addition, cytomegalic interneurons have been identified in pediatric cases of FCD with evidence for their hyperexcitability including increased firing rates. Activation of proinflammatory pathways in FCD type IIb has been shown, which also has a proconvulsant effect, for example, through activation of toll-like receptor signaling. In addition, the contribution of astrocytes, which
Andre VM, Wu N, Yamazaki I, et al. (2007) Cytomegalic interneurons: A new abnormal cell type in severe pediatric cortical dysplasia. Journal of Neuropathology and Experimental Neurology 66: 491–504. Blumcke I, Thom M, Aronica E, et al. (2011) The clinicopathologic spectrum of focal cortical dysplasias: A consensus classification proposed by an ad hoc Task Force of the ILAE Diagnostic Methods Commission. Epilepsia 52: 158–174. Cepeda C, Andre VM, Levine MS, et al. (2006) Epileptogenesis in pediatric cortical dysplasia: The dysmature cerebral developmental hypothesis. Epilepsy and Behavior 9: 219–235. Chamberlain WA, Cohen ML, Gyure KA, et al. (2009) Interobserver and intraobserver reproducibility in focal cortical dysplasia (malformations of cortical development). Epilepsia 50: 2593–2598. Hildebrandt M, Pieper T, Winkler P, et al. (2005) Neuropathological spectrum of cortical dysplasia in children with severe focal epilepsies. Acta Neuropathologica 110: 1–11. Iyer A, Zurolo E, Spliet WG, et al. (2010) Evaluation of the innate and adaptive immunity in type I and type II focal cortical dysplasias. Epilepsia 51: 1763–1773. Lamparello P, Baybis M, Pollard J, et al. (2007) Developmental lineage of cell types in cortical dysplasia with balloon cells. Brain 130: 2267–2276. Orlova KA, Tsai V, Baybis M, et al. (2010) Early progenitor cell marker expression distinguishes type II from type I focal cortical dysplasias. Journal of Neuropathology and Experimental Neurology 69: 850–863. Palmini A, Najm I, Avanzini G, et al. (2004) Terminology and classification of the cortical dysplasias. Neurology 62: S2–S8. Taylor DC, Falconer MA, Bruton CJ, and Corsellis JA (1971) Focal dysplasia of the cerebral cortex in epilepsy. Journal of Neurology, Neurosurgery and Psychiatry 34: 369–387. Thom M, Eriksson S, Martinian L, et al. (2009) Temporal lobe sclerosis associated with hippocampal sclerosis in temporal lobe epilepsy: Neuropathological features. Journal of Neuropathology and Experimental Neurology 68: 928–938. Thom M, Martinian L, Sen A, et al. (2007) An investigation of the expression of G1-phase cell cycle proteins in focal cortical dysplasia type IIB. Journal of Neuropathology and Experimental Neurology 66: 1045–1055. Yasin SA, Latak K, Becherini F, et al. (2010) Balloon cells in human cortical dysplasia and tuberous sclerosis: Isolation of a pathological progenitor-like cell. Acta Neuropathologica 120: 85–96.
See also: Epilepsy Pathology. Epilepsy; Surgery. Epilepsy Treatment Strategies. Immunohistochemistry and Brain Tumors. Magnetic Resonance (MR); Overview
Introduction Focal cortical dysplasia (FCD) is an intriguing brain disorder that has a strong association with epilepsy. It is considered to be a developmental abnormality but its precise cause remains unknown. The epilepsy associated with this condition is usually resistant to available drug treatments. However, with advances in neuroimaging, many of the lesions are clearly visible on magnetic resonance imaging (MRI) and surgical treatment is often a successful option. It represents one of the commonest abnormalities in epilepsy surgical series. Through study of the removed tissues, neuropathologists have gained insight into the characteristics of FCD and cellular abnormalities that might indicate how it arises during development and how it becomes epileptogenic. Over the past decades with the expansion of epilepsy surgical programs, it has become apparent through more detailed neuropathology studies that a spectrum of dysplasias exists with divergent degrees of neuropathological abnormalities. It has been necessary to develop classification systems so that similar terminology is being used both between centers and across clinical disciplines, including neuroradiology and neuropathology. These classifications have evolved over the years up to the most recent system, the International League Against Epilepsy (ILAE) 2011 classification.
