Updates from the International League Against Epilepsy Classification of Epilepsy (2017) and Focal Cortical Dysplasias (2022): Imaging Phenotype and Genetic Characterization.

The International League Against Epilepsy (ILAE) is an organization of 120 national chapters providing the most widely accepted and updated guidelines on epilepsy. In 2022, the ILAE Task Force revised the prior (2011) classification of focal cortical dysplasias to incorporate and update clinicopathologic and genetic information, with the aim to provide an objective classification scheme. New molecular-genetic information has led to the concept of "integrated diagnosis" on the same lines as brain tumors, with a multilayered diagnostic model providing a phenotype-genotype integration. Major changes in the new update were made to type II focal cortical dysplasias, apart from identification of new entities, such as mild malformations of cortical development and cortical malformation with oligodendroglial hyperplasia. No major changes were made to type I and III focal cortical dysplasias, given the lack of significant new genetic information. This review provides the latest update on changes to the classification of focal cortical dysplasias with discussion about the new entities. The ILAE in 2017 updated the classification of seizure and epilepsy with 3 levels of diagnosis, including seizure type, epilepsy type, and epilepsy syndrome, which are also briefly discussed here.

DNA methylation-based classification of malformations of cortical development in the human brain.

Malformations of cortical development (MCD) comprise a broad spectrum of structural brain lesions frequently associated with epilepsy. Disease definition and diagnosis remain challenging and are often prone to arbitrary judgment. Molecular classification of histopathological entities may help rationalize the diagnostic process. We present a retrospective, multi-center analysis of genome-wide DNA methylation from human brain specimens obtained from epilepsy surgery using EPIC 850 K BeadChip arrays. A total of 308 samples were included in the study. In the reference cohort, 239 formalin-fixed and paraffin-embedded (FFPE) tissue samples were histopathologically classified as MCD, including 12 major subtype pathologies. They were compared to 15 FFPE samples from surgical non-MCD cortices and 11 FFPE samples from post-mortem non-epilepsy controls. We applied three different statistical approaches to decipher the DNA methylation pattern of histopathological MCD entities, i.e., pairwise comparison, machine learning, and deep learning algorithms. Our deep learning model, which represented a shallow neuronal network, achieved the highest level of accuracy. A test cohort of 43 independent surgical samples from different epilepsy centers was used to test the precision of our DNA methylation-based MCD classifier. All samples from the test cohort were accurately assigned to their disease classes by the algorithm. These data demonstrate DNA methylation-based MCD classification suitability across major histopathological entities amenable to epilepsy surgery and age groups and will help establish an integrated diagnostic classification scheme for epilepsy-associated MCD.

Definitions and classification of malformations of cortical development: practical guidelines.

Malformations of cortical development are a group of rare disorders commonly manifesting with developmental delay, cerebral palsy or seizures. The neurological outcome is extremely variable depending on the type, extent and severity of the malformation and the involved genetic pathways of brain development. Neuroimaging plays an essential role in the diagnosis of these malformations, but several issues regarding malformations of cortical development definitions and classification remain unclear. The purpose of this consensus statement is to provide standardized malformations of cortical development terminology and classification for neuroradiological pattern interpretation. A committee of international experts in paediatric neuroradiology prepared systematic literature reviews and formulated neuroimaging recommendations in collaboration with geneticists, paediatric neurologists and pathologists during consensus meetings in the context of the European Network Neuro-MIG initiative on Brain Malformations (https://www.neuro-mig.org/). Malformations of cortical development neuroimaging features and practical recommendations are provided to aid both expert and non-expert radiologists and neurologists who may encounter patients with malformations of cortical development in their practice, with the aim of improving malformations of cortical development diagnosis and imaging interpretation worldwide.

[Malformations of cortical development and epilepsy]. / Epilepsias en las malformaciones del desarrollo cortical.

