Parkinson's Disease

Parkinson’s Disease

Parkinson’s Disease Edited by

Manuchair Ebadi, Ph.D., FACCP Chester Fritz Distinguished Professor of Pharmacology Associate Vice President for Medical Research University of North Dakota School of Medicine and Health Sciences

Ronald F.Pfeiffer, M.D. Professor and Vice Chairman University of Tennessee Health Science Center College of Medicine Department of Neurology

Boca Raton London New York Washington, D.C.

This edition published in the Taylor & Francis e-Library, 2006. “To purchase your own copy of this or any of Taylor & Francis or Routledge’s collection of thousands of eBooks please go to http://www.ebookstore.tandf.co.uk/.” Library of Congress Cataloging-in-Publication Data Parkinson’s disease/[edited by] Manuchair Ebadi, Ronald F.Pfeiffer. p.cm. Includes bibliographical references and index. ISBN 0-8493-1590-5 (alk. paper) 1. Parkinson’s disease. I. Ebadi, Manuchair S. II. Pfeiffer, Ronald. [DNLM: 1. Parkinson’s Disease. WL 359 P24666 2004] RC382.P242 2004 616.8'33–dc22 2004054497 This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequences of their use. Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage or retrieval system, without prior permission in writing from the publisher. All rights reserved. Authorization to photocopy items for internal or personal use, or the personal or internal use of specific clients, may be granted by CRC Press, provided that $1.50 per page photocopied is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA. The fee code for users of the Transactional Reporting Service is ISBN 0-8493-15905/05/$0.00+$ 1.50. The fee is subject to change without notice. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. The consent of CRC Press LLC does not extend to copying for general distribution, for promotion, for creating new works, or for resale. Specific permission must be obtained in writing from CRC Press LLC for such copying. Direct all inquiries to CRC Press LLC, 2000 N.W. Corporate Blvd., Boca Raton, Florida 33431. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation, without intent to infringe. Visit the CRC Press Web site at www.crcpress.com © 2005 by CRC Press No claim to original U.S. Government works ISBN 0-203-50859-9 Master e-book ISBN

ISBN 0-203-61281-7 (Adobe e-Reader Format) International Standard Book Number 0-8493-1590-5 (Print Edition) Library of Congress Card Number 2004054497

Dedication We dedicate this book humbly and reverently to the individuals who have suffered, are suffering, or will suffer from Parkinson’s disease. We have high hope that the etiology of this mysterious disease will be discovered soon and a cure and prevention will be found in the very near future.

In books lie the souls of the whole past time, The articulate audible voice of the past, When the body and material substances Of it have altogether vanished like a dream. —Thomas Carlyle

In Memoriam In loving memory of Dr. Benjamin Pfeiffer, who faced the trials of Parkinson’s disease with tremendous courage and served as an inspiration to so many, and Irene Pfeiffer, who filled the often lonely role of caregiver with unfailing dedication and love.

Preface What we know today as Parkinson’s disease (PD) was first described by James Parkinson in his 1817 Essay on the Shaking Palsy. However, it is probable that PD was present long before this landmark description. A disease known as kampavata, consisting of shaking (kampa) and lack of muscular movement (vata), existed in ancient India as long as 4500 years ago. It was not until more than 100 years after Parkinson’s original description that the loss of dopamine-containing cells in the substantia nigra (SN), characteristic of PD, was recognized. Although neuropathological examination documented the distinctive presence of Lewy bodies (LB) and degeneration of the SN as hallmarks of PD, no definitive clinical test or procedure to diagnose PD exists, and the diagnosis must be made on the basis of clinical features alone. The progressive loss of dopaminergic and other neurons that characterizes PD neuropathologically leads to a sometimes bewildering array of clinical features whose identification and management can challenge even the most astute clinician. Four cardinal signs constitute the core clinical complex of parkinsonism: tremor, akinesia or bradykinesia, rigidity, and loss of postural reflexes. In addition to these cardinal signs, a variety of additional motor features may develop in PD, produced at least in part by combinations of the four cardinal features. Speech becomes both soft and poorly articulated. Dysphagia is often present and may lead to aspiration. Handwriting becomes micrographic, sometimes displaying a fatigue-like quality in which it starts out at normal size but becomes progressively smaller in prolonged writing. Posture becomes flexed and gait is characterized by small, shuffling steps on a narrow base, sometimes with a propulsive, or festinating, quality to it. With advancing parkinsonism, patients may experience transient freezing, typically upon initiation of gait, but sometimes also in narrow confines, such as doorways. Although they have received less attention, a number of nonmotor features also characterize PD. Autonomic abnormalities may include bowel dysfunction, urinary difficulties, sexual disturbances, cardiovascular changes, and thermoregulatory alterations. Behavioral changes, such as depression and anxiety, are frequently present in PD, while, with advancing PD, cognitive impairment may also become evident. A variety of sleep disturbances also may appear in PD, as can fatigue and progressive weight loss. To further complicate matters, most of these nonmotor features can also be triggered or accentuated by the medications used to treat PD. While no preventive or curative treatment for PD has been discovered to date, the evolution of treatment for PD has been characterized by a fascinating, and in many respects dramatic, progression to more effective symptomatic therapies. In tandem with these advances, therapeutic attention has also begun to focus on treatment that might actually alter or slow progression of the disease process itself.

A common cause of parkinsonism in 1920 was encephalitis, which prompted an attempt to develop a vaccine that would prevent the development of postencephalitic parkinsonism. This earlier effort to develop protective immunologic therapy, has now been replaced by trials investigating agents that may represent neuroprotective therapy. Potential examples include coenzyme Q10 (anti-oxidant and mitochondrial stabilizer) and minocycline (anti-inflammatory/antiapoptotic). Advances in our understanding of the neuropathological processes and genetic factors that produce PD have also unfolded at a dizzying pace. Over the past few years, several genes for monogenically inherited forms of PD have been mapped or cloned. In a small number of families with autosomal dominant inheritance and typical LB pathology, mutations have been identified in the gene for α-synuclein. Aggregation of this protein in LB may be a crucial step in the molecular pathogenesis of both familial and sporadic PD. On the other hand, mutations in the parkin gene result in an autosomal recessive form of parkinsonism, which appears to be a relatively frequent cause of PD in patients with very early onset. In this form of PD, nigral degeneration is not accompanied by LB formation. Parkin has been implicated in cellular protein degradation pathways, as it has been shown that it functions as a ubiquitin ligase. The potential importance of this pathway is also highlighted by the finding of a mutation in the gene for ubiquitin Cterminal hydrolase L1 in another small family with PD. Other loci have been mapped on chromosome 2p and 4p, respectively, in a small number of families with dominantly inherited PD, but those genes have not yet been identified. The identification of specific mutations that cause a parkinsonian phenotype has caused confusion and raised some valid questions as to whether the term PD, which implies a single unitary disease process, is still valid. The contribution of genetic factors and a defect of complex I of the mitochondrial respiratory chain have been confirmed at the biochemical level. Disease specificity of this defect has been demonstrated for the parkinsonian SN. These findings and the observation that the neurotoxin, 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP), which causes a parkinson-like syndrome in humans, acts via inhibition of complex I, have triggered research interest in the mitochondrial genetics of PD. Oxidative phosphorylation consists of five proteinlipid enzyme complexes located in the mitochondrial inner membrane that contain flavins (FMN, FAD), quinoid compounds (coenzyme Q10, CoQ10), and transition metal compounds (iron-sulfur clusters, hemes, protein-bound copper). These enzymes are designated complex I (NADH:ubiquinone oxidoreductase, EC 1.6.5.3), complex II (succinatei:ubiquinone oxidoreductase, EC 1.3.5.1), complex III (ubiquinol:ferrocytochrome c oxidoreductase, EC 1.10.2.2), complex IV (ferrocytochrome c: oxygen oxidoreductase or cytochrome c oxidase, EC 1.9.3.1), and complex V (ATP synthase, EC 3.6.1.34). A defect in mitochondrial oxidative phosphorylation, in terms of a reduction in the activity of NADH CoQ reductase (complex I) has been reported in the striatum of patients with PD. The reduction in the activity of complex I is found in the SN, but not in other areas of the brain, such as globus pallidus or cerebral cortex. Therefore, the specificity of mitochondrial impairment may play a role in the degeneration of nigrostriatal dopaminergic neurons. This view is supported by the fact that MPTP, generating 1-methyl-4-phe-nylpyridine (MPP+), destroys dopaminergic neurons in the SN. Although the serum levels of CoQ10 are normal in patients with PD, CoQ10 is able to attenuate the MPTP-induced loss of striatal dopaminergic neurons.

Oxidative stress is believed to play a key role in the degeneration of dopaminergic neurons in the SN of PD patients. An important biochemical feature of PD is a significant early depletion in levels of the thiol antioxidant compound glutathione (GSH), which may lead to the generation of reactive oxygen species, mitochondrial dysfunction, and ultimately to subsequent neuronal cell death. GSH has been reported to be markedly reduced in PD, particularly in patients with advanced disease. Furthermore, the GSH decrease seems to appear before neurodegeneration in presymptomatic PD and is not a consequence thereof. This suggests that a link may exist between these two events, although it remains to be established whether or not the loss of GSH can induce neurodegeneration. R-lipoic acid acts to prevent depletion of GSH content and preserve the mitochondrial complex I activity, which normally is impaired as a consequence of GSH loss. Nitric oxide (NO) has been also implicated in neurodegenerative disease. Several studies have reported markers that suggest a NO overproduction in PD brains. NO radicals have been detected in PD SN, as have increased nitrosilated proteins, such as αsynuclein. Increased nitrite concentration has also been described in cerebrospinal fluid. Finally, the core of the LB is immunoreactive for nitrotyrosine. Decreased GSH may predispose cells to the toxicity of other insults that selectively target dopaminergic neurons. GSH depletion synergistically increases the selective toxicity of MPP+ in dopamine (DA) cell cultures and the toxicity of 6-hyroxydopamine (6OHDA) and MPTP in vivo. GSH peroxidase (GPx)-knockout mice show increased vulnerability to MPTP. There is evidence that NO may play an important role in DA cell death and functionality. A redox-based mechanism for the neuroprotective effects of NO and related nitroso-compounds has been postulated. In this regard, GSH is an endogenous thiol that reacts with NO to form S-nitrosoglutathione and which protects DA neurons from oxidative stress. Metallothioneins, low-molecular-weight zinc-binding proteins, are able to scavenge free radicals, including hydroxyl radicals implicated in PD. In addition, metallothionein averts α-synuclein nitration, enhances the elaboration of coenzyme Q10, increases the activity of complex I and the synthesis of ATP, and as an antioxidant is 50 times more potent than GSH. This growing recognition of the mechanisms and pathways potentially involved in the death of dopaminergic neurons in PD is leading to an ever-expanding array of investigative approaches whose aim is to achieve effective neuroprotective or even neurorestorative treatment. Avenues being investigated encompass not only traditional (and nontraditional) pharmacological approaches, but also innovative and frontiercrossing surgical and other modalities such as gene therapy, stem cell therapy, and neurotransplantation. In this volume, an impressive armada of authorities has been assembled to address the challenging topic of PD. Historical background, basic neuropathological and neurophysiological characteristics, epidemiological considerations, clinical features, current treatment approaches, and potential future therapeutic modalities of PD are addressed in a fashion that is, we hope, both comprehensive and comprehensible.

The editors also fervently hope that in 2017, when the 200th anniversary of James Parkinson’s original description of the disease that now bears his name is marked, it will be firmly established fact that the etiology of the disease has been unraveled, unfailingly effective treatment established, and its cause(s) averted. M.Ebadi, Ph.D. Grand Forks, North Dakota R.Pfeiffer, M.D. Memphis, Tennessee

Acknowledgments The authors express their appreciation to Barbara Norwitz, Life Sciences publisher for CRC Press, for her gracious invitation to prepare a book on Parkinson’s disease. The authors acknowledge the effort of Patricia Roberson, the project coordinator assigned to bring this manuscript to completion. The authors salute the magnificent contributions of Gail Renard, production e ditor, and her capable staff for polishing and refining this book. The authors remain grateful to Jeffrey K.Eckert for his diligence in preparing and typesetting all chapters and producing the book in a timely fashion. The authors express their delight and joy in the artistic talent of Victoria Swift in completing various art works for the book. The authors appreciate the secretarial assistance of Lori Wagner and JoAnn Johnson (UND) and Sharon Williams (UT) in helping in the various stages of preparing this book. The authors remain indebted to Dani Stramer for her relentless dedication to her job, unmatched work ethics, and incredible secretarial skills in typing various chapters and supervising the composition of this project. Ronald Pfeiffer, M.D., expresses his sincere appreciation to William Pulsinelli, M.D., Ph.D., Chairman of the Department of Neurology, University of Tennessee, College of Medicine, for his visionary leadership and support of the Division of Neurodegenerative Diseases. Manuchair Ebadi, Ph.D., pays an affectionate tribute and extends his heartfelt gratitude to H.David Wilson, M.D., Dean and Vice President for Health Affairs, University of North Dakota School of Medicine and Health Sciences, for his unyielding support, solomonic wisdom, and genuine friendship in facilitating the completion of this book.

About the Editors

Manuchair Ebadi earned a B.S.degree in chemistry from Park University (Parkville, Missouri, 1960), an M.S. degree in pharmacology from the University of Missouri College of Pharmacy (Kansas City, 1962), and a Ph.D. degree in pharmacology from the University of Missouri College of Medicine (Columbia, 1967). He completed his postdoctoral training in the Laboratory of Preclinical Pharmacology at the National Institute of Mental Health (Washington, D.C., 1970), under the able direction of Erminio Costa, M.D., an eminent member of the National Academy of Sciences. Dr. Ebadi served as Chairman of the Department of Pharmacology at the University of Nebraska College of Medicine from 1970 until 1988, and subsequently as Professor of Pharmacology, Neurology, and Psychiatry from 1988 through 1999. In July 1999, he was appointed Professor and Chairman of the Department of Pharmacology and Toxicology at the University of North Dakota School of Medicine and Health Sciences. In September 1999, Dr. Ebadi became Professor and Chairman of the newly created Department of Pharmacology, Physiology, and Therapeutics; in November 1999, he became Professor of Neuroscience; and in December 1999, he was appointed Associate Dean for Research and Program Development. In September 2000, Dr. Ebadi was appointed Director of the Center of Excellence in Neurosciences at the University of North Dakota School of Medicine and Health Sciences, and in March 2002, Associate Vice President for Medical Research at the University of North Dakota. During his academic career, Professor Ebadi has received 36 awards, including the Burlington Northern Faculty Achievement Award (1987), the University of Nebraska’s system-wide Outstanding Teaching and Creative Activity Award (1995); and was inducted into the Golden Apple Hall of Fame (1995) for having received 11 Golden Apple awards. He is a member of 18 research and scholarly societies including Alpha Omega Alpha Honor Medical Society. In 1976, Dr. Ebadi became the Mid-America State Universities Association (MASUA) honor lecturer; in 1987, he received an award for Meritorious Contributions to

Pharmaceutical Sciences from the University of Missouri Alumni Association; in 1995, he was honored by a Resolution and Commendation of the Board of Regents of the University of Nebraska for having developed a sustained record of excellence in teaching, including creative instructional methodology; and in 1996, he received the Distinguished Alumni Award from Park University, his alma mater. In November 2002, Dr. Ebadi received a Recognition Award in appreciation of his outstanding contribution to the UND School of Medicine. In May 2003, Dr. Ebadi received the Outstanding Block Instructor Award for outstanding performance “in the encouragement, enrichment, and education of tomorrow’s physicians.” In 2003, Dr. Ebadi was elected to the Prestigious Cosmos Club (Washington, D.C.) for individuals who have distinguished themselves in art, literature, or science. Professor Ebadi discovered and characterized brain metallothioneins isoforms in 1983 and subsequently showed that they are able to scavenge free radicals implicated in Parkinson’s disease. In addition, he showed that metallothionein averts α-synuclein nitration, enhances the elaboration of coenzyme Q10, increases the activity of complex I, enhances the synthesis of ATP, and as an antioxidant is fifty times more potent than glutathione. His research programs have been supported in the past and currently by the National Institute on Aging (AG 1705906); the National Institute of Environmental Health Sciences (NIEHS 03949); the National Institute of Child Health and Human Development (NICHD 00370); the National Institute of Neurological Disorders and Stroke (NINDS 08932, NINDS 34566, and NINDS 40160); and the Office of National Drug Control Policy, Counter Drug Technology Assessments Center (DATM 05–02-C1252). Professor Ebadi has written seven textbooks. The Pharmacology text was translated into Japanese in 1987 (Medical Science International LTD, Tokyo); the Core Concepts in Pharmacology was translated into Chinese in 2002 (Ho-Chi Book Publishing of Taiwan); and the Pharmacodynamic Basis of Herbal Medicine (CRC Press 2002) became a best seller. On February 26, 2004, Dr. Ebadi received the University of North Dakota Foundation’s Thomas J.Clifford Faculty Achievement Award for Excellence in Research and, on September 7, 2004, he received from President Charles E.Kupchella, the designation of Chester Fritz Distinguished Professor of Pharmacology, the highest honor bestowed by the University of North Dakota.

Ronald Frederick Pfeiffer earned a B.S. degree from the University of Nebraska (Lincoln, 1969), graduating with honors and becoming a member of Phi Beta Kappa. He completed his M.D. degree at the University of Nebraska College of Medicine (Omaha, 1973). Dr. Pfeiffer completed his internship in internal medicine (1974) and residency in neurology (1977) at Walter Reed Army Medical Center in Washington, D.C. Dr. Pfeiffer completed a student research fellowship in the Laboratory of Preclinical Pharmacology (1972) under the able direction of Erminio Costa, an eminent member of the National Academy of Sciences. From 1975 to 1977, during his neurology residency, he was a guest fellow at the Experimental Therapeutics Branch, NINDS, participating in research programs under the tutelage of D.B.Calne, D.M. In 2001, Professor Pfeiffer received an honorary Doctor of Laws degree from Concordia University in Nebraska. Dr. Pfeiffer served as Professor and Chief of the Section of Neurology (1987–1993) at the University of Nebraska College of Medicine. Thereafter, he was appointed Professor of Neurology (1994-present) and then Vice Chairman of the Department of Neurology (1996-present) at the University of Tennessee College of Medicine. Professor Pfeiffer is board certified in psychiatry and neurology (1979-present) and is a member of various medical and scientific societies, including the American Neurological Association. He has participated in numerous clinical trials of experimental agents for the treatment of PD and has written and lectured extensively about nonmotor aspects of PD, especially GI dysfunction.

Contributors John R.Adams, M.D., M.Sc. Neurodegenerative Disorders Centre Vancouver, BC, Canada J.Eric Ahlskog, M.D., Ph.D. Department of Neurology Mayo Clinic Rochester, MN Amornpan Ajjimaporn, Ph.D. School of Medicine and Health Sciences University of North Dakota Grand Forks, ND Andrea Antal, Ph.D. Department of Clinical Neurophysiology Georg-August University of Göttingen Göttingen, Germany Yasuhiko Baba, M.D. Department of Neurology Mayo Clinic Jacksonville, FL Yacov Balash, M.D., Ph.D. Movement Disorders Unit Department of Neurology Tel Aviv Sourasky Medical Center Tel Aviv, Israel Anne L.Barba, Ph.D. Parkinson’s Disease and Movement Disorders Center Albany Medical Center Albany, NY John Bertoni, M.D., Ph.D. Department of Neurology Creighton University Omaha, NE

Pierre J.Blanchet, M.D., Ph.D. Department of Stomatology University of Montreal Montreal, Canada Ivan Bodis-Wollner, M.D., DSC Department of Neurology SUNY Health Science Center at Brooklyn Brooklyn, NY Daryl Bohac, Ph.D. Department of Psychiatry University of Nebraska Medical Center Omaha, NE William Burke, M.D. Department of Psychiatry University of Nebraska Medical Center Omaha, NE L.Cartwright, B.Sc. Department of Medicine Edgbaston, Birmingham, UK Donald B.Calne, D.M., F.R.S.C. Pacific Parkinson’s Research Centre Vancouver Hospital and Health Sciences Centre Vancouver, BC, Canada Susan Calne, C.M., R.N. Pacific Parkinson’s Research Centre University Hospital UBC Vancouver, BC, Canada M.Angela Cenci, M.D., Ph.D. Wallenberg Neurosciences Center Neurobiology Division University of Lund Lund, Sweden Jaturaporn Chagkutip, Ph.D. University of North Dakota School of Medicine and Health Sciences Grand Forks, ND

Kelvin L.Chou, M.D. Department of Clinical Neurosciences Brown University School of Medicine, and Division of Neurology Memorial Hospital of Rhode Island Pawtucket, RI Thomas L.Davis, M.D. Division of Movement Disorders Vanderbilt University School of Medicine Nashville, TN Ruth Djaldetti, M.D. Department of Neurology Sackler Medical School Tel Aviv University Tel Aviv, Israel John E.Duda, M.D. Department of Neurology University of Pennsylvania School of Medicine and Parkinson’s Disease Research, Education and Clinical Center Philadelphia Veterans Affairs Medical Center Philadelphia, PA Manuchair Ebadi, Ph.D. Department of Pharmacology, Physiology and Therapeutics University of North Dakota School of Medicine & Health Sciences Grand Forks, ND Larry Elmer, M.D., Ph.D. Department of Neurology Medical College of Ohio Toledo, OH Stewart A.Factor, D.O. Department of Neurology Albany Medical College Albany, NY Ciaran J.Faherty, Ph.D. Department of Developmental Neurobiology St. Jude Children’s Research Hospital Memphis, TN

Stanley Fahn, M.D. Columbia University College of Physicians and Surgeons New York, NY Robert G.Feldman, M.D. Department of Neurology and Pharmacology and Environmental Health Boston University Schools of Medicine and Public Health Boston, MA Blair Ford, M.D. Center for Parkinson’s Disease Columbia-Presbyterian Medical Center New York, NY Tatiana Foroud, Ph.D. Department of Medical and Molecular Genetics Indiana University School of Medicine Indianapolis, IN Joseph H.Friedman, M.D. Department of Clinical Neurosciences Brown University School of Medicine Providence, RI Raul de la Fuente-Fernandez, M.D. Neurodegenerative Disorders Centre University of British Columbia Vancouver, BC, Canada Carol Ewing Garber, Ph.D. Department of Cardiopulmonary and Exercise Sciences Bouve College of Health Sciences Northeastern University Boston, MA Gaëtan Garraux, M.D. Human Motor Control Section NINDS, NIH Bethesda, MD Thomas Gasser, M.D. Department of Neurodegenerative Disorders Hertie-Institute for Clinical Brain Research and Program Development

University of Tubingen Tubingen, Germany Nir Giladi, M.D. Movement Disorders Unit Department of Neurology Tel Aviv Sourasky Medical Center Tel Aviv, Israel Christopher G.Goetz, M.D. Rush University Medical Center Chicago, IL Lawrence I.Golbe, M.D. Department of Neurology UMDNJ—Robert Wood Johnson Medical School New Brunswick, NJ Jennifer G.Goldman, M.D. Rush University Medical Center Chicago, IL John L.Goudreau, D.O., Ph.D. Department of Neurology Department of Pharmacology and Toxicology Michigan State University East Lansing, MI J.Timothy Greenamyre, M.D., Ph.D. Department of Neurology Emory University Atlanta, GA James G.Greene, M.D., Ph.D. Department of Neurology Emory University Atlanta, GA Ruth A.Hagestuen, R.N., M.A. National Parkinson Foundation Miami, FL Mark Hallett, M.D. Human Motor Control Section NINDS, NIH Bethesda, MD

Svenja Happe, M.D. Department of Clinical Neurophysiology University of Göttingen Göttingen, Germany Jeffrey M.Hausdorff, Ph.D. Sackler School of Medicine Tel Aviv University Tel Aviv, Israel Robert A.Hauser, M.D., M.B.A. Department of Neurology Movement Disorder Center University of South Florida Tampa, FL Donald S.Higgins, M.D. Parkinson’s Disease and Movement Disorders Center Albany Medical Center Albany, NY S.L.Ho, M.D. Division of Neurology Department of Medicine University of Hong Kong, China Robert G.Holloway, M.D., M.P.H. Department of Neurology University of Rochester School of Medicine and Dentistry Rochester, NY Sandra L.Holten, M.T., B.C. Struthers Parkinson’s Center Golden Valley, MN Zhigao Huang, M.D., Ph.D. Pacific Parkinson’s Research Centre Vancouver Hospital and Health Sciences Centre Vancouver, BC, Canada Serena W.Hung, M.D. Toronto West Hospital Movement Disorders Clinic Division of Neurology Toronto, ON, Canada

Howard I.Hurtig, M.D. Department of Neurology University of Pennsylvania Health Systems Parkinson’s Disease and Movement Disorders Center Pennsylvania Hospital Philadelphia, PA Bahman Jabbari, M.D. Yale University School of Medicine New Haven, CT Michael W.Jakowec, Ph.D. Department of Neurology Keck School of Medicine University of Southern California Los Angeles, CA Joseph Jankovic, M.D. Department of Neurology Parkinson Disease Center Baylor College of Medicine Houston, TX Danna Jennings, M.D. Department of Neurology The Institute for Neurodegenerative Disorders New Haven, CT Monica Korell, M.Ph. The Parkinson’s Institute Sunnyvale, CA Ajit Kumar, D.M. Pacific Parkinson’s Research Centre Vancouver Hospital and Health Sciences Centre Vancouver, BC, Canada Sandra Kuniyoshi, M.D., Ph.D. Department of Neurology Parkinson Disease Center and Movement Disorders Clinic Baylor College of Medicine Houston, TX

Roger Kurlan, M.D. Department of Neurology University of Rochester Rochester, NY Anthony E.Lang, M.D., F.R.C.R Toronto West Hospital Movement Disorders Clinic Division of Neurology Toronto, ON, Canada Yuen-Sum Lau, Ph.D. Division of Pharmacology School of Pharmacy University of Missouri, Kansas City Kansas City, MO Mark S.LeDoux, M.D., Ph.D. Department of Neurology University of Tennessee Health Science Center Memphis, TN Stuart E.Leff, Ph.D. Emory University Atlanta, GA Sarah C.Lidstone, B.Sc. Pacific Parkinson’s Research Centre Vancouver, BC, Canada Kelly E.Lyons, Ph.D. Department of Neurology University of Kansas Medical Center Kansas City, KS Scott Maanum Department of Pharmacology School of Medicine and Health Services University of North Dakota Grand Forks, ND Kirsten Maier, M.A. Pacific Parkinson’s Research Centre Vancouver Hospital and Health Sciences Centre Vancouver, BC, Canada

Ronald J.Mandel, Ph.D. Department of Neuroscience Powell Gene Therapy Center McKnight Brain Institute University of Florida College of Medicine Gainesville, FL Fredric P.Manfredsson, B.S. Department of Neuroscience Powell Gene Therapy Center McKnight Brain Institute University of Florida College of Medicine Gainesville, FL Ken Marek, M.D. Department of Neurology The Institute for Neurodegenerative Disorders New Haven, CT Katerina Markopoulou, M.D., Ph.D. Department of Neurology University of Nebraska Medical Center Omaha, NE Christopher J.Mathias, D.Phil., D.S.C., F.R.C.P. Imperial College School of Medicine St. Mary’s Hospital London, UK Eldad Melamed, M.D. Department of Neurology Rabin Medical Center, Beilinson Campus Sackler Medical School Tel Aviv University Tel Aviv, Israel Yoshikuni Mizuno, M.D. Department of Neurology Juntendo University School of Medicine Tokyo, Japan Eric S.Molho, M.D. Department of Neurology Albany Medical College Albany, NY

Erwin B.Montgomery, Jr., M.D. Department of Neurology National Regional Primate Center University of Wisconsin—Madison Madison, WI John C.Morgan, M.D., Ph.D. Department of Neurology Medical College of Georgia Augusta, GA L.Charles Murrin, Ph.D. Department of Pharmacology Nebraska Medical Center Omaha, NE Lisa A.Newman, Sc.D. Army Audiology and Speech Center Walter Reed Army Medical Center Washington, DC Ann Nolen, Psy., O.T.R. University of Tennessee Health Science Center, CAHS Memphis, TN Katia Noyes, Ph.D., M.P.H. Department of Neurology University of Rochester School of Medicine and Dentistry Rochester, NY Padraig O’Suilleabhain, M.B., B.Ch. Department of Neurology University of Texas, Southwestern Medical School Dallas, TX Rajesh Pahwa, M.D. Department of Neurology University of Kansas Medical Center Kansas City, KS Pramod Kumar Pal, D.M. National Institute of Mental Health and Neurosciences (NIMHANS) Bangalore, India

Nathan Pankratz, Ph.D. Department of Medical and Molecular Genetics Indiana University School of Medicine Indianapolis, IN R.B.Parsons, Ph.D. School of Biosciences Edgbaston, Birmingham, UK Walter Paulus, M.D. Department of Clinical Neurophysiology Georg-August University of Göttingen Göttingen, Germany Rene Pazdan, M.D. Department of Neurology Uniformed Services University Bethesda, MD Carmen S.Peden, Ph.D. Department of Neuroscience Powell Gene Therapy Center McKnight Brain Institute University of Florida College of Medicine Gainesville, FL Ronald F.Pfeiffer, M.D. Department of Neurology University of Tennessee Health Science Center Memphis, TN Giselle M.Petzinger, M.D. Department of Neurology Keck School of Medicine University of Southern California Los Angeles, CA Brad A.Racette, M.D. Department of Neurology Washington University School of Medicine St. Louis, MO Ali H.Rajput, M.D. Royal University Hospital University of Saskatchewan Saskatoon, SK, Canada

D.B.Ramsden, Ph.D. Queen Elizabeth Hospital Edgbaston, Birmingham, UK Marcia H.Ratner, Ph.D. Departments of Neurology and Pharmacology Boston University School of Medicine Boston, MA Christopher A.Robinson, B.Sc., M.Sc., M.D., F.R.C.P.C. Department of Pathology Royal University Hospital University of Saskatchewan and Saskatoon Health Region Saskatoon, SK, Canada Robert L.Rodnitzky, M.D. Department of Neurology University of Iowa Hospital Iowa City, IA Edgardo Rodriguez, Ph.D. Department of Neuroscience Powell Gene Therapy Center McKnight Brain Institute University of Florida College of Medicine Gainesville, FL Anthony J.Santiago, M.D. Parkinson’s Disease and Movement Disorders Center Albany Medical Center Albany, NY John Seibyl, M.D. Department of Neurology The Institute for Neurodegenerative Disorders New Haven, CT Kapil D.Sethi, M.D. Department of Neurology Medical College of Georgia Augusta, GA Surya Shah, Ph.D. College of Allied Health Sciences University of Tennessee Health Science Center Memphis, TN

Kathleen M.Shannon, M.D. Department Neurological Sciences Rush Presbyterian St. Luke’s Medical Center Chicago, IL Sushil K.Sharma, Ph.D. University of North Dakota School of Medicine and Health Sciences Grand Forks, ND Shaik Shavali, Ph.D. University of North Dakota School of Medicine and Health Sciences Grand Forks, ND Holly Shill, M.D. Muhammad Ali Parkinson Research Center Phoenix, AZ Andrew Siderowf, M.D. Department of Neurology University of Pennsylvania Philadelphia, PA Carlos Singer, M.D. Department of Neurology University of Miami Miami, FL Richard J.Smeyne, Ph.D. Department of Developmental Neurobiology St. Jude Children’s Research Hospital Memphis, TN S.W.Smith, M.B.Ch.B. Department of Medicine Edgbaston, Birmingham, UK Janice Smolowitz, R.N., Ed.D., ANP Neurological Institute Columbia University New York, NY Dennis A.Steindler, Ph.D. Department of Neuroscience McKnight Brain Institute

University of Florida College of Medicine Gainesville, FL Matthew B.Stern, M.D. Parkinson’s Disease Research, Education and Clinical Center Philadelphia Veteran’s Affairs Medical Center University of Pennsylvania School of Medicine Parkinson’s Disease and Movement Disorders Center Pennsylvania Hospital Philadelphia, PA A.Jon Stoessl, M.D., F.R.C.P.C. Neurodegenerative Disorders Centre University of British Columbia Vancouver, BC, Canada Daniel Strickland, MSPH, Ph.D. Kaiser Permanente, Southern California Pasadena, CA Oksana Suchowersky, M.D., F.R.C.P. Department of Clinical Neurosciences University of Calgary Calgary, AB, Canada Caroline M.Tanner, M.D., Ph.D. The Parkinson’s Institute Sunnyvale, CA Daniel Tarsy, M.D. Department of Neurology Harvard Medical School Movement Disorders Center Boston, MA James W.Tetrud, M.D. Movement Disorders Treatment Center The Parkinson’s Institute Sunnyvale, CA Claudia M.Trenkwalder, M.D. Center of Parkinsonism and Movement Disorders University of Göttingen Göttingen, Germany

Michael Trew, M.D., F.R.C.P.C. Department of Psychiatry University of Calgary Calgary Health Region Calgary, AB, Canada Joel M.Trugman, M.D. Department of Neurology University of Virginia Health System Charlottesville, VA Ryan J.Uitti, M.D. Department of Neurology Mayo Clinic Jacksonville, FL Mayo Clinic College of Medicine Rochester, MN Leo Verhagen Metman, M.D., Ph.D. Department of Neurological Sciences Rush University Medical Center Chicago, IL Mervat Wahba, M.D. Movement Disorder Center Department of Neurology University of South Florida Tampa, FL Sawitri Wanpen, Ph.D. University of North Dakota School of Medicine and Health Sciences Grand Forks, ND R.H.Waring, D.Sc. School of Biosciences Edgbaston, Birmingham, UK Cheryl Waters, M.D., F.R.C.P. Neurological Institute Columbia University New York, NY

Mickie D.Welsh, R.N., D.N.Sc. Keck School of Medicine University of Southern California Los Angeles, CA Steven P.Wengel, M.D. Department of Psychiatry University of Nebraska Medical Center Omaha, NE Robert E.Wharen, Jr. M.D. Department of Neurology Mayo Clinic Jacksonville, FL Mayo Clinic College of Medicine Rochester, MN Rose Wichmann, P.T. Struthers Parkinson’s Center Golden Valley, MN A.C.Williams, M.D., F.R.C.P. Queen Elizabeth Hospital Edgbaston, Birmingham, UK James B.Wood, M.D. Department of Radiology Veterans Affairs Medical Center Memphis, TN Zbigniew K.Wszolek, M.D. Department of Neurology Mayo Clinic Jacksonville, FL Mayo Clinic College of Medicine Rochester, MN Theresa A.Zesiewicz, M.D. Movement Disorder Center Department of Neurology University of South Florida Tampa, FL

Table of Contents I. Overview Chapter James Parkinson 1 Jennifer G.Goldman and Christopher G.Goetz

1

Chapter Paralysis Agitans—Refining the Diagnosis and Treatment 2 Larry Elmer

16

Chapter The Role of Dopamine in Parkinson’s Disease: A Historical Review 3 L.Charles Murrin

32

Chapter Parkinson’s Disease: Where Are We? 4 Ajit Kumar, Zhigao Huang, and Donald B.Calne

40

II. Epidemiology Chapter Epidemiology of Parkinson’s Disease: An Overview 5 Monica Korell and Caroline M.Tanner

59

Chapter Environmental Toxins and Parkinson’s Disease 6 Marcia H.Ratner and Robert G.Feldman

77

Chapter Rural Environment and Parkinson’s Disease 7 Daniel Strickland

96

Chapter Industrial and Occupational Exposures and Parkinson’s Disease 8 Brad A.Racette

111

Chapter Tetrahydroisoquinolines and Parkinson’s Disease 9 Mark S.LeDoux

122

Chapter Xenobiotic Metabolism and Idiopathic Parkinson’s Disease 10 L.Cartwright, D.B.Ramsden, S.W.Smith, R.H.Waring, R.B.Parsons, S.L.Ho, and A.C.Williams Chapter Progressive Neurodegeneration in the Chronic MPTP/Probenecid 11 Model of Parkinson’s Disease Yuen-Sum Lau

147

166

III. Genetics Chapter Alpha-Synuclein and Parkinson’s Disease. 12 Lawrence I.Golbe

177

Chapter Parkin and Its Role in Parkinson’s Disease 13 Thomas Gasser

194

Chapter Heredofamilial Parkinsonism 14 Pramod Kumar Pal and Zbigniew K.Wszolek

208

Chapter Other Mutations: Their Role in Parkinson’s Disease 15 Nathan Pankratz and Tatiana Foroud

239

IV. Clinical Features of Parkinson’s Disease Chapter Classical Motor Features of Parkinson’s Disease 16 Kelvin L.Chou and Howard I.Hurtig

258

Chapter Clinical Evaluation and Treatment of Gait Disorders in Parkinson’s 17 Disease Yacov Balash, Jeffrey M.Hausdorff, and Nir Giladi

275

A. Nonmotor Symptoms Chapter Sensory Symptoms and Sensorimotor Distortion in Parkinson’s 18 Disease Padraig O’Suilleabhain Chapter Pain in Parkinson’s Disease 19 Blair Ford

286

Chapter Fatigue: A Common Comorbidity in Parkinson’s Disease 20 Carol Ewing Garber and Joseph H.Friedman

313

Chapter Sleep Disorders in Parkinson’s Disease 21 Svenja Happe and Claudia M.Trenkwalder

325

Chapter Visual Function in Parkinson’s Disease 22 Robert L.Rodnitzky

344

Chapter Visuocognitive Dysfunctions in Parkinson’s Disease 23 Andrea Antal, Walter Paulus, and Ivan Bodis-Wollner

357

Chapter Olfactory Dysfunction in Parkinson’s Disease and Parkinsonian 24 Syndromes Katerina Markopoulou

376

298

B. Autonomic Dysfunction Chapter Gastrointestinal Dysfunction in Parkinson’s Disease 25 Ronald F.Pfeiffer

391

Chapter Urinary Dysfunction in Parkinson’s Disease 26 Carlos Singer

416

Chapter Sexual Dysfunction 27 Cheryl Waters and Janice Smolowitz

434

Chapter Cardiovascular Autonomic Dysfunction in Parkinson’s Disease and 28 Parkinsonian Syndromes Christopher J.Mathias Chapter Disorders of Thermoregulation in Parkinson’s Disease 29 Thomas L.Davis

446

Chapter Respiratory Dysfunction. 30 Holly Shill

493

487

C. Behavioral Dysfunction Chapter Depression in Parkinson’s Disease 31 Steven P.Wengel, Daryl Bohac, and William J.Burke

502

Chapter Anxiety and Parkinson’s Disease 32 Oksana Suchowersky and Michael Trew

517

Chapter Dementia in Parkinson’s Disease 33 Anne L.Barba, Eric S.Molho, Donald S.Higgins, Anthony J.Santiago, and Stewart A.Factor

529

V. Pathophysiology of Parkinson’s Disease Chapter Animal Models of Basal Ganglia Injury and Degeneration and Their 34 Application to Parkinson’s Disease Research Giselle M.Petzinger and Michael W.Jakowec Chapter The Neuropathology of Parkinson’s Disease and Other 35 Parkinsonian Disorders Christopher A.Robinson and Ali H.Rajput Chapter Pathophysiology of the Motor Disorder 36 Gaëtan Garraux and Mark Hallett

560

611

638

A. Neurochemical Pathology Chapter MPTP Disrupts Dopamine Receptors and Dopamine Transporters 37 Manuchair Ebadi and Jaturaporn Chagkutip

659

Chapter Pathophysiology of Parkinson’s Disease, Neurochemical Pathology: 38 Other Neurotransmitters. Yoshikuni Mizuno

676

B. Theories of Pathogenesis Chapter Metallothionein Isoforms Attenuate Peroxynitrite-Induced 39 Oxidative Stress in Parkinson’s Disease Manuchair Ebadi, Sushil K.Sharma, Sawitri Wanpen, and Shaik Shavali Chapter Excitotoxicity in Parkinson’s Disease 40 James G.Greene and J.Timothy Greenamyre

731

Chapter Inflammation. 41 Roger Kurlan

787

Chapter Cell Death in Parkinson’s Disease 42 Ciaran J.Faherty and Richard J.Smeyne

811

Chapter Weaver Mutant Mouse in Progression of Neurodegeneration in 43 Parkinson’s Disease Manuchair Ebadi, Sushil K.Sharma, Amornporn Ajjimaporn, and Scott Maanum

832

766

VI. Diagnosis of Parkinson’s Disease Chapter Differential Diagnosis of Parkinson’s Disease 44 Serena W.Hung and Anthony E.Lang

863

Chapter Diagnostic Criteria for Parkinson’s Disease 45 Daniel Tarsy

883

Chapter Neuroleptic-Induced Movement Disorders 46 Manuchair Ebadi

898

Chapter The Placebo Effect in Parkinson’s Disease 47 Sarah C.Lidstone, Raul de la Fuente-Fernandez, and A. Jon Stoessl

966

Chapter Dopamine Transporter Imaging Using SPECT in Parkinson’s 48 Disease Danna Jennings, Ken Marek, and John Seibyl

978

Chapter MR Imaging of Parkinsonism 49 James B.Wood

994

Chapter Clinical Batteries 50 Erwin B.Montgomery, Jr.

1017

Chapter Rating Scales 51 Kathleen M.Shannon

1030

VII. Treatment of Parkinson’s Disease

A. Symptomatic Medical Treatment Chapter Treatment of Parkinson’s Disease with Anticholinergic Medications 1053 52 Bahman Jabbari and Rene Pazdan Chapter Amantadine 53 Kelly E.Lyons and Rajesh Pahwa

1065

Chapter The Role of MAO-B Inhibitors in the Treatment of Parkinson’s 54 Disease John Bertoni and Larry Elmer Chapter Catechol-O-Methyltransferase Inhibitors in the Treatment of 55 Parkinson’s Disease Mervat Wahba, Theresa A.Zesiewicz, and Robert A. Hauser Chapter Symptomatic Treatment of Parkinson’s Disease: Levodopa 56 John L.Goudreau and J.Eric Ahlskog

1074

Chapter Dopamine Agonists in Parkinson’s Disease 57 Sandra Kuniyoshi and Joseph Jankovic

1134

1095

1107

B. Surgical Treatment Chapter Parkinson’s Disease: Surgical Treatment—Stereotactic Procedures 58 Yasuhiko Baba, Robert E.Wharen, Jr., and Ryan J.Uitti

1158

Chapter Neurotransplantation in Parkinson’s Disease 59 Ronald F.Pfeiffer

1193

C. Nonpharmacological Treatment Modalities Chapter The Role of Physical Therapy in Management of Parkinson’s 60 Disease Rose Wichmann Chapter Swallowing Function in Parkinson’s Disease 61 Lisa A.Newman

1208

Chapter Restorative and Psychosocial Occupational Therapy in Parkinson’s 62 Disease Surya Shah and Ann Nolen Chapter Music Therapy for People with Parkinson’s 63 Sandra L.Holten

1232

1220

1257

D. Treatment Issues Chapter Pathogenesis of Motor Response Complications in Parkinson’s 64 Disease: “Mere Conjectural Suggestions” and Beyond Leo Verhagen Metman Chapter Treatment of Early Parkinson’s Disease 65 John C.Morgan and Kapil D.Sethi

1272

Chapter Moderate Parkinson’s Disease 66 John E.Duda and Matthew B.Stern

1320

Chapter Management of Advanced Parkinson’s Disease 67 James W.Tetrud

1332

1302

E. Potential Future Therapy Chapter Future Symptomatic Therapy in Parkinson’s Disease 68 Ruth Djaldetti and Eldad Melamed

1354

Chapter Restorative Therapy in Parkinson’s Disease 69 Joel M.Trugman

1369

Chapter Gene Therapy for Parkinson’s Disease 70 Ronald J.Mandel, Edgardo Rodriguez, M.Angela Cenci, Stuart E.Leff, Fredric P.Manfredsson, and Carmen S. Peden Chapter Translating Stem Cell Biology to Regenerative Medicine for 71 Parkinson’s Disease Dennis A.Steindler

1380

1429

F. Clinical Trials Chapter Alternative Drug Delivery in the Treatment of Parkinson’s Disease 72 Pierre J.Blanchet

1463

Chapter The Role and Designs of Clinical Trials for Parkinson’s Disease 73 Andrew Siderowf and Stanley Fahn

1495

Chapter Positron Emission Tomography in Parkinson’s Disease 74 John R.Adams and A.Jon Stoessl

1516

VIII. Social Issues in Parkinson’s Disease Chapter Economics of Parkinson’s Disease 75 Katia Noyes and Robert G.Holloway

1537

Chapter Informal Caregivers: A Valuable Part of the Health Care Team 76 Kirsten Maier and Susan Calne

1552

Chapter Quality of Life in Parkinson’s Disease: A Conceptual Model 77 Mickie D.Welsh

1567

Chapter The Evolution and Potential of the National Parkinson 78 Organizations: A Brief Overview Ruth A.Hagestuen

1578

Index

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1 James Parkinson Jennifer G.Goldman and Christopher G.Goetz Rush University Medical Center 0-8493-1590-5/05/$0.00+$1.50 © 2005 by CRC Press

Although James Parkinson may be best remembered in the medical profession for his Essay on the Shaking Palsy (1817) describing cases of paralysis agitans, he was also a prolific and respected writer in other fields such as politics, social reform, mental health, chemistry, and geology. His writings demonstrate his keen sense of observation, breadth of knowledge, and devotion to humanity. This introductory chapter explores the background of James Parkinson, his medical training, his writings on diverse subjects, and lastly, the contributions of his Essay on the Shaking Palsy. FAMILY MEDICAL TRADITION James Parkinson was born on April 11, 1755, at No. 1 Hoxton Square in the parish of St. Leonard’s, Shoreditch, England, to John and Mary Parkinson. Hoxton, now a London neighborhood but then a separate village, grew from a medieval town to a place of gardens and large residential homes in the seventeenth and eighteenth centuries. Subsequently, Hoxton ceded to industrial development, overcrowding, and poverty in the eighteenth and nineteenth centuries.1–4 The parish church of St. Leonard’s remained a focal point, and here Parkinson was baptized, married, and buried. Parkinson practiced medicine nearby in a two-storied house behind the main house at No. 1 Hoxton Square. He was born into the medical tradition, as his father John Parkinson was an apothecary and surgeon in Hoxton for many years. While James was a child, his father received the Grand Diploma of the Corporation of Surgeons of London in 1765 and served as Anatomical Warden of the Company at Surgeon’s Hall from 1775 to 1776.1,5 It is possible that James Parkinson’s apprenticeship to his father included anatomical studies.6,7 While an apprentice, James often accompanied his father on resuscitation and recovery operations for the Royal Humane Society. The father and son team published several cases illustrating their resuscitative measures.1 Regarding family life, it is known that James Parkinson had a younger brother, William, and a sister, Mary Sedgwick, who married Parkinson’s close friend, John Keys. During his apprenticeship, James Parkinson married Mary Dale in 1781 in St. Leonard’s church. James and Mary Parkinson had six children, of which one, John William Keys (b. 1785), became a physician.1,2 James Parkinson served as an apprentice to his father from 1802 to 1808 and then received his diploma from the Royal College of Surgeons. He joined his father in medical practice at No. 1 Hoxton Square, where he practiced until 12

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years after his father’s death. In turn, his son, James Keys, became a Licentiate of the Society of Apothecaries in 1834 and practiced with his father in Hoxton until his father’s death in 1838. James Parkinson died from a stroke at the age of 69 on December 21, 1824, at No. 3 Pleasant Row, Kingsland Road, Hoxton. Addressing the Board of Trustees of the Poor of the Parish of St. Leonard’s, John William Keys Parkinson reported his father’s sudden onset of severe rightsided paralysis and inability to speak. Despite attempts made for his recovery, Parkinson died three days later. MEDICAL EDUCATION Parkinson studied at the London Hospital Medical College for six months in 1776 as one of the school’s earliest medical students.1 While an apprentice, he performed rescues for drownings in London Waterways. He received the Honorary Silver Medal of the Royal Humane Society in 1777 for the rescue of a Hoxton man who had hanged himself, and this case was reported by his father. Parkinson obtained his diploma of the Company of Surgeons in April 1784 shortly after his father’s death. His election to Fellow of the Medical Society of London in 1787 followed the delivery of his first paper to the society. This paper, “Some Account of the Effects of Lightning,” (1789) describes injuries sustained by two men whose house was struck by lightning.1,8 The description focused on the dermatological and neurological sequelae of lightning injuries. Parkinson attended the surgical lectures of the English surgeon and experimentalist, John Hunter (1728–1793) in 1785.1,5,9 His shorthand notes of the lectures were later transcribed and published by his son, John William Keys, in a volume entitled, Hunterian Reminiscences (1833). Whether Parkinson attended Hunter’s lectures on tremor and paralysis remains speculative. In his notes, Parkinson quotes Hunter’s illustrations of tremor, but these examples date from 1776 and 1786, and his attendance at these particular lectures is not established. Parkinson’s notes cite Hunter’s case on the “wrong actions of parts or tremor.” A lady, at the age of seventy-one, had universal palsy: every part of the body shook which was not fully supported. The muscles of respiration were so affected, that respiration was with difficulty effected; but in sleep the vibratory motions of the muscles ceased, and the respiration was performed more equably: any endeavor of the will to alter these morbid actions increased them.10 In his Croonian lecture on muscular motion in 1776, Hunter portrays the case of Lord L. For instance, Lord L’s hands are almost perpetually in motion, and he never feels the sensation in them of being tired. When he is asleep his hands, &c., are perfectly at rest; but when he wakes in a little time they begin to move.10 Since sources do not indicate that Parkinson was among those pupils identified by Hunter, their acquaintance is not established.10–12

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Overall, little is known about Parkinson’s early medical training, but much information is inferred from his outline of a “sound liberal education” in The Hospital Pupil (1800).13 He was likely versed in Latin and Greek, shorthand, and drawing. In The Hospital Pupil (1800), Parkinson offers opinions on medical education and prerequisites for medical or surgical careers. Written as a letter advising an anonymous friend whose son contemplates a medical career, this book provides a glimpse of medical education in eighteenth century England. In this system, on completion of a common school education, students apprenticed for seven years and then went to a metropolitan hospital to attend lectures and witness the practice for a year or less. Parkinson argues that this model does not adequately train physicians in the community and neglects studies of observation, anatomy, and physiology. Traditionally, the first four or five years were spent “almost entirely appropriated to the compounding of medicines; the art of which, with every habit of necessary exactness, might be just as well obtained in as many months.”13 The remainder of the apprenticeship focused on the “art of bleeding, of dressing a blister, and, for the completion of the climax—of exhibiting an enema.”13 Instead, Parkinson proposes the following curriculum: anatomy, natural philosophy, physiology, chemistry, physics, French, and German during the first two years; clinical lectures during the third year; morbid anatomy and clinical work during the fourth year; and clinical work as a dressing pupil and lectures during the fifth year. Personal characteristics of “sympathetic concern, and a tender interest for the sufferings of others…the object of which should be to mitigate or remove, one great portion of the calamities to which humanity is subject” were deemed important.13 Parkinson even outlines strategies for good study habits, taking notes, maintaining concentration, and optimizing one’s education. He concludes with advice on patient relations and business and legal aspects in medicine. Many of these principles remain true in the current study and practice of medicine. Political Writings and Plots Parkinson’s publications in the decade after his medical career began focused on politics. Dramatic political changes, reforms, and revolutions were occurring in England and France at the time. He belonged to the political societies, Society for Constitutional Information (est. 1780) and the London Corresponding Society (est. 1792), which espoused parliamentary reform, representation of the people, and universal suffrage.1,9 Parkinson’s political beliefs emerged in multiple pamphlets written between 1793 and 1796 under the pseudonym of “Old Hubert.” Several notable works by “Old Hubert” included Pearls cast before Swine (1793) and An Address to the Honorable Edmund Burke from the Swinish Multitude (1793), which refuted antireform sentiments presented in Edmund Burke’s “Reflections on the Revolution in France” (1790).14–16 His political endeavors involved acting as witness before the Privy Council in a trial for high treason regarding the Pop-Gun Plot in 1795. This plot implicated several members of the London Corresponding Society in an attempted assassination of King George III with an air gun. As a witness, Parkinson tried to prevent incrimination of himself in his radical political roles but eventually confessed to being “Old Hubert,” the mysterious political pamphlet author. Despite this revelation, he provided pertinent trial information and helped a prisoner-friend obtain necessary medical attention. After the

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Pop-Gun Plot trial, Parkinson published several political works but shifted his focus to other medical and scientific matters. MEDICAL WRITINGS Parkinson’s publications embrace a multitude of scientific and medical topics. An early work, Observations on Dr. Hugh Smith’s Philosophy of Physic (1780), although published anonymously, already demonstrates his inquisitiveness and writing skills as he questions current scientific theories.1 Merely a young student in medicine, Parkinson challenges Dr. Smith’s ideas on the definition of glands, the role of “Vital Air” in circulation, and respiratory function.1,5 In a politely apologetic but determined, scientific style that recurs in many of his works, Parkinson states in the preface, These observations, Sir, are dedicated to you, with that earnestness, which the subject demands, that deference, which is due you, and that diffidence, which ought to accompany an opposition to opinions, which are said to be founded on experiments and confirmed by physiological researching and the closest method of reasoning.5 Several common themes of environmental injuries and accidents, approaches to common ailments for the lay person, social issues, and medical cases arise in Parkinson’s medical works. Accidents and Dangers Writings on accidents and resuscitation stem from his service as rescuer for the Royal Humane Society. A later work, Dangerous Sports, a Tale Addressed to Children (1808), addresses potential dangers and injuries associated with childhood play and pranks.17 In contrast to other works on injuries, this book assumes a literary quality as a tale for children presented by an old cripple named Millson. The reader meets old lame Millson after he saves the life of a young boy found in the snow with a head wound and hypothermia. The story unfolds as Millson, a guest at the rescued boy’s birthday party, lectures the mischievous children on jumping from high places, throwing stones, swimming, throwing snowballs with pebbles hidden in them, walking on frozen ponds, tasting unknown medications, and playing with gun-powder and pistols. One child’s prank of altering Millson’s crutches causes him to fall. To this child, Millson states, Before you determine on a frolic, consider first the probable consequences; if then you discover it is innocent, and cannot injure any person, or even hurt their feelings, go through it with spirit; but if you see that any one may really suffer by it, give it up at once, for where, for instance, would have been the joke of breaking the legs of such a poor old cripple as I am.17d Millson offers constructive suggestions for safe and productive play. Rather than climbing great heights, he recommends that the leader

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…perform some act of real ingenuity, calling the powers of the mind into action; or some feat of useful dexterity, and let him then be imitated…may it be tried who can get most lines by rote in a certain space of time; who can spell the most difficult words, or who can most readily find the corresponding words, in French, or Latin.17 Question and answer games might incorporate subjects with …some curious circumstance in the natural history of animals and vegetables. In the summer time the exercise might be, to discover the names of the various plants in the fields, and of the trees in the woods. In the evening… the talk might now be to mark the constellations, the planets, and the larger stars.17 Through his protagonist, Parkinson’s curiosity in nature and science shines. Millson amazes the children with a microscope magnifying common objects and electrical experiments that provoke shock-like sensations to the servant, who thinks him a conjuror. Despite concerns that he is a conjuror, Millson instills in the children, as well as the reader, not only a sense of safety and awareness but also an interest in science and nature. Medical Advice for the Public Parkinson wrote several medical handbooks for the lay public. Medical Admonitions (first published in 1799) instructs families to recognize symptoms of both minor and major illnesses.18 The first section includes a table of common symptoms listed alphabetically from Anxiety, “When fever is accompanied by extreme anxiety, the patient sustaining, at the same time, a considerable loss of spirits and strength, the fever may be judged to be of a malignant kind, and to require the most powerful aid,” to Yawning, “Generally occurs at the commencement of the ague fit.”18 In addition to general medical topics such as breathing, palpitations, and swelling, he defines certain neurologic conditions: Convulsions: Of the whole body, with frothing at the mouth, and total loss of sensibility, characterize Epilepsy, or the Falling Sickness; so termed from the subjects of this disease falling suddenly on the coming on of the fit” and “With a sensation as if a ball was rising in the throat, flutterings and rumbling in the bowel, show the disease to be Hysterics. Stupor: After wounds, or blows on the head, requires particular attention. Tremor: In fever, a sign of great disability.18 The majority of the text includes medical information regarding symptoms and treatments with the aim, To prevent you, on the one hand, from unnecessarily incurring the expense of medical attendance in the various trifling ails to which you and your family may be subjected; and, on the other, from sacrificing a friend,

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or perhaps a beloved child, by delay or improper interference, in some insidious disease.18 Parkinson seeks to expose evils arising from quackery and from the wealthy acting as “dispensers of physic to all their poor neighbors;” he would rather that the rich contribute to the community by supporting public hospitals.18 He describes symptoms, treatments, and prevention of a spectrum of diseases ranging from inflammation of different organs; infections with croup, mumps, measles, and smallpox; dental problems of toothaches and teething; to pulmonary consumption; hydrocephalus; cancer; and fractures. Parkinson reiterates his beliefs on studying anatomy, physiology, pathology, and chemistry to understand human disease. He recommends several texts including Dr. Gregory’s Oeconomy of Nature and of the Medical Extracts, the lectures of Dr. A.F.M.Willich, information for nurses by Dr. Hamilton, Physician to the General Dispensary, and instructional material for parents in Dr. Darwin’s Essay on the Education of Females. He includes a section entitled “Observations on the Excessive Indulgence of Children,” which discloses harmful effects of indulgence on health and difficulties occasioned in treatment of illness. He writes of those children, …continually undergoing either disappointment or punishment; or engaged in extorting gratifications, which he often triumphs at having gained by an artful display of passion; his time passes on, until at last the poor child manifests ill nature sufficient to render him odious to all around him, and acquires pride and meanness sufficient to render him the little hated tyrant of his playfellows and inferiors. Can the duties of a parent have been fulfilled in this case? Can the child owe any duty, in return for such conduct? Certainly not.18 Parkinson asserts that indulgence of a child leads to certain diseases and affects a child’s health care “when the expressions of impatience magnify one particular symptom, and conceal the rest; the nicest investigation may prove insufficient to obtain the necessary information.”18 Moreover, indulgent parents often restrict treatments for their children: “The medicines he shall prescribe, he will, very likely, be told, must not only not be illflavored, but, if he expects they shall be gotten down by his patient, they must be absolutely without any taste.”18 The Villager’s Friend and Physician (1800) offers another medical resource for the lay public on disease and health preservation.19 He proposes the following thoughts on exercise, labor, and drunkenness: …moderate and regular labour [which] coils up the main spring of life, but wild and irregular sallies may break it. He that is steady is ever ready. Regular exercise will demand regular rest.19 …would it be if we all knew, as well, the mischiefs arising, from taking a little too frequently, what is called a little drop, so that we might be sufficiently on our guard against that insidious enemy, the love of drink. This is an enemy against whom you should always be on your guard, for he uses every trick of war: sometimes he comes on by flow and

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unheeded approaches; sometimes his attacks are open and violent; and oftentimes will he fight under false colours, and whilst he is received as a friend, cruelly deprive those he has deluded of every comfort, and at last of life itself.19 Parkinson teaches how to assess the severity of fevers and pain. For example, If pain in the head, light-headedness, fever, redness of the eyes, and impatience at viewing much light, or hearing loud noises, succeed to shiverings, INFLAMMATION OF THE BRAIN, OR ITS MEMBRANES may be feared to exist. This must be followed with death in a very few days, if not opposed by the exertions of some skilful person. Bleeding profusely, blisters, the strictest regimen and proper medicines must be here employed, with that degree of firmness and decision, as cannot be hoped for, but where they are directed by a person of real skill, and where the attendants are impressed with the danger of the smallest deviation from orders.19 In contrast, he describes the common cold, …pointed out by the ticking, which occasions a frequent troublesome cough. This may in general be removed by obtaining a copious perspiration at the commencement of the complaint. By drinking freely of treacle posset, vine-gar or orange whey, barley water or gruel; but without having recourse to any considerable increase of bed clothes, or of the temperature of the room. Bleeding in general, is not here necessary.19 Many passages resemble those presented in his Medical Admonitions. Nevertheless, the two books complement each other by elaborating on different aspects of diseases and therapeutic regimens. Social Issues of Child Abuse and Education Although no longer known as “Old Hubert,” Parkinson still expressed his social viewpoints, particularly when related to medical care and reform. Comments on child abuse and parenting appear in The Villager’s Friend and Physician (1800) under the section on “Dropsy of the brain, or watery head,” since vigorous correction of children was another cause of dropsy: Parents too often forget the weight of their hands and the delicate structure of a child. You must excuse the digression—it was but yesterday I passed the cottage of one you all know to have always neglected his children; I heard the plaintive and suppliant cries of a child, and rushed into the cottage; where I saw the father, whose countenance was dreadful, from the strong marks of passion and cruelty which it bore, beating most unmercifully his son, about ten years old.19,20

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In Remarks on Mr. Whitbread’s Plan for the Education of the Poor; with Observations of Sunday School, and on the State of the Apprenticed Poor (1807), Parkinson opposes a bill in the House of Commons to establish parochial schools for the education of poor children in the countryside.21 Parkinson, secretary to St. Leonard’s Sunday school, worries that attendance, and therefore religious and moral education, at the Sunday Schools would suffer. The proposal would “crush those institutions to which religion, morality, and the good order of society are already most highly indebted, and that the establishments which are to succeed these will fail in two most material points—the promoting of industry, and the inculcation of religious sentiments.”21 He anticipates arguments between justices and parish officers in governing the locations, curriculum, and management of the schools. He also discusses the dilemma of eliminating a day of the child’s labor, and thus, family’s income, for the purpose of education. He argues that since Sunday School …prevents no labour, nor the obtaining of the necessary earning, so it does not break in upon nor destroy those habits, on the powerful influence of which chiefly depends the prosperity of the possessor. The varied employments of the Sunday School, the change of scene, and the visit to the church, all excite sufficient interest to make the return of the day of instruction wished for through the succeeding week; whilst, as it opposes not useful habits, it throws no obstacles in the way of industrious exertions.21 Reform measures by Parkinson included the creation of a Register Book for St. Leonard’s Church of children educated in Sunday School who were willing and fit for service. This register provided names, ages, qualifications, and behaviors of the children and whether they might be employed. Often, the unprotected, poor children apprenticed in the parish were “left to almost the unrestrained caprice of their masters, no law existing by which the duties of the master are defined, or any inspectors of his conduct appointed.”21 As a result, Parkinson supported measures to monitor working conditions: …children be apprenticed in the parish whenever proper masters can be obtained…with the direction to apply to him (Vestry clerk) in case of actual ill treatment—that children already apprenticed out of the parish, and within the bills of mortality, be visited by a committee of the trustees and overseers of the poor twice every year.21 Mental Health As a visiting doctor for 30 years to a madhouse in Hoxton, Parkinson gained experience in the area of mental health.22,23 In the late seventeenth and early eighteenth centuries, three private madhouses in Hoxton housed many of the lunatics in London and its surroundings, and conditions were often squalid. The case of Mary Daintree brought Parkinson back to the court of law in a trial in 1810. He had signed a certificate of insanity for Mary Daintree who was confined in Holly House in Hoxton, but she later charged that her relatives conspired to confine her illegally. Parkinson was accused of

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declaring her insane based on her relatives’ testimony rather than the patient’s arguments of sanity. He was much criticized by the newspapers, but after the trial, the newspapers published his account of the case and views on the regulation of madhouses. In Observations on the Act for Regulating Mad-Houses (1811), Parkinson argues that only physicians and surgeons rather than apothecaries should sign orders for confinement to madhouses. One should provide “not merely that such person is a lunatic, but that such person is proper to be received into such house or place as a lunatic.”22 Not all lunatics require confinement, and other maladies of the mind such as delirium or dementia, apart from madness, necessitate confinement. Obtaining direct evidence of insanity by history and declaration from the patient was often difficult. Testimony from relations of the patient was sometimes needed to determine a patient’s insanity and safety risks to themselves and others. Parkinson suggests that …perhaps the evidence of the relatives, where the medical examiner cannot himself obtain proof, ought to be required upon oath; and as it is a case in which the safety of society is concerned, the justice of peace administering the oath, might, if he thinks that evidence sufficiently strong, either give his order for the confinement of the party, or add his signature to the certificate.22 Scientific Writings on Chemistry and Geology Parkinson published The Chemical Pocket Book (1800) as a short book for beginners to complement the well-known chemistry texts of Lavoisier, Fourcroy, Chaptal, and Nicholson.1,24 His book provided useful information for novices and inspired questions for more advanced readers. The Chemical Pocket Book presents information on elements and compounds that was up to date with early nineteenth century scientific literature. Chemical properties of earths, calorics, light, gases, alkalis, acids, metallic substances, stones, and vegetable and animal substances are outlined. Twenty-one different metals ranging from platina, gold, and silver to arsenic, molybdenite, and tungstenite are described. For example, the entry for gold begins, Its colour is orange red, or reddish yellow… Melts at 32°… It may be volatilized and calcined, in high and long continued heats. It is the most perfect, ductile, tenacious, and unchangeable of all the known metals. Not being combinable with Oxygen, Sulphur, &c. in low heats, it can never be found, strictly speaking, mineralized.24 He describes bile, blood, urine and other components such as fat, tooth enamel, synovia, and feathers of animals. It is possible that knowledge of these animal substances corresponded with his understanding of human physiology and disease. Parkinson was a renowned geologist or oryctologist (known today as a paleontologist). His museum at No. 1 Hoxton Square housed a notable collection of fossils, shells, metals, coins, and medals. Parkinson’s interests in oryctology paralleled scientific advancements in the eighteenth and nineteenth centuries, spanning the period

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from 1790 to 1820, known as “The Heroic Age of Geology,” during which fossils and rocks were studied individually and then in the context of their respective strata.1 Parkinson’s interests in geology and chemistry were intertwined, and his knowledge of chemical properties likely influenced his discovery of using muriatic acid to demonstrate presence of animal membranes in marble fossils. Parkinson published his first book on geology, Organic Remains of a Former World. An Examination of the mineralized remains of the vegetables and animals of the antediluvian world generally termed extraneous fossils, in 1804. It contained about 42 plates with 700 fig-ures, many of which came from his specimen collection. This book became a standard text on paleontology for half a century. The second and third quarto volumes were devoted to “The Fossil Zoophytes” and “Fossil starfish, Echini, Shells, Insects, Amphibia, Mammalia, &c.,” respectively. Parkinson also was one of 13 founding members of the Geological Society in 1807. He published “Observations on some of the Strata in the neighbourhood of London, and on the Fossil Remains contained in them” (1811) in the first volume of the Transactions of the Geological Society. Two years before his death, Parkinson wrote Outlines of Oryctology. An Introduction to the Study of Fossil Organic Remains (1822), which he humbly considered an adjunct to the valuable work, Outlines of the Geology of England and Wales, by Rev. W.D. Conybeare and W.Phillips, published several months before his book.1,25 Essay on the Shaking Palsy Parkinson’s Essay on the Shaking Palsy (1817) is often thought to represent his greatest contribution to medicine.26,27 The study is based on six cases, some never actually examined by Parkinson but observed on the streets. The five chapters of this 66-page octavo volume include I. Definition—History—Illustrative Cases, II. Pathognomic symptoms examined—Tremor Coactus—Scelotyrbe Festinians, III. Shaking Palsy distinguished from other disease with which it may be confounded, IV. Proximate cause—Remote causes—Illustrative cases, V. Considerations respecting the means of cure. Apologizing for mere conjecture regarding the etiology of the shaking palsy, Parkinson states his “duty to submit his opinions to the examination of others, even in their present state of immaturity and imperfection” and mission to inspire research on this disease.26 Parkinson recognized the long duration and slowly progressive nature of the disease. His first chapter commences with an often-quoted definition of shaking palsy: …involuntary tremulous motion, with lessened muscular power, in parts not in action and even when supported; with a propensity to bend the trunk forward, and to pass from a walking to a running pace: the senses and intellect being uninjured.26

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Similar tremors were noted years before by Galen, Sylvius de la Boe, Juncker, and Cullen, and these different types of tremor are further discussed in his second chapter. Parkinson illustrates the insidious onset and progression of this condition: So slight and nearly imperceptible are the first inroads of this malady, and so extremely slow is its progress, that it rarely happens, that the patient can form any recollection of the precise period of its commencement. The first symptoms perceived are, a slight sense of weakness, with a proneness to trembling in some particular part; sometimes in the head, but most commonly in one of the hands and arms.26 As the disease progresses, other features appear: After a few more months the patient is found to be less strict than usual in preserving an upright posture: this being the most observable whilst walking, but sometimes whilst sitting or standing. Sometime after the appearance of this symptom, and during its slow increase, one of the legs is discovered slightly to tremble, and is also found to suffer fatigue sooner than the leg of the other side.26 Inevitably, a state of immobility and dependence occurs with disturbances of sleep and bodily functions of bowels, speech, and swallowing. Parkinson’s descriptions quite accurately elaborate on the cardinal symptoms associated with the disease. He also comments on the asymmetric onset of disease, patients’ perceptions of weakness, and problems with sleep, constipation, hypophonia, and sialorrhea. Observations in years following his publication would lead to recognition of other features such as hypomimia, rigidity, and dementia. The six cases reported differ in severity as well as depth of Parkinson’s observation. The first case features a man older than 50 years, with left upper extremity tremor, who we are told succinctly had almost all symptoms reported in Parkinson’s first chapter. Parkinson actually examined only three of the six cases directly. Of those observed casually in the street, he includes the following cases: …a sixty-two year old man with an eight to ten year history of symptoms of tremor, interrupted speech, flexed posture, and gait impairment; a sixtyfive year old man with agitation of his whole body, flexed posture, and festinating gait; and a man with “inability for motion except in a running pace.”26 Case four, a 55-year-old man with trembling of his arms for 5 years and costal inflammation necessitating drainage, was examined but lost to follow-up. The sixth case provides a more comprehensive account of the patient’s afflictions—gradually progressive tremor, interrupted speech, constipation, intelligible handwriting, gait disturbance, and inability to feed himself. More striking was the occurrence of a stroke in this patient, which suppressed his tremor while his affected arm was paralyzed.

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Parkinson systematically dissects each symptom described in his first chapter. Past distinctions between tremors occurring during terror, anger, advanced age, or palsy were explored. Parkinson comments on the useful classification of tremor at rest (tremor coactus) and action by Sylvius de la Boe (1614–1672) and Sauvages (1706–1767). It is possible that he learned about tremors during his study of Latin and Greek and attendance at John Hunter’s lectures.10 He examines the origins of flexed posture and running gait. Sauvages described this gait as Scelotyrbe festinans, “a peculiar species of scelotyrbe, in which the patients, whilst wishing to walk in the ordinary mode, are forced to run” and differentiated it from Chorea Viti: …the patients make shorter steps, and strive with a more than common exertion or impetus to overcome the resistance; walking with a quick and hastened step, as if hurried along against their will. Chorea Vit…attacks the youth of both sexes, but this disease only those advanced in years.26 Parkinson differentiated tremor observed in the shaking palsy from that seen in apoplexy, epilepsy, worms, alcohol and caffeine use, and advanced age. He used the term “palsy” as a synonym for weakness and did not appreciate the unique quality of bradykinesia. He did not discuss rigidity. These distinctions were added later by Trousseau in his “Fifteenth Lecture on Clinical Medicine.”28 The medulla spinalis and medulla oblongata were the proposed neuroanatomical localization of this disease. Cases with features similar to the shaking palsy were suspected to have involvement of the medulla with “some slow morbid change in the structure of the medulla, or its investing membranes, or theca, occasioned by simple inflammation, or rheumatic or scrophulous affection.”26 Despite contributions of spine fractures, venereal disease, and rheumatism in these cases, Parkinson suggests how pathology in the medulla might underlie the weakness, gait disturbance, and bulbar symptoms seen in these examples. Parkinson’s arguments for involvement of the medulla spinalis and oblongata reflect understanding of the nervous system in the eighteenth and nineteenth centuries. It was not until the latter part of the nineteenth century, with observations and anatomo-clinical correlates on amyotrophic lateral sclerosis, tabes dorsalis, and multiple sclerosis from physicians such as Charcot, that functions of the brain and spinal cord were better understood.29 The nigral degeneration implicit to Parkinson’s disease was not suggested until the late nineteenth century and not systematically studied until Tretiakoff in his 1919 thesis.1,30 Parkinson’s belief, however, in clinical and pathological correlations to understand disease mechanisms is clearly stated: Before concluding these pages, it may be proper to observe once more, that an important object proposed to be obtained by them is, the leading of the attention of those who humanely employ anatomical examination in detecting the causes and nature of diseases, particularly to this malady. By their benevolent labours its real nature may be ascertained, and appropriate modes, of relief, or even of cure, pointed out.26

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FIGURE 1.1 Title pages from Parkinson’s Chemical Pocket Book, Medical Admonitions, Essay on the Shaking Palsy, and Outlines of Oryctology, and Plate IV from Outlines of Oryctology, from the collection of Dr. Christopher Goetz (gift of Dr. Robert Currier). In his final chapter, Parkinson enumerates treatments for the shaking palsy. He expresses the potential for neuroprotection as …it seldom happens that the agitation extends beyond the arms within the first two years…in this period, it is very probable, that remedial means might be employed with success: and even, if unfortunately deferred to a

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later period, they might then arrest the farther progress of the disease, although the removing of the effects already produced, might be hardly to be expected.26 Recommended treatments were bleeding from the upper part of the neck, application of vesicatories, and resultant drainage of purulent discharge; the use of internal medicines was not justified until more knowledge of the disease was available. Overall, his essay was well received in the English medical community. The first review, appearing in The London Medical and Physical Journal in 1818, did criticize his speculation on localization and causes but largely recommended it for reading.31 Other reviews in The London Medical Repository and The Medico-chirurgical Journal praised his observations and excused his speculations on the basis of his respectable reputation.31 It was not until the 1860s that Charcot and Vulpian coined Parkinson’s disease as an eponym for paralysis agitans. Parkinson’s Legacy Parkinson’s legacy encompasses not only medical works such as the well known Essay on the Shaking Palsy, but also a diverse assortment of writings on politics, medical care, chemistry, and geology. Although these writings provide insight into Parkinson’s character, no portrait of him exists. A plaque designates his house in Hoxton Square, now a factory site, and an inscribed marble tablet, a gift by St. Leonard’s Hospital to commemorate his bicentennial in 1955, can be seen in St. Leonard’s Church.1,32 Several pieces from his fossil collection are in possession of the British Museum of Natural History.32 His Essay on the Shaking Palsy is nearly impossible to find in original, although several reprints exist. Other writings can be found in libraries and among antiquarians. These writings share the same sense of combined clarity, humility, and competence revealed in the celebrated Essay. Charcot’s proclivity for eponyms introduced the term Parkinson’s disease, a name that has retained its place of continued honor in modern neurology. REFERENCES 1. Morris A.D. James Parkinson: His life and times. Birkhauser, Boston, 1989. 2. Morris A.D. James Parkinson. The Lancet 1955; 761–763. 3. A.Hoxton and Shoreditch Walk: Route and what to see. From http://www.londonfootprints.co.uk/ 4. Shoreditch andHoxton—Medieaval Village. From http://learningcurve.pro.gov.uk/ 5. Rowntree L.G. James Parkinson. Bulletin of the Johns Hopkins Hospital 1912; 23:33–45. 6. Critchley, M. (Ed.). James Parkinson (1755–1824). Macmillan and Co., Ltd., New York, 1955. 7. Jefferson M. James Parkinson 1755–1824. British Medical Journal 1973; 2:601–603. 8. Parkinson J. “Some account of the effects of lightning.” Memoirs of the Medical Society of London, 1789; Vol. 2 pp. 193; 493–503. In Morris A.D. James Parkinson: His life and times. Birkhauser, Boston, 1989. 9. Bett, W.R., James Parkinson: Practitioner, pamphleteer, politician and pioneer in Neurology. Proceedings of the Royal Society of Medicine 1955; 48:865.

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10. Currier, R.D., Did John Hunter give James Parkinson an idea? Archives of Neurology 1996; 53:377–378. 11. Allen, E., Turk J.L., Murley R. (Eds.).The case books of John Hunter FRS. Royal Society of Medicine Services Limited, London, 1993. 12. Gloyne, S.R., John Hunter. E & S Livingstone, Ltd., Edinburgh, 1950. 13. Parkinson, J., The Hospital pupil; Or an essay intended to facilitate the study of Medicine and Surgery. In Four Letters. H.D.Symonds, London, 1800. 14. Parkinson J., Pearls cast before swine, by Edmund Burke, scraped together by Old Hubert. D.I.Eaton, London, 1793. 15. Parkinson J., An address to the Hon. Edmund Burke from the swinish multitude by Old Hubert. J.Ridgeway, London, 1793. 16. Tyler, K.L., Tyler, H.R. The secret life of James Parkinson (1755–1824): The writings of Old Hubert. Neurology 1986; 36:222–224. 17. Parkinson, J., Dangerous sports: A tale addressed to children. H.D.Symonds, London, 1808. 18. Parkinson, J., Medical admonitions to families, respecting the preservation of health, and the treatment of the sick. 4th ed., H.D.Symonds, London, 1801. 19. Parkinson, J., The Villager’s friend and physician; or a familiar address on the preservation of health. H.D. Symonds, London, 1800. 20. Currier, R.D., Currier, M.M., James Parkinson: on child abuse and other things. Archives of Neurology 1991; 48: 95–97. 21. Parkinson, J., Remarks of Mr. Whitbread’s plan for the education of the poor. H.D.Symonds, London, 1807. 22. Parkinson, J., Mad-Houses: Observations of the act for regulating mad-houses. Whittingham and Rowland, London, 1811. 23. McMenemey, W.H., A note on James Parkinson as a reformer of the Lunacy Acts. Proceedings of the Royal Society of Medicine 1955; 48:593–594. 24. Parkinson, J., The Chemical pocket book; Or memoranda chemica; Arranged in a compendia of Chemistry. D.H., Symonds, London, 1800. 25. Parkinson, J., Outlines of Oryctology: An introduction to the study of fossil organic remains. London, 1822. 26. Parkinson, J., An Essay on the Shaking Palsy (1817). In Medical Classics 1938; 2:10. 27. Williamson, R.T., James Parkinson and his essay on paralysis agitans. Janus 1925; 29:193–197. 28. Pearce, J.M.S., Aspects of the history of Parkinson’s Disease. Journal of Neurology, Neurosurgery, and Psychiatry 1989; 6–10. 29. Goetz, C.G., Bonduelle, M., Gelfand, T., Charcot: Constructing Neurology. Oxford University Press, New York, 1995. 30. Duvoisin, R.C., A brief history of parkinsonism. Neurologic Clinics 1992; 10:301–316. 31. Herzberg, L., An essay on the shaking palsy: Reviews and notes on the journals in which they appeared. Movement Disorders 1990; 5:162–166. 32. Eyles, J.M., James Parkinson (1755–1824). Nature 1955; 176:580–581.

2 Paralysis Agitans—Refining the Diagnosis and Treatment Lawrence Elmer Department of Neurology, Medical College of Ohio 0-8493-1590-5/05/$0.00+$1.50 © 2005 by CRC Press

During the decades after the publication of James Parkinson’s seminal article,1 the definition of paralysis agitans was debated, discussed, and further refined through observations and publications in the medical community. This process, common to all newly described disease entities, clarified the essential clinical features of paralysis agitans, the treatment of this disorder, and the pathology underlying the syndrome. Historically, progress in understanding Dr. Parkinson’s namesake was not without misunderstandings and confusion before a more distinct and accurate picture of this disease developed. Physicians worldwide tried to diagnose and describe cases of paralysis agitans in light of the description given by Dr. Parkinson. Initially, most of these manuscripts were simply restatements of the original clinical description and appeared in textbooks, sometimes quoting directly from Parkinson’s treatise. Other articles described cases that were clearly not parkinsonian in nature, reflecting other neurological diseases. However, some of the clinical descriptions met the diagnostic criteria of Parkinson’s disease and thus give insight into the clinical acumen of this age.2 In this chapter, examination will first be made of the early reports and descriptions of cases corresponding to paralysis agitans prior to Charcot. Subsequently, the contributions of Charcot in clarifying and expanding on the diagnosis of paralysis agitans will be reviewed. Finally, the contributions of neurologists andother physicians to the diagnosis and management of Parkinson’s disease after Charcot and before the advent of levodopa therapy will be discussed. THE EARLY YEARS (1817–1861) One of the most prolific writers during this time period was Dr. John Elliotson, a practitioner from St. Thomas’ Hospital in London. While Dr. Elliotson described some cases that were clearly not parkinsonian, his writings and lectures reveal much about the diagnosis and treatment of neurological disorders in the first two decades after Dr. Parkinson’s publication.

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In his earliest article, Elliotson first comments on a common practice in the management of neurological diseases, the oral administration of subcarbonate of iron. A multitude of neurological disorders were reportedly cured by the administration of 15 to 30 gr of the iron subcarbonate per dose repeated until the desired benefit was obtained. For example, for the treatment of neuralgia, the usual quantity was described as 90 gr over a period of 24 h. (Elliotson mentioned that Dr. Sydenham’s favorite form of the iron subcarbonate for administration to patients was iron filings but others suggested that simple rust was just as effective as any other preparation and could actually be easier on the stomach!)3 Elliotson described multiple cases of nonparkinsonian movement disorders, commonly chorea in children and young adults. These patients were given the typical prescription of subcarbonate of iron, leeches, blistering agents, and purgatives. In many of these cases, the patients were described as exhibiting significant improvement in their choreiform disorders. However, Dr. Elliotson went on to lament, I have failed with the largest quantities of iron in epilepsy, cancer, and lupus, but found it very beneficial in chronic neuralgia, and various chronic ulcerations and chronic pustular diseases, as well as those diseases of debility in which it is so justly celebrated.3 Elliotson’s lecture then elaborates on his first case of paralysis agitans, which he treated with the iron subcarbonate regimen. The patient was described as a male, 28 years of age, who had symptoms approximately 1 year before his encounter with Elliotson. The clinical symptoms consisted of constant shaking of the legs and arms of variable intensity. According to Elliotson, Till within the last week, the agitation would sometimes cease for a few hours or even the whole day, but for the last week (it) has been constant. At first, sometimes only one leg was affected, sometimes both. He has pain in the head, loins, and legs, and vertigo, and cannot fix his attention.3 The first treatment described for this unfortunate young man involved the application of tartarized antimony ointment to produce pustules on both legs. He then received orally administered oil of turpentine followed by zinc sulfate, but this was stopped due to nausea. Finally, he received the subcarbonate of iron prescription accompanied by the administration of leeches to his temples daily. Within four days of the subcarbonate of iron and leech administration, the patient was described as feeling better—the dose of the subcarbonate of iron was increased and the leeches were continued. Within 28 days following the initiation of this prescription, the patient was described as dramatically improved, at least insofar as the shaking was concerned. Unfortunately, the pustules, leeches, and treatments other than the subcarbonate of iron had failed to relieve the patient’s headache, vertigo, other pain, and smarting of his eyes. Therefore, all treatments other than the subcarbonate of iron were discontinued. The patient significantly improved. He continued to receive the subcarbonate of iron prescription for a total of six weeks. At the end of this time, the patient was discharged from the hospital and was seen several months later in perfect health.3 In this case, the presumptive diagnosis was “paralysis agitans,” while the true diagnosis almost certainly was not!

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Dr. Elliotson went on to describe multiple other cases referred to as paralysis agitans. Most of these cases probably did not represent paralysis agitans at all, which confused the diagnosis for students of neurology during that day. Several of these cases are reviewed here and in other historical reviews.4 Unfortunately, the apparent effectiveness of the treatments administered may have resulted from the fact that the cases did not represent true paralysis agitans. Elliotson himself comments on the lack of efficacy of these treatments in some individuals, most likely those with true paralysis agitans.3 In a separate publication,5 Dr. Elliotson attends to another presumed positive case of paralysis agitans. This monograph describes an individual 54 years of age admitted under the care of Dr. Elliotson. His symptoms began after a frightening episode in which he fell into water. Following that all of his extremities were described as a “continual state of tremor: head and jaw also affected.” He was given subcarbonate of iron four times daily with alternating cold and warm baths. Reportedly, he recovered but then relapsed after a fortnight, “when he was suddenly seized with pain in the head, and giddiness, soon followed by his old complaint; since then, articulation has been indistinct, and his superior and inferior extremities have been in a constant state of tremor, and he has constantly complained of pain in the head.” He was readmitted to the hospital, treated extensively with various preparations and was felt to have significant improvement. He was subsequently discharged from the hospital however, due to his frequent habit of drinking alcohol on short jaunts away from a hospital!5 In another case presentation from March 21, 1831, Dr. Elliotson relates a case of paralysis agitans that resulted from fright. I spoke of this disease before. The patient was a man 50 years of age; and usually, I believe, it arises at such an age from an organic cause, for I have never been able to cure a person of it at or after middle life. I cured one between 30 and 40 years of age, but he was the oldest. In this case it came on from fright, and therefore there may be nothing organic, and perhaps I shall cure him. He is taking the carbonate of iron, and is much better. The man regularly receives me with a smile, and fancies he is getting well. It would not be right at present to give a decided prognosis.6 It is likely that these cases represented essential tremor or tremulousness associated with toxins or psychiatric symptoms, simply misdiagnosed as paralysis agitans. However, Dr. Elliotson did attempt to distinguish paralysis agitans from the tremulousness seen in alcoholics. This disease is to be carefully distinguished from the tremulous motions with which drunkards are affected. It is entirely distinct from the effect produced by habitual intoxication…. The shaking is continuous, and it is only by discontinuing their use that the tremors cease. This trembling, too, will be produced temporarily by occasional strong doses only. It generally, also, affects both hands, and is seen chiefly when any effort is made by the individual; if, for instance, a pen is taken in the hand, a shaking comes on the moments an attempt is made to write; or if a cup or glass be lifted, the contents are spilled over. The greater, too, the effort

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which is made, the more excessive is the tremor that follows. But in paralysis agitans exactly the reverse of this is observable, for a strong effort will, for the time, overcome the disease. By this, and by the affection occurring pretty equally in both hands, you may distinguish nervous trembling from paralysis agitans. You are aware that strong passions, as fear and rage, will also, like strong tea, coffee, or tobacco, produce a trembling.7 The misdiagnoses described above should not discount the value of this physician’s contributions. It is likely that many other physicians attempted to accurately diagnose this newly described syndrome of “paralysis agitans.” It is also likely that while many incorrect diagnoses followed for those physicians as well, Elliotson had the courage to record his observations and opinions permanently for future evaluation. Indeed, Elliotson did observe and correctly diagnose some cases of “paralysis agitans.” In one of his clinical lectures on paralysis agitans, delivered on October 11, 1830, Elliotson described a patient of age 38 who developed symptoms that were interpreted as representing the shaking palsy. In this clinical discussion, Dr. Elliotson expounds on the symptoms of shaking palsy, describing characteristic features of the tremors, gait, festination, dysphagia, hypophonia, and ultimately death.7 Now this disease usually commences in some one part of the frame, as, for instance in the head; but it more frequently begins in one hand, or in the arm; there it will sometimes remain for many months, and even for years, before it spreads, and perhaps it never spreads at all. Sometimes, however, it increases in degree and extent, and other parts become affected, until, at last, the whole body is in a constant shake. Though the tremulous motions in this disease are involuntary, yet they may be checked by an effort of the will. The effort exerted, however, must be of a powerful nature, and then it will for a few moments stop the shaking. As the disease extends, first one extremity and then another becomes affected, at length the head and trunk bend forwards, the individual walks in some measure upon his toes, the motion of walking becomes gradually quickened, at last it is altogether lost, and the man unconsciously gets into a trot, and has all the appearance of a person in a most violent hurry. This change is owing to the disease being slightly under the will. The individual who was afflicted, finds that a powerful exertion of the muscles will stop the tremors, and as running requires more effort than walking, running answers better to control them; or we may say, that when he is walking, the same effort which he makes to check them, forces him to run, which state he continues, because he finds that he thus partly conquers the tremulous motions,—that they do not so much get the better of him and impede him. In the usual progress of paralysis agitans, the voice is not affected until the muscles of the upper extremity and head have been so for a long time. At last, however, speech becomes involved, and the muscles employed in the acts of deglutition and mastication are affected, and speaking, chewing, and swallowing, are extremely difficult to be

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performed. By and by the urine and feces pass away involuntarily, general emaciation ensues, entire decay of the powers, and ultimately death.7 In some cases, the physicians of this era did record their observations. As mentioned above, many cases probably did not reflect “paralysis agitans” but rather involved another neurological disorder. For example, Dr. Thomas Gowry describes a case of paralysis agitans “intermittens” in which the symptoms were intermittent in nature and cured by treatment. A woman of age 26 presented as a patient to Dr. Gowry on June 18, 1831. She was experiencing involuntary tremors of the upper and lower extremities which would continue for about five or six minutes at a time and occurred up to three times per hour. During that time she had complete loss of function of her limbs. Her lips and mouth were also involved, the tongue protruded intermittently, and the paroxysm was terminated with a heavy sigh. The patient also complained of vertigo, heaviness of her head, and great difficulty supporting her head on her shoulders. Her treatment consisted of cathartics, following which she developed syncopal episodes. A prescription change occurred and she underwent other therapy including leeches resulting in complete resolution of her symptoms!8 In a case presentation dated September 6, 1839, Dr. Matthew Gibson described a case of “paralysis agitans.” A girl, age 14, developed “constant and violent involuntary motion or shaking of the right forearm, and slightly of the arm; the motion is so violent that it cannot be stopped, though held down.” The patient was treated with blistering agents over her spinal column (described as tender) and was given a combination of calomel, opium, and cinnamon. Four days later this case of “paralysis agitans” was reportedly almost completely cured.9 Another popular treatment for diseases of the nervous system in the mid 1800s was the application of direct galvanic current. Again, it is unclear whether the symptoms undergoing treatment truly represent “paralysis agitans” at all. One such case is described in a publication of the Lancet dated December 3, 1859, where Dr. Russell Reynolds treated a case of “paralysis agitans.” The patient was a male 57 years old, who for the prior 2 years before his examination had experienced intermittent tremors of the right arm and leg. These tremors were present with multiple inciting variables including exasperation, exces-sive physical exertion, cold temperatures, attempting to drink liquid substances, or fully extending the arm and forearm. He came to the attention of Dr. Reynolds when he had an episode of severe vertigo, aching in his knee joints, and a feeling of general disturbance. At this point, the shaking was reported as violent in the right upper extremity. The tremors occurred with activity and were aggravated by emotional upset or any attempt at voluntary movement of the extremity. The treatment for this tremor was the application of direct galvanic current to the right arm and forearm. After five minutes of electrical stimulation, the tremor was noted to be absent and emotional excitement failed to reproduce the exacerbation of tremor seen previously. The tremors returned after three hours following the first treatment with electrical stimulation. Subsequent application of electrical stimulation was applied to the arm on a daily basis followed by an every other day basis for a total of almost two months. At this point, the patient’s tremor was felt “cured” except for a very slight tremulousness when he raised something to his mouth.

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This dramatic improvement in the subject’s symptoms was regarded as evidence that electricity could cure a case of “paralysis agitans.” Dr. Reynolds proceeded to write, …the above case requires, I think, no comment. It is more important that a fact of this character should be placed on record than that any speculation should be advanced in regard to the pathology of paralysis agitans, or the modus operandi of the continuous galvanic current. The term which I have employed to denote the case involves no theory; it is but the name of a prominent symptom—a symptom which, in this instance, constituted almost the whole of the affection, and which, after a fortnight’s duration without the slightest tendency to improvement, was quickly, but progressively and effectually, removed by a special form of treatment. Clearly, it was the opinion of Dr. Reynolds that the application of electrical current to the limbs of patients with “paralysis agitans” was the definitive treatment requiring no further explanation. Unfortunately, the clinical description appears far more typical for a patient with essential or familial tremor.10 Some physicians concentrated solely on the gait abnormalities in paralysis agitans, using that symptom as the only criterion for a diagnosis of “paralysis agitans.” For example, in a clinical description from 1855, Dr. Paget outlines the case of a 41-year-old male who developed giddiness 6 weeks before his first examination. He subsequently experienced loss of vision and was found by his wife at home reclining in a chair, unresponsive, with one side of his mouth drawn and both arms and legs rigid and immovable. His coma lasted about 24 h, after which time he recovered use of his arms and legs. When he presented to the hospital, he was weak and could not walk without assistance. He couldn’t feed himself and had bowel and bladder incontinence. He also experienced emotional incontinence and apparently had some difficulty with language. Due to his involuntary tendency to fall precipitately forwards, this patient was considered to have a tentative diagnosis of “paralysis agitans.”11 Again, unfortunately, the diagnosis is certainly in question and reflects a measurable amount of uncertainty during this time period about what truly constituted a diagnosis of “paralysis agitans.” THE CONTRIBUTIONS OF CHARCOT While multiple authors attempted to refine the clinical description of “paralysis agitans,” the diagnosis was still confounded until J.-M.Charcot and colleagues evaluated, diagnosed, and accurately revised, refined, and reiterated the clinical description of James Parkinson. These physicians contributed a wealth of insight and clarification to the original treatise, mostly as a result of exposure to large numbers of invalid patients at the La Salpetriere in Paris. Charcot provided clarification of the differential diagnosis between paralysis agitans and other tremor disorders. Charcot was also the first to refer to this disorder as “Parkinson’s disease.” Charcot’s lectures and publications were all in French but fortunately were translated in 1877 by G.Sigerson.12 One of Charcot’s greatest contributions was the differentiation

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of Parkinson’s rest tremor from the kinetic tremor associated with essential and familial tremor as well as tremors associated with multiple sclerosis. CHARCOT ON TREMOR Initially, Charcot distinguishes between the rest tremor and the kinetic tremor.12 As mentioned in the paragraphs above, accurate diagnosis of Parkinson’s disease was confounded by the presence of multiple other tremorogenic disorders, including essential tremor, tremor associated with multiple sclerosis, chorea, as well as abnormal movements from intoxicating substances including alcohol. Charcot eloquently differentiates between the tremors of Parkinson’s disease and the tremors of multiple sclerosis, Let it suffice that we have put prominently forward those characters which can be recognized by the simplest observation, irrespective of any theoretical prepossession. It is because these have not been considered, that the two affections which are to form the object of our first clinical studies—paralysis agitans and disseminated sclerosis—have remained until today, confounded under the same rubric, although they are, in every respect, perfectly independent of each other. Both, indeed, reckon tremor amongst their most important symptoms; but, in the first, the rhythmical oscillations of the limbs are nearly quite permanent, whilst in the second they only supervene on the attempt to execute intended movements.(12, pp 132,133)

CHARCOT ON THE FUNDAMENTAL CHARACTERISTICS OF PARKINSON’S DISEASE In the next section of his lectures, Charcot gives an overview of Parkinson’s disease with respect to its etiology and diagnostic features. He begins by proposing that the disease itself is a neurosis, absent of a true physiological and pathological basis. This conclusion Charcot based on the absence of clear neuropathological abnormalities seen in postmortem examination of patients who died with Parkinson’s. He states, “Paralysis agitans, separated from foreign elements, is, gentlemen, at present a neurosis, in this sense that it possesses no proper lesion.”12, p. 134 Charcot next turned his attention to the age of onset and the potential causes of Parkinson’s disease. It assails persons already advanced in age, those especially who have passed their fortieth or fiftieth year. Frequently the causes remain unknown. However, of the etiological data two deserve to be cited: 1, damp cold, such as that arising from a prolonged sojourn in a badly ventilated apartment, or in a low dark dwelling on the ground floor; 2, acute moral emotions. The latter cause appears to be tolerably common.12, pp. 134,135

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The discussion of the pertinence and applicability of symptoms in the diagnosis of Parkinson’s disease serves as the next topic of discussion. In this discourse, Dr. Charcot refers to the tremors, postural instability, and bradykinesia. The symptoms of paralysis agitans are not all of the same value. The most striking symptom consists of the tremor, existing even when the individual reposes, limited at first to one member, then little by little becoming generalized, whilst respecting, however, the head. To this phenomenon is superadded sooner or later an apparent diminution of muscular strength…. A singular symptom is that which, frequently at an early, but usually at a late period, comes to complicate the situation—the patient loses the faculty of preserving equilibrium whilst walking. In some patients also we notice a tendency to propulsion or to retropulsion…. A peculiar attitude of the body and its members, a fixed look, and immobile features should also be enumerated among the more important symptoms of this disease.12, p. 135 Charcot then turned his attention to the progressive nature of Parkinson’s disease as well as the circumstances surrounding the demise of individuals afflicted with this particular disorder. The march of paralysis agitans is slow, and progressive. Its duration is long—sometimes it has gone on for 30 years. The fatal term supervenes either by the advance of age, or because of intercurrent diseases. In the first case, an acute disease, such as pneumonia, occurs. In the second, death takes place from a sort of nervous exhaustion, nutrition degenerates, the patient cannot sleep, eschars are formed and conclude the morbid scene.12, pp. 135,136 CHARCOT ON THE PROGRESSIVE NATURE OF PARKINSON’S DISEASE What follows next in Charcot’s discourse is a more elaborate and detailed discussion on the “manner of its invasion,” when referring to the shaking palsy. In the immense majority of cases, the invasion is insidious, the disease first showing itself as slight and benignant. The tremor is circumscribed to the foot, the hand, or the thumb. At this stage of the disease the tremor may be merely passing and transitory. It breaks out when least expected, the patient enjoying complete repose of mind and body, and it frequently occurs without his being conscious of it. The act of walking (even where the upper extremities are affected), the act of grasping, lifting, taking a pen, writing, any effort at all of the will, may at this epoch often suffice to suspend the tremor. Later on, it will be no longer so. Moreover, as it augments in intensity and persistence, the tremor invades little by little, and not without observing certain rules in its progress, the parts which

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have hitherto remained sound. If, for instance, it first affected the right hand, at the end of some months or of some years, the turn of the right foot will come; next the left hand, and after that the left foot will be, successively, assailed.12, p. 136 Charcot deliberately pointed out that the symptoms of Parkinson’s usually began unilaterally, only later to cross over to the unaffected side. However, he had seen cases where the symptoms of Parkinson’s began on opposite sides of the body. He also elaborated on the nonmotor aspects of paralysis agitans, such as fatigue and pain. Decussated invasion is more rare. I have, however, at least twice seen the affection first seize the right upper extremity, and at next to the left lower extremity. It is much more common to see the tremor confined for a long time to the members of one side of the body (hemiplegic type), or to the two lower extremities (paraplegic type). The tremor is not absolutely the first symptom recorded. It may possibly be preceded sometimes by a very remarkable feeling of fatigue, sometimes by rheumatoid or neuralgic pains, which are occasionally most severe, occupying the member or the regions of the members which shall soon be seized, but secondarily, by the convulsive agitation.12, pp. 136, 137 Charcot distinguishes the slow invasion from the abrupt invasion. The abrupt invasion usually followed an emotional trauma, and frequently only involved one limb. The symptoms usually would persist only for days and then depart just as quickly. However, most of these patients would later manifest the symptoms of Parkinson’s in a more persistent manner. After persisting for a few days it may possibly improve or even vanish. But, later on, after a series of alternate improvements and exacerbations, it takes up its abode in a permanent manner.12, p. 137 Finally, Charcot defines the period of stationary intensity. This is best described as a period of time when the tremor has been completely established in the patient’s life but fluctuations in the intensity of that tremor still occur. Emotional upset and other crises were noted as situational protagonists of the tremor.12, p. 137,138 CHARCOT ON BRADYKINESIA AND RIGIDITY Charcot clearly describes masked facies as an essential component of Parkinson’s disease. While James Parkinson mentioned face and voice abnormalities in his clinical cases and definitively described bradykinesia in his patients, he did not elaborate on this symptom nor did he include masked facies in his definition of shaking palsy. Charcot elaborates extensively on this topic. Far from trembling, the muscles of the face are motionless, there is even a remarkable fixity of look, and the features present a permanent expression

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of mournfulness, sometimes of stolidness or stupidity. There is no real difficulty of speech, but the utterance is slow, jerky, and short of phrase: the pronunciation of each word appears to cost a considerable effort of the will. Finally, the patients seem to speak between their teeth. Deglutition is accomplished with ease, though perhaps slowly; frequently in cases of somewhat old standing the saliva, accumulated in the mouth, is involuntarily allowed to escape.”12, pp. 139,140 Charcot is recognized as the first prominent physician-scientist to describe and document the rigidity seen in Parkinson’s disease. This symptom was either missed or not documented by James Parkinson. Regardless, Charcot contributed significantly to the accurate diagnosis of Parkinson’s disease by his observations and clear description of the change in muscle tone.“ We shall now point out the characteristic which, we believe, was overlooked by Parkinson as well as by most of his successors: we allude to the rigidity to be found, at a certain stage of the disease, in the muscles of the extremities, of the body, and, for the most part, in those of the neck also. When this symptom declares itself, the patients complain of cramps, followed by stiffness, which, at first transient, is afterwards more or less lasting, and is subject to exacerbations. Thus on account of the rigidity of the anterior muscles of the neck, the head, as Parkinson remarked, is greatly bent forward, and, as one might say, fixed in that position; for the patient cannot, without much effort, raise it up, or turn it to the right or left. The body also was almost always slightly inclined forward, when the patient is standing.12, p. 140 The posture of the hands and the upper extremities was documented in his lectures and recorded in drawings. The elbows are habitually held a little apart from the chest, the forearms being slightly flexed upon the arms; the hands, flexed upon the forearms, rest upon the stomach …Commonly, the thumb and index are extended and apposed, as if to hold a pen; the fingers, slightly inclined towards the palm, are all deviated outwards to the ulnar side. 12, p. 141 In reference to the bradykinesia, Dr. Charcot states, You will readily discover, in some of the patients whom I have shown you, that laboriousness in the execution of movements which is dependent neither on the existence of tremors, nor on that of muscular rigidity; and is somewhat attentive examination will enable you to recognize the significant fact that, in such cases, there is a rather retardation in the execution of movements than real enfeeblement of the motor powers. The patient is still able to accomplish most of the motor acts, in spite of the trembling, but goes about performing them with extreme slowness. We

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noticed this fact a few moments ago, in its relation to the faculty of speech; there is a comparatively considerable lapse of time between the thought and the act.12, p. 144 CHARCOT ON GAIT DISTURBANCES IN PARKINSON’S DISEASE Charcot also described freezing of gait, festination, propulsion, and retropulsion. Yet a word upon the gait peculiar to patients affected by paralysis agitans. You have seen some of our patients get up slowly and laboriously from their seats, hesitate for some seconds to step out, then, once started, go off in spite of themselves at a rapid rate. Several times they threatened to fall heavily forward. Does this irresistible tendency to adopt a running pace depend exclusively on the center of gravity being displaced forward by the inclination of the head and body? There are, in fact, certain patients who, in contradistinction to those described, tend to run backwards when in motion, and to fall backwards, although their bodies are manifestly inclined forward. Besides, propulsion, like retropulsion, is not absolutely connected with the bent attitude of the body, for it is sometimes seen at an early period of the disease, even before there is any inclination of the body at all.12, p. 145,146 CHARCOT ON NONMOTOR SYMPTOMS OF PARKINSON’S DISEASE There is also elaboration on the more subtle physical, emotional and psychiatric nuances of paralysis agitans. Paralysis agitans is not merely one of the saddest of diseases, in as much as it deprives the patients of the use of their limbs, and sooner or later reduces them to almost absolute inaction; it is also a cruel affection, because of the unpleasant sensations which the sufferers experience. Usually, indeed, (the neuralgic cases which we have already described being excepted), they are not affected by acute pains, but by disagreeable sensations of a special order. They complain of cramps, or rather of a nearly permanent sensation of tension and traction in most of the muscles. There is also a feeling of utter prostration, of fatigue, which comes on especially after the fits of trembling; in short, an indefinable uneasiness, which shows itself in a perpetual desire for change of posture. Seated, the patients every moment feel obliged to get up; standing, after a few steps they require to sit down. This need for change of position is principally exhibited at night in bed by the more infirm, who are incapable of attending on themselves. The nurses charged with their care will tell you: “They must be turned now on the right side, now on the left, now on the back.” Half an hour, a quarter of an hour, has scarcely elapsed until they

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require to be turned again, and if their wish be not immediately gratified they give vent to moans, which sufficiently testify to the intense uneasiness they experience.12, p. 147 Charcot described symptoms in his patients most consistent with autonomic dysfunction and temperature deregulation, which are nonetheless described as extremely uncomfortable in nature from the standpoint of the patient. But there is one very troublesome sensation which the patients experience, in which I have not found mentioned in any description; this is an habitual sensation of excessive heat, so that you shall see them in the heart of winter throw off the bed clothes, and in the daytime only retain the lightest garments. All the cases under our charge give evidence in favor of this assertion. It appears to obtain its maximum after the paroxysms of trembling, and is then frequently accompanied by profuse perspiration, which is sometimes so great as to necessitate a change of linen; but it may also be found in patients who do not thus perspire and who are but little troubled with tremor.12, p. 147 CHARCOT ON THE TERMINAL EVENTS OF PARKINSON’S DISEASE Charcot details the events leading to death in patients with Parkinson’s disease. The affection pursuing its course, the difficulty of movement increases, and the patients are obliged to remain, the whole day long, seated on a chair, or are altogether confined to the bed. Then, nutrition suffers, especially the nutrition of the muscular system. There may supervene, as I have twice observed, a genuine fatty wasting of the muscles. At a given moment, the mind becomes clouded and the memory is lost. General prostration sets in, the urine and feces are passed unconsciously, and eschars appear upon the sacrum. In such cases, the patients succumb to the mere progress of their disease, by a sort of exhaustion of the nervous system; and it is perfectly true, as several authors have remarked, that at this terminal period the tremor, however intense it was before, is frequently seem to diminish and even to disappear.12, p. 149 CHARCOT ON TREATMENT ALTERNATIVES FOR PARKINSON’S DISEASE Lastly, Charcot comments on some of the treatment alternatives, although he seems to have taken a skeptical view of its effectiveness. Everything, or almost everything, has been tried against this disease. Among the medicinal substances that have been extolled, in which I have administered without any beneficial effect, I need only enumerate a few.

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Strychnine, praised by Trousseau, appears to me rather to exasperate the trembling than to calm it. Ergot of rye and belladonna, recommended on account of their anticonvulsive qualities, have not yielded any very profitable results. The same verdict must be given in reference to opium, which, on the contrary, augments reflex excitability, and which was supposed capable of moderating the tremor because of diminishing the pain. Latterly I have made use of hyoscyamine, from which some patients have obtained relief; its action, however, is simply palliative.12, p. 155 This is one of the first descriptions of a centrally acting anticholinergic medication used for the treatment of Parkinson’s disease. Subsequent practitioners drew from Charcot’s experience and treated patients for years with various preparations of other derivatives of hyoscyamine. While Charcot speculated extensively on the pathology and etiology of paralysis agitans, no significant contribution was made at this time.12, pp. 150–152 However, his work allowed future neuropathologists to distinguish Parkinson’s disease from the multitude of other neurological disorders with which this disorder was confused. In a very real sense, then, the careful scientific documentation of Charcot set the stage for the determination of the precise pathological abnormality causing Parkinson’s. PARKINSON’S DISEASE AFTER CHARCOT It is not clear that Dr. Parkinson distinguished the rigidity of paralysis agitans from the spasticity associated with spinal cord damage, mentioning repeatedly his belief that the pathology of paralysis agitans resided in the medulla. In 1871, Dr. Meynert described damage to the corpus striatum and the lenticular nucleus.13 This may have been the first suggestion that the tremor of paralysis agitans as well as chorea might involve the basal ganglia. Drs. Murchison and Cayley described a case in 1871 of paralysis agitans.14 There was shrinkage of the cerebral hemispheres, thickening of the spinal cord and infiltration of the spinal cord with connective tissue and inflammatory cells probably related to typhus. In 1878, Dr. Dowse described a case of a patient who died at age 43.15 No gross lesions were found the central nervous system; however, there was pigmented granular degeneration of nerve cells along the spinal cord and diffuse sclerosis in white matter tracts. Miliary degeneration was seen throughout the dentate nucleus, cerebellum, corpora striata and the thalamus. Further progress in elucidating the pathological hallmarks of paralysis agitans was limited by the pervasive opinion that sclerosis of the spinal cord was the only definite pathological change. Dr. Gowers remarked that Hughlings Jackson favored the cerebellum as the source of pathological change.16 In 1899, Dr. Gowers stated, “whatever anatomical changes may underlie the symptoms they are too minute to be at present within the reach even of the microscope.” Dr. Gowers felt that the motor cortex was the cause of paralysis agitans and postulated “chronic senile change in the nutrition of the branching processes of the motor nerve cells.”17 As late as 1910, Dr. Gowers still felt that the cortex was involved but noted,

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The most careful search has failed to reveal any microscopic changes peculiar to paralysis agitans. Those which have been found are such as are common at the time of life at which its subjects die. Due to the position of the hands in paralysis agitans, and the similarity of this position to patients experiencing tetany, some authors speculated about the possible role of the thyroid and parathyroid glands in the etiology of paralysis agitans. Other authors, including Charcot and others considered paralysis agitans a neurosis, the disease without pathology. However, in light of its progressive nature and the inability to cure it by psychotherapy, most neurologists rejected this theory. In 1926, Byrnes suggested that the rigidity seen in paralysis agitans was actually due to degeneration of the muscle spindles.18 This theory gradually lost favor at the lack of evidence according a corticospinal or peripheral etiology that failed to materialize. There was a short report published in 1893 and 1894 of a patient with unilateral symptoms of parkinsonism. The doctors were Blocq and Marinesco.19 Autopsy on a 38-year-old man with unilateral parkinsonism revealed a tuberculoma in the midbrain destroying the substantia nigra. This report encouraged Dr. Brissaud in 1895 to suggest the substantia nigra as the source of Parkinson’s disease.20 His writings however were largely ignored until 1919, when Tretiakoff published his thesis regarding the involvement of the substantia nigra in the etiology of Parkinson’s disease and encephalitis lethargica.21 From this point forward, the role of the substantia nigra grew in importance until the time of Cotzias,22 when the dopamine deficiency hypothesis, confirmed by biochemical and neuropathological studies, came full circle resulting in the first remarkably effective treatment of Parkinson’s disease. This development is discussed further in subsequent chapters. The author gratefully acknowledges the editorial and technical assistance of David Velliquette, friend and colleague. REFERENCES 1. Parkinson, J., An Essay on the Shaking Palsy, Whittingham and Rowland, London, 1817. 2. Louis, E.D., Paralysis Agitans in the nineteenth century, in Parkinson’s Disease Diagnosis and Clinical Management, Factor, S.A. and Weiner, W.J., Eds., Demos, New York, 2002, Chapter 2. 3. Elliotson, J., On the medical properties of the subcarbonate of iron, Medico. Chirurgic. Transact. 13, 232, 1827. 4. Louis, E.D., Paralysis agitans in the nineteenth century, in Parkinson’s Disease: Diagnosis and Clinical Management, Factor S.A. and Weiner, W.J., Eds., Demos, New York, 2002, Chapter 2. 5. Hospital reports St. Thomas’s Hospital, Paralysis agitans, London Med. Surg. J., 11, 605, 1832. 6. Elliotson J., Clinical lecture, The Lancet, I:289–297, 1831. 7. Elliotson, J., Clinical lecture on paralysis agitans, The Lancet, 119, 1880. 8. Gowry, T.C., Case of paralysis agitans intermittens, The Lancet, II, 1831, 651. 9. Gibson, M., On spinal irritation, The Lancet, 567, 1839. 10. Reynolds, J.R., Report of a case of paralysis agitans removed by continuous galvanic current, The Lancet, II, 558, 1859. 11. Paget, G.E.,Case of involuntary tendency to fall precipitately forwards, with remarks. Med. Times Gaz., 10, 178, 1855.

