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This copy has been deposited in the Library of ------------------------ ^ This copy has been deposited in the UrUniversity of London Library, Senate House, Malet Street, London WC1E 7HU. ^v>ru^uiviio MtUlb IHAR ROOM 261 UNIVERSITY OF LONDON SENATE HOUSE MALET STREET LONDON WC1E7HU FRONTAL LOBE EPILEPSY, SLEEP AND PARASOMNIAS Christopher Paul Derry MBBS MRCP Thesis submitted for the degree of Doctor of Philosophy September 2006 Institute of Neurology, UCL University of London 1 UMI Number: U592789 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. Dissertation Publishing UMI U592789 Published by ProQuest LLC 2013. Copyright in the Dissertation held by the Author. Microform Edition © ProQuest LLC. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 DECLARATION OF AUTHORSHIP AND ORIGINALITY I, Christopher Paul Derry, confirm that the work presented in this thesis is my own. Where information has been derived form other sources, this is acknowledged in the text. In particular, for the studies presented in Chapter 11, radiosynthesis of l8F-MPPF was undertaken by Rachel Mulligan at the Austin Hospital and Didier Le Bars in Lyon. The (3-microprobe experiment in this study was designed by me, and I was present during the experiments, but these were primarily conducted by Dr Luc Zimmer from CERMEP, Lyon. Molecular genetic analysis for the families presented in Chapter 14 was undertaken by Ms Sarah Heron and A/Prof J. Mulley at the Department of Genetic Medicine, Women’s and Children’s Hospital, Adelaide, Australia. Christopher Paul Derry 2 DEDICATION For my wife and best friend, Natalie 3 ABSTRACT A close relationship exists between sleep and epilepsy. While many forms of epilepsy may be influenced by the sleep-wake cycle, this phenomenon is particularly evident in frontal lobe epilepsy where affected individuals may experience seizures exclusively during sleep (nocturnal frontal lobe epilepsy, NFLE). In this thesis, three aspects of the relationship between sleep and frontal lobe epilepsy are examined. Firstly, serotonergic neurotransmission across the human sleep-wake cycle was studied using the novel PET ligand l8F-MPPF, a serotonergic 5 HT ia receptor radioligand sensitive to endogenous serotonin release. Fourteen individuals with narcolepsy underwent l8F-MPPF PET scans during sleep and wakefulness. The study demonstrated a 13% increase in l8F-MPPF binding potential (p<0.01) during sleep, indicating a reduction in serotoninergic neurotransmission, in line with existing animal data. Secondly, the characterisation of benign, non-epileptic parasomnias and their distinction from nocturnal frontal lobe seizures was addressed in two studies. The first comprised an analysis of the historical features of these conditions, and included the development and validation of a clinical scale for the diagnosis of nocturnal events. The second comprised a detailed semiological analysis of a series of parasomnias recorded on video-EEG monitoring, and a statistical comparison with seizures in NFLE. Although similarities between NFLE and parasomnias were observed, the results provide an evidence base for the confident distinction of these disorders. Finally, the familial form of NFLE (autosomal dominant nocturnal frontal lobe epilepsy, ADNFLE) is associated with mutations in genes for nicotinic acetylcholine receptor subunits, but recognised mutations account for only a minority of reported cases. The last study presented here is a clinical and genetic analysis of two large families with an unusually severe ADNFLE phenotype. Affected individuals had refractory epilepsy and increased rates of mental retardation and psychiatric disorders 4 and, in one family, linkage studies suggest a previously unrecognised underlying mechanism. 5 ACKNOWLEDGEMENTS There are many people whose help and support were invaluable to me during my PhD studies, both from a professional and personal point of view, and whom 1 would like to thank. Firstly I must express my gratitude for the inspiration, support and guidance provided by my supervisors, Professor Sam Berkovic and Professor John Duncan. Their clear thinking, scientific rigour and clinical acumen have been invaluable during these studies, and they set clinical and research standards which I can only strive to emulate during my own career. I also was fortunate enough to work with many other outstanding researchers and clinicians during the course of my studies. In particular Professor David Reutens, Dr Simon Harvey, Professor Ingrid Scheffer, and Dr Peter Bladin were all actively involved in individual projects within this thesis, and I benefited greatly from their guidance and clinical expertise. In addition, I would like to thank Dr Murray Johns, Dr Matthew Walker, Dr Margot Davey, Dr Carla Marini, Professor Graham Jackson, and Dr Mark Newton, all of whom I worked with, either on a clinical or research basis, and from whose experience and skills I also benefited greatly. I must also acknowledge the encouragement and friendship of the other epilepsy fellows with whom I worked in Melbourne: Nigel Tan, Angelo Labate, Marco Fedi, Saul Mullen, Paulo Federico, Lata Vadlamudi, Ingo Helbig and Isabella Taylor. I am indebted to a number of other individuals for technical and scientific input to this work. The staff of the PET centre at the Austin Hospital, particularly Rachel Mulligan and Henri Tochon Danguay, contributed greatly to the l8F-MPPF study, and Luc Zimmer, Nicholas Costes and Henri Le Bars from CERMEP in Lyon enabled the accompanying animal experiment to be undertaken. Associate Professor Ian Gordon from the University of Melbourne gave statistical advice on several areas in this thesis. Associate Professor John Mulley and Ms Sarah Heron the Department of Genetic Medicine, Women’s and Children’s Hospital, 6 Adelaide, Australia undertook the molecular analysis of the familes presented in Chapter 14. The EEG technicians at the Austin Hospital (Ann Godsil, Josie Curatolo, Louise Feiler, Jan Barchett, Nadia Farrell and Jo Leach), as well as Cathy Bailey from the Royal Children’s Hospital, Melbourne and Catherine Scott from the national Hospital for Neurology and Neurosurgery all provided essential assistance. Last, but not least, I must thank Lisa Johnston, Yvette Reading and Jewell Gardener, and all the research assistants from the Epilepsy Research Centre (Bronwyn Grinton, Jacinta MacMahon, Sam Turner, Danya Vears, Deborah Glencross, Katie Kron, Jodie Malone and Kate Lawrence), for their help and friendship during these studies. Finally, on a more personal note, 1 am deeply grateful to my family for their patience and support during my fellowship. My parents and my brother Andrew, although many miles away, were always ready to help, advise, and sometimes just listen to me through this time. Above all, though, my most profound thanks go to my wife Natalie. She has been with me every step of the way, through the highs and the lows, and has been an unfailingly positive source of love and support. 7 PRIZES AND PEER-REVIEWED PUBLICATIONS Prizes Awarded ILAE (UK) Gowers’ Young Physician Award (2006) Peer Reviewed Publications Derry C, Benjamin C, Bladin P, le Bars H, Tochon-Danguay H, Berkovic SF, Zimmer L, Costes N, Mulligan R, Reutens D (2006). Increased serotonin receptor availability in human sleep: evidence from an [18F] MPPF PET study in narcolepsy. Neuroimage; 30: 341-8. Derry C.P, Davey M, Johns M, Kron K, Glencross D, Marini C, Scheffer IE, Berkovic SF, (2006)