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Clinical and Functional Studies of Autoimmune Disorders of Neuromuscular Transmission

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Clinical and Functional Studies of Autoimmune Disorders of Neuromuscular Transmission Clinical and functional studies of autoimmune disorders of neuromuscular transmission Dr Jennifer Spillane A thesis submitted to University College London for the degree of Doctor of Philosophy Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology September 2014 1 Declaration I, Jennifer Spillane confirm that the work presented in this thesis is my original research work. Where contributions of others are involved, this has been clearly indicated in the text. 2 Abstract Inherited and acquired disorders of the neuromuscular junction are an important cause of muscle weakness and fatigability. In this thesis I focus on the autoimmune disorders of neuromuscular transmission. Myasthenia Gravis (MG) is the most common of these diseases and is typically caused by antibodies against the post-synaptic acetylcholine receptor. Lambert Eaton Myasthenic Syndrome (LEMS) is a pre-synaptic disorder typically caused by antibodies against voltage gated calcium channels (VGCC). With regard to LEMS, my main aim was to gain a more complete understanding of the pathomechanisms of the disease. To date, the direct effect of LEMS IgG on presynaptic neurotransmitter release had not been investigated in detail. I examined how LEMS IgG affects neurotransmitter release by imaging action potential dependent vesicle exocytosis using a fluorescent dye. I found that LEMS IgG significantly inhibited the rate of synaptic vesicle release but this effect was lost in synapses from a Cacna1a knockout mouse. These data provide direct evidence that LEMS is caused by impaired neurotransmitter release due to an effect on P/Q-type VGCCs. With regard to MG, I studied the long-term outcome of patients with thymomatous and non-thymomatous MG after thymectomy and found that in general the outcome was favourable in the majority of patients with 34% of patients achieving complete stable remission. I also reviewed the long-term outcome of patients after a severe exacerbation of MG requiring ITU admission. Despite the significant mortality associated with severe exacerbations of MG, it was found that specialised neuro- intensive care was associated with a good long-term prognosis in the majority of 3 patients. There were no significant differences in outcome in those with early or late onset MG. Overall the data presented in this thesis provide new insights into the pathomechanisms of LEMS IgG and provide new information regarding the long-term outcome of patients with MG. 4 Acknowledgments I would like to thank a number of people who have helped me in various ways during my PhD. First of all I would like to extend my deepest thanks to my supervisor, Professor Dimitri Kullmann. I am indebted to him for his enthusiastic support, patient advice and unfailing commitment to my research. I was privileged to have him as a supervisor. I would also like to thank my secondary supervisor, Professor Michael Hanna for his support and ongoing encouragement. I am deeply grateful to Dr Kirill Volynski who took a special interest in my research. I was very fortunate to be able to work with him and make use of his extensive knowledge and expertise and much of my PhD would not have been possible without his help. Thank you to Dr Robin Howard for his help with the clinical aspects of my research. It was a privilege to be able to see patients with him and I learnt an incredible amount from our Thursday afternoons in the NHNN. I would like to thank Professor Angela Vincent for her invaluable support, advice and interest in this project. I am very grateful to Dr Bethan Lang for providing and preparing the IgG samples used in this thesis. There are countless people who helped me in the Dept. of Clinical and Experimental Epilepsy and UCL. I would like to thank Dr Stuart Martin for his help with genotyping. Heartfelt thanks go to Dr Yarik Ermolyuk who provided kind and patient help in the 5 laboratory on an almost daily basis. I must thank Dr Marife Cano for her help in making neuronal cultures, her advice regarding immunohistochemistry experiments but most especially for her enthusiasm and encouragement. I would like to thank many of the other PhD students and the post-doctoral researchers in the lab. but particular thanks go to Drs Sarah Crisp, Umesh Vivekananda and Yamina Bakiri for their helpful and insightful comments on my thesis. Dr Iris Oren and Dr Felicity Alder provided invaluable help and support, particularly when I was “new” in the lab. I am grateful to Dr Alex Moreau who shared a desk with me for his daily IT help. I must also thank Juliet Solomon for her calm efficiency and warm support. Dr Brian Sweeney, Dr Aisling Ryan and Dr Sean O’Sullivan all deserve thanks for encouraging me during my early stages in the field of Neurology and being excellent mentors. I am deeply grateful to the Myasthenia Gravis Association for funding my PhD. Their generous support and unfailing commitment to research in this area has made this work possible. I would like to thank the patients who donated serum samples that I used in my experiments. I have been fortunate enough to meet many patients with MG and LEMS during my research and have been inspired and amazed by their knowledge and interest in scientific research. 