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12. Charcot, J.M., Lectures on diseases of the nervous system Lecture V, The New Sydenham Society, London 1877, 129. 13. Meynert, Beitage zur differentiel Dianose des paralytischen Irrsinns, Wien. Med. Pr., Vol. XII, p. 645, 1871. 14. Murchison, C. and Cayley, W., Case of paralysis agitans, Trans. Path Soc., Vol. XXII, p. 24, 1871. 15. Dowse, T.S.The pathology of the case of paralysis agitans or Parkinson’s disease, Trans. Path. Soc., Vol. XXIXX,p. 17, 1878. 16. Gowers, W.R., A manual of the disease of the nervous system ,Vol. II, p. 589, Churchill, London, 1888. 17. Gowers, W.R., A system of medicine, Vol. VII, 2nd ed., p. 473, Macmillan & Co., London, 1910. 18. Byrnes, C.M., A contribution to the pathology of paralysis agitans, Arch. Neurol Psychiat., Vol. XV, p. 407, 1926. 19. Blocq, P. and Marinesco, G., Sur un cas de tremblent parkinsonien hemiplegique symtomatique dune tumeur du peduncule cerebrale, Bull. Et Mem. Soc. 20. Brissaud, Lecons sur les maladies nereuses, Vols. XXII and XXIII, Masson, Paris 1895. 21. Tretiakoff, C., Contribution a l’etude de l’anatomie pathologique du locus niger, These de Paris, 1919. 22. Cotzias, G.C., Van Woert, M.H., and Schiffer, L.M., Aromatic amino acids and modifications of parkinsons, N.Eng. J.Med., pp. 276, 374, 1967.

3 The Role of Dopamine in Parkinson’s Disease: A Historical Review L.Charles Murrin Department of Pharmacology, Nebraska Medical Center 0-8493-1590-5/05/$0.00+$1.50 © 2005 by CRC Press

Dopamine is universally known as the neurotransmitter most intimately involved with Parkinson’s disease and the severe loss of this neurotransmitter has been shown to be associated with most of the primary symptoms of the disease. However, even though James Parkinson described the neurological disease named after him almost two centuries ago, it required the development of relatively modern techniques to identify dopamine as the critical neurotransmitter in Parkinson’s disease and to realize the consequent therapeutic advances that were based on this discovery. In this review, I have focused on the discoveries, both in animals and man, that presented us with the concept of a nigrostriatal pathway that uses dopamine as neurotransmitter, that plays a key role in control of motor function, and that is central to Parkinson’s disease. More detailed and personal accounts of some aspects of this subject are available.1,2 In addition, after dopamine became a focus of research related to Parkinson’s disease, many advances have been made concerning the dopamine receptors and the other neurotransmitter pathways involved in Parkinson’s disease. These subjects are covered in other chapters in this volume. DISCOVERY OF THE NIGROSTRIATAL PATHWAY One of the most dramatic aspects of the pathology of Parkinson’s disease, the loss of neuronal cell bodies containing neuromelanin in the substantia nigra zona compacta, was reported as early as 1895 and has been confirmed by numerous investigators since then (see Ref. 3). At this early time, however, the terminal fields and even the function of the substantia nigra were unknown. For decades, most anatomists thought that the nigrostriatal neurons projected primarily to the globus pallidus. Numerous attempts were made to determine the anatomy of the nigral projection systems using retrograde axonal degeneration.4–6 Ferraro postulated that the major terminal field for the substantia nigra was the corpus striatum, with the greatest projection to the putamen.5 Mettler, in a more extensive study using similar techniques, came to the same conclusion.6 However, these studies were characterized by the inability to demonstrate the entire axonal pathway and so unequivocally establish a direct connection between the substantia nigra and the

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corpus striatum. This inability to demonstrate the complete pathway, probably due to the very fine unmyelinated nature of these neurons, left room for doubt. The first clear demonstration of a pathway from the substantia nigra to the corpus striatum was published by Rosegay in 1944 using a combination of Nissl and Marchi techniques to allow cross-checking and so identification of very fine fibers with more confidence.7 Since then, improvements in anatomic techniques have allowed numerous investigators to confirm this work (e.g., Refs. 8, 9). The many studies delineating the nigrostriatal pathway laid critical groundwork for subsequently connecting the known pathology of Parkinson’s disease with a loss of dopaminergic neurons. DISCOVERY OF DOPAMINE AS A NEUROTRANSMITTER The concept of neurohumoral transmission arose around the turn of the twentieth century with the work of Lewan-dowsky, Langley, and Elliott (see Ref. 10), and epinephrine was the first candidate neurotransmitter. A little over a decade later, norepinephrine began to emerge as the leading candidate for the neurohumoral substance released by the sympathetic nervous system. In subsequent years, the role of norepinephrine was clearly delineated,11 and research in this area led to the awarding of the Nobel Prize in Medicine in 1970 to U.S. von Euler and Julius Axelrod, along with Sir Bernard Katz. In the course of these studies, it became clear that the immediate precursor to norepinephrine is 3,4dihydroxyphenylethylamine, or dopamine. The discovery that dopamine itself is a neurotransmitter, similar to norepinephrine and acetylcholine, proved to be a major scientific breakthrough for the understanding of several neurological and psychiatric diseases, including Parkinson’s disease and schizophrenia, but it required another 20 years work to establish this. Dopamine was known to be an intermediate in the synthesis of norepinephrine and epinephrine, the product of aromatic amino acid decarboxylase acting on L-dihydroxyphenylalanine. Initially, dopamine was thought to be simply a precursor to norepinephrine and epinephrine, since it was found in extremely low levels and norepinephrine had been shown to be the primary transmitter of the sympathetic nervous system.12 The presence of dopamine in greater than trace amounts was demonstrated by Holtz and von Euler in urine, and in the adrenal gland and the heart of sheep by Goodall.13–15 This began to raise the question of whether dopamine was only a metabolic intermediate. However, the techniques available for these studies were relatively insensitive for dopamine and made study in other tissues difficult. A further step in uncovering dopamine as worthy of study in its own right was the demonstration by Montagu16 of a compound in whole brain from several species, including man, that was tentatively identified as dopamine (hydroxytyramine). Carlsson and Waldeck, in a similar time frame, discovered that a change in pH provided a marked improvement to the fluorescence assay of WeilMalherbe and Bone, and this allowed a more definitive detection of dopamine in tissue samples.17 Based on this, they demonstrated that dopamine (3-hydroxytyramine) was indeed present in whole brain of rabbits at levels equivalent to those of norepinephrine.18 The fact that dopamine concentrations equalled those of norepinephrine suggested to them that dopamine might have an independent function beyond being the precursor for norepinephrine. In this paper, Carlsson and co-workers carried out an experiment that

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foreshadowed the future treatment of Parkinson’s disease when they administered high doses of dopa, albeit the racemic form, to rabbits and found that this led to a marked increase in the levels of dopamine in brain while having far less impact on norepinephrine levels. There quickly followed a series of papers from a strongly collaborating group of Swedish scientists that provided further evidence for dopamine as a neurotransmitter, independent of its role in norepinephrine synthesis. Using the technique developed by Carlsson and Waldeck, Bertler and Rosengren examined the brains of numerous mammalian species and found dopamine present in all and at concentrations similar to those of norepinephrine.19,20 They also demonstrated that most of the dopamine present in brain (about 80%) was in the corpus striatum. In general, they found that, in areas with high concentrations of dopamine, norepinephrine was usually at low levels. Conversely, in regions where norepinephrine concentration was highest, dopamine was quite low. These data supported the idea that dopamine had a function of its own beyond being a precursor for norepinephrine. These authors also suggested that, since dopamine was found concentrated in the corpus striatum, it probably was important for the function of that region, i.e., control of motor function. This idea was supported by the fact that reserpine, which depleted the brain of dopamine (among other neurotransmitters) produced motor hypoactivity, while administration of high doses of levodopa produced motor hyperactivity,21 presumably due at least in part to production of excess dopamine. Interestingly, the authors make a comparison between the motor effects of reserpine and the symptoms of Parkinson’s disease. Based on these and other studies, Carlsson22 marshaled three arguments supporting dopamine’s role in controlling motor functions: 1. Large amounts of dopamine are present in the corpus striatum, known to be an important component of the extrapyramidal system. 2. Hypokinesis is produced by administration of reserpine, which depletes dopamine from the corpus striatum. 3. Levodopa, the immediate precursor to dopamine, is able to counteract the hypokinetic effects produced by reserpine. All of these ultimately pointed to a role for dopamine in Parkinson’s disease. At about the same time that the fluorescence biochemical assay to quantitatively measure dopamine (and other monoamines) was being established, fluorescence histochemical procedures were developed that allowed semiquantitative analysis of these same monoamines in tissue sections.23,24 This approach, known as the Falck-Hillarp technique, provided high-resolution anatomical data to complement the biochemical and pharmacological data. Based on the data demonstrating that the substantia nigra sends fibers to the neostriatum, that the neostriatum contains very high levels of dopamine, and that the substantia nigra has dopamine-containing nerve cells, Andén and colleagues postulated that the substantia nigra neu-rons were the source of dopamine in the neostriatum.3 Using a series of lesions of either the substantia nigra or of the neostriatum, they found support for their ideas. Lesion of the substantia nigra led to a loss of fluorescence in the neostriatum that correlated well with the extent of loss of catecholamine nerve cells in substantia nigra, particularly the cells in the pars compacta. Conversely, removal of the neostriatum allowed demonstration of flu-orescent nerve fibers from the substantia nigra

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up to the neostriatum due to the apparent backup of dopamine and its synthetic enzymes in the lesioned axons. Given these data and the findings that the pars compacta has a much higher dopamine content than the pars reticulata in man25 and that the characteristic lesion in Parkinson’s disease is loss of neuromelanin containing cells in the pars compacta [see Ref. 3], the authors suggested that parkinsonism is due to selective degeneration of nigroneostriatal dopamine neurons. Later animal studies, including those using the glyoxylic acid fluorescence technique,26 provided more detailed analyses of catecholamine pathways, terminal regions, and cell bodies in both brain and spinal cord.27−33 They supplied evidence for dopamine-rich areas outside the neostriatum, such as the olfactory tubercles, nucleus accumbens, hypothalamus, and frontal cortex. Other studies substantiated the idea that the catecholamine cell bodies give rise to catecholamine-containing terminal regions,34 analogous to those previously described in the peripheral nervous system, and that terminal regions contained dopamine in varicosities at very high concentrations.35 In the years following the initial suggestion that dopamine functions as a neurotransmitter, this catecholamine has been the subject of intense research. Numerous laboratories have provided evidence that dopamine fulfills the classic criteria for a neurotransmitter: localization and synthesis in nerve terminals, release from neurons on stimulation, production of the same effects as the endogenous compound released by nerve stimulation, metabolic machinery in the appropriate locations, and appropriate pharmacology.36, pp. 225–270 These basic science studies provided the foundation for and, at the same time, were chronologically intertwined with similar studies on human tissue that substantiated the key role dopamine plays Parkinson’s disease. Research on dopamine played a major role in the Nobel Prize in Medicine and Physiology awarded in 2000 to Carlsson, Greengard, and Kandel. DOPAMINE AND HUMAN STUDIES As mentioned above, it has been known for 100 years that a cardinal feature of Parkinson’s disease is loss of neuromelanin-containing neurons in the substantia nigra, particularly in the zona compacta. A nigrostriatal pathway was postulated in humans by Ferraro, but this proved difficult to substantiate because of the necessity of using postmortem tissue. Today, however, the existence of this and other related pathways37 is widely accepted and is the basis for our understanding of the anatomy and pathology of Parkinson’s disease.38 The early work demonstrating that dopamine was a probable neurotransmitter in mammals and that a dopaminergic nigrostriatal pathway appeared to be a major component of the extrapyramidal pathway led to investigations of human tissue. It was reasoned that a similar pathway existed in humans, analogous to that found in many other species. In addition, since it was known that Parkinson’s disease was characterized by loss of nigral neurons and a primary feature was loss of motor control, it seemed likely that loss of dopamine neurons would be an important pathological feature of this disease. The presence of high concentrations of dopamine in the neostriatum and in the substantia nigra of human brain39−41 provided evidence for the existence of this pathway. The dramatic loss of dopamine in neostriatum and substantia nigra of Parkinson’s patients

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demonstrated by Hornykiewicz and colleagues25,41 helped confirm the involvement of these neurons in the disease process. These findings were further supported by the strong correlation between the loss of dopamine and the loss of nigral neurons in humans, by a similar correlation between severity of the disease and the degree of loss of dopamine neurons, and by the finding that in hemiparkinsonism the dopamine deficiency was much more severe in the neostriatum contralateral to the side of the symptoms.42 Since these early studies, loss of the neuromelanin-containing dopamine neurons in the substantia nigra zona compacta has become the diagnostic hallmark of Parkinson’s disease. One of the drawbacks of the studies examining dopamine levels in human brain was the fact that postmortem tissue samples were the source of all the data. As a result, the possibility of artifacts due to tissue storage and handling or due to postmortem changes could not be ruled out completely. More recently, though, the development of positron emission tomography (PET) and single positron emission computed tomography (SPECT) have provided methods that allow examination of markers for dopamine neurons in living brain. The development of [18F]fluorodopa as a marker for dopamine neurons that is applicable to PET studies in humans 43 allowed further in vivo examination in Parkinson’s patients. These studies confirmed a severe loss of dopamine terminals in living patients,44,45 in agreement with previous studies. As would be expected, other markers specific to dopamine neurons, such as the dopamine transporter, were also dramatically reduced in Parkinson’s patients when compared to control subjects.46–48 Thus, these studies with technically far more sophisticated techniques confirmed in living patients the early findings in this field. DOPAMINE AND TREATMENT OF PARKINSON’S DISEASE Given this pathology, a logical approach to treating Parkinson’s disease would be to try to restore the levels of dopamine in the CNS. It was well known that dopamine does not cross the blood-brain barrier because of its positive charge. However, zwitterionic amino acids had the advantage of broadly specific transport systems to carry them across this barrier into the brain. Based on this, a top candidate for increasing dopamine levels in the CNS would be its immediate precursor, L-dihydroxyphenylalanine or L-dopa. Not only could L-dopa be transported across the blood-brain barrier, it also had the advantage of by-passing the rate limiting step in the synthesis of catecholamines, tyrosine hydroxylase. This, in turn, provided two advantages. First, it avoided the slowest step in the synthetic process. In addition, tyrosine hydroxylase had been shown to be present only in catecholaminecontaining neurons in the CNS, the very neurons that were disappearing in Parkinson’s disease. Second, aromatic amino acid decarboxylase (dopa decarboxylase), the enzyme converting L-dopa to dopamine, although shown to be primarily in dopamine neurons in the corpus striatum, was also clearly found in non-dopamine cells (i.e., serotonin and norepinephrine terminals).19,49 As a result, the loss of this enzyme in Parkinson’s disease was not as dramatic as the loss of tyrosine hydroxylase,50 and so use of dopa decarboxylase as a critical enzymatic step in treatment would be expected to be more successful than going through tyrosine hydroxylase.

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Several groups tried administering large doses of L-dopa to Parkinson’s patients and found promising results, particularly in combating akinesia.51–53 There were, however, significant side effects associated with this therapy, and they threatened to severely limit its usefulness. Several significant improvements were made in an extensive study by Cotzias and colleagues.54 In their own initial studies, they had used racemic dopa and had encountered serious side effects.53 In the later study,54 they used only L-dopa, as had others previously, and found that the use of the stereoisomer instead of the racemic mixture reduced the incidence of side effects greatly, including avoiding some of the most problematic, such as reversible granulocytopenia. They found that slowly increasing the dose also reduced the incidence of side effects. Perhaps most important, they introduced the use of a peripheral dopa decarboxylase inhibitor. They reasoned that many of the side effects that had been encountered could be explained by the conversion of Ldopa to dopamine and norepinephrine in the periphery. If this peripheral conversion could be reduced or stopped, the side effects should be reduced, and more L-dopa would be available for transport into the CNS. Animal studies had provided support for this notion.55,56 Using this approach, Cotzias and colleagues were very successful in reducing side effects and in allowing a reduction in the dosage of Ldopa necessary to produce beneficial effects in Parkinson’s patients.54 These early studies in humans introducing Ldopa therapy as a means of partially restoring central dopamine levels, and hence countering the symptoms of Parkinson’s disease, initiated what is currently the most common therapeutic approach to treating Parkinson’s disease. CONCLUSION Since this early work, our understanding of the pathology of Parkinson’s disease and of potential approaches to treatment have become much more detailed and sophisticated. While this review has focused on the nigrostriatal dopamine pathway as being central to Parkinson’s disease, it is becoming increasingly clear that the basal ganglia circuitry is quite complex, with multiple parallel circuits subserving specific functions.37,57 Indeed, not only are there regional differences in the loss of neurons within the substantia nigra,58,59 but dopamine neuronal systems besides the nigrostriatal pathway are also affected,60 although usually to a lesser extent. The loss of these other dopamine neurons contributes to a number of the characteristic symptoms of Parkinson’s disease. It also is clear that the dopamine neuronal system is not the only neurotransmitter system affected in Parkinson’s disease61–63 and that loss of other neurotransmitter neurons probably plays a significant role in Parkinson’s disease. These must now be taken into consideration in our understanding of the symptomatology and, hopefully, the treatment of Parkinson’s disease. It has been suggested that dopamine itself may be, in a certain sense, a contributor to the development of Parkinson’s disease,64,65 an idea that is disputed.66 Our understanding of these areas is covered in detail in other chapters of this volume. Nevertheless, it is clear that our current knowledge of the pathology, symptomatology and therapy of Parkinson’s disease has, as its base, the early studies in animals and man that provided evidence there is a nigrostriatal pathway critical for motor function, that dopamine is a neurotransmitter in the central nervous system and specifically in the

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nigrostriatal pathway, and that degeneration of this pathway is the hallmark of Parkinson’s disease. REFERENCES 1. Dahlstrom, A. and Carlsson, A., Making visible the invisible. Recollections of the first experiences with the histochemical fluorescence method for visualization of tissue monoamines, in Discoveries in Pharmacology. Vol. 3. Chemical Pharmacology and Chemotherapy, M. J.Parnham, J.Bruinvels, Eds., Elsevier: Amsterdam, 1986j. pp. 97–125. 2. Carlsson, A., Annual Review of Neuroscience, 10, 19, 1987. 3. Anden, N.E., Carlsson, A., Dahlstrom, A., Fuxe, K., Hillarp, N.A., and Larsson, K., Life Sciences., 3, 8, 523, 1964. 4. von Monakow C., Arch. f. Psychiat. u. Nervenkr., 27, 1, 1895. 5. Ferraro, A., Arch. Neurol. Psychiat.,19, 177, 1928. 6. Mettler, F.A., Journal of Comparative Neurology, 79, 185, 1943. 7. Rosegay, H., Journal of Comparative Neurology, 80, 293, 1944. 8. Carpenter, M.B., McMaster, R.E., American Journal of Anatomy, 114, 293, 1964. 9. Moore, R.Y., Bhatnager, R.K., Heller, A., Brain Research, 30, 119, 1971. 10. Hoffman, B.B. and Taylor, P., Neurotransmission. The autonomic and somatic motor nervous systems, in Goodman and Gilman’s, The Pharmacological Basis of Therapeutics, J.G.Hardman, and L.E.Limbird, Eds., McGraw-Hill, New York, 2001, Chapter 6, pp. 115–153. 11. von Euler, U.S., Noradrenaline: Chemistry, Physiology, Pharmacology and Clinical Aspects, Thomas: Springfield, IL, 1–382, 1956. 12. von Euler, U.S. Acta Physiologica Scandinavica. 12, 73, 1946. 13. Holtz, P., Credner, K., and Kroneberg, G., NaunynSchmiedeberg’s Arch. Exp. Pathol. Pharmakol., 204, 228, 1947. 14. von Euler, U.S., Hamberg, U., and Hellner, S., Biochemical Journal, 49, 655, 1951. 15. Goodall, M., Acta Physiologica Scandinavica, 24, Suppl. 85, 1, 1951. 16. Montagu, K.A., Nature, 180, 244, 1957. 17. Carlsson, A., Waldeck, B., Acta Physiologica Scandinavica, 44, 293, 1958. 18. Carlsson, A., Lindqvist, M., Magnusson, T., Waldeck, B., Science, 127, 471, 1958. 19. Bertler, A., Rosengren, E., Acta Physiologica Scandinavica. 47, 350, 1959. 20. Bertler, A., Rosengren, E., Experientia,15, 10, 1959. 21. Carlsson, A., Lindqvist, M., Magnusson, T., Nature,180, 1200, 1957. 22. Carlsson, A., Pharmacological Reviews, 11, 490, 1959. 23. Falck, B., Acta Physiologica Scandinavica,56, Suppl. 197, 1, 1962. 24. Falck, B., Hillarp, N.A., Thieme, G., Torp, A., Journal of Histochemistry and Cytochemistry. 10, 348, 1962. 25. Hornykiewicz, O., Wien. klin. Wsch.,75, 309, 1963. 26. Lindvall, O., Bjorklund, A., Histochemistry, 39, 97, 1974. 27. Dahlström, A., Fuxe, K., Acta Physiologica Scandinavica,62, 1, 1964. 28. Fuxe, K., Acta Physiologica Scandinavica, S247, 37, 1965. 29. Anden, N.E., Dahlstrom, A., Fuxe, K., Larsson, K., Olson, L., Ungerstedt, U., Acta Physiologica Scandinavica, 67, 313, 1966. 30. Ungerstedt, U., Acta Physiologica Scandinavica, Supp., 367, 1, 1971. 31. Lindvall, O. and Björklund, A., Acta Physiologica Scandinavica, Supp. 412, 1, 1974. 32. Lindvall, O., Bjorklund, A., Divac, I., Brain Research, 142, 1, 1978. 33. Björklund, A., Lindvall, O.,Dopamine-containing systems in the CNS, inHandbook of Chemical Neuroanatomy, A.Björklund, Ed., Elsevier: Amsterdam, pp. 55–122, 1984. 34. Fuxe, K., Zeitschrift fur Zellforschung und Mikroskopische Anatomie,65, 573, 1965.

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35. Anden, N.E., Fuxe, K., Hamberger, B., Hokfelt, T., Acta Physiologica Scandinavica, 67, 306, 1966. 36. Cooper, J.R., Bloom, F.E., Roth, R.H., The Biochemical Basis of Neuropharmacology, Oxford Univ Press: Oxford, pp. 1–405, 2003. 37. Alexander, G.E., DeLong, M.R., Strick, P.L., Annual Review of Neuroscience, 9, 357, 1986. 38. Fletcher, N.,Movement disorders, in Brain’s Diseases of the Nervous System, M.Donaghy, Ed., Oxford University Press: Oxford, Chapter 32, p. 1015–1095, 2001. 39. Bertler, A., Acta Physiologica Scandinavica,51, 97, 1961. 40. Sano, I., Gamo, T., Kakimoto, Y., Taniguchi, K., Takesada, M., Nishinuma, K., Biochimica et Biophysica Acta, 32, 586, 1959. 41. Ehringer, H., Hornykiewicz, O., Klin. Wschr, 38, 1236, 1960. 42. Hornykiewicz, O., Research Publication of the Association for Research in Nervous & Mental Disease, 50, 390, 1972. 43. Garnett, E.S., Firnau, G., Nahmias, C., Nature. 305, 137, 1983. 44. Leenders, K.L., Palmer, A.J., Quinn, N., Clark, J.C., Firnau, G., Garnett, E.S., Nahmias, C., Jones, T. and Marsden, C.D., Journal of Neurology, Neurosurgery and Psychiatry, 49(8), 853, 1986. 45. Leenders, K.L., Salmon, E.P., Tyrrell, P., Perani, D., Brooks, D.J., Sager, H., Jones, T., Marsden, C.D., and Frackowiak, R.S.J., Archives of Neurology, 47, 1290, 1990. 46. Frost, J.J., Rosier, A.J., Reich, S.G., Smith, J.S., Ehlers, M.D., Snyder, S.H., Ravert, H.T. and Dannals, R.F., Annals of Neurology, 34, 423, 1993. 47. Seibyl, J.P., Marek, K.L., Quinlan, D., Sheff, K., Zoghbi, S., Zea-Ponce, Y., Baldwin, R.M., Fussell, B., Smith, E.O., Charney, D.S., Hoffer, P.B. and Innis, R. B., Annals of Neurology, 38, 589, 1995. 48. Innis, R.B., Seibyl, J.P., Scanley, B.E., Laruelle, M., Abi-Dargham, A., Wallace, E., Baldwin, R.M., ZeaPonce, Y., Zoghbi, S. and Wang, S., Proc. Natl. Acad. Sci. USA, 90 (24), 11965, 1993. 49. Lloyd, K., Hornykiewicz, O., Brain Research, 22, 426, 1970. 50. Lloyd, K.; Hornykiewicz, O., Science, 170, 1212, 1970. 51. Birkmayer, W., Hornykiewicz, O., Wien. klin. Wsch, 73, 787, 1961. 52. Birkmayer, W., Hornykiewicz, O., Arch. Psychiat. Nervenkr, 203, 560, 1962. 53. Cotzias, G.C., Van Woert, M.H., Schiffer, L. M., New England Journal of Medicine, 276(7), 374, 1967. 54. Cotzias, G.C. ,Papavasiliou, P.S., Gellene, R., New England Journal of Medicine, 280(7), 337, 1969. 55. Sjoerdsma, A., Vendsalu, A., Engelman, K., Circulation, 28, 492, 1963. 56. Udenfriend, S., Zaltzman-Nirenberg, P., Gordon, R.and Spector, S., Molecular Pharmacology, 2, 95, 1966. 57. Parent, A., Sato, F., Wu, Y., Gauthier, J., Levesque, M. and Parent, M., Trends in Neuroscience, 23, Suppl., S20, 2003. 58. Fearnley, J.M., Lees, A.J., Brain, 114(5), 2283, 1991. 59. Gibb, W.R.G., Lees, A.J., Journal of Neurology, Neurosurgery and Psychiatry, 54, 388, 1991. 60. Rakshi, J.S., Uema, T., Ito, K., Bailey, D.L., Morrish, P.K., Ashburner, J.,Dagher, A., Jenkins, I.H., Friston, K.J. and Brooks, D.J., Brain, 122(9), 1637, 1999. 61. Przuntek, H., Müller, T., Journal of Neurology, 247, Suppl. 2, II/2, 2000. 62. Braak, H., Braak, E., Journal of Neurology, 247, Suppl. 2, II/3, 2000. 63. Stokes, A.H., Hastings, T.G., Vrana, K.E., Journal of Neuroscience Research, 55, 659, 1999. 64. Fahn, S., Advances In Neurology, 69, 477, 1996. 65. Olanow, C.W., Stocchi, F., European Journal of Neurology, 1, Suppl. 7, 3, 2000. 66. Mytilineou, C., Walker, R.H., JnoBaptiste, R., Olanow, C.W., Journal of Pharmacology and Experimental Therapeutics, 304(2), 792, 2003.

4 Parkinson’s Disease: Where Are We? Ajit Kumar, Zhigao Huang, and Donald B.Calne Pacific Parkinson’s Research Centre, Vancouver Hospital and Health Sciences Centre, University of British Columbia 0-8493-1590-5/05/$0.00+$1.50 © 2005 by CRC Press

Since the original description of the “Shaking Palsy” by James Parkinson in 1817, knowledge about Parkinson’s disease (PD) made slow progress for over a century. Beginning in the late 1950s, our understanding of PD has progressed by leaps and bounds, largely through the advent of better biomedical technology and extraordinary progress in allied medical disciplines such as neuropharmacology, neurochemistry, neuropathology, molecular biology, and genetics. The advances made thus far can be discussed from the broad perspectives of etiopathogenesis and management. ETIOPATHOGENESIS The definition of PD is rather difficult. A practical definition with the recognition that the brunt of the pathology falls on the dopaminergic nigrostriatal pathway suffices for most clinicians. There is evidence to suggest that PD may actually be a syndrome with many causes.1 Phenotypes identical to sporadic PD have been described in patients with the parkin mutation, spinocerebellar ataxia type 2, and mutations in the alpha-synuclein gene.2−5 Similarly, parkinsonism indistinguishable from PD has been described after viral encephalitis. These observations suggest that PD may not be a single homogenous entity. This view assumes particular importance with regard to causation, as there may be several causes for the PD phenotype. The cause(s) of PD are still largely unknown. There has been considerable debate about the relative importance of genetic versus environmental factors. These factors are not mutually exclusive, as genetic susceptibility may confer selective vulnerability to specific environmental factors. The role of heredity in the etiology of PD has been fortified by the discovery of some kindreds with rare genetic forms of PD. However, the cause remains unresolved in the vast majority of patients.6 Environmental risk factors, including exposure to pesticides and metals, viruses, well-water drinking, rural living, and farming, have been investigated in many recent case-control and epidemiological studies.7–10 In addition, there is evidence that aging is also a likely contributory factor.11

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GENETIC FACTORS The discovery of families with inherited forms of parkinsonism has generated considerable interest over the past few years. These inherited forms account only for a miniscule proportion of PD patients. However, their discovery has provided insight into the possible pathogenesis of PD, particularly with regard to the role of abnormal protein processing at the subcellular level.6 Parkinsonism has been associated with mutations in four genes thus far: α-synu-clein, on locus 4q21–23,4,5 parkin on locus 6q25–27,3 ubiquitin C-terminal hydrolase L1 (UCH-L1) on locus 4p1412 and DJ-1 on 1p36.13 Other gene loci with linkage to inherited parkinsonism identified include 2p13,14 4p14–1615 and 12p11-q1316 (See Table 4.1). There is evidence for additional loci being involved as well.17 Two disease-causing mutations, A53T and A30P, have been identified in the αsynuclein gene.4–5 Multiple mutations have been described in the parkin gene.18,19 Mutations in the α-synuclein and UCH-L1genes are associated with a phenotype resembling sporadic PD (young onset form is common with the former), whereas mutations in the parkin gene are usually associated with a juvenile form of PD with no Lewy bodies in the brain.6,20 Monogenic forms of parkinsonism due to genetic mutations result in abnormalities of protein processing, particularly the ubiquitin mediated pathway of protein degradation. These abnormalities presumably set off a cascade of adverse events at the cellular level that eventually culminate in cell death. Abnormal protein processing is further discussed later under ‘pathogenetic mechanisms’ (see discussion below). ENVIRONMENTAL FACTORS Many epidemiological studies have shown a tenuous link between environmental factors and PD. This, together with the observation that the vast majority of PD patients lack the genetic abnormalities described earlier, makes a case for examining the environmental theory of PD causation. Familial occurrence of PD does not necessarily imply genetic causation. A large survey comparing monozygotic and dizygotic twins failed to reveal a higher concordance rate in the monozygotic group in the age range when PD usually starts.21 Family members share their environment as well as their genes. Another study demonstrated that the risk of developing PD for a child in a parent-child cluster depended on the child’s age when the parent started to show symptoms rather than the age of the parent; the younger the child, the greater the risk.22 This suggests a significant role for shared environment. An older study showed that PD is commoner in the north compared to the south in the United State, irrespective of race, again suggesting a role for environmental factors.23 The discovery that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) leads to selective destruction of the nigrostriatal pathway opened up a new line of thinking among neuroscientists on the potential role of toxins in PD causation.24 Transient exposure to MPTP can also lead to delayed death of nigral neurons after a long latent period.25 There is no evidence to date that MPTP is involved in the causation of sporadic PD. There have been several reports on the relation of exposure to herbicides, fungicides and pesticides, and the development of PD. 8–10,26,27 A recent meta-analysis seems to lend some credibility to these reports.28 It is interesting that the pesticide rotenone, which has a

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somewhat similar structure to MPTP, can cause alpha synuclein accumulation and neuronal death in animals.29 Rotenone-induced dopaminergic neuronal degeneration is thought to result from selective dysfunction of mitochondrial Complex I, as is the case for the other selective dopaminergic neurotoxin, MPTP. Other environmental factors proposed to be associated with a higher risk of developing PD include rural living, wellwater drinking, and farming.9 Young-onset parkinsonism in particular has been associated with exposure to well water.30 No toxic constituents have been identified, and well-water drinking may simply be a marker for rural

TABLE 4.1 Genes Associated with Parkinsonism Gene

Locus

Inheritance

Phenotype

Reference

α-synuclein 4q21−q23 Autosomal dominant Early onset PD Kruger et al., 1998 [4] Parkin 6q25.2−q27 Autosomal recessive Juvenile onset PD Kitada et al., 1998 [3] UCH-L1 4p14 Autosomal dominant Typical PD Leroy et al., 1998 [12] DJ-1 1p36 Autosomal recessive Early onset Bonifati et al., 2003 [13] PARK3 2p13 Autosomal dominant Typical PD Gasser et al., 1998 [14] PARK4 4p14-p16 Autosomal dominant PD/Essential tremor Farrer et al., 1999 [15] PARK6 1p35-p36 Autosomal recessive Early onset Valente et al., 2001 [15a] PARK8 12p11.2-q13.1 Autosomal dominant Typical PD Funayama et al., 2002 [16]

environment, which may in turn point to pesticide exposure.6 Associations between PD and exposure to plastic or epoxy resins, and metals such as manganese have also been reported.7,31 An inverse risk between smoking and the risk for developing PD has been reported by some studies, including one on monozygotic twins.32 There is controversy as to whether this relationship is real or merely reflects a “rigid” premorbid personality trait described in PD patients33 that prevents them from smoking. Recent studies suggest that nicotine may play a protective role by acting on toxin-neutralizing enzymatic pathways or by inducing neurotrophic factors in the striatum.34,35 It has also been proposed that caffeine intake has a protective effect and prevents PD independent of the protective effect of smoking.36 This effect could possibly be mediated through the neuroprotective effect of adenosine receptor blockade as demonstrated in animal models of parkinsonism.37,38 A possible role for infection, particularly viruses, has been speculated about since the epidemic of Von Economo’s encephalitis in the early years of the last century. Parkinsonism was frequently a sequel, sometimes after a delay of several years.39 Symptom progression has been documented in these patients despite the absence of markers of persisting viral infection.40 There has been renewed interest in the possible role of viruses in PD causation. Positron emission tomography (PET) scanning has demonstrated selective lesions of the nigrostriatal pathway in human subjects with parkinsonism following viral encephalitis.41 Japanese workers have shown that certain strains of Influenza A virus are selectively tropic to the nigral neurons and can gain access to the brain via the nasal passages in mice.42–44 Another study showed that antibodies to the Epstein-Barr virus cross react with alpha synuclein in the brains of patients with PD.45 Though no markers of viral infection have been shown in autopsy

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studies in PD, a persistent atypical inflammatory reaction has been demonstrated in the substantia nigra.46–48 A recent epidemiological report suggests that the prevalence of PD is increased in teachers, medical workers, loggers and miners.9 One explanation for this would be an infectious etiology as teachers and medical workers come in contact with large numbers of the public. In the case of miners and loggers, increased prevalence could be related to the cramped poorly ventilated living quarters they share. Another recent study examined occupational risk factors in pairs of monozygotic twins discordant for PD and found a highly significantly increased risk in the teaching and health care professions.49 PATHOGENETIC MECHANISMS Abnormal protein processing, oxidative stress, mitochondrial dysfunction, apoptosis, excitotoxicity, and inflamma-tion have all been thought to contribute to cell death in PD.6 These mechanisms are not mutually exclusive and may indeed be intimately related. These pathogenetic mechanisms are ostensibly set off by a trigger that, as discussed earlier, may be genetic, environmental, or the result of a complex gene-environment interaction. Abnormal Protein Processing Abnormalities in the ubiquitin-mediated pathway of protein degradation are associated with some monogenic forms of parkinsonism. Proteins destined to be degraded by the ubiquitin-mediated pathway are labeled with polyubiquitin chains through a series of enzymatic reactions and then degraded by the proteasome, a multicatalytic complex, or by the lysosomal system.50,51 α-synuclein and ubiquitin are major components of the filaments associated with Lewy bodies.52 Parkinsonism associated with mutations of the α-synuclein gene is characterized by the presence of Lewy bodies in surviving neurons of the substantia nigra. Mutant A53T or A30P α-synuclein are associated with the formation of small ubiquitinated aggregates and autophagic cellular degeneration.4,53 Defects occur in the lysosomal and proteasomal degradation systems and may be a consequence of the above effects.51,54 Accumulation of mutant α-synuclein in the neuron possibly contributes to cell death. There is experimental evidence supporting this notion.55,56 Degeneration of dopaminergic terminals is seen in mice and in Drosophila with transgenic expression of human mutant α-synuclein.57 The degeneration is particularly marked in the Drosophila model when mutant human α-synuclein (either A30P or A53T) is expressed and is associated with the formation of abnormal inclusion bodies resembling Lewy bodies.57 Dopamine-dependent apoptosis is enhanced by α-synuclein accumulation, and this may be one explanation for the selective vulnerability seen in PD.56 Mutations of the parkin gene result in a juvenile form of PD characterized by selective loss of nigral dopamine neurons without Lewy bodies.3,20 The gene product, parkin, functions as an E3 ubiquitin-protein ligase and is responsible for the attachment of ubiquitin to substrates such as synaptic vesicle-associated protein, PNUTL1 (drosophila peanut-like gene 1 protein)/CDCrel-1,58 parkin-associated endothelin receptor-like receptor (PaelR),59 and a glycosylated form of α-synuclein.60 Mutations in the parkin

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gene ostensibly result in abnormal accumulation of substrate proteins leading to insoluble Pael-R mediated cell death.59 UCH-L1 is an enzyme that hydrolyzes small C-terminal adducts of ubiquitin to generate ubiquitin monomers, which can then be recycled and used to label other proteins. Mutation in the UCH-L1 gene results in an abnormal form of the enzyme with reduced activity and this in turn leads to impaired protein processing by the ubiquitinproteasome pathway.50 The recently discovered DJ-1 gene encodes a ubiquitous highly conserved protein whose function remains largely unknown though it has been suggested that it may be involved in the oxidative stress response.13 Mutations in this gene result in a young onset form of PD. Oxidative Stress Indicators for a role for oxidative stress in PD include changes in the substantia nigra in the form of increased lipid peroxidation, reduced glutathione (GSH) levels, and high concentrations of iron and reactive oxygen free radicals (ROS).50,61,62 While there is evidence for increased lipid peroxidase and abnormally oxidized DNA in PD, these findings are not restricted to the substantia nigra.63,64 Deficiency of reduced GSH has been shown in the substantia nigra of parkinsonian subjects and this may contribute to reduced clearance of hydrogen peroxide.65 GSH deficiency appears to result at least in part from increased activity of the degradative enzyme γ-glutamyltranspeptidase. Experimental evidence that shows reduction of the neurotoxic effect of 6hydroxydopamine (6-OHDA) in the laboratory with exogenous administration of antioxidants such as cysteine, N-acetyl cysteine or glutathione lends some support to the oxidative hypothesis.66 Dopamine itself can undergo both enzymatic and nonenzymatic reactions resulting in the formation of toxic radicals.67 While high concentrations of levodopa in artificial conditions can result in oxidative cell death,68 there is no in vivo evidence that levodopa can be toxic to substantia nigra neurons.69 On the contrary, studies have shown that levodopa could actually be neuroprotective not only in rodent models but also in humans.70,71 Mitochondrial Dysfunction The elucidation of the mechanism by which MPTP produces parkinsonism in experimental animals has contributed to the understanding of the possible role of mitochondrial dysfunction in the pathogenesis of PD. MPTP is first deaminated by MAO-B in glial cells resulting in the formation of the active moiety, the 1-methyl-4phenylpyri-dinium ion (MPP+). MPP+ is then selectively accumulated in dopamine nerve terminals by the plasma membrane dopamine transporter. Once inside the dopamine nerve terminals, MPP+ generates hydrogen peroxide and other free radicals that interfere with mitochondrial respiration. MPP+ is concentrated in mitochondria, where it impairs mitochondrial respiration by inhibiting complex I of the electron transfer complex and consequently causing cell death.72 Complex I deficiency specific to the substantia nigra has been reported in human PD brains.73,74 Also, selective nigral death following chronic

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exposure to rotenone, a well-known inhibitor of complex I, has been reported.29 No such defect of oxidative phosphorylation has been found in multiple system atrophy.75 Similarly, no complex I abnormality has been shown in the Lewy body rich cingulate cortex of diffuse Lewy body dementia brains.73 Apoptosis Altered expression of pro-apoptotic genes has been reported to be associated with PD. Activated caspase-3, which is the major downstream caspase involved in the execution phase of neuronal cell death, has been detected in the substantia nigra of PD patients.76 Other studies have shown that activated forms of caspase-8 and caspase-9, upstream caspases that are known to cleave and activate caspase-3, are present in dopaminergic neurons of the substantia nigra in MPTP-treated mice.77 Caspase-mediated parkin cleavage that compromises parkin function has also been demonstrated in cell lines.78 The significance of these observations is at yet indeterminate, especially as there are studies that do not support the notion of active apoptosis in PD.79,80 Other Mechanisms Excitatory neurotransmission may result in neurotoxicity through impaired mitochondrial function.81 Prolonged survival in PD has been claimed with the use of amantadine, which is a weak N-methyl-D-aspartate (NMDA) antagonist.82 Activated microglia have been shown in the substantia nigra in PD.46,83 Inflammatory and glial responses have also been observed in the substantia nigra of patients exposed to MPTP and in MPTP-treated primates.84 The pathogenetic role of atypical inflammation is unclear at present, especially whether it represents a primary or secondary phenomenon. MANAGEMENT To date, no intervention has been convincingly shown to slow down, arrest, or reverse the progression of PD. However, there are indicators from recent research that effective neuroprotective agents for PD may be available in the not too distant future as our understanding of the pathogenetic mechanisms steadily grows. There have also been considerable advances in the symptomatic treatment of PD over the past few years. These are discussed below under the broad headings of pharmacological, surgical, and nonpharmacological interventions. PHARMACOLOGICAL The Placebo Effect There is a prominent placebo effect associated with PD. Placebo treatment significantly increases the release of endogenous DA in the striatum.85 The degree of DA release induced by a placebo in PD is comparable to that induced by antiparkinson medication.85 DA is involved in mediating the expectation of, as well as the response to reward, and

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increased expectation of therapeutic benefit results in greater DA release in the striatum. This study reinforces the necessity of having a placebo arm while evaluating therapies for PD. Dopamine Agonists Since loss of nigrostriatal dopaminergic function is the basic underlying pathophysiology in PD, drugs that enhance dopminergic function in the striatum remain the cornerstone treatment. Levodopa is still the most widely used and the most effective drug for PD, though there has been a rapidly increasing trend for the use of DA agonists in the past few years. One of the main reasons for this trend has been the concern that early use of levodopa may predispose patients to developing long-term motor complications such as “wearing off,” “on-off,” and dyskinesia. The reported prevalence of these complications ranges from 50 to 75% or higher after five years of treatment.86–90 Motor fluctuations and dyskinesias have a negative impact on the quality of life of patients and are often difficult to manage. Ideally, the goal of treatment would be reduction of parkinsonian symptoms without risk of long-term side effects. The theoretical benefits of DA agonists over levodopa are a longer half-life, resulting in less pulsatile stimulation of dopamine receptors, and no dependence on degenerating presynaptic DA nerve terminals, thereby reducing the risk of development of motor fluctuations and dyskinesias. Once functional disability in PD requires treatment with a dopaminergic agent, the choice of levodopa versus a dopamine agonist has largely been arbitrary. Results from more recent clinical trials claim to shed some light on this contentious issue. The study of cabergoline versus levodopa by Rinne et al. found that the Unified Parkinson’s Disease Rating Scale (UPDRS) motor scores decreased by 40 to 50% with both drugs during the first year of therapy.91 Levodopa appeared to be better than cabergoline for improvement in UPDRS motor scores as well as activities of daily living (ADL). After four years in the clinical trial, levodopa treated subjects still showed an average of 30% improvement in motor disability, while patients treated with cabergoline showed a 22% improvement. There was a risk reduction of 12% for the development of “motor complications” in patients on cabergoline compared to levodopa. The study of ropinirole versus levodopa by Rascol et al. found that levodopa treatment resulted in a significantly greater increase in motor improvement than ropinirole in patients who completed the study (five years).92 They also reported that there was no significant difference in ADL scores between the two groups at five years. The risk reduction for motor complications was 14% in the ropinirole group. The pramipexole versus levodopa study by the Parkinson Study Group (PSG) found that levodopa resulted in a significantly greater improvement than pramipexole in both the UPDRS motor scores as well as in ADL scores after 23.5 months of treatment.93 Motor complications, defined as dyskinesias, wearing off, and on-off motor fluctuations, were significantly less common in the pramipexole group (28%) versus levodopa-treated patients (51%) at the end of 23.5 months. However, the incidence of hallucinations, peripheral edema, and somnolence were significantly higher in the pramipexole group than in the levodopa group. The above studies suggest that the incidence of motor complications is lower with DA agonists compared to levodopa. However, both motor scores and activities of daily living are better with levodopa. It is unclear whether the higher incidence of complications in

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the levodopa treated groups is in part simply a reflection of greater therapeutic efficacy. Also, DA agonists have a longer halflife than levodopa and the lower incidence of complications may reflect a smoother pattern of receptor stimulation. COMT Inhibitors In early PD, the motor response to levodopa administration lasts longer than would be inferred from the plasma half-life of levodopa. Presumably, this phenomenon is related to surviving nigrostriatal neurons being able to store dopamine (DA) synthesized from exogenous levodopa, thus serving a buffer function. In more advanced PD, especially with the appearance of “wearing-off,” the motor response tends to correlate more with plasma levodopa levels.94 Degeneration of nigrostriatal DA nerve terminals leading to loss of buffering capacity has been suggested as one mechanism for this effect.95 With the onset of fluctuations, there is steepening of the doseresponse curve resulting in narrowing of the dose range of levodopa that produces a clinically significant antiparkinsonian response, resembling an “all-or-none” response.96 In such a situation, even slight variations of plasma levodopa levels, resulting from pharmacokinetic factors such as absorption and changes in transport across the blood-brain barrier, can result in a highly variable antiparkinsonian response. This mechanism may contribute to the “on-off’ effect.96 Increased DA turnover has also been implicated in the pathogenesis of motor fluctuations. Uptake and decarboxylation of levodopa, release in to the synaptic cleft, and reuptake by the presynaptic neuron are all accelerated resulting in high synaptic levels of DA for a very brief period in the synaptic cleft. This has been demonstrated in a PET study where synaptic DA levels were estimated using the 11C-raclopride binding paradigm. One hour after administration of a dose of levodopa, fluc-tuators not only had a synaptic DA level three times higher than stable responders, but also faster clearance of DA from the synaptic cleft.97 This suggests that increased DA turnover leading to marked swings in synaptic DA levels contributes to motor fluctuations. Whatever the mechanism, maintenance of steady plasma levels of levodopa in the therapeutic range over a sustained period is helpful in PD, especially when fluctuations set in. Strategies for achieving this goal include more frequent dosing, sustained-release preparations of levodopa, longacting DA agonists, monoamine oxidase (MAO-B) inhibitors to inhibit DA metabolism, and catechol-O-methyltransferase (COMT) inhibitors to increase bioavailability of levodopa. Current evidence indicates that use of COMT inhibitors is sometimes an effective option to deal with fluctuations, particularly “wearing-off.”94 COMT catalyzes transfer of a methyl group from Sadenosyl-methionine to endogenous catechols.98 Levodopa is O-methylated by COMT to form 3-O-methyldopa (3OMD).99 Peripheral decarboxylation and methylation result in only 1% of an oral dose of levodopa reaching the brain.100 Furthermore, 3-OMD may itself contribute to decreased brain levels of levodopa by competing with levodopa for absorption from the GI tract and transport into the brain. When COMT inhibition is added to levodopa/AADC (aromatic L-amino acid decarboxylase) inhibitor therapy (carbidopa and benserazide), peripheral levodopa metabolism is further reduced. Consequently, a greater level of levodopa becomes available for entry into the brain and conversion to DA. Another potential benefit of adding a COMT inhibitor to antiparkinson drugs is the sparing of Sadenosylmethionine, the methyl donor for Omethylation reactions. Low concentrations of

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S-adenosylmethionine in the cerebrospinal fluid have been associated with depression and dementia; both common comorbidities associated with PD.101 Entacapone, a selective and reversible COMT inhibitor, increases both the peripheral (and thus central) concentration of levodopa by preventing its biotransformation to 3OMD. When entacapone is added to levodopa/AADCinhibitor therapy, its ability to inhibit COMT results in greater and more sustained plasma and central nervous system levels of DA than with levodopa/AADC-inhibitor alone.102 This leads to a prolonged duration of antiparkinsonian action, which translates into improvement in motor function and better ability to perform activities of daily living. Also, [18F] 6-fluorodopa (18FD) PET studies have shown a significant increase in striatal uptake of 18FD in PD patients when coadministered with COMT inhibitors, as compared to without.103 This indicates the effectiveness of COMT inhibitors in indirectly enhancing striatal levodopa uptake by increasing the peripheral concentration of levodopa. Results from a number of trials in PD patients who experience motor fluctuations while on levodopa have shown an increase in levodopa bioavailability resulting from COMT inhibition.102,104,105These patients show prolongation of the clinical benefit of levodopa therapy with specific improvement in “on” time. Correspondingly, decreases in the daily “off” time, and to a lesser extent in UPDRS motor scores, have been observed. Another COMT inhibitor, tolcapone, has been studied in stable PD patients.106 The required levodopa doses were much less in stable patients than in fluctuators when combining treatment with tolcapone. There was significant improvement in activities of daily living and motor function in stable PD patients treated with a combination of levodopa and tolcapone. Adverse effects of COMT inhibitors are usually related to increased plasma levels of levodopa and include increased risk of dyskinesias and neuropsychiatric disturbances102. Diarrhea is a specific side effect of entacapone. Tolcapone is seldom used now because of hepatotoxicity. Neuroprotective Agents Over the past few years, there has been renewed interest in designing interventions that potentially slow, stop, or reverse the neurodegenerative process in PD. This has in part been due to the proliferation of theories of the pathogenetic processes involved in cell death in PD such as oxidative stress, mitochondrial dysfunction, excitotoxicity, and apoptosis.107 The DATATOP study and other similar later clinical trials suggested that selegiline may have a neuroprotective effect in PD.108–112 However, these studies have been confounded by the symptomatic effect of selegiline as changes in the UPDRS motor score were used as primary outcome measures.107 Even a study with a two-week washout of selegiline111 that suggested a neuroprotective effect has been criticized as a recent report suggests that even this time frame may be insufficient to eliminate the symptomatic effect of antiparkinson medication.113 A study with rasagiline, which is a selective and irreversible inhibitor of MAO B, showed significant clinical benefit, but again this study may have been confounded by a symptomatic effect.114 It has been suggested, based on both in vitro and in vivo studies, that propargylamines such as selegiline and rasagiline may have a protective and antiapoptotic effect independent of their monoamino oxidase B (MAO B) inhibiting capability.114–117 This effect may be

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mediated through altered expression of genes involved in apoptosis such as superoxide dismutase (SOD) 1, SOD 2, BCL 2, BAX, c-JUN, glutathione peroxidase, and glyceraldehydes-3-phosphate dehydrogenase (GAPDH).116,118 Rasagiline is currently undergoing testing for neuroprotection in PD. Glutamate mediated excitotoxic cell damage in dopaminergic neurons has been reported to be prevented by N-methyl-D-aspartate (NMDA) antagonists in vitro and in animal models of PD.119–121 One report suggests that amantadine, which has weak NMDA antagonist activity, may be neuroprotective.82 Other NMDA antagonists such as remacemide and riluzole have not shown any neuroprotective effect.122,123 Exposure to rotenone, a pesticide that inhibits complex 1 of the mitochondria, has been associated with PD.29 A trial last year with coenzyme Q10, a bioenergetic agent, showed a trend for clinical improvement with doses of 1200 mg or more.124 The results have to be interpreted with caution, as the study was a small one. DA agonists have been shown to have a neuroprotective effect both in vitro and in vivo in experimental setting. The CALM-PD SPECT study evaluated the neuroprotective effect of pramipexole using striatal β-CIT (a marker for the DA transporter) uptake as measured by single photon emission tomography (SPECT) as an outcome measure and concluded that pramipexole had a neuroprotective effect.93 There have been technical concerns with the interpretation of surrogate markers of nigrostriatal function. More importantly, there was no clinical benefit observed in the patients treated with the DA agonists though they had better PET scans. On the contrary, the levodopa treated patients had better motor scores. Another study evaluated the putative neuroprotective effect of ropinirole using striatal 18fluorodopa uptake measured by PET as an outcome measure and concluded that ropinirole did not have a neuroprotective effect in PD.125 Glial-derived neurotrophic factor (GDNF) has been shown to protect dopaminergic neurons from toxins in vitro as well as restore dopaminergic function in MPTP lesioned primates.126,127 A trial with intraventricular GDNF in human PD subjects showed no benefit.128 One of the reasons for this is believed to be inability of GDNF to penetrate into brain tissue. Significant improvement has been noted in MPTP lesioned primates that received GDNF using a lenti virus vector to deliver the drug into the striatum.129 In summary, none of the interventions thus far have convincingly shown a neuroprotective effect sufficient to make clinical claims. SURGICAL THERAPIES The past decade has seen renewed interest in surgery for the treatment of PD.130 The limitations of drug treatment, a better understanding of disordered basal ganglia physiology, and the significant clinical benefits of surgery have made this option more attractive. Advances in neuroimaging, stereotactic surgery, and better physiological localization with techniques such as microelectrode recording and macrostimulation have also made surgery more accurate and therefore safer.130 The two techniques employed are ablation and deep brain stimulation. The latter has become popular because of reversibility and the ability to adjust the stimulus and thus potentially “follow” the disease. Disadvantages include technical difficulties, high cost, and potential surgical complications such as infection and migration of electrodes.131 Neural structures targeted include the ventral intermediate nucleus of the thalamus (for tremor), the posteroventral

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pallidum (for bradykinesia and drug-induced dyskinesia), and the subthalamic nucleus (for bradykinesia, and dyskinesia indirectly by virtue of reduction in the dose of antiparkinson medication following surgery). There remain unresolved issues such as guidelines for optimal patient selection and timing of the surgery.132 Restorative surgery with transplantation of fetal nigral cells into the striatum has been claimed to show clinical benefit and evidence of increased striatal18 fluorodopa uptake in PD patients. No improvement has been noted in quality of life measures.133,134 Also, these patients have have severe persistent “off” period dyskinesia, the pathophysiology of which is not well understood.135,136 A xenotransplant study using porcine fetal nigral cells showed no benefit.137 Embryonic neural stem cell transplants have shown promise in rodent models of PD though there are no human studies to date.138,139 Another promising approach has been intrastriatal implantation of cultured human retinal pigment epithelial cells capable of producing levodopa and DA. A preliminary report with six patients indicates significant improvement in UPDRS motor scores at one and two years after surgery without any “off-state” dyskinesia.140 CONCLUSION Advances over the last few years have resulted in a better understanding of PD and consequently better patient care. Specific genetic mutations result in the PD phenotype in a minority of instances. In the vast majority, the etiology remains unknown. Environmental and possibly complex genetic-environmental interactions may be involved. Recent research indicates that abnormal protein processing leading to aberrant protein accumulation is a major pathogenetic mechanism. Other processes possibly implicated in cell death in PD include oxidative stress, impaired mitochondrial function, apoptosis and excitotoxicity. The availability of a larger repertoire of drugs together with a better understanding of their action has greatly improved the symptomatic treatment of PD. Refinement in stereotactic surgery has provided an effective option for symptomatic relief in PD. Neuroprotective agents and restorative techniques such as transplant surgery have yet to translate into meaningful clinical benefit for human PD. Growing understanding of the pathogenesis of PD makes it likely that more effective treatment is likely in the future, for symptoms and perhaps even for neuroprotection. ACKNOWLEDGMENTS The authors wish to thank the Canadian Institutes of Health Research, the Parkinson Foundation of Canada, the National Parkinson Foundation, and the Pacific Parkinson Research Institute for supporting this work.

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115. Mytilineou, C., Radcliffe, P., Leonardi, E.K., Werner, P., Olanow, C.W., L-deprenyl protects mesencephalic dopamine neurons from glutamate receptor-mediated toxicity in vitro, J. Neurochem., 68(1):33–39, 1997. 116. Tatton, W.G., Chalmers-Redman, R.M., Ju, W.J.,Mammen, M., Carlile, G.W., Pong, A.W., et al., Propargylamines induce antiapoptotic new protein synthesis in serum- and nerve growth factor (NGF)-withdrawn, NGF-differentiated PC-12 cells, J. Pharmacol. Exp. Ther., 301(2):753–764, 2002. 117. Carlile, G.W., Chalmers-Redman, R.M., Tatton, N. A., Pong, A., Borden, K.E., Tatton, W.G., Reduced apoptosis after nerve growth factor and serum withdrawal: conversion of tetrameric glyceraldehyde-3phosphate dehydrogenase to a dimer, Mol. Pharmacol., 57(1):2–12, 2000. 118. Tatton, W.G., Ju, W.Y., Holland, D.P., Tai, C., Kwan, M.,(-)-Deprenyl reduces PC12 cell apoptosis by inducing new protein synthesis, J. Neurochem., 63(4):1512–1515, 1994. 119. Doble, A., The role of excitotoxicity in neurodegenerative disease: implications for therapy, Pharmacol. Ther, 81(3):163–221, 1999. 120. Turski, L., Bressler, K., Rettig, K.J., Loschmann, P.A., Wachtel, H., Protection of substantia nigra from MPP+ neurotoxicity by N-methyl-D- aspartate antagonists, Nature, 349(6308):414−418, 1991. 121. Greenamyre, J.T., Eller, R.V., Zhang, Z., Ovadia, A., Kurlan, R., Gash, D.M., Antiparkinsonian effects of remacemide hydrochloride, a glutamate antagonist, in rodent and primate models of Parkinson’s disease, Ann. Neurol., 35(6):655–661, 1994. 122. A multicenter randomized controlled trial of remacemide hydrochloride as monotherapy for PD, Parkinson Study Group, Neurology, 54(8):1583–1588, 2000. 123. Rascol, O., Olanow, C.W., Brooks, D.J., et al., A 2year multicenter placebo-controlled, double-blind parallel group study of the effect of riluzole on Parkinson’s disease progression, Mov. Disord., 17:39, 2003. 124. Shults, C.W., Oakes, D., Kieburtz, K., Beal, M.F., Haas, R., Plumb, S., et al., Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing of the functional decline, Arch. Neurol., 59(10):1541–1550, 2002. 125. Rakshi, J.S., Pavese, N., Uema, T., Ito, K., Morrish, P. K., Bailey, D.L., et al., A comparison of the progression of early Parkinson’s disease in patients started on ropinirole or L-dopa: an 18F-dopa PET stud, J. Neural Transm., 109(12): 1433–1443, 2002. 126. Lin, L.F., Doherty, D.H., Lile, J.D., Bektesh, S., Collins, F., GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons, Science, 260(5111):1130–1132, 1993. 127. Herbert, M.A., Hoffer, B.J., Zhang, Z., et al., Functional effects of GDNF in normal and parkinsonian rats and monkeys, In: Tuszynski, M.,Kordower, J.H., Eds., CNS regeneration: basic science and clinical advances, Academic Press, NY, 419–436, 1999. 128. Kordower, J.H., Palfi, S., Chen, E.Y., Ma, S.Y., Sendera, T., Cochran, E.J., et al., Clinicopathological findings following intraventricular glial-derived neurotrophic factor treatment in a patient with Parkinson’s disease, Ann. Neurol., 46(3):419–424, 1999. 129. Kordower, J.H., Emborg, M.E., Bloch, J., Ma, S.Y., Chu, Y., Leventhal, L., et al., Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson’s disease, Science, 290(5492):767–773, 2000. 130. Koller, W.C., Wilkinson, S., Pahwa, R., Miyawaki, E. K., Surgical treatment options in Parkinson’s disease, Neurosurg. Clin. N. Am., 9(2):295–306, 1998. 131. Hariz, M.I., Complications of deep brain stimulation surgery, Mov. Disord., 17 Suppl. 3:S162–S166, 2002. 132. Lang, A.E., Widner, H., Deep brain stimulation for Parkinson’s disease: patient selection and evaluation, Mov. Disord., 17 Suppl. 3:S94–101, 2002. 133. Olanow, C.W., Kordower, J.H., Freeman, T.B., Fetal nigral transplantation as a therapy for Parkinson’s disease, Trends Neurosci., 19(3):102–109, 1996.

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5 Epidemiology of Parkinson’s Disease: An Overview Monica Korell and Caroline M. Tanner The Parkinson’s Institute 0-8493-1590-5/05/$0.00+$1.50 © 2005 by CRC Press

This chapter provides a brief overview of the epidemiology of Parkinson’s disease. The primary focus is a review of descriptive epidemiological findings and a discussion of how these patterns might help us understand the causes of disease. The last section summarizes risk factors that will be covered in greater detail in later chapters. INTRODUCTION The first step to a better understanding of Parkinson’s disease is to identify and describe the people who have the disease. The ability to identify shared characteristics such as age, gender, occupation, residence, or family membership among persons with Parkinson’s disease will bring us closer to solving the mystery of what causes the disease. These observations are most informative when they apply to all cases of disease within a population, referred to as complete ascertainment. When ascertainment is not complete, conclusions may be misleading, because those persons missed may be different from those identified. However, there are many challenges faced when trying to determine the frequency and distribution of Parkinson’s disease within populations. The first challenge lies in quantifying the number of Parkinson’s disease cases. Because there is not a diagnostic test for Parkinson’s disease, epidemiological studies must rely on the clinical examination to determine the number of cases. Accuracy of the clinical diagnosis of Parkinson’s disease depends on both the experience of the examiner and the duration of disease in each individual examined. Inexperienced investigators may confuse Parkinson’s disease with other disorders such as essential tremor or atypical parkinsonism, or even with senescent changes in movement and balance. Mutch et al. found that 57 out of 393 of their original Parkinson’s disease referrals had a different diagnosis when examined, most commonly essential tremor.1 Similarly, a study conducted in Finland found that 26% of the subjects identified as having Parkinson’s disease based on medical record review instead were found to have essential tremor upon physical examination.2 Even experienced examiners can misdiagnose Parkinson’s disease early in the course of disease, when distinguishing features of other disorders may not yet be present. Therefore, estimates of incident disease may have more misclassification than prevalence estimates.

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Comparisons across studies are hampered not only by differences in the experience of the diagnostician, but by differences in the study diagnostic criteria. These may vary greatly over time but can also be quite different among contemporaneous studies. For example, some early studies grouped all forms of parkinsonism together, combining atypical parkinsonism, secondary parkinsonism (such as post-encephalitic and druginduced parkinsonism), and Parkinson’s disease. Anderson and colleagues reviewed several prevalence surveys of Parkinson’s disease and concluded that the prevalence comparisons between surveys can have diminished value if the surveys used different diagnostic criteria for Parkinson’s disease.3 They found that the differences in prevalence estimates between surveys could be explained by the differences in diagnostic criteria in some instances. Three general approaches have been used to identify Parkinson’s disease cases for epidemiologic studies: (1) evaluating clinic patients, (2) searching health utilization records (medical charts, prescription registries, disease registries, billing databases), and (3) directly screening a population to identify persons with Parkinson’s disease living within a defined area. Each approach has strengths and weaknesses. The first method, relying on information derived from clinics, while relatively inexpensive and easy to perform, may be influenced by social and economic factors determining attendance at the facility studied. This could result in mistaken conclusions about disease frequency—for example, patients at a referral center and those at a neighborhood clinic may differ in many ways (socioeconomic status, race/ethnicity, gender), but none of these differences may be specific to Parkinson’s disease. The second approach, relying on the review of health utilization records, while subject to some of the same biases, can provide good estimates where health care is universally available. Both of these methods will miss those cases of Parkinson’s disease who have never been diagnosed.4–6 The proportion of undiagnosed cases will also vary across populations, reflecting variations in such factors as health resources and disease awareness. The third method, identifying persons with Parkinson’s disease within a geographic area, typically employs a staged, communitybased ascertainment method such as a door-to-door survey. This study design attempts to minimize undercounting of previously undiagnosed cases by surveying all households within a targeted area. When all households are surveyed in a community using a screening interview followed up by examination of individuals suspected of having disease, this method is more likely to identify all prevalent cases of Parkinson’s disease in a community. Expert application of stringent diagnostic criteria is important, however, to avoid overestimation of cases. In addition, the large amount of time and great expense involved in the latter method limit its application. DESCRIPTIVE EPIDEMIOLOGY INCIDENCE Incidence, the number of new cases of a disease occurring in a specific population during a given period of time, is the best measure of disease frequency, because it is not affected by survival or migration. Parkinson’s disease is a relatively rare disorder. Therefore, large numbers of people must be studied to obtain reliable estimates of incidence. Because

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Parkinson’s disease is rare before age 50 and increases with increasing age thereafter, the age distribution of the sample population can influence the number of cases observed. For this reason, direct comparison of crude incidence estimated from different populations may be misleading. For example, estimated crude incidence ranges from 5 to 20/100,000/year in different reports.7–9 Because the age distribution of these populations differed, as did case ascertainment methods and diagnostic criteria among these studies, it is possible that this fourfold difference reflects these factors, rather than a true difference in disease frequency. Estimated incidence is more similar in studies including only those with Parkinson’s disease. Some examples of recent studies using similar diagnostic criteria, adjusted for age to the 1990 U.S. census to allow direct comparison, are shown in Table 5.1. PREVALENCE Prevalence measures the total number of individuals in a population who have disease at a specific point in time. Even greater differences are observed in estimates of crude prevalence. When Zhang and Roman reviewed studies published through 1991,10 they found that crude prevalence ranged from 10/100,000 in Igbo-Ora, Nigeria, to 405/100,000 in Uruguay, Montevideo. While this 40-fold difference across populations is reduced by age adjustment, the range of estimated PD prevalence remained broad. Some of these differences likely reflect variations in ascertainment and diagnostic criteria. However, real differences in prevalence may be due to shortened survival in some populations. Some examples of more recent studies of PD prevalence are shown in Table 5.2. MORTALITY Parkinson’s disease is not a direct cause of death per se, although death may occur as a secondary result of severe

TABLE 5.1 Age-Adjusted Totala and Age-Specific Incidence of Parkinson’s Disease from Selected Studies Age Strata Reference Population Total Age85 Adjusted3 Studied 44 49 54 59 64 69 74 79 84 Incidence/100,000 Person-Years Bower 199918 Mayeux 199515 Van Den Eden

Olmsted County, MN, USA New York, NY, USA Northern, CA, USA

13.8

0.44

17.4

13.5

0

10.7

13.9

0.15

2.5

9.8

52.5

93.1

54.2 38.8

79.1

136.6

107.2

180.9

119.0

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200322 Fall 199617 SE Sweden 9.7 1.6 3.3 9.0 22.4 59.4 79.5 Ilan County, 11.3 NA 0 18.5 47.4 100.2 0 Chen Taiwan 200112 Yanago 11.7 0 0 4.2 23 16.7 27.2 51.5 81.1 76.8 113.7 26.0 Kusumi City, Japan 199626 a. Age-adjusted to the 1990 U.S. Census. NA=not available.

TABLE 5.2 Age-Adjusted Totala Reference Population Total 85

Mayeux New York, 114.6 1.3 99.3 509.5 1192.9 823.8 199515 NY, USA Svenson Alberta, NA NA 46.6 77.9 254.0 839.6 1925 1991123 Canada Morgante Sicily, Italy 258.8 0 115.6 621.4 1978.3 3055 1995b De Rijk Netherlands NA NA 300 1000 3100 4300 19956,b Chen 37.8 122.5 546.7 819.7 2197.8 Ilan County, 168.8a NA 200112 Taiwan Kinmen, NA NA 273 535 565 1839 Wang Taiwan 199626 Yanago 104.7 104.7 0 8.4 41.8 23.3 71.5 210.0 457.9 669.1 850.5 750.0 Kusumi City, Japan 199626 Beijing, NA NA 289.7 1157.2 3534.0 3472.2 Zhang China 200335,b a. Age-adjusted to the 1990 U.S. Census, b. Assumes no cases 20 mutations) FTDP-17 SCA2 (Ataxin-2) SCA2 SCA3 (Ataxin-3) MJD/SCA3 — DYT12 —

DYT3

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Known genetic mutation Complex 1 Unknown genetic mutation Complex 1

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ND4 —

— —

characterized by prominent behavioral disturbances, including disinhibition, aggression, obsessive behavior, and hyperorality. Subsequently, other cases of familial frontotemporal dementia, as defined by the LundManchester criteria,117 were reported with varied clinical manifestations apart from dementia (e.g., personality or behavioral changes, parkinsonism, amyotrophy, dystonias). These familial disorders were given different clinical specific eponyms, such as (1) pallido-ponto-nigral degeneration,118 (2) disinhibition-dementia-parkinsonismamyotrophy complex,119 (3) familial progressive subcortical gliosis,120 (4) familial multiple system tauopathy with presenile dementia,36 or (5) hereditary dysphasic disinhibition dementia.121 The term “FTDP-17" was introduced during an International Consensus Conference in Ann Arbor, Michigan, in 1996,122 when it was found that many of these families shared a common locus on chromosome 17q21– 22.123–125 At the time, reports were presented on 13 families with relatives affected by syndromes linked to chromosome 17q21–22. With increased awareness of this disorder, reports of additional families came in from different parts of world, including the United States, the United Kingdom, Japan, the Netherlands, France, Canada, Australia, Italy, Germany, Israel, Ireland, Spain, and Sweden. About 80 families are known to have or have had relatives affected with FTDP-17. Probably fewer than 50 of these persons are still alive. Clinical Features The onset of symptoms is usually insidious. The average age at onset is 49 yr (range, 25 to 76 yr), and the average duration of the clinical course is 8.5 yr (range, 2 to 26 yr). There are three major categories of symptoms: (1) behavioral and personality disturbances, (2) cognitive deficits, and (3) motor dysfunction (most often signs of Parkinsonplus syndrome) (Table 14.4).122 In the fully developed stage of the disease, affected patients have at least two of

TABLE 14.4 Symptomatology of FTDP-17 (Frontotemporal Dementia and Parkinsonism Linked to Chromosome 17) Disorders Behavioral and personality disturbances Apathy, depression Psychosis, verbal and physical aggressiveness, family abuse Obsessive-compulsive stereotyped behavior Defective judgment Hyper-religiosity, alcoholism, illicit drug addiction Hyperorality, hyperphagia Loss of personal awareness, poor hygiene, disinhibition

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Cognitive deficits Early stage Aphasia of nonfluent type Impaired executive functions Relatively well preserved memory, orientation, and visuospatial functions Late stage Global deterioration of cognitive functions Increased repetition (echolalia, palilalia) Verbal and vocal preservations Mutism (finally) Motor dysfunctions Parkinsonism (early or late manifestation) Axial and limb rigidity Bradykinesia Postural instability poorly responding to levodopa Resting tremor (uncommon) Other motor signs Pyramidal signs Dystonia Supranuclear gaze palsy Weakness due to amyotrophy, myoclonus, dysphagia

these groups of symptoms. Depending on the clinical presentation, families with FTDP17 are often classified into one of two broad types: (1) families with the dementiapredominant phenotype or (2) families with the parkinsonism-predominant phenotype, such as pallido-ponto nigral degeneration, disinhibition-dementiaparkinsonism-amyotrophy complex, or multisystem tauopathy with presenile dementia. Although FTDP-17 is an uncommon disorder without any strict clinical diagnostic criteria, it should be considered in the differential diagnosis in the presence of one or more of the following:126 1. Onset of symptoms in the third to fifth decades 2. Rapid disease progression 3. Neuropsychiatric symptoms or frontotemporal dementia 4. Parkinson-plus syndrome with levodopa-nonresponsive parkinsonism, frequent early falls, supranuclear gaze palsy, or (less commonly) apraxia, dystonia, or lateralization 5. Occasionally, early progressive speech difficulties 6. Poorly controlled seizure disorder superimposed on dementia and parkinsonism 7. Positive family history suggestive of an autosomal dominant inheritance of a neurodegenerative disorder, although variability of clinical presentation may be present even in persons of the same kindred Genetic Aspects FTDP-17 is inherited in an autosomal dominant pattern. Mutations in the tau gene, which is located on chromosome 17q21–22, have been linked to some families with FTDP-17.

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The human tau gene consists of 16 exons, only 11 of which are expressed in the central nervous system. The mutations are either exonic or intronic. The exonic mutations are missense, deletion, or silent. In more than 60 separately ascertained families, more than 31 different mutations have been reported on exons 1, 9, 10, 12, and 13 and on the intron after exon 10 in the tau gene.126−130 Recently, Rosso et al.131 described a novel missense mutation, S320F, in exon 11 of the tau gene in a family with presenile dementia. Phenotypic-Genotypic Correlation Both interkindred (different mutations) and intrakindred (same mutation) variability in clinical manifestations have been observed in the FTDP-17 disorders, and a precise phenotype-genotype correlation is not yet possible. In general, a parkinsonismpredominant phenotype develops in the families with an exon 10 missense or a 5′-splicesite intronic mutation, whereas a dementia-predominant phenotype develops in those with nonexon 10 missense mutations. Neuropathologically, in the former group, there is cortical and subcortical neuronal and glial deposition of filaments containing 4R tau isoforms, whereas in the latter, there are widespread cortical neuronal accumulations of straight filaments composed of six tau isoforms. Pathologic Characteristics The consistent feature in the FTDP-17 kindred is severe frontotemporal neocortical atrophy; quite frequently, there is destruction of the basal ganglia and the substantia nigra (especially in N279K kindred).122,132 Medial temporal lobe structures are variably involved. The common denominator of all brains affected by FTDP-17 is the pathologic accumulation of the tau protein in neurons or glia (tauopathy). The tau protein is a microtubule-associated protein present in healthy brain tissue, and it promotes assembly and stabilization of microtubules responsible for axonal transport.133 It consists of six major isoforms resulting from the splicing exon 2, 3, or 10 of the tau gene. In the physiologic state of the adult brain, the ratio of 3 repeat to 4 repeat is equal to 1.134 In tauopathies, hyperphosphorylation of the tau protein leads to its reduced solubility and the formation of pathologic filaments and inclusions.135 Tauopathies include disorders with parkinsonism, abnormal movements, and dementia in varied combinations, such as progressive supranuclear palsy, corticobasal degeneration, Alzheimer disease, Pick disease, subacutesclerosing panencephalitis, or Niemann-Pick disease type C.136 FTDP17 is the most important familial tauopathy in which mutations in the tau gene lead to an accumulation of either 3 repeat or 4 repeat tau isoforms in the neurons and glia. REPRESENTATIVE FTDP-17 KINDREDS Mutations in Exon 10 N279K Missense This mutation is the third most prevalent mutation of the tau gene. It was originally described in the pallido-pontonigral degeneration family from the United States

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(genealogically traced to the colonial settlement of Virginia), and this kindred is still the largest among all the FTDP17 families. It has 43 affected members in 8 generations.118,137,138 Three Japanese families and one French family were subsequently described with this mutation139–142 (reviewed by Tsuboi et al.139). Affected members of this kindred have a disease presentation early in the fifth decade, usually with parkinsonian features (akinetic limb and axial rigidity, most often symmetric, postural instability, absence of resting tremor), followed by behavioral changes and dementia (frontal type). On presentation, one-third of the affected persons have personality changes or dementia alone or either or both in combination with parkinsonism. Other features include dystonia, ocular abnormalities, pyramidal tract dysfunction, bladder dysfunction, and perseverative vocalizations. The parkinsonism is usually poorly responsive to levodopa, although, in the initial stages, some response may be found. A retrospective analysis of the clinical features of affected persons shows that there may be two broad phenotypes: one with corticobasal degeneration and the other with progressive supranuclear palsy.126 PET studies show a marked reduction in striatal 18 F-labeled dopa uptake.143 The course of illness is relentlessly progressive, with death occurring within eight to nine years after the onset of clinical manifestations. Autopsy shows severe destruction of the globus pallidus and the substantia nigra, variable neocortical atrophy, ballooned neurons, and widespread compact phosphorylated tau (ptau) inclusions within neurons and striking p-tau inclusions within oligodendroglia.138,144 P301L Missense This mutation has been identified in 22 separately ascertained kindreds and is the most prevalent FTDP-17 mutation, with a worldwide distribution.125,127,145–152 The important families are the family F in Seattle (English-FrenchCanadian), comprising 15 affected members in 2 generations, and the Dutch 1 family (the Netherlands), comprising 49 affected members in 6 generations. The usual presenting symptoms include behavioral disturbances and personality changes, disinhibition, loss of executive function, and language abnormalities, followed later by parkinsonism. Autopsy findings include severe destruction of basal ganglia, substantia nigra, frontotemporal atrophy, neurofibrillary tangles, ballooned neurons, and neuronal and glial p-tau inclusions. P301S Missense Thus far, four kindreds have been reported with this mutation: Italian (family P),153 German,154 Japanese,155 and Jewish-Algerian.130 Patients present in the third or fourth decade with symptoms of either affective disorder or movement disorder, followed by a rapidly progressive dementia and parkinsonism. Distinctive features include refractory epilepsy in the German kindred, myoclonus in the German and Italian families, and early bilateral pyramidal syndrome in the Jewish-Algerian patients. Magnetic resonance imaging has documented frontal and caudate atrophy. Mutations of Intron Following Exon 10 Seven mutations (+3, +11, +12, +13, +14, +16, +19) have been described in the intron following exon 10, clustered in the 5′-splice-site of the intron, which affects the alternative splicing of exon 10.127,129,156−159

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The +16 intronic mutation is the second most frequent mutation after the P301L mutation of exon 10. Eight separate families with a total of 78 affected persons have been reported with this mutation. The important kindreds are Aus I (Australia) with 28 affected members in 5 generations;127,160,161 familial, rapidly progressive subcortical gliosis (U.S.A.) with 17 affected members in 5 generations;156 and Duke family (U.S.A.) with 14 affected members in 3 generations.162 Personality and behavioral changes and other frontal lobe dysfunctions are early and prominent manifestations, and parkinsonian features are late and not always present. Neuropathologic features are frontotemporal atrophy, ballooned neurons, and neuronal and glial p-tau inclusions. The neuronal p-tau inclusions may be diffuse or shaped like dots or Pick bodies.156,162 The +14 intronic mutation has been described in a family of Irish descent (U.S.A.) with disinhibitiondementia-parkinsonism-amyotrophy complex. This kindred is the first one linked to chromosome 17, and it is the only one with this mutation. The kindred has 13 affected members in 3 generations. Clinical characteristics include personality changes, dementia of frontotemporal type, parkinsonism, and amyotrophy. A long prodromal period may be present and characterized by behavioral aberrations, such as inappropriate sexual advances, overeating, shoplifting, or excessive religiosity.126 There is frontotemporal atrophy, degeneration of the substantia nigra, ballooned neurons, and intraneuronal and glial inclusions.163 The hippocampus is spared. The +3 intronic mutation has been reported so far in only a single family having 41 affected members in 7 generations (U.S.A.) with multisystem tauopathy and presenile dementia. The presenting symptoms are disequilibrium and short-term memory loss, followed by parkinsonism and superior gaze palsy.144 The reported neuropathologic findings include cortical atrophy; neuronal loss in the hippocampus, substantia nigra, cerebellum (Purkinje cell loss), and other subcortical areas; degeneration and demyelination of the spinal cord; and intraneuronal and intraglial p-tau inclusions.129,132,164 Mutations Not in Exon 10 Mutations outside exon 10 include those localized on exons 1, 9, 12, and 13 (reviewed in detail by Wszolek et al.126 and Ghetti et al.165). The clinical features include early personality changes, behavioral and cognitive dysfunctions, psychological manifestations, and variable and late onset of parkinsonian features.126 OTHER TYPES OF FAMILIAL PARKINSONISM WITH PARKINSON-PLUS SYNDROME PHENOTYPE SPINOCEREBELLAR ATAXIAS WITH LEVODOPARESPONSIVE PARKINSONISM Ataxin-2 (SCA2) The ataxin-2 (SCA2) mutation causing a CAG repeat expansion within the coding region of the cytoplasmic protein (ataxin-2) on chromosome 12q has been reported in several

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patients of Chinese origin who have doparesponsive familial parkinsonism.166–168 Members of a large ethnic Chinese family with SCA2 mutation and autosomal dominant inheritances have been described as having typical dopa-responsive asymmetric Parkinson’s disease, parkinsonism-ataxia, or parkinsonism resembling progressive supranuclear palsy.166 Shan et al.167 also reported expanded CAG repeats in the SCA2 gene in two patients of Chinese origin who presented with doparesponsive familial parkinsonism at the age of 50 yr. Both of these patients presented predominantly with 4 Hz resting tremor of the legs that responded to treatment with levodopa in one patient and to alcohol, primidone, or trihexiphenidyl in the other patient. Overt signs of cerebellar dysfunction were absent, and there was mild slowing of the ocular saccades and gait hesitation suggestive of Parkinson-plus syndrome. Gait ataxia has been reported to occur as much as 25 yr after the onset of dopa-responsive parkinsonism.168 Neuroimaging studies have shown features typical of idiopathic Parkinson’s disease, such as reduced 18F-labeled dopa uptake in the striatum with a rostrocaudal gradient,169 bilateral asymmetric reduction of striatal dopamine transporters,168 and normal 11Craclopride binding of the striatum.169 However, Shan et al.167 reported a severe involvement of the caudate nucleus unlike that observed in patients with sporadic Parkinson’s disease. The dopa-responsive parkinsonism phenotype of SCA2 is observed mainly in Chinese persons. Kock et al.170 did not find any expanded trinucleotide repeats in the SCA2 gene in all 270 unrelated patients of mixed ethnicity who had dopa-responsive parkinsonism (young-onset familial, young-onset sporadic, or late-onset familial), and thus far there is only one published report of an SCA2 mutation in a family of non-Chinese origin (English family in Alberta, Canada) with levodopa-responsive parkinsonism without cerebellar abnormalities.169 Ataxin-3 (SCA3) Parkinsonism and ataxia have been described in patients with SCA3 or Machado-Joseph disease, both of which have identical mutation on chromosome 14q24.3–q32; currently, these two terms have become interchangeable.171–174 Levodopa-responsive parkinsonism and levodopa-responsive motor complications have been reported in patients with the SCA3 mutation.166,175,176 FAMILIAL DYSTONIA PARKINSONISM Rapid-Onset Dystonia Parkinsonism This autosomal dominant movement disorder is characterized by the abrupt onset of dysarthria, dysphagia, dys tonic spasms, bradykinesia, or postural instability.177 The onset of symptoms usually occurs in late childhood or early adulthood and may be triggered by stressful events. Treatment with levodopa/carbidopa is usually unsatisfactory. Linkage has been established to chromosome 19q13, and the locus has been named DYT12, but the mutation is unknown.177

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X-Linked Dystonia Parkinsonism or Lubag Lubag, reported in men from the island of Panay in the Philippines,178 is characterized by parkinsonism, action tremor, or dystonia manifesting usually in the fourth or fifth decade but also occurring as early as adolescence.179–182 The neuropathologic features of this form of parkinsonism, which responds poorly to levodopa, are neuronal loss restricted to the caudate and the putamen, without evidence of Lewy bodies.180 Linkage has been established to chromosome Xq13.1, and the gene has been named DYT.183,184 Familial Parkinsonism Related to Mitochondrial Dysfunction Mitochondrial DNA (mtDNA) represents a well recognized non-Mendelian genetic system, abnormalities of which cause a multitude of human diseases.185 The mtDNA codes for constituents of the mitochondrial electron transport chain, such as the nicotinamide-adeninedinucleotide ubiquinone reductase (complex 1). A role of decreased activity of complex 1 in the pathogenesis of Parkinson’s disease comes from observations that (1) 1methyl-4-phenyl-1,2,3,6-tetrahydropyridine, which produces clinical and pathologic features of Parkinson’s disease, is an inhibitor of complex 1,186 or that (2) complex 1 patients with Parkinson’s disease exhibit decreased activity.187–191 Swerdlow et al.191 reported a large family with multiple members in three generations who were affected with levodopa-responsive Parkinson’s disease (age at onset, 35 to 79 yr; mean, 42 yr) through exclusively maternal lines. This kindred had complex 1 dysfunction in mtDNA of maternal descendants with Parkinson’s disease and in asymptomatic young maternal descendants. In another large family with maternally inherited, adultonset, multisystem degeneration and prominent parkinsonism, a G-to-A missense mutation was found at nucleotide position 11778 of the mitochondrial ND4 gene of complex 1 that converts a highly conserved arginine to a histidine.192 This family had variable clinical features that included levodopa-responsive parkinsonism, dementia, dystonia, dysarthria, areflexia or hyperreflexia, spasticity, ptosis, and progressive external ophthalmoplegia. Neuropathologic findings in one patient showed a marked loss of pigmented neurons in the substantia nigra, the loss of large neurons in the caudate and the putamen, and the absence of Lewy bodies, neurofibrillary tangles, or amyloid plaques. The identification of the G11778A mutation demonstrates that adult-onset, multisystem, neurodegenerative disease with prominent parkinsonism can be associated with an inherited mtDNA mutation.192 Familial Parkinsonism with Central Hypoventilation (Perry Syndrome) The clinical features of this syndrome include the onset of symptoms at 45 to 50 yr of age, autosomal dominant inheritance, parkinsonism in the form of bradykinesia and resting tremor not responding to levodopa, depression, dementia, weight loss, sleep disorders, and central hypoventilation.193,194 After its initial description, other cases were reported in Canada, the United States, the United Kingdom, France, Turkey,195 and Japan.196–200 The disease progresses relentlessly, and persons die suddenly or of respiratory failure in 4 to 8 yr.197,198 Neuropathologic studies show the presence of severe

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neuronal loss and gliosis mainly in the substantia nigra, with or without scarce Lewy bodies.196−200 Family A (German-Canadian) The characteristic features of this family include autosomal dominant inheritance, symptom onset at a mean age of 51 yr, levodopa-responsive parkinsonism (resting tremor, bradykinesia, rigidity, and postural instability), amyotrophy, dementia, and dystonia.201 Affected persons have a reduction in the uptake of striatal 18F-labeled dopa (increased caudate-putamen ratio) and an increase in 11C-raclopride binding, whereas neuropathologic findings in autopsied patients have included neuronal loss and gliosis but an absence of Lewy bodies in the substantia nigra.202 The affected persons in the Canadian branch of this family have been found to have linkage to the PARK8 locus on chromosome 12p11.23-q13.11.59 Members of the Sagamihara family, the first to be linked to the PARK8 locus,62 typically have the Parkinson’s disease phenotype, which indicates the marked variability of phenotypic expression in the PARK8-linked disorders. CONCLUSIONS The recent explosion of genetic information in familial parkinsonism, and in Parkinson’s disease in particular, underscores the importance of genes in the pathogenesis of these disorders. Although family history may not always be present, Parkinson’s disease is undoubtedly a complex disorder with a strong genetic basis for the early onset of disease. Several genetic studies of patients with late-onset, sporadic Parkinson’s disease also indicate that genetic factors may play a crucial role in at least a subset of such patients. There are several genetically, clinically, and pathologically distinct forms of Parkinson’s disease and Parkinson-plus syndrome (e.g., synucleinopathy, tauopathy, polyglutamine disorders) that can be caused by mutations in α-synuclein, parkin, UCH-L1, DJ-1, NR4A2, tau, ND4, or still unknown causative genes, which initiate a cascade of events that culminate in the death of nigral neurons. However, in spite of the identification of several mutations and susceptibility loci and of distinct forms of familial parkinsonism, the origin of Parkinson’s disease in most patients is still unresolved. Moreover, phenotypic variability in persons having the same mutations suggests that Parkinson’s disease is a highly heterogeneous disorder in which multiple gene-to-gene and gene-to-environment interactions may play a critical role in the onset of disease and in phenotypic variability. Apart from family history, an early age at onset of symptoms is still the most reliable clue for suspecting a genetic basis of parkinsonism. Most families with early-onset parkinsonism display clinical and pathologic features consistent with Parkinson-plus syndrome rather than with Parkinson’s disease. Thus, among familial parkinsonism, the Parkinson-plus phenotype is more likely than the Parkinson’s disease phenotype to have an underlying genetic disorder. Finally, the future holds promise for the prevention of familial parkinsonism through risk prediction and genetic counseling. At the same time, neuroprotective and curative strategies are being developed to target the abnormal protein or metabolic pathways that result from genetic mutations.

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195. Elibol, B., Koboyashi, T. and Atac, F.B., Familial parkinsonism with apathy, depression, and central hypoventilation (Perry’s syndrome), in Mapping the Progress of Alzheimer’s and Parkinson’s Disease, Mizuno, Y., Fisher, A., and Hanin, I., Eds., Kluwer Academic/Ple-num Publishers, New York, 2002, 285. 196. Tsuboi, Y., et al., Japanese family with parkinsonism, depression, weight loss, and central hypoventilation, Neurology, 58, 1025, 2002. 197. Purdy, A. et al., Familial fatal Parkinsonism with alveolar hypoventilation and mental depression. Ann. Neurol., 6, 523, 1979. 198. Roy, E.P, III, et al., Familial parkinsonism, apathy, weight loss, and central hypoventilation: successful long-term management. Neurology, 38, 637, 1988. 199. Lechevalier, B., et al., Familial parkinsonian syndrome with athymhormia and hypoventilation [French], Rev. Neurol. (Paris), 148, 39, 1992. 200. Bhatia, K.P., Daniel, S.E. and Marsden, C.D., Familial parkinsonism with depression: a clinicopathological study. Ann. Neurol., 34, 842, 1993. 201. Wszolek, Z.K., et al., German-Canadian family (Family A) with parkinsonism, amyotrophy, and dementia: longitudinal observations. Parkinsonism Relat. Disord., 3, 125, 1997. 202. Wszolek, Z.K., Uitti, R.J. and Markopoulou, K., Familial Parkinson’s disease and related conditions: clinical genetics. Adv. Neurol., 86, 33, 2001.

15 Other Mutations: Their Role in Parkinson’s Disease Nathan Pankratz and Tatiana Foroud Department of Medical and Molecular Genetics, Indiana University School of Medicine 0-8493-1590-5/05/$0.00+$ 1.50 © 2005 by CRC Press

INTRODUCTION Only a generation ago, the number of chromosomes in the human body was correctly determined to be 46. Then, in rapid succession, studies were begun to identify the genes underlying Mendelian, single-gene disorders. Initially, success was limited by the number of molecular markers that were available for analysis. However, during the past two decades, the field of gene mapping has been revolutionized by the advent of new molecular technologies that have made the rapid identification of genetic mutations possible. These developments have included the identification of thousands of molecular markers located throughout the human genome that can be easily genotyped and used to pinpoint the location of a disease gene to a small chromosomal segment. Then, through the careful examination of genes located within the narrowed critical interval, researchers have successfully identified the causative gene for nearly all of the common, Mendelian disorders such as cystic fibrosis and Duchenne muscular dystrophy. The identification of disease genes was thought to provide the key to the development of improved therapies that would ameliorate clinical symptoms. The newly identified disease genes have proven amenable in many instances to molecular screening, which may be used presymptomatically, prenatally, or diagnostically. Unfortunately, for most genetic disorders, knowledge of the molecular mutation leading to disease has not resulted in substantially improved clinical outcome. Despite this initial disappointment, identification of disease genes is critical to the greater understanding of the causes of disease and has, in many cases, led to the recognition of novel disease pathways that would not have been identified without gene mapping studies. The field of Parkinson’s disease (PD) genetics research is only now beginning to reap the benefits of a decade of research designed to identify disease genes. As discussed in this chapter and elsewhere, there have been important discoveries that have revolutionized our conceptualization of disease pathogenesis. However, many more genes contributing toward the risk for PD must still be identified.

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EVIDENCE FOR THE ROLE OF GENES IN PD Evidence for a familial contribution to PD dates back over 100 yr, when Leroux1–2 and Gowers3 both noted that 15% of PD patients reported an affected family member. In the intervening century, the view of the scientific community has fluctuated with regard to the importance of genetics in the etiology of PD. Several studies provided additional evidence for a genetic role in disease causation.4–7 In contrast, a few studies have strongly argued against a genetic role in PD. Most of the negative data have arisen from samples of monozygotic twins with low concordance rates for PD. The largest, a sample of World War II veteran twins, found greater concordance among twins with early-onset PD but concluded that the genetic contribution to late-onset disease susceptibility was minimal.8 A major limitation of most twin studies is that they are usually cross-sectional in nature. In the case of PD, where the age at onset is quite variable, a cross-sectional study may fail to identify concordant twin pairs with widely differing ages of onset. In one instance, the age at onset of PD in a pair of monozygotic twins differed by 20 yr.9 Functional imaging of the brain has suggested that some apparently normal co-twins actually have decreased function of the nigrostriatal dopaminergic system and may be presymptomatic, implying that the concordance rates for both monozygotic (MZ) and dizygotic (DZ) twins may be higher than previously estimated.10,11 Another established method used to better understand the role of genetics in a complex disease is the analysis of familial aggregation. When applied to PD, this approach compares the familial aggregation of PD in first and/or second-degree relatives of patients with the rate of disease observed in the general population. Most studies of this type will obtain information about the clinical status of the first and/or second degree relatives through family report rather than direct clinical evaluation. Despite the potential limitations of using family reported rates of PD to estimate familial aggregation, studies from around the world have provided evidence that genetic risk factors are involved in the pathogenesis of the idiopathic form of PD. Estimates of the increase in the relative risk to first-degree relatives of an affected individual range from 2.7 to 3.5 in the United States,12–13 2.9 in Finland,14 6.7 in Iceland,15 7.7 in France,16 3.2 in three centers within Europe,17 5.0 in Canada,18 13.4 in Italy,19 and 7.1 in Germany.20 The growing body of evidence accumulating in the literature supports a role for genetics in the etiology of PD. It is also apparent that the genetics of PD is complex. Researchers have identified a subset of families in which PD appears to be inherited in a simple Mendelian fashion, in some cases autosomal dominant and in others autosomal recessive. Several other chapters in this book describe the current knowledge about the genes that have already been identified (i.e., alpha synuclein and parkin). Many of the causative genes have not yet been identified. SINGLE GENE MUTATIONS RESULTING IN PD One approach that has been employed to dissect the genetic etiology of late onset neurodegenerative disorders is the study of families segregating a mutation(s) in a single causative gene. Once families are identified with these strongly genetic inheritance patterns, it is critical that all family members are carefully evaluated neurologically so as to identify individuals with symptoms of disease and also to identify family members

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who lack any features of the disorder. In this way, the segregation of the mutant disease gene is characterized. Once a sufficient number of families sharing a common pattern of inheritance have been identified, molecular studies are performed to determine the chromosomal region harboring the disease gene. In this approach, the entire genome is evaluated, typically by testing DNA sequences with a variable number of copies of a 2, 3, or 4 base pair sequence (termed microsatellite markers). If the marker being tested is in close physical proximity to a gene influencing the phenotype, then family members with the disease would be expected to have inherited the same marker allele, and the marker and the disease gene are “linked.” Thus, the basic principle underlying linkage analysis is the detection, within a family, that a particular marker allele cosegregates with the disease phenotype. A strength of the genome-wide approach is that it allows susceptibility genes to be identified when we have only limited knowledge about the underlying pathophysiology of the disease process. This genetic approach to the elucidation of disease genes has been successfully employed in the study of families with early onset, autosomal dominant Alzheimer disease. Studies performed by numerous laboratories using many different families led to the identification of mutations in three genes, amyloid precursor protein (APP), presenilin I (PS1), and presenilin II (PS2), which can cause AD. A similar approach has been applied to PD. At present, four genes or linkages have been implicated in autosomal dominant forms of parkinsonism, and three genes or linkages have been associated with autosomal recessive forms of parkinsonism (Table 15.1). The first gene, alpha-synuclein, was identified by studying a large Italian kindred, in which PD was pathologically confirmed.21 The same mutation in alpha-synuclein observed in the Italian kindred (Ala53Thr in exon 4) was later found in three Greek families, most of whom could trace their ancestry to a very small geographical area on the Peloponesos in Southern Greece.21 Mutations in alpha-synuclein have been reported in eight additional individuals from six different families located in central and southwestern Greece.22 Given the close historical ties to Southern Italy, these mutation results suggest the presence of a founder effect.23 These individuals are very similar clinically and pathologically to idiopathic PD, with a response to levodopa and the presence of Lewy bodies; however, the age at onset is significantly earlier, with a mean of 46 yr. Two mutations in other parts of the gene (Ala30Pro in a German family24 and Glu46Lys in a Spanish family,92 both in exon 3) were later identified. Another autosomal dominant locus (PARK4 at chromosome 4p15)25 was recently revealed to be a triplication of a large region that contained alpha-synuclein.26 Still, since mutations in alphasynuclein have not been identified in the large number of patients with sporadic or

TABLE 15.1 Loci Linked to PD and Their Corresponding Genes, if Known Locus

Chr. Region

PARK1 4q21–23 PARK2 6q25–27

Causative Gene Mode of Inheritancea

Age of Onsetb

Lewy Bodies

α-synuclein parkin

Middle Juvenile

Present Absent

AD AR

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PARK3 2p13 AD Typical Present PARK5 4p14 UCH-L1 AD Middle Unknown PARK6 1p35-p36 PINK1 AR Early Unknown PARK7 1p36 DJ-1 AR Early Unknown PARK8 12p11–q13 AD Middle Absent a AD=autosomal dominant; AR=autosomal recessive. b Juvenile (mean age of onset 5) occur in up to one-third of patients with untreated PD and even more commonly with increasing age.27 PLMS may be associated with arousals or awakenings and therefore can disturb sleep continuity. Symptoms of restless legs syndrome (RLS) are also common in patients with PD; however, except in patients with a family history of RLS, they seem to reflect a secondary phenomenon, and its prevalence is not higher than in the normal population.39 To date, there is no evidence that RLS symptoms early in life predispose to a subsequent development of PD.40 Fragmentary irregular nocturnal myoclonus is another motor phenomenon in PD patients that can be precipitated by levodopa. It occurs primarily during light nonREM sleep and is characterized by brief bursts of up to 150 ms in a random fashion without periodicity.41 Repetitive muscle contractions followed by tremor may occur, particularly in the limb that is primarily affected by the disease. These muscle contractions can result in a painful extension of the great toe, finger, or foot as a sign for off-dystonia. Early-morning foot dystonia reflects the low concentration of dopamine after the last intake of dopaminergic medication at night and may occur just before waking or soon thereafter. Painful offdystonia and early morning akinesia are frequent complaints of PD patients in an advanced stage of the disease that require adequate nocturnal treatment.38 Increased muscle tone, as well as abnormal simple and complex movements during sleep, are common in PD patients. It must be kept in mind that they can complicate the scoring of polysomnograms, in contrast to the quiescence of sleep in normal persons. Therefore, a special experience in analyzing sleep recordings of patients with parkinsonism is of importance. SLEEP BENEFIT Patients with a so-called “sleep benefit” show a better morning motor function, although no alterations in the sleep pattern can be detected.42 A sleep benefit is defined as “restoration of mobility on awakening from sleep prior to drug intake,”43 about one-third of PD patients experience sleep benefit.44 Marked diurnal variations in rigidity and dystonia, with little rigidity soon after arising and worsening during the day, can be observed in some patients with familial early-onset Parkinson’s disease. These symptoms also improve after naps.45 REM SLEEP BEHAVIOR DISORDER (RBD) Schenck and co-workers described first criteria for RBD which are now defined46 as complex, mild to harmful movements during REM sleep with a loss of skeletal muscle atonia (Figure 21.1, shows a typical PSG recording of RBD). Body movements are associated with dream mentation and nightmares; dreams appear to be “acted out,” all leading to a disrupted sleep continuity. Although the underlying cause of RBD is still unknown, it most likely reflects a dysfunction in the brain-stem circuitry and the dorsolateral pontine tegmentum. In these areas, REM sleep without atonia can be induced

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in animal experiments. RBD may represent a preclinical marker of neurodegeneration in synucleinopathies such as PD and MSA and may precede motor symptoms for years.47 Fifteen48 to 30%49 of an unselected population of PD patients revealed RBD, more often in polysomnographically investigated patients. The percentage of RBD was up to 90% and more in patients with MSA, again increasing when investigated in the sleep laboratory as compared to “pure” clinical diagnosis. RBD preceded by more than one year the clinical onset of MSA in 44% of the cases, and PSG could differentiate between patients with pure autonomic failure and those developing MSA with autonomic failure.50 In neuroimaging MRI studies, no specific region could be detected in relation to RBD.51 Neuroimaging studies of dopamine receptors showed a significant reduction of striatal dopamine transporter binding in RBD patients as a sign of reduced dopamine release, indicating early or preclinical PD or MSA.4,52 RBD seems to be particularly frequent in patients with PD and psychosis or hallucinations and is an important differential diagnosis of both, sometimes requiring PSG.53 NOCTURNAL RESPIRATORY DISORDERS Obstructive ventilatory deficits are common in moderate to severe PD patients during the day. They are apparently caused by a combination of upper airway obstruction, probably due to an abnormal tone in the upper airway muscles, and respiratory muscle weakness with decreased effective muscle strength.54 Levodopa cannot improve these deficits, although they correlate to some extent with the severity of rigidity and tremor. Dyskinetic movements of glottic and supraglottic structures can also lead to intermittent airway closure in some patients.55 Disorganized patterns of respiration with central apneas, obstructive apneas, or episodes of hypoventilation can be observed in parkinsonism.56,57 Patients with autonomic disturbances tend to have more severe respiratory abnormalities than those without. Daytime respiratory abnormalities include reduced ventilatory responses to hypercapnia and hypoxia.58,59 PSG studies have demonstrated obstructive sleep apnea as well as other abnormal breathing patterns, including central sleep apnea, variableamplitude respirations, and arrhythmic respirations during night.60,61 Stridor, laryngeal stenosis, and obstruction may be caused by abnormal vocal cord function, which appears to be a major contributor to abnormal breathing during sleep in parkinsonism.62

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FIGURE 21.1 Thirty seconds polysomnographical recording of a 45year-old male PD patient (Hoehn and Yahr, stage 2) with subclinical REM sleep behavior disorder. The chin EMG shows a highly elevated muscle tone, multiple motor activity occurs in the recording, and typical increased muscle tone also appears in the linked EMG channel of the legs. Channels from top down: 1–2, EEG; 3–4, EOG, eye movement showing typical REM sleep pattern; 5, chin-EMG with increased muscle tone; 6, linked EMG of both legs with increased muscle tone; 7–9, respiratory recording with airflow, thoracic, and abdominal belts, showing typical irregular breathing pattern during REM sleep; 10, ECG. EXCESSIVE DAYTIME SLEEPINESS (EDS) EDS is a well known phenomenon in PD patients. The neurodegenerative process itself, with disturbances of the reticular activating system, sleep disorders such as sleep apnea syndrome and narcolepsy, RBD, mood disorders as well as various drugs, can contribute to EDS.21 Studies in recent years described an increased risk for causing motor vehicle

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accidents by sudden sleep onset, so-called “sleep attacks,” in PD patients.3 Those episodes were primarily attributed to the intake of non-ergot dopamine receptor agonists.3 It was suggested that the sedating effect of nonergot dopamine receptor agonists may be due to their stronger D3 receptor activity as compared to other dopamine receptor agonists.3,63 However, reports from more recent studies let suggest that sedation may be rather a class effect of dopaminergic medication in general, since EDS was generally more frequent in patients taking dopaminergic drugs.64,65 Sleepiness does not result only from pharmacotherapy or sleep abnormalities but is also related to the pathology of the disease itself.66 Dopaminergic medication may exacerbate sleepiness in a subset of patients, but the primary pathology seems to be the greatest contributor to the development of EDS. Those patients may benefit from wakepromoting agents such as bupropion, modafinil, or traditional psychostimulants.67 The most serious question concerning EDS in parkinsonism is whether those patients are allowed to drive. It is necessary to advice PD patients that sudden sleepiness may occur in the course of the disease and may be attributed individually to specific dopaminergic drugs. However, the patients themselves are finally responsible for their ability to drive and may decide individually. Physicians who prescribe dopamine receptor agonists in PD patients must inform their patients about possible “sleep attacks” during the treatment. It must be kept in mind that, in PD patients with complaints of EDS, diagnostic testings including PSG and daytime recordings of sleep preponderance are needed to exclude secondary causes of EDS as the basis for therapeutical interventions and to document and to quantify the severity of EDS. DIAGNOSTIC EVALUATIONS IMPORTANCE OF MEDICAL HISTORY AND CLINICAL EXAMINATION A number of factors can contribute to the frequent sleepwake disturbances in parkinsonism. Those factors include disease specific alterations, medication, nocturnal motor activity, sleep-wake rhythm abnormalities, and nocturnal respiratory disorders (see Table 21.1). However, sleep disturbances are rarely the presenting complaint of a patient with parkinsonism. To determine whether a sleep disorder exists and which factors are most important, the clinical history of the patient and desirable of partners or caregivers is extremely important. Questions concerning the sleep complaint should include all the features the physician would obtain from any patient with a sleep complaint. Additionally, it needs to include disease specific questions on nocturnal akinesia, daytime drowsiness, or EDS in relation to drug intake and psychiatric symptoms. The use of a disease specific questionnaire, the Parkinson’s disease sleep scale (PDSS), can be helpful for diagnostic evaluation as for assessment of follow-up.68 The bed partner needs to be asked for a careful description of the presence and frequency of movements during sleep as well as their timing, arousals and awakenings, snoring and episodes of apneas, and periods and durations of daytime sleepiness. The knowledge of the drug schedule is important: If dopaminergic drugs are not taken in the evening, nocturnal rigidity and

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akinesia may contribute to a relevant degree to the sleep disturbances; on the other hand, excessive evening doses of dopamine receptor agonists may be responsible for sleeponset insomnia. The clinical examination may further hint to a specific sleep disturbance or motor pattern. TECHNICAL RECORDINGS OF SLEEP AND EXCESSIVE DAYTIME SLEEPINESS (EDS) During actigraphy, muscle activity is monitored by a small portable actimeter, usually worn at the wrist or the ankle. Actigraphic recordings can be performed for some days up to several weeks and may show an increased motor activity during night and a reduced motor activity during the day, reflecting, e.g., periods of EDS during the day. However, actigraphy cannot differ between sleep and wakefulness and is therefore only of limited value for analyzing sleep-wake disturbances in parkinsonism.69 Some patients with parkinsonism and sleep complaints require a further evaluation for the differential diagnosis of the underlying etiology. Polysomnography can be used as a last step for an exact evaluation and for analyzing nocturnal motor and breathing patterns.69 In patients with the main complaint of EDS, a sleep apnea syndrome needs to be verified or excluded using a full cardio-respiratory PSG. Patients who present with symptoms that may underlie either an RBD or a psychosis need a PSG for the differential diagnosis as their treatment options are different. Simultaneous video monitoring and surface EMG recordings of all four limbs are often helpful for a better analysis of nocturnal motor patterns and their relevance for sleep disruptions. If EDS is the most prominent complaint, daytime recordings are needed. The multiple sleep latency test (MSLT) and the maintenance of wakefulness test (MWT) are used to objectively determine its severity and circa dian variation. It is best to do the recordings while the patient is under the usual medication schedule. However, if drugs appear to be a major factor for the sleep disturbances, definite diagnosis may require two or more nights of PSG with different medication schedules. TREATMENT OPTIONS The treatment of sleep disturbances in patients with parkinsonism is a great challenge for the physician, because treatment of the daytime motor symptoms in PD may affect sleep. Both, parkinsonism itself and its treatment with dopaminergic agents can lead to sleep fragmentation, nocturnal movements and vocalizations, abnormal muscle tone during sleep, as well as psychiatric symptoms such as depressive and psychotic behavior. The biphasic actions of dopaminergic drugs must be considered as low dosages may promote sleep, whereas high dosages may lead to increased waking effects, reduction of slowwave sleep, and decreased sleep continuity.70–72 Therefore, the variety of sleep disturbances in parkinsonism need different management strategies.