Around 15% of childhood epilepsies are resistant to antiepileptic drugs, 40% of which are caused by malformations of cortical development (MCD). The current classification scheme for MCD is based on the primary developmental steps of cell proliferation, neuronal migration, and cortical organization. Considering the clinic and molecular alterations, a classification based on main pathways disruption and imaging phenotype has been proposed. MCD were divided into four groups: megalencephaly and focal cerebral dysplasia; tubulinopathies and lissencephalies; polymicrogyria syndromes and heterotopia syndromes. More than 100 genes have been reported to be associated with different types of MCD. Genetic and biological mechanisms include different stages of cell cycle regulation - especially cell division -, apoptosis, cell-fate specification, cytoskeletal structure and function, neuronal migration, and basement-membrane function. The associated epileptic syndromes are varied ranging from early-onset epileptic encephalopathies to focal epilepsies. As MCD are common causes of refractory epilepsy, a prompt diagnosis and the development of different therapeutic options in order to improve the outcome of the patients are essential.

Alrededor del 15% de las epilepsias en pediatría son fármaco-resistentes y en el 40% de este grupo la etiología es una malformación del desarrollo cortical (MDC). El esquema de clasificación actual de las MDC se basa en las etapas primarias de desarrollo de la proliferación celular, migración neuronal y organización cortical. Teniendo en cuenta la clínica y las alteraciones moleculares, se propuso una clasificación basada en la disrupción de las vías principales y el fenotipo neurorradiológico. Se dividió a las MDC en cuatro grupos: la megalencefalia y las displasias corticales focales; las tubulinopatías y lisencefalias; el espectro de las polimicrogirias y las heterotopías. Hasta el momento, más de 100 genes han sido asociados con uno o más tipos de MDC. Los mecanismos biológicos y genéticos incluyen la regulación del ciclo celular en varios estadios, división celular), apoptosis, diferenciación celular, función y estructura del citoesqueleto, migración neuronal y membrana basal. El espectro de síndromes epilépticos asociados con las MDC es amplio e incluye desde encefalopatías epilépticas de comienzo temprano a epilepsias focales de debut más tardío. Teniendo en cuenta que la evolución de la epilepsia hacia la refractariedad en las MDC es importante, el diagnóstico precoz y la elección de la mejor opción terapéutica influirán en el pronóstico de los pacientes.

Epilepsias en las malformaciones del desarrollo cortical / Malformations of cortical development and epilepsy

Alrededor del 15% de las epilepsias en pediatría son fármaco-resistentes y en el 40% de este grupo la etiología es una malformación del desarrollo cortical (MDC). El esquema de clasificación actual de las MDC se basa en las etapas primarias de desarrollo de la proliferación celular, migración neuronal y organización cortical. Teniendo en cuenta la clínica y las alteraciones moleculares, se propuso una clasificación basada en la disrupción de las vías principales y el fenotipo neurorradiológico. Se dividió a las MDC en cuatro grupos: la megalencefalia y las displasias corticales focales; las tubulinopatías y lisencefalias; el espectro de las polimicrogirias y las heterotopías. Hasta el momento, más de 100 genes han sido asociados con uno o más tipos de MDC. Los mecanismos biológicos y genéticos incluyen la regulación del ciclo celular en varios estadios, división celular), apoptosis, diferenciación celular, función y estructura del citoesqueleto, migración neuronal y membrana basal. El espectro de síndromes epilépticos asociados con las MDC es amplio e incluye desde encefalopatías epilépticas de comienzo temprano a epilepsias focales de debut más tardío. Teniendo en cuenta que la evolución de la epilepsia hacia la refractariedad en las MDC es importante, el diagnóstico precoz y la elección de la mejor opción terapéutica influirán en el pronóstico de los pacientes.

Around 15% of childhood epilepsies are resistant to antiepileptic drugs, 40% of which are caused by malformations of cortical development (MCD). The current classification scheme for MCD is based on the primary developmental steps of cell proliferation, neuronal migration, and cortical organization. Considering the clinic and molecular alterations, a classification based on main pathways disruption and imaging phenotype has been proposed. MCD were divided into four groups: megalencephaly and focal cerebral dysplasia; tubulinopathies and lissencephalies; polymicrogyria syndromes and heterotopia syndromes. More than 100 genes have been reported to be associated with different types of MCD. Genetic and biological mechanisms include different stages of cell cycle regulation - especially cell division -, apoptosis, cell-fate specification, cytoskeletal structure and function, neuronal migration, and basement-membrane function. The associated epileptic syndromes are varied ranging from early-onset epileptic encephalopathies to focal epilepsies. As MCD are common causes of refractory epilepsy, a prompt diagnosis and the development of different therapeutic options in order to improve the outcome of the patients are essential.

Genomic DNA methylation distinguishes subtypes of human focal cortical dysplasia.

