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Cited by 88Tuberous Sclerosis Complex ResearchEpilepsy research and treatmentGenetic and rare skin diseases.

Novel Histopathological Patterns in Cortical Tubers of Epilepsy Surgery Patients with Tuberous Sclerosis Complex

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Mühlebner, Angelika, van Scheppingen, Jackelien, Hulshof, Hanna M., Scholl, Theresa, Iyer, Anand M., Anink, Jasper J., van den Ouweland, Ans M. W., Nellist, Mark D. +14 more·2016·PLOS ONE
DOI 10.1371/journal.pone.0157396PMC PMC4905625
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Abstract

Tuberous Sclerosis Complex (TSC) is a genetic hamartoma syndrome frequently associated with severe intractable epilepsy. In some TSC patients epilepsy surgery is a promising treatment option provided that the epileptogenic zone can be precisely delineated. TSC brain lesions (cortical tubers) contain dysmorphic neurons, brightly eosinophilic giant cells and white matter alterations in various proportions. However, a histological classification system has not been established for tubers. Therefore, the aim of this study was to define distinct histological patterns within tubers based on semi-automated histological quantification and to find clinically significant correlations. In total, we studied 28 cortical tubers and seven samples of perituberal cortex from 28 TSC patients who had undergone epilepsy surgery. We assessed mammalian target of rapamycin complex 1 (mTORC1) activation, the numbers of giant cells, dysmorphic neurons, neurons, and oligodendrocytes, and calcification, gliosis, angiogenesis, inflammation, and myelin content. Three distinct histological profiles emerged based on the proportion of calcifications, dysmorphic neurons and giant cells designated types A, B, and C. In the latter two types we were able to subsequently associate them with specific features on presurgical MRI. Therefore, these histopathological patterns provide consistent criteria for improved definition of the clinico-pathological features of cortical tubers identified by MRI and provide a basis for further exploration of the functional and molecular features of cortical tubers in TSC.

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  • Tubers contain heterogeneous populations of dysmorphic neurons, dysplastic and gliotic astrocytes, activated microglia and giant or balloon cells within a background of normal-appearing cells.

    “On a cellular level, tubers contain heterogeneous populations of dysmorphic neurons, dysplastic and gliotic astrocytes, activated microglia and giant or balloon cells within a background of normal-appearing cells7,8,9.”

    From mTORC1 drives cell-autonomous astrocyte reactivity in tuberous sclerosis (2026) · cites this paper as [9]

    The Introduction and Results (Patterns of cortical tubers; Inflammation and small vessel density; mTORC1 activation, neuronal quantity and gliosis; pages unavailable) support dysmorphic neurons, giant cells, microglial activation and gliosis in tubers. They do not establish dysplastic astrocytes, balloon cells as a distinct category, or normal-appearing cells within tubers; the histologically normal cortex examined was perituberal. (LLM, conf=0.86)

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References 40 · Cited by 88

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Authors
Mühlebner, A., van Scheppingen, J., Hulshof, H. M., Scholl, T., Iyer, A. M., Anink, J. J., van den Ouweland, A. M. W., Nellist, M. D., Jansen, F. E., Spliet, W. G. M., Krsek, P., Benova, B., Zamecnik, J., Crino, P. B., Prayer, D., Czech, T., Wöhrer, A., Rahimi, J., Höftberger, R., Hainfellner, J. A., Feucht, M., & Aronica, E.
Affiliations
  • Amsterdam UMC Location University of Amsterdam (NL)
  • University Medical Center Utrecht (NL)
  • Medical University of Vienna (AT)
  • Erasmus MC (NL)
  • Temple University (US)
Corresponding author
Aronica, Eleonora
ORCID
Venue
PLOS ONE
Publisher
Public Library of Science (PLoS)
Published
2016-06-13
Volume
11
Issue
6
Pages
e0157396
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0157396
PMC
PMC4905625
OpenAlex
W2438878101
Cited by
88
References
40
Citations by year
2026: 4 · 2025: 11 · 2024: 6 · 2023: 9 · 2022: 8 · 2021: 13 · 2020: 8 · 2019: 10 · 2018: 8 · 2017: 8 · 2016: 3
FWCI
7.78
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, public-domain)
  • PubMed Central (publishedVersion, public-domain)
  • PubMed (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
  • UvA-DARE (University of Amsterdam) (submittedVersion, public-domain)
  • Pure Amsterdam UMC (submittedVersion, other-oa)
  • RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
  • Figshare (submittedVersion, cc-by)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
Funders
  • Seventh Framework Programme (602391)
  • Austrian Science Fund (J3499)
  • Ministerstvo Zdravotnictví Ceské Republiky (IGA NT/11443-5, 00064203)
Topics
  • Health Sciences › Medicine › Physiology › Tuberous Sclerosis Complex Research
  • Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and rare skin diseases.
Keywords
tuberous sclerosis complex, cortical tubers, epilepsy surgery, histological classification, dysmorphic neurons, giant cells, calcification, mTORC1 activation, epileptogenic zone, oligodendrocytes, gliosis, angiogenesis, inflammation, myelin
MeSH terms
Mechanistic Target of Rapamycin Complex 1, Adolescent, Adult, Cerebral Cortex, Child, Child, Preschool, Epilepsy, Female, Gliosis, Humans, Male, Middle Aged, Myelin Sheath, Neurons, Tuberous Sclerosis, Multiprotein Complexes, Young Adult, TOR Serine-Threonine Kinases

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