Definition The current best definition for FCD is a presumed developmental abnormality of the cortical plate, associated with clinical seizures, manifesting as abnormal cytoarchitecture, restricted in extent, and with preservation of the gyral pattern.
Evolution of Classification Systems Cortical dysplasia was first described as a distinct neuropathological entity in the seminal paper by Taylor and colleagues. Published in 1971 and based on observations in 10 patients from the early epilepsy surgical programs, Taylor and colleagues considered FCD to be a developmental neuropathology, a view most workers in the field still share. The term ‘cortical dysplasia,’ literally meaning abnormal formation of the cortex, became rather freely used through the 1990s for varied malformations seen on neuroimaging, ranging from abnormalities of the cortical gryal pattern such as polymicrogyria to subtler abnormalities such as microdysgenesis. Classification schemes therefore evolved, using neuropathology as the gold standard and grouping together cases with distinct features. This was necessary to facilitate clarity in clinico–radiological–pathological correlations. The first universally accepted classification scheme was the Palmini system in 2004, which in essence separated the dysplasias with
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abnormal lamination (the ‘architectural’ dysplasias) from those with abnormal cytology (‘the cytoarchitectural’ dysplasias, equivalent to Taylor’s dysplasia); these were classified as FCD types I and II, respectively. The features of microdysgenesis were also separated from the FCDs into a group called mild malformations of cortical development. The recently revised 2011 ILAE classification has taken the further step of adding a third tier, FCD type III. This is in recognition of dysplasias that are associated with a second epileptogenic pathology and have different patho-etiological and clinical features from the ‘isolated’ dysplasias types I and II (Table 1). The necessity of revising classifications is to integrate new pathological information and to provide clear definitions that are reproducible following testing, scientifically valid, and can be consistently applied between centers, in order to allow meaningful clinical outcome data to emerge for future surgical planning and patient management.
Pathology Features Macroscopic Features The majority of FCD cases are diagnosed in surgical resection specimens and there are relatively few reports of postmortem examples. Following fixation and slicing of the tissue sample, the dysplastic region may be (but not always) visible to the naked eye, FCD type II being more readily identified macroscopically (Figures 1(a) and (b)). The gyral pattern appears normal but the region of dysplasia may appear firmer (due to local gliosis) with poorer definition between the gray and white matter as compared to the adjacent normal cortex. As noted in Taylor’s original paper, there is a tendency for FCD type II to be centered on the bottom of a sulcus (Figures 1(c)–(f)), although in some cases the abnormality can extend over several adjacent gyri or rarely it can be multifocal. In terms of lobar involvement, distribution around the central sulcus, frontal, and temporal lobes is more common in surgical series.
Microscopic Features Focal cortical dysplasia type I FCD type I is characterized by the presence of abnormal radial and/or tangential alignment of neurons but without significant abnormalities of neuronal morphology. Care has to be taken in the differentiation of FCD type I from normal regional variations in cortical cytoarchitecture. In fact some studies have demonstrated that the intra- and interobserver reproducibility for the diagnosis of FCD type I is much less than for FCD type II and the diagnosis open to subjective lower interpretation. There is a need for molecular or immunohistochemical diagnostic markers that can discriminate FCD type I from normal cortex as well as other dysplasias. For
Encyclopedia of the Neurological Sciences, Volume 2
doi:10.1016/B978-0-12-385157-4.00590-X
Focal Cortical Dysplasia
Table 1
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The International League Against Epilepsy (2011) classification scheme for focal cortical dysplasia
Dysplasia type
Pathological features
FCD type I (isolated)
Focal cortical dysplasia with abnormal radial cortical lamination (FCD type Ia)
FCD type II (isolated)
Focal cortical dysplasia with dysmorphic neurons (FCD type IIa)
FCD type III (associated with principal lesion)
Cortical lamination Cortical lamination Cortical lamination Cortical lamination abnormalities in the abnormalities adjacent abnormalities abnormalities adjacent to any other lesion acquired temporal lobe to a glial or adjacent to glioneuronal tumor vascular during early life, for associated with (FCD type IIIb) malformation example, trauma, ischemic hippocampal sclerosis (FCD type (FCD type IIIc) injury, encpehalitis (FCD type IIId) IIIa) FCD III (not otherwise specified (NOS)): if a clinically/radiologically suspected principal lesion is not available for microscopic examination Rare association of FCD type II with hippocampal sclerosis, tumors, or vascular malformation should not be classified as FCD type III
Focal cortical dysplasia with abnormal tangential cortical lamination (FCD type Ib)
Focal cortical dysplasia with abnormal radial and tangential cortical lamination (FCD type Ic)
Focal cortical dysplasia with dysmorphic neurons and balloon cells (FCD type IIb)
Source: Adapted from Blumcke I, Thom M, Aronica E, et al. (2011) The clinicopathologic spectrum of focal cortical dysplasias: A consensus classification proposed by an ad hoc Task Force of the ILAE Diagnostic Methods Commission. Epilepsia 52: 158–174.
