The clinicopathologic spectrum of focal cortical dysplasias: A consensus classification proposed by an ad hoc Task Force of the ILAE Diagnostic Methods Commission1

Blümcke, Ingmar; Thom, Maria; Aronica, Eleonora; Armstrong, Dawna; Vinters, Harry V.; Palmini, André; Jacques, Thomas S.; Avanzini, G.; Barkovich, A. James; Battaglia, Giorgio; Becker, Albert; Cepeda, Carlos; Cendes, Fernando; Colombo, Nadia; Crino, Peter B.; Cross, J. Helen; Delalande, Olivier; Dubeau, François; Duncan, John S.; Guerrini, Renzo; Kahane, Philippe; Mathern, Gary W.; Najm, Imad; Özkara, Çiğdem; Raybaud, Charles; Represa, Alfonso; Roper, Steven N.; Salamon, Noriko; Schulze‐Bonhage, Andreas; Tassi, Laura; Vezzani, Annamaria; Spreafico, Roberto

doi:10.1111/j.1528-1167.2010.02777.x

Cited by 1,563 publications

(1,672 citation statements)

References 58 publications

Supporting

Mentioning

1,545

Contrasting

Unclassified

Order By: Relevance

“…Rnd2‐deficient neurons in mouse fail to transit from the multipolar to the bipolar stage,32 suggesting that the excessive levels of RND2 in FCD type II are detrimental to the organization and orientation of radially migrating neurons, which could ultimately be implicated in the complete dyslamination observed in the dysplastic tissue. Furthermore, abnormal cell migration speed could be consistent with the presence of heterotopic clusters of neurons located within the white matter (see Fig 5B),8 as well as an increase in the number of neurons found in the upper cortical layers, mainly in the molecular layer, as noticed in pediatric patients with FCD 34…”

Section: Discussionsupporting

confidence: 62%

“…We also used tissue from patients with tuberous sclerosis complex (TSC; n = 3). After surgery, FCD type II and TSC were confirmed by 2 neuropathologists according to the International League against Epilepsy classification (see Fig 1C–E) 7, 8. Clinical and pathological characteristics are summarized in Table 1.…”

Section: Methodsmentioning

confidence: 99%

“…FCDs are associated with dysmorphic neurons and occasionally with balloon cells,7 being an important cause of severe drug‐resistant epilepsy. The current classification of FCDs is based upon neuropathological examination of surgical specimens 8. In the present study, we examined FCD type II, which presents as an isolated lesion characterized by cortical dyslamination and dysmorphic neurons without (type IIa) or with balloon cells (type IIb).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Dysregulation of NEUROG2 plays a key role in focal cortical dysplasia

Avansini

Torres

Vieira

et al. 2018

Annals of Neurology

Self Cite

View full text Add to dashboard Cite

ObjectiveFocal cortical dysplasias (FCDs) are an important cause of drug‐resistant epilepsy. In this work, we aimed to investigate whether abnormal gene regulation, mediated by microRNA, could be involved in FCD type II.MethodsWe used total RNA from the brain tissue of 16 patients with FCD type II and 28 controls. MicroRNA expression was initially assessed by microarray. Quantitative polymerase chain reaction, in situ hybridization, luciferase reporter assays, and deep sequencing for genes in the mTOR pathway were performed to validate and further explore our initial study.Resultshsa‐let‐7f (p = 0.039), hsa‐miR‐31 (p = 0.0078), and hsa‐miR34a (p = 0.021) were downregulated in FCD type II, whereas a transcription factor involved in neuronal and glial fate specification, NEUROG2 (p < 0.05), was upregulated. We also found that the RND2 gene, a NEUROG2‐target, is upregulated (p < 0.001). In vitro experiments showed that hsa‐miR‐34a downregulates NEUROG2 by binding to its 5′‐untranslated region. Moreover, we observed strong nuclear expression of NEUROG2 in balloon cells and dysmorphic neurons and found that 28.5% of our patients presented brain somatic mutations in genes of the mTOR pathway.InterpretationOur findings suggest a new molecular mechanism, in which NEUROG2 has a pivotal and central role in the pathogenesis of FCD type II. In this way, we found that the downregulation of hsa‐miR‐34a leads to upregulation of NEUROG2, and consequently to overexpression of the RND2 gene. These findings indicate that a faulty coupling in neuronal differentiation and migration mechanisms may explain the presence of aberrant cells and complete dyslamination in FCD type II. Ann Neurol 2018;83:623–635

show abstract

Section: Discussionsupporting

confidence: 62%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Dysregulation of NEUROG2 plays a key role in focal cortical dysplasia

Avansini

Torres

Vieira

et al. 2018

Annals of Neurology

Self Cite

View full text Add to dashboard Cite

show abstract

“…b CNPase staining versus Olig2 positive cells/mm2. Sector 1 indicates cases with reactive oligodendroglial hyperplasia and normal myelin content, sector 2 cases with normal myelin and oligodendrocyte numbers and sector 3 burnout of oligodendroglia either with normal myelin levels (3a) or with severe cell and myelin loss (3b).…”

Section: Resultsmentioning

confidence: 99%

“…The majority of these lesions are Focal Cortical Dysplasias (FCDs) 38. FCDs are currently diagnosed according to the International League Against Epilepsy (ILAE) classification scheme introduced in 2011 3. This classification system distinguishes three FCD categories: Type I describes isolated focal lesions with architectural abnormalities, type II includes isolated focal lesions with architectural abnormalities and aberrant cell forms, and type III refers to cortical disorganization associated with—or adjacent to—other principal lesions 3.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

Self Cite

View full text Add to dashboard Cite

Conventional antiepileptic drugs suppress the excessive firing of neurons during seizures. In drug‐resistant patients, treatment failure indicates an alternative important epileptogenic trigger. Two epilepsy‐associated pathologies show myelin deficiencies in seizure‐related brain regions: Focal Cortical Dysplasia IIB (FCD) and cortical tubers in Tuberous Sclerosis Complex (TSC). Studies uncovering white matter‐pathology mechanisms are therefore urgently needed to gain more insight into epileptogenesis, the propensity to maintain seizures, and their associated comorbidities such as cognitive defects. We analyzed epilepsy surgery specimens of FCD IIB (n = 22), TSC (n = 8), and other malformations of cortical development MCD (n = 12), and compared them to autopsy and biopsy cases (n = 15). The entire lesional pathology was assessed using digital immunohistochemistry, immunofluorescence and western blotting for oligodendroglial lineage, myelin and mTOR markers, and findings were correlated to clinical parameters. White matter pathology with depleted myelin and oligodendroglia were found in 50% of FCD IIB and 62% of TSC cases. Other MCDs had either a normal content or even showed reactive oligodendrolial hyperplasia. Furthermore, myelin deficiency was associated with increased mTOR expression and the lower amount of oligodendroglia was linked with their precursor cells (PDGFRa). The relative duration of epilepsy (normalized to age) also correlated positively to mTOR activation and negatively to myelination. Decreased content of oligodendroglia and missing precursor cells indicated insufficient oligodendroglial development, probably mediated by mTOR, which may ultimately lead to severe myelin loss. In terms of disease management, an early and targeted treatment could restore normal myelin development and, therefore, alter seizure threshold and improve cognitive outcome.

show abstract