Multilobar unilateral hypoplasia with emphasis on the posterior quadrant and severe epilepsy in children with FCD ILAE Type 1A.

OBJECTIVE: Focal cortical dysplasia (FCD) Type 1 and its three subtypes have yet not been fully characterized at the clinical, anatomopathological, and molecular level (International League Against Epilepsy [ILAE] FCD classification from 2011). We aimed to describe the clinical phenotype of patients with histopathologically confirmed FCD1A obtained from a single epilepsy center between 2002 and 2016. METHODS: Medical records were retrieved from the hospital's archive. Results from electroencephalography (EEG) video recordings, neuroimaging, and histopathology were reevaluated. Magnetic resonance imaging (MRI) post-processing was retrospectively performed in nine patients. DNA methylation studies were carried out from archival surgical brain tissue in 11 patients. RESULTS: Nineteen children with a histopathological diagnosis of FCD1A were included. The average onset of epilepsy was 0.9 years (range 0.2-10 years). All children had severe cognitive impairment and one third had mild motor deficits, yet fine finger movements were preserved in all patients. All patients had daily seizures, being drug resistant from disease onset. Interictal electroencephalography revealed bilateral multi-regional epileptiform discharges. Interictal status epilepticus was observed in 8 and countless subclinical seizures in 11 patients. Regional continuous irregular slow waves were of higher lateralizing and localizing yield than spikes. Posterior background rhythms were normal in 16 of 19 children. Neuroimaging showed unilateral multilobar hypoplasia and increased T2-FLAIR signals of the white matter in 18 of 19 patients. All children underwent tailored multilobar resections, with seizure freedom achieved in 47% (Engel class I). There was no case with frontal involvement without involvement of the posterior quadrant by MRI and histopathology. DNA methylation profiling distinguished FCD1A samples from all other epilepsy specimens and controls. SIGNIFICANCE: We identified a cohort of young children with drug resistance from seizure onset, bad EEG with posterior emphasis, lack of any focal neurological deficits but severe cognitive impairment, subtle hypoplasia of the epileptogenic area on MRI, and histopathologically defined and molecularly confirmed by DNA methylation analysis as FCD ILAE Type 1A.

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

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.

Histopathological Findings in Brain Tissue Obtained during Epilepsy Surgery.

BACKGROUND: Detailed neuropathological information on the structural brain lesions underlying seizures is valuable for understanding drug-resistant focal epilepsy. METHODS: We report the diagnoses made on the basis of resected brain specimens from 9523 patients who underwent epilepsy surgery for drug-resistant seizures in 36 centers from 12 European countries over 25 years. Histopathological diagnoses were determined through examination of the specimens in local hospitals (41%) or at the German Neuropathology Reference Center for Epilepsy Surgery (59%). RESULTS: The onset of seizures occurred before 18 years of age in 75.9% of patients overall, and 72.5% of the patients underwent surgery as adults. The mean duration of epilepsy before surgical resection was 20.1 years among adults and 5.3 years among children. The temporal lobe was involved in 71.9% of operations. There were 36 histopathological diagnoses in seven major disease categories. The most common categories were hippocampal sclerosis, found in 36.4% of the patients (88.7% of cases were in adults), tumors (mainly ganglioglioma) in 23.6%, and malformations of cortical development in 19.8% (focal cortical dysplasia was the most common type, 52.7% of cases of which were in children). No histopathological diagnosis could be established for 7.7% of the patients. CONCLUSIONS: In patients with drug-resistant focal epilepsy requiring surgery, hippocampal sclerosis was the most common histopathological diagnosis among adults, and focal cortical dysplasia was the most common diagnosis among children. Tumors were the second most common lesion in both groups. (Funded by the European Union and others.).

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.

Critique of the 2017 epileptic seizure and epilepsy classifications.

This article critiques the International League Against Epilepsy (ILAE) 2015-2017 classifications of epilepsy, epileptic seizures, and status epilepticus. It points out the following shortcomings of the ILAE classifications: (1) they mix semiological terms with epileptogenic zone terminology; (2) simple and widely accepted terminology has been replaced by complex terminology containing less information; (3) seizure evolution cannot be described in any detail; (4) in the four-level epilepsy classification, level two (epilepsy category) overlaps almost 100% with diagnostic level one (seizure type); and (5) the design of different classifications with distinct frameworks for newborns, adults, and patients in status epilepticus is confusing. The authors stress the importance of validating the new ILAE classifications and feel that the decision of Epilepsia to accept only manuscripts that use the ILAE classifications is premature and regrettable.