OBJECTIVES: Focal cortical dysplasia (FCD) is a major cause of drug-resistant focal epilepsy in children, and the clinicopathological classification remains a challenging issue in daily practice. With the recent progress in DNA methylation-based classification of human brain tumors we examined whether genomic DNA methylation and gene expression analysis can be used to also distinguish human FCD subtypes. METHODS: DNA methylomes and transcriptomes were generated from massive parallel sequencing in 15 surgical FCD specimens, matched with 5 epilepsy and 6 nonepilepsy controls. RESULTS: Differential hierarchical cluster analysis of DNA methylation distinguished major FCD subtypes (ie, Ia, IIa, and IIb) from patients with temporal lobe epilepsy patients and nonepileptic controls. Targeted panel sequencing identified a novel likely pathogenic variant in DEPDC5 in a patient with FCD type IIa. However, no enrichment of differential DNA methylation or gene expression was observed in mechanistic target of rapamycin (mTOR) pathway-related genes. SIGNIFICANCE: Our studies extend the evidence for disease-specific methylation signatures toward focal epilepsies in favor of an integrated clinicopathologic and molecular classification system of FCD subtypes incorporating genomic methylation.

A distinct clinicopathological variant of focal cortical dysplasia IIId characterized by loss of layer 4 in the occipital lobe in 12 children with remote hypoxic-ischemic injury.

OBJECTIVE: In 2011, the International League Against Epilepsy (ILAE) proposed a consensus classification system of focal cortical dysplasia (FCD) to distinguish clinicopathological subtypes, for example, "isolated" FCD type Ia-c and IIa-b, versus "associated" FCD type IIIa-d. The histopathological differentiation of FCD type I and III variants remains, however, a challenging issue in everyday practice. We present a unique histopathological pattern in patients with difficult-to-diagnose FCD, which highlights this dilemma, but also helps to refine the current ILAE classification scheme of FCD. METHODS: We present a retrospective series of 11 male and one female patient with early onset pharmacoresistant epilepsy of the posterior quadrant (mean age at seizure onset = 4.6 years). All surgical specimens were reviewed. Clinical histories were retrieved and extracted from archival patient files. RESULTS: Microscopic inspection revealed abnormalities in cortical architecture with complete loss of layer 4 in all surgical samples of the occipital lobe, as confirmed by semiquantitative measurements (p < 0.01). Clinical history reported early transient hypoxic condition in nine patients (75%). Magnetic resonance imaging (MRI) revealed abnormal signals in the occipital lobe in all patients, and signal changes suggestive of subcortical encephalomalacia were found in seven patients. Surgical treatment achieved favorable seizure control (Engel class I and II) in seven patients with an available follow-up period of 6.1 years. SIGNIFICANCE: Prominent disorganization of cortical layering and lack of any other microscopically visible principle lesion in the surgical specimen would result in this neuropathological pattern hitherto being classified as FCD ILAE type Ib. However, perinatal hypoxia with distinctive MRI changes suggested primarily a hypoxemic lesion and acquired pathomechanism of neuronal cell loss in the occipital lobe of our patient series. We propose, therefore, classifying this distinctive clinicopathological pattern as a separate variant of FCD ILAE type IIId.

Putting the new ILAE classification of focal cortical dysplasia into practice in western China.

PURPOSE: To re-examine drug-resistant epilepsy cases using the revised 2011 ILAE classification of focal cortical dysplasia (FCD). METHODS: Patients with drug-resistant epilepsy who have undergone epilepsy surgery in West China Hospital between July 2012 and Jun 2014 were included. Clinical histories, pathological diagnoses, and surgical outcomes were reviewed. A questionnaire was developed to investigate the clinical practice of the new classification. A short-term training program on FCD was carried out to improve pathological diagnosis accuracy. RESULTS: 260 consecutive cases (177 male and 83 female) were included. Pathological diagnosis was changed in 70 cases (26.9%) after re-examination. The five most common pathological types were hippocampal sclerosis (19.2%, 50/260), brain tumors (17.7%, 46/260), vascular malformations (16.2%, 42/260), glial scars (11.2%, 29/260) and FCD (10.0%, 26/260). The most common subtype of isolated FCD was FCD IIb (53.8%, 14/26), followed by FCD IIa (42.3%, 11/26) and FCD Ib (3.8%, 1/26). In addition, forty-five cases were diagnosed as associated FCD type III (17.3%, 45/260). Half of patients with FCD achieved Engel class I at two-year follow-up. Questionnaire investigation suggested most participant pathologists lack sufficient knowledge on the new classification. The diagnostic sensitivity for different FCD subtypes was significantly improved by two to six folds after short-term training. CONCLUSIONS: FCD is an important etiology of drug-resistant epilepsy in western China. It is essential to provide continuing trainings to improve diagnostic precision of FCD in developing countries.