6 I have met many wonderful people during my PhD. In particular, I am lucky to call Dr Rahima Begum, Dr Stjepana Kovac and Dr Karen Doherty friends. They all provided so much support to me both in and outside the lab and I am truly grateful for this. I was fortunate to have two fantastic flatmates during my PhD, Julie and Blaithin who listened to endless lab anecdotes with humour and patience and I am so glad for their friendship. I would like to give thanks to Aidan who provided so much encouragment and advice. Thank you to Ria and Fiona for their long distance support and friendship from Ireland and Australia. Special thanks go to my wonderful family to whom I owe so much. My parents, Jerh and Avril, have been a constant source of support and encouragement in everything I have ever done. I have always been so proud of my sister, Susan and her own research successes have been a source of inspiration for me. Finally, to James, my fiancé, I was incredibly lucky to meet you during my PhD, thank you for everything. 7 Publications Papers Spillane, J., Beeson, D.J., and Kullmann, D.M. (2010). Myasthenia and related disorders of the neuromuscular junction. J. Neurol. Neurosurg. Psychiatry 81, 850–857. Spillane, J., and Kullmann, D. (2010). History central to diagnosing myasthenia gravis. The Practitioner 254, 15–18, 2. Leite, M.I., Coutinho, E., Lana-Peixoto, M., Apostolos, S., Waters, P., Sato, D., Melamud, L., Marta, M., Graham, A., Spillane, J., et al. (2012). Myasthenia gravis and neuromyelitis optica spectrum disorder: a multicenter study of 16 patients. Neurology 78, 1601–1607. Rajakulendran, S., Viegas, S., Spillane, J., and Howard, R.S. (2012). Clinically biphasic myasthenia gravis with both AChR and MuSK antibodies. J. Neurol. 259, 2736–2739. Spillane, J., Higham, E., and Kullmann, D.M. (2012). Myasthenia gravis. BMJ 345, e8497. Finlayson, S., Spillane, J., Kullmann, D.M., Howard, R., Webster, R., Palace, J., and Beeson, D. (2013). Slow channel congenital myasthenic syndrome responsive to a combination of fluoxetine and salbutamol. Muscle Nerve 47, 279–282. Spillane, J., Hayward, M., Hirsch, N.P., Taylor, C., Kullmann, D.M., and Howard, R.S. (2012). Late recurrent thymoma in myasthenia gravis: a case series. J. Neurol. Neurosurg. Psychiatry 83, 1030–1031. 8 Spillane, J., Hayward, M., Hirsch, N.P., Taylor, C., Kullmann, D.M., and Howard, R.S. (2013). Thymectomy: role in the treatment of myasthenia gravis. J. Neurol. 260, 1798–1801. Spillane, J., Hirsch, N.P., Kullmann, D.M., Taylor, C., and Howard, R.S. (2014). Myasthenia gravis--treatment of acute severe exacerbations in the intensive care unit results in a favourable long-term prognosis. Eur. J. Neurol. 21, 171–173. Spillane J., Ermolyuk Y., Cano-Jaimez M., Lang B., Vincent A., Volynski KE., Kullmann DM. (2014). Lambert-Eaton syndrome IgG inhibits transmitter release via P/Q Ca2+ channels. Neurology. 2015 Jan 14 [Epub ahead of print Jan 15] 9 Table of Contents Declaration.................................................................................................................................... 2 Abstract ......................................................................................................................................... 3 Acknowledgments ........................................................................................................................ 5 Publications .................................................................................................................................. 8 Table of figures ........................................................................................................................... 18 Table of tables ............................................................................................................................ 22 List of abbreviations. ................................................................................................................. 23 1. Introduction ............................................................................................................................ 30 1.1. Synaptic transmission ........................................................................................................... 32 1.1.1. Electrical and chemical synapses ......................................................................................
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