Altered Gray Matter Myelin in Type IIb Focal Cortical Dysplasia

Abstract

Background and objectives: Myelin is altered in several neurologic disorders. Published data demonstrate reduced white matter myelin content and lower oligodendrocyte cell number in postsurgical brain specimens obtained from patients with focal cortical dysplasia (FCD) and temporal lobe epilepsy; a pathogenic role of dysfunctional myelin in focal epilepsies has been proposed. Based on this evidence, our study aims to investigate the myelination status in the gray matter in postsurgical brain specimens from patients with FCDIIb.

Methods: We collected specimens from patients with a histopathologic diagnosis of FCDIIb who underwent surgery between 1995 and 2022 in 2 epilepsy surgery centers in Milano; we used nonlesional samples and perilesional tissue within the same FCDIIb specimen as controls. Immunohistochemistry for myelin basic protein (MBP) and electron microscopy were used to quantify myelin alterations in the lesional core of FCDIIb specimens compared with nonlesional and perilesional control areas. Olig2 and breast carcinoma amplified sequence 1 immunohistochemistry, markers of oligodendrocytes, were also evaluated.

Results: Sixteen patients with FCDIIb (24 ± 14 mean years at surgery, 44% female) and 4 controls (3 histopathology-negative epileptic patients and 1 patient with nonepileptic tumor; 32 ± 11 mean years at surgery, 50% female) were included. The cortical myeloarchitecture was disorganized in the FCD core lesion. MBP immunostained fiber density from 11 paired samples that included both the FCD lesional core and adjacent perilesional cortex in the same tissue section did not reveal a significant difference. Ultrastructural examination performed in the gray matter of 6 specimens from FCDIIb patients (both in the core and in the adjacent perilesional areas) and 2 controls revealed that exclusively in the FCDIIb core, myelinated fiber density was reduced and axons featured thin or no myelin coating and pathologic vacuoles. These changes were associated with a reduction of Olig2-immunostained cells in the FCDIIb cortex core.

Discussion: Our findings demonstrate that the gray matter at the core of postsurgical FCDIIb specimens contains a high number of poorly myelinated axons and less oligodendrocytes; these findings suggest a potential contribution of altered myelination in the pathogenesis of FCDIIb.