Seizure-onset patterns in focal cortical dysplasia and neurodevelopmental tumors: Relationship with surgical prognosis and neuropathologic subtypes.

OBJECTIVES: The study of intracerebral electroencephalography (EEG) seizure-onset patterns is crucial to accurately define the epileptogenic zone and guide successful surgical resection. It also raises important pathophysiologic issues concerning mechanisms of seizure generation. Until now, several seizure-onset patterns have been described using distinct recording methods (subdural, depth electrode), mostly in temporal lobe epilepsies or with heterogeneous neocortical lesions. METHODS: We analyzed data from a cohort of 53 consecutive patients explored by stereoelectroencephalography (SEEG) and with pathologically confirmed malformation of cortical development (MCD; including focal cortical dysplasia [FCD] and neurodevelopmental tumors [NDTs]). RESULTS: We identified six seizure-onset patterns using visual and time-frequency analysis: low-voltage fast activity (LVFA); preictal spiking followed by LVFA; burst of polyspikes followed by LVFA; slow wave/DC shift followed by LVFA; theta/alpha sharp waves; and rhythmic spikes/spike-waves. We found a high prevalence of patterns that included LVFA (83%), indicating nevertheless that LVFA is not a constant characteristic of seizure onset. An association between seizure-onset patterns and histologic types was found (p = 001). The more prevalent patterns were as follows: (1) in FCD type I LVFA (23.1%) and slow wave/baseline shift followed by LVFA (15.4%); (2) in FCD type II burst of polyspikes followed by LVFA (31%), LVFA (27.6%), and preictal spiking followed by LVFA (27.6%); (3) in NDT, LVFA (54.5%). We found that a seizure-onset pattern that included LVFA was associated with favorable postsurgical outcome, but the completeness of the EZ resection was the sole independent predictive variable. SIGNIFICANCE: Six different seizure-onset patterns can be described in FCD and NDT. Better postsurgical outcome is associated with patterns that incorporate LVFA.

Early resective surgery causes favorable seizure outcome in malformations of cortical development.

PURPOSE: We analyzed consecutive cases of a large cohort of the spectrum of malformations of cortical development (MCDs) including focal cortical dysplasias (FCDs) who underwent presurgical evaluation through our epilepsy program from January 2000-December 2010. We analyzed factors predicting surgical candidacy, predictors of seizure outcome and reasons for deferring surgery. METHODS: 148 patients with MCD underwent detailed presurgical evaluation and 69 were operated. MCD was diagnosed based on characteristic findings in MRI and re-confirmation by histopathology in operated patients. Post-operative seizure outcome of non-operated and operated patients were assessed every 3 and 12 months and yearly intervals. Multivariate analysis and backward step-wise logistic regression analyzed factors predicting seizure outcome. Kaplan-Meier analysis predicted seizure-free survival rates. RESULTS: 66.67% patients were seizure-free and aura-free at last follow-up. On multivariate logistic regression, the predictors of seizure freedom in operated MCDs were completeness of resection (odds ratio 8.2; 95% CI 1.43-64.96, p=0.01), shorter duration of epilepsy (odds ratio 1.19, 95% CI 1.02-1.39, p=0.02), and absence of spikes in post-operative EEG at one year (odds ratio 4.2; 95% CI 2.52-16.6; p<0.002). In FCD sub-group, shorter duration of epilepsy (11.1 versus 16.1 years, p=0.03), absence of secondary generalized seizures (p=0.05), absence of spikes in post-operative EEG on seventh day (p=0.009) and one year (p=0.002) were associated with favorable seizure outcome. CONCLUSION: Majority of patients with MCD and refractory epilepsy when operated early remains seizure-free. Shorter duration of epilepsy is the single most important pre-operative variable and absence of spikes in post-operative EEG, predicts a long-term favorable seizure outcome.

