Medicine (RMH) - Theses
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ItemRadiological and molecular factors associated with seizures in patients with supratentorial gliomas( 2013)Tumour associated epilepsy (TAE) is a common and disabling symptom experienced by patients with supratentorial gliomas. The pathogenesis of TAE is likely to involve a complex interplay between macroscopic anatomical factors, molecular factors and individual patient factors. The overarching hypothesis of this thesis is that patients with TAE have tumours with different radiological, molecular and genetic features compared to those without TAE. Furthermore, identification of these features may allow the identification of patients who are at increased risk of the development of TAE, and provide tailored, individualized treatment of these patients. An improved understanding of the genetic and molecular features associated with TAE may also inform the development of novel therapeutic strategies for these patients. There is an increasing body of evidence implicating glutamate, the most abundant neurotransmitter in the mammalian central nervous system, in the pathogenesis of TAE. Magnetic resonance spectroscopy (MRS) provides a non-invasive method to quantify brain metabolites in-vivo, but has not yet been validated for glutamate. In this thesis we firstly demonstrate that MRS quantification of glutamate has a modest, but statistically significant, correlation with concentrations of glutamate measured from tumour biopsy specimens. We then demonstrate that these MRS measurements of glutamate are useful in predicting not only glioma grade, but also the incidence of TAE. We also demonstrate that patients with low-grade gliomas and TAE are more likely to have larger tumours than patients without TAE. The opposite is found in patients with high-grade gliomas and TAE. There is also evidence that common pathological processes, including glutamate excitotoxicity, may be involved in TAE and neurodegenerative conditions such as Alzheimer’s disease, the sequelae of traumatic head injury and idiopathic epilepsy. A number of molecular factors associated with neurodegeneration and excitotoxicity are therefore investigated for their association with TAE. Phosphorylation of tau was found to be lower in patients with TAE compared to those without TAE. Over-expression of glycogen synthase kinase (GSK3β) was found to correlate with TAE, as was loss of glutamic acid decarboxylase 67 (GAD67), potentially reflecting a selective loss of inhibitory interneurons. Finally, the expression of the IDH1-R132H mutation, the most common mutation in low-grade gliomas, is shown to correlate with TAE. In conclusion, TAE results from a complex interaction of patient, environmental and tumour factors, including glutamate excitotoxicity, selective loss of inhibitory interneurons and IDH1-R132H expression. Not only do the results presented in this thesis suggest that TAE differs from other epileptic syndromes, but also that the mechanisms may differ between low and high-grade gliomas. Collaboration between neurosurgeons, neurologists, radiologists, pathologists and basic scientists will be essential for further investigation of this debilitating disease.
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ItemNeurobiological factors predisposing to tumour associated seizures( 2010)Tumour associated seizures (TAS) are a common, disabling co-morbidity of gliomas. The pathogenesis of TAS and its associated implications for survival remain poorly understood. Elevations in glutamate levels, due to alterations in expression of membrane transporters, have been reported in gliomas in vitro. As glutamate is highly epileptogenic and cytotoxic we examined whether elevations of glutamate levels and alterations in transporters were specifically associated with TAS and survival. Our comprehensive study of two large cohorts of patients (290 in total) is the first human evidence showing associations between preoperative seizure risk and clinicopathological and molecular factors in patients with glioma. We found the clinicopathological factors that were independent predictors for preoperative TAS to be earlier age at diagnosis, temporal lobe location of tumour and tumour types of anaplastic astrocytoma or those with oligodendroglial components. A strong predictor for postoperative TAS was preoperative TAS adding credence to the philosophy “seizures beget seizures”. We found of the molecular factors, raised glutamate levels in tumour and peritumoural tissue as well as altered expression of astrocytic glutamate transporters EAAT2 and xCT all to be significantly associated with preoperative TAS. We also found neuronal HCN channelopathies, particularly downregulation of peritumoural HCN2 expression, to be associated with seizures due to glioma. This is further support for the concept of peritumoural tissue holding the key to TAS pathogenesis and we suggest it should be a subject for further investigation. These findings strongly support the “glutamate hypothesis” which proposes that glioma, due to dysfunction of the glial glutamate transporters among other factors, produces abnormally high levels of glutamate which then leads to excitotoxic changes in surrounding neuronal networks that ultimately manifest as seizures. Looking for further insights into the prognosis of glioma, we have also assessed the effects of preoperative seizures and raised glutamate levels on survival. This has suggested a positive influence. Postoperative seizures on the other hand, were associated with worse survival. Through a pilot study, we also explored the feasibility of using MRS for glutamate as a non invasive clinical diagnostic and monitoring tool in the management of TAS. We did not find any statistical significance of spectroscopically derived glutamate levels with TAS but the study did highlight some improvements in design required for a larger validation study in the future. This is still a promising prospect and could lead the way in the non invasive workup of people with TAS. The importance of the study of epilepsy and tumours hinges on the therapeutic and diagnostic contributions that are possible. Understanding the underlying mechanism of TAS, particularly the significance of the peritumoural tissue in this process, could revolutionize current drug treatments as well as redefine surgical objectives for the patient with TAS.