Multiple System Atrophy

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1 Multiple System Atrophy

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3 Gregor K. Wenning Alessandra Fanciulli Editors Multiple System Atrophy

4 Editors Gregor K. Wenning, MD, PhD, MSC Division of Neurobiology Department of Neurology Innsbruck Medical University Innsbruck Austria Alessandra Fanciulli, MD Department of Neuroscience, Mental Health and Sensory Organs Sapienza University of Rome Rome Italy Division of Neurobiology Department of Neurology Innsbruck Medical University Innsbruck Austria ISBN ISBN (ebook) DOI / Springer Wien Heidelberg Dordrecht London New York Library of Congress Control Number: Springer-Verlag Wien 2014 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. Exempted from this legal reservation are brief excerpts in connection with reviews or scholarly analysis or material supplied specifically for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work. Duplication of this publication or parts thereof is permitted only under the provisions of the Copyright Law of the Publisher's location, in its current version, and permission for use must always be obtained from Springer. Permissions for use may be obtained through RightsLink at the Copyright Clearance Center. Violations are liable to prosecution under the respective Copyright Law. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. While the advice and information in this book are believed to be true and accurate at the date of publication, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Printed on acid-free paper Springer is part of Springer Science+Business Media (

5 Foreword Multiple system atrophy (MSA) is one of the most challenging diseases within the spectrum of neurodegenerative movement disorders. Early accurate diagnosis is almost impossible on clinical grounds where the parkinsonian variant of MSA can be so strikingly similar to idiopathic Parkinson s disease, that initial misclassification is common even in the hands of highly specialised movement disorder experts. When presenting as a cerebellar syndrome, MSA may hide for years behind the screen of conditions subsumed under the label of idiopathic late-onset cerebellar ataxia, and presentations with autonomic failure lead into yet another differential diagnostic arena. MSA is also one of the fastest progressing among the atypical parkinsonian disorders and still largely lacks effective symptomatic, let alone disease- modifying, therapy. Neuropathologists and clinicians alike continue to be puzzled by the enigmatic histopathological hallmark of glial cytoplasmic inclusions of misfolded and aggregated alpha-synuclein which seems to point to a primary non-neuronal origin of disease. For the past 20 years, Gregor Wenning has devoted most of his career as a clinician scientist to the study of MSA, and, for the past 18 years, I have had the privilege to accompany his career from his days as a resident in the Department of Neurology at Innsbruck Medical University in Austria to his becoming chief of the Division of Clinical Neurobiology within our department. Through all these years, he and his team of postdocs, fellows and colleagues have never tired in their pursuit of unravelling the nature of MSA in order to be able to provide better treatments for those suffering from it. These efforts have led to the refinement of animal models and clinical diagnostic algorithms and have also led to the establishment of international collaborative research consortia to better understand the epidemiology, natural history and etiopathogenesis of MSA most recently through the formation of the Movement Disorder Society (MDS) MSA study group. It is fair to say that Dr. Wenning has become one of the world s leading experts in the MSA field and there is probably not a single clinician or scientist who would have published more on the subject. In this concise monograph, Gregor Wenning and his team of co-workers have set out to present and summarise the state of current knowledge about MSA covering concepts of etiopathogenesis as they have evolved from human neuropathology, animal models and in vitro research as well as the state of the art of MSA research v

6 vi Foreword and clinical practice. The result is a superb reference source for experts and novices as well as a most useful clinical companion for every neurologist seeing patients with movement disorders. Innsbruck, Austria Werner Poewe

