Polymicrogyria includes fusion of the molecular layer and decreased neuronal populations but normal cortical laminar organization

Abstract

Malformations of cortical development are frequently identified in surgical resections for intractable epilepsy. Among the more frequently identified are cortical dysplasia, pachygyria, and polymicrogyria. The pathogenesis of these common developmental anomalies remains uncertain. Polymicrogyria is particularly vexing because there are multiple described forms (2, 4, and 6 layers) that have been attributed to multiple etiologies (e.g. ischemic, genetic, infectious, and toxic). We reviewed the pathology in 19 cases and performed cortical laminar analysis in 10 of these cases. Our data indicate that a defining feature of polymicrogyriais fusion of the molecular layer and that most often there is a well-defined gray matter-white matter junction. Unexpectedly, the cortical laminae were normally positioned, but there were reduced neuronal populations within these laminae, particularly in the subgranular layers. On the basis of these data, we propose that the categorization of polymicrogyria according to the number of lamina is artificial and should be abandoned, and polymicrogyria should be defined according to the presence or absence of coexisting neuropathological features. Furthermore, our data indicate that polymicrogyria is not a cell migration disorder, rather it should be considered a postmigration malformation of cortical development.

Figure 1

Examples of various forms of polymicrogyria (PMG). (A) 2-layer (unlayered) PMG. (B) 4-layer PMG. (C) 6-layer PMG. H&E stain. Magnification: 100×.

Figure 2

Polymicrogyria (PMG) (arrow) with adjacent dysplastic cortex (left of arrow) lacking layer organization or molecular layer fusion. H&E stain. Magnification: 100×.

Figure 3

Immunohistochemistry for Reelin, Calretinin, Ctip2 and Tbr1 in control and polymicrogyria (PMG) brains. (A, B) Reelin-labeled Cajal-Retzius neurons are present in the molecular layer of both the control and PMG brains (arrows). (C, D) Calretinin-labeled neurons are found in all cortical layers of control and PMG brains with predominance in layers 3 and 5 in controls but not in PMG for layer 5 (see also Fig. 4). (E, F) Most Ctip2+ neurons are located in layer 5 with scattered positive cells in more superficial layers. This pattern is observed in both control and PMG brains, although again there are fewer positive cells in layer 5. (G, H) Tbr1 is predominately expressed in cortical layer 6 in both control and PMG brains. Magnification: 100×.

Figure 4

Labeling index according to cortical layers for Reelin, Calretinin, Ctip2 and Tbr1. Light grey diamonds correspond to control regions; dark grey squares to correspond to polymicrogyria. Layer 1 = molecular layer; layer 7 = white matter; layers 2 through 6 correspond to relative depth in the cortex.