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NOCTURNAL AKINESIA Nocturnal motor symptoms may disappear with adequate dopaminergic treatment during the day in the early and mild stages of the disease.73 In more advanced cases, a controlled-release formulation containing 200 mg of levodopa plus 50 mg of a decarboxylase inhibitor given at bedtime or the introduction of a long-lasting dopamine receptor agonist therapy appear to improve sleep.74–76 Early-morning akinesia is improved as well by these treatment schemes. REM SLEEP BEHAVIOR DISORDER (RBD) RBD with the occurrence of violent episodes during the night may disrupt the relationship between the patient and caregiver48 and can be one of the main reasons for nursing home admittance. Therefore, and for the patient’s and bedpartner’s safety, violent or injurious behavior during sleep should be treated immediately. Loud sleep talking or screaming can be disturbing for the caregiver in a similar way. An early diagnosis is warranted, as RBD can easily be treated in most patients with small dosages of 0.5 to 2 mg clonazepam at bedtime.77 PERIODIC LIMB MOVEMENTS DURING SLEEP (PLMS) AND RESTLESS LEGS SYNDROME (RLS) Increased nocturnal dopaminergic stimulation, either by levodopa or dopamine receptor agonists, improves symptoms of PLMS and RLS.76 A reduction of rigidity and bradykinesia during the day with consecutive improvement of nocturnal mobility, reduced numbers of PLMS, disappearance of RLS symptoms, and normalization of sleep muscle activity are some factors that may contribute to an improved sleep due to an optimized dopaminergic treatment.78 Nonperiodic movements and fragmentary myoclonus are best treated with benzodiazepines and may benefit from a reduction of dopaminergic medication.47,79 INSOMNIA Assessment of psychosocial and behavioral factors that may contribute to sleep disturbances is the first step for treating insomnia. Concurrent psychiatric disorders need to be addressed: If nocturnal hallucinations occur, related drugs should be reduced as much as possible and therapy with clozapine or quetiapine should be started. Tricyclic antidepressants are drugs of first choice to improve depression in PD patients also suffering from problems of sleep initiation, sleep maintenance, and early awakenings.80 In more advanced stages of the disease, the patient’s spouse should be encouraged to sleep in a different bed or even a different room. Bad sleep for the patients also leads to bad sleep and inadequate rest for the spouses and can reduce quality of life in both groups.81 Patients under high dosages of dopaminergic drugs may require further medication for insomnia. Next to tricyclic antidepressants with sedating properties such as amitryptiline (25 to 50 mg), the newer antidepressant mirtazapine (7.5 to 30 mg),

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which is well tolerated without influencing motor symptoms, is efficacious to improve sleep.82 However, no controlled studies are available to date. The anticholinergic effects of tricyclic antidepressants may have therapeutic benefits for daytime parkinsonian symptoms and depression as well, but it must be kept in mind that they can also induce nocturnal delirium, particularly in patients with cognitive impairment. Dyskinetic nocturnal movements leading to insomnia may respond to a reduction of the evening dopaminergic medication. Nocturia is a common problem in patients with PD and is sometimes difficult to control. However, optimal urological treatment and easy provisions to go to the toilet during the night (e.g., with urinals or night-stools) should be provided. If insomnia is unresponsive to all these interventions, one may use benzodiazepines such as triazolam or clonazepam, or benzodiazepine receptor agonists such as zolpidem and zopiclone for a short period of time to normalize the sleep-wake schedule. Considerations of sleep hygiene and stimulus control mechanisms should always form the basis of getting a good night’s sleep in all sleep-disordered persons. NOCTURNAL HALLUCINATIONS, PSYCHOSIS, AND CONFUSION Unfortunately, dopaminergic drugs can induce entirely new sleep problems when used during the day or in the evening. Up to 30% of patients with parkinsonism taking levodopa, and an even higher number of those taking dopamine receptor agonists, experience vivid dreams, nightmares, and night terrors, particularly those with cognitive impairment.83 These symptoms may necessitate a reduction of the afternoon or evening dosages of the dopaminergic drugs, which might worsen motor symptoms. Nocturnal confusion and hallucinations are often so disruptive for demented patients with PD that only low dosages of levodopa can be used with complete withdrawal of dopamine receptor agonists. The medication of first choice is still clozapine (starting with 6.25 to 25 mg), followed by quetiapine, as limited controlled data are available on quetiapine in PD patients with psychosis. Small dosages of clomethiazol at bedtime are sometimes also helpful in such cases. Low dosages of clozapine should be used and slowly increased until complete remission of nocturnal hallucinations is achieved.84 Patients who do not tolerate clozapine may be switched to low dosages of quetiapine (12.5 to 50 mg).85,86 NOCTURNAL RESPIRATORY DISTURBANCES In parkinsonism, the treatment of sleep-related respiratory disturbances is similar to their treatment in all other persons and patients. Nasal continuous positive airway pressure (nCPAP) ventilation offers the best chance of success in patients with obstructive sleep apnea syndrome. Upper airway surgery should be regarded with caution—it may help some patients with redundant palatal or pharyngeal tissue, but the abnormal motor activity of the upper airways is still present after surgery. Tracheostomy may be necessary in some patients with MSA and severe vocal cord dysfunction. Appropriate nCPAP may improve the condition of a PD patient substantially. It can normalize nocturnal blood pressure, and neuropsychiatric symptoms, daytime drowsiness, and EDS may be improved immediately.

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EXCESSIVE DAYTIME SLEEPINESS (EDS) As a first step, respiratory disturbances, such as sleep apnea syndrome and snoring, and the relevance of pharmacologically induced EDS need to be excluded before EDS is treated with psychostimulants.67,87 If possible, PSG should be performed for exclusion of treatable causes of EDS. If medication adjustments such as giving of amantadine or discontinuation of dopamine receptor agonists and benzodiazepines are not effective, agents specifically designed to promote daytime alertness may be beneficial. Previous reports have shown that amphetamines can increase daytime alertness in PD patients.88 Therefore, psychostimulants may be considered as optional therapy for EDS in patients with PD.67 Recently, it could be shown that EDS improved under treatment with modafinil, a psychostimulant drug acting on postsynaptic alpha-1 adrenergic receptors, however, the exact mode of action of modafinil is still being debated. Modafinil (up to 200 mg) is the agent best investigated in PD patients, and a number of open and some controlled studies are available.89–91 Some authors recommend modafinil even if EDS is druginduced.92 As long-term studies are still lacking, we do not know if the effects remain stable. PD patients suffering from cognitive impairment or psychotic episodes should only be very cautiously treated with modafinil, as the risk of side effects may be increased. ABBREVIATIONS EDS

excessive daytime sleepiness

EEG

electroencephalography

EMG

electromyography

EOG

electrooculogram

MRI

magnetic tomographic investigation

MSLT

multiple sleep latency test

MWT

maintenance of wakefulness test

nCPAP

nasal continuous positive airway pressure ventilation

PD

Parkinson’s disease

PDSS

Parkinson’s disease sleep scale

PS

Parkinsonian syndrome

PSG

polysomnography

RBD

REM sleep behavior disorder

REM

rapid eye movements

RLS

restless legs syndrome

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REFERENCES 1. Parkinson, J., Essay on the Shaking Palsy, Sherwood, Neely, and Jones, London, England, 1817:17. 2. Charcot, J.M., Lectures on the diseases of the nervous system (trans. by G.Siegerson), The New Sydenham Society, Lecture V, London, England, 1877:147. 3. Frucht, S., Rogers, J.D., Greene, P.E. et al., Falling asleep at the wheel: motor vehicle mishaps in persons taking pramipexole and ropinirole, Neurology, 52:1908–1910, 1999. 4. Eisensehr, I., Linke, R., Noachtar, S. et al., Reduced striatal dopamine transporters in idiopathic rapid eye movement sleep behavior disorder. Comparison with Parkinson’s disease and controls, Brain, 123:1155–1160, 2000. 5. Braak, H., R.B.U., Gai, W.P., Del Tredici, K., Idiopathic Parkinson’s disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen, J. Neural. Transm., 110:517–536, 2003. 6. Del Tredici, K., R.B.U., De Vos, R.A. et al.,. Where does Parkinson’s disease pathology begin in the brain? Neuropathol Exp. Neurol., 61:413–426, 2002. 7. Forno, L.S., Neuropathology of Parkinson’s disease, J. Neuropathol Exp. Neurol., 55:259–272, 1996. 8. Jellinger, K., Pathology of parkinsonism, In Fahn, S., Marsden, C.D., Jenner, P. et al., (Eds.), Recent Developments in Parkinson’s disease, New York, Raven Press. 33–66, 1986. 9. Zweig, R.M., Jankel, W.R., Hedreen, J.C. et al., The pedunculopontine nucleus in Parkinson’s disease, Ann. Neurol., 26:41–46, 1989. 10. Javoy-Agid, F., Agid, Y., Is the mesocortical dopaminergic system involved in Parkinson’s disease? Neurology, New York, 30:1326–1330, 1980. 11. De Keyser, J., Ebinger, G., Vauquelin, G., Evidence for a widespread dopaminergic innervation of the human cerebral neocortex, Neurosci. Lett., 104:281–285, 1989. 12. Ongini, E., Caporali, M.G., Massotti, M., Stimulation of dopamine-D–1 receptors by SKF 38393 induces EEG desynchronization and behavioural arousal, Life Sci., 37:2327–2333, 1985. 13. Bo, P, Ongini, E., Giorgetti, A. et al., Synchronization of the EEG and sedation induced by neuroleptics depend upon blockade of both Dl and D2 dopamine receptors, Neuropharmacology, 27:799, 1988. 14. Chianchetti, C., Dopamine agonists and sleep in man, In Wauquier, A., Gaillard, J.M., Monti, J.M. et al., (Eds.), Sleep: Neurotransmitters and Neuromodulators, Raven Press, New York, 121–134, 1985. 15. Bagetta, G., De Sarro, G., Priolo, E. et al., Ventral tegmental area site through which dopamine D2–receptor agonists evoke behavioural and electrocortical sleep in rats, Br. J. Pharmacol., 95:860–866, 1988. 16. Svensson, K., Alfoldi, P., Hajos, M. et al., Dopamine autoreceptor antagonists: effects of sleepwake activity in the rat, Pharmacol. Biochem. Behav., 26:123–129, 1987. 17. Trampus, M., Ferri, N., Monopoli, A. et al., The dopamine Dl receptor is involved in the regulation of REM sleep in the rat, Eur. J. Pharmacol., 194:189–194, 1991. 18. Tandberg, E., Larsen, J.P., Karlsen, K., Excessive daytime sleepiness and sleep benefit in Parkinson’s disease: a community-based study, Mov. Disord., 922–927, 1999. 19. Menza, M.A., Rosen, R.C, Sleep in Parkinson’s disease: the role of depression and anxiety, Psychosomatics, 36:262–266, 1995. 20. Comella, C.L., Tanner, C.M., Ristanovic, R.K., Polysomnographic sleep measures in Parkinson’s disease patients with treatment-induced hallucinations, Ann. Neurol., 34:710–714, 1993. 21. Chokroverty, S., Sleep and degenerative neurologic disorders, Neurol. Clin., 4:807–826, 1996.

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22. Kales, A., Ansel, R.D., Markham, C.H. et al., Sleep in patients with Parkinson’s disease and normal subjects prior to and following levodopa administration, Clin. Pharmacol. Ther., 12:397–406, 1971. 23. Bergonzi, P., Chiurulla, C., Gambi, D. et al., L-dopa plus dopadecarboxylase inhibitor: sleep organization in Parkinson’s syndrome before and after treatment, Acta Neurol. Belg., 75:5–10, 1975. 24. Puca, F., Bricolo, A., Rurella, G., Effect of L-dopa or amantadine therapy on sleep spindles in parkinsonism, Clin. Neurophysiol., 35:327–330, 1973. 25. Mouret, J., Differences in sleep in patients with Parkinson’s disease, Electroencephalogr. Clin. Neurophysiol., 38:653–657, 1975. 26. Friedman, A., Sleep pattern in Parkinson’s disease, Acta Med. Pol., 21:193–199, 1980. 27. Wetter, T.C., Collado-Seidel, V., Pollm cher, T. et al., Sleep and periodic leg movement patterns in drug-free patients with Parkinson’s disease and multiple system atrophy, Sleep, 23:361–367, 2000. 28. Brunner, H., Wetter, T.C, Högl, B., et al., Microstructure of the non-rapid eye movement sleep electroencephalogram in patients with newly diagnosed Parkinson’s disease: effects of dopaminergic treatment, Mov. Disord., 17:928–933, 2002. 29. Plazzi, G., Corsini, R., Provini, F. et al., REM sleep behaviour disorder in multiple system atrophy, Neurology, 48:1094–1097, 1997. 30. Martinelli, P., Coccagna, G., Rizzuto, N. et al., Changes in systemic arterial pressure during sleep in Shy-Drager syndrome, Sleep, 4:139–146, 1984 1981. 31. Aldrich, M.S., Foster, N.L., White, R.F. et al., Sleep abnormalities in progressive supranuclear palsy, Ann. Neurol., 25:577–581, 1989. 32. Fish, D.R., Sawyers, D., Allen, P.J. et al., The effect of sleep on the dyskinetic movements of Parkinson’s disease, Gille de laTourette syndrome, Huntington’s disease, and torsion dystonia, Arch. Neurol., 1991, 48:210–214. 33. Rye, D.B., Bliwise, D.L., Movement disorders specific to sleep and the nocturnal manifestations of waking movement disorders, in Watts, R.L., W.C., Koller, (Eds.), Neurologic Principles and Practice, McGrawHill, New York, 687–713, 1997. 34. van Hilten, J.J., Weggeman, M., van der Velde, E.A. et al., Sleep, excessive daytime sleepiness and fatigue in Parkinson’s disease, J. Neural. Transm., 5:235–244, 1993. 35. April, R.S., Observations on parkinsonian tremor in allnight sleep, Neurology, New York, 16:720–724, 1996. 36. Stern, M., Roffwarg, H., Duvoisin, R., The parkinsonian tremor in sleep, J. Nerv. Ment. Dis., 147:202–210, 1968. 37. Askenasy, J.J. M., Yahr, M.D., Parkinsonian tremor loses its alternating aspect during nonREM sleep and is inhibited by REM sleep, J. Neurol. Neurosurg. Psychiatry, 53:749–753, 1990. 38. Lees, A.J., Blackburn, N.A., Campbell, V.L., The nighttime problems of Parkinson’s Disease, Clin. Neuropharmacol., 11:512–519, 1988. 39. Garcia-Borreguero, D., Odin, P., Serrano, C., Restless legs syndrome and PD: a review of the evidence for a possible association, Neurology, 61 (Suppl. 3):S49–55, 2003. 40. Ondo, W.G., Vuong, K.D., Jankovic, J., Exploring the relationship between Parkinson disease and restless legs syndrome, Arch. Neurol., 59:421–424, 2002. 41. Broughton, R., Tolentino, M., Krelina, M., Excessive fragmentary myoclonus in NREM sleep. A report of 38 cases, Electroencephalogr. Clin. Neurophysiol., 61:123–133. 1985. 42. Högl, B.E., Gomez-Arevalo, G., Garcia, S. et al., A clinical, pharmacologic, and polysomnographic study of sleep benefit in Parkinson’s disease, Neurology, 50:1332–1339, 1998. 43. Bateman, D.E., Levett, K., Marsden, C.D., Sleep benefit in Parkinson’s disease, J. Neurol. Neurosurg. Psychiatry, 67:384–385, 1999. 44. Currie, L.J., Bennett, J.P., Jr., Harrison, M.B. et al., Clinical correlates of sleep benefit in Parkinson’s disease, Neurology, 48:1115–1117, 1997.

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45. Yamamura, Y., Sobue, L, Ando, K. et al., Paralysis agitans of early onset with marked diurnal fluctuation of symptoms, Neurology, New York, 23:239–244, 1973. 46. American Sleep Disorders Association, International classification of sleep disorders, revised: diagnostic and coding manual, American Sleep Disorders Association, Rochester, 1997. 47. Olson, E.J., Boeve, B.F., Silber, M.H., Rapid eye movement sleep behaviour disorder: demographic, clinical and laboratory findings in 93 cases, Brain, 123:331–339, 2000. 48. Comella, C.L., Nardine, T.M., Diederich, N.J. et al., Sleep-related violence, injury, and REM sleep behavior disorder in Parkinson’s disease, Neurology, 51:526–529, 1998. 49. Gagnon, J.F., Bedard, M.A., Fantini, M.L. et al., REM sleep behavior disorder and REM sleep without atonia in Parkinson’s disease, Neurology, 59:585–589, 2002. 50. Plazzi, G., Cortelli, P., Montagna, P. et al., REM sleep behaviour disorder differentiates pure autonomic failure from multiple system atrophy with autonomic failure, J. Neurol. Neurosurg. Psychiatry, 64:683–685, 1998. 51. Schenck, C., Mahowald, M., REM sleep behavior disorder: clinical, developmental, and neuroscience perspectives 16 years after its formal identification in sleep, Sleep, 25:120–138, 2002. 52. Eisensehr, I., Lindeiner, H., Jäger, M. et al., REM sleep behavior disorder in sleep-disordered patients with versus without Parkinson’s disease: is there a need for polysomnography? J. Neurol. Sci., 186:7–11, 2001. 53. Arnulf, I., Bonnet, A.M., Damier, P. et al., Hallucinations, REM sleep, and Parkinson’s disease: a medical hypothesis, Neurology, 55:281–288, 2000. 54. Hovestadt, A., Bogaard, J.M., Meerwaldt, J.D. et al., Pulmonary function in Parkinson’s disease, J. Neurol. Neurosurg. Psychiatry, 52:329–333, 1989. 55. Vincken, W.G., Gauthier, S.G., Dollfuss, R.E. et al., Involvement of upper-airway muscles in extrapyramidal disorders: a cause of airflow limitation, N. Engl J. Med., 311:438–442, 1984. 56. Hardie, R.J., Efthimiou, J., Stern, G.M., Respiration and sleep in Parkinson’s disease, J. Neurol. Neurosurg. Psychiatry, 49:1326, 1986. 57. Apps, M.C. P, Sheaff, P. C, Ingram, D.A. et al., Respiration and sleep in Parkinson’s disease, J. Neurol. Neurosurg. Psychiatry, 48:1240–1245, 1985. 58. Chokroverty, S., Sharp, J.T., Barron, K.D., Periodic respiration in erect posture in Shy-Drager syndrome, J. Neurol. Neurosurg. Psychiatry, 41:980–986, 1978. 59. McNicholas, W.T., Ruhterford, R., Grossman, R., et al., Abnormal respiratory pattern generation during sleep in patients with autonomic dysfunction, Am. Rev. Respir. Dis., 128:429– 433, 1983. 60. Guilleminault, C, Briskin J.G., Greenfield, M.S. et al., The impact of autonomic nervous system dysfunction on breathing during sleep, Sleep, 4:263–268, 1981. 61. Kenyon, G.S., Apps, M.C. P., Traub, M., Stridor and obstructive sleep apnea in Shy-Drager syndrome treated by laryngofissure and cord lateralization, Laryngoscope, 94:1106–1108, 1984. 62. Isozaki, E., Naito, A., Horiguchi, S. et al., Early diagnosis and stage classification of vocal cord abductor paralysis in patients with multiple system atrophy, J. Neurol. Neurosurg. Psychiatry, 60:399–402, 1996. 63. Ryan, M., Slevin, J.D., Wells, A., Non-ergot dopamine agonist-induced sleep attacks, Pharmacotherapy, 20:724–726, 2000. 64. Pal, S., Bhattacharya, K. E, Agapito, C. et al., A study of excessive daytime sleepiness and its clinical significance in three groups of Parkinson’s disease patients taking pramipexole, cabergoline and levodopa mono and combination therapy, J. Neural Transm., 108:71–77, 2001. 65. Happe, S., Berger, K., The association of dopamine agonists with daytime sleepiness, sleep problems and quality of life in patients with Parkinson’s disease. A prospective study, J. Neurol., 248:1062–1067, 2001. 66. Arnulf, I., Konofal, E., Merino-Andreu, M. et al., Parkinson’s disease and sleepiness: an integral part of PD, Neurology, 58:1019–1024, 2002.

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67. Rye, D., Sleepiness and unintended sleep in Parkinson’s disease, Curr. Treat. Options, Neurol., 5:231–239, 2003. 68. Chaudhuri, K.R., Pal, S., DiMarco, A. et al., The Parkinson’s disease sleep scale: a new instrument for assessing sleep and nocturnal disability in Parkinson’s disease, J. Neurol. Neurosurg. Psychiatry, 73:629–633, 2002. 69. Happe, S., Trenkwalder, C., Movement disorders in sleep: Parkinson’s disease and Restless Legs Syndrome, Biomed. Tech., 48:62–67, 2003. 70. Leeman, A.L., O’Neill, C.J., Nicholson, P.W. et al., Parkinson’s disease in the elderly: response to and an optimal spacing of night time dosing with levodopa, Br. J. Clin. Pharmacol., 24:637– 643. 1987. 71. Monti, J.M., Hawkins, M., Jantos, H. et al., Biphasic effects of dopamine D–2 receptor agonists on sleep and wakefulness in the rat, Psychopharmacology, 95:395–400, 1988. 72. Cantor, C.R., Stern, M.B., Dopamine agonists and sleep in Parkinson’s disease, Neurology, 58:S71–78, 2002. 73. Askenasy, J.J., Yahr, M.D., Reversal of sleep disturbance in Parkinson’s disease by antiparkinsonian therapy: a preliminary study, Neurology, 35:527–532, 1985. 74. Jansen, E.N., Meerwaldtt, J.D., Madopar, H.B.S., in nocturnal symptoms of Parkinson’s disease, Adv. Neurol., 53:527–531, 1990. 75. Koller, W.C., Hutton, J.T., Tolosa, E. et al., Immediate-release and controlled-release carbidopa/levodopa in PD: a 5–year randomized multicenter study, Carbidopa/Levodopa Study Group, Neurology, 53: 1012–1019, 1999. 76. Högl, B., Rothdach, A., Wetter, T.C. et al., The effect of cabergoline on sleep, periodic leg movements in sleep, and early morning motor function in patients with Parkinson’s disease, Neuropsychopharmacology, 28:1866–1870, 2003. 77. Schenck, C., Mahowald, M., A polysomnographic, neurologic, psychiatric and clinical outcome report on 70 consecutive cases with REM sleep behavior disorder (RBD): sustained clonazepam efficacy in 89,5 percent of 57 treated patients, Clev. Clin. J. Med., 57:10–24, 1990. 78. Lang, A.E., Quinn, N., Brincat, S. et al., Pergolide in late-stage Parkinson disease, Ann. Neurol., 12:243–247, 1982. 79. Lapierre, O., Montplaisir, J., Polysomnographic features of REM sleep behaviour disorder: Development of a scoring method, Neurology, 42:1371–1374, 1992. 80. Poewe, W., Seppi, K., Treatment options for depression and psychosis in Parkinson’s disease, J. Neurol., 248 (suppl. S3):12–21, 2001. 81. Happe, S., Berger, K., The association between caregiver burden and sleep disturbances in partners of patients with Parkinson’s disease, Age Ageing, 31:349–354, 2002. 82. Gordon, P.H., Pullman, S.L., Louis, E.D. et al., Mirtazapine in Parkinsonian tremor, Parkinsonism Relat. Disord., 9:125–126, 2002. 83. Scharf, B., Moskovitz, C., Lupton, M.D. et al., Dream phenomena induced by chronic levodopa therapy, J. Neural Transm., 43:143–151, 1978. 84. The Parkinson Study Group. Low-dose clozapine for the treatment of drug-induced psychosis in Parkinson’s disease, N. Engl J. Med., 340:757–763, 1999. 85. Fernandez, H.H., Friedman, J.H., Jacques, C. et al., Quetiapine for the treatment of druginduced psychosis in Parkinson’s disease, Mov. Disord., 14:484–487, 1999. 86. Reddy, S., Factor, S.A., Molho, E.S. et al., The effect of quetiapine on psychosis and motor function in parkinsonian patients with and without dementia, Mov. Disord., 17:676–681, 2002. 87. Braga-Neto, P., Pereira da Silva-Junior, F., Sueli Monte, F., de Bruin, P.F., de Bruin, V.M., Snoring and excessive daytime sleepiness in Parkinson’s disease, J. Neurol. Sci., 217:41–45, 2004. 88. Parkes, J.D., Tarsy, D., Marsden, C.D. et al., Amphetamines in the treatment of Parkinson’s disease, J. Neurol. Neurosurg. Psychiatry, 38:232–237, 1975. 89. Happe, S., Pirker, W., Sauter, C. et al., Successful treatment of excessive daytime sleepiness in Parkinson’s disease with modafinil, J. Neurol., 248:632–634, 2001.

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90. Nieves, A.V., Lang, A.E., Treatment of excessive daytime sleepiness in patients with Parkinson’s disease with modafinil, Clin. Neuropharmacol., 25:111–114, 2002. 91. Högl, B., Saletu, M., Brandauer, E. et al., Modafinil for the treatment of daytime sleepiness in Parkinson’s disease: a double-blind, randomized, crossover, placebocontrolled polygraphic trial, Sleep, 25:905–909, 2002. 92. Hauser, R.A., Wahba, M.N., Zesiewicz, T.A., McDow-ell, Anderson, W., Modafinil treatment of pramipexoleassociated somnolence, Mov. Disord., 15:1269–1271, 2000.

22 Visual Function in Parkinson’s Disease Robert L.Rodnitzky Roy J. and Lucile A. Carver College of Medicine, University Hospitals, University of lowa 0-8493-1590-5/05/$0.00+$1.50 © 2005 by CRC Press

INTRODUCTION Visual function is adversely affected in a great variety of ways in Parkinson’s disease (PD).1,2 Most of the visual dysfunction seen in this condition is relatively subtle from the patient’s and physician’s point of view. Although there are functional consequences under certain circumstances, the impairment resulting from visual symptoms in PD is seldom of sufficient severity to replace motoric dysfunction as the primary source of the patient’s clinical disability. The visual abnormalities linked to PD are, for the most part, demonstrable in the very early clinical phase of the illness and possibly in the preclinical phase as well. Parkinson’s disease is predominantly a disorder of the elderly, and patients in this age group commonly become aware of visual symptoms such as declining acuity, visual blurring, difficulty reading, impaired near vision, and abnormal light sensitivity. When these same symptoms occur in an elderly individual who also has PD, both the patient and the clinician may naturally wonder what contribution to these symptoms, if any, derives from the underlying neurological disorder. When visual complaints are formally solicited from PD patients, the most common are tired eyes or blurred vision when reading and diplopia.3 Can the origin of such complaints be linked to the known pathophysiology of Parkinson’s disease? To explore this possible relationship, this chapter will discuss the known aberrations of visual function that occur in PD as well as their pathogenesis. Since most forms of visual dysfunction in PD are clinically subtle, special attention will be paid to electrophysiologic and psychophysical techniques that are useful in demonstrating and quantifying them. DOPAMINE AND VISION An appreciation of the role of dopamine in the visual system and its abnormalities in PD is critical to understanding the aberrations of visual function seen in this condition. Dopamine is present in several anatomical structures that subserve vision. Most notable is its localization within the amacrine and interplexiform cells of the retina.4 Several observations support the concept that dopamine subserves specific functions in the retina of primates. The chemical protoxin MPTP (1-methyl, 4-phe-nyl, 1-2-5-6-

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tetrahydropyridine) not only produces a clinical parkinsonian syndrome when injected into primates, it also significantly lowers retinal dopamine. This latter change is associated with abnormalities in the latency and amplitude of both the pattern visual evoked potential (VEP) and the electroretinogram, both of which can be reversed by the administration of the dopamine precursor levodopa.5 Similarly, intravitreal injection of the neurotoxin 6-hydroxydopamine into aphakic monkeys results in abnormalities in both the phase and amplitude of the pattern electroretinogram (PERG) and the pattern VEP, especially for stimuli with higher spatial frequencies,6 a finding that suggests a role for dopamine in retinal spatial tuning. In idiopathic PD as well, the visual evoked response7 and pattern electroretinogram8 are abnormal, and both can be improved by the administration of levodopa, especially the latter.9 That these abnormalities in PD patients are related to retinal dopamine deficiency is supported by an autopsy study of PD patients in which retinal dopamine concentration was shown to be decreased;10 however, in those patients who had received levodopa shortly before death, it was normal, suggesting that this therapy might be instrumental in reversing visual dysfunction related to retinal dopamine deficiency. Dopaminergic innervation within the visual system has been demonstrated in structures other than the retina, including the lateral geniculate11 and the visual cortex.12 Single unit recordings in the lateral geniculate body of cats during simultaneous iontophoretic application of dopamine suggest that dopamine influences visual function in this structure by directly inhibiting relay cells through Dl receptors and by both directly facilitating relay cell function and exciting inhibitory neurons through D2 receptors.13 Asymmetric primary visual cortex glucose hypometabolism has been demonstrated in PD, with the most severe abnormality appearing ipsilateral to the most severe motoric dysfunction.14 The laterality of this abnormality suggests that it is more likely related to pathology in the nigrostriatal system than the retina, since the former structure is asymmetrically involved in PD, whereas the latter, even if asymmetrically affected, has bilateral input to the visual cortices and would be expected to result in symmetrical hypometabolism. Clinical evidence supporting possible cortical visual dysfunction in PD can be found in the observation that left hemiParkinson patients display a tendency to neglect the left upper visual field.15 Notwithstanding the potential widespread influence of dopamine within the visual system, its role in the retina seems to be most important. Dopamine content in the retina exhibits distinct circadian rhythms that can be driven by light/dark cycles or, in total chronic darkness, by the cyclic presence of melatonin.16,17 Dopaminergic neurons are thought to subserve a modulatory role in the retina and may mediate center-surround functions that are important to receptive field organization.18 An investigation in which the PERG spatial contrast response was recorded after administration of dopamine D1or D2 antagonists or a Dl agonist suggested that D1 receptors may be most important for the surround organization of retinal ganglion cells, while D2 receptors may play a role in center response amplification of other ganglion cells.19 Within the D2 receptor family, D4 receptors predominate in the retina and appear to modulate the dopaminergic control of light sensitive cAMP.20 Since dopamine receptors in the retina are not only found at synapses but at extrasynaptic sites as well, it appears that dopamine acts in this structure both as neurotransmitter and a neuromodulator.21,22

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VISUAL ACUITY It is generally accepted that there is not a severe or clinically impressive decline of visual acuity in PD, although careful group comparisons between PD patients and controls do reveal a difference. Repka et al.3 tested highcontrast (Snellen chart) visual acuity in 39 PD patients and an equal number of age-matched controls. In this study, a small but statistically significant difference in visual acuity was found between PD patients (20/39) and controls (20/28). Visual acuity decline in PD patients correlated with increasing disease severity, in support of the notion that this abnormality is linked to the progressive pathology of the underlying Parkinson’s disease. It is not certain whether loss of visual acuity in PD is related to retinal or cortical dysfunction, but the authors speculated that the reduction of retinal dopamine known to occur in PD might result in an increase in the receptive field size leading to the decrease in visual acuity. While the severity of visual acuity loss in PD may be related to advancing disease, it does not appear to be reversible with treatment, since high-contrast visual acuity has been found to be similarly impaired, whether patients are on or off dopaminergic drugs.23 One other link between dopamine content and visual acuity is the clinical observation that administration of levodopa improves human amblyopia in both children and adults.24 Whether this effect is exerted at the retinal or cortical level, or both, is still uncertain.25 Although not directly related to visual acuity, another common efferent visual problem in PD that can significantly reduce visual efficiency, is convergence insufficiency.3 This condition, which is extremely common in PD, is associated with an abnormally distant near point of convergence, greater than 10 cm, and slow convergence amplitude. It is typically associated with the subjective complaint of asthenopia or eyestrain. Convergence insufficiency may also impair reading, especially in patients using bifocal eyeglasses for reading, since their proper use requires intact convergence. Impaired near vision in some affected patients may be amenable to correction with the use of prisms to compensate for impaired convergence or by instruction in the practice of monocular occlusion while reading. A recent report suggests that convergence insufficiency in PD can be improved by therapy with levodopa,26 supporting the link between this form of dysfunction and dopamine deficiency. COLOR VISION Abnormal color discrimination has frequently been reported in patients with Parkinson’s disease.27,28 In many studies, this impairment has been found to be most prominent in the tritan (blue-yellow) axis.29,30 Abnormalities of color perception have been demonstrated using both bedside clinical testing techniques such as the FarnsworthMunscll (FM) 100hue test30 or more elaborate psychophysical means such as a computer-generated assessment of color contrast sensitivity.29 Haug et al.29 offered an explanation as to why the tritan contrast threshold is most affected in Parkinson’s disease. In general, the blue cone system is preferentially affected in retinal disease, because its response range is limited, and it has the greatest vulnerability. The relatively selective involvement in PD can be explained by the fact that these short-wavelength-sensitive cones are relatively scarce in number in the retina and spaced widely apart, such that maintenance of their

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large receptive fields is dependent on interaction across considerable distances, a function mediated by the dopaminergic interplexiform and amacrine cells of the retina, the precise retinal elements that are most affected in PD. Involvement of these same retinal cells in PD may result in other forms of visual dysfunction but not necessarily related to the same pattern of impaired cellular connectivity. Pieri et at.31 studied both color discrimination and contrast sensitivity in PD and found impairment of the two forms of visual dysfunction to be independent variables, suggesting that different retinal mechanisms underlie each. The abnormality of color vision seen in PD can be demonstrated in very early patients who have not yet begun antiparkinson drug therapy. It can be reversed by treatment with levodopa.32,33 Paradoxically, in one case, color vision was worsened after treatment with the dopamine agonist pramipexole.34 Color discrimination testing in untreated, de novo PD patients has shown a significant correlation between the error score of the FM test and the severity of clinical parkinsonian signs as measured by the motor and activities of daily living subscales of the Unified Parkinson’s Disease Rating Scale (UPDRS).35 When PD patients are followed longitudinally over time, color discrimination scores decline progressively as the underlying disease worsens,36–37 although, in one study, the decrementing scores only correlated with decline in the UPDRS activities of daily living (ADL) score,37 and in another with both the UPDRS motor and ADL scores.36 Despite the consistent correlation with disease severity by one measure or another, one investigation demonstrated that the magnitude of color vision abnormality in PD does not correlate with dopaminergic nigral degeneration as reflected by I123 β-CIT single photon emission tomography of the dopamine transporter. This observation s consistent with the prevailing notion that the visual abnormality in PD is largely extranigral in origin.38 A plausible explanation of why color discrimination impairment does not correlate with nigral degeneration, yet parallels the clinical severity of PD, is that retinal dopamine depletion, although independent of nigral dopamine depletion, occurs contemporaneously at a relatively constant pace over time. Regan et al.39 questioned whether abnormalities uncovered during color discrimination testing in Parkinson’s disease patients are just an epiphenomenon related to the motor disability of Parkinson’s disease, since the FM test, used to demonstrate impaired color vision in many studies of PD, requires a motor response to correctly identify varying hues of color. They questioned whether it is the manual impairment of PD patients rather than a primary visual disorder that causes PD patients to fail this test and at the same time explains why levodopa, which corrects the motoric abnormality, improves the color discrimination score. These investigators utilized a computer-controlled test of color vision that did not require a motor response and found that PD patients performed as well as a control group. Their hypothesis, however, fails to explain why other investigators utilizing computer testing techniques29 did uncover abnormalities of color vision in PD, or why most studies have revealed a preferential loss in the tritan color axis with little or no abnormality in the protan (red-green) axis, both of which should have been similarly affected were the abnormal test scores simply a reflection of parkinsonian motor impairment. There is additional evidence that supports the validity of a primary color vision abnormality in PD. Abnormalities of the visual evoked response produced by color pattern stimuli are more responsive to levodopa therapy than are those evoked by blackand-white stimuli.40 Similarly, color contrast sensitivity in PD patients is most impaired

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along the tritan axis.29 Lastly, other medical conditions characterized by impairment of dopaminergic transmission have been associated with abnormalities of color vision. In patients undergoing cocaine withdrawal, a relative hypodopaminergic state exists, and a similar tritan axis deficit in color discrimination has been noted. The same abnormality of color vision was not seen however during their hyperdopaminergic intoxication phase.41 In schizophrenia, on the other hand, color discrimination abnormalities have been found to be general and not hue specific, leading to the hypothesis that axisspecific color discrimination abnormalities are a reflection of depletion of dopamine rather than its general dysregualtion.42 VISUAL CONTRAST SENSITIVITY Visual contrast sensitivity (VCS) is a function that is not commonly tested by neurologists, yet it is an important sensory function that pervades many activities of daily living. It is probably a more meaningful reflection of functional vision than standard visual acuity tests as measured in most clinical settings. VCS has consistently been found to be abnormal in Parkinson’s disease. VCS is measured by determining the minimal contrast required to distinguish objects from one another presented at a given spatial frequency. Visual targets spaced very closely together are said to have a high spatial frequency, and those spaced farther apart represent a low spatial frequency. Spatial frequency is expressed in cycles per degree of visual angle. The spectrum of contrast can be thought of as ranging from black on white (high contrast) to white on white (low contrast), with all shades of grey on black or grey on white in between. Another way to depict the concept of VCS is to ask how low in contrast adjacent images displayed at a given spatial frequency (distance apart) must be before they appear to be indistinguishable from a visually homogeneous field. The lower the contrast at which one can still detect a difference between adjacent objects, the higher the contrast sensitivity. Sinusoidal gratings of various spatial frequencies are among the most sensitive visual stimuli for testing VCS in humans. In this context, the term “sinusoidal” refers to the gradual diminution and then reconstitution of contrast between adjacent targets rather than a precipitous contrast change such as would be seen between adjacent black and white squares on a checkerboard. The peak of normal human contrast sensitivity is found at intermediate spatial frequencies. In Parkinson’s disease, VCS is most reduced at these intermediate spatial frequencies.43–45 This VCS abnormality is most exaggerated when the gratings are temporally modulated at medium frequencies of 4 to 8Hz.43 In addition, VCS is sometimes less attenuated at lower spatial frequencies in PD than it is in normal individuals.46 These abnormalities are different from the declining VCS function associated with normal aging.47 In some studies, VCS loss has been found to correlate with the overall severity of PD,48 but in others it has not.45 However, during the course of an individual day, there appears to be a more consistent correlation with the underlying severity of parkinsonian symptoms. VCS has been shown to exhibit a circadian variability that conforms to the common pattern of improved morning and worsened afternoon motoric disability seen in PD.45 Recent evidence demonstrating a distinct circadian cycle of retinal dopamine content is consistent with this observation.16,17 Similarly, VCS function can change in parallel to motor symptoms during transient “on”

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and “off” phases in fluctuating PD patients49 and can be improved by the administration of levodopa.50 Whether the basic abnormality underlying abnormal VCS in PD resides in the retina, the visual cortex, or in both is still unclear. The fact that there are interocular differences in VCS45,51 suggests the presence of retinal pathology. Moreover, the pattern electroretinogram, which largely reflects retinal ganglion cell activity, has been found to be abnormal in PD52,53 with a characteristic amplitude loss at intermediate spatial frequencies similar to those associated with the greatest abnormality of VCS in PD.52 As is the case with VCS, levodopa therapy improves the PERG abnormality in PD.52,53 Langheinrich et al.54 demonstrated that contrast discrimination threshold in PD patients correlated with frequency-specific PERG abnormalities (a retinal phenomenon) but not VEP impairment (a cortical phenomenon) and viewed these findings as further evidence that the VCS abnormality in PD is predominantly a result of retinal dysfunction. However, there is also evidence suggesting that cortical dysfunction may contribute to the VCS abnormality in PD. VCS impairment in PD patients has been found to be orientation specific in that the VCS deficit is more severe for horizontally oriented patterns than those arrayed vertically.43,44 Other dopamine deficiency syndromes, such as drug-induced parkinsonism, are also associated with VCS loss that is orientation dependent.55 Although orientation specificity may be partially subserved by the lateral geniculate,56 this perceptual function is felt to largely reside in the orientation-tuned receptive fields of the visual cortex.57 While the presence of orientation specific VCS loss clearly raises the possibility of a central contribution to the VCS abnormality in PD, other investigators have noted that the cortically mediated function of contrast adaptation is preserved in PD and consider this finding evidence that cortical pathology is not significant in these patients and is not likely to play a major role with respect to reduced contrast sensitivity.58 Like the color vision abnormality in PD, VCS impairment progressively increases over time as the underlying neurologic condition worsens.36 This worsening is accelerated at the intermediate spatial frequencies that are known to be most affected in PD, rather than at higher spatial frequencies, which would be expected to show the greatest rate of decline if the progressive worsening were solely due to aging.59 As VCS worsens over time in PD, there is a contemporaneous progressive reduction in amplitude and lengthening of latency of the ERG, once again supporting the notion that abnormal VCS in this patient population is linked to retinal dysfunction.60 The use of low-contrast letter charts in patients with PD and other medical conditions has been found to detect visual dysfunction that was not appreciated through the use of standard visual acuity charts, which are confined to extremely high-contrast, high-spatialfrequency visual stimuli.61,62 Parkinson’s disease patients and their physician are usually unaware of this contrast sensitivity abnormality, but the patient may have noticed an inexplicable impairment in everyday visual tasks. This subtle abnormality, largely affecting VCS at the intermediate spatial frequencies, can impair such critical functions as facial recognition or proper and early identification of highway signs.63 Additional functional correlates of this VCS deficit are possible.64,65 Abnormal VCS might impair the ability to drive a motor vehicle in a low-contrast environment such as might exist at dusk or dawn. Intact spatiotemporal vision is functionally important on a day-to-day basis, since much of the visual world is periodic in array,66 and is important for the

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normal perception of depth and depth discrimination.67 It has been suggested that, in PD, abnormal contrast sensitivity might predispose to gait freezing. Mestre et al.68 described a PD patient exhibiting increased contrast sensitivity to low and intermediate spatiotemporal frequencies who experienced gait freezing in the presence of environmental stripes arrayed at these low frequencies but not at higher spatial frequencies or with his eyes closed. They postulated that a hypersensitivity to low frequency visual stimuli resulted in an adaptive “braking” reflex leading to gait freezing. Of interest is the observation that levodopa therapy may preferentially increase VCS at these low spatial frequencies,69 a fact that is consistent with the observation that dopaminergic therapy can paradoxically worsen gait freezing in some patients. Other investigators have demonstrated that the gait of PD patients improves in the presence of well illuminated periodic stimuli (lines) in the visual environment,70 and that parameters of gait such as stride length are related to visual cues.71 VISUAL HALLUCINATIONS Visual hallucinations occur commonly in advanced PD. Sanchez-Ramos et al.72 recorded this complication in over 25% of 214 consecutive PD patients. In addition to known risk factors such as age, dementia, and drug therapy, visual loss can also contribute to the development of complex visual hallucinations in this patient population.73–75 Visual hallucinations that occur in visually impaired but psychologically normal individuals are considered a form of the Charles Bonnet syndrome.76–78 Patients afflicted with this syndrome are typically cognitively intact with retained insight such that this form of hallucinosis, which is usually devoid of personal meaning, tends to be somewhat less emotionally upsetting. Functional magnetic resonance imaging of patients with the Charles Bonnet syndrome has revealed increased activity in the ventral extrastriate region,79 but whether this abnormal signal and the clinical syndrome with which it is associated reflect abnormal cortical excitation, a release phenomenon, or disrupted reentry signals is not yet known. While the Charles Bonnet syndrome is most typically associated with a significant loss of visual acuity,74,77,80 in Parkinson’s disease it has been associated with more covert visual abnormalities including abnormal color discrimination, reduced visual contrast sensitivity,75 or impaired color contour perception.73 In these studies, patients exhibiting the Charles Bonnet syndrome had otherwise normal visual acuity, confirming that any one of a wide range of visual abnormalities may be sufficient to predispose a PD patient to hallucinosis. The appearance of Charles Bonnet syndrome in PD patients and its predominance in elderly individuals has led some to postulate that some degree of underlying cerebral degeneration is critical to the development of the syndrome.80 Treatment of the Charles Bonnet syndrome can be difficult. Therapy with neuroleptics that improve other forms of PD-related hallucinosis has been largely ineffective.81 Improvement in the syndrome has been reported after institution of optical aids that result in improved functional vision,82 raising the possibility that in some PD patients, whose hallucinations are predominantly related to abnormal VCS and/or color discrimination, treatment with dopaminergic drugs might reverse this symptom rather than exacerbate it.

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CLINICAL UTILITY OF VISUAL TESTING IN PARKINSON’S DISEASE Although, abnormalities such as impaired visual contrast sensitivity and abnormal color discrimination are unlikely to be apparent to the PD patient, it is still important that the clinician be aware that a wide variety of functional impairments as diverse as gait freezing, defective depth perception, impaired driving, and visual hallucinations might be related to these forms of visual impairment. Another clinically important question that arises is whether uncovering abnormalities of vision might be useful in identifying early or presymptomatic PD or in distinguishing PD from other parkinsonian syndromes. The possibility or differentiation between idiopathic Parkinson’s disease and multiple system atrophy has been investigated in this regard, and distinct group differences between the two conditions have been identified in mean VEP latency and visual contrast thresholds.58,51 However, it is not clear that these group differences would be useful in making a clinical distinction between the two conditions in individual patients. In progressive supranuclear palsy, mean VCS performance has been found to be more severely impaired than in PD but not so consistently abnormal in individual patients as to be useful in distinguishing this syndrome from other parkinsonian conditions.54 In regard to the use of color testing as a diagnostic aid, Birch et al.30 found that 23% of PD patients had tritan color vision deficits, while none of 40 age-matched controls were abnormal. These results suggest that the presence of impaired blue-yellow discrimination supports a diagnosis of Parkinson’s disease, but normal function does not rule it out. The prospect for using visual tests to identify PD in its earliest stage, or even prior to the onset of motoric symptoms, is slightly more promising but still not certain. In one study, color discrimination was found to be abnormal in mild de novo PD patients very early in the course of the illness, suggesting that the abnormality may have antedated the clinical diagnosis of Parkinson’s disease.28 However, a later investigation noted abnormal color discrimination in only a small percentage of such PD patients and no difference at all in mean performance compared to normal controls.83 Perhaps the most useful application of VCS testing in the diagnosis of PD is its use in association with other assessments as part of a battery. Camicioli et al.84 administered a battery consisting of tapping rate combined with either olfactory assessment or measurement of visual contrast sensitivity and found that it discriminated between mild PD patients and control subjects with greater than 90% accuracy. SUMMARY Involvement of the visual system in Parkinson’s disease has been clearly demonstrated through electrophysiologic tests such as the electroretinogram or visual evoked potentials and by psychophysical tests of color discrimination and contrast sensitivity. There is abundant evidence that the visual system dysfunction seen, both in experimental parkinsonism and human Parkinson’s disease is linked to retinal dopamine deficiency. The potential functional implications of the types of visual impairment found in PD are only beginning to be appreciated. The fact that convergence insufficiency, impaired VCS and reduced color discrimination all seem amenable to therapy with dopaminergic drugs

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provides hope that future advances in our understanding of the biology of dopamine in the visual system, and further development of neuroprotective or restorative therapies for Parkinson’s disease can also effectively ameliorate the visual dysfunction associated with this condition. REFERENCES 1. Rodnitzky, R.L., Visual dysfunction in Parkinson’s disease, Clinical Neuroscience, 5(2):102– 106, 1998. 2. Bodis-Wollner, I., Visualizing the next steps in Parkinson disease, Archives of Neurology, 59(8):1233–1234, 2002. 3. Repka, M.X., Claro, M.C., Loupe, D.N., Reich, S.G., Ocular motility in Parkinson’s disease, Journal of Pedi-atric Ophthalmology and Strabismus, 33(3):144–147 1996. 4. Frederick, J.M., Rayborn, M.E., Laties, A.M., Lam, D.M., Hollyfield, J.G., Dopaminergic neurons in the human retina, J. Comp. Neurol., 210(l):65–79, 1982. 5. Ghilardi, M.E, Chung, E., Bodis-Wollner, I., Dvorzniak, M., Glover, A., Onofrj, M., Systemic 1methyl,4-phenyl, 1-2-3-6-tetrahydropyridine (MPTP) administration decreases retinal dopamine content in primates, Life Sciences, 43(3):255–262, 1988. 6. Ghilardi, M.F., Marx, M.S., Bodis-Wollner, I., Camras, C.B., Glover, A.A., The effect of intraocular 6-hydrox-ydopamine on retinal processing of primates, Annals of Neurology, 25(4):357–364, 1989. 7. Bodis-Wollner, I., Yahr, M.D., Measurements of visual evoked potentials in Parkinson’s disease, Brain, 101(4):661–671, 1978. 8. Peppe, A., Stanzione, P., Pierelli, F., Stefano, E., Rizzo, P.A., Tagliati, M. et al., Low contrast stimuli enhance PERG sensitivity to the visual dysfunction in Parkinson’s disease, Electroencephalography and Clinical Neurophysiology, 82(6):453–457, 1992. 9. Peppe, A., Stanzione, P, Pierelli, F., De Angelis, D., Pierantozzi, M., Bernardi, G., Visual alterations in de novo Parkinson’s disease: pattern electroretinogram latencies are more delayed and more reversible by levodopa than are visual evoked potentials, Neurology, 45(6):1144– 1148, 1995. 10. Harnois, C., Di Paolo, T., Decreased dopamine in the retinas of patients with Parkinson’s disease, Investigative Ophthalmology and Visual Science, 31(11):2473–2475, 1990. 11. Papadopoulos, G.C., Parnavelas, J.G., Distribution and synaptic organization of dopaminergic axons in the lateral geniculate nucleus of the rat, Journal of Comparative Neurology, 294:356– 361, 1990. 12. Parkinson, D., Evidence for a dopaminergic innervation of cat primary visual cortex, Neuroscience, 30(1):171–179, 1989. 13. Zhao, Y., Kerscher, N., Eysel, U., Funke, K., D1 and D2 receptor-mediated dopaminergic modulation of visual responses in cat dorsal lateral geniculate nucleus, Journal of Physiology, 539(Pt. 1):223–238, 2002. 14. Bohnen, N.I., Minoshima, S., Giordani, B., Frey, K.A., Kuhl, D.E., Motor correlates of occipital glucose hypometabolism in Parkinson’s disease without dementia, Neurology, 52(3):541–546, 1999. 15. Lee, A.C., Harris, J.P., Atkinson, E.A., Nithi, K., Fowler, M.S., Dopamine and the representation of the upper visual field: evidence from vertical bisection errors in unilateral Parkinson’s disease, Neuropsychologia, 40(12):2023–2029, 2002. 16. Doyle, S.E., Mclvor, W.E., Menaker, M., Circadian rhythmicity in dopamine content of mammalian retina: role of the photoreceptors, J. Neurochem., 83(1):211–219, 2002. 17. Doyle, S.E., Grace, M.S., McIvor, W., Menaker, M., Circadian rhythms of dopamine in mouse retina: the role or melatonin, Vis Neurosci., 19(5):593–601, 2002.

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39. Regan, B.C., Freudenthaler, N., Kolle, R., Mollon, J. D., Paulus, W., Colour discrimination thresholds in Parkinson’s disease: results obtained with a rapid computercontrolled colour vision test, Vision Research, 38(21):3427–3431, 1998. 40. Barbato, L., Rinalduzzi, S., Laurenti, M., Ruggieri, S., Accornero, N., Color VEPs in Parkinson’s disease, Electroencephalography and Clinical Neurophysiology, 92(2):169–172, 1994. 41. Desai, P, Roy, M., Brown, S., Smelson, D., Impaired color vision in cocaine-withdrawn patients, Arch. Gen. Psychiatry, 54(8):696–699, 1997. 42. Shuwairi, S.M., Cronin-Golomb, A., McCarley, R.W., O’Donnell, B.F., Color discrimination in schizophrenia, Schizophr. Res., 55(1–2):197–204, 2002. 43. Regan, D., Maxner, C., Orientation-selective visual loss in patients with Parkinson’s disease, Brain, 110(Pt. 2):415–432, 1987. 44. Bulens, C., Meerwaldt, J.D., van der Wildt, G.J., Effect of stimulus orientation on contrast sensitivity in Parkinson’s disease, Neurology, 38(1):76–81, 1988. 45. Struck, L.K., Rodnitzky, R.L., Dobson, J.K., Circadian fluctuations of contrast sensitivity in Parkinson’s disease, Neurology, 40(3 Pt. 1):467–470, 1990. 46. Bodis-Wollner, I., The visual system in Parkinson’s disease, Vision and the Brain, Raven Press, 297–316, 1990. 47. Mestre, D., Blin, O., Serratrice, G., Pailhous, J., Spatiotemporal contrast sensitivity differs in normal aging and Parkinson’s disease, Neurology, 40(11):1710–1714, 1990. 48. Hutton, J.T., Morris, J.L., Elias, J.W., Varma, R., Poston, J.N., Spatial contrast sensitivity is reduced in bilateral Parkinson’s disease, Neurology, 41(8):1200–1202, 1991. 49. Bodis-Wollner, I., Marx, M.S., Mitra, S., Bobak, P, Mylin, L., Yahr, M., Visual dysfunction in Parkinson’s disease. Loss in spatiotemporal contrast sensitivity, Brain, 110(Pt. 6):1675–1698, 1987. 50. Hutton, J.T., Morris, J.L., Elias, J.W., Levodopa improves spatial contrast sensitivity in Parkinson’s disease, Archives of Neurology, 50(7):721–724, 1993. 51. Delalande, L, Hache, J.C., Forzy, G., Bughin, M., Benhadjali, J., Destee, A., Do visual-evoked potentials and spatiotemporal contrast sensitivity help to distinguish idiopathic Parkinson’s disease and multiple system atrophy? Movement Disorders, 13(3):446–452, 1998. 52. Tagliati, M, Bodis-Wollner, I., Yahr, M.D., The pattern electroretinogram in Parkinson’s disease reveals lack of retinal spatial tuning, Electroencephalography and Clinical Neurophysiology, 100(1):1–11, 1996. 53. Peppe, A., Stanzione, P, Pierantozzi, M., Semprini, R., Bassi, A., Santilli, A.M. et al., Does pattern electroretinogram spatial tuning alteration in Parkinson’s disease depend on motor disturbances or retinal dopaminergic loss? Electroencephalography and Clinical Neurophysiology, 106(4):374–382, 1998. 54. Langheinrich, T., Tebartz, V.E., Lagreze, W.A., Bach, M., Lucking, C.H., Greenlee, M.W., Visual contrast response functions in Parkinson’s disease: evidence from electroretinograms, visually evoked potentials and psychophysics, Clinical Neurophysiology, 111(1):66–74, 2000. 55. Bulens, C, Meerwaldt, J.D., van der Wildt, G.J., Keemink, C.J., Visual contrast sensitivity in druginduced Parkinsonism, Journal of Neurology, Neurosurgery and Psychiatry, 52(3):341– 345, 1989. 56. Xu, X., Ichida, J., Shostak, Y., Bonds, A.B., Casagrande, V.A., Are primate lateral geniculate nucleus (LGN) cells really sensitive to orientation or direction? Vis. Neurosci., 19(1):97–108, 2002+. 57. Hubel, D.H., Wiesel, T.N., Stryker, M.P., Orientation columns in macaque monkey visual cortex demonstrated by the 2-deoxyglucose autoradiographic technique, Nature, 269:328–330, 1977. 58. Tebartz, V.E., Greenleem, M.W., Foleym, J.M., Lucking, C.H., Contrast detection, discrimination and adaptation in patients with Parkinson’s disease and multiple system atrophy, Brain, 120(Pt. 12):2219–2228, 1997.

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59. Kline, D.W., Ageing and the spatiotemporal discrimination performance of the visual system, Eye, 1, 323–329, 1987. 60. Ikeda, H., Head, G.M., Ellis, C.J., Electrophysiological signs of retinal dopamine deficiency in recently diagnosed Parkinson’s disease and a follow up study, Vision Research, 34(19):2629– 2638, 1994. 61. Regan, D., Neima, D., Low-contrast letter charts in early diabetic retinopathy, ocular hypertension, glaucoma, and Parkinson’s disease, British Journal of Ophthalmology, 68(12):885–889, 1984. 62. Kupersmith, M.J., Shakin, E., Siegel, I.M., Lieberman, A., Visual system abnormalities in patients with Parkinson’s disease, Archives of Neurology, 39(5):284–286, 1982. 63. Evans, D.W., Ginsburg, A.P., Contrast sensitivity predicts age-related differences in highwaysign discriminability, Human Factors, 27(6):637–642, 1985. 64. West, S.K., Rubin, G.S., Broman, A.T., Munoz, B., Bandeen-Roche, K., Turano, M., How does visual impairment affect performance on tasks of everyday life? The SEE project, Salisbury Eye Evaluation, Archives of Ophthalmology, 120(6):774–780, 2002. 65. Ginsburg, A.P., Contrast sensitivity and functional vision, International Ophthalmology Clinics, 43(2):5–15, 2003. 66. DeValois, R., DeValois, K., Spatial Vision, Oxford University Press, Inc., New York, 1988. 67. Rohaly, A.M., Wilson, H.R., The effects of contrast on perceived depth and depth discrimination, Vision Research, 39:9–18, 1999. 68. Mestre, D., Blin, O., Serratrice, G., Contrast sensitivity is increased in a case of nonparkinsonian freezing gait, Neurology, 42(1):189–194, 1992. 69. Giladi, N., Treves, T.A., Simon, E.S., Shabtai, H., Orlov, Y., Kandinov, B. et al., Freezing of gait in patients with advanced Parkinson’s disease, Journal of Neural Transmission—General Section, 108(1):53–61, 2001. 70. Azulay, J. P., Mesure, S., Amblard, B., Blin, O., Sangla, I., Pouget, J., Visual control of locomotion in Parkinson’s disease, Brain, 122(Pt. 1):111–120, 1999. 71. Lewis, G.N., Byblow, W.D., Walt, S.E., Stride length regulation in Parkinson’s disease: the use of extrinsic, visual cues, Brain, 123(Pt. 10):2077–2090, 2000. 72. Sanchez-Ramos, J.R., Ortoll, R., Paulson, G.W., Visual hallucinations associated with Parkinson disease, Archives of Neurology, 53(12):1265–1268, 1996. 73. Buttner, T., Kuhn, W., Muller, T., Welter, F.L., Federlein, J., Heidbrink, K. et al., Visual hallucinosis: the major clinical determinant of distorted chromatic contour perception in Parkinson’s disease, Journal of Neural Transmission—General Section, 103(10):1195–1204, 1996. 74. Lepore, F.E., Visual loss as a causative factor in visual hallucinations associated with Parkinson disease, Archives of Neurology, 54(7):799, 1997. 75. Diederich, N.J., Goetz, C.G., Raman, R., Pappert, E. J., Leurgans, S., Piery, V., Poor visual discrimination and visual hallucinations in Parkinson’s disease, Clinical Neuropharmacology, 21(5):289–295, 1998. 76. Pfeiffer, R.F, Bodis-Wollner, I., Charles Bonnet syndrome, J. Am. Geriatr. Soc., 44(9):1128– 1129, 1996. 77. Antal, A., Pfeiffer, R., Bodis-Wollner, I., Simultaneously evoked primary and cognitive visual evoked potentials distinguish younger and older patients with Parkinson’s disease, Journal of Neural Transmission—General Section, 103(89):1053–1067, 1996. 78. Teunisse, R.J., Cruysberg, J.R., Hoefnagels, W.H., Verbeek, A.L., Zitman, F.G., Visual hallucinations in psychologically normal people: Charles Bonnet’s syndrome, Lancet, 347:794– 797, 1996. 79. Ffytche, D.H., Howard, R.J., Brammer, M., David, A., Woodruff, P, Williams, S., The anatomy of conscious vision: an fMRI study of visual hallucinations, Nat. Neurosci., 1(8), 738–742, 1998.

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23 Visuocognitive Dysfunctions in Parkinson’s Disease Andrea Antal and Walter Paulus Department of Clinical Neurophysiology, Georg-August University of Göttingen Ivan Bodis-Wollner Parkinson’s Disease and Related Disorders Clinic, Center of Excellence, State University of New York, Downstate Medical Center 0-8493-1590-5/05/$0.00+$1.50 © 2005 by CRC Press

INTRODUCTION Of all human senses, vision is crucial among sensory functions in shaping our perceptions and accurate actions. We need satisfactory visual processing for navigation; for recognizing faces, objects, buildings, and places; for writing and counting; and for a wide range of motor actions starting from eye movements ending with the execution of a motor response. Accurate visual information processing is also necessary for the satisfactory functioning of the visual memory. The processing and transfer of primary visual input to higher-order cortical areas is quick, almost automatic. Due to this efficient transfer process, most of our daily activities require not too much effort. However, when processing is impaired at a stage of the visual information flow, even simple actions may be significantly delayed and distorted. Indeed, in many neurological disorders, impaired vision is not the primary dominant symptom; however, unsatisfactory visual processing is likely to contribute to difficulties in daily living. Frequently studied relevant problems include consciously controlled visual information processing, sustained and selective attention, planning, problem solving, response selection, and decision making. The clinical syndrome of parkinsonism is characterized by slowly progressive bradykinesia, rigidity, tremor, and postural changes that become disabling. Therefore, Parkinson’s disease (PD) is generally known as a movement disorder due to the dopaminergic deficiency affecting the basal ganglia. However, in recent decades, several studies have demonstrated that beyond or parallel with the progressive motor impairments, nonmotor symptoms are also present, including visuospatial, visual perceptual, visuomotor, and visuocognitive dysfunctions. Visual abnormalities in PD are usually hidden and not likely to be uncovered during a routine neurological examination or even by ordinary high-contrast visual acuity (VA) testing. Most commonly, these nonspecific visual or visuocognitive symptoms are not considered as part of PD, known to be a “movement disorder.” Furthermore, patients are not aware of sensory deficits,

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since they develop very slowly and, if present at all, may be attributed to the underlying aging process. To what extent a visual deficiency can go unnoticed may be evidenced in congenitally color blind subjects. For them, the outside world may look perfect, and they are confronted with their deficiency only when forced to make a direct comparison. In this chapter, visual electrodiagnostic, psychophysical, and imaging data on visual and visuocognitive processing will be described in PD. Impairment of visualspatial working memory and attentional set shifting are already implicated in the early stages of the disease. It will be shown that the dopaminergic dysregulation of prefronto-striatal circuits and the related posterior cortical areas in Parkinson patients lead to higher-level cognitive dysfunctions that are not passively caused by dopaminergic retinal or primary visual cortical impairments. Before the conclusion is made that these impairments represent higher-order cortical and subcortical dysfunctions, the relationship to lowerlevel visual impairments should be critically viewed. PRIMARY VISUAL IMPAIRMENTS IN PD THE ROLE OF DOPAMINE IN RETINAL PROCESSING In the last decades pharmacological studies related to the electroretinogram (ERG) in normal human volunteers and in PD patients have suggested a specific role of dopamine (DA) in retinal processing of visual input.21,37,93,99 Going beyond the limitations of human studies, extensive neuropharmacological and neurotoxicological studies affecting the dopaminergic system in the monkey and lower vertebrates have led to a more detailed understanding of visual impairment in PD. (For a review, see References 17 and 21.) Various types of DA receptors, broadly classified into D1 and D2 subtypes, are located on different neurons of the retina.59 The dual physiologic action of DA on distal D1 and D2 receptors located on neuronal structures has been studied in detail only in the retina of lower vertebrates with larger neurones.36 However, studying the effects of selective DA receptor ligands on massed electrophysiological retinal responses (ERG) in the monkey22 has led to an understanding of the final retinal output in primates due to DA-s push-pull role in mediating centersurround interaction for establishing the receptive field structure of ganglion cells.26 Visual electrophysiological and psychophysical abnormalities, originally observed in PD patients,15,16,62 have also been reported in neuroleptic treated normal volunteers,12 in neuroleptics-induced parkinsonism in humans,53,64 and also in parkinsonian animal models.42–44 Taken together, the results of these studies suggest that dopaminergic deficiency, irrespective of the cause, results in characteristic visual impairment of spatial processing. The deficits are similar in experimental models and in idiopathic PD. EVIDENCE FOR RETINAL AND CORTICAL DOPAMINERGIC DYSFUNCTION IN PD It was originally reported by Bodis-Wollner and Yahr15 that more than half of the examined PD patients had delayed visual evoked potentials (VEPs) (see Figure 23.1). This finding remained controversial until it became clear that the appropriate visual

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stimuli, preferentially Gabor filtered stimulus containing only one spatial frequency, should be used. The widely distributed checkerboard pattern, still ideal because of its robustness for a variety of patients, usually fails to reveal abnormalities in PD. (For reviews, see References 21, 25, and 26.) Now it is apparent that the VEP and pattern ERG (PERG) abnormality in PD is most evident for foveal stimuli of medium and high spatial frequencies (SFs) [above 2 cycles/degree (cpd)] where normal observers are most sensitive for the visual stimuli (see Figure 23.2).18,95,100 Consistent with the results of the electrophysiological studies, in PD, contrast sensitivity (CS) is most reduced above 2 Cpd.19,21,29,33,34,70,88,95,102 However, reduced CS in PD goes undocumented in the majority of patients, as many vision care specialists are not aware of testing for a potentially profound CS deficit in a patient with near normal VA.

FIGURE 23.1 Scatter plot showing the latency of the major positive VEP deflection in 35 patients with PD (triangles) and 26 control subjects (dots). Numerals indicate the number of measurements falling on the same locus. Values for the left and right eye are shown on the ordinate and

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abscissa, respectively. An ellipse has been drawn within which 95% of the normal population would be expected to fall, based on the statistics of the control group (dark dots). Over twothirds of the PD patients are outside the ellipse. (Source: Bodis-Wollner and Yahr,15 with permission of Brain.) Contrast sensitivity loss in PD becomes more profound when the stimulus grating is temporally modulated at 4 to 8Hz,20,68,88 suggesting that a dopaminergic deficiency state also affects distal temporal processing.67 It has been shown, however, that increasing stimulus strength can normalize some select temporal deficits seen in PD patients.8 In summary, the spatial and temporal selectivity of visual losses detected with CS in PD is consistent with the results of electrophysiological tests (PERG and VEP). The interpretation of visual deficits in PD suggests that the disease process causes progressive, select pathology of dopaminergic neuronal processing in the human retina, leading to loss of spatio-temporal tuning and distorted retinal input to higher visual centers. An essential proof of visual system involvement in PD and the relationship of visual and motor changes was recently provided by a longitudinal study of visual dysfunction in PD patients: CS impairs in parallel with the worsening of motor score.34 These results therefore suggest that the visual system shares with the motor system progressive degeneration of dopaminergic neurons and/or progressive failure of the effect of L-dopa therapy. The delay of the P100 component is observed in both de novo and also in treated PD patients using stimuli at middle (2 to 6 cpd) spatial frequencies.49,75,80 It was reported that treated patients can exhibit longer delays.75 This apparently paradoxical result is likely due to the more advanced disease in treated patients, which per se results in worse retinal visual responses.34,100 While both ERG and VEP can improve with therapy, there is an apparent difference: levodopa therapy improves PERG abnormalities to a higher degree than it does VEP deficits.80 One possible interpretation is that VEP changes in PD are secondary to retinal pathology and, at the cortical level, represent chronic and not exclusively dopaminergic alterations in visual processing. However, there is evidence of visual cortical dopaminergic innervation, even in the absence of retinal visual input.86 The question emerges: Is the visual dysfunction really an integral part of PD? It has been observed that the deficit fluctuates with motor symptoms in “on-off” patients19 and worsens with the progression of motor symptoms.34 While the role of DA deficiency is strongly implied by the above-mentioned studies, DA deficiency may not be exclusively responsible for visual changes in PD. For example, a higher onset/offset VEP amplitude ratio was found in PD patients compared to controls using sinusoidal grating as visual stimuli in on-off mode.10 It is known that onset versus offset retinal responses may be separated using selective glutamate receptor blockers.91 The relevance of dopaminergic deficiency or other neurotransmitter alteration, such as the involvement of selective glutamate receptor subtypes in the retina and beyond, in generating the “supernormal” offset VEP in PD is not yet

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FIGURE 23.2 (a) The PERG tuning function in PD: PERG spatial transfer function obtained in patients (squares) and age-matched subjects (diamonds). The functions are parallel at lower SF and very close at the higher SF tested (6.9 cpd). Note lack of tuning of the PERG transfer function in PD. (Source: Tagliati et al.100 with permission of Clinical Neurophysiology.) (b) Effects of Ldopa therapy on PERG amplitude. PERG amplitude obtained in agematched subjects (triangles), PD patients receiving (squares) and not receiving (diamonds) L-dopa are plotted as a function of SF. PD patients receiving L-dopa show higher values and better tuning compared to untreated patients, although they rarely achieve normal values. The dashed line represents the mean noise level during recordings. Error bars indicate SE. (Source: Tagliati et al.100 with

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permission of Clinical Neurophysiology.) established. Although the findings appear robust and intriguing, no other studies have yet compared onset with offset responses on PD. Are Visual Deficits in PD Solely Determined by Retinal Dopaminergic Dysfunction? PERG changes in PD are definitely caused by retinal dopaminergic deficiency.25,57 However, a retinal abnormality may passively cause visual deficits in subsequent processing, or other anatomical areas may also, independently of the retina may be affected in PD. The LGN1 and the visual cortex also have dopaminergic innervation.79,82,86,87 Asymmetrically lateralized primary visual cortex glucose hypometabolism has been demonstrated in PD with the most severe abnormalities contralateral to the most severe motoric dysfunction.28 Although more confirmatory evidence is needed, it is possible that occipital hypometaboism indirectly reflects basal ganglia dysfunction or intrinsic cortical pathology. Pattern orientation dependent CS losses have been reported in PD88 more severe for horizontal than for vertical patterns29 (see Figure 23.3). This finding cannot be due to retinal dopaminergic deficiency; rather, the deficit suggests the presence of intrinsic cortical pathology. However, contrast adaptation, which has a cortical origin, is spared in PD.103 VISUOCOGNITIVE PROCESSING IN PD A correlation between cortical DA innervation and expression of cognitive capacities has been claimed (Nieoullon, 2002).74 Impaired cognitive processing in PD is not surprising, due to the connections and loops110 between the basal ganglia and various sensory cortical areas. However, DA is apparently involved in a more specific manner than just “gating” bottom up visual information flow. Several aspects of consciously controlled information processing, such as planning, problems solving, decision making, and response selection, are associated with the functions of fronto-striatal circuits.41,46,50,65,76,77 A dopaminergic dysreg ulation of this subcortico-cortical system in PD leads to higherlevel cognitive dysfunctions.31,41,69,77,78 Recent electrophysiological, neurophysiological, and functional imaging studies attempt to link cognitive symptoms and specific neuronal circuits of the basal ganglia and its connections.

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FIGURE 23.3 Effect of orientation on visual contrast sensitivity. Ordinates plot CS for flicker perception (filled dots) and for pattern perception (open dots) versus grating orientation (abscissa). Vertical is=deg. and 180 deg. on the abscissa, and horizontal is 90 deg. The vertical bars show the upper normal limits for orientational tuning, and the horizontal arrows show lower normal limits for absolute sensitivities (99% limits). The grating had a spatial frequency of 2 cpd and a temporal frequency of 8 Hz. A= left eye, B=right eye. (Source: Regan and Maxner,88 with permission of Brain.) ELECTROPHYSIOLOGY: THE RELATIONSHIP OF PRIMARY VEP-S AND THE CONCURRENTLY OBTAINED P300 Identifiable positive and negative deflections of eventrelated potentials (ERPs) provide indices for the timing in information processing including stimulus evaluation, response selection, and context updating.63 ERPs are recorded in response to an external stimulus or event to which the subject is consciously paying attention. They are often elicited when the subject distinguishes one stimulus (target) from other stimuli (nontargets). The most extensively studied ERP component is the P300, appearing 300 to 400 ms after the onset of the target stimulus.96 P300 amplitude is maximal at the midline

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electroencephalographic (EEG) electrodes (Cz and Pz) and is inversely related to the probability of the eliciting event. Many visual ERP studies yielded a delayed P300 only in demented PD patients,48,94,98,106,109 although other studies reported a delayed P300 in nondemented PD patients.7,23,24,89,97 This suggests that the slowness of visual information processing may be independent or that it precedes global dementia. LATENCY Comparing the P100 and P300 of the concurrently obtained visual ERP resulted in a somewhat surprising finding in two independent and ethnically different groups of PD patients. A prolongation of the normalized P300 latency (P300-P100 latency difference, called central processing time) differentiated younger PD patients from controls.7,89 These data suggest that younger PD patients could be differentiated from other types of PD using a concurrent VEP and visual P300 recording. Amantidine also shortened the latency of the visual P300 in PD with little or no effect on the primary VEP component.11 AMPLITUDE Few studies have examined P300 amplitude in PD. In general, P300 amplitude increases when more attention is allocated, as in the case of unexpected or in complex tasks. However, it is conceivable that the interpretation of raw amplitude can be misleading, since a nonspecific, agerelated, low-voltage EEG recording could cause low P300 amplitude.7 Measuring the P300/P100 amplitude ratio therefore gives a more reliable measure on the nature of amplitude alterations.7 This individually normalized P300 amplitude provided a significant distinction of younger nondemented PD patients from older patients and from age matched control subjects.7,89 N200 OF THE VISUAL ERP IN PD Apparently, P100 and P300 are independently affected in PD. To localize the stage of visual processing at which this independence becomes established, earlier cognitive ERP components such as N200 were analyzed and showed that this component is also independently changing from P300.7 The visual N200 probably represents a visual form of the auditory mismatch negativity.101 This component is more negative for the infrequent stimuli and distributed over the extrastriate visual areas and the posteriortemporal cortex. N200 latency was delayed in nondemented PD patients, even when P300 was not prolonged using a simple visual paradigm.7 In a semantic discrimination task, a similar result was found.97 These data further suggest that visual deficits and processes indexed by the P300 may reflect processing that is either parallel to or well beyond the interface of bottom-up and top-down visual inputs.32,60

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THE PHARMACOLOGY OF P300: DOES THE P300 ABNORMALITY REPRESENT ONLY DOPAMINERGIC DYSFUNCTION? A study in MPTP-treated monkeys suggests that levodopa therapy alone does not affect the visual P300,44 however D2 receptor blockade can influence the visual P300 in monkeys (see Figure 23.4).6 Cellular electrophysiological evidence shows however that D1 receptors are involved in visual working memory in the prefrontal area (for a review, Reference 47), which was also identified as one of the generators of P300.51 It is therefore conceivable that the synergistic action of D1 and D2 receptors is necessary to improve the visual P300. Levodopa treatment shortens the latency of P300 in PD 92,94 However, some investigators have described a prolonged P300 latency in medicated patients.52,85 One

FIGURE 23.4 ERP traces illustrating the effects of Sulpiride (D2 receptor antagonist) in different time intervals (B=baseline) at centro-parietal registration in a Cynomolgus monkey. Note the increasing latency and amplitude of P300. (Source: Antal et

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al.,6 with permission of Neurosci. Letters.) possibility is that medicated patients are more severely affected, and the P300 correlates with disease severity. Such correlation has not been studied in detail; this question therefore is still open. The modulation of P300 by nondopaminergic agents has been frequently studied in healthy subjects.35,40 Cognitive slowing in PD could also be caused by abnormalities of nondopaminergic systems,83 although there is little direct evidence of correlation of the P300 in PD with cholinergic or other types of neurotransmitter alterations. Pretreatment delayed P300 improved in PD patients following treatment with amantidine, a lowaffinity uncompetitive NMDA receptor antagonist.11 Amantidine is closely related to memantine, advocated for the treatment of cognitive impairment in Alzheimer’s disease. Amantidine’s effect was noticeable not only as a monotherapy, but also in patients treated with levodopa. It is unknown how amantidine exercised this beneficial effect. It is often asserted that amantidine has DA-mimetic properties, and it cannot be therefore excluded that amantidine improves cognitive ERPs in PD as a DA-mimetic agent. IMPAIRMENT OF “COGNITIVE GAMMA SUPPRESSION” IN PD Cognitive processes require the interaction between distributed neuronal groups. The so called “binding hypothesis” (for a review, see Reference 39) essentially assumes that different brain areas have to be “bound” together within very short time intervals so as to solve perceptualcognitive tasks, probably by synchronized or desynchronized activities of neuronal assemblies. The frequency range between 20 and 60 Hz is known as “gammaband” activity. This rhythm exists spontaneously and/or can be evoked, induced, or emitted in different structures of the CNS in response to olfactory, auditory, somatosensory, and visual stimuli or in concomitance with attentional/perceptualcognitive processes. In normal observers, gamma has been shown to accompany primary visual evoked responses and being suppressed during the P300.25,26 Generally, this cortical suppression is thought to reflect competitive hippocampal gamma activation associated with P300 target processing,13 and therefore hippocampal gamma activation may be due to short-term memory updating. However, this suppression does not exist in PD.24 In PD patients the lack of “cognitive” gamma suppression may reflect visuocognitive processing deficits during the performance of the task.24 Cortico-cortical frequency coherence can be modified by L-dopa therapy in PD.30 Using a simple visual tracking task, a coherence increase was found after levodopa therapy whereas, without levodopa, the coherence was much reduced when compared to age-matched normals. It appears that ascending dopaminergic projections from the mesencephalon may modulate the pattern and extent of cortico-cortical coupling in visuomotor tasks. Additionally, it seems that time-frequency analysis of visual ERPs might contribute to differentiate patients with and without hippocampal dysfunction or, more generally, it could help us to better understand of binding of different cortical areas in dysfunctional cognitive processing in PD.

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DOES P300 ABNORMALITY REFLECT WORKING MEMORY IMPAIRMENT IN PD? Working memory (WM) refers to the short-term, attention-demanding maintenance and manipulation of information for purposeful actions.9 WM is closely related to the notions of stimulus-representation matching and decision making. In the previously mentioned experiments, in which classic odd-ball paradigm has been used to elicit the P300 component, a target stimulus has to be stored in the active memory to compare that with subsequently presented stimuli for a same-different decision making. In addition, cortical areas identified as generators of P300 (dorsolateral prefrontal and parietal cortices) have also roles in WM processes.51 One part of the WM system, the visuospatial sketchpad that related to the maintaining of visual information9 shows a specific selective impairment in PD: while the visual subsystem responsible for the object-related visual analysis seems to be spared until the later stages of the disease, the visual processing of spatial location, motion, and three-dimensional properties is impaired.66,72,77,84 In a delayed-response test, PD patients with mild symptoms were unable to briefly maintain the memory trace of spatial locations of irregular polygons, whereas they successfully kept on-line the shapes of the same stimuli.84 PD patients also make significantly more errors in mental rotation of three-dimensional wire-frame figures.72 Wang et al.108 have combined the oddball paradigm with a delayed-response test (S1-S2 paradigm). In this procedure, first a simple geometric design is presented (S1), followed by another (S2) stimulus, which can be the same as S1. P300 is recorded only for S2 stimuli. It was shown that, when the time interval between S1 and S2 increases, nondemented PD patients show particular deficits, suggesting impaired working memory for visual shapes. VISUAL CATEGORIZATION IMPAIRMENT IN PD Categorization, the evocative organization of our surrounding environment, plays a crucial role in our everyday life. Many neuroimaging and electrophysiological studies provided evidence for a discrete categorical organization of the human brain. In particular, there are specific representations of different categories in the occipitotemporal cortex and surrounding areas, such as faces in the occipitotemporal and the fusiform face area,2 human body representation in the lateral occipito-temporal cortex,38 animals in the right fusiform cortex,58 buildings in the right lingual sulcus,3 man-made tools in the left posterior middle temporal cortex,71 and plants in the right lateral occipital cortex.58 Although previous studies have suggested that the visual subsystem responsible for the object-related visual analysis seems to be spared until the later stages of PD,66,72,77,84 recent electrophysiological studies have found that it is not always the case.4,5 Categorization does not occur with the same latency as visual recognition. It was suggested that the basic visual feature encoding and initiating stages of perceptual categorization take place in the first 200 ms post-stimulus period, whereas conceptual and semantic properties are represented in later stages of information processing.55,90 Thorpe and his associates found that non-animal scenes elicited more negative responses than images with animals, even at 150 ms following stimulus onset (N1)105,107 In spite of relatively preserved P100, this difference was not observable in PD patients4,5 (see Figure 23.5). The latter authors have hypothesized that the neostriatum may mediate feature

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weighting and extraction processes and the differential N1 may refer to this function. Consistent with this theory, multi-unit recordings from the basal ganglia of human volunteers revealed different neuronal responses when the subjects were asked to focus on distinct stimulus features. (For review, see Reference 61.) This suggests an attentionbiased stimulus processing in the striatum, mediating the weighting and selecting of behaviorally relevant attributes. In PD, this weighting and selecting process is possibly dysfunctional, as reflected by the diminished differential N1. VISUOMOTOR INTERACTION IN PD: THE POSSIBLE ROLE OF IMPAIRED SACCADES Various, in particular saccadic, eye movement abnormalities have been described in PD.56 Saccadic eye movements bring a new target into center of regard. Synchronized gamma range EEG rhythms of the occipital cortex have been recorded accompanying saccades in healthy subjects,26 whereas, in nondemented PD patients, a desynchronization of the gamma rhythm was observed.24 It is not clear whether this desynchronization occurs as a result of intrinsic visual cortical discrepancy or deficient subcortical input to the cortex. CONCLUSIONS In the last two decades, many specific and nonspecific visual abnormalities in patients with PD were found, such as abnormal PERG tuning,81,94,100 longer latencies in visual evoked potentials,15 and reduced CS mainly in the medium (2 to 5 cpd) spatial

FIGURE 23.5 Grand averaged ERPs for non-animal/distractor and for

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animal/target stimuli in the control group (continuous line) and in the PD group (dotted line). Note that, while there is an amplitude difference of N1 component for distractors, there is no N1 difference for targets. (Source: Antal et al.,4 with permission of Cogn. Brain. Res.) frequencies and 4 to 8 Hz temporal frequency range.19,21,67,68 Improvement of these abnormalities by L-dopa therapy and the animal models of this disorder have established a link between the visual symptoms observed in PD and dopaminergic dysfunction. Beyond these results, recent literature on the electrophysiology, neuropsychology, and functional neuroimaging of PD also suggest that dopaminergic dysregulation of the cortico-subcortical system in PD patients may lead to higher-level visuocognitive dysfunctions. However, the picture is far from complete. The experimental results are often controversial, probably due to the heterogeneity of patients, the different paradigms, and designs of the studies. Additionally, evidence suggests that L-dopa substitution ameliorates these visuocognitive symptoms only in the initial phase of the disease. As the disease advances, dopaminergic treatment seems to be less effective, possibly because of the progressive loss of dopaminergic neurons and because of nondopaminergic deficiencies (noradrenergic, serotonergic, and cholinergic deficits and cortical Lewy bodies) in PD.77,26 Second, based on the available evidence, it is unlikely to find single anatomical loci to be responsible for complex visual deficits. In the last decades, it became obvious that, in visuocognitive processes, distributed parallel pathways, brain areas, and neuronal assemblies are involved according to well organized time plans. For instance, in attempting to explore the visual world, a sequence of visuospatial attentional shift and saccadic eye movements have been evidenced in psychophysical,54 monkey,104 and human fMRI14 studies. In PD, in addition to (or as a consequence of) distal loss of stimulus strength,8 the temporal time keeping may be defective in the visual system.67 It is a challenging thought that, in progressive disorders such as PD, once a critical number of neurons is lost, not only sensitivity to stimuli but also the synchrony of distributed neuronal groups lose the precision needed for task-related cooperation. In summary, it is plausible that, in PD, as a consequence of anatomical dopaminergic lesions, a significant part of visuocognitive impairments reflects temporal dysfunction of distributed neuronal assemblies among the visual, parietal, and frontal areas and the basal ganglia. REFERENCES 1. Albrecht, D., Quaschling, U., Zippel, U., Davidowa, H., Effects of dopamine on neurons of the lateral geniculate nucleus: an iontophoretic study, Synapse, 23, 70–78, 1996. 2. Allison, T., Puce, A., Spencer, D.D., McCarthy, G., Electrophysiological studies of human face perception. I: Potentials generated in occipitotemporal cortex by face and non-face stimuli, Cereb Cortex, 9, 415–30, 1999.

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24 Olfactory Dysfunction in Parkinson’s Disease and Parkinsonian Syndromes Katerina Markopoulou Department of Neurological Sciences, University of Nebraska Medical Center 0-8493-1590-5/05/$0.00+$1.50 © 2005 by CRC Press

ABSTRACT The olfactory system is a complex network whose organization and function depends on both peripheral and central input. It is commonly affected in Parkinson’s disease (PD), parkinsonism-plus syndromes (PPS), other neurodegenerative disorders [e.g., Alzheimer’s disease, (AD)], and in normal aging. Olfactory dysfunction usually appears early in the disease process. In PD, olfactory function is commonly impaired whereas, in PPS, olfactory function is only mildly impaired or preserved. Olfactory function is also impaired in familial forms of parkinsonism associated with a monogenic defect. In contrast to individuals with sporadic PPS, affected members of PPS kindreds do show olfactory impairment. Interestingly, olfactory dysfunction does not appear to be due to a dopamine deficiency. The neuropathological changes in the olfactory system appear to be disease specific. This suggests that olfactory dysfunction in neurodegenerative disorders may reflect a central rather than a peripheral process. The organization of the normal olfactory system is gradually being elucidated at the molecular, cellular, and system levels. The mechanisms underlying olfactory dysfunction in PD and other neurodegenerative diseases remain unknown. OLFACTORY SYSTEM STRUCTURE AND ORGANIZATION The olfactory system is composed of the olfactory epithelium, the olfactory nerves, the olfactory bulbs, the olfactory tracts, and the median and lateral olfactory striae that terminate in the contralateral hemisphere or the ipsilateral amygdaloid nucleus, septal nuclei, and hypothalamus. The olfactory epithelium is located on the superior-posterior aspect of the nasal septum and the lateral walls of the nasal cavity and contains the olfactory sensory neurons (OSNs). The OSNs are generated in situ from stem cells. Aging OSNs are replaced by cell division that persists into adulthood and throughout the adult life. The life span of an OSN is in the range of weeks to months. The OSNs are bipolar neurons, the axons of which form the olfactory nerves and pass through the

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cribiform plate and terminate in the olfactory bulb, where they synapse with secondorder neurons and interneurons. In the olfactory bulb, the OSN axon terminates in a glomerulus, which is a globoid neural structure. The size of the glomerulus differs in different mammalian species. The axons of the secondorder neurons form the olfactory tracts located in the orbital surfaces of the frontal lobes. As it courses centrally, the olfactory tract becomes divided into the median and lateral olfactory striae. In an organization analogous to that of the visual pathways, median stria fibers decussate through the anterior commisure, join fibers from the opposite olfactory tract, and terminate in the contralateral hemisphere, while lateral striae fibers reach the primary olfactory cortex (piriform cortex) and terminate in the ipsilateral amygdaloid nucleus, septal nuclei, and hypothalamus.1 In humans, odor detection of airborne odorants appears to be very efficient, but odor discrimination is considerably less efficient. Olfactory perception is initiated by the activation of odorant receptors by odorous ligands. Airborne odorants stimulate the olfactory sensory neurons (OSNs), contained in the olfactory epithelium. It is thought that the functional heterogeneity of the OSNs is derived from a very large number of odorant receptors (OR) that are expressed in the OSNs. In the last decade, approximately 1000 odorant receptor (OR) genes have been identified in humans. These represent approximately 1% of the human genome. Interestingly, a large subset (almost two-thirds) of these genes appears to be nonfunctional; i.e., they are pseudogenes. The OR genes are distributed in clusters on all chromosomes except chromosome 20 and the Y chromosome. This clustering has been observed in many different species, including mice, rats, zebrafish and humans. There does not appear to be any particular pattern to the clustering of the OR genes, and they can often be intermixed with other gene families such as the T-cell receptor and beta-globin genes. The OR genes are intronless and have open reading frames (ORF) of approximately 1 kb. Based on amino acid similarity they have been categorized into families and subfamilies. The predicted amino acid sequence indicates the presence of seven transmembrane domains, a characteristic of G-protein coupled receptors. Each OSN expresses a single allele of a single OR gene2 and therefore the olfactory epithelium consists of distinct OSN populations (reviewed in References 82 through 84). How is the sensitivity of the OSN translated into the specificity of individual smell? The principles underlying this specificity are still a matter of debate, but some interesting patterns are emerging. Both peripheral and central mechanisms seem to play an important role. In the periphery, specificity appears to be generated both by the OSN expressing a single allele of a single OR gene and by the pattern of connections that the OSN forms. All neurons expressing a single OR gene project axons that synapse in one medial and one lateral glomerulus of the olfactory bulb, which represents the first relay station of the olfactory pathway. It appears that the OR plays a role of organizing the connectivity of the olfactory map.3 The glomerulus containing the second order neurons appears to serve as an “odorant feature detector” via mechanisms involving lateral feedback inhibition and excitation and temporal synchrony. Interestingly, in rodents, voltagesensitive dye imaging has revealed that there are differences in the response latency and the response timecourse across different glomeruli in the olfactory bulb. The pattern of activity at the level of the glomerulus evolves over time and depends also on the identity of the different glomeruli. Both the temporal and the spatial context of the odor-evoked response is

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critical. The temporal patterning may be imposed both by the odor carrier medium, the sampling activity, or by the inherent neural dynamics of the cells comprising the olfactory bulb.4–5 At the system level, it has been proposed that all odors are initially encoded as “objects” in the piriform cortex and that odor perception depends on higher cognitive functions such as memory and neural plasticity.6 Odors have long been thought to be linked to emotional responses, yet an association at the anatomical level has only recently been clearly demonstrated. Studies of patients with focal brain injuries suggest that the caudal orbitofrontal and medial temporal cortices are involved in odor perception. Using event-related fMRI,7 researchers were able to show that responses could be identified in the piriform cortex in a rostrocaudal axis. The amygdala was activated bilaterally by all odors, regardless of valence. In the posterior orbitofrontal cortex, pleasant odors segregated in the medial aspects, whereas unpleasant odors segregated in the lateral aspects. fMRI studies have shown that odors can activate the cerebellum in a concentration-dependent manner.8 These studies provide direct evidence in humans of the heterogeneity of brain regions involved in odor processing and that there is coupling between olfaction, emotion, and higher cognitive processes. At the same time, this heterogeneity of brain regions involved in normal nervous system function indicates its vulnerability in disease states and neurodegenerative processes. In summary, the analysis of the olfactory system at the molecular, cellular, and system levels has identified a rather complicated organization that implicates both peripheral and central components in the function of the olfactory system. The characterization of the olfactory deficit in neurodegenerative disorders—specifically in Parkinson’s disease and parkinsonian syndromes—has the potential to provide significant insights into the function of the olfactory system. Not only should it provide insight into its function in the normal and disease states, it should provide insight into the interplay of different aspects of central nervous system function in neurodegeneration. ASSESSMENT OF OLFACTORY FUNCTION In humans, different methods have been developed to assess distinct aspects of olfactory function, such as odor identification, threshold detection, and odor recognition memory. A number of these methods have achieved widespread use both in the research and clinical domain. A commonly used test is the University of Pennsylvania Smell Identification Test (UPSIT), developed by Doty et al.9–10 Its widespread use is based on the ease of administration, the relatively short completion time and its high test-retest reliability. This test uses 40 odorants that are released by using a pencil to scratch the surface of a strip containing a microencapsulated odorant. The subject is asked to identify each odorant by choosing among four items in a multiple-choice fashion. A simplified version of UPSIT is the CC-SIT developed by Cain and Rubin.11 In that test, odor identification is combined with threshold testing. Threshold testing is performed using plastic squeezebottles containing successive dilutions of n-butanol in water, using 4% n-butanol as the highest concentration. For odor identification, the subjects sniff eight glass bottles containing different odorants and choose in a multiple-choice fashion from a uniform list

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of 16 items. More recently, Hummel et al. developed a new test using a pen-like odordispensing device.12 This test assesses odor threshold (by using nbutanol in a stepwise presentation), odor discrimination (16 pairs of odorants and triple-forced choice), and odor identification (by using 16 common odorants and a multiple forced-choice from among four verbally stated options per odorant). Other tests include the San Diego Odor Identification Test,13 the Scandinavian Odor Identification test,14 the Viennese Olfactory Test Battery15 and Smell Threshold Test.16 Olfactory event-related potentials (OERP) have been recorded in control and affected individuals in response to randomized stimulation with different odorants and the OERP latencies have been determined in control and affected individuals.17 Statistical reliability of the OERP was established by Thesen et al.,18 and it was shown that reliability of OERPs is comparable to that of visual and auditory evoked potentials. The generators for the OERP waveforms are not known. The early waveform (P1) is thought to originate in the olfactory bulb and the late waveform (P3) in the olfactory cortex.19 To determine whether anatomical changes are associated with olfactory dysfunction, endoscopic techniques have been developed to obtain olfactory epithelium from human subjects under either general or topical anesthesia.21,22 The tissue is examined by light and/or electron microscopy and histochemistry.23 The usefulness of this procedure is limited, since it is invasive and may require general anesthesia. The olfactory epithelium and the anterior olfactory nucleus can also be obtained postmortem and examined histologically and histochemically.24 In summary, a number of methods are currently available to assess olfactory function in humans. The choice of method depends on the ease of administration and on the aspect of olfactory function that is being assessed. OLFACTORY DYSFUNCTION IN NORMAL AGING A number of studies have shown that olfactory function is affected by aging.25–27 Olfactory impairment associated with normal aging involves odor identification, threshold detection,26 and odor recognition memory.28 Olfactory function declines after age 65 and is severely affected after age 80. Interestingly, in women, olfactory impairment appears later than in men.25 It is useful to consider olfactory dysfunction contextually in light of findings that the olfactory epithelium undergoes continuous regeneration throughout development and adult life. A number of endogenous and exogenous mechanisms are implicated in maintaining a balance between regeneration and degeneration. Recently, Wu et al.29 have shown that signals from neurons within the olfactory epithelium have the ability to inhibit the generation of new neurons by neural progenitors. In more general terms, it appears that neural repair of the mature CNS may be inhibited by the cellular and molecular microenvironment.30 It is not clear what the role of these mechanisms is in aging or neurodegenerative disease. Cumulative exposure to environmental toxins, chemicals, upper respiratory viral infections, or head injury could contribute to gradual olfactory impairment by interfering with the endogenous mechanism of regeneration.

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OLFACTORY DYSFUNCTION IN PARKINSON’S DISEASE (PD) Olfactory dysfunction has been clearly demonstrated in sporadic PD. Olfactory dysfunction in this disorder includes impairment in odor identification, threshold detection, and odor recognition memory.31 It has been shown that olfactory dysfunction is present early in the disease process and appears to remain stable as the disease progresses.32 Studies have attempted to correlate olfactory dysfunction with disease parameters such as disease stage, duration, subtype, cognitive dysfunction, and therapy. Interestingly, olfactory dysfunction appears to be independent of disease stage and disease duration.32 In contrast, olfactory dysfunction appears to be dependent on disease subtype, suggesting that disease subtype confers the specificity of the olfactory impairment. In a study by Stern et al., olfactory function was assessed in different PD subtypes.33 Olfactory function was more impaired in advanced PD (Hoehn and Yahr stage III or greater) than early PD (Hoehn and Yahr stage II or less for four or more years). Both postural instability-gait disorder (PIGD) predominant PD (defined as UPDRS mean tremor score/mean PIGD score 1.5) subtypes exhibited olfactory impairment, but the impairment was more severe in the PIGD form than in the tremor predominant form of PD. It is conceivable that differences in the degree of olfactory impairment between the disease subtypes may reflect different pathophysiological processes in the two disease subtypes. The olfactory deficits associated with PD appear to be independent of the cognitive dysfunction associated with the disease.34 Olfactory dysfunction in PD is bilateral and does not respond to antiparkinsonian therapy.35 Olfactory impairment in PD has been attributed to the pathological changes, including neuronal loss and the presence of Lewy bodies identified in the olfactory cortex24 and the amygdala.36 Interestingly, sniffing impairment appears to contribute to the olfactory impairment in PD.8 OLFACTORY DYSFUNCTION IN PARKINSONISM-PLUS SYNDROMES (PPSs) Olfactory function has also been assessed in multiple system atrophy (MSA), Shy-Drager syndrome,37–38 progressive supranuclear palsy (PSP),38–39 and the parkinsonismdementia complex of Guam.40 Wenning et al.38 compared olfactory dysfunction in a large series of patients with either PD, MSA, corticobasal degeneration (CBD), or PSP. They showed that impairment of olfactory function was significantly more pronounced in PD than in PPS. In particular, olfactory impairment was mild in MSA, whereas olfactory function was preserved in CBD and PSP The findings from a study by Muller et al. (2002) appear to confirm this difference in olfactory impairment between sporadic PD and PPS.41 Additional studies have also demonstrated normal olfactory function in PSP.39 This consistent difference in olfactory function can therefore be used as an aid in the differential diagnosis of PD and PPS. Olfactory dysfunction has also been reported in the ALS-parkinsonism-dementia complex of Guam (PDC).42 All four forms of the syndrome (ALS, pure parkinsonism, pure dementia, and parkinsonism-dementia complex) show impairment of olfactory

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function. This suggests a common mechanism of olfactory impairment in the different forms of the syndrome. There are no significant differences in the degree of the olfactory impairment in PD and PDC, making it impossible to distinguish these two entities on the basis of olfactory impairment.40 In contrast to what is seen in the sporadic forms of PPS, olfactory function is impaired in familial forms of PPS. Affected members of PPS kindreds show impairment similar to that seen in kindreds with idiopathic PD (IPD) phenotypes. Markopoulou et al.43 assessed olfactory function in several multigenerational kindreds with an IPD phenotype as well as in kindreds with a PPS phenotype. Olfactory dysfunction appears to be a component of the clinical phenotype in kindreds types of kindreds. No statistically significant differences in the degree of olfactory impairment were observed between these two phenotypes. Thus, it appears that, in regard to olfactory function, sporadic and familial forms of PD and PPS behave differently. Three different genes are associated with the forms of parkinsonism assessed by Markopoulou et al. One is the α-synuclein gene (Family H),43 a second is the gene for the microtubule-associated protein tau (pallido-pontonigral degeneration, PPND Family),44 and the third is an as-yet unidentified gene on chromosome 2pl3.45 The expression of αsynuclein, along with that of its congeners β- and γ-synuclein, has been assessed in the olfactory mucosa of patients with PD, Lewy body disease, MSA, AD, and healthy controls.46 While the synucleins are differentially expressed in the olfactory epithelium, and α-synuclein is the most abundantly expressed protein, there is no significant difference between affected individuals and healthy controls. However, it is conceivable that α-synuclein may play a role in the regeneration of the olfactory epithelium. This hypothesis is supported by other studies in which α-synuclein has been implicated in neuronal survival.47–48 To summarize, the presence of olfactory dysfunction in familial forms of parkinsonism associated with a monogenic defect suggests that genetic factors either directly or indirectly underlie olfactory dysfunction. OLFACTORY DYSFUNCTION IN ATYPICAL PARKINSONIAN SYNDROMES (PPSs) Olfactory function has been assessed in other atypical parkinsonian syndromes such as MPTP-induced parkinsonism. In this entity, olfactory function is preserved.49 Olfactory function is also preserved in two syndromes that may be associated with PD, essential tremor,50–51 and idiopathic restless leg syndrome.52 While in sporadic forms of these syndromes, they appear to behave as independent disorders; in familial forms of PD, PD and essential tremor phenotypes appear to be associated at the genetic level and possibly reflect differential expressivity of the same monogenic defect.53

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OLFACTORY DYSFUNCTION IN OTHER NEURODEGENERATIVE DISEASES Perhaps not surprisingly, olfactory function is impaired in other neurodegenerative diseases such as Alzheimer’s disease (AD),15,19,31 motor neuron disease (MND),54–56 and Huntington’s disease (HD).57–60 In AD, the olfactory impairment appears to occur early in the disease process.61 Interestingly, the ApoE epsilon-4 allele, a known risk factor for AD, appears to correlate with cognitive impairment and odor identification decline.62,63 A meta-analysis of studies of olfactory function in AD and PD31 suggests that olfactory impairment is relatively uniform in these diseases. This is consistent with the phenotypic overlap observed in the clinical manifestations of AD and PD. However, interesting differences exist in the olfactory impairment between AD and PD. In both PD and AD, odor identification is impaired,64 but AD patients showed a higher olfactory threshold and poorer odor memory performance. In AD, olfactory impairment also appears to be a function of disease duration,64 whereas this is not the case in PD.32 In AD, the olfactory bulb, AON, piriform cortex, amygdala, and hippocampus show neurofibrillary tangles and amyloid plaques.65– 67 In PD, there is neuronal loss and Lewy bodies (LB) in the AON. The LB, however, resemble more the cortical than the nigral LB.24 In addition, there are specific changes in the amygdala of PD patients.68 In motor neuron disease, the reports are somewhat conflicting. Some studies report olfactory impairment,54–55 while others do not.56 This could reflect selection bias and heterogeneity in the patient cohorts included in those studies. In HD, the olfactory deficit is found only in affected individuals and not in genepositive asymptomatic individuals.58 The olfactory deficit involves primarily impairment of olfactory detection and odor identification but not odor recognition memory. As in AD and PD, the olfactory deficit in HD appears early in the disease process.59–60 A list of the neurodegenerative diseases associated with olfactory impairment associated discussed in this chapter is presented in Table 24.1.

TABLE 24.1 Olfactory Function in Neurodegenerative Diseases Disease

Olfactory Function

Parkinson’s disease Impaired Lewy body disease Impaired Familial Parkinson’s disease (both IPD and PPS phenotypes) Impaired Progressive supranuclear palsy Preserved Multiple system atrophy Mildly impaired Corticobasal ganglionic degeneration Preserved Parkinsonism-dementia of Guam Impaired MPTP-induced Parkinsonism Preserved Essential tremor Mildly-moderately impaired

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Impaired Impaired/preserved Impaired

OLFACTORY DYSFUNCTION IN THE CONTEXT OF CURRENT KNOWLEDGE OF NORMAL OLFACTION The mechanism(s) underlying olfactory dysfunction in neurodegenerative diseases and normal aging have not yet been elucidated. However, a considerable body of information has accumulated over the last decade regarding the function of the olfactory system at the molecular, cellular, and system levels, both at the periphery and centrally. While several aspects of olfactory system function remain a mystery, a more complete understanding of the complex organization of the olfactory system is emerging from these analyses. We now know that in the periphery, olfaction is initiated by binding of an odorous ligand to the ORs that are expressed in olfactory neurons (ORN), located within the olfactory epithelium. The ORs reflect the first organizational level at which specificity is established, as each neuron expresses only one receptor type. The spatial organization of the neurons that express one type of receptor in the olfactory epithelium reflects the second organizational level at which specificity is established. The third level of organization occurs at the olfactory bulb where the second-order neurons form connections in specific stereotypic sites in the olfactory bulb. The axons of firstorder neurons form heterogeneous fascicles that defasciculate in the olfactory bulb and refasciculate with neurons expressing the same OR. Both permissive and inhibitory cues may contribute to this organizational process. This axon targeting may constitute another level of organization. Finally, behaviorally induced plasticity in the olfactory bulb may add yet another level of organizational complexity.69 It will be important to understand whether the neurodegenerative process affects one or more levels of organization and the associated functions of the olfactory system. Since the establishment of an association of olfactory dysfunction with PD and other neurodegenerative diseases, two broadly crafted, alternate hypotheses have been proposed to account for the nature of the olfactory deficits. According to the first hypothesis, the observed olfactory impairment is due to peripheral processes such as environmental insults to the olfactory system. According to the second hypothesis, the olfactory impairment is due to central processes. Support for the second hypothesis is provided by the fact that in both PD and AD the olfactory system appears to be affected in a disease-specific manner. In patients with autopsy-proven PD, the AON contains dystrophic neurites and Lewy bodies (LBs). These LB are morphologically more similar to cortical than to nigral LB.70 In addition, there is considerable neuronal loss in the AON. The degree of neuronal loss correlates strongly with disease duration.24 This is in apparent contradiction with the observation that olfactory dysfunction is independent of disease duration in PD. In AD, neurofibrillary tangles and amyloid plaques are seen in the AON. PD-specific pathology is also observed in the amygdala.68 The amygdala is part of the limbic system and forms a large number of connections with the hippocampus and the entorhinal cortex as well as the neocortex. It is involved in memory, behavior, and regulation of endocrine and autonomic function and olfaction. In the amygdala, the

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neuropathological changes appear to accumulate slowly over time as the disease progresses. However, in PD patients, the severity of amygdala involvement appears to be independent of cognitive deficits.68 Furthermore, the olfactory bulb is rich in dopamine neurons, and a physiological role for dopamine in the olfactory bulb has been demonstrated in the rat olfactory system. Dopamine suppresses the electrical activity of mitral cells,71 and the olfactory bulb is also rich in dopamine receptors (both D1 and D2). In the olfactory bulb, there is a differential distribution pattern of the dopamine receptors.72 Recently, it has been demonstrated that, in the rat olfactory bulb, dopamine receptor subtypes can modulate the response of GABAA receptors and could be instrumental in odor detection, odor discrimination, and olfactory learning.73 Interestingly, in clinical studies, the olfactory dysfunction observed in PD appears not to be a manifestation of dopamine deficiency,74 olfactory func-tion was assessed in a small series of hyposmic PD patients before and after the administration of apomorphine, a potent, short-acting dopamine agonist, and no difference was observed. While the numbers of parkinsonian individuals tested in this study was small, the fact that olfactory dysfunction appears to be independent of disease stage or duration32 provides indirect support for this hypothesis. However, this may also be explained by the fact that the early appearance of symptoms of olfactory dysfunction may reflect a threshold phenomenon that is achieved earlier in the olfactory system than in other areas of the CNS. The complexity of the olfactory system’s organization and its extensive connections to many cortical regions, the basal ganglia, and cerebellum suggest that defects in any of a number of different molecular, cellular, or physiological processes may lead to olfactory dysfunction at the level of odor discrimination, recognition, and memory. In humans, many olfactory receptor genes (approximately 72%) are nonfunctional and are distributed on nearly all chromosomes. A large number of olfactory receptor genes are found in telomeric chromosomal regions.75 Given the association of telomere length with senescence76 as well as the known association of olfactory dysfunction with aging, it is tempting to speculate that the telomeric location of OR genes may make them more prone to deletion/inactivation that may in turn lead to age-dependent olfactory dysfunction. It is unclear whether such a process might play a role in the mechanisms underlying olfactory dysfunction associated with PD and neurodegenerative diseases. System-level approaches have provided a valuable perspective on the role of central mechanisms in the development and function of the olfactory system. It is thought that the brain can determine which neurons are excited by analyzing a topographic map in the olfactory bulb.78 Activity-dependent mechanisms and stimulus-specific synchronization of neuronal groups may be involved in olfactory processing.79–80 Network dynamics can also be instrumental by creating odor representation and optimizing their distribution. Both slow, nonperiodic processes and fast, oscillatory processes may contribute to the coding that is inherent in the olfactory system.81 It will be important to understand whether and how these central mechanisms are altered in neurodegenerative disease.

