Medicine (RMH) - Theses

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Author: Neal, Andrew × Subject: IDH1 × Subject: epilepsy ×

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    Clinical and molecular factors associated with post-operative glioma associated epilepsy
    Neal, Andrew ( 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.