Different parvalbumin and GABA expression in human epileptogenic focal cortical dysplasia.

OBJECTIVE: Several studies have reported that inhibitory networks are altered in dysplastic tissue obtained from epilepsy surgery specimens. A consistent decrease in the number of inhibitory interneuronal subpopulation that expresses parvalbumin (PV) was reported in postsurgical tissue from patients with focal cortical dysplasia (FCD). We tested if the decrease in PV protein expression observed in epileptic tissue corresponds to a parallel impairment in the γ-aminobutyric acid (GABA)ergic compartment. METHODS: We analyzed postsurgical tissue from 30 surgically treated patients who underwent surgery for intractable epilepsy including 26 patients with FCD (types I, II, and III) and 4 patients without any microscopic visible lesion (cryptogenic) as controls. Serial sections were processed using in situ hybridization with GAD-65 and GAD-67 probes and immunocytochemistry with antibody against PV. The density of inhibitory PV-immunoreactive interneurons in relation to GABAergic cells was estimated in controls and in all different pathologic groups by using a two- and three-dimensional (2D and 3D) cell-counting technique. Field fraction and line profile analyses were added to estimate immunostaining proportion and distribution of PV signal generated in gray matter. RESULTS: A reduction of PV-positive cells and PV-immunoreactivity was observed exclusively in FCD type I/III specimens compared with cryptogenic tissue from control patients with a poor postsurgical outcome. In FCD type II, a profound rearrangement in the cortical distribution of PV immunoreactivity was observed, without a quantitative reduction of the number of neurons and terminals. In situ hybridization did not reveal significant variations of GAD expression in any FCD subtype. SIGNIFICANCE: Our study suggests a preservation of inhibitory networks in FCD postsurgical tissue, demonstrated by a substantial normal count of GABAergic neurons. A selective PV expression impairment is demonstrated in FCD type I and III and an abnormal, but not reduced, distribution of PV cells and terminals is confirmed in type II FCD. Possible functional consequences are discussed.

Whole-brain MRI phenotyping in dysplasia-related frontal lobe epilepsy.

OBJECTIVE: To perform whole-brain morphometry in patients with frontal lobe epilepsy and evaluate the utility of group-level patterns for individualized diagnosis and prognosis. METHODS: We compared MRI-based cortical thickness and folding complexity between 2 frontal lobe epilepsy cohorts with histologically verified focal cortical dysplasia (FCD) (13 type I; 28 type II) and 41 closely matched controls. Pattern learning algorithms evaluated the utility of group-level findings to predict histologic FCD subtype, the side of the seizure focus, and postsurgical seizure outcome in single individuals. RESULTS: Relative to controls, FCD type I displayed multilobar cortical thinning that was most marked in ipsilateral frontal cortices. Conversely, type II showed thickening in temporal and postcentral cortices. Cortical folding also diverged, with increased complexity in prefrontal cortices in type I and decreases in type II. Group-level findings successfully guided automated FCD subtype classification (type I: 100%; type II: 96%), seizure focus lateralization (type I: 92%; type II: 86%), and outcome prediction (type I: 92%; type II: 82%). CONCLUSION: FCD subtypes relate to diverse whole-brain structural phenotypes. While cortical thickening in type II may indicate delayed pruning, a thin cortex in type I likely results from combined effects of seizure excitotoxicity and the primary malformation. Group-level patterns have a high translational value in guiding individualized diagnostics.

Clinical characteristics and post-surgical outcomes of focal cortical dysplasia subtypes.

We retrospectively studied 105 patients with a focal cortical dysplasia (FCD) diagnosed on pathological examination, and investigated the long term postoperative seizure outcomes, different clinical characteristics of the three FCD subtypes, particularly type I and II, and surgical outcomes for each group. FCD is a common cause of drug-resistant epilepsy, which is divided into three different subtypes according to its involvement at different stages of brain development. Each of these groups may have different characteristics and may even have different surgical outcomes. After treatment, 55% of patients were completely seizure-free, with two significant predictive variables for poorer outcomes: focal MRI findings and electrode implantation. FCD type I had relatively poor surgical outcomes compared to FCD type II and type IIIa. Compared with FCD type I, type II, particularly IIb, had a higher frequency of seizure attacks, predominantly located in the extratemporal lobes, and was more readily detected and diagnosed via focal lesions on MRI and localized electroencephalogram abnormalities. FCD type II patients seem to show better surgical outcomes than FCD type I, but the difference was not significant. Larger cohort studies are needed for further evaluation of the seizure outcomes of different FCD subtypes.

