Lancet neurology
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Paediatric neurological disorders encompass a large group of clinically heterogeneous diseases, of which some are known to have a genetic cause. Over the past few years, advances in nosological classifications and in strategies for molecular testing have substantially improved the diagnosis, genetic counselling, and clinical management of many patients, and have facilitated the possibility of prenatal diagnoses for future pregnancies. However, the increasing availability of genetic tests for paediatric neurological disorders is raising important questions with regard to the appropriateness, choice of protocols, interpretation of results, and ethical and social concerns of these services. In this Review, we discuss these topics and how these concerns affect genetic counselling.
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Hereditary spastic paraplegia (HSP) describes a heterogeneous group of genetic neurodegenerative disorders in which the most severely affected neurons are those of the spinal cord. These disorders are characterised clinically by progressive spasticity and weakness of the lower limbs, and pathologically by retrograde axonal degeneration of the corticospinal tracts and posterior columns. ⋯ Here, we describe the clinical and diagnostic features of the various forms of HSP. We also discuss the genes that have been identified and the emerging pathogenic mechanisms.
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A severe form of encephalitis associated with antibodies against NR1-NR2 heteromers of the NMDA receptor was recently identified. We aimed to analyse the clinical and immunological features of patients with the disorder and examine the effects of antibodies against NMDA receptors in neuronal cultures. ⋯ A well-defined set of clinical characteristics are associated with anti-NMDA-receptor encephalitis. The pathogenesis of the disorder seems to be mediated by antibodies.
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Biography Historical Article
Profile: Richard Lipton: migraines, magnets, and much, much more.
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Despite optimum treatment with surgery, radiation therapy, and chemotherapy, most patients with malignant glioma have a poor prognosis. Malignant gliomas are vascular tumours that produce vascular endothelial growth factor (VEGF), which is an important mediator of angiogenesis. Preclinical data indicate that angiogenesis is essential for the proliferation and survival of malignant glioma cells, which suggests that inhibition of angiogenesis might be an effective therapeutic strategy. Anti-angiogenic therapies that target VEGF and the VEGF receptor (VEGFR) are effective adjuncts to the treatment of solid tumours. Normalisation of dilated and leaky tumour vasculature might also enable anti-angiogenic therapy to increase the efficacy of radiation therapy and cytotoxic chemotherapy. ⋯ Several studies have investigated the use of bevacizumab--a humanised monoclonal antibody against VEGF--for patients with recurrent malignant glioma. Treatment with bevacizumab is commonly combined with cytotoxic chemotherapy and results in dramatic responses seen on radiographs, prolongation of progression-free survival, and less need for corticosteroids. Similar results have been shown with small-molecule inhibitors of VEGFR, such as cediranib. Anti-angiogenic treatment is generally well tolerated but common adverse effects include hypertension and proteinuria, whereas the potentially more serious adverse effects, such as thromboembolic disease and haemorrhage, occur infrequently. At least half of patients fail to respond to anti-angiogenic treatment and the response duration is variable. Resistance to anti-angiogenic therapy might implicate alternative pro-angiogenic factors, such as basic fibroblast growth factor, stromal-derived factor-1alpha, the angiopoietin receptor Tie2, and placental growth factor. Anti-angiogenic therapy might also lead to mobilisation of circulating endothelial cells towards the tumour, which supports angiogenesis. Another possible mechanism of resistance of malignant glioma cells might be upregulation of pro-invasive molecules, which would result in increased infiltrative tumour growth along the blood vessels. WHERE NEXT?: Although anti-angiogenic therapies are promising, the duration of response with available regimens is modest. Continuing investigations will determine whether these drugs are best used for newly diagnosed or recurrent tumours and will establish the optimum combinations with radiation, cytotoxic chemotherapy, and other targeted molecular compounds. As yet, there are no effective treatments for patients on anti-angiogenic therapies whose tumours progress. Further understanding of the mechanisms of resistance to anti-angiogenic therapies and better selection of patients will be crucial to improve outcomes for patients with malignant glioma.