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Autonomic Function and Non-Motor Symptoms in Primary Chronic Autonomic Failure Disorders

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Autonomic Function and Non-Motor Symptoms in Primary Chronic Autonomic Failure Disorders Autonomic function and non-motor symptoms in primary chronic autonomic failure disorders Ekawat Vichayanrat Department of Medicine, Imperial College London Thesis submitted for the degree of Doctor of Philosophy 2013 1 Copyright Declaration The copyright of this thesis rests with the author and is made available under a Creative Commons Attribution Non-Commercial No Derivatives licence. Researchers are free to copy, distribute or transmit the thesis on the condition that they attribute it, that they do not use it for commercial purposes and that they do not alter, transform or build upon it. For any reuse or redistribution, researchers must make clear to others the licence terms of this work. Declaration of originality I declare that all studies presented in this thesis are my own work which were undertaken during my studies at Imperial College London and have never been submitted for any other degree or professional qualification. Apart from described below, all data were prospectively collected and analysed by myself. Any information or details from previous works that were conducted by others have been explicitly acknowledged. Cardiovascular autonomic function data were recorded by clinical autonomic scientists as part of routine clinical tests at the Autonomic Unit, National Hospital for Neurology and Neurosurgery (NHNN) or the Neurovascular Autonomic Unit, St Marys Hospital. These data was then reduced and used to analyse various quantitative cardiovascular autonomic function measures in Chapter 4.1.1 (Quantitative cardiovascular autonomic function in patients with chronic autonomic failure), Chapter 4.1.3 (Pressor tests in MSA, Parkinson’s disease with and without autonomic failure), Chapter 4.1.4 24 hour-Ambulatory Blood Pressure Monitoring (24 hr-ABPM) in MSA, Parkinson’s disease with and without autonomic failure and its efficacy to detect orthostatic hypotension using diary) and Chapter 6 (Initial symptoms and clinical characteristics in Pure Autonomic Failure). 2 Abstract The autonomic nervous system innervates and influences every organ in the body through two major efferent pathways; the sympathetic and parasympathetic nervous systems. Autonomic dysfunction, especially orthostatic hypotension (OH) and olfactory dysfunction, are commonly present in a variety of neurological disorders, particularly, multiple system atrophy (MSA) and allied disorders, such as Parkinson’s disease (PD) and Pure Autonomic Failure (PAF) and can significantly impact quality of life and cause significant morbidity. Similarly, non-motor symptoms have been increasingly recognized in PD. The overlapping autonomic features of PD, PAF and MSA, e.g., OH, can sometimes make it difficult to differentiate a diagnosis between these conditions. The further evaluation of autonomic function, e.g., cardiovascular, olfactory and gastrointestinal function, in patients with primary chronic autonomic failure disorders could offer better diagnostic accuracy, improve the understanding of disease progression and inform the development of treatments. Cardiovascular autonomic function screening tests are commonly used to confirm a diagnosis of autonomic failure, e.g., orthostatic hypotension, but OH is not often reliable for distinguishing between PD and MSA. Novel indices of cardiovascular autonomic function in patients with chronic autonomic failure have therefore been evaluated as well as the severity of olfactory dysfunction and other non-motor (e.g., daily activities and depression) symptoms in MSA, PD and PAF. Results demonstrated that baroreflex sensitivity and blood pressure recovery time (BRPT) in response to the Valsalva Manoeuvre are useful for differentiating MSA from PD with autonomic failure (PD+AF). BPRT was also significantly prolonged in PD patients compared to healthy controls. In addition, an association of BPRT and disease duration in PD also suggests that this index may be useful for monitoring disease progression in PD. Other findings indicated that assessing olfactory function is also helpful for distinguishing between PD, MSA and PAF. A greater degree of depression and impairment of daily activities in MSA relative to PD and PAF were also evident. In order to further investigate the presenting symptoms and features of PAF, a time when diagnosis is often still unclear, and other disorders, such as MSA, can be suspected, the clinical characteristics and laboratory investigations, in a large cohort of PAF patients were examined. Results indicated that abnormal white matter lesions are prevalent in PAF. Furthermore, gastrointestinal symptoms were also evident in PAF and can also occur in other autonomic disorders, e.g., MSA. Using electrogastrography, impaired indexes of gastric motility were also evident in PAF. 3 Acknowledgements I would like to first thank the many patients, their relatives and all participants who volunteered to participate in the studies contained in this thesis. I am forever indebted to my supervisor, Professor Christopher Mathias who has given me a great opportunity to study such fascinating aspects of autonomic function in primary chronic autonomic disorders and for his invaluable advice and support throughout the studies. I am most grateful to Dr. David Low for the opportunity to work with him and for his support, mentoring and invaluable advice. I would also like to thank Dr Valeria Iodice and Mr. Andrew Owens for their support and guidance and friendship. This thesis would not have been possible without them. I would like to thank all the Clinical Scientists at the Pickering Unit, St Mary’s Hospital and the Autonomic Unit at The National Hospital for Neurology & Neurosurgery and Sister Catherine Best for all their help. I would also like to specifically thank Professor Andrew Lees and Dr Laura Silveira-Moriyama for their guidance and help during my studies. I am especially indebted to my parents for their encouragement and support and I would finally like to thank my wife, Sukritta, and my children, Atitiya and Atiruth, for their love and unending support they have given me throughout this journey. 4 Table of contents Abstract...................................................................................................................................2 Acknowledgements...............................................................................................................3 List of Tables..........................................................................................................................8 List of Figures......................................................................................................................11 Abbreviations.......................................................................................................................13 Chapter 1 Introduction.........................................................................................................18 Chapter 2 Literature Review................................................................................................25 2.1 Autonomic Nervous System (ANS) Function...................................................................26 2.2 Neurotransmitters in the ANS..........................................................................................28 2.3 Cardiovascular Autonomic Function................................................................................30 2.4 Classification of autonomic disorders...............................................................................32 2.5 Primary chronic autonomic failure (CAF).........................................................................33 2.5.1 Non-motor symptoms in Primary CAF.......................................................................35 2.5.1.1 Cardiovascular autonomic symptoms in Primary CAF..........................................35 2.5.1.2 Cardiovascular autonomic screening tests...........................................................39 2.5.1.3 Novel quantitative cardiovascular autonomic function tests.................................43 2.5.2 Other non-motor features in patients with Primary CAF............................................44 2.5.2.1 The olfactory system and pathology in Primary CAF...........................................44 2.5.2.1.1 Assessment of olfactory function....................................................................47 2.5.2.1.2 Olfactory function in Primary CAF...................................................................48 5 2.5.2.2 Gastrointestinal dysfunction.................................................................................49 2.5.2.2.1 Neural control of the gastrointestinal function................................................49 2.5.2.2.2 Gastrointestinal dysfunction in Primary CAF..................................................53 2.5.3 Quality of life in patients with Primary CAF................................................................56 Chapter 3 General Methods................................................................................................59 3.1 Participant recruitment.....................................................................................................60 3.2 Experimental group design..............................................................................................60 3.3 Study preparation.............................................................................................................62 3.4 Cardiovascular autonomic function tests.........................................................................62
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