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CONCLUDING REMARKS AND FUTURE DIRECTIONS In conclusion, olfactory dysfunction is a consistent feature of PD and other neurodegenerative diseases. The molecular and cellular mechanisms underlying the disease-specific dysfunction remain unclear. The specificity of the neuropathological changes observed in the olfactory system in these diseases suggest that olfactory dysfunction is a result of the specific neurodegenerative process. It further suggests that disruption of the olfactory system at potentially different levels and by potentially different mechanisms can lead to the same end result. In considering the complexity of the olfactory system and its connections, as well as the complexity of CNS involvement in PD and other neurodegenerative diseases, it seems a daunting task to systematically address the mechanism(s) underlying olfactory dysfunction and its relationship to neurodegeneration. For example, how does the different neuropathology of AD and PD result in a similar olfactory deficit? Given the specificity of neuropathological changes in the olfactory system in both PD and AD, a central process would appear more likely. A possible route of inquiry could make use of familial cases of PD, PPS, and AD where the genetic defect is known. A more systematic and extensive assessment of different aspects of olfactory function in such cases may provide significant insights into which particular olfactory deficit(s) are associated with which gene defect. The study of the olfactory system in neurodegeneration offers a unique arena in which to employ a combination of analytical approaches at the molecular, cellular, physiological, and system levels. This uniqueness is not system-specific but, rather, the result of simultaneous advances in many scientific fronts. An important advance is the identification of the primary genetic defect in a number of neurodegenerative disorders. Another important advance is the development of genomic and proteomic analyses in which the simultaneous expression of thousands of genes in different tissues including brain tissue can be analyzed (e.g., using microarrays). Another advance is the analysis of the olfactory system by a dynamical systems approach that has led to significant insights into the organization and complexity of the olfactory system. Finally, the advent of functional imaging, including fMRI and PET, allows the in vivo functional characterization of olfaction and related higher cognitive processes in normal and diseased states. Understanding how the olfactory system is affected by neurodegeneration will require a synthesis of these conceptually different approaches. The field is in a particular moment in its development that a synthesis will open up new insights into both the functional understanding of the olfactory system as well as the neurodegenerative process. REFERENCES 1. Brazis, P.W., Masdeu, J.C., Biller, J., Localization in Clinical Neurology, 3rd ed., Little, Brown and Company, Boston, MA, p.p. 109–114, 1996. 2. Buck, L.B., The molecular architecture of odor and pheromone sensing in mammals, Cell, 100:611–618, 2000.

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45. Gasser, T., Muller-Myhsok, B., Wszolek, Z.K., Oehlmann, R., Calne, D.B., Bonifati, V., Bereznai, B., Fabrizio, E., Vieregge, P., Horstmann, R.D., A susceptibility locus for Parkinson’s disease maps to chromosome 2p13, Nat. Genet., 18:262–265, 1998. 46. Duda, J.E., Shah, U., Arnold, S.E., Lee, V.M., Trojanowski, J.Q., The expression of alphabeta- and gamma synucleins in olfactory mucosa from patients with and without neurodegenerative disease, Exp. Neurol., 160:515–522, 1999. 47. Kaplan, B., Ratner, V., Haas, E., Alpha-synuclein: its biological function and role in neurodegenerative diseases, J. Mol. Neurosci., 20:83–92, 2003. 48. Lucking, C.B., Brice, A., Alpha-synuclein and Parkinson’s disease, Cell Mol Life. Sci., 57:1894–1908, 2000. 49. Doty, R.L., Singh, A., Tetrud, J., Langston, J.W., Lack of major olfactory dysfunction in MPTP-induced parkinsonism, Ann. Neurol., 32:97–100, 1992b. 50. Busenbark, K.L., Huber, S.J., Greer, G., Pahwa, R., Koller, W.C., Olfactory function in essential tremor, Neurology, 42:1631–1632, 1992. 51. Louis, E.D., Bromley, S.M., Jurewicz, E.C., Watner, D., Olfactory dysfunction in essential tremor, Neurology, 59:1631–1633, 2002. 52. Adler, C.H., Gwinn, K.A., Newman, S., Olfactory function in restless leg syndrome, Mov. Disord., 13:563–565, 1998. 53. Farrer, M., Gwinn-Hardy, K., Muenter, M., Wavrant,DeVrieze F., Crook, R., Perez-Tur, J., Lincoln, S., Maraganore, D., Adler, C., Newman, S., MacElwee, K., McCarthy, P., Miller, C., Waters, C., Hardy, J., A chro mosome 4p haplotype segregating with Parkinson’s disease and postural tremor, Hum. Mol. Genet., 8:81–85, 1999. 54. Elian, M., Olfactory impairment in motor neuron disease: a pilot study, J. Neurol. Neurosurg. Psychiatry, 54:927–928, 1991. 55. Sajjadian, A., Doty, R.L., Gutnick, D., Chirurgi, R.J., Sivak, M., Perl, D.O.,(1994) Olfactory dysfunction in amyotrophic lateral sclerosis, Neurodegeneration, 3:153–157, 1994. 56. Hawkes, C.H., Shephard, B.C., Geddes, J.F., Body, G.D., Martin, J.E., Olfactory disorder in motor neuron disease, Exp. Neurol., 50:248–253, 1998. 57. Nordin, S., Paulsen, J.S., Murphy, C., Sensory- and memory-mediated olfactory dysfunction in Huntington’s disease, J. Int. Neuropsychol. Soc., 1:281–290, 1995. 58. Bylsma, F.W., Moberg, P.F., Doty, R.L., Brandt, J., Odor identification in Huntington’s disease patients and asymptomatic gene carriers, J. Neuropsychiatry Clin. Neurosci., 9:598–600, 1997. 59. Moberg, P.J., Doty, R.L., Olfactory function in Huntington’s disease patients and at-risk offspring, Int. J. Neurosci., 89:133–139, 1997. 60. Hamilton, J.M., Murphy, C., Paulsen, G.S., Odor detection, learning and memory in Huntington’s disease, J. Int. Neuropsychol. Soc., 5:609–615, 1999. 61. Christen-Zaech, S., Kraftsik, R., Pillevuit, O., Kiraly, M., Martins, R., Khalili, K., Miklossy, J., Early olfactory involvement in Alzheimer’s disease, Can. J. Neurol. Sci., 30:20–25, 2003. 62. Wang, Q.S., Tian, L., Huang, Y.L., Qin, S., He, L.Q., Zhou, J.N., Olfactory identification and apolipoprotein E epsilon 4 allele in mild cognitive impairment, Brain Res., 951:77–81, 2002. 63. Graves, A.B., Bowen, J.D., Rajaram, L., McCormick, W.C., McCurry, S.M., Schellenberg, G.D., Larson, E. B., Impaired olfaction as a marker for cognitive decline: interaction with apolipoprotein E epsilon 4 status, Neurology, 53:1480–1487, 1999. 64. Lehrner, J. P., Brucke, T., Dal-Bianco, P., Gatterer, G., Kryspin-Exner, I., Olfactory functions in Parkinson’s disease and Alzheimer’s disease, Chem. Senses, 22:105–110, 1997. 65. Hyman, B.T., Arriagada, P.V., Van Hoesen, G.W., Pathologic changes in the olfactory system in aging and Alzheimer’s disease, Ann. N.Y. Acad. Sci., 640:14–19, 1991. 66. Reyes, P.F., Deems, D.A., Suarez, M.G., Olfactoryrelated changes in Alzheimer’s disease: a quantitative neuropathologic study, Brain Res. Bull., 32:1–5, 1993. 67. ter Laak, H.J., Renkawek, K., vanWorkum, F., P., The olfactory bulb in Alzheimer’s disease: a morphologic study of neuron loss, tangles and senile plaques in relation to olfaction, Alzheimer’s Dis. Assoc. Disord., 8:38–48, 1994.

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25 Gastrointestinal Dysfunction in Parkinson’s Disease Ronald F.Pfeiffer Department of Neurology, University of Tennessee Health Science Center 0-8493-1590-5/05/$0.00+$1.50 © 2005 by CRC Press

INTRODUCTION Although gastrointestinal (GI) dysfunction is conventionally referred to as one of the “nonmotor” features of Parkinson’s disease (PD), this is actually somewhat of a misnomer. Many (though certainly not all) aspects of GI function are clearly motor in character, and it is the more obscure sensory aspects of GI function that are often overlooked with regard to involvement in disease processes. What does distinguish GI dysfunction from the traditional motor features of PD is that the motor systems involved belong primarily, though not exclusively, to the autonomic and enteric, rather than somatic, nervous systems, and the muscles affected by the nervous system dysfunction are largely (though once again not exclusively) of the smooth, rather than striated, type. Awareness of GI dysfunction in the setting of PD dates all the way back to James Parkinson and his remarkable 1817 treatise, in which he very clearly and concisely identified so many of the features of PD recognized today, including those involving the GI system. He described drooling (and even was aware that it is due to disordered swallowing), “…the saliva fails of being directed to the back part of the fauces, and hence it is continually draining from the mouth…”; dysphagia, “…food is with difficulty retained in the mouth until masticated; and then as difficultly swallowed…”; and bowel dysfunction, including both constipation, “…the bowels which had all along been torpid, now in most cases, demand stimulating medications of very considerable power…” and defecatory dysfunction, “…the expulsion of the feces from the rectum sometimes requiring mechanical aid.”1 In the years that followed, however, other neurological masters paid perfunctory attention, at best, to the GI features of PD. Romberg briefly mentions difficulty chewing, drooling, dysphagia, and constipation in his description of PD,2 while Charcot provides only passing mention of dysphagia and drooling,3 and neither Hammond nor Gowers, in their textbooks of neurology, mention the GI features of PD at all.4,5 In fact, very little mention of GI dysfunction in PDsurfaces in the post-Parkinson neurological literature until 1965, when Eadie and Tyrer 6 published their analysis of GI dysfunction in 107 patients with parkinsonism, 76 of whom had been diagnosed with idiopathic PD. A group of comparably aged persons with “acute orthopedic” disorders

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served as controls. Masticatory difficulty, drooling, dysphagia, frequent “heartburn,” and constipation were found to be present more often in individuals with PD than in controls. Study of the GI aspects of PD then devolved again into relative dormancy until 1991, when Edwards and colleagues resurrected interest in the topic with their survey of 98 patients with PD and 50 comparably aged spousal controls.7 The GI features they identified in this and expanded upon in a subsequent series of reports8–16 closely parallel those identified by both Eadie and Tyrer and by Parkinson himself, and include disordered salivation (drooling), dysphagia, nausea, constipation (decreased bowel movement frequency), and defecatory dysfunction (difficulty with the act of defecation). Other investigators have also subsequently contributed immensely to the expanding literature on the GI features of PD. This burgeoning literature is reviewed in this chapter. GI ANATOMY AND PHYSIOLOGY The GI system, like the nervous system, performs its vital tasks largely hidden from view and without conscious planning or effort (eating and evacuating being the obvious exceptions). It encompasses a rather astounding length and surface area between its oral and anal portals. Just as the study of the nervous system has been slowed by its complexity and inaccessibility, so has study of the GI system in many respects. While the function of the GI system seems quite straightforward—to process and absorb nutrients necessary for function, while eliminating waste—the control and coordination necessary between the nervous system and the GI system and within the GI system itself to perform this function is remarkably complex. The oral cavity is the jumping off point for the journey food and drink take through the GI system. In the mouth, the teeth and masticatory muscles combine to grind and macerate food, mixing it with salivary gland secretions for lubrication and initiation of digestion. The tongue then forms the food into a bolus and propels it backward to the pharyngeal inlet where, in a piston-like action, it delivers the bolus into the pharynx. The act of swallowing itself is a surprisingly intricate and complex action that is partly voluntary, partly reflex in character and is carried out by a combination of 26 pairs of pharyngeal and laryngeal muscles (not counting muscles used for chewing) under the control of 5 cranial nerves.17 Swallowing is traditionally divided into three components: oral, pharyngeal, and esophageal. The oral component, described above, is largely under voluntary control, while the pharyngeal and esophageal phases are principally reflexive in character. The reflex component of swallowing is coordinated at a brain-stem level by central pattern generators within the medial reticular formation of the rostral medulla and the reticulum adjacent to the nucleus solitarius, which contain the neural programs that conduct the symphony of swift, sequential movements of the oral, pharyngeal, and esophageal musculature that seal off the nasal passages and trachea while the upper esophageal sphincter (UES) relaxes and allows the food bolus to enter the esophagus.18,19 The volitional component of swallowing reflects involvement of the motor cortex and additional centers in the supplementary motor cortex, insula, and cerebellum.20 The esophagus is a tube, 18 to 26 cm in length, whose lumen is collapsed when not swallowing but can distend to several centimeters in diameter to accommodate food

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being swallowed.21 Esophageal muscle composition, which consists of an inner circular muscle layer and an outer longitudinal layer, can be roughly divided into thirds: the proximal third (some report this as only 5%22) primarily striated muscle, the distal third smooth muscle, and the middle third of a mixture of the two. The UES is striated muscle, while the lower esophageal sphincter (LES) has a smooth muscle composition. Both are contracted at rest; contraction of the UES prevents air from entering the esophagus, while contraction of the LES prevents reflux of stomach contents into the esophagus. Esophageal skeletal muscle is under control of motor neurons originating in the nucleus ambiguus in the brain stem, while smooth muscle in the middle and distal esophagus is under autonomic direction with parasympathetic innervation from the dorsal motor nucleus of the vagus and sympathetic from the intermediolateral column in the spinal cord. The autonomic efferent fibers do not actually synapse on the muscle cells in the esophagus but, rather, on ENS neurons in Auerbach’s plexus. The stomach is a reservoir that serves several functions in the digestive process. It accommodates and stores food while grinding the solid particles down to appropriately small size, finally releasing the processed contents in a controlled fashion into the small intestine. In adults, the stomach typically has the capacity to hold 1.5 to 2.0 L of material. The grinding and propulsive movements of the stomach originate from “gastric pacemaker” cells at a site along the greater curvature of the stomach, which generate gastric slow waves at a rate of approximately three per minute.23 The pacemaker cells have been identified as interstitial cells of Cajal (ICCs), which are a component of the ENS. The next destination on the route through the GI tract is the small intestine, which is divided into three segments (duodenum, jejunum, and ileum) and in adults reaches the rather astounding length of approximately 6 m.24 The small intestine is responsible for absorption of nutrients, salt, and water. Motility within the small intestine is produced by contractions of the circular and longitudinal muscle layers that compose the intestinal walls. As in the stomach, ICCs generate electrical slow waves that serve a pacemaker function and migrate in an aborad direction. When spike bursts are superimposed on the slow wave, actual muscle contraction occurs, which then travels for an undetermined, but probably short, distance in either direction along the small intestine. Two distinct patterns of small intestinal motor function have been identified.25 The fed (postprandial) pattern, which appears within 10 to 20 min following a meal, is characterized by more segmental, and less propulsive, contractions that assist in the mixing of digestive enzymes with the chyme and maximize mucosal contact, thus promoting nutrient absorption. The second pattern, termed the fasting (interdigestive) pattern, appears 4 to 6 hr after a meal and is divided into three phases. The first is a period of relative motor quiescence, followed by increasingly prominent contractions in the subsequent two phases that presumably serve to “flush” solid residues from the small intestine, which prevents bezoar formation and minimizes bacterial accumulation. This complex pattern of small intestinal motility is under the direct control of the ENS but modulated by both autonomic and hormonal influences. The colon, approximately 1.0 to 1.5 m in length in adults, is composed of the same two muscle layers—circular and longitudinal—found in the small intestine.24,26 The ileocecal valve, which divides the colon from the small intestine, is not a true sphincter but still effectively regulates colonic filling and prevents colo-ileal reflux. The colon

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stores material marked for excretion and performs an important role in the regulation of fluid, electrolyte, and short-chain fatty acid absorption. It can increase fluid absorption up to fivefold in appropriate circumstances. As in the stomach and small intestine, ICCs perform a pacemaker function in the generation of the pressure waves that regulate colonic motility. For the most part, motor control of colonic motility is directly mediated through the ENS but modulated by the ANS. Parasympathetic innervation of the ascending and transverse colon is vagal in origin, while the descending and rectosigmoid regions receive their innervation via the pelvic nerves. Sympathetic supply to the colon originates in the thoracic spinal cord and reaches the colon via the inferior mesenteric and pelvic plexuses. Sympathetic activity produces vasoconstriction of mucosal and submucosal blood vessels, downregulates motility, and inhibits secretion (thus limiting water loss), while parasympathetic activity increases enteric motor activity and colonic motility.26 The rectum serves to store feces until a convenient opportunity to evacuate its contents is reached. Egress from the rectum is blocked by the internal and external anal sphincter muscles, which are tonically contracted. In the rectum, the longitudinal smooth muscle layer, which in the colon had been concentrated into the muscle bands called taenia, spreads out into an encircling sheath; the internal anal sphincter (IAS) consists of smooth muscle that is continuous with the circular muscle layer of the rectum.26 In contrast, the external anal sphincter (EAS) is a band of striated muscle distal to the IAS. The IAS is under autonomic control via the pelvic plexus; the EAS under the control of motor neurons in the sacral spinal cord via the pudendal nerve. The puborectalis muscle also contributes to the maintenance of fecal continence by means of tonic contraction that pulls the rectum anteriorly, forming an anorectal angle that impedes rectal emptying.27 The act of defecation is characterized by relaxation of the two anal sphincters and the puborectalis muscle, which results in a straightening or opening of the anorectal angle, and by contraction of the glottic, diaphragmatic, and abdominal wall muscles, which elevates intra-abdominal pressure and encourages evacuation of the rectal contents. CLINICAL FEATURES WEIGHT LOSS Progressive weight loss is a frequent feature of PD. Although generally mild, in a minority of individuals, it can reach alarming proportions. In one study, weight loss was observed in 52% of PD patients, with loss of over 28 lb in 22%.28 In another study, individuals with PD were four times as likely as controls to report weight loss of greater than 10 lb.29 In some studies, the weight loss correlates with disease progression,29 but in a recent study using data from two large prospective cohorts, Chen and colleagues discovered that weight loss in PD often begins even before the conventional motor features are identified.30 In the 174 individuals with PD in their study, the average weight loss was 5.2 lb in the 10 years prior to diagnosis and 7.7 lb in the 8 years following diagnosis. The bulk of the prediagnosis weight loss occurred in the 4 years immediately prior to diagnosis.

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Obscurity shrouds the explanation for weight loss in PD. For weight loss to occur in anyone, there must be either reduced energy intake or increased energy expenditure. In a dialog reminiscent of the well known beer commercial (more taste!—less filling!) theories and evidence favoring each mechanism have been advanced with regard to the PD patient. Reduced energy intake can be the result of either reduced food intake or impaired food absorption. A bevy of factors, such as difficulty manipulating silverware, slowed chewing, and impaired swallowing, may incline PD patients to consume less food, while olfactory impairment may make food less enticing. However, when dietary intake has actually been assessed in PD patients, no significant differences from controls have been noted,28,31 and increased energy intake has actually been noted in some studies.30–32 Although intestinal absorption has not been extensively studied in PD, malabsorption has not been a generally recognized feature. However, using the differential sugar absorption test, Davies and colleagues found that PD patients displayed reduced mannitol, but not lactulose, absorption, suggesting impairment of nonmediated uptake across the enterocyte brush border membrane.33 Controversy has also swirled around the question of increased energy expenditure in PD. Energy expenditure can be divided into two components: energy expended at rest, which accounts for 60 to 80% of total expenditure, and energy expended during physical activity, which accounts for the remaining 20 to 40%.31 Both increased energy expenditure due to parkinsonian rigidity34 and increased expenditure as a consequence of dyskinesia35 have been postulated. However, not all PD patients who lose weight suffer dyskinesia, and other investigators have demonstrated an overall 15% reduction in energy expenditure in PD patients, attributable to reduced physical activity.31 Weight gain often occurs following stereotactic pallidal and subthalamic neurosurgical procedures for PD, and some investigators have attributed this to reduction in dyskinesia.36 However, others have noted no correlation between post-pallidotomy weight gain and changes in dyskinesia.37 Neurochemical and hormonal factors could conceivably also be playing a role in parkinsonian weight loss. Dopamine has recently been shown to play a role in eating behaviors. In a series of studies utilizing11 C-raclopride positron emission tomography (PET), Volkow, Wang, and their colleagues have demonstrated decreased D2 dopamine receptor availability in obese individuals and have also documented significant increases of extracellular dopamine in dorsal but not ventral striatum in response to food stimulation, which correlated with selfreported hunger and desire for food.38–40 Similar experiments have not been reported in PD patients, but both PD itself and antiparkinson medications could conceivably have an effect. The possible role of hormonal influences on weight loss in PD is also largely uncharted. Leptin is a hormone produced in adipocytes and the hypothalamus that reduces food intake and increases energy expenditure. To investigate the hypothesis that leptin might be increased in patients with PD, leptin levels were measured in PD patients with and without weight loss, but no significant differences were found.41 The possible role in parkinsonian weight loss of gastric-derived peptide hormones, such as ghrelin and peptide YY, or other substances such as α-melanocyte-stimulating hormone, neuropeptide Y, and agouti-related protein, that may play a role in longterm control of food intake and energy expenditure, has not been investigated.42,43

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ORAL DYSFUNCTION DENTAL It is generally perceived that individuals with PD are prone to develop dental dysfunction.44–47 Difficulty with the repetitive motions necessary for teeth brushing, pooling of saliva in the mouth, or (alternatively) dry mouth, jaw muscle rigidity, difficulty retaining dentures, and involuntary jaw movements are problems that may be encountered by the person with PD.48–50 The propensity of patients with PD to have a penchant for sweets has also led to concerns that this might promote dental decay, although such confectionary consumption does not seem to alter the oral microflora.51 It is, then, interesting to note that in at least two formal studies of dental problems, PD patients had significantly more teeth and fewer decayed, missing, or filled teeth than either a control group of comparable age52 or compared to national statistics.53 In the Japanese cohort described by Fukayo,53 the superior dental status of the PD patients was attributed to the fact that an astounding 68% of the group (21/31) brushed their teeth three times a day. Whether this figure would be replicated in other populations is unknown, but the results of a study in Greek PD patients, in which 98% were found to be denture wearers and extensive oral problems were present in all participants,54 might suggest that it would not be. Other problems may also surface in PD patients. A burning sensation in the mouth was documented in 24% of PD patients surveyed in one questionnaire study.55 Bruxism has also been reported, both as a presenting feature of PD56 and as a complication of levodopa therapy.57 Mandibular dislocation58 and temporomandibular joint dysfunction59 have also been described. Because patients with PD often have difficulty adjusting to complete dentures, the use of mandibular dental implants combined with overdentures has been advocated.60 Concerns about potential mercury toxicity as a cause for PD61 have led some individuals to have their amalgam fillings removed, although firm proof of such an association is lacking. SALIVARY EXCESS Excess saliva in the mouth, often with some degree of drooling, has been a recognized feature of PD since Parkinson’s original description.1 The frequency with which it occurs is reflected in the major survey studies, which record its presence in 70 to 78% of individuals with PD, compared with only 6% of control subjects.6,7 Contrary to many patients’ perceptions, saliva production is not increased in PD and is actually, in most instances, diminished.62–64 Rather, the salivary excess is the consequence of inefficient and infrequent swallowing. Some treatment implications flow from this recognition. Drooling is embarrassing and frustrating for PD patients and may produce a reluctance to go out in public. Although not dangerous in most instances, in individuals prone to dysphagia-related aspiration, the pooled saliva provides an ever-present source of aspirate. Improved swallowing efficiency can sometimes be attained by optimization of antiparkinson medication, but this is not invariably effective (see below). In social situations, the problem can be temporarily masked by chewing gum or sucking on hard candy, which projects a more voluntary component to the swallowing act but does not

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provide any permanent solution. Employment of a portable metronome brooch to cue swallowing has also been tested.65 Most therapeutic attention, however, has focused on a number of more specific medical treatment techniques that have been advocated. The traditional treatment approach has been to employ anticholinergic drugs, such as trihexyphenidyl or benztropine, to dry up the mouth. However, the adverse effect profile of these medications in elderly PD patients, including urinary retention, constipation, memory impairment, and even psychosis, renders them risky agents to use in this setting. An approach that may limit (though not eliminate) the potential for anticholinergic toxicity but still effectively reduce saliva production is the employment of one drop of 1% atropine ophthalmic solution sublingually twice daily.66 Such prescriptions may, however, raise pharmacists’ eyebrows. Perhaps the most encouraging treatment for drooling in PD was introduced by Bhatia and colleagues in 1999 when they performed intraparotid injections of botulinum toxin type A (BTX) in four patients, one of whom had PD.67 The possibility of using BTX in this fashion had first been suggested in 1997 by Bushara, who actually had patients with amyotrophic lateral sclerosis in mind when making the proposal.68 Subsequent open label studies in PD patients confirmed subjective reduction of drooling in 67 to 88% of subjects and objective reduction in saliva production in 88 to 89% of patients tested.69–71 Recent double-blind studies have further demonstrated the safety and efficacy of this technique.72,73 BTX doses employed have varied considerably, from the 5 units per parotid employed by Friedman and Potulska71 to the 225 units per side used by Mancini and colleagues, who injected both parotid and submandibular glands.73 The latter investigators also performed their injections under ultrasonographic guidance, which they advocate as a means of improving accuracy and safety of the injections. The duration of effect of the injections has most often been reported to be in the range of 6 to 8 weeks,69,71,73 although improvement for as long as 4 to 7 months has also been described.70 Although no significant complications have been reported in studies thus far, the potential for problems such as excessively dry mouth, dysphagia due to pharyngeal muscle weakness, and even facial nerve and artery damage from the injections has been emphasized by some investigators.74 Surgical approaches for the treatment of salivary excess in PD have also been employed. Tympanic neurectomy, in which both the chorda tympani and Jacobson’s nerve are severed, is sometimes advocated for refractory drooling,75 but formal studies of the procedure in PD patients have not been performed. Loss of taste in the anterior tongue accompanies tympanic neurectomy, and the reduction in salivation may not be permanent. DYSPHAGIA As noted earlier in this chapter, the act of swallowing requires multiple muscles in the mouth, throat, and esophagus to produce a precisely controlled and coordinated cascade of movement. This, perhaps not surprisingly, turns out to be difficult for the individual with PD. Survey studies reveal a rather broad range of positive responses when PD patients are asked whether they perceive difficulty swallowing. While the two large survey studies6,7 each catalogued a subjective sense of dysphagia in approximately 50%

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of participants with PD, other studies have suggested that anywhere from 30 to 82% of PD patients may be aware of difficulty swallowing.76–79 The reason for this broad range is uncertain but may simply reflect the degree of detail in the questionnaire.79 While most attention regarding dysphagia in PD has centered on oropharyngeal abnormalities, it is clear that esophageal dysfunction may also play a role in the generation of dysphagia in some individuals. OROPHARYNGEAL DYSPHAGIA Objective studies of swallowing generally have demonstrated an even higher frequency of swallowing abnormalities than the subjective survey studies. The most frequently employed test has been the modified barium swallow (MBS) test, and various investigators have reported abnormalities on MBS in 75 to 97% of PD subjects tested.80– 83 An array of abnormalities in both the oral and pharyngeal phases of swallowing have been identified during MBS testing. Within the oral phase, alterations in lingual control and oral mobility, presumably due to rigidity and bradykinesia, result in abnormal bolus formation, delayed initiation of swallowing, repeated tongue pumping to accomplish the swallow, piecemeal deglutition, and the presence of residual material on the tongue or in the lateral or anterior sulci following swallowing.84–89 An equally impressive roster of abnormalities have been identified in the pharyngeal phase, including pharyngeal dysmotility, misdirected swallows, pharyngeal and vallecular stasis, vallecular residue, and reflux of material from the vallecular and pyriform sinuses into the mouth.81,84,85 With MBS testing, it has become abundantly clear that dysphagia can be present in individuals with PD, even if they have no symptoms to alert either patient or physician to its presence. An important and potentially serious ramification of dysphagia in PD is the development of aspiration. Studies suggest that aspiration occurs in a significant proportion of PD patients, with the range of reported frequencies extending from 15 to 56%.81,84,86,87,90,91 As is true with dysphagia itself, it has also become quite clear that symptoms alone are not sufficient predictors of the presence of aspiration in persons with PD. Entirely asymptomatic aspiration has been documented in 15 to 33% of PD patients.81,86,92 Even this surprising figure may underestimate the potential problem. Bird and colleagues noted the presence of vallecular residue, an abnormality indicative of increased aspiration risk, in 88% of 16 PD patients they studied, all of whom were without any symptomatic dysphagia.92 The high frequency of dysphagia and aspiration, both symptomatic and asymptomatic, in individuals with PD, and the recognition that the development of these abnormalities may be independent of disease severity, has led at least one investigator to suggest that screening videofluoroscopy be performed early in the course of PD to identify those patients with subclinical dysphagia and institute appropriate treatment measures.91 In the large survey studies, the presence of symptomatic dysphagia seemed to correlate with disease progression.7 However, this correlation is not clearly evident when objective testing of swallowing is employed. Bushman and colleagues noted the presence of MBS abnormalities in approximately 50% of patients with early (Hoehn and Yahr stages 1 and 2) PD,81 and other investigators have emphatically confirmed that the development of both dysphagia and aspiration is independent of both disease duration and severity.90,91

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Cricopharyngeal muscle dysfunction is yet another source of swallowing impairment in PD. The cricopharyngeal muscle, serving as the UES, is tonically contracted, opening in response to the piston-like propulsive force of the tongue as it drives the food bolus into the pharynx. In individuals with PD those propulsive forces may be inadequate to trigger adequate cricopharyngeal relaxation, resulting in difficulty swallowing.90 In some individuals, however, the cricopharyngeal muscle itself may be the source of the problem, with failure to relax resulting in cricopharyngeal bar formation.90 In one study, 22% of PD patients referred for evaluation of dysphagia were found to have cricopharyngeal bars or Zenker’s diverticula.93 Zenker’s diverticula, which form in Killian’s triangle and are felt to be the consequence of incomplete cricopharyngeal relaxation, are another structural source of dysphagia that, in addition to causing a sense of food hanging up in the throat, can also produce delayed regurgitation of undigested food that had been trapped in the diverticulum and halitosis. Perforation, especially during instrumentation such as nasogastric tube placement, with consequent mediastinitis, is a potentially life-threatening complication. ESOPHAGEAL DYSPHAGIA Esophageal dysfunction and its role in parkinsonian dysphagia has not been as extensively studied and thoroughly delineated as its oropharyngeal counterpart. However, videofluoroscopic abnormalities have been described in 5 to 86% of patients studied with PD 10,82,87,39,94,95 and disordered function during esophageal manometry in 61 to 73%.96,97 An array of abnormalities have been observed, including slowed esophageal transit, segmental esophageal spasm, repetitive spontaneous contractions of the proximal esophagus, multiple simultaneous contractions producing diffuse esophageal spasm, ineffective or tertiary contractions with air trapping, aperistalsis, esophageal dilatation, and reduced pressure at the LES.89,94–99 LES dysfunction has also been observed in PD, where advanced reflux disease with consequent esophagitis may produce dysphagia, in addition to the more typical gastroesophageal symptoms.93 TREATMENT OF DYSPHAGIA Behavioral, pharmacological, and surgical treatment methods have all been employed in the treatment of dysphagia in PD. Behavioral management approaches may include compensatory techniques, such as postural strategies and swallowing maneuvers, and are useful for some individuals. In contrast to the very predictable improvement in the conventional motor features of PD that occurs with levodopa treatment, there is conflicting evidence regarding the response of oropharyngeal dysphagia to standard antiparkinson medications. Improvement in dysphagia, sometimes striking, has been noted by some investigators, including Cotzias and colleagues in their pioneering studies.100–103 However, more formal studies employing MBS have demonstrated objective improvement in only 33 to 50% of patients following levodopa or apomorphine administration.81,83,104 Formal studies evaluating other dopamine agonists in this regard have not been published. The basis for this inconsistent response to dopaminergic medication is uncertain but may simply reflect the intricacy of movement necessary for normal swallowing and the difficulty

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reconstructing this with systemic drug administration, like trying to do calligraphy with a paint roller. Anticholinergic drugs have been reported to both improve98 and exacerbate105 dysphagia in PD patients. Cricopharyngeal dysfunction may be amenable to more specific treatment maneuvers. Percutaneous injection with BTX has been successfully employed,106 as has cricopharyngeal myotomy.107 However, cricopharyngeal myotomy (and probably BTX injection also) should not be performed if the concomitant presence of esophageal dysmotility might leave the individual at greater risk for aspiration following myotomy.107 Improvement in esophageal dysphagia has been reported with apomorphine administration,108,109 although extensive testing has not been undertaken. It has been suggested that sildenafil might be of benefit in the treatment of spastic esophageal motor disorders110 because of its effect on nitric oxide, but there have been no published reports of its use for this purpose in PD. It is worth noting that transient esophageal obstruction has been attributed to levodopa, with resolution following drug discontinuation.111 It is very unusual for dysphagia in idiopathic PD to become sufficiently severe to require percutaneous endoscopic gastrostomy placement, but this procedure can be employed as a final step in patients in whom other treatment approaches have failed and both adequate nutritional support and medication administration have become impossible.12,112 GASTRIC DYSFUNCTION Perhaps the first hint that patients with PD might have impaired gastric emptying (gastroparesis) can be found in the 1981 report of Evans and colleagues, who, although not specifically studying PD, identified delayed gastric emptying in a group of elderly individuals, 55% of whom did have PD, compared to young controls.113 Subsequent investigators, using a variety of techniques, have confirmed that gastroparesis is, indeed, a common component of PD 114–118 In one study? the average time to empty one-half of the gastric contents (GET1/2) was 59 min in a group of 28 untreated PD patients, compared with 43.4 min in a control group of slightly younger individuals.115 The clinical ramifications of delayed gastric emptying in PD have not been extensively explored. In patients with gastroparesis due to other sources of autonomic dysfunction, such as diabetes mellitus, early satiety, abdominal discomfort with a sense of bloating, nausea, vomiting, weight loss and even malnutrition may occur. Edwards and colleagues suggested that the nausea present in 24% of the PD patients they surveyed, including 16% of those not on PD treatment, might be due to impaired gastric emptying.7 They also reported that almost 45% of the PD patients (including 43% of those untreated), experienced a sense of bloating, compared to 25% of the spousal controls, although this difference was not statistically significant. Beyond the clinical symptoms described above, delayed gastric emptying also has potentially important pharmacokinetic implications for the PD patient taking levodopa. Absorption of levodopa takes place in the proximal small intestine.119–121 Slowed gastric emptying might, therefore, be expected to result in delayed clinical response to levodopa doses. This supposition finds support in the report by Djaldetti and colleagues, who found

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the average GET1/2 to be 221 min in PD patients with motor fluctuations compared to 85 min in those without fluctuations,116 but seems to be at odds with that of Hardoff and colleagues in which PD patients with motor response fluctuations had a shorter GET1/2 than those with a smooth response to levodopa.115 Several additional factors might further promote inconsistent responses to administered levodopa. Because aromatic amino acid decarboxylase is present in the gastric mucosa, delayed gastric emptying may also allow increased gastric conversion of levodopa to dopamine, rendering it unavailable for subsequent intestinal absorption. Moreover, the dopamine thus formed in the stomach could stimulate gastric dopamine receptors, which promote receptive relaxation of the stomach and inhibit gastric motility, and lead to further delays in gastric emptying.122,123 TREATMENT OF GASTROPARESIS Drugs that block dopamine receptors accelerate gastric emptying, presumably by their action on the gastric dopamine receptors mentioned above. Both metoclopramide and domperidone are dopamine receptor antagonists and effective agents in the treatment of gastroparesis. However, because metoclopramide crosses the bloodbrain barrier, it also can block striatal dopamine receptors and adversely impact motor function, rendering it contraindicated in persons with PD. Domperidone demonstrates little or no ability to cross the blood-brain barrier and, thus, can be safely and effectively used in PD patients,124 although rare reports of domperidone producing extrapyramidal dysfunction can be found.125 Domperidone is available throughout much of the world, including Canada, but is not approved for use in the U.S.A. Other medications have also demonstrated efficacy as prokinetic agents. Cisapride, which stimulates acetylcholine release from myenteric cholinergic neurons,126 was used successfully in PD patients but is no longer readily available, because of cardiac toxicity. While not specifically studied in PD, the macrolide antibiotic erythromycin, which also is a motilin agonist, accelerates gastric emptying in healthy volunteers127 and has been reported to be superior to metoclopramide, domperidone, and cisapride as a prokinetic agent in patients with gastroparesis.128 However, concerns about its long-term antibiotic effects have limited its use in chronic disease processes. Drug delivery methods that bypass the stomach completely are another possible treatment for PD patients with severe gastroparesis. Direct jejunal infusion of drug via tube placement is effective129 but impractical. Constant subcutaneous infusions of both apomorphine and lisuride have also been used very successfully,130,131 but this technique is also technically challenging. Trials with the dopamine agonist rotigotine, administered transdermally, are ongoing.132 Gastric pacemaker placement has been successfully utilized in individuals with severe refractory gastroparesis,133 but no published reports of its use in PD exist. SMALL INTESTINE DYSMOTILITY The fate of small intestinal function in PD is largely unknown, since very few studies have directed their attention toward this most secluded and inaccessible component of the

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GI tract. Orocecal transit time, a measure of combined gastric and small intestine transit speed, was shown to be markedly prolonged in 15 patients with PD compared with 15 age- and sex-matched control individuals.33 Abnormalities in small intestinal motor patterns in PD patients have also been demonstrated with small intestine manometry.134 Small intestinal dilatation has also been observed.135 In the laboratory disruption of the migrating myoelectric complex has been documented in rats administered MPTP, along with reduction in jejunal myenteric plexus dopamine levels.136 Whether similar changes occur in PD is unknown. The clinical consequences of small intestinal dysfunction in PD have not been documented. It is conceivable that the very uncomfortable bloating sensation experienced by some individuals with PD, primarily as an “off” phenomenon, might be related to small intestinal dysmotility, but no study has actually addressed this issue. If this is so, agents that accelerate small intestinal transit time, such as the serotonin-4 receptor agonist prucalopride,137 might be beneficial for patients with these symptoms. COLONIC DYSMOTILITY When patients report the presence of bowel dysfunction, they typically use the term constipation as an all-inclusive descriptor that encompasses both decreased bowel movement frequency, often with hard stools, and difficulty with the act of defecation itself in the form of increased straining and sometimes incomplete evacuation.138 From both a physiological and clinical standpoint, however, these two problems are quite different and a separate classification and discussion of each is warranted. Even within its more narrow medical definition as decreased bowel movement frequency, constipation (or colonic inertia) has undergone a redefinition in recent decades. In the past, it was standard to label anything less frequent than a daily bowel movement as abnormal, but the current definition of constipation has been pegged as fewer than three bowel movements weekly. Recognition of this definitional revision is important when reviewing reported frequencies of constipation in PD. Older studies indicate the presence of constipation in recent communications using the contemporary definiroughly 50 to 67% of PD patients,6,139,140 but in more tion, frequencies of 20 to 29% have been reported.7,141 Multiple studies have documented that the physiological basis for decreased bowel movement frequency in PD is slowed colonic transit of fecal material. Colon transit studies, employing radiopaque markers, have indicated that as many as 80% of persons with PD may have abnormally prolonged transit times.142 Reported colon transit times in PD patients have varied rather widely for reasons that are not clear. Jost and Schimrigk initially reported an average colon transit time (CTT) of 5 to 7 days (120 to 168 hr) in a group of 20 persons with PD,142 and in a subsequent study of 22 subjects in whom CTT could be measured, the average time was 130 hr.143 These times contrast with the report by Edwards and colleagues in a study of 13 PD participants, in which mean CTT was 44 hr, compared to 20 hr in spousal controls.10 A more recent study further confirms that CTT is slowed in PD, although the times reported (82.4 min in PD patients and 39 min in controls) appear to be incorrectly labeled in minutes rather than hours.144 Thus, despite the variance in average CTT in published reports, there seems to be ample agreement that

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CTT is prolonged in PD. Survey studies have suggested that constipation becomes more severe as PD progresses.7,145 This is supported by another study by Jost and Schimrigk in recently diagnosed PD patients, where average CTT was 89 hr,146 compared with the considerably longer CTT’s reported in their earlier studies cited above, which included individuals with more advanced disease. Prolongation of the CTT in untreated individuals underscores that constipation is not simply medication-induced (although this certainly can occur), but part of the disease process itself. As with other aspects of GI dysfunction, objective abnormalities on testing do not necessarily translate into clinical symptoms, and prolongation of CTT has been noted in PD patients without symptomatic constipation.147 While constipation is most frequently recognized in persons who have already developed the motor features of PD, some individuals can retrospectively identify the presence of bowel dysfunction prior to the appearance of the more classical PD motor features.11 A recent provocative epidemiological study has also identified an association between frequency of bowel movements and the risk of developing PD.148 In the Honolulu Heart Program study, men who reported a bowel movement frequency of fewer than one per day were found to have a 2.7 times greater risk of developing PD than men who had daily bowel movements, and a fourfold higher risk than those with two or more bowel movements daily. While these findings may simply be a reflection that constipation may herald conventional PD motor features, other hypothetical explanations can also be advanced. Perhaps rapid transit of material through the GI tract, implied by frequent bowel movements, limits exposure to, and absorption of, some toxic substance capable of damaging dopaminergic neurons. The pathophysiological basis of constipation in PD has not been completely clarified. Both central and peripheral factors may be operative. Animal studies employing intraventricular injection of dopaminergic agents have demonstrated that activation of central D1 and D2 receptors stimulates colonic motility by increasing colonic spike bursts.149 It has also been suggested that this may be coordinated through Barrington’s nucleus (also known as the pontine micturition center), which lies adjacent to, or possibly within,150 the locus coeruleus in the pons.144,151–153 Support for a peripheral basis for slowed colonic transit in PD also arises from a number of sources. Kupsky and colleagues, in 1987, were the first to document the presence of Lewy bodies in the colonic myenteric and submucosal plexuses of individuals with PD.154 This plentiful presence of colonic Lewy bodies was subsequently confirmed by several other groups,155–157 who noted the Lewy bodies to be present both in dopaminergic neurons and in those containing vasoactive intestinal peptide. Using immunohistochemical methods, Singaram and colleagues were also able to demonstrate a very striking reduction in the number of dopaminergic neurons in the colonic myenteric plexus of PD patients, compared to both healthy controls and individuals with idiopathic constipation.157 Other abnormalities within colonic tissue have also been documented in individuals with constipation. Serotonin receptor immunoreactivity was recently found to be reduced in colonic tissue of individuals who underwent subtotal colectomy for treatment of colonic inertia.158 Other studies of patients with chronic idiopathic intestinal pseudoobstruction or slow transit constipation have documented a marked loss of interstitial cells of Cajal (ICC), which are believed to function as pacemaker cells in the gut 159,160

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whether these abnormalities are also present in patients with PD suffering from constipation is unknown. TREATMENT OF COLONIC DYSMOTILITY The treatment of slow transit constipation in PD is largely empirical, since very few treatment modalities have undergone rigorous testing in this patient population.161 Many studies have confirmed that increased dietary fiber reduces CTT in normal individuals,162 most probably by increasing bulk within the colonic lumen. A daily fiber intake of 15 g, along with at least 1.5 L of water, has been recommended.163 Since daily fiber consumption is deficient in many PD patients,7 increased dietary fiber or fiber supplements, such as psyllium, can be effective in increasing stool frequency.147 Improved motor function, presumably reflecting increased levodopa bioavailability, has also been documented with increased fiber intake.164 Adding a stool softener, such as docusate, can also be useful. If these simple measures are insufficiently effective, an osmotic laxative, such as lactulose or sorbitol, can be a very useful next step. A lactulose dose of 30 ml once or twice daily can be used, with subsequent downward titration of dosage if necessary. Because sorbitol is less expensive than lactulose, it might be considered as a costeffective alternative.165 More recently, the effectiveness of polyethylene glycol electrolyte balanced solutions, well known as colon-cleansing agents prior to colonoscopy, administered on a regular or even daily basis in smaller amounts, has been demonstrated in PD patients.166,167 Patients often turn to irritant laxatives, such as senna-containing compounds, that are available without prescription. These compounds can be effective, but daily use should probably be discouraged because of concerns of potential ENS damage from chronic use, even though such damage has not actually been definitively proven. The role of prokinetic agents in the treatment of slow transit constipation is uncertain. Cisapride was reported to be effective in PD patients, at least in the short term,168,169 but is no longer available. Prucalopride, a serotonin-4 agonist, has more recently been shown to be effective as a prokinetic agent in patients with severe chronic constipation,137,170 but its effect in individuals with PD has not been specifically reported. Anecdotal reports have described the effectiveness of the cholinomimetic agents, pyridostigmine171 and neostigmine,172 in the treatment of constipation in PD, but no formal studies of these compounds have been reported. The efficacy of neurotrophin-3 in a small double-blind study of PD patients with constipation has been reported in abstract form.173 Other potentially effective agents include misoprostol174 and colchicine.175 Potentially life-threatening complications of slow transit constipation in PD include megacolon,135,154,176,177 intestinal pseudoobstruction, volvulus, and even bowel perforation.6,12,176,177 Surgical treatment in the form of colectomy may be necessary in such situations.

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ANORECTAL DYSFUNCTION Anorectal dysfunction, characterized by excessive straining and often accompanied by pain and a sense of incomplete evacuation, is actually the more prevalent form of bowel dysfunction in PD. In their survey study, Edwards and colleagues7 differentiated between decreased bowel movement frequency and defecatory dysfunction and noted the latter in 67% of PD patients, compared with only 29% who reported decreased bowel movement frequency (see above). As with slow transit constipation, anorectal dysfunction can also appear early in the course of PD.178 Clinical neurophysiological and radiographic studies have shed considerable light on the pathophysiological basis for disordered defecation in PD. As described earlier, for effective defecation to occur the coordinated contraction and relaxation of a surprising array of muscles must take place. It is now clear from studies such as anorectal manometry, anorectal electromyography, and defecography that this does not always occur in individuals with PD and that dyscoordination may actually be the rule. In one study such abdominopelvic (or pelvic floor) dyssynergia was present in over 60% of PD patients.178 Lower basal sphincter pressure and difficulty maintaining sphincter pressure have been noted on anorectal manometry in PD patients, as have some more distinctive abnormalities, including unusual phasic contractions of the sphincter muscles during voluntary contraction and a “paradoxical” hypercontractile response of the external anal sphincter and puborectalis muscles on rectosphincteric (rectoanal inhibitory) reflex testing, where sphincter relaxation, rather than contraction, is expected.10,179–181 Failure of the external anal sphincter and puborectalis muscles to relax during attempted defecation, producing functional outlet obstruction, was originally observed by Mathers and colleagues182,183 and subsequently confirmed by others.10 It has been suggested that this is a focal dystonic phenomenon.182,183 These abnormalities of anorectal muscle function appear to be distinctive for PD and not simply a reflection of constipation in general.184 Moreover, fluctuation in the severity of the anorectal abnormalities in response to dopaminergic medications has been documented, with deterioration during “off” periods and improvement in function when patients are “on.”180 Evaluation of defecation with rectoanal videomanometry has provided objective confirmation of the subjective sense of incomplete emptying during defecation experienced by many PD patients by demonstrating that incomplete defecation with the presence of significant post-defecation residuals is common in PD.144 TREATMENT OF ANORECTAL DYSFUNCTION The array of treatment options for anorectal dysfunction is somewhat limited. While softening the stool by various measures will make it easier to expel, such measures do not correct the fundamental defect in muscular coordination producing the problem. In fact, laxatives and other measures that hasten the arrival of stool to the rectum may sometimes accentuate the problem, producing a situation that might be likened to a crowd of frantic people trying to exit a burning building through a narrow, or even blocked, exit.

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Some evidence suggests that dopaminergic medications may improve anorectal function in individuals with PD. As noted above, improvement in anorectal manometric and electromyographic measures of anorectal function during “on” periods, with deterioration during “off” episodes has been described,183,185 and improvement following apomorphine injections has also been reported.183,185 Occasional patients on levodopa will also report that it is easier for them to have a bowel movement when they are “on” than when they are “off.” Injection of BTX into the puborectalis muscle under transrectal ultrasonographic guidance has been successfully employed to treat defecatory dysfunction in PD patients.186,187 The duration of benefit has not been thoroughly defined, but improvement lasting two to three months has been noted. Although these reports are encouraging, the risk for producing fecal incontinence is present with this procedure and perianal thrombosis has also been reported.188 Behavioral techniques, such as defecation training and biofeedback measures, have been successfully employed in the treatment of pelvic floor disorders, but they have not been specifically examined in PD patients. Sacral nerve stimulation is a technique that might conceivably have some application in PD patients, but has not yet been evaluated. Surgical treatment, such as colectomy, is rarely necessary in PD patients. CONCLUSION Recognition that nonmotor features, such as GI dysfunction, are an extremely important and frequent component of PD is rapidly growing. Such recognition, and the investigation that is prompted by it, will hopefully lead to a better understanding of the mechanisms responsible for such dysfunction and eventually to more effective treatment. For the individual with PD experiencing these problems, that time cannot come soon enough. REFERENCES 1. Parkinson, J., An Essay on the Shaking Palsy, Whittingham and Rowland, London, 1817. 2. Romberg, M.H., Nervous Diseases of Man, Sydenham Society, London, 1853. 3. Charcot, J.M., Lectures on the Diseases of the Nervous System, Vol. 1, New Sydenham Society, London, 1877. 4. Hammond, W.A., A Treatise on Diseases of the Nervous System, Appleton and Company, New York, 1871. 5. Gowers, W.R., Diseases of the Nervous System, P.Blakiston and Company, Philadelphia, 1888. 6. Eadie, M.J. and Tyrer, J.H., Alimentary disorder in parkinsonism, Aust. Ann. Med., 14, 13, 1965. 7. Edwards, L.L. et al., Gastrointestinal symptoms in Parkinson’s disease, Mov. Disord., 6, 151, 1991. 8. Edwards, L.L. et al., Gastrointestinal dysfunction in Parkinson’s disease: frequency and pathophysiology, Neurology, 42, 726, 1992. 9. Edwards, L.L. et al., Gastrointestinal symptoms in Parkinson’s disease: 18 month follow-up study, Mov. Disord. 8, 83, 1993. 10. Edwards, L.L. et al., Characterization of swallowing and defecation in Parkinson’s disease, Am. J. Gastroenterol., 89, 15, 1994.

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109. Kempster, P.A. et al., Off-period belching due to a reversible disturbance of oesophageal motility in Parkinson’s disease and its treatment with apomorphine, Mov. Disord., 4, 47, 1989. 110. Bortolotti, M. et al., Effects of sildenafil on esophageal motility of patients with idiopathic achalasia, Gastroenterology, 118, 253, 2000. 111. Kellner, H. et al., Reversible esophageal dysfunction as a side effect of levodopa, Bildgebung, 63, 48, 1996. 112. Luman, W. et al., Percutaneous endoscopic gastrostomy—indications and outcome of our experience at the Singapore General Hospital, Singapore Med. J., 42,460, 2001. 113. Evans, M.A. et al., Gastric emptying rate in the elderly: implications for drug therapy, J. Am. Geriatr. Soc., 29, 201, 1981. 114. Sulla, M. et al., Gastric emptying time and gastric motility in patients with untreated Parkinson’s disease, Mov. Disord., 11 (Suppl. 1), 167, 1996 (abstract). 115. Hardoff, R. et al., Gastric emptying time and gastric motility in patients with Parkinson’s disease, Mov. Disord., 16, 1041, 2001. 116. Djaldetti, R. et al., Gastric emptying in Parkinson’s disease: patients with and without response fluctuations, Neurology, 46, 1051, 1996. 117. Krygowska-Wajs, A. et al., Gastric electromechanical dysfunction in Parkinson’s disease, Funct. Neurol., 15, 41, 2000. 118. Soykan, I. et al., Gastric myoelectrical activity in patients with Parkinson’s disease: evidence of a primary gastric abnormality, Dig. Dis. Sci., 44, 927, 1999. 119. Wade, D.N., Mearrick, P.T., and Morris, J., Active transport of L-dopa in the intestine, Nature, 242, 463, 1973. 120. Sasahara, K. et al., Dosage from design for improvement of bioavailability of levodopa: absorption and metabolism of levodopa in intestinal segment of dogs, J. Pharm. Sci., 70, 1157, 1981. 121. Nutt, J.G. and Fellman, J.H., Pharmacokinetics of levodopa, Clin. Neuropharmacol, 7, 35, 1984. 122. Valenzuela, J.E., Dopamine as a possible neurotransmitter in gastric relaxation, Gastroenterology, 71, 1019, 1976. 123. Berkowitz, D.M. and McCallum, R.W., Interaction of levodopa and metoclopramide on gastric emptying, Clin. Pharmacol. Ther., 27, 414, 1980. 124. Soykan, I. et al., Effect of chronic oral domperidone therapy on gastrointestinal symptoms and gastric emptying in patients with Parkinson’s disease, Mov. Disord., 12, 952, 1997. 125. Barone, J.A., Domperidone: a peripherally acting dopamine2-receptor antagonist, Ann. Pharmacother., 33, 429, 1999. 126. Wiseman, L.R. and Faulds, D., Cisapride, An updated review of its pharmacology and therapeutic efficacy as a prokinetic agent in gastrointestinal motility disorders, Drugs, 47, 116, 1994. 127. Boivin, M.A., Carey, M.C., and Levy, H., Erythromycin accelerates gastric emptying in a dose-response manner in healthy subjects, Pharmacotherapy, 23, 5, 2003. 128. Sturm, A. et al., Prokinetics in patients with gastroparesis: a systematic analysis, Digestion, 60, 422, 1999. 129. Syed, N. et al., Ten years’ experience with enteral levodopa infusions for motor fluctuations in Parkinson’s disease, Mov. Disord., 13, 336, 1998. 130. Vaamonde, J., Luquin, M.R., and Obeso, J., Subcutaneous lisuride infusion in Parkinson’s disease. Response to chronic administration in 34 patients, Brain, 114,604, 1991. 131. Stibe, C.M. et al., Subcutaneous apomorphine in parkinsonian on-off oscillations, Lancet, 1, 403, 1988. 132. Behrens, S. and Sommerville, K., Non-oral drug delivery in Parkinson’s disease: a summary from the symposium at the 7th International Congress of Parkinson’s Disease and Movement Disorders. November 10–14, 2002, Miami, FL, U.S.A., Expert Opin. Pharmacother., 4, 595, 2003.

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133. McCallum, R.W. and George, S.J., Gastric dysmotility and gastroparesis, Curr. Treat. Options Gastroenterol., 4, 179, 2001. 134. Bozeman, T. et al., Small intestinal manometry in Parkinson’s disease, Gastroenterology, 99, 1202, 1990 (abstract). 135. Lewitan, A., Nathanson, L., and Slade, W.R., Megacolon and dilatation of the small bowel in parkinsonism, Gastroenterology, 17, 367, 1952. 136. Eaker, E.Y. et al., Chronic alterations in jejunal myoelectric activity in rats due to MPTP, Am. J. Physiol., 253, G809, 1987. 137. Emmanuel, A.V. et al., Prucalopride, a systemic enterokinetic, for the treatment of constipation, Aliment. Pharmacol. Ther., 16, 1347, 2002. 138. Stark, M.E., Challenging problems presenting as constipation, Am. J. Gastroenterol., 94, 567, 1999. 139. Schwab, R.S. and England, A.C., Parkinson’s disease, J. Chron. Dis., 8, 488, 1958. 140. Pallis, C.A., Parkinsonism: natural history and clinical features, B. M. J., 3, 683, 1971. 141. Siddiqui, M.F. et al., Autonomic dysfunction in Parkinson’s disease: a comprehensive symptom survey, Parkinsonism Relat. Disord., 8, 277, 2002. 142. Jost, W.H. and Schimrigk, K., Constipation in Parkinson’s disease, Klin. Wochenschr., 69, 906, 1991. 143. Jost, W.H. and Schimrigk, K., The effect of cisapride on delayed colon transit time in patients with idiopathic Parkinson’s disease, Wien Klin. Wochenschr., 106, 673, 1994. 144. Sakakibara, R. et al., Colonic transit time and rectoanal videomanometry in Parkinson’s disease, J. Neurol. Neurosurg. Psychiatry, 74, 268, 2003. 145. Sakakibara, R. et al., Questionnaire-based assessment of pelvic organ dysfunction in Parkinson’s disease, Auton. Neurosci., 92, 76, 2001. 146. Jost, W.H. and Schrank, B., Defecatory disorders in de novo parkinsonians—colonic transit and electromyogram of the external anal sphincter, Wien Klin. Wochenschr., 110, 535, 1998. 147. Ashraf, W. et al., Constipation in Parkinson’s disease: objective assessment and response to psyllium, Mov. Disord., 12, 946, 1997. 148. Abbott, R.D. et al., Frequency of bowel movements and the future risk of Parkinson’s disease, Neurology, 57, 456, 2001. 149. Bueno, L. et al., Involvement of central dopamine and D1 receptors in stress-induced colonic motor alterations in rats, Brain Res. Bull., 29, 135, 1992. 150. Ding, Y.Q. et al., Localization of Barrington’s nucleus in the pontine dorsolateral tegmentum of the rabbit, J. Hirnforsch., 39, 375, 1999. 151. Pavcovich, L.A. et al., Novel role for the pontine micturition center, Barrington’s nucleus: evidence for coordination of colonic and forebrain activity, Brain Res., 784, 355, 1998. 152. Valentino, R.J., Miselis, R.R., and Pavcovich, L.A., Pontine regulation of pelvic viscera: pharmacological target for pelvic visceral dysfunctions, Trends Pharmacol. Sci., 20, 253, 1999. 153. Vizzard, M.A., Brisson, M., and de Groat, W.C., Transneuronal labeling of neurons in the adult rat central nervous system following inoculation of pseudorabies virus into the colon, Cell Tissue Res., 299, 9, 2000. 154. Kupsky, W.J. et al., Parkinson’s disease and megacolon: concentric hyaline inclusions (Lewy bodies) in enteric ganglion cells, Neurology, 37, 1253, 1987. 155. Wakabayashi, K. et al., Parkinson’s disease: an immunohistochemical study of Lewy-body containing neurons in the enteric nervous system, Acta Neuropathol, 79, 581, 1990. 156. Wakabayashi, K. et al., Lewy bodies in the visceral autonomic nervous system in Parkinson’s disease, in Parkinson’s Disease. From Basic Research to Treatment (Advances in Neurology, Vol. 60), Narabayashi, H. et al., Eds., Raven Press, New York, 1993, 609. 157. Singaram, C. et al., Dopaminergic defect of enteric nervous system in Parkinson’s disease patients with chronic constipation, Lancet, 346, 861, 1995. 158. Zhao, R.H. et al., Reduced expression of serotonin receptor(s) in the left colon of patients with colonic inertia, Dis. Colon Rectum, 46, 81, 2003.

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159. Lyford, G.L. et al., Pan-colonic decrease in interstitial cells of Cajal in patients with slow transit constipation, Gut, 51, 496, 2002. 160. Jain, D. et al., Role of interstitial cells of Cajal in motility disorders of the bowel, Am. J. Gastroenterol., 98, 618, 2003. 161. Wiesel, P.H., Norton, C., and Brazzelli, M., Management of faecal incontinence and constipation in adults with central neurological diseases, Cochrane Database Syst. Rev., 4, CD002115, 2001. 162. Müller-Lissner, S.A., Effect of wheat bran on weight of stool and gastrointestinal transit time: a meta-analysis, B. M. J., 296, 615, 1988. 163. Corazziari, E. and Badiali, D., Management of lower gastrointestinal tract dysfunction, Semin. Neurol., 16, 289, 1996. 164. Astarloa, R. et al., Clinical and pharmacokinetic effects of a diet rich in insoluble fiber on Parkinson’s disease, Clin. Neuropharmacol, 15, 375, 1992. 165. Lederle, F.A. et al., Cost-effective treatment of constipation in the elderly: a randomized double-blind comparison of sorbitol and lactulose, Am. J. Med., 89, 597, 1990. 166. Corazziari, E. et al., Small volume isosmotic polyethylene glycol electrolyte balanced solution (PMF-100) in treatment of chronic nonorganic constipation, Dig. Dis. Sci., 41, 1636, 1996. 167. Eichorn, T.E. and Oertel, W.H., Macrogol 3350/electrolyte improves constipation in Parkinson’s disease and multiple system atrophy, Mov. Disord., 16, 1176, 2001. 168. Jost, W.H. and Schimrigk, K., Cisapride treatment of constipation in Parkinson’s disease, Mov. Disord., 8, 339, 1993. 169. Jost, W.H. and Schimrigk, K., Long-term results with cisapride in Parkinson’s disease, Mov. Disord., 12, 423, 1997. 170. Coremans, G. et al., Prucalopride is effective in patients with severe chronic constipation in whom laxatives fail to provide adequate relief. Results of a double-blind, placebo-controlled clinical trial, Digestion, 67, 82, 2003. 171. Sadjadpour, K., Pyridostigmine bromide and constipation in Parkinson’s disease, J. A. M. A., 249, 1148, 1983. 172. Koornstra, J.J. et al., Neostigmine treatment of acute pseudo-obstruction of colon (Ogilvie syndrome), Ned. Tijdschr. Geneeskd., 145, 586, 2001. 173. Pfeiffer, R.F. et al., Effect of NT-3 on bowel function in Parkinson’s disease, Mov. Disord., 17, S223, 2002 (abstract). 174. Roarty, T.P. et al., Misoprostol in the treatment of chronic refractory constipation: results of a long-term open label trial, Aliment. Pharmacol. Ther., 11, 1059, 1007. 175. Sandyk, R. and Gillman, M.A., Colchicine ameliorates constipation in Parkinson’s disease, J. R. Soc. Med., 77, 1066, 1984. 176. Caplan, L.H. et al., Megacolon and volvulus in Parkinson’s disease, Radiology, 85, 73, 1965. 177. Rosenthal, M.J. and Marshall, C.E., Sigmoid volvulus in association with parkinsonism. Report of four cases, J. Am. Geriatr. Soc., 35, 683, 1987. 178. Bassotti, G. et al., Manometric investigation of anorectal function in early and late stage Parkinson’s disease, J. Neurol. Neurosurg. Psychiatry, 68, 768, 2000. 179. Stocchi, F. et al., Anorectal function in multiple system atrophy and Parkinson’s disease, Mov. Disord., 15, 71, 2000. 180. Ashraf, W. et al., Anorectal function in fluctuating (onoff) Parkinson’s disease: evaluation by combined anorectal manometry and electromyography, Mov. Disord., 10, 650, 1995. 181. Normand, M.M. et al., Simultaneous electromyography and manometry of the anal sphincters in parkinsonian patients: technical considerations, Muscle Nerve, 19, 110, 1996. 182. Mathers, S.E. et al., Constipation and paradoxical puborectalis contraction in anismus and Parkinson’s disease: a dystonic phenomenon? J. Neurol. Neurosurg. Psychiatry, 51, 1503, 1988. 183. Mathers, S.E. et al., Anal sphincter dysfunction in Parkinson’s disease, Arch. Neurol., 46, 1061, 1989.

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184. Ashraf, W., Pfeiffer, R.F., and Quigley, E.M. M., Anorectal manometry in the assessment of anorectal function in Parkinson’s disease: a comparison with chronic idiopathic constipation, Mov. Disord., 9, 655, 1994. 185. Edwards, L.L. et al., Defecatory function in Parkinson’s disease: response to apomorphine, Ann. Neurol., 33, 490, 1993. 186. Albanese, A. et al., Severe constipation in Parkinson’s disease relieved by botulinum toxin, Mov. Disord., 12, 764, 1997. 187. Albanese, A. et al., Treatment of outlet obstruction constipation in Parkinson’s disease with botulinum neurotoxin A, Am. J. Gastroenterol., 98, 1439, 2003. 188. Jost, W.H. et al., Perianal thrombosis following injection therapy into the external anal sphincter using botulinum toxin, Dis. Colon Rectum, 38, 781, 1995.

26 Urinary Dysfunction in Parkinson’s Disease Carlos Singer Department of Neurology, University of Miami School of Medicine 0-8493-1590-5/05/$0.00+$ 1.50 © 2005 by CRC Press

INTRODUCTION Parkinson’s disease (PD) is defined by motor manifestations of tremor, bradykinesia, rigidity, gait disorder, postural instability and freezing. However, it is associated with multiple nonmotor problems including voiding difficulties. Urological symptoms in PD have a stereotypical presentation and character with its pathophysiology localized in the basal ganglia. A neurologist who obtains a thorough clinical history and who is acquainted with the neuro-urology of PD can play an important role in the management of this particular problem. PREVALENCE OF URINARY SYMPTOMS IN PD There is a surprising dearth of information covering the prevalence of urinary symptoms in the parkinsonian population at large. Murnaghan22 specifically investigated the presence of urological symptoms in 29 PD patients in the prelevodopa era, who had been selected to undergo basal ganglia surgery. Eleven (38%) had urological symptoms. Porter and Bors25 investigated a similar group of 62 patients being considered for basal ganglia surgery. Fortyfour patients (71%) had urinary symptoms, but the group was primarily male. These figures have a selection bias. It is likely that older and feeble individuals were excluded. Singer et al.33 reported on a group of consecutive parkinsonian male patients attending a movement disorders clinic and compared the prevalence of autonomic symptoms with a group of healthy elderly controls. They found that the prevalence of urinary urgency (46%) and sensation of incomplete bladder emptying (42%) was significantly higher than in controls (3% and 16% respectively). Sakakibara et al.29 studied 115 PD patients (52 men and 63 women) and compared them to controls. All urinary symptoms were significantly higher in PD. Urgency (42% women, 54% men); daytime frequency (28% women, 16% men); nighttime frequency (53% women, 63%men); urge incontinence (25% women, 28% men); retardation in initiating urination (44% men); prolonga tion/poor stream (70% men); straining upon urination (28% women).

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Lemack et al.17 selected 80 men and 39 women with mild to moderate PD (Hoehn and Yahr lower than stage 3) and performed a questionnaire-based assessment using the American Urological Association Symptom Index (AUASI) in men and the Urogenital Distress Inventory-6 (UDI-6) in women. Men scored higher than age-matched controls with similar values to those of men with symptomatic benign prostatic hyperplasia. Results were less clear with PD women, who scored higher than non-agematched volunteers but lower than an age-matched group of women (unaffected neurologically) presenting for urological evaluation. DISTRIBUTION AND CHARACTERISTICS OF URINARY SYMPTOMS Urinary symptoms are grouped either as irritative, encompassing frequency, urgency and urge incontinence, or as obstructive, represented by hesitancy and weak urinary stream. Irritative symptoms invariably predominate. Murnaghan22 found a proportion of 73% (8/11) irritative versus 27% (3/11) obstructive. Raz27 examined 15 urologically symptomatic PD patients who were not on anticholinergics. Seventy three percent (11/15) had irritative symptoms and 36% (4/11) obstructive. Pavlakis et al.24 reported a distribution of 57% irritative, 23% obstructive, and 20% mixed symptomatology in a group of 30 PD patients. Berger et al.7 reported a distribution of 83% irritative and 17% obstructive in a group of 29 PD patients. Eighty five per cent of the Chandiramani et al.9 retrospective study of 41 PD patients (35/41) had urgency and frequency (but not incontinence), while only 15% (6/41) had troublesome incontinence as their main complaint, without mentioning if it was preceded by urgency. Niimi et al.23 studied seven patients with autonomic failure due to PD. Autonomic failure in PD was defined by the following criteria: 1. Progressive, systemic autonomic failure with predominant cardiovascular dysregulation, including orthostatic hypotension or postprandial hypotension 2. Parkinsonism as sole somatic neurologic manifestation 3. Responsiveness of parkinsonism to levodopa over a long period 4. Exclusion of drug-induced and other secondary forms of parkinsonism by neuroimaging and neurophysiological examinations 5. Absence of cerebellar and pontine atrophy on magnetic resonance imaging All patients were assessed after being taken off medications for one week. Irritative symptoms were present in five, while obstructive symptoms were present in none. Raudino26 reported on the presence of nonmotor symptoms during off periods in 22 patients. Urinary symptoms of frequency and urgency were reported in two and three instances, respectively. Using depression as an example, the author suggested that it is necessary to determine whether any particular nonmotor symptom coincides with an off period or is independent of it. Obstructive symptoms are less consistently present. They may sometimes be absent,23,25 even in the presence of detrusor arreflexia,25 a urodynamic finding well known for its association with hesitancy and weak urinary stream.

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Certain urinary symptoms are mentioned in only a few reports. “Urinary retention” was reported in 10% of one series.24 These symptoms may be related to the “sensation of incomplete bladder emptying” mentioned by others.33 Post-void dribbling was seen in 7% of the same series.24 The so-called “insensitive” incontinence is, in the opinion of one reviewer,35 seen in patients with more advanced disease, but no additional data are provided. Objective incomplete bladder emptying can occur in PD but is not a frequent finding—but perhaps it is not consistently searched for. Chandiramani et al.7 reported that only 16% (5/32) of their PD patients had a post-void residual (PVR) of more than 100 ml. Specific correlation with obstructive symptoms was not offered. There is limited information regarding the time of appearance of urinary symptoms in PD in relation to the motor symptoms. One of the few reports that specifically investigated the issue of time of appearance of urinary symptoms in relation to motor symptomatology was Chandiramani et al.9 They found that urological symptoms in PD would usually follow the motor symptoms by an average of 5.75 years. There is also data suggestive that disease severity correlates with presence of urological symptoms. In the Araki et al.6 study of 70 PD urologically symptomatic patients, symptom index scores increased with disease severity, in particular the obstructive component of the score and its best urodynamic correlate was an elevated post-void residual. Sakakibara et al.30 studied 123I-β-CIT SPECT scans of seven PD patients with urinary dysfunction and compared them to four PD patients free of urinary symptoms. The uptake was significantly reduced in the former group, suggesting a link between severity of the nigrostrial dopaminergic deficit and presence of urinary symptomatology. Although the seven urologically symptomatic PD patients had higher mean Unified Parkinson’ Disease Rating scale (UPDRS) score and a higher mean Hoehn and Yahr stage, the difference did not achieve significance. No difference was noted in terms of duration of disease. In conclusion, urological symptoms are more prevalent in the PD population at large, but especially in men. They tend to be irritative rather than obstructive. Urological symptoms may follow motor symptoms by a few years. Although they are commonly seen even in the early stages of the disease, they become more prevalent as the disease progresses. DETRUSOR HYPERREFLEXIA Detrusor hyperreflexia is a cystometric finding characterized by the presence of involuntary detrusor contractions in response to bladder filling that the patient is unable to inhibit, with pressure values exceeding 15 cm of water.5,24,20 This “hyperactive” bladder is able to generate a subjective perception of fullness and a desire to void at an early stage in the course of filling the bladder.25 A correlation has been described of irritative symptom scores with low maximum cystometric capacity and low volume at initial desire to void.6 Detrusor hyperreflexia therefore represents the immediate underlying cause of the irritative urinary symptoms.

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Cystometric studies have revealed a very high incidence of detrusor hyperreflexia in PD6,7,22,25 and other etiologies of parkinsonism.15 The reported prevalence of detrusor hyperreflexia among urologically symptomatic individuals ranges from 45% to 100%.4,6,7,13,15,22,24,25,27 Araki et al.6 assessed 70 PD consecutive PD patients referred for evaluation of urinary symptoms in whom obstructive etiologies had been excluded. Detrusor hyperreflexia was present in 67% (47/70) (free of additional abnormalities in the voiding phase). Moreover, detrusor hyperreflexia may also be found in urologically asymptomatic PD patients. Murnaghan22 reported that 25% (7/28) of PD patients in his study had unhibited contractions. Two of these patients had no urinary symptoms.22 Stocchi et al.36 reported a 37% (11/30) prevalence of detrusor hyperreflexia in 30 PD patients, of which 73% (8/11) had no urinary symptoms. Raz reported a very close clinical correlation of irritative symptoms with detrusor hyperreflexia.27 However, in a small numbers of cases detrusor hyperreflexia may coincide with obstructive symptoms (Murnaghan 1961; Galloway, 1983; Pavlakis et al., 1983; Fitzmaurice et al., 1985, Berger et al., 1987).7,13,15,22,24 Araki et al. also found a similar correlation.6 There is limited information regarding conditions that predispose to the development of detrusor hyperreflexia. Stocchi et al.36 reported that, of their 30 PD patients, those with a normal urodynamic pattern (36.6%) had significantly less severity of disease and a shorter duration of disease in years than those who had abnormal patterns. Araki et al.6 studied 70 PD patients who had been referred for urological evaluation and who were free of obstructive etiologies. Sixty seven percent (47/70) had pure hyperreflexia, with the majority (42/47) being in Hoehn and Yahr stage 3 or higher. DETRUSOR ARREFLEXIA Detrusor arreflexia, is a cystometrograhic finding where there is a decreased sensation during filling and an increased bladder capacity25,27 on the order of 600 ml or higher, and a desire to void usually first experienced at a high filling volume.3 The post-void residual volume is higher than 100 ml.3 This results in hesitancy and weak urinary stream.27 DETRUSOR ARREFLEXIA IS UNCOMMON IN PD Prevalence figures in series of urologically symptomatic patients3,13,22,24 have ranged from 0% (0/9)13 through 11%6 to 27% (4/15).27 The only report with unusually high prevalence figures for detrusor arreflexia comes from Porter and Bors, with a figure of 43% (19/44),25 a discrepancy that remains unexplained. Once faced with detrusor arreflexia in a PD patient, the clinician should consider anticholinergic effect, multiple system atrophy, and myogenic arreflexia. According to some,20 anticholinergics are the most common cause of detrusor arreflexia in PD patients. Although the concurrent use of anticholinergics is frequently mentioned in series reporting findings of detrusor arreflexia in PD, many studies lack careful detail in their clinical correlations.7,22,24,25

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There are few reports of urologically symptomatic PD patients in which the confounding effect of anticholinergics has been factored in. Raz withdrew anticholinergics one week prior to the urodynamic investigations.27 He still found a prevalence of 27% for detrusor arreflexia. On the other hand, Stocchi et al.36 did not find detrusor arreflexia in any of their 30 PD patients—symptomatic or asymptomatic—who were studied with urodynamics with anticholinergics also having been withheld. Moreover, Araki et al.,6 when reporting on 70 PD patients with urological symptoms, included 20 who were on anticholinergics and in whom they could not find a urodynamic correlation with atonia. Once drug effect has been excluded, the next step is to consider benign prostatic hypertrophies and other forms of obstruction (see section below, “Coexistent Obstructive Uropathies”) causing muscle fiber injury by overdistention, also known as “myogenic arreflexia.”35 However, a similar process may also occur in the absence of obstruction. Araki et al.6 studied 70 PD patients referred for urological evaluation and who were free of obstructive etiologies. They found six patients (9%)—all stage 4—who had hyperreflexia with impaired contractile func tion.* To explain this finding, the authors raised a superimposed myopathic process similar to what has been reported in the aged.28 Perhaps this process explains older reports in which some cases of detrusor arreflexia were associated with irritative rather than obstructive symptomatology.3,7,22,25 Finally, detrusor arrefleixa, especially in the absence of anticholinergic effect or “myogenic arreflexia,” should raise the possibility of multiple system atrophy. Please refer to the section, “Differentiation of PD from Multiple System Atrophy,” in this chapter. Although less clearly understood, detrusor arreflexia may also be asymptomatic. Murnaghan22 studied 18 PD patients selected for basal ganglia surgery and who were asymptomatic from the urological standpoint. Three patients had detrusor arreflexia. However, this finding has not been reproduced in more recent series. COEXISTENT OBSTRUCTIVE UROPATHIES Obstructive uropathies (i.e., benign prostatic hypertrophy in the man, stenosis of the bladder neck in the woman) have been recognized as causes in their own right of both irritative and obstructive symptoms in the general population.35 Such irritative symptoms associated with obstructive uropathies are equally the product of a detrusor hyperreflexia and indistinguishable from the purely neurogenic type. Certain investigations have pointed to the presence of obstructive uropathies as contributing causes of urinary symptoms in some PD patients.4,7,13,24 The prevalence figures vary from 17% to 33%.7,13,24 However, correlation with specific obstructive symptoms is at times not outlined with sufficient clarity.7,13,24 DYSFUNCTION OF INFRAVESICAL MECHANISMS The dysfunction of infravesical mechanisms (DIVM) encompasses the dysfunction of the striated urethral sphincter and that of the pelvic floor. Either dysfunction may occur alone

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or in combination. DIVM has been inconsistently reported in variable numbers,3,22,24,36 including its complete absence.13 Correlation with clinical symptomatology is frequently inadequate or lacking,3,22,24 and therefore its clinical significance is unclear. Different kinds of dysfunctions have been described. In some cases, the descriptions are poorly characterized and may not be confirmed again in other reports. The presence of DIVM was suggested by a number of early reports where an elevated urethral pressure profile was noted in a proportion of PD patients. Eighteen per cent of patients (2/11) in a series of PD patients with urinary symptoms had evidence of increased urethral resistance at the external sphincter level.22 Adequate correlation with symptoms was not presented in this particular report. Berger et al.7,8 performed uroflow studies in 15 urologically symptomatic patients and demonstrated decreased flow in 10 (less than 12 ml per second). Only in 5 of these 10 patients was there evidence of an obstructive uropathy. A clear clinical correlation with obstructive symptoms or other manifestations was not available in this report. Although the possibility could be raised that the other five patients may have harbored a DIVM, no such activity was documented on sphincter EMG testing during voluntary detrusor contraction. Raz was able to demonstrate changes in urethral pressure profile as a result of dopaminergic treatment in 66% (10/15) of a group of PD patients with urinary symptoms who were off anticholinergics and free of BPH.27 Treatment with L-dopa reduced the closure pressure of the urethra as measured by urethral pressure. Interruption of treatment for a week resulted in an increase in the urethral pressure profile. Raz proposed that outlet dysfunction played an important role in the urinary symptomatology of PD by way of an increased tone of the external sphincter, the absence of a well coordinated pelvic floor relaxation during micturition and the lack of normal external sphincter function during interruption of micturition. The most consistent DIVM consists of delayed relaxation of the striated urethral sphincter and pelvic floor, also known as sphincter bradykinesia. To understand this phenomenon, one must first understand that there is a normal guarding reflex where there is an increase in striated muscle activity during vesical filling before the onset of detrusor contraction. Sphincter bradykinesia would be an abnormality where involuntary EMG activity persists through at least the initial part of the expulsive phase of the CMG.24 In the Pavlakis et al. series,24 11% (3/28) had sphincter bradykinesia. Galloway15 reported that 42% (5/12) of his urologically symptomatic patients were unable to relax the external urethral sphincter with voiding and were associated with low flow rates. Andersen et al.3 studied 24 urologically symptomatic patients with parkinsonism (the words “Parkinson’s disease” are not used). The same authors subsequently revised their data in a subsequent article.5 They reported electromyographic findings in these 24 PD patients. The authors did not specify whether all 24 patients were symptomatic. Twentyone per cent (5/24) had impaired sphincter control defined as poor ability to contract or relax the sphincter on command. *Detrusor hyperreflexia with impaired contractile function was defined as an overactive bladder with uninhibited detrusor contractions associated with low maximum detrusor pressure during the voiding phase of less than 40 cm of water with a slow pressure increase and a large postvoid residual volume.6

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Pavlakis et al.24 also found pseudodyssynergia in two patients. This phenomenon was defined as “an attempt at continence by voluntary contraction of the pelvic musculature during an involuntary detrusor contraction.”35 These two patients were part of a group of ten in which the maximum flow rate was decreased. The clinical role of this phenomenon was not defined because of coexistent prostatic obstruction. Pseudodyssynergia has not been reported in any of the subsequent articles of this review. Sphincter “tremor” described in 11/12 patients of Galloway’s series,15 has also not been confirmed in subsequent reports. While Pavlakis et al.24 called attention to the absence of vesicosphinter dyssynergia, Andersen et al.3,5 also reported two patients with an abnormality they initially called “dyssynergia” in their first article3 but later labeled “spasticity.”5 In the Araki et al.6 series of 70 PD patients referred for urological evaluation and who were free of obstructive etiologies, they found 2 patients (3%) who had both hyperreflexia and detrusor-sphincter dyssynergia (2/70). DIVM may also be asymptomatic. Berger et al.7,8 studied 29 PD patients (24 men and 5 women) who were urologically symptomatic. They reported sporadic involuntary electromyography activity of the external sphincter during involuntary detrusor contractions in 61% (14/23 patients so tested) without any case resulting in obstruction. They termed this phenomenon involuntary sphincteric activity. Because the phenomenon was not associated with radiographic or manometric evidence of obstruction at the level of the membranous urethra, the authors concluded that it did not meet criteria for the definition of detrusor sphincter dyssynergia. This activity is reminiscent of pseudodyssynergia in that both occur in response to involuntary detrusor contractions, but pseudodyssynergia is seen as a voluntary or conscious act. Stocchi et al.36 studied 30 PD patients irrespective of presence of urological symptoms. They found that 27% (8/30) had an inability to relax the perineal muscles immediately and completely when asked to initiate micturition. This was their only abnormal finding (they had normal cystometrics). Not a single one is described with hesitancy or weak urinary stream. This subgroup of 8 patients had more severity and longer duration of disease than 11 patients with totally normal findings. An additional three patients (10%) had the same abnormality but associated with detrusor hyperreflexia. One of the three patients had urinary incontinence, diurnal and nocturnal, but the authors do not specify if preceded by urge incontinence (no mention of hesitancy or weak urinary stream). Pavlakis et al.24 reported “neuropathic potentials” in two of their patients. Andersen et 5 al. also reported two patients as having a “sphincter paralysis” in their 1976 report and as “flaccid sphincter” in their 1985 report. These cases most likely represent multiple system atrophy rather than PD. EFFECT OF DOPAMINERGIC MEDICATION One has to distinguish between effects during bladder emptying and effects during bladder filling. The effects on bladder emptying are frequently referred to as effects on voiding efficiency and include parameters such as bladder contractility, urethral pressure, and urethral flow. The effects on bladder filling are particularly focused on the effects on

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detrusor hyperreflexia, although effects on other parameters are also of interest such as urethral closure pressure. Effect on Bladder Emptying Phase (a.k.a. Voiding Efficiency) 1. One of the earliest reports on the effect of dopaminergic treatment on urinary function of the parkinsonian patient suggested an “obstructive” effect of L-dopa.21 The authors studied 24 PD patients (only one woman), questioning for urinary symptoms and performing air cystometrograms and excretory urography including voiding cystourethrograms (only 1 patient did not have a voiding cystourethrogram). They compared two subgroups: 18 patients receiving L-dopa (1.25 to 12 gr/day) and 6 patients not on L-dopa. These authors reported that 83% (15/18) of the 18 patients on L-dopa had radiographic evidence of bladder outlet obstruction, excluding a single patient with BPH. Specifically they reported “absence of the normal bladder neck funnel and a prominent lip of the posterior vesical neck, protruding into the urethral lumen.” Ten of the 15 “radiologically obstructed” patients had obstructive symptoms (so did the one patient with BPH), 1 patient had irritative symptoms, and 5 patients were asymptomatic. Murdock et al.21 contrasted this group with six patients who were not on L-dopa. One was demented and could not be adequately interviewed. Only one of the other five had obstructive symptoms but also had an enlarged prostate. The rest (two with irritative symptoms and two with no symptoms) had no radiographic evidence of obstruction. Murdock et al.21 concluded that a pharmacological bladder neck obstruction could be caused by the alpha-adrenergic properties of the metabolites of levodopa. They postulated also that beta-adrenergic activity exerted by this drug could result in a decrease in bladder tone. We believe, however, that the postulated alpha-sympathomimetic activity of Ldopa metabolites as a cause of functional obstruction should be much less of a factor at present, given the concomitant use of dopa decarboxylase inhibitors in current practice. Moreover, Murdock et al.’s results are contradicted by all subsequent investigations on the subject. 2. Raz performed experiments in anesthetized dogs where urethral pressure profile (UPP) was measured before and after an infusion of Ldopa.27 L-dopa produced a rapid and persistent drop in closure pressure of the urethra. Treatment with a curare-like striated muscle relaxant produced a similar effect without further enhancement with L-dopa. L-dopa therefore appeared to exert its action on the distal part of the urethra (external sphincter) and probably has no effect on the smooth muscle component of the urethral closure mechanism.27 Raz also performed in vitro studies on excised urethra and bladder tissue of mongrel dogs.27 The normal inhibition of basic rhythm and tone of bladder smooth muscle when exposed to a bath of noradrenaline was not modified by preor post-treatment with L-dopa. The normal increased rhythmic activity and basic tonus of the smooth muscle of the urethra when exposed to noradrenaline was

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similarly unaffected by the addition of L-dopa. This corroborated that there was no effect of L-dopa on the smooth muscle of these tissues. Raz then demonstrated a decrease in the UPP after treatment was instituted with L-dopa in 10 PD patients affected with urological symptoms.27 In patients whose treatment with L-dopa was interrupted for one week (number of patients not specified), he reported an increase in UPP. In our opinion, Raz’s important work has to be viewed as reflective of effect on PD patients when first exposed to L-dopa in contrast to subsequent work performed in more advanced cases such as fluctuators.37 3. In Stocchi et al.’s series of 30 PD patients,36 studied irrespective of presence of urological symptoms), there were 11 with delayed or incomplete perineal floor relaxation. They all experienced greatly improved perineal muscle control after subcutaneous injection of apomorphine (4 mg). There was no effect on the detrusor hyperactivity. 4. In Christmas et al.’s10 series of 10 PD patients with urinary symptoms, urodynamic studies were performed before and after subcutaneous administration of apomorphine, a dopamine receptor agonist. Voiding efficiency improved after apomorphine injection, with an overall decrease in bladder outflow obstruction. There was an increase in mean and maximum flow rate in nine patients and reduction in postmicturition residual volume in six patients. This was accompanied by fluoroscopic evidence of widening of the urethra at the level of the distal sphincter mechanism. Of additional interest was that three patients were unable to void during the off state despite considerable discomfort and a feeling of bladder fullness. 5. Uchiyama et al.37 reported effects of a single dose of CD/LD 100 mg on urinary function of 18 PD patients who had severe wearing off. Patients were on L-dopa and dopamine agonists but not on anticholinergics. On one hand, there was an increase in detrusor contraction (force of contraction); on the other hand, there was an increase in urethral obstruction. The net effect favored the increase in bladder contraction with a decrease in residual volume. Consequently, one can say there was a consistent improvement in voiding efficiency. In summary, the reports by Stocchi et al.,36 Christmas et al.,10 and Uchiyama et al.37 have helped to buttress the idea of an active role of dopaminergic stimulation in improving voiding efficiency. The two first reports used apomorphine and demonstrated a decrease in bladder outflow resistance including promoting relaxation of the perineal floor during micturition. In contrast, the last report used levodopa and showed increase in bladder obstruction, but the net effect—via improved bladder contractility—was similarly an improvement in voiding efficiency. Effect on Bladder Filling Phase (a.k.a. Bladder Storage) 1. Fitzmaurice et al.13 reported on nine urologically symptomatic patients with detrusor hyperreflexia. The effects of levodopa were variable. Six patients had less severe detrusor hyperreflexia when off (including one patient whose hyperreflexia disappeared when off), while three were better when on levodopa. A description of impact of treatment on the actual symptoms was not provided.

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2. In Christmas et al.’s report, detrusor function during filling and voiding was altered, albeit inconsistently, by apomorphine10 with detrusor hyperreflexia improved in some cases and exacerbated in others. However, in three patients, poor detrusor contractility contributed to voiding dysfunction during the off state. After apomorphine injection, voiding detrusor pressure in these three patients increased, while calculated bladder outflow resistance fell, resulting in considerable improvement in voiding. No information was provided as to whether these patients were on anticholinergics. Christmas et al.10 pointed out that, since their patients were all premedicated with domperidone, a peripheral dopamine antagonist, it follows that the effect both on smooth and striated musculature of the lower urinary tract are mediated by changes in the central dopaminergic transmission. 3. Uchiyama et al.,37 in their study of 18 patients with PD who had severe wearing off, showed an unpredictable effect on bladder function during filling. Urinary urgency (with or without detrusor hyperreflexia or low compliance bladder) was aggravated in nine patients (50%), alleviated in three (17%) and unchanged in six (33%). Uchiyama’s population represented a particular type of PD patient, namely advanced disease, with severe wearing off, and not receiving anticholinergic therapy. In summary, the effect of dopaminergic stimulation on detrusor behavior during filling is not predictable, with both improvement and aggravation of detrusor hyperreflexia as possibilities. Additional factors must be playing a role. DIFFERENTIATION OF PD FROM MULTIPLE SYSTEM ATROPHY A proportion of patients with parkinsonism do not have PD but other forms of degenerative disease such as Lewy body disease, progressive supranuclear palsy, and multiple system atrophy (MSA). In MSA, there is a progressive cell loss in the motor nuclei of the striated sphincters located in the S2–S4 segments of the spinal cord (Onuf’s nucleus), a finding that has not been reported in PD.14,38 MSA frequently courses with prominent urological symptoms. Since this disease carries a worse prognosis, early differentiation from PD may allow for more rational management.38 Investigators have consequently searched for clinical, urodynamic and electrophysiological differences with PD. Chandiramani et al.9 performed a retrospective study of 52 patients with MSA and 41 patients with IPD. Sixty percent (31/52) of MSA patients had urinary symptoms preceding or coinciding with the diagnosis of the disease. Sixteen patients reported frequency, urgency, or incontinence before the onset of parkinsonism, and 15 patients developed urinary symptoms at the same time as parkinsonism. In contrast, in 94% of IPD patients, the urogenital symptoms clearly followed the neurological diagnosis by a few years. The mean duration of IPD was 9 years of age (range 1 to 25) while the mean duration of urinary symptoms was 3.25 years (range 1 to 10). Only two patients had urinary symptoms at the time of diagnosis of IPD. Two other series identified in a review by Fowler also confirm a 60% prevalence of early urinary symptoms in MSA.14

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The severity of the urinary symptoms, including incontinence in patients with MSA, is more marked than in PD.14 In Chandiramani’s series,9 patients with MSA were more likely to suffer from troublesome incontinence (73%). They were also more likely to have elevated postvoid residuals than PD patients (66% versus 16%, respectively). Among the males with MSA in Chandiramani et al’s series, 93% had erectile dysfunction (ED), including 48% where this complaint preceded the diagnosis of MSA. However, ED can also be seen in PD, although the proportion of early ED is less.32 One would also expect poor response to urological surgery targeting prostatism, even poorer than with PD. All 11 men with MSA in Chandiramani et al.’s series9 who had a TURP were incontinent postoperatively. See the section below, Effects of Urological Surgery. Fowler14 has proposed the following five urogenital criteria as favouring the diagnosis of MSA: 1. Urinary symptoms preceding or presenting with parkinsonism 2. Male ED preceding or presenting with parkinsonism 3. Urinary incontinence 4. Significant post-micturition residue (>100 ml) 5. Worsening bladder control after urological surgery However, none of these criteria is sufficiently specific and each requires analysis within the context of the individual case. Berger et al.8 reported that all patients with ShyDrager-Syndrome (a variant of MSA with prominent orthostatic hypotension) evaluated with a voiding cystourethrogram had an open bladder neck at rest. In cases of PD, only those patients who had undergone a prior prostatectomy had this finding. Therefore, the presence of an open bladder neck during filling in someone who has not had prior surgery would point to the presence of sympathetic dysfunction and be suggestive of a diagnosis of MSA. The cell loss in Onuf’s nucleus reported in MSA has been associated with electromyographic changes of denervation (fibrillations and positive sharp waves) and reinnervation (abnormal polyphasic potentials of prolonged duration). Such urethral sphincter EMG abnormalities are also reflected in the anal sphincter,11 a more easily accessible structure. Stocchi et al.36 found EMG to provide important differentiating data between MSA and PD. The main differentiating feature of the 32 MSA patients compared to 30 PD patients was abnormal sphincter EMG in 24/32 (75%) MSA patients as compared to none in the PD patients. Vodusek conducted a comprehensive review on the subject.38 He concluded that anal sphincter EMG abnormalities could distinguish MSA from PD in the first five years after the onset of symptoms and signs, if other causes for sphincter denervation (such as surgeries) had been ruled out. With such criteria, however, as Vodusek readily admits, sphincter EMG offers a low sensitivity. PATHOGENESIS OF VOIDING DYSFUNCTION IN PD Voiding is a function of the autonomic nervous system with a core segmental representation in the spinal cord. As the bladder fills, afferent stimuli are conducted to the S2–S4 segments.

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During filling, the external and internal urethral sphincters are tonically contracted, and there is an increased tone of striated musculature of the pelvic floor. At a certain level of bladder distention, a reflex efferent response is triggered by activated motor neurons, which stimulate the detrusor muscle via the pelvic nerve (parasympathetic) and relax the internal urethral sphincter via parasympathetic inhibition of sympathetic terminals that innervate the bladder neck. At the same time, inhibition of Onuf’s nucleus and pudendal motor nuclei cause relaxation of the striated urethral sphincter and the perineal floor. This segmentally organized function is subject to facilitatory and inhibitory impulses from higher neurologic centers that allow for voluntary control of the detrusor reflex. Specifically, impulses from the cortical micturition center in the mesial frontal lobes36 would connect to the pontine-mesencephalic reticular formation. This pathway is further influenced by the basal ganglia, the thalamic nuclei, and the anterior vermis of the cerebellum (Pavlakis et al., 1983; Andersen et al., 1985).5,24 Micturition is also influenced by the anterior cyngulate gyrus, the locus coeruleus, and the nucleus tegmento lateralis dorsalis.36 Based on a series of experiments and subsequent experience with basal ganglia surgery, it is currently believed that the basal ganglia exert an inhibitory effect on the ponto-mesencephalic micturition center. Lesions of basal ganglia, as in PD, would result in partial or total disconnection of the micturition reflex from voluntary control. The result would be unhibited detrusor contractions elicited at low volume threshold (detrusor hyperreflexia).5 In PD, the presence of detrusor hyperreflexia with vesicosphincter synergy is therefore suggestive of a suprapontine lesion. In contrast, in multiple sclerosis, the finding of detrusor-sphincter-dyssynergia denotes a lesion of the connections between the pontine micturition center and the spinal cord centers of micturition. Lewin et al. performed pivotal experimental studies in cats that are still being cited as backbone for current theory on pathophysiology.18,19 Lewin et al. stimulated the thalamus and different sites of the basal ganglia and found that the stimulation was inhibitory of detrusor contractions. The inhibition ranged from prolongation of intercontraction interval of the detrusor to occasional complete suppression of detrusor contractions with the activity only resuming after stimulation was stopped. It is interesting to note that stimulation of the red nucleus, the subthalamic nucleus, and the substantia nigra was more inhibitory than that of the thalamus. This may suggest that current deep brain stimulation procedures may be more effective in improving voiding dysfunction if STN rather than the thalamus is the target. Stereotaxic thalamotomy in parkinsonian patients, on the other hand, demonstrated an increase in detrusor activity.22,25 The understanding of the pathophysiology of urethral sphincter dysfunction owes a lot to Raz’ work.27 Raz pointed out that, in the initiation of normal micturition, one of the important stages is relaxation occurring prior to maximal bladder contraction. In Parkinson’s disease, there can be failure of the perineal muscle floor/shincter to relax rapidly before the detrusor contraction.24 This delay in the normal relaxation of the pelvic floor would produce hesitancy and slow stream. This phenomenon of sphincter bradykinesia seems to be a condition peculiar to the parkinsonian patient, albeit not universally present. Pavlakis et al. believe that it represents a manifestation of skeletal muscle hypertonicity involving the perineal floor.

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Studies in conscious rats suggest that D1 receptors (linked to stimulation of adenylate cyclase39) tonically inhibit the micturition reflex.31 Administration of mixed D1/D2 agonists in anesthetized MPTP-lesioned monkeys increased their pathologically reduced bladder volume threshold.40 This effect could be antagonized by pretreatment with a D1 antagonist. This inhibitory effect of the D1 receptors would presumably be exerted via the forebrain system,39 perhaps through a potentiation of the GABAergic system in the basal ganglia.40 The loss of D1 activation in Parkinson’s disease may therefore underlie the bladder overactivity in Parkinson’s disease. On the other hand, similar studies in conscious rats suggest that D2 receptors are involved in facilitation of the micturition reflex.31 The pure D2 agonist bromocriptine administered to MPTP-lesioned monkeys decreases their already pathologically reduced bladder volume threshold even further.40 This excitatory effect of D2 receptors on the micturition reflex would be exerted directly on the brain stem.39 This combination of effects would result in a D1 effect during bladder filling and a D2 effect during bladder emptying. We would expect a salutary effect of D1 agonists on bladder control in Parkinson’s disease. Studies comparing the effects of currently available “pure” D2 versus mixed D1/D2 receptor agonists on the voiding dysfunction of PD patients would be of interest. We are only aware of one study (reported in abstract form) where patients with Parkinson’s disease affected with urinary urgency and frequency while on bromocriptine experienced an improvement in their symptoms when switched to pergolide.16 TREATMENT TREATMENT OF IRRITATIVE SYMPTOMS The irritative symptoms in PD—themselves a manifestation of detrusor hyperreflexia— frequently respond to anticholinergics,5,20 although there are no reports specifically evaluating the effectiveness and safety in PD.34 Examples of commonly prescribed anticholinergics include oxybutinin (Ditropan®), propantheline bromide (Pro-banthine), hyoscyamine sulfate (Cystopaz® and other), flavoxate hydrochloride (Urispas®), and tolteridone tartrate (Detrol®).1 Oxybutinin is possibly the most frequently used of these medications, with dosages ranging between 2.5 mg at hs and 5 mg t.i.d. Side effects include the production of symptoms of obstructive type20 such as hesitancy and weak urinary stream. Other well known side effects include dry mouth, difficulty with visual accommodation, constipation, and aggravation of glaucoma. Tolterodine and its major active metabolite, DD 01, are muscarinic receptor antagonists that, in animals, are more active on the bladder than on the salivary glands. Based on an analysis of four 12-week double-blind studies in more than 1,000 patients, the dose of 2 mg PO BID has been proven effective. Tolterodine decreases the number of incontinence episodes per 24 hr, decreases by 20% the number of micturitions per day (same as oxybutinin), and increases the volume voided per micturition by 22% (oxybutinin increased it by 32%).1 Tolterodine may cause less side effects,1 such as a lower incidence of severe dry mouth as compared to oxybutinin (4% versus 29%). Cardiac and cognitive effects are

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alleged to be less, but the origi nal trials excluded those patients with history of “serious side effects” on oxybutinin. In addition, precautions related to narrow angle glaucoma or urinary retention remain relevant to tolterodine as they are to the other anticholinergics. Some experts have suggested using the extendedrelease form of anticholinergics to prevent high serum levels during therapy with the idea that this may result in less likelihood of cognitive dysfunction.34 Examples include tolterodine LA at doses of 2 to 4 mg QD and oxybutinin LA at doses of 5 to 30 QD.1 More recently, oxybutinin transdermal (Oxytrol®) has been released. This route avoids first-pass metabolism, resulting in a lower concentration of its active metabolite. Since this metabolite has a higher affinity in vitro for parotid cells than for bladder cells, it may explain the low incidence of dry mouth reported with transdermal oxybutinin.2 If therapy with a single anticholinergic agent proves to be suboptimal, the tricyclic antidepressant imipramine hydrochloride (Tofranil®) can be used in combination, since it has a different receptor site profile.35 TREATMENT OF OBSTRUCTIVE SYMPTOMS The successful treatment of the “obstructive” symptoms of hesitancy and weak urinary stream begins with a careful drug history, searching for medications with an anticholinergic effect. Urodynamic studies should follow, investigating for the presence of detrusor arreflexia, DIVM, or an obstructive uropathy. A frequent clinical setting for the development of detrusor arreflexia in PD occurs when symptomatic detrusor instability (hyperreflexia) is treated with anticholinergics. This may result in urodynamic findings of involuntary bladder contractions associated with incomplete emptying secondary to unsustained detrusor contractions.35 In that case, management consists in combining anticholinergics with clean intermittent catheterization by self or others.35 Successful management is will also help in preventing recurrent urinary tract infections. The frequency with which catheterizations should be performed will depend on the degree of hesitancy or the volume of the post void residual.35 The patient who attains continence at the cost of not being able to void at all will have to undergo catheterization every 5 to 8 hr, depending on the residual volume, which should be maintained below 500 cc.35 Finding detrusor arreflexia in the absence of anticholinergic treatment and in the absence of overdistention injury (“myogenic arreflexia”) secondary to BPH (or other obstructive uropathies) raises the possibility of multiple system atrophy. Patients with MSA are also more likely to have poor bladder compliance and sphincter insufficiency.8 This could result in episodes of incontinence, including overflow, and stress incontinence (in addition to hesitancy and weak stream). Intermittent catheterization with or without anticholinergics (i.e., oxybutinin) may be the initial treatment.8,9 In some cases desmopressin spray may be of use.9 Due to the motor dysfunction, treatment may evolve to permanent indwelling catheterization or suprapubic cystostomy.8,34 Stress incontinence in females can be treated with urethral suspension or a sling procedure, but if there is concurrent detrusor hyperreflexia, the result may be suboptimal.34 Another possible cause of obstructive symptoms is represented by DIVM. In the cases of external urethral sphincter bradykinesia or pseudodyssynergia with high voiding

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pressures (above 90 cm H2O), certain authors recommend anticholinergics and intermittent catheterization (similar to mixed detrusor hyperreflexia with incomplete bladder emptying).35 The reason is that persistent high pressures are certain to result in damage to the bladder and, ultimately, to the upper urinary tract.35 Sphincter bradykinesia has also been shown to be responsive to dopaminergic treatment,10,27,36 while pseudodyssynergia may be correctable with biofeedback.24 EFFECT OF UROLOGICAL SURGERY Obstructive uropathies coexistent with PD may also cause obstructive symptoms, and at the same time they may trigger detrusor hyperreflexia in their own right. The obstructive symptoms may be further enhanced by an overdistention injury to the bladder (“myogenic arreflexia”), which may gradually resolve after relief of the obstruction. (It should be noted that “myogenic arreflexia” may also be secondary to a temporary obstruction of the bladder outlet).35 The surgical relief of a well documented bladder outlet obstruction is well advised in the PD affected patient. However, the patient should understand clearly that such surgeries (i.e., prostatectomy) are primarily indicated for relief of the obstruction and to avoid the need of catheterization,7 but they may not resolve the sometimes coexistent irritative symptoms. Resolution of the detrusor instability can be expected in 60 to 70% of patients postoperatively if the instability is the result of prostatic obstruction.35 Berger et al.7 reported persistence of urge incontinence in eight PD men who had undergone prostatic surgery with evidence of detrusor hyperreflexia in seven. They could not find any urodynamic parameters to predict preoperatively which hyperreflexic bladder would stabilize after successful relief of the obstruction.7 If urge incontinence persists after surgery, anticholinergic therapy may be added. If it still persists, a condom catheter drainage may be necessary. There are no urodynamic parameters capable of predicting preoperatively which hyperreflexic bladder will stabilize after successful relief of the obstruction. Urologists should be aware of the need to rule out MSA prior to surgery. In Chandiramani et al.’s series,9 postoperative results were very different for PD and MSA patients. These authors reported that three of the five IPD patients operated who underwent TURP reported a good result. One patient with an adequate flow rate had persistent urgency despite oral oxybutinin but improved considerably after intravesical oxybutinin. Another patient had a large PVR (post-void residual) after TURP and was said to have an atonic bladder of unknown etiology. Chandiramani et al. also reported that all 11 men with MSA who had a TURP were incontinent postoperatively. Nine (82%) had the problems immediately, and two (18%) eventually became incontinent within the year. Similarly, five anti-incontinence procedures in three women were unsuccessful.

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EFFECTS OF BASAL GANGLIA SURGERY There is very limited information on the effects of basal ganglia surgery on urological dysfunction. The few reports present contradictory results. Murnaghan reported results of basal ganglia surgery on urological symptoms and urological findings in 29 PD patients. Eight complained of bladder disturbances, and 11 had abnormal cystometrograms. Eleven patients had cystometrograms performed preand postoperatively. and only five were unchanged postoperatively. Normal bladder function was converted into hyperreflexic bladder in two out of four patients examined before and after stereotaxic lesions on the thalamic nuclei, whereas stereotactic lesions of the posterior limb of the internal capsule normalized three out four uninhibited bladders. Murnaghan concluded that thalamotomy may be associated with increased bladder tonus, pallidotomy with decreased bladder tonus and capsulotomy may decrease tonus but bladder sensation may be affected.22 In 1971, Porter and Bors25 also reported on the effects of thalamotomy on bladder function. They studied the effects of uni- and bilateral thalamotomy on 49 patients with PD (11 of whom had normal function). They concluded that neurogenic bladder dysfunction was more frequently seen in bilateral than in unilateral cases. It was only after bilateral stereotaxic surgery that improvement of bladder function could be consistently documented. The same authors then followed up on the status of 40 patients over a “long term” (4 to 8 months after their last operation, uni- or bilateral). These patients had somatic manifestations that had been “significantly improved” after the surgery (no quantification provided). The results indicated to the authors that the neurogenic bladder of the parkinsonian patient was responsive to surgical therapy, although the response was not as prompt or as successful as the treatment of the somatic manifestations. Furthermore, the subjective response of the individual was often more pronounced than the objective evidence of improvement. The authors also postulated that thalamotomy improved the post-void residual volume by relaxing the bladder floor and especially in the “hypoactive bladder,” by increasing the activity of detrusor muscle.25 This is consistent with the findings of Murnaghan. It would have been of interest to learn if the use of anticholinergics had decreased postoperatively as a possible alternative explanation to decrease in post-void residual. Andersen et al.4 examined 44 patients with parkinsonism, including 8 who had undergone thalamotomies. None of the eight patients had normal bladder function. The authors concluded that stereotactic operations on the thalamus could produce uninhibited bladder contractions with subsequent risks of urological disturbances. To date, there is only one report of effect of basal ganglia surgery on parkinsonian voiding dysfunction stemming from the new era that started in the 1990s.12 The authors studied five patients who had undergone bilateral implantation of subthalamic nucleus electrodes. These patients had not been assessed urologically preoperatively. Instead, they were studied urodynamically 4 to 9 months after surgery with comparisons made between the stimulator-on and stimulator-off states (no mention made as to being on or off levodopa during the procedures). The authors found consistent improvement in

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bladder capacity (bladder volume at which urinary leakage was observed or if leakage did not occur, bladder volume at unbearable desire to void) and reflex volume (bladder volume at first hyperreflexic detrusor contraction). REFERENCES 1. Abramovicz, M. et al., Tolterodine for Overactive Bladder, Medical Letter, 40:101–103, 1998. 2. Abramovicz, M. et al., Oxybutinin Transdermal (Oxytrol) For Overative Bladder, Medical Letter, 45(1156):38–39, 2003. 3. Andersen, J.T., Bradley, W.E., Cystometric, sphincter and electro-myelographic abnormalities in Parkinson’s disease, J. of Urol., 16:75–78, 1976. 4. Andersen, J.T., Hebjorn, S., Frimodt-Moller, C., Walter, S., Worm-Petersen, J., Disturbances of Micturition in Parkinson’s Disease, Acta Neurol. Scandinav., 53: 161–170, 1976. 5. Andersen, J.T., Disturbances of Bladder and Urethral Function in Parkinson’s Disease, Int. Urol. Nephrol., 1: 35–41, 1985. 6. Araki, L., Kitahara, M., Tomoyuki, O., Kuno, S., Voiding Dysfunction and Parkinson’s Disease: Urodynamic Abnormalities and Urinary Symptoms, J. Urol., 164(5): 1640–1643, 2000. 7. Berger, Y., Blaivas, J.G., DeLaRocha, E.R., Salinas, J. M., Urodynamic findings in Parkinson’s disease, J. Urol., 138:836–83, 1987. 8. Berger, Y., Salinas, J.N., Blaivas, J.G., Urodynamic differentiation of Parkinson Disease and the Shy Drager Syndrome, Neurourology and Urodynamics, 9:117–121, 1990. 9. Chandiramani, V.A., Palace, J., Fowler, C.J., How to recognize patients with parkinsonism who should not have neurological surgery, Brit. J. Urol., 80:100–104, 1979. 10. Christmas, T.J., Chapple, C.R., Lees, A.J., Kempster, P.A., Frankel, J.P., Stern, G.M., Milroy, E.J.G., Role of subcutaneous apomorphine in parkinsonian voiding dysfunction, The Lancet, pp. 1451–1454, December 24/31, 1998. 11. Eardley, L., Quinn, N.P., Fowler, C.J., Kirby, R.S., Parkhouse, H.F., Marsden, C.D., Bannister, R., The value of urethral sphincter electromyography in the differential diagnosis of parkinsonism, Brit. J. Urol., 64:360–362, 1989. 12. Finazzi-Agrò, E., Peppe, A., D’Amico, A., Petta, F., Mazzone, P., Stanzione, P., Micali, F., Caltagirone, C., Effects of Subthalamic Nucleus Stimulation on Urodyanmic Findings in patients with Parkinson’s Disease. 13. Fitzmaurice H., Fowler, C.J., Rickards, D., Quinn, N. P., Marsden, C.D., Milroy, E.J.G., Turner-Warwick, R.T., Micturition Disturbance in Parkinson’s Disease, Brit. J. Urol., 57:652– 656, 1985. 14. Fowler, C.J., Urinary Disorders in Parkinson’s Disease and Multiple System Atrophy, Funct. Neurol., 16: 277–282, 2001. 15. Galloway, N.T. M., Urethral Sphincter Abnormalities in Parkinsonism, Brit. J. Urol., 55:691– 693, 1983. 16. Kuno, S., Mizuta, E., Yoshimura, N., Differential effects of D1 and D2 agonists on neurogenic bladder in parkinson’s disease and MPTP-induced parkinsonian monkeys, Mov. Disord., 12 (Suppl. 1):63, 1997. 17. Lemack, G.E., Dewey, Jr., R.B., Roehrborn, C.G., O’Suilleabhain, P.E., Zimmern, P.E., Questionnaire-Based Assessment of Bladder Dysfunction in Patients with Mild to Moderate parkinson’s Disease, Urology, 56:250–4, 2000. 18. Lewin, R.J., Porter, R.W., Inhibition of spontaneous bladder activity by stimulation of the globus pallidus, Neurology, (Minneap) 15:1049–1052, 1965. 19. Lewin, R.J., Dillard, G.U., Porter, R.W., Extrapyramidal Inhibition of the Urinary Bladder. Brain Research, 4:301–307, 1967.