7 Preface About 30 years ago, when I had just been appointed lecturer in neurology to the late Professor David Marsden at King s College Hospital in South London, we had a young elective medical student from Germany attached to our unit who stood out for his interest in neurology, particularly movement disorders, and his perceptive questions. At King s, I had the good fortune, unusual for trainees, to stay with David Marsden for 7 years and to personally follow-up our large parkinsonian population. By seeing very many parkinsonian patients, I became familiar with the typical, and thereby attuned to what was atypical, and also saw postmortem results on those who died. This experience was what started my interest in atypical parkinsonism and especially MSA. When I moved with David to Queen Square in 1988, that same student turned up again on another elective and, on departing, told me that if ever he might have an opportunity to return as a research fellow, he would jump at it, so I filed his CV. I then had the good fortune to be awarded a 3-year grant from the UK Parkinson s Disease Society to study the clinical features, natural history and epidemiology of MSA, so Gregor returned just 1 year after qualifying in Tubingen and set about the project with his characteristic enthusiasm and industry. He enlarged the scope of his endeavours to include clinicopathological studies in the Queen Square Brain Bank and embarked on the first rodent experimental studies on the consequences of single or combined nigral and striatal lesions and the results of nigral and striatal grafts, laying down the foundations of his later experimental work with Nadia Stefanova. We never quite managed to get the epidemiology part off the ground, but this was then admirably tackled by Anette Schrag. I am doubly indebted to Werner Poewe for sending me Anette from Berlin, which he was leaving, and, when he then took up the chair of neurology in Innsbruck, for giving Gregor a post and the support to establish a strong MSA team there. One of the early struggles in MSA was to define its limits, which in the 1980s were still fuzzy. David Oppenheimer had done a great service by introducing the term MSA, but even he was not certain at the time what it included or excluded. I had the privilege to meet and correspond with him and thought it would be of interest to record here the following unpublished extract from our correspondence: vii

8 viii Preface Fig. 1 Cartoon of an elephant ( the beast ) drawn by Prof. N. Quinn in 1989 to represent different presentations giving a different picture of MSA to different specialists I am a bit worried by the use of the term MSA as the name of a disease, like MS (multiple sclerosis). I originally used the term in the context of autonomic failure, when I became convinced that there were two distinguishable conditions in which autonomic failure occurred, one characterised by Lewy bodies and the other by striatonigral degeneration (SND). As the latter condition was so frequently linked with olivopontocerebellar atrophy (OPCA), I felt that a term was needed to cover both SND and OPCA. I chose multiple system atrophy probably unwisely, as this term would seem to be applicable to other conditions such as Friedreich s Ataxia. What I did not do, was to define the limits of applicability of the term MSA. I could not even reach a firm opinion on whether all cases of OPCA with or without autonomic failure were suffering from one and the same disease. During that time, I had become clinically convinced that hereditary OPCA was separate from sporadic OPCA and that MSA was a specific entity among many multisystem degenerations and strongly expressed this view in Multiple system atrophy-the nature of the beast, an invited article in the special supplement of JNNP that marked David Marsden stepping down after 10 years as editor (in fact, as the supplement was prepared in secret, David spent some time berating me for not being more productive at the time!). Fortuitously, at exactly the same time, the key pathological paper by Lantos, Papp and Khan describing glial cytoplasmic inclusions appeared, giving pathological underpinning to the delineation of MSA as a single entity.

9 Preface ix Fig. 2 Photograph of Prof. N. Quinn in front of an Asian elephant at the 4th International Congress on MSA held in 2012 in the Museum d Histoire Naturelle in Toulouse, France Gregor and I decided that we should write a duograph on MSA. We even signed a contract and were embarrassed to find the book advertised before we had even begun to write it. We made a sterling effort to get it started in 1998 when we stayed for 5 days in the beautiful home of Prof. Olivier Rascol in Aurignac but still never managed to get it off the ground. I am therefore delighted to see this wonderful and comprehensive book on MSA that Gregor and his three colleagues from Innsbruck, together with Kurt Jellinger from Vienna, have produced. They really have done a magnificent job, and it is fitting that this, the very first book entirely devoted to MSA, should come from Austria, where so much excellent MSA research has been conducted. London, UK Niall P. Quinn

