William Harkness

Benign central neurocytoma

“Central neurocytoma” is classically considered as an intraventricular benign tumor, largely based on data from small retrospective series. The authors present prospective data on 12 patients with tumors diagnosed as central neurocytoma, to highlight the diverse nature of this tumor and challenge the classic notion.

Cognitive outcome after extratemporal epilepsy surgery in childhood

Purpose:u2002 The present study aims to describe the cognitive profile of children with medically refractory extratemporal epilepsies who undergo focal surgery and to identify determinants for preoperative and postoperative cognitive level.

mTOR-dependent abnormalities in autophagy characterize human malformations of cortical development: evidence from focal cortical dysplasia and tuberous sclerosis

Focal cortical dysplasia (FCD) is a localized malformation of cortical development and is the commonest cause of severe childhood epilepsy in surgical practice. Children with FCD are severely disabled by their epilepsy, presenting with frequent seizures early in life. The commonest form of FCD in children is characterized by the presence of an abnormal population of cells, known as balloon cells. Similar pathological changes are seen in the cortical malformations that characterize patients with tuberous sclerosis complex (TSC). However, the cellular and molecular mechanisms that underlie the malformations of FCD and TSC are not well understood. We provide evidence for a defect in autophagy in FCD and TSC. We have found that balloon cells contain vacuoles that include components of the autophagy pathway. Specifically, we show that balloon cells contain prominent lysosomes by electron microscopy, immunohistochemistry for LAMP1 and LAMP2, LysoTracker labelling and enzyme histochemistry for acid phosphatase. Furthermore, we found that balloon cells contain components of the ATG pathway and that there is cytoplasmic accumulation of the regulator of autophagy, DOR. Most importantly we found that there is abnormal accumulation of the autophagy cargo protein, p62. We show that this defect in autophagy can be, in part, reversed in vitro by inhibition of the mammalian target of rapamycin (mTOR) suggesting that abnormal activation of mTOR may contribute directly to a defect in autophagy in FCD and TSC.

Psychopathology in children before and after surgery for extratemporal lobe epilepsy

Aimu2002 To establish the rates and types of psychiatric disorder in children before and after surgery for extratemporal epilepsy. Relationships between psychiatric morbidity and demographic/clinical variables were examined.

Hippocampal sclerosis in children with lesional epilepsy is influenced by age at seizure onset

Summary:u2002 Purpose: Hippocampal sclerosis (HS) is the most common lesion underlying drug‐resistant temporal lobe epilepsy. Whether HS is a developmental or acquired pathology remains unclear. Whereas HS has been causally linked to prolonged febrile convulsions in childhood, evidence also exists that it may coexist with extrahippocampal abnormalities, the concept of “dual pathology.” The aims of this study were to address whether hippocampal abnormality consistent with HS (a) occurs in children with lesional extrahippocampal epilepsy, (b) is more commonly seen in association with developmental rather than acquired extrahippocampal pathologies, and (c) whether any effect of age at seizure onset is found on the occurrence of HS in lesional extrahippocampal epilepsy.

Epigenetic genome-wide analysis identifies BEX1 as a candidate tumour suppressor gene in paediatric intracranial ependymoma.

Promoter hypermethylation and transcriptional silencing is a common epigenetic mechanism of gene inactivation in cancer. To identify targets of epigenetic silencing in paediatric intracranial ependymoma, we used a pharmacological unmasking approach through treatment of 3 ependymoma short-term cell cultures with the demethylating agent 5-Aza-2-deoxycytidine followed by global expression microarray analysis. We identified 55 candidate epigenetically silenced genes, which are involved in the regulation of apoptosis, Wnt signalling, p53 and cell differentiation. The methylation status of 26 of these genes was further determined by combined bisulfite restriction analysis (COBRA) and genomic sequencing in a cohort of 40 ependymoma samples. The most frequently methylated genes were BEX1 (27/40 cases), BAI2 (20/40), CCND2 (18/40), and CDKN2A (14/40). A high correlation between promoter hypermethylation and decreased gene expression levels was established by real-time quantitative PCR, suggesting the involvement of these genes in ependymoma tumourigenesis. Furthermore, ectopic expression of brain-expressed X-linked 1 (BEX1) in paediatric ependymoma short-term cell cultures significantly suppressed cell proliferation and colony formation. These data suggest that promoter hypermethylation contributes to silencing of target genes in paediatric intracranial ependymoma. Epigenetic inactivation of BEX1 supports its role as a candidate tumour suppressor gene in intracranial ependymoma, and a potential target for novel therapies for ependymoma in children.