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20. Martignoni, E., Pacchetti, C., Godi, L., Micieli, G., Nappi, G., Autonomic Disorders in Parkinson’s Disease, J. Neural Transm., (Suppl.) 45:11–19, 1995. 21. Murdock, M.L., Olsson, C.A., Sax, D.S., Krane, R.J., Effects of levodopa on the bladder outlet, J. Urol., 113:803–805, 1975. 22. Murnaghan, G.F., Neurogenic Disorders of the Bladder in parkinsonism, Brit. J. Urol., 33:403– 409, 1961. 23. Niimi, Y., Ieda, T., Hirayama, M., Koike, Y., Sobue, G., Hasegawa, Y., Takahashi, A., Clinical and physiological characteristics of autonomic failure with parkinson’s disease, Clin. Auton. Res., 9:139–144, 1999. 24. Pavlakis, A.J., Siroky, M.B., Goldstein, L., Krane, R. J., Neurourologic Findings in Parkinson’s Disease, J. Urol., 129:80–83, 1983. 25. Porter, R.W., Bors, E., Neurogenic bladder in parkinsonism: effect of thalamotomy, J. Neurosurg., 34: 27–32, 1971. 26. Raudino, F., Non motor off in Parkinson’s disease, Acta Neurol. Scand., 104:312–313, 2001. 27. Raz, S., Parkinsonism and Neurogenic Bladder. Experimental and Clinical Observations, Urol. Res., 4:133–138, 1976. 28. Resnick, N.M., Yalla, S.V., Detrusor hyperactivity with impaired contractile function. An unrecognized but common cause of incontinence in elderly patients, JAMA, 257(22):3076–81, 1987. 29. Sakakibara, R., Shinotoh, H., Uchiyama, T., Sakuma, M., Kashiwado, M., Yoshiyama, M., Hattori, T., Questionnaire-based assessment of pelvic organ dysfunction in Parkinson’s disease, Autonomic Neuroscience: Basic and clinical, 92:76–85, 2001. 30. Sakakibara, R., Shinotoh, H., Uchiyama, T., Yoshiyama, M., Hattori, T., Yamanishi, T., SPECT imaging of the dopamine transporter with [123I]-β-CIT reveals marked decline of nigrostriatal dopaminergic function in Parkinson’s disease with urinary dysfunction, J. Neurol. Sci., 187:55– 59, 2001. 31. Seki, S., Igawa, Y., Kaidoh, K., Ishizuka, O., Nishizawa, O., Andersson, K.E., Role of Dopamine D1 and D2 Receptors in the Micturition Reflex in Conscious Rats, Neurology and Urodynamics, 20:105–113, 2001. 32. Singer, C., Weiner, W.J., Sanchez-Ramos, J., Ackerman, M., Sexual dysfunction in men with Parkinson’s disease, J. Neurol. Rehab., 3(4):199–204, 1989. 33. Singer, C., Weiner, W.J., Sanchez-Ramos, J.R., Autonomic Dysfunction in Men with Parkinson’s Disease, Eur. Neurol., 32:134–140, 1992. 34. Siroky, M.B., Neurological disorders. Cerebrovascular disease and parkinsonism, Urol. Clin. N. Am., 30:27–47, 2003. 35. Sotolongo, J.R., Voiding Dysfunction in Parkinson’s disease, Seminars Neurol., 8:166–9, 1988. 36. Stocchi, F., Carbone, A., Inghilleri, M., Monge, A., Ruggieri, S., Berardelli, A., Manfredi, M., Urodynamic and neuro-physiological evaluation in Parkinson’s disease and multiple system atrophy, J. Neurol. Neurosurg. Psychiatry, 62:507–511, 1997. 37. Uchiyama, T., Sakakibara, R., Hattori, T., Yamanishi, T., Short-Term Effect of a Single Levodopa Dose on Micturition Distubance in parkinson’s Disease Patients with Wearing-Off Phenomenon, Mov. Disord., 18(5): 573–578, 2003. 38. Vodusek, D.B., Sphincter, E.M.G., Differential Diagnosis of Multiple System Atrophy, Mov. Disord., 16: 600–7, 2001. 39. Yokoyama, O., Komatsu, K., Ishiura, Y., Akino, H., Kodama, K., Yotsuyanagi, S., Moriyama, N., Nagasaka, Y., Ito, Y., Namiki, M., Overactive bladder—Experimental Aspects, Scand. J. Urol. Nephrol, Suppl., 210: 59–64, 2002. 40. Yoshimura, N., Mizuta, E., Yoshida, O., Kuno, S., Therapeutic Efficacy of Dopamine D1/D2 Receptor Agonists on Detrusor Hyperreflexia in 1-Methyl-4-Phenyl-1,2,3,6-TetrahydropiridineLesioned Parkinsonian Cynomolus Monkeys, J. Pharmacol. Exp. Therap., 286:2280–233, 1998.

27 Sexual Dysfunction Cheryl Waters and Janice Smolowitz Division of Movement Disorders, Department of Neurology, Columbia University 0-8493-1590-5/05/$0.00+$1.50 © 2005 by CRC Press

INTRODUCTION Sexual interest and behavior may be altered in persons with Parkinson’s disease (PD).1–25 Impairment of sexual function may take the form of underactivity or impotence.1–10 However, there exists a literature of anecdotal reports and uncontrolled studies describing resumption of sexual activity, increased interest in sex, and hypersexuality in PD patients as a result of antiparkinsonian therapy.11–25 This chapter provides an overview of the literature to assist clinicians in identifying an aspect of disease that is not frequently discussed but greatly affects quality of life. IMPAIRED SEXUAL FUNCTION Impaired sexual function may result from emotional and physical illnesses as well as increasing age.26–28 A variety of sexual functions and related variables have been studied in adults with PD using validated, self report questionnaires and interviews of men and women with PD, couples with one spouse affected by PD, men with PD, and women with PD. Comparison groups have included healthy adults matched for age and gender as well as age matched controls with chronic, nonneurological disease with motor impairment. There are no studies with quantitative measures that objectively evaluate sexual function. The following three studies have described sexual function in men and women with PD. Thirty-six men and 14 women with idiopathic PD and no signs of mental deterioration completed a structured questionnaire that addressed sexual activity, function, and libido.1 Participants mean age was 57.9 years, standard deviation 10.1 years. The duration of disease was 7.01 years, standard deviation 3.9 years. Sixty-eight percent of participants reported decreased sexual activity. Twenty-six percent described decreased libido. Erectile dysfunction (ED) was reported in 38.8% of men. ED was described more frequently in men over 61 years of age. To determine whether adults with PD differed in sexuality from similarly aged healthy adults, 121 adults with PD and 126 controls matched for age and gender participated in a study comparing opinions about public sexual attitudes, emotion from personal sexual practice, personal sexual function, and general health perception.2 Adults with PD were

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recruited from a PD self-support organization and physicians’ patient lists. Controls were recruited for participation from a community registry. A physician investigator examined the adults with PD and reviewed their medical records. The physician completed the motor portion of the Unified Parkinson’s Disease Rating Scale (UPDRS),29 the Hoehn and Yahr30 score, and interviewed participants about disease variables and sociodemographic data. In the presence of the investigator, participants completed a 33item multiple-choice self-report questionnaire that addressed different aspects of sexuality,31 a depression scale,32 and the Wechsler Adult Intelligence scale33 to measure the influence of education. All subjects reported that they were currently living in heterosexual relationships. Frequency of intercourse did not differ between adults with PD and controls. The average age of adults with PD was 45 years. Adults with PD reported greater disagreement with present attitudes about sexuality than controls. Significantly, more adults with PD were unemployed and depressed. Adults with PD indicated greater dissatisfaction with their personal sexual lives than controls. Those with depression expressed greater sexual dissatisfaction than those without depression. Men with PD reported greater dissatisfaction than women. Depressed, unemployed adults with PD were more often dissatisfied with their current sexual relationship, felt lonely more often, and were less able to enjoy small flirtations. Adults with PD were less satisfied with their lives, felt older than their stated age, and perceived their health to be poorer than controls. Twenty-five patients with PD, 15 men and 10 women, younger than age 56, were interviewed on sexual function.3 A female neurologist conducted the interviews and physical examinations. Participants’ mean age was 50.3 years. The mean age of onset of disease was 44.7 years. Changes in libido were not statistically different between men and women, although women reported more marked changes in libido. Women reported more changes in sexual activity than men. Causes of sexual dysfunction in men included ED (n=3), reduced libido after initiation of medication (n=2), change in orgasm (n=2), and lack of partner’s acceptance (n=1). Four women reported reduced libido after initiation of medication, three women reported change in orgasm, three women reported vaginal dryness, five women reported sexual dysfunction due to rigidity, and one woman reported lack of partner’s acceptance. Four women and four men reported urinary incontinence. There was one female with major depression on the Beck Depression Inventory (BDI).34 She was not sexually active. Fifty-five percent of the participants in this sample of optimally treated PD patients were found to have changes in sexual function. Two studies have described patients’ and spouses’ perceptions of the affected partners’ sexual function and aspects of the couples’ relationship.4,5 Thirty-six men and 14 women with PD, and their spouses, were recruited from a movement disorder clinic for participation in an investigation of the relationship of autonomic nervous system (ANS) dysfunction, depression, medication, motor disabilities, and sexual difficulties.4 Patients and their spouses completed separate, self-report questionnaires. The patients were asked to answer the Geriatric Depression Scale (GDS),35 a questionnaire of degree of sexual interest, arousal, and performance skills,36 a medical history, a medication history, ANS function (increased sweating, constipation, or urinary difficulties). Spouses completed a questionnaire that addressed sexual interest, arousal, and performance of the affected spouse as well as their own sexual interests.

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Patient mean age was 67.3 years, and the mean duration of disease was 6.96 years. Eighty percent of men stated that their sexual frequency had decreased since diagnosis of PD. Forty-four percent of men reported decreased sexual interest and drive. Fifty-four percent were not able to achieve an erection. Fourteen percent reported they were able to maintain an erection. Depression was present in 19% of the male patients. Sexual dysfunction was present in 1.7% of these patients. Sixty-nine percent of male patients had ANS dysfunction. Of these, 70 percent reported problems with sexual function. Seventy-nine percent of the female patients stated that their sexual frequency had decreased since diagnosis. Seventy-one percent of women patients reported a decrease in sexual interest. Thirty-eight percent of women were unable to achieve orgasm. Thirtyeight percent reported vaginal dryness during intercourse. Sixty-seven percent felt it was more difficult to be aroused. Seventyfive percent stated that frequency of orgasm was reduced since diagnosis. Depression was present in one woman. Seventy-eight percent of couples shared the same bed. A decrease in the affected partner’s sexual interest was noted by 54% of the spouses. Young onset PD patients and spouses, attending a weekend residential meeting in the United Kingdom, were surveyed for the purpose of estimating the prevalence of sexual dysfunction in patients with PD and their partners, describing the nature of sexual difficulties experienced and the relationship between sexual dysfunction, psychological morbidity, psychosocial stress, physical disability and autonomic dysfunction.5 Fortyfour couples attended the meeting. Thirty-four couples and four spouses of PD patients participated in the study. Twenty-three male and 11 female patients completed questionnaires. Data describing age of onset of PD, current medications, and physical disability were collected independently from patients and partners. Sexual function was assessed by the Golombok Rust Inventory of Sexual Satisfaction.37 Marital function was assessed using the Golombok Rust Inventory of Marital Status.38 Depression and anxiety in patients and spouses was assessed using the BDI34 and the State Trait Scale Anxiety Inventory.39 Patients completed an acceptance of illness scale.40 Spouses completed a caregiver strain index.41 Autonomic dysfunction was rated by questionnaire. Three neurologists rated the likelihood of autonomic dysfunction based on answers to the questionnaire. Male patients (mean age 51.9 years, SD 8.9 years) were significantly older and had a later onset of disease than female patients (mean age 44.7 years, SD 7.2 years). A statistically significant difference was not found in the duration of illness or degree of disability for male and female patients. Sexual dissatisfaction and perception that sexual problems existed were greatest in couples where the patient was male. Marital dissatisfaction was highest in male patients and their partners. BDI scores were highest in the male and female patient groups. Thirty-six percent of the female patients and 29% of the male patients were depressed. Fifteen percent of female spouses were depressed. Female spouses demonstrated significantly greater trait anxiety than male spouses (p2 SD below the normal mean; 11 out of 23 PD patients without orthostatic hypotension also showed diffuse loss of 6-[(18)F]fluorodopamine-derived radioactivity. In the literature, there is a good agreement in the involvement of post-ganglionic sympathetic fibers in PD. Degeneration of the cardiac sympathetic nerve fibers can be visualized by the absence of MIBG uptake using SPECT. Loss of MIBG uptake appears to be specific for Lewy body diseases (PD, DLBD, and pure autonomic failure with Lewy bodies). Usually, MIBG uptake is retained in MSA, PSP, and AD. Thus, this is a useful test for the differential diagnosis of parkinsonism and dementia. Examples of MIBG SPECT are shown in Fig. 38.4. NORADRENERGIC MARKERS IN PARKINSON’S DISEASE Norepinephrine in the Brain NE is decreased in various parts of the brain from PD patients. Ehringer and Hornykiewicz95 first reported loss of dopamine in the brain from PD patients. They also noted loss of NE in various parts of the brain from PD patients. Riederer et al.96 also found decrease in NE in various brain areas from PD patients. Nagatsu et al.97 measured the activity of DBH in various brain regions of PD patients. They found significant reduction in the DBH activity in hypothalamus of PD patients. Scatton et al.65 reported decrease in NE in frontal cortex. Kish et al.98 reported decrease in NE in the cerebellar cortex from PD patients.

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Cash et al.99 measured NE, MHPG and homovanillic acid (HVA) levels in LC in demented and nondemented PD patients. They were decreased in seven demented patients but within normal ranges in eight nondemented PD patients. Shannak et al.68 reported decrease in hypothalamic NE (53% reduction compared with the controls) from PD patients. Ohara et al.67 measured NE in the striatum and the cerebral cortex of five DLBD patients. NE was reduced in both regions compared with the controls. Noepinephrine and Its Metabolite in CSF There are many studies on the CSF NE, MHPG, and DBH. Davidson et al.76 measured CSF MHPG in 54 untreated PD patients. They found no significant difference com

FIGURE 38.4 Cardiac MIBG SPECT. PD: Parkinson’s disease, DLBD: diffuse Lewy body disease, PSP: progressive supranuclear palsy, SND: striatonigral degeneration, AD: Alzheimer’s disease. In the control, clear cardiac MIBG uptake is seen indicating the presence of intact cardiac sympathetic terminals. In PD and DLBD, marked reduction in MIBG uptake is seen indicating the loss of cardiac sympathetic terminals. In PSP, SND, and in AD, cardiac images are clearly seen indicating the preservation of cardiac sympathetic

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fibers in these disorders. This test is very useful to differentiate PD and DLBD from PSP, MSA, and AD. pared with the controls. Mitsui et al.100 reported significantly decreased DBH activity in CSF of PD patients. Hurst et al.101 reported 41% decrease in CSF dopamine betahydroxylase (DBH) activity in PD patients compared with the controls. Martignoni et al.102 measured CSF NE and MEPH in 29 PD patients. They found significant decrease in NE in PD patients, however, MHPG levels were not unchanged compared with the controls. Tohgi et al.103 examined CSF norepinephrine in PD and correlated with the severity of the disease. CSF norepinephrine was reduced in PD patients and the decrease correlated positively with the Hoehn and Yahr stage. Adrenergic Receptors 104

Cash et al. measured the amount of alpha 1, alpha 2, beta 1, and beta 2 adrenergic receptors in the prefrontal cortex of parkinsonian patients postmortem. Alpha 1 and beta 1 receptors were increased in number, particularly in demented parkinsonian patients, while alpha 2 receptors decreased. The affinity constants were unchanged. It is likely that increases in alpha 1 and beta 1 receptors represent denervation supersensitivity, and decease in alpha 2 receptor suggests that alpha 2 receptors are located mainly in the presynaptic terminals of noradrenergic fibers from LC. Summary of Noradrenergic Systems in Parkinson’s Disease Results on noradrenergic markers are summarized in Table 38.4. In the literature, there is a good agreement in the involvement of LC noradrenergic neurons in PD. The involvement appears to be more prominent in demented PD patients. Loss of CSF NE and DBH appears to be good markers of the involvement of LC; however, MHPG level is not a good marker.

TABLE 38.4 Noradrenergic Markers in Parkinson’s Disease Authors

Results References

Norepinephrine in brain Ehringer and Hornykiewicz decreased Riederer et al. decreased Scatton et al. decreased Kish et al. decreased Cash et al. decreased Shannak et al. decreased Ohara et al. decreased Dopamine beta-hydroxylase (DBH) Nagatsu et al. decreased

Remarks

95 96 65 98 99 68 67

striatum and cortex striatum and cortex frontal cortex cerebellar cortex locus coeruleus hypothalamus striatum and cortex, DLBD

97

hypothalamus

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Norepinephrine, MHP, and DBH in CSF Davidson et al. unchanged Mitsui et al. decreased Hurst et al. decreased Martignoni et al. decreased Martignoni et al. unchanged Tohgi et al. decreased Adrenergic receptors Cash et al. increased Cash et al. decreased

694

76 100 101 102 102 103

MHPG DBH DBH NE MHPG NE

104 104

alpha-1, beta-1 alpha-2

EPINEPHRINE Epinephrine (EP) is synthesized from NE by phenylethanolamine N-methyltransferase (PNMT) (Figure 38.2); EP is metabolized by MAO and COMT to MHPG (Figure 38.5). EP is a neurotransmitter in limited numbers of neurons in the medulla oblongata (C1, C2, and C3).105 Not many studies have been done on EP in PD. Nagatsu et al.97 first measured the activity of PNMT in PD patients. They detected PNMT activity in hypothalamus, thalamus, and cerebellar nucleus of the control human brain, and the PNMT activity was reduced in hypothalamus of PD patients. Halliday et al.61 studied brain stem nuclei in PD patients and found that the number of adrenaline-synthesizing and neuropeptide Y-containing neurons in the rostral ventrolateral medulla was reduced in PD patients., Gai et al.106 studied Cl, C2, and C3 adrenergic neurons in the medulla oblongata using antibody against PNMT and immunohistochemistry in 7 PD patients. The number of immuno-positive neurons was reduced by 47% in C1 and by 12% in C3 groups. They observed Lewy bodies in neu

FIGURE 38.5 Metabolism of epinephrine. Epinephrine is

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metabolized by monoamine oxidase B and catechol-O-methyltransferase. The end products are essentially same as those of norepinephrine, i.e., MHPG and VMA. rons positive for PNMT. C2 group neurons were not reduced. Cl is located in the ventrolateral part of the medulla oblongata, C2 is located in the region of the nucleus of the solitary tract, and C3 is located in the dorsal midline region near the hypoglossal nucleus.105 Tohgi et al.103 examined CSF epinephrine and found that epinephrine was increased in demented PD patients compared with nondemented PD patients. Stoica and Enulescu107 measured urinary EP and NE in PD patients. EP excretion was increased in PD patients compared with the controls. While NE excretion was unchanged. The major source of epinephrine in the urine is the adrenal medulla. Stoddard et al.108 reported that the amount of total adrenal catecholamines were decreased in PD patients. Thus, by reviewing the literature, we find that EP neurons of the brain are also involved in PD. The functions of these EP neurons have yet to be studied. HISTAMINE Histamine is synthesized from histidine by histidine decarboxylase. The cell bodies of histaminergic neurons are located in the hypothalamus and projecting to the widespread cortical, subcortical, and brain stem areas,109 The central histaminergic system is one of the subcortical aminergic projection systems interacting extensively with the dopaminergic systems.110 Anichtchik et al.110 examined the distribution of histaminergic fibers in SN from PD patients with a specific immunohistochemical method. They found increase in the density of histaminergic fibers in the middle portion of SNC and SNR in PD brains. In PD the morphology of histaminergic fibers were thinner than in controls and had enlarged varicosities. Rinne et al.111 measured histamine content in PD brains. They found significant increase in histamine in the putamen (to 159% of the control mean), SNC (to 201%), GPI (to 234%), and GPE (to 200%). They concluded that their finding might have implications in developing new drug therapies for PD. Activities of histaminergic neurons appear to be increased. How such increase relates to symptoms of PD is yet to be studied. It is interesting to note that antihistamine drugs were used in the treatment of PD before the introduction of trihexyphenidyl and L-dopa. It has been claimed that the effects of antihistamines for PD may be mediated by their anticholinergic properties. But this proposal should be reinvestigated in the presence of new findings on histaminergic systems in PD. GAMMA-AMINO BUTYRIC ACID

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GABAERGic NEURONS IN THE NERVOUS SYSTEM Gamma-amino butyric acid (GABA) is a neutral amino acid that does not become a component of proteins. GABA is the major inhibitory neurotransmitter in the brain. GABAergic neurons are ubiquitously present in the brain, including the Purkinje cells in the cerebellum. The highest concentration of GABA is found in GPI and SNR. These areas receive GABAergic innervation from the striatum (putamen and caudate nucleus). Medium-sized spiny neurons are the major projecting neurons in the striatum. Substance P (SP) and dynorphin (DYN) co-localize with these striopallidal and strionigral pathways.112,113 This strio-internal pallidal pathway has been called the direct pathway. Another set of medium sized spiny neurons in the striatum contains GABA and methionine-enkephalin (Met-Enk) as neurotransmitters and projects to the external segment of GP (GPE) making inhibitory synapses with GABAergic neurons. GABAergic neurons in GPE project to the subthalamic nucleus (STN) making inhibitory synapses. Glutamatergic neurons in STN project to GPI and making excitatory synapses with GABAergic neurons there. This striato-internal pallidal circuit through GPE and STN has been called the indirect pathway112 (Figure 38.6). GABAergic neurons in GPI make inhibitory synapses with thalamic neurons in the ventrolateral nucleus and the anterior ventral nucleus. Alexander and Crutcher112 proposed that these parallel pathways between the striatum and GPI are very important regulating voluntary movements and the muscle tone. Also, pathologic states of these parallel pathways are considered to be responsible for the pathogenesis of bradykinesia, rigidity, and abnormal involuntary movements such as chore, dystonia, and ballisums.112,114 Nigrostriatal dopaminergic neurons make synapses with both of the GABAergic projecting neurons in the striatum (direct and indirect pathways). Dopamine is believed to make excitatory synapses with GABA-SP neurons and inhibitory synapses with GABAEnk neurons.112 Thus, in PD, the direct pathway is thought to be hypoactive and the direct pathway is thought to be hyperactive. There is no evidence to indicate that striatal GABAergic neurons are morphologically abnormal in PD. METABOLISM OF GABA GABA is synthesized from glutamic acid by glutamic acid decarboxylase (GAD). Upon excitation of the GABAergic neurons, GABA is released into the synaptic space and binds to GABA receptors. The action of GABA as a transmitter is ceased by reuptake into the previous neurons or to glia cells through high affinity GABA transporters.115 Intracellularly, GABA is metabolized by GABA transaminase that is an intracellular enzyme.

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GABAERGic MARKERS IN PARKINSOIN′S DISEASE GABA Content in the Brain 116

Perry et al. measured the content of GABA and the activities of GAD in whole putamen from 13 PD patients. Mean GABA content was significantly elevated (by 28%) in the putamen of the PD patients. GAD activity was unchanged in PD. They interpreted their results as indicating increased activities of GABA-enkephalin neurons due to loss of dopamine. Kish et al.117 also found increase in GABA level that was most prominent in the caudal subdivision of the putamen; this striatal subdivision also showed the most severe dopamine loss. They found, in the caudal putamen, a significant negative correlation between the (elevated) GABA and (reduced) dopamine levels. Rinne et al.118 measured GABA content in the caudate nucleus and temporal cortex of demented and nondemented PD patients. They found no significant changes in GABA contents. Gerlach et al.119 measured GABA content in the basal ganglia and the thalamocortical areas in PD patients and found decrease in GABA only in the centrum medianum nucleus of the thalamus compared with the controls. SNR neurons are one of the major output neurons of the basal ganglia projecting to the thalamic neurons and neurons in the superior colliculus. They are GABAergic neurons. Hardman et al.120 examined SNR neurons in PD using antibody against paralbumin that is expressed in SNR GABAergic neurons. There was a significant loss of paralbuminimmunoreactivity, though there was no evidence of actual cell loss. Glutamic Acid Decarboxylase in Parkinson’s Disease Bernheimer and Hornykiewicz121 first reported about 50% decrease in the GAD activity in putamen from PD patients. On the other hand, McGeer and McGeer37 found normal or only slightly decreased GAD activity in striatum from PD patients. Lloyd and Hornykiewicz122 found decrease in striatal GAD activity in PD patients who had not been treated with L-dopa and normal activity in patients who had been treated with L-dopa. Rinne et al.123 also reported essentially the same results on GAD. Javoy-Agid et al.38 measured GAD activity in SNC and SNR in PD patients. GAD activity was high and greater laterally and in the middle of the rostro-caudal extent in the controls. GAD activity was reduced to a uniformly low distribution in PD. Monfort et al.124 found no difference in striatal and cortical GAD activity when 10 control and 9 parkinsonian brains were selected for an optimal premortem state. On the other hand, Nishino et al.40 found significantly reduced GAD activities in the caudate nucleus and SN compared to normal controls, but these were normal when the values from protracted terminal illness cases were used as the controls. Levy et al.125 measured GAD67 mRNA by quantitative in situ hybridization in PD patients who had been treated with L-dopa. GAD67 mRNA expression was significantly decreased in all GABAergic neurons, in the

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FIGURE 38.6 Parallel pathways between the striatum and GPI, adapted from Alexander and Crutcher, 1900.103 Nigrostriatal dopaminergic neurons make excitatory synapses with GABASP neurons in the striatum and inhibitory synapses with GABA-Enk neurons in the striatum. The GABA-SP neurons make inhibitory synapses with GABAergic neurons in GPI. This pathway is called the direct pathway. The GABA-Enk neurons make inhibitory synapses with GABAergic neurons in GPE, and GPE neurons make inhibitory synapses with glutamatergic neurons in STN. The STN neurons make excitatory synapses with GABAergic neurons in GPI. This

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multisynaptic pathway is called the indirect pathway. Loss of striatal dopamine induces hypoactivity of GABA-SP neurons and hyperactivity of GABA-Enk neurons that results in hyperactivity of glutamatergic neurons of STN. The net results are marked hyperactivity of GABAergic neurons in GPI going to ventrolateral and anterior ventral nuclei of the thalamus. This marked inhibition of thalamic neurons going to motor areas is thought to be the pathophysiologic mechanism of bradykinesia in PD. (Adapted from Alexander and Crutcher, 1990.112) caudate nucleus (by 44%), putamen (by 43.5%), and ventral striatum (by 26%). In MPTP-treated monkeys, the expression of GAD67 mRNA was increased, and the increase was reversed by L-dopa treatment. Herrero et al.126 measured GAD67 mRNA by quantitative in situ hybridization in GPI of PD patients who had been treated with L-dopa and in monkeys rendered parkinsonian by 1methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In MPTP-treated monkeys, the expression of GAD67 mRNA was increased in cells from GPI, and this effect was abolished by L-dopa treatment. There were no differences in the levels of GAD67 mRNA between patients with PD, who were all treated with L-dopa, and control subjects. They interpreted their results as indicating that the level of GAD67 mRNA was increased in the cells of GPI after nigrostriatal dopaminergic denervation and that this increase could be reversed by L-dopa therapy. GABAergic neurons in GPI are believed to be overacting in untreated PD patients and the increase in GAD mRNA may be the result of this increased activity. Vila et al.127 also found no difference in the expression of GAD67 mRNA in SNR of PD patients, including the basal ganglia. by in situ hybridization. They concluded that SNR GABAergic neurons were essentially unchanged in PD. CSF GABA in Parkinson’s Disease There are many studies on CSF GABA content in PD. Manyam128 measured CSF GABA in PD patients. The mean (±SD) CSF GABA levels were 200±70 pmole/ml in controls and 121±52 pmole/ml in PD patients. In the untreated PD patients, the CSF GABA level was 95±31 pmole/ml (n=7) and in those who were treated with Ldopa and carbidopa the level was 144±53 pmole/ml (n=8). Araki et al.129 also found significant decrease in GABA levels in 14 PD patients. They found a positive correlation between the decreased GABA A levels and severity of parkinsonism. Tohgi et al.130 also found significant

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decrease in PD patients compared with controls. On the other hand, Jimenez-Jimenez et al.131 reported higher than the control CSF GABA levels in 31 PD patients. In contrast, Bonnet et al.132 reported normal CSF GABA level in PD. Perschak et al.133 measured GABA level in the ventricular CSF from PD patients and the GABA levels were essentially unchanged in PD patients compared with the control subjects (cerebellar tremor or pain syndrome). Also, the ventricular GABA level was similar to that of lumber CSF levels reported in the literature. GABA Receptors in Parkinson’s Disease 134

Lloyd et al. measured GABA binding using [3H]GABA and radioreceptor binding assay in various regions including the basal ganglia and cortical areas from PD patients. They found marked reduction in the [3H]GABA binding in SN but not in other brain areas examined. They concluded that GABA receptors were present in the nigral dopaminergic cell bodies. Nishino et al.40 measured GABAA receptors using [3H]muscimol as a ligand for radioreceptor assay. GABAA receptor densities were significantly decreased in both the cortical and subcortical brain regions. They interpreted their results as indicating the loss of ascending monoaminergic neurons including nigral dopaminergic neurons. GABAA receptors are believed to be located at least in part in the presynaptic terminals of these monoaminergic neurons. On the other hand, Lloyd et al.135 reported unchanged cortical GABA receptors in PD patients using [35S]TBPS (tbutylbicyclophosphorothionate) as a ligand for binding assay. Calon and Di Paolo136 correlated GABA receptor densities and motor fluctuations such as dyskinesias and wearing-off phenomenon. They found increased preproenkephalin expression in the putamen and increased GABA(A) receptors content in GPI in dyskinetic parkinsonian patients compared to nondyskinetic patients. They concluded that increased enkephalinergic activity in the putamen and increased sensitivity of GABA(A) receptors in the GPI were implicated in the pathogenesis of Ldopainduced dyskinesias in PD. Calon et al.137 studied striatal GABA(A) and GABA(B) receptor using (35)S-labeled tbutylbicyclophosphorothionate ([(35)S]TBPS) and [(3)H]flunitrazepam as ligands for GABA(A) receptors and [(125)I]CGP 64213 as a ligand for GABA(B) receptors in 14 PD patients, 10 of whom had developed motor fluctuations while receiving dopaminergic therapy. GABA(A) receptors were increased in the putamen of patients with wearing-off compared to those without. GABA(B) receptors were decreased in the putamen and GPE in PD patients. SUMMARY OF GABAERGIC MARKERS IN PARKINSON’S DISEASE Results on GABAergic markers in PD are summarized in Table 38.5. There is no morphological evidence to indicate neurodegenerative changes in the GABAergic neurons in the striatum and globus pallidus in PD, although the functional states of those neurons may be altered. GABA contents in putamen were reported as either unchanged or increased. GABA tends to increase postmortem.138 Regarding GAD activity, there appears to be an agreement indicating that striatal GAD is unchanged in PD patients. However, earlier studies reported decreased striatal

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GAD in L-dopa untreated PD patients. The decrease is likely secondary to dopaminergic degeneration. Therefore, there is no clear evidence to indicate involvement of GABAergic neurons in the striatum, GPE, and GPI in PD from the biochemical stand point of view. Regarding CSF GABA, again there is controversy in the results. CSF GABA levels were reported as either decreased or unchanged.

TABLE 38.5 GABAergic Markers in Parkinson’s Disease Authors

Results References

GABA in brain Perry et al. increased Kish et al. increased Rinne et al. unchanged Gerlach et al. unchanged Hardman et al. unchanged Glutamic acid decarboxylase (GAD) Bernheimer and Hornykiewicz decreased McGeer and McGeer unchanged Lloyd and Hornykiewicz decreased Lloyd and Hornykiewicz unchanged Rinne et al. decreased Rinne et al. unchanged Javoy-Agid et al. decreased Perry et al. unchanged Monfort et al. unchanged Nishino et al. decreased Levy et al. decreased Herrero et al. unchanged GABA in CSF Manyam decreased Araki et al. decreased Tohgi et al. decreased Jimenez-Jimenez et al. increased Bonnet et al. unchanged Perschak et al. unchanged GABA receptors Iloyd et al. unchanged Nishino et al. decreased Lloyd et al. unchanged Calon and DiPaolo increased Calon et al. unchanged Calon et al. decreased

Remarks

116 117 118 119 120

putamen putamen caudate and temporal cortex putamen SNR, paralbumin (+) cell count

121 37 122 122 123 123 38 116 124 40 125 126

putamen putamen putamen, untreated PD putamen, L-dopa treated PD putamen, untreated PD putamen, L-dopa treated PD SNC, SNR putamen putamen and cortex caudate and SN putamen and caudate, mRNA GPT, mRNA

128 129 130 131 132 133

GABA GABA GABA GABA GABA GABA

135 40 135 136 137 137

SN putamen and cortex, GABAA frontal cortex GPI, GABAA, dyskinetic PD putamen, GPE, GABAA putamen, GPE, GABAB

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Overall evidence seems to indicating the absence of significant degenerative changes in GABAergic neurons in the striatum, GPE, and GPI. More information is needed to answer the question whether GABAergic neurons in SNR are involved in PD. Regarding GABA receptors, once again there is controversy in the results. GABA(A) receptors are expressed in neurons in the striatum, GPE, and GPI as well as in cortical neurons. They are expressed in the putaminal GABA neurons as autoreceptors as well. They are also expressed in SNR neurons and in some of the SNC neurons.139 Further studies are needed to make any definite conclusion about GABA receptors in PD. GLUTAMIC ACID Glutamic acid is the major excitatory neurotransmitter of the brain. In the basal ganglia, neurons in the subtha lamic nucleus are glutamataergic, and hyperactive state of this glutamatergic input to GPI is considered to be a cause of bradykinesia in PD.112 Also, excitatory input from the cerebral cortex to the basal ganglia are mostly glutamatergic. GLUTAMATERGIC MARKERS IN PARKINSON’S DISEASE Kish et al.117 measured glutamate concentration in postmortem specimens of nine PD patients. They found elevated levels of striatal glutamate in three of the nine patients with PD. Rinne et al.118 measured glutamate content in the caudate nucleus and temporal cortex of demented and nondemented PD patients. They found no significant changes in glutamate contents. On the other hand, aspartate content in the temporal cortex was increased in nondemented PD patients. Gerlach et al.119 found no change in glutamate and aspartate in the basal ganglia and the thalamocortical areas in PD. Glutamate+glutamine level can be estimated by magnetic resonance spectroscopy. Clarke et al.140 found no difference in the striatum between PD patients and the controls by this method. Taylor-Robinson et al.141 also found normal glutamate+glutamine content using magnetic resonance spectroscopy in dyskinetic and nondyskinetic PD patients. They found no evidence of increased striatal glutamate in either dyskinetic or nondyskinetic Parkinson’s disease. Tohgi et al.130 reported reduction in CSF glutamate and aspartate in PD patients. Mally et al.142 also reported a decrease in CSF glutamate in PD. On the other hand, JimenezJimenez et al.131 found normal CSF glutamate and aspartate levels in 31 PD patients. Perschak et al.133 measured glutamate level in the ventricular CSF from PD patients, and the glutamate levels were essentially unchanged in PD patients compared with the control subjects (cerebellar tremor or pain syndrome). Also, the ventricular glutamate level was similar to that of lumber CSF levels reported in the literature. GLUTAMATE RECEPTORS IN PARKINSON’S DISEASE Difazio et al.143 measured four subtypes of glutamate binding sites autoradiographically in PD midbrains. N-MethylD-aspartate (NMDA) binding sites were very low in control and were reduced in SNC from PD patients (p80% decrease in caudate nucleus DA content, they found a threefold increase in Met-Enk level in GPI. In contrast, in patients showing an approximately 50% reduction in DA content in caudate, Met-Enk was markedly reduced (approximately 80%) in GPI. Met-Enk level in GPE was unchanged in PD. Fernandez et al.158 found reduction in the levels of Met-Enk in the caudate nucleus, putamen, and substantia nigra in PD. Leu-enkephalin levels were decreased in the putamen and were undetectable in the substantia nigra in PD. They also analyzed samples from incidental Lewy body disease. The changes in basal ganglia peptide levels in incidental Lewy body disease generally followed a trend similar to those seen in PD but were less marked. They concluded that their data would suggest that they were an integral part of the pathology of the illness and not secondary to DA neuronal loss or a consequence of prolonged drug therapy. There are four reports on Met-Enk mRNA expression in PD. Levy et al.160 studied the striatal expression of Met Enk together with SP genes by in situ hybridization in PD patients. They found no significant difference in striatal expression of these two neuropeptide mRNAs compared with control subjects. Nisbet et al.161 found a statistically significant increase in preproenkephalin messenger RNA expression in the body of the caudate (109% increase, P< 0.05) and in the intermediolateral putamen (55% increase, P CCK8unsulfated (IC50=40 nM)>CCK4 (IC50 = 125 nM). The regional distribution of [3H]CCK8S binding in the mouse brain was highest in the olfactory bulb (34.3±5.6 fmol/mg/protein)>cerebral cortex>cerebellum>olfactory tubercle>striatum>ponsmedulla>midbrain>hippocampus>hypothalamus (12.4±2.1 fmol/mg/protein).417 CCK peptides share certain properties with neuroleptics in that they induce catalepsy, antagonize conditioned avoidance behavior, antagonize stereotyped behavior, induce hypothermia, induce ptosis, and antagonize certain actions of amphetamine. In addition, ceruletide, CCK8, or CCK33 may produce rapid, effective, and persistent antipsychotic effects, especially in some neurolepticresistant patients.414 The aforementioned data led neuroscientists to study the effects of acute or chronic administration of neuroleptics, including haloperidol, on the concentrations of CCK and

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its receptor sites. The results of these studies provided interesting but inconclusive observations. The varied effects of haloperidol on the concentration of CCK418–420 might depend on the varied mammalian species studied, the areas of brain examined, the nature of the experiments conducted, and especially the ligand used to determine either the content or the density of receptor sites for the octapeptide. Indeed, a study by Zetler421 has shown that CCK-like peptides with neuroleptic activity were able to antagonize stereotyped behaviors caused by dopaminergic receptor agonists, but the mechanism of action of the peptides was not due to a simple clear-cut neuroleptic-like blockade of postsynaptic dopamine receptors. The coexistence of CCK peptides in the nigrostriatal and mesolimbic dopaminergic systems might modulate the synthesis, storage, and/or functions of dopamine and provide additional insight into the efficacy of neuroleptics and the psychopathology of schizophrenia. However, the nonuniform distribution of CCK8S receptors in the central nervous system signifies a broader function for the octapeptide than once anticipated, deserving further in-depth investigation.416 NEUROLEPTIC-OPIOID INTERACTION Experimental evidence suggests close interaction between neuroleptic therapy and the endogenous opioid peptides140 (see Table 46.8). The experimental evidence and clinical findings strongly support the contention that a modification in the metabolism and/or action of dopamine-opioid and dopamine-CCK transmission in part might have both beneficial and harmful effects with regard to the neuroleptic-induced movement disorders. TREATMENT OF TARDIVE DYSKINESIA BUSPIRONE IN L-DOPA-INDUCED DYSKINESIAS Buspirone is an azaspirodecandeione drug with an anxiolytic efficacy comparable to that of the benzodiazepines, but without any sedative, muscle relaxant, or anticonvulsant effects.422,423 Unlike the benzodiazepines, buspirone does not interact with GABAbenzodiazepine chloride channel complex, is thought to exert its neuropharmacological properties as an agonist for serotonin 5-HT1A receptor subtype, and blocks presynaptic dopamine D2 receptors.424 By stimulating 5-HT1A autoreceptors located on raphe neurons, buspirone inhibits the firing of serotonergic neurons, leading to a decrease of serotonin transmission in the brain. Moreover, it interacts directly with 5-HT1A postsynaptic receptors in the hippocampus, an action that has been invoked to explain, at least in part, its anxiolytic effects.425 Bonifati et al.425 reported that buspirone (10 mg orally twice a day) for 3 weeks significantly lessened the severity of the L-dopa-induced dyskinesia without worsening parkinsonism. Buspirone in relatively large doses of 180 mg/day (the recommended dosage of buspirone in anxiety is 20 to 60 mg/day) has been shown to be effective in the treatment of tardive dyskinesia.

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TABLE 46.8 Experimental Evidence Suggesting Close Interaction between Neuroleptic Therapy and the Endogenous Opioid Peptides Areas of the central nervous system, such as striatum and nucleus accumbens, contain high concentrations of both dopamine and opioid receptors.430–434 The interrelationship between dopaminergic and enkephalinergic neurons435 is further extended by studies showing that the number of mesolimbic opioid binding sites is reduced after denervation of dopaminergic neurons.436 Chronic injection of haloperidol,434 but not clozapine,435 increased the concentration of enkephalins selectively in the striatum. Neuroleptic-induced supersensitivity in the mesolimbic dopaminergic receptor is reduced by naloxone, an opioid receptor antagonist.436 Opioids might participate in the pathogenesis of neuroleptic-induced akathisia.437,438 Methadone, a narcotic used to detoxify individuals addicted to heroin, can produce choreic movements.439 Conversely, naloxone, an opioid receptor antagonist, has been reported to palliate the symptoms associated with tardive dyskinesia.440,441 Cortical and basal ganglia levels of opioid receptor binding are altered in L-dopa-induced dyskinesia. Moreover, the fact that dyskinetic and nondyskinetic animals often show opposite changes in opioid radioligand binding suggests that the motor response to L-dopa is determined, at least in part, by compensatory adjustments of brain opioid receptors.

Improvement was also observed in neuroleptic-induced parkinsonism and akathisia. Although the dosages administered were considerably higher than those used in the treatment of anxiety, drug side effects were reported to be mild.426 Although dyskinetic movements may improve with reduction in anxiety,427 Moss et al.426 believed that the observed antidyskinetic effect associated with buspirone treatment occurred independently of buspirone’s effects on anxiety. VITAMIN E AND DYSKINESIA Vitamin E (1200 mg daily) for 1 month significantly ameliorated the severity of tardive dyskinesia.428 Moreover, Dannon et al.429 treated 16 patients with tardive dyskinesia with vitamin E in an open trial of on-off-on design. Abnormal involuntary movement scale (AIMS) ratings were performed in every phase of the study. The patients exhibited a significant reduction in their mean AIMS scores during vitamin E treatment. Thus, this finding may suggest a possible role for vitamin E in the treatment of tardive dyskinesia. AMANTADINE IN TARDIVE DYSKINESIA 442

Angus et al. reported that amantadine, initially 100 mg/day during the first week and then 300 mg/day during the third week, produced an improvement in dyskinesia without exacerbation of psychosis even with prolonged administration.

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CLOZAPINE IN AXIAL TARDIVE DYSTONIA Functionally disabling tardive dystonia is a well recognized subtype of tardive dyskinesia for which treatment is often ineffective.159,443–445 Trugman et al.446 reported a patient with severe axial tardive dystonia who showed improvement for 4 years after treatment with the atypical antipsychotic drug clozapine (625 mg/day). Clozapine differs from conventional neuroleptics in that it has higher affinity for dopamine D1 and lower affinity for dopamine D2 receptors than do conventional antipsychotics, which are relatively selective dopamine D2 antagonists. CHOLECYSTOKININ IN TARDIVE DYSKINESIA CCK is known to modulate the nigrostriatal and mesolimbic dopamine neuronal system.2,416 Kojima et al.447 in a double-blind, placebo-controlled, and matched-pairs study, reported on the effectiveness of ceruletide (0.8 µg/kg/week), an analog of CCK, in suppressing the symptoms of neuroleptic-induced tardive dyskinesia. Global evaluation of the severity of tardive dyskinesia symptoms over the 8-week study period revealed a significant improvement with ceruletide as compared with placebo. Analysis of the therapeutic response to ceruletide over the course of treatment revealed a slow but longlasting improvement of tardive dyskinesia symptoms. Side effects, which were mild and transient, consisted mainly of nausea and epigastric discomfort. The incidence of side effects did not differ between the ceruletide- and placebotreated groups. Ceruletide appears to be a novel and practical treatment that can substantially alleviate the symptoms of dyskinesia. RISPERIDONE AND TARDIVE DYSKINESIA Risperidone is a novel benzisoxazole derivative that is characterized as a potent central serotonin receptor antagonist with less potent dopamine D2 receptor antagonist properties.448,449 The incidence of tardive dyskinesia with risperidone is low. In all studies to date, no cases of tardive dyskinesia have been conclusively attributed to risperidone. For example, in a Canadian multicenter, doubleblind clinical trial of risperidone, 135 hospitalized chronic schizophrenic patients were randomly assigned to one of six parallel treatment groups for 8 weeks: risperidone, 2, 6, 10, or 16 mg/day, haloperidol, 20 mg/day; or placebo. Risperidone (6 to 16 mg)-treated patients showed significantly (PIDI= and >DID=) in response to L-dopa therapy by Parkinson’s disease, Mayo Clin. Proc. 52, 163– 174, 1977. 152. Lees, A.J. and Stern, G.M., Bromocriptine in treatment of levodopa-induced end-of-dose dystonia, Lancet 2, 215–216, 1980. 153. Ilson, J., Fahn, S., and Cote, L., Painful dystonic spasms in Parkinson’s disease, Adv. Neurol. 40, 395–398, 1984. 154. Meldrum, B.S., Gill, M., Anlezark, G.M., and Marsden, C.D., Acute dystonia as an idiosyncratic response to neuroleptic drugs in baboons, Brain 100, 313–326, 1977. 155. Bateman, D.N., Rawlins, M.D. and Simpson, J.M., Extrapyramidal reactions with metoclopramide, Br. Med. J. 291, 930–932, 1985. 156. Chadwick, D., Reynolds, E.H. and Marsden, C.D., Anticonvulsant-induced dyskinesias: A comparison with dyskinesias induced by neuroleptics, J. Neurol Neurosurg. Psychiatry 39, 1210–1218, 1979. 157. Critchley, E.M.R. and Phillips, M., Unusual idiosyncratic reaction to carbamazepine, J. Neurol Neurosurg. Psychiatry 51, 1238, 1988. 158. Crawford, J.P., Dystonic reactions to high dose propranolol, Br. Med. J. 2, 1156–1157, 1977. 159. Burke, R.E., Fahn, S., and Jankovic, J., Tardive dystonia: Late-onset and persistent dystonia caused by antipsychotic drugs, Neurology 32, 1335–1346, 1982. 160. Lavenstein, B.L. and Cantor, F.K., Acute dystonia: An unusual reaction to diphenhydramine, J. Am. Med. Assoc. 236, 291, 1976. 161. Smith, R.E. and Domino, E.F, Dystonic and dyskinetic reactions induced by H1 antihistaminic medication, in Tardive Dyskinesia: Research Treatment, Ed. by W.E.Fann, R.C.Smith, and J.M.Davis, Spectrum, New York, pp. 325–332, 1980. 162. Howrie, D.L., Rowley, A.H., and Krenzelok, E.P., Benztropine-induced acute dystonic reaction, Ann. Emerg. Med. 15, 141–143, 1986.

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163. Rupniak, N.M.J., Jenner, P., and Marsden, C.D., Acute dystonia induced by neuroleptic drugs, Psychopharmacology 88, 403–419, 1986. 164. Sramek, J.J., Simpson, G.M., Morrison, R.L., and Heiser, J.F, Anticholinergic agents for prophylaxis of neuroleptic-induced dystonic reactions: A prospective study, J. Clin. Psychiatry 47, 305–309, 1986. 165. Swett, C., Drug-induced dystonia, Am. J. Psychiatry 132, 532–534, 1975. 166. Chiles, J.A., Extrapyramidal reactions in adolescents treated with high-potency antipsychotics, Am. J. Psychiatry135, 239–240, 1978. 167. Keepers, G.A. and Casey, D.E., Clinical management of acute neuroleptic-induced extrapyramidal syndromes, Curro. Psychiatr. Ther. 23, 139–157, 1986. 168. Kumor, K., Haloperidol-induced dystonia in cocaine addicts. Lancet 2, 1341–1342, 1986. 169. Pratty, J.S., Ananth, J., and O’Brien, J.E., Relationship between dystonia and serum calcium levels, J. Clin. Psychiatry 47, 418–419, 1986. 170. Freed, E., Alcohol-triggered neuroleptic-induced tremor, rigidity and dystonia, Med. J. Aust. 445, 1981. 171. Sovner, R. and McGorrill, S., Stress as a precipitant of neuroleptic-induced dystonia, Psychosomatics 23, 707–709, 1982. 172. Malen, R.L., The role of psychological factors in reversible, drug-related dystonic reactions, Mt. Sinai J. Med. 43, 46–70, 1976. 173. Dick, D.J. and Saunders, M., Persistent involuntary movements after treatment with flupenthixol, Br. Med. J. 282, 1756, 1981. 174. Wood, G.M. and Waters, A.L., Prolonged dystonic reaction of chlorpromazine in myxedema coma, Post grad. Med. J. 56, 192–193, 1980. 175. Gospe, S.M., Jr. and Jankovic, J., Drug-induced dystonia in neuronal ceroidlipofuscinosis, Pediatr. Neurol. 2, 236–237, 1986. 176. Pettit, H.O., Pan, H.T., Parsons, L.H., and Justice, J. B., Jr., Extracellular concentrations of cocaine and dopamine are enhanced during chronic cocaine administration, J, Neurochem. 55, 798–804, 1990. 177. Flaherty, J.A. and Lahmeyer, H.W., Laryngeal-pharyngeal dystonia as a possible cause of asphyxia with haloperidol treatment, Am. J. Psychiatry 135, 1414–1415, 1978. 178. McDanal, C.E., Jr., Brief letter on case of laryngealpharyngeal dystonia induced by haloperidol, relieved by benztropine, Am. J. Psychiatry 138, 1262–1263, 1981. 179. Menuck, M., Laryngeal-pharyngeal dystonia and haloperidol, Am. J. Psychiatry 138, 394–395, 1981. 180. Ravi, S.D., Borge, G.F., and Roach, F.L,. Neuroleptics laryngeal-pharyngeal dystonia, and acute renal failure, J. Clin. Psychiatry 43, 300, 1982. 181. Holmes, V.F., Adams, F., and Fernandez, F., Respiratory dyskinesia due to antiemetic therapy in a cancer patient, Cancer Treat. Rep. 71, 415, 1987. 182. Corre, K.A., Nieman, J.T., and Bessen, H.A., Extended therapy for acute dystonic reactions, Ann. Emerg. Med. 13, 194–197, 1984. 183. Gardos, G., Cole, J.O., Salomon, M. and Schniebolk, S., Clinical forms of severe tardive dyskinesia, Am. J. Psychiatry 144, 895–902, 1987. 184. Carella, F., Girotti, F, Scigliano, G., Caraceni, T., JoderOhlenbusch, A.M., and Schechter, P.J., Double-blind study of oral γ-vinyl GABA in the treatment of dystonia, Neurology 36, 98–100, 1986. 185. Nygaard, T., and Duvoisin, R., Hereditary dystonia-parkinsonism syndrome of juvenile onset, Neurology 36, 1424–1428, 1986. 186. Rondot, P. and Ziegler, M., Dystonia-L-dopa responsive or juvenile parkinsonism? J. Neural Trans. 19, 273–281, 1983. 187. Poewe, W.H. and Lees, A.J., The pharmacology of foot dystonia in parkinsonism, Clin. Neuropharmacol 10, 47–56, 1987.

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188. Faulstich, M.E., Carnrike, C.L.M., and Williamson, D.A., Blepharospasm and Meige syndrome: A review of diagnostic, aetiological and treatment approaches, J. Psychosom. Res. 29, 89–94, 1985. 189. Frueh, B.R., Felt, D.P., Wojno, T.H., and Musch, D. C., Treatment of blepharospasm with botulinum toxin, Arch. Ophthalmol 102, 1464–1468, 1984. 190. Carruthers, J. and Stubbs, H.A., Botulinum toxin for benign essential belpharospasm, hemifacial spasm and age-related lower eyelid entropion, Can. J. Neurol. Sci. 14, 42–45, 1987. 191. Olney, J.W., Price, M.T., and Labruyere, J., Anti-parkinsonian agents are phencyclidine agonists and Nmethyl-aspartate antagonists, Eur. J. Pharmacol 142, 319–320, 1987. 192. Cremonesi, E. and Murata, K.N., Infiltration of a neuromuscular relaxant in diagnosis and treatment of torticollis, Anesth. Anal. 65, 1077–107, 1986. 193. Stahl, S.M. and Berger, P.A., Bromocriptine in dystonia, Lancet 745, 1981. 194. Stahl, S.M., Davis, K.L., and Berger, P.A., The neuropharmacology of tardive dyskinesia, spontaneous dyskinesia, and other dystonias, J. Clin. Psychopharmacol. 2, 321–328, 1982. 195. Stahl, S.M., Thornton, J.E., Simpson, M.L., Berger, P.A., and Napoliello, M.J., γ-VinylGABA treatment of tardive dyskinesia and other movement disorders, Biol Psychiatry 20, 888– 893, 1985. 196. Ortiz, A., Neuropharmacological profile of Meige’s disease: overview and a case report, Clin. Neuropharmacol 6, 297–304, 1983. 197. Keegan, D.L. and Rajput, A.H., Drug induced dystonia tarda: Treatment with L-dopa, Dis. Nerv. Syst. 38, 167–169, 1973. 198. Bartels, M., Riffel, B., and Stohr, M., Tardive dystonie: Eine seltene nebenwirkung nach neuroleptika-langzeitbehandlung, Nervenarzt 53, 674–676, 1982. 199. Peatfield, R.C. and Spokes, E.G.S., Phenothiazineinduced dystonias, Neurology 34, 260, 1984. 200. Guy, N., Raps, A., and Assael, M., The Pisa syndrome during maintenance antipsychotic therapy, Am. J. Psychiatry 143, 1492, 1986. 201. Gimenez-Roldan, S., Mateo, D.,and Bartolome, P., Tardive dystonia and severe tardive dyskinesia, Acta Psychiatr. Scand. 71, 488–494, 1985. 202. Greene, P., Baclofen in the treatment of dystonia, Clin. Neuropharmacol. 15, 276–288, 1992. 203. Kao, I., Drachrnan, D.B., and Price, D.L., Botulinum toxin: Mechanism of presynaptic blockade, Science (Washington, DC) 193, 1257–1258, 1976. 204. Lange, D.J., Brin, M.F., Fahn, S., and Lovelace, R.E., Distant effects of locally injected botulinum toxin: Incidence and course, Adv. Neurology 50, 609–613, 1988. 205. Scott, A.B., Botulinum toxin injection of eye muscles to correct strabismus, Trans. Am. Ophthalmol. Soc. 79, 734–770, 1981. 206. Tsoy, E.A., Buckley, E.G., and Dutton, J.J., Treatment of blepharospasm with botulinum toxin, Am. J. Ophthalmol. 99, 176–179, 1985. 207. Scott, A.B., Kennedy, R.A., and Stubbs, H.A., Botulinum, A toxin injection as a treatment for ble-pharospasm, Arch. Ophthalmol 103, 347–350, 1985. 208. Shorr, N., Seiff, S., and Kopelman, J., The use of botulinum toxin in blepharospasm, Am. J. Ophthalmol 99, 542–546, 1985. 209. Elston, J., and Russell, R., Effect of treatment with botulinum toxin on neurogenic blepharospasm, Br. Med. J. 290, 1857–1859, 1985. 210. Mauriello, J.A., Blepharospasm, Meige syndrome and hemifacial spasm: Treatment with botulinum toxin, Neurology 35, 1499–1500, 1985. 211. Fahn, S., List, T., Moskowitz, C., Brin, M.F, Bressman, S., Burke, R., and Scott, A., Doubleblind controlled study of botulinum toxin for blepharospasm, Neurology 35, 271, 1985. 212. Perman, K., Baylis, H., Rosenblum, A., and Kirschen, D., The use of botulinum toxin in the medical management of benign essential blepharospasm, Ophthalmology 93, 1–3, 1986. 213. Elston, J.S. Botulinum toxin treatment of ble-pharospasm, Adv. Neurol. 50, 579–581, 1988. 214. Tsui, J.K., Eisen, A., Mak, E., Carruthers, J., Scott, A., and Calne, D.B., A pilot study on the use of botulinum toxin in spasmodic torticollis, Can. J. Neurol. Sci. 12, 314–316, 1985.

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357. Wirshing, W.C., Freidenberg, D.L., Cummings, J.L., and Bartzokis, G., Effects of anticholinergic agents on patients with tardive dyskinesia and concomitant druginduced Parkinsonism, J. Clin. Psychopharmacol. 9, 407–411, 1989. 358. Ganzini, L., Casey, D.E., Hoffman, W.F., and Heintz, R.T., Tardive dyskinesia and diabetes mellitus, Psychopharmacol Bull. 28, 281–286, 1992. 359. Saller, C.F. and Chiodo, L.A., Glucose suppresses basal firing and haloperidol-induced increases in the firing rate of central dopaminergic neurons, Science 210, 1269–1271, 1980. 360. Mouret, J., Khomais, M., Lemoine, P., and Sebert, P,. Low doses of insulin as a treatment of tardive dyskinesia: Conjuncture or conjecture? Eur. Neurol. 312, 199–203, 1991. 361. Luquin, M.R., Scipioni, O., Vaamonde, J., Gershanik, O., and Obeso, J.A., Levodopa-induced dyskinesias in Parkinson’s disease: Clinical and pharmacological classification, Movement Disorders, 7, 117–124, 1992. 362. Jelliffe, S.E. Psychological components in postencephalitic oculogyric crises: Contributions to a genetic interpretation of compulsive phenomena, Arch. Neurol. Psychiatry 21, 491–532, 1929. 363. Dorevitch, A., Neuroleptics as causes of oculogyric crises, Arch. Neurol. 41, 15–16, 1984. 364. Sachdev, P., Tardive and chronically recurrent oculogyric crises, Movement Disorders 8, 93– 97, 1993. 365. Davis, J.B., Borde, M., and Sharma, L.N., Tardive dyskinesia and type II schizophrenia, Brit. J. Psychiatry 160, 253–256, 1992. 366. Goetz, C.G., Weiner, W.J., Nausieda, P.A., and Klawans, H.L., Tardive dyskinesia: Pharmacology and clinical implications, Clin. Neuropharmacol 5, 3–22, 1982. 367. Bartholini, G., Lloyd, K.G., Worms, P., Constantinidis, J., and Tissot, R., GAB A and GABAergic medication: Relation to striatal dopamine function and parkinsonism, Adv. Neurol. 24, 253–257, 1979. 368. Bartholini, G., Scatton, B., Zivkovic, B., and Lloyd, K. G., On the mode of action of SL 76002, a new GABA receptor agonist, in GAB A Neurotransmitters: Pharmacochemical, Biochemical and Pharmacological Aspects, Proceedings of the 12th Alfred Benzon Symposium, Ed. by P.Krogsgaard-Larsen, J.Scheel-Kruger, and H. Kofod, Munksgaard, Copenhagen, pp. 326–339, 1979. 369. Christensen, A.V. and Hyttel, J., Prolonged treatment with the GABA agonist THIP increases dopamine receptor binding more than it changes dopaminergic behavior in mice, Drug Dev. Res. 1, 255–263, 1981. 370. Christensen, A.V., Arnt, J., and Scheel-Kruger, J., Decreased antistereotypic effect of neuroleptics after additional treatment with a benzodiazepine, a GABA agonist or an anticholinergic compound, Life Sci. 24, 1395–1402, 1979. 371. Fibiger, H.C. and Lloyd, K.G., Neurobiological substrates of tardive dyskinesia: The GABA hypothesis, Trends Neurosci. 7, 462–464, 1984. 372. Cassady, S.L., Thaker, G.K., Moran, M., Birt, A., and Tamminga, C.A., GABA agonistinduced changes in motor, oculomotor, and attention measures correlate in schizophrenics with tardive dyskinesia, Bioi. Psychiatry 32, 302–311, 1992. 373. Gunne, L.M. and Haggstrom, J.E., Reduction of nigral glutamic acid decarboxylase in rats with neuroleptic induced oral dyskinesia. Psychopharmacology (Berlin) 81, 191–194, 1983. 374. Gunne, L.M., Haggstrom, J.E. and Sjoquist, B., Association with persistent neuroleptic induced dyskinesia of regional changes in brain GABA synthesis, Nature 309, 347–349, 1984. 375. Bird, E.D., MacKay, A.V.P., Rayner, C.N., and Iversen, L.L., Reduced glutamic acid decarboxylase activity of post mortem brain in Huntington’s chorea, Lancet 1, 1090–1092, 1973. 376. Carlsson, A. and Lindquist, M., Effect of chlorpromazine or haloperidol on formation of 3methoxytyramine and normetanephrine in mouse brain, Acta Pharmacal Toxicol. 20, 140–144, 1963. 377. McGeer, P.L., McGeer, E.G., and Fibiger, H.C., Choline acetylase and glutamic acid decarboxylase in Huntington’s chorea, Neurology 23, 912–917, 1973.

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378. Walters, J.R. and Chase, T.N., GABA systems and extrapyramidal function. in Neurotransmitter Function: Basic and Clinical Aspects, Ed. by W.S. Fields, Stratton Intercontinental, New York, 1977. 379. Tamminga, C.A., Crayton, J.W., and Chase, T.N., Improvement in tardive dyskinesia after muscimol therapy, Arch. Gen. Psychiatry 36, 595–598, 1979. 380. Tamminga, C.A., Thaker, G.K., and Goldberg, S.T., Tardive dyskinesia: GABA agonist treatment, in Catecholamines: Neuropharmacology and Central Nervous System-Therapeutic Aspects, Ed. by E.Usdin, A.Carlsson, A.Dahlstrom and J.Engel, Alan R.Liss, New York, pp. 69–72, 1984. 381. Singh, M.M., Becker, R.E., Pitman, R.K., Nasrallah, H.A., and Lal, H., Sustained improvement in tardive dyskinesia with diazepam: Indirect evidence for corticolimbic involvement, Brain Res. Bull. 11, 179–185, 1983. 382. Sandyk, R., Successful treatment of neuroleptic-induced akathisia with baclofen and clonazepam, A case report, Eur. J. Neurol. 24, 286–288, 1985. 383. Hama, Y. and Ebadi, M., The nullification by diazepam of haloperidol-induced increases in the level of striatal dopamine but not in the activity of glutamatic acid decarboxylase, Neuropharmacology 15, 1235–1242, 1986. 384. Mithani, S., Atmadja, S., Baimbridge, K.G. and Fibiger, H.C., Neuroleptic-induced oral dyskinesias: Effects of progabide and lack of correlation with regional changes in glutamic acid decarboxylase and choline acetyltransferase activities, Psychopharmacology (Berlin) 93, 94– 100, 1987. 385. Berger, P.A., Endorphins in emotions, behavior and mental illness, in Mind and Medicine: Emotions in Health and Illness, Ed. by L.Temoshok, C.Van Dike, and L.S.Vegans, Grune and Stratton, New York, pp. 153–166, 1983. 386. Bissette, G., Nemeroff, C.B. and MacKay, A.V.P., Neuropeptides and schizophrenia, in Progress in Brain Research, Ed. by P.C.Emson, M.N.Rossor and M. Tohyama, Elsevier, Amsterdam, Vol. 66, pp. 161–174, 1986. 387. Buchsbaum, M.S., Davis, G.C., and van Kammen, D.P., Diagnostic classification and the endorphin hypothesis of schizophrenia. Individual differences and psychopharmacological strategies, in Perspectives in Schizophrenia Research, Ed. by C.Baxter and T.Melnechuk, Raven Press, New York, pp. 177–191, 1980. 388. Davis, G.C., Buchsbaum, M.S., and Bunney, W.E., Research in endorphins and schizophrenia, Schizophr. Bull. 5, 244–250, 1979. 389. Koob, G., LeMoal, M, and Bloom, F.E., The role of endorphins in neurobiology, behavior and psychiatric disorders, in Peptides, Hormones and Behavior, Ed. by C.B.Nemeroff and A.J.Dunn, Spectrum, New York, pp. 349–384, 1984. 390. MacKay, A.V.P., Endorphins and the psychiatrist, Trends Neurosci. 4, R9–R11, 1981. 391. Terenius, L., The implications of endorphins in pathological states, in Characteristics and Function of Opioids, Ed. by J.M.van Ree and L.Terenius, NorthHolland, Amsterdam, pp. 143– 158, 1978. 392. Van Praag, H.M. and Verhoeven, W.M.A., Endorphins and schizophrenia, in Hormones and the Brain, Ed. by D.De Wied and P.A.Van Keep, University Park Press, Baltimore, pp. 141– 153, 1980. 393. Van Ree, J.M. and De Wied, D., Endorphins in schizophrenia, Neuropharmacology 20, 1271– 1277, 1981. 394. Vereby, K., Volavka, J., and Clouet, D., Endorphins in psychiatry, Arch. Gen. Psychiatry 35, 877–888, 1978. 395. Nair, N.P.V., Lal, S., and Bloom D.M., Cholecystokinin and schizophrenia, in Progress in Brain Research, Ed. by J.M.van Reeand S.Matthysse, vol. 65, Elsevier, Amsterdam, pp. 237– 258, 1986. 396. Vanderhaeghen, J.J., Signeua, J.C., and Gepts, W., New peptide in the vertebrate CNS reacting with anti gastrin antibodies, Nature 257, 604–605, 1975.

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397. Beinfeld, M.C., Meyer, D.K., Eskay, R.L., Jensen, R. T., and Brownstein, M.J., The distribution of cholecystokinin immunoreactivity in the central nervous system of the rat as determined by radioimmunoassay, Brain Res. 212, 51–57, 1981. 398. Dockray, G.J. and Gregory, R.A., Relations between neuropeptides and gut hormones, Proc. R. Soc. Lond. Ser. B. 210, 151–164, 1980. 399. Simon-Assmann, P.M., Yazigi, R., Greeley, G., Rayford, P.L., and Thompson, J.C., Biologic and radioimmunologic activity of CCK in regions of mammalian brains, J. Neurosci. Res. 10, 165–173, 1983. 400. Straus, E. and Yalow, R.S., Gastrointestinal peptides in the brain, Fed. Proc. 38, 2320–2324, 1979. 401. Ziegler, M., Fournier, V., Bathien, N., Morselli, P.L., and Rondot, P., Therapeutic response to progabide in neuroleptic- and L-dopa-induced dyskinesias. Clin. Neuropharmacol. 10, 238–246, 1987. 402. Kaufmann, C., Jeste, D.V., Shelton, R.C., Linnoila, M., Kafka, M., and Wyatt, R.J., Noradrenergic and neuroradiological abnormalities in tardive dyskinesia, Biol. Psychiatry 21, 799–812, 1986. 403. Karoum, F., Karson, C.N., Bigelow, L.B., Lawson, W. B. and Wyatt, R.J., Preliminary evidence of reduced combined output of dopamine and its metabolites in chronic schizophrenia, Arch. Gen. Psychiatry 44, 604–607, 1987. 404. Casey, D.E., and Gerlach, J., Is tardive dyskinesia due to dopamine hypersensitivity? Clin. Neuropharmacol. 9, 134–136, 1986. 405. Duvoisin, R.C., Reserpine for tardive dyskinesia, N Eng. J. Med. 286, 611, 1972. 406. Brandrup, E., Tetrabenazine treatment in persisting dyskinesias caused by psychopharmaca, Am. J. Psychiatry 118, 551–552, 1961. 407. Kazamatsuri, H., Chien, C., and Cole, J.O., Treatment of tardive dyskinesias, I. Clinical efficacy of dopamine depleting agent, tetrabenazine, Arch. Gen. Psychiatry 27, 95–99, 1972. 408. Kazamatsuri, H., Chien, C., and Cole, J.O., Long-term treatment of tardive dyskinesia with haloperidol and tetrabenazine, Am. J. Psychiatry 130, 479–483, 1973. 409. MacCallum, W.A.G., Tetrabenazine for extrapyramidal motor disorders, Br. Med. J. (Clin. Res.) 1, 760, 1970. 410. Jus, A., Jus, K., and Fontaine, P., Long-term treatment of tardive dyskinesia, J. Clin. Psychiatry 30, 73–79, 1979. 411. Hokfelt, T., Skirboll, L., Rehfeld, J.F., Goldstein, M., Markey, K., and Dann, O., A subpopulation of mesencephalic dopamine neurons projecting to limbic areas contains a cholecystokinin-like peptide: Evidence from immunohistochemistry combined with retrograde tracing, Neuroscience 5, 2093–2124, 1980. 412. Skirboll, L.R., Crawley, J.N., and Hommer, D.W., Functional studies of cholecystokinindopamine coexistence: Electrophysiology and behavior, in Progress in Brain Research, Ed. by T.Hokfelt, K.Fuxe, and B. Pemow, Vol. 68, Elsevier, Amsterdam, pp. 357–370, 1986. 413. Nair, N.P.V., Lal, S., and Bloom, D.M, Cholecystokinin peptides, dopamine and schizophrenia, Prog. Neuropsychopharmacol. Biol. Psychiatry 9, 515–524, 1985. 414. Wang, R.Y, White, F.J., and Voigt, M.M, Cholecystokinin, dopamine and schizophrenia, Trends Pharmacol. Sci. 9, 436–438, 1984. 415. Dumbrille-Ross, A. and Seeman, P., Dopamine receptor elevation by cholecystokinin, Peptides 5, 1207–1212, 1984. 416. Worms, P., Martinez, J., Briet, C., Castro, B., and Biziere, K., Evidence for dopaminomimetic effect of intrastriatally injected cholecystokinin octapeptide in mice, Eur. J. Pharmacal 121, 395–401, 1986. 417. Hama, Y. and Ebadi, M., Characterization of [3H]chole-cystokinin octapeptide binding to mouse brain synaptosomes, Neurochem. Res. 12, 729–737, 1987. 418. Govoni, S., Yang, H.Y.T., Bosio, A., Pasinetti, G., and Costa, E., Possible interaction between cholecystokinin and dopamine, Adv. Biochem. Psychopharmacol 33, 437–444, 1982.

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419. Chang, R.S.L., Lotti, V.J., Martin, G.E., and Chen, T.B., Increase in brain 125I-cholecystokinin (CCK) receptor binding following chronic haloperidol treatment, intracisternal 6hydroxydopamine or ventral tegmental lesions, Life Sci. 32, 871–878, 1983. 420. Frey, P., Cholecystokinin octapeptide levels in rat brain are changed after subchronic neuroleptic treatment, Eur. J. Pharmacol 95, 87–92, 1983. 421. Zetler, G., Antistereotypic effects of cholecystokinin octapeptide (CCK-8), ceruletide and related peptides on apomorphine-induced gnawing in sensitized mice, Neuropharmacology 24, 251–259, 1985. 422. Eison, A.S. and Temple, D.L., Buspirone: Review of its pharmacology and current perspectives on its mechanism of action, Am. J. Med. 80, 1–9, 1986. 423. Goa, K.L. and Ward, A., Buspirone: A preliminary review of its pharmacological properties and therapeutic efficacy as an anxiolytic, Drugs 32, 114–129, 1986. 424. McMillen, B.A., Matthews, R.T., Sanghera, M.K., Shepard, P.D., and German, D.C., Dopamine receptor antagonism by the novel antianxiety drug, buspirone, J. Neurosci. 3, 733– 738, 1983. 425. Bonifati, V., Fabrizio, E., Cipriani, R., Vanacore, N., and Meco, G., Buspirone in levodopainduced dyskinesias, Clin. Neuropharmacol 17, 73–82, 1994. 426. Moss, L.E., Neppe, V.M., and Drevets, W.C., Buspirone in the treatment of tardive dyskinesia, J. Clin. Psychopharmacol 13, 204–209, 1993. 427. Sathananthan, G.L., Sanghvi, I., Phillips, N., and Gershon, S., MJ 9022: Correlation between neuroleptic potential and stereotype, Curr. Ther. Res. 18, 701–705, 1975. 428. Peet, M., Laughame, J., Rangarajan, N., and Reynolds, G.P., Tardive dyskinesia, lipid peroxidation, and sustained amelioration with vitamin E treatment, Int. Clinc. Psychopharmacol 8, 151–153, 1993. 429. Dannon, P.N., Lepkitker, E., Iancu, I., Ziv, R., Horesh, N., and Kotler, M., Vitamin E. treatment in tardive dyskinesia, Human Psychopharmacol 12, 217–220, 1997. 430. Bloom, F., Battenberg, E., Rossier, J., Ling, N., and Guillemin, R., Neurons containing betaendorphin in rat brain exist separately from those containing enkephalin: Immunocytochemical studies, Proc. Natl. A cad. Sci. USA 75, 1591–1595, 1978. 431. Chang, K.J., Cooper, N.R., Hazum, E., and Cuatrecasas, P., Multiple opiate receptors: Different regional distribution in the brain and differential binding of opiates and opioid peptides, Mol. Pharmacol. 1, 691–104, 1979. 432. Biggio, G., Casu, M., Corda, M.G., DiBello, C., and Gessa, G.L., Stimulation of dopamine synthesis in caudate nucleus by intrastriatal enkephalins and antagonism by naloxone, Science (Washington, DC) 200, 552–554, 1978. 433. Pollard, H., Llorens, C., Schwartz, J.C., Gros, C., and Dray, F., Localization of opiate receptors and enkephalins in the rat striatum in relationship with the nigrostriatal dopaminergic system: Lesion studies, Brain Res. 151, 392–398, 1978. 434. Hong, J.S., Yoshikawa, K., Kanamatsu, T., and Sabol, S.L., Modulation of striatal enkephalinergic neurons by antipsychotic drugs, Fed. Proc. 44, 2535–2593, 1985. 435. Sayers, A.C., Burki, H.R., Ruch, W., and Asper, H., Neuroleptic-induced hypersensitivity of striatal dopamine receptors in the rat as a model of tardive dyskinesias. Effects of clozapine, haloperidol, loxapine and chlorpromazine, Psycho Pharmacologia 4, 197–104, 1975. 436. Seeger, T.F., Nazzaro, J.M., and Gardner, E.L., Selective inhibition of mesolimbic behavioral supersensitivity by naloxone, Eur. J. Pharmacol 65, 435–438, 1980. 437. Gillman, M.A., Sandyk, R., and Lichtigfeld, F.J., Evidence for under activity of the opioid system in neuroleptic-induced akathisia, Psychiatry Res. 13, 187, 1984. 438. Walters, A., Hening, W., and Chokroverty, S., Opioid responsiveness of neuroleptic-induced akathisia, Ann. Neurol. 18, 137, 1985. 439. Wasserman, S. and Yahr, M.D., Choreic movements induced by the use of methadone, Arch. Neurol. 37, 727–728, 1980.

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47 The Placebo Effect in Parkinson’s Disease Sarah C.Lidstone, Raul de la Fuente-Fernandez, and A.Jon Stoessl Pacific Parkinson’s Research Centre 0-8493-1590-5/05/$0.00+$1.50 © 2005 by CRC Press

INTRODUCTION Since the first medical practices and healing rituals were performed in ancient civilizations, the ability of the mind to influence the healing of the body has been recognized across many cultures. Modern medical research has termed this the placebo effect, which is essentially the patient’s ability to demonstrate improvement in condition in response to some type of “inert” treatment—whether it be a pill, an injection, or even sham surgery—but not from any properties that the treatment itself possesses. In 1811, Hooper’s Medical Dictionary defined a placebo as “an epithet given to any medicine adapted more to please than to benefit the patient.”1 Ironically, scientific investigation, in the realization of this phenomenon, needed to account for the placebo effect in the interpretation of experimental results, and thus the placebo effect was largely considered to be a nuisance obscuring the true effects of the active treatment. However, with the growing amount of research available from clinical drug trials, the ability of placebos to produce therapeutic benefit in patients who suffer from various neurological disorders has proven to be real and effective. It is now accepted that a prominent placebo effect may be present in pain disorders, depression, and Parkinson’s disease.2–4 In the case of the latter, several randomized, placebo-controlled trials aimed at testing new pharmaceutical therapies have shown objective improvements in motor performance following placebo administration.5 However, the precise neuropsychological and biochemical mechanisms underlying the placebo effect are only beginning to be unraveled. The original observation by Levine and colleagues in the late 1970s that placebo analgesia can be blocked by naloxone suggested that the placebo effect in pain disorders involves the release of endogenous opioids.6 Following recent studies revealing direct biochemical evidence that a patient’s expectation is central to the placebo response in Parkinson’s disease,7 research is currently directed at characterizing the psychological and biochemical links between the expectation of benefit and the improvement of motor function in patients. This “expectation theory” of the placebo effect is thought to depend on reward circuitry in the brain, and more specifically, as recent evidence suggests, to dopamine release in the ventral striatum.

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PLACEBOS AND THE PLACEBO EFFECT It is important to make the distinction between a placebo and the placebo effect. A large number of definitions for placebo and placebo effect have been put forth over the years,8 each one slightly different from the next and emphasizing different aspects of this complex phenomenon. Certainly, a placebo is “inert,” or devoid of any specific effect for the medical condition being treated. Wolf provides a straightforward and concise explanation, defining the placebo effect as “any effect attributable to a pill, potion, or procedure, but not to its pharmacodynamic properties.”9 Essentially, any sort of treatment can act as a placebo—pills, injections, or surgical procedures, for example—but it is the response of the patient to that treatment that determines whether there is an actual placebo effect. The placebo effect itself also depends on the type of placebo administered; it has been shown that the magnitude of the response to the placebo varies according to its supposed potency.10 For example, placebo surgery seems to be more effective than a placebo pill,1,11,12 and, as a recent study for arthroscopic knee surgery suggested, may produce the same outcome as the actual surgical procedure.13 The term nocebo effect has also been used to describe the situation in which the patient exhibits a worsening condition in response to a placebo.14 In this case, the placebo is referred to as a nocebo, since it produces a negative outcome. As an example, Benedetti et al. demonstrated that motor performance in Parkinsonian patients worsened with the induction of a negative verbal expectation, yet the induction of a positive verbal expectation blocked this “nocebo” effect.15 In other words, the patient’s expectation of improved motor performance reversed the motor worsening at the opposite (negative) suggestion. Another aspect that confounds the attempt to define the placebo effect is the lack of consistency that has been associated with it.16 It has been shown that an individual may respond to a particular placebo at a given time yet fail to maintain a placebo effect on subsequent exposures to the same placebo or respond to a different placebo. In addition, the placebo effect can be very specific,17 and this specificity depends on the information that is made available to the recipient (i.e., the recipient’s expectation). For example, placebos have been shown to have opposite effects on heart rate or blood pressure, depending on whether they are given as tranquilizers or stimulants.18 Two alternative theories have developed with respect to the underlying psychological mechanisms of the placebo effect. The mentalistic or expectation theory previously mentioned proposes that the patient’s expectation is the primary basis for the placebo effect, and the conditioning theory states that the placebo effect is essentially a conditioned response.19 Original investigation into the placebo effect yielded models that supported one or the other of these theories.17,20–22 In Parkinson’s disease, and quite likely in pain and depression as well, recent research suggests that it is the expectation of clinical benefit that is directly related to the underlying biochemical mechanisms responsible for dopamine release.7 A recent study demonstrated that hand movement velocity in Parkinsonian patients following subthalamic nucleus stimulation was affected by different expectations of motor performance.23 This does not rule out the conditioning theory; naturally, it is possible that both mechanisms contribute to the placebo effect in any given patient, although their precise roles in different circumstances are, for the most

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part, largely unknown. The distinction may indeed be somewhat artificial, in that conditioning will enhance the level of expectation, and, particularly in sentient animals, it is the expectation itself rather than the final physiological effector response that may be conditioned. Benedetti and colleagues recently investigated the different roles of expectation and conditioning in different placebo responses.15 In the study design, they compared a “conscious” or cognitive placebo response that would occur in ischemic arm pain in healthy subjects and motor performance in Parkinson patients versus the unconscious physiological process of hormone (growth hormone and cortisol) secretion. They found that verbally induced expectations of analgesia/hyperalgesia and motor improvement/worsening completely removed the effects of a conditioning procedure in the first two classes of patients, whereas verbally induced expectations had no effect on hormone secretion. These findings reveal that conscious expectation and unconscious conditioning play different roles in different circumstances in both the placebo and nocebo effect and, importantly, that when conscious perception is involved, expectation replaces conditioning.15 INVESTIGATION OF THE PLACEBO EFFECT As previously emphasized, in accordance with the expectation model the patient’s “belief” or “faith” that a treatment may be beneficial is the factor thought to determine the placebo effect.24 The simple act of taking a pill or having a sham operation may only be regarded as the trigger of the placebo response.25 Any meaningful investigation into the placebo effect must then be able to account for the participants’ expectations and measure the resulting behavior of the participants. Thus, when selecting candidates for placebo research, certain requirements must be present within the participant population so as to detect the presence of a placebo effect with confidence. Patients must be conscious,26 mental faculties must be preserved, and the disorder must result in symptoms of sufficient severity for the patient to be motivated to desire improvement if the researcher is to have the optimum chance of detecting a placebo effect.25 There must be a reasonable expectation of obtaining benefit; thus, trials in which a placebo is tested against no treatment, or where there is at best a one-third chance of obtaining active treatment, are unlikely to demonstrate a significant placebo effect. In addition, it should be noted that, in contrast to pain and depression, Parkinson’s disease is a disorder in which the response to treatment can be assessed directly by the examiner, and this direct measurability might allow a better evaluation of the placebo effect by clinicians.25 This being said, it is equally important to emphasize that the clinical scales used for measuring motor function are subjective themselves. Also, patients may be less prone to report clinical changes than the clinicians are to observe them,27 adding another dimension of subjectivity. Aside from the selection of the experimental subjects, there is a host of problematic subtleties inherent in all placebo research. In studying depression, the placebo effect has proved to be a major issue in interpreting results, with some studies concluding that the entire observed response was due to the placebo effect.28 Thus, study design is fundamental to ensuring that the researcher ends up investigating what is intended, whether it be an active drug, a surgical procedure, or the placebo effect itself. The

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literature on the placebo effect is largely based on standard two-group randomized controlled trials, where the changes in the placebo group with respect to baseline are attributed to the placebo effect. Many investigators have assumed that such a study design—a placebo group and an untreated group—should be ideal for detecting and quantifying the placebo effect.26,29,30 Paradoxically however, with this study design and adequate informed consent, neither of the two groups will expect any benefit from the experiment and consequently, no full placebo intervention can be evaluated. The real placebo power in this scenario is lost, since a patient with no expectation of clinical benefit is not likely to manifest a placebo effect. Another approach is the three-group study31 in which patients are randomly assigned to one of three groups: the active drug group, the placebo group, or the untreated group. However, even in this study design, the patients’ expectation of benefit may be too low, because a fully informed patient may realize that there is only a one-inthree chance of getting some benefit. In addition, patients who volunteer for studies with low probability of benefit may have particularly low expectations and may therefore not be representative of the population as a whole. It is therefore unsurprising that many studies with these designs have failed to demonstrate a placebo effect.29 In their meta-analysis of clinical trials involving two or three groups— including a placebo group and a no-treatment group—Hrobjartsson and Gotzsche concluded that, with the exception of pain disorders, placebos offered no beneficial clinical effects.29 The subsequent letters published in response to that claim independently brought up the same point about the low expectations of benefit associated with three-group studies and the detection of the placebo effect. However, the results can be interpreted in another way; this observation shows that the simple act of being exposed to a placebo is not necessarily sufficient to provide clinical benefit to the patient.25 As noted above, patients with no expectation of benefit are not likely to manifest a placebo effect. Another psychological factor to consider is the patient’s knowledge about the disease, the efficacy of available drugs, and the potential for placebos to affect the particular disease. The patient’s knowledge about the possibility of receiving a placebo during the study might affect the placebo response. For example, the placebo effect may be greater in patients who have not been informed that they might receive a placebo during the study.32 So, from a technical point of view, the best way to detect a placebo effect might be deliberately not to inform the patients that they may be receiving an inactive treatment, but this approach would clearly be unethical in most circumstances. However, it is interesting to see the patients’ attitudes toward participating in placebocontrolled studies, for they volunteer for the study in full recognition that there is a chance they will not receive any treatment. Goetz and colleagues questioned Parkinson’s disease patients after their completion of placebo-controlled trials and the revelation that they had received placebo treatment,33 The patients’ impressions were significantly more frequently positive than negative, and a large proportion (88%) of the respondents expressed that if another placebo-controlled trial were offered, they would be interested in participating. Another confounding factor to consider when investigating the placebo effect is its interaction with the active drug. For example, the placebo effect associated with the simple act of ingesting a pill may potentiate the actual physiological effect of the drug (positive interaction). Conversely, the placebo effect could diminish the physiological response to the drug, especially in patients with a strong placebo effect (negative

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interaction). In both cases, if present, the placebo effect can obscure the actual results of the study and may jeopardize the randomized controlled trial if ignored in the statistical analysis.34 This phenomenon strengthens the idea that the effects of placebos and active drugs may not summate in a simple fashion, and it is an important consideration in study design, as a negative interaction between the effect of an active drug and the placebo effect in Parkinson’s disease may occur.7,19 Research on antidepressants has shown a particularly strong placebo effect, which in some cases can demonstrate results indistinguishable from those of the active drug.35 Kirsch and Sapirstein concluded, from their meta-analysis of 19 trials of antidepressants, that about 75% of the effectiveness of these drugs results from the placebo effect.28 As previously mentioned, such a strong placebo effect may result in a negative interaction with the effect of the active drug, which would make detection of the effect related to active treatment very difficult. In addition to depression, pain disorders have also shown significant susceptibility to the placebo effect. As mentioned earlier, the first direct demonstration of the physiology underlying the placebo effect was the observation that placebo analgesia could be blocked by naloxone, which indicated that the placebo could induce the release of endogenous opioids.6 Indeed, subsequent research has revealed dopamine-opioid interactions in the mesolimbic and mesocortical pathways.36 There is anatomical evidence that this relationship is bidirectional;16 dopaminergic projections from the ventral tegmental area can control opioid release in the periaqueductal gray—a major center for pain regulation—and opioid release can in turn modulate dopamine release in the nucleus accumbens (described in detail in Reference 16). It has been shown that pain, opioids, and placebo analgesics activate cortical and subcortical areas that receive dopaminergic projections.37,38 This implies that dopamine release can play a role in the transmission and perception of pain, which indicates a possible link between reward pathways and pain alleviation, and hence a potential mechanism for placebo-induced analgesia. Indeed, enhanced activity of dopamine in the nucleus accumbens seems to play a role in analgesia.39 THE RESULTS OF CLINICAL TRIALS Several randomized controlled trials aimed at assessing the clinical efficacy of pharmaceutical therapies in Parkinson’s disease have yielded evidence of a strong placebo effect. For example, in a double-blind trial of pergolide, a dopamine agonist used as a treatment for Parkinson’s disease, Diamond and colleagues40 found a significant improvement with respect to baseline in both the pergolide-treated group (17% improvement after 4 weeks and 30% after 24 weeks) and the placebo group (16% improvement after 4 weeks and 23% after 24 weeks). In fact, there was no significant difference between the drug and placebo groups. Shetty and colleagues5 conducted a relevant review of 98 articles that were published between 1969 and 1996 and selected 36 that satisfied their inclusion criteria. Of these articles, 12 reported an improvement following placebo treatment in Parkinson’s disease. The magnitude of improvement ranged from 9 to 59% of that seen in the active drug groups. Two other studies worth mentioning here were retrospective analyses of large, randomized, placebo-controlled clinical trials. The first study was an analysis of the placebo group from the large clinical

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trial of Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP), which found that 21% of patients demonstrated a blinded investigator-determined “objective” improvement in motor function during placebo therapy over a six-month period.41 In this study, the predominant purpose was to determine whether selegiline had a neuroprotective effect; thus, the expectation of symptomatic benefit was not high. Furthermore, contrary to predictions, the placebo effect was not restricted to the early evaluations but was distributed approximately equally across the duration of the observations. Similarly, Goetz and colleagues reported that 14% of the patients enrolled in a six-month, randomized, multicenter, placebo-controlled clinical trial of ropinirole monotherapy achieved a 50% improvement in motor function while on placebo treatment.42 In this particular study, all domains of parkinsonian disability were subject to the placebo effect—88% of the patients showing improvement in multiple domains—but, interestingly, bradykinesia and rigidity tended to be more susceptible than tremor, gait, or balance. Pharmacological clinical trials have demonstrated a strong placebo effect in Parkinson’s disease, but surgical intervention (e.g., transplantation of fetal mesencephalic tissue grafts) has yet to demonstrate a consistent placebo response in this disorder. The importance of including of a placebo group when investigating the efficacy of surgical procedures for treating Parkinson’s disease has been emphasized by several authors3 but also refuted by other authors.43 The ethics of using sham surgery in the assessment of the efficacy of neural grafting in Parkinson patients continues to be a matter of debate. The inclusion of a placebo group to test surgical procedures arose to parallel the randomized, double-blind, placebo-controlled trials that have become the gold standard in biomedical research and evidence-based medicine,44 yet the clinical benefits of such practices have been called into question. In a recent study for surgery to treat Parkinson’s disease, the degree of motor performance improvement at 18 months was substantial, but the same after a sham operation as after stereotactic intrastriatal implantation of fetal porcine ventral mesencephalic tissue.45 In one recently reported, multicenter, randomized, doubleblind, sham surgery-controlled study of human fetal transplantation for Parkinson’s, there was no significant clinical benefit of the transplant compared to sham surgery,46 even though pilot studies performed using identical technique had demonstrated substantial benefit.47 Although there was no improvement in the sham operated group, this does not necessarily mean that the disparate results could not arise from the placebo effect. Thus, patient expectations may conceivably have been much higher at the time of the pilot studies, resulting in an augmented placebo effect in the earlier, uncontrolled studies. Freed and colleagues also found the effect of an imitation operation to be modest.27 Several factors could explain the differences in the magnitude of the placebo response between different trials. Variations in the information given to the patients, differences in group characteristics, and/or the surgical procedures could contribute to a range of placebo responses.25 Naturally, ethical issues and consideration of the risks and benefits inherent in the conduct of the study will dictate whether a placebo treatment group is feasible. However, there is development in medical research involving surgical treatment for Parkinson’s disease. In a recent small phase 1 clinical trial, Gill and colleagues48 conducted direct intra-putamenal GDNF infusion in patients with Parkinson disease, resulting in significant increases in dopamine storage in three regions of the putamen.

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Placebo-controlled studies are now underway to confirm the benefit demonstrated in this pilot study. DOPAMINE, EXPECTATION, AND REWARD Recent investigation of the placebo effect in Parkinson’s disease has linked it to the release of dopamine in areas of the brain related to reward mechanisms as well as motor control. The dopaminergic system has long been implicated in reward mechanisms.49,50 Animal experiments have shown that the midbrain dopaminergic cell groups A8, A9, and A10 are activated by primary rewards, reward-predicting stimuli, and novel stimuli.51,52 Although three major dopamine-containing pathways (the nigrostriatal, mesolimbic, and mesocortical pathways) participate in these responses, the projection to the nucleus accumbens has received the greatest attention.50,51 In particular, it has been shown that most drugs of abuse (including cocaine, amphetamine, opioids, alcohol, and nicotine) increase dopamine levels in the nucleus accumbens, and, in fact, the basis of drug dependence seems to be related to dopamine release.53 Of most relevance to the placebo effect is that dopamine release appears to be more related to the expectation of the reward than to the reward itself.7 In an elegant experiment using an intracranial self-stimulation paradigm—in which an animal repeatedly presses a lever to stimulate its own dopaminergic projections—Garris and colleagues provided evidence that, although electrical intracranial stimulation in animals will occur only when the electrodes are positioned to stimulate dopamine release in response to experimenter-derived stimulation, self-stimulation itself does not result in the release of dopamine.54 This result is consistent with pervious experiments showing that dopaminergic neurons are activated after stimuli that predict a reward.52 Naturally, these observations led to the development of the following hypothesis: if the expectation of a reward triggers dopamine release, not only in the nucleus accumbens but also in the nigrostriatal pathway, the placebo effect in patients with Parkinson’s disease could be related to the expectation of clinical benefit and could be mediated by the release of dopamine in the striatum. A link between the placebo effect, reward mechanisms, and dopamine release was demonstrated in a recent study using PET with [11C] raclopride (RAC).7 It was found that patients with Parkinson’s disease release substantial amounts of dopamine in the dorsal striatum (i.e., caudate and putamen) in response to subcutaneous injections of saline (placebo). Changes in RAC binding between baseline and post-activation states—in this case, in response to placebo injection—reflected the release of endogenous dopamine, which displaces RAC binding to synaptic dopamine receptors. Placebo-induced changes in striatal RAC binding potential (17% in the caudate nucleus, 19% in the putamen) were of similar magnitude to those obtained after therapeutic doses of levodopa or amphetamine.7,55 All patients showed a biochemical placebo effect (i.e., changes in RAC binding potential), but only half reported clinical benefit in motor function after placebo administration. Interestingly, the amount of dopamine release in the dorsal striatum was greater in those patients who perceived a placebo effect than in those who did not (22% and 12% decreases in RAC binding potential in the caudate nucleus, respectively; 24% and 14% decreases in the putamen, respectively). Given the known relationship between dopamine levels in the putamen and motor function, it was concluded that the placebo effect in

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Parkinson’s disease was triggered by the expectation of reward, in this case the reward being the clinical benefit. This idea was confirmed when the placebo-induced changes in the ventral striatum (nucleus accumbens) were analyzed; the region demonstrated a decline in RAC binding, similar to that seen in the caudate and putamen. However, in contrast to the results from the dorsal striatum, the magnitude of placebo-induced changes was not significantly different between patients who experienced clinical benefit and those who did not.56 Because the perception of clinical benefit must be considered rewarding, this finding lends further support to the view that the release of dopamine is related to the expectation, and not the experience, of a reward. Benedetti and colleagues60 recently provided further evidence of a physiological underpinning for the placebo effect in Parkinson’s disease. They recorded neuronal activity from single cells in the subthalamic nucleus (STN) at the time of electrode implantation for deep brain stimulation. In patients who had been preconditioned with apomorphine and then received an injection of placebo, the mean firing rate in the STN declined in response to placebo injection in those patients who showed a clinical response to placebo. Furthermore, the firing pattern of STN neurons in these patients changed from a bursting pattern to a more regular pattern. The authors concluded that their findings were compatible with striatal dopamine release in those patients who demonstrated a placebo response. IMPLICATIONS FOR TREATMENT OF PARKINSON’S DISEASE Can the power of placebos be harnessed to provide therapeutic benefit to Parkinson’s disease patients? Clearly, the placebo effect can result in therapeutic benefit in some Parkinson’s patients, so is it possible that, eventually, placebos could be used to augment the benefit derived from standard therapies? At this point, further research needs to be conducted into the precise mechanism by which placebos exert their positive effects. The relationship between the expectation that motor performance will improve and the actual improvement in physical function must be more clearly understood, as must be the means of maximizing the placebo effect. Thus, recent studies in monkeys suggest that dopaminergic activity is maximal when there is uncertainty regarding the likelihood of reward.57 Placebos could potentially be involved in treatment in several different capacities. The most likely possibility is for placebos to supplement active medication; it is possible that, by reducing the requirement for active medication, some of the toxicity associated with use of the active drug might be diminished. This is not necessarily the case, however. In the case of Parkinson’s disease, for example, a reduction in levodopa dose could potentially lead to reduced dyskinesias, but this might be offset by placeboinduced dopamine release, particularly if this were to occur in a pulsatile fashion. Furthermore, the interaction between the placebo effect and the effect of the active medication may vary among individuals and even within the same individual, and this may modify the response to therapy. It is as yet unresolved whether the response to placebo might be sustained over a prolonged period of time, but if so, it is almost certain that placebo substitution would have to be given according to a variable schedule. In addition, given that the ability to respond to a particular placebo is not associated with a

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specific psychological profile,1,12 would that same response be maintained across a population of patients with similar profiles and levels of disease progression? It is likely that treatment regimens that incorporate a placebo would require individual tailoring. Another possibility is for a placebo to act as a complete substitute for the active drug. This idea has already begun to be practiced in long-term substitution programmes for the treatment of drug addiction.9 As it has been shown that placebos induce the release of endogenous dopamine in the nucleus accumbens, as do most drugs of abuse, it is then possible to use a placebo in lieu of the drug. There are reports of successful saline substitution for the active drug in morphine addicts,58 and methadone substitution programs for heroin addicts can also benefit from placebo use.59 However, care must be taken to avoid the addiction to “cross” from the drug to the placebo, for there is evidence to suggest that placebos can be addictive, causing withdrawal symptoms when treatment is discontinued.1,9 CONCLUSION The placebo effect is a very real, widespread phenomenon with a significant role in medical history, and it occupies a prominent position in current clinical research, not only in Parkinson’s disease but also in other neurological disorders. A great deal of progress has been made in identifying the areas of the brain that respond to placebos and give rise to a placebo response, and some of the biochemical bases of the placebo effect have already been elucidated.16 In Parkinson’s disease, the placebo effect has been associated with the release of endogenous dopamine in the striatum in response to the expectation of clinical benefit, and is likely secondary to activation of the reward circuitry of the brain. This raises the possibility that dopamine release may play a role in the placebo responses of other medical disorders, at least in part. Dopamine release has already been implicated in analgesia, and dopamine-opioid interactions might mediate the placebo effect that has been observed in pain disorders. The expectation theory of the placebo effect has strong implications for the design of future placebo studies. Certain elements must be present for the placebo effect to be detected to its full extent. Recognition of this is important not only in the design and interpretation of clinical trials but also for experiments designed to study the placebo effect itself. Thus, major advances in knowledge about the placebo effect will continue to stem from active drug trials, surgical procedure studies, and placebodirected research. The results from this research will determine whether the placebo effect comes to represent a viable component of treatment of Parkinson’s disease and other CNS disorders in clinical practice. REFERENCES 1. Brody, H., Placebos and the Philosophy of Medicine: Clinical, Conceptual, and Ethical Issues, Chicago: University of Chicago Press, 1980. 2. Enserink, M., Can the placebo be the cure? Science, 284:238, 1999.

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3. Freeman, T.B., Vawter, D.E., Leaverton, P.E., Godbold, J.H., Hauser, R.A., Goetz, C.G., et al. Use of placebo surgery in controlled trials of a cellular-based therapy for Parkinson’s disease, N. Engl. J. Med., 341(13): 988–992, 1999. 4. Turner, J.A., The importance of placebo effects in pain treatment and research, J. Am. Med. Assoc., 271:1609, 1994. 5. Shetty, N., Friedman, J.H., Kieburtz, K., Marshall, F. J., Oakes, D., The placebo response in Parkinson’s disease, Parkinson Study Group, Clin. Neuropharmacol., 22(4):207–212, 1999. 6. Levine, J.D., Gordon, N.C, Fields, H.L., The mechanism of placebo analgesic, Lancet, ii:654, 1978. 7. de la Fuente-Fernandez, R., Ruth, T.J., Sossi, V., Schulzer, M., Calne, D.B., Stoessl, A.J., Expectation and dopamine release: mechanism of the placebo effect in Parkinson’s disease, Science, 293(5532):1164–1166, 2001. 8. Macedo, A., Farre, M., Banos, J.E., Placebo effect and placebos: what are we talking about? Some conceptual and historical considerations, Eur. J.Clin. Pharmacol, 59:337, 2003. 9. Wolf, S., The pharmacology of placebos, Pharmacol Rev., 11:689, 1959. 10. de Craen, A.J., Tijssen, J.G., de Gans, J., Kleijnen, J., Placebo effect in the acute treatment of migraine: subcutaneous placebos are better than oral placebos, J. Neurol., 247(3):183–188, 2000. 11. Kaptchuk, T.J., Goldman, P., Stone D,A., Stason, W. B., Do medical devices have enhanced placebo effects? J. Clin. Epidemiol., 53(8):786–792, 2000. 12. Shapiro, A.K., Shapiro, E., The placebo: is it much ado about nothing? Cambridge, Massachusetts: Harvard University Press, 1997. 13. Moseley, J.B., O’Malley, K., Petersen, N.J., Menke, T. J., Brody, B.A., Kuykendall, D.H., et al., A controlled trial of arthroscopic surgery for osteoarthritis of the knee, N. Engl J. Med., 347(2):81–88, 2002. 14. Kennedy, W.P., The nocebo reaction, Med. Exp. Int. J. Exp. Med., 95:203–205, 1961. 15. Benedetti, F., Pollo, A., Lopiano, L., Lanotte, M., Vighetti, S., Rainero, I., Conscious expectation and unconscious conditioning in analgesic, motor, and hormonal placebo/nocebo responses, J. Neurosci., 23(10):4315–4323, 2003. 16. de la Fuente-Fernandez, R., Stoessl, A.J., The biochemical bases for reward, implications for the placebo effect, Eval Health. Prof., 25(4):387–398, 2002. 17. Kirsch, I., Specifying nonspecifics: psychological mechanisms of placebo effects, in Harrington, A., Ed., The Placebo Effect: An Interdisciplinary Exploration, Cambridge, Massachusetts: Harvard University Press, 166–186, 1997. 18. Flaten, M.A., Simonsen, T., Olsen, H., Drug-related information generates placebo and nocebo responses that modify the drug response, Psychosom. Med., 61(2):250–255, 1999. 19. de la Fuente-Fernandez, R., Stoessl, A.J., The placebo effect in Parkinson’s disease, Trends Neurosci., 25(6):302–306, 2002. 20. Ader, R., The role of conditioning in pharmacotherapy, in Harrington, A., Ed., The Placebo Effect: An Interdisciplinary Exploration, Cambridge, Massachusetts: Harvard University Press, 138–165, 1997. 21. Evans, F.J., Expectancy, therapeutic instructions, and the placebo response, in White, L., Tursky, B., Schwartz, G.E., Eds., Placebo: Theory, Research, and Mechanisms, New York: Guilford Press, 215–228, 1985. 22. Wickramasekera, I.A., Conditioned response model of the placebo effect: predictions from the model, in White, L., Tursky, B., Schwartz, G.E., Eds., Placebo: Theory, Research, and Mechanisms, New York: Guilford Press, 255–287, 1985. 23. Pollo, A., Torre, E., Lopiano, L., Rizzone, M., Lanotte, M., Cavanna, A., et al., Expectation modulates the response to subthalamic nucleus stimulation in Parkinsonian patients, NeuroReport, 13(11):1383–1386, 2002. 24. Altman, D.G., Practical Statistics for Medical Research, London: Chapman & Hall, 1991.

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25. Fuente-Fernandez, R., Schulzer, M., Stoessl, A.J., The placebo effect in neurological disorders, Lancet Neurol., 1(2):85–91, 2002. 26. Ernst, E., Resch, K.L., Concept of true and perceived placebo effects., BMJ, 311(7004):551– 553, 1995. 27. Freed, C.R., Greene, P.E., Breeze, R.E., Tsai, W.Y., DuMouchel, W., Kao, R., et al., Transplantation of embryonic dopamine neurons for severe Parkinson’s disease, N. Engl. J. Med., 344(10):710–719, 2001. 28. Kirsch, I., Sapierstein, G., Listening to Prozac but Hearing Placebo: A Meta-Analysis of Antidepressant Medications, Prevention & Treatment, 1(0002a), 1998. 29. Hrobjartsson, A., Gotzsche, P.C., Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment, N. Engl. J. Med., 344(21):1594–1602, 2001. 30. Kaptchuk, T.J., Powerful placebo: the dark side of the randomised controlled trial, Lancet., 351(9117): 1722–1725, 1998. 31. Rosenthal, R., Designing, analyzing, interpreting, and summarizing placebo studies, in White, L., Tursky, B., Schwartz, G.E., Eds., Placebo: Theory, Research, and Mechanisms, New York: Guilford Press, 110–136, 1985. 32. Kaptchuk, T.J., The double-blind, randomized, placebocontrolled trial: gold standard or golden calf? J. Clin. Epidemiol., 54(6):541–549, 2001. 33. Goetz, C.G., Janko, K., Blasucci, L.M., Jaglin, J.A., Impact of placebo assignment in clinical trials of Parkinson’s disease, Mov. Disord., 18(10):1146–1149, 2003. 34. Kleijnen J., de Craen, A.J., van Everdingen, J., Krol, L., Placebo effect in double-blind clinical trials: a review of interactions with medications, Lancet, 344(8933): 1347–1349, 1994. 35. Mayberg, H.S., Silva, J.A., Brannan, S.K., Tekell, J. L., Mahurin, R.K., McGinnis, S., et al., The functional neuroanatomy of the placebo effect, Am. J. Psychiatry, 159(5):728–737, 2002. 36. Sesack, S.R., Pickel, V.M., Dual ultrastructural localization of enkephalin and tyrosine hydroxylase immunoreactivity in the rat ventral tegmental area: multiple substrates for opiatedopamine interactions, J. Neurosci., 12(4): 1335–1350, 1992. 37. Petrovic, P., Kalso, E., Petersson, K.M., Ingvar, M., Placebo and opioid analgesia—imaging a shared neuronal network, Science, 295(5560): 1737–1740, 2002. 38. Zubieta, J.K., Smith, Y.R., Bueller, J.A., Xu, Y, Kilbourn, M.R., Jewett, D.M., et al., Regional mu opioid receptor regulation of sensory and affective dimensions of pain, Science, 293(5528):311–315, 2001. 39. Altier, N., Stewart, J., The role of dopamine in the nucleus accumbens in analgesia., Life Sci., 65(22): 2269–2287, 1999. 40. Diamond, S.G., Markham, C.H., Treciokas, L.J., Double-blind trial of pergolide for Parkinson’s disease, Neurology, 35(3):291–295, 1985. 41. Goetz, C.G., Leurgans, S., Raman, R., Placebo-associated improvements in motor function: comparison of subjective and objective sections of the UPDRS in early Parkinson’s disease, Mov. Disord., 17(2):283–288, 2002. 42. Goetz, C.G., Leurgans, S., Raman, R., Stebbins, G.T., Objective changes in motor function during placebo treatment in PD, Neurology, 54(3):710–714, 2000. 43. Macklin, R., The ethical problems with sham surgery in clinical research, N. Engl. J. Med., 341(13):992–996, 1999. 44. Dekkers, W., Boer, G., Sham neurosurgery in patients with Parkinson’s disease: is it morally acceptable? J. Med. Ethics., 27(3):151–156, 2001. 45. Watts, R.L., Freeman, T.B., Hauser, R.A., Bakay, R. A.E., Ellias, S.A., Stoessl, A.J., et al., A double-blind, randomised, controlled, multicenter clinical trial of the safety and efficacy of stereotaxic intrastriatal implantation of fetal porcine ventral mesencephalic tissue (Neurocell™PD) vs. imitation surgery in patients with Parkinson’s disease (PD), Parkinsonism & Related Disorders, 7:S87, 2001.

