The ILAE consensus classification of focal cortical dysplasia: An update proposed by an ad hoc task force of the ILAE diagnostic methods commission

Abstract

Ongoing challenges in diagnosing focal cortical dysplasia (FCD) mandate continuous research and consensus agreement to improve disease definition and classification. An International League Against Epilepsy (ILAE) Task Force (TF) reviewed the FCD classification of 2011 to identify existing gaps and provide a timely update. The following methodology was applied to achieve this goal: a survey of published literature indexed with ((Focal Cortical Dysplasia) AND (epilepsy)) between 01/01/2012 and 06/30/2021 (n = 1349) in PubMed identified the knowledge gained since 2012 and new developments in the field. An online survey consulted the ILAE community about the current use of the FCD classification scheme with 367 people answering. The TF performed an iterative clinico-pathological and genetic agreement study to objectively measure the diagnostic gap in blood/brain samples from 22 patients suspicious for FCD and submitted to epilepsy surgery. The literature confirmed new molecular-genetic characterizations involving the mechanistic Target Of Rapamycin (mTOR) pathway in FCD type II (FCDII), and SLC35A2 in mild malformations of cortical development (mMCDs) with oligodendroglial hyperplasia (MOGHE). The electro-clinical-imaging phenotypes and surgical outcomes were better defined and validated for FCDII. Little new information was acquired on clinical, histopathological, or genetic characteristics of FCD type I (FCDI) and FCD type III (FCDIII). The survey identified mMCDs, FCDI, and genetic characterization as fields for improvement in an updated classification. Our iterative clinico-pathological and genetic agreement study confirmed the importance of immunohistochemical staining, neuroimaging, and genetic tests to improve the diagnostic yield. The TF proposes to include mMCDs, MOGHE, and "no definite FCD on histopathology" as new categories in the updated FCD classification. The histopathological classification can be further augmented by advanced neuroimaging and genetic studies to comprehensively diagnose FCD subtypes; these different levels should then be integrated into a multi-layered diagnostic scheme. This update may help to foster multidisciplinary efforts toward a better understanding of FCD and the development of novel targeted treatment options.

Keywords: brain; classification; epilepsy; focal cortical dysplasia; genes; seizure.

FIGURE 1

Patterns of architectural and cytoarchitectural abnormalities in focal cortical dysplasia (FCD) subtypes. A panel of classic examples taken at the same objective magnification and with same immunohistochemical stainings neuronal nuclear antibodies (NeuN). A, Normal homotypic neocortex obtained from the temporal lobe with its characteristic five neuronal cell layers (L2‐L6) and the neuron sparse L1 on top and white matter at the bottom (WM). B, FCDIa of the occipital lobe is defined by abundant neuronal microcolumns with often small neurons vertically arrayed like parallel strings of pearls. C, FCDIb of the temporal lobe without any layered neocortical organization. Also note the dramatically thinned cortical diameter. D, FCDIIb of the frontal lobe is characterized by lack of any cortical layering. Instead, large dysmorphic neurons appear randomly placed throughout the cortical ribbon (arrow). Balloon cells are not visible in this NeuN immunohistochemistry. E, FCDIIIa in the temporal neocortex of a patient with hippocampal sclerosis. Note the neuronal cell loss in supragranular layers L2 and L3 (arrow). F, FCDIIIc in a patient with Sturge–Weber syndrome and a vascular malformation (VM), that is, meningeal angiomatosis. The adjacent neocortex is thin and shows abundant microcolumns (as in FCDIa). G, FCDIIId of the parietofrontal region in a patient with perinatal stroke. Note the patchy disruption of cortical layers (arrow). H, FCDIIId of the occipital region in a boy with perinatal hypoxemic injury. Note the loss of layer 4 neurons (arrow). Scale bar = 500 μm, applies to all images

FIGURE 2

Multichannel‐immunofluorescence whole slide imaging of a bottom‐of‐sulcus focal cortical dysplasia (FCDIIb). Dysmorphic neurons are labeled with anti‐nonphosphorylated neurofilament H–specific antibodies and were concentrated at the bottom of a sulcus (orange arrow; sulcal surface indicated by small white arrowheads in the upper right). Vimentin‐positive balloon cells (in green color) aggregated in the underlying white matter (green arrow). In addition, vascular myocytes expressing smooth muscle actin were visualized in magenta pseudo‐color and all cell nuclei in blue color. Scale bar = 2 mm. Modified from.

FIGURE 3

Histopathological hallmarks of FCDIa. An 18‐year‐old female patient. Cognitive decline with onset of daily and medically intractable seizures at age 10 years. Arrows: note the multiple regions with abundant microcolumnar organization of the neocortex, which is partially also thinned (<2.5 mm). Asterisks: Abundant heterotopic neurons in the white matter of the same gyri. Neuronal nuclear antigen immunohistochemistry of a 4‐μm thin FFPE section

FIGURE 4

Histopathology findings in ILAE FCDIIa and IIb. A, A 42‐year‐old female patient with frontal lobe epilepsy since age 5 years and histopathologically confirmed FCDIIa. The arrow points to the sharp border between the cortical FCD and the normal‐appearing white matter (WM). Normal six‐layer neocortex (NCx). Neurofilament‐immunohistochemistry, scale bar = 2,5 mm (applies also to B). B, A 19‐year‐old female patient with frontal lobe epilepsy since age 9 years, and histopathologically confirmed FCDIIb at a bottom‐of‐sulcus (BOS). The boundary toward the white matter is less well pronounced (arrow). C, Hematoxylin and eosin (H&E) staining at higher magnification of FCDIIb with opalesque balloon cells (BCs), enlarged dysmorphic neurons (DNs), and normal appearing pyramidal cells (PZs). D, Nueonal nuclear antigen immunohistochemistry demonstrating clusters of anatomically abnormally positioned dysmorphic neurons next to pyramidal cells (on the left) in FCDII. E, Balloon cells frequently stain with antibodies directed against vimentin, but also pS6 or alpha B‐crystallin (not shown). Scale bar = 100 μm, applies also to C and E

FIGURE 5

Histopathology findings in mild malformations of cortical development (mMCD) and mild malformations of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE). A, Microtubule associated protein 2 (MAP2) immunohistochemistry from white matter obtained from a patient with temporal lobe epilepsy (TLE) demonstrating the rare presence of heterotopic neurons. Scale bar = 100 μm. The optical field represents ~0.25mm² (500 × 500 μm), which applies also to B‐D. B, MAP2 immunohistochemistry demonstrating abundance of heterotopic neurons in mMCD. The visual contains eight neurons accounting to >30 neurons/mm² as defined for mMCD. C, Olig2 immunohistochemistry showing an almost normal density of oligodendrocytes (<1000 mm^{2 20} ). Image taken from a region adjacent to MOGHE, as shown in D. D, Olig2 immunohistochemistry showing a significant increase of oligodendroglial cell density above 2200/mm², a cutoff published by Schurr et al. in 2017. In this example, the density would account for even more than 10 cells in a microscopically measurable optical field of 50 × 50 μm (black square)