Predicting hand function after hemidisconnection.

Hemidisconnections (i.e. hemispherectomies or hemispherotomies) invariably lead to contralateral hemiparesis. Many patients with a pre-existing hemiparesis, however, experience no deterioration in motor functions, and some can still grasp with their paretic hand after hemidisconnection. The scope of our study was to predict this phenomenon. Hypothesizing that preserved contralateral grasping ability after hemidisconnection can only occur in patients controlling their paretic hands via ipsilateral corticospinal projections already in the preoperative situation, we analysed the asymmetries of the brainstem (by manual magnetic resonance imaging volumetry) and of the structural connectivity of the corticospinal tracts within the brainstem (by magnetic resonance imaging diffusion tractography), assuming that marked hypoplasia or Wallerian degeneration on the lesioned side in patients who can grasp with their paretic hands indicate ipsilateral control. One hundred and two patients who underwent hemidisconnections between 0.8 and 36 years of age were included. Before the operation, contralateral hand function was normal in 3/102 patients, 47/102 patients showed hemiparetic grasping ability and 52/102 patients could not grasp with their paretic hands. After hemidisconnection, 20/102 patients showed a preserved grasping ability, and 5/102 patients began to grasp with their paretic hands only after the operation. All these 25 patients suffered from pre- or perinatal brain lesions. Thirty of 102 patients lost their grasping ability. This group included all seven patients with a post-neonatally acquired or progressive brain lesion who could grasp before the operation, and also all three patients with a preoperatively normal hand function. The remaining 52/102 patients were unable to grasp pre- and postoperatively. On magnetic resonance imaging, the patients with preserved grasping showed significantly more asymmetric brainstem volumes than the patients who lost their grasping ability. Similarly, these patients showed striking asymmetries in the structural connectivity of the corticospinal tracts. In summary, normal preoperative hand function and a post-neonatally acquired or progressive lesion predict a loss of grasping ability after hemidisconnection. A postoperatively preserved grasping ability is possible in hemiparetic patients with pre- or perinatal lesions, and this is highly likely when the brainstem is asymmetric and especially when the structural connectivity of the corticospinal tracts within the brainstem is asymmetric.

DEPDC5 mutations in genetic focal epilepsies of childhood.

Recent studies reported DEPDC5 loss-of-function mutations in different focal epilepsy syndromes. Here we identified 1 predicted truncation and 2 missense mutations in 3 children with rolandic epilepsy (3 of 207). In addition, we identified 3 families with unclassified focal childhood epilepsies carrying predicted truncating DEPDC5 mutations (3 of 82). The detected variants were all novel, inherited, and present in all tested affected (n=11) and in 7 unaffected family members, indicating low penetrance. Our findings extend the phenotypic spectrum associated with mutations in DEPDC5 and suggest that rolandic epilepsy, albeit rarely, and other nonlesional childhood epilepsies are among the associated syndromes.

Epilepsies associated with focal cortical dysplasias (FCDs).

Focal cortical dysplasias (FCDs) are increasingly recognized as one of the most common causes of pharmaco-resistant epilepsies. FCDs were recently divided into various clinico-pathological subtypes due to distinct imaging, electrophysiological, and outcome characteristics. In this review, we will overview the international consensus classification of FCDs in light of more recently reported clinical, electrical, imaging and functional observations, and will also address areas of ongoing debate. In addition, we will summarize our current knowledge on pathobiology and epileptogenicity of FCDs as well as its underlying molecular and cellular mechanisms. The clinical (electroencephalographic, imaging, and functional) characteristics of major FCD subtypes and their implications on the presurgical evaluation and surgical management will be discussed in light of studies describing these characteristics and postoperative seizure outcomes in patients with medically intractable focal epilepsy due to histopathologically confirmed FCDs.

Electro-clinical-pathological correlations in focal cortical dysplasia (FCD) at young ages.