example, there is no activation of the mammalian target of rapamycin complex 1 (mTORC1) in FCD type I and absent expression of progenitor cell markers as observed in FCD type II (see next section). In another study of FCD type I from young patients utilizing cortical layer markers, abnormal expression of Otx1 and Tbr1 was noted in small immature neurons at the junction of layers I and II; similar cells were also positive for doublecortin, attesting to their immaturity, and these were not noted in other FCD types or in normal controls.
Focal cortical dysplasia type II This dysplasia subtype is characterized by the identification of dysmorphic neurons. These are large, abnormally shaped, and orientated neurons that may reside in any of the cortical laminae (and often present throughout the cortical thickness) except layer I. These neurons do not respect laminar or tangential ordering of the normal cortex, which gives rise to a haphazard arrangement at low magnification (Figures 1(c) and (d), and Figures 2(c) and (d)). Dysmorphic cells have a ‘tigroid’ pattern on hematoxylin and eosin (H&E) and cresyl violet stain (Figure 3(a)). Dysmorphic neurons are also present in the white matter beneath the dysplasia where they may be orientated in a more horizontal direction. In some cases neurons in the superficial cortical layers retain a more pyramidal morphology whereas dysmorphic neurons in deeper layers are more globoid in shape. In between dysmorphic neurons more normal cortical pyramidal and smaller neurons are visible. The abnormal area merges with normal cortex at the margins and often isolated dysmorphic neurons may be identified at some distance away from the main focus of dysplasia. In pediatric FCD type II cases there is an impression of a greater packing density of neurons as verified by quantitative data. The second prominent cell component that is observed in FCD type IIb is the balloon cell (Figure 3(a)). These are large, round cells with ‘frosted glass’ cytoplasm on H&E and an eccentrically placed nucleus. Multinucleated balloon cells may be present. They may be present in groups or clusters, and
are often found in the white matter immediately beneath the abnormal cortex or aggregating in layer I, although they can be present throughout the cortex. Balloon cells often trail into the deep white matter toward the ventricle and this is often associated with a reduction of density of myelinated fibers (Figures 2(a) and (b)). Abnormalities of the cortical myeloarchitecture are also present in the region of dysplasia (Figure 2(f)). In some dysplasias, balloon cells are the dominant cell type, whereas in others they are less visible. Their identification, which may be aided by immunohistochemistry (see later), is a requisite for the classification as FCD type IIb (Table 1). Occasional cells may be observed that have cytological features intermediate between balloon cells and dysmorphic neurons (Figure 3(d)). There appears to be a decline in neuronal density in FCD with aging (Figure 2(d)). In addition, premature accumulation of neurofibrillary tangles and phosphorylated tau in dysmorphic neurons but not balloon cells have been shown, possibly implying accentuated vulnerability to aging and neurodegeneration in these abnormal cell types. Immunohistochemistry of focal cortical dysplasia type II In FCD type IIb, the contrasting morphology of dysmorphic neurons and balloon cells is supported by their distinct immunoprofiles with many markers (Table 2). The abnormal position, shape, and somato-dendritic morphology of dysmorphic neurons becomes apparent on immunohistochemistry for NeuN and both phosphorylated and nonphosphorylated neurofilament proteins (Figures 3(b) and 4(a)); balloon cells are usually negative for these markers. Dysmorphic neurons appear surrounded by synaptic proteins, particularly visible in the white matter (Figure 4(b)). They may additionally retain expression of developmentally regulated proteins such as Pax6, Otx1, doublecortin (Figure 4(e)), and nestin (Figure 4(c)). Overall dysmorphic neurons express markers supporting their origins from radially migrating neurons (Otx1, Pax6 immunopositivity) from the ventricular zone, rather than tangentially
(a)
(b)
(c)
(d)
(e)
(f)
Figure 1 Macroscopic findings in FCD. A case of surgically resected FCD type IIb. (a) Normal adjacent gyrus with good demarcation between the gray and the white matter. (b) In the region of FCD the demarcation becomes less clear with the cortex merging with the white matter (arrowhead). (c) NeuN staining of the abnormal gyrus shown in (b) shows normal laminar pattern of neurons at the crown (star) but in the depths of the sulcus the neurons become randomly spaced with loss of laminar order. Similarly, (d) in neurofilament stain (SMI32), in the normal cortex (star) the expression is mainly axonal but in the region of dysplasia single large neurons are evident at low power. (e) Myelin basic proteins also confirm alteration to the myeloarchitecture in the region of dysplasia with increased cortical myelinated fibers in the region of dysplasia (arrowhead). (f) CD34 staining at low magnification highlights aberrant expression of this stem cell protein particularly in the sulcal depths at the cortical–white matter junction.
