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«Magnetic Resonance Spectroscopy as applied to epilepsy Robert Simister, MRCP Department of Clinical and Experimental Epilepsy, Institute of ...»

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Magnetic Resonance Spectroscopy as applied to epilepsy

Robert Simister, MRCP

Department of Clinical and Experimental Epilepsy,

Institute of Neurology,

University College London (UCL),

Queen Square,

London

WC1N 3BG

Thesis submitted to University College London for the Degree of Doctor in

Philosophy, 2010

Page |2

Table of Contents:

Abstract

p.003

Statement of involvement p.007

Acknowledgements p.008 List of Tables p.009 List of Figures p.010 Published articles and presentations p.012 Main Index p.015 List of Abbreviations p.020 Introduction and Background p.024 Methods p.125 Results p.143 3.1 p.144 3.2 p.168 3.3 p.188 3.4 p.205 3.5 p.224 3.6 p.234 3.7 p.252 Thesis Conclusions and Further Work p.267 Bibliography p.273 Page |3

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 controlgroup 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 Page |4 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.

Page |5 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.

–  –  –

Experimental design was decided by myself for experiments [3.2] to [3.7]) and by Friedrich Woermann (experiment [3.1]) following discussion with the other members of the NSE MRS group (Mary McLean, John Duncan and Gareth Barker).

I was responsible for patient recruitment for experiments [3.2] to [3.7]. Experiment [3.1] was commenced by and all subjects were recruited by Friedrich Woermann.

–  –  –

I would like to take the opportunity to particularly thank my supervisors Mary McLean and John Duncan for their support and guidance throughout the period of this research. They will remember how many drafts and revisions they have very patiently reviewed before the completion of the work presented in this thesis.

I would also like to thank:

Gareth Barker who has also played a major role in guiding and reviewing this work.

Friedrich Woermann who generously passed over to me the work that he had started on the first experiment in this thesis.

Tuuli Salmenpera who helped to identify, recruit and often transport patients to the scanner in the post-ictal series.

My contemporaries at the MRI Unit at The National Society for Epilepsy from February 2000 to March 2004 and particularly Sofia Eriksson, Maxime Guye, Rebecca Liu, Martin Merschenke, Tejal Mitchell, Robert Powell, Fergus Rugg-Gunn, Afraim Salek-Haddadi and Tuuli Salmenpera for their time (often as control subjects) and friendship.

The MRI Unit Radiography Department who regularly organised scans for me and usually at short notice on busy days.

–  –  –

1.6.1 Natural abundance, nuclear spin and resonant frequency for several commonly studied nuclei 1.7.1 Chemical shifts and coupling constants for GABA 3.1.1 Demographics of subject groups in MRSI TLE study (MRSI in TLE) 3.1.2 Metabolite concentrations across temporal lobes (MRSI in TLE) 3.2.1 Demographics of subject groups (OLE/IGE study) 3.2.2 Metabolite concentrations across groups (OLE/IGE study) 3.2.3 Correlation coefficients between metabolites (OLE/IGE study) 3.3.1 Demographics of subject groups (frontal GABA+ in IGE study) 3.3.2 Metabolic concentrations across groups (frontal GABA+ in IGE study) 3.4.1 Demographics of subject groups (GABA+ in MCD study) 3.4.2 Metabolite concentrations across groups (GABA+ in MCD study) 3.4.3 Individual patient metabolite concentrations (GABA+ in MCD study) 3.5.1 Demographics of subject groups (Effect of VPA study) 3.6.1 Demographics of subject groups (GABA+ in TLE study) 3.6.2 Temporal lobe metabolite concentrations (GABA+ in TLE study) 3.6.3 Contralateral temporal lobe concentrations in surgical group (GABA+ in TLE study) 3.7.1 Demographics of subject groups (Post ictal study) 3.7.2 Metabolite concentrations across groups (Post ictal study) P a g e | 10

List of Figures:

–  –  –

Original Papers:

Proton MR Spectroscopy of Metabolite Concentrations in Temporal Lobe Epilepsy and Effect of Temporal Lobe Resection. Epilepsy Res. 2009; 83: 168-76. Simister RJ, McLean MA, Barker GJ, Duncan JS.