The prevalence of focal cortical dysplasia (FCD) in pediatric patients with focal epilepsy is not exactly known because authors of publications in which the etiologies of epilepsies are listed, but which are not dealing specifically with epilepsy surgery issues, tend to lump together the many kinds of malformations of cortical development (MCD), of which FCDs, because of their relative frequency, are the most relevant subtypes. Out of 561 patients with MCD (children and adults) operated at centers in Europe who do feed data into the "European Epilepsy Brain Bank," 426 (76 %) had FCD.

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

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.

Clinical functional MRI of the language domain in children with epilepsy.

Functional MRI (fMRI) for the assessment of language functions is increasingly used in the diagnostic workup of patients with epilepsy. Termed "clinical fMRI," such an approach is also feasible in children who may display specific patterns of language reorganization. This study was aimed at assessing language reorganization in pediatric epilepsy patients, using fMRI. We studied 26 pediatric epilepsy patients (median age, 13.05 years; range, 5.6-18.7 years) and 23 healthy control children (median age, 9.37 years; range, 6.2-15.4 years), using two child-friendly fMRI tasks and adapted data-processing streams. Overall, 81 functional series could be analyzed. Reorganization seemed to occur primarily in homotopic regions in the contralateral hemisphere, but lateralization in the frontal as well as in the temporal lobes was significantly different between patients and controls. The likelihood to find atypical language organization was significantly higher in patients. Additionally, we found significantly stronger activation in the healthy controls in a primarily passive task, suggesting a systematic confounding influence of antiepileptic medication. The presence of a focal cortical dysplasia was significantly associated with atypical language lateralization. We conclude that important confounds need to be considered and that the pattern of language reorganization may be distinct from the patterns seen in later-onset epilepsy.

A retrospective study of the relation between vaccination and occurrence of seizures in Dravet syndrome.

Dravet syndrome is a severe epileptic encephalopathy starting in the first year of life. Mutations in SCN1A can be identified in the majority of patients, and epileptic seizures in the setting of fever are a clinical hallmark. Fever is also commonly seen after vaccinations and provocation of epileptic seizures by vaccinations in patients with Dravet syndrome has been reported, but not systematically assessed. In a retrospective evaluation of 70 patients with Dravet syndrome and SCN1A mutations, seizures following vaccinations were reported in 27%. In 58% of these patients vaccination-related seizures represented the first clinical manifestation. The majority of seizures occurred after DPT vaccinations and within 72 h after vaccination. Two-thirds of events occurred in the context of fever. Our findings highlight seizures after vaccinations as a common feature in Dravet syndrome and emphasize the need for preventive measures for seizures triggered by vaccination or fever in these children.

Glucose transporter-1 deficiency syndrome: the expanding clinical and genetic spectrum of a treatable disorder.

Glucose transporter-1 deficiency syndrome is caused by mutations in the SLC2A1 gene in the majority of patients and results in impaired glucose transport into the brain. From 2004-2008, 132 requests for mutational analysis of the SLC2A1 gene were studied by automated Sanger sequencing and multiplex ligation-dependent probe amplification. Mutations in the SLC2A1 gene were detected in 54 patients (41%) and subsequently in three clinically affected family members. In these 57 patients we identified 49 different mutations, including six multiple exon deletions, six known mutations and 37 novel mutations (13 missense, five nonsense, 13 frame shift, four splice site and two translation initiation mutations). Clinical data were retrospectively collected from referring physicians by means of a questionnaire. Three different phenotypes were recognized: (i) the classical phenotype (84%), subdivided into early-onset (<2 years) (65%) and late-onset (18%); (ii) a non-classical phenotype, with mental retardation and movement disorder, without epilepsy (15%); and (iii) one adult case of glucose transporter-1 deficiency syndrome with minimal symptoms. Recognizing glucose transporter-1 deficiency syndrome is important, since a ketogenic diet was effective in most of the patients with epilepsy (86%) and also reduced movement disorders in 48% of the patients with a classical phenotype and 71% of the patients with a non-classical phenotype. The average delay in diagnosing classical glucose transporter-1 deficiency syndrome was 6.6 years (range 1 month-16 years). Cerebrospinal fluid glucose was below 2.5 mmol/l (range 0.9-2.4 mmol/l) in all patients and cerebrospinal fluid : blood glucose ratio was below 0.50 in all but one patient (range 0.19-0.52). Cerebrospinal fluid lactate was low to normal in all patients. Our relatively large series of 57 patients with glucose transporter-1 deficiency syndrome allowed us to identify correlations between genotype, phenotype and biochemical data. Type of mutation was related to the severity of mental retardation and the presence of complex movement disorders. Cerebrospinal fluid : blood glucose ratio was related to type of mutation and phenotype. In conclusion, a substantial number of the patients with glucose transporter-1 deficiency syndrome do not have epilepsy. Our study demonstrates that a lumbar puncture provides the diagnostic clue to glucose transporter-1 deficiency syndrome and can thereby dramatically reduce diagnostic delay to allow early start of the ketogenic diet.

