Neuropathologic measurements in focal cortical dysplasias: validation of the ILAE 2011 classification system and diagnostic implications for MRI

Abstract

Focal cortical dysplasias (FCD) which represent a composite group of cortical malformations are increasingly recognized as morphological substrate for severe therapy-refractory epilepsy in children and young adults. However, presurgical evaluation remains challenging as not all FCD variants can be reliably detected by high-resolution magnetic resonance imaging (MRI). Here, we studied a cohort of 52 epilepsy patients with neuropathological evidence for FCD using the 2011 classification of the International League against Epilepsy (ILAE) and systematically analysed those histopathologic features applicable also for MRI diagnostics. Histopathologic parameters included quantitative measurements of cellular profiles, cortical thickness, heterotopic neurons in white matter, and myelination that were compared between FCD subtypes and age-/localization-matched controls (n = 36) using multivariate analysis. Dysmorphic neurons in both FCD Type II variants showed significantly increased diameter of their cell bodies and nuclei. Cortical thickness was also increased with a distinct loss of myelin content specifying FCD Type IIb from IIa. The data further suggested that myelination deficits in FCD Type IIb result from compromised oligodendroglial lineage differentiation and we concluded that the "transmantle sign" is a unique finding in FCD Type IIb. In contrast, FCD Type Ia was characterized by a smaller cortical ribbon and higher neuronal densities, but these parameters failed to reach statistical significance (considering age- and location-dependent variability in controls). All FCD variants showed abnormal grey-white matter boundaries with increased numbers of heterotopic neurons. Similar results were obtained also at deep white matter location. Thus, many FCD variants may indeed escape visual MRI inspection, but suspicious areas with increased or decreased cortical thickness as well as grey-white matter blurring may be uncovered using post-processing protocols of neuroimaging data. The systematic analysis of well-specified histopathological features could be helpful to improve sensitivity and specificity in MRI detection during pre-surgical work-up of patients with drug-resistant focal epilepsies.

Impaired oligodendroglial turnover is associated with myelin pathology in focal cortical dysplasia and tuberous sclerosis complex

“…However, the number of oligodendroglial cells in MCDs is the subject of ongoing debate 12, 23, 35. We showed for the first time that the number of oligodendroglial cells may vary from case to case even within the same type of lesion (tubers, FCD IIB).…”

“…It is still unclear if the observed myelin pathology in epilepsy surgery specimens is primarily associated with the underlying malformative process, or is just a secondary phenomenon of ongoing epileptic seizures. Recent studies identified an association between myelin reduction and a lower number of oligodendrocytes, supporting the hypothesis that myelin pathology is the primary reason for seizures 23, 49. However, results remain controversial: while Shepherd et al indicated a positive correlation between white matter reduction and the duration of epilepsy 35, studies performed on patients with temporal lobe epilepsy and mild malformations of cortical development showed an increased amount of oligodendroglia compared to controls 34, 40.…”

Magnetic resonance imaging abnormalities in the resection region correlate with histopathological type, gliosis extent, and postoperative outcome in pediatric cortical dysplasia

“…Other possibilities for the abnormal white matter and cortical signal commonly seen in Type II CD would include neuronal heterotopia; hypo-, de-, or dys-myelination; and presence of balloon cells or cellular edema. 24 Differentiation between these possibilities was not possible with the methods used in our study and represents an area for further research.…”

mTOR Signaling in Epilepsy: Insights from Malformations of Cortical Development

“…Focal MCDs show a range of cytoarchitectural alterations, from subtle cortical dyslamination with malpositioned or heterotopic neurons to grossly disorganized or absent cortical lamination and abnormal cell morphology (Krsek et al 2008;Blumcke and Muhlebner 2011;Muhlebner et al 2012). All focal MCDs show some degree of disorganized cortical lamination.…”