Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/34241
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dc.contributor.authorMacdonald-Laurs, Emma-
dc.contributor.authorWarren, Aaron E L-
dc.contributor.authorFrancis, Peter-
dc.contributor.authorMandelstam, Simone A-
dc.contributor.authorLee, Wei Shern-
dc.contributor.authorColeman, Matthew-
dc.contributor.authorStephenson, Sarah E M-
dc.contributor.authorBarton, Sarah-
dc.contributor.authorD'Arcy, Colleen-
dc.contributor.authorLockhart, Paul J-
dc.contributor.authorLeventer, Richard J-
dc.contributor.authorHarvey, A Simon-
dc.date2023-
dc.date.accessioned2023-11-15T05:28:12Z-
dc.date.available2023-11-15T05:28:12Z-
dc.date.issued2023-11-06-
dc.identifier.citationBrain : A Journal of Neurology 2023-11-06en_US
dc.identifier.issn1460-2156-
dc.identifier.urihttps://ahro.austin.org.au/austinjspui/handle/1/34241-
dc.description.abstractBottom-of-sulcus dysplasia (BOSD) is increasingly recognised as a cause of drug-resistant, surgically-remediable, focal epilepsy, often in seemingly MRI-negative patients. We describe the clinical manifestations, morphological features, localisation patterns, and genetics of BOSD, with the aims of improving management and understanding pathogenesis. We studied 85 patients with BOSD diagnosed between 2005-2022. Presenting seizure and EEG characteristics, clinical course, genetic findings, and treatment response were obtained from medical records. 3T-MRI and 18F-FDG-PET scans were reviewed systematically for BOSD morphology and metabolism. Histopathological analysis and tissue genetic testing were performed in 64 operated patients. BOSD locations were transposed to common imaging space to study anatomical location, functional network localisation, and relationship to normal MTOR gene expression. All patients presented with stereotyped focal seizures with rapidly escalating frequency, prompting hospitalisation in 48%. Despite 42% patients having seizure remissions, usually with sodium channel blocking medications, most eventually became drug-resistant and underwent surgery (86% seizure-free). Prior developmental delay was uncommon but intellectual, language and executive dysfunction were present in 24%, 48% and 29% when assessed preoperatively, low intellect being associated with greater epilepsy duration. BOSDs were missed on initial MRI in 68%, being ultimately recognised following repeat MRI, 18F-FDG-PET or image post-processing. MRI features were grey-white junction blurring (100%), cortical thickening (91%), transmantle band (62%), increased cortical T1 signal (46%) and increased subcortical FLAIR signal (26%). BOSD hypometabolism was present on 18F-FDG-PET in 99%. Additional areas of cortical malformation or grey matter heterotopia were present in eight patients. BOSDs predominated in frontal and pericentral cortex and related functional networks, mostly sparing temporal and occipital cortex, and limbic and visual networks. Genetic testing yielded pathogenic mTOR pathway variants in 63% patients, including somatic MTOR variants in 47% operated patients and germline DEPDC5 or NPRL3 variants in 73% patients with familial focal epilepsy. BOSDs tended to occur in regions where the healthy brain normally shows lower MTOR expression, suggesting these regions may be more vulnerable to up-regulation of MTOR activity. Consistent with the existing literature, these results highlight (1) clinical features raising suspicion of BOSD, (2) the role of somatic and germline mTOR pathway variants in patients with sporadic and familial focal epilepsy associated with BOSD and (3) the role of 18F-FDG-PET alongside high-field MRI in detecting subtle BOSD. The anatomical and functional distribution of BOSDs likely explain their seizure, EEG, and cognitive manifestations, and may relate to relative MTOR expression.en_US
dc.language.isoeng-
dc.subjectMRI-negativeen_US
dc.subjectepilepsy surgeryen_US
dc.subjectfocal cortical dysplasiaen_US
dc.subjectmechanistic target of rapamycinen_US
dc.titleThe clinical, imaging, pathological and genetic landscape of bottom-of-sulcus dysplasia.en_US
dc.typeJournal Articleen_US
dc.identifier.journaltitleBrain : A Journal of Neurologyen_US
dc.identifier.affiliationDepartment of Neurology, The Royal Children's Hospital, Parkville, Victoria, 3052  Australia.;Murdoch Children's Research Institute, Parkville, Victoria, 3052, Australia.;Department of Paediatrics, The University of Melbourne, Parkville, Victoria, 3052, Australia.en_US
dc.identifier.affiliationMurdoch Children's Research Institute, Parkville, Victoria, 3052, Australia.en_US
dc.identifier.affiliationDepartment of Medical Imaging, The Royal Children's Hospital, Parkville, Victoria, 3052, Australia.en_US
dc.identifier.affiliationMurdoch Children's Research Institute, Parkville, Victoria, 3052, Australia.;Department of Paediatrics, The University of Melbourne, Parkville, Victoria, 3052, Australia.;Department of Medical Imaging, The Royal Children's Hospital, Parkville, Victoria, 3052, Australia.en_US
dc.identifier.affiliationBruce Lefroy Centre, Murdoch Children's Research Institute, Parkville, Victoria, 3052, Australia.en_US
dc.identifier.affiliationDepartment of Paediatrics, The University of Melbourne, Parkville, Victoria, 3052, Australia.;Bruce Lefroy Centre, Murdoch Children's Research Institute, Parkville, Victoria, 3052, Australia.en_US
dc.identifier.affiliationMedicine (University of Melbourne)en_US
dc.identifier.affiliation;Department of Paediatrics, The University of Melbourne, Parkville, Victoria, 3052, Australia.en_US
dc.identifier.affiliationDepartment of Pathology, The Royal Children's Hospital, Parkville, Victoria, 3052, Australia.en_US
dc.identifier.affiliationDepartment of Paediatrics, The University of Melbourne, Parkville, Victoria, 3052, Australia.en_US
dc.identifier.affiliationMurdoch Children's Research Institute, Parkville, Victoria, 3052, Australia.;Department of Paediatrics, The University of Melbourne, Parkville, Victoria, 3052, Australia.en_US
dc.identifier.doi10.1093/brain/awad379en_US
dc.type.contentTexten_US
dc.identifier.orcid0000-0002-9894-4610en_US
dc.identifier.orcid0000-0001-6534-2800en_US
dc.identifier.orcid0000-0001-6287-0819en_US
dc.identifier.orcid0000-0002-9108-0258en_US
dc.identifier.orcid0000-0001-8627-3322en_US
dc.identifier.orcid0000-0001-7860-9527en_US
dc.identifier.orcid0000-0001-7077-0906en_US
dc.identifier.orcid0000-0002-6483-3226en_US
dc.identifier.orcid0000-0003-2531-8413en_US
dc.identifier.orcid0000-0003-0362-5607en_US
dc.identifier.orcid0000-0001-6388-7444en_US
dc.identifier.pubmedid37939785-
item.fulltextNo Fulltext-
item.languageiso639-1en-
item.openairetypeJournal Article-
item.grantfulltextnone-
item.openairecristypehttp://purl.org/coar/resource_type/c_18cf-
item.cerifentitytypePublications-
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