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46. Olanow, C.W., Goetz, C.G., Kordower, J.H., Stoessl, A.J., Sossi, V., Brin, M.F., et al., A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson’s disease, Ann. Neurol., 54(3):403–414, 2003. 47. Hauser, R.A., Freeman, T.B., Snow, B.J., Nauert, M., Gauger, L., Kordower, J.H., et al., Longterm evaluation of bilateral fetal nigral transplantation in Parkinson disease, Arch. Neurol., 56(2): 179–187, 1999. 48. Gill, S.S., Patel, N.K., Hotton, G.R., O’Sullivan, K., McCarter, R., Bunnage, M., et al., Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease, Nat. Med., 9(5):589–595, 2003. 49. Phillips, A.G., Fibiger, H.C., Neufoanatomical bases of intracranial self-stimulation: untangling the Gordian knot, in Liebman, J.M., Cooper, S.J., Eds., The Neuropharmacological Basis of Reward, Clarendon Press, 66–105, 1989. 50. Wise, R.A., Rompre, P.P., Brain dopamine and reward, Annu. Rev. Psychol., 40:191–225, 1989. 51. Rebec, G.V., Christensen, J.R., Guerra, C., Bardo,M. T., Regional and temporal differences in real-time dopamine efflux in the nucleus accumbens during freechoice novelty, Brain Res., 776(1–2):61–67, 1997. 52. Schultz, W., Reward signaling by dopamine neurons, Neuroscientist, 7(4):293–302, 2001. 53. Robinson, T.E., Berridge, K.C., The neural basis of drug craving: an incentive-sensitization theory of addiction, Brain Res. Brain Res. Rev., 18(3):247–291, 1993. 54. Garris, P.A., Kilpatrick, M., Bunin, M.A., Michael, D., Walker, Q.D., Wightman, R.M., Dissociation of dopamine release in the nucleus accumbens from intracranial self-stimulation, Nature, 398(6722):67–69, 1999. 55. de la Fuente-Fernandez, R., Lu, J.Q., Sossi, V., Jivan, S., Schulzer, M., Holden, J.E., et al., Biochemical variations in the synaptic level of dopamine precede motor fluctuations in Parkinson’s disease: PET evidence of increased dopamine turnover, Ann. Neurol., 49(3): 298– 303, 2001. 56. de la Fuente-Fernandez, R., Phillips, A.G., Zamburlini, M., Sossi, V., Calne, D.B., Ruth, T.J., et al., Dopamine release in human ventral striatum and expectation of reward, Behav. Brain Res., 136(2):359–363, 2002. 57. Fiorillo, C.D., Tobler, P.N., Schultz, W., Discrete Coding of Reward Probability and Uncertainty by Dopamine Neurons, Science, 299(5614): 1898–1902, 2003. 58. Leslie, A., Ethics and practice of placebo therapy, Am. J. Med., 16(6):854–862, 1954. 59. Curran, H.V., Bolton, J., Wanigaratne, S., Smyth, C., Additional methadone increases craving for heroin: a double-blind, placebo-controlled study of chronic opiate users receiving methadone substitution treatment, Addiction, 94(5):665–674, 1999. 60. Benedetti, F., Colloca, L., Torre, E., Lanotte, M., Melcarne, A., Pesare, M., Bergamasco, B., and Lopiano, L., Placebo-responsive Parkinson patients show decreased activity in single neurons of subthalamic nucleus, Nat. Neurosci., 7:587–588, 2004.

48 Dopamine Transporter Imaging Using SPECT in Parkinson’s Disease Danna Jennings, Ken Marek, and John Seibyl The Institute for Neurodegenerative Disorders 0-8493-1590-5/05/$0.00+$1.50 © 2005 by CRC Press

INTRODUCTION Over the past decade, development of functional neuroimaging of the nigrostriatal dopaminergic system has improved our understanding of the natural history of pathophysiological changes in Parkinson’s disease (PD). PD is characterized by degeneration of the nigral dopaminergic cells and their striatal terminals, resulting in decreased striatal dopamine and a loss in dopamine transporters. Functional neuroimaging uses radioactively labeled molecules called ligands as markers in conjunction with single photon emission tomography (SPECT) and positron emission tomography (PET) imaging to evaluate neurochemical systems in the brain. These methods offer a unique advantage in PD over structural imaging, such as computed tomography or magnetic resonance imaging. PET and SPECT provide a means to visualize the neurochemistry of the brain. Ligands targeting the dopamine transporter (DAT) have been developed as markers of dopaminergic neuronal cell loss. In this chapter, the role of DAT imaging as a marker for evaluating disease progression, severity, or stage of disease, and as a diagnostic tool in parkinsonian syndrome, is reviewed. SINGLE PHOTON EMISSION COMPUTED TOMOGRAPHY OF THE DOPAMINERGIC SYSTEM Dopaminergic system function in the brain can be visualized in vivo using either PET or SPECT imaging. Both PET and SPECT have been shown to be sensitive measures of the brain neurochemistry.1,2 PET cameras have better resolution, but the availability of PET cameras and ligands are more limited due to the resources required to acquire and maintain a PET facility. In addition, the available PET ligands have a short half-life requiring an onsite cyclotron for successful synthesis and use. The widespread availability of SPECT cameras and the relatively long half-life of the radioligands used with SPECT makes it a more practical choice as a diagnostic tool in clinical practice and as a marker for disease progression in performing large clinical studies.

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The strengths and limitations of in vivo neuroreceptor imaging studies depend on the imaging technology utilized to measure brain neurochemistry as well as the ligand or biochemical marker used to tag a specific brain neurochemical system. Currently available ligands have made it possible to visualize, in vivo, both the presynaptic nigrostriatal dopamine neurons and postsynaptic dopamine D2 receptors using PET and SPECT ligands.3,4 Specific ligands of the dopaminergic system have been developed to evaluate patients with PD, and the most extensively studied ligands include 18Fflurodopa,3,5–9 11C-vesicular monoamine transporter Type 2 (VMAT2),10–12 and dopamine transporter (DAT)13–17 ligands. DAT is a presynaptic protein located on the membrane of the dopaminergic neuron terminals. The function of DAT is to actively reuptake dopamine from the synaptic cleft after termination of its interaction with the postsynaptic dopamine receptors.18–19 Imaging the DAT using specific ligands in conjunction with SPECT or PET offers the opportunity to measure the striatal uptake of the DAT ligand providing an in vivo assessment of the integrity of the presynaptic dopaminergic nerve terminals (Figure 48.1). Of the DAT and SPECT radioligands in development, [123I]β-CIT has been the most widely evaluated ligand.14,20 The unique binding kinetics of [123I]β-CIT, characterized by a relatively long period of radiotracer uptake and slow elimination from the DAT sites in the striatum, allow reliable quantitative determination of the dopamine transporter density. THE ROLE OF DAT IMAGING IN THE DIAGNOSIS OF PD The diagnosis of PD currently relies on clinical examination and is based on the identification of well recognized cardinal motor signs of rigidity, bradykinesia, and resting tremor. Long-term clinicopathologic studies of the diagnostic accuracy of PD demonstrate that the diagnoses most commonly mistaken for PD are PSP and MSA.21,22 However, the diagnoses most commonly mistaken for PD early in its course include essential tremor, vascular parkinsonism, drug-induced parkinsonism, psychogenic parkin

FIGURE 48.1 Dopamine pre- and postsynaptic neuronal receptors for

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radioligand targets. (Adapted from Marek, K. and Seibyl, J., Science, 289, 409–411, 2000. With permission.) sonism, and Alzheimer’s disease.23,24 Factors making the diagnosis of PD more challenging include the subtlety of initial symptoms, variability of disease presentation, the slow rate of disease progression, and the lack of a convincing response to dopaminergic medications in some patients. In addition, the parkinsonian signs of bradykinesia and stiffness are relatively common in elderly subjects, making the diagnosis increasingly challenging in this population. In one series, 35% of individuals over the age of 65 years have been reported to have subtle extrapyramidal signs on neurological evaluation.25,26 Prevalence estimates for clinically diagnosed parkinsonian syndromes in similarly aged subjects are much lower, at around 3%. Misdiagnosing other conditions as PD may lead to futile therapy with dopamine-replacing agents, often resulting in unnecessary side effects. In addition, significant resources are spent on medication trials and CT or MRI brain scans, which are performed in an attempt to clarify the diagnosis. If the diagnosis of a parkinsonian syndrome is in question, the most common diagnostic approach is to perform serial examinations over several months to years until sufficient signs are present to determine a more definitive diagnosis. In many cases, a trial of dopaminergic replacement therapy is administered to clarify the diagnosis. Unfortunately, even a short trial of medications carries the risk of side effects related to dopaminergic therapy, and often the response to therapy is disappointingly unclear. This “wait and watch” approach has been the standard of practice; however, as disease modifying agents become available, identification of the disease state as early as possible will be essential. In vivo dopamine transporter imaging studies have demonstrated a reduction in dopamine transporter density in PD patients compared to healthy controls. The reduction in dopamine transporter density in PD is both region specific (putamen>caudate) and asymmetric, consistent with both pathologic assessment of the dopamine transporter loss and clinical presentation of PD. Similar to 18F Dopa and PET, dopamine transporter imaging using SPECT can discriminate patients with PD from control subjects with a sensitivity of greater than 95%.9,20,27 The dopamine transporter density, quantitatively measured by [123Iβ-CIT and SPECT imaging, has documented losses of 30 to 55% in early PD. The degree of loss of dopaminergic neurons is not as great as the loss of endogenous dopamine, reported in postmortem human tissue samples (>80%) to be in the range of in subjects with PD, but these are from subjects with more advanced PD. Difficulty in accurately diagnosing individuals early in the course of PD clearly impacts the clinical care of individuals and may also have implications when recruiting subjects for early PD clinical trials. Two recent studies involving early, untreated parkinsonian subjects suggest that imaging may identify individuals without typical PD at the time of enrollment. In the REAL-PET study, comparing ropinirole and levodopa as initial treatments in untreated patients, 11% (21/193) of enrolled subjects had scans without evidence of reduction in 18F-dopa uptake at baseline and after two years.28 In the ELLDOPA-CIT study,29 comparing initial levodopa therapy to placebo in recently diagnosed patients, 14% (21/142) of enrolled subjects had scans without evidence of

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reduction in [123I]β-CIT uptake at baseline and again at 9 months (19/19, 2 terminated). The uncertainty of clinical diagnosis is an important factor in the design and critical analysis of clinical therapeutic trials. Inclusion of subjects who do not have PD increases estimates of disease frequency and confounds efficacy studies of agents that may alter the rate of progression of disease. Data from these studies underscores the difficulty in accurately diagnosing parkinsonian patients in the early stages, based solely on clinical evaluation. Dopamine transporter imaging offers an objective measure of the density of the presynaptic dopaminergic neurons. Several studies have shown that DAT ligand uptake is already reduced by about 50% when compared to age-corrected controls indicating a role for DAT and SPECT in confirming a diagnosis of PD in patients with early symptoms30,31 (Figure 48.2). In a recent blinded, prospective study, 35 patients with symptoms of suspected early parkinsonian syndrome (PS) were referred for DAT imaging, using [123I]β-CIT and SPECT, by community neurologists who were unsure of their diagnosis.31 In this study, PS was defined as any condition expected to have a reduction in dopamine transporter density, including PD, PSP, MSA, DLBD, SND, and CBGD. To evaluate the accuracy of DAT imaging as a diagnostic tool in this population, patients were followed clinically over a six-month period. Two movement disorder experts assigned a clinical diagnosis at the time of referral. One movement disorder expert remained blind to the imaging data and evaluated and assigned a clinical diagnosis at the six-month interval. The six-month clinical diagnosis served as the “gold standard” diagnosis for the study. Figure 48.3 shows data from the subjects compared to healthy control database of 73 subjects. Based on this study, the sensitivity of the [123I]β-CIT and SPECT imaging diagnosis was 0.92, while the specificity of the imaging was 1.0 when compared to the clinical “gold standard” diagnosis at six-month follow-up. Two subjects referred with a questionable diagnosis of PS have a diagnosis of PS by the clinical “gold standard,” while their imaging showed no deficit of DAT uptake. Longer followup of these subjects is necessary to clarify the diagnosis. In a similar study of subjects with an inconclusive diagnosis, [123I]FP-CIT and SPECT were performed, and subjects were followed over a two- to four-year period. In this study, the clinicians were aware of the imaging results and utilized this information in making a final diagnosis. In 9/33 subjects, dopaminergic neuronal degeneration was found, and in all cases a diagnosis of PS was confirmed clinically. In 24 subjects, there was no evidence of dopaminergic neuronal degeneration, and other non-PS diagnoses were assigned in 19 of these subjects at follow-up.30 Both studies suggest that the positive predictive value of DAT imaging in the diagnosis of PS is high; however, the negative predictive value is lower. Combining data from DAT with the clinical evaluation improves the diagnostic accuracy of PS in difficult-to-diagnose cases.

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FIGURE 48.2 Dopamine transporter imaging utilizing [123I]β-CIT and SPECT in a healthy control (left) and a subject with early Parkinson’s disease (right). (A color version of this figure follows page 518.)

FIGURE 48.3 [123I]β-CIT uptake in the putamen of 73 healthy controls and 35 subjects with suspected parkinsonian symptoms. The clinical diagnosis is congruent with the imaging diagnosis in 33/35 subjects. Two subjects with a clinical diagnosis

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of parkinsonian syndrome at six-month follow-up have putamenal uptakes in the range of the healthy controls. DAT IMAGING IN THE DIFFERENTIAL DIAGNOSIS OF PARKINSONIAN SYNDROME Atypical Parkinsonian Syndromes Distinguishing between PD and atypical parkinsonisms (such as progressive supranuclear palsy, striatonigral degeneration, diffuse Lewy body disease, or multiple systems atrophy) is important in offering information about prognosis and making appropriate treatment decisions. Differentiating PD from an atypical parkinsonian syndrome is difficult based on clinical exam alone and error rates can be as high as 25%.21 Even in specialized movement disorders centers, the positive predictive value of a clinical diagnosis of PSP or MSA is only between 80 to 85%.32 Most of the atypical parkinsonian syndromes are characterized pathologically by a loss of nigrostriatal dopaminergic neuronal loss in addition to other changes. Similar to PD, there is a reduction in striatal uptake of DAT tracers as a result of the pathology. The severity of DAT loss alone does not distinguish PD from the atypical parkinsonian syndromes. However, the pattern of loss in the atypical parkinsonisms is less region-specific than in idiopathic PD, with the caudate and putamen being more equally effected.27,33,34 Although studies using DAT and SPECT imaging are unable to significantly differentiate these atypical forms of parkinsonism from idiopathic PD, individuals with a relatively symmetric loss of DAT uptake have been shown to more likely have either PSP or MSA.33,35 The more widespread pathology associated with the atypical parkinsonisms is more effectively evaluated with postsynaptic dopamine receptor imaging. Imaging of the postsynaptic dopamine receptors shows a decrease in ligand uptake in atypical parkinsonian syndromes, while patients with idiopathic PD have uptake in the postsynaptic receptors that appears to be similar to controls. The evaluation of presynaptic dopaminergic loss coupled with postsynaptic dopamine receptor imaging and clinical evaluation may improve our ability to distinguish PD from other atypical forms of parkinsonism. Essential Tremor Classic essential tremor (ET) with bilateral postural and action tremor of the limbs or head in the absence of any signs of rigidity or tremor can usually be differentiated from PD clinically. Diagnostic difficulties frequently arise when there is evidence of tremor that appears to be at rest, mild cogwheel rigidity, mild bradykinesia, or asymmetry of symptoms. Studies investigating the potential of DAT imaging to differentiate ET from PD have found a sensitivity and specificity of about 95% of DAT and SPECT for successfully discriminating between the two disorders.27,36,37 DAT and SPECT imaging reliably and effectively distinguishes between individuals with PD or parkinsonian syndrome and ET.

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Drug-Induced Parkinsonism Parkinsonism secondary to drug exposure is common particularly in the elderly and in populations with psychiatric disorders. Dopamine receptor blockers, used primarily as antipsychotics and antiemetics, are most frequently the offending medications in druginduced parkinsonism (DIP). Only a few patients exposed to dopamine receptor blockers develop parkinsonism, which suggests that there must be an individual susceptibility in those who develop parkinsonism. Differentiating DIP from a parkinsonian syndrome with nigrostriatal degeneration can be difficult clinically but has significant implications regarding treatment. Withdrawal from the dopamine receptor blocking medication, when possible, can require several months to reach full resolution of parkinsonian symptoms. Evaluating the integrity of the presynaptic dopamine neurons using DAT imaging can be useful in determining if there is a loss in nigrostriatal neurons and thus differentiating DIP from a parkinsonian syndrome. While there are few reports in the literature of patients with DIP who have undergone DAT imaging, 4 subjects from our center with DIP based on 6- to 12-month follow-up clinical examination all had [123I]β-CIT and SPECT imaging that was within the range of age-corrected healthy controls. DAT imaging appears to be a useful tool in evaluating whether parkinsonian symptoms are related to striatonigral dopaminergic neuronal loss in patients treated with dopamine receptor blocking medications. Vascular Parkinsonism Over the years, the term vascular parkinsonism has remained a poorly defined syndrome.38,39 Diagnostic questions often arise when a patient presents with parkinsonism and diffuse white matter ischemic changes or lacunar lesions localized to the basal ganglia. Vascular parkinsonism typically presents with symptoms of rigidity and bradykinesia predominantly in the lower extremities, resulting in a frontal gait disorder and postural instability. When parkinsonian patients present with lower extremity predominant symptoms, it is difficult to distinguish PD from vascular parkinsonism, especially early in its course. Pathological studies have shown preservation of the presynaptic dopaminergic circuitry in vascular parkinsonism patients.40,41 It has been hypothesized that deep periventricular white matter lesions disrupt connections between the primary motor cortex and the supplementary motor cortex with the cerebellum and the basal ganglia. A definitive diagnosis of vascular parkinsonism requires neuropathological evaluation postmortem. However, at least one study of 13 subjects who fulfilled the criteria for a clinical diagnosis of vascular parkinsonism demonstrated preservation of striatal binding and the putamen to caudate ratio with [123I]β-CIT and SPECT imaging.38 In studies from our group evaluating [123I]β-CIT and SPECT imaging in difficult-todiagnose cases, it has become clear that patients presenting with lower body parkinsonism are diagnostically challenging. In our studies, a subset of 12 patients with lower body parkinsonism (LBP) have been referred for DAT to determine if there is evidence of dopaminergic degeneration in these cases.31 Three of the 12 LBP patients had a decrease in uptake of [123I]β-CIT and SPECT imaging consistent with PS, while 9 patients had scans without evidence of dopamine neuronal deficiency. A 12-month clinical follow-up demonstrated that two patients who had a DAT imaging with no

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evidence of dopaminergic neuronal loss at baseline did not have PS clinically. One patient was given a final diagnosis of NPH following a remarkable improvement with VP shunt. The second patient was diagnosed with vascular parkinsonism based on an MRI with marked white matter ischemic changes and a lack of response to levodopa. Given the long-term clinical follow-up resulting in the more definitive diagnoses of NPH and vascular parkinsonism in two cases correlating with a negative imaging diagnosis, we expect the imaging diagnosis at baseline will ultimately predict the 12-month follow-up clinical diagnosis. DAT imaging appears to be a particularly useful diagnostic tool in gait difficulties of the elderly. Psychogenic Parkinsonism Psychogenic parkinsonism (PsyP) is a rare form of secondary parkinsonism, which can be difficult to diagnose. Reported cases of PsyP reported in the literature have demonstrated a combination of parkinsonian symptoms that places them in the differential of parkinsonism; however, the parkinsonian symptoms may have atypical features. Recognizing these atypical features requires referral to a movement disorder specialist with considerable experience in the evaluation and treatment of PD. Experts often need to follow an individual patient during several months through treatment trials to definitively differentiate PsyP from PD or other parkinsonism with striatonigral degeneration. Adding to the complexity of this difficult to diagnose condition, previous studies have shown 10 to 25% of patients with psychogenic movement disorders had features of both organic and psychogenic disease.42,43 In a study reported by Lang et al.,44 one of their subjects had combined psychogenic and true parkinsonian features with decreased fluorodopa uptake on one side consistent with organic parkinsonism. Dopaminergic neuronal degeneration has not been shown to occur in PsyP Using DAT imaging in these cases provides additional objective information to help differentiate PsyP from parkinsonian syndrome related to striatal dopaminergic degeneration. There are a limited number of reports with small numbers of subjects with suspected PsyP who have undergone DAT imaging in patients with PsyP.30,42 These reports suggest that those with a clinical diagnosis of PsyP have DAT imaging within the range of healthy controls. In a pilot study, we have performed DAT imaging with [123I]β-CIT in ten patients with psychogenic features as described.45 DAT imaging in these difficult-to-diagnose cases demonstrated a loss of [123I]β-CIT uptake consistent with PS in four of the ten subjects, while six of the ten subjects had scans without evidence of dopaminergic deficit. In the four subjects with a loss in [123I]β-CIT uptake, the loss of uptake was asymmetric correlating with the clinically most affected side and more pronounced in the putamen; patterns that have been described in PD.37,46,48 Clinical follow-up of one patient with a reduction in [123I]β-CIT uptake has led to a more definitive diagnosis of PD, as there has been gradual progression of parkinsonian symptoms and a convincing response to dopaminergic therapy. In the patients with no evidence of a reduction in [123I]β-CIT uptake, three patients have been followed for a period of at least two years; two have had resolution of their symptoms, and one continues to have unusual clinical symptoms that appear to be psychogenic in nature. Further prospective studies involving long-term follow-up of patients with suspected PsyP are needed to confirm the diagnostic accuracy of DAT imaging in these patients.

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Dopa-Responsive Dystonia Dopa-responsive dystonia (DRD) is a dominantly inherited condition with a recognized mutation in the GTPcyclohydrolase I gene.49–51 This gene defect results in impaired synthesis of dopamine without degeneration of the striatonigral neurons.52 The clinical presentations of DRD are broad, often making it difficult to differentiate diagnostically; however, initial symptoms usually include young-onset dystonia and parkinsonism. Discriminating DRD from adult-onset PD and juvenile parkinsonism (JP) can be especially challenging, given that all of these conditions respond to dopamine replacement therapy. Establishing the diagnosis has important implications for prognosis and long-term treatment. Ultimately, the diagnosis is clarified clinically through followup evaluations over months to years. Reports in the literature have shown no reduction in radiotracer uptake in patients with a clinical diagnosis of DRD,53,54 consistent with the lack of striatonigral neuronal loss shown pathologically in this condition.55 The use of DAT imaging in patients with dystonia and parkinsonism that is responsive to dopamine may be helpful in clarifying the diagnosis at an earlier stage of the illness. PRECLINICAL DIAGNOSIS An important goal in PD research is to develop biomarkers to identify individuals with neurochemical changes before the onset of symptoms. Preclinical identification of effected individuals is particularly important as we develop interventions that may slow or prevent disease progression. Several agents with disease modifying potential are being currently being tested in clinical trials. Both clinical and imaging data from longitudinal studies of patients with PD suggest that the preclinical phase of PD may be several years in duration. Specifically, DAT and SPECT imaging in patients with very early PD has improved our understanding of the duration between initiation of the pathophysiological process and the first appearance of clinical symptoms. In most patients with PD, the initial presentation is characterized by a unilateral onset of motor symptoms, which progresses to affect the limbs bilaterally over time. Imaging studies of the DAT consistently demonstrate a decrease in uptake of the radiotracer in the striatum bilaterally, even in patients with unilateral symptoms.13,46,56 In these patients, imaging of the DAT shows about a 50% reduction in the putamen contralateral to the symptomatic side and a 25% reduction in the putamen ipsilateral to the symptomatic side relative to healthy subjects. Based on these studies, DAT imaging appears to be a valuable test for the evaluation of presymptomatic PD, with the capability of identifying changes occurring in the brain before manifestation of clinical symptoms. While it is not financially or logistically feasible to perform imaging studies on the population at large to identify individuals with evidence of early dopaminergic neuronal loss, identifying at-risk populations provides a more practical approach to identify preclinical PD. The recent identification of genes associated with the PD phenotype in familial PD provides an opportunity to evaluate an at-risk population, both clinically and with in vivo imaging studies.57–60 Specific environmental risk factors are also being recognized, thus identifying individuals or populations of individuals that may be at risk for PD.61–62 Performing sequential imaging studies to evaluate for dopaminergic neuronal cell loss and the rate of loss of time is essential in identifying and understanding

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characteristics of the preclinical phase. Another approach to more generally identify atrisk populations is the development of screening batteries, such as olfactory testing, neurocognitive evaluations, or mood and personality scales. Berendse et al.63 studied relatives of subjects with PD, an abnormal reduction in striatal DAT binding was found in 4 out of 25 relatives who had a reduction in olfaction. Two of these individuals subsequently developed clinical parkinsonism. In the relatives with normal olfaction, none of the 24 individuals had abnormal DAT binding. This important study demonstrates that reductions in DAT binding can be detected in asymptomatic relatives of PD patients using [123I]β-CIT and SPECT. As additional atrisk populations are recognized, imaging will play an essential role in identifying individuals with early dopaminergic neuronal loss, a population that serves to gain the most benefit from neuroprotective agents as they become available. DAT IMAGING AS A MEASURE OF DISEASE SEVERITY The motor manifestations of PD can primarily be attributed to dopamine deficiency, which occurs as a result of progressive dopaminergic neuronal degeneration in the substantia nigra. Clinical examination and standardized rating scales are frequently used to measure the severity of PD; however, in the treated patient, the examination is often confounded by the masking affects of dopaminergic therapy. In addition, there is a variability in symptoms that occurs as a function of the time of day of the evaluation, anxiety, and other psychological factors that are not easily controlled. DAT imaging offers an objective marker of disease severity. Several cross-sectional studies have shown a significant correlation between severity of PD and DAT imaging.14,20,64 In a study using [123I]β-CIT and SPECT, a correlation between both stage and severity of PD was demonstrated.20 Correlation between striatal uptake and UPDRS scores was also found in a study using [123I] FP-CIT throughout Hoehn and Yahr stages I–IV.36,65 Interestingly, when specific PD symptoms are compared, the loss of dopaminergic activity measured by imaging correlates best with severity of bradykinesia and a relatively poor correlation with tremor scores.20,66 These correlations of DAT imaging with clinical ratings suggest that striatal uptake of DAT ligands is a useful marker of disease severity in PD, which enhances its utility as a measure of disease progression. DAT IMAGING AS A MEASURE OF PROGRESSION IN PARKINSON’S DISEASE PD is a progressive neurodegenerative disorder; however, the rate of progression for an individual is unpredictable and variable. One of the primary goals of PD research over the past several years has been to develop medications that slow disease progression. Several clinical trials are underway to evaluate whether neuroprotective candidate drugs may modify the rate of progression in PD, most of which rely on clinical outcome measures. The clinical ratings are useful tools to evaluate the subjects’ status at the time of the examination; however, the examination is often confounded by the affects of medication. In addition, the timing of medications may influence clinical ratings during the study visits. Objective measures of disease progression are becoming imperative as neuroprotective agents for PD are developed and tested. In vivo imaging studies provide

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the opportunity to evaluate dopaminergic neuronal degeneration longitudinally through serial imaging scans. Several studies utilizing neuroreceptor imaging have been performed to monitor progressive dopaminergic neuron loss in PD and to determine the rate of decline. These studies have been performed with DAT and 18F-flurodopa and have demonstrated loss from baseline of approximately 4 to 10% per year of both DAT and 18F-fluorodopa in patients with early PD.67–71 This rate of loss of dopaminergic neurons in PD is significantly greater than that of healthy controls, which has been shown to be 0 to 2.5% annually.72 Several longitudinal studies evaluating the diseasemodifying potential of medications have already utilized neuroreceptor imaging as a secondary outcome measure. Recently, two studies that were similarly designed were conducted to compare the effect of initial treatment with dopamine agonist (pramipexole in the CALM-PD CIT trial73) and ropinerole in the REAL-PET trial28) or levodopa on the progression of PD as measured by [123I]β-CIT SPECT or 18F-DOPA PET imaging. These two clinical imaging studies targeting dopamine function with different imaging ligands and technology both demonstrate slowing in the rate of loss of [123I]β-CIT or 18F-DOPA uptake in early patients treated with dopamine agonists compared to levodopa. The relative reduction in the percent loss from baseline of [123I]β-CIT uptake in the pramipexole versus levodopa group was 47% at 22 months, 44% at 34 months, and 37% at 46 months after initiating treatment (Figure 48.4). The relative reduction of 18F-DOPA uptake in the ropinerole group versus the levodopa group was 35% at 24 months. These data suggest that treatment with a dopamine agonist may slow dopaminergic degeneration compared to treatment with levodopa. It is unclear whether this change represents a reduction in neuronal degeneration related to the dopamine agonist or accelerated neuronal loss as a result of levodopa treatment. However, questions have been raised regarding the potential

FIGURE 48.4 Percent change from baseline in [123I]β-CIT and 5F-dopa

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uptake by treatment assignment in the CALM-PD and REAL-PET studies. for pharmacologic effects of the study drugs on the imaging outcome measures used in these studies that might provide an alternative explanation for the imaging results. There is no clear evidence of a regulatory effect on the dopamine transporter as a result of exposure to levodopa or dopamine agonists in human studies;69,73–76 however, larger studies are underway to more definitely address this question. While the results from the CALM-PD CIT and REAL-PET studies have generated more questions than answers, we have begun to think more broadly about trial design and the potential for neuropharmacologic effects on both clinical and imaging outcome measures as a result of medication exposure. Ultimately, the upshot of these imaging results is initiation of additional studies to improve our understanding of dopaminergic neuronal function. Specifically, studies are underway to evaluate if current medications may have an effect on the uptake of radioligands by the dopamine transporter. CONCLUSIONS Dopamine transporter imaging with SPECT has become an important tool for clinical evaluation and research application in PD. The expanding utility of DAT imaging in improving the diagnostic accuracy of PD in early and difficult-to-diagnose cases, in the evaluation of at-risk populations, and in monitoring disease progression demonstrate the potential for the application of neuroreceptor imaging in answering key clinical questions. As screening tools become validated and more widely available for identification of early parkinsonian signs, DAT and SPECT imaging can be applied to establish disease onset at its earliest stages. As disease modifying treatments become available, it will become essential to identify individuals who would serve derive the most benefit from these potentially neuroprotective agents and monitor disease progression with time. REFERENCES 1. Phelps, M., Positron emission tomography (PET), in Clinical Brain Imaging: Principles and Applications, J. Mazziota and S.Gilman, Eds., Philadelphia: F.A.Davis, pp. 71–107, 1992. 2. Lassen, N., Holm, S., Single photon emission computerized tomography (SPECT), in Clinical Brain Imaging: Principles and Applications, J.Mazziota and S.Gilman, Eds., Philadelphia: F.A.Davis, pp. 108–134, 1992. 3. Brooks, D.J., Advances in imaging in Parkinson’s disease, Curr. Opin. Neurol., 10:327–331, 1997. 4. Innis, R.B., Single photon emission computed tomography imaging of dopaminergic function: presynaptic transporter, postsynaptic receptor, and “intrasynaptic” transmitter, Adv. Pharmacol., 42:215–219, 1998. 5. Leenders, K., Antonimi, A., PET 18F-Fluorodopa (FD) uptake and disease progression in Parkinson’s disease, Neurology, 45:A220, 1995.

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6. Eidelberg, D., Moeller, J.R., Ishikawa, T. et al., Early differential diagnosis of Parkinson’s disease with 18F-fluorodeoxyglucose and positron emission tomography, Neurology, 45:1995– 2005, 1995. 7. Snow, B.J., Tooyama, J., McGreer, E.G., et al., Human positron emission tomographic [18F]fluorodopa studies correlate with dopamine cell counts and levels, Ann. Neurol., 34:324– 330, 1993. 8. Piccini, P., Brooks, D.J., Etiology of Parkinson’s disease: contributions from 18F-Dopa positron emission tomography, Adv. Neurol., 80:227–231, 1999. 9. Sawle, G.V., Playford, E.D., Burn, D.J., et al., Separating Parkinson’s disease from normality. Discriminate function analysis of fluordopa F-18 positron emission tomography data, Arch. Neurol., 51:237–243, 1994. 10. Frey, K.A., Koeppe, R.A., Kilbourn, M.R., et al., Presynaptic monoaminergic and cholinergic vesicular transporters in the brain, Adv. Pharmacol., 40:873–884, 1996. 11. Frey, K.A., Wieland, D.M., Kilbourn, M.R., Imaging of monoaminergic and cholinergic vesicular transporters in the brain, Adv. Pharmacol., 42:269–272, 1998. 12. Frey, K.A., Koeppe, R.A., Kilbourn, M.R., Imaging the vesicular monoamine transporter, Adv. Neurol., 86; 237–247, 2001. 13. Booij, T., Tissingh, G., Boer, G., [123I]FP-SPECT shows a pronounced decline of striatal dopamine transporter labeling in early and advanced Parkinson’s disease, J. Neurol. Neurosurg. Psychiatry, 62:133–140, 1997. 14. Brucke, T., Asenbaum, S., Pirker, W., et al., Measurement of the dopaminergic degeneration in Parkinson’s disease with [123I]β-CIT and SPECT, J. Neural Transm. Suppl., 50:9–24, 1997. 15. Fischman, A.J., Bonab, A.A., Babich, J.W., et al., Rapid detection of Parkinson’s disease by SPECT with altropane: a selective ligand for dopamine transporters, Synapse, 29:128–141, 1998. 16. Innis, R.B., Seibyl, J.B., Scanley, B.E., et al., Single photon emission computed tomographic imaging demonstrates loss of striatal dopamine transporters in Parkinson’s disease, Proc. Natl. Acad. Sci. USA, 90:11965–11969 1993. 17. Tatsch, K., Schwarz, J., Mosley, P., Linker, R., Poglarell, O., Oertel, W., Fieber, R., Hahn, K., Kung, H., Relationship between clinical features of parkinson’s disease and presynaptic dopamine transporter binding assessed with [123I]IPT and single-photon emission tomography, Eur. J. Nucl. Med., 24:415–421, 1997. 18. Amara, G., Kuhar, M.J., Neurotransmitter transporters: recent progress, Ann. Rev. Neurosci., 16:73–93, 1993. 19. Jaber, M., Jones, S., Giros, B., Caron, M.G., The dopamine transporter: a crucial component regulating dopamine transmission, Mov. Disord., 12:629–633, 1997. 20. Seibyl, J.P., Marek, K.L., Quinlan, D., et al., Decreased single-photon emission computed tomographic [123I]β-CIT striatal uptake correlates with symptoms severity in Parkinson’s disease, Ann. Neurol., 38:589–598, 1995. 21. Hughes, A.J., Daniel, S.E., Kilford, L., Lees, A.J., The accuracy of clinical diagnosis in Parkinson’s disease: a clinicopathological study of 100 cases, J. Neurol. Neurosurg. Psychiatry, 55:181–4, 1992. 22. Rajput, A.H., Rozdilsky, B., Rajput, A., Accuracy of clinical diagnosis of parkinsonism—a prospective study, Can. J. Neuol. Sci., 18:275–278, 1993. 23. Quinn, N., Parkinsonism—recognition and differential diagnosis, Br. Med. J., 310:447–452, 1995. 24. Meara, J., Bhowmick, B., Hobson, P., Accuracy of diagnosis in patients with presumed Parkinson’s disease, Age and Ageing, 28:99–102, 1999. 25. Bennett, D.A., Beckett, L.A., Murray, A.M., et al., Prevalence of parkinsonism signs and associated mortality in a community population of older people, N. Engl. J. Med., 334:71–76, 1996.

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26. Richards, M., Stern, Y., Mayeux, R., Subtle extrapyramidal signs can predict the development of dementia in elderly individuals, Neurology, 43:2184–2188, 1993. 27. Parkinson Study Group, A multicenter assessment of dopamine transporter imaging with DOPASCAN/SPECT in parkinsonism, Neurology, 55:1540–1547, 2000. 28. Whone, A., Remy, P., Davis, M.R., Sabolek, M., Nahmias, C., Stossel, A.J., Watts, R.L., Brooks, D.J., The REAL-PET study: slower progression in early Parkinson’s disease treated with ropinerole compared with Ldopa, Neurology, 58 (Suppl. 3):A82–A83, 2002. 29. Fahn, S., Parkinson disease, the effects of levodopa and the ELLDOPA trial, Arch. Neurol., 56:529–535, 1999. 30. Booij, J., Speelman, J.D., Horstink, M.W., Wolters, E. C., The clinical benefit of imaging striatal dopamine transporter with [123I]FP-CIT SPET in differentiating patients with presynaptic parkinsonism from those with other forms of parkinsonism, Eur. J. Nucl. Med., 28(3):266–72, 2001. 31. Jennings, D.L., Seibyl, J.P., Oakes, D., Eberly, S., Murphy, J., Marek, K., [123I]β-CIT and SPECT Imaging versus clinical evaluation in parkinsonian syndrome: Unmasking an early diagnosis, Arch. Neurol., 2004. 32. Hughes, A.J., Daniel, S.E., Ben-Shlomo, Y., Lees, A. J., The accuracy of diagnosis of parkinsonism syndromes in a specialist movements disorders service, Brain, 125(pt. 4):861– 870, 2002. 33. Varrone, A., Marek, K.L., Jennings, D., Innis, R.B., Seibyl, J.P., [123I]beta-CIT SPECT imaging demonstrates reduced density of striatal dopamine transporter in Parkinson’s disease and multiple systems atrophy, Mov. Disord., 16(6):1023–32, 2001. 34. Pirker, W., Asenbaum, S., Bencsits, G., Prayer, D., Gershlager, W., Deecke, L., Brucke, T., [123I]beta-CIT SPECT in multiple systems atrophy, progressive supranuclear palsy, and corticobasal degeneration, Mov. Disord., 15(6):1158–67, 2001. 35. Brucke, T., Asenbaum, S., Pirker, W., Djamshidian, S., Wenger, S., Wober, C., Muller, C., Podreka, I., J. Neural. Tram. Suppl., 50:9–24, 1997. 36. Benamer, H.T.S., Patterson, J., Wyper, D.J., Hadley, D.M., Macphee, G.J.A., Grosset, D.G., Correlation of Parkinson’s disease severity and duration with 123I-FP-CIT SPECT striatal uptake, Mov. Disord., 15(4):692–698, 2000. 37. Asenbaum, S., Pirker, W., Angelberger, P., Bencsits, G., Pruckmayer, M., Brucke, T., [123I]βCIT and SPECT in essential tremor and Parkinson’s disease, J. Neural Transm., 105:1213– 1228, 1998. 38. Gerschlager, W., Bencsits, G., Pirker, W., Bloem, B., Asenbaum, S., Prayer, D., Zijlmans, J., Hoffman, M., Brucke T., [123I]β-CIT SPECT distinguishes vascular parkinsonism from Parkinson’s disease, Mov. Disord., 17(3):518–523, 2002. 39. Winikates, J., Jankovic, J., Clinical correlates of vascular parkinsonism, Arch. Neurol., 56; 98– 102, 1999. 40. Jellinger, K.A., Parkinsonism due to Binswanger’s subcortical arteriosclerotic encephalopathy, Mov. Disord., 11:461–462, 1996. 41. Yamanouchi, H., Nagura, H., Neurological signs and frontal white matter lesions in vascular parkinsonism, Stroke, 28:965–969, 1997. 42. Factor, S.A., Podskalny, G.D., Molho, E.S., Psychogenic movement disorders: frequency, clinical profile, characteristics, J. Neurol. Neurosurg. Psychiatry, 59:406–412, 1995. 43. Ranawaya, R., Riley, D., Lang, A., Psychogenic dyskinesias in patients with organic movement disorders, Mov. Disord., 5(2):127–133, 1990. 44. Lang, A.E., Koller, W.C., Fahn, S., Psychogenic parkinsonism, Arch. Neurol., 52:802–810, 1995. 45. Williams, D.T., Ford, B., Fahn, S., Phenomenology and psychopathology related to psychogenic movement disorders, Adv. Neurol., 65:231–257, 1995.

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46. Marek, K., Seibyl, J., Scanley, B., Zea-Ponce, Y., Baldwin, R.M., Fussell, B., et al., [123I]β-CIT and SPECT imaging demonstrates bilateral loss of dopamine transporters in hemi-Parkinson’s disease, Neurology 46:231–237, 1996. 47. Seibyl, J.P., Marek, K., Scheff, K., Zoghbi, S., Baldwin, R.M., Charney, D.S., vanDyck, C.,Innis, R.B., Iodine-123-β-CIT and Iodine-123-FPCIT SPECT measurement of dopamine transporter in healthy subjects and Parkinson’s patients, J. Nucl. Med., 39:1500–1508, 1998. 48. Brooks, D.J., Ibanez, V., Sawle, G.V., et al., Differing patterns of striatal [18F]-Dopa uptake in Parkinson’s disease, multiple systems atrophy and progressive supranuclear palsy, Ann. Neurol., 28:547–555, 1990. 49. Ichinose, H., Ohye, T., Takahi, E., et al., Hereditary progressive dystonia with marked diurnal fluctuations caused by mutations in the GTP cyclohydrolase I gene, Nat. Genet, 236–242, 1994. 50. Furukawa, Y., Shimadzu, M., Rajput, A.H., et al., GTPcyclohydrolase I gene mutations in hereditary progressive and dopa-responsive dystonia, Ann. Neurol., 39:609–17, 1996. 51. Hirano, M., Tamaru, Y., Ito, H., et al., Mutant GCPcyclohydrolase I mRNA levels contribute to doparesponsive dystonia onset, Ann. Neurol., 40:796–798, 1996. 52. Rajput, A.H., Gibb, W.R.G., Zhong, X.H., et al., DOPA-responsive dystonia: pathological and biochemical observations in a case, Ann. Neurol., 39:343–351, 1994. 53. Jeon, B.S., Jeong, J.M., Park, S.S., et al., Dopamine transporter density measured by [123I]β-CIT single photon emission computed tomography is normal in doparesponsive dystonia, Ann. Neurol., 43:792–800, 1998. 54. Huang, C, Yen, T., Weng, Y., Lu, C., Normal dopamine transporter binding in dopa responsive dystonia, J. Neurol., 249(8):1016–1020, 2002. 55. Gibb, W.R.G., Narabayashi, H., Yakochi, M., Iizuka, R., Lees, A.J., New observations in juvenile onset parkinsonism with dystonia, Neurology, 41:820–822, 1991. 56. Guttman, M., Burkholder, J., Kish, S.J., Hussey, D., Wilson, A., DaSilva, J., Houle, S., [11C]RTI-32 PET studies of the dopamine transporter in early dopa-naïve Parkinson’s disease: implications for the symptomatic threshold, Neurology, 48(6):1578–1583, 1997. 57. Dekker, M.C., Bonifati, V., vanDuijn, C.M., Parkinson’s disease: piecing together a genetic puzzle, Brain, 126(pt. 8):1722–33, 2003. 58. Baptista, M.J., Cookson, M.R., Miller, D.W., Parkin and alpha-synuclein: opponent actions in the pathogenesis of Parkinson’s disease, Neuroscientist, 10(1):63–72, 2004. 59. Bertoli-Avella, A.M., Oostra, B.A., Heutink, P., Chasing genes in Alzheimer’s and Parkinson’s disease, Hum. Genet., 114(5):413–438, 2004. 60. Pankratz, N., Nichols, W.C, Uniacke, S.K., Halter, C., Rudolph, A., Shults, C., Conneally, P.M., Foroud, T., Parkinson Study Group, Significant linkage of Parkinson’s disease to chromosome 2q36–37, Am. J. Hum. Genet., 72(4): 1053–1057, 2003. 61. Di Monte, D.A., Lavasani, M., Manning-Bog, A.B., Environmental factors in Parkinson’s disease, Neurotoxicology, 23(4–5)487–502, 2002. 62. Di Monte, D.A., The environment and Parkinson’s disease: is the nigrostriatal system preferentially targeted by neurotoxins? Lancet Neurol., 2(9):531–538, 2003. 63. Morrish, P.K., Sawle, G.V., Brooks, D.J., An [18F]Dopa-PET and clinical study of the rate of progression of Parkinson’s disease, Brain, 119 (pt2):585–591, 1996. 64. Berendse, H.W., Booij, J., Francot, C.M., Bergnmans, P.L., Hijman, R., Stoof, J.C., Wolters, E.C, Subclinical dopaminergic dysfunction in asymptomatic Parkinson’s disease patients’ relatives with a decreased sense of smell, Ann. Neurol., 50(1):34–41, 2001. 65. Ishikawa, T., Dhawan, V., Kazumata, K., et al., Comparative nigrostriatal dopaminergic imaging with iodine123-β CIT-FP/SPECT and fluorine-18-FDOPA/PET, J. Nucl. Med., 37:1760–1765, 1996. 66. Vingerhoets, F.J., Schulzer, M., Calne, D.B., Snow, B. J,. Which clinical sign of Parkinson’s disease best reflects the nigrostriatal lesion? Ann. Neurol., 41:58–64, 1997.

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67. Marek, K., Innis, R., van Dyck, C., Fussell, B., Early, M., Eberly, S., Oakes, D., Seibyl, J., [123I]β-CIT SPECT imaging assessment of the rate of Parkinson’s disease progression, Neurology, 57:2089–2094, 2001. 68. Morrish, P., Rakshi, J., Bailey, D., Sawle, G., Brooks, D., Measuring the rate of progression and estimating the preclinical period of Parkinson’s disease with [18F]dopa PET, J. Neurol Neurosurg. Psychiatry, 64:314–319, 1998. 69. Nurmi, E., Bergman, J., Eskola, O., Solin, O., Hinnkka S,M., Sonninen, P., Rinne, J.O., Reproducibility and effect of levodopa on dopamine transporter function measurements: a [18F]CFT PET study, J. Cereb. Blood Flow. Metab., 20:1604–1609, 2000. 70. Nurmi, E., Ruottinen, H., Kaasinen, V., Bergman, J., Haaparanta, M., Solin, O., Rinne, J., Progression in Parkinson’s disease: a 6-[18F]fluoro-L-dopa PET study, Mov. Disord., 16:608– 615, 2001. 71. Pirker, W., Dj jamshidian, S., Asenbaum, S., Gerschlager, W., Tribl, G., Hoffman, M., Bruecke, T., Progression of dopaminergic degeneration in Parkinson’s disease and atypical parkinsonism: a longitudinal β-CIT SPECT study, Mov. Disord., 17:45–53, 2002. 72. vanDyck, C.H., Seibyl, J., Malison, R., Laurelle, M., Zoghbi, S., Baldwin, R.M., Innis. R, B., Age-related decline in dopamine transporter: analysis of striatal subregions, nonlinear effects, and hemispheric asymmetries, Am. J. Geriatr. Psychiatry., 10(1):36–43, 2002. 73. Parkinson Study Group, Dopamine transporter brain imaging to assess the effects of Pramipexole vs. levodopa on Parkinson disease progression, JAMA, 287: 1653–1661, 2002. 74. Innis, R., Marek, K., Sheff, K., Zogbi, S., Castrnuovo, J., Feigin, A., Seibyl, J., Treatment with carbidopa/levodopa and selegiline on striatal transporter imaging with [123I]β-CIT, Mov. Disord. 11999:4: 436–443. 75. Ahlskog, J.E., Uitti, R.J., O’Connor, M.K., et al., The effect of dopamine agonist therapy on dopamine transporter imaging in Parkinson’s disease, Mov. Disord., 4:940–946, 1999. 76. Guttman, M., Stewart, D., Hussey, D., Wilson, A., Houle, S., Kish, S., Influence of L-dopa and pramipexole on striatal dopamine transporter in early PD, Neurology, 56(11)1559–64, 2001.

49 MR Imaging of Parkinsonism James B.Wood Neuroradiology, Memphis VA Hospital and Radiology, University of Tennessee Health Science Center 0-84930-1590-5/05/$0.00+$1.50 © 2005 by CRC Press

INTRODUCTION Parkinson’s disease is a slowly progressive neurodegenerative disorder of unknown origin. MRI is a powerful evolving imaging modality which is advancing in several directions to demonstrate this complex disease. With better understanding of the pathophysiology of the disease and the continuing advancement of MR technology, this modality will play a more active role in diagnosis and management of this disease. This chapter presents the progress to date. The diagnosis of idiopathic Parkinson disease (IPD) is based on clinical criteria. Early diagnosis can be difficult. As demonstrated by Hughes, even adhering to strict clinical criteria, 24% of the time, the diagnosis was inaccurate when compared to pathologic specimens in 100 cases.1 Hughes later showed, using current diagnostic criteria by movement disorder experts, that this number can be decreased to 10%.2 The false positives are mainly the Parkinson plus diseases: multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and cortical basal ganglionic syndrome (CBD).1 However, toxins, medications, hydrocephalus, tumors, and vascular disease also can cause Parkinson-like features. MRI can help differentiate these diseases. EVALUATION OF INHERENT VALUES OF TISSUES BY MRI MRI allows evaluation of several inherent properties of tissue, including T1 and T2 relaxation times of the hydrogen nucleus, diffusion of water, and chemical composition.3,4 The temporal change in these properties allows MR to evaluate blood flow. Blood flow not only demonstrates perfusion, it also correlates with neuronal function. Compare this with CT, which is only able to demonstrate the property of density. PET and SPECT with labeling metabolites demonstrate functioning tissue but with decreased spatial resolution. Fusion imaging with MRI helps locate the abnormalities. Also, these modalities have some limitations because of the ionizing effect on tissue, availability, and expense. The process of imaging the brain has become very complicated. However, the objective of all modalities continues to be just one thing—contrast. This includes

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contrasting one normal structure from another, normal from abnormal tissue, and functioning from abnormally functioning tissue. Once contrast has been established, resolving the area of contrast into one point or two points is the next step. The contrast is derived from a signal from the object being scanned. The signal reflects an inherent property such as density in CT or T1 relaxation of the hydrogen nucleus in MR. In a digital world, the cube (volume element or voxel) of the tissue being analyzed has more signal if large. However, if the voxel is large, it cannot resolve small structures. If one makes the cube smaller, the resolution is better, but the signal goes down and may be lost in the background noise. Here is where technology has helped tremendously. Often, the signal can be increased without increasing the cube size, such as by increasing the magnet size from 1.5 to 3.0 Tesla. Also, the speed of collecting the signal can be increased so that several samples of the signal from the same small cube can be collected and averaged, giving a more accurate measure of the inherent property. Thus, better resolution between very small objects, even with small differences in contrast, can be obtained. PATHOLOGY OF PARKINSONISM Armed with these powerful tools, the challenge is to display the abnormalities of Parkinson’s disease. Radiologists have attempted to demonstrate some of the main pathological changes—the neuronal loss and gliosis and also the changing iron deposits in the substantia nigra. Because 70 to 80% of dopaminergic neurons projecting from the substantia nigra to the striatum are lost before symptoms develop, potentially asymptotic patients could be demonstrated. To help differentiate from the false positives obtained with clinical exam, close evaluation of the putamen, the cerebellum, brain stem, and frontal lobes is also done. These findings help differentiate the Parkinson plus diseases. Parkinson and the Parkinson plus diseases involve many structures not mentioned above, and the lack of function of all of these structures has a cascade affect on other structures in the complex circuitry of the basal ganglia. Therefore, pathologic change in these slowly progressive diseases with varied compensating affects is a challenge to image. In the future, when a more robust signal can be detected from the other pathologic changes, increased sensitivity and specificity can be obtained. Other less problematic diseases with Parkinson-like features can be differentiated with well known radiographic features of vascular disease, tumors, or hydrocephalus.3,4 T1 AND T2 FINDINGS A routine screening MRI can demonstrate abnormalities in some patients with Parkinson or Parkinson plus diseases.5–22 IPD demonstrates a decrease in the width of the pars compacta results from increased iron deposition in this area adjacent to the pars reticulum, which normally is already iron rich. The increased iron deposits are thought to be associated with oxidative stress.41,42 The other border of the pars compacta is another normally iron-rich-containing structure, the red nucleus. Iron increases the T2 relaxation value of brain tissue. The best way to demonstrate this has presented a challenge. Several

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people demonstrated the resultant loss of signal on a T2 weighted image. Oikawa et al. concluded that iron changes in the substantia nigra are better demonstrated on the proton density weighted spin echo and fast STIR than on the T2 weighted images (Figures 49.1, 49.2, and 49.3).44 Thus, the enlarging area of iron (normal and abnormal deposits) causes the pars compacta to appear to shrink. Some refer to this as smudging of the border the two pars of the substantia nigra. Unfortunately, overlap with controls is present in this small structure.

FIGURE 49.1 Schematic drawing of the three-dimensional anatomy of the SN from the left superoposterolateral aspect. The SN is located mainly beneath the red nucleus. (From Reference 44. With permission.) Another problem is normal aging also result in iron deposits in the pars compacta. However, the progression from medial to lateral is different from IPD, which is from lateral to medial. Another problem described in some people with IPD is loss of the normal low signal in the pars reticulum, thought to be from depletion of normal iron by increased cellular metabolic activity or by local cell death.45 Using a more novel pulse sequence, partial refocused interleaved multiple echo (PRIME), Graham et al. accentuated increased iron concentration in the substantia nigra.23 However the amount of the decreased width continues to overlap with controls and is also seen in PSP and SND.9,11 The diminishing of pars compacta also reflects selective neural loss. Occasionally, patients with IPD have hyperintense foci on T2 weighted images in SN, possibly due to cell loss and gliosis.10 Hutchinson and Raff24 used a combination of two different inversion recovery sequences, one for white matter suppression (WMS) of the crus cerebri and one for nigral gray matter suppression (GMS) to obtain a more robust signal reflecting both iron increase and also cell loss and gliosis. A ratio image (WMS/GMS) was then computed (Figure 49.4). Images showed loss of signal in a lateral to medial gradient corresponding to the known neuropathologic pattern of degeneration in Parkinson’s disease. Also, a radiologic index was calculated to reflect this signal change (Figure 49.5). The index was highly correlated with the Unified Parkinson’s Disease

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Rating Scale score without overlap with controls. Hu confirmed these results but concluded that Fdopa PET was more reliable than inversion recovery MRI in discriminating patients with moderately severe PD from normal subjects. However, the structural changes detected within the ratio image in his study did correlate with measures of striatal dopaminergic function using18 F-dopa PET.25 Hutchinson and Raff have recently refined

FIGURE 49.2 Axial MR images through the upper midbrain. (A) Axial T2-weighted image in a healthy control subject, a 55-year-old woman. A hypointense area, believed to be SNr, is located in the anteromedial part of the crus cerebri (arrow). No hyperintense gray matter area, representing the SN, is visible. (B) Proton density-weighted image in the same section as in (A). The SN (n) is clearly identified as an area of hyperintense gray matter surrounded by the hypointense red nucleus (r) and the crural fibers (c). (C) T1-weighted image in the same section as in A. The SN is not evident. (D) Fast STIR image in the same section as in (A).

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The SN (n) is readily identified as a structure with gray matter signal intensity. The red nucleus (r) with surrounding white matter and the crural fibers (c) are identified as areas with relatively low signal intensity. (E) Video-reversed fast STIR image onto which the hypointense areas on a T2weighted image are superimposed (shaded areas). The hypointense area on the T2-weighted image includes the crural fibers and the anterior part of the SN. (F) Corresponding axial-section specimen obtained from a human cadaver. (From Reference 44. With permission.) their technique enabling a more detailed assessment of the morphologic changes to increase specificity—seg-mented inversion recovery ratio imaging (SIRRIM).26 To date, they have not yet completed a large-scale study. Probably more useful on the screening MR (excluding the SIRRIM sequence) are specific findings in patient with Parkinson plus diseases. Multiple system atrophy with predominant parkinsonian features (MSA-P) has putaminal hypointensities and atrophy. Atrophy in the putamen is not associated with IPD. In addition, a hyperintense slit signal is seen in the lateral portion of the putamen with MSA-P. Certain sequences and field strengths affect the amount of this sign.27 Macia et al., in a letter, describe their retrospective evaluation of 106 patients with PD and PD plus disease, finding similar hypointensities and slit signals in the putamen in 14 of 21 patients with MSA-C, 3 of 26 WITH PSP, 2 of 26 with CBD, but 0 of 33 with PD.28 Thus, the sign may not be that specific for MSA-P Another finding associated with MSA-P is the “hot cross bun” sign of the pons. Bhattacharyak29 derived a useful diagnostic algorithm using the above findings on a screening MRI to differentiate IPD from MSA (Figure 49.6). High-quality images in this article give an excellent demonstration of the findings of these diseases (Figures 49.7 through 49.11). Progressive supranuclear palsy demonstrates atrophy of the midbrain30,31 and of the frontal lobe.32 Asymmetrical atrophy in the posterior frontal and parietal regions contralateral to the side of the clinical manifestations is characteristic of corticobasal degeneration. Unfortunately, atrophy is either a subjective finding by an expert or an objective, time-consuming finding involving postprocessing exercises such as pixel counting (pixel are picture elements that represent cubes of tissue—voxels).

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DIFFUSION IMAGING Diffuse weight imaging demonstrates the property of random movement of water molecules in the brain. If the structure is homogeneous, the water can diffuse in all directions equally (isotropic). A drop of ink in a glass of water is one such example. Water in the extra cerebral space in a patient with vasogenic edema is another. How-

FIGURE 49.3 Axial MR images through the lower midbrain. (A) Axial T2-weighted image in the same control subject as in Figure 49.2. A hypointense area is visible on only the anteromedial end of the crus cerebri (arrow). An area with relatively high signal intensity suggestive of the SN is not depicted. (B) Proton densityweighted image in the same section as in (A). The SN (n) is clearly depicted as a structure with hyperintense gray matter between the crural fibers (c) and the medial lemniscus (m). (C) T1weighted image obtained at the same section as in (A). The SN is not visible.

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(D) Fast STIR image in the same section as in (A). The SN (n) is identified as an area of hyperintense gray matter posterior to the crural fibers (c). The medial lemniscus (m) and the decussation of superior cerebellar peduncle (d) show relatively low signal intensity. (E) Videoreversed fast STIR image onto which the hypointense areas on a T2weighted image are superimposed (shaded areas). The hypointense areas on the T2-weighted image are located on the anteromedial part of the peduncular fibers, but they barely include the SN. (F) Axial-section specimen obtained in a human cadaver through the lower end of the midbrain. The SN (n) is not present on this section. It is located between the crural fibers cerebri (c) and medial lemniscus (m). (From Reference 44. With permission.) ever, because the brain is not perfectly homogenous like a glass of water, the diffusion is referred to as an apparent diffusion. Thus, the diffusion coefficient is referred to as the apparent diffusion coefficient (ADC). In a brain with a two-hour-old infarct, the water collects in a swollen cell, because the sodium ATP pump has failed. The water cannot diffuse in any direction. The ADC value goes down, and an image can be made to demonstrate the contrast.33 Some normal structures like white matter fiber tracts allow diffuse in one direction but not another (anisotropic). Thus, a MR tensor image that reflects directionality with color coding can be created (Figures 49.12 and 49.13). Each cube of tissue (voxel) has a value, fractional anisotropy (FA) indicating the amount of directionality of water in different structures in the brain. Water in CSF is isotropic and has a FA of 0. Highly anisotropic (highly directional) structures have a FA approaching 1. An abnormal value indicates a focal lesion. However, different etiologies could give a similar appearance. A celery stalk hit with a hammer would appear similar to a fungal infection, causing a focal loss of directionality (FA) on MR diffusion tensor imaging. A recent study by Yoshikawa et al.34 was able to demonstrate early pathologic changes in the parkinsonian brain diffusion tensor MRI (Figure 49.14, Table 49.1). Seppi et al. demonstrated focal abnormal values of ADC in basal ganglia in PSP patients within a few years of onset, discriminating them

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from patients with PD with a sensitivity of 90% and a positive predictive value of 100% but not from those with MSA-P.35 SPECTROSCOPY Spectroscopy allows the measurement of a specific biochemical in the brain.3,4 Different molecules have specific frequencies in a given magnetic field. Changing the field strength (1.5 to 3.0 Tesla) also changes the frequency for a particular molecule. However, the change is proportional to the change in field strength. Therefore, a convention of parts per million (PPM) can be used in all field

FIGURE 49.4 Upper row displays an example of axial WMS and GMS MR acquisition images of the mesencephalon in a control participant. The cerebral peduncle (second row, left) extracted from the WMS midbrain image serves as a template to extract the GMS image of the cerebral peduncle shown on the right. The SNC is seen as a bright arch in the peduncular WMS image, whereas it appears as a dark band in the corresponding GMS image. Note also the substantia nigra pars reticulata

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SNR) reaching across the crus cerebri toward the SNC. The ratio image (WMS/GMS) of the two images in the second row yields the color-coded ratio image displayed on the bottom. All black-and-white images are shown using a standard display of 256 gray levels. The color image uses a 256– pseudocolor lookup table. Ratio images of the cerebral peduncle displayed in pseudo colors show the morphologic characteristics of the SNC in two control participants (C1 and C2) and the structural changes in two patients with Parkinson’s disease (P1 and P2). The substantia nigra pars reticulata (SNR) is indicated for participant C1. Notice that the SNC in control participants reaches out toward the peduncular edge in the upper section, taking on the form of an arch. In the images of patient P1, who has Parkinson’s disease, thinning and loss of signal can be seen in the lateral segment of the SNC in the upper section. The lower section shows islands of cell loss on both sides of the SNC. Note the considerable thinning and loss of signal in both upper and lower sections of the images of patient P2, who has late-stage Parkinson’s disease. Left and right sides show two rims of preserved signal. (From Reference 24. With permission.) (A color version of this figure follows page 518.)

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FIGURE 49.5 Radiologic indices are displayed for the six control participants and the six patients with Parkinson’s disease. There is no overlap between the groups, which are distinct by Student’s t test (P90% and a time to peak plasma concentration of 2 hr. Only 20% is protein bound, and it is excreted unmetabolized from the kidneys.17,18 PRAM can be administered without regard to meals (protein load) or concern regarding interactions with drugs metabolized through the hepatic cytochrome P450 enzymes. The halflife ranges from 8 to 12 hr. The half-life is influenced by age, increased in the elderly (~12 hr), probably secondary to the decreased glomerular filtration rate. Dosing frequency should be reduced in patients with impaired renal function, i.e., b.i.d. in patients with a creatinine clearance of 35 to 59 ml/min and q.d. in patients with a creatinine clearance of 15 to 34 ml/min. PRAM can be titrated over three weeks to a conventional dose of 0.5 to 1.5 mg t.i.d.68 Randomized double-blind placebo-controlled trials with adequate power showed significant improvement in both part II and part III of the UPDRS. PRAM appears to be well tolerated and, in the majority of cases, upwards of two-thirds of the subjects completed the study.69–72 In the Parkinson’s study group, there was a 20% improvement in part II of UPDRS versus placebo. Initial PRAM treatment resulted in significantly less development of wearing off, dyskinesias, or on-off motor fluctuations (28%) compared

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with LD (51%) (hazard ratio, 0.45; 95% confidence interval [CI], 0.30 to 0.66; P867.5 mg; odds ratio, 4.2; 95% confidence interval, 1.3–13.7). Subjective accounts of daytime sleep and wakefulness, as indexed by scores on the Epworth Sleepiness Scale, were not related to impaired daytime sleepiness or wakefulness (chi(2)(1) [n=80], 0.13; P=0.72).141 Fatigue is a similar complaint frequently encountered among patients with PD. Interestingly, 41 patients with PD and controls, after 5 weeks patients taking PRG, showed significant improvement in the fatigue scale (from 5.1±0.7 SD to 4.4±0.55 SD), but patients taking BCP did not (from 4.8±0.9 SD to 4.7±0.8 SD).132 TITRATING AND SWITCHING DOPAMINE AGONISTS Slow titration of DA is recommended to prevent initial side effects such as nausea, hypotension, and drowsiness. As found in the BRC study, the rate of titration must be weighed against the patient’s frustration during the subtherapeutic undermedicated state of the titration. Premedication with domperidone up to two days before and continued during the PRG titration period has been shown to effectively prevent gastrointestinal side effects. After rather quick titration of PRG with coadministration of domperidone, no symptomatic side effects were seen except for light-headedness in one patient, which disappeared after dose reduction.119 In patients already on DA therapy, switch to an alternative DA can be made quickly, essentially overnight.133,134 Few systematic clinical trials have been performed with combination DA therapy. Complexity of study design and lack of pharmaceutical funding probably contribute. As DA and LD monotherapy appear to have less adverse effects of somnolence and simplify the medication regimen, it is probably reasonable to push DA to the point of asymptote of clinical benefit or side effects.

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SUMMARY AND CONCLUSION LD remains an imperfect solution to the progressive degeneration of the brain stem nuclei and downstream basal ganglia motor systems in Parkinson’s disease. It does not delay the progression of the degeneration, and there is evidence that it may exacerbate the degenerative process. In contrast, there is evidence that DAs have a neuroprotective effect and may delay the progression of the disease. Although clinical data do not support the superiority of DA over LD, motor fluctuations and dyskinesia appear to a lesser degree in patients treated with DA. These findings suggest that DA monotherapy should be initiated in early PD, particularly in those with onset before age 50. Addition of LD should be initiated if and when required for symptom relief. Advanced age and cognitive impairment are regarded as relative contraindications for DA, as the adverse effects of psychosis are poorly tolerated. Age alone should not prevent a trial of a dopamine agonist in a patient with intact cognitive function. The nonergot-derived DA have a similar pharmacologic profile without the risk of serosal fibrosis. They are well tolerated and have similar adverse effect profiles. Metaanalysis suggests that PRAM has a higher risk of hallucinations and ROP of hypotension. The development of novel nonoral (i.e., transdermal, subcutaneous injection, intravenous, and intranasal) formulations of DA allow rapid distribution and a stable serum concentrations. Avoidance of the nonphysiologic pulsatile fluctuations associated with LD and DA with a shorter half-life should prevent the associating plastic changes in the striatum that result in wearing off and dyskinesia. ABBREVIATIONS APO

apomorphine

BCP

bromocriptine

CAB

cabergoline

CI

confidence interval

DA

dopamine agonists

LD

levodopa

LID

levodopa-induced dyskinesias

PD

Parkinson’s disease

PRAM

pramipexole

PRG

pergolide

ROP

ropinirole

SD

standard deviation

UPDRS

Unified Parkinson Disease Rating Scale

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127. Erreira, J.J., Galitzky, M., Montastruc, J.L., Sleep attacks and Parkinson’s disease treatment, Lancet, 355:1333–1334, 2000. 128. Frucht, S., Rogers, J.D., Greene, P.E., Gordon, M.F., Fahn, S., Falling asleep at the wheel: motor vehicle mishaps in persons taking pramipexole and Ropinirole, Neurology, 52:1908– 1910, 1999. 129. Arnulf, I., Konofal, E., Merino-Andreu, M. et al, Parkinson’s disease and sleepiness: an integral part of PD, Neurology, 58:1019–1024, 2002. 130. Paus, S., Brecht, H.M. Koster, J. et al., Sleep attacks, daytime sleepiness, and dopamine agonists in Parkinson’s disease, Mov. Disord., 18:659–667, 2003. 131. Nieves, A.V., Lang, A.E., Treatment of excessive daytime sleepiness in patients with Parkinson’s disease with modafinil, Clin. Neuropharmacol., 25:111–114, 2002. 132. Abe, K., Takanashi, M., Yanagihara, T., Sakoda, S., Pergolide mesilate may improve fatigue in patients with Parkinson’s disease, Behav. Neurol., 13:117–121, 2001. 133. Canesi, M., Antonini, A., Mariani, C.B. et al., An overnight switch to Ropinirole therapy in patients with Parkinson’s disease. Short communication, J. Neural. Transm., 106:925–929, 1999. 134. Goetz, C.G., Blasucci, L., Stebbins, G.T., Switching dopamine agonists in advanced Parkinson’s disease: is rapid titration preferable to slow? Neumlogy, 52:1227–1229, 1999. 135. Tseng, K.Y, O’Donnell, P., Dopamine-glutamate interactions controlling prefrontal cortical pyramidal cell excitability involve multiple signaling mechanisms, J. Neurosci., 2:5131–5139, 2004. 136. Picconi, B., Centonze, D., Rossi, S., Bernardi, G., and Calabresi, P., Therapeutic doses of Ldopa reverse hypersensitivity of corticostriatal D2-dopamine receptors and glutamatergic overactivity in experimental parkinsonism, Brain, 127:1661–1669, 2004. 137. Hoglinger, G.U., Rizk, P., Muriel, M.P., Duyckaerts, C., Oertel, W.H., Caille, I., and Hirsch, E.C., Dopamine depletion impairs precursor cell proliferation in Parkinson disease, Nat. Neurosci., 7:726–735, 2004. 138. Golberg, J.F., Burdick, K.E., and Endick, C.J., Preliminary randomized, double-blind, placebo-controlled trial of pramipexole added to mood stabilizers for treatment-resistant bipolar depression, Am. J. Psychiatry, 16:564–566, 2004. 139. Titner, R., Manian, P., Gauthier, P., and jankovic, J., Pleuropulmonary fibrosis after chronic treatment with dopamine agonists for Parkinson’s disease, Arch. Neurol., 2004 (in press). 140. Parkinson Study Group, Pramipexole vs. levodopa as initial treatment for Parkinson disease: A 4-year randomized controlled trial, Arch. Neurol., 61:1044–1053, 2004. 141. Razmy, A., Lang, A.E., and Shapiro, C.M., Predictors of impaired daytime sleep and wakefulness in patients with Parkinson disease treated with older (ergot) vs. newer (nonergot) dopamine agonists, Arch. Neurol., 61:97–102, 2004.

58 Parkinson’s Disease: Surgical Treatment— Stereotactic Procedures Yasuhiko Baba, Robert E.Wharen, Jr., and Ryan J.Uitti Mayo Clinic, Jacksonville 0-8493-1590-5/05/$0.00+$1.50 © 2005 by CRC Press

INTRODUCTION Surgical treatments for Parkinson’s disease (PD) reemerged in the 1990s after essentially two decades of relative obscurity. Prior to the late 1960s, treatment of PD consisted of the use of marginally beneficial pharmacological therapy and lesioning operations. Lesioning operations, including thalamotomy, were employed mainly in attempts to treat severe tremor. Major limitations encountered with surgical treatments in the first half of the 20th century included inconsistent targeting and side effects from lesioning. Inconsistent targeting occurred because of the lack of reliable radiological assistance for stereotactic procedures. Retrospective review of historic surgical records suggests that attempted thalamotomies, especially those deemed as particularly clinically successful for parkinsonism, were probably often subthalamotomies judging from notation of immediate, transient, postoperative chorea.* Lesioning side effects, even in instances with accurate targeting, such as dysphonia or dysarthria in bilateral lesioning operations, also limited enthusiasm for surgical treatment of PD. With the introduction of levodopa in the 1960s, there was a precipitous decline in surgical treatment for PD. An expanding armamentarium of pharmacological agents, including dopamine (DA) agonists and inhibitors of DA catabolism, led to a two-decade period in which surgery was rarely employed. Two factors led to re-emergence of surgery in the 1990s: (a) recognition of limitations in pharmacological therapy and (b) improvement in stereotactic neurosurgical technology. Despite optimal pharmacological therapy, it is generally agreed that approximately 30% of PD patients experience motor complications after approximately five years of treatment.1 While the severity of such complications varies tremendously, it is clear that a substantial proportion of PD patients eventually come to experience “intolerable” fluctuations in motor ability (by individual patients’ definition). Unfortunately, some of the more disabling clinical problems related to PD, namely dementia and postural instability/gait difficulties, become increasingly prevalent with prolonged disease and are typically resistant or potentially exacerbated by pharmacological or surgical treatments

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aimed at improving motor symptoms. It is in the midst of these complicated clinical scenarios when surgical treatments are most commonly contemplated. Improvements in radiology (computed tomography, CT, and magnetic resonance imaging, MRI) and stereotactic (software guidance systems) have dramatically reduced the frequency of adverse effects and increased the reliability of outcomes associated with all forms of surgery. However, as with all forms of new surgery, the apparent safety and efficacy of treatment may vary substantially on the basis of available equipment, expertise, and experience, not to mention patient selection. Surgery for PD is presently thought of as predominantly symptomatic therapy, although it is conceivable that surgical treatments may have some influence on the natural progression of PD. The balance of the chapter discussion is divided into topics based on surgical type and target. SURGICAL OPTIONS It is convenient to subdivide surgery for PD into three groups: 1. Ablation/lesioning 2. High-frequency electrical stimulation/deep brain stimulation 3. Transplantation/neuroregenerative Targets for these forms of treatment are generally shared between ablative and stimulation surgeries, although these modalities may well operate with different mechanism. The three main forms of surgery will be discussed sequentially, followed by conclusions regarding implementation and selection of specific procedures for individual PD patients. LESIONING/ABLATION Thalamotomy 2

Since Cooper reported a patient who provided relief of tremor by ligation of anterior choroidal artery, surgical lesioning of the thalamus has been employed for treatment of tremor in patients with PD. In 1962, microelectrode recording techniques employed during the course of functional stereotactic surgery were introduced by Albe-Fessard et al.3 These electrophysiologic studies helped to determine the ventral intermediate (VIM) nucleus of the thalamus as the optimal target for treatment of tremor. These techniques were used commonly with thousands of thalamotomies being carried out during the 1950s and 1960s.4–6 While elucidation of the anatomic basis of tremor in PD is still inadequate, Elble and others has suggested that central oscillation in the cortico-basal ganglia-thalamocortical loop plays an important role in the production of tremor.7 Interrupting these centrally driven tremor activities, with destruction of the VIM nucleus of the thalamus, can effectively control tremor. Additionally, VIM thalamotomy is useful for treatment of medically intractable tremor from not only parkinsonism, but also essential tremor, cerebellar, Holmes’

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* Personal communication with Ross Miller, MD, one of the premier neurosurgeons of this era.

(midbrain), post-traumatic, and post-stroke tremor.8–11 Thalamotomy has also been employed for treatment of other hyperkinetic disorders such as dystonia, hemiballism, and dyskinesias with various etiologies.12,13 Marked to complete relief of tremor is made by lesions as small as 2 mm located within the VIM nucleus. Tremor cells within VIM may be identified by neuronal firing at frequencies that coincide with electromyographic (EMG) tremor activity.14 Thalamotomy can also improve levodopa-induced dyskinesias with optimal lesion sites reported as the ventral oral posterior (Vop) nucleus of the thalamus.15 While other signs of parkinsonism (such as rigidity and bradykinesia) are not ameliorated by thalamotomy, this surgical treatment is often far more effective in reducing tremor than any pharmacological agent. Pallidotomy Pallidotomy has been performed with the intent to alleviate parkinsonism, especially tremor, since the 1950s.16–20 Narabayashi and Okuma17 and Cooper and Bravo19,20 performed chemopallidotomy with injection of procaine and alcohol, or procaine oil. Initial pallidotomies targeted the anterodorsal region in the internal segment of the globus pallidus (GPi). However, lesioning in this location did not provide satisfactory results. Svennilson et al.21 demonstrated that posteroventral pallidotomy could produce marked amelioration of parkinsonism. With the advent of the levodopa era and advances made with thalamotomy, pallidotomy became infrequently performed.6 In 1992, Laitinen et al.22,23 reports fostered new interest in pallidotomy as a procedure that resulted in longterm, marked or complete relief of tremor, rigidity, hypokinesia, and levodopa-induced dyskinesia. Based on these results, pallidotomy of the posteroventral portion of the GPi was the most frequently performed lesioning/ablation procedure in the 1990s.6 Interestingly, Laitinen has argued that lesioning of the caudal portions of GPe may also produce good results (personal communication). GPi, which receives projections from the striatum, external segment of globus pallidus (GPe), and subthalamic nucleus (STN), is a major output nucleus of the basal ganglia.24 Additionally, GPi receives projections from the sensorimotor subloop arising from primary motor and sensory cortical areas in the basal gangliathalamocortical loop.25 In models of PD, loss of DA cells in the pars compacta of the substantia nigra leads to alteration of neuronal activity in the GPi through the putamen. Subsequent excessive inhibitory outflow from GPi causes changes in the neuronal activity in the thalamus. Dysfunction of the thalamocortical circuit is considered responsible for the motor signs of parkinsonism.24 Unilateral posteroventral pallidotomy may lead to improvements in (a) contralateral parkinsonism (resting tremor, rigidity and akinesia/bradykinesia) and, to a lesser extent, (b) levodopa-induced side effects (dyskinesia and “on/off” fluctuations), and (c) axial disabilities (postural instability and gait disturbance) in advanced and elderly patients with PD22,23,26–36 Therefore, pallidotomy has more sweeping benefit than thalamotomy, which principally affects tremor.

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Subthalamotomy STN drives activity in the external segment of the globus pallidus (GPe), the pars compacta of the substantia nigra (SNc), and GPi/pars reticulata of the substantia nigra (SNr).37 The STN is also a port of entry to the basal ganglia for cortical output. The dorsolateral STN is a sensorimotor territory by virtue of its afferents from motor cortex.25 Since the 1960s, subthalamotomy has been performed as a surgical procedure for PD. The location of the lesioning in the 1960s was probably in the vicinity of the fields of Forel and the zona incerta based on the technology available in that era. In the 1980s, application of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP), which was discovered unexpectedly following illicit drug use, led to develop of an important PD animal model. Subsequently, Bergman et al.38 demonstrated that abnormal neuronal activity in the STN as well as the GPi play a role in forming the parkinsonian animal model. In this model, lesioning of the STN provided significant improvement of parkinsonism and reversal of the increased neuronal activity in the GPi and SNr.39–42 Furthermore, Bergman et al.39 reported two MPTP-treated monkeys that showed improvements of contralateral tremor, rigidity, and akinesia after ibotenic acid injection in the ipsilateral STN. Guridi et al.42 reported MPTP-treated monkeys that received kainic acid injections in the unilateral STN showed bilateral improvement of tremor, spontaneous activity, bradykinesia, and freezing. These monkeys also developed hemichorea after surgery. Additionally, PD patients were also reported to show amelioration of parkinsonism after STN hemorrhage.43,44 Thus, a number of lines of evidence support the rationale for STN to be considered as a suitable target for functional surgery in PD. The efficacy of subthalamotomy in PD patients has also been apparent.45–47 Most patients show improvement of contralateral tremor, rigidity, and bradykinesia with reduction in the requirement of levodopa. Some of these patients experience hemichorea, hemiballism, and/or dyskinesia as a complication of the procedure, but these are less frequent than reported in the MPTP-treated animal model of parkinsonism. DEEP BRAIN STIMULATION Thalamic Stimulation In the 1960s, shortly after introduction thalamotomy, it was recognized that highfrequency stimulation in the VIM of the thalamus produced relief of tremor.48,49 In the late 1980s, Benabid et al.50 reintroduced high-frequency VIM stimulation as a surgical procedure for parkinsonian and essential tremor with similar efficacy and fewer complications. Thalamic stimulation is recommended as a treatment for medically refractory disabling tremor in PD, essential tremor, and multiple sclerosis (MS).51 Thalamic stimulation is generally preferable to thalamotomy for tremor suppression.51,52 Thalamic stimulation, as well as deep brain stimulation (DBS) in other targets, produces reversible changes and does not cause damage to adjacent brain parenchyma.53 Because of lower risk for dysphasia and dysarthria, thalamic DBS is also practical to perform bilaterally.54 Additionally, thalamic stimulation may be advantageous over static

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lesioning, as treatment can be modified over time. On the other hand, DBS procedures may carry a higher risk for infection, lead fracture, and hardware malfunction as well as greater equipment costs and need for periodic generator replacement. It is assumed that high-frequency stimulation alters abnormal brain activity by one or more of the following mechanisms: 1. Depolarizing block 2. “Jamming” of neural activity 3. Channel blocking 4. Neuronal energy depletion 5. Synaptic failure 6. Antero- and/or retrograde effects 7. Activation of inhibitory and/or inactivation of excitatory neurotransmission 8. Effects on non-neuronal cells 9. Effects on local concentration of iron or neuroactive molecules55 However, the specific mechanism of action of DBS is not fully understood. CeballosBaumann et al.56 investigated the functional effect of VIM DBS, and found that VIM DBS provides increased regional cerebral blood flow (rCBF) in the ipsilateral motor cortex. They suggested that the beneficial effect of VIM DBS is associated with increased synaptic activity in motor cortex, probably occurring as a result of activation of thalamocortical projection, or frequency-dependent neuroinhibition that overrides the abnormal periodic neuronal pattern underlying tremor. Perlmutter et al.57 also found increased blood flow in the ipsilateral supplementary motor area, which is a terminal field of thalamocortical projections, in patients with VIM DBS. Pallidal Stimulation Achievement of thalamic stimulation brought a new technological achievement for the surgical treatment of movement disorders. Subsequently, targets of DBS for parkinsonism expanded to include VIM, GPi, and STN, on the basis of evidence that abnormal neural activity is present in GPi and STN in the MPTP-treated animal model. DBS in GPi and STN provided benefits for all forms of tremor and parkinsonism. Pallidal stimulation shows similar clinical effects as pallidotomy and can be performed relatively safely, even in the context of bilateral surgery. Studies of efficacy and safety between unilateral pallidotomy and pallidal stimulation generally conclude these as being comparable.58 Many studies have reported that pallidal stimulation improves all forms of parkinsonism and levodopa-induced dyskinesia 59–63 Theeffects of pallidal stimulation are related to the location of the stimulating electrode within the GPi. Stimulation of dorsal GPi significantly improves parkinsonian features, including rigidity, akinesia, and gait disturbance, and can induce “off” state dyskinesia. On the other hand, stimulation of posteroventral GPi dramatically improves levodopa-induced dyskinesia and worsens gait and akinesia.64 Stimulation of the most ventral part of the GPi leads to improvement of rigidity and complete relief of levodopa-induced dyskinesia but also produces severe akinesia. On the other hand, stimulation of the most dorsal part of the GPi leads to moderate improvement of akinesia and drug-induced dyskinesia.65 Durif et al.66 reported that stimulation of the anteromedial part of the GPi, which corresponds to the ventral

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pallidum and contains a greater number of fibers at the origin of the outflow pathways, is safe and improves cardinal parkinsonian signs and levodopa-induced dyskinesia. Motor performance improvements from pallidal stimulation are also reflected by increased of regional blood flow in the sensorimotor cortex, supplementary motor area, and anterior cingulate cortex on positron emission tomography (PET).67 Subthalamic Stimulation High-frequency stimulation of the STN showed efficacy for amelioration of parkinsonism in MPTP-treated monkeys.68 Subsequently, antiparkinsonian effects associated with subthalamic stimulation were proved also in PD patients;69 the study of this procedure developed rapidly in the mid-1990s. Subthalamic stimulation not only ameliorates cardinal parkinsonian signs and symptoms, it can also reduce the daily levodopa dose equivalent.70,71 Bilateral procedures provide further benefits including improvement of axial instability.72,73 In severely affected PD patients, subthalamic stimulation may be recommended unilaterally or bilaterally. Patients in whom unilateral or bilateral subthalamic stimulation has been performed may need to take antiparkinsonian medicine for ameliorating parkinsonism on the side ipsilateral to the implantation. To date, although anecdotal reports exist that generally favor subthalamic stimulation,74–77 there have been no large randomized studies comparing relative efficacy of subthalamic versus pallidal stimulation or lesioning procedures. Electrostimulation procedures have also been performed following failed lesioning operations, with good results.78–81 Moreover, it has been reported that patients in whom stimulation of the globus pallidus failed to give long-term relief may respond successfully to bilateral subthalamic stimulation.77 Most experts suggest that patients with parkinsonism who do not benefit from levodopa therapy are poor candidates for subthalamic or pallidal stimulation. A patient with vascular parkinsonism, without response to levodopa, showed no beneficial response to bilateral subthalamic stimulation.82 Pre- or intraoperative use of apomorphine, a short-acting DA agonist, has also been reported to be a good predictor of motor responsiveness to motor outcome from subthalamic stimulation.83 Further patient selection criteria and technical specifics remain to be fully delineated. Age, disease duration, and the severity of levodoparelated motor complications are not predictive factors for outcome of subthalamic stimulation. On the other hand, parkinsonian motor disability tends to be more improved in patients with younger age, shorter disease duration, and less axial symptoms. Therefore, older patients and/or patients with significant axial symptoms, such as gait disturbance and postural instability, who are poorly responsive to levodopa, may be not optimal surgical candidates for subthalamic stimulation.84 Cortical Stimulation 85

In 1979, Woolsey et al. reported two PD patients who showed marked improvement of tremor and rigidity by primary motor cortex stimulation with subthreshold stimulation. Subsequently, repetitive transcranial magnetic stimulation (r-TMS) was introduced as a

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treatment for PD motor signs.86 To date, extradural motor cortex stimulation (MCS) has been mainly used as a procedure for central and neuropathic pain with minimal morbidity/mortality risk,87 but some PD patients have also been reported to benefit with MCS.88,89 Because motor symptoms of PD may reflect dysfunction of the thalamocortical circuit,24 MCS may be logical treatment. In fact, modifications of motor cortex metabolism that probably accompany with improvement of motor symptom are demonstrated in PET studies of VIM, GPi, and STN DBS procedures.56,90,91 Extradural MCS has also been reported to reduce dyskinesia, and levodopa equivalent daily requirements.88,89 However, reports concerning extradural MCS stimulation procedures in PD are few and describe anecdotal experiences. Therefore, much more systematic analysis of outcome with extradural MCS is required. REGENERATIVE/GRAFTING Fetal Mesencephalic Tissue Transplantation PD is characterized by selective and progressive degeneration of neuronal cells, frequently leading to severe and uncontrollable disability. The goal of organ transplantation therapy is to regenerate specific neuronal cells or recreate the functional equivalent of those lost in the disorder. In 1979, Bjorklund and Steveni92 and Perlow et al.93 demonstrated that fetal mesencephalic tissue that was implanted in the striatum of 6hydroxydopamine (6-OHDA) animal model reduced motor abnormalities in conjunction with neuronal survival. Implantation of fetal nigral cells to in the striatum of MPTPtreated monkeys provides manufacture of DA and amelioration of motor symptoms.94,95 On the basis of these animal model studies and some anecdotal reports, clinical trials of transplants using adrenal autografts were performed in PD patients, with poor results.96–98 Implantation of fetal nigral tissue in the MPTP-treated animals and PD patients provided modest benefits with effects varying between studies.99–107 The reasons for inconstant results may reflect tissue collection, donor selection, grafting techniques, target site, tissue volume, and use of immunosuppression. Some researchers have limited fetal transplantation to young patients with parkinsonism responsive to DA or DA agonist, whose major symptoms are rigidity and hypokinesia.108 Functional imaging (PET) demonstrates that dopaminergic grafts restore striatal dopaminergic function, with extracellular dynamics of DA that are different from those of intact striatum. These grafts can normalize ambient DA levels and permit transmission over an extended sphere.109 Putaminal 18F-fluorodopa uptake may also improve in selected patients, typically preceding improvements in clinical function. GDNF Regeneration Glial cell line-derived neurotrophic factor (GDNF) is a potent neurotrophic factor for dopaminergic neurons. GDNF may increase survival and growth and prevent apoptosis of dopaminergic neurons.110 GDNF has also been studied in MPTP-treated monkeys111 and PD patients. In animal models that were performed with intraventricular or intraputamenal infusion, GDNF treatment provides up to 60% improvements in rigidity,

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bradykinesia, and axial instability without significant adverse effect. Postmortem studies have demonstrated that nigral DA neuron cell size was increased by up to 30%, and DA metabolite levels in the striatum were increased by up to 70%. Moreover, DA levels in the periventricular striatum increased by 233%. Human Amniotic Epithelial Cell Transplantation Human amniotic epithelial (HAE) cells are generated from amnioblasts on the eighth day after fertilization. HAE cells release brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), which have trophic activities on cultured dopaminergic neurons.112 In the 6-OHDA rat model, HAE cells were found to survive without evidence of overgrowth two weeks after midbrain infusion, and the number of nigral dopaminergic cells was significantly increased in the substantia nigra.113 HAE cells may be part of further preventive or regenerative therapy for PD. Porcine Mesencephalic Tissue Transplantation Transplantation treatment using porcine tissue can overcome societal and ethical limitations and provide a large source of implantable tissue. It has been suggested that the pig is most suitable species for xenotransplantation.114 Porcine fetal ventral mesencephalic transplantation provided functional recovery and reinnervation of striatum in PD animal models.115 In recent studies in PD patients, however, functional recovery was minimal, and total Unified Parkinson’s Disease Rating Scale (UPDRS) score in the “off” state was improved by 19% at 12 months after unilateral transplantation.116,117 Moreover, a prospective, randomized, double-blind, surgical placebo-controlled study in PD reported that there was no significant statistical difference in total UPDRS score in the “off” state between control and treated groups at 18 months after transplantation.118 A postmortem study in a single PD patient over seven months after fetal porcine transplantation was found to show minimal graft survival.119 Additionally, 18F-fluorodopa uptake after 12 months after surgery did not reveal significant changes on the side of transplant.117 There is a risk of transmission of porcine endogenous retroviruses to host cells. Transmission of porcine endogenous retroviruses, with graft survival, has been detected in animals with severe combined immunodeficiency (SCID) performed porcine islet transplants.120 These potential problems with porcine tissue transplantation have led to concerns regarding immunosuppression used to prevent xenograft rejection with heteroplastic transplantation. Such concerns have slowed development and enthusiasm in this mode of regenerative therapy for PD. METHODOLOGY PATIENT SELECTION Appropriate patient selection is the most important key to obtain a favorable outcome from any surgical procedure. Thorough neurological, neuropsychological,

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pharmaceutical, radiological, and systematic medical evaluations are best comprehensively performed by the surgical team: neurologist, neurosurgeon, neuroradiologist, and neuropsychologist. The risks and potential benefits of brain surgery dictate that PD patients are best treated initially with pharmacological agents, with surgery reserved for circumstances in which medication fails to provide consistent benefit. Parkinsonian signs and symptoms that are not responsive to levodopa therapy rarely obtain significant benefit from any form of surgery. Consequently, patients who have little or no response from pharmacological therapy are generally considered poor surgical candidates. The one symptom/sign that does not follow this rule is tremor. Surgery may be effective in ameliorating tremor, even if minimally or unaffected by medication trials. Parkinsonian patients with neurodegenerative disorders other than PD (suggested by the presence of typical features such as supranuclear gaze palsy, predominant axial symptom, absence of tremor, pyramidal tract signs, and marked autonomic disturbance) respond poorly to surgical procedures. Relative contraindications for all surgery include major psychiatric disturbances (major depression, psychosis) and dementia. The surgical procedures themselves may lead to cognitive decline in elderly PD patients with early stage concomitant dementia.121,122 Medication side effects, such as hallucinations or hypotension from dopaminergic agents, are not contraindications as long as they are modest and resolve with reduction in medication dosages. Pallidotomy and thalamotomy can result in postoperative dysarthria and dysphagia, especially when done bilaterally.123– 126 Therefore, significant abnormalities of speech and swallowing are relative contraindications, particularly for lesioning operations, although specific guidelines may vary between centers.127 Chronic anticoagulation is not an absolute surgical contraindication, but careful perioperative management is required. The presence of severe hypertension, brain atrophy, and white matter signal changes that may increase the occurrence of intracerebral hemorrhage. Additionally, the presence of intracranial lesions on MRI or CT may compromise accurate radiological target determination.127 Patients with other severe medical illness are generally not surgical candidates, because of higher risk for the surgical procedure and limited life span. Patients with cardiac pacemakers/defibrillators or spinal cord stimulators have generally not been treated with DBS. However, several patients treated with DBS have subsequently been successfully treated with cardiac pacemakers/ defibrillators when required,128 and therefore these devices are not absolute contraindications for DBS. There are no absolute contraindications to the surgical treatment of movement disorders in pregnancy, although the relative risks of the procedure contemplated must be weighed with the benefits. Because most movement disorders are chronic, it would be reasonable to defer surgery until the patient is postpartum. SELECTIONS OF SURGICAL TARGET AND TYPE Selection of target and surgical type must be selected by virtue of each individual patients need. Consequently, it is essential to delineate the patient’s current and potential future needs that most influence daily life. While DBS can be performed with less neurologic complication than lesioning procedures, it does require potentially frequent adjustments in stimulation parameters and occasional pulse generator change, and it involves potential

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risk for infection and delayed complications with hardware. On the other hand, lesioning procedures are performed relatively easily, without high cost. While some patients have had DBS contralateral to lesioning procedures, it remains to be seen whether such a practice offers substantial benefits. Tremor A thalamic target provides beneficial results for parkinsonian tremor, but not for other cardinal parkinsonian features51,52,129 (Figure 58.1). Therefore, PD patients with long-term tremor-dominant disability are good candidates for thalamic procedure. There is no significant difference in effect for tremor between thalamotomy and VIM DBS, but VIM DBS are performed with less adverse effects than thalamotomy.51 Pallidal and subthalamic targets also provide good results for tremor. However, quantitative efficacy of thalamic target may be superior to those of pallidal or subthalamic target. Rigidity, Bradykinesia/Akinesia, Axial Symptoms Both pallidal and subthalamic targets provide benefit for rigidity, bradykinesia/akinesia, and axial symptoms such as gait disturbance and postural instability. Pallidotomy can improve moderately to markedly these signs. Longterm efficacy studies with unilateral pallidotomy demonstrate maintained contralateral benefit.130–133 However, bilateral procedures carry risk for severe adverse effects.124,134 Nevertheless, pallidotomy may be a reasonable option for a patient with severe, relatively unilateral parkinsonism and levodopa-induced dyskinesia. Subthalamotomy also produces improvement of cardinal symptoms of PD, and these effects endure.45–47 Effects for axial symptoms are measurable but not long-lived with unilateral procedures.47 GPi and STN DBS provide similar effects to lesioning procedure corresponding to each target but also with less complication, especially when per

FIGURE 58.1 Effects on tremor in VIM DBS, label. Left: presurgery. Drawing difficulty was seen for tremor. Right: postsurgery, “on.” formed bilaterally. Effects for rigidity, bradykinesia/akinesia, and axial symptoms from both GPi and STN DBS are also similar, but efficacy in relieving bradykinesia/akinesia with STN DBS is likely mildly superior to GPi DBS.65

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Dyskinesia A pallidal target provides marked to complete and longterm relief of levodopa-induced dyskinesia.63,135–141 Unilateral pallidotomy improves levodopa-induced dyskinesia, not only contralaterally but also ipsilateral to the side of the lesioning. Elimination of levodopa-induced dyskinesia is dramatic with bilateral GPi DBS. Subthalamic nucleus targets also result in amelioration of levodopainduced dyskinesia. Both subthalamotomy and STN DBS allow marked to complete reduction of levodopa equivalent medication intake, which may account for dyskinesia relief.32,45–47,70,71,142–145 The thalamic Vop target may also improve levodopa-induced dyskinesia.15 OPERATIVE METHODOLOGY CT or MRI of the brain is obtained prior to and sometimes following the procedure to assess for hematoma and edema and to verify lesion placement. Because pallidotomy may result in visual field deficits, pre- and postoperative assessment of visual fields may be useful.26 Prior to surgery, cerebral angiography may occasionally be performed to delineate surrounding blood vessels in the target area, although high-quality MRI usually would obviate the need for angiography. Stereotaxic surgery was developed so as to better determine the relationship of the surgical target to nearby structures, which can be visualized radiographically, and then to direct an electrode or other probe to the target with minimal damage to surrounding structures.146 The optimal means for targeting continues to be the subject of debate147 but always includes neural imaging. Initial targeting is guided by integration of CT or MRI, with frames for stereotactic surgery, via specially designed computer software.127,148 While MRI tends to be preferred, CT imaging may be acceptable, and the only randomized study evaluating this issue suggested no difference between MRI and CT for preoperative localization (in pallidotomy).149 Small statistical differences in MRI versus CT-derived targets have been identified and, although direct comparison with clinical outcomes have not been made, most institutions have concluded that MR-based target localization is superior to CT.150 Comparisons of MRIguided and ventriculography-based stereotactic surgery for PD have concluded that each results in similar clinical outcomes, concerning efficacy and complications.151 Lesions in pallidotomy and thalamotomy are made using stereotactic radio frequency ablation, often following electrophysiological recordings and stimulation procedures.152 It has been determined that electrophysiologic recording typically leads to final placement of lesions usually within 2 to 3 mm of MRI targets, with the actual lesion overlapping the MRI theoretical target in 40 to 50% of patients.153 Experienced centers using MRI and microelectrode recordings typically require only one or two trajectories for performance of pallidotomy.154 Additionally, occasionally deep brain stimulation electrodes are employed in the process of directly making lesions.155 Surgical techniques for all types of surgical procedures vary between centers. This discussion provides descriptions of only some of the techniques commonly used. Pallidotomy, thalamotomy, and deep brain stimulation procedures are performed under local anesthesia so that the patient can be monitored with clinical criteria

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intraoperatively.148,152 Usually, after the stereotactic frame is placed under local anesthesia, CT or MRI is performed to locate the coordinate of the anterior commissure (AC) and posterior commissure (PC). Computer programs allow for subsequent simulation with the patient’s MRI of the precise trajectory and distance to target from the burr hole (Figure 58.2). Stereotactic devices are subsequently fixed to the frame, and microelectrode recording/stimulation ensues. Electrophysiological assessment of the activity of the target is used to ensure proper targeting and placement of the electrode. The tip of the electrode, which is used for recording, has a diameter of 0.01 to 0.02 mm and an impedance of 0.3 to 1 MΩ at 1,000 Hz. The sensorimotor region is delineated by recording the increases in neuronal discharge on passive manipulation of the limbs and during active movement. In the GPi and STN, the arm and face are in the most lateral region and leg slightly more medial. The reverse is the case for the VIM, where the leg is lateral to the arm.156 After localization of the target by electrophysiological recording, in ablative procedures, lesioning is performed along the tra-

FIGURE 58.2 MRI stereotactic plan for VIM-thalamic target, label: T1 weighted axial (A), parasagittal (B), and coronal (C, D) imaging. The thalamic target is shown as light gray dots. jectory (Figure 58.3). In DBS procedures, electrode implantation is performed in the sensorimotor region of each target nucleus. The electrode is placed into the intended target with X-ray confirmation followed by intraoperative stimulation and characterization of stimulation effects (Figures 58.4 through 58.6). In thalamotomy, a burr hole is made and, based on previously delineated coordinates, a monopolar microelectrode is advanced to identify somatotopy in the thalamic somatosensory nucleus, ventralis posterior. Moving anteriorly to sensory recordings made following tactile stimulation of the contralateral hand or face leads to stimulation of the ventralis intermedius nucleus, which has a characteristic spontaneous discharge coincident with tremor activity.146 A separate, monopolar, stimulating electrode may subsequently be used, noting tremor suppression once the correct area is reached.146 The

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operation is monitored clinically in terms of speech, manual and foot dexterity, sensation, tone, and tremor, and electri-

FIGURE 58.3 MRI findings in pallidotomy, label: T1 weighted parasagittal (A), coronal (B), and axial (C) imaging. Left pallidal lesion is confirmed (white arrow).

FIGURE 58.4 Implantation of deep brain stimulation electrode. Electrode positioning following MR targeting is confirmed with intraoperative lateral X-ray of the head.

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FIGURE 58.5 Lateral skull X-ray of bilateral subthalamic DBS electrodes (brain and extension leads and connections are visible).

FIGURE 58.6 MRI findings of bilateral subthalamic deep brain stimulation electrode implant, label: T1 weighted axial (A), parasagittal (B), and coronal (C) imaging of bilateral subthalamic stimulation. cally, in response to proprioceptive, kinesthetic, and electrical stimulation of the involved limb.127,157,158 Once the appropriate coordinates are determined, a lesion is made with a lesioning electrode.146,157 This electrode is hollow to allow the insertion of a thermocouple device, which uses radio frequency current to create the lesion.146 In pallidotomy, a microelectrode recording probe is introduced through a frontal burr hole and advanced to confirm somatotopic localization within the globus pallidus interna, which has been previously targeted with stereotactic information and CT or MRI.26,148

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Single-cell electrical recording is performed using tungsten-tipped, disposable microelectrodes and analyzed for responses during passive and active movement.152 Electrical stimulation prior to lesioning is performed to prevent injury to the internal capsule and optic tracts adjacent to the globus pallidus interna.152 Specific clinical signs have also been described that may occur and influence targeting decisions during surgery. For example, authors have reported a patient who had marked, sustained, contraversive eye deviation by stimulation during pallidal surgery. This may occur as a result of excitation of internal capsular fibers by volume conducted current spread. Such conjugate eye deviation therefore may not necessarily indicate incorrect electrode placement.159 If electrical stimulation does not result in weakness or visual field loss, a lesion is made.148 The probe is then withdrawn several millimeters, with repeated lesioning, creating a three-dimensional lesion along the track (or tracks).26,148 Further lesions are performed based on clinical responses measured in the contralateral hemibody (i.e., reduction in parkinsonian signs). Some believe that bilateral pallidotomy can be safely done during the same procedure, and that the localization information from the first lesion is helpful in determining that of the second.160 However, most centers favor performing only unilateral pallidotomy. Visual evoked potentials to photic stimulation of the eyes intraoperatively during pallidotomy are believed by some to facilitate the accuracy of the determination of the globus pallidus interna.156,161 A consensus statement regarding pallidotomy has been reported suggesting, among other conclusions, that pallidotomy should be performed only at centers where a dedicated team of physicians has compiled substantial experience in the field.162 Lesions of the STN can be created in a similar fashion to those in pallidotomy and thalamotomy, but these lesions are technically more difficult, because neuroimaging techniques are less able to localize this target, and lesioning of the STN may cause hemiballism, chorea, or other adverse effects. However, stimulation of the STN is routinely performed in many experienced surgical centers and offers significant advantage in allowing the possibility of performing a bilateral procedure due to the relative lack of risk of irreversible dysphonia. Issues still debated include the need for microelectrode recording,136,152,163,164 the number of lesions and lesion size, and the wisdom of making bilateral lesions. In a survey of 28 centers performing pallidotomy in North America, most centers were using MRI alone (50%) or with CT (n=6) to localize the target. The median values of pallidal coordinates were stated as 2 mm anterior to the midcommissural point, 21 mm lateral to the midsagittal plane, and 5 mm below the intercommissural line, with a total of three permanent lesions placed 2 mm apart. According to the survey, lesions are typically made employing a median temperature of 75°C for 1 min. Microelectrode recording was performed by 50% of the centers surveyed, with the main target defining criteria being (1) the firing pattern of spontaneous neuronal discharge and (2) the response to passive manipulation of a limb. Proponents for microelectrode recordings indicate that such recordings altered the final target in almost every instance, with one of nine targets being more than 4 mm from the image-guided site.154 Motor and visual evaluation was also done intraoperatively.165 Microvascular doppler evaluation, performed in order to identify intracerebral vessels in proximity to targets for thermocoagulation (in thalamotomy or pallidotomy), has been described as a means to minimize risk of vascular injury. A prominent vascular sound

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was identified in 3 of 13 cases in one series.166 It is unclear whether use of this technique significantly impacts on safety in these lesioning operations. In thalamic stimulation, placement of the stimulating quadripolar lead is performed under local anesthesia with subsequent implantation of an external, programmable stimulator being placed under general anesthesia.167 Contrast ventriculography is used by some to allow advancement of the electrode through a burr hole toward the ventralis intermedius nucleus target.167 Most centers employ MR- or CT-guided software to prepare a surgical targeting trajectory for placement of the stimulation lead. Electrophysiological confirmation of the target proceeds as with thalamotomy. When stimulation through the quadripolar lead suppresses tremor, the electrode is implanted and connected to a percutaneous lead that is tunneled to the implanted pulse generator.167 A similar technique has been described for placement of the stimulator for pallidal and STN stimulation.69 Microelectrode recordings in the STN suggest a somatotopic arrangement that may aid in electrode placement.168 The effects of intravenous anesthesia with propofol on intraoperative electrophysiologic monitoring were studied in patients during pallidotomy and thalamotomy. Infusion of this agent needed to be reduced to detect neural noise levels required for targeting in some patients but generally serves as a useful anesthetic agent for electrophysiological monitoring during functional neurosurgery.169 Gamma knife thalamotomy has been reported using stereotactic guidance.170–172 Ohye and colleagues used 140 to 150 Gy and 4 mm collimators with microelectrode recording guidance similar to that described above in thalamotomy and pallidotomy.170 Pan and colleagues have used slightly higher doses of radiation, 160 to 180 Gy maximum dose, also with 4 mm collimators.171 Because of the delay in response and relative inaccuracy and unpredictability of radiation lesions, most specialists suggest other modes of surgical treatment be used in most instances.173 The surgical techniques used for fetal mesencephalic transplantation for PD vary between centers.174 The ideal fetal age, amount of tissue, tissue handling methods, and preferred location of transplant remain in debate. Some researchers believe that storage of fetal tissue in liquid nitrogen is reasonable prior to transplantation, which would allow harvesting this scarce tissue source well in advance of transplantation.175 Others perform fetal transplantation within 4 hours of the abortion, without freezing the tissue.105 Some recommend the use of tissue from fetal cadavers of 6 to 11 weeks gestational age.105,175 Others have used fetuses of 11 to 19 weeks’ gestation.176 Fetal transplants have been placed in the caudate nucleus, in the putamen, or in both (usually 1 fetal graft in the caudate and 3 in the putamen), and bilaterally or unilaterally, depending on the center performing the procedure.99,100, 105,175 Tissue for transplantation is obtained from fetuses following suction abortion, and the mesencephalic region is dissected microscopically.177 Testing of the maternal serum and recipient serum prior to transplantation includes studies to rule out HIV, hepatitis, and other infectious diseases.108,178 ABO typing is done by some centers for donor/recipient compatibility.177 Implantation is performed under general anesthesia.108 Using stereotactic techniques, approximately 10 to 15 strands of fetal mesencephalic tissue are inserted via injection cannula into one or both lenticular nuclei of the recipient.177 The importance of postoperative immunosuppression is not known, and its use varies between centers.108,177– 179 One study found that immunosuppression did not improve clinical outcome.180 Use of

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fetal porcine tissue for transplantation is also now under study, as are issues relating to cell suspension versus solid graft transplant, use of neurotrophic factors, and routine immunosuppression. Follow-up Care Evaluation after surgery is of paramount important. Carefully follow-up observation is recommended to look for neurological deficit or procedure-related complications as well as to modify other pharmacological treatment. CT or MRI examination may be performed to confirm lesioning or implanted electrode site, and to find procedure-related complications. In DBS procedures, stimulators are often tuned “on” and programmed. Patients should be evaluated every one to three months for the first year following surgery and annually thereafter. At each visit, information regarding neurological examination, levodopa equivalent dosage, duration of “on” time, and severity of dyskinesia should be noted. Interviewing the patient’s family is also important in discovering other psychological symptoms. Quantitative assessment following UPDRS, Dyskinesia Rating Scale (CAPIT) score, Parkinson’s Disease Quality of Life Questionnaire (PDQL), and Mini-Mental State Examination (MMSE) may also be recorded. DBS related complications or side effects may occur at various times following implantation and stimulation. These include disturbances in consciousness, seizures, confusion and bradyphrenia, and cerebral hemorrhage accompanying electrode implantation. Infection, skin erosion, and malfunction of brain and extension lead may occur as later complications. External magnetic devices and other electronic tools may cause inadvertent turning “off” of a pulse generator. Rarely, patients who suddenly lose stimulation may show sudden neurological deterioration, requiring emergency treatment.181 One patient with STN DBS was left in a vegetative state from permanent brain stem lesioning after receiving pulsatile radio frequency diathermy for a dental condition.182 As such, all surgical invasive procedures are best carried out only after consultation with the DBS device manufacturer. OUTCOMES LESIONING/ABLATION Thalamotomy Recent long-term follow up studies in PD patients who underwent unilateral thalamotomy report complete abolition of contralateral tremor in 86%183,184 with reduced levodopa requirements. Immediate postoperative complications consist of mild contralateral weakness (34 to 42%), dysarthria (29 to 36%) and cognitive impairment (14 to 23%), with some side effects in approximately 58 to 67%. These complications usually resolve rapidly during the postoperative period. Potential persistent complications include contralateral hemiparesis, seizures, paresthesia, ataxia, apraxia, hypotonia, abulia, and gait disturbance. Hemorrhagic complications may accompany the procedure, causing

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serious or lethal morbidity in 1 to 2% of patients. However, the benefits in surgery usually outweigh potential complications at experienced surgical centers. Bilateral thalamotomy has a high incidence of complications including dysarthria, dysphagia, and hypophonia, typically on the order of 30%. The mortality risk for thalamotomy in PD is less than 0.3%.185 Causes of death include hemorrhage in deep gray matter, postoperative infection, and pulmonary embolism. Thalamotomy vs. Thalamic Stimulation 51

Schuurman et al. reported the effect of thalamotomy and thalamic stimulation on functional abilities of patients with severe tremor due to PD, essential tremor, and multiple sclerosis. After two years of follow-up, thalamotomy and thalamic stimulation showed equal effect for the suppression of tumor, but thalamic stimulation was associated with significantly fewer adverse effects than thalamotomy and resulted in greater functional improvement. Schuurman et al.186 demonstrated that thalamotomy and thalamic stimulation are associated with a small overall risk of cognitive deterioration. Worsening of verbal and reading tasks occurred after left-sided surgery in both thalamic procedures. PALLIDOTOMY The proportion of improvement in motor function varies in each study, with improvement of total UPDRS score ranging from 17.8 to 65% during short-term follow-up after surgery.26–28,139,187 The UPDRS score in the “off” state reveals improvement ranging from 13.6 to 31%.27,28,34,135,137,139,140,187,188 Ameliorations of motor symptoms are striking contralateral to surgery. Some studies also report improvements of tremor, rigidity, bradykinesia, and tests of finger and foot tapping ipsilateral to surgery.26,27,34,137,139,187 Such improvements are usually transient and undetectable six to nine months postoperatively. Axial disabilities such as postural instability and gait disturbance improve by 22 to 44% but, again, are not longlived.27,136,137,188 The most obvious and reliable beneficial effect of pallidotomy is improvement of levodopa-induced dyskinesia; the degree of reduction in dyskinesia ranges from 50 to 92% improvement in the contralateral side, and by 32 to 45% ipsilaterally.135–137,139,140 Reports of benefit of pallidotomy on activity of daily living (ADL) and quality of life (QOL) scores vary, ranging from 17 to 44%,27,28,137,139,190 and from 35 to 77%,139,190 respectively. Laitinen et al.22 reported that the dosage of levodopa could be reduced by 50 to 75% after pallidotomy. However, in most long-term follow-up studies, there is no change in dose of antiparkinsonian drug, including levodopa.137 Pallidotomy provides around equivalent improvement of motor functioning in both younger and elderly PD patients.28 Improvement in cognitive function after pallidotomy emerges only in “off” state measures.191 On the other hand, verbal fluency is reported to decrease after pallidotomy,28,123,191,192 and left-sided lesioning produces more impairment in verbal fluency.192 However, verbal fluency changes typically recover during long-term follow-

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up after surgery.193 Additionally, the presence of cognitive impairment after pallidotomy does not correlate with volume of lesion.192 Long-term follow-up studies after unilateral pallidotomy over periods of 4 to 5.5 years report sustain improvements of parkinsonism and levodopa-induced dyskinesia in the contralateral side compared with baseline,130–133,193 and improvement of tremor is strikingly preserved.131,132, 193 However, most other signs gradually return to preoperative levels, and signs deteriorate with disease progression. Adverse effects with pallidotomy vary between studies. Because optic tract and internal capsule each reside adjacent to GPi, inaccurate targeting may cause visual and motor system problems. Adverse effects include facial paresis, dysarthria, acute confusion or somnolence, dysphagia, hemiparesis, changes in personality or behavior, worsening of handwriting, visual field defect, hypersalivation, and cerebrovascular accident. In these adverse effects, acute confusion or somnolence is likely to be a transient symptom after surgery. The occurrence rate of total adverse effects of unilateral pallidotomy is 30.2%, and of permanent adverse effects is about 13.8%.194 Occurrence of adverse events may vary substantially between surgical centers. Some series report unilateral pallidotomy without serious permanent adverse effects.28,190 Symptomatic brain infarction and hemorrhage are seen in 3.9%, and mortality in 1.2% of patients with unilateral pallidotomy.194 Bilateral pallidotomy also produces abolition of levodopa-induced dyskinesia and motor fluctuations. However, because of more frequent and severe complications, including neuropsychological and psychiatric changes, and corticobulbar syndromes in many patients,123–126 such bilateral lesioning is usually avoided. Staged bilateral pallidotomy is also associated with increased risk of adverse effects, though most patients experience moderate benefit.134 SUBTHALAMOTOMY Recent studies reported that unilateral subthalamotomy can improve all cardinal features of parkinsonism and reduce the required dose of levodopa.45–47 Total scores of UPDRS II (motor score) and III (ADL score) in the “off” period show significant improvement after surgery, and these efficacies last for at least 6 to 24 months. Additionally, “on/off” fluctuations are reduced and tremor improved contralateral to the lesion.45 In addition to improvements of rigidity and bradykinesia on the side contralateral to the lesion, transient benefit may occur ipsilateral to surgery.45 Noteworthy ameliorations in axial disabilities, such as gait disturbance and postural instability, are obtained by unilateral subthalamotomy.45,47 These improvements decrease gradually from about one year after surgery.47 The levodopa equivalent daily intake reduces by 42 to 59%, and some patients may stop medical treatment after surgery,45–47 subsequently resulting in significant reductions in dyskinesias.46,47 Postoperative dyskinesia such as hemichorea and hemiballism are rarely seen,46 ranging from 5 to 25 %.45–47 Other adverse effects include cerebrovascular accident with or without clinical symptoms. Patel et al.46 report that combined lesioning of the dorsolateral and pallidofugal fibers (H2 field of Forel)/zona incerta is particularly effective for parkinsonism and dyskinesia.

