A Developmental and Genetic Classification for Malformations of Cortical Development

Update 2012

A. James Barkovich; Renzo Guerrini; Ruben I. Kuzniecky; Graeme D. Jackson; William B. Dobyns


Brain. 2012;135(5):1348-1369. 

In This Article

Group III: Malformations Secondary to Abnormal Postmigrational Development

Group III.A: Polymicrogyria and Schizencephaly

Polymicrogyria has been known for many years to be a spectrum of disorders classified under a single name and many discussions of 'true' polymicrogyria and variants of microgyria have appeared in the literature (Volpe and Adams, 1972; Evrard et al., 1989; Barkovich, 2010a). However, the term is still widely used to describe disorders that have different causes, somewhat different gross appearance, association with different accompanying malformations or disruptions, and different microscopic appearance, making it difficult to understand and properly classify the disorders (Judkins et al., 2011). Polymicrogyria has been described in conjunction with many genetic disorders (listed in Appendix 1, Group III.A.3). Unfortunately, little is understood of the range of histopathology seen in polymicrogyria, partly because few large scale pathological studies have been performed. The paucity of pathological data stems from polymicrogyria often being located in eloquent cortical areas; thus, it is rarely resected when causing intractable epilepsy (Leventer et al., 2010). Recent studies suggest a great deal of heterogeneity in the gross (Barkovich, 2010b; Leventer et al., 2010) and microscopic (Judkins et al., 2011) appearance of polymicrogyria, supporting the concept that polymicrogyria is heterogeneous in cause, embryogenesis and gross characteristics. In addition, it has been speculated that the underlying mechanisms by which polymicrogyria develops in patients with mutations and infections may be vascular (Robin et al., 2006). Many authors describe malformations resulting from disruption of the radial glial fibre attachment to the pial limiting membrane and the consequent gaps in that membrane as polymicrogyria (Jaglin and Chelly, 2009), but (as discussed in the previous section) others believe that cortical malformations associated with pial membrane defects are distinct from polymicrogyria and are better classified as cobblestone malformations (Jansen and Andermann, 2005; Leventer et al., 2010; Judkins et al., 2011). To determine the mechanisms leading to polymicrogyria, a first step will be to perform histological and molecular studies on resected tissue or autopsy specimens, in addition to developing appropriate animal models, before the differences among the many patterns can be understood.

In this classification, we have put polymicrogyria into four groups: Group III.A. with schizencephalic clefts or calcifications, presumably due to infection or vascular causes; Group III.B. without clefts or calcifications, which may be genetic or disruptive; Group III.C. as part of genetically defined multiple congenital anomaly syndromes (some of these have atypical histology); and Group III.D. in conjunction with inborn errors of metabolism (these also have atypical histology). These groups should be refined as new studies of the pathology and pathogenesis of polymicrogyria are performed.

Although past work suggested that mutations of EMX2 are a common cause of schizencephaly (Granata et al., 1997), recent work has shown that EMX2 mutations are highly unlikely to be a cause of schizencephaly (Tietjen et al., 2007; Merello et al., 2008); the authors recommend against testing for this gene, as the results would be uninterpretable. Furthermore, a large population study of <4 million births in California from 1984 to 2001 found an association with young maternal age and with monozygotic twin pregnancies (Curry et al., 2005). One-third of cases had a non-CNS abnormality, over half of which could be classified as secondary to vascular disruption (including gastroschisis, bowel atresias and amniotic band syndrome) (Curry et al., 2005). The authors concluded that schizencephaly is a disorder with heterogeneous causes, many of which are vascular disruptive in origin (Curry et al., 2005). It is unquestionably associated with polymicrogyria of disruptive aetiology. Accordingly, it is classified in Group III.A and by clinical characteristics.

Group III.C: Focal Cortical Dysplasias

Certain FCDs are classified as 'Malformations secondary to abnormal postmigrational development' because evidence supports proposals that they can result from injury to the cortex during later stages of cortical development. Evidence has been published that prenatal and perinatal insults including severe prematurity, asphyxia, shaking injury, bleeding, hydrocephalus and stroke, occur in children with mild malformation of cortical development or FCDI (Marin-Padilla et al., 2002; Krsek et al., 2010). Patients with significant prenatal and perinatal risk factors had more abnormal neurological findings, lower IQ scores, and slower background EEG activity than subjects with mild malformation of cortical development/FCD without prenatal or perinatal brain injury (Krsek et al., 2010). As FCDIII are, by definition, associated with injury, vascular malformation or epileptogenic tumour, it is very possible that FCDIII are caused by seizures or by the lesion causing the seizures. A subtype of FCDI has increased neuronal densities and decreased cortical thickness, with an abundance of cortical microcolumns (Blümcke et al., 2010); the affected hemisphere is significantly smaller than the non-epileptogenic contralateral side. These observations support the concept that FCDI is a heterogeneous group of disorders that may result from late insult/injury to the developing cortex.

Group III.D: Postmigrational Microcephaly

Postmigrational microcephaly and the rationale for placing it in this section was discussed in the earlier 'Microcephaly' section.