Focal Cortical Dysplasia
Luxol fast blue/cresyl violet
Normal
FCD II
VI
WM
(a)
(b)
I
329
migrating neurons from the medial ganglion eminence (Dlx1, Dlx2 immunonegativity). Their phenotype (Tbr1, Map1b, and N200 immunopositivity) supports the notion that they most closely resemble intermediate progenitor cells that give rise to mature cortical pyramidal cells. In contrast, a proportion of balloon cells label strongly with glial fibrillary acidic protein (GFAP), in support of astroglial lineage; balloon cells may also be GFAP negative (Figure 3(c)). Additional labeling with developmentally regulated intermediate filaments such as vimentin, nestin, and GFAP-delta (Figure 4(d)) supports a more immature glial phenotype. In addition, stem cell proteins such as CD133, b-integrin, and CD34 (Figures 3(e) and (f)) are often expressed in balloon cells, the latter displaying a typical peripheral labeling pattern, enhancing multipolar processes. Coexpression of neuronal markers has been demonstrated in a proportion of balloon cells in several studies, suggesting aberrant differentiation or a pluripotency with abnormal cellfate specification of these cells. Bcl-2 expression in balloon cells also raises the possibility of excessive antiapoptotic activity and abnormal postdevelopmental survival. Studies of cell cycle proteins, including mcm2, cdk4 (Figure 4(g)), and p53, confirm their ongoing proliferative capacity, but balloon cells appear arrested in the early G1 phase of the cell cycle, failing to either divide or die. Immunophenotypical characteristics, including expression of Pax6, ER81, and Otx1, lend support to the hypothesis of the derivation of balloon cells from radial glial stem cells that have failed to regress.
NeuN
Focal cortical dysplasia type III
IV
SMI94 (myelin)
(c)
(d)
VI
(e)
(f)
Figure 2 Myelo- and cytoarchitecture in FCD IIb. In the left-hand column normal cortex is compared to the region of FCD on the right and labeled with luxol fast blue (a,b), NeuN (c,d), and SMI94 (e,f). Poor demarcation is observed between layer VI and the white matter (b) with an abnormal distribution of neurons (d) and evidence of a reduction in their overall density and more horizontal orientation of deeper cortical neurons. The SMI94 stain shows normal radial bundles of myelinated fibers in (e) with an anarchic pattern of fibers in the region of dysplasia (f).
FCD type III refers to cortical laminar abnormalities associated with a principal (presumed epileptogenic) lesion; often the dysplasia is adjacent or contiguous with the main lesion. FCD type IIIa is a dysplasia of the temporal neocortex associated with hippocampal sclerosis. One of the commonest cortical abnormalities noted has been termed temporal lobe sclerosis (TLS) and is observed in approximately 11% of patients who have hippocampal sclerosis in surgical epilepsy series. It is characterized by neuronal loss from the deeper parts of layers II and III with preservation of residual neurons in the outer part of layer II (Figure 5(a)). This is associated with laminar gliosis in layer II, and hence the term ‘sclerosis’ in recognition that the neuronal loss appears ‘acquired’ in a previously mature six-layered cortex. Superimposed on this process, there appear to be reorganizational changes in the remaining neurons in layer II including clustering, abnormal orientation, and enhanced expression of neurofilament proteins. The inhibitory interneurons in the outer cortex appear unaffected. In some cases abnormal horizontal myelinated fibers run through the superficial cortex. In approximately 40% of cases this pathology preferentially affects the temporal pole. Overall, the histology supports abnormal maturation and organization of the superficial cortex, primarily involving layer II in the TLS types of FCD IIIa as representing a postmigrational, acquired dysplastic lesion, as a result of the early frequent seizures that also cause the hippocampal sclerosis. However, recent studies using cortical layer markers have suggested that some neurons in superficial layers in TLS are misplaced layer V (ER81-positive) neurons, propose that there is an underlying dyslaminar cortical dysplasia.