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DEEP BRAIN STIMULATION Thalamic Stimulation Thalamic stimulation produces significant reduction in both essential tremor and parkinsonian tremor contralateral to the side of stimulation in randomized controlled studies.195,196 Koller et al.195 reported that combined blinded tremor ratings (ranging from 0 to 4) of “on” stimulation scores in PD patients with unilateral thalamic stimulation were 0.6 compared to 3.2 for those of “off” stimulation; 58% of patients showed complete relief of tremor. Limousin et al.196 reported resting tremor of the contralateral upper limb reduced in 85% of patients (Schwab and England scale, and UPDRS II items 6, 8). Double-blind long-term studies by Rehncrona et al.197 demonstrated that thalamic stimulation provide significant improvement of the total motor score, not only by suppressing tremor but also by decreasing akinesia in the contralateral to the side of stimulation at the six- to seven-year follow-up evaluation. Thalamic stimulation also can be beneficial in reducing midline tremor with bilateral thalamic stimulation being superior to unilateral.128 All forms of tremor appear responsive to thalamic stimulation, with changes in postural tremor being associated with greatest functional improvement.198 Thalamic stimulation has been recommended as treatment for disabling tremor in PD, essential tremor,167 and multiple sclerosis. Based on experience with 118 patients, Benabid and colleagues found that complete arrest of tremor is frequently encountered.167 Others authors have noted that repeated programming changes may be required in patients.199 Thalamic stimulation contributes benefit only for tremor, but it has been reported that relief of tremor by thalamic stimulation may also improve postural instability in PD patients.83 However, in another study, gait comparisons in seven patients undergoing VIM stimulation for PD found no changes with stimulation.200 Improvements in levodopa-induced dyskinesia have been shown to occur with thalamic stimulation inferior, medial, and more posterior to VIM, probably within the center median and parafascicularis complex.201 Significant cognitive decline is generally not encountered with thalamic stimulation.202 It is reported that longterm cognitive functioning is maintained with improvement of QOL measures in patients with thalamic stimulation.203 Some of patients with thalamic stimulation show improvement of depression score, semantic verbal fluency, or reaction time, with inconsistent worsening of immediate word recall, but not significantly.202,204 Sleep and sleep spindles do not appear to be affected by VIM stimulation, which theoretically might induce sleep because of the close proximity to thalamic reticular nuclei.205 Another study reporting the influence of Vim stimulation on sleep found no modification of sleep quality or architecture between “on” (130 Hz, 2 to 3 V, unilateral and bilateral stimulation) and “off” states, suggesting that low-frequency stimulation of regions adjacent to the reticular nuclei do not induce sleep.206 However, high-frequency stimulation of the STN in PD actually appeared to improve total sleep time in ten patients, likely on the basis of improved nighttime motor ability.205 Thalamic stimulation may lead to some adverse effects, which are commonly mild and acceptable to patients. Dysarthria is the most common, especially in bilateral procedures,

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and occurs in 20% of patients.54,207 Other adverse effects include feelings of unsteadiness, limb numbness, muscle cramp, and dystonia. Pallidal Stimulation Pallidal stimulation, as well as pallidotomy, shows efficacy for amelioration of parkinsonian signs and symptoms, and dramatic effects on levodopa-induced dyskinesia. Bilateral pallidal stimulation appears to be more effective than unilateral pallidal stimulation for improvement of parkinsonism. It improves drug-induced dyskinesia by 80% and gait disturbance and postural disturbance by 40 to 50%.208 Bilateral procedures improve “off” state UPDRS motor score by 40 to 50% and reduce the amount and severity of on/off fluctuations.63,65,138 Unilateral pallidal stimulation appears to be relatively safe in either dominant or nondominant hemispheres from a cognitive perspective.209 Bilateral pallidal stimulation does not bring a change of overall cognitive function in PD patients without dementia.210 One case report exists showing a recurrent manic episode associated with pallidal stimulation.211 Bilateral pallidal stimulation has been shown to be beneficial two years following surgery, although the magnitude of benefit declined after one year.63,138 Durif et al.141 reported that significant improvement of dyskinesia severity and ADL was maintained at three years followup after surgery, but other efficacies induced by pallidal stimulation, including improvements of the “off” period overall UPDRS score (UPDRS I+II+III), UPDRS motor score, and mean daily “off” state duration were lost at three years followup after bilateral procedures. In addition to common hardware-related complication, adverse effects with pallidal stimulation include confusion, depression, increasing in akinesia, and induction of gait or speech disturbance.212 SUBTHALAMIC STIMULATION While differences exist in study design, patient selection and evaluative method in each report, many investigators have reported the effects for cardinal parkinsonian signs and symptoms, and dyskinesia. In studies of 6 to 36 months follow-up after bilateral implantations, UPDRS motor scores in the “off” period are improved by 42 to 75% 32,79,142–145,213,214 and UPDRS III (ADL) scores improved by 30 to 70%.32,71,142–145,214 Beneficial effect for tremor is most striking improvement in the cardinal symptoms of PD, ranging between 55 and 90%.32,70,142,190,214 Rigidity and bradykinesia are improved each by 52 to 72%,32,70,142,190,214 withsimilar improvements being noted in axial symptoms.142,190,214,215 Bejjani et al.215 and Pinto et al.216 also observed that bilateral subthalamic stimulation can improve not only limb motor function but also axial symptoms, including speech impairment. The greatest benefit of DBS on motor function is that this form of therapy produces marked reduction (about 80%) in “off” time duration and leads to practical amelioration of motor fluctuations.32,142,214 Reductions in levodopa-induced dyskinesia are clear; levodopa-induced dyskinesia is reduced by 65 to 90%,142–144,190,214 and those effects last long-term after surgery. Bilateral subthalamic stimulation also provides complete or significant improvement of “off” state dystonia.70,142

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The levodopa dose equivalent is reduced by 40 to 81% following subthalamic stimulation,32,70,71,142–145 and some patients no longer require antiparkinsonian drugs after surgery. The decrease of levodopa is commonly recognized within a few months after surgery. In an assessment of the impact of this procedure, using Parkinson’s disease Quality of Life scale, by Lagrange et al.,143 all subscales, including parkinsonian motor symptoms (+48%), systemic symptoms (+34%), emotional functioning (+29%), and social functioning (+63%) significantly improved with long-term follow-up after surgery. Subthalamic stimulation also provides improvements in sleep.71,218 These effects are probably due to increase nocturnal mobility and reduction of sleep fragmentation. Potential adverse effects accompanying subthalamic stimulation include paresthesia, unilateral anisocoria, dysarthria/dysphonia, diplopia, eyelid opening apraxia, depressive mood, mania, delusion, and suicidal attempts.32,70,71,142–144,213 Subthalamic stimulation may also produce ballism and chorea when the voltage is increased over a given threshold. Pallidal Stimulation and Subthalamic Stimulation Recent studies suggested that subthalamic stimulation might have advantage over pallidal stimulation in amelioration for overall disabilities with PD.61,63,75,219 In prospective, nonrandomized, multicenter studies of patients with advanced PD treated with pallidal stimulation or subthalamic stimulation,219,220 motor functions (compared with no stimulation) were greatly improved by 49% in subthalamic stimulation and 37% in pallidal stimulation. Between the baseline and six-month follow-up evaluation, the percentage of time during the day that patients had good mobility without involuntary movements increased from 27 to 74% with subthalamic stimulation and from 28 to 64% with pallidal stimulation. The daily levodopa dose equivalents were reduced by 37% in the subthalamic stimulation, with no decrease found with pallidal stimulation. Other studies also report results that support the aforementioned study. Krack et al.61 reported a six-month follow-up study in PD patients with young onset that UPDRS motor scores in the “off” state were improved by 71% in the subthalamic stimulation and 39% with pallidal stimulation. Rigidity and tremor showed equal improvement in both procedures, but efficacy for akinesia with subthalamic stimulation was superior to pallidal stimulation. While there was a marked improvement in levodopainduced dyskinesia with pallidal stimulation, subthalamic stimulation led to an indirect reduction of levodopainduced dyskinesia similar to that of pallidal stimulation because of the fact that the daily levodopa dose equivalents were reduced by 56% in the subthalamic stimulation. In a one-year follow-up study of PD patients treated with subthalamic stimulation or pallidal stimulation,221 the motor symptoms in the “off” state were improved by 67% in the subthalamic stimulation and 54% in the pallidal stimulation, but speech and swallowing (UPDRS subscale) deteriorated significantly in patients with subthalamic stimulation. The investigators of this study suggested that significant reductions in levodopa dose equivalent with subthalamic stimulation also brought patient economic benefits. A study of PD patients with unsatisfactory results (n=40 out of 211) following pallidal or subthalamic stimulation concluded that the main causes for poor results were advanced

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age, abnormal MRI, and preoperative symptoms that were unresponsive to levodopa. Alternatively, misplacement of the electrode occurred in 5% of patients. Bilateral subthalamic stimulation or pallidal stimulation affects neither memory nor executive functions three to six months after surgery.210 In “on” stimulation, psychomotor speed and working memory are improved in patients treated with subthalamic stimulation. Except for a mild deterioration in lexical fluency, subthalamic or pallidal stimulation does not appear to affect cognitive performance.222 Cortical Stimulation Only rare case reports have been reported to date, but extradural MCS may improve cardinal symptoms of PD. Canavero and Paolotti88 reported an advanced PD patient with extradural MCS at cortical area corresponding to the left arm. The effects were seen in all limbs immediately after surgery. At three months after surgery, rigidity was improved markedly to completely. Choreiform dyskinesia, cogwheeling, and dysphagia were relieved completely. The patient became able to stand without assistance and walk. Execution of other movements also improved dramatically. Total UPDRS scores in the “off” state were improved by 46%, and levodopa equivalent dose was reduced by 80%. These benefits lasted about three years, with absence of rigidity and tremor in all limbs.89 In another advanced PD patient extradural MCS at a cortical area corresponding to right arm (central sulcus),89 at six months after surgery, tremor was relieved completely. Bradykinesia, gait disturbance, hypophonia, and dysarthria were also improved. Levodopa equivalent dose was reduced by 73%. Target-related adverse effects were not revealed in these case reports. REGENERATIVE/GRAFTING Fetal Mesencephalic Tissue Transplantation Brundin et al.223 reported that UPDRS motor scores and percent time “on” were improved each by a mean 40% and 25% at two years after transplantation. Levodopa dose equivalent was reduced by 54% compared with before surgery. PET showed a mean 61% increase of 18F-fluorodopa uptake in the putamen. Hagell et al.224 reported a retrospective, long-term follow-up (11 years after transplantation) study; maximum UPDRS motor score was improved by 39%, and levodopa dose equivalent was reduced by 36% during follow-up after surgery. These effects maintained several years after transplantation but gradually decreased thereafter. There was no significant amelioration of percent time “off” and percent time “on” dyskinesia. Recently, the first double-blind, placebo-controlled study in advanced PD (at least seven years disease duration) was reported by Freed et al.106 Forty patients were enrolled and stratified into younger than 60 years and older than 60 years. These patients were randomized to receive either four embryonic transplants or sham operation. At one year after surgery, there were no statistically significant differences between the mean global rating score of the transplanted and sham operated patients. The total UPDRS score in the “off” state also did not show statistically significant difference between the patient groups. However, in younger patients with transplant procedure, the UPDRS motor score

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in the “off” state (34% decrease) and the Schwab-England score (31% improvement) improved significantly compared with sham operated patients or older patients who received transplants. There are significant improvements in rigidity and bradykinesia in younger patients who received transplants, but no patient showed improvement of motor fluctuations and axial disability. In 19 transplanted patients who demonstrated that 18Ffluorodopa uptake showed significant average improvement of 40% in the putamen, the result did not correlate with improvement of UPDRS scores except for in younger patients. At 12 months after surgery, severe dystonia and dyskinesia were seen in 9 patients. These late-onset dyskinesia were uncontrollable and did not response to levodopa. A postmortem examination of another patient 18 months after transplantation demonstrated viability of large grafts obtained from 7 fetal mesencephalic donors.225 Processes from these neurons had grown out of the grafts and provided extensive dopaminergic reinnervation to the striatum in a patch-matrix pattern. However, the neuronal processes extended only 5 to 7 mm away from the graft and reinnervated only 30% to 50% of the putamen (failing to reach any of the anterior putamen). Ungrafted regions of the putamen showed sparse dopaminergic innervation, and there was no evidence of any sprouting of host dopaminergic processes. This patient had also gained significant clinical improvement and enhanced 18F-fluorodopa with uptake on PET scanning in association with survival of the grafts and dopaminergic reinnervation of the striatum. Effects of fetal transplantation are quite variable in each study. There are patients with clear benefit and those with minimal or no benefit. These inconsistencies may reflect differences in patient selection, transplant location, preparation of transplant cells, and immunosuppressive treatment. The study of Freed et al.106 also raised a new problem: “off” state dyskinesia with fetal transplantation. Hagell et al.224 suggested that “off” state dyskinesias probably did not result from excessive growth of grafted dopaminergic neurons, because the severity of dyskinesia was inversely correlated with uptake in the striatum. However, the cause of “off” state dyskinesia remains unknown, and these severe dyskinesias, which may lead to joint dislocation, have led to dampened enthusiasm for this mode of treatment. RECOMMENDATIONS To date, several stereotactic procedures have been established as surgical options for PD, while others await more systematic evaluation. Each procedure should be chosen on the basis of symptoms and individual background of each individual patient. Further studies will hopefully continue to clarify which surgical procedure is optimal for individual PD patients with particular clinical characteristics. REFERENCES 1. Ahlskog, J.E. and Muenter, M.D., “Frequency of Levodopa-Related Dyskinesias and Motor Fluctuations as Estimated from the Cumulative Literature,” Mov. Disord., 16, 448, 2001.

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144. Tavella, A. et al., “Deep Brain Stimulation of the Subthalamic Nucleus in Parkinson’s Disease: Long-Term Follow-Up,” Neurol. Sci., 23 Suppl., 2, S111, 2002. 145. Thobois, S. et al., “Subthalamic Nucleus Stimulation in Parkinson’s Disease: Clinical Evaluation of 18 Patients,” J. Neurol., 249, 529, 2002. 146. Andrew, J., “Surgical Treatment of Tremor.” In: Movement Disorders, Tremor, Edited by Findley, Leslie and Capildeo, Rudy, 339, Oxford University Press, New York, N.Y., 1984. 147. Zonenshayn, M. et al., “Comparison of Anatomic and Neurophysiological Methods for Subthalamic Nucleus Targeting,” Neurosurgery, 47, 282, 2000. 148. Laitinen, L.V., “Pallidotomy for Parkinson’s Disease,” Neurosurg. Clin. N. Am., 6, 105, 1995. 149. Honey, C.R. and Nugent, R.A., “A Prospective Randomized Comparison of Ct and MRI PreOperative Localization for Pallidotomy,” Can J. Neurol. Sci., 27, 236, 2000. 150. Holtzheimer, P.E., 3rd, Roberts, D.W. and Darcey, T. M., “Magnetic Resonance Imaging Versus Computed Tomography for Target Localization in Functional Stereotactic Neurosurgery,” Neurosurgery, 45, 290, 1999. 151. Meneses, M.S. et al., “Comparison of MRI-Guided and Ventriculography-Based Stereotactic Surgery for Parkinson’s Disease,” Arq. Neuropsiquiatr., 55, 547, 1997. 152. Vitek, J.L. et al., “Microelectrode-Guided Pallidotomy: Technical Approach and Its Application in Medically Intractable Parkinson’s Disease,” J. Neurosurg., 88, 1027, 1998. 153. Guridi, J. et al., “Stereotactic Targeting of the Globus Pallidus Internus in Parkinson’s Disease: Imaging Versus Electrophysiological Mapping,” Neurosurgery, 45, 278, 1999. 154. Alterman, R.L. et al., “Microelectrode Recording During Posteroventral Pallidotomy: Impact on Target Selection and Complications,” Neurosurgery, 44, 315, 1999. 155. Oh, M.Y. et al., “Deep Brain Stimulator Electrodes Used for Lesioning: Proof of Principle,” Neurosurgery, 49, 363, 2001. 156. Guridi, J. et al., “Targeting the Basal Ganglia for Deep Brain Stimulation in Parkinson’s Disease,” Neurology, 55, s21, 2000. 157. Kelly, P.J. et al., “Computer-Assisted Stereotactic Ventralis Lateralis Thalamotomy with Microelectrode Recording Control in Patients with Parkinson’s Disease,” Mayo Clin. Proc., 62, 655, 1987. 158. Narabayashi, H., “Stereotaxic Vim Thalamotomy for Treatment of Tremor,” Eur. Neurol., 29, 29, 1989. 159. Anagnostou, E. et al., “Contraversive Eye Deviation During Deep Brain Stimulation of the Globus Pallidus Internus,” Neurology, 56, 1396, 2001. 160. Iacono, R.P. et al., “The Results, Indications, and Physiology of Posteroventral Pallidotomy for Patients with Parkinson’s Disease,” Neurosurgery, 36, 1118, 1995. 161. Yokoyama, T. et al, “Visual Evoked Potential Guidance for Posteroventral Pallidotomy in Parkinson’s Disease,” Neurol. Med. Chir. (Tokyo), 37, 257, 1997. 162. Bronstein, J.M., DeSalles, A., and DeLong, M.R., “Stereotactic Pallidotomy in the Treatment of Parkinson Disease: An Expert Opinion,” Arch Neurol., 56, 1064, 1999. 163. Eskandar, E.N. et al., “Stereotactic Pallidotomy Performed without Using Microelectrode Guidance in Patients with Parkinson’s Disease: Surgical Technique and 2-Year Results,” J. Neurosurg., 92, 375, 2000. 164. Giller, C.A. et al., “Stereotactic Pallidotomy and Thalamotomy Using Individual Variations of Anatomic Landmarks for Localization,” Neurosurgery, 42, 56, 1998. 165. Favre, J. et al., “Pallidotomy: A Survey of Current Practice in North America,” Neurosurgery, 39, 883, 1996. 166. Kamiryo, T. and Laws, E.R., Jr., “Identification and Localization of Intracerebral Vessels by Microvascular Doppler in Stereotactic Pallidotomy and Thalamotomy: Technical Note,” Neurosurgery, 40, 877, 1997. 167. Benabid, A.L. et al., “Chronic Electrical Stimulation of the Ventralis Intermedius Nucleus of the Thalamus as a Treatment of Movement Disorders,” J. Neurosurg., 84, 203, 1996.

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168. Rodriguez-Oroz, M.C. et al., “The Subthalamic Nucleus in Parkinson’s Disease: Somatotopic Organization and Physiological Characteristics,” Brain, 124, 1777, 2001. 169. Fukuda, M. et al., “Intraoperative Monitoring for Functional Neurosurgery During Intravenous Anesthesia with Propofol,” No Shinkei Geka, 25, 231, 1997. 170. Ohye, C. et al., “Gamma Thalamotomy for Parkinsonian and Other Kinds of Tremor,” Stereotact. Funct Neurosurg., 66, 333, 1996. 171. Pan, L. et al., “Stereotactic Gamma Thalamotomy for the Treatment of Parkinsonism,” Stereotact. Funct. Neurosurg, 66, 329, 1996. 172. Pollak, P. et al., “Treatment of Parkinson’s Disease. New Surgical Treatment Strategies,” Eur. Neurol., 36, 400, 1996. 173. Niranjan, A. et al., “Functional Outcomes after Gamma Knife Thalamotomy for Essential Tremor and MsRelated Tremor,” Neurology, 55, 443, 2000. 174. Ahlskog, J.E., “Cerebral Transplantation for Parkinson’s Disease: Current Progress and Future Prospects,” Mayo Clin. Proc., 68, 578, 1993. 175. Spencer, D.D. et al., “Unilateral Transplantation of Human Fetal Mesencephalic Tissue into the Caudate Nucleus of Patients with Parkinson’s Disease,” N. Engl. J. Med., 327, 1541, 1992. 176. Henderson, B.T. et al., “Implantation of Human Fetal Ventral Mesencephalon to the Right Caudate Nucleus in Advanced Parkinson’s Disease,” Arch Neurol., 48, 822, 1991. 177. Freed, C.R. et al., “Transplantation of Human Fetal Dopamine Cells for Parkinson’s Disease. Results at 1 Year,” Arch Neurol., 47, 505, 1990. 178. Remy, P. et al., “Clinical Correlates of [18f] Fluorodopa Uptake in Five Grafted Parkinsonian Patients,” Ann. Neurol., 38, 580, 1995. 179. Freeman, T.B. et al., “Bilateral Fetal Nigral Transplantation into the Postcommissural Putamen in Parkinson’s Disease,” Ann. Neurol., 38, 379, 1995. 180. Freed, C.R. et al., “Immunosuppressants May Not Improve Transplant Success after Human Fetal Dopamine Cell Implants for Parkinson’s Disease,” Neurology, 44, A323, 1994. 181. Hariz, M.I. and Bergenheim, A.T., “A 10-Year Followup Review of Patients Who Underwent Leksell’s Posteroventral Pallidotomy for Parkinson Disease,” J. Neurosurg., 94, 552, 2001. 182. Nutt, J.G. et al., “DBS and Diathermy Interaction Induces Severe CNS Damage,” Neurology, 56, 1384, 2001. 183. Fox, M.W., Ahlskog, J.E., and Kelly, P.J., “Stereotactic Ventrolateralis Thalamotomy for Medically Refractory Tremor in Post-Levodopa Era Parkinson’s Disease Patients,” J. Neurosurg., 75, 723, 1991. 184. Jankovic, J. et al., “Outcome after Stereotactic Thalamotomy for Parkinsonian, Essential, and Other Types of Tremor,” Neurosurgery, 37, 680, 1995. 185. Selby, G.,“Stereotactic surgery,” in Handbook of Parkinson’s Disease, Koller, W.C., Ed., New York, Marcel Dekker, p. 421, 1987. 186. Schuurman, P.R. et al., “A Comparison of Neuropsychological Effects of Thalamotomy and Thalamic Stimulation,” Neurology, 59, 1232, 2002. 187. Shannon, K.M. et al., “Stereotactic Pallidotomy for the Treatment of Parkinson’s Disease. Efficacy and Adverse Effects at 6 Months in 26 Patients,” Neurology, 50, 434, 1998. 188. Ondo, W.G. et al., “Assessment of Motor Function after Stereotactic Pallidotomy,” Neurology, 50, 266, 1998. 189. Uitti, R.J. et al., “Neurodegenerative Overlap Syndrome: Clinical and Pathological Features of Parkinson’s Disease, Motor Neuron Disease, and Alzheimer’s Disease” Parkinsonism and Related Disorders (unpublished). 190. Martinez-Martin, P. et al., “Pallidotomy and Quality of Life in Patients with Parkinson’s Disease: An Early Study,” Mov. Disord., 15, 65, 2000. 191. Alegret, M. et al., “Effects of Unilateral Posteroventral Pallidotomy on “on-Off” Cognitive Fluctuations in Parkinson’s Disease,” Neuropsychologia, 38, 628, 2000. 192. Junque, C. et al., “Cognitive and Behavioral Changes after Unilateral Posteroventral Pallidotomy: Relationship with Lesional Data from MRI,” Mov. Disord., 14, 780, 1999.

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193. Alegret, M. et al., “Cognitive Effects of Unilateral Posteroventral Pallidotomy: A 4-Year Follow-up Study,” Mov. Disord., 18, 323, 2003. 194. de Bie, R.M. et al., “Morbidity and Mortality Following Pallidotomy in Parkinson’s Disease: A Systematic Review,” Neurology, 58, 1008, 2002. 195. Koller, W. et al., “High-Frequency Unilateral Thalamic Stimulation in the Treatment of Essential and Parkinsonian Tremor,” Ann. Neurol., 42, 292, 1997. 196. Limousin, P. et al., “Multicentre European Study of Thalamic Stimulation in Parkinsonian and Essential Tremor,” J. Neurol. Neurosurg. Psychiatry, 66, 289, 1999. 197. Rehncrona, S. et al, “Long-Term Efficacy of Thalamic Deep Brain Stimulation for Tremor: Double-Blind Assessments,” Mov. Disord., 18, 163, 2003. 198. Hubble, J.P. et al., “Effects of Thalamic Deep Brain Stimulation Based on Tremor Type and Diagnosis,” Mov. Disord., 12, 337, 1997. 199. Montgomery, E.B. Jr., “Evaluation of Surgery for Parkinson’s Disease: Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology,” Neurology, 55, 154, 2000. 200. Defebvre, L. et al., “Effect of Thalamic Stimulation on Gait in Parkinson Disease,” Arch Neurol., 53, 898, 1996. 201. Caparros-Lefebvre, D.et al., “Improvement of Levodopa Induced Dyskinesias by Thalamic Deep Brain Stimulation Is Related to Slight Variation in Electrode Placement: Possible Involvement of the Centre Median and Parafascicularis Complex,” J. Neurol. Neurosurg. Psychiatry, 67, 308, 1999. 202. Fields, J.A. and Troster, A.I., “Cognitive Outcomes after Deep Brain Stimulation for Parkinson’s Disease: A Review of Initial Studies and Recommendations for Future Research,” Brain Cogn., 42, 268, 2000. 203. Woods, S.P. et al., “Neuropsychological and Quality of Life Changes Following Unilateral Thalamic Deep Brain Stimulation in Parkinson’s Disease: A One-Year Follow-Up,” Acta Neurochir (Wien), 143, 1273, 2001. 204. Flament, D. et al., “Reaction Time Is Not Impaired by Stimulation of the Ventral-Intermediate Nucleus of the Thalamus (Vim) in Patients with Tremor,” Mov. Disord., 17, 488, 2002. 205. Arnulf, I. et al., “Effect of Low and High Frequency Thalamic Stimulation on Sleep in Patients with Parkinson’s Disease and Essential Tremor,” J. Sleep Res., 9, 55, 2000. 206. Arnulf, I. et al., “Improvement of Sleep Architecture in PD with Subthalamic Nucleus Stimulation,” Neurology, 55, 1732, 2000. 207. Pahwa, R. et al., “Bilateral Thalamic Stimulation for the Treatment of Essential Tremor,” Neurology, 53, 1447, 1999. 208. Lozano, A.M., “Deep Brain Stimulation for Parkinson’s Disease,” Parkinsonism Relat. Disord., 7, 199, 2001. 209. Vingerhoets, G. et al., “Cognitive Outcome after Unilateral Pallidal Stimulation in Parkinson’s Disease,” J. Neurol. Neurosurg. Psychiatry, 66, 297, 1999. 210. Ardouin, C. et al., “Bilateral Subthalamic or Pallidal Stimulation for Parkinson’s Disease Affects Neither Memory nor Executive Functions: A Consecutive Series of 62 Patients,” Ann. Neurol., 46, 217, 1999. 211. Miyawaki, E. et al., “The Behavioral Complications of Pallidal Stimulation: A Case Report,” Brain Cogn., 42, 417, 2000. 212. Hariz, M.I., “Complications of Deep Brain Stimulation Surgery,” Mov. Disord., 17 Suppl., 3, S162, 2002. 213. Martinez-Martin, P. et al., “Bilateral Subthalamic Nucleus Stimulation and Quality of Life in Advanced Parkinson’s Disease,” Mov. Disord., 17, 372, 2002. 214. Ostergaard, K., Sunde, N., and Dupont, E., “Effects of Bilateral Stimulation of the Subthalamic Nucleus in Patients with Severe Parkinson’s Disease and Motor Fluctuations,” Mov. Disord., 17, 693, 2002.

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215. Bejjani, B.P. et al., “Axial Parkinsonian Symptoms Can Be Improved: The Role of Levodopa and Bilateral Subthalamic Stimulation,” J. Neurol. Neurosurg. Psychiatry, 68, 595, 2000. 216. Pinto, S. et al., “Bilateral Subthalamic Stimulation Effects on Oral Force Control in Parkinson’s Disease,” J. Neurol., 250, 179, 2003. 217. Roberts-Warrior, D.et al., “Postural Control in Parkinson’s Disease after Unilateral Posteroventral Pallidotomy,” Brain (unpublished). 218. Iranzo, A. et al., “Sleep Symptoms and Polysomnographic Architecture in Advanced Parkinson’s Disease after Chronic Bilateral Subthalamic Stimulation,” J. Neurol. Neurosurg. Psychiatry, 72, 661, 2002. 219. “Deep-Brain Stimulation of the Subthalamic Nucleus or the Pars Interna of the Globus Pallidus in Parkinson’s Disease,”N. Engl. J. Med., 345, 956, 2001. 220. Obeso, J.A., Olanow, C.W., and Lang, A., “Deep-brain stimulation in Parkinson’s disease, N. Engl. J. Med., 346, 452, 2002. 221. Volkmann, J. et al., “Safety and Efficacy of Pallidal or Subthalamic Nucleus Stimulation in Advanced PD,” Neurology, 56, 548, 2001. 222. Pillon, B. et al., “Neuropsychological Changes between “Off’ and “on” STN or GPi Stimulation in Parkinson’s Disease,” Neurology, 55, 411, 2000. 223. Brundin, P. et al, “Bilateral Caudate and Putamen Grafts of Embryonic Mesencephalic Tissue Treated with Lazaroids in Parkinson’s Disease,” Brain, 123 (Pt. 7), 1380, 2000. 224. Hagell, P. et al., “Dyskinesias Following Neural Transplantation in Parkinson’s Disease,” Nat. Neurosci., 5, 627, 2002. 225. Kordower, J.H. et al., “Neuropathological Evidence of Graft Survival and Striatal Reinnervation after the Transplantation of Fetal Mesencephalic Tissue in a Patient with Parkinson’s Disease,”N. Engl. J. Med., 332, 1118, 1995.

59 Neurotransplantation in Parkinson’s Disease Ronald F.Pfeiffer Department of Neurology, University of Tennessee Health Science Center 0-8493-1590-5/05/$0.00+$1.50 © 2005 by CRC Press

INTRODUCTION The emergence of effective symptomatic treatment during the past four decades has made a tremendous impact on the lives of individuals with Parkinson’s disease (PD), providing them with an almost normal life expectancy1 and, for many, a reasonable quality of life. However, as described in other chapters in this text, the improvement afforded by the currently available pharmacological armamentarium is far from perfect. The combination of continued progression of PD and cumulative complications of medical treatment, particularly in the form of motor fluctuations and dyskinesia, eventually affects virtually all PD patients to some degree and poses significant difficulty for a distressing proportion of them. Recognition of these therapeutic shortcomings has led a growing cadre of intrepid investigators to conceive and nurture the concept of neurotransplantation as a potential means of replenishing the supply of dopaminergic neurons lost as a fundamental part of the PD disease process. Developments in both the laboratory and the clinical arenas have generated excitement and anticipation within the scientific and medical communities. They have also attracted considerable media attention, which has sometimes led to misconceptions and unwarranted expectations by patients and family members, at times inadvertently advanced by organizations promoting fundraising for PD research. One misconception that sometimes surfaces among patients (and even physicians) when the topic of neurotransplantation arises is that this technique will provide a“cure” for PD. In this context it is important to remember that PD involves more than simple dopamine deficiency due to nigrostriatal dopaminergic neuronal loss, although this is certainly the most prominent and striking feature of the pathological process. Other structures within the central nervous system (CNS), such as the locus ceruleus and the dorsal motor nucleus of the vagus, also sustain damage in the course of PD, and other neurotransmitter abnormalities are also present.2–5 Furthermore, dopamine depletion itself in PD is not completely confined to the nigrostriatal system. Other dopaminergic neuronal populations are also affected by the pathological process, both within the CNS and beyond. Dopamine deficiency in PD has been identified in structures as varied as the retina6 and the enteric nervous system in the gut.7,8 Neurotransplantation of cells into either the substantia nigra or striatum (or both) cannot reasonably be expected to eliminate, or even affect, these components of PD.

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Nevertheless, the possibility that neurotransplantation of cells into the nigrostriatal system might be able to both restore lost motor function and even provide some protection against further damage within that system is a tremendously exciting prospect that is reviewed in this chapter from the perspective of a practicing clinical neurologist. BACKGROUND The roots of cellular transplantation for the treatment of PD date back over 30 years to the reports of Olson and colleagues, who described the successful transplantation of chromaffin cells from the adrenal medulla into the anterior eye chamber of rats.9 This procedure was then extended to the transplantation of fetal brain tissue to the same location.10,11 These successes set the stage for subsequent undertakings involving transplantation of tissue to the brain proper. In 1979, two groups of investigators reported the successful transplantation of fetal mesencephalic tissue containing dopaminergic neurons into the brains of rats that had been rendered hemiparkinsonian by unilateral 6-hydroxydopamine (6-OHDA) administration.12,13 These initial procedures entailed the rather crude placement of solid transplanted tissue into either cortical cavities12 or lateral ventricles,13 and subsequent substantial refinements in experimental technique (cell preparation, graft location, tissue handling and storage) quickly followed.14 These rodent studies and subsequent studies in nonhuman primates firmly documented the ability of grafts of fetal mesencephalic tissue to survive and reinnervate denervated striatum, with consequent improvement in motor function, and provided the proof of principle and justification for the next step to human transplantation studies.14–16 ADRENAL MEDULLARY TRANSPLANTATION While the evaluation and refinement of fetal tissue transplantation was being methodically pursued, the first steps into the realm of neurotransplantation in humans with PD were taken using autologous adrenal medullary tissue. In 1985, Backlund and colleagues reported the results of the first implantation (performed in 1982) of adrenal medullary tissue into an individual with PD,17 and in a second communication described short-term benefit in two additional patients.18 A subsequent report of dramatic functional improvement in individuals with PD following adrenal medullary transplantation19 created a flurry of excitement and led to a rush of additional clinical trials that were unable to duplicate or substantiate the earlier dramatic results, and also recorded significant morbidity from the surgical procedure, which involved laparotomy for unilateral adrenalectomy in addition to the cerebral implantation.20–24 These unfavorable reports, coupled with recognition that the grafted adrenal tissue generally did not survive, led to abandonment of adrenal transplantation as a treatment approach for PD.25–27 Ideas regarding the potential use of adrenal medullary tissue obtained from liver transplantation donors also foundered on the recognition that the tissue was not viable.*

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HUMAN FETAL MESENCEPHALIC TRANSPLANTATION The first transplantation of fetal mesencephalic tissue into two patients with PD was undertaken by Lindvall and colleagues in 1987, in Sweden, and reported in 1989.28 Cellular suspensions of tissue from three aborted fetuses (euphemistically termed “donors”) were utilized and grafted into both caudate and putamen. Modest clinical improvement was documented, evident 4 to 6 months after grafting, but positron emission tomography (PET) with 18F-fluorodopa (FD) did not demonstrate increased uptake, and the initial benefit had disappeared in one of the two patients by approximately one year.29 Subsequent adjustments, improvements, and refinements in technical factors (amount of implanted tissue, tissue handling, tissue transport, surgical instrumentation) resulted in improved results in subsequent procedures performed on patients with PD and on individuals with MPTP-induced parkinsonism.29–32 The encouraging results from these Swedish trials were subsequently supplemented by reports from a number of additional centers.33–43 Although it is difficult to arrive at an exact figure, it appears that, by 2001, approximately 300 individuals had received fetal tissue transplantation for treatment of PD,44 and a more recent estimate asserts that more than 400 have undergone the procedure.45 The vast majority of studies have been completed under nonblinded conditions with widely divergent trial designs, involving significant differences in variables such as patient selection, cell preparation, surgical implantation sites, surgical implantation techniques, immunosuppressive treatment, and assessment parameters14–16,27,29,46–49 In light of this variability, it is, perhaps, not surprising that reported results from these clinical trials have also shown considerable variability. Despite the difficulties imposed by the disparate data, assessment of available information from this collection of “open-label” clinical trials has led some investigators to draw a number of conclusions regarding the effectiveness of fetal mesencephalic transplantation for the treatment of PD. In a 1999 review, Lindvall provided some general assertions, stating that “grafted embryonic neu* Source: R.McComb and R.F.Pfeiffer, unpublished observations.

rons can exhibit short- and long-term survival in idiopathic PD” and that “grafts can give rise to long-term symptomatic relief of therapeutic value to patients with Parkinson’s disease, but the symptomatic relief in most patients is incomplete with respect to both degree and pattern of functional recovery.”50 The evidence for the first assertion was based on the presence of increased 18FD uptake on PET compared to preoperative values in several studies42,51–53 and histopathologic evidence of surviving graft tissue upon autopsy studies of deceased individuals.54–56 Varying levels of investigator agreement have been achieved with regard to certain transplantation parameters. Some suggestions and evidence supporting the use of tissue from spontaneous abortions have been published,57–58 but tissue from elective abortions has been utilized because of concerns regarding viability, potential defects, and availability of spontaneously aborted fetuses.27 Optimal age of the fetus from whom tissue is recovered has been found to be between 5.5 and 8.0 weeks postconception for cell suspension grafts, and between 6.5 and 9.0 weeks for solid grafts.48 The number of

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fetuses utilized in transplantation procedures has varied considerably. From animal studies and clinical trials it is known that only 5 to 20% of implanted dopamine neurons survive.16,48,50 Extrapolating from this, investigators have suggested that, to achieve clinically meaningful improvement, it is necessary to implant tissue from three to five fetuses per side,50,59–61 with some investigators recommending as many as six per side.48 Differences of opinion regarding issues such as tissue storage and preparation and the necessity of immunosuppressive treatment posttransplantation have not been settled and have been the source of discussion and debate in the context of two recently completed double-blind, placebo surgery-controlled trials (discussed below). The cumulative experience from nonblinded open clinical trials has demonstrated an overall improvement in motor scores on the Unified Parkinson’s Disease Rating Scale in the range of 6 to 40% following transplantation.14,50 Functional improvement typically does not begin until several months following the transplant procedure, and then may gradually grow over a period of up to 2 to 3 years, probably reflecting maturation and integration of the implanted neurons into the host striatum.15,46 Placement of grafted tissue into the posterior putamen has produced results superior to caudate tissue placement; bilateral grafting is more effective than unilateral.15,27,46,62 Graft survival and clinical improvement have been documented for periods over ten years in PD patients.15,46,63,64 The variable results reported in nonblinded clinical protocols have led to the performance of two doubleblind, placebo surgery-controlled trials in the U.S.A.65,66 In the first of the two to be completed, Freed and colleagues65 studied 40 patients with advanced PD; 20 received bilateral putaminal transplantation of fetal mesencephalic tissue, and 20 underwent sham surgery in which burr holes were placed but the dura was not penetrated. Immunosuppressive treatment was not employed in this study. After one-year follow-up, there was no difference between the two groups in a subjective global rating of change in disease severity, which was the primary study outcome measure. However, some improvement in objective measures of motor function (UPDRS motor “off” score improvement of 34%, Schwab/England “off” score improvement of 31%) was evident in the portion of participants under age 60 in the transplantation group.15,65 Improvement was not detectable in the over-age-60 group. Increased FD uptake was present in 85%17,20 of transplanted patients at one year, consistent with graft survival. After one year, patients in the sham-surgery group were given the opportunity to undergo transplantation, and 14 chose to do so. Clinical improvement in this group was identical to that seen in the original transplant group.15 The second double-blind protocol was carried out by Olanow and colleagues.66 In this study 34 patients were enrolled and randomized into one of three groups: 11 received sham surgery in which partial burr holes were placed but the inner table of the skull was not penetrated; 11 received putaminal placement of tissue from 1 fetus per side; 12 received putaminal placement of tissue from four fetuses per side. Participants were then followed for 24 months. In this study, the primary outcome measure utilized was the change in UPDRS motor “off” score. No significant differences were present between the three groups in this measure at 24 months. Unlike the earlier double-blind trial, no treatment effect was evident in patients younger than age 60, but patients with less severe disease (baseline UPDRS motor score of 49 or less) who received tissue from four fetuses

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per side demonstrated statistically significant improvement compared with those with less severe disease in the sham-surgery group Both of the double-blind clinical trials were marked by the unexpected development of dyskinesia in some individuals that persisted despite reduction or even complete cessation of antiparkinson medication. Such dyskinesia, labeled by some as “runaway dyskinesia,”67 developed in 15% of transplant recipients in the earlier study65 and in 56% in the later trial.66 Prompted by these developments, other investigators retrospectively reviewed their data and identified 14 individuals in whom off-phase dyskinesias also had developed.68 Several hypotheses have been advanced to account for the development of these offphase dyskinesias. It was originally suggested, based on PET data, that these dyskinesias might be the consequence of unbalanced regional increases in striatal dopaminergic function due to overgrowth of grafted dopaminergic neurons.65,69 Other investigators, however, have proposed that culturing of the fetal tissue prior to transplantation might be in some way responsible68 or that the off-phase dyskinesias represent a variant of diphasic dyskinesia and reflect partial graft survival.66 The two double-blind trials have also provoked some additional controversy. The decision by Freed and colleagues65 not to employ immunosuppression has been criticized, as has their implantation technique, which utilized a strand, or “noodle,” of tissue rather than cell suspension, and which entailed keeping the fetal tissue in culture for up to one month prior to implantation.70,71 Olanow and colleagues employed immunosuppression with cyclosporine for six months following grafting and actually noted some functional deterioration that seemed to coincide with discontinuation of the immunosuppressive therapy.66 Both criticism72–76 and support77 have also been voiced regarding the performance of sham surgery as a placebo procedure. Significant complications from fetal tissue transplantation procedures are unusual but have been reported. A patient who received both intrastriatal implantation and intraventricular infusion of fetal tissue subsequently developed left lateral and fourth ventricular obstruction due to proliferation of intraventricular fetal tissue (containing ectodermal and mesenchymal, but not neural, elements) and died suddenly.78 Another patient died as a result of a herniation syndrome secondary to formation of a large putaminal cyst, possibly containing choroid plexus tissue arising from the fetal graft.79 One death has also been reported as a consequence of intraoperative surgical complications.62 Other transplantation-related complications have included intracerebral hemorrhage, subdural hematoma, transient confusion, and enhanced psychiatric problems.49 Brain abscess and partial motor seizures have also been described.27 The current status of transplantation of fetal mesencephalic tissue for treatment of PD is uncertain, clouded not only by the inability of the double-blinded studies to document clear-cut improvement, but also by the inconsistent benefit achieved by patients in the nonblinded studies, inconsistencies that are evident both between centers and among groups of patients within centers themselves.15 Two additional factors also stand in the way of routine clinical employment of fetal mesencephalic tissue transplantation. Ethical and religious objections to the use of fetal tissue are, and will continue to be, deeply and sincerely held by a significant segment of the population. Even if these moral reservations could be surmounted (which is unlikely), it has become clear that logistical limitations also are present in that the amount of fetal

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tissue available from elective abortions will never be sufficient to meet the demand, given the amount of fetal tissue currently required for successful grafting.14–16,27,47,50,59,61,62,80–82 In response to these barriers, a very active and innovative search for alternatives to direct fetal tissue transplan tation has developed. Alternatives that have been proposed and studied include the use of other tissue sources, amplification of fetal tissue with trophic factors, use of embryonic stem cells or stem cells from other sources, gene therapy, and xenotransplantation. Stem cell strategies and gene therapy are addressed in other chapters of this text and therefore are not covered in detail here. Adequate coverage of the many approaches that are being investigated with regard to manipulating and altering fetal tissue to increase viability and survival (such as cografting, trophic factor supplementation, antioxidant treatment, and many others) falls beyond the scope of this chapter. Instead, the remaining paragraphs focus on alternative tissue sources that are being investigated for potential treatment of PD. OTHER TISSUE SOURCES FOR TRANSPLANTATION CAROTID BODY GLOMUS CELLS Carotid body glomus cells are physiologic arterial oxygen sensors that release dopamine in response to hypoxia.83 This capability has prompted investigation of these cells as potential tissue for autologous transplantation into the striatum in persons with PD. Initial studies employing intrastriatal grafting of aggregates of these cells in rats produced improvement in motor function.84 The cells retained the ability to secrete dopamine and, with time, dopaminergic fibers were found to reinnervate surrounding striatum. Subsequent studies on monkeys with MPTP-induced parkinsonism demonstrated similar findings.85 Carotid body cells also express high levels of glial cell line-derived neurotrophic factor (GDNF), and it has recently been proposed that the motor improvement seen following intrastriatal grafting of carotid body cell aggregates into hemiparkinsonian rats is due to release of GDNF and its subsequent trophic action on surviving striatal neurons, rather than dopamine release by the implanted carotid body cells.86 These animal studies paved the way for a pilot clinical trial in humans in which six patients underwent bilateral autotransplantation of carotid body cell aggregates into striatum.87 Improvement was noted in five of six patients and was maximal at six months post-transplantation, with reduction in the off-motor score of the UPDRS ranging between 26 and 74%. At one year, improvement was maintained in three individuals, with the other two patients demonstrating a diminution, but not total loss, of benefit. The fact that both GDNF and dopamine are apparently secreted by the implanted carotid body cells, and the fact that the tissue is autologous, obviating the need for immunosuppression, are very appealing characteristics of this approach. However, the apparent reduction in benefit over time is troublesome and raises ques-tions about graft survival. Much additional information regarding this procedure is needed, and further study certainly seems warranted.

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CERVICAL SYMPATHETIC GANGLION CELLS The knowledge that cells in the superior cervical sympathetic ganglion produce catecholamines, including dopamine, has prompted evaluation of these cells as potential tissue for CNS grafting in patients with PD. Successful autologous transplantation of the superior cervical ganglion (SCG) into the caudate nuclei of monkeys was reported in 1990; histofluorescence studies demonstrated survival of the graft.88 That same year, apparently with little additional animal experimentation, SCG was grafted into the caudate nuclei of three patients with PD, and improved motor function was described.89 By 1997, Itakura and colleagues had performed SCG autotransplantation on 35 patients with PD and noted that approximately half demonstrated some improvement in function, primarily in bradykinesia and gait dysfunction, but not in tremor and rigidity.90 In a more recent report from the same group of investigators, four patients who had undergone unilateral intrastriatal autografting of SCV were studied one year post-surgery.91 Motor scores were not improved, but “off” time had diminished. The authors speculated that this might be due to the ability of the grafted neurons to convert exogenous levodopa into dopamine and store it. The relatively sparse experimental data available regarding SCG transplantation does not appear to be as encouraging as other treatment approaches. HUMAN RETINAL PIGMENT EPITHELIAL CELLS Human retinal pigment epithelial (hRPE) cells are support cells that are found in the posterior layer of the retina, adjacent to the choroid and the neural elements of the retina.80 They secrete dopamine or dopamine precursors and, thus, have caught the attention of investigators as a potential source of readily available tissue for transplantation in patients with PD. These cells also may have trophic functions and have been reported to produce platelet-derived growth factor, epidermal growth factor, and vascular endothelial growth factor.80 Another very appealing feature, from the standpoint of potential utility in transplantation, is that they can be grown and expanded in tissue culture and survive prolonged storage.80 Subramanian and colleagues studied the response of 6-OHDA-induced hemiparkinsonian rats to intrastriatal placement of hRPE cells attached to gelatin microcarriers and noted sustained reduction in apomorphineinduced rotations in animals receiving hRPE cells attached to the microcarriers, but not in animals who received hRPE cells alone.92 Subsequent pathological examination demonstrated only a minimal host response to the implanted xenographic tissue. Additional studies in three monkeys with MPTP-induced hemiparkinsonism also demonstrated improvement in motor function and minimal inflammatory response, and FD PET imaging in one of the monkeys revealed increased uptake at the transplantation site, suggesting that the implanted hRPE cells were actively taking up and metabolizing the FD.80 In a follow-up study, the behavioral examiners were blinded as to whether the monkey subjects had undergone implantation of low dose hRPE, high dose hRPE, microcarrier implantation alone, or sham surgery.80 Once again, hRPE-treated animals displayed improved motor function compared to those who had undergone sham surgery or had only received the microcarriers. With this background, human trials were initiated and carried out in an open-label fashion on six individuals with PD.93,94 No

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immunosuppression was utilized. The UPDRS motor “off” scores were improved by 33% at six months (n=6), 42% at nine months (n=6), and 48% at 12 months (n=3). No significant complications were encountered, and no “off” period dyskinesias were seen. The implantation of hRPE cells attached to gelatin microcarriers (Spheramine) thus displays promise as a potential treatment for PD. It is not a procedure that will reinnervate striatum, but rather will function as an implanted dopamine-producing “pump.” Further studies are clearly needed before any firm assessment regarding the effectiveness of this technique can be made. The potential use of encapsulated cell technology has also been promoted by other investigators,95–97 and encapsulated PC12 cells, capable of secreting dopamine, have been transplanted successfully into monkeys.98 XENOTRANSPLANTATION Humans have used animals for food and worn animal hides and other animal parts for clothing and adornment dating back to the mists and shadows of prehistory. The employment of animals or animal parts, ingested or externally applied, for medical treatment also has a long history. The idea of actually incorporating animal parts into humans as part of medical treatment, however, is relatively new and strange. To some, it is also a source of fear and consternation. The use of porcine skin grafts for cardiac valve replacement no longer raises eyebrows, but the idea of possibly using animal organs for transplantation purposes, such as hepatic and renal, conjures up more ambivalent feelings.99 In recent years, the brain has become another frontier in the investigation of xenotransplantation, with human trials of porcine cell transplantation for the treatment of PD already undertaken. PORCINE FETAL MESENCEPHALIC TISSUE The pig has a number of characteristics that favor it as a potential source of tissue for xenografting procedures.59,80 The size of a pig brain is similar to that of a human, and there are similarities between their major histocompatibility complex (MHC) antigens. Pigs are also relatively easy to breed and have large litters, thus assuring a ready supply of tissue. Nevertheless, the potential for tissue rejection, the risk of zoonotic infection, and the issue of ultimate functional capacity are major questions confronting those investigating the prospect of using porcine tissue xenografting for the treatment of PD.59 An abundance of animal studies have been carried out in evaluating the potential of porcine fetal mesencephalic tissue for transplantation procedures in the setting of PD. When porcine fetal mesencephalic tissue is transplanted into rats, the tissue undergoes rejection over a period of approximately five weeks, due to both humoral and cellular mechanisms, the latter being more prominent.100 Humans, however, possess high levels of naturally occurring antibodies to the glycoprotein α-galactosyl epitope, which is present on porcine neural cells and would likely incite a hyperacute rejection reaction if porcine neural tissue were to be transplanted into the human brain without immunosuppressive measures being taken.15,59 It has been demonstrated in rats that cyclosporine alone does not fully protect against rejection;101 presumably, this would also

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be so in humans. In an effort to deal with these rejection issues, genetically modified pigs that lack the α-galactosyl epitope have been developed, and more effective immunosuppressive therapies have been sought.15 Nevertheless, rejection issues, particularly over the long term, remain a major barrier to the effective use of porcine xenografting in humans. A second important issue with regard to xenografting of porcine tissue is the potential for introducing a zoonotic infection into humans. In particular, there is concern about the possibility that porcine endogenous retrovirus (PERV) might be transmitted to human cell lines following xenotransplantation, although this has not yet been documented.102 This possibility might eventually be circumvented by cloning PERV-free pigs. The ultimate functional capacity of porcine xenografts has been difficult to ascertain with confidence because of problems with tissue rejection, but improved function in lesioned animals has been documented, and microscopic studies have demonstrated some integration of porcine xenografts, with axonal extension and synapse formation.15,59,103,104 The jump to human testing of porcine xenografts has already been made. In an unblinded Phase I study, 12 individuals with PD underwent unilateral striatal implantation of porcine fetal mesencephalic tissue.105 Six of the subjects received immunosuppressive treatment with cyclosporine, while the other six were treated with a monoclonal antibody directed against MHC class I. No serious operative complications were encountered. At one year post-transplantation, total UPDRS “off” scores had improved approximately 19%. The motor UPDRS “off” score had not improved, although a score assessing postural instability and gait did demonstrate improvement in the “off” state. Scores obtained in the “on” state did not reveal any improvement. Functional improvement did not correlate with changes on FD PET. One patient died from acute pulmonary emboli 7.5 months following transplantation. Neuropathological analysis with immunohistochemistry to tyrosine hydroxylase detected the presence of approximately 650 dopaminergic neurons in the grafts. In a subsequent Phase II trial, 18 individuals with PD were enrolled and, in a doubleblind fashion, assigned to undergo either porcine striatal xenografting or sham surgery.107 At 18 months post-surgery, the 10 patients in the treatment group experienced a 24.6% improvement in the UPDRS, but the 8 subjects in the sham surgery group displayed a 21.6% improvement. There was no significant difference between the two groups due to the robust placebo response in the sham surgery group. Thus, there currently is no firm evidence of clinically meaningful benefit to transplantation of porcine fetal mesencephalic xenotransplantation in PD. The PET data and the neuropathologic examination of the one individual who died in the Phase I study would seem to indicate that insufficient survival of grafted tissue is responsible. Work is progressing looking for methods to overcome the apparent immunologic barriers to porcine xenotransplantation.102 Porcine expanded neural precursor cells may be less immunogenic and more advantageous than primary cells.108,109 Combined treatment employing both caspase inhibition and complement inhibition might also enhance xenograft survival.110 Other studies have suggested that testicular-derived Sertoli cells might provide protection to xenografts.111 However, much needs to be accomplished in the laboratory before porcine xenografting returns to the clinical arena.

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TISSUE FROM OTHER SOURCES Even more exotic xenotransplantation studies have been described in isolated reports. Microencapsulated bovine chromaffin cells have been successfully transplanted into hemiparkinsonian rats, with a stable reduction in apomorphine-induced turning.112 Finally, a mixture of human fetal brain and Notch Drosophila melanogaster neural embryonic tissues has been transplanted into the ventrolateral thalamic nucleus of patients with PD with subsequent sustained improvement in tremor.113 SUMMARY The field of neurotransplantation is a rapidly advancing, constantly changing, enormously complex frontier of neuroscience that holds tremendous promise for improving our ability to effectively treat individuals with neurodegenerative disorders such as PD. While it is important to convey this excitement to patients with PD, it is equally important that patients recognize that, at the present time, neurotransplantation techniques and approaches are still within the realm of research rather than routine clinical care. REFERENCES 1. Herlofson, K. et al., Mortality and Parkinson disease. A community based study, Neurology, 62, 937, 2004. 2. Zarow, C. et al., Neuronal loss is greater in the locus coeruleus than nucleus basalis and substantia nigra in Alzheimer and Parkinson diseases, Arch. Neurol., 60, 337, 2003. 3. Halliday, G.M. et al., Neuropathology of immunohistochemically identified brainstem neurons in Parkinson’s disease, Ann. Neurol., 27, 373, 1990. 4. Kerenyi, L. et al., Positron emission tomography of striatal serotonin transporters in Parkinson disease, Arch. Neurol., 60, 1223, 2003. 5. Srinivasan, J. and Schmidt, W.J., Potentiation of parkinsonian symptoms by depletion of locus coeruleus noradrenaline in 6-hydroxydopamine-induced partial degeneration of substantia nigra in rats, Eur. J. Neurosci., 17, 2586, 2003. 6. Harnois, C. and Di Paolo, T., Decreased dopamine in the retinas of patients with Parkinson’s disease, Invest. Ophthalmol Vis. Sci., 31, 2473, 1990. 7. Singaram, C. et al., Dopaminergic defect of enteric nervous system in Parkinson’s disease patients with chronic constipation, Lancet, 346, 861, 1995. 8. Wakabayashi, K. et al., Parkinson’s disease: an immunohistochemical study of Lewy-body containing neurons in the enteric nervous system, Acta Neuropathol., 79, 581, 1990. 9. Olson, L. and Malmfors, T., Growth characteristics of adrenergic nerves in the adult rat. Fluorescence histochemical and 3H-noradrenaline uptake studies using tissue transplantation into the anterior chamber of the eye, Acta Physiol. Scand., 348, S1, 1970. 10. Olson, L. and Seiger, Å., Brain tissue transplanted to the anterior chamber of the eye. I. Fluorescence histochemistry of immature catecholamine and 5-hydroxytriptamine neurons innervating the iris, Z. Zellforsch., 195, 175, 1972. 11. Olson, L., Seiger, A. and Strömberg, I., Intraocular transplantation in rodents: a detailed account of the procedure and examples of its use in neurobiology with special reference to brain tissue grafting, Adv. Cell. Neurobiol., 4, 407, 1983.

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12. Björklund, A. and Stenevi, U., Reconstruction of the nigrostriatal dopamine pathway by intracerebral transplants, Brain Res., 177, 555, 1979. 13. Perlow, M.J. et al., Brain grafts reduce motor abnormalities produced by destruction of nigrostriatal dopamine system, Science, 204, 643, 1979. 14. Dunnett, S.B., Björklund, A. and Lindvall, O., Cell therapy in Parkinson’s disease—stop or go? Nat. Rev. Neurosci., 2, 365, 2001. 15. Björklund, A. et al., Neural transplantation for the treatment of Parkinson’s disease, Lancet Neurol., 2, 437, 2003. 16. Clarkson, E.D. and Freed, C.R., Development of fetal neural transplantation as a treatment for Parkinson’s disease, Life Sci., 65, 2427, 1999. 17. Backlund, E.O. et al., Transplantation of adrenal medulla to the striatum in parkinsonism: first trials, J. Neurosurg., 62, 169, 1985. 18. Lindvall, O. et al., Transplantation in Parkinson’s disease: two cases of adrenal medulla grafting to the putamen, Ann. Neurol., 22, 457, 1987. 19. Madrazo, I. et al., Open microsurgical autograft of adrenal medulla to the right caudate nucleus in two patients with intractable Parkinson’s disease, N. Engl. J. Med., 316, 831, 1987. 20. Goetz, C.G. et al., Multicenter study of autologous adrenal medullary transplantation to the corpus striatum in patients with advanced Parkinson’s disease, N. Engl. J. Med., 320, 337, 1989. 21. Olanow, C.W. et al., Autologous transplantation of adrenal medulla in Parkinson’s disease: 18month results, Arch. Neurol., 47, 1286, 1990. 22. Allen, G.S. et al., Adrenal medullary transplantation to the caudate nucleus in Parkinson’s disease. Initial clinical results in 18 patients, Arch. Neurol., 46, 487, 1989. 23. Jankovic, J. et al., Clinical, biochemical, and neuropathologic findings following transplantation of adrenal medulla to the caudate nucleus for treatment of Parkinson’s disease, Neurology, 39, 1227, 1989. 24. Goetz, C.G. et al., United Parkinson Foundation neurotransplantation registry on adrenal medullary transplants: presurgical and 1- and 2-year follow-up, Neurology, 41, 1719, 1991. 25. Quinn, N.P., The clinical application of cell grafting techniques in patients with Parkinson’s disease, Prog. Brain Res., 82, 619, 1990. 26. Ahlskog, J.E., Cerebral transplantation for Parkinson’s disease: current progress and future prospects, Mayo Clin. Proc., 68, 578, 1993. 27. Olanow, C.W., Freeman, T.B., and Kordower, J.H., Neural transplantation as a therapy for Parkinson’s disease, Adv. Neurol., 74, 249, 1997. 28. Lindvall, O. et al., Human fetal dopamine neurons grafted into the striatum in two patients with severe Parkinson’s disease: a detailed account of methodology and a 6 months follow-up, Arch. Neurol., 46, 615, 1989. 29. Widner, H., The case for neural tissue transplantation as a treatment for Parkinson’s disease, Adv. Neurol., 80, 641, 1999. 30. Lindvall, O. et al., Grafts of fetal dopamine neurons survive and improve motor function in Parkinson’s disease, Science, 247, 574, 1990. 31. Lindvall, O. et al., Transplantation of fetal dopamine neurons in Parkinson’s disease: one-year clinical and neurophysiological observations in two patients with putaminal implants, Ann. Neurol., 31, 155, 1992. 32. Widner, H. et al., Bilateral fetal mesencephalic grafting in two patients with severe parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), N. Engl. J. Med., 327, 1556, 1992. 33. Huang, S. et al., Transplant operation of human fetal substantia nigra tissue to caudate nucleus in Parkinson’s disease: first clinical trials, Chin. J. Neurosurg., 5, 210, 1989. 34. Freed, C.R. et al., Transplantation of human fetal dopamine cells for Parkinson’s disease: results at one year, Arch. Neurol, 47, 505, 1990. 35. Henderson, B.T.H. et al., Implantation of human ventral mesencephalon to the right caudate nucleus in advanced Parkinson’s disease, Arch. Neurol., 48, 822, 1991.

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36. Subrt, O. et al., Grafting of fetal dopamine neurons in Parkinson’s disease: the Czech experience with severe akinetic patients, Acta Neurochir. Suppl. (Wien), 52, 51, 1991. 37. Molina, H. et al., Transplantation of human fetal mesencephalic tissue in caudate nucleus as a treatment for Parkinson’s disease: the Cuban experience, in Intracerebral Transplantation in Movement Disorders, Lindvall, O., Björklund, A., and Widner, H. Eds., Elsevier Science Publishing, Amsterdam, 99, 1991. 38. Spencer, D.D. et al., Unilateral transplantation of human fetal mesencephalic tissue into the caudate nucleus of patients with Parkinson’s disease, N. Engl J. Med., 327, 1541, 1992. 39. Iacono, R.P. et al., Bilateral fetal grafts for Parkinson’s disease: 22 months’ results, Stereotact. Funct. Neurosurg., 58, 84, 1992. 40. Peschanski, M. et al., Bilateral motor improvement and alteration of L-dopa effect in two patients with Parkinson’s disease following intrastriatal transplantation of foetal ventral mesencephalon, Brain, 117, 487, 1994. 41. Zabek, M. et al., A long term follow-up of foetal dopaminergic neuronal transplantation into the brains of three parkinsonian patients, Res. Neurol. Neurosci., 6, 97, 1994. 42. Freeman, T.B. et al., Bilateral fetal nigral transplantation as a treatment for Parkinson’s disease, Ann. Neurol., 38, 379, 1995. 43. Jacques, D.B. et al., Outcomes and complications of fetal tissue transplantation in Parkinson’s disease, Stereotact. Funct. Neurosurg., 72, 219, 1999. 44. Clarkson, E.D., Fetal tissue transplantation for patients with Parkinson’s disease: a database of published results, Drugs Aging, 18, 773, 2001. 45. Linazasoro, G., Stem cells: solution to the problem of transplants in Parkinson’s disease? Neurologia, 18, 74, 2003. 46. Isacson, O., The production and use of cells as therapeutic agents in neurodegenerative diseases, Lancet Neurol., 2, 417, 2003. 47. Isacson, O., Bjorklund, L.M., and Schumacher, J.M., Toward full restoration of synaptic and terminal function of the dopaminergic system in Parkinson’s disease by stem cells, Ann. Neurol., 53 (Suppl. 3), S135, 2003. 48. Olanow, C.W., Kordower, J.H., and Freeman, T.B., Fetal nigral transplantation as a therapy for Parkinson’s disease, Trends Neurosci., 19, 102, 1996. 49. No Author Listed.Surgical treatment for Parkinson’s disease: neural transplantation, Mov. Disord., 17 (Suppl. 4), S148, 2002. 50. Lindvall, O., Neural transplantation: can we improve the symptomatic relief? Adv. Neurol., 80, 635, 1999. 51. Sawle, G. et al., Transplantation of fetal dopamine neurons in Parkinson’s disease: positron emission tomography [18F]-6-L-fluorodopa studies in two patients with putaminal implants, Ann. Neurol., 31, 166, 1992. 52. Remy, P. et al., Clinical correlates of [18F] fluorodopa uptake in five grafted parkinsonian patients, Ann. Neurol., 38, 580, 1995. 53. Lindvall, O. et al., Evidence for long-term survival and function of dopaminergic grafts in progressive Parkinson’s disease, Ann. Neurol., 35, 172, 1994. 54. Kordower, J.H. et al., Neuropathological evidence of graft survival and striatal reinnervation after the transplantation of fetal mesencephalic tissue in a patient with Parkinson’s disease, N. Engl. J. Med., 332, 1118, 1995. 55. Kordower, J.H. et al., Functional fetal nigral grafts in a patient with Parkinson’s disease: chemoanatomic, ultrastructural, and metabolic studies, J. Comp. Neurol., 370, 203, 1996. 56. Kordower, J.H. et al., Fetal grafting for Parkinson’s disease: expression of immune markers in two patients with functional fetal nigral implants, Cell Transplant., 6, 213, 1997. 57. Branch, D.W. et al., Suitability of fetal tissue from spontaneous abortions and from ectopic pregnancies for transplantation, J.A.M.A., 273, 64, 1995.

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58. Kondoh, T. et al., Functional effects of transplanted human fetal ventral mesencephalic brain tissue from spontaneous abortions into a rodent model of Parkinson’s disease, Transplant. Proc., 26, 335, 1994. 59. Barker, R.A., Repairing the brain in Parkinson’s disease: where next? Mov. Disord., 17, 233, 2002. 60. Cochen, V. et al., Transplantation in Parkinson’s disease: PET changes correlate with the amount of grafted tissue, Mov. Disord., 18, 928, 2003. 61. Hagell, P. and Brundin, P., Cell survival and clinical outcome following intrastriatal transplantation in Parkinson disease, J. Neuropathol. Exp. Neurol., 60, 741, 2001. 62. Freeman, T.B. et al., Neural transplantation in Parkinson’s disease, Adv. Neurol., 86, 435, 2001. 63. Piccini, P. et al., Dopamine release from nigral transplants visualized in vivo in a Parkinson’s patient, Nat. Neurosci., 2, 1137, 1999. 64. Barker, R.A. and Dunnett, S.B., Functional integration of neural grafts in Parkinson’s disease, Nat. Neurosci., 2, 1047, 1999. 65. Freed, C.R. et al., Transplantation of embryonic dopamine neurons for severe Parkinson’s disease, N. Engl. J. Med., 344, 710, 2001. 66. Olanow, C.W. et al., A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson’s disease, Ann. Neurol., 54, 403, 2003. 67. Piccini, P., Dyskinesias after transplantation in Parkinson’s disease, Lancet Neurol., 1, 472, 2002. 68. Hagell, P. et al., Dyskinesias following neural transplantation in Parkinson’s disease, Nat. Neurosci., 5, 627, 2002. 69. Ma, Y. et al., Dyskinesia after fetal cell transplantation for parkinsonism: a PET study, Ann. Neurol., 52, 628, 2002. 70. Isacson, O., Bjorklund, L., and Pernaute, R.S., Parkinson’s disease: interpretations of transplantation study are erroneous, Nat. Neurosci., 4, 553, 2001. 71. Brundin, P. et al., Transplanted dopamine neurons: more or less? Nat. Med. 7, 512, 2001. 72. Macklin, R., The ethical problems with sham surgery in clinical research, N. Engl J. Med., 341, 992, 1999. 73. Dekkers, W. and Boer, G., Sham neurosurgery in patients with Parkinson’s disease: is it morally acceptable? J. Med. Ethics, 27, 151, 2001. 74. Redmond, D.E. Jr., Sladek, J.R., and Spencer D.D., Transplantation of embryonic dopamine neurons for severe Parkinson’s disease, N. Engl J. Med., 345, 146, 2001. 75. Boer, G.J. and Widner, H., Clinical neurotransplantation: core assessment protocol rather than sham surgery as control, Brain Res. Bull., 58, 547, 2002. 76. London, A.J. and Kadane, J.B., Placebos that harm: sham surgery controls in clinical trials, Stat. Methods Med. Res., 11, 413, 2002. 77. Albin, R.L., Sham surgery controls: intracerebral grafting of fetal tissue for Parkinson’s disease and proposed criteria for use of sham surgery controls, J. Med. Ethics, 28, 322, 2002. 78. Folkerth, R.D. and Durso, R., Survival and proliferation of nonneural tissues, with obstruction of cerebral ventricles, in a parkinsonian patient treated with fetal allografts, Neurology, 46, 1219, 1996. 79. Mamelak, A.N. et al., Fatal cyst formation after fetal mesencephalic allograft transplant for Parkinson’s disease, J. Neurosurg., 89, 592, 1998. 80. Subramanian, T. Cell transplantation for the treatment of Parkinson’s disease, Semin. Neurol., 21, 103, 2001. 81. Freed, C.R., Will embryonic stem cells be a useful source of dopamine neurons for transplant into patients with Parkinson’s disease? Proc. Natl. Acad. Sci. U.S.A., 99, 1755, 2002. 82. Borlongan, C.V. and Sanberg, P.R., Neural transplantation for the treatment of Parkinson’s disease, Drug Discov. Today, 7, 674, 2002. 83. Toledo-Aral, J.J. et al., Dopaminergic cells of the carotid body: physiological significance and possible therapeutic applications in Parkinson’s disease, Brain Res. Bull., 57, 847, 2002.

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84. Espejo, E.F. et al., Cellular and functional recovery of Parkinsonian rats after intrastriatal transplantation of carotid body cell aggregates, Neuron, 20, 197, 1998. 85. Luquin, M.R. et al., Recovery of chronic parkinsonian monkeys by autotransplants of carotid body cell aggregates into putamen, Neuron, 22, 743, 1999. 86. Toledo-Aral, J.J. et al., Trophic restoration of the nigrostriatal dopaminergic pathway in longterm carotid bodygrafted parkinsonian rats, J. Neurol., 23, 141, 2003. 87. Arjona, V. et al., Autotransplantation of human carotid body cell aggregates for treatment of Parkinson’s disease, Neurosurgery, 53, 321, 2003. 88. Nakai, M., Itakura, T., and Komai, N., Transplantation of autologous superior cervical ganglion into the brain of parkinsonian monkeys, Stereotact. Funct. Neurosurg., 54–55, 337, 1990. 89. Horvath, M. et al., Autotransplantation of superior cervical ganglion to the caudate nucleus in three patients with Parkinson’s disease (preliminary report), Neurosurg. Rev., 13, 119, 1990. 90. Itakura, T. et al., Transplantation of autologous sympathetic ganglion into the brain with Parkinson’s disease. Long-term follow-up of 35 cases, Stereotact. Funct. Neurosurg., 69, 112, 1997. 91. Nakao, N. et al., Enhancement of the response to levodopa therapy after intrastriatal transplantation of autologous sympathetic neurons in patients with Parkinson’s disease, J. Neurosurg., 95, 275, 2001. 92. Subramanian, T. et al., Striatal xenotransplantation of human retinal pigment epithelial cells attached to microcarriers in hemiparkinsonian rats ameliorates behavioral deficits without provoking an immune response, Cell. Transplant., 11, 207, 2002. 93. Watts, R.L. et al., Stereotaxic intrastriatal implantation of human retinal pigment epithelial (hRPE) cells attached to gelatin microcarriers: a potential new cell therapy for Parkinson’s disease, J. Neural Transm. Suppl. , 65, 215, 2003. 94. Bakay, R.A. et al., Implantation of Spheramine in advanced Parkinson’s disease (PD), Front. Biosci., 9, 592, 2004. 95. Lanza, R.P., Hayes, J.L. and Chick, W.L., Encapsulated cell technology, Nat. Biotechnol., 14, 1107, 1996. 96. Emerich, D.F. et al., A novel approach to neural transplantation in Parkinson’s disease: use of polymer-encapsulated cell therapy, Neurosci. Biobehav. Rev., 16, 437, 1992. 97. Chang, T.M. and Prakash, S., Therapeutic uses of microencapsulated genetically engineered cells, Mol. Med. Today, 4, 221, 1998. 98. Yoshida, H. et al., Stereotactic transplantation of a dopamine-producing capsule into the striatum for treatment of Parkinson disease: a preclinical primate study, J. Neurosurg., 98, 874, 2003. 99. Lundin, S. and Widner, H., Attitudes to xenotransplantation: interviews with patients suffering from Parkinson’s disease focusing on the conception of risk, Transplant. Proc., 32, 1175, 2000. 100. Barker, R.A. et al., A role for complement in the rejection of porcine ventral mesencephalic xenografts in a rat model of Parkinson’s disease, J. Neurosci., 20, 3415, 2000. 101. Pakzaban, P. and Isacson, O., Neural xenotransplantation: reconstruction of neuronal circuitry across species barriers, Neuroscience, 62, 989, 1994. 102. Brevig, T., Holgersson, J., and Widner, H., Xenotransplantation for CNS repair: immunological barriers and strategies to overcome them, Trends Neurosci., 23, 337, 2000. 103. Galpern, W.R. et al., Xenotransplantation of porcine fetal ventral mesencephalon in a rat model of Parkinson’s disease: functional recovery and graft morphology, Exp. Neurol., 140, 1, 1996. 104. LeBlanc, C.J. et al., Morris water maze analysis of 192-IgG-saporin-lesioned rats and porcine cholinergic transplants to the hippocampus, Cell Transplant., 8, 131, 1999. 105. Schumacher, J.M. et al., Transplantation of embryonic porcine mesencephalic tissue in patients with PD, Neurology, 54, 1042, 2000. 106. Deacon, T. et al., Histological evidence of fetal pig neural cell survival after transplantation into a patient with Parkinson’s disease, Nat. Med., 3, 350, 1997.

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107. Freeman, T.B. et al., A prospective, randomized, double-blind, surgical placebo-controlled trial of intrastriatal transplantation of fetal porcine ventral mesencephalic tissue (Neurocell-PD) in subjects with Parkinson’s disease, Exp. Neurol., 175, 426, 2003 108. Armstrong, R.J.E. et al., Porcine neural xenografts in the immunocompetent rat: immune response following grafting of expanded neural precursor cells, Neuroscience, 106, 201, 2001. 109. Armstrong, R.J.E. et al., The potential for circuit reconstruction by expanded neural precursor cells explored through porcine xenografts in a rat model of Parkinson’s disease, Exp. Neurol., 175, 98, 2002. 110. Cicchetti, F. et al., Combined inhibition of apoptosis and complement improves neural graft survival of embryonic rat and porcine mesencephalon in the rat brain, Exp. Neurol, 177, 376, 2002. 111. Emerich, D.F., Hemendinger, R., and Halberstadt, C. R., The testicular-derived Sertoli cell: cellular immunoscience to enable transplantation, Cell Transplant., 12, 335, 2003. 112. Xue, Y. et al., Microencapsulated bovine chromaffin cell xenografts into hemiparkinsonian rats: a drug-induced rotational behavior and histological change analysis, Artif. Organs, 25, 131, 2001. 113. Saveliev, S.V. et al., Chimeric brain: theoretical and clinical aspects, Int. J. Dev. Biol., 41, 801, 1997.

60 The Role of Physical Therapy in Management of Parkinson’s Disease Rose Wichmann Struthers Parkinson’s Center 0-8493-1590-5/05/$0.00+$1.50 © 2005 by CRC Press

INTRODUCTION A 2001 research synthesis published in the Archives of Physical Medicine and Rehabilitation supported the hypothesis that Parkinson’s disease (PD) patients benefit from physical therapy (PT) added to their standard regimen of medication.1 An integral member of an interdisciplinary team approach to management of Parkinson’s, the physical therapist plays an important role throughout the continuum of care from time of diagnosis to advanced stages of the disease. Parkinson’s disease compromises patient mobility in a variety of ways, and physical therapy is helpful for patients experiencing difficulties with bed mobility, transfers, gait, or balance loss/falling. Referrals to physical therapy also are instrumental in the development of an individualized exercise program, posture awareness, and pain control. Patient/family education provided by physical therapists offers greater understanding of issues relating to safety, stress reduction, movement enhancement strategies, and compensation techniques. PATIENT/CLIENT MANAGEMENT The physical therapy patient management process begins with examination. A history is usually gathered through patient/client interview, providing a process for obtaining information as well as an opportunity for initial assessment of patient’s communication and cognitive skills. It should be noted that facial masking and reduction of automatic movement seen in Parkinson’s patients might affect the normal expressions, gestures, and body postures typically seen during an examination. Many health professionals frequently use these observations during the evaluation process and may misinterpret their absence as depression, confusion, or disinterest. Asking patients to “describe an average day” provides great insight into workplace issues, leisure interests, activities of daily living (ADL) tasks, and activity levels. This description also allows the therapist to begin observing patterns in the patient’s routine related to medication timing, motor fluctuations, and/or fatigue. It is important to clarify patient use of medical terminology and description of symptoms to prevent

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misunderstanding. Family member observations and input are valuable in providing further insight into a patient’s daily function but should be “balanced” so patient input is not lost in the process. The patient will be asked to provide a listing of all medications, including herbs and other supplements. Physical therapy professionals need to familiarize themselves with potential side effects of common Parkinson’s medications that impact patient mobility, including dyskinesia, dystonia, edema, orthostatic hypotension, confusion, and hallucinations. A relevant systems review is included within the comprehensive examination. It should not be assumed that all reported symptoms are related to the diagnosis of Parkinson’s disease. Many patients have other medical conditions that should be considered when developing appropriate interventions and treatment plans. The systems review also provides an opportunity for patient education, as those living with Parkinson’s may mistakenly attribute all medical symptoms they experience to this chronic illness. A variety of standardized scales are used by neurologists and researchers for assessment of Parkinson’s disease symptoms, including the Hoehn and Yahr Rating Scale and the Unified Parkinson’s Disease Rating Scale (UPDRS). Familiarity with and use of elements from these numerical scales provide a common language among health professionals when rating Parkinson’s primary and secondary symptoms. A patientscored questionnaire using the UPDRS ADL scale can provide a good overview of patient problems and concerns during the examination process. While it is helpful for physical therapists to be familiar with and use components of these scales for rating PD symptoms, they are usually not sensitive for use as a measure of functional impairments, or to determine progress based on treatment interventions. Specific tests and measures should be selected to establish a functional baseline, assess the level of impairment, and help accurately assess progress toward anticipated goals and expected outcomes during the course of treatment. A variety of validated test measures can be used during physical therapy examination of individuals with Parkinson’s disease. Functional tests, including the Five Times Sit to Stand,2 Physical Performance Test,3 Timed Up and Go,4 Parkinson Activity Scale,5 Berg Balance Test,6 gait velocity and activity tolerance (i.e., two- or six-minute walk7) testing, may be used during the evaluation process. Goniometric measurement, sitting/standing blood pressure screening, sensory/proprioceptive testing, posture grids, digital photography, pain scales, vestibular screening, and other assessment tools also may be used, based on reported problems and concerns. A physical therapist will make clinical judgments based on data gathered during the examination to establish an appropriate physical therapy diagnosis, prognosis, and interventions. Physical therapists must be aware of current research evidence when choosing specific tests and measures for the Parkinson’s population. Some functional tests commonly used in physical therapy examination have been shown to be inappropriate for evaluating clients with PD. For example, the Tinetti gait assessment was studied and found not to be sensitive for detecting changes in persons with Parkinson’s.8 Functional reach testing also was found to be an insensitive instrument for determining fall risk within the Parkinson’s population.9 There are a variety of mental and emotional factors to be considered when performing an examination of a patient with Parkinson’s disease. Depression frequently is seen as a

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secondary symptom. When depressed, patients often describe sleep disturbances, appetite changes, or decreased activity levels, or complain of generalized weakness and fatigue. If untreated, depression may have a significant negative impact on physical therapy treatment. Patients experiencing depression should be referred to their physicians or other members of the interdisciplinary team as appropriate. It also is important to consider mental/emotional factors that impact fall risk. A 2002 research study published in the Journal of the American Geriatric Society showed that individuals who fall develop a risk for fear of falling, which adds spiraling risk for additional falling, greater fear, and functional decline.11 Physical therapists may wish to use balance “confidence scales” such as the Modified Falls Efficacy Scale10 or the Activities Specific Balance Confidence Scale11 to assess the fear of falling in their patients with Parkinson’s disease. Cognitive testing is needed to assess each individual’s ability to learn and retain movement enhancement strategies prior to developing a treatment approach. Input from testing done by other members of the interdisciplinary team (i.e., occupational therapy, speech pathology, and/or neuropsychology) will be helpful in determining PT interventions. Noted impairments in executive function, shortterm memory, orientation, or other cognitive skills necessitate more education and involvement of the family members/care partners during treatment. Visual perceptual changes alter the patient’s ability to perform safe and efficient transfers, ambulation, or ADL tasks. Decreased contrast sensitivity causes distortion of the environment and adds to transfer difficulties, problems with stair climbing, and home safety concerns, especially in lowlight conditions. Figure ground distortion creates a “clutter” of visual stimuli, causing increased difficulty and confusion during mobility tasks. Psychosocial factors should also be considered during physical therapy evaluation of the PD patient. A physical therapist must be aware of the patient’s living environment, current services, and care partner availability to develop the most appropriate plan. Factors including cultural diversity, financial resources, geography and access to services, personal beliefs, and education also may influence individual response to recommended interventions. All data gathered throughout the physical therapy examination are evaluated and organized into clusters, syndromes, or categories to determine appropriate interventions and treatment. This process may include referrals to other members of the interdisciplinary team if identified problems are deemed outside the scope of physical therapy practice. A prognosis of anticipated physical therapy goals and expected outcomes is established. Interventions should be based on the impact Parkinson’s symptoms create on patient function, and treatment goals should be written to accurately measure improvement of these daily functional tasks. PHYSICAL THERAPY IN EARLY-STAGE PARKINSON’S DISEASE The widely accepted Parkinson’s treatment algorithm notes the importance of exercise in early stages of Parkinson’s. Unfortunately, many PD patients do not receive a referral to physical therapy at this time. Patients may read PD literature that refers to the importance

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of movement and exercise yet remain unsure of what exercises would be most beneficial. Early referral to physical therapy offers an opportunity for the development of an individualized exercise program, as well as an introduction to effective use of an interdisciplinary team throughout the continuum of care. Patients may also have questions regarding posture changes, stress reduction, workplace issues, leisure interests, or pain at this stage of Parkinson’s. A multidimensional exercise routine is most effective at addressing deficits in balance, mobility, and fall risk.13 Progressive changes in flexibility are often not observed by the patient until significant limitation is present. Exercises should include a foundation of stretching activities due to muscle rigidity and its accompanying potential for flexibility loss. Inclusion of exercises promoting spinal flexibility appears to be particularly needed in early stages of Parkinson’s.14 Even when made aware of the importance of regular stretching, patients frequently require instruction in proper stretching technique, including benefits of sustained stretches for 20 to 30 sec, maintaining deep breathing, and relaxing throughout the exercise activity. Additional flexibility activities, including tai chi or yoga, also may be recommended. Movement enhancement strategies with attention to making motions more mindful and complete can further enhance exercise performance.15 Many PD patients report feelings of muscle weakness, even when conventional muscle testing appears to show no significant deficits. It appears that bradykinetic movement combined with muscle rigidity may contribute to the PD patient’s perceptions of lessened muscle strength. A research study published in the American Journal of Physical Medicine and Rehabilitation found no significant strength deficits between individuals with Parkinson’s and normal subjects, with the exception of abdominal strength.16 This seems to suggest a need for particular attention to strengthening core muscles of stability when designing the exercise program. Incorporating functional movements (i.e., practicing sit to stand from varying chair seat heights) into a strengthening exercise routine also proves beneficial and ensures regular followthrough. Regular conditioning exercises are incorporated in a comprehensive routine to maintain activity tolerance and cardiovascular fitness. It has been found that PD patients benefit from aerobic exercise just as much as those without PD.17 A variety of conditioning exercise activities or fitness equipment can be used, depending on availability and patient preferences. Special consideration should be given to the safety of certain types of exercise equipment (i.e., electric treadmills may move too quickly for safe operation in those with significant bradykinesia.) Mood and subjective reports of well-being also were shown to improve by participation in sports activities in early- to medium-stage PD patients.18 Family members may be the first to comment about observations of the patient’s changing posture or gait pattern. A patient may first become aware of postural change when viewing recent photographs, or notice frequent tripping or “clumsiness” when walking on uneven terrain. Developing self-awareness of posture and gait is often advantageous to patients with early-stage Parkinson’s disease. Performing frequent “posture checks” throughout the day promotes postural awareness and good alignment. Use of lumbar and/or cervical pillows help to improve sitting and sleeping postures. Exercises promoting axial extension, pelvic mobility, and back/abdominal strength also are helpful in posture training. Gait training is usually minimal in early-stage PD, though

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patients can benefit from instruction in self-monitoring skills and attentional strategies to increase velocity and heel strike in certain situations. It is estimated that approximately 30% of individuals diagnosed with Parkinson’s remain active in the work force.19 Work site evaluation may prove helpful for determining areas of difficulty and recommendations for improved body mechanics, task performance, and safety. Physical or occupational therapists are appropriate referral sources for PD patients who have questions or concerns related to their work environment. Instruction in appropriate relaxation activities should be included in the design of a comprehensive program. Reduced activity tolerance may necessitate dividing work, ADL, or leisure tasks into several components to allow adequate rest. The importance of stress reduction often must be emphasized, as most patients find that their PD symptoms exacerbate when they are under physical or emotional stress. Patients may benefit from tai chi, meditation, progressive relaxation, guided imagery, or other modes of relaxation based on individual preferences and interests. Referrals to other members of the interdisciplinary team or community resources may be included when designing appropriate relaxation activities. Patient education is a primary component in all stages of Parkinson’s disease. Physical therapy plays an important role in early-stage Parkinson’s by answering patient and family member questions and providing information on treatment options beyond medications. The physical therapist also plays a supportive role in enhancing patient mobility by encouraging an active lifestyle that maximizes quality of life. Therapists should be knowledgeable about education and resource support services within their local communities, and offer this information to patients and families who are facing the sometimes overwhelming task of coping with a new diagnosis of Parkinson’s disease. PHYSICAL THERAPY IN MODERATE-STAGE PARKINSON’S DISEASE As Parkinson’s disease progresses, patients begin to experience greater difficulties with physical mobility skills. Clients may note greater difficulty with attempts to get out of bed, rise from a chair, or get into the car. Gait pattern changes become more pronounced, with increased shuffling, difficulty turning, or occurrence of festination and/or freezing. Many patients experience significant balance problems and frequently begin to report episodes of falling. Motor fluctuations may develop, further complicating mobility skills as patients experience variations in function throughout the day. Family care partners often need to become more involved in providing assistance with routine activities. Physical therapy can be helpful with all these mobility challenges and offer interventions and instruction to more effectively cope with changes in these daily tasks. Many PD patients report problems turning in bed at night as one of the first difficulties noted with general mobility. Axial rigidity, with lack of dissociation between head and upper and lower trunk, combine to produce limited trunk rotation and difficulty rolling. Physical therapy can work with patients in breaking down the rolling sequence into a series of steps, focusing with conscious attention to detail during each individual movement. Mentally rehearsing each movement prior to performance often is beneficial.

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Compensatory strategies iriclude wearing “slippery” fabric nightclothes or using a satinbased drawsheet through the middle of the bed. Installing a side rail also may be included within the physical therapy intervention plan. Clients may note difficulty with getting in or out of bed. Bed mobility instruction in proper body positioning and movement enhancement strategies improves transfer ease and allows the patient to retain maximized independence. Chair, car, and toilet transfers become more effortful for a variety of reasons. Bradykinesia interferes with a patient’s ability to generate upward momentum. Lack of flexibility or decreased muscle strength may result from a sedentary lifestyle and decreased activity levels. Most often, patients are observed attempting to stand using poor body mechanics, failing to place their center of gravity over their base of support. This results in reduced trunk flexion and improper foot placement when attempting to rise. Some clients also exhibit significant difficulty with body alignment as they attempt to sit down. Physical therapy offers transfer training, instruction in compensatory strategies, adaptive equipment, and appropriate exercise to improve these transfers. Gait changes in Parkinson’s disease include a narrowed base of support, decreases in step size, heel strike and arm swing, en bloc turns, and reduced gait velocity. Excessive dyskinesia or dystonic posturing also can negatively affect the gait pattern. It has been shown that patients experience increased gait difficulties when attempting to multitask, with added cognitive or motor tasks shown to be equally demanding.20 Motor fluctuations cause some individuals with Parkinson’s to experience only periodic deficits or to demonstrate different types of difficulties when on and off. Retropulsion, festination, and freezing are frequently seen at this stage of Parkinson’s, requiring gait training through physical therapy to most effectively cope with these deficits. There are a variety of techniques that can be used when working with clients who experience freezing. A physical therapist will provide assessment to help recognize individual freezing “triggers,” determine locations where freezing is most likely to occur, and offer recommendations for appropriate environmental modifications. Other compensatory strategies, including visual, auditory, tactile, or kinesthetic cueing, are often helpful. The use of a laser pointer, step-over wand, or inverted walking stick is frequently used during gait training. Physical therapists may choose to work collaboratively with music therapists to provide gait training using rhythmic auditory stimulation, which has been shown to improve gait velocity, symmetry, stride length, and step cadence.21 Many patients with Parkinson’s disease find it necessary to use a gait assistive device to maximize safety when ambulating. A referral to physical therapy is essential to receive recommendations regarding the most appropriate device and ensure proper sizing. Patients often are unaware of all assistive device options and make choices that do not offer maximized safety and support. As a general rule, four-post walkers and quad canes do not work well for those with Parkinson’s. These devices interrupt the flow of movement and require divided attention/multitasking, which contributes to difficulties with balance stability. Single-end canes or walking sticks seem to work best for patients requiring unilateral support. Many patients benefit from the use of specialty walkers available with swivel casters, hand brakes, and a bench seat. These walkers offer more options for walker speed and control, improving turning stability. Some have an added “slow down” feature, especially helpful for those experiencing episodes of festination.

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The bench seat also is helpful for those with reduced activity tolerance or sudden “off” periods, although patients should receive instruction in safe transfers on and off these seats. Patients also require gait training to use these devices safely in a variety of situations, including varied floor surfaces and outdoor terrain. Recommendations for proper footwear and good foot health aid in improving gait stability. Physical therapists are also a resource for information about locations for equipment purchase and medical reimbursement. Postural instability is the primary symptom of Parkinson’s that is least responsive to available medications. Muscle rigidity and decreased flexibility combine with a narrowed base of support and decreased postural righting reflexes to produce balance changes. Many patients report frequent episodes of significant balance loss or falling. Retropulsion results in involuntary backward balance loss, worsened with attempts to reach overhead, open a door, or carry objects up against the body. Festination usually causes forward balance loss, as a patient experiences uncontrolled increases in gait velocity while step size declines. Physical therapy referrals for instruction in gait training, counterbalancing techniques, and movement enhancement strategies are helpful for patients experiencing these difficulties. An emphasis on falls prevention is an integral part of the physical therapy intervention plan. A 2002 survey of 1061 patients with Parkinson’s disease showed 55.4% reporting at least one fall within the past year, with 65.3% of fallers reporting injury, and 32.9% of fallers reporting a fracture.21 Since a large number of patients with PD are diagnosed later in life, many have secondary complications such as osteoporosis, degenerative joint disease, or vision changes that increase fall injury risk. An assessment of the home environment may be needed to reduce barriers and remove potential hazards. Recommendations for furniture placement, visual cues, and installation of adaptive equipment also should be included. Some highrisk patients may benefit from use of protective kneepads or “hip saver” clothing to reduce potential for injury. In the event of a fracture, illness, or other injury, a physical therapy referral should be initiated as soon as the patient is medically stable. It is typical to see Parkinson’s symptoms exacerbate during times when a patient is under significant physical or emotional stress. Prolonged bedrest or inactivity significantly impairs mobility and complicates the rehabilitation process. Early physical therapy intervention allows timely mobilization and reduces risk of complications. It should be noted that the rehabilitation process might be slowed significantly for a patient with Parkinson’s. Expected outcomes should reflect this slower progress, and interventions should be designed accordingly. As PD symptoms progress, daily activities should be assessed to ensure safety and a balance of activity and rest in the daily routine. Modification of the exercise program usually is needed as balance declines. Patients may need to perform more of their exercise routine in seated or supine positions for maximized safety. Leisure interests also may need to be modified. Raised gardening beds, use of a stationary versus regular bike, and moving daily walking from outdoor terrain to an indoor location are all examples of modifications that allow clients to remain safe while performing activities. Many patients enjoy involvement in community exercise groups for regular follow-through and support. Physicians and other members of the interdisciplinary team need to be alert to changes in patient mobility during each encounter, providing referrals as appropriate. An early

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introduction to physical therapy also allows patients to recognize changes or need for modification and seek referral for additional services as needed. Care partner instruction should not be overlooked in this stage of Parkinson’s disease. Many family care partners begin to offer assistance with transfers, exercises, or other daily cares without instruction in proper technique or body mechanics. The likelihood of care partner injury can be significant without proper instruction. If a patient is falling, instruction in safe techniques to get up from the ground is essential to minimize further injury risk. Instruction in providing clear, concise cues with a reduction of excessive verbal stimuli is particularly helpful and reduces frustration for both patient and care partner. PHYSICAL THERAPY IN ADVANCED-STAGE PARKINSON’S DISEASE: In advanced stages of Parkinson’s disease, medications often become less effective for symptom control. Medication side effects also may become more prominent. Patients experience increasing immobility and require assistance with almost all activities of daily living. Although each individual experience with Parkinson’s disease is unique, many clients develop cognitive changes that further complicate independence and safety. Care partners play a larger role in care of the patient and frequently need instruction, support, and respite care to cope with these complicated problems. Although some physicians and other members of the health care team may feel that an individual lacks “rehab potential,” there is still a role for physical therapy in comprehensive management of individuals with advanced-stage Parkinson’s disease. Physical therapy referrals are beneficial in areas of posture, positioning, pain control, and care partner assisted exercise. Continued instruction in care partner body mechanics is needed as patient care needs change and increase. The physical therapist also plays an important role in teaching other health care team members proper transfer techniques, compensatory strategies, and increased awareness of common challenges experienced by those with Parkinson’s disease. If gait and balance changes prevent safe ambulation, many clients begin to use a wheelchair for general mobility. A referral to physical therapy is helpful in determining proper wheelchair size, type, and features required. A lack of automatic movement and excessive muscle rigidity increase the risk of integumentary changes, and a proper cushion must be chosen to prevent skin breakdown. Seating systems offering reclining backrests, lateral trunk support, or elevating leg rests are often needed to achieve proper positioning. Consideration to chair size and width must be given to ensure that the wheelchair works within the home environment and that a care partner is able to lift the chair into the car trunk if needed. A physical therapist may work collaboratively with an occupational therapist in making these recommendations or decisions. Instruction in proper positioning throughout the day and night is needed. Positioning for eating is especially important due to a significant risk of aspiration in many clients with advanced-stage Parkinson’s. Some clients may use a recliner or other chair when not in a wheelchair. As posture declines, many patients begin to use excessive pillows under the head, shoulders, and knees while in bed, which may further promote flexed posture. Instruction in proper bed positioning offers maximized comfort and good body

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alignment. As patient immobility increases, family care partners or other assistants often need to return to physical therapy for additional instruction in proper body mechanics, use of a transfer belt, and safe methods to perform pivot transfers. Assessment for and instruction in the use of mechanical lifts may be needed for those with severe rigidity or balance impairments. Clients with advanced-stage Parkinson’s disease usually require assistance with performance of a daily exercise program. Emphasis on assisted range of motion and stretching helps to maximize flexibility and improve patient comfort. It is the author’s experience that many family caregivers report receiving extensive, time-consuming home programs of assisted exercise for their family member with PD. These complicated routines often are impractical for families already overwhelmed with a variety of other caregiving tasks. Physical therapists should be mindful of these caregiver responsibilities and design simplified programs of exercise that can be more easily incorporated into the daily routine. Examples include adding a few extra arm and leg motions during assisted dressing and bathing, or performing assisted standing at a grab bar/counter to increase lower extremity weight bearing and ability to retain transfer skills. Involvement in adapted recreational tasks or household chores also may be successfully used as part of a movement and exercise program. Pain may be reported more frequently in advancedstage Parkinson’s. This is often due to excessive rigidity, inability to change position independently, excessive dystonia/dyskinesia, or injuries sustained in falling. Crying, wandering, and agitation may be seen as pain-related behaviors in those with significant cognitive changes. Caregiver instruction in the use of superficial heat or cold, repositioning, or massage is often helpful. Additional physical therapy, musculoskeletal evaluation, and interventions focusing on pain control also may be appropriate. As care needs increase, many patients are faced with the transition to a new living environment. A move to assisted living, a skilled nursing facility, or other new environment can be extremely stressful for both patients and their care partners. Unfortunately, not all health care providers within these facilities are familiar with the symptoms or challenges of living with Parkinson’s. Physical therapy evaluation of the new living environment is helpful to maximize patient safety and comfort. A physical therapist can help provide staff education for assisting patients experiencing fluctuating mobility, freezing, or other mobility challenges related to Parkinson’s disease. Instruction in Parkinson’s symptoms, as well as specific transfers and movement-enhancement strategies, aids staff understanding and improves patient care. PHYSICAL THERAPY WITHIN A HOLISTIC MODEL OF CARE Patients and family members often choose to incorporate complementary therapies into their comprehensive treatment plan. These specialty programs provide opportunities for a variety of creative physical therapy interventions. A physical therapist may successfully collaborate with a variety of professionals and/or programs, designing interventions to achieve desired outcomes while offering maximized quality of life. For example, many clients enjoy gardening as a leisure interest. Therapeutic horticulture programs offer unique opportunities for physical therapy interventions. These

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include movement and exercise through gardening, transfer training opportunities to practice getting up and down from the ground, or instruction in balance safety strategies for walking on uneven terrain. Horticulture programs also offer methods for relaxation/stress management and exercise through performance of familiar tasks for clients with dementia. Using animal-assisted therapy programs within physical therapy also can be successful for clients with Parkinson’s disease. Working with therapy animals offers a wealth of opportunities for creative program design. Stroking, grooming, throwing, catching, tug of war, and other games with these pets are incorporated to achieve needed stretching motions and strengthening exercise. Therapy dogs also build confidence during gait and transfer training or may offer a “connection” to clients with dementia. It is recommended to work only with therapy animals certified through accrediting organizations such as Delta Society, and to work closely with the animal handlers when planning these programs. Animal assisted therapy is not appropriate for all clients, and careful screening of client interest, allergies, and past animal experiences should be conducted prior to initiating a program. Access to music therapy offers opportunities for creative collaboration to achieve desired outcomes. It is helpful to work with board-certified music therapists trained in specific neurological music therapy techniques when working with clients with Parkinson’s disease. Achieving exercise follow-through using therapeutic instrumental music performance (TIMP), and physical therapy gait training incorporating rhythmic auditory stimulation, are examples of potential collaborative efforts with music therapy. Music can also be successfully used to enhance movement during community exercise groups or incorporated into relaxation training sessions. There are many other holistic programs and complementary therapies that offer collaborative opportunities for physical therapists. Working with these programs can help achieve anticipated goals and expected outcomes within the physical therapy plan of care. Physical therapy interventions also provide activity accommodation and adaptations allowing continued participation in a client’s leisure interests and other activities designed to maximize quality of life. THE INTERDISCIPLINARY TEAM Comprehensive management of Parkinson’s disease requires the skills of a full interdisciplinary team. Ongoing communication and understanding of each team member’s role are vital to success of this approach. The patient, family members, health care professionals, and community resources must interact to effectively coordinate a plan designed to provide recommendations and treatment options focused on maximizing quality of life. Each team member must be able to recognize changes or areas of concern and be prepared to refer to other members of the team as needed. The physical therapist plays an important role on the interdisciplinary team. Prompt communication of physical therapy evaluation results and planned interventions ensures coordination of needed patient services. Skilled observations obtained during a physical therapy session can be helpful to physicians in regard to optimizing patient medications or managing secondary symptoms. Posture training interventions and breath work

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designed in physical therapy work collaboratively with the efforts of a speech pathologist focused on improving communication and voice volume. Movement enhancement strategies learned in physical therapy benefit ADL training performed in occupational therapy. Information shared by a client or family member during a physical therapy session may indicate psychosocial concerns requiring referral to social services or other members of the interdisciplinary team. The physical therapist serves an important role as educator for other team members who may be less familiar with the mobility challenges seen in individuals with Parkinson’s disease. Instruction in helpful compensation techniques and movement enhancement strategies results in improved understanding and patient care from all disciplines. Physical therapy instructions apply to other allied health disciplines as well as to workers in home health care, adult day services, senior centers, assisted living, skilled nursing facilities, community exercise programs, or others who may be involved in the client’s comprehensive care plan. Presentations for patient conferences, support groups, or other community events also prove useful. Education of all team members provides information needed to recognize patient changes, more effective transitions between skilled medical services and community programming, and prompt referrals back to physical therapy as new problems are identified. EVIDENCE-BASED PRACTICE: RESEARCH AND PHYSICAL THERAPY An increasing amount of research has been published that demonstrates the effectiveness of physical therapy for patients with Parkinson’s disease. A continued focus on evidencebased practice is needed to establish benefits of treatment and best practice patterns for all physical therapy professionals. Research based practice also establishes credibility for the role of physical therapy in Parkinson’s disease management and provides important information to referring physicians, consumers, policy makers, and insurers. A comprehensive explanation of current physical therapy practice is available in the Guide to Physical Therapist Practice, a collaborative work published by the American Physical Therapy Association.22 Physical therapists use the information developed for the Guide within their clinical practice, as well as for professional education purposes. The Guide defines physical therapy’s scope of practice and provides preferred practice patterns grouped into several major categories. REFERENCES 1. deGoede C.,Keus, S., Kwakkel, G., Wagenaar, R., “The effects of physical therapy in Parkinson’s disease: A research synthesis,” Arch Phys. Med. Rehabil, 82 (4), 2001. 2. Csuka, M., McCarty, D.J., “Simple Method for Measurement of Lower Extremity Muscle Strength,” Amer. J. Med., 78(1):77–81, 1985. 3. Reuben, D.B., Siu, Al, “An objective measure of physical dysfunction of elderly outpatients. The Physical Performance Test,” J. Amer. Ger. Soc., 38:1105–1112, 1990.

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4. Shumway-Cook, A., Brauer, A., Woollacott, M., “Predicting the Probability for Falls in Community-Dwelling Older Adults Using the Time Up and Go Test,” Phys. Ther., September 2000. 5. Nieuwboer, A., DeWeerdt, W., Dom, R., Bogaerts, K., Nuyens, G., “Development of an Activity Scale for Individuals with Advanced Parkinson’s Disease; Reliability and “On-Off” Variability,” Phys. Ther., November 2000. 6. Berg, K., Wood-Dauphinne, S., William, J.I. et al., “Measuring Balance in the Elderly: Preliminary Development of an Instrument,” Physiotherapy Canada, 41:240B, 1989. 7. Light, K.E., Behrman, A.L., Thigpen, M.,Triggs, W. J., “The 2-minute Walk Test: A Tool for Evaluating Walking Endurance in Clients with Parkinson’s Disease,” Neurology Report, Vol. 21. 8. Behrman, A.L., Light., K.F., Flynn, S.M., Thigpen, M. T., “Is the Functional Reach test useful for identifying falls risk among individuals with Parkinson’s disease?” Arch Phys. Med. Rehabil, 83(4):538–42, April 2002. 9. Behrman, A.L., Light. K.E., Miller, G.M., “Sensitivity of the Tinetti Gait Assessment for detecting change in individuals with Parkinson’s disease,” Clin. Rehabil., 16(4):399–405, June 2002. 10. Friedman, S.M., Munoz, B., West, S., Rubin, G.S., Fried. L.P., “Falls and Fear of Falling: Which Comes First? A Longitudinal Model Suggests Strategies for Primary and Secondary Prevention,” J. Amer. Ger. Soc., 50(8): 1329, August 2002. 11. Cheal, B., Clemson, L., “Older people enhancing self efficacy in fall risk situations,” Australian Occupational Therapy Journal, 48:80–91, 2001. 12. Powell, L.E., Myers, A.M., “The Activities Specific Balance Confidence (ABC) Scale,” Jour. Geren., 50A(1), M28–M34, 1995. 13. Shumway-Cook, A., Gruber, W., Baldwin, M., Liao, S., “The effect of multidimensional exercises on balance, mobility, and fall risk in community dwelling older adults,” Phys. Ther., 77; (1):46–57, January 1977. 14. Schenkman, M., Morey, M., Kuchibhaita, M., “Spinal Flexibility and balance control among community dwelling adults with and without Parkinson’s disease,” J. Gerontol A. Biol. Sci., 55(8):M441–5, August 2000. 15. Morris, M., Movement Disorders in People with Parkinson’s Disease: A Model for Physical Therapy,” Physical Therapy, 80(6): 578–597, June 2000. 16. Scandalis, T.A., Bosak, A., Berliner, J.C., Helman, L. L., Wells, M.R., “Resistance training and gait function in patients with Parkinson’s disease,” Am. J. Phys. Med. Rehabil, 80(1):38–43, January 2001. 17. Bergen, J.L., Toole, T., Elliott, R.G., Wallace, B., Maitland, Robinson K., “Aerobic exercise intervention improves aerobic capacity and movement initiation in Parkinson’s disease patients,” Neurorehabilitation, 17(2):161–8, 2002. 18. Reuter, I., Engelhardt, M., Stecker, K., Baas, H., “Therapeutic value of exercise training in Parkinson’s disease,” Med. Sci. Sports Exerc., 31(11):1544–9, November 1999. 19. O’Shea, S., Morris, M.E., Iansek, R., “Dual task interference during gait in people with Parkinson’s disease. Effects of motor versus cognitive secondary tasks, Phys. Ther., 82(9):888– 97, September 2002. 20. McIntosh, G.C., Rice, R.R. and Thaut, M.H., “Rhythmic—auditory facilitation of gait patterns in Patients with Parkinson’s disease,” Journal of Neurology, Neurosurgery and Psychiatry, 62, 22–26, 1997. 21. Parashos, S., Wielinski, C., Erickson-Davis, C., Wichmann, R., Walde, Douglas M., “Injuries due to falls in Parkinsonian Patients,” Abstract presented at International Congress of Movement Disorders, Miami, FL, 2002. 22. The Guide to Physical Therapy Practice, 2nd ed., American Physical Therapy Association.

