Authors: Canevini M.P., Kotulska-Jozwiak K., Curatolo P., La Briola F., Peron A., Slowinska M., Strzelecka J., Vignoli A., Jozwiak S.

Am J Med Genet C Semin Med Genet. 2018 Sep;26. doi: 10.1002/ajmg.c.31652


Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disease affecting approximately 1 in 6,000 people, and represents one of the most common genetic causes of epilepsyEpilepsy affects 90% of the patients and appears in the first 2 years of life in the majority of them. Early onset of epilepsy in the first 12 months of life is associated with high risk of cognitive decline and neuropsychiatric problems including autism. Prenatal or early infantile diagnosis of TSC, before the onset of epilepsy, provides a unique opportunity to monitor EEG before the onset of clinical seizures, thus enabling early intervention in the process of epileptogenesis. In this review, we discuss the current status of knowledge on epileptogenesis in TSC, and present recommendations of American and European experts in the field of epilepsy.

Authors: Bongaarts A., Prabowo A.S., Arena A., Anink J.J., Reinten R.J., Jansen F.E., Spliet W.G.M., Thom M., Coras R., Blümcke I., Kotulska K., Jozwiak S., Grajkowska W., Söylemezoglu F., Pimentel J., Schouten-van Meeteren A.Y.N., Mills J.D., Iyer A.M., van Vliet E.A., Mühlebner A., Aronica E.

Oncotarget 2018 Jun 15;9(46):28103-28115. doi: 10.18632/oncotarget.25563


Glioneuronal tumours, including gangliogliomas and dysembryoplasticneuroepithelialtumours, represent the most common low-grade epilepsy-associated brain tumours and are a well-recognized cause of intractable focal epilepsy in children and young adults. Classification is predominantly based on histological features, which is difficult due to the broad histological spectrum of these tumours. The aim of the present study was to find molecular markers that can be used to identify entities within the histopathology spectrum of glioneuronal tumours. The focus of this study was on microRNAs (miRNAs). miRNAs are important post-transcriptional regulators of gene expression and are involved in the pathogenesis of different neurological diseases and oncogenesis. Using a miRNA array, miR-519d and miR-4758 were found to be upregulated in gangliogliomas (n=26) compared to control cortex (n=17), peritumoural tissue (n=7), dysembryoplasticneuroepithelialtumours (n=9) and astrocytomas (grade I-IV; subependymal giant cell astrocytomas, n=10; pilocytic astrocytoma, n=15; diffuse astrocytoma grade II, n=10; grade III, n=14 and glioblastoma n=15). Furthermore, the PI3K/AKT3/P21 pathway, which is predicated to be targeted by miR-519d and miR-4758, was deregulated in gangliogliomas. Functionally, overexpression of miR-519d in an astrocytic cell line resulted in a downregulation of CDKN1A (P21) and an increase in cell proliferation, whereas co-transfection with miR-4758 counteracted this effect. These results suggest that miR-519d and miR-4758 might work in concert as regulators of the cell cycle in low grade gliomas. Furthermore, these miRNAs could be used to distinguish gangliogliomas from dysembryoplasticneuroepithelialtumours and other low and high grade gliomas and may lead to more targeted therapy.

Authors: Baumer F.M., Peter J.M., Clancy S., Prohl A.K., Prabhu S.P., Scherrer B., Jansen F.E., Braun K.P.J., Sahin M., Stamm A., Warfield S.K.

Cereb Cortex 2018 Oct 1;28(10):3665-3672. doi: 10.1093/cercir/bhx247.


INTRODUCTIONNeurological manifestations in Tuberous Sclerosis Complex (TSC) are highly variable. Diffusion tensor imaging (DTI) may reflect the neurological disease burden. We analyzed the association of autism spectrum disorder (ASD), intellectual disability (ID) and epilepsy with callosal DTI metrics in subjects with and without TSC.


186 children underwent 3T MRI DTI: 51 with TSC (19 with concurrent ASD), 46 with non-syndromic ASD and 89 healthy controls (HC). Subgroups were based on presence of TSC, ASD, ID, and epilepsy. Density-weighted DTI metrics obtained from tractography of the corpus callosum were fitted using a 2-parameter growth model. We estimated distributions using bootstrapping and calculated half-life and asymptote of the fitted curves.


TSC was associated with a lower callosal fractional anisotropy (FA) than ASD, and ASD with a lower FA than HC. ID, epilepsy and ASD diagnosis were each associated with lower FA values, demonstrating additive effects. In TSC, the largest change in FA was related to a comorbid diagnosis of ASD. Mean diffusivity (MD) showed an inverse relationship to FA. Some subgroups were too small for reliable data fitting.