Focal Cortical Dysplasia.

Focal cortical dysplasias are common malformations of cerebral cortical development and are highly associated with medically intractable epilepsy. They have been classified into neuropathological subtypes (type Ia, Ib, IIa, IIb, and III) based on the severity of cytoarchitectural disruption--tangential or radial dispersion, or loss of laminar structure--and the presence of unique cells types such as cytomegalic neurons or balloon cells. Most focal cortical dysplasias can be identified on neuroimaging and many require resective epilepsy surgery to cure refractory seizures. The pathogenesis of focal cortical dysplasias remains to be defined, although there is recent evidence to suggest that focal cortical dysplasias arise from de novo somatic mutations occurring during brain development. Some focal cortical dysplasia subtypes show a link to the mammalian target of rapamycin signaling cascade; this has now extended to other cortical malformations, including hemimegalencephaly.

Malformations of cortical development and epilepsy.

Malformations of cortical development (MCDs) are an important cause of epilepsy and an extremely interesting group of disorders from the perspective of brain development and its perturbations. Many new MCDs have been described in recent years as a result of improvements in imaging, genetic testing, and understanding of the effects of mutations on the ability of their protein products to correctly function within the molecular pathways by which the brain functions. In this review, most of the major MCDs are reviewed from a clinical, embryological, and genetic perspective. The most recent literature regarding clinical diagnosis, mechanisms of development, and future paths of research are discussed.

mTOR signaling in epilepsy: insights from malformations of cortical development.

Over the past decade enhanced activation of the mammalian target of rapamycin (mTOR)-signaling cascade has been identified in focal malformations of cortical development (MCD) subtypes, which have been collectively referred to as "mTORopathies." Mutations in mTOR regulatory genes (e.g., TSC1, TSC2, AKT3, DEPDC5) have been associated with several focal MCD highly associated with epilepsy such as tuberous sclerosis complex (TSC), hemimegalencephaly (HME; brain malformation associated with dramatic enlargement of one brain hemisphere), and cortical dysplasia. mTOR plays important roles in the regulation of cell division, growth, and survival, and, thus, aberrant activation of the cascade during cortical development can cause dramatic alterations in cell size, cortical lamination, and axon and dendrite outgrowth often observed in focal MCD. Although it is widely believed that structural alterations induced by hyperactivated mTOR signaling are critical for epileptogenesis, newer evidence suggests that mTOR activation on its own may enhance neuronal excitability. Clinical trials with mTOR inhibitors have shown efficacy in the treatment of seizures associated with focal MCD.

Focal cortical dysplasias in temporal lobe epilepsy surgery: Challenge in defining unusual variants according to the last ILAE classification.

OBJECTIVE: Focal cortical dysplasias (FCDs) represent a common architectural cortical disorder underlying pharmacoresistant focal epilepsy. The recent ILAE classification defines different types of FCDs based on their histopathological features, MRI imaging, and presumed pathogenesis; however, their clinical features and their prognostic significance are still incompletely defined. In addition, the combination of different histopathological abnormalities can represent "unusual" subtypes that can be difficult to classify. The aim of our study was to analyze the incidence and the significance of these "unusual" subtypes of FCDs in drug-resistant mesial temporal lobe epilepsy (MTLE). METHODS: We retrospectively analyzed 133 patients consecutively submitted to tailored anteromesial temporal lobe resection for pharmacoresistant MTLE. Seizure onset, seizure duration, age at surgery, and postoperative seizure outcome were evaluated in relation to the different neuropathological groups defined according to the new ILAE classification. RESULTS: Focal cortical dysplasias were found in 80 out of 133 patients. Six patients were affected by isolated FCD type I, 12 patients by FCD type II, and 44 patients by FCD type III. Furthermore, we found 18 "atypical" cases (20.5% of all FCD cases and 26.6% of FCDs associated with a principal lesion): 10 cases of associated FCD type II-hippocampal sclerosis (HS) and 8 cases associated with FCD II-epilepsy-associated tumors (EATs). CONCLUSION: Our results indicate that "unusual" subtypes of FCDs, in particular associated FCD type II, are not uncommon findings, suggesting that they deserve a classification recognition. Similarities in seizure outcome and immunohistochemical and molecular evidences, shared by FCD type II+EATs and EATs, suggest a common pathogenic link. The choice to create a specific unifying class or, on the contrary, to also include "associated FCD type II" in the definition of the new unifying class FCD type III should be further discussed.

