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 epileptogenic cortical malformations: 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 different 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 H2O2. OS markers were higher 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 H2O2 increased expression of TLR4, IL-1β and COX-2. We found that NF-κB signaling was activated only upon stimulation with 100 µM H2O2 leading 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, antioxidant treatments may prevent the switch to inflammation in neurons thus targeting multiple epileptogenic processes at once.

/pdf/oxidative-stress-and-inflammation-in-a-spectrum-of-2npbvgo9ym.pdf

Oxidative stress and inflammation in a spectrum of epileptogenic cortical malformations: molecular insights into their interdependence.

Tuberous sclerosis complex (TSC) is an autosomal dominant syndrome that presents with diverse and complex clinical features and involves multiple human systems. TSC-related neurological abnormalities and organ dysfunction greatly affect the quality of life and can even result in death in patients with TSC. It is widely accepted that most TSC-related clinical manifestations are associated with hyperactivation of the mammalian target of rapamycin (mTOR) pathway caused by loss‑of‑function mutations in TSC1 or TSC2. Remarkable progress in basic and translational research has led to encouraging clinical advances. Although mTOR inhibitors (rapamycin/everolimus) demonstrate great potential in TSC management, two major concerns hamper their generalized application. One is the frequent manifestation of adverse events, such as stomatitis, infections, and menstrual disorders; and the other is the poor response in certain patients. Thus, indicators are required to effectively predict the efficacy of mTOR inhibitors. Herein, we have summarized the current utilization of mTOR inhibitors in the treatment of TSC and focused on their efficacy and safety, in an attempt to provide a reference to guide the treatment of TSC. 

/pdf/perfect-match-mtor-inhibitors-and-tuberous-sclerosis-complex-1o79301p.pdf

Perfect match: mTOR inhibitors and tuberous sclerosis complex

Cystic lung disease (CLD) is a group of lung disorders characterized by the presence of multiple cysts, defined as air-filled lucencies or low-attenuating areas, bordered by a thin wall (usually < 2 mm). The recognition of CLDs has increased with the widespread use of computed tomography. This article addresses the mechanisms of cyst formation and the diagnostic approaches to CLDs. A number of assessment methods that can be used to confirm CLDs are discussed, including high-resolution computed tomography, pathologic approaches, and genetic/ serologic markers, together with treatment modalities, including new therapeutic drugs currently being evaluated. The CLDs covered by this review are lymphangioleiomyomatosis, pulmonary Langerhans cell histiocytosis, Birt-Hogg-Dube syndrome, lymphocytic interstitial pneumonia/follicular bronchiolitis, and amyloidosis.

/pdf/diagnosis-and-treatment-of-cystic-lung-disease-40eo81xllh.pdf

Diagnosis and treatment of cystic lung disease

Tuberous sclerosis complex

Development of the cornea, lens, ciliary body and iris within the anterior segment of the eye involves coordinated interaction between cells originating from the ciliary margin of the optic cup, th ...

/pdf/a-novel-mouse-model-of-anterior-segment-dysgenesis-asd-44p6jily9m.pdf

A novel mouse model of anterior segment dysgenesis (ASD): conditional deletion of Tsc1 disrupts ciliary body and iris development.

Tuberous sclerosis complex (TSC) is a rare genetic multisystem disorder, characterized by predominantly benign tumors in potentially all organ systems. System involvement, severity of clinical symptoms and the response to treatment are age-dependent and heterogeneous. Consequently, the disorder is still not recognized in a considerable number of patients. The diagnostic criteria and the guidelines for surveillance and management of patients with TSC were revised, and the establishment of specialized TSC-centers was strongly recommended during an International Consensus Conference in 2012. TOSCA (TuberOus SClerosis registry to increase disease Awareness), an international patient registry, was started to allow new insights into the causes of different courses. Finally, there are—since the approval of the mTOR inhibitor Everolimus—promising new therapeutic approaches. This review focuses on the various TSC related symptoms occurring at different ages, the novel recommendations for diagnosis and treatment as well as the need for multidisciplinary follow-up.

Tuberous Sclerosis Complex: new criteria for diagnostic work-up and management

OBJECTIVES: In the course of a tumor in the area of the optic chiasm the optochiasmal system is often exposed to compressive and vascular irritations. This study deals with the functional results (visual acuity and visual field) before and after surgery based on the primary situation and morphology of the tumor in order to give a prognosis on this matter. METHODS: 62 patients (41 female, 21 male) suffering from tumors in the area of the optic chiasm were retrospectively reviewed. The duration of the follow-up was an average of 25.82 months, +/- 20.04. Among the tumors investigated there were 36 pituitary adenomas, 20 meningiomas, 4 craniopharyngiomas, one histiozytosis X and one gangliozytoma. For visual field examination the Humphrey Field Analyzer, program 30-2, was used. 34 tumors (54.8%) were excised by the transsphenoidal approach, 28 patients (45.2%) underwent transcranial surgery. RESULTS: As for visual acuity, of the 124 eyes 53 eyes (42.8%) improved after surgery, 64 eyes (51.6%) remained unchanged, 7 eyes (5.6%) deteriorated. Of the patients who underwent transsphenoidal surgery, 28 eyes (41.2%) improved after operation, 36 eyes (52.9%) remained unchanged, and 4 eyes (5.9%) worsened. In case of transcranial surgery, 25 eyes (44.6%) improved, 28 eyes (50.0%) remained unchanged, whereas 3 eyes (5.4%) worsened. There was a postoperative improvement in 53.2% of the visual fields, 37.1% remained unchanged, whereas 9.7% deteriorated. CONCLUSION: Both the transsphenoidal and transcranial approaches showed excellent visual outcome. Our experience indicates an excellent prognosis for improvement of visual acuity and visual fields provided an adequate procedure. Results depend, however, on the primary functional and morphological situation. In the case of a large supra-/parasellar tumor component a postoperative deterioration of vision may occur.

Functional assessment before and after interventions on the optic chiasm system

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Tuberous Sclerosis Complex: new criteria for diagnostic work-up and management

Functional assessment before and after interventions on the optic chiasm system