Using a cross-disorder approach, this study demonstrates cumulative abnormality of callosal whitematter diffusion with increasing neurological comorbidity.

Authors: Arena A., Zimmer T.S., van Scheppingen J., Korotkov A., Anink J.J., Mühlebner A., Jansen F.E., van Hecke W., Spliet W.G., van Rijen P.C., Vezzani A., Baayen J.C., Idema S., Iyer A.M., Perluigi M., Mills J.D., van Vliet E.A., Aronica E. 

Brain Pathol 2018 Oct 10. doi: 10.1111/bpa.12661.


Oxidative stress (OS) occurs in brains of patients with epilepsy and coincides with brain inflammation, and both phenomena contribute to seizure generation in animal models. We investigated whether expression of OS and brain inflammation markers co-occurred also in resected brain tissue of patients with epileptogeniccorticalmalformations: hemimegalencephaly (HME), focal cortical dysplasia (FCD) and cortical tubers in tuberous sclerosis complex (TSC). Moreover, we studied molecular mechanisms linking OS and inflammation in an in vitro model of neuronal function. Untangling interdependency and underlying molecular mechanisms might pose new therapeutic strategies for treating patients with drug-resistant epilepsy of differing etiologies. Immunohistochemistry was performed for specific OS markers xCT and iNOS and brain inflammation markers TLR4, COX-2 and NF-κB in cortical tissue derived from patients with HME, FCD IIa, IIb and TSC. Additionally, we studied gene expression of these markers using the human neuronal cell line SH-SY5Y in which OS was induced using H2 O2 . OS markers were increased in dysmorphic neurons, and balloon/giant cells in cortex of patients with FCD IIb or TSC. Expression of OS markers was positively correlated to expression of brain inflammation markers. In vitro, 100 μM, but not 50 μM, of H2 O2 increased expression of TLR4, IL-1β and COX-2. We found that NF-κB signaling was activated only upon stimulation with 100 μM H2 O2leading to upregulation of TLR4 signaling and IL-1β. The NF-κB inhibitor TPCA-1 completely reversed this effect. Our results show that OS positively correlates with neuroinflammation and is particularly evident in brain tissue of patients with FCD IIb and TSC. In vitro, NF-κB is involved in the switch to an inflammatory state after OS. We propose that the extent of OS can predict the neuroinflammatory state of the brain. Additionally, anti-oxidant treatments may prevent the switch to inflammation in neurons thus targeting multiple epileptogenic processes at once.

Authors: Slowinska M., Jozwiak S., Peron A., Borkowska J., Chmielewski D., Sadowski K., Jurkiewicz E., Vignoli A., La Briola F., Canevini M.P., Kotulska-Jozwiak K.

Orphanet. J. Rare Dis. 2018 Jan 29;13(1):25.


Background: Tuberous sclerosis complex (TSC) is a genetic disorder with an incidence of 1:6000 live births and associated with the development of benign tumors in several organs. It is also characterized by high rates of neurological and neuropsychiatric abnormalities, including epilepsy affecting 70-90% of patients and being one of the major risk factors of intellectual disability. The first seizures in TSC patients appear usually between the 4th and the 6th months of life. Recent studies have shown the beneficial role of preventative antiepileptic treatment in TSC patients, with the possibility for improvement of cognitive outcome. Moreover, European recommendations suggest early introduction of Vigabatrin if ictal discharges occur on EEG recordings, with or without clinical manifestation. The aim of this study was to define the most useful approach to make the diagnosis of TSC before seizure onset (before age 4th months), in order to start early EEG monitoring with possible preventative treatment intervention. 

Methods: We performed a retrospective review of children who were suspected of having TSC due to single or multiple cardiac tumors as the first sign of the disease. We analyzed the medical records in terms of conducted clinical tests and TSC signs, which were observed until the end of the 4th month of age. Subsequently, we described the different clinical scenarios and recommendations for early diagnosis. 

Results:82/100 children were diagnosed with TSC within the first 4 months of life. Apart from cardiac tumors, the most frequently observed early TSC signs were subependymal nodules (71/100, 71%), cortical dysplasia (66/100, 66%) and hypomelanotic macules (35/100, 35%). The most useful clinical studies for early TSC diagnosis were brain magnetic resonance imaging (MRI), skin examination and echocardiography. Genetic testing was performed in 49/100 of the patients, but the results were obtained within the first 4 months of life in only 3 children. 

Conclusions: Early diagnosis of TSC, before seizure onset, is feasible and it is becoming pivotal for epilepsy management and improvement of cognitive outcome. Early TSC diagnosis is mostly based on clinical signs. Brain MRI, echocardiography, skin examination and genetic testing should be performed early in every patient suspected of having TSC.