Technical aspects of pediatric epilepsy surgery: Report of a multicenter, multinational web-based survey by the ILAE Task Force on Pediatric Epilepsy Surgery

Surgical techniques may vary extensively between centers. We report on a web‐based survey aimed at evaluating the current technical approaches in different centers around the world performing epilepsy surgery in children. The intention of the survey was to establish technical standards. A request was made to 88 centers to complete a web‐based survey comprising 51 questions. There were 14 questions related to general issues, 13 questions investigating the different technical aspects for children undergoing epilepsy surgery, and 24 questions investigating surgical strategies in pediatric epilepsy surgery. Fifty‐two centers covering a wide geographic representation completed the questionnaire. The median number of resective procedures per center per year was 47. Some important technical practices appeared (>80% of the responses) such as the use of prophylactic antibiotics (98%), the use of high‐speed drills for bone opening (88%), nonresorbable material for bone flap closure (85%), head fixation (90%), use of the surgical microscope (100%), and of free bone flaps. Other questions, such as the use of drains, electrocorticography (ECoG) and preoperative withdrawal of valproate, led to mixed, inconclusive results. Complications were noted in 3.8% of the patients submitted to cortical resection, 9.9% hemispheric surgery, 5% callosotomy, 1.8% depth electrode implantation, 5.9% subdural grids implantation, 11.9% hypothalamic hamartoma resection, 0.9% vagus nerve stimulation (VNS), and 0.5% deep brain stimulation. There were no major differences across regions or countries in any of the subitems above. The present data offer the first overview of the technical aspects of pediatric epilepsy surgery worldwide. Surprisingly, there seem to be more similarities than differences. That aside many of the evaluated issues should be examined by adequately designed multicenter randomized controlled trials (RCTs). Further knowledge on these technical issues might lead to increased standardization and lower costs in the future, as well as definitive practice guidelines.

Comprehensive molecular characterisation of epilepsy-associated glioneuronal tumours

Glioneuronal tumours are an important cause of treatment-resistant epilepsy. Subtypes of tumour are often poorly discriminated by histological features and may be difficult to diagnose due to a lack of robust diagnostic tools. This is illustrated by marked variability in the reported frequencies across different epilepsy surgical series. To address this, we used DNA methylation arrays and RNA sequencing to assay the methylation and expression profiles within a large cohort of glioneuronal tumours. By adopting a class discovery approach, we were able to identify two distinct groups of glioneuronal tumour, which only partially corresponded to the existing histological classification. Furthermore, by additional molecular analyses, we were able to identify pathogenic mutations in BRAF and FGFR1, specific to each group, in a high proportion of cases. Finally, by interrogating our expression data, we were able to show that each molecular group possessed expression phenotypes suggesting different cellular differentiation: astrocytic in one group and oligodendroglial in the second. Informed by this, we were able to identify CCND1, CSPG4, and PDGFRA as immunohistochemical targets which could distinguish between molecular groups. Our data suggest that the current histological classification of glioneuronal tumours does not adequately represent their underlying biology. Instead, we show that there are two molecular groups within glioneuronal tumours. The first of these displays astrocytic differentiation and is driven by BRAF mutations, while the second displays oligodendroglial differentiation and is driven by FGFR1 mutations.

The Causes of Epilepsy: Ganglioglioma, dysembryoplastic neuroepithelial tumor, and related tumors

© Cambridge University Press 2011. Introduction Tumors account for around 30% of cases of drug-resistant epilepsy in surgical series (reviewed in Thom et al. 2008). Most of these tumors are low-grade glioneuronal tumors; the two best described are dysembryoplastic neuroepithelial tumors (DNT) and ganglioglioma. Diagnosis of these tumors is important because they are potentially curable causes of drug-resistant epilepsy. The majority of tumors that present with epilepsy comprise a group of tumors that include DNTs, ganglioglioma, gangliocytoma, and the more recently described angiocentric glioma. These tumors are the main focus of this chapter and their management is predominantly focused on seizure control rather than oncological concerns. However, as over 40% of patients with supratentorial tumors present with seizures, a much wider range of glial tumors may present with intractable epilepsy including pilocytic astrocytoma, diffuse and anaplastic astrocytoma, pleomorphic xanthoastrocytoma, and oligodendroglioma. Several of these tumors carry a much greater risk of tumor progression and so management involves not only seizure control but also the involvement of the multidisciplinary oncology team (Louis et al. 2007a). Ganglioglioma and DNTs are the commonest tumors presenting with epilepsy, accounting for 40–50% and 10–20% of cases, respectively (Frater et al. 2000; Benifla et al. 2006; Bauer et al. 2007; Becker et al. 2007). However, there is variation in the reported figures and this is likely to be due to variations in diagnostic criteria, surgical practice, and local referral patterns. For example in our practice, DNT is more common than these figures suggest.