Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/34241
Title: The clinical, imaging, pathological and genetic landscape of bottom-of-sulcus dysplasia.
Austin Authors: Macdonald-Laurs, Emma;Warren, Aaron E L;Francis, Peter;Mandelstam, Simone A;Lee, Wei Shern;Coleman, Matthew;Stephenson, Sarah E M;Barton, Sarah;D'Arcy, Colleen;Lockhart, Paul J;Leventer, Richard J;Harvey, A Simon
Affiliation: Department 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.
Murdoch Children's Research Institute, Parkville, Victoria, 3052, Australia.
Department of Medical Imaging, 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.;Department of Medical Imaging, The Royal Children's Hospital, Parkville, Victoria, 3052, Australia.
Bruce Lefroy Centre, Murdoch Children's Research Institute, Parkville, Victoria, 3052, Australia.
Department of Paediatrics, The University of Melbourne, Parkville, Victoria, 3052, Australia.;Bruce Lefroy Centre, Murdoch Children's Research Institute, Parkville, Victoria, 3052, Australia.
Medicine (University of Melbourne)
;Department of Paediatrics, The University of Melbourne, Parkville, Victoria, 3052, Australia.
Department of Pathology, The Royal Children's Hospital, Parkville, Victoria, 3052, Australia.
Department of Paediatrics, The University of Melbourne, Parkville, Victoria, 3052, Australia.
Murdoch Children's Research Institute, Parkville, Victoria, 3052, Australia.;Department of Paediatrics, The University of Melbourne, Parkville, Victoria, 3052, Australia.
Issue Date: 6-Nov-2023
Date: 2023
Publication information: Brain : A Journal of Neurology 2023-11-06
Abstract: Bottom-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.
URI: https://ahro.austin.org.au/austinjspui/handle/1/34241
DOI: 10.1093/brain/awad379
ORCID: 0000-0002-9894-4610
0000-0001-6534-2800
0000-0001-6287-0819
0000-0002-9108-0258
0000-0001-8627-3322
0000-0001-7860-9527
0000-0001-7077-0906
0000-0002-6483-3226
0000-0003-2531-8413
0000-0003-0362-5607
0000-0001-6388-7444
Journal: Brain : A Journal of Neurology
PubMed URL: 37939785
ISSN: 1460-2156
Type: Journal Article
Subjects: MRI-negative
epilepsy surgery
focal cortical dysplasia
mechanistic target of rapamycin
Appears in Collections:Journal articles

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