Medicine (RMH) - Theses
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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.