Pathomorphological Diagnostic Criteria for Focal Cortical Dysplasias and Other Common Epileptogenic Lesions-Review of the Literature

Abstract

Focal cortical dysplasia (FCD) represents a heterogeneous group of morphological changes in the brain tissue that can predispose the development of pharmacoresistant epilepsy (recurring, unprovoked seizures which cannot be managed with medications). This group of neurological disorders affects not only the cerebral cortex but also the subjacent white matter. This work reviews the literature describing the morphological substrate of pharmacoresistant epilepsy. All illustrations presented in this study are obtained from brain biopsies from refractory epilepsy patients investigated by the authors. Regarding classification, there are three main FCD types, all of which involve cortical dyslamination. The 2022 revision of the International League Against Epilepsy (ILAE) FCD classification includes new histologically defined pathological entities: mild malformation of cortical development (mMCD), mild malformation of cortical development with oligodendroglial hyperplasia in frontal lobe epilepsy (MOGHE), and "no FCD on histopathology". Although the pathomorphological characteristics of the various forms of focal cortical dysplasias are well known, their aetiologic and pathogenetic features remain elusive. The identification of genetic variants in FCD opens an avenue for novel treatment strategies, which are of particular utility in cases where total resection of the epileptogenic area is impossible.

Keywords: focal cortical dysplasia; mild malformation of cortical development; pharmacoresistant epilepsy.

Figure 1

FCD type I. (A) FCD type Ia—Hematoxylin and eosin (H&E) staining with vertical organisation of pyramidal cells (yellow dotted line). (B) Microcolumnar arrangement of the neocortex (NeuN IHC). (C) FCD Ic pattern—H&E staining with vertical (yellow dotted line) and horizontal (red dotted line) cortical dyslamination of the neocortex. (D) FCD Ic pattern—vertical (yellow dotted line) and horizontal (red dotted line) cortical dyslamination of the neocortex (NeuN IHC).

Figure 2

FCD type II. (A) FCD type IIa—H&E staining showing dysmorphic neurones with enlarged cell bodies as well as enlarged nuclei, and abnormal Nissl substance (white arrows). (B) FCD IIb—H&E staining with dysmorphic neurone (white arrow) and balloon cells (yellow arrows). (C) The dysmorphic neurones with prominent accumulation of neurofilament protein (SMI32 IHC). (D) FCD IIb pattern—vimentin immunohistochemistry labels the balloon cells (white arrows, Vimentin IHC).

Figure 3

HS. (A) HS—H&E staining showing fibrillary astrogliosis (white arrows) and neuronal loss (yellow dotted line). (B) HS—The granule cell layer with a bi-laminated architecture (H&E). (C) HS—pyramidal cell loss (NeuN IHC). (D) HS—fibrillary astrogliosis (GFAP IHC).

Figure 4

GG, AGG, and DIGG. (A) GG—H&E staining showing an astroglial component with small, round to oval nuclei with open chromatin structure and microcalcifications (white arrow). Dysplastic neurones are also visible (yellow dotted line). (B) Areas of CD34 immunopositive tumour cells and tumour cell satellites (CD34 IHC). (C) Synaptophysin-positive dysplastic neurones (white arrows, synaptophysin IHC). (D) MAP2 immunopositive tumour cells (MAP2 IHC). (E) AGG—H&E staining showed a tumour with increased cellularity and necrotic changes (yellow dotted line). The majority of tumour cells show rhabdoid features. (F) Anaplastic ganglioglioma—rhabdoid cells show a preserved nuclear expression of the marker INI1 (IHC). (G) DIGG—H&E staining showing tumour component (white triangle) and sharply demarcated neocortex (white rhombus) (HE). (H) DIGG—areas of CD34 immunopositive tumour cells (white triangle) and negative reaction in the sharply demarcated neocortex (white rhombus) (CD34 IHC).

Figure 5

DNET, PXA, and APXA. (A) DNET—glial nodule (yellow dotted line), and characteristic glioneuronal complexes (HE). (B) DNET, histochemical examination—Alcian blue. (C) DNET—IHC—S-100-protein positivity in oligodendrocytic-like cells. (D) DNET—low proliferative index, Ki-67 IHC. (E) PXA—“xanthoastrocytes” with foam cytoplasm (white arrows) and eosinophilic globular bodies (yellow arrows). (F) Anaplastic PXA—a high-grade tumour with palisading cells around a central focus of necrosis (yellow dotted line), HE.

Figure 6

RFGNT and HH. (A) RFGNT with perivascular pseudorosettes (yellow dotted circles) and neurocytic rosettes (red dotted circle) (HE). (B) RFGNT with perivascular pseudorossettes (black dotted circles, synaptophysin IHC). (C) HH—ependymal cells lining the third ventricle (white arrows) and neuronal clustering (yellow dotted line). (D) HH—NeuN immunohistochemistry labels the neurones (NeuN IHC).

Figure 7

Vascular malformations. (A) Cavernous hemangioma (HE). (B) Leptomeningeal angiomatosis (asterisk) and with underlying neocortex (white rhombus) (HE). (C) Leptomeningeal angiomatosis and microcalcifications (white arrows) in the neocortex of a patient with Sturge–Weber syndrome (HE). (D) Meningioangiomatosis—spindle cell meningothelial proliferation around microcirculatory blood vessels (yellow dotted circles) (HE).

Figure 8

Rasmussen’s encephalitis: (A) lymphoid infiltrates in superficial cortical areas (yellow dotted rectangle) (HE); (B) microglial cells clustering (white arrows) (HE); (C) “cellular” gliosis (GFAP IHC); (D) cytotoxic T-lymphocytes surrounding blood vessels (red asterisks—vessel lumen) (IHC-CD8).

Figure 9

MOGHE. (A) The dotted line demarcates the blurred grey–white matter boundary (HE); (B) heterotopic neurones in the cerebral white matter (white arrows) (HE); (C) immunohistochemical labelling of heterotopic neurones with NeuN (IHC).