330
Focal Cortical Dysplasia
(a)
(b)
(c)
(d)
(e)
(f)
Figure 3 Cell types in FCD IIb. Dysmorphic neuron is shown on the left and balloon cells in the right of figure (a) stained with hematoxylin and eosin. (b) NeuN staining confirms enlarged neurons present in the cortex with interspersed more normal-sized neurons. In addition, note the negative balloon cell. (c) Glial fibrillary acidic protein (GFAP) labels a proportion of balloon cells; labeling of dysmorphic neurons or intermediated cells is not seen with GFAP. (e and f) CD34 labeling identifies a subset of balloon cells with prominent membranous and multipolar processes.
FCD type IIIb is a dysplasia associated with tumors and is more often reported in the context of low-grade glioneuronal tumors such as dysembryoplastic neuroepithelial tumors (DNT) and gangliogliomas (World Health Organization grade I). Again, similar to reporting of FCD type I, there is variability in the recognition and reporting of FCD type IIIb. For example,
in a review of all reported DNT series (624 tumors) the variability in the association of FCD type I with DNT was 8.3–82% and for FCD type II 9–69%. Care must be taken not to interpret disrupted and subtly infiltrated cortex at the margins of the tumor as dysplasia (Figures 5(b) and (c)). The etiology and pathogenesis of FCD type IIIb, where confirmed,
Focal Cortical Dysplasia
331
Table 2 Immunohistochemistry profile of the main cell types in FCD type IIB in relation to the proposed lineage of the cell type, maturation, abnormal function, and proliferative status that has been supported in some studies Cell type
Balloon cells
Dysmorphic neurons
Other cell types
Mature cell lineage markers
GFAPm ork(small proportion coexpress neuronal markers)
Nonphosphorylated neurofilament (e.g., SMI31)m Phosphorylated neurofilament (e.g., SMI32)m NeuN-
Calbindin-positive neurons-k
Immature, developmentally regulated markers
Nestinm, GFAP-deltam
Otx1m, Pax6m
Doublecortinm, Doublecortinlike proteinm, vimentinm b1-integrinm, CD34m
Doublecortinm
CD133m, Pax6m, Otx1m ER81m SOX2, Oct-4m Cell functional status/ inflammatory mediators
Synaptic vesicle protein 2A (SV2A) k Adhesion molecule on glia (AMOG)m Toll-like receptor2 m
pS6 (mTOR pathway activation) and p4E-BP1m pAKt (PiK3 pathway) m IL-1bm VEGFAm Proliferation status
Parvalbumin-positive neurons -k Calretinin-positive neurons -k
Doublecortin-like proteinm, nestin-m Tbr1m, Map1bm MASH1m Synaptophysin m
HLA-DR þ microgliam
VGlut (vesicular glutamate transporter)NKCC1 (chloride channel)m, C1q and C3d (complement pathway)m, IL-1bm Toll-like receptor 4m VEGFA, B and VEGFR1 & 2m
Mcm2m Cdk4, p53m
m, increased expression compared to normal adult cortex; k, reduced or no expression ;-, expression not altered.
is unknown but it is considered likely to be an acquired process. In addition, there is uncertainty regarding the contribution of the adjacent cortex to seizure activity, which merits further investigation. FCD types IIIc and d refer to cortical changes adjacent to vascular malformation or early cortical injury or scar, respectively. In FCD IIId often there are striking abnormalities of the cortical myeloarchitecture, with marbling, islands of residual neurons, and intervening gliosis in early acquired lesions resulting in striking reorganizational changes to the cortex (Figures 5(d)–(f)). In the context of Rasmussen’s chronic encephalitis in epilepsy, coexisting cortical dysplasialike changes are frequently reported including dysmorphic neurons (Figures 5(g)–(i)). Rather than this representing a dual pathology (FCD type II plus encephalitis), it is more likely that these are reorganizational changes secondary to the primary inflammatory encephalitis (FCD type IIId).