61 Swallowing Function in Parkinson’s Disease Lisa A.Newman Walter Reed Army Medical Center 0-8493-1590-5/05/$0.00+$1.50 © 2005 by CRC Press

INTRODUCTION Swallowing is the primary mode of maintaining one’s nutritional status. One of the complications of Parkinson’s disease (PD) is impaired swallowing, with an incidence reported to be as high as 95%.1 Swallowing is an intricate and complex physiologic and neurologic process. Thus, when neurologic damage occurs, as in the case of PD, swallowing may be adversely affected. Dysphagia is defined as impaired swallowing, which can occur any where from the mouth to the stomach, resulting from impaired function of the jaw, lips, tongue, velum, larynx, pharynx, upper esophageal sphincter, or esophagus2,3 More specifically, oropharyngeal dysphagia refers to swallowing disorders involving the oral and pharyngeal cavities, which are distinguished from primary esophageal disorders. Before one can understand the effect of PD on swallowing, an understanding of normal swallowing is essential. This chapter incorporates the following aspects of swallowing: normal swallowing, diagnosis of swallowing disorders, swallowing disorders in PD, and treatment options for swallowing dysfunction in PD. NORMAL SWALLOWING Swallowing can be divided into four stages:4 1. The oral preparatory stage 2. The oral stage 3. The pharyngeal stage 4. The esophageal stage The oral preparatory stage involves mastication of semisolid or solid food and formation of a bolus, which renders the food into an appropriate consistency for swallowing with the bolus being lubricated and chemically altered by mixing with saliva.5 This stage involves lips closure, rotary and lateral motion of the jaw, buccal or facial tone, and rotary and lateral motion of the tongue.4 Neurologically, this stage is under voluntary control of the patient; however, sensory information is processed from sensory receptors throughout the oral cavity.4

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The oral stage of swallowing is also under the voluntary control of the patient and involves the transport of food to the posterior area of the oral cavity. Two distinct patterns of tongue movement during the oral stage have been described: the “tipper” and the “dipper.”6,7 The “tipper” is when the bolus is initially on the tongue dorsum with the tongue tip pressed against the posterior surface of the maxillary incisors. The “dipper” takes place when the bolus is initially in the anterior sublingual sulcus, which requires the tongue to elevate the bolus to a supralingual position, and the oral stage continues in a similar fashion to the “tipper” type swallow. The oral stage requires intact labial musculature that prevents drooling, intact buccal musculature preventing food from pocketing in the buccal cavity, normal palatal muscles, functional lingual musculature and movement, and the ability to breathe through the nose.4 Physiologically, four events signal the onset of the oral phase of swallowing: tonguetip movement, tongue-base movement, superior hyoid movement, and submental elctromyographic (EMG) activity.6 There is variability in tongue movement, depending on the type of bolus, suggesting that the sensory feedback of the oral phase is necessary to monitor the bolus and adjust tongue function.8 The pharyngeal stage of swallowing serves a twofold purpose: guiding the bolus through the pharynx into the esophagus and protection of the airway. It is an automatic phase of swallowing governed by the brain stem. Normal pharyngeal swallowing involves palatal closure, bolus transport through the pharynx, base of tongue propulsion to the posterior pharyngeal wall, glottal closure to prevent aspiration, and upper esophageal sphincter (UES) opening and transsphincteric fluid flow.9 Transport of the bolus through the pharynx is mainly accomplished by the pressure applied by the tongue base directly onto the bolus in the oropharynx.10 The anatomic and neurologic integrity of the tongue plays an important role in bolus transport during both the oral and pharynx stages of swallowing. The pharyngeal stage is considered to be a swallowing response (as opposed to a swallowing reflex), as it varies with changes in bolus volume and/or viscosity. There are several phenomena that change during the pharyngeal phase. There is a progressive increase in the magnitude of superior hyoid movement with increases in the size of the bolus.11 The upward motion of cricopharyngeus or upper esophageal sphincter (UES) increases with enlarging volumes of liquid. The diameter and duration of UES sphincter opening also increase with larger volumes.12 Increasing viscosity to a thick paste results in greater magnitude of anterior hyoid displacement and greater diameter and duration of UES sphincter opening as compared to the same volumes of a low-density liquid.13,14 For food to pass into the esophagus, there must be an opening of the upper esophageal sphincter (UES). The mechanism of UES opening occurs during the pharyngeal phase of swallowing due to an interrelationship between hyoid/laryngeal movement and UES opening. Anatomically, the cricoid cartilage is linked to the hyoid by muscular and ligamentous connections, and it is an insertion point for the cricopharygeus muscle (the lower portion of the UES). As the hyoid moves superiorly and anteriorly during the swallow, the larynx also elevates, which in turn elevates and opens the cricopharygeus muscle. As a result, the passage of food across the upper esophageal sphincter occurs while the hyoid is at its highest and most anterior excursion.11 There must be coordination between respiration and swallowing, and this occurs at the level of the larynx. The larynx must be opened during respiration and closed during the

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pharyngeal stage of swallowing.8 Laryngeal closure is a three-tier protective adduction. From superior to interior anatomic location, the first level of adduction involves the approximation of the aryepiglottic folds to cover the superior inlet of the larynx.15 The downward, backward movement of the epiglottis completes the superior level of closure, preventing any material from entering the laryngeal vestibule. The second layer of adduction is the false vocal foods. The final layer is a forceful adduction at the level of the true vocal folds.4,15,16 The esophageal phase of swallowing is a reflexive stage that involves the descent of the bolus of food down the esophagus. This is accomplished by peristaltic action of the esophagus and relaxation of the lower esophageal sphincter. Above the bolus, the circular muscle contracts, and the longitudinal muscle relaxes. This combined action produces the bolus propulsion that travels the length of the esophagus.17 The esophagus consists of both striated and smooth muscle. Neurologic innervation of the esophagus switches between motoneurons located in the CNS and autonomically located motoneurons in the periphery as the tissue changes from striated to smooth muscle.8 Relaxation of the lower esophageal sphincter occurs during the esophageal phase of swallowing or with distention of the esophagus. Neurologically, it depends on descending motor fibers in the vagus nerve.8 EVALUATION OF OROPHARYNGEAL DYSPHAGIA Swallowing disorders or dysphagia are common in patients with Parkinson’s disease. Complications of swallowing disorders include malnutrition, dehydration, and respiratory complications of aspiration, all of which can be life threatening. Therefore, accurate diagnosis of the parameters that impair swallowing and management is absolutely vital. The swallowing process is complex and cannot be observed clinically. Swallowing is a rapidly moving process that is best assessed with a dynamic instrumental technique. Two methods have been used most frequently for examining oropharyngeal swallowing: videofluoroscopy and fiber optic endoscopic evaluation of swallowing (FEES). This section describes both methods and focuses on videofluoroscopy, which is used most frequently. Fiber optic endoscopic evaluation of swallowing (FEES) consists of passing an endoscope transnasally to view the larynx and pharynx while the patient swallows measured volumes of food and liquid dyed with food coloring.18 The advantages of FEES are as follows: 1. The procedure can be done at bedside. 2. Real food is used. 3. There is no radiation exposure. 4. Fiber optic endoscopes are available in medical settings. The disadvantages of FEES are the following: 1. It provides no ability to view the oral phase of swallowing. 2. Deflection of the epiglottis, which covers the laryngeal introitus, obstructs visualization of the pharyngeal response. 3. There is no visualization of the cervical esophageal stage of swallowing.

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It is therefore difficult to diagnose the parameters that cause dysphagia, which may affect treatment options.19 Videofluoroscopy has been cited as the best method for evaluating the dynamic process of swallowing.6,20,21 It is the only procedure designed to study the anatomy and physiology of the oral preparatory, oral, pharyngeal, and cervical esophageal stages of swallowing.4 Videofluoroscopy uses a fluoroscope, which permits the radiologic observation of the dynamic process of swallowing. A recording device, most recently digital recording instrumentation, is interfaced with the fluoro-scope, allowing the radiographic procedure to be recorded. Swallowing is a very rapid process, and evaluation of the detailed parameters is impossible in real time. Therefore, recording the procedure to play back immediately or after the study is necessary. In the case of a generative disease process such as Parkinson’s disease, previous studies can be archived to compare changes over time. During videofluoroscopy, patients are viewed in the lateral and/or A-P projections on a tilt-table fluoroscope in the upright position.22 Measured volumes of a liquid barium suspension are given to the patient. Smaller amounts of liquid are initially administered to minimize the risk of aspiration and allow visualization of the anatomic structures that can be obliterated by large quantities of radiopaque material.23 Different viscosities of barium should be assessed; e.g., nectar thick liquid, honey thick liquids, and pudding. Finally, mastication of a solid material, e.g., a cookie covered with barium pudding, should be visualized. Changes in bolus volumes and viscosities also serve as factors for observing changes in swallowing function given different sensory stimuli and motor requirements for each bolus. Every study should also include strategies to improve swallowing function when appropriate, e.g., therapeutic maneuvers or position changes. If the patient demonstrates severe swallowing difficulties that are not amenable to treatment strategies, the study can be terminated, thus minimizing the danger of aspiration to the patient. Following completion of the videofluoroscopy or FEES, two factors must be immediately considered in managing the patient with Parkinson’s disease: can the patient swallow safely with or without therapeutic strategies, and can the patient consume adequate calories orally to maintain or improve nutritional status?19 An instrumental assessment is the only method to evaluate swallowing reliably. Management of oropharyngeal dysphagia is possible only after the pathophysiology of the swallowing mechanism is diagnosed. SWALLOWING DISORDERS IN PARKINSON’S DISEASE Gastrointestinal dysfunction, which includes dysphagia, is a frequent and occasionally dominating symptom of Parkinson’s disease, originally described by James Parkinson in 1817. Specifically, he described the swallowing disorder as “the food is with difficulty retained in the mouth until masticated; and then as difficulty swallows” and drooling as “the saliva fails of being directed to the back part of the fauces, and hence is continually draining from the mouth.”24 Complications of dysphagia are present in advanced stages of PD: aspiration, pneumonitis, weight loss, malnutrition, and dehydration. When

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unrecognized, dysphagia plays a role in weight loss and the recurrent airway infections in patients with Parkinson’s disease.25 Excess saliva and drooling (as described by Parkinson himself) have been noted as a problem in patients with Parkinson’s disease. Bagheri et al.26 measured saliva production in PD patients across all stages of the disease and in some patients who were not receiving any dopaminergic drugs. This study revealed that saliva production was significantly lower in PD patients than age- and sex-matched controls across all stages of the disease.26 One may question whether the administration of dopaminergic drugs may affect saliva production. In a small subset of patients not receiving any dopaminergic medication, saliva production was also lower than in age- and sex-matched controls.26 The excess saliva and drooling experienced by Parkinson’s disease patient is probably not the result of too much saliva, but rather a consequence of swallowing difficulties. When a patient swallows infrequently, there will be a buildup of saliva. The tendency for the mouth to drop open and posture to become more stooped as Parkinson’s disease progresses further magnifies the problem.24 Patients with Parkinson’s disease have a long period of time between disease onset and swallowing difficulties, with a mean latency of 130 months.27 However, survival time between the onset of dysphagia and death was short, ranging from 15 to 24 months.27 The late onset of dysphagia may be attributed to what is perceived and reported by the patient. Patients with Parkinson’s disease may in fact have dysphagia; however, due to sensory deficits, they may not complain of difficulties until symptoms become severe. Patients with all stages of Parkinson’s disease, including those who are asymptomatic for dysphagia, have been shown to have swallowing deficits. Abnormal findings on EMG and esophageal scintigraphy were noted during swallowing in PD patients who were both symptomatic and asymptomatic of dysphagia.28 Clinical and videofluo-roscopic examinations of patients with Parkinson’s disease who were asymptomatic of dysphagia revealed abnormalities of swallowing29 Early-stage Parkinson’s patients with no symptoms of dysphagia had a high percentage of objective swallowing abnormalities demonstrated on videofluoroscopy,30 and there was no relationship between complaints of swallowing difficulties and swallowing function.31 Studies have also revealed that swallowing abnormalities do not correspond to the Hoehn and Yahr stages of Parkinson’s disease or other clinical symptoms, e.g., tremor.30,32–34 There are clinical symptoms and signs of swallowing that can alert the clinician to the possibility of a swallowing disorder. A questionnaire sent to Parkinson’s patients revealed that the risk of choking on food or drink is the most frequently noted problem, with 41% of the patients indicating that mastication and swallowing are more difficult than prior to their disease.35 On clinical examination, the following abnormalities were observed in a group of 65 Parkinson’s patients:36 1. Impaired mouth opening and palatal elevation (60%) 2. Poor lingual protrusion (70%) 3. Wet vocal quality after swallowing liquids (40%) 4. A cough after swallowing liquids (40%) The cough is a mechanism to protect the airway from aspirated material. The absence of a cough upon aspiration is termed “silent aspiration.” Silent aspiration occurs frequently in

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patients with Parkinson’s disease32 and more often than other neurologic disorders.37 Silent aspiration makes it difficult to observe symptoms of aspiration in Parkinson’s disease patients and demonstrates the necessity of an instrumental examination of swallowing. Various studies have demonstrated swallowing deficits during all four stages of swallowing in patients with Parkinson’s disease. Beginning with the oral preparatory and oral stage of swallowing, the task of taking liquid through a straw revealed reduced peak suction pressures and lower bolus volumes across all Hoehn and Yahr stages of patients with Parkinson’s disease as compared to controls.33 Other oral phase deficits included prolonged oral transit time, soft palate tremor, and abnormal lingual activity; specifically, premature loss of liquid, repetitive tongue pumping so that several tongue pumps are required to move the bolus posteriorly, tongue tremor, and piecemeal deglutition (several swallows of portion of the bolus rather than a single swallow or oral residue, which is cleared with several swallows), and increased occurrence of respiration during repetitive swallows.32–34,38,39 Deficits in lingual function have been attributed to rigidity and bradykinesia of the tongue.32,33 As stated earlier, bolus transport through the pharynx is mainly accomplished by the pressure applied by the tongue base directly onto the bolus in the oropharynx.10 Therefore, rigidity and bradykinesia resulting in lingual deficits in the oral phase would also affect the pharyngeal phase of swallowing. Clearing of the space between the tongue base and epiglottis (valleculae) is largely the result of tongue base movement.4 Residue in the valleculae on fluoroscopy would indicate problems with tongue base movement. Vallecular residue was noted to be one of the most significant findings in patients with Parkinson’s disease in multiple studies.30,34,38–40 Residue in the valleculae and pyriform sinuses would account for aspiration after the swallow. Residue in the pyriform sinuses was also a significant finding, as was aspiration after the swallow 30,32,34,40 A delayed pharyngeal response and slow/reduced laryngeal closure will cause aspiration before and during the swallow respectively.32 A delayed pharyngeal response with subsequent aspiration has been documented.30,32,34,38,40 Bradykinesia may be responsible for a significantly prolonged reaction time to initiate the swallowing reflex as compared to controls.41 Aspiration may also be silent due to decreased cough reflexes and lack of sensation, thus patients may not cough in response to material in the airway.32 Other pharyngeal stage deficits include epiglottic dysmotility, pharyngeal constrictor dysfunction, and reduced mean sagittal UES diameter as compared to controls; slow laryngeal excursion, slow and/or incomplete vocal fold closure, and prolonged pharyngeal transit times.34,39,40,42 There has been limited examination of the esophageal stage of swallowing in patients with Parkinson’s disease. However, there have been documented disorders during esophageal transit, including prolongation of transit time and retention in the lower part of the esophagus. These signs were more severe in PD patients with clinical symptoms of dysphasia than PD patients without clinical symptoms.28 Prolonged esophageal transit may be the result of esophageal dysmotility. Specific documented esophageal dysmotility has included stasis, tertiary contractions, reverse peristalsis, reduced peristalsis, aperistalsis, and esophageal tortuosity or patulency. In addition, confirmed GE reflux was present in a group of 40 of 50 patients, and the LES failed to close in 21 of 50 patients with PD.42

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The mean age of onset of Parkinson’s disease is 54.8 yr in females and 55.6 yr in males, and patients live for a relatively long period of time with the disease.43 Therefore, age-related changes might affect swallowing in addition to the disease process. In a group of 16 patients with Hoehn and Yahr Stage III–V, durational measures of oral and pharyngeal transit times were not significantly different from those of age-matched controls, although the PD patients had vallecular and pyriform sinus residue not seen in controls.38 In a study of 19 patients with PD, both with and without dysphagia, the group with dysphagia tended to be older and had a shorter duration of the disease than the nondysphagia group, although this did not reach statistical significance.34 However, one must consider that age-related changes may further exacerbate swallowing decompensation. TREATMENT OPTIONS FOR SWALLOWING IN PARKINSON’S DISEASE Treatment options for swallowing dysfunction in Parkinson’s disease have been limited. One possible option to improve swallowing may be the pharmocologic treatment of Parkinson’s. However, as the following studies illustrate, dopaminergic medications do not reliably improve dysphagia.31,44 In three studies, antiparkinsonian medication was withheld for a minimum of eight hours, and videofluoroscopy was performed.30,31,45 Bushman et al.31 found that, after patients took their usual dose of levodopa, there was improvement in swallowing function in 5 out of 15 patients, with the greatest changes in decreasing vallecular residue and improving transit times for thick boluses.31 Half of the 12 patients in study by Fuh et al.30 showed swallowing function improved within 90 min after administration of 200 mg levadopa in combination with 50 mg bensarazide.30 Specific oral and pharyngeal phase improvements included reduction in oral tremor, improved tongue elevation, and elimination of aspiration in two out of three patients. In each of these studies, there was one patient whose swallowing worsened after drug treatment 30,31 Both of these studies included patients who were symptomatic and asymptomatic for swallowing difficulties. Hunter et al.45 examined 15 patients who were symptomatic of dysphagia. Patients were first assessed after antiparkinsonian medication was withheld for at least eight hours, assessed again after a single oral dose of 250 mg levodopa and 25 mg carbidopa, and assessed a third time after a dose of apomorphine (mean dose 3.5 mg, range of 1.5 to 6 mg). The authors found few significant differences after levodopa or apomorphine. The only differences were reduced pharyngeal transit time with semisolids, less vallecular residue with solids after apomorphine, and fewer swallows to clear a solid bolus after levodopa. Surprisingly, there was an increase in oral transit time with solids after levodopa.45 Drooling remains a significant problem for the patient with Parkinson’s disease. One study compared two therapeutic strategies to control drooling: botulinum toxin to both parotid glands, which reduced the amount of saliva produced, and a behavioral intervention program. The behavioral program, conducted by a speech-language pathologist, consisted of patient education; completion of a drooling awareness chart for dry swallows, three times a day for seven days; and a swallow reminder brooch that signaled the wearer to swallow at regular intervals by emitting a beep. The subject was

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instructed to wear the brooch for 30 min per day.46 Both the botulinum toxin injections and the behavioral approaches were successful in reducing drooling as compared to baseline and aged-matched controls at one month. At three months, however, the degree of improvement was not fully maintained for the behavioral approach, while the botulinum toxin was still effective. The authors concluded that for the therapy program to be effective, reinforcement after the three-month period would need to be offered.46 Various swallowing parameters have been examined before and after surgical or behavioral treatment. One session of oral motor and swallowing exercises reduced the premotor time defined as the initiation time of the pharyngeal phase.41 Cricopharyngeal myotomy showed mixed results in improving cricopharyngeal dysfunction in four case studies of Parkinson’s disease patients with a Zenker’s diverticulum, cricopharyngeal bar, or discoordination between pharyngeal contraction and cricopharyngeal relaxation.44 A voluntary airway protection technique and variation of the supraglottic swallow technique4 (consisting of holding breath, tilting the chin to the chest, swallow, cough, and then swallow again) eliminated silent aspiration in two out of three patients.31 Treatment programs used to improve voice and speech in patients with Parkinson’s disease have also been shown to improve swallowing.47,48 Patients reported an improvement in swallowing, although not documented instrumentally, after one month of treatment including increasing loudness, pushing exercises, and overarticulation.47 The Lee Silverman Voice Treatment (LSVT) is a 1-month, 16-session program designed to improve the perceptual characteristics of voice through training high phonatory effort tasks that stimulate increased vocal fold adduction and respiratory support.48 Patients underwent this therapy program to test its effects on swallowing function. Videofluoroscopy before and after treatment revealed an overall 51% reduction in the number of swallowing motility disorders, including the following significant improvements: reduction in oral transit time, reduction in oral residue after 3- and 5-ml liquid swallows, elimination of a delayed pharyngeal response during swallows of liquid, a 66% reduction in paste and cookie, reduced pharyngeal transit time, reduction in laryngeal penetration before the swallow, reduction in pharyngeal residue, and improvement in tongue base propulsion.48 LSVT holds promise for significant improvements in swallowing function in patients with Parkinson’s disease. CONCLUSIONS Swallowing is a complex physiologic and neurologic process, which has been categorized into four stages: oral preparatory, oral, pharyngeal, and esophageal. Dysphagia is impaired swallowing in any of these four stages and is common in patients with Parkinson’s disease. Due to the physiologic complexity of swallowing, dysphagia cannot be observed or diagnosed on clinical examination. Therefore, an instrumental assessment is necessary to accurately diagnose the parameters that impair swallowing and is a mechanism for testing management techniques. Two instrumental techniques commonly used are videofluoros-copy and fiber optic endoscopic evaluation of swallowing (FEES). Complications of dysphagia, including aspiration, pneumonitis, weight loss, malnutrition, and dehydration, play a role in weight loss and recurrent airway infections in patients with Parkinson’s disease. Due to the swallowing disorders, patients with PD

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are less likely to swallow and therefore have a buildup of saliva, causing drooling. There is also a tendency for the mouth to drop open and posture to become more stooped as PD progresses, further magnifying the problem. Patients with PD are more likely to be asymptomatic of their swallowing difficulties until late in the disease process. However, asymptomatic patients have been shown to have swallowing deficits necessitating an instrumental evaluation of swallowing. Parkinson’s disease affects all four stages of swallowing. Oral preparatory and oralstage swallowing deficits have included smaller bolus volumes, prolonged oral transit times, soft palate tremor, poor lingual control, repetitive tongue pumping, tongue tremor, and increased occurrence of respiration. Pharyngeal stage deficits have included a delayed swallowing response, prolonged pharyngeal transit times, reduced tongue base movement, slow laryngeal excursion, slow or incomplete vocal fold closure, slow or reduced laryngeal closure, residue in the valleculae and pyriform sinuses, and aspiration. Patients with PD may not have sensation to aspirated material or may have reduced cough reflexes and therefore will not have visible symptoms of aspiration. Esophageal disorders may be the result of esophageal dysmotility in addition to gastroesophageal reflux. As Parkinson’s disease patients tend to be older and age during the course of the disease, age related changes might further exacerbate swallowing difficulties. Treatment options for the swallowing disorders in the PD population have been limited. Dompaminergic medications have not reliably improved dysphagia. Botulinum toxin and behavioral therapy have been effective in improving drooling. Behavioral therapy techniques have shown some improvement in swallowing, specifically oral motor and swallowing exercises and airway protection techniques. Treatment programs used to improve voice and speech have also been successful in improving swallowing function in patients with Parkinson’s disease and warrant further investigation. Unfortunately, Parkinson’s disease is a progressive degenerative disease. Swallowing function will usually mirror the progression of the disease despite all treatment attempts. However, treatment for swallowing may improve the quality of life and reduce dysphagia complications in the short term. The opinions expressed herein are not to be construed as official or as reflecting the policies of either the Departments of the Army or Defense. REFERENCES 1. Blonsky, E.R., Logemann, J.A., Boshes, B., Fisher, H. B., Comparison of speech and swallowing function in patients with tremor disorders and in normal geriatric patients: a cinefluorographic study, J. Gerontol, 30(3):299–303, May, 1975. 2. Perlman, A., Schulze-Delrieu, K., Deglutition and its disorders: anatomy, physiology, clinical diagnosis, and management, Singular Publishing Group, Inc., San Diego, CA, 1997. 3. Horner, J., Massey, E.W., Managing dysphagia. Special problems in patients with neurologic disease, Postgmd. Med., 89(5):203–206, 211–203, April 1991. 4. Logemann, J., Evaluation and treatment of swallowing disorders, 2nd ed., Pro-ed, Austin, TX, 1998. 5. Kennedy, J., Kent, R., Physiological substrates of normal deglutition, Dysphagia, 3:24–37, 1988. 6. Cook, I.J., Dodds, W.J., Dantas, R.O. et al., Timing of videofluoroscopic, manometric events, and bolus transit during the oral and pharyngeal phases of swallowing, Dysphagia, 4(1):8–15, 1989.

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7. Dodds, W.J., Taylor, A.J., Stewart, E.T., Kern, M.K., Logemann, J.A., Cook, I.J., Tipper and dipper types of oral swallow, Am. J. Roentgenol,. 153(6):1197–1199, December, 1989. 8. Miller, A., The Neuroscientific Principles of Swallowing and Dysphagia, Singular Publishing Group, Inc., San Diego, CA, 1999. 9. Dodds, W.J., Stewart, E.T., Logemann, J.A., Physiology and radiology of the normal oral and pharyngeal phases of swallowing, Am. J. Roentgenol., 154(5): 953–963, May 1990. 10. McConnel, F.M., Cerenko, D., Hersh, T., Weil, L.J., Evaluation of pharyngeal dysphagia with manofluorography, Dysphagia, 2(4):187–195, 1988. 11. Dodds, W.J., Man, K.M., Cook, I.J., Kahrilas, P.J., Stewart, E.T., Kern, M.K., Influence of bolus volume on swallow-induced hyoid movement in normal subjects, Am J. Roentgenol., 150(6):1307–1309, June 1988. 12. Kahrilas, P.J., Dodds, W.J., Dent, J., Logemann, J.A., Shaker, R., Upper esophageal sphincter function during deglutition, Gastroenterology, 95(1):52–62, July 1988. 13. Dantas, R.O., Kern, M.K., Massey, B.T. et al., Effect of swallowed bolus variables on oral and pharyngeal phases of swallowing, Am. J. Physiol., (258):G675–681, 1990. 14. Dantas, R., Dodds, W., Massey, B., Kern, M.K., The effect of high- vs. low-density barium preparations on the quantitative features of swallowing, Am. J. Roentgenol,. 153:1191–1195, 1989. 15. Sasaki, C.,Isaacson, G., Functional anatomy of the larynx, Otolaryngol Clin. North Am., 21:595–611, 1988. 16. Ardran, G., Kemp, F., The mechanism of the larynx II, the epiglottis and closure of the larynx, Br. J. Radiol., 40:372–389, 1967. 17. Hendrix, T.T., Coordination of peristalsis in the pharynx and esophagus, Dysphagia, 8:74–78, 1993. 18. Langmore, S., Schatz, K., Olson, N., Endoscopic and videofluoroscopic evaluations of swallowing and aspiration, Ann. Otol. Rhinol. Laryngol., 100:678–681, 1991. 19. Newman, L., Cannito, M., Dysphagia and dysarthria: evaluation and management, in Gluckman, J., Ed., Renewal of Certification Study Guide in Otolaryngology Head and Neck Surgery, Kendall/Hunt Publishing Company, Dubuque, IA, 286–295, 1998. 20. Jones, B., Kramer, S., Donner, M., Dynamic imaging of the pharynx, Gastroint. Radiol., 10:213–224, 1985. 21. Jing, B., The pharynx and larynx; roentgenographic technique, Sem. Roentgenol., 9:259–265, 1974. 22. Beck, T., Gayler, B., Image quality and radiation levels in videofluoroscopy for swallowing studies: a review, Dysphagia, 5:118–128, 1990. 23. Logemann, J.A., Manual for the Videofluorographic Study of Swallowing, Pro-Ed, Austin, TX, 1993. 24. Pfeiffer, R., Gastrointestinal dysfunction in Parkinson’s Disease, Clinical Neuroscience, 5(2):136–146, 2000. 25. Volonte, M., Porta, M., Comi, G., Clinical assessment of dysphagia in early phase of Parkinson’s disease, Neurol. Sci., 23:S121–S122, 2002. 26. Bagheri, H., Damase-Michel, C., Lapeyre-Mastre, M., et al., A study of salivary secretion in Parkinson’s disease, Clinical Neuropharmacol., 22(4):213–215, 1999. 27. Muller, J., G.K., W., Verny, M. et al, Progression of dysarthria and dysphagia in postmortemconfirmed Parkinsonian disorders, Arch Neurol., 58(Feb.):259–264, 2001. 28. Potulska, A., Friedman, A., Krolicki, L., Spychala, A., Swallowing disorders in Parkinson’s disease, Parkinsonism and Related Disorders, 9:349–353, 2003. 29. Bird, M, Woodward, M., Gibson, E., Phyland, D., Fonda, D., Asymptomatic swallowing disorders in elderly patients with Parkinson’s disease: a description of findings on clinical examination and videofluoroscopy in sixteen patients, Age and Ageing, 23:251–254, 1994. 30. Fuh, J.L., Lee, R.C., Wang, S.J. et al., Swallowing difficulty in Parkinson’s disease, Clin. Neurol. Neurosurg, 99(2): 106–112, May 1997.

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31. Bushmann, M., Dobmeyer, S.M., Leeker, L., Perlmutter, J.S., Swallowing abnormalities and their response to treatment in Parkinson’s disease, Neurology, 39(10): 1309–1314, October 1989. 32. Robbins, J.A., Logemann, J.A., Kirshner, H.S., Swallowing and speech production in Parkinson’s disease, Ann. Neurol., 19(3):283–287, March 1986. 33. Nilsson, H., Ekberg, O., Olsson, R., Hindfelt, B., Quantitative assessment of oral and pharyngeal function in Parkinson’s disease, Dysphagia, 11:144–150, 1996. 34. Ali, G.N., Wallace, K.L., Schwartz, R., DeCarle, D.J., Zagami, A.S., Cook, I.J., Mechanisms of oral-pharyngeal dysphagia in patients with Parkinson’s disease, Gastroenterology, 110(2):383– 392, February 1996. 35. Hartelius, L., Svensson, P., Speech and swallowing symptoms associated with Parkinson’s disease and multiple sclerosis: a survey, Folia Phoniatr. Logop., 46(1):9–17, 1994. 36. Volonte, M.A., Porta, M., Comi, G., Clinical assessment of dysphagia in early phases of Parkinson’s disease, Neurol. Sci,. 23 Suppl., 2:8121–122, September 2002. 37. Mari, F., Matei, M., Ceravolo, M.G., Pisani, A., Montesi, A., Provinciali, L., Predictive value of clinical indices in detecting aspiration in patients with neurological disorders, J.N.N.P., 63(4):456–460, 1997. 38. Nagaya, M., Kachi, T., Yamada, T., Igata, A., Videoflu-orographic study of swallowing in Parkinson’s disease, Dysphagia, 13(2):95–100, Spring 1998. 39. Bird, M.R., Woodward, M.C., Gibson, E.M., Phyland, D.J., Fonda, D., Asymptomatic swallowing disorders in elderly patients with Parkinson’s disease: a description of findings on clinical examination and videofluoros: copy in sixteen patients, Age Ageing, 23(3):251–254, May 1994. 40. Leopold, N.A., Kagel, M.C., Pharyngo-esophageal dysphagia in Parkinson’s disease, Dysphagia, 12(1):11–18; discussion 19–20, Winter 1997. 41. Nagaya, M., Kachi, T., Yamada, T., Effect of swallowing training on swallowing disorders in Parkinson’s disease, Scand. J. Rehabil Med., 32(1):11–15, March 2000. 42. Leopold, N.A., Kagel, M.C., Laryngeal deglutition movement in Parkinson’s disease, Neurology, 48(2): 373–376, February, 1997. 43. Hoehn, M.M., Yahr, M.D., Parkinsonism: onset, progression, and mortality, Neurology, 17:427–442, 1967. 44. Born, L.J., Harned, R.H., Rikkers, L.F., Pfeiffer, R. F., Quigley, E.M., Cricopharyngeal dysfunction in Parkinson’s disease: role in dysphagia and response to myotomy, Mov. Disord., 11(1):53–58, January 1996. 45. Hunter, P.C.,Crameri, J., Austin, S., Woodward, M.C., Hughes, A.J., Response of parkinsonian swallowing dysfunction to dopaminergic stimulation, J. Neurol. Neurosurg. Psychiatry, 63(5):579–583, November 1997. 46. Marks, L., Turner, K., O’Sullivan, J., Deighton, B., Lees, A., Drooling in Parkinson’s disease: a novel speech and language therapy intervention, Int. J. Lang. Commun. Disord., 36 Suppl., 282– 287, 2001. 47. De Angelis, E.C., Mourao, L.F., Ferraz, H.B., Behlau, M.S., Pontes, P.A.L., Andrade, L.A.F., Effect of voice rehabilitation on oral communication of Parkinson’s disease patients, Acta Neurol. Scand., 96:199–205, 1997. 48. Sharkawi, A.E., Ramig, L., Logemann, J.A. et al., Swallowing and voice effects of Lee Silverman Voice Treatment (LSVT): A pilot study, J. of Neurol Neurosurg. Psychiatry, 72(1):31–36, January 2002.

62 Restorative and Psychosocial Occupational Therapy in Parkinson’s Disease Surya Shah and Ann Nolen University of Tennessee Health Science Center, College of Allied Health Services 0-8493-1590-5/05/$0.00+$1.50 © 2005 by CRC Press

INTRODUCTION This chapter focuses on neurological restitution and pathophysiological issues that contribute to neurological recovery and the associated psychosocial abilities that occupational therapists address to maximize capabilities of persons with Parkinson’s. Management of these patients has changed in the last decade. Therefore, it is essential for occupational therapists to determine what and how the hallmark signs and symptoms and various therapeutic approaches discussed in earlier chapters affect function in Parkinson’s. These would lead to utilizing occupation related assessments and intervention strategies for the stipulated deficits. Occupational therapists can then function as a member of the multidisciplinary team, and plan and implement novel solutions. Such occupational therapy approaches would maximize restitution (by considering the uniqueness of each individual), hasten their rehabilitation, and improve their quality of life. HALLMARK ISSUES AFFECTING OCCUPATIONAL THERAPY To determine occupational therapy intervention strategies, the manifestations of this chronic progressive condition are grouped as either negative or positive. Negative symptoms are the direct result of damage to the structures implicated in Parkinson’s. The direct damage results in patients having difficulties in accessing motor plans and sequencing motor programs as a whole that organize the temporal progression of movements to eliminate robotlike sequencing effects, such as when movement control is acquired and learned by an infant from inherited mass patterns. Negative symptoms also include akinesia, bradykinesia, postural instability, gait disturbances, depression, and other psychosocial dysfunctions. Akinesia is difficulty in initiating movement and lack or loss of movement. Bradykinesia results from strial dopamine deficiency and results in slowness in executing movement from increased reaction time, delayed correction of an inaccurate attempt, prolonged time to recommence correct movement, and easy fatigue. These two negative manifestations are not due to a patient’s perceptual difficulties but

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result from the paucity of self-generated voluntary movements.1 Akinesia and bradykinesia are closely related but could be independent and present in absence of rigidity. Akinesia is also considered an extreme form of bradykinesia.2 Due to deficits in movement preparation, patients are unable to transform general goals into specific motor actions. The prevailing predominance of movement exe-cution difficulty is thought to result from the lack of control of muscle activation and regulation.2 Once the reverberating circuits or their interlinking elements of corticonigral, nigropallidal, pallidothalamic, and thalamocortical are damaged, learned responses must be brought back to conscious effort. This damage makes the performance of a well rehearsed, learned, and automated task slow and deliberate. The lack of excitatory γ innervation from supraspinal segments not only results in a lack of dexterous movements, it requires increased and forceful efforts to drive the uninterrupted innervation. Such forceful efforts exhaust the remaining intact structures. There is also reduced ability to switch rapidly between sets of movements.3 With akinesia, automatic execution of learned motor plans is altered, but with dyskinesia, the motor plan can be executed and completed by compensatory methods, indicating that the form of plan is preserved, but individual motor programs, which make up the motor plan, remain distorted.4–5 The slowness of movement can be influenced by an external stimulus, followed by an optimal use of therapeutic activities that further influence these deficits to move to the required level of spontaneity in performance. Also, the cortical control is parallel and not hierarchical, thereby allowing intact structures to execute some of the functions.6 In contrast, positive symptoms (e.g., lead-pipe or cogwheel rigidity) are the result of overactivity of intact structures that have been released or escaped from the control of the implicated structures. Parkinson’s rigidity is diffuse, pervasive, and not selective like spasticity. It affects both agonists and antagonists and is uniform throughout the passive range. In the limbs, this perceived resistance to passive motion is irrespective of joint position or direction of limb movement. The cogwheeling seen on passive range of movement is generally in the upper limbs and more pronounced in distal joints such the wrist. Lead pipe rigidity is felt when there is no tremor and predominates in the lower limb. The internal loop of the intrafusal muscle fibers with group II afferents contributes to rigidity by degenerating of inhibitory dopaminergic projections from the substantia to the putamen. This degeneration leads, in turn, to biased output from the globus pallidus to γ2 efferents. Rigidity is also considered to be a release phenomenon normally suppressed by the globus pallidus, because a lesion of the medial internal zone of the globus pallidus abolishes rigidity. Rigidity is also the result of α excitation, so normalizing muscle tone is an important goal of occupational therapy.7 Associated postural instability is attributed to structures connected with the basal ganglia but remote to subcortical areas such as the globus pallidus efferent to vestibular nuclei. Resting tremor of 4 to 5.5 Hz is rhythmic, sinusoidal, and oscillatory from rhythmical contractions of agonists and antagonists and at times occurs when the same posture is maintained for a period of time. Resting tremor can be a side effect of drugs and can be exaggerated when the patient is emotionally excited, when conscious of being watched, and following exercise and fatigue. However, the tremor disappears during sleep. As a dorsal rhizotomy does not block the tremor, it appears that there is depressed γ activity and augmented α activity, as well as direct thalamic or cortical activation, contribute to the tremor.8 The problem in reporting and quantifying clinical disorders resulting from

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damage to deeper structures is that conditions that affect those structures and cause movement disorders do not selectively damage one region but affect multiple areas. The neurological, pathological, and physiological implications of the symptoms and occupational therapy contributions affecting these are discussed in later sections. OCCUPATIONS AND ACTIVITIES Using purposeful, motivational, and preparatory activities in occupational therapy helps patients develop movements that lead to functional abilities that in turn enhance engagement in daily life tasks and occupations.9–10 For example, occupations are tasks such as housekeeping tasks for a housewife, playing golf for a professional golfer, skilled manipulations for a machinist, manual labor for an unskilled laborer, or those tasks that have a unique meaning and purpose that influence how persons with Parkinson’s spend time and how they make decisions.11 The activities, on the other hand, are participation in tasks that are goal directed but not central to one’s being. Occupational therapists believe that engaging in such therapeutic activities, or in occupations or elements that lead to occupations, helps maintain health status, prevents primary and secondary complications, encourages recovery from disease, and increases a person’s ability to adapt despite Parkinson’s.12–13 Such therapeutic activities help minimize the effects of impairment, activities limitations, and restrictions imposed by Parkinson’s. Activities and occupations also facilitate the essential adaptive process. Adaptive abilities allow patients to change functional requirements as environmental demands alter and help individuals survive and self-actualize. Occupational therapy is participatory and requires patients to take responsibility for their personal wellbeing and to participate with the therapist in decision making.14 According to the American Occupational Therapy Association, there are three basic tiers of patient activities and occupations.9,13 Top-level occupations allow patients to engage in age-appropriate activities that are unique to them and match their goals: a job for earning a living, dressing the lower body independently, purchasing their own groceries, doing their own laundry, managing money, or activities purely for pleasure, for example. At the next level are occupations that allow patients to engage in goal-directed activities during therapeutic interventions designed to maximize restitution, subsequently leading to the desired occupational functioning: washing vegetables for a meal, drawing nongeometrical designs that lead to arm and hand control, engaging in safe ways of getting in and out of car to go to work, or role playing to mimic real situations. These two levels of occupations and activities require ballistic (or open-loop) type and corrective (or closed-loop) type components of voluntary movements.15 The third level refers to the preparatory activities that are meaningful interventions or are components of performance skills that prepare patients to isolate and develop mastery in performing essential ingredients of purposeful occupations and activities. Performing such tasks by patients is marred by increased reaction times, greater firing rate, and an increase in movement amplitude. These components cannot be varied according to task demands and are limited in spontaneity until the patient is systematically retrained during restorative occupational therapy. In acquiring control, patients would first understand the overall requirements for accomplishing the task before acquiring the necessary speed, force, and duration of each

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of the movement components. Finally, with repetitive practice, patients are freed from concentrating on the entire movement, which becomes automatic and spontaneous. Acquired control is then integrated with higherlevel task requirements seen in levels 1 and 2 of the three tiers.9,16–17 Learning of movements in the third preparatory level could be a fundamental, instinctive, primitive, natural, and unlearned mass patterns movement execution in an inherited diagonal pattern. Movements then progress to break away from such patterns of motion so as to allow isolated and precise execution to be developed. Use of exteroceptive or proprioceptive inputs and the use and application of various modalities facilitate the maximum response in such learned tasks. Functional and diagonal proprioceptive neuromuscular facilitation patterns need to commence in a shortened range and progress to the stretched positions, with progression beyond basic diagonal patterns to help maintain the required stretch, and to help build combinations of movements that help improve the repertoire of complex movement abilities. Possible lack of effectiveness of such attempts in rebuilding abilities to perform occupational tasks at levels 1 and 2 have been reported by Protas et al.18 However, Protas was challenged by Murphy and Tickle-Degnen,19 who concluded, based on their research, that interventions have positive effects. The research showed that 31% of patients improved without restorative occupational therapy, while 63% improved with restorative occupational therapy. According to the model of occupational functioning,20 and based on the systematic review by Murphy and Tickle-Degnen,19 the capabilities and abilities level of control evident in preparatory tasks have certain outcomes such as motor control, cocoordination, dexterity, and balance. The activities and tasks levels include outcomes of performance on a patient’s ability to transfer, on performing activities of daily living, and on the ability to move. The roles level assists in classifying participants’ perceived level of social resources and support (ICIDH-2 =levels of body functions and structure, activity, and participation). Finch et al.21 and Christiansen and Townsend11 recommend that the associated costs and utility as determined by self-report and quality of life become integral parts of considerations in determining occupational and activities choices and levels. Murphy and Tickle-Deanne19 concluded positive occupation-centered treatment outcomes in 13 of 16 studies. In the same study, 10 of 16 studies showed positive effects on capabilities and abilities levels. Evidence also suggests that patients’ participation in activities has a positive influence. Furthermore, patients engaging in these activities or their components need to have elements of a given skill mastered so as to perform the whole task meaningfully.11 These sequential processes in occupational performance reinforce the globus pallidus facilitated functions of premovement programming, ability to initiate movement, the speed with which movement is executed, how body posture is maintained, and how movement elicitation occurs. These capabilities promote maximum adaptation.21–22 Hinojosha and Youngsstrom23 stated that a patient’s ability to participate in self-chosen occupations for increased independence, with or without assistance, and achieving the desired goals contribute to increased independence achieved in a participatory, empowering, and satisfying manner. Control of complex goal-directed motor activities (such as writing letters of an alphabet, cutting paper with scissors, hammering a nail, shooting a basketball, shoveling dirt, throwing darts, punching a bag, and other ballistic movement tasks) become an integral part of occupational reeducation. Control of such goal-directed tasks facilitates participation by

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people with Parkinson’s in actual occupations that are part of their own context and that match their performance expectations, and it further facilitates engagement in goaldirected activities.10 Participatory, occupational therapy interventions enable patients to return home following rehabilitative care and remain actively functioning with improved quality of life. Goaldirected activities, such as combing hair and brushing teeth, would be further influenced when the diseasecaused neural degeneration extends to the left frontal gyrus and intraparietal sulcus. These structures are responsible for control of goaldirected occupational tasks.24 It is now conclusive that, when Lewy body dementia is diagnosed with Parkinson’s, it would become necessary to look beyond occupational dysfunction and evaluate and plan to improve executive functions, such as memory, cognition, and psychological function to maximize restitution and improved quality of life.25 While the environments are not the focus of this chapter, occupa-tional therapists adapt and maximize the person-environment fit to promote wellness. Environments have a significant impact on performances; for example, the use of an aquarium with bright colored fish, gliding motion, and the sound of water trickling have been shown to be effective in pacifying patients, in improving nutritional status of elderly patients, and in cutting costs of rehabilitation.26 ASSESSMENTS Assessment of patients with Parkinson’s is complicated by many factors.27 Because of the introduction of new therapeutic strategies, the development of more advanced surgical procedures, findings of oxygen extraction studies, and deep brain stimulation studies, occupational therapists should summate not only neurological restitution measures (vital signs, skin, mental status, cranial nerves, motor, sensory, superficial and deep reflexes, tone, tremor, cerebellar signs, gait, posture, and others), but also selfcare ability and patients’ ability to interact within their own environment in tasks such as meal preparation, shopping, managing money, cleaning, and going to a place of worship.28 Lang 27 suggests that therapists undertaking to assess and quantify the findings should be aware of the following: progressive disease related consequences, medication-related fluctuations, psychosocial effects of the disease, the importance of having a “comments section” following self-care, and instrumental activities of daily living assessments to account for possible variations in items within the scales. With recent research reporting sudden and slow onset sleepiness in patients with Parkinson’s, it is vital for the therapists to determine the times of the day that are most suitable for introducing assessments, treating executive functions, and commencing motor reeducation.29–30 When simple and chosen reaction times for movement preparation are examined to determine what would be required for a patient to select a movement or combination of movements among the repertoire of possibilities, the evaluation and intervention strategies become evident. Movement performance times are particularly important when pre-post-test changes need definitive evaluation. Reaction-time paradigm preparatory processes are also required when the therapist is evaluating the extent of premovement abnormalities, such as whether the patients are slower in planning a movement, slower in choosing between response alternatives from the repertoire of rehearsed options, or slower in the use of advance information from previous rehearsals. Electromyographic

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analysis is equally relevant when determining whether the deficiencies are due to force, displacement, or volitional control and whether the ballistic movements are conceptualized as agonist and/or antagonist or as an agonist sequence of muscle action.31 Kinematic analysis is evaluated if learned movements have one cycle of acceleration and deceleration or if there is irregularity, asymmetry, variation in frequency of cycles, or lack of precise control over termination or commencement trajectories.32–34 A number of methods can be used. Chang et al.35 uses video monitoring software to quantify posture and movement changes without the usual markers used in virtual reality. This video monitoring is 90% accurate, and further trials to improve accuracy and clinical utility are underway. Lang27 developed a videotaping method and a videotape analysis system, while Graziano36 developed a video to identify and address mobility problems. SpyersAshby et al.37 utilize 3Space Fastrak® multidimensional movement analysis to differentiate limb tremor over six degrees of freedom. The system is capable of differentiating between postural tremor in unimpaired persons and persons with Parkinson’s. It has a potential to be useful not only as an objective clinical tool to record progress but also as a diagnostic tool. One of the measures used for measuring frailty and risk for falls is the Functional Reach Test. Multiple factors are involved in falls (e.g., progression, freezing, turning while attempting a task at hand, step length, cognitive and attention deficits,38 and environmental factors including lighting, wet floors, loose carpet, flexibility, and weakness). The Functional Reach Test is recommended for identifying patients at risk of falling. A reach of 17.78 cm, according to this test, is regarded as a good marker of frailty. Also, people 70 years and over with a reach of 25.4 cm are at risk of recurrent falls.38 Many preparatory and manipulatory tests are also in use (e.g., Purdue pegboard). When Purdue pegboard does not show finger dexterity improvement, physical and motor abilities improve, as does the disease staging ranking and thus quality of life following occupational therapy. The Disability and Distress Index39 has four domains of concern: self-care, social and personal relations, mobility, and usual activities. The responses obtained are combined and scores converted to a formula. The Euroqol System (EQ-5D)40 has multidimensional items: self-care, mobility, pain and discomfort, usual activities, and anxiety and depression. Responses obtained on various items are combined to produce a summary score. The Health and Utilities Index II (HUI)41 has items on sensation, emotion, cognition, self-care, mobility, pain, and fertility. Its scoring system converts responses to a numerical score. The Unified Parkinson’s Disease Rating scale (UPDRS)42 covers multidimensional items, and the scores are added to make a composite score. The scoring is negative, meaning the higher the score (199), the greater the disability. Items include cognition, activities of daily living, and motor function. Its use is widespread and is also recommended in occupational therapy studies,43 yet the reliability, validity, and consequences of adding items of multidimensionality have not been adequately addressed. Hohen and Yahr Scale42 provide severity categories ranging from unilateral symptoms, unilateral and axial, bilateral, bilateral with impairment of postural reflexes, severe disability but ambulatory, to wheelchair-bound and bedridden. The PD Questionnaire-39 (PDQ-39)44 is a diseasespecific quality of life instrument with eight domains: self-care, mobility, emotional well-being, stigma, cognition, communication, bodily discomfort, and social support.45 Beck Depression Inventory46 is also frequently

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used. As evidenced by Siderowf et al.,47 in a cost cutting climate, utilizing expensive neurosurgical and other interventions needs to be justified by outcome measures that are both reliable and valid, and it is vital that occupational therapists undertake costeffectiveness analysis using preference-based measures for quality of life. Other areas needing evaluation are energy conservation and work simplification; degree of contractures and prevention by positioning and alignment to counterbalance forces of gravity, imbalance, or faulty position; flexibility; control in antigravity muscles; degree of disuse and compensation; quality reciprocal movements; and the ability to utilize the trunk statically and dynamically in sitting and standing, rolling, turning, walking, and dynamic balancing.43,48 Other important and useful measures with biometric and psychometric qualities include the Barry Rehabilitation In-patient Screening of Cognition (BRISC), a brief neurological assessment battery with established psychometric properties.49 It is a valid screening tool of cognition for those 39 years and older and requires less than 30 min. It has eight subtests that point to specific deficits that might need attention: reading, design copy, verbal concepts, orientation, mental imagery, mental control, initiation, and memory. The BRISC provides a maximum composite score of 135. A total score between 110 and 120 needs to be interpreted cautiously in older adults. The computer-based Brain Train® software for carefully planned cognitive testing and training, developed by Sandford,50 has many modules, e.g., attention skills, visual motor skills, conceptual skills, and higher faculty modules. Along with self-care abilities, abilities to interact within the environment are vital to ensure maximum independent functioning in the community. The Moss Kitchen Assessment Revised51 is a method of gauging community functioning of patients with Parkinson’s. A succinct review of available meal preparation assessments for persons with neurological impairment and the importance of meal preparation ability as an instrumental activities of daily living, and as a basic task was published by Harridge and Shah.28 The Moss Kitchen Assessment,52 as revised by Harridge and Shah,51 grades meal preparation performance on six hierarchical task levels in order of difficulty from serving and eating a cold meal to preparing a complex hot meal and cleaning. The performance on each task level can be evaluated on a five-point Likert-type scale from “unable” to “independent with or without assistive devices.” The performance is then given ratings of relative contribution to each criterion and the ratings summed to obtain a score out of the 100 maximum points. These and the activities of daily living (ADL) scores help determine effectiveness of intervention, length of patient care, cost of rehabilitation, burden of care, housing requirements, likely outcomes, and other audit-based outcome comparisons. The Barthel Index is considered to be comprehensive and the most researched ADL scale. It measures the individual’s performance on ten ADL tasks. It is an empirically derived scale that measures performances in personal hygiene, bathing self, feeding, toilet, bowel control, bladder control, dressing, ambulation, stair climbing, and transfers. However, its sensitivity remained a concern. The Modified Barthel Index (MBI), by Shah et al.,53 provides the required sensitivity in scoring those individuals who require assistance of some nature to perform the tasks. The increased sensitivity was achieved by expanding the number of categories used to record improvement in each ADL item. The modifications ensured that the minimum and maximum values assigned to each of the ten

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weighted tasks remained the same and that none of the underlying assumptions was violated or mutilated. Suggested changes and plausible explanations developed in 1989 were further modified, based on feedback from users, to include not only the amount of physical assistance required to perform the task but to accommodate cognitive aspects such as wandering, prompting, cuing, and standby supervision.54 The MBI is valid and has with proven interobserver and testretest reliability, internal consistency, portability, and appropriate psychometric and biometric qualities.55 Corbett56 used a number of measures to identify prepost-test changes and found that the Functional Independence Measure did not identify any significant changes; therefore, it is not considered to be sensitive to detecting changes in functional ability. A test consisting of basic nongraphic designs would help screen and evaluate perceptual deficits that might affect on Parkinson’s patients’ performance and daily function. Shah et al.57 selected six reliable and valid domain items from the Burke Perceptual profile58 and reported the normative data. The timed tests consist of six subtest sets and include picture sequences, body puzzle, 3-D space visualization, block design, figure-ground, and fine motor planning. The tests are unidimensional and provide specific domain strengths and weaknesses without possible nullifying from multidimensionality. Precise noting of functional difficulties during ADL evaluation is crucial, as patients report clumsiness, awkwardness, minimal unobservable lack of associated movements, and unsteadiness from tremor. Careful observation of people reporting difficulties is of paramount importance for an early diagnosis of Parkinson’s disease. Teive and Sa59 reported a patient who was always late for appointments when his self-winding wristwatch was worn on the left wrist but was never late when he wore his watch on the right wrist or when he used a batteryoperated watch. Such first signs of a lack of natural arm movement during walking, a slight foot drag leading to tripping, a slight intentional tremor when drinking water at a dining table, or difficulty during shaving become crucial in early diagnosis.60 POSTULATED FUNCTIONS, DEFICITS EXPERIENCED, AND RESOLUTIONS Findings by Jones et al.61 suggest that Parkinson’s patients have difficulty in inhibiting a current movement and in preparing a new movement in the opposite hemisphere. These deficits are due to a lack of preprogramming of the new sequence. Stelmach and Phillips62 identify arrest of motor activity, contralateral turning, circling around the base of support, limb flexion, chewing, licking, and swallowing as modifications of cortically induced movements. Firing of medial and lateral zones of globus pallidus neurons results in the onset of predictive, self-directed, and sequential movements. Released responses from the neostriatum, particularly anterior caudate, result from cues from the prefrontal cortex that prepare for tasks requiring initiation of movement or behavioral responses to environmental cues. Other parts of the caudate are involved in pattern-specific habituation from repeated visual stimuli, inattention, and in orientation to a changed visual stimulus pattern. These responses from the two parts of the caudate are the result of influences from prefrontal and inferior temporal cortical projections; For patients with globus pallidus disorders, once such purposeful activities are initiated, motor tasks

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requiring bilateral alternating movements such as pronation and supination, grasp and release, and reach and return followed by the ability to transfer occupations from one to the next hemisphere, should commence.63 The slowness of movements also affects participation in structured occupational tasks that require patients to initiate standing and walking, and it manifests difficulties in generating sequence of submovements, preparing for movement, and executing movement. Furthermore, damage to the pedunculopontine nucleus may be responsible for the deficits in initiating programmed movements.64 The paucity of movements, which is not due to paralysis, becomes more pronounced when more than one act is requested, such as getting up from a chair and extending a hand to greet someone, talking on the phone and writing a message, preparing a meal and responding to a dialogue, or turning around a base of support to pick up an ingredient while stirring a hot meal. Paucity in such activities is attributed to difficulty in recruiting the peripheral nervous system following altered γ2 innervation. Planned occupations excite intact reverberating circuits that activate γ1 and γ2 motor neurons, minimize inhibitory influences of the damaged neurons, and allow the intact cells to be efficiently utilized. In Parkinson’s, the occupations and activities that are at the apex encourage goal direction, purpose, and a unique meaning to their being, and they activate a visual open-loop where amplitude, force, direction of movement, and accurate and precise termination of hand movements are determined. As these tasks are mastered, automatic corrections are performed using a closed-loop control where patients focus and visually ascertain each element of movement. As the akinesia improves in occupationally embedded tasks, movements become automatic and ballistic with decreased reaction time and increased spontaneity.3,15 The influence of exteroceptive stimuli, such as fast brushing and icing for preparing for a motor response via the reticular activating system, allows the diffuse and nonspecific central nervous system (CNS) to percolate and, via association areas, prepare the CNS to respond. A prepared, alert, and ready-to-receive CNS is further activated by a proprioceptive input such as a friction, rubbing, pressure, or a light static stretch while attempting to perform selected occupations while facilitating intrafusal muscle fibers to be activated to fire through 1a afferents.62,65 These efforts maintain and increase range, maintain and increase strength, increase speed of muscle contraction, and prevent contractures, phlebitis, and other inactivity-related complications from developing. In volition, movements and their components are superimposed, making volition a smooth and fluid skilled movement. However, the lack of ability to sequence movements and provide spontaneity by determining where the next muscle contraction should begin and where precisely to end the previous muscle contraction manifests robotic-type sequences, with one movement requiring completion before the emergence of the next. Hocherman and Aharon-Peretz66 first identified difficulty in performing manual tracking tasks and the need for practice in the preparatory phase of task mastery. Carey et al.67 further substantiated these findings and indicated that, in preparing patients to engage in productive occupations, occupational therapists need to provide practice in tracking tasks using compatible and incompatible hand and arm positions. There is also evidence to suggest that active participation in planned activities is paramount.18 In holding objects still, no such deficits are evident, indicating intactness of static and tonic activity. Tonic

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and static contractions do not have such difficulties except for minimal slowness, the time taken to commence, and the delay in producing maximum force required for that task. Fine finger facility, manipulative ability, individual, isolated, and combined finger movements; accuracy; and preciseness are improved with individualized, goaldirected activities such as spool knitting, link belts, cane work, bench and assembly work, toothpick-type projects, use of personal diaries, keyboard applications, computer keyboards and touch screen, and immersive virtual reality uses. Manual dexterity is further enhanced with purposeful activities such as using pegs in solitaire, placing washers, folding and putting a letter in an envelope, using scissors, hammering nails, dribbling and shooting a basketball, passing a football, shoveling dirt, and throwing darts. Patients need to participate in activities that require movement sequence as a whole, as it helps superimpose elements of movement components, maintain the computed force, initiate and increase variability of movements, and utilize visual guidance for ballistic movements. When difficulties are encountered, observing and copying another person, receiving verbal or tactile cues, imagining and/or visualizing an object may instill initiation required to perform the functional tasks.68 Writing letters of the alphabet and tasks that require a quick and spontaneous response, progressively decreasing in reaction time, and increasing difficulty in providing alternating force within a movement sequence are improved by practicing nongeometrical designs. Such activities allow progression from unstructured control of the upper limb to precise manipulative writing skill. Introducing group or individual relaxation and activities using music, hand clapping to music, rhythm and movement, gentle rocking, and the rotation of trunk and extremities can improve the entire body range of motion. Hand clapping helps decrease cortical inhibition and abnormal EMG activity, and music facilitates movements. If the speed of movement is increased along with precision, dexterity, and coordinated tasks, overall performance is enhanced. Keeping patients as physically active as possible, practicing in learning to stop movements at a precise moment, and using ball games or musical chairs helps to maintain health status and agility. Games and leisure activities requiring spontaneity of movement (e.g., paying bills, balancing budget, writing checks, figuring taxes, using the internet and web sites) further advance patients’ ability to master cognitive and daily skills. Heightening abilities thus facilitates coping with the progressive nature of the disease and improves the quality of life. Experiments to produce peak forces reveal that Parkinson’s does not impair intension, but it does impair the rate at which force develops and is produced, initiation, timing, and spacing; hence, there is a need to intentionally alter these. Patients perform a sequence of movements at a fast or a slow pace to improve the force of muscle contraction, to maximize recruitment of motor units, and to control amplitude. Selecting manipulatory tasks that require repetitive performance with occluded vision makes provides good rehearsal for task performance. In micrographia, the ability to maintain the required amplitude rather than duration for which the force has to be maintained, the time between the generated pressure for a given word and the next, as well as the ability to maintain speed are vital. It might become necessary to increase pauses between movements for increased accuracy. Practicing nongeometrical shapes prior to controlled writing minimizes these difficulties. Based on inverted writing in nonmirror transformations, such tasks excite supplementary motor areas.69

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Motor control of released movements by caudate enhances excitatory neurotransmitter glutamate and nigrostriatal inhibitory dopaminergic effects. Examining anatomical processing of stimuli relevant to motor actions and single neuron responses,70 and the above motor release control, imply that striatum contributes to the resulting modulation on the anterior horn with corticospinal and other systems, and the firing of efferents from basal ganglia go to the supplementary motor area to primary cortex and back to the final pathway to pre-prepare for the task demands. The automaticity required in motor tasks is provided by the supplementary motor area’s ability to prepare for the next movement that has been rehearsed.71 Functions and deficits are somatotopically organized with leg and arm control in globus pallidus and neck and head control in substantia nigra.72 Activation of the basal ganglia cells precedes limb movements, indicating their involvement in preparing for movement that requires alterations to axial postural muscles prior to activating limb movements. Putamen, its cortical projections, and supplementary motor areas are functional system components. Putamen is involved in behavior of all movements that are associated with rewards. However, if there is no goal to be attained, or if a response is required without a motivation, then putamen activation is not evoked. Substantia nigra cells show no phasic activity to peripheral stimulation; however, the subthalamic nuclei show phasic activity somototopically. Globus pallidus firing is variable with some firing preceding phasic activity, some after movement has commenced73 and the rest firing in relation to each discrete movement. This is termed a set dependent response. Globus pallidus and substantia nigra could be activated to stretch and other deep proprioceptors. However, cutaneous receptor stimulation does not evoke a response. Thus, cortex, basal ganglia, cerebellum, and thalamus have highly specific afferent, efferent, internuncial, and commissural connections. This linking of data makes it possible to divide cortico-striato-pallido-thalamo-cortical loop into motor functions feedback circuit and the other loop for occulomotor and orbitofrontal functions.74 A behavior generated and released by the cortex is focused by the basal ganglia on the desired motor actions. Once activities are released from striatum, the pallidum executes with spontaneity and swiftness. The pallidum executes learned motor plans and allows well rehearsed tasks to be implemented with ease. When damaged in Parkinson’s, the individual reverts to a slower, deliberate, conscious, less accurate, and less automatic movement. In considering basal ganglia function and disorders, occupational therapists must consider motor manifestations and behavioral changes to hasten the process of remediation. Movements and occupational therapy interventions are most effective during the “on” periods. While restorative occupational therapy is considered beneficial in Parkinson’s, some75 have suggested that motor learning itself could also be affected. However, it has been shown that manual pursuits and sequence learning can be learned. Platz et al.75 investigated the question of such practices, leading to increased movement speed and its contribution in visually guided aiming movement. Platz et al.75 and Sheridan et al.76 found that training either to move fast or move accurately, but not both, quickly and accurately helped Parkinson’s patients with difficulty in moving. The ability to use spatial, temporal, and forcemonitored movements was learned or transferred via cerebellar and cortical areas and further facilitated by auditory cues during rehearsal.

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Deficits in force requirements in acceleration and deceleration between agonist and antagonist forces and sensory-motor integration are facilitated by initial adjustment, early preplanning, and by fine tuning final corrective movement requirements. Rascol et al.77 showed that Parkinson’s patients could learn to decrease their movement time when visually guided occupations are used. The untrained opposite limb also shows significant improvement in anticipation of movement initiation. Auditory cues did not specifically help in this experiment, but humans are capable of activating α motor neurons and the final common pathways that are directly innervating the extrafusal skeletal muscles in gross movement and in strong muscle contractions. However, when fine, precise, and delicate, manipulatory movements are required,7 the γ motor system has to be activated. The γ system has a central bag of nuclei with contractile elements at the two terminals. These centrally located nuclei are sensitized by a proprioceptive input such as a stretch put to the polar ends by active contraction or by a passive stretch. The Ia then fires and directly communicates with large α motor neurons. Thus, those muscles that are precise manipulators have a rich supply of intrafusal muscle fibers while muscles like lattisimus dorsi have a sparse supply. Suprasegmental control and corticomotor connections influence the final common pathway in two ways. Direct influence is via α but, in most instances, via γ for precise augmentation, as γ innervation precedes α. In Parkinson’s, the altered α and γ balance is altered: γ is depressed, and α is enhanced leading to freezing from tonic exaggeration. Reduced dopamine has the same effect on movement execution. While physical rehabilitation is vital in improving daily functioning,78 individual and group interventions focus on neurological deficits (impairments) to maximize restitution such as reaching, grasping, relaxing, and breathing. Tasks requiring simple to complex block designs, visual figure ground perceptions in extracting complex embedded tasks, and facial recognition are some of the first skills lost when premotor area is involved.79 Lazaruk80 reported difficulties in global visuospatial ability and changes in language, abstraction abilities, processing skills from complex stimuli, and visual memory from diminished ability in using the storage subsystem. These deficits emerge more frequently in later stages of Parkinson’s. It is therefore vital to incorporate screening for such deficits, but not timed tests, because fatigue and medication can influence the outcome. Their effect on functional performance needs to be studied to measure functioning at home and work. A Canadian occupational and physical therapist designed an excellent self-referral plan for patients and their spouses to bring about health behavior changes by problem-solving the needed aspects of education and exercise. The program emphasizes selfmanagement to affect quality of life by prioritizing activities so patients can adjust their life style in a manner that controls fatigue and encourages ease and endurance of daily tasks.81–82 Instrumental activities facilitate developing interaction between volition, α and γ coactivation, cognition, and sensory-perceptual patterns. The goal-oriented retraining helps neurons to recruit and fire at a high level; develop synchronic patterns: and reinforce basic, fundamental, natural, instinctive central pattern generators. Functional tasks focus on daily living skills and mobility, hobbies and leisure, social interaction, and other activities to increase selfesteem and motivation to decrease dependence.34 Deane et al.83 compared seven published trials and concluded that, because of methodology limitations and extreme variations in treatments, the data did not support or

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refute the effectiveness of therapeutic interventions. In another systematic review of 23 studies, researchers found that heterogeneous intervention methods and methodological flaws required further trials.84 Manson and Caird85 investigated sedentary and passive activities such as watching TV, listening to the radio, reading a newspaper or book, and knitting, and found that these activities were well preserved in most patients. Eighty-three percent did indoor gardening; 31% were active in the house or gardening and performed such manual dexterity activities such as sewing or knitting; and 29% required transport to leave the house, move and in and around the house, perform gardening indoors or outdoors, and engage in do-it-yourself activities. Thirty-three percent were active outside the house (e.g., going to the theater, cinema, restaurant, place of worship, and clubs). A considerable number did not have hobbies and interests apart from those of a sedentary and domestic kind, and they need further investigation. APPLYING FUNCTIONAL ABILITIES TO AMBULATORY SKILLS Festination (shuffling, hurried small steps, turning), freezing, lack of arm swing, decreased velocity, and stride length and width are some of the difficulties encountered by patients with Parkinson’s.34 When functional abilities are applied to ambulatory skills and novel postural adjustment situations, the difficulties are said to be due to rigidity, reduced preparatory postural adjustment, reweighing of sensory motor loops, and fluent adaptation to altered postural deviations.86 Daily walks, dance routines such as ballroom and tap dance, confidence in shifting weight, just walking in a mall that has even terrain, and the ability to shop or go to a place of worship facilitate increased awareness of lower limbs. Swimming is considered good for toning and endurance and for transferring volitional effort to more automated tasks such as walking in open areas and using a stepping mechanism, which use the unaffected swing and stance times and enhance the ability to tilt forward and backward. Rocking from side to side, walking from side to side to free freeze, and inverting a cane and stepping over it prevent the arrest of walking. Line and tap dancing allow for fast and slow weight shift, whereas ballroom dancing facilitates increased awareness of lower extremities. For Parkinson’s patients, thinking of the steps of a complex task, such as walking, makes it a fall-free event as the task is brought under volition. Side walking, ascending and descending three steps, overstepping, and using heels rather than toes helps overcome freezing and falling. The judicious use of throw rugs and minimizing clutter eases walking and prevents falls. These types of ambulation facilitate confidence and prevent falls that result from a fear of falling and a lack of swiftness. A high incidence of hip fracture from falls in elderly women patients with Parkinson’s have been reported by Johnell et al.87 Learned, well rehearsed, and automated tasks facilitate increased awareness and minimize deliberation that lead to fragmenting performance. Leather shoes are considered superior to rubber or corrugated soles. The resulting socialization and participation can help minimize predisposition to fatigue. Maintaining posture and learning to squat and kneel helps prevent tightness when the distribution of rigidity affects one group of muscles more than others. A wider base of support, learning to lean right or left, lifting rather than dragging the feet, and sliding

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heels to 90° and beyond when standing up counter freezing and facilitate the initiation of movement. Walking, stair climbing, and other daily tasks can be rehearsed with or without external cues. Facilitatory stimuli, such as rhythm, result in improved speed of walking and stride length, and they increase muscle activity as evidenced by increased EMG activity. In EMG patterns, the number of bursts in a given time frame is thought to be due to peripheral control and is increased by therapy for Parkinson’s patients who display slowness and irregularity to produce the required speed and range. While the EMG amplitude of burst is said to be due to central control, the observed jerkiness and periodic tremor are not.6,31 To improve accuracy, we employ neurorehabilitation approaches such as proprioceptive neuromuscular facilitation using visual cues and focusing on quality of movement rather than the end product. Auditory cues, such as counting, clapping, or verbalizing the steps in walking, have been reported to improve motor performance.85 Brain activity using imagery in simple walking, repetitive movements, or programmed complex acts, or mentally rehearsing a complex movement sequences when integrated, have been effective therapies.88 These authors showed increases in regional cerebral metabolism and regional cerebral blood flow provoked by visual imagery, in particular, with the strongest blood flow seen in the cortical areas involved in movement execution. Miyai et al.89 demonstrated that body-weight-supported treadmill training, using external cues such as attentional strategies, has a lasting effect in improving and maintaining stride length. Body weight support used during occupationally embedded tasks also ensures maintenance and an increase in stride length.17,89 To make walking more meaningful, occupational therapists need to incorporate occupation-centered tasks that require change in direction, change in speed, shift in weight for reach and return, angle of foot placement, and modifiable body position to accommodate carpeted and linoleum type surfaces and terrains.90 Well planned activities and games that involve patients walking in a corridor; entering and exiting doorways; walking on colored paper squares adhered to the floor; and turning, entering a confined space, and exiting help minimize freezing and improve initiation, velocity, acceleration, and the ability to constantly shift the center of gravity.91 Practice facilitates the ability to anticipate component placing of leg and foot at a required angle while focusing on such occupational tasks as cooking, cleaning, sitting up, and rotating the body from a supportive phase to a new direction and position. Morris et al.17 showed that the ability to generate a normal walking pattern is not lost in Parkinson’s patients. The observed difficulties stem from an inability to activate the motor control system, which can be summoned to perform by appropriate cueing. Kinetic analyses during routine tasks help better understand the functional components that need to be emphasized.92–93 The required subconscious adaptation in all routine and automated tasks increases flexibility; modifies weight bearing; helps shift weight; improves arm swing and overall participation that requires walking as a component; and counters flexed posture with protracted shoulder joint complex, flexed elbows, flexed head and neck, dorsal, lumbar, and sacral spine, and flexed hip and knee.94 The tendency to fall backward emanates from not lifting the feet, prolonged standing, and standing with the feet together. Freezing and falling are further addressed by stepping over an object, rocking medially and laterally to avoid sticking to the floor, and maintaining bilateral arm swing. Many activities contribute to improved functional walking and overall confidence, such as reaching

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overhead with one hand while the other helps to stabilize the person; installing a vertical grab bar on doors opening inward; forming a habit to carrying objects in one hand and close to the body; lifting a knee to move rather than backing away from stove, sink, dresser or turning to one side; feeling the back of a chair before reaching back for the armrest; moving slowly to change position; and breaking down the actions in steps by deliberately pausing for a few seconds. There has been a growing trend to provide walkers to patients with Parkinson’s to minimize freezing and to improve speed, balance, and visual guidance to facilitate walking. However, this practice has been refuted and criticized by Susman95 and others. The authors state that the use of walkers and walkers equipped with wheels and other devices used to minimize freezing and to improve speed of walking are ineffective and actually impede ambulatory ability. SURGERY, BRAIN STIMULATION, IMPLANTS, DRUGS, AND DIET To participate in randomized, single-case, pre-post-test and other trials that estimate functional gains; that improve movement participation and quality of life in the short and long run for patients, family, and caregivers; and that determine which patients undergo which therapeutic procedures, occupational therapists need to understand current surgical procedures, current and planned therapeutic interventions, participatory inhibitory deep brain stimulation, and the implications of such procedures.96–98 Hubble and Berchou104 suggested that patients treated with excessive levadopa, carbidopa, pargolide, bromocriptine, or dopamine agonist develop involuntary movements similar to chorea and athetosis and secondary changes of psychosis, vomiting, abdominal discomfort, loss of appetite, confusion, hallucination, low blood pressure, psychosis, motor fluctuations, and a marked inability to use volitional movements. Difficulty in judging force, amplitude, and duration is also evident. The dopamine D2 receptor blockers, the butyrophenones, and the phenothiazines make rigidity, bradykinesia, and tremor worse. Dopamine deficiency blocks movements in one direction and increases the magnitude of choice reaction time. Levadopa with decarboxylase inhibitor helps with nausea, vomiting, abdominal discomfort, and entacapone reduces motor fluctuations.105–106 Parkinson’s patients benefit from anticholinergic drugs, while cholinergic agonists aggravate symptoms because of a decrease in dopamine and an increase in acetylcholine. The normal balance between the neurotransmitters acetylcholine (excitatory) and dopamine (inhibitory) is essential for normal muscle tone. Trickling of γ amino butyric acid from basal ganglia provides the stability of motor control. Neurosurgical procedures to neutralize rigidity, akinesia, tremor, and drug-induced dyskinesia have included pyramidotomy and stereotactic surgery in the 1970s, stereotactic lesions of medial pallidum and ansa lenticularis renewed interest in pallidotomy in the 1980s, and for levadopa-induced movement dyskinesia and motor control fluctuations, transplanting of fetal dopamine cells, and other graft transplants. The consequences of these and other surgeries demand that occupational therapists move

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beyond traditional assessments and restorative care avenues to accommodate unforeseen changes.99–101 Kishore et al.72 concluded that it is possible to affect “on phase” dyskinesias following pallidotomy, depending on the amount of necrosed volume excised. Thermal lesions, chemopallidotomy, and targeting the ventrointermediate nucleus of thalamus alleviate levadopa induced “on phase” dyskinesia. Surgery does not reverse the degenerative process and, hence, activating implicated cortical areas by implant counters the progression and helps modulate the output. Implantation of embryonic substantia nigra neurons from fetal dopamine and adrenal cells to alleviate rigidity has had some success. Kishore et al.72 also concluded that there is a direct correlation between the amount of coagulated globus pallidus with the amount of improvement observed in levadopainduced dyskinesia or “on signs.” Montgomery and Rezai,102 in discussing deep brain stimulation, caution therapists using diathermy, therapeutic ultrasound, shortwave, and other thermal modalities in patients with implanted neurostimulation systems, as these could cause severe injuries or death. It is also important to recognize the lack of certainty of affecting features of Parkinson’s following surgical lesions of the medial globus pallidus. Saint-Cyr and coworkers100–101 found that the negative effects of such interventions could include memory impairment and diminished mental processing, encoding visuospatial information such as nongraphic designs, and motor speed and coordination. Another therapeutic side effect is decreased cognitive functioning following administration of coenzyme Q10 for improved mitochondrial function.103 Documenting adverse effects from therapeutic effects of drugs, surgery, and brain stimulation that complicate rehabilitation is also warranted. The importance of engaging persons in occupations to build strength and endurance following surgery and therapeutic interventions cannot be emphasized enough. Participation by patients at all levels in occupational therapy, activities of daily living, instrumental activities of daily living, and leisure and work activities is essential for a fuller and improved quality of life.44 Research showing that pedunculopontine nucleus is significant as the newly found site for akinesia,100–101,107 and the influences of glutamatergic pedunculopontine neurons on initiating programmed movements and the cholinergic pedunculopontine neurons on maintaining steady state,64 are significant for occupational therapists to counter adverse influences. A community-based study of 124 patients with Parkinson’s demonstrated that dyskinesias are related to duration of levadopa treatment, and resulting motor fluctuations are strongly correlated to the length of Parkinson’s from onset and quantity of levadopa administered.106 Occupational therapists should also be aware of dietary implications for their patients, because diet can influence manifestations and their intensity. Contaminants in dairy products can adversely affect male patients’ sexual performance.67,108–109 Despite advances in therapeutic management, considerable disability and engaging in productive activities remain a challenge.110 McNaught et al.111 noted the importance of abnormal protein levels and resulting cytotoxicity, which can adversely influence the ability of the central cell bodies to respond to occupational therapy restitution attempts. Extra precautions in working with elderly women with Parkinson’s are necessary because of both increased incidence of hip fracture from limited mobility and osteoporosis and reduced bone mineral deficiencies.112 Botulinum toxin has been used successfully to

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therapeutically paralyze the rigid muscle in a graduated and reversible manner to facilitate self-care and other functions.113–114 New drugs on the horizon include dopaminergic compounds and formulations for replenishing of depleted dopamine, nondopaminergic drugs from different neurochemical mechanisms, and neuroprotective and neurorestorative drugs that are said to reverse disease progression. Catechol-Omethyltransferase inhibitors and other new therapeutic agents such as oxidase inhibitors provide muchneeded flexibility in minimizing secondary motor consequences with levadopa therapy.115 The U.S. Food and Drug Administration has recently approved Stalevo116 for Parkinson’s. These new drug therapies should allow occupationally embedded tasks and therapeutic strategies to improve patient function and quality of life.117 FUNCTIONAL ISSUES IN DAILY LIVING Ample information is available at the local, state, national, and international levels, from Parkinson’s disease-related organizations and web sites, about functional issues such as activities of daily living, home adaptations, and prescription of devices and aids. Therefore, only a few such issues will be addressed here. Driving is considered an important activity and, when compromised, it severely affects the Parkinson’s patients. It has received a priority rating by the American Occupational Therapy Association.118 Sleep attacks caused by dopamine drugs have been thought to contribute to car crashes. As a result, some provinces in Canada have restricted driving privileges.119 The crashes occurred with nearly 23% of patients who experienced either slow or sudden onset of drowsiness or abrupt episodes of sleep during activities of daily living.119 This problem was further complicated by a lack of awareness by passengers of the driver’s reduced vigilance. However, McConnell120 emphasizes that Parkinson’s patients do not cause more road accidents than a matched control subjects and that limiting driving can be an improper decision, as it severely limits quality of life of persons with Parkinson’s. Ondo et al.119 analyzed 303 questionnaires to determine the factors contributing to daytime sleepiness and concluded that sleepiness correlated with a more advanced state of Parkinson’s and the use of dopamine agonists. Male patients were more prone to such episodes. Clinical trials using Modafinil show that, on a subjective and a behavioral level, there is a significant improvement in daytime sleepiness. These findings also have implications for occupational therapy intervention.121 Whatever the level of participation, it is important that the focus of occupational therapy remain on engagement in activities and occupation. de Goede et al.3 analyzed 19 studies and concluded that activities of daily living, ambulation, stride length, mobility, and transfers could be much improved by occupational therapy. Improving safety in kitchens and bathrooms, taking large steps, dropping a handkerchief to take a step, inverting a cane and stepping over it, and not succumbing to freezing are important daily skills. To reiterate, with limited functioning in bilateral cases, ambulatory devices requiring the use of upper limbs can help or hinder, depending on festination quality.122 For spontaneity and easy rising from sitting, the use of lift chairs, satin sheets for rolling, and reclining bed with adjustable foot and head ends for transferring is essential. Palmar pockets help maintain the stability of foods when arm supination and pronation are used

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to reach to a plate for food and to reach the mouth. Long shoehorns for putting on shoes, a friction-suction mat in the bathtub, and a shower chair or bench can easily improve daily activities. Also, a shower is safer than a bath. Holding a toothpick or chewing gum and holding an an appointment card help minimize tremulousness. Some ways to facilitate independence include lip and tongue exercises, gently blowing candles, practice with speaking, learning not to speak toward the end of exhalation, breathing deeply from abdomen, swallowing semisolids then liquids to prevent food from entering the windpipe, and smelling strong pungent odors to encourage facial expression. Anticholinergics help reduce the volume of saliva and thus drooling. Posture should be as erect as possible to facilitate lung functioning. Guithier et al.78 found that it was not the tremor at rest that affected activities of daily living, but the lack of postural stability that is resistant to levadopa that also led to difficulties at home and work. Impairment in functional activities increases with the progression of the disease. Trunk mobility and postural control are the first to interfere with functional independence, followed by increased difficulty in manipulative and skilled tasks. Based on the Barthel Index findings, the treatment group significantly improved in ADL following occupational therapy. Rigidity and bradykinesia can affect occupational performance such as cutting food, buttoning, writing, smiling, and interacting socially. α-synuclein, found in household pesticides, is a major contributor to the development of free radicals in the brain, and patients need to understand how to handle these with care and avoid setting off chemical reactions that intensify Parkinson’s symptoms.123 Despite advances in pharmaceuticals that improve mobility and capabilities, Beattie124 found that many patients continue to have functional limitations. On 6 to 18 months follow-up, the author found that 28% were independent, 26% were dependent and needed help, and 46% were dependent in self-care. In addition, 80% needed a bath rail and mat, and 10% needed a bath seat, board, rail, and mat. Thirteen percent benefited from a grab bar attached to the wall next to a toilet, and 5% needed a raised toilet seat. Feeding aids prevent scattering of food, dislodgement of plates, and difficulty using cups. Kitchen aids facilitate opening jars and cans. Miscellaneous other aids help with turning over, sitting in bed, and other tasks. These include a rope ladder, can opener, tap turner, trolley, telephone amplifier, doorbell, ramp, wheelchair, hand-held shower nozzle, walking frame, card holder, shoehorn, helping hand, raised chair, high-back chair, and incontinence pads. “On” and “off” phases lead to changes in motor control, akinesia, bradykinesia, and diffuse rigidity, all influencing movements and performance in selfcare and environmental interactions and the quality of life for persons with Parkinson’s. An independent means of transport is likely to prevent disengagement in activities and, although the amount and variety vary, participation could remain high despite selfconsciousness. The lack of high participation or the lack of various activities can relate to dissatisfaction with life.124 In nutritional matters, “eat well, stay well” with Parkinson’s disease clearly highlights the food, fluid, and vitamin needs and requirements. AOTA13,125 consumer reports advise patients that environment fitness is important, and occupational therapists contribute to modifications for increased accessibility in every room in the home. In the bathroom, a hand-held shower head, large shower and bath controls, grab bars, and faucets with levers are such improvements. In the kitchen, they include adjusting sinks and countertops and designing the workspace to avoid twisting and turning while preparing a meal. In hallways and doorways, clearing clutter, providing

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unobstructed openings, securing carpet, and adding handrails will help. In the living room and bedroom, arranging furniture for clear passage, making the telephone accessible, and increased security are important. All these improvements will promote efficiency in completing daily tasks, promote energy conservation, and help prevent falls and other home injuries.126–128 It is important to recognize that advances, such as therapeutic interventions and surgical procedures, therapeutic use of drugs, and occupational therapy and rehabilitation strategies, are alone not enough. The importance of psychosocial management and perceived inner need and drive by Parkinson’s patients contribute to their success. PSYCHOSOCIAL OCCUPATIONAL THERAPY AND PARKINSON’S DISEASE Among the domains composing the quality of life index, although no universal criteria exist, is the individual’s psychosocial status.47 To gain optimal understanding of patients’ perception and self-evaluation of how PD has altered their social and emotional functioning, the occupational therapist uses a client-centered approach, empowering the patient to manage the PD.129 One such tool that assists the patient in delineating life satisfaction is the Canadian Occupational Performance Measure (COPM), a semistructured interview that allows the patient to prioritize areas that are most important to maintain a quality of life and that often center around psychosocial needs, such as maintaining interpersonal interactions and continuing in family, religious, and leisure roles.70,129 Using a semistructured interview approach, Mainson and Caird85 spoke with 74 PD patients who were living at home to determine the impact of the disease on the meaningful activities (hobbies) they had pursued prior to diagnosis, particularly relating to changes over the past 5 years. While 95% continued involvement in sedentary and passive activities around the house, such as watching TV or reading, only 31% maintained involvement in activities, such as knitting and sewing, that require fine motor dexterity. Eighty-three percent of indoor gardeners maintained their passion, but the interest in outdoor gardening saw a marked decline. Less than one-third of the PD patients continued to engage in community social activities—going to a place of worship, going out to lunch, or seeing a movie. While lack of mobility contributed to this decline, the embarrassment resulting from the tremor and social anxiety, experienced by twothirds of the patients, were obstacles.85 Not believing that one can maintain control over the illness impedes self-efficacy.128 Individuals who took up a new hobby since the PD diagnosis were the exception; however, a few risked cycling and swimming.85 The overwhelming trend to go out less and engage in sedentary in-home activities was a concern of the researchers,85 who conceded that the absence of motivation is inherent in the disease. They emphasized, however, the importance in continuing interests into one’s mid-life. Concern about the participation and motivation of PD patients in social activities led Gauthier et al.78 to implement a study of occupational therapy treatment groups. Using pretreatment evaluations, randomly assigning patients to either a treatment or control group, they followed up by evaluating approximately 30 participants in each group after therapy after 6 months and then at the end of 1 year. The experimental group

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received 20 hr of occupational therapy group treatment, 10 sessions, twice weekly over 5 weeks, consisting of mobility, functional, educational, and dexterity exercises, with interspersed with socialization. The Bradburn Index of psychological well-being showed that patients perceived greater psychological well-being after therapy, even noting a regression in their symptoms as compared with the control group that showed no change. Additionally, patients in the treatment group showed increased attention to grooming and demonstrated a clearer understanding of PD, which investigators linked to increased selfconfidence. Over the ten, sessions the researchers also observed initial egocentric attitudes among the group participants changing to concern and interest in the well-being of others.78 Davis130 concluded that group activities designed to maintain a patient’s level of functional activity and socialization, such as frisbee, shuffleboard, ball tossing and kicking, volleyball, hot potato, basketball, matching, sing-a-long with rhythm instruments, bean bag toss, and bowling, are optimal for patients to show encouragement and support for one another. While the effect of socialization on functional activity in the groups is speculative, Gauthier et al.78 noted that one of the major motor systems (bradykinesia) improved along with psychological well-being and positive behavioral change. Through involvement ingroup activities, PD patients are able to remain active longer,78,130 and the social support and improved motivation are by-products of the group participation. Maintenance of interpersonal relationships in friends and family may ultimately determine the PD patient’s connection to occupation and the world at large.85 ACKNOWLEDGMENTS The authors wish to thank David L.Armbruster, Ph.D., Scientific Publications, and Emeritus Professor Mary Ellis Gaston, University of Tennessee Health Science Center, for their editorial assistance with sections of this chapter. REFERENCES 1. Hallett, M., Analysis of abnormal voluntary and involuntary movements with surface electromyography, Adv. Neurol., 33, 387–414, 1983. 2. Paulson, H.L. and Stern, M.B., Clinical manifestations in Parkinson’s disease, in Movement Disorders: Neurologic Principles and Practice, Watts, R.L. and Kohler, W.C., Eds., McGrawHill, New York, 184–1997. 3. De Goede, C.J.T. et al., The effects of physical therapy in Parkinson’s disease, Arch. Phys. Med. Rehabil, 82, 509–515, 2001. 4. Marsden, C.D., Parkinson’s disease, J. Neurol. Neurosurg., Psychiatry., 57, 672–681, 1994. 5. Penney, J.B., and Young, A.B., Speculations on the functional anatomy of BG disorders, Annu. Rev. Neurosci., 6, 73–94, 1983. 6. Hallet, M. and Khoshbin, S., A physiological mechanism of Bradykinesia, Brain, 103, 301–322, 1980. 7. Jankovic, J. and Stacy, M., Movement disorders, in Textbook of Clinical Neurology, Goetz, C.G. and Pappert, E.J., Eds., Saunders, Philadelphia, PA, 655–679, 1999. 8. Alexander, G.E., DeLong, M.R., and Strick, P.L. Parallel organization of functionally segregated circuits linking basal ganglia and cortex, Annu. Rev. Neurosci., 9, 357–381, 1986.

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9. American Occupational Therapy Association. Occupational therapy practice framework: Domain and practice, Am. J. Occup. Ther., 56, 609–639, 2002. 10. Law, M. Participation in the occupation of everyday life, Am. J. Occup. Ther., 56, 640–649, 2002. 11. Christiansen, C. and Townsend, E. An introduction to occupation, in C.H.Christiansen, C.H. and Townsend, E.A., Eds., Introduction to Occupation, Prentice Hall, Upper Saddle River, New Jersey, 1–28, 2003. 12. Wilcock, A.A., The Dorris Sym Memorial Lecture: Developing a philosophy of occupation for health, Br. J. Occup. Ther., 62. 192–198, 1999. 13. American Occupational Therapy Association. Modifying your home for independence, AOTA Consumer Information—Tip Sheets, AOTA.org, Maryland, 1–3, 2003. 14. Poglar, J.M. and Landry, J.E., Occupations as a means for individual and group participation in life, in Christiansen, C.H. and Townsend, E.A., Eds., Introduction to Occupation, Prentice Hall, Upper Saddle River, New Jersey, 197–220, 2003. 15. Flowers, K.A., Visual closed-loop and open-loop characteristics of voluntary movements in patients with Parkinsonism and intentional tremor, Brain, 99, 269–310, 1976. 16. Kannenberg, K. and Greene, S., Infusing occupation into practice, OT Pract., 8, 27–34, 2003. 17. Morris, M.E. et al., Stride length regulation in Parkinson’s disease, Normalization strategies and underlying mechanisms, Brain, 119, 551–568, 1996. 18. Protas, E.J., Stanley, R.K. and Jankovic, J., Exercise and Parkinson’s disease, Crit. Rev. Phys. Rehabil Med., 8, 253–266, 1996. 19. Murphy, S. and Tickle-Degnen, L., The effectiveness of occupational therapy-related treatments for persons with Parkinson’s disease: A meta-analytic review, Am. J. Occup. Ther., 55, 385–392, 2001. 20. Trombly, C.A., Conceptual foundations for practice, in Occupational Therapy for Physical Dysfunction, Trombly, C.A.and Radomski, M.A., Eds., 5th Ed., Lippincott, Williams and Wilkins, Philadelphia, PA, 1–16, 2002. 21. Finch, E. et al., Physical Rehabilitation Outcome Measures: A Guide to Enhanced Clinical Decision Making, 2nd Ed., Lippincott, Williams and Wilkins, Philadelphia, PA, 6–60, 2003. 22. World Health Organization. ICIDH-2 International classification of functioning, disability, and health, WHO, Geneva, 2001. 23. Hinojosha, J. and Youngsman, M.J. broadening the construct of independence, Am. J. Occup. Ther., 56. 660, 2002. 24. Haaland, K.Y., Harrington, D.L. and Knight, R.Y., Neural representation of skilled movement, Brain, 123, 2306–2313, 2002. 25. Khotianov, N., Singh, R., and Singh, S., Lewy Body dementia: Case report and discussion, J. Am. Board Fam. Pract., 15, 50–54, 2002. 26. Edwards, N., Aquariums may pacify Alzheimer’s patients. Purdue University News, http://[email protected]./, 1–4, 1999. 27. Lang, A.E., Clinical rating scales and videotape analysis, in Therapy for Parkinson’s Disease, Koller, W.C. and Paulson, G., Eds., Dekker, New York, 3–15, 1991. 28. Harridge, C. and Shah, S., The Moss Kitchen assessment revised, N. Z. J. Occup. Ther., 46, 5– 9, 1995b. 29. Ivanzo, A. et al., Sleep symptoms and polysomnographic architecture in advanced Parkinson’s disease after chronic bilateral; subthalamic stimulation, J. Neurol. Neurosurg. Psychiatry., 72, 661–664, 2002. 30. Short, R., Modafinil reduces sleepiness in Parkinson’s disease, Sleep, 25, 905–909, 2002. 31. Hallett, M., Shahani, B.T. and Young, R.R., Analysis of stereotyped voluntary movement at the elbow in patients with Parkinson’s disease, J. Neurol. Neurosurg. Psychiatry., 40, 1129–1135, 1977. 32. Duncan, P.W. et al., Functional reach: predictive validity in a sample of elderly male veterans, J. Gerontol., 47, M93–98, 1992.

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33. Weiner, D.K. et al., Functional reach: A marker of physical frailty, J. Am. Geriatr. Soc., 40. 203–207, 1992. 34. Melnick, M.E., Radtka, S., and Piper, M.P., Gait analysis and Parkinson’s disease, Rehab. Manag., 15, 46–48, 2002. 35. Chang, R., Guan, L., and Burne, J.A., An automated form of video image analysis applied to classification of movement disorders, Disabil. Rehabil, 22, 97–108, 2002. 36. Graziano, M., Common mobility problems and how to address them, Adv. Clin. Neurosci. Rehabil., 3, 38, 2003. 37. Spyers-Ashby, J.M. et al., Classification of normal and pathological tremors using a multidimensional electromagnetic system, Med. Eng. Phys., 21. 713–723, 1999. 38. Behrman, A.L. et al., Is the functional reach useful for identifying falls risk among individuals with Parkinson’s disease, Arch. Phys. Med. Rehabil, 83, 538–542, 2002. 39. Rosser, R.M., and Kind, P., A scale of valuations of states if illness: is there a social conscious? Int. J. Epidemiol, 7, 347–358, 1978. 40. The Euroqol Group. Euroqol: a new facility for the measurement of health related quality of life, Health Policy, 16, 199–208, 1990. 41. Glaser, A.W. et al., Applicability of the Health Utilities Index to a population of childhood survivors of CNS tumors in the U.K, Eur. J. Cancer., 35, 256–261, 1999. 42. Stern, M.B., The clinical characteristics of Parkinson’s disease and parkinsonian syndromes: diagnosis and assessment, in The Comprehensive Management of Parkinson’s Disease, Stern, M.B. and Hurlig, H.I., Eds., PMA Publishing, New York, 3–50, 1987. 43. Gaudet, P., Measuring the impact of Parkinson’s disease: An occupational therapy perspective, Can. J. Occup. Ther., 69, 104–113, 2002. 44. Hoehn, M., and Yahr, M., Parkinsonism: onset, progression, and mortality, Neurol., 17, 427– 442, 1967. 45. Peto, V., Jenkinson, C., and Fitzpatrick, R., PDQ-39. A review of the development, validation, and application of a Parkinson’s disease quality of life questionnaire and its associated measures, J. Neurol., 245(Suppl. 1), S10–S14, 1998. 46. Beck, A.T. et al., An inventory for measuring depression, Arch. Gen. Psychiatry, 4, 53–63, 1961. 47. Siderowf, A., Cianci, H.J. and Rorke, T.R., An evidence-based approach to management of early Parkinson’s disease, Hosp. Physician, 37, 63–76, 2001. 48. Copperman, L.F., Forwell, S.J., and Hugos, L., Neurodegenerative diseases, in Occupational Therapy for Physical Dysfunction, Trombly, C.A. and Radomski, M.V., Eds., 5th ed., Lippincott, Williams and Wilkins, Philadelphia, PA, 895–908, 2002. 49. Barry, P. et al., Rehabilitation inpatient screening of early cognitive recovery, Arch. Phys. Med. Rehabil., 70, 902–906, 1989. 50. Sandford, J.A., Browne, R.J. and Turner, A., Software for Cognitive Training & Psychological Testing, Brain Train, Richmond, VA, 2003. 51. Harridge, C. and Shah, S., A review of meal preparation ability as a measure of instrumental activities of daily living, N. Z. J. Occup. Ther., 46, 5–12, 1995a. 52. Hays, C.A., Kassimir, J. and Parkin, J., Eds., Sample Forms for Occupational Therapy, American Occupational Therapy Association, Rockville, MD, 1996. 53. Shah, S., Vanclay, F. and Cooper, B., Improving the sensitivity of the Barthel Index for stroke rehabilitation, J. Clin. Epidemiol., 42, 703–709, 1989. 54. Shah, S., Guidelines for the Barthel Index (Expanded) or Modified Barthel Index, in Compendium of Quality of Life Instruments, Salek, S., Ed., Wiley & Sons, New York, 1–9, 1998. 55. Shah, S., Biometric and psychometric qualities of the Barthel Index, Physiotherapy, 80, 769– 771, 1994.

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56. Corbett, P.J., Focus on research: Functional assessment in Parkinson’s disease: An investigation into the sensi tivity of commonly used assessments to determine change, pre-and postamorphine intervention, Br. J. Occup. Ther., 61, 464, 1998. 57. Shah, S., Cooper, B., and Maas, F., Performance of perceptual tasks by neurologically unimpaired adults using the dominant right hand, Aust. Occup. Ther. J., 40.165–178, 1993. 58. Figenson, J.S., Polkow, L. and Keegan, N., Burke Perceptual Profile (BUPP), American Neurological Foundation, New York, 1980. 59. Teive, H.A.G., and Sa, D.S., The Rolex sign first manifestation of Parkinson’s disease, Arq. Neuropsiquiatr., 58, 1–4, 2002. 60. Baylor Neurology Patient #33, http://www.hom.bcm.tmc.edu/, Department of Neurology, Baylor College of Medicine, 2002. 61. Johnson, K.A. et al., Bimanual coordination in Parkinson’s disease, Brain, 121, 743–753, 1998. 62. Stelmach, G.E. and Phillips, J.G., Movement disorders in Parkinson’s disease, in Physical Therapy Management of Parkinson’s Disease, Turnbull, G.I., Ed., Churchill Livingstone, New York, 37–48, 1992. 63. Laplane, D. et al., Clinical consequences of corticectomies involving the supplementary motor area in man, J. Neurol Sci., 34, 301–314, 1977. 64. Pahapill, P.A. and Lozano, A.M., The pedunculopontine nucleus in Parkinson’s disease, Brain, 123, 1767–1783, 2000. 65. Stockmeyer, S.A., An interpretation of the approach by Rood to the treatment of neuromuscular dysfunction, Am. J. Phys. Med., 46, 900–961, 1967. 66. Hocherman, A. and Aharon-Peretz, A., Two-dimensional tracing and tracking in patients with Parkinson’s disease, Neurol., 44, 111–116, 1994. 67. Carey, J.R. et al., Sex differences in tracking performance in patients with Parkinson’s disease, Arch. Phys. Med. Rehabil., 83, 972–977, 2002. 68. Quintyn, M. and Cross, E., Factors affecting the ability to initiate movement in Parkinson’s disease, Phys. Occup. Ther. Geriatr., 4, 51–60, 1986. 69. Chan, J.L. and Ross, E.D., Left-handed mirror writing following anterior cerebral artery infarction: evidence for non-mirror transformation of motor programs by right SMA, Neurol., 38, 59–63, 1988 70. Connor, N.P. and Abbs, J.H., Sensorimotor contributions of the basal ganglia: Recent advances, Phys. Ther., 70, 864–872, 1990. 71. Fahn, S., Hyperkinesia and hypokinesia, in Textbook of Clinical Neurology, Goetz, C.G. and Pappert, E.J., Eds., Saunders, Philadelphia, PA, 267–284, 1999. 72. Kishore, A. et al., Evidence of somatotopy in GPI from results of pallidotomy, Brain, 123, 2491–2500, 2000. 73. Weiner, W.J. and Singer, A.C., Parkinson’s disease and non-pharmacological treatments, J. Am. Geriatr. Soc., 37, 359–363, 1989. 74. DeLong, M.R., The neurophysiologic basis of abnormal movements in basal ganglia disorders, Neurobehav. Toxicol. Teratol., 12, 366–375, 1983. 75. Platz, T., Brown, R.G. and Marsden, C.D., Training improves the speed aimed at movements in Parkinson’s disease, Brain, 121, 505–514, 1998. 76. Sheridan, M.R., Flowers, K.A. and Hurrell, J., Programming and execution of movements in Parkinson’s disease, Brain, 110, 1247–1271, 1987. 77. Rascol, O. et al., Cortical motor over activation in Parkinson’s patients with L-dopa-induced peak-dose dysfunction, Brain, 121, 527–533, 1998. 78. Gauthier, L., Dalziel, S., and Gauthier, S., The benefits of group therapy for patients with Parkinson’s disease, Am. J. Occup. Ther., 41, 360–365, 1987. 79. Levin, B. et al., Visuospatial impairment in Parkinson’s disease, Neurol., 41, 365–369, 1991. 80. Lazaruk, L., Visuospatial impairment in persons with idiopathic Parkinson’s disease: A literature review, Phys. Occup. Ther. Geriatr., 12, 37–48, 1994.

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81. Shah, S., Cooper, B. and Lyons, M., Investigation of the transient ischemia workload and its incidence: Implications for occupational therapy research, Occup. Ther. J. Res., 12, 357–373, 1992. 82. Brownbridge, E., Unique Parkinson’s program emphasizes self-management, Ger. Aging, 2, 3– 27, 1999. 83. Deane, K.H.O. et al., Systematic review of paramedical therapies for Parkinson’s disease, Mov. Disord., 117, 984–991, 2002. 84. Deane, K.H. et al., Comparison of physiotherapy techniques for Parkinson’s disease, Cochran Database of Sys. Rev., 1, CD002815, 2001. 85. Mason, L., and Caird, F.L, Survey of the hobbies and transport of patients with Parkinson’s disease, Br. J. Occup. Ther., 48, 199–200, 1985. 86. Nieuwboer, A. et al., The effect of a home physiotherapy program for persons with Parkinson’s disease, J. Rehabil. Med., 33, 266–272, 2001. 87. Johnell, O. et al., Fracture risk in patients with Parkinson’s: a population based study in Olmsted County, Minnesota, Age Aging, 21, 32–38, 1992. 88. Hummelsheim, H., Hauptmann, B. and Neumann, S., Influence of physiotherapeutic facilitation techniques on motor evoked potentials in centrally paretic hand extensor muscles, Electroencephalogr. Clin. Neurophysiol., 97, 18–28, 1995. 89. Miyai, I. et al., Long-term effect of body weight-supported treadmill training in Parkinson’s disease: a randomized control trial, Arch. Phys. Med. Rehabil, 83, 1370–1373, 2002. 90. Grillner, S., Control of locomotion in bipeds, in Handbook of Physiology, Brooks, V.B., Ed., American Physiological Society, Bethesda, MD, 1179–1236, 1981. 91. Halliday, S.E. et al., The initiation of gait in young, elderly, and Parkinson’s disease subjects, Gait Posture, 8, 8–14, 1998. 92. Bronstein, A.M. et al., Visual control of balance in cerebellar and parkinsonian syndromes, Brain, 113, 767–779, 1990. 93. Winter, D.A. and Eng, P., Kinetics: Our window into the goals and strategies of the central nervous system, Behav. Brain Res., 67:111–120, 1995. 94. http://www.geocities.com/parkinson.html/2003. 95. Susman, E., ANA: Walkers do not benefit freezing in Parkinson’s disease patients, Doctor’s Guide, http://www.docguide.com/news/content.nsf/new.../, P\S\L Consulting Group Inc., 2002. 96. Ahmad, S.O., Mu, K.L. and Scott, S.A., Meta-analysis of functional outcome in patients treated with unilateral pallidotomy, Neurosci. Lett., 6, 2001. 97. de Bie, R.M. et al., Outcome of unilateral pallidotomy in advanced Parkinson’s disease: Cohort study of 32 patients, J. Neurol. Neurosur. Psychiatry., 71, 375–382, 2001. 98. Aziz, T. and Yianni, J., Surgical treatment of Parkinson’s disease, Adv. Clin. Neurosci. Rehabil., 2, 21–22, 2003. 99. The Deep-Brain Stimulation for Parkinson’s Disease Study Group, Deep-brain stimulation of the subthalamic nucleus or the pars interna of the globus pallidus in Parkinson’s disease, N. Engl. J. Med., 345, 956–963, 2001. 100. Saint-Cyr, J.A. et al., Neuropsychological consequences of chronic bilateral stimulation of the subthalamic nucleus in Parkinson’s disease, Brain, 123, 2091–2108, 2001. 101. Saint-Cyr, J.A. and Trepanier, L.L., Neuropsychologic assessment of patients for movement disorder surgery, Mov. Disord., 15, 771–783, 2000b. 102. Montgomery, E.B., Jr. and Rezai, A.R., Deep brain stimulation for Parkinson’s disease: Is it right for your patient? Cleveland: The Cleveland clinic center for functional and restorative neuroscience, http://www.clevelandclinicmeded.com/ 103. Shults, C.W. et al., Effects of coenzyme Q10 in ear of patients with Parkinson’s disease, Arch. Neurol., 59, 1541–1550, 2002. 104. Hubble, J.P. and Berchou, R.C., Parkinson’s disease: Medications and side effects, http://www.parkinsonism.org/, 2003.

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105. Sylvester, B. Entacapone extends benefits of leva-dopa and improves condition of Parkinson’s disease patients, Doctor’s Guide News, 1–2, 2002. 106. Danisi, F.Parkinson’s disease: Therapeutic strategies to improve patient function and quality of life, Geriat., 57, 46–50, 2002. 107. Nandi, D. et al., Reversal of Akinesia in experimental Parkinsonism by GABA antagonist microinjections in the pedunculopontine nucleus, Brain, 125, 2418–2430, 2002. 108. Chen, H. et al., Dairy products and Parkinson’s disease, Ann. Neurol., 52, 793–801, 2002. 109. Siebert, C., Aging in place: implications for occupational therapy, OT Pract., 8, CE-1-CE-7, 2003. 110. Lander, C., Parkinson’s disease: Diagnosis and management, Mod. Med. Aust., 5, 18–26, 1995. 111. McNaught, K.S.P. et al.,Lewy bodies and aggresomes: altered protein handling and Parkinson’s disease, Eur. J. Neurosci., 16, 2136–2148, 2002. 112. Sato, Y. et al., Vitamin K. deficiency and osteopenia in vitamin D-deficient elderly women with Parkinson’s disease, Arch. Phys. Med. Rehabil., 83, 86–91, 2002. 113. Pacchetti, C. et al., “off” painful dystonia in Parkinson’s disease treated with botulinum toxin, Mov. Disord., 10, 333–336, 1995. 114. Childers, M.K. et al., Treatment of painful muscle syndromes with botulinum toxin: A review, J. Back Musculoskeletal Rehabil, 10, 89–96, 1998. 115. Lees, A.J., New advances in the management of late stage Parkinson’s disease, Adv. Clin. Neurosci. Rehabil., 1, 7–8, 2001. 116. Novatis., The US FDA approves Stalevo for treatment of Parkinson’s, Doctor’s Guide, 1–4, June 2003. 117. Schrag, A. and Quinn, N., Dyskinesias and motor fluctuations in Parkinson’s disease, Brain, 123, 2279–2305, 2000. 118. Lee, H.C., Lee, A.H. and Cameron, D., Measuring visual attention skill of older drivers by using a driving simulator, Am. J. Occp. Ther., 57,324–328, 2003. 119. Ondo, W.G. et al., Daytime sleepiness and other sleep disorders in Parkinson’s disease, Neurol., 57, 1392–1396, 2001. 120. McConnell, H., No reason to stop driving by Parkinson’s patients taking dopamine drugs, Br. Med. J., 324, 1483–1487, 2002. 121. Sa, D.S. and Chen, R., Parkinson’s disease: An update on therapeutic strategies, Geriatr. Aging, 5, 8–14, 2002. 122. Thaut, M.H. et al., Rhythmic auditory stimulation in gait training for Parkinson’s disease patients, Mov. Disord., 11, 193–200, 1996. 123. Spillantini, M.G. et al., Alpha-synuclein in Lewy bodies, Nature, 388, 839–840, 1997. 124. Beattie, A., Aids to daily living for the patient with Parkinson’s disease, Br. J. Occup. Ther., 44, 53–55, 1981. 125. Griffin, J. and McKenna, K., Influence on leisure and life satisfaction of elderly people, Phys. Occup. Ther. Geriatr, 15, 1–16, 1998. 126. Deane, K.H.O. et al., A survey of current occupational therapy practice for Parkinson’s disease in the United Kingdom, Br. J. Occp. Ther., 66, 193–197, 2003. 127. Majsak, M.J. et al., The reaching movements of patients with Parkinson’s disease under selfdetermined maximal speed and visually cued conditions, Brain, 121, 755–766, 1998. 128. Montgomery, E.B., Jr. et al., Patient education and health promotion can be effective in Parkinson’s disease: A randomized controlled trial, Am. J. Med., 97: 429–435, 2001. 129. Cohn, E.S. et al., Introduction to evaluation and interviewing, in Willard & Spackman’s Occupational Therapy, Crepeau, E.B. et al., Eds., 10th