Focal cortical dysplasia

Harvey B Sarnat MD FRCPC MS (

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

)
Originally released November 28, 1994; last updated June 2, 2018; expires June 2, 2021

This article includes discussion of focal cortical dysplasia and cerebral cortical dysplasia. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

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 (Mischel et al 1995). 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" (Meencke and Janz 1984), "dysplastic cortical architecture" (Rorke 1994), "focal cortical dysplasia" (Taylor et al 1971), "generalized cortical dysplasia" (Marchal et al 1989), "synaptic dysgenesis" (Becker 1991), and "cerebral dysgenesis" (Sarnat 1992) 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 (Taylor et al 1971), now corresponding to focal cortical dysplasia type 2. Dysplastic and megalocytic neurons were first identified by Crome and colleagues in 1957 (Crome 1957).

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 (Palmini et al 2004). Various classification schemes of cortical dysplasias have been proposed (Vinters et al 1993; Mischel et al 1995; Palmini et al 2004; Krsek et al 2009a; Spreafico and Blü;mcke 2010). 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 (Blümcke et al 2011), and has been validated by an international consortium of neuropathologists with experience in epilepsy (Coras et al 2012). This scheme has a built-in flexibility for future revisions as new 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 new ILAE classification is that although based primarily upon 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 (Ulfig 2002; Sarnat 2013; Sarnat 2014). Recent 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 (Beaumont et al 2012; Dachet et al 2015; Nakagawa et al 2017), require consideration for updating the neuropathological classification. The ILAE Commission on Neuropathology is currently addressing these issues, and a revised classification is expected to be published in 2018. 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 (Jette et al 2015).

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 new 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 (Najm et al 2018), 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 (Blümcke et al 2016).

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 2 subtypes.

Perhaps the most important revision of the ILAE classification scheme relates to type III and its various subtypes (Najm et al 2018). 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 2013a). 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 (Prabowo et al 2015; Sarnat and Scantlebury 2017). 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 (Blümcke et al 2016). The interpretation and incorporation of these new 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 is currently under 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 II is a postzygotic somatic mutation; its extent depends upon timing in the 33 mitotic cycles of the early fetal neuroepithelium, so that small lesions limited to 1 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 (HME) are the same disorder with difference in timing.

 

• 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.

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