Medicine (RMH) - Theses
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ItemClinical and molecular factors associated with post-operative glioma associated epilepsy( 2018)Post-operative seizures are common in patients with supratentorial diffuse gliomas. Pharmacoresistant seizures occur in up to one third of patients in the post-operative period and for many patients, particularly those with lower grade tumours, seizures are a major determinant of quality of life. More effective anti-epileptic treatments are needed in this patient group. To help achieve this goal, a better understanding of the clinical and molecular factors associated with post-operative glioma associated seizures is required. The intention of this thesis was to help move the tumour associated epilepsy field closer towards an era of individualised, directed pharmacotherapy for glioma associated epilepsy. This thesis has three components i) retrospective analyses of the clinical and molecular factors associated with post-operative seizures, ii) a prospective study examining glutamate quantification in gliomas with 7T MRI and iii) the design and initiation of two pilot randomized controlled trials examining the role of perampanel, a glutamate receptor antagonist, in the prevention and control of post-operative seizures in grade II-III diffuse gliomas. A retrospective database of 216 patients with supratentorial diffuse gliomas was developed and post-operative seizure outcome were examined in detail. The major findings from the retrospective studies were that: i) distinct patterns of seizure outcome can be defined in the post-operative period, with a fluctuating pattern being the most common amongst those with glioma associated epilepsy. This relapsing-remitting outcome was associated with grade II-III gliomas, pre-operative seizure and histological progression; ii) treatment response to anti-epileptic medications in glioma associated epilepsy is poorer than the historical non-tumour epilepsy population; iii) increased glutamate concentration in peritumoural tissue is associated with post-operative seizures; iv) IDH1-R132H mutations in supratentorial gliomas are associated with poorer post-operative seizure outcome and v) glutamate concentration is not associated with IDH1 or IDH2 mutated gliomas. Twelve patients with a radiological or histological diagnosis of supratentorial glioma were imaged with a novel 7 Tesla magnetic resonance glutamate imaging protocol, encompassing GluCEST and magnetic resonance spectroscopy (MRS) sequences. Increased tumour GluCEST signal was associated with features of more aggressive diffuse gliomas, increased peritumoural GluCEST correlated with tumour associated seizures and three unique GluCEST contrast patterns, with distinct clinical and radiological features were defined. Finally, two concurrent phase II multi-centre randomised controlled trials which will examine the role of perampanel in the prevention and control of glioma associated seizures were designed and initiated. All participants will receive pre-operative 7T GluCEST and MRS imaging in addition to tissue analysis for glutamate concentrations. These trials build on findings from the retrospective and prospective studies of this thesis and aim to interrogate a core hypothesis generated from this thesis: Can tissue and imaging glutamate biomarkers select patients for individualised anti-epileptic, anti-epileptogenic and even anti-tumour therapies that target the glutamate pathway.
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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.