Angelika Mühlebner
University of Amsterdam
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Publication
Featured researches published by Angelika Mühlebner.
Acta Neuropathologica | 2013
Katja Kobow; Anthony Kaspi; Kn Harikrishnan; Katharina Kiese; Mark Ziemann; Ishant Khurana; Ina Fritzsche; Jan Hauke; Eric Hahnen; Roland Coras; Angelika Mühlebner; Assam El-Osta; Ingmar Blümcke
Epilepsy is a frequent neurological disorder, although onset and progression of seizures remain difficult to predict in affected patients, irrespective of their epileptogenic condition. Previous studies in animal models as well as human epileptic brain tissue revealed a remarkably diverse pattern of gene expression implicating epigenetic changes to contribute to disease progression. Here we mapped for the first time global DNA methylation patterns in chronic epileptic rats and controls. Using methyl-CpG capture associated with massive parallel sequencing (Methyl-Seq) we report the genomic methylation signature of the chronic epileptic state. We observed a predominant increase, rather than loss of DNA methylation in chronic rat epilepsy. Aberrant methylation patterns were inversely correlated with gene expression changes using mRNA sequencing from same animals and tissue specimens. Administration of a ketogenic, high-fat, low-carbohydrate diet attenuated seizure progression and ameliorated DNA methylation mediated changes in gene expression. This is the first report of unsupervised clustering of an epigenetic mark being used in epilepsy research to separate epileptic from non-epileptic animals as well as from animals receiving anti-convulsive dietary treatment. We further discuss the potential impact of epigenetic changes as a pathogenic mechanism of epileptogenesis.
Epilepsia | 2012
Roland Coras; Onno J. de Boer; Dawna L. Armstrong; Albert Becker; Ts Jacques; Hajime Miyata; Maria Thom; Harry V. Vinters; Roberto Spreafico; Buge Oz; Gianluca Marucci; José Pimentel; Angelika Mühlebner; Josef Zamecnik; Anna Maria Buccoliero; Fabio Rogerio; Nathalie Streichenberger; Nobutaka Arai; Marianna Bugiani; Silke Vogelgesang; Rob Macaulay; Carolin Salon; Volkmar Hans; Marc Polivka; Felice Giangaspero; Dyah Fauziah; Jang Hee Kim; Lei Liu; Wang Dandan; Jing Gao
Purpose: An International League Against Epilepsy (ILAE) consensus classification system for focal cortical dysplasias (FCDs) has been published in 2011 specifying clinicopathologic FCD variants. The aim of the present work was to microscopically assess interobserver agreement and intraobserver reproducibility for FCD categories among an international group of neuropathologists with different levels of experience and access to epilepsy surgery tissue.
Epilepsia | 2014
Roland Coras; Gloria Milesi; Ileana Zucca; Alfonso Mastropietro; Alessandro Scotti; Matteo Figini; Angelika Mühlebner; Andreas Hess; Wolfgang Graf; Giovanni Tringali; Ingmar Blümcke; Flavio Villani; Giuseppe Didato; Carolina Frassoni; Roberto Spreafico; Rita Garbelli
Hippocampal sclerosis (HS) is the major structural brain lesion in patients with temporal lobe epilepsy (TLE). However, its internal anatomic structure remains difficult to recognize at 1.5 or 3 Tesla (T) magnetic resonance imaging (MRI), which allows neither identification of specific pathology patterns nor their proposed value to predict postsurgical outcome, cognitive impairment, or underlying etiologies. We aimed to identify specific HS subtypes in resected surgical TLE samples on 7T MRI by juxtaposition with corresponding histologic sections.
Epilepsy Research | 2014
Angelika Mühlebner; Gudrun Gröppel; Anastasia Dressler; Edith Reiter-Fink; Gregor Kasprian; Daniela Prayer; Christian Dorfer; Thomas Czech; Johannes A. Hainfellner; Roland Coras; Ingmar Blümcke; Martha Feucht
UNLABELLED To determine long-term efficacy and safety of epilepsy surgery in children and adolescents with malformations of cortical development (MCD) and to identify differences in seizure outcome of the various MCD subgroups. Special focus was set on the newly introduced International League Against Epilepsy (ILAE) classification of focal cortical dysplasia (FCD). STUDY DESIGN This is a single center retrospective cross-sectional analysis of prospectively collected data. INCLUSION CRITERIA age at surgery <18 years, pre-surgical evaluation and epilepsy surgery performed at the Vienna pediatric epilepsy center, histologically proven MCD, complete follow-up data for at least 12 months. Clinical variables evaluated: type and localization of MCD, type of surgery and a variety of clinical characteristics reported to be associated with (un-)favorable outcomes. MCD were classified following the existing classification schemes (Barkovich et al., 2012. Brain. 135, 1348-1369; Palmini et al., 2004. Neurology. 62, S2-S8) and the ILAE classification for FCD recently proposed by Blümcke in 2011. Seizure outcome was classified using the ILAE classification proposed by Wieser in 2001. RESULTS 60 Patients (51.7% male) were included. Follow up was up to 14 (mean 4.4 ± 3.2) years. Mean age at surgery was 8.0 ± 6.0 (median 6.0) years; mean age at epilepsy onset was 2.9 ± 3.2 (median 2.0) years; duration of epilepsy before surgery was 4.8 ± 4.4 (median 3.0) years. 80% of the patients were seizure free at last follow-up. AEDs were successfully withdrawn in 56.7% of all patients. Extended surgery, lesion localization in the temporal lobes and absence of inter-ictal spikes in postsurgical EEG recordings were predictive of favorable seizure outcomes after surgery. However, no association was found between outcome and MCD sub-types. Epilepsy surgery is highly effective in carefully selected drug-resistant children with MCD. Surrogate markers for complete resection of the epileptogenic zone remain the only significant predictors for seizure freedom after surgery.
