Investigation of multiple sclerosis spinal cord using high field MRI with multi-transmit technology Hugh Kearney, MB BCh BAO MRCPI NMR Research Unit Queen Square MS Centre UCL Institute of Neurology Thesis submitted for: Doctor of Philosophy Neurology UCL Date of Submission July 2014 1 Declaration I, Hugh Kearney, confirm that the work presented in this thesis is my own. Where work has been derived from other sources, I confirm that this has been indicated in my thesis. I obtained the images and clinical data for chapter four from several European centres participating in the MAGNIMS (MAGNetic Imaging in Multiple Sclerosis) collaborative group. Spinal cord lesion classification in chapter six was done with assistance from Dr Katherine Miszkiel (Consultant Neuroradiologist, National Hospital for Neurology and Neurosurgery, London, UK). Statistical analysis was performed by Dr Daniel R. Altmann (Medical Statistics Department, London School of Hygiene and Tropical Medicine, London, UK). 2 Abstract This thesis explores abnormalities in the multiple sclerosis (MS) spinal cord and their relationship with physical disability through the use of conventional and quantitative magnetic resonance imaging (MRI). Firstly, an hypothesis was tested that spinal cord atrophy would be associated with disability, independently from brain atrophy and lesion load, in long disease duration MS. The results presented confirm that cord atrophy is significantly associated with higher levels of physical disability after more than twenty years of MS. Following this observation, the next experiment investigated whether a combination of an active surface model (ASM) and high resolution axial images, would provide a more reproducible measure of spinal cord cross-sectional area; compared to previously described methodologies. The results presented show the superior reproducibility of the ASM combined with axial images for the measurement of cord area in MS, which may be of relevance to future clinical trials utilising cord atrophy as an outcome measure. The pathology of MS in the spinal cord was also explored in several ways using MRI. Firstly, spinal cord lesion morphology was studied, to investigate whether focal lesions, that traversed two or more spinal cord columns and involved the grey matter, would be associated with progressive MS. The results presented confirm this association and also that diffuse abnormalities are more frequently seen in progressive disease. 3 Secondly, spinal cord lesion load was measured quantitatively on axial images, to investigate if this measure would be associated with disability independently from cord atrophy. The functional importance of focal lesions in MS is highlighted by demonstrating an independent association between lesion load and disability. Thirdly, magnetisation transfer ratio (MTR) measures of the outer spinal cord were obtained, in an area expected to contain the pia mater and subpial tissue, to investigate whether outer cord abnormalities could be seen in MS compared to healthy controls and if such abnormalities would be associated with cord atrophy. The results presented show that significant decreases in MTR occur in the outer cord early in the disease course, prior to the development of cord atrophy and further decreases in MTR were seen in progressive MS. Furthermore, an independent association is presented between outer cord MTR and cord atrophy, suggesting that spinal cord meningeal inflammation may be associated with axonal loss in MS. Lastly, diffusion tensor imaging was used in the spinal cord grey matter, in order to investigate whether microstructural abnormalities in this structure would be associated with physical disability. The results of this study identified an association between grey matter radial diffusivity and disability, independently from cord atrophy, suggesting a significant contribution of spinal cord grey matter pathology to clinical dysfunction. In summary, this thesis shows that MS spinal cord abnormalities may be visualised and quantified using high field MRI, and are significantly associated with disability. The observations presented may of relevance to future MRI 4 studies and clinical trials in MS that aim to understand and potentially prevent the pathological processes underlying irreversible physical disability. 