Neuroradiology The majority of FCD type II are visible with conventional MRI. The typical features are blurring of the gray–white matter boundaries and abnormal signal intensity in the white matter on T2 and fluid-attenuated inversion recovery (FLAIR) sequences typically forming a funnel-shaped zone toward
the ventricle. It is estimated that approximately 20–30% of FCD type II are MRI negative, but increased detection can be achieved with morphometric analysis. In one series of FCD type IIIa (TLS associated with hippocampal sclerosis) the neocortical abnormalities were not detected on preoperative MRI or even following morphometric analysis. There are at present no reliable or consistent presurgical imaging changes for FCD type I, although some pediatric cases are associated with cortical and cerebral hypoplasia on MRI.
Outcome Following Surgery Paradoxically, the histologically more severe or abnormalappearing dysplasia of FCD type II has a better outcome following surgical resection than FCD type I. Seizure-free outcomes following resection of FCD type II are approximately 75% and between 20% and 43% for FCD type I. Completeness of resection of the cortical abnormality may improve chances of a seizure-free outcome, removal of the cortical rather than the white matter component being more critical. In one series the presence or absence of FCD type IIIa in addition to hippocampal sclerosis did not influence outcome, with similar seizure-free outcomes for patients with hippocampal sclerosis alone.
332
Focal Cortical Dysplasia
Synaptophysin
SMI32
(a)
(b)
Nestin
Delta-GFAP
(c)
(d)
DCX
Calbindin
(e)
(f)
cdk4
GFAP
(g)
Figure 4 Immunostaining characteristics of FCD. (a) Neurofilament stains as SMI32 highlight the dysmoprhic neurons and their processes. (b) Synaptophysin shows a peripheral labeling pattern, (c) nestin highlights dysmorphic cell adjacent to a balloon cell. (d) Delta-glial fibrillary acidic protein (GFAP) typically shows strong labeling of balloon cells and their processes. (e) Doublecortin shows strong labeling of dysmorphic cells in FCD and calbindin (f) also highlights mulitpolar hypertrophic cells. (g) Cell cycle proteins expressed in a proportion of balloon cells suggest they are licensed for replication.
Focal Cortical Dysplasia
What is the Cause of Focal Cortical Dysplasia? Most consider that FCD type II is a cortical malformation, but the precise timing and critical events causing this lesion are unclear. The ‘dysmature cerebral hypothesis of cortical
NeuN I
I
NeuN
CD34
II
III II
IV III
V
(a)
(b)
(c)
GFAP
I
II
VI (d)
(e)
(f)
CD68
(h)
Neurofilament
(g)
(i)
333
dysplasia’ of Cepeda in 2006 proposes, based on histological and electrophysiological evidence, that balloon cells represent radial glia and dysmorphic neurons, subplate cells that have failed to degenerate or regress perinatally and have become integrated with normal postnatal neurons. There is anecdotal evidence that FCD type II is perhaps not a static lesion and ‘matures’ over time, supported by the observation of more frequent multilobar involvement in children compared to localized FCD lesions in adult brain. Indeed, a recent study of FCD type II in children confirmed in vitro isolation of a pathological cell with the phenotype of a progenitor cell/stem cell and the morphology of balloon cells. However, these cells may contribute to the formation of FCD lesions; unlike tumor stem cells, they do not show significant deoxyribonucleic acid synthesis or undergo cell division, suggesting a restricted capacity for proliferation. Owing to histological similarities between FCD type IIb and tuberous sclerosis (TSC), several studies have confirmed the activation of the pi3K-mTOR (mammalian target of rapamycin) signaling pathway in FCD type IIb, with evidence that this represents a primary pathogenic mechanism. mTOR normally regulates a number of physiological functions governing cell growth, metabolism, proliferation, and cell survival, and promotes protein synthesis including ribosomal S6 proteins and eIF43. The proteins tuberin and hamartin (mutated in TSC) normally inhibit the mTOR pathway and prevent excess cell growth and proliferation. Although in FCD, disease-causing mutations of TSC genes TSC1 and TSC2 have not been identified, there is evidence for dysregulation of mTOR signaling with activated ribosomal S6 and eIF43, which may indicate alternative activation pathways, possibly through insulin/Pi3K/Akt. Some efficacy with treatment of rapamycin in TSC lesions confirms the functional importance of this pathway in reversing their size. The molecular pathogenesis that distinguishes FCD types I–III has not been fully elucidated. However, there is no confirmation of mTOR pathway dysfunction in FCD type I, suggesting that FCD types I and II are both histologically and biologically distinct. A further possibility that deserves study is the contribution of normal residual progenitor cells to FCD. Seizures themselves or abnormal cellular activity early in life could result in abnormal recruitment of progenitor cells, with cortical reorganization and deranged gliogenesis and neurogenesis resulting in aberrant expression of developmentally regulated proteins. In support of this, cytoarchitectural
Figure 5 FCD type III subtypes. (a) The features of temporal lobe sclerosis, which is one subtype of FCD IIIa, show aggregation of remaining neurons in layer II and loss of neurons in deeper layer III. (b,c) The differential of FCD type IIIb includes cortical infiltration. In this section (b) NeuN staining is suggestive of architectural dysplasia; however, a corresponding section is labeled with CD34. (c) Confirms widespread infiltration by tumor cells. (d–f) FCD IIId. The cortex adjacent to a neonatal infarct shows ‘marbeling’ of the cortex with myelin bundles and nodules of neurons in the cortex as well as patchy gliosis (f). (g) Rasmussen’s encephalitis showing a region with cortical collapse and (h) microglial nodules. (i) Neurofilament stain shows scattered dysmorphic-appearing neurons at the margins of the atrophied cortex. This corresponds to FCD IIId and not additional FCD II.
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Focal Cortical Dysplasia
alterations have been reported in the context of known acquired postnatal lesions including early infarcts, traumatic lesions, chronic encephalitis, and mesial temporal sclerosis, which are now grouped under FCD type III. Plasticity of the maturing brain with possibly maladaptive changes in response to injury may contribute to the cellular pathology of such ‘reorganizational dysplasias’, as well as to their epileptogenicity.
regulate glutamate synthesis and removal as well as alteration of glutamate transporters, may play a role in local excitability.
What Makes Focal Cortical Dysplasia Epileptogenic?
Further Reading
It remains unclear whether seizures start within the lesions themselves or in the surrounding cortex in all FCD. In many cases of FCD type IIb, as removal of the lesion results in permanent seizure freedom, this would support the notion of intrinsic epileptogenicity. The abnormality promoting seizures may arise at the circuit level with a reduction of g-aminobutyric acid (GABA)ergic inhibitory cells and overbalance of excitatory connections. In support of this, in tissue resections a reduction in the ratio of inhibitory interneurons, including calretinin-, calbindin-, and parvalbumin-positive neurons, has been observed in FCD type II. Alternatively, at the single-cell level, alterations in the coassembly of glutamatergic receptors has been shown in dysmorphic neurons, including a-amino-3-hydroxy5-methyl-isoxazole-4-propionic acid (AMPA) and N-methylD-aspartate (NMDA). Additionally, abnormal expression of Na þ /K þ chloride co-transporter (NKCC1) identified, as a reflection of neuronal immaturity has been shown. Functional overexpression of NKCC1 can lead to higher intracellular chloride concentrations within dysplastic neurons, making it more difficult for GABA to generate inhibitory hyperpolarizing potentials in these neurons, or even causing GABA to become excitatory. Electrophysiological studies using single-cell recordings support that cytomegalic neurons have hyperexcitable intrinsic membrane properties whereas balloon cells in contrast appear nonexcitable. In addition, cytomegalic interneurons have been identified in pediatric cases of FCD with evidence for their hyperexcitability including increased firing rates. Activation of proinflammatory pathways in FCD type IIb has been shown, which also has a proconvulsant effect, for example, through activation of toll-like receptor signaling. In addition, the contribution of astrocytes, which
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See also: Epilepsy Pathology. Epilepsy; Surgery. Epilepsy Treatment Strategies. Immunohistochemistry and Brain Tumors. Magnetic Resonance (MR); Overview