Glia | 2016
J. van Scheppingen; Anand M. Iyer; Avanita S. Prabowo; Angelika Mühlebner; Jasper J. Anink; T. Scholl; Martha Feucht; Floor E. Jansen; Wim G. M. Spliet; Pavel Krsek; Josef Zamecnik; A. M. Buccoliero; F. Giordano; L. Genitori; Katarzyna Kotulska; Sergiusz Jozwiak; J. Jaworski; E. Liszewska; E.A. van Vliet; E. Aronica
Tuberous sclerosis complex (TSC) is a genetic disease presenting with multiple neurological symptoms including epilepsy, mental retardation, and autism. Abnormal activation of various inflammatory pathways has been observed in astrocytes in brain lesions associated with TSC. Increasing evidence supports the involvement of microRNAs in the regulation of astrocyte‐mediated inflammatory response. To study the role of inflammation‐related microRNAs in TSC, we employed real‐time PCR and in situ hybridization to characterize the expression of miR21, miR146a, and miR155 in TSC lesions (cortical tubers and subependymal giant cell astrocytomas, SEGAs). We observed an increased expression of miR21, miR146a, and miR155 in TSC tubers compared with control and perituberal brain tissue. Expression was localized in dysmorphic neurons, giant cells, and reactive astrocytes and positively correlated with IL‐1β expression. In addition, cultured human astrocytes and SEGA‐derived cell cultures were used to study the regulation of the expression of these miRNAs in response to the proinflammatory cytokine IL‐1β and to evaluate the effects of overexpression or knockdown of miR21, miR146a, and miR155 on inflammatory signaling. IL‐1β stimulation of cultured glial cells strongly induced intracellular miR21, miR146a, and miR155 expression, as well as miR146a extracellular release. IL‐1β signaling was differentially modulated by overexpression of miR155 or miR146a, which resulted in pro‐ or anti‐inflammatory effects, respectively. This study provides supportive evidence that inflammation‐related microRNAs play a role in TSC. In particular, miR146a and miR155 appear to be key players in the regulation of astrocyte‐mediated inflammatory response, with miR146a as most interesting anti‐inflammatory therapeutic candidate. GLIA 2016;64:1066–1082
PLOS ONE | 2016
Angelika Mühlebner; Jackelien van Scheppingen; Hanna M. Hulshof; Theresa O. Scholl; Anand M. Iyer; Jasper J. Anink; Ans van den Ouweland; Mark Nellist; Floor E. Jansen; Wim G. M. Spliet; Pavel Krsek; Barbora Benova; Josef Zamecnik; Peter B. Crino; Daniela Prayer; Thomas Czech; Adelheid Wöhrer; Jasmin Rahimi; Romana Höftberger; Johannes A. Hainfellner; Martha Feucht; Eleonora Aronica
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.
Brain Pathology | 2017
Johannes Schurr; Roland Coras; Karl Rössler; Tom Pieper; Manfred Kudernatsch; Hans Holthausen; Peter A. Winkler; Friedrich G. Woermann; Christian G. Bien; Tilman Polster; Reinhard Schulz; Thilo Kalbhenn; Horst Urbach; Albert Becker; Thomas Grunwald; Hans-Juergen Huppertz; Antonio Gil-Nagel; Rafael Toledano; Martha Feucht; Angelika Mühlebner; Thomas Czech; Ingmar Blümcke
The histopathological spectrum of human epileptogenic brain lesions is widespread including common and rare variants of cortical malformations. However, 2–26% of epilepsy surgery specimens are histopathologically classified as nonlesional. We hypothesized that these specimens include also new diagnostic entities, in particular when presurgical magnetic resonance imaging (MRI) can identify abnormal signal intensities within the anatomical region of seizure onset. In our series of 1381 en bloc resected epilepsy surgery brain specimens, 52 cases could not be histopathologically classified and were considered nonlesional (3.7%). An increase of Olig2‐, and PDGFR‐alpha‐immunoreactive oligodendroglia was observed in white matter and deep cortical layers in 22 of these patients (42%). Increased proliferation activity as well as heterotopic neurons in white matter were additional histopathological hallmarks. All patients suffered from frontal lobe epilepsy (FLE) with a median age of epilepsy onset at 4 years and 16 years at epilepsy surgery. Presurgical MRI suggested focal cortical dysplasia (FCD) in all patients. We suggest to classify this characteristic histopathology pattern as “mild malformation of cortical development with oligodendroglial hyperplasia (MOGHE).” Further insights into pathomechanisms of MOGHE may help to bridge the diagnostic gap in children and young adults with difficult‐to‐treat FLE.
