Simister, RJ; (2012) Magnetic Resonance Spectroscopy as applied to epilepsy. Doctoral thesis , UCL (University College London).

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Abstract

Epilepsy is the most common serious disease of the brain. Magnetic Resonance Spectroscopy (MRS) is a novel imaging technique that offers the opportunity for co-localising biochemical information relating to metabolites specific to the study of epilepsy with high resolution MRI. Aims: The work included in this thesis was undertaken with two fundamental aims. The first was to apply a standardised MRS methodology in order to gain reproducible semi-quantitative information about the variation of relevant neuro-metabolites such as gamma amino butyric acid (GABA), glutamate (as glutamate plus glutamine [GLX]), N acetyl aspartate (NAA), myo-inositol (Ins) and creatine plus phosphocreatine (Cr) within epilepsy syndromes or pathological groups. The second main aim was to test a series of hypotheses relating to the regulation of the concentrations of these metabolites in the region of epileptic seizures, immediately following seizures and associated with particular medical and surgical treatment interventions. Methods: Seven experiments were performed in this thesis. In all seven studies the findings in the patient groups were compared against results from an acquired control group made up of healthy volunteers. In the first experiment [3.1] twenty patients with temporal lobe epilepsy, with (10), and without hippocampal sclerosis were studied using multi voxel magnetic resonance spectroscopic imaging (MRSI) sequences in order to examine for differences in the obtained metabolites N acetyl aspartate (NAA), creatine plus phosphocreatine (Cr), choline containing compounds (Cho), GLX and myo-inositol (Ins) across the pathological groups and against a control population. In experiments [3.2], [3.3], [3.4] and [3.6] an MRS protocol that incorporated a double quantum filter acquisition sequence was applied in order to allow measurement of GABA+ (a combined measure of GABA plus homocarnosine) in addition to measurement of the metabolites examined in [3.1]. Studies were performed in the occipital lobes in patients with idiopathic generalised epilepsy (IGE) (n =10) or occipital lobe epilepsy (n = 10) [3.2], in the frontal lobes in patients with IGE (n = 21) and within regions of the MRI visible pathology in patients with large focal malformations of cortical development (MCD, n =10) [3.4]. In the last experiment using this technique patients with hippocampal sclerosis and temporal lobe epilepsy (n = 16) were studied in the ipsilateral and also in the contralateral temporal lobes and following temporal lobe surgery (n = 10) [3.6]. In experiment [3.5] ten patients were examined whilst taking and when not taking sodium valproate in order to further examine for an effect of this medication on the measured metabolite concentrations. In experiment [3.7] ten patients were studied immediately after an epileptic seizure and then again during a subsequent inter-ictal period in order to examine for an influence of the recent seizure on the measured concentrations of the main metabolites. Results: MRSI in the temporal lobes in patients with temporal lobe epilepsy identified low NAA in the anterior hippocampus that was most severe in those patients with hippocampal sclerosis. GLX elevation was a feature in the patients without hippocampal sclerosis. Metabolic abnormality was most marked in the anterior compared to the posterior hippocampal regions. GABA+ levels were elevated in patients with MCD and in the ipsilateral temporal lobe in temporal lobe epilepsy associated with hippocampal sclerosis but levels were not altered in patients with IGE or OLE. GLX was also elevated in MCD in the region of MRI visible abnormality and in IGE patients when measured in the frontal lobes. Low NAA was a feature of TLE and MCD. Patients with IGE showed normal NAA levels in the occipital lobes but reduced frontal lobe concentrations. Cr concentrations were abnormal in the immediate post ictal period but normalised within 120 minutes. NAA was not altered and no significant change in lactate concentrations was observed. Finally sodium valproate treatment was associated with a reduction in the levels of Ins and with unchanged NAA and GLX levels. Main Conclusions: MRS techniques demonstrate metabolite abnormalities in epileptic patients. NAA is the most sensitive metabolite marker of chronic pathology but levels are insensitive to recent seizure history. These findings repeat earlier observations of the usefulness of NAA measurement in the assessment of chronic epilepsy whilst illustrating ongoing uncertainty as to the correct patho-physiological interpretation of reduced NAA levels. Measurable changes in the combined Cr signal are detectable whilst elevated lactate is not reliably observed following brief epileptic seizures at 1.5T. This finding indicates a potential role for MRS in functional activation studies. Malformations of cortical development have abnormal levels of both GABA+ and GLX and MCD sub-types may well demonstrate different metabolite profiles. This finding suggests that MRS could be a useful tool in the MRI classification of MCD and in the pre-surgical assessment of patients with focal malformations. Following successful temporal lobe surgery levels of NAA remain unchanged but NAA/Cr levels appear to normalise in the contralateral temporal lobe. NAA and GLX/NAA levels were altered in the frontal lobes but not in the occipital lobes in Idiopathic Generalised Epilepsy. This finding provides imaging support for frontal lobe dysfunction as a cause or consequence of IGE. Metabolite levels are affected by administered antiepileptic drugs. Sodium valproate reduces the levels of MRS visible Ins levels whilst topiramate and gabapentin appear to be associated with higher GABA+ levels. These findings may be of major importance in the assessment of treatment effect or in the investigation of patients with possible drug resistance. The effect of valproate on Ins levels may become particularly interesting in the light of a growing understanding of the role of astrocyte dysfunction in a range of neurological conditions which include migraine, epilepsy, Alzheimer’s disease, motor neurone disease and in ischaemic lesions.

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