Focal cortical dysplasia type 1.

The ILAE classification of Focal Cortical Dysplasia (FCD) from 2011 has quickly gained acceptance in clinical practice and research and is now widely used around the world. This histopathology-based classification scheme proposed three subtypes, that is, FCD Type 1 (with architectural abnormalities of the neocortex), FCD Type 2 (with cytoarchitectural abnormalities of the neocortex) and FCD Type 3 (architectural abnormalities of the neocortex associated with another principle lesion acquired during early life). Valuable knowledge was gathered during the last decade validating the clinical, pathological and genetic classification of FCD Type 2. This is in contrast to FCD subtype 1 and 3 with only few robust or new insights. Herein, we provide an overview about current knowledge about FCD Type 1 and its three subtypes. Available data strengthened, however, FCD Type 1A in particular, whereas a comprehensive clinico-pathological specification for FCD Type 1B and 1C subtypes remain to be shown. The lack of a valid animal model for FCD Type 1 further supports our call and the ongoing need for systematic research studies based on a careful clinico-pathological and genetic stratification of patients and human brain tissues.

A distinct variant of focal cortical dysplasia type I characterised by magnetic resonance imaging and neuropathological examination in children with severe epilepsies.

Focal Cortical Dysplasias (FCDs) present with a large clinicopathological spectrum. FCDs are believed to relate directly to an epileptogenic condition, although seizure control by surgical resection is variable. This applies in particular to young children with multilobar FCDs, suffering from severe epilepsies and psychomotor retardation. Herein, we performed a comparative analysis of presurgically available data and microscopic inspection of resected cortical specimens to further characterise the pathomorphological spectrum of FCD. Multilobar resection procedures were performed in a consecutive series of 18 young children (mean 7.6 years) with severe pharmaco-resistant epilepsies following extensive presurgical surface-/invasive video-EEG monitoring intraoperative electro-corticography (iECoG), as well as high resolution MRI. In all cases, systematic neuropathological examination of surgical specimens was performed with respect to architectural abnormalities and cell density measurements. These histomorphological data were compared with volumetric MRI analysis. Histopathological examination revealed increased neuronal densities correlating with decreased cortical thickness and abundance of neuronal microcolumns in all cases. Intriguingly, the affected cerebral hemisphere was significantly smaller, relative to the non-epileptogenic contralateral side, in 16 children of our patient series. In conclusion, hypoplastic neocortex and columnar architectural disorganisation point to compromised cortical development, and appear as distinct FCD I subtype in children suffering from severe epilepsies and psychomotor retardation.

Correlates of intellectual development before and after hemispherotomy: an analysis of 75 children and adolescents.

This study describes the intellectual development of 75 children and adolescents who underwent hemispherotomy. Furthermore, we aimed to reveal predicting factors on pre- and postsurgical development with a focus on the role of aetiology. We analysed presurgical and six-month postsurgical developmental and intellectual data of 75 patients (age range: 0.87-19.78 years) and divided them into two groups: a not severely impaired group in which outcome of intellectual functioning was reported based on FSIQ score, and a severely impaired group (not testable by IQ tests) in which intellectual developmental outcome was described based on developmental quotients instead. In the not severely impaired group (n = 31), the preoperative level of intellectual functioning was a strong predictor of postoperative intellectual outcome; for 22/31 (71%) patients, postoperative FSIQ and its subscales were similar to preoperative levels. Improvements were observed for FSIQ in five patients, only for Verbal IQ in one patient and only for Performance IQ in one further patient; significant losses occurred in two patients, only for Performance IQ in both. In the severely impaired group, 30/40 (75%) patients showed further development after surgery, nine (23%) patients had the same results as before surgery, and one (2%) patient showed regression. Longer duration of presurgical epilepsy was related to a marginally lower presurgical developmental level, and good seizure outcome was a predictor of better postoperative development. For all patients, early age at seizure onset and early lesion origin correlated with poorer presurgical intellectual development. Although an entire hemisphere was disconnected, most patients exhibited ongoing development after hemispherotomy or had at least the same preoperative intellectual status; deterioration was rare.