Brain Pathology | 2017
Theresa Scholl; Angelika Mühlebner; Gerda Ricken; Victoria Gruber; Anna Fabing; Sharon Samueli; Gudrun Gröppel; Christian Dorfer; Thomas Czech; Johannes A. Hainfellner; Avanita S. Prabowo; Roy J. Reinten; Lisette Hoogendijk; Jasper J. Anink; Eleonora Aronica; Martha Feucht
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.
Neurobiology of Disease | 2016
Gabriele Ruffolo; Anand M. Iyer; Pierangelo Cifelli; Cristina Roseti; Angelika Mühlebner; Jackelien van Scheppingen; Theresa O. Scholl; Johannes A. Hainfellner; Martha Feucht; Pavel Krsek; Josef Zamecnik; Floor E. Jansen; Wim G. M. Spliet; Cristina Limatola; Eleonora Aronica; Eleonora Palma
Tuberous sclerosis complex (TSC) is a rare multi-system genetic disease characterized by several neurological disorders, the most common of which is the refractory epilepsy caused by highly epileptogenic cortical lesions. Previous studies suggest an alteration of GABAergic and glutamatergic transmission in TSC brain indicating an unbalance of excitation/inhibition that can explain, at least in part, the high incidence of epilepsy in these patients. Here we investigate whether TSC cortical tissues could retain GABAA and AMPA receptors at early stages of human brain development thus contributing to the generation and recurrence of seizures. Given the limited availability of pediatric human brain specimens, we used the microtransplantation method of injecting Xenopus oocytes with membranes from TSC cortical tubers and control brain tissues. Moreover, qPCR was performed to investigate the expression of GABAA and AMPA receptor subunits (GABAA α1-5, β3, γ2, δ; GluA1, GluA2) and cation chloride co-transporters NKCC1 and KCC2. The evaluation of nine human cortical brain samples, from 15 gestation weeks to 15years old, showed a progressive shift towards more hyperpolarized GABAA reversal potential (EGABA). This shift was associated with a differential expression of the chloride cotransporters NKCC1 and KCC2. Furthermore, the GluA1/GluA2 mRNA ratio of expression paralleled the development process. On the contrary, in oocytes micro-transplanted with epileptic TSC tuber tissue from seven patients, neither the GABAA reversal potential nor the GluA1/GluA2 expression showed similar developmental changes. Our data indicate for the first time, that in the same cohort of TSC patients, the pattern of both GABAAR and GluA1/GluA2 functions retains features that are typical of an immature brain. These observations support the potential contribution of altered receptor function to the epileptic disorder of TSC and may suggest novel therapeutic approaches. Furthermore, our findings strengthen the novel hypothesis that other developmental brain diseases can share the same hallmarks of immaturity leading to intractable seizures.
Epilepsy Research | 2015
Anastasia Dressler; Petra Trimmel-Schwahofer; Eva Reithofer; Gudrun Gröppel; Angelika Mühlebner; Sharon Samueli; Viktoria Grabner; Klaus Abraham; Franz Benninger; Martha Feucht
OBJECTIVE To evaluate the efficacy and safety of the ketogenic diet (KD) in infants (< 1.5 years of age) compared with older children. METHODS Patients with complete follow-up data of ≥ 3 months after initiation of the KD were analyzed retrospectively. Infants < 1.5 years at initiation of the KD (Group A) were compared with children > 1.5 years (Group B). RESULTS 127 children were screened, 115 (Group A: 58/Group B: 57) were included. There were no significant differences between groups with respect to responder rates (63.8% vs. 57.9% at 3 months), but more infants became seizure free (34.5% vs. 19% at 3 months; 32.7% vs. 17.5% at 6 and 12 months). This result remained stable also after termination of the KD (30.6% vs. 3.9% at last follow-up) (p = 0.000). Looking at infants < 9 months of age separately (n = 42), this result was even stronger with significantly more infants being seizure free at 6 and at 12 months (p = 0.005, p = 0.014, respectively). In addition, a significantly higher number of infants remained seizure free in the long-term (p = 0.001). No group differences between infants and children with respect to safety were observed. Overall 52/115 patients (45.21%) reported side effects, but withdrawal of the KD was only necessary in one infant. Acceptance of the KD was better in infants compared with children at 3 months (0 vs. 14, p = 0.000), but became difficult when solid food was introduced (16 vs. 14; n.s.). SIGNIFICANCE According to our results, the KD is highly effective and well tolerated in infants with epilepsy. Seizure freedom is more often achieved and maintained in infants. Acceptance of the diet is better before the introduction of solid food. Therefore, we recommend the early use of the KD during the course of epilepsy.