5 Acknowledgements I would like to express my sincere gratitude to all of the people with multiple sclerosis and healthy controls who volunteered their time to participate in this study. I would also like to thank the radiographers Marios Yiannakas, Alaine Berry, Luke Hoy and Chichi Ugorji. I would like to acknowledge their assistance, patience and compassion towards all those who participated in this study. I am indebted to Nils Muhlert, Varun Sethi, David Paling, Rhian Raftopoulos, Moreno Pasin, Frank Riemer, Marie Braisher and Ifrah Iidow for their assistance in image analysis, recruitment and moral support during this study. The statistical analysis for this study would not have been possible without the ongoing assistance and support from Dr. Daniel Altmann. The recording of spinal cord lesions was also made possible by the expertise and assistance of Dr. Katherine Miszkiel. I also wish to thank Jon Steel for his assistance in answering and addressing the very frequent questions I had about my computer. The technical aspects of the image analysis also required a large input from the physics team and I would like to thank Drs. Claudia Wheeler Kingshott, Becky Samson, Dan Tozer and Torben Schneider for their support and expertise. The long duration MAGNIMS study was supervised by Dr. Declan Chard and I would also like to acknowledge the assistance of the other collaborators for their input in this study including: Drs. Rocca, Valsasina, Balk, Sastre-Garriga, 6 Reinhardt, Ruggieri, Stippich, Sprenger, Tortorella, Gasperini as well as Professors Rovira, Kappos, Polman, Barkhof and Filippi. I would particularly like to acknowledge the support and help of my two supervisors Dr. Ciccarelli and Professor Miller. An often used Irish expression says that: ‘is fada an bóthar nach mbíonn casadh ann’ (it’s a long road without a turn) and I would like to thank both supervisors, who in their own ways supported me unconditionally through the many twists and turns I encountered in completing this thesis. 7 Publications associated with this thesis Kearney H., et al. Improved MRI quantification of spinal cord atrophy in multiple sclerosis. J Magn Reson Imaging 2013 2014; 39:617-23 Kearney H., et al. A pilot MRI study of white and grey matter involvement by multiple sclerosis spinal cord lesions. Multiple Sclerosis and Related Disorders Volume 2, Issue 2, April 2013:103–108 Kearney H., et al. Magnetic resonance imaging correlates of physical disability in relapse onset multiple sclerosis of long disease duration. Mult Scler. 2014 Jan;20(1):72-80 Kearney H., et al. Investigation of magnetisation transfer ratio-derived pial and subpial abnormalities in the multiple sclerosis spinal cord. Brain 2014 Sep;137(Pt 9):2456-68. Kearney H., et al. Spinal cord grey matter abnormalities are associated with secondary progression and physical disability in multiple sclerosis. J Neurol Neurosurg Psychiatry 2014 [Epub ahead of print] Kearney H, et al. Cervical cord lesion load is associated with disability independently from atrophy in MS. Neurology 2014 [In press] 8 TABLE OF CONTENTS Declaration Abstract Acknowledgements Publications associated with this thesis Table of contents List of tables List of figures 1. The spinal cord and multiple sclerosis 1.1 The spinal cord 1.1.1 External structure 1.1.2 Internal structure 1.1.3 Physiology 1.2 Multiple sclerosis 1.2.1 Natural history 1.2.2 Environmental factors 1.2.3 Genetics 1.2.4 Pathology 1.2.5 Diagnosis 1.2.6 Differential diagnosis 2. Magnetic Resonance Imaging 2.1 Magnetic resonance imaging principles 2.2 T1 – longitudinal relaxation 2.3 T2 – transverse relaxation 2.4 Pulse sequences 2.5 Spin Echo sequences 9 2.6 Gradient Echo sequences 2.7 Image contrast 2.7.1 T-weighted imaging 2.7.2 T2-weighted imaging 2.7.3 Proton density imaging 3. Spinal cord magnetic resonance imaging in multiple sclerosis 3.1 Introduction 3.1.1 Spinal cord imaging in clinically isolated syndrome 3.2 Utility of spinal cord MRI in diagnosis 3.3 Spinal cord atrophy on MRI 3.4 Association between spinal cord MRI abnormalities and disability 3.5 Inversion recovery MRI in the spinal cord 3.5.1 Short T1 inversion recovery 3.5.2 Phase sensitive inversion recovery 3.5.3 Double inversion recovery imaging 3.6 Quantitative spinal cord MRI 3.6.1 Magnetic resonance spectroscopy 3.6.2 Magnetisation transfer imaging 3.6.3 Diffusion weighted imaging 4. Spinal cord atrophy in long disease duration multiple sclerosis 4.1 Introduction 4.2 Methods 4.2.1 Patients 4.2.2 MRI acquisition 4.2.3 Image analysis 4.2.4 Statistical analysis 4.3 Results 10 4.3.1 Correlations between MRI features 4.3.2 MRI features and clinical subgroups 4.3.3 MRI features and physical disability (EDSS) 4.4 Discussion 5. Evaluation of methodologies for improved quantification of spinal cord atrophy 5.1 Introduction 5.2 Methods 5.2.1 Subjects 5.2.2 MRI Protocol 5.2.3 Image Analysis 5.2.3.1 Calculation of relative contrast 5.2.3.2 Reproducibility 5.2.4 Statistics 5.2.4.1 Reproducibility 5.2.4.2 Change in cord area over six months and correlation with disability at baseline 5.2.4.3 Sample size calculation for clinical trials 5.3 Results 5.3.1 Comparison of relative contrast between PSIR and 3D-TFE 5.3.2 Differences