Cortical Gray-White Matter Blurring and Cognitive Morbidity in Focal Cortical Dysplasia.

Focal cortical dysplasia (FCD) is a malformation of cortical development that is associated with high rates of cognitive morbidity. However, the degree to which specific irregularities of dysplastic tissue directly impact cognition remains unknown. This study investigates the relationship between blurring of the cortical gray and white matter boundary on magnetic resonance imaging (MRI) and global cognitive abilities in FCD. Gray-white blurring (GWB) is quantified by sampling the non-normalized T1 image intensity contrast above and below the gray and white matter interface along the cortical mantle. Spherical averaging is used to compare resulting GWB for patients with histopathologically verified FCD with matched controls. Whole-brain correlational analyses are used to investigate the relationship between blurring and general cognitive abilities, controlling for epilepsy duration. Results show that cognitive performance is reduced in patients with FCD relative to controls. Patients show increased GWB in bilateral temporal, parietal, and frontal regions. Furthermore, increased GWB in these regions is linearly related to decreased cognition and mediates group differences in cognitive performance. These findings demonstrate that GWB is a marker of reduced cognitive efficiency in FCD that can potentially be used to probe general and domain-specific cognitive functions in other neurological disorders.

The power button sign: a newly described central sulcal pattern on surface rendering MR images of type 2 focal cortical dysplasia.

PURPOSE: To compare the occurrence of several central sulcus variants and to assess the reproducibility of a sulcal pattern named the power button sign (PBS) in patients with type 2 focal cortical dysplasia (FCD2) and healthy control subjects. MATERIALS AND METHODS: The local institutional review board approved the study, and written informed consent was waived for patients and was obtained from control subjects. Four readers reviewed three-dimensional (3D) T1-weighted magnetic resonance (MR) images in 37 patients (13 with negative MR imaging findings) with histologically proven FCD2 of the central region and 44 control subjects on the basis of a visual analysis of a 3D reconstruction of cortical folds. They searched for central sulcus variations (interruptions, side branches, and connections) and for a particular sulcal pattern, namely, the interposition of a precentral sulcal segment between the central sulcus and one of its hook-shaped anterior ascending branches (ie, PBS). Inter- and intraobserver reliability, specificity, and sensitivity were calculated. RESULTS: The central sulcus showed a greater number of side branches (P < .001) and was more frequently connected to the precentral sulcus (P < .001) in patients with FCD2 than in control subjects. The PBS was found in 23 (62%) of 37 total patients with FCD2, in six (46%) of 13 with negative MR imaging findings, and in only one control subject. Inter- and intraobserver rates were excellent (0.88 and 0.93, respectively) for the detection of PBS. FCD2 was located either in the depth of the ascending branch of the central sulcus (14 of 23, 61%) or in its immediate vicinity (nine of 23). CONCLUSION: Given its excellent reproducibility and specificity, the PBS, when present, could become a useful qualitative diagnostic MR criterion of FCD2 in the central region.

Classification and pathological characteristics of the cortical dysplasias.

BACKGROUND: Focal cortical dysplasias (FCD) are a well-recognized cause of medically intractable epilepsy. They are defined as malformations of cortical development and are marked by abnormalities of cortical layering and neuronal differentiation and maturation. A number of classification approaches have been devised over the last four decades, indicating controversies surrounding issues of recognition, definition, and philosophical approach. More recent attempts have attempted to correlate morphologic phenotype with clinical or developmental parameters in order to provide a clinical relevance. DISCUSSION: This short review provides an overview of the issues which account for the varied historical approaches to FCD classification and descriptions of gross pathologic findings associated with FCD and an overview of two more recently developed and widely used schema, the Palmini et al. (Neurology 62: S2-8, 2004) and the International League Against Epilepsy (ILAE) classifications Blumcke et al. Epilepsia 52: 158-174, 2011. The pathologic features of these two approaches will be reviewed and compared, including discussion of their limitations.