title: Impaired oligodendroglial turnover is associated with myelin pathology in focal cortical dysplasia and tuberous sclerosis complex.
abstract: Conventional antiepileptic drugs suppress the excessive firing of neurons during seizures. In drug-resistant patients, treatment failure indicates an alternative important epileptogenic trigger. Two epilepsy-associated pathologies show myelin deficiencies in seizure-related brain regions: Focal Cortical Dysplasia IIB (FCD) and cortical tubers in Tuberous Sclerosis Complex (TSC). Studies uncovering white matter-pathology mechanisms are therefore urgently needed to gain more insight into epileptogenesis, the propensity to maintain seizures, and their associated comorbidities such as cognitive defects. We analyzed epilepsy surgery specimens of FCD IIB (n = 22), TSC (n = 8), and other malformations of cortical development MCD (n = 12), and compared them to autopsy and biopsy cases (n = 15). The entire lesional pathology was assessed using digital immunohistochemistry, immunofluorescence and western blotting for oligodendroglial lineage, myelin and mTOR markers, and findings were correlated to clinical parameters. White matter pathology with depleted myelin and oligodendroglia were found in 50% of FCD IIB and 62% of TSC cases. Other MCDs had either a normal content or even showed reactive oligodendrolial hyperplasia. Furthermore, myelin deficiency was associated with increased mTOR expression and the lower amount of oligodendroglia was linked with their precursor cells (PDGFRa). The relative duration of epilepsy (normalized to age) also correlated positively to mTOR activation and negatively to myelination. Decreased content of oligodendroglia and missing precursor cells indicated insufficient oligodendroglial development, probably mediated by mTOR, which may ultimately lead to severe myelin loss. In terms of disease management, an early and targeted treatment could restore normal myelin development and, therefore, alter seizure threshold and improve cognitive outcome.
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
authors.forename: Theresa
authors.initials: T
authors.lastname: Scholl
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
authors.forename: Angelika
authors.initials: A
authors.lastname: Mühlebner
authors.affiliation: Institute of Neurology, Medical University of Vienna, Vienna, Austria.
authors.forename: Gerda
authors.initials: G
authors.lastname: Ricken
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.|Institute of Neurology, Medical University of Vienna, Vienna, Austria.
authors.forename: Victoria
authors.initials: V
authors.lastname: Gruber
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.|Institute of Neurology, Medical University of Vienna, Vienna, Austria.
authors.forename: Anna
authors.initials: A
authors.lastname: Fabing
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
authors.forename: Sharon
authors.initials: S
authors.lastname: Samueli
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Gröppel
authors.affiliation: Department of Neurosurgery, Medical University of Vienna, Vienna, Austria.
authors.forename: Christian
authors.initials: C
authors.lastname: Dorfer
authors.affiliation: Department of Neurosurgery, Medical University of Vienna, Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Czech
authors.affiliation: Institute of Neurology, Medical University of Vienna, Vienna, Austria.
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Hainfellner
authors.affiliation: Department of (Neuro) Pathology, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Avanita S
authors.initials: AS
authors.lastname: Prabowo
authors.affiliation: Department of (Neuro) Pathology, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Roy J
authors.initials: RJ
authors.lastname: Reinten
authors.affiliation: Department of (Neuro) Pathology, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Lisette
authors.initials: L
authors.lastname: Hoogendijk
authors.affiliation: Department of (Neuro) Pathology, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Jasper J
authors.initials: JJ
authors.lastname: Anink
authors.affiliation: Department of (Neuro) Pathology, Academic Medical Centre, Amsterdam, The Netherlands.|Swammerdam Institute for Life Sciences, Centre for Neuroscience, University of Amsterdam, Amsterdam, The Netherlands.|Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede, The Netherlands.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Aronica
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
authors.forename: Martha
authors.initials: M
authors.lastname: Feucht
mesh_terms: D000293:Adolescent; D000328:Adult; D001921:Brain / Q000473:pathology; D001927:Brain Diseases / Q000473:pathology; D002540:Cerebral Cortex / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D004827:Epilepsy / Q000473:pathology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D054220:Malformations of Cortical Development / Q000473:pathology; D065703:Malformations of Cortical Development, Group I / Q000473:pathology*; D009186:Myelin Sheath / Q000473:pathology; D055495:Neurogenesis; D009474:Neurons / Q000378:metabolism; D009836:Oligodendroglia / Q000473:pathology / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D014402:Tuberous Sclerosis / Q000378:metabolism* / Q000473:pathology
chemical_list: C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: epilepsy; oligodendroglial hyperplasia; region of interest (ROI) based image analysis