Could the 2017 ILAE and the four-dimensional epilepsy classifications be merged to a new "Integrated Epilepsy Classification"?

Over the last few decades the ILAE classifications for seizures and epilepsies (ILAE-EC) have been updated repeatedly to reflect the substantial progress that has been made in diagnosis and understanding of the etiology of epilepsies and seizures and to correct some of the shortcomings of the terminology used by the original taxonomy from the 1980s. However, these proposals have not been universally accepted or used in routine clinical practice. During the same period, a separate classification known as the "Four-dimensional epilepsy classification" (4D-EC) was developed which includes a seizure classification based exclusively on ictal symptomatology, which has been tested and adapted over the years. The extensive arguments for and against these two classification systems made in the past have mainly focused on the shortcomings of each system, presuming that they are incompatible. As a further more detailed discussion of the differences seemed relatively unproductive, we here review and assess the concordance between these two approaches that has evolved over time, to consider whether a classification incorporating the best aspects of the two approaches is feasible. To facilitate further discussion in this direction we outline a concrete proposal showing how such a compromise could be accomplished, the "Integrated Epilepsy Classification". This consists of five categories derived to different degrees from both of the classification systems: 1) a "Headline" summarizing localization and etiology for the less specialized users, 2) "Seizure type(s)", 3) "Epilepsy type" (focal, generalized or unknown allowing to add the epilepsy syndrome if available), 4) "Etiology", and 5) "Comorbidities & patient preferences".

Different presurgical characteristics and seizure outcomes in children with focal cortical dysplasia type I or II.

PURPOSE: Cortical dysplasia (FCD) is a frequent cause of epilepsy in childhood. Two major pathological variants are distinguished, FCD type I and II. The aim of the study was to characterize differences between FCD type I and II with respect to imaging and EEG findings, clinical and neuropsychological presentations, and surgical outcome. METHODS: Forty children with refractory epilepsy and histopathologically confirmed FCD were retrospectively analyzed. FCD type I was identified in 24 and FCD type II in 16 patients. RESULTS: Characteristic MRI abnormalities in FCD type I included subtle white matter signal changes and regional reduction of the white matter volume. Typical MRI findings in FCD type II were increased cortical thickness, transmantle sign, gray-white matter junction blurring, fluid-attenuated inversion recovery (FLAIR) and proton density (PD) gray matter signal changes as well as T1w, and PD white matter signal changes. Continuous EEG slowing was significantly more common in patients with FCD type I. Children with FCD type I presented with lower levels of intelligence and were suffering more often from maladaptive behavior and behavioral disorders. Surgical outcome was significantly worse in the FCD type I group (seizure freedom was achieved in 21% FCD type I patients and in 75% FCD type II subjects, p < 0.001). CONCLUSIONS: Clinically important differences were found in children with distinct histopathological subtypes of FCD. Due to prominent neuropsychological deficits and worse seizure outcome, treatment strategies in FCD type I are more challenging than previously reported and these children should be recognized and specifically addressed within the incoherent group of patients with malformative brain disorders.

Increased frequency of distinct TSC2 allelic variants in focal cortical dysplasias with balloon cells and mineralization.

Focal cortical dysplasias with balloon cells (FCD(IIb)) usually present with characteristic imaging and molecular features, that is, a transmantle sign on fluid-attenuated inversion recovery MRI and abundance of allelic variants of the tuberous sclerosis gene 1 (TSC1). Recently, we observed several mineralized lesions (n = 5) lacking this MRI pattern and which surprisingly turned out as FCD(IIb) upon neuropathological examination. These mineralized FCD(IIb) revealed an increased frequency of TSC2 allelic variants but not TSC1 (intron 31: 60% vs. 11% in controls; P = 0.0164, exon 41: 40% vs. 6.5% in controls; P = 0.0441). Mineralized FCD(IIb) have a favorable postsurgical outcome and need consideration in the presurgical differential diagnosis of calcified lesions associated with pharmacoresistant focal epilepsies.