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11 Contents 1 Historical Review Alessandra Fanciulli and Gregor K. Wenning 2 Epidemiology Florian Krismer and Gregor K. Wenning 3 Neuropathology Kurt Jellinger 4 Aetiopathogenesis Kurt Jellinger and Florian Krismer 5 Animal Models Nadia Stefanova 6 Clinical Presentation Alessandra Fanciulli and Gregor K. Wenning 7 Clinical Diagnostic Criteria Alessandra Fanciulli and Gregor K. Wenning 8 Natural History Alessandra Fanciulli and Gregor K. Wenning 9 Investigations Florian Krismer and Gregor K. Wenning 10 Treatment Alessandra Fanciulli and Gregor K. Wenning Index xi

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13 Contributors Alessandra Fanciulli, MD Department of Neuroscience, Mental Health and Sensory Organs, Sapienza University of Rome, Rome, Italy Division of Neurobiology, Department of Neurology, Innsbruck Medical University, Innsbruck, Austria Kurt Jellinger, MD Institute of Clinical Neurobiology, Medical University Vienna, Vienna, Austria Florian Krismer, MD Division of Neurobiology, Department of Neurology, Innsbruck Medical University, Innsbruck, Austria Niall P. Quinn, MA, MD, FRCP, FAAN, FANA National Hospital for Neurology and Neurosurgery, London, UK Nadia Stefanova, MD, PhD, PD Division of Neurobiology Laboratory for Neurodegenerative Disease Research, Department of Neurology, Innsbruck Medical University, Innsbruck, Austria Gregor K. Wenning, MD, PhD, MSC Division of Neurobiology, Department of Neurology, Innsbruck Medical University, Innsbruck, Austria xiii

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15 Abbreviations 3-NP 3-nitropropionic acid 6-OHDA 6-hydroxydopamine AD Alzheimer s disease ADL Activities of daily living AG Argyrophilic grains ALS Amyotrophic lateral sclerosis ARP Apoptosis related protein αsyn α-synuclein BDNF Brain-derived neurotrophic factor BiPAP Biphasic positive airway pressure BP Blood pressure CBD Corticobasal degeneration CNMSA-SG Chinese Multiple System Atrophy study group DARPP-32 Dopamine and cyclic adenosine regulated phosphoprotein DLB Dementia with Lewy bodies EDS Excessive daytime sleepiness EMSA-SG European Multiple System Atrophy study group FTLD Frontotemporal lobe dementia GCIs Glial cytoplasmic inclusions GDNF Glial cell line-derived neurotrophic factor GFAP Glial fibrillary acidic protein GNIs Glial nuclear inclusions GWAS Genome-wide association study inos Inducible nitric oxide synthase ivig Intravenous immunoglobulins JAMSAC Japanese Multiple System Atrophy Consortium LB Lewy bodies LRRK-2 Leucine-rich repeats kinase 2 MBP Myelin basic protein MPO Myeloperoxidase MPTP: 4-phenyl-1,2,3,6-tetrapyridin MSA-C Multiple system atrophy cerebellar variant MSA-P Multiple system atrophy parkinsonian variant xv

16 xvi MSC NAMSA-SG NCIs NNIs NNIPPS NH OH OPCA OS OSA PAF PD PEG PLP PPH PSI PSP QA QSART RBD ROS SCA SDS SH SN SND SNP TCS TDP-43 tg TPPP UMSARS Abbreviations Mesenchymal stem cells North America Multiple System Atrophy study group Neuronal cytoplasmic inclusions Neuronal nuclear inclusions Neuroprotection and Natural History in Parkinson Plus Syndromes Nocturnal hypertension Orthostatic hypotension Olivopontocerebellar atrophy Oxidative stress Obstructive sleep apnoea Pure autonomic failure Parkinson s disease Percutaneous endoscopic gastrostomy Proteolipid protein Postprandial hypotension Proteasome inhibition Progressive supranuclear palsy Quinolinic acid Quantitative sudomotor axon reflex test REM sleep behaviour disorder Reactive oxidative species Spinocerebellar ataxia Sodium dodecyl sulphate Supine hypertension Substantia nigra Striatonigral degeneration Single nucleotide polymorphism Transcranial sonography 43-kDa transactive response DNA-binding protein Transgenic Tubulin polymerisation-promoting protein Unified Multiple System Atrophy Rating Scale