The effect of epileptic seizures on proton MRS visible neurochemical concentrations.

Epilepsy Res. 2007 74, 215—219. Simister RJ, McLean MA, Salmenpera TM, Barker GJ, Duncan JS.

The effect of sodium valproate on proton MRS visible neurochemical concentrations.

Epilepsy Res. 2007;74:215-9. Simister RJ, McLean MA, Barker GJ, Duncan JS.

Proton magnetic resonance spectroscopy of malformations of cortical development causing epilepsy. Epilepsy Res. 2007;74(2-3):107-15. Simister RJ, McLean MA, Barker GJ, Duncan JS Discrimination between neurochemicals and macromolecular signals in human frontal lobes using short echo time proton magnetic resonance spectroscopy.

Faraday Discuss 2004; 126:93-105 Mclean M, Simister R, Barker G, Duncan J.

Proton Magnetic Resonance Spectroscopy Reveals Frontal Lobe Metabolite Abnormalities in Idiopathic Generalised Epilepsy. Neurology 2003;61:897-902 Simister R, McLean M, Barker G, Duncan J A proton magnetic resonance spectroscopy study of metabolites in the occipital lobes in epilepsy Epilepsia 2003; 44: 550-558 Simister R, McLean M, Barker G, Duncan J

–  –  –

A short-echo-time proton magnetic resonance spectroscopic imaging study of temporal lobe epilepsy. Epilepsia 2002; 43: 1021-1031 Simister R, Woermann F, McLean M, Bartlett P, Barker G, Duncan J In vivo short echo time 1H-magnetic resonance spectroscopic imaging (MRSI) of the temporal lobes. Neuroimage 2001; 14: 501-509 McLean M, Woermann F, Simister R, Barker G, Duncan J

Abstracts:

Cerebral metabolite and neurotransmitter concentrations in idiopathic generalised epilepsy measured with short echo time proton MR spectroscopy. Proceedings of the ABN. JNNP 2002 73: 219. Simister R, Mclean M, Barker G, Duncan J A comparison of metabolite concentrations in primary generalised epilepsy and partial epilepsy using short echo time proton spectroscopy and a double quantum GABA filter. Proc 10th ISMRM 2002; 420. Simister R, McLean M, Barker G, Duncan J Metabolite nulling improves reliability of LCModel analysis of short echo time spectroscopy Proc 10th ISMRM 2002; 529. McLean M, Simister R, Barker G, Duncan J A short echo time proton magnetic resonance spectroscopic imaging study of metabolites in temporal lobe epilepsy Proc 9th ISMRM 2001; 387. Simister R, Woermann F, McLean M, Barker G, Duncan J

–  –  –

“A 1H magnetic resonance spectroscopy study of metabolites in idiopathic generalised epilepsy” Association of British Neurologists Meeting April 2002 Simister R, McLean M, Barker G, Duncan J “A short echo time proton magnetic resonance spectroscopy imaging in temporal lobe epilepsy” 9th ISMRM (International Society for Magnetic Resonance Imaging in Medicine) Glasgow, 2001. Simister R, Woermann F, McLean M, Barker G, Duncan J “A short echo time MRS study of metabolites in the occipital lobes in epilepsy” 10th ISMRM, Hawaii, USA 2002 Simister R, McLean M, Barker G, Duncan J

Poster presentations:

“Idiopathic generalised epilepsy is associated with disturbance in frontal lobe neurochemical concentrations” American Epilepsy Society, Seattle, USA 2002 Simister R, McLean M, Barker G, Duncan J

–  –  –

1.8 Application of 1H MRS to the investigation of epilepsy p. 106 1.8.1 Introduction 1.8.2 Ex vivo MRS of epileptic tissue 1.8.3 Findings in temporal lobe epilepsy 1.8.4 Findings in extra-temporal lobe epilepsy 1.8.5 Findings in malformations of cortical development 1.8.6 Association of MRS findings with seizure history 1.8.7 Effect of antiepileptic drugs on MRS metabolites 1.8.8 31P and 13C MRS findings in epilepsy 1.8.9 Correlation of MRS findings with other imaging modalities

–  –  –



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