Medicine (RMH) - Theses
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ItemGlutamate as a biomarker of post-stroke epilepsy( 2021)Stroke is one of the most important causes of acquired epilepsy in adults. Patients with seizures after stroke have higher mortality and disability than those without seizures. There is a building body of evidence to suggest that post-stroke epilepsy may be mediated by dysregulation of glutamate homeostasis, given the central role of glutamate in the pathogenesis of both stroke and seizures. There is currently no evidence to support the use of antiseizure medications as primary prevention of epilepsy in stroke patients. Ideally, anti-epileptogenic treatment would be targeted at those stroke patients at highest risk of epilepsy according to established biomarkers – studying glutamate as one such biomarker has been limited by a reliance on invasive procedures including lumbar puncture to quantify concentrations of glutamate in the brain. This thesis focuses on the role of 7T MRI as a method of brain glutamate quantification in the setting of stroke. The research has been conducted in the Department of Neurology, Royal Melbourne Hospital, the Department of Medicine (The Royal Melbourne Hospital), University of Melbourne, and the Melbourne Node of the National Imaging Facility, Department of Radiology, University of Melbourne. 22 patients with acute ischaemic or haemorrhagic stroke were recruited from the inpatient stroke unit at Royal Melbourne Hospital, with 7T MRI scans performed at the Melbourne Brain Centre Imaging Unit, University of Melbourne. In addition, peripheral blood samples were collected and underwent metabolomics analysis for plasma glutamate quantification at the Monash Institute of Pharmaceutical Sciences, Parkville. Across the patient cohort, glutamate concentration was lower in the region of infarction than in the corresponding hemisphere, when measured by Magnetic Resonance Spectroscopy. When measured by glutamate weighted chemical exchange saturation transfer imaging (GluCEST), the results were more heterogeneous, ranging from decreased to increased, ipsilateral to infarction. One patient in the cohort developed post-stroke epilepsy, with a GluCEST profile similar to the population overall. A single haemorrhagic stroke patient suffered a seizure prior to scan acquisition, with a pattern of increased cortical GluCEST contrast consistent with a post-seizure effect. The second part of the thesis focuses on a study protocol examining the anti-epileptogenic potential of the glutamate receptor antagonist and antiseizure medication perampanel in a population at high risk of post-stroke epilepsy. This involves a collaboration of clinicians at four Melbourne Hospitals (Alfred Hospital, Royal Melbourne Hospital, Monash Medical Centre, Austin Hospital), led by the candidate. Finally, there is evidence that patients with epilepsy have an increased risk of developing cerebrovascular or cardiovascular disease, although it is unclear whether this is due primarily to the epilepsy itself, or non-epilepsy factors such as antiseizure medications. The third part of the thesis comprises a data linkage study in the Department of Neurology, Royal Melbourne Hospital, based on medical records from a database of admitted video EEG monitoring patients from 1995 to 2015. It was found that the incidence of new-onset cerebrovascular disease was higher in epilepsy patients compared with the general Victorian population, although there was no difference in the composite incidence of cerebrovascular disease, cardiovascular disease and peripheral vascular between epilepsy and non-epilepsy patients in the cohort. Furthermore, patients taking treatment with valproic acid were at lower risk than both those taking enzyme-inducing antiseizure medications and those taking neither valproic acid nor enzyme-inducing antiseizure medications. Collectively, these results emphasise the role of non-epilepsy factors such as social determinants of health, medical comorbidity, and epilepsy treatment, in influencing vascular risk.
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ItemMultimodal Ultra-High-Field MRI Biomarkers of Epilepsy( 2020)The Default Mode Network (DMN), whose major hub is the PCC/precuneus, is one of the key resting-state networks in the brain. Many research groups have investigated its role in a range of neurological and psychiatric conditions. In particular, resting-state fMRI has demonstrated DMN alterations in various forms of epilepsy. However, most of these studies recruited patients with either focal or generalised epilepsy, and few comparisons were made between the fMRI characteristics of these conditions. Magnetic resonance spectroscopy (MRS) was employed in several studies of patients with epilepsy. The concentrations of metabolites such as glutamate and gamma-amino butyric acid (GABA), the major excitatory and inhibitory neurotransmitters in the CNS, and glutathione, the major free radical scavenging compound in the brain, could not be accurately determined in magnetic fields up to 4T due to overlapping resonances from other molecules using conventional vendor supplied sequences. The advent of 7T MRI may help improve quantification of these metabolites. In this study we developed a multimodal protocol consisting of resting-state fMRI and MRS of a cubic 8 mL voxel located in the PCC/precuneus using the stimulated echo acquisition mode (STEAM) sequence with ultrashort TE at 7T. Resting-state fMRI was acquired from 12 right-handed healthy volunteers, and reproducibility of quantitative MRS of glutamate, glutathione and GABA was assessed in 10 of these volunteers. We later recruited 35 right-handed patients with epilepsy (19 with temporal lobe epilepsy and 16 with idiopathic generalised epilepsy) who underwent 7T MRI scans using a protocol comprising resting-state fMRI and a single MRS sequence identical to the ones used in the healthy controls. We discovered a linear correlation between the ratio of glutamate to GABA concentration in the PCC/precuneus of healthy controls and a similar linear correlation with age of the functional connectivity of the PCC/precuneus to other major DMN hubs. However, no independent correlation was seen between PCC/precuneus functional connectivity and glutamate, GABA, or the ratio of their concentrations, thus lending further support to the use of both MRS and fMRI as complementary methods in a multimodal pipeline exploring the effects of epilepsy in the patient groups. Analysis of MRS results demonstrated an overall increased concentration of glutathione in patients with idiopathic generalised epilepsy as compared to healthy controls. Analysis of fMRI data led to the identification of several cortical clusters, whose functional connectivity, and in some cases also pattern of activation, is different between patients with idiopathic generalised epilepsy and temporal lobe epilepsy. Subgroup analysis related to seizure focus laterality and short-term seizure-freedom was also performed. No significant correlation was found between the glutamate/GABA ratio or the mean functional connectivity of the PCC/precuneus with age or duration of epilepsy in the patient groups. In conclusion, multimodal MRI sequences have demonstrated distinct patterns of resting-state connectivity and metabolic profiles that are different between patients and controls and between patient subgroups. If corroborated in larger cohorts, such findings may be useful in the diagnosis and management of patients with epilepsy, and especially in expediting the diagnosis of the important subgroup of patients with drug-resistant epilepsy.