Unfolding Polymicrogyria

Jeffrey A. Golden; Brian N. Harding

Disclosures

Abstract and Introduction

Abstract

Malformations of cortical development are commonly associated with epilepsy and intellectual disabilities. Polymicrogyria is one of the most frequent cortical malformations but remains largely enigmatic. A new multicenter clinical and radiographic study of patients with polymicrogyria has identified anatomical patterns that could shed new light on the underlying pathogenesis of this condition.

Introduction

Malformations of cortical development frequently result in epilepsy and intellectual disabilities,[1] and four principal forms have been identified.[2] The first, lissencephaly, manifests as a reduction in cerebral folding, leading to a smooth brain. The second, cortical dysplasia, is a disorganization of the cortical lamination pattern with abnormal neurons. The third is a malpositioning of cortical gray matter within the white matter fiber tracts, also known as heterotopia. The fourth, polymicrogyria, is characterized by excessive folding of the cortical surface (Figure 1). The various forms are morphologically distinct, but can be found in combination or even with overlapping features, making them difficult to tell apart in practice.

Figure 1.

Polymicrogyria. a | Cytoarchitecturally normal cortex and b | polymicrogyria from a 10 day-old child. In contrast to the well-defined sulci (S) and gyri (G) in the normal cortex, the sulci in the polymicrogyria cortex are very shallow and show fusion of the superficial layers. The cortex is thin (compare lengths of boxes, which span full thickness of cortex) and folded in on itself, giving an artificially thick appearance. The many and small gyri give rise to the name polymicrogyria. In both specimens, a well-defined junction (arrows) is visible between the cortex and underlying white matter.

Polymicrogyria is among the most common of the malformations of cortical development, and pathology is the current 'gold standard' of diagnosis. The initial description of polymicrogyria—an abnormally thin, disorganized cortex with too many small and fused convolutions—remains the accepted standard.[3] The pathogenesis of polymicrogyria remains unresolved, and is likely to involve multiple mechanisms. Well-defined etiologies include acquired brain injury related to abnormal perfusion and/or oxygenation of the fetal brain, and infection during intrauterine life.[2] During development, polymicrogyria seems to arise during a relatively narrow time window, from the early second trimester to the beginning of the third trimester.[4] The presence of polymicrogyria in association with several metabolic disorders provides another potential pathogenetic mechanism.[2] In addition, an increasing number of familial reports, along with the identification of rare genetic aberrations in some patients, suggests an underlying genetic basis in many cases. This latter speculation is supported by the fact that many cases show a similar distribution of polymicrogyria, suggesting that different genetic causes can produce similar neuroanatomical patterns of polymicrogyria.

To date, elucidation of the pathogenesis of polymicrogyria has been hampered by the lack of a large cohort of case material characterizing the clinical and anatomical distributions of this malformation, which could, in turn, provide a foundation for gene identification studies. An important step towards fulfilling this need has now been made. A multicenter collaboration has collected and reported on 325 patients, ranging in age from infancy to adulthood, with polymicrogyria diagnosed on the basis of high-quality MRI.[5] In this study, Leventer and colleagues have confirmed many previously described patterns of polymicrogyria, as well as adding a number of novel distributions.

Consistent with previous anecdotal reports and smaller series, the most common pattern involved the cortex around the Sylvian fissures, usually bilaterally. Leventer et al. and others contend that this pattern could reflect the vascular anatomy of the brain and the vulnerability of certain areas to hypoperfusion. However, other patterns, such as a more generalized bilateral polymicrogyria or the combination of polymicrogyria with multiple periventricular heterotopias, are more indicative of a genetic etiology. Unfortunately, familial information was not provided for the cases reported. Rarer forms also emerged, such as a relationship with Sturge–Weber syndrome (two cases), a vascular malformation, and polymicrogyria related to schizencephaly or, in another instance, to a cleft underlying a previously resected encephalocele (congenital herniation of the brain). The association with encephaloceles, which is well known to pathologists, highlights one of the problems inherent in using imaging studies that might not accurately report an entity that is defined histopathologically.

Leventer et al. are confident that the criteria they used to diagnose polymicrogyria are supported by the limited data in the literature correlating imaging with actual pathological studies. However, the level of resolution presently obtained in practice still sometimes leads to uncertainty, even for the most experienced of neuroradiologists. Indeed, the authors refer to the difficulty of differentiating polymicrogyria from otherwise damaged cortex in Sturge–Weber syndrome. In our personal experience, examination of many samples of epilepsy-provoking cortex from patients with Sturge–Weber syndrome has not shown polymicrogyria. On the other hand, polymicrogyria has previously been seen within encephaloceles, although not identified by imaging. This morphological detail is one of the more tantalizing aspects that is inevitably missing in a pure imaging study. Polymicrogyria has variable patterns of faulty layering that can bear on pathogenesis and cannot be addressed by imaging alone. Finally, architectonics—the regional variations in cortical organization—cannot be determined without pathology. Pathological studies of polymicrogyria reveal that the primary visual cortex is often preserved, yet on imaging this region can appear to be affected, possibly reflecting a change in its anatomical position as a result of cortical reorganization.

The unquestionable strength of the Leventer et al. study is the opportunity to more clearly define and group patients with polymicrogyria into distinct subtypes, which will substantially enhance gene identification and help us to obtain a greater understanding of the pathogenesis of this condition. Despite mounting evidence that polymicrogyria has a genetic basis, relatively few candidate genes have been identified. Autosomal recessive inheritance has been ascribed to many patterns, including bilateral forms of frontal, frontoparietal, perisylvanian and generalized polymicrogyria; however, only a small number of genes (PAX6, TBR2, KIAA1279, RAB3GAP1 and COL18A1) have been implicated to date.[6] Mutations in GPR56 have been associated with bilateral frontoparietal polymicrogyria, although pathological confirmation has not been obtained for any case.[7] Deletions of 22q11.2, as well as an X-linked form (Xq28), have also been described,[8,9] although mutations in specific genes have not been defined. Mutations in SRPX2, which is located in the Xq28 region, have been associated with polymicrogyria, but families with Xq28-linked polymicrogyria do not seem to have mutations in this gene.[10]

We now await further studies—facilitated by the work of Leventer et al.—to delineate the genetic and embryological pathogenesis of this very interesting and important malformation of cortical development.

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