Focal cortical dysplasias …

Harvey B Sarnat MD FRCPC MS

Developmental Malformations

Updated 05.18.2024
Released 11.28.1994
Expires For CME 05.18.2027

Focal cortical dysplasias

Author: Harvey B Sarnat MD FRCPC MS

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Focal cortical dysplasias

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Introduction

Overview

Focal cortical dysplasias are cytoarchitectural abnormalities most likely representing malformations of cortical development. Ranging from known genetic abnormalities to spontaneous mutations, these abnormalities most frequently present with intractable epilepsy. The author of this clinical article reviews the most recent proposed classification scheme for these disorders and looks at some of the recent genetic findings.

Historical note and terminology

The term "cerebral cortical dysplasia" encompasses a spectrum of malformations of the cerebral cortex that arise during development and are associated with epilepsy in infants and children (156). Initially, cortical malformations were referred to largely by their gross characteristics (eg, lissencephaly, agyria or pachygyria, hemimegalencephaly, microgyria). As investigators discovered the range of microscopic cortical malformations that produce epilepsy but show no (or milder) gross abnormalities, additional terms such as "microdysgenesis" (153), "dysplastic cortical architecture" (196), "focal cortical dysplasia" (238), "generalized cortical dysplasia" (145), "synaptic dysgenesis" (18), and "cerebral dysgenesis" (202) were added to the literature. The term "focal cortical dysplasia" was first used to describe a specific malformation of the brain that consisted of disorganized cortex with enlarged irregular neurons and enlarged ballooned cells in some, but not all, cases (238), now corresponding to focal cortical dysplasia type 2. Dysplastic and megalocytic neurons were first identified by Crome and colleagues in 1957 (51).

Neuropathological classification scale. A classification scale to unify terminology of malformations caused by abnormalities of cortical development with emphasis on focal cortical dysplasias associated with epilepsy was proposed by a group of epileptologists, neuropathologists, and neuroradiologists (169). Various classification schemes of cortical dysplasias have been proposed (255; 156; 169; 115; 233). A resulting 2011 classification scheme was published under the auspices of the International League Against Epilepsy (ILAE); it represents a consensus statement with contributions by multiple European, North American, Japanese, and Australian neuropathologists who have special interest and long experience in epilepsy surgery (29), and has been validated by an international consortium of neuropathologists with experience in epilepsy (45). This scheme has a built-in flexibility for future revisions as data become available and interpretations evolve. It includes both focal isolated dysplasias of the cortex and also those associated with other lesions. It is expected that this scheme will become the template for uniform criteria in the neuropathological diagnosis of cortical dysplasias, analogous to the WHO (World Health Organization of the United Nations) classification of nervous system tumors, another consensus statement now accepted by neuropathologists throughout the world, who nearly always note the WHO grade when preparing reports describing primary cerebral neoplasms in surgical resections and autopsies. Another strength and modern approach of the ILAE classification is that although based primarily on neuropathological features, it also considers and incorporates aspects of neuroimaging and clinical aspects to be integrated with interdisciplinary correlations. Molecular, genetic, and immunocytochemical characterization of these cortical dysplasias will be added to the ILAE scheme. The temporal expression of neuronal proteins during cellular differentiation and the immunocytochemical demonstration of synaptogenesis are now better defined and often are altered in malformations, either as delayed, arrested, or precocious maturation (245; 203; 209). Developments in demonstrating tissue markers of lamina-specific gene expression and transcription products in specific layers of the cerebral cortex as well as previously unrecognized patterns of focal cortical dysplasia than those described in 2011, such as geographical microlesions of the cortex (17; 54; 163), require consideration for updating the neuropathological classification. The ILAE Commission on Neuropathology addressed these issues in 20108, and a revised classification scheme is proposed that also includes newly recognized entities such as minimal focal cortical dysplasias and oligodendrocyte proliferations (MOGHE) (160). Even more integrative proposals to incorporate genetic, imaging, and clinical data have been suggested (19; 165; 207). The neuropathological classification shown in Table 1 should not be confused, however, with other ILAE clinical and electroencephalographic classifications of epilepsies, including ICD coding for epilepsy and EEG criteria (99).

Table 1 summarizes the neuropathological criteria of focal cortical dysplasias. The principal difference between types 1 and 2 is that individual neurons are normal in morphology and size in type 1 and are dysplastic and megalocytic (enlarged) in type 2; both types exhibit abnormal cortical architecture with displaced and disoriented neurons and abnormal lamination. In type 2, subtype 2b includes balloon cells as well, large globoid cells of mixed cellular lineage that often express both neuronal and glial proteins, in addition to primitive proteins of early stages of differentiation, such as vimentin and nestin, also found in progenitor “stem” cells. Type 3 is not a distinctive or unique focal dysgenesis as are types 1 and 2, but represents type 1 associated with other lesions.

Table 1. 2011 ILAE Classification of Focal Cortical Dysplasias

Focal cortical dysplasia type 1 (isolated)
	• 1a: Focal cortical dysplasia with abnormal radial cortical lamination • 1b: Focal cortical dysplasia with abnormal tangential cortical lamination • 1c: Focal cortical dysplasia with abnormal radial and tangential cortical lamination
Focal cortical dysplasia type 2 (isolated)
	• 2a: Focal cortical dysplasia with dysmorphic neurons • 2b: Focal cortical dysplasia with dysmorphic neurons and balloon cells
Focal cortical dysplasia type 3 (type 1 associated with principal lesions)
	• 3a: Cortical lamination abnormalities in the temporal lobe associated with hippocampal sclerosis • 3b: Cortical lamination abnormalities adjacent to a glial or glioneuronal tumor or any other cerebral tumor • 3c: Cortical lamination abnormalities adjacent to a vascular malformation • 3d: Cortical lamination abnormalities adjacent to any other lesion acquired during early life (eg, trauma, ischemic injury, infarct, encephalitis)

Revision of 2011 ILAE classification. Since 2011, considerably more experience and data regarding the pathogenesis and the genetic basis of focal cortical dysplasias have been gained (see below); therefore, a proposal to revise the above original classification scheme has been published (160), as well as recommendations about the neuropathological examination of surgically resected dysplasias at the gross and microscopic levels. Special histochemical and immunocytochemical applications reveal metabolic and cell lineage features not disclosed by hematoxylin-eosin stain (24).

The principal changes recommended are to simplify the scheme by combining or eliminating some subtypes. In type I, subtype Ia consists of radial micro-columnar architecture with little horizontal lamination; this pattern is well documented, has a developmental basis, and is recommended to be retained. Subtype Ib, by contrast, abnormalities of horizontal lamination, is much less well documented, is rare, and may have many causes unrelated to primary developmental malformation, including even ischemic laminar necrosis of the cortex. Subtype Ic is a combination of types Ia and Ib, hence, is not really a distinctive category. Type I is thus simplified to Ia, and Ib and Ic are deleted. Type II focal cortical dysplasia has dysmorphic, megalocytic neurons unlike type I in which neurons are morphologically normal but disoriented and displaced architecturally. The distinction between subtypes IIa and IIb is the absence or presence of balloon cells and, until it is better established whether this difference is important in pathogenesis or clinical presentation and prognosis, the revised ILAE classification will retain these two subtypes.

Perhaps the most important revision of the ILAE classification scheme relates to type III and its various subtypes (160). Type III is not really a distinctive form, but rather the presence of focal cortical dysplasia adjacent to another principal lesion. Subtype IIIa is problematic because it is a focal cortical dysplasia in the temporal lobe adjacent to hippocampal sclerosis. However, hippocampal sclerosis is never congenital; it is always an acquired lesion, so it is difficult to conceptualize how a developmental focal cortical dysplasia presumably from fetal life can form postnatally after hippocampal sclerosis appears. Subtype IIIb is adjacent to a brain tumor, usually a cortical epileptogenic tumor such as ganglioglioma. If these tumors are regarded as developmental dysplasias (see below), it is conceivable that focal cortical dysplasia may form at the same time. Subtype IIIc is focal cortical dysplasia Ia that forms next to a vascular malformation of the brain. This also is a feasible development because chronic ischemia induced by the vascular lesion may inhibit cortical maturation with persistence of the fetal architecture of focal cortical dysplasia Ia (see below), as it often does in cortex adjacent to a porencephalic cyst acquired in fetal life (Sarnat and Flores-203a). Subtype IIId is adjacent to almost any other lesion; in the case of porencephaly or infarcts in fetal life, the same reasoning can be applied as in focal cortical dysplasia IIIc. Focal cortical dysplasia adjacent to inflammatory lesions may be understood if cerebral inflammation occurs in fetal life, as it does in tuberous sclerosis and other developmental lesions (177; 217). Focal cortical dysplasia adjacent to postnatal cerebral contusions or other traumatic lesions is dubious.

The revised ILAE classification of focal cortical dysplasia still relies mainly on microscopic histopathology, but the neuropathological study of resected brain tissue with focal cortical dysplasia also requires immunocytochemical markers of cellular lineage and maturation, and recommendations for the technical study of such tissue also is progress (24). Incorporation of genetic profiles is also under consideration, as has been done with the WHO classification of brain tumors since 2016. The interpretation and incorporation of these data will likely influence revised classification in future.

	• Focal cortical dysplasias are congenital developmental malformations of grey matter limited to focal zones in any lobe of the cerebral cortex.
	• Focal cortical dysplasias are the most frequent cause of focal epilepsy in infants and children; seizures are the presenting symptom.
	• The 2011 ILAE Neuropathological Classification of focal cortical dysplasia underwent revision in 2018.
	• Focal cortical dysplasia type I is a focal malformation with morphologically normal neurons but abnormal cortical lamination and architecture: predominant microcolumnar rather than horizontal lamination.
	• Microcolumnar architecture in focal cortical dysplasia I is reminiscent of the normal architecture of the fetal cortical plate in the first half of gestation and suggests that focal cortical dysplasia I is a maturational arrest.
	• Focal cortical dysplasia type II consists of dysplastic, megalocytic neurons, and also abnormal cortical lamination/architecture.
	• Focal cortical dysplasia type I does not yet have a genetic mutation as a correlate.
	• Focal cortical dysplasia II is a postzygotic somatic mutation; its extent depends on timing in the 33 mitotic cycles of the early fetal neuroepithelium, so that small lesions limited to one gyrus are expressed late in the mitotic cycles, and large, extensive lesions are from expression in an early cycle, so that focal cortical dysplasia II and hemimegalencephaly are the same disorder with difference in timing.
	• Focal cortical dysplasia II and hemimegalencephaly are the same disorder, with timing of onset of genetic expression determining the anatomical extent of the focal dysplasia.
	• Focal cortical dysplasia type III is not a distinctive type in itself; it is focal cortical dysplasia I or II adjacent to another primary lesion, such as hippocampal sclerosis, tumour, vascular malformation, fetal cerebral infarct or porencephalic cyst, and others.
	• Grey matter developmental tumors (ganglioglioma and dysembryoplastic neuroepithelial tumors) are now regarded as primary dysplasias more than neoplasias or dysplasias undergoing neoplastic transformation; hence, they are another form of focal cortical dysplasia.
	• Major molecular genetic advances in identifying genes in the mTOR, AKT, PIK3CA, and RAS signalling pathways provide the etiology of focal cortical dysplasia II, hemimegalencephaly isolated or associated with neurocutaneous syndromes, and tuberous sclerosis complex, but not focal cortical dysplasia I.
	• Minimal focal cortical dysplasia with oligodendrocytosis (MOGHE) is another distinct entity with a genetic basis demonstrated in some cases.

Clinical manifestations

Presentation and course

All focal cortical dysplasias are epileptogenic and the onset of seizures is usually the presenting symptom that leads to investigation by imaging and diagnosis. In some patients, seizures may begin as early as the neonatal period and may even begin by severe infantile epilepsies such as epileptic (infantile) spasms. Seizures also can begin in later infancy, childhood, or adolescence and often are progressive and refractory to medical control with antiepileptic and other drugs or the ketogenic diet. Early onset severe epilepsies are more often associated with tuberous sclerosis, hemimegalencephaly, or other type 2 dysplasias. As with other conditions that cause pediatric epilepsy, there is not a strict correspondence between the clinical phenomenology and the neuropathologic substrate. MRI often can distinguish foci of focal cortical dysplasia type 1 from type 2, but EEG patterns are less definitive in this regard (161). Even in MRI, histopathological type I lesions may not be detected because they consist of abnormal architecture and lamination of the cortex, but since the number and density of neurons is unchanged, microscopic cortical rearrangement or failure to mature beyond midgestational radial microcolumnar architecture does not necessarily cause a change in signal intensity or behave as a mass lesion; hence, the brain MRI may be designated as “nonlesional.” However, a frequent subtle MRI lesion in focal cortical dysplasia type I is the blurring of the grey/white junction at the site of the dysplasia, by contrast with sharp demarcation in other normal gyri of the same brain. The paucity of MRI findings in focal cortical dysplasia type I has even led some neuroradiologists to question the very existence of focal cortical dysplasia type I, but this would be a denial of histopathological abnormalities below the resolution of MRI. Functional MRI characteristics, such as hypometabolism, in regions of focal cortical dysplasia do not correlate with seizure onset (55).

The clinical form, age at onset of symptoms, and severity of epilepsy that a given patient with cortical dysplasia manifests appear to depend more on when during cerebral development the lesion occurred than on the specific type or topographic distribution of lesions (153; 95; 161). In general, the more severe the cortical dysplasia, the earlier the onset of symptoms and the more severe the epileptic syndrome (156). This may explain some of the heterogeneity of neuropathologic lesions seen in patients with pediatric epilepsy, because the clinical phenotype results not only from the lesion or putative "insult" to the developing CNS, but also from the subsequent developmental processes it affects. Infantile spasms, West syndrome, Lennox-Gastaut syndrome, complex partial seizures, partial motor seizures, and secondary generalized seizures have all been associated with cortical dysplasia (168). It was early recognized that in the focal cortical dysplasias of infancy, infantile spasms were generally easy to treat with vigabatrin or ACTH, but focal seizures were almost uniformly pharmacoresistant (140). Despite the histological appearance of more severe dysplasia, because neuronal cytology is involved in addition to disrupted tissue architecture, type 2 focal cortical dysplasias have a better prognosis for control of epilepsy than do type 1 focal cortical dysplasias, even with surgical resections. This difference may in part be related to more extensive lesions in type 1, so that the entire dysplasia is not resected. In one older adult case, epilepsia partialis continua occurred for 50 years before the correct diagnosis of a focal cortical dysplasia was finally made (88).

Developmental delays may be seen in patients with cortical dysplasia, but no clear relationship with the underlying pathology has been established (156), except in the context of specific diseases such as tuberous sclerosis complex or epidermal nevus syndrome. Focal neurologic deficits are rarely seen, and, when present, usually exist in association with an intrauterine destructive lesion or with extensive dysplastic lesions such as hemimegalencephaly or extensive polymicrogyria. The following are frequent in school-age children: global developmental delay in infancy and early childhood, cognitive impairment, attention deficits, and school learning disabilities (115; 86; 85; 46). A higher than control risk of autistic spectrum disorders occurs as well (72).

Genotype-phenotype correlations in focal cortical dysplasia (phenotype including clinical manifestations, imaging and electrophysiological findings, and neuropathological lesions) have been extensively studied and form a basis for integrated neuropathological as well as clinical diagnosis (23).

Prognosis and complications

Prognosis depends on the extent of the cortical dysplasia, its location, and whether it is focal, multifocal, or diffuse (especially bihemispheric). Furthermore, the severity of the seizure disorder is associated with the histological grade (156). If the seizures are intractable, early surgical intervention leads to improved outcome. Focal lesions that can be surgically resected tend to have a better prognosis. The more complete the resection, the better the outcome in pediatric patients (114). Postoperatively, focal cortical dysplasia type 2 tends to do better in the long term than type 1 despite more severe cytological changes in individual neurons and glial cells (161). This apparent incongruity may be due to the often smaller lesions in focal cortical dysplasia type 2 and more extensive ones in focal cortical dysplasia type 1; hence, total surgical resection is more feasible in focal cortical dysplasia 2. In genetically determined generalized malformations of cortical development, biochemically associated abnormalities of the defective DNA may be important in both pathogenesis and prognosis. For example, a longer polyalanine expansion mutation in the ARX gene causes early infantile epileptic encephalopathy such as Ohtahara syndrome (106).

Tables 2 and 3 summarize the comprehensive features of the two principal types of focal cortical dysplasia.

Table 2. Summary of Features of Focal Cortical Dysplasia Type 1

	• Neuropathology: micro-columnar cortical architecture; neurons not dysmorphic or enlarged. Synaptic plexi in U-fiber layer beneath focal dysplasias.
	• Localization: posterior temporal, parietal, occipital.
	• Clinical features: highly epileptogenic; onset of focal seizures in infancy or early childhood; high incidence of infantile spasms; developmental delay, cognitive deficits, school learning disabilities common; autistic spectrum disorder in some.
	• Neuroimaging features: MRI shows blurring of grey/white junction in some, not all; no transmantle dysplasias; fMRI and PET may show hypometabolism at focus.
	• EEG features: epileptiform focus not always well localized, even with intraoperative electrocorticography or depth electrodes.
	• Genetics: SLC35A2 mutation in a minority of patients.
	• Outcome of surgical resection: recurrent seizures more frequent than in focal cortical dysplasia type II, probably because of subtotal resection.

Table 3. Summary of Features of Focal Cortical Dysplasia Type 2

	• Neuropathology: neurons megalocytic and dysmorphic; transmantle dysplasias; cortical lamination disorganized with displaced and disoriented neurons, but micro-columnar architecture is not as prominent a feature as in FCD type 1a. Hemimegalencephaly may be isolated or associated with neurocutaneous syndromes, particularly epidermal nevus syndromes. Cortical tubers in tuberous sclerosis similar to other focal cortical dysplasia type 2 lesions and may have micro-calcifications in addition.
	• Localization: any site of cortex, often temporal, frontal or insular.
	Clinical features: highly epileptogenic; onset of focal seizures in infancy, childhood, or adolescence; developmental delay and cognitive deficits not characteristic except in tuberous sclerosis complex and epidermal nevus with hemimegalencephaly; autistic spectrum disorder infrequent.
	• Neuroimaging features: MRI shows characteristic cortical lesions, usually at depths of sulci; transmantle dysplasias frequent; fMRI and PET may show hypometabolism at focus.
	• EEG features: epileptiform focus often well localized even in scalp recordings but especially with intraoperative electrocorticography or depth electrodes.
	• Genetics: postzygotic somatic mutation involving mTOR signaling pathway and pathways influencing mTOR AKT, GATOR, PIK3C, PTEN) and also TSC1 and TSC2 in tuberous sclerosis.
	• Outcome of surgical resection: often complete abolition of epilepsy with total resection of lesion; in tuberous sclerosis, resection of most epileptogenic tubers improves frequency and severity of seizures. Hemispherectory or hemispheric disconnection for hemimegalencephaly may leave other focal neurologic deficits postoperatively, such as hemiparesis or hemianopia.

Clinical vignette

A 37-weeks’-gestation male infant developed typical infantile spasms at the age of 5 days. Examination revealed increased head circumference (43 cm) and hypotonia. By 3 months of age he manifested significant developmental delay. Seizures were unresponsive to phenobarbital and prednisone. MRI scan showed left hemimegalencephaly with lissencephaly of the involved left cerebral cortex; the right cerebral hemisphere appeared normal by MRI. An anatomical hemispherectomy was performed at 3.4 months of age; histopathology showed typical features of severe cortical dysplasia, and neuronal dysplasia and cytomegaly with cytoskeletal abnormalities but no neoplasia. Subsequently, the child showed modest improvement in developmental milestones and a decrease in seizure frequency with improved responsiveness to antiepileptic medications.

Biological basis

Etiology and pathogenesis

Though the etiology of focal cortical dysplasia type 1 remains somewhat elusive in most cases, a mutation of SLC35A2 gene is now demonstrated (121). Somatic pathogenic mutation of this gene also is associated with oligodendroglial hyperplasia in epilepsy (10). The mechanism of pathogenesis is now better understood in focal cortical dysplasia type I (see below) and suggests a focal event in the developing fetal brain that causes focal maturational arrest in organization of the cortex. Type 2 focal cortical dysplasia, by contrast, is now shown to be a postzygotic somatic mutation, which explains the cellular dysmorphism, and the extent of the lesion depends on the mitotic cycle of the periventricular neuroepithelium (see below). Specific genetic mutations and chromosomopathies are the underlying etiology of some cortical dysplasias, but these dysplasias usually are generalized and not focal. Genetic etiologies for cortical dysplasia have been proposed on both theoretical and empirical grounds (90; 219; 196). There are over 25 different syndromes of abnormal neuroblast migration, which are associated with a variety of inheritance patterns including autosomal dominant, autosomal recessive, and X-linked patterns, as well as familial cases with an unclear inheritance pattern (166). Familial cases with sibling involvement also are reported (129). Though distinct patterns of causation have not yet emerged for most types of cortical dysplasia, neurogenetic studies have demonstrated mutations within a number of genes (or chromosomal loci), which are associated with neuroblast migratory abnormalities, recognizing that cellular migration is only part of the pathogenetic mechanism.

Genomic DNA methylation is an increasingly recognized important factor in some focal cortical dysplasias and may distinguish histopathological subtypes (112; 259). Abnormal DNA methylation is already a known molecular mechanism in some other epigenetic disorders of cerebral development with clinical neurologic sequelae after birth, such as the “fetal alcohol spectrum disorder.” Dysregulation of the adenosine system is another pathological feature shared in both focal cortical dysplasia types I and II (79). Perilesional cortex adjacent to focal cortical dysplasias, often a highly epileptogenic zone, may be associated with disturbance in expression of Wingless (WNT) genes beyond the primary mTOR pathway of the focal cortical dysplasia itself (147).

Embryology of the developing cerebral cortex. Neocortical development can roughly be considered to be the result of a series of overlapping processes: (a) proliferation, (b) differentiation, (c) migration, (d) programmed cell death of neuronal precursors and neurons, (e) synapse formation and elimination, and (f) cortical remodeling (202; 196). Abnormalities of these processes result in abnormalities of cortical architecture and resultant electrophysiological properties.

At approximately 4 weeks' gestational age, the neural tube forms and is covered by simple pseudostratified neuroepithelium, the component cells of which proliferate around the developing ventricular system. This zone is a mosaic of precursors giving rise to neurons, astrocytes, oligodendroglia, and ependyma of the developing brain (258).

The complex processes of cellular proliferation, determination of cell type, and differentiation are influenced both by cell lineage programs and by diffusible and soluble factors such as trophic factors, growth factors, and chemoattractant and chemorepellant molecules in the extracellular matrix. Cell surface interactions between cells and with the extracellular matrix also play a crucial role in these processes. Interactions are guided by cell adhesion and disadhesion molecules and extracellular matrix receptors. The influence of cell surface interactions and trophic factors may be critical in helping precursor cells determine their ultimate cellular fate. Cellular migration may use many of the same fundamental signals, as well as diffusible factors in initiating and maintaining appropriate migration.

Cells destined for the cerebral cortex migrate from their original location around the periventricular region to assume their appropriate location. About 80% of cortical neurons arrive at the cortical plate by radial migration along radial glial fibers of specialized cells for this purpose that really are progenitor cells themselves. Most of these neurons are glutaminergic. The other 20%, representing the population of GABAergic inhibitory interneurons, arrive not by radial but rather tangential migration along axons from the ganglionic eminence, a specialized part of the periventricular germinal matrix. Migration of neuroblasts to the cerebral cortex occurs in an "inside-out" fashion, with neuroblasts destined for the deepest cortical layers migrating initially and those destined for the more superficial cortical layers bypassing them (04; 229). Whereas cell adhesion molecules are needed to attach neuroepithelial cells to the radial glial fibers in the subventricular zone, disadhesion molecules are needed to detach these neuroblasts from the radial glia when they arrive at the cortical plate so that those behind them on the same radial glial fiber can bypass them to reach more superficial parts of the cortical plate. The bulk of neuroblast migration occurs between 7 and 16 weeks’ gestation. The initial architecture of the cortical plate during the first half of gestation is a radial microcolumnar arrangement or radial lamination. This histological organization changes to horizontal lamination, which is superimposed and gradually predominates, to remodel into a 6-layered cerebral cortex. Even after this time, however, some neuroblasts continue to migrate through the intermediate zone (future white matter), in a process that can continue up to a few months after birth (202). Synaptogenesis within the cortical plate is initiated at about 22 weeks’ gestation (214). Even during the physiological microcolumnar stage in the first half of gestation, and especially during the transition to tangential (horizontal) histological layering, there is already a distribution of specific types of neurons and primordial synaptic preparations forming horizontal lamination (201; 84). A complex combination of migratory patterns, including the radial glial scaffolding, allows for the development of a highly organized, 3-dimensional nervous system (182). Even in mature brains, a functional columnar organization continues to exist as functional columns or barrels (176; 87; 158; 183; 109; 107). In the occipital (visual) cortex, the on/off (ie, light/dark) inputs enable an invariant columnar architecture or barrel (125), and this is also the basis for the topographic visual sensory mapping in the cortex (113). Columnar functional and microscopic structural architecture is a general pattern in the developing forebrain, so that even the olfactory bulb exhibits such an arrangement (108; 263). Finally, some migratory neuroblasts appear not to use either radial glia or axons for guidance. The mechanisms guiding this type of migration are still unknown, although investigators have suggested that some neuronal precursors may migrate in closely associated chains (138).

Cajal-Retzius neurons of layer 1 of the neocortex and subplate neurons are crucial for normal cortical organization (16; 146; 208). The preplate, which consists of these neurons and a superficial plexus of corticopetal nerve fibers, is split by the newly arriving migrating neurons destined for the mature cortical plate. The reeler mouse is a mutant murine model in which there is failure of the normal “inside-out” pattern of neocortical formation (64; 56). A human genetic malformation in which inversion of the cortical layers often occurs is holoprosencephaly (211). The marginal zone before radial migration and the molecular zone (layer 1) after the cortical plate begins to form also provides another site of neurogenesis and gliogenesis in the early development of the cerebral cortex (47).

Throughout the second and early third trimesters, there is a transitory “subplate zone” beneath the developing cortical plate that contains large multipolar neurons. Subplate neurons mostly disappear in early postnatal life, but they are important in the fetus in organizing cortical connections in the developing cerebrum and in forming interconnections between the thalamus and cortical plate (208). Some subplate neurons are probably incorporated into layer 6, and others may contribute to the neuronal dispersion in the U-fiber later as the cortex matures. They may act as pioneer corticofugal axons. The U-fiber layer develops beginning at mid-gestation; its neurons, by contrast, are local short connections that do not project subcortically or in commissures (215). The subplate zone is structurally laminated as two layers at mid-gestation, which can be recognized postmortem in 3-Tesla MRI and confirmed neuropathologically; presumably the two layers are demonstrable prenatally by fetal MRI (175). Golgi impregnations and autoradiography also indicate lamination of the subplate zone, which blends with cortical layer 6 in the rat (249).

Programmed cell death or apoptosis is an essential mechanism of normal neural development. In the normal embryonic brain there is an overproduction of neuroblasts, many of which will undergo programmed cell death (102). It is an active process involving gene transcription and protein synthesis. It includes, but is not confined to, apoptotic cell death. In vitro experiments using nerve growth factor provided the paradigm for programmed cell death in the nervous system (130). Competition of neurons for limited amounts of trophic factors at the time they are reaching their targets helps to create a competitive environment for trophic support, ensuring survival of the "best-connected neurons." However, the process of programmed cell death may play a far wider role in the developing nervous system than initially appreciated. This may serve as selection process for potential cortical neurons with the desired phenotype. In accord with this experimental finding, other investigators have found, using morphometric techniques to study human brain development, up to 70% loss of cortical neurons after the 28th week of intrauterine gestation; this suggests that programmed cell death within the cortex may play a larger developmental role than was initially appreciated (181).

The failure of normal programmed cell death in the genesis of some glioneuronal malformations has been investigated (267). The authors examined regions of poorly circumscribed cell clusters consisting of small oligodendroglial-like cells mixed with randomly oriented neurons. These clusters, which have been called “glioneuronal hamartias” (265), are present in some patients with cortical dysplasia and intractable epilepsy, although they are also seen in association with other epilepsy producing lesions. The small round cell component of these lesions expresses an embryonic form of the neural cell adhesion molecule and is negative for proliferation markers, suggesting a postmitotic state (265). Further, these cells strongly express the anti-apoptotic protooncogene Bcl2, which is not normally expressed in mature brain tissue (267), suggesting a role for an abnormality of normal programmed cell death in these epilepsy-associated lesions.

Supplemental to programmed cell death, a conspicuous elimination of synapses occurs during development and is essential to remodeling of the cortex. Synapse elimination is highly intertwined with the remodeling of cortical connections and is a highly dynamic process (180), demonstrated both in vivo and in vitro (250). The process of synapse formation, elimination, and remodeling continues beyond the period of development, and many of the molecules that are essential for these processes in development appear to continue to play a role in synaptic plasticity in the mature brain.

Continuing neuronogenesis. In addition to the fetal ventricular zone of the “germinal matrix,” the marginal/molecular zone of the early cerebral cortex and the external granular layer of the cerebellar cortex until 18 months of age, two sites of persistent resident progenitor stem cells are found in the fetal brain persist in the mature brain: olfactory bulb and hippocampus (218). The latter population of bipolar progenitor cells are located in the hilus of the dentate gyrus, just beneath the inner granule cell layer, and is known as the polymorphic zone. One of its polar processes extends through the dentate gyrus. These cells are capable of generating new dentate granule cells in particular and may involve a continuous turnover of granule cells during life, including new synaptogenesis, the proliferation increasing in epilepsy arising in the hippocampus (230; 228; 223). A role in the generation of new memory engrams throughout life is speculated, but the evidence remains inconclusive. Focal cortical dysplasia can be associated with hippocampal sclerosis as focal cortical dysplasia type 3a.

Pathogenesis of focal cortical dysplasias. Type 1 focal cortical dysplasia appears to be arrested maturation of the cortical plate. The radial microcolumnar architecture is normal in the first half of gestation but becomes pathological if tangential (horizontal layering) does not predominate in the second half or if microcolumnar architecture persists postnatally (212). Abnormal tangential lamination may result in some cases from selective lack of neurons from either radial or tangential migration. Totally disorganized cortex with no recognizable architecture might result from failure of disadhesion of neuroblasts from their radial glial fiber when they reach the cortical plate, so that neuroblasts behind cannot bypass them (209). Microcolumnar architecture in focal cortical dysplasia type 1 involves not only the arrangement of the neurons in the cortex, but also the synaptic layers that are vertical rather than horizontal, as demonstrated by synaptophysin immunocytochemistry (212). Radial synaptic lamination is not seen during the normal phase of microcolumnar architecture because there are no synapses or synaptophysin reactivity in the cortical plate until 22 weeks’ gestation (214; 212). Generalized cortical dysplasias type 1 may present neuropathologically as radial microcolumnar architecture involving all regions of cortex, exemplified in DiGeorge syndrome (22q11.2 deletions of maternal origin) and methylmalonic academia (212). These genetic diseases are germline mutations that occur at the time of fertilization; hence every cell in the body carries the same genetic mutation.

The mechanism of type 2 focal cortical dysplasia is different than type 1. The cellular dysmorphism and dysregulation of growth is due to a postzygotic somatic mutation that affects some but not all premigratory neuroepithelial cells in the ventricular zone, destined for both radial and tangential migration, hence a mixture of normal and dysplastic neurons in the cortical plate. This somatic mutation is similar to that of tuberous sclerosis complex and in hemimegalencephaly associated with mutations of the AKT3 gene in the isolated form or the AKT1 gene in Proteus syndrome (135; 174; 74).

The timing of the mitotic cycle in which the mutation occurs determines the extent of the resulting malformation and whether other tissues than the brain are involved (204; Sarnat and Flores-209). Of the estimated 33 mitotic cycles needed to produce all of the neurons of the human cerebral cortex (32), if the mutation occurs in a late cycle, a small focal cortical dysplasia lesion occurs; if the mutation is in an earlier cycle, the lesion is more extensive and may involve more than one gyrus; and even earlier mitotic cycle involvement produces even more extensive lesions as hemimegalencephaly or “total hemimegalencephaly,” which includes the ipsilateral cerebellum and brainstem because the neuroepithelium is continuous between the supra- and infratentorial space in late embryonic life (Sarnat and Flores-209; 204). Hemimegalencephaly is, thus, a spectrum of neuroanatomical extent (53). Earliest involvement may result not only in hemimegalencephaly but other organ involvement, hence the close association of hemimegalencephaly with epidermal nevus syndrome (68). The neuroembryological demonstration that focal cortical dysplasia type 2 and hemimegalencephaly are merely different timings of onset of expression in the same genetic/metabolic disease has been confirmed by another approach of genetic studies (123; 58; 59).

Glutamate signaling is one of the strongest dysregulations in epilepsy, with layer-specific transcriptomic changes in multiple glutamate receptor genes (171). Axodendritic synapses of the molecular zone of the cerebral cortex are glutamatergic, but loss of dendritic spines can occur in focal cortical dysplasia type II and may be due to dysregulation of the complement system, which is important in the physiological removal of redundant microglia-mediated spines and is likely reactivated in focal dysplasia type II (197).

Astrocytes are another integral part of synaptic junctions. Astroglial vascular endothelial growth factor regulates glutamate transporter-1 expression via mTOR activation in experimental pilocarpine-induced status epilepticus in rodents and likely contributes to epileptogenesis of excitatory glutamatergic synapses in human cerebral cortex as well (97). Synaptic connectivity differs between focal cortical dysplasias types I and II, type I having a greater degree and wider area of cortical hyperexcitability than type II (225). Sleep-related epilepsy has a higher risk independent of seizure localization, even small lesions increasing the risk by 2.18 times in all focal cortical dysplasias (261). Maturational arrest of progenitor neuroepithelial cells also may contribute later to immaturity and compromise in the formation of neural networks in focal cortical dysplasias (05).

MRI provides a means not only of detecting focal cortical dysplasias but of providing clues to embryonic and fetal cerebral maldevelopment mechanisms (12; 02). Precise imaging of type 2 focal cortical dysplasias using a 7 Tesla MRI scanner are interpreted as defects in myelination at the grey/white junction where the normal sharp delineation is lost (277; 14; 260; 247), but this interpretation must consider patient age and the expected state of myelination of U-fibers that border gyri, serving to separate cortical grey matter from deeper white matter; except the amount of the perisylvian region and calcarine fissure, U-fibers are very late to myelinate relative to deep white matter, sometimes requiring years to even decades (215). Abnormal myelination in focal cortical dysplasia should not be confused with delayed normal myelination sequences of U-fibers. U-fibers are short axons that interconnect different parts of the same gyrus or immediately adjacent gyri. Because diffusion tensor imaging (DTI) is sensitive to axoplasm rather than myelin, it can show stronger contrast between grey and white matter, further improving presurgical delineation of focal cortical dysplasias and the boundary at the ventral surface of the cortex (122). Another advance in neuroimaging is functional MRI (fMRI) that suggests disrupted connectivity in large-scale neural networks including not only the cerebral cortex but also frontotemporal-cerebellar projections (136).

Additional factors that characterize focal cortical dysplasia type 2 are that they exhibit activation of the mTOR signalling pathway similar to tuberous sclerosis complex (48; 49; 199; 203; 244; 08; 133; 132; 111; 159; 237). Furthermore, mTOR disorders also exhibit upregulation of abnormally phosphorylated tau protein (203; 204). Tau is a microtubule-associated protein, as are many other proteins of genetic neuroblast migratory disorders, such as LIS1, doublecortin, and ARX. If tau overexpression occurs in the mature nervous system, late-onset adult tauopathies are characterized clinically by dementia but not epilepsy, and neuropathologically by neuronal degeneration and loss. Microtubules are essential cytoskeletal elements of developing neurons, and determine cellular lineage, orientation, polarity, growth, formation of neurites, and synaptogenesis. Abnormal phosphorylated tau in the immature neuroblast thus may cause cytological dysmorphism and growth abnormalities, as well as affect neuronal function. Such tau is upregulated in focal cortical dysplasia type 2 (but not types 1 or 3), in hemimegalencephaly, in tuberous sclerosis complex, and in a unique tumor; ganglioglioma in which the neurons are dysplastic and glial cells are neoplastic (203; 209; 204). This group of postzygotic somatic mutations has been called “infantile tauopathies”, though they lack some of the other associated abnormal proteins of adult dementia tauopathies, such as alpha-synuclein and beta-amyloid precursors (204). A murine model of autism improves with tau reduction (236), but whether this model might serve to study focal cortical dysplasia is not yet known.

Glial participation in focal cortical dysplasias is another factor that has not received the same attention as the neurons. Cytomegaly of glial cells in focal cortical dysplasia type 2 is well documented. Glial-neuronal interactions in focal cortical dysplasia type 2 are less well understood, as with dysplastic neurons and balloon cells, in terms of their epileptogenic potential (33). In focal cortical dysplasia type 2a, oligodendrocyte proliferation is impaired and maturation delayed, so myelination is also delayed (220; 61). Meningeal defects can be associated with focal cortical dysplasias (63). This may reflect a neural crest defect at the time that the cortical dysplasia was forming, but further data are needed.

Oligodendrocyte proliferation also might be a factor in the pathogenesis of subcortical white matter oligodendroglial hyperplasia in epilepsy (MOGHE) associated with some minimal focal cortical dysplasias. MOGHE occurs in young children with early onset and difficult-to-treat frontal lobe epilepsy. It is defined histopathologically by oligodendroglial hyperplasia and heterotopic neurons in the shallow subcortical white matter (222; 81; 254). Somatic variants of the gene SLC35A1 are identified in some MOGHE cases (232; 264; 09; 154). Some early cases were published in the literature as minimal malformations of cortical development (mMCD) or as variants of focal cortical dysplasia type 1. Somatic mutation of the SLC35A2 gene is demonstrated to be associated with both focal cortical dysplasia type I and also oligodendrocyte hyperplasia (121; 10). It is recommended that a revised ILAE neuropathological classification scheme recognize MOGHE as a specific disease entity preferentially affecting white matter (25).

Proteoglycans are intracellular matrix glycoprotein molecules in the CNS, secreted by astrocytes, that serve for axonal guidance because they repel glutamatergic (excitatory) axons and facilitate GABAergic (inhibitory) axons during fetal development. The most important proteoglycan in the nervous system of all vertebrates and most invertebrates is keratan sulfate (not keratin of fingernails). Keratan sulfate prevents aberrant decussation of ascending axons in the dorsal columns of the spinal cord and is also present in the forebrain (205). In the cerebral cortex, it first appears in the molecular zone at mid-gestation, then has a transitory patchy distribution within the cortical plate, and eventually is most concentrated in the deep cortical layers 5 and 6 and in the U-fiber layer, where it prevents axonal penetration from deep white matter heterotopia that mature late and project potentially epileptogenic axons after the keratan sulfate U-fiber barrier has formed. Though keratan sulfate is mostly in the intercellular matrix as granulofilamentous deposits, it binds to neuronal somatic membranes, except dendritic spines. Its transmitter specificity explains why axosomatic synapses are inhibitory and axodendritic synapses are mostly excitatory (205). Furthermore, keratan sulfate envelops axonal fascicles, including long tracts such as the corticospinal and short tracts such as the intrinsic axonal bundles within the globus pallidus and the pencil bundles of Wilson in the corpus striatum. This keratan “insulation” of fascicles and tracts ensures that axons cannot exit until they reach their destination and that axons from grey matter en route cannot enter the fascicle. Its presence in layer 6 of the cerebral cortex and in the underlying U-fiber layer serves to repel axons from deep white matter heterotopia, thus, preventing them from integrating into abnormal epileptic networks (215; 205). Keratan sulfate is also present in some other tissues, with the highest concentration in the cornea and in cartilage. Peripheral nerves do not penetrate cartilage.

It is recognized that inflammation may play an important role in the pathogenesis of cortical tubers in tuberous sclerosis complex, and many inflammatory markers are demonstrated in the brain tissue of fetuses with tuberous sclerosis complex (177). Inflammatory response and microglial activation is confirmed by other authors not only in tuberous sclerosis complex but in focal cortical dysplasia type 2, also an activation of the mTOR pathway (235).

Type 3 focal cortical dysplasia is usually type 1 microcolumnar cortical architecture, but at times can be type 2. It is associated with other types of lesions. If next to a porencephalic cyst, for example (type 3d) or next to a vascular malformation (type 3c), chronic ischemia during fetal life may be the cause of the arrested maturation of the cortical plate (212). Histopathological features are variable in the cortex adjacent to vascular malformations of cortex associated with epilepsy, with pseudolaminar necrosis, neuronal loss, and astrogliosis in addition to micro-columnar architecture (157). Focal cortical dysplasia type IIIa in the temporal neocortex near to hippocampal sclerosis is well recognized histopathologically (89).

Although focal cortical dysplasia types 1 or 2 can occur anywhere in the cerebral cortex, there are patterns of distribution for each. Classical focal cortical dysplasia type I of infants and young children typically occurs in the posterior hemisphere: posterior temporal, parietal, and occipital cortices (Table 2). The insula is increasingly recognized as a site of focal cortical dysplasia of both major types and an epileptogenic cortical region that produces complex clinical manifestations of autonomic regulation, olfaction, and mood and behavioral responses as a component of the “limbic system” (101). Because it is a deep structure, scalp EEG may be misleading, falsely negative, or mislocalizing, but intraoperative depth electrode recordings are more reliable (101).

Genetics. A number of genes have been identified, which are associated with normal ontogenesis and mutations or deletions of which result in brain pathology, many of which fall into the spectrum of cortical dysplasias. Type 1 lissencephaly and its association with mutations in the LIS1 gene, X-linked lissencephaly and its association with the doublecortin gene, tuberous sclerosis complex and its association with mutations in the TSC1 and TSC2 genes, and X-linked periventricular heterotopia and its association with the filamin-1 gene are well characterized examples. These genetically programmed malformations usually cause generalized rather than focal cortical dysplasia.

Many genetically-determined disorders of cortical development and neuroblast migratory disorders exhibit abnormal cortical lamination and organization in a generalized rather than focal distribution, and subcortical heterotopia: lissencephalies 1 and 2 polymicrogyria, schizencephaly, subcortical laminar “band” heterotopia, and periventricular nodular heterotopia. Despite a known genetic basis for most of these and the fact that many are highly epileptogenic, none are focal cortical dysplasias; hence, they are outside the scope of this review.

Focal cortical dysplasia is not usually familial, but familial cases are described that suggest a Mendelian inheritance, usually an autosomal recessive trait, in some families, but nearly all focal cortical dysplasia type 2 (129; 231). Tuberous sclerosis is a prototype form of multiple focal cortical dysplasias (ie, cortical tubers) of autosomal dominant transmission, and some familial simple cortical dysplasias type 2 are associated with the mTOR gene or its regulator, NPRL3 (164; 231), or with the PIK3CA/AKT pathway (134), as metabolic/genetic links to tuberous sclerosis. In tuberous sclerosis the defective mTOR (mTORC1) pathway begins in fetal life (177; 244), and it does so as well in focal cortical dysplasia II and hemimegalencephaly. Furthermore, variants of PIK3C initiate cerebral hyperactivity during gliomagenesis as in subependymal gliomas in tuberous sclerosis (272). Cortical tubers of tuberous sclerosis are essentially multiple focal cortical dysplasias. Abnormal RNA microarrays in focal cortical dysplasia II are useful in identifying defects in the Hippo signaling pathway as well, which is another genetic cascade (131). A unifying model for mTORC1-mediated regulation of mRNA translation is suggested with much supporting evidence (243). Pooled RNA sequences from multiple transcriptomes of patients with focal cortical dysplasia type II help characterize the single cell signatures in subtypes IIa and IIb (73). Tuberous sclerosis is an example of both germline mutation with Mendelian inheritance and also postzygotic somatic mutation related to a defective mTOR signaling pathway. An infant with a STXBP1 germline mutation and focal cortical dysplasia type 2 was described (227). In focal cortical dysplasia type II, potentially deleterious somatic variants in brain-expressed genes of the mTOR pathway were identified in six of 17 brain resections (274).

In addition to the mTOR pathway being a common defective metabolism in tuberous sclerosis complex, focal cortical dysplasia II, hemimegalencephaly both isolated and associated with epidermal nevus and other neurocutaneous disorders, and ganglioglioma, other related integrated genetic metabolic pathways also are now demonstrated to also be defective and can contribute to dysmorphic neurons and altered neuronal function including epileptogenesis. The most important is the PIK3CA/AKT pathways (173; 93; 03). These pathways are known causes of hemimegalencephaly and epidermal nevus syndrome including variants such as the multi-organ overgrowth syndromes Proteus and CLOVES/MCAT (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis, skeletal, and spinal/megalencephaly-capillary malformation syndrome) (117; 68; 69; 110; 137; 148). Lymphatic and other vascular overgrowth syndromes, including Klippel-Trenaunay syndrome, are other somatic mutations due to PIK3CA mutations (142; 248). RAS pathways also are linked to these other genetic pathways and may be involved in these and other neurocutaneous syndromes, such as neurocutaneous melanocytosis (68).

Though a genetic defect in focal cortical dysplasia type I remains unknown, a minority of patients (four of 48 cases = 8%) exhibit mutation of the SLC35A2 gene (121).

Mild focal cortical dysplasias with oligodendrocyte hyperplasia (MOGHE) show recurrent pathogenetic variants in the SLC3SA2 gene with mosaicism (172; 10). This mutation is present in a minority of cases of focal cortical dysplasia type I as well (121).

Destructive lesions associated with cortical dysplasia. Destructive lesions also appear to be capable of inducing cortical dysplasia, as evidenced by a number of animal models, and by clinicopathologic examples of cortical dysplasia in association with destructive lesions.

Cortical dysplasia has been noted in close proximity to small cystic infarcts (possibly occurring in utero) (156), adjacent to porencephalic cysts that formed due to middle cerebral artery occlusion at midgestation or earlier (212), other vascular lesions (190), and in association with intrauterine infections such as cytomegalovirus (82). These are designated in the ILAE classification as “type IIId”. In one autopsy series of patients with infantile spasms, 10% of the patients showed evidence for both malformative and destructive lesions (95). Another illuminating case report highlighted the role of discontinuities in the pial-glial barrier in association with massive neuroglial heterotopia into the subarachnoid space (40). Toxic and environmental insults may also cause cortical dysplasia, as they can affect the developing cortex during its time of greatest vulnerability. The presence of neuronal heterotopia in the survivors of the atomic bomb at Hiroshima (irradiation occurred between weeks’ 10 and 17 of development) clearly illustrates this point (182). Damage to radial glia and to the glia limitans has been suggested as a potential mechanism for generating the dysplasia.

Perhaps most convincingly, a variety of environmental insults ranging from chemicals, freezing injury, and gamma irradiation have all been used in animal models to produce lesions resembling cortical dysplasia. These data, which suggest that cortical dysplasia may be associated with both genetic and intrauterine destructive lesions, highlight the point that the pathology of cortical dysplasia is related to both the timing and the nature of the "disruption" of cortical development.

An initial report that papillomavirus was an acquired cause of focal cortical dysplasias (50) could not be confirmed by other investigators (226; 242; 27).

Animal models of cortical dysplasia. A number of important animal models have been developed in order to study the molecular basis of cortical dysplasia. These models range from naturally occurring genetic mutations to environmentally induced cortical dysplasia caused by exposure of the embryo or fetus to teratogenic toxins, including drugs and alcohol that the mother may consume early in gestation. Though good animal models of mTOR pathway disorders and focal cortical dysplasia type 2 have been developed, there presently are no animal models of focal cortical dysplasia type 1 (46). In a rat model of focal cortical dysplasia type II, electrographic epileptiform discharges appeared during the third postnatal week, and the first clinical seizures occurred a week later (103). In a murine model with mTOR mutation, not only was there a reduction in the number of GABAergic inhibitory interneurons in dysplastic cortex, but there were also postsynaptic alterations in GABA synaptic genes independent of interneuron paucity (275).

All animals use the mTOR signalling pathway, and it can be studied even in nematodes: upstream regulators that convey amino acid signals and mTOR complex I (mTORC1) controls cellular growth in response to amino acid levels (60). SAR1B senses leucine levels to regulate mTORC1 signaling by binding to leucine and targeting its activator GATOR2; silencing SAR1B results in lung cancer in mice but may also affect neuroepithelial cell growth and differentiation (37).

Spontaneous models. The tish rat is a spontaneously occurring autosomal recessive mutant, characterized by bilateral subcortical heterotopia beneath the frontal and parietal neocortices (127). These heterotopia, which project to subcortical targets, have bidirectional connections with the thalamus (221). They appear to be heterotopic nests of neurons intended for the neocortex and have the expected subcortical projections of neocortex, but they have a disorganized architecture and a “rim-to-core” orientation as opposed to the normal inside-out orientation of neocortex. They also bear electrophysiological properties similar to the seizures associated with human cortical dysplasia. Other work has shed light on the origin of these heterotopic neurons. As mentioned above, proliferation of cells destined for the cerebral cortex occurs in the ventricular or subventricular zones. However, in the tish rat, there appear to be two zones: (1) a ventricular or subventricular zone that gives rise to the normal neocortex and (2) a second misplaced proliferative zone within the intermediate zone that gives rise to both the normotopic and heterotopic neurons. These data show that this abnormality occurs early in development and is initiated before the migration of most cortical plate cells (124). Other genetic rodent models include the Reeler mutant rat, the Eker rat, and the ihari mutant rats (189; 162). Epilepsy in young Tsc+/- mice exhibits age-dependent expression that mimics that of human tuberous sclerosis complex (75).

Environmentally induced models. A number of environmentally induced models have been developed, highlighting the role of environmental factors in the development of cortical dysplasia, as well as providing an opportunity for studying the electrophysiology and molecular pathogenesis of these lesions. Methylazoxymethanol is a potent neurotoxin with anti-proliferative effects on dividing, but not quiescent, neuroepithelial cells. Intrauterine administration of methylazoxymethanol has been shown to result in epilepsy, producing lesions in the treated rats, which bear many pathologic features of cortical dysplasia, including abnormal cortical lamination, single heterotopic neurons in the neocortical molecular layer, marginal glioneuronal heterotopia, persistent subpial granular cells, and periventricular nodular heterotopia (39; 76; 43). Electrophysiologic, in vitro slice culture and connection tracing studies have shown the presence of abnormal electrophysiologic activity and kindling behavior (39; 77) with abnormal connections between heterotopic neurons in the CA1 region of the hippocampus and the neocortex (39; 77).

Other environmental models of cortical dysplasia include superficial cortical freeze lesions in which morphological analysis has been paired with electrophysiology to study the abnormal responses (141; 276). Redecker and colleagues have used the glutamatergic agonist ibotenate to induce cortical dysplasia-like lesions in order to study the electrophysiology and glucose metabolism of these lesions (187). Roper has utilized in utero irradiation followed by electrophysiology of slice cultures to study the electrophysiologic properties of these dysplastic areas (195; 194).

Neuropathology. Cortical dysplasia is best evaluated microscopically and can be characterized with regard to easily identifiable abnormalities, summarized in Table 2. These microscopic features reflect disruption of normal developmental processes and can be used to stratify the lesions as resulting from early, intermediate, or late gestational events, which correspond, respectively, to severe, moderate, and mild cortical dysplasia (156). Other investigators have suggested that cortical dysplasia can be grouped into three main patterns: (1) cortical laminar disorganization, (2) neuronal cytomegaly with cytoskeletal abnormalities and balloon cells, and (3) hypercellular cortical molecular layer (179). The most important distinction in this regard is between (1) abnormal tissue architecture or distribution, arrangement and orientation of neurons and synaptic layers, and (2) cytological abnormalities with dysplastic and megalocytic neurons (26). Laminar-specific expression of gene products are demonstrated in some cases and can be shown in sections of resected brain tissue (54; 163). In a multicenter, international collaborative study involving neuropathologists in15 countries, it was demonstrated that the use of immunocytochemical reactivities brought greater diagnostic precision and agreement than simple hematoxylin-eosin histology alone, but that the integration of genetic profiles with neuropathology further enhanced this precision and agreement (25). Moreover, in situ hybridization in surgical specimens of focal cortical dysplasia type II demonstrates lamina-specific genetic expression in which the morphologically normal neurons show migration to correct layers of the cortex, unlike dysmorphic neurons and balloon cells that migrate abnormally and are displaced within the cortex (198).

The unique “balloon cell” is characteristic of focal cortical dysplasia IIb, hemimegalencephaly, and tuberous sclerosis complex. Histologically, they are large globoid cells with eccentric nuclei and a homogenous eosinophilic cytoplasm. They have multiple short coarse processes that are not usually appreciated with hematoxylin-eosin stain but are well demonstrated by immunoreactivity for primitive proteins vimentin and nestin and also by heat-shock proteins such as alpha-B-crystallin. Balloon cells have mixed lineage, many expressing neuronal proteins including synaptophysin and also glial proteins, some showing a predominance of one and others of the other, as well as all constantly exhibiting immunoreactivity to filaments of progenitor “stem” cells (70; 269; 206). They are distributed throughout all layers of the cerebral cortex and also in subcortical white matter heterotopia.

Table 4. Microscopic Findings Associated with Cortical Dysplasias

	• Cortical laminar disorganization or disorientation as radial rather than tangential (horizontal) orientation
	• Neurons in the neocortical molecular layer that are not Cajal-Retzius neurons\|
	• Single heterotopic white matter neurons not forming a neuronal aggregate\|
	• Persistent remnants of the subpial granule cell layer of Brun
	• Marginal glioneuronal heterotopia
	• Neuronal heterotopia in aggregate or sheets
		- Nodular - Laminar
	• Abnormally formed convolutions as polymicrogyria with or without fused gyri, pachygyria, and lissencephaly
	• Neuronal dysmorphism and cytomegaly with cytoskeletal abnormalities
	• Balloon cells, usually of mixed cellular lineage and expressing primitive, progenitor proteins, as well as both neuronal and glial proteins

Cortical laminar disorganization in focal cortical dysplasia (photomicrograph)

Cortical laminar disorganization characterized by loss of normal pattern of orderly cortical lamination, with irregular clustering of neurons in cortical layers 2 and 3. (Kluver-Barrera stain) (Contributed by Dr. Paul Mischel.)
Cortical molecular layer in focal cortical dysplasia (photomicrograph)

Representative section showing increased cellularity in the cortical molecular layer with scattered neurons. (Kluver-Barrera stain) (Contributed by Dr. Paul Mischel.)
Single heterotopic white matter neurons in focal cortical dysplasia (photomicrograph)

Abundant single heterotopic neurons scattered in the subcortical white matter. (Kluver-Barrera stain) (Contributed by Dr. Paul Mischel.)
Remnants of the subpial granule cell layer in focal cortical dysplasia (photomicrograph)

Residual subpial granule cell layer consisting of a row of small round cells beneath the pial surface. (Hematoxylin-eosin) (Contributed by Dr. Paul Mischel.)
Marginal glioneuronal heterotopia in focal cortical dysplasia (photomicrograph)

Marginal glioneuronal heterotopia consisting of an excrescence of glioneuronal tissue (top) extending above the underlying pial surface of the cerebral cortex (bottom), and protruding into the subarachnoid space. (Hematoxylin-eosi...
Neuronal heterotopia in focal cortical dysplasia (photomicrograph)

Multiple nodules of neuronal heterotopia in the white matter. The ventricular surface is at the bottom, and the small nodular islands of neuronal heterotopia can be seen within the adjacent white matter. (Kluver-Barrera stain) (Co...
Polymicrogyria in focal cortical dysplasia (photomicrograph)

Polymicrogyria consisting of small fused meandering gyri. (Kluver-Barrera stain) (Contributed by Dr. Paul Mischel.)
Cytomegalic neuron in focal cortical dysplasia (photomicrograph)

High-magnification view of the cerebral cortex with a cytomegalic neuron exhibiting a neurofibrillary tangle-like cytoplasmic inclusion. (Bielschowsky stain) (Contributed by Dr. Paul Mischel.)
Balloon cells in focal cortical dysplasia (photomicrograph)

Balloon cells are present in this resection specimen from a child with severe cortical dysplasia. These cells are identical to the cells seen in the tubers of patients with tuberous sclerosis complex. Note the abundant opalescent ...

Though many neurons still reside in the intermediate zone or white matter in the last trimester of pregnancy and even into postnatal life (229), the phenomenon of single heterotopic neurons in the white matter is accentuated in cortical dysplasia (153). It was present in the vast majority of patients with cortical dysplasia, and has been demonstrated using morphometric techniques (151). It is important to recognize that a certain number of subcortical white matter neurons are normal, particularly in the temporal lobe, so it is a semiquantitative distinction of how many such single displaced neurons cross the line from physiological to pathological. These white matter neurons were often called “isolated” single cells, but synaptophysin, a marker protein of the synaptic vesicle membrane, demonstrates that such cells are not isolated at all, but are in synaptic contact with others and with the overlying cortex; hence they are capable of contributing to epileptic circuitry (214).

It was initially hypothesized that heterotopic white matter neurons result from injury to the radial glial fibers, resulting in becoming "stranded" or arrested in migration. However, more compelling data utilizing radioactive thymidine autoradiography and immunohistochemistry for microtubule-associated protein 2 and neuropeptides demonstrated that the subcortical neurons in the cat are remnants of subplate neurons (41). This suggests that the increased number of heterotopic neurons seen in cortical dysplasia may result from a failure of programmed cell death. The "normal" number of subcortical neurons has not been clearly established, and some regions of the brain, such as the temporal lobes, may contain a significantly higher population of heterotopic neurons than other lobes (193). Therefore, assessment of an increased number of neurons in the subcortical white matter may be difficult and may, unless obvious, require unbiased morphometric assessment.

Morphometric analysis has demonstrated a statistically significant increase in the number of neurons within the molecular layer of the cortex in epileptic patients versus controls (152), although the significance of this finding is unknown. Marginal glioneuronal heterotopia are excrescences of disorganized neuroglial tissue extending from the pial surface into the subarachnoid space. The persistence of the subpial granule cell layer has been seen in association with many cortical malformations (31). In some malformations, such as holoprosencephaly and some cases of lissencephaly, by contrast, the subpial granular glial layer of Brun may be deficient or absent, and glioneuronal heterotopia appear to result from overmigration beyond the pial barrier (202). Though this subpial granular layer of Brun may persist normally in the frontal sulci up to 2 to 4 months postnatally, its presence is considered a sensitive marker for cortical malformations. Marginal glioneuronal heterotopia may be associated with a failure of the glia limitans (40).

White matter neuronal heterotopia consist of disorganized masses of neurons in the white matter that usually occur in a periventricular position with a nodular morphology, although rare instances of laminar subcortical bands of heterotopic gray matter have been known to produce the appearance of a "double cortex" (71). It has been suggested that these are associated with injury to a group of radial glia leading to failure of a group of neuroblasts to migrate (202). Alternatively, a defect in genes controlling neuroglial interactions, neuroblast proliferation, and programmed cell death has been suggested as being causal (196).

Polymicrogyria describes aggregates of small gyri, often with bridging of the sulci by fusion of the molecular layers. Classic 4-layered polymicrogyria is most frequently considered to result from a destructive lesion that occurs at approximately 20 to 24 weeks' gestation, whereas an unlayered form is thought to result from an insult earlier in development (approximately 13 to 16 weeks’ gestation) (13). Whether polymicrogyria represents a destructive lesion with secondary malformation or a primary malformative lesion continues to be debated, but it is often seen as a feature in a variety of cerebral cortical malformations. Polymicrogyria often involves cortex lining both frontal and temporal lips of the lateral cerebral (Sylvian) fissure in schizencephaly and perisylvian polymicrogyria associated with severe epilepsy. One of the major defects that explain polymicrogyria is multiple discontinuities in the pial membrane that facilitates fusion of the molecular layer of adjacent gyri and overmigration of neuronal-glial heterotopia into the leptomeninges (234; 92; 206).

Neuronal cytomegaly describes the enlarged irregular neurons that are a distinctive feature of cortical dysplasia. Although not all cases of neuronal migration disorders contain these bizarre neurons, they were one of the characteristic features used in initially defining cortical dysplasia (238) and are seen in most cases of severe cortical dysplasia. These neurons, which are often present in hemimegalencephalic cortex, bear an extremely complex dendritic arborization as well as an abundance of perisomatic synapses and a paucity of axosomatic synapses (191; 57). Their increased neuronal size is associated with increased DNA and RNA content and increased nuclear and nucleolar volume suggestive of heteroploidy (20; 144). Many of these cytomegalic neurons contain cytoskeletal abnormalities. Argyrophilic neurofibrillary-like tangles and cytoplasmic vacuoles have been demonstrated within many of the cytomegalic neurons (256), as has the existence of paracrystallin intracytoplasmic structures visible on ultrastructural examination (57). These neurofibrillary-like cytoplasmic inclusions are, like the neurofibrillary tangles seen in Alzheimer disease, strongly immunoreactive with antibodies to high- and medium-molecular weight neurofilament, ubiquitin, and tau protein. However, they differ from the neurofibrillary tangles of Alzheimer disease in that they are not immunoreactive for paired helical filaments (62). Both phosphorylated and nonphosphorylated neurofilaments are found within the cell bodies of these cytomegalic neurons, suggesting abnormal phosphorylation of cytoskeletal proteins (62). A study showed that microtubule-associated protein 2 is strongly expressed in these enlarged neurons (268), particularly the embryonic isoform microtubule-associated protein 2c. Because microtubule-associated protein 2 (and especially its embryonic form microtubule-associated protein 2c) plays a role in growth and sprouting of neuronal processes, the authors suggest that this increased microtubule-associated protein 2 activity reflects elevated plasticity within the enlarged dysplastic neurons (268). Increased or aberrant expression of intermediate filaments may contribute to disruption of migration in the dysplastic neurons (239). Circulating micro-RNAs from serum exosomes may serve as a biomarker for diagnosis and even has possible therapeutic potential (38). Such micro-RNAs and also DNA methylation are two epigenetic mechanisms that have functional roles in focal cortical dysplasias (98). The actin cross-linking protein filamin-A is increased in resected cortical tissue in humans with epilepsy due to focal cortical dysplasia type 2 and also in murine model of this malformation, but its role in epileptogenesis remains poorly defined (273).

Immunocytochemical data analyzing the abnormal expression of glutamate receptor subunits in the dysplastic neurons of cortical dysplasia have generated a potentially interesting explanation for their abnormal electrophysiologic properties (06; 270). This group demonstrated that dysplastic neurons express NMDAR2A/B subunits and some differentially spliced forms of NMDAR1 proteins, which may result in a hyperexcitability of dysplastic neurons in cortical dysplasia (06; 270).

Calcium-binding proteins, such as calretinin and parvalbumin, are associated with GABAergic inhibitory interneurons that arrive at the cortical plate by tangential, rather than radial, migration, and also are strongly expressed in Cajal-Retzius neurons of the molecules later and neurons of the subplate zone in the fetal cortex; they are well demonstrated immunocytochemically (203; 204). These proteins exhibit differential reactivities in epileptogenic focal cortical dysplasias with selective parvalbumin impairment in dysplasias types 1 and 3, and abnormal but not reduced immunoreactivity in type 2 (150). In some cases in which GABAergic calcium-binding protein neurons are deficient in focal cortical dysplasia, this defect may be associated with type 2 potassium-chloride cotransporter immaturity (80).

Balloon cells have eccentric nuclei and ballooned opalescent eosinophilic cytoplasm. They often are binucleated and have dysmorphic nuclei. They tend to cluster at the cortex–white matter junction (256), sometimes extending into the subcortical white matter. Ultrastructurally, they are packed with filaments ranging in size from 400 to 600 nm in length and 30 nm in thickness, interspersed with nonmembrane-bound electron dense helical structures (65). Some of these balloon cells show dual staining with antibodies to both neuronal and glial markers (synaptophysin and glial fibrillary acidic protein, respectively) (256), implying either a failure of the cells to commit to a specific phenotype or a "dedifferentiation." Another interpretation is that balloon cells are of mixed cellular lineage (206). In any case, these findings suggest that an abnormality of development has occurred during the first trimester of intrauterine life. The resemblance of these balloon cells to cells found within the cortical tubers of tuberous sclerosis complex has suggested the possibility that cases of cortical dysplasia bearing balloon cell change may represent a forme fruste of tuberous sclerosis complex (168; 57; 65; 192). Balloon cells do not possess voltage-gated Na+ or K+ currents, hence cannot initiate epileptic activity, but dysplastic neurons may do so (34; 01). They do, however, express the synaptic vesicle protein synaptophysin at their plasma membrane (206). Balloon cells do not show electrophysiological association with interictal spikes, fast gamma activity, and ripples that do dysmorphic neurons (184).

U-fibers surrounding cortical gyri often are selectively preserved in white matter edema, experimentally in cats, attributed to the richer capillary perfusion network in this region of white matter (35). Pericytes that surround intracerebral arterioles are involved in the pathogenesis of autosomal dominant arteriopathy that results in subcortical infarcts (78), but whether pericytes might play a role in the pathogenesis of subcortical lesions in focal cortical dysplasias is unknown. The U-fiber layer often exhibits “neuronal dispersion” or an excessive number of neurons displaced from layer 6 of the overlying cortex, particularly at the bases of gyri and depths of sulci, where most focal cortical dysplasia occur. These heterotopic single neurons form complex synaptic plexi that integrate into epileptic networks because many of their axons that do not form synapses with neighboring U-fiber neurons enter the grey matter of the adjacent cortex (215). Synaptic interactions initially form local circuits or plexi (170) and later extend these plexi to more distant sites in forming networks.

Differential diagnosis

One of the most important differential diagnoses is the distinction between isolated focal cortical dysplasia and association with another type of lesion. Type 1 focal cortical dysplasias are isolated; type 3 is the same as type 1 except that it is adjacent to or associated with hippocampal sclerosis (3a, always in the temporal neocortex), a tumor (3b), vascular malformation (3c), or another lesion, such as an infarct, porencephalic cyst, zone of chronic ischemia, zone of inflammation, etc. (3d). Type 2 focal cortical dysplasias may be isolated or exhibit more extensive brain tissue involvement (eg, hemimegalencephaly) or involvement of multiple organs (eg, skin, in the case of neurocutaneous syndromes; skin, heart, and kidney in tuberous sclerosis complex). Another important distinction is whether the cortical dysplasia is indeed focal or is more generalized throughout the cerebral cortex, as occurs in some chromosomopathies (eg, DiGeorge syndrome, trisomy-13) and in some inborn metabolic diseases beginning prenatally (eg, methylmalonic academia) (68).

The differential diagnosis for cortical dysplasia includes a variety of structural and nonstructural epilepsy-producing lesions. Nonstructural causes of seizures such as electrolyte imbalances, toxic causes, and febrile seizures always need to be excluded. Structural epilepsy-producing lesions, which are usually detectable with appropriate imaging, can be categorized into six broad groups: (1) malformative, (2) neoplastic (eg, ganglioglioma, dysembryoplastic neuroepithelial tumor), (3) familial or metabolic, (4) vascular or traumatic, (5) infectious or inflammatory (eg, Rasmussen encephalitis), and (6) hippocampal sclerosis (255). A combination of clinical, EEG, and imaging data can usually be used to differentiate these entities. One area of potential difficulty exists with the dysembryoplastic neuroepithelial tumor, which is an epileptogenic tumor of children and which has a multifocal pattern with adjacent cortical dysplasia. This diagnosis is confirmed by neuropathologic examination of biopsy or resected tissue, in conjunction with neuroimaging (44). Finally, it should be stressed that although cortical dysplasia (in the broad sense) is the most frequent malformative lesion associated with pediatric epilepsy, other malformations such as Sturge-Weber-Dimitri syndrome, vascular malformations, or meningioangiomatosis can all be causal.

Epileptogenic developmental cortical tumors. Two grey matter tumors of the cerebral cortex are regarded as a “borderland” between dysplasia and neoplasia: ganglioglioma and dysembryoplastic neuroepithelial tumor (DNET or DNT). The dysplastic part of the tumors is the neuronal elements, whereas the glial elements are regarded as the neoplastic component. These tumors do not metastasize, but they can enlarge disproportionate to brain growth in infants and children. They are almost certainly congenital lesions, but their clinical expression as epilepsy may be delayed for months or years though rarely until adult life. It is now questioned whether they are really malignant neoplasms at all, or another form of focal cortical dysplasia (241). Genetically, they share many mutations with focal cortical dysplasia II and hemimegalencephaly. Furthermore, ganglioglioma also shares an upregulation of abnormally phosphorylated tau protein with the others (204).

Focal cortical dysplasia-like histopathological features can be found incidentally in a subset of diffusely infiltrative gliomas of the brain, but the relationship is unclear (21).

In tuberous sclerosis, the cortical tubers are hamartomata that include both neuronal and glial elements, but periventricular nodules and subependymal giant cell astrocytomas are comprised of astrocytes without neurons that become benign tumors because of their growth and proximity to the foramen of Monro where they can cause obstructive hydrocephalus. Retinal astrocytic hamartomata also occur (185).

Confusing conditions

Focal cortical dysplasias may be causally associated with migraine and its pathogenesis in patients with both migraine headaches and epilepsy (67).

X-irradiation of the brain may induce neuronal hypertrophy and dysplasia, resembling focal cortical dysplasia type II (224).

Diagnostic workup

The diagnostic workup for cortical dysplasia includes careful history (including family history), physical examination, EEG, and electrolyte, metabolic, and toxicological screens. Imaging (preferably MRI) is warranted to determine if a structural lesion is present and even to define the type of focal cortical dysplasia (104; 186).

Cortical dysplasia (MRI) (1)

Coronal spoiled gradient inversion recovery image (A) and coronal oblique FLAIR image (B) shows a focal area of gray matter thickening with blurring of the gray-white matter junction and corresponding high signal in the left paras...
Cortical dysplasia (MRI) (2)

Coronal T2 (A), spoiled gradient recall (B), and FLAIR (C) weighted sequences demonstrate a focal area of cortical thickening (arrow) and abnormal signal in the left fusiform gyrus of the temporo-occipital lobe in a patient with r...

Neuropsychologic testing may also be indicated. If a high likelihood of cortical dysplasia is established, the location and extent of resection can be determined by the localization of the structural lesion. The zones of epileptogenesis can be mapped using preoperative EEG and intraoperative electrocorticography. Stereoscopic EEG is a application for identifying epileptogenic foci in patients who do not exhibit an MRI lesion and may not even show a histopathological lesion at the EEG focus (120). There is an association between seizure-onset patterns in scalp and intracranial cortical surface EEG between histological types 1 and 2 focal cortical dysplasia (119; 91). In focal cortical dysplasia type IIIa, adjacent to hippocampal sclerosis, the type of dysplasia does not predict seizure onset, which can emanate from either the hippocampus or from temporal neocortex, based on depth electrode recordings (66).

The use of 7 or 9.4 Tesla MRI scanners, rather than the standard 1.5 Tesla or improved 3 Tesla apparatus, enables more precise diagnosis of type 2 focal cortical dysplasia and correlations with histopathological findings (188; 277; 240). Caution must be exercised in the interpretation of MRI intensity changes in lesions, however, because some changes may be transitory or reversible, probably due to epileptic discharge activity (118). Automated detection of focal cortical dysplasias using morphometric analysis in T1-weighted MRI may be useful in supplementing subjective visual identification of lesions (15). Automated detection of cortical dysplasias in high-resolution MRI and the application of artificial intelligence is an initial approach to supplement visual interpretation (100; 257). Multimodal mapping of regional cerebral vulnerability was studied in 337 patients with focal cortical dysplasias from 13 sites worldwide and found to show promise as another tool of correlating cytoarchitectural alterations, postnatal synaptogenesis, and genetic mutations (126).

Diffusion tensor imaging reveals alterations in cortical tubers and perituberal cortex in tuberous sclerosis and is useful in detecting epileptogenic tubers from those that are less likely to produce seizures (271), but data are not yet sufficient to determine whether other types of focal cortical dysplasias display similar findings. Advanced diffusion MRI maps intracellular volume and diffusivity for multimodal imaging that includes functional MRI that show different changes across histopathological subtypes of focal cortical dysplasias (139). PET and SPECT increases the yield of identifying lesions that are not evident or ambiguous with standard MRI sequences and also help in predicting surgical outcome (94; 07). PET and electrocorticography abnormalities in cortex surrounding focal cortical dysplasia type II are likely secondary epileptogenic rather than the primary epileptic focus (143). Transcranial ultrasonography is usually limited to neonates and young infants with open fontanelles, but intraoperative ultrasonography of the exposed brain is another useful tool to help guide surgical resections (178).

Because focal cortical dysplasia type II nearly always presents a lesion in MRI, usually at the base of a gyrus, depth of a sulcus, or as a “transmantle dysplasia” of grey matter heterotopia extending continuously from the ventricular wall to the base of gyrus, focal cortical dysplasia type I often shows no lesion evident on MRI because abnormal cortical lamination with normal neurons and with normal cellular density does not present contrast with surrounding normal cortex (246; 247). Blurring of the grey-white junction should be examined carefully because the neuronal dispersion and synaptic plexi in the U-fiber layer are adjacent to the junction (206). Furthermore, repeat brain MRI in children with “non-lesional” MRI may reveal a lesion not initially seen (96). More advanced myelination in infants may account for better visualization of some lesions.

Tissue adherent to explanted stereo-electroencephalographic electrodes in the presurgical evaluation of refractory epilepsy in patients with focal cortical dysplasia type II may assist in diagnosis and improve precision medicine by detecting somatic mutations (36).

A web-based classification of neuropathological features of focal cortical dysplasia provides a unique algorithm guide as a novel educational approach for pathologists with limited experience in cortical developmental lesions (116).

Management

Medical management, primarily with antiepileptic drugs, versus surgical resection depends on the extent, severity, and localization of the lesions. The extent of surgical resectability also needs to be considered, as well as location within or adjacent to the “eloquent” cortex, such as speech areas of the left hemisphere and primary motor and visual cortices. In the case of multiple cortical tubers in tuberous sclerosis, not all tubers are equally epileptogenic, and also in widespread hemispheric dysplasia in hemimegalencephaly, meticulous pre- and intra-operative electrophysiological studies are needed to identify those tubers or regions in which resection is likely to yield clinical benefit by seizure reduction.

The mTOR inhibitors, such as everolimus and sirolimus, have been used effectively for the subependymal nodules and giant cell astrocytomas in tuberous sclerosis. They do not cause as dramatic a reduction in size of cortical tubers as they do periventricular lesions, but they are often effective in treating the epilepsy associated with some tubers (200; 167; 52). A few non-tuberous sclerosis complex patients with mTORopathies, including hemimegalencephaly and focal cortical dysplasia II also have responded well (266; 105). The toxicity and risk of these medications is low, but because there is insufficient documentation of evidence for effectiveness or clinically controlled trials, especially in children, it is difficult to secure permission to administer such drugs unless it is part of an approved protocol with the endorsement of an ethics committee. Thus, progress is slow in this promising treatment. The ketogenic diet may be effective in some cases because it inhibits the mTOR pathway (149).

Some cases of adolescents and adults with focal cortical dysplasia may tolerate surgery awake, without general anesthesia, so that intraoperative brain stimulation can induce functional responses (155). Anterior temporal lobectomy in type 3a (associated with hippocampal sclerosis) often provides effective seizure control, particularly if the lesion is in the right hemisphere (83).

Finally, antiseizure gene therapy shows promise with translational potential to treat the epileptic phenotype of mTOR-related focal cortical dysplasias type II, though still in the investigative phase (11).

Outcomes

Effective pharmacological seizure control is achieved in only a minority of patients with focal cortical dysplasia, but freedom from seizures is important for cognitive functioning and quality of life as well as the epilepsy itself. Focal cortical dysplasia is the cause of epilepsy in about half of all children who undergo surgical resection because of drug-resistant seizures (86).

The clinical outcome or prognosis of seizure control in surgically treated focal cortical dysplasia depends largely on the completeness of resection of the epileptogenic focus and of the dysplastic cerebral tissue. Complete resection is not always feasible, particularly if it involves eloquent regions of the cortex essential to motor or linguistic functions. The use of pre- and intraoperative EEG monitoring and specialized neuroimaging improves the outcome of seizure control and often results in improved postoperative cognitive and intellectual functioning, even in mild or anatomically small focal cortical dysplasia lesions (252; 253; 94). Intervention with surgery in early infancy in large focal cortical dysplasia type 2 causing pharmacologically resistant neonatal seizures is feasible and can improve long-term outcome (30). For extensive focal cortical dysplasias or hemimegalencephaly, hemispherectomy may be the most practical approach for abolishing refractory seizures, particularly if the involved hemisphere has little physiological function, such as for motor control, vision, or language. A valid scale of seizure recurrence risk based on 1237 patients across 32 centers with intractable epilepsy who underwent hemispherectomy was developed and showed 30% total cure of epilepsy and better control in many others (262). Functional hemispherectomy, consisting of cutting white matter connections without removing much tissue, is now used in some centers as an alternative to resection hemispherectomy, but results are not yet well established. Meta-analysis documents that the timing of surgical resection of epileptogenic dysplasias is a major factor in influencing long-term epileptic prognosis (251). Functional MRI mapping of cortical networks also may help predict postoperative seizure outcome (42). A metaanalysis documents that the timing of surgical resection of epileptogenic dysplasias is a major factor in influencing long-term epileptic prognosis (251). Functional MRI mapping of cortical networks also may help predict postoperative seizure outcome (42).

Despite the more severe cytological appearance in focal cortical dysplasia type II than in focal cortical dysplasia type I, surgical resection often is more effective for abolishing a seizure focus in focal cortical dysplasia II than I. The main reason is that the lesion of focal cortical dysplasia type I is often more extensive than in focal cortical dysplasia type II, and the margins are not as easily identified by neuroimaging or intraoperatively; therefore, focal cortical dysplasia type I resections are often subtotal, and epileptogenic tissue remains (128; 85). EEG studies also demonstrate that the epileptic zone extends beyond the apparent anatomical lesion (22; 85).

Media

References

01: Abdijadid S, Mathern GW, Levine MS, Cepeda C. Basic mechanisms of epileptogenesis in pediatric cortical dysplasia. CNS Neurosci Therap 2015;21(2):92-103. PMID 25404064
02: Ahmad R, Maiworm M, Noth U, et al. Cortical changes in epilepsy patients with focal cortical dysplasia: new insights with T2 mapping. J Magn Reson Imaging 2020;52(6):1783-9. PMID 32383241
03: Alcantara D, Timms AE, Gripp K, et al. Mutations of AKT3 are associated with a wide spectrum of developmental disorders including extreme megalencephaly. Brain 2017;140(10):2610-22. PMID 28969385
04: Angevine GB Jr, Sidman RL. Autoradiographic study of cell migration during histogenesis of cerebral cortex in the mouse. Nature 1961;193:766-8. PMID 17533671
05: Avansini S, Puppo F, Adams JW, et al. Junctional instability in neuroepithelium and network hyperexcitability in a focal cortical dysplasia human model. Brain 2022;145(6):1962-77. PMID 34957478
06: Babb TL, Ying Z, Hadam J, Penrod C. Glutamate receptor mechanisms in human epileptic dysplastic cortex. Epilepsy Res 1998;32(1-2):24-33. PMID 9761306
07: Bacon EJ, Jin C, He D, et al. Cortical surface analysis for focal cortical dysplasia diagnosis by using PET images. Helion 2023;10(1):e23605. PMID 38187332
08: Baek ST, Copeland B, Yun EJ, et al. An AKT3-FOXG1-reelin network underlies defective migration in human focal malformations of cortical development. Nat Med 2015;21(12):1445-54. PMID 26523971
09: Baldassari S, Ribierre T, Marsan E, et al. Dissecting the genetic basis of focal cortical dysplasia: a large cohort study. Acta Neuropathol 2019;138(6):885-900. PMID 31444548
10: Balestrini S, Barba C, Thom M, Guerrini R. Focal cortical dysplasia: a practical guide for neurologists. Pract Neurol 2023;practneurol-2022-003404. PMID 36823117
11: Barbanoj AA, Graham RT, Maffei B, et al. Anti-seizure gene therapy for focal cortical dysplasia. Brain 2024;147(2):542-53. PMID 38100333
12: Barkovich AJ, Dobyns WB, Guerrini R. Malformations of cortical development and epilepsy. Cold Spring Harb Perspect Med 2015;5(5):a022392. PMID 25934463
13: Barth PG. Disorders of neuronal migration. Can J Neurol Sci 1987;14:1-16. PMID 3545413
14: Bartolini E, Cosottini M, Costagli M, et al. Ultra-high-field targeted imaging of focal cortical dysplasia: the intracortical black line sign in type IIb. Am J Neuroradiol 2019;40(12):2137-42. PMID 31727747
15: Bastian D, Kröll-Seger J, Schuch F, et al. External alidation of automated focal cortical dysplasia detection using morphometric analysis. Epilepsia 2021;62(4):1005-21. PMID 33638457
16: Bayer SA, Altman J. Development of layer I and the subplate in the rat neocortex. Exp Neurol 1990;107:48-62. PMID 2295319
17: Beaumont TL, Yao B, Shah A, Kapatos G, Loeb JA. Layer-specific CREB target gene induction in human neocrotical epilepsy. J Neurosci 2012;32(41):14389-401. PMID 23055509
18: Becker LE. Synaptic dysgenesis. Can J Neurol Sci 1991;18:170-80. PMID 1829978
19: Benova B, Jacques TS. Genotype-phenotype correlations in focal malformations of cortical development: a pathway to integrated pathological diagnosis in epilepsy surgery. Brain Pathol 2019;29(4):473-84. PMID 30485578
20: Bignami A, Palladini G, Zappella M. Unilateral megalencephaly with nerve cell hypertrophy. An anatomical and quantitative histochemical study. Brain Res Dev Brain Res 1968;9:103-14. PMID 5699812
21: Bitar M, Chomenkyy Y, Flanagan ME, et al. The frequency of focal cortical dysplasia-like histologic features near adult-type diffuse gliomas. J Neuropathol Exp Neurol 2022;81(1):48-53. PMID 35062028
22: Blenkmann A, Seifer G, Princich JP, et al. Association between equivalent current dipole source localization and focal cortical dysplasia in epilepsy patients. Epilepsy Res 2012;98(2-3):223-31. PMID 22018907
23: Blümcke I. It is time to move on: commentary to: genotype-phenotype correlations in focal cortical malformations of cortical development: a pathway to integrated pathological diagnosis in epilepsy surgery. Brain Pathol 2019;29(4):467-8. PMID 30868684
24: Blümcke I, Aronica E, Miyata H, Sarnat HB, Thom M, Roessler K, et al. International recommendation for a comprehensive neuropathological work-up of epilepsy surgery brain tissue: a consensus Task Force report from the ILAE Commission on Diagnostic Methods. Epilepsia 2016:57:348-58. PMID 26839983
25: Blümcke I, Coras R, Busch RM, et al. Toward a better definition of focal cortical dysplasia: an iterative histopathological and genetic agreement trial. Epilepsia 2021;62(6):1416-28. PMID 33949696
26: Blümcke I, Sarnat HB, Coras R. Surgical neuropathology of focal epilepsies: textbook and atlas. Montrouge, France: John Libbey Eurotext, 2015:18-53.**
27: Blümcke I, Sarnat HB. Somatic mutations rather than viral infection classify focal cortical dysplasia type II as mTORopathy. Curr Opin Neurol 2016;29(3):388-95. PMID 26840044
28: Blümcke I, Spreafico R, Haaker G, et al. Histopathological findings in brain tissue obtained during epilepsy surgery. N Engl J Med 2017;377:1648-56. PMID 29069555
29: Blümcke I, Thom M, Aronica E, et al. The clinicopathologic spectrum of focal cortical dysplasias: a consensus classification proposed by an ad hoc Task Force of the ILAE Diagnostic Methods Commission. Epilepsia 2011;52(1):158-74. PMID 21219302
30: Borggraefe I, Tacke M, Gerstl L, et al. Epilepsy surgery in the first months of life: a large type IIb focal cortical dysplasia causing neonatal drug-resistant epilepsy. Epileptic Disord 2019;21(1):122-7. PMID 30782583
31: Brun A. The subpial granular layer of the fetal cerebral cortex in man. Acta Pathol Microbiol Scand 1965;Suppl 179:3-98. PMID 5854019
32: Caviness VS Jr, Pinto-Lord MC, Evrard P. The development of laminated patterns in the mammalian neocortex. In: Morphogenesis and pattern formation. Connelly TG, ed. NY: Raven Press, 1981:103-26.
33: Cepeda C, André VM, Vinters HV, Levine MS, Mathern GW. Are cytomegalic neurons and balloon cells generators of epileptic activity in pediatric cortical dysplasia? Epilepsia 2005;46(Suppl 5):82-8. PMID 15987258
34: Cepeda C, Hurst RS, Flores-Hernandez J, et al. Morphological and electrophysiological characterization of abnormal cell types in pediatric cortical dysplasia. J Neurosci Res 2003;72(4):472-86. PMID 12704809
35: Cervós-Navarro J, Lafuente JV, Gutiérrez E, Kannuki S. Subcortical U-fibers layer preservation in brain edema. Acta Neurochir Suppl (Wien) 1994;60:151-4. PMID 7976531
36: Checri R, Chipaux M, Ferrand-Sorbets S, et al. Detection of brain somatic mutations in focal cortical dysplasia during epilepsy presurgical workup. Brain Commun 2023;5(3):fcad174. PMID 37324239
37: Chen J, Ou Y, Luo R, et al. SAR1B senses leucine levels to regulate mTORC1 signalling. Nature 2021;596(7871):281-4. PMID 34290409
38: Chen SD, Pan HY, Huang JB, et al. Circulating micro-RNAs from serum exosomes may serve as a putative biomarker in the diagnosis and treatment of patients with focal cortical dysplasia. Cells 2020;9(8):1867. PMID 32785072
39: Chevassus-Au-Louis N, Congar P, Represa A, Ben-Ari Y, Gaiarsa JL. Neuronal migration disorders: heterotopic neocortical neurons in CA1 provide a bridge between the hippocampus and the neocortex. Proc Natl Acad Sci U S A 1998;95:10263-8. PMID 9707635
40: Choi BH, Matthias SC. Cortical dysplasia associated with massive ectopia of neurons and glial cells within the subarachnoid space. Acta Neuropathol 1987;73:105-9. PMID 3604578
41: Chun JJ, Schatz CJ. Interstitial cells of the adult neocortical white matter are the remnant of the early generated subplate neuron population. J Comp Neurol 1989;282:555-69. PMID 2566630
42: Cohen NT, Xie H, Gholipour T, Gaillard WD. A scoping review of the functional magnetic resonance imaging-based functional connectivity of focal cortical dysplasia-related epilepsy. Epilepsia 2023;64(12):3130-42. PMID 37731142
43: Colacitti C, Sancini G, De Biasi S, et al. Prenatal methylazoxymethanol treatment in rats produces brain abnormalities with morphological similarities to human developmental brain dysgeneses. J Neuropathol Exp Neurol 1999;58(1):92-106. PMID 10068317
44: Colombo N, Citterio A, Galli C, et al. Neuroimaging of focal cortical dysplasia: neuropathologic correlations. Epileptic Disord 2003:5(Suppl 2);S67-72. PMID 14617423
45: Coras R, de Boer O, Armstrong D, et al. Good interobserver and intraobserver agreement in the evaluation of the new ILAE classification of focal cortical dysplasias. Epilepsia 2012;53(8):1341-8. PMID 22642611
46: Coras R, Holthausen H, Sarnat HB. Focal cortical dysplasia type 1. Brain Pathol 2021;31(4):e12964. PMID 34196986
47: Costa MRF, Kessaris N, Richardson WD, et al. The marginal zone/layer I as a novel niche for neurogenesis and gliogenesis in developing cerebral cortex. J Neurosci 2007;27(42):11376-88. PMID 17942732
48: Crino PB. Molecular pathogenesis of focal cortical dysplasia and hemimegalencephaly. J Child Neurol 2005;20(4):330-6. PMID 15921235
49: Crino PB. Focal brain malformations: seizures, signalling, sequencing. Epilepsia 2009;50 Suppl 9:3-8. PMID 19761448
50: Crino PB. Reply: HPV in focal cortical dysplasia. Ann Neurol 2015;77(2):353. PMID 25523244
51: Crome L. Infantile cerebral gliosis with giant nerve cells. J Neurol Neurosurg Psychiatry 1957;20(2):117-24. PMID 13429380
52: Curatolo P, Moavero R, van Scheppingen J, Aronica E. mTOR dysregulation and tuberous sclerosis-related epilepsy. Expert Rev Neurotherap 2018;18(3):185-201. PMID 29338461
53: Cvetkovska E, Kuzmanovski I, Boskovski B, Babunovska M, Gordana Trencevska KG. Widespread frontal lobe cortical dysplasia or partial hemimegalencephaly: a continuum of the spectrum. Epileptic Disord 2019;21(5):471-4. PMID 31617492
54: Dachet F, Bagla S, Keren-Aviram G, et al. Predicting novel histopathological microlesions in human epileptic brain through transcriptional clustering. Brain 2015;138(Pt 2):356-70. PMID 25516101
55: Danckert J, Mirsattari SM, Biharri F, et al. Functional MRI characteristics of a focal region of cortical malformation not associated with seizure onset. Epilepsy Behav 2007;10(4):615-25. PMID 17482882
56: Dernoncourt C, Ruelle D, Goffinet AM. Estimation of genetic distances between “reeler” and nearby loci on mouse chromosome 5. Genomics 1991;11:1167-9. PMID 1783386
57: DeRosa MJ, Secor DL, Barsom M, Fisher RS, Vinters HV. Neuropathologic findings in surgically treated hemimegalencephaly: immunohistochemical, morphometric, and ultrastructural study. Acta Neuropathol 1992;84:250-60. PMID 1414279
58: D’Gama AM, Geng Y, Couto JA, et al. Mammalian target of rapamycin pathway mutations cause hemimegalencephaly and focal cortical dysplasia. Ann Neurol 2015;77:720-5.** PMID 25599672
59: D’Gama AM, Woodworth MB, Hossain AA, et al. Somatic mutations activating the mTOR pathway in dorsal telencephalic progenitors cause a continuum of cortical dysplasias. Cell Rep 2017;21(13):3754-66. PMID 29281825
60: Dibble CC, Manning BD. Signal integration by mTORC1 coordinates nutrient input with biosynthetic output. Nat Cell Biol 2013;15(6):555-64. PMID 23728461
61: Donkels C, Peters M, Fariña Nuñez MT, et al. Oligodendrocyte lineage and myelination are compromised in the gray matter of focal cortical dysplasia type IIa. Epilepsia 2020;61(1):171-84. PMID 31872870
62: Duong T, DeRosa MJ, Poukens V, Vinters HV, Fisher RS. Neuronal cytoskeletal abnormalities in human cerebral cortical dysplasia. Acta Neuropathol 1994;87:493-503. PMID 8059602
63: Ellis EM, Trybula SJ, Adney SK, Lee PKJ, Bandt SK. Meningeal defects and focal cortical dysplasia: an unrecognized relationship? Illustrative case. J Neurosurg Case Lessons 2022;4(11):22112. PMID 36097744
64: Falconer DS. Two new mutants, ‘trembler’ and ‘reeler’, with neurological actions in the house mouse (Mus Muscululus L). J Genet 1951;50:192-201. PMID 24539699
65: Farrell MA, DeRosa MJ, Curran JG, et al. Neuropathologic findings in cortical resections (including hemispherectomies) performed for the treatment of intractable childhood epilepsy. Acta Neuropathol 1992;83:246-59. PMID 1557956
66: Fauser S, Schulze-Bonhage A. Epileptogeniticity of cortical dysplasia I temporal lobe dual pathology: an electrophysiological study with invasive recordings. Brain 2006;129(Pt 1):82-95. PMID 16317023
67: Fila M, Przysio L, Derwich M, Pawlowska E, Blasiak J. Potential of focal cortical dysplasia in migraine pathogenesis. Cereb Cortex 2024;34(4);bhae158. PMID 38615241
68: Flores-Sarnat L. Neurocutaneous melanocytosis. In: Dulac O, Lassonde M, Sarnat HB, editors. Elsevier handbook of clinical neurology: paediatric neurology. Vol. 111, 3rd series. Edinburgh, London, NY, Toronto: Elsevier, 2013;111:369-88.
69: Flores-Sarnat L. Epilepsy in neurological phenotypes of epidermis nevus syndrome. J Pediatr Epilepsy 2016;5:97-110.
70: Flores-Sarnat L, Sarnat HB, Dávila-Gutiérrez G, Álvarez A. Hemimegalencephaly: part 2. Neuropathology suggests a disorder of cellular lineage. J Child Neurol 2003;18(11):776-85. PMID 14696906
71: Friede RL. Developmental neuropathology. 2nd ed. Berlin: Springer-Verlag, 1989.
72: Fujimoto A, Enoki H, Niimi K, et al. Patients with epilepsy secondary to focal cortical dysplasia may be associated with autism spectrum disorder. Epilepsy Behav 2021;120:107990. PMID 33957439
73: Galvão I, Kandratavicius L, Messias L, et al. Identifying cellular markers of focal cortical dysplasia type II with cell-type deconvolution and single-cell signatures. Sci Rep 2023;13(1):13321. PMID 37587190
74: Garcia CAB, Carvalho SCS, Yang X, et al. mTOR pathway somatic mutations and the molecular pathogenesis of hemimegalencephaly. Epilepsia Open 2020;5(1):97-106. PMID 32140648
75: Gataullina S, Lemaire E, Wendling F, et al. Epilepsy in young Tsc(+/-) mice exhibits age-dependent expression that mimics that of human tuberous sclerosis complex. Epilepsia 2016;57(4):648-59. PMID 26873267
76: Germano IM, Sperber EF. Transplacentally induced neuronal migration disorders: an animal model for the study of the epilepsies. J Neurosci Res 1998;51(4):473-88. PMID 9514201
77: Germano IM, Sperber EF, Ahuja S, Moshe SL. Evidence of enhanced kindling and hippocampal neuronal injury in immature rats with neuronal migration disorders. Epilepsia 1998;39(12):1253-60. PMID 9860059
78: Ghosh M, Balbi M, Hellal F, Dichgans M, Lindauer U, Plesnila N. Pericytes are involved in the pathogenesis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Ann Neurol 2015;78(6):887-900. PMID 26312599
79: Guo M, Zhang J, Wang J, et al. Aberrant adenosine signaling in patients with focal cortical dysplasia. Mol Neurobiol 2023;60(8):4396-417. PMID 37103687
80: Han P, Welsh CT, Smith MT, Schmidt RE, Carroll SL. Complex patterns of GABAergic neuronal deficiency and type 2 potassium-chloride cotransporter immaturity in human focal cortical dysplasia. J Neuropathol Exp Neurol 2019;78(4):365-72. PMID 30856249
81: Hartlieb T, Winkler P, Coras R, et al. Age-related MR characteristics in mild malformation of cortical development with oligodendroglial hyperplasia and epilepsy (MOGHE). Epilepsy Behav 2018;91:68-74. PMID 30061008
82: Hayward JC, Titelbaum DS, Clancy RR, Zimmerman RA. Lissencephaly-pachygyria associated with congenital cytomegalovirus infection. J Child Neurol 1991;6(2):109-14. PMID 1646253
83: He X, Liu D, Yang Z, Zhang J, Li S, Yang Z. Side of lesions predicts surgical outcomes in patients with drug-resistant temporal lobe epilepsy secondary to focal cortical dysplasia type IIIa. Front Neurol 2020;11:580221. PMID 33362691
84: Hevner RF. Layer-specific markers as probes for neuron type identity in human neocortex and malformations of cortical development. J Neuropathol Exp Neurol 2007;66(2):101-9. PMID 17278994
85: Holthausen H, Coras R, Tang Y, et al. An anatomo-electro-clinical syndrome of seere multilobar unilateral hypoplasia and FCD 1A. Epilepsia 2021; in press.
86: Holthausen H, Pieper T, Winkler P, et al. Electro-clinical-pathological correlations in focal cortical dysplasia (FCD) at young ages. Childs Nerv Syst 2014;306(12):2015-26.
87: Hubel DH, Wiesel TN. Anatomical demonstration of columns in the monkey striate cortex. Nature 1969:221(5182):747-50. PMID 4974881
88: Ikeda KM, Aldosari MM, Mirsattari SM, AlGhefari H, Hammond RR. Focal cortical dysplasia type IIa manifesting as epilepsia partialis continua for 50 years. Can J Neurol Sci 2018;45(1):106-8. PMID 28965498
89: Jadav D, Gupta V, Khera S, Meshram V. Focal cortical dysplasia with hippocampal sclerosis. Autops Case Rep 2023;13:e2023420. PMID 36741591
90: Jan YN, Jan LY. Genes required for specifying cell fates in Drosophila embryonic sensory nervous system. Trends Neurosci 1990;13:493-8. PMID 1703680
91: Janca R, Jezdik P, Ebel M, et al. Distinct patterns of interictal intracranial EEG in focal cortical dysplasia type I and II. Clin Neurophysiol 2023;151:10-7. PMID 37121217
92: Jansen AC, Robitaille Y, Honavar M, et al. The histopathology of polymicrogyria: a series of 71 brain autopsy studies. Dev Med Child Neurol 2016:58(1):39-48. PMID 26179148
93: Jansen LA, Mirzaa GM, Ishak GE, et al. PI3K/AKT pathway mutations cause a spectrum of brain malformations from megalencephaly to focal cortical dysplasia. Brain 2015;138(Pt 6):1613-28. PMID 25722288
94: Jayalakshmi S, Nanda SK, Vooturi S, et al. Focal cortical dysplasia and refractory epilepsy: role of multimodality imaging and outcome of surgery. AJNR Am Neuroradiol 2019; 40(5):892-8. PMID 31000525
95: Jellinger K. Neuropathological aspects of infantile spasms. Brain Dev 1987;9:349-57. PMID 3324792
96: Jeon TY, Kim JH, Lee J, Yoo SY, Hwang SM. Value of repeat brain MRI in children with focal epilepsy and negative findings on initial MRI. Korean J Radiol 2017;18(4):729-38. PMID 28670168
97: Jeong KH, Cho KO, Lee MY, et al. Vascular endothelial growth factor receptor-3 regulates astroglial glutamate trasporter-1 expression via mTOR activation in reactive astrocytes following pilocarpine-induced status epilepticus. Glia 2021;69(2):296-309. PMID 32835451
98: Jesus-Ribeiro J, Pires LM, Daniel-Melo J, et al. Genomic and epigenetic advances in focal cortical dysplasia types I and II: a scoping review. Front Neurosci 2021;14:580357. PMID 33551717
99: Jette N, Beghi E, Hesdorffer D, et al. ICD coding for epilepsy: past, present, and future – a report by the International League Against Epilepsy Task Force on ICD codes in epilepsy. Epilepsia 2015;56(3):348-55. PMID 25684068
100: Jiménez-Murillo D, Castro-Opina AE, Duque-Muñoz L, et al. Automatic detection of focal cortical dysplasia using MRI: a systematic review. Sensors (Basel) 2023;23(16):7072. PMID 37631608
101: Jobst BC, González-Martínez J, Isnard J, et al. The insula and its epilepsies. Epilepsy Curr 2019;19(1):11-21. PMID 30838920
102: Johnson EM, Deckwerth TL. Molecular mechanisms of developmental neuronal death. Annu Rev Neurosci 1993;16:31-406. PMID 8460896
103: Kao HY, Hu S, Mihaylova T, et al. Defining the latent period of epileptogenesis and epileptogenic zone in a focal cortical dysplasia type II (FCDII) rat model. Epilepsia 2021;62(5):1268-79. PMID 33735460
104: Kassubek J, Huppertz HJ, Spreer J, Schultze-Bonhage A. Detection and localization of focal cortical dysplasia by voxel-based 3-D MRI analysis. Epilepsia 2002;43(6):596-602. PMID 12060018
105: Kato M, Kada A, Shiraishi H, et al. Sirolimus for epilepetic seizures associated with focal cortical dysplasia type II. Ann Clin Transl Neurol 2022;9(2):181-92. PMID 35040598
106: Kato M, Saaitoh S, Kamei A, et al. A longer polyalanine expansion mutation in the ARX gene causes early infantile epileptic encephalopathy with suppression-burst pattern (Ohtahara syndrome). Am J Hum Genet 2007;81(2):361-6. PMID 17668384
107: Kätzel D, Zemelman BV, Buetfering C, Wölfel M, Miesenböck G. The columnar and laminar organization of inhibitory connections to neocortical excitatory cells. Nat Neurosci 2011;14(1):100-7. PMID 21076426
108: Kauer JS, Cinelli AR. Are there structural and functional modules in the vertebrate olfactory bulb? Microsc Res Tech 1993;24(2):157-67. PMID 8457727
109: Keil W, Schmidt KF, Löwel S, Kaschube M. Reorganization of columnar architecture in the growing visual cortex. Proc Natl Acad Sci USA 2010;107(27):12293-8. PMID 20566883
110: Keppler-Noreuil KM, Sapp JC, Lindhurst MJ, et al. Clinical delineation and natural history of the PIK3CA-related overgrowth spectrum. Am J Med Genet A 2014;164A(7):1713-33. PMID 24782230
111: Kim SH, Choi J. Pathological classification of focal cortical dysplasia (FCD): personal comments for well understanding FCD classification. J Korean Neurosurg Soc 2019;62(3):288-95. PMID 31085954
112: Kobow K, Ziemann M, Kaipananickal H, et al. Genomic DNA methylation distinguishes subtypes of human focal cortical dysplasia. Epilepsia 2019;60(6):1091-103. PMID 31074842
113: Kremkow J, Lin J, Wang Y, Alonso JM. Principles underlying sensory map topography in primary visual cortex. Nature 2016;533(7601):52-7. PMID 27120164
114: Krsek P, Maton B, Jayakar P, et al. Incomplete resection of focal cortical dysplasia is the main predictor of poor postsurgical outcome. Neurology 2009b;72(3):217-23. PMID 19005171
115: Krsek P, Pieper T, Karlmeier A, et al. Different presurgical characteristics and seizure outcomes in children with focal cortical dysplasia type I or II. Epilepsia 2009a;50(1):125-37. PMID 18513354
116: Kubach J, Mühlebner-Fahrngrüber A, Soylemezoğlu F, et al. Same but different: a web-based deep learning application revealing classifying features for the histopathologic distinction of cortical malformations. Epilepsia 2020;61(3):421-32. PMID 32080846
117: Kurek KC, Lucs VL, Ayturk UM, et al. Somatic mosaic activating mutations in PIK3CA cause CLOVES syndrome. Am J Med Genet 2012;90(6):1108-15. PMID 22658544
118: Kuroda N, Fujimoto A, Enoki H, Arai Y, Okanishi T. A case of focal cortical dysplasia type Ib atypically showing reversible intensity changes on magnetic resonance imaging which could be affected by epileptic discharge activity. Childs Nerv Syst 2019;35(5):883-7. PMID 30810857
119: Lagarde S, Bonini F, McGonigal A, et al. Seizure-onset patterns in focal cortical dysplasia and neurodevelopmental tumors: relationship with surgical prognosis and neuropathologic subtypes. Epilepsia 2016;57(9):1426-35. PMID 27406939
120: Lagarde S, Scholly J,Popa I, et al. Can histologically normal epileptogenic zone share common electrophysiological phenotypes with focal cortical dysplasia? SEEG-based study in MRI-negative epileptic patients. J Neurol 2019;266(8):1907-18. PMID 31055634
121: Lai D, Gade M, Yang E, et al. Somatic variants in diverse genes leads to a spectrum of focal cortical malformations. Brain 2022;145(8):2704-20. PMID 35441233
122: Lampinen B, Zampeli A, Björkman-Burtscher IM, et al. Tensor-valued diffusion MRI differentiates cortex and white matter in malformations of cortical development associated with epilepsy. Epilepsia 2020;61(8):1701-13. PMID 32667688
123: Lee JH, Huynh M, Silhavy JL, et al. De novo somatic mutations in components of the P13K-AKT3-mTOR pathway cause hemimegalencephaly. Nat Genet 2012;44(8):941-5. PMID 22729223
124: Lee KS, Collins JL, Anzivino MJ, Frankel EA, Schottler F. Heterotopic neurogenesis in a rat with cortical heterotopia. J Neurosci 1998;18(22):9365-75. PMID 9801375
125: Lee KS, Huang X, Fitzpatrick D. Topology of ON and OFF inputs in visual cortex enables an invariant columnar architecture. Nature 2016;533(7601):90-4. PMID 27120162
126: Lee HM, Hong SJ, Gill R, et al. Multimodal mapping of regional brain vulnerability to focal cortical dysplasia. Brain 2023;146(8):3404-15. PMID 36852571
127: Lee KS, Schottler F, Collins JL, et al. A genetic animal model of human neocortical heterotopia associated with seizures. J Neurosci 1997;17:6236-42. PMID 9236234
128: Lerner JT, Salamon N, Hauptman JS, et al. Assessment and surgical outcomes for mild type I and severe type II cortical dysplasia: a critical review and the UCLA experience. Epilepsia 2009;50(6):1310-35. PMID 19175385
129: Leventer RJ, Jansen FE, Mandelstam SA, et al. Is focal cortical dysplasia sporadic? Familial evidence for genetic susceptibility. Epilepsia 2014;55(3):e22-6. PMID 24502525
130: Levi-Montalcini R. The nerve growth factor 35 years later. Science 1987;237:1154-62. PMID 3306916
131: Li L, Liu CQ, Li TF, et al. Analysis of altered micro RNA expression profiles in focal cortical dysplasia IIB. J Child Neurol 2016;31(5):613-20. PMID 26442942
132: Lim JS, Gopalappa R, Kim SH, et al. Somatic mutations in TSC1 and TSC2 cause focal cortical dysplasias. Am J Hum Genet 2017;100(3):454-72. PMID 28215400
133: Lim JS, Kim WI, Kang HC, et al. Brain somatic mutations in mTOR cause focal cortical dysplasia type II leading to intractable epilepsy. Nat Med 2015;21(4):395-400. PMID 25799227
134: Lin YX, Lin K, Liu XX, et al. PI3K-AKT pathway polymerase chain reaction (PCR) array analysis of epilepsy induced by type II focal cortical dysplasia. Genet Mol Res 2015;14(3):9994-10000. PMID 26345935
135: Lindhurst MJ, Sapp JC, Teer JK, et al. A mosaic activating mutation in AKT1 associated with the Proteus syndrome. N Engl J Med 2011;365(7):611-9. PMID 21793738
136: Liu W; Lin M, Yue Q, Gong Q, Zhou D, Wu X. Brain functional connectivity patterns in focal cortical dysplasia related epilepsy. Seizure 2021;87:1-6. PMID 33636448
137: Loconte DC, Grossi V, Bozzao C, et al. Molecular and functional characterization of three different postzygotic mutations in PIK3CA-related overgrowth spectrum (PROS) patients: effects on PI3K/AKT/mTOR signaling and sensitivity to PIK3 inhibitors. PLoS One 2015;10(4):e0123092. PMID 25915946
138: Lois C, Garcia-Verdugo JM, Alvarez-Buylla A. Chain migration of neuronal precursors. Science 1996;271:978-81. PMID 8584933
139: Lorio S, Adler S, Gunny R, et al. MRI profiling of focal cortical dysplasia using multi-compartment diffusion models. Epilepsia 2020;61(3):433-44. PMID 32065673
140: Lortie A, Plouin P, Chiron C, Delalande O, Dulac O. Characteristics of epilepsy in focal cortical dysplasia in infancy. Epilepsy Res 2002;51(1-2):133-55. PMID 12350389
141: Luhmann HJ, Karpuk N, Qu M, Zilles K. Characterization of neuronal migration disorders in neocortical structures. II. Intracellular in vitro recordings. J Neurophysiol 1998;80(1):92-102. PMID 9658031
142: Luks VL, Kamitaka N, Vivero MP, et al. Lymphatic and other vascular malformative/overgrowth disorders are caused by somatic mutations in PIK3CA. J Pediatr 2015;166(4):1048-54. PMID 25681199
143: Macdonald-Laurs E, Warren AEL, Lee WS, et al. Intrinsic and secondary epileptogenicity in focal cortical dysplasia type II. Epilepsia 2023;64(2):348-63. PMID 36527426
144: Manz HJ, Phillips TM, Rowden G, McCullough DC. Unilateral megalencephaly, cerebral cortical dysplasia, neuronal hypertrophy and heterotopia: cytomorphometric, fluorometric cytochemical, and biochemical analyses. Acta Neuropathol 1979;45:97-103. PMID 419942
145: Marchal G, Andermann F, Tampieri D, et al. Generalized cortical dysplasia manifested by diffusely thick cerebral cortex. Arch Neurol 1989;46:430-4. PMID 2495785
146: Marin-Padilla M. Three-dimensional structural organization of layer I of the human cerebral cortex: a Golgi study. J Comp Neurol 1990;299:89-105. PMID 2212113
147: Marinowic DR, Zanirati GG, Xavier FAC, et al. WNT pathway in focal cortical dysplasia compared to perilesional tissue in refractory epilepsy. BMC Neurol 2023;23(1):338. PMID 37749503
148: Martínez-López A, Blasco-Morente G, Pérez-López I, et al. CLOVES syndrome: review of a PIK3CA-related overgrowth spectrum (PROS). Clin Genet 2017;91(1):14-21. PMID 27426476
149: McDaniel SS, Rensing NR, Thio LL, Yamada KA, Wong M. The ketogenic diet inhibits the mammalian target of rapamycin (mTOR) pathway. Epilepsia 2011;52(3):e7-e11. PMID 21371020
150: Medici V, Rossini L, Deleo F, et al. Different parvalbumin and GABA expression in human epileptogenic focal cortical dysplasia. Epilepsia 2016;57(7):1109-19. PMID 27173597
151: Meencke HJ. The density of dystopic neurons in the white matter of the gyrus frontalis inferior in epilepsies. J Neurol 1983;30:171-81. PMID 6197512
152: Meencke HJ. Neuron density in the molecular layer of the frontal cortex in primary generalized epilepsy. Epilepsia 1985;26:450-4. PMID 4043013
153: Meencke HJ, Janz D. Neuropathological findings in primary generalized epilepsy: a study of eight cases. Epilepsia 1984;25:8-21. PMID 6692795
154: Miller KE, Koboldt DC, Schieffer KM, et al. Somatic SLC35A2 mosaicism correlates with clinical findings in epilepsy brain tissue. Neurol Genet 2020;6(4):e460. PMID 32637635
155: Minkin K, Gabrowski K, Karazapryanov P, et al. Awake epilepsy surgery in patients with focal cortical dysplasia. World Neurosurg 2021;151:e257-64. PMID 33872840
156: Mischel PS, Nguyen L, Vinters HV. Cerebral cortical dysplasia associated with pediatric epilepsy. Review of neuropathologic features and proposal for a grading system. J Neuropathol Exp Neurol 1995;54:137-53. PMID 7876884
157: Miyata H, Kuwashige H, Hori T, et al. Variable histopathology features of neuronal dyslamination in the cerebral neocortex adjacent to epilepsy-associated vascular malformations suggest complex pathogenesis of focal cortical dysplasia ILAE type IIIc. Brain Pathol 2022;32(5):e13052. PMID 35001442
158: Mountcastle VB. The columnar organization of the neocortex. Brain 1997;120(Pt 4):701-22. PMID 9153131
159: Mühlebner A, Bongaarts A, Sarnat HB, Scholl T, Aronica E. New insights into a spectrum of developmental malformations related to mTOR dysregulations: challenges and perspectives. J Anat 2019;235(3):521-42. PMID 30901081
160: Najm I, Sarnat HB, Blümcke I. The international consensus classification of focal cortical dysplasia – a critical update 2018. Neuropathol Appl Neurobiol 2018;44(1):18-31. PMID 29359399
161: Najm IM, Tassi L, Sarnat HB, et al. Epilepsies associated with focal cortical dysplasias (FCDs). Acta Neuropathol 2014;128(1):5-19.** PMID 24916270
162: Najm IM, Tilelli CQ, Oghlakian R. Pathophysiological mechanisms of focal cortical dysplasia: a critical review of human tissue studies and animal models. Epilepsia 2007;48(suppl 2):21-32. PMID 17571350
163: Nakagawa JM, Donkels C, Fauser S, Schulze-Bonhage A, Prinz M, Zeentner J, Haas CA. Characterization of focal cortical dysplasia with balloon cells by layer-specific markers: evidence for differential vulnerability of interneurons. Epilepsia 2017;58(4):635-45. PMID 28206669
164: Nakashima M, Saitsu H, Takei N, et al. Somatic mutations in the MTOR gene cause focal cortical dysplasia type IIb. Ann Neurol 2015;78(3):375-86. PMID 26018084
165: Najm IM, Lai D, Alonso M, et al. The ILAE consensus classification of focal cortical dysplasia (FCD): an update proposed by an ad hoc task force of the ILAE Diagnostic Methods Commission. Epilepsia 2022;63(8):1899-919. PMID 35706131
166: Norman MG, McGillivray BC, Kalousek DK, et al. Congenital malformations of the brain. Pathologic, embryologic, clinical, radiologic and genetic aspects. New York: Oxford Univ Pr, 1995.
167: Overwater IE, Rietman AB, Bindels-de Heus K, et al. Sirolimus for epilepsy in children with tuberous sclerosis complex: a randomized trial. Neurology 2016;87(10):1011-8. PMID 27511181
168: Palmini A, Andermann F, Olivier A, et al. Neuronal migration disorders and intractable partial epilepsy: a study of 30 patients. Ann Neurol 1991;30(6):741-9. PMID 1789691
169: Palmini A, Najm A, Avanzini G, et al. Terminology and classification of the cortical dysplasias. Neurology 2004;62(6 Suppl 3):S2-8. PMID 15037671
170: Peron S, Pancholi R, Voelcker B, et al. Recurrent interactions in local cortical circuits. Nature 2020;579(7798):256-9. PMID 32132709
171: Pfisterer U, Petukhov V, Demharter S, et al. Identification of epilepsy-associated neuronal subtypes and gene expression underlying epileptogenesis. Nature Commun 2020;11(1):5038. PMID 33028830
172: Pinheiro J, Honavar M. Focal cortical dysplasia: updates. Indian J Pathol Microbiol 2022;65(suppl):S189-97. PMID 35562149
173: Poduri A, Evrony GD, Cai X, et al. Somatic activation of AKT3 causes hemispheric developmental malformations. Neuron 2012;74(1):41-8. PMID 22500628
174: Poduri A, Evrony GD, Cai X, Walsh CA. Somatic mutation, genomic variation, and neurological disease. Science 2013;341(6141):1237758.** PMID 23828942
175: Pogledic I, Schwartz E, Mitter C, et al. The subplate layers: the superficial and deep subplate can be discriminated on 3 Tesla human fetal postmortem MRI. Cereb Cortex 2020;30(9):5038-48. PMID 32377685
176: Powell TP, Mountcastle VB. Some aspects of the function organization of the cortex of the postcentral gyrus of the monkey: a correlation of findings obtained in a single unit analysis with cytoarchitecture. Bull Johns Hopkins Hosp 1959;105:133-62. PMID 14434571
177: Prabowo A, Anink J, Lammens M, et al. Fetal brain lesions in tuberous sclerosis complex: TORC1 activation and inflammation. Brain Pathol 2013;23(1):45-59. PMID 22805177
178: Prada F, Gennari AG, Del Bene M, et al. Intraoperative ultrasonography (ioUS) characteristics of focal cortical dysplasia (FCD) type II b. Seizure 2019;69:80-6. PMID 30999253
179: Prayson RA, Estes ML. Cortical dysplasia: a histopathologic study of 52 cases of partial lobectomy in patients with epilepsy. Hum Pathol 1995;26:493-500. PMID 7750933
180: Purves D, Lichtman JW. Elimination of synapses in the developing nervous system. Science 1980;210:153-7. PMID 7414326
181: Rabinowicz T, De Courten-Myers GM, Petotot JM, Xi G, De Los Reyes E. Human cortex development: estimates of neuronal numbers indicate major loss late during gestation. J Neuropathol Exp Neurol 1996;55:320-8. PMID 8786390
182: Rakic P. Principles of neural cell migration. Experientia 1990;46:882-91. PMID 2209797
183: Rakic P. Radial unit hypothesis of neocortical expansion. Novartis Found Symp 2000;228:30-42; discussion 42-51. PMID 10929315
184: Rampp S, Rössler K, Hamer H, et al. Dysmorphic neurons as cellular source for phase-amplitude coupling in focal cortical dysplasia type II. Clin Neurophysiol 2021;132(3):782-92. PMID 33571886
185: Rashid M, Mandelstam SA. Retinal astrocytic hamartomas in tuberous sclerosis complex. J Pediatr Neurol 2012;10:75-6.
186: Raybaud C, Widjaja E. Development and dysgenesis of the cerebral cortex: malformations of cortical development. Neuroimag Clin N Amer 2011;21(3):483-543. PMID 21807310
187: Redecker C, Hagemann G, Witte OW, Marret S, Evrard P, Gressens P. Long-term evolution of excitotoxic cortical dysgenesis induced in the developing rat brain. Brain Res Dev Brain Res 1998;109(1):109-13. PMID 9706396
188: Reeves C, Tachrount M, Thomas D, et al. Combined ex vacuo 9.4T MRI and quantitative histopathological study in normal and pathological neocortical resections in focal epilepsy. Brain Pathol 2016;26(3):319-33. PMID 26268959
189: Rennebeck G, Kleymenova EV, Anderson R, Yeung RS, Artzt K, Walker CL. Loss of function of the tuberous sclerosis 2 tumor suppressor gene results in embryonic lethality characterized by disrupted neuroepithelial growth and development. Proc Natl Acad Sci U S A 1998;95(26):15629-34. PMID 9861021
190: Reutens DC, Berkovic SF, Kalnins RM, McKelvie P, Saling MM, Fabinyi GC. Localised neuronal migration disorder and intractable epilepsy: a prenatal vascular aetiology. J Neurol Neurosurg Psychiatry 1993;56:314-6. PMID 8459251
191: Robain O, Chiron C, Dulac O. Electron microscopic and Golgi study in a case of hemimegalencephaly. Acta Neuropathol 1989;77:664-6. PMID 2750482
192: Robitaille Y, Rasmussen T, Dubeau F, Tampieri D, Kemball K. Histopathology of non-neoplastic lesions in frontal lobe epilepsy. In: Chauvel P, Delgado-Escueta AV, et al, editors. Advances in neurology. Vol. 57. New York: Raven, 1993:499-513.
193: Rojiani AM, Emery JA, Anderson KJ, Massey JK. Distribution of heterotopic neurons in normal hemispheric white matter: a morphometric analysis. J Neuropathol Exp Neurol 1996;55:178-83. PMID 8786376
194: Roper SN. In utero irradiation of rats as a model of human cerebrocortical dysgenesis: a review. Epilepsy Res 1998:32(1-2):63-74. PMID 9761309
195: Roper SN, King MA, Abraham LA, Boillot MA. Disinhibited in vitro neocortical slices containing experimentally induced cortical dysplasia demonstrate hyperexcitability. Epilepsy Res 1997;26:443-9. PMID 9127725
196: Rorke LB. A perspective: the role of disordered genetic control of neurogenesis in the pathogenesis of migration disorders. J Neuropathol Exp Neurol 1994;53:105-17. PMID 8120535
197: Rossini L, De Santis D, Ceccini E, et al. Dendritic spine loss in epleptogenic type II focal cortical dysplasia: role of enhanced classical complement pathway activation. Brain Pathol 2023;33(3):e13141. PMID 36564349
198: Rossini L, Medici V, Tassi L, et al. Layer-specific gene expression in epileptogenic type II focal cortical dysplasia: normal-looking neurons reveal the presence of a hidden laminar organization. Acta Neuropathol Commun 2014;2:45. PMID 24735483
199: Russo E, Citraro R, Constanti A, de Sarro G. Them TOR signaling pathway in the brain: focus on epilepsy and epileptogenesis. Mol Neurobiol 2012;46(3):662-81. PMID 22825882
200: Sadowski K, Kotulska-Jóźwiak K, Jóźwiak S. Role of mTOR inhibitors in epilepsy treatment. Pharmacol Rep 2015;67(3):636-46. PMID 25933981
201: Sanes JR, Yamagata M. Formation of lamina-specific synaptic connections. Curr Opin Neurobiol 1999;9(1):79-87. PMID 10072367
202: Sarnat HB. Cerebral dysgeneses: embryology and clinical expression. New York: Oxford Univ Pr, 1992.
203: Sarnat HB. Clinical neuropathology practice guide 5-2013: markers of neuronal maturation. Clin Neuropathol 2013:32(5):340-69. PMID 23883617
204: Sarnat HB. Immunocytochemical markers of neuronal maturation in human diagnostic neuropathology. Cell Tiss Res 2015;359(1):279-94. PMID 25227552
205: Sarnat HB. Proteoglycan (keratan sulfate) barrier in developing human forebrain isolates cortical epileptic networks from deep heterotopia, insulates axonal fascicles and explains why axosomatic synapses are inhibitory. J Neuropathol Exp Neurol 2019;78(12):1147-59.** PMID 31633782
206: Sarnat HB. New neuropathological concepts in focal cortical dysplasias. In: Wyllie E, editor. Wyllie’s treatment of epilepsy. 7th ed. Philadelphia: Lippincott Williams & Wilkins, 2021:263-71.
207: Sarnat HB, Blümcke I, Miyata H, Vinters HV. Neuropathology of developmental disorders associated with epilepsy. In: Epilepsy: A Comprehensive Textbook. 3rd edition. Chapter 13. Philadelphia: Walters Kluwers, 2023.
208: Sarnat HB, Flores-Sarnat L. Cajal-Retzius and subplate neurons: their role in cortical development. Eur J Paediat Neurol 2002;6(2):91-7. PMID 11995962
209: Sarnat HB, Flores-Sarnat L. Genetics of epilepsy: morphogenesis timing of genetically programmed brain malformations in relation to epilepsy. Progr Brain Res 2014;213:181-98.** PMID 25194490
210: Sarnat HB, Flores-Sarnat L. Infantile tauopathies: Hemimegalencephaly; tuberous sclerosis complex; focal cortical dysplasia 2; ganglioglioma. Brain Dev 2015;37(6):553-62.** PMID 25451314
211: Sarnat HB, Flores-Sarnat L. Precocious and delayed neocortical synaptogenesis in fetal holoprosencephaly. Clin Neuropathol 2013b;32(4):255-68. PMID 23380462
212: Sarnat HB, Flores-Sarnat L. Radial micro-columnar cortical architecture: maturational arrest or focal cortical dysplasia? Pediatr Neurol 2013a;48(4):259-70.** PMID 23498558
213: Sarnat HB, Flores-Sarnat L. Excitatory/inhibitory synaptic ratios in polymicrogyria and Down syndrome help explain epileptogenesis in malformations. Pediatr Neurol 2021;116:41-54. PMID 33450624
214: Sarnat HB, Flores-Sarnat L, Trevenen CL. Synaptophysin immunoreactivity in the human hippocampus and neocortex from 6 to 41 weeks of gestation. J Neuropathol Exp Neurol 2010;69(3):234-45. PMID 20142767
215: Sarnat HB, Hader W, Flores-Sarnat L, Bello-Espinosa L. Synaptic plexi of the U-fibre layer beneath focal cortical dysplasias: role in epileptic networks. Clin Neuropathol 2018;37(6):262-76. PMID 30232955
216: Sarnat HB, Philippart M, Flores-Sarnat L, Wei X-C. Timing in neural development: arrest, delay, precociousness, and temporal determination of malformations. Pediatr Neurol 2015;52(5):473-86.** PMID 25797487
217: Sarnat HB, Scantlebury MH. Novel inflammatory neuropathology in immature brain: (1) fetal tuberous sclerosis; (2) febrile seizures; (3) α-B-crystallin; (4) role of astrocytes. Semin Pediatr Neurol 2017;24(3):152-260. PMID 29103422
218: Sarnat HB, Yu W. Maturation and dysgenesis of the human olfactory bulb. Brain Pathol 2016;26(3):301-18. PMID 26096058
219: Schmahl W, Knoedlseder M, Favor F, Davidson D. Defects of neuronal migration and the pathogenesis of cortical malformations are associated with Small eye (Sey) in the mouse, a point mutation at the Pax-6-locus. Acta Neuropathol 1993;86:126-35. PMID 8213068
220: Scholl T, Mühlebner A, Ricken G, et al. Impaired oligodendroglial turnover is associated with myelin pathology in focal cortical dysplasia and tuberous sclerosis complex. Brain Pathol 2017;27(6):770-80. PMID 27750396
221: Schottler F, Couture D, Rao A, Kahn H, Lee KS. Subcortical connections of normotopic and heterotopic neurons in sensory and motor cortices of the tish mutant rat. J Comp Neurol 1998;395(1):29-42. PMID 9590544
222: Schurr J, Coras R, Rössler K, et al. Mild malformation of cortical development with oligodendroglial hyperplasia in frontal lobe epilepsy: a new clinico-pathological entity. Brain Pathol 2017;27(1):26-35. PMID 26748554
223: Seki T. From embryonic to adult neurogenesis in the dentate gyrus. In: Seki T, Sawamoto K, Parent JM, Álvarez-Buylla, editors. Neurogenesis in the adult brain I. Neurobiology. London, NY: Springer, 2011:193-216.
224: Shaffer A, Pozin M, Nasr S, et al. Refractory seizures secondary to radiation-induced focal cortical dysplasia/neuronal gigantism: illustrative case. J Neurosurg Case Lessons 2023;6(21):CASE23374. PMID 37992306
225: Shahabi H, Taylor K, Hirfanoglu T, et al. Effective connectivity differs between focal cortical dysplasia types I and II. Epilepsia 2021;62(11):2753-65. PMID 34541666
226: Shapiro KA, McGuone D, Deshpande V, Sadow PM, Stemmer-Rachamimov A, Staley KJ. Failure to detect human papillomavirus in focal cortical dysplasia type IIb. Ann Neurol 2015;78(1):63-7. PMID 25893423
227: Sharkov A, Dulac O, Gataulline S. STXBP1 germline mutation and focal cortical dysplasia. Epileptic Disord 2021;23(1):143-7. PMID 33632674
228: Shors TJ. Saving new brain cells. Sci Am 2009;300(3):46-54. PMID 19253773
229: Sidman RL, Rakic P. Neuronal migration, with special reference to developing human brain: a review. Brain Res 1973;62:1-35. PMID 4203033
230: Siebzehnrubl FA, Blümcke I. Neurogenesis in the human hippocampus and its relevance to temporal lobe epilepsies. Epilepsia 2008;49 Suppl 5:55-65. PMID 18522601
231: Sim JC, Scerri T, Fanjul-Fernández M, et al. Familial cortical dysplasia caused by mutation in the mammalian target of rapamycin regulator NPRL3. Ann Neurol 2016;79(1):132-7. PMID 26285051
232: Sim NS, Seo Y, Lim JS, et al. Brain somatic mutations in SLC35A2 cause intractable epilepsy with aberrant N-glycosylation. Neurol Genet 2018;4(6):e294. PMID 30584598
233: Spreafico R, Blümcke I. Focal cortical dysplasias: clinical implication of neuropathological classification systems. Acta Neuropathol 2010;120(3):359-67. PMID 20607544
234: Squier W, Jansen A. Polymicrogyria: pathology, fetal origins and mechanisms. Acta Neuropathol Commun 2014;2:80.** PMID 25047116
235: Sun FJ, Zhang CQ, Chen X, et al. Downregulation of CD47 and CD200 in patients with focal cortical dysplasia type IIb and tuberous sclerosis complex. J Neuroinflammation 2016;13(1):85. PMID 27095555
236: Tai C, Chang CW, Yu GQ, et al. Tau reduction prevents key features of autism in mouse models. Neuron 2020;106(3):421-37. PMID 32126198
237: Tarkowski B, Kuchcinska K, Blazejczyk M, Jaworski J. Pathological mTOR mutations impact cortical development. Hum Mol Genet 2019;28(13):2107-19. PMID 30789219
238: Taylor DC, Falconer MA, Bruton CJ, Corsellis JA. Focal dysplasia of the cerebral cortex in epilepsy. J Neurol Neurosurg Psychiatry 1971;34(4):369-87. PMID 5096551
239: Taylor JP, Sater R, French J, Baltuch G, Crino P. Transcription of intermediate filament genes is enhanced in focal cortical dysplasia. Acta Neuropathol (Berl) 2001;102(2):141-8. PMID 11563628
240: Thapaliya K, Urriola J, Barth M, Reutens DC, Bollman S, Vegh V. 7T GRE-MRI signal compartments are sensitive to dysplastic tissue in focal dysplasia. Magn Reson Imaging 2019;61:1-8. PMID 31075420
241: Thom M, Liu J, Bongaarts A, et al. Multinodular and vacuolating neuronal tumors in epilepsy: dysplasia or neoplasia? Brain Pathol 2018;28(2):155-71. PMID 28833756
242: Thom M, Liu J, Reeves C, et al. A cautionary note in the interpretation of human papillomavirus E6 immunohistochemistry in focal cortical dysplasia. Ann Neurol 2015;77(2):352-3. PMID 25515675
243: Thoreen CC, Chantranupong L, Keyes HR, Wang T, Gray NS, Sabatini DM. A unifying model for mTORC1-mediated regulation of mRNA translation. Nature 2012;485(7396):109-13. PMID 22552098
244: Tsai V, Parker W, Orlova KA, et al. Fetal brain mTOR pathway activation in tuberous sclerosis complex. Cerebr Cortex 2014;24(2):315-27. PMID 23081885
245: Ulfig N. Calcium-binding proteins in the human developing brain. Adv Anat Embryol Cell Biol 2002;165:III-IX, 1-92. PMID 12236093
246: Urbach H, Heers M, Altenmueller D-M, et al. ”Within a minute” detection of focal cortical dysplasia. Neuroradiology 2022a;64(4):715-26. PMID 34625834
247: Urbach H, Kellner E, Kremers N, Blumcke I, Demerath T. MRI of focal cortical dysplasia. Neuroradiology 2022b;64(3):443-52. PMID 34839379
248: Vahidnezhad H, Youssefian L, Uitto J. Klippel-Trenaunaay syndrome belongs to the PIK3CA-related overgrowth spectrum (PROS). Exp Dermatol 2016;25(1):17-9. PMID 12236093
249: Valverde F, Facal-Valverde MV, Santacana M, Heredia M. Development and differentiation of early generated cells of sublayer VIb in the somatosensory cortex of the rat: a correlated Golgi and autoradiographic study. J Comp Neurol 1989;290(1):118-40. PMID 2480368
250: van Huizen F, Romijn HJ, Corner MA. Indications for a critical period for synapse elimination in developing rat cerebral cortex cultures. Brain Res Dev Brain Res 1987;31:1-6. PMID 3815105
251: Vasilica AM, Winsor A, Chari A, Scott R, Baldeweg T, Tisdall M. The influence of disease course and surgery on quality of life in children with focal cortical dysplasia and long-term epilepsy-associated tumours: a systematic review and meta-analysis. Epilepsy Res 2023;192:107132. PMIS 37023554
252: Veersema TJ, Swampillai B, Ferrier CH, et al. Long-term seizure outcome after epilepsy surgery in patients with mild malformations of cortical development and focal cortical dysplasia. Epilepsy Open 2018;4(1):170-5. PMID 30868127
253: Veersema TJ, van Schooneveld MMJ, Ferrier CH, et al. Cognitive functioning after epilepsy surgery in children with mild malformation of cortical development and focal cortical dysplasia. Epilepsy Behav 2019;94:209-15. PMID 30974349
254: Verentzioti A, Blumcke I, Alexoudi A, et al. Epileptic patient with mild malformation of cortical development with oligodendroglial hyperplasia and epilepsy (MOGHE): A case report and review of the literature. Case Rep Neurol Med 2019;9130780. PMID 31281692
255: Vinters HV, Armstrong DL, Babb TL, et al. The neuropathology of human symptomatic epilepsy. In: Engel J Jr, editor. Surgical treatment of the epilepsies. 2nd ed. New York: Raven, 1993:593-608.
256: Vinters HV, Fisher RS, Cornford ME, et al. Morphological substrates of infantile spasms: studies based on surgically resected cerebral tissue. Childs Nerv Syst 1992;8:8-17. PMID 1315619
257: Walger L. Adler S, Wagstyl K, et al. Artificial intelligence for the detection of focal cortical dysplasia: challenges in translating algorithms into clinical practice. Epilepsia 2023;64(5):1093-112. PMID 36721976
258: Walsh C, Cepko CL. Cell lineage and cell migration in the developing cerebral cortex. Experientia 1990;46:940-7. PMID 2209803
259: Wang DD, Katoch M, Jabari S, et al. The specific DNA methylation landscape in focal cortical dysplasia ILAE type 3D. Acta Neuropathol Commun 2023;11(1):129. PMID 37559109
260: Wang I, Oh S, Blümcke I, et al. Value of 7T MRI and post-processing in patients with nonlesional 3T MRI undergoing epilepsy presurgical evaluation. Epilepsia 2020;61(11):2509-20. PMID 32949471
261: Wang Y, He C, Chen C, et al. Focal cortical dysplasia links to sleep-related epilepsy in symptomatic focal epilepsy. Epilepsy Behav 2022;127:108507. PMID 34968776
262: Weil AG, Lewis EC, Ibrahim GM, et al. Hemispherectomy outcome prediction scale : development and validation of a seizure freedom prediction tool. Epilepsia 2021;62(5):1064-73. PMID 33713438
263: Willhite DC, Nguyen KT, Masurkar AV, Greer CA, Shepherd GM, Chen WR. Viral tracing identifies distributed columnar organization in the olfactory bulb. Proc Natl Acad Sci U S A 2006;103(33):12592-7. PMID 16895993
264: Winawer MR, Griffin NG, Samanamud J, et al. Somatic SLC35A2 variants in the brain are associated with intractable neocortical epilepsy. Ann Neurol 2018;83(6):1133-46. PMID 29679388
265: Wolf HK, Wellmer J, Muller MB, Wiestler OD, Hufnagel A, Pietsch T. Glioneuronal malformative lesions and dysembryoplastic neuroepithelial tumors in patients with chronic pharmacoresistant epilepsies. J Neuropathol Exp Neurol 1995;54:245-54. PMID 7876892
266: Xu Q, Uliel-Sibony S, Dunham C, et al. mTOR inhibitors as a new therapeutic strategy in treatment resistant epilepsy in hemimegalencephaly: a case report. J Child Neurol 2019;34(3):132-8. PMID 30514132
267: Yachnis AT, Powell SZ, Olmsted JJ, Eskin TA. Distinct neurodevelopmental patterns of Bcl-2and Bcl-x expression are altered in glioneuronal hamartias of the human temporal lobe. J Neuropathol Exp Neurol 1997;56:186-98. PMID 9034373
268: Yamanouchi H, Zhang W, Jay V, Becker LE. Enhanced expression of microtubule-associated protein 2 in large neurons of cortical dysplasia. Ann Neurol 1996;39(1):57-61. PMID 8572667
269: Yasin SA, Latak K, Becherini F, et al. Balloon cells in human cortical dysplasia and tuberous sclerosis: isolation of a pathological progenitor-like cell. Acta Neuropathol 2010;120(1):85-96. PMID 20352236
270: Ying Z, Babb TL, Comair YG, Bingaman W, Bushey M, Touhalisky K. Induced expression of NMDAR2 proteins and differential expression of NMDAR1 splice variants in dysplastic neurons of human epileptic neocortex. J Neuropathol Exp Neurol 1998;57(1):47-62. PMID 9600197
271: Yogi A, Hirata Y, Karavaeva E, et al. DTI of tuber and perituberal tissue can predict epileptogenicity in tuberous sclerosis. Neurology 2015;85(23):2011-5. PMID 26546629
272: Yu K, Lin CCL, Hatcher A, et al. PIK3CA variants selectively initiate brain hyperactivity during gliomagenesis. Nature 2020;178(7793):166-71. PMID 31996845
273: Zhang L, Huang T, Teaw S, et al. Filamin A inhibition reduces seizure activity in a mouse model of focal cortical malformations. Sci Transl Med 2020a;12(531):eaay0289. PMID 32075941
274: Zhang Z, Gao K, Liu Q, et al. Somatic variants in new candidate genes identified in focal cortical dysplasia type II. Epilepsia 2020b;61(4):667-78. PMID 32216069
275: Zhong S, Zhao Z, Xie W, et al. GABAergic interneuron and neurotransmission are mTOR-dependently disturbed in experimental focal cortical dysplasia. Mol Neurobiol 2021;58(1):156-69. PMID 32909150
276: Zilles K, Qu M, Schleicher A, Luhmann HJ. Characterization of neuronal migration disorders in neocortical structures: quantitative receptor autoradiography of ionotropic glutamate, GABA(A) and GABA(B) receptors. Eur J Neurosci 1998;10(10):3095-106. PMID 9786204
277: Zucca I, Milesi G, Medici V, et al. Type II focal cortical dysplasia: ex vivo 7T magnetic resonance imaging abnormalities and histopathological comparisons. Ann Neurol 2016;79(1):42-58. PMID 26448158

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Harvey B Sarnat MD FRCPC MS

Dr. Sarnat of the University of Calgary has no relevant financial relationships to disclose.
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Former Authors

David A Griesemer MD
Paul S Mischel MD
Harry V Vinters MD

Patient Profile

Age range of presentation: 0 month to 44 years
Sex preponderance: male=female
Heredity: heredity may be a factor
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-10: Congenital malformation of nervous system, unspecified: Q07.9
ICD-11: Cortical dysplasia: LA05.51
OMIM: Focal cortical dysplasia, type II: %607341

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Focal cortical dysplasias

Associated Disorders

Cerebral dysgenesis
Cortical dysplastic lesion
Dysembryoplastic neuroepithelial tumor
Dysplastic cortex
Epilepsy
- Focal neuroblast migratory disorder
- Ganglioglioma
- Hemimegalencephaly
- Microdysgenesis
- Neuroglial hamartias

Differential Diagnosis

another type of lesion
chromosomopathies
DiGeorge syndrome
trisomy-13
inborn metabolic diseases beginning prenatally
- methylmalonic academia
- electrolyte imbalances
- toxic causes of seizures
- febrile seizures
- ganglioglioma
- dysembryoplastic neuroepithelial tumor
- vascular/traumatic lesions
- infectious lesions
- inflammatory lesions
- Rasmussen encephalitis
- Ammon horn (hippocampal) sclerosis
- Sturge-Weber-Dimitri syndrome
- vascular malformations
- meningioangiomatosis

Also Relevant

Epileptic spasms
Epilepsia partialis continua of Kozhevnikov
Epilepsy
Familial focal epilepsy with variable foci
Hemimegalencephaly
- Septo-optic-pituitary dysplasia complex

Clinical Categories

Developmental Malformations

Focal cortical dysplasias

Introduction

Overview

Historical note and terminology

Table 1. 2011 ILAE Classification of Focal Cortical Dysplasias

Clinical manifestations

Presentation and course

Prognosis and complications

Table 2. Summary of Features of Focal Cortical Dysplasia Type 1

Table 3. Summary of Features of Focal Cortical Dysplasia Type 2

Clinical vignette

Biological basis

Etiology and pathogenesis

Table 4. Microscopic Findings Associated with Cortical Dysplasias

Epidemiology

Differential diagnosis

Confusing conditions

Diagnostic workup

Management

Outcomes

Special considerations

Anesthesia

Media

References

Contributors

Author

Former Authors

Patient Profile

ICD & OMIM codes

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Questions or Comment?

Also in This Category

Vein of Galen malformations

Epileptic lesions due to malformation of cortical development

Agenesis of the corpus callosum

Epidermal nevus syndromes: neurologic phenotypes

Norrie disease

Aqueductal stenosis

Klippel-Feil syndrome

Cerebellar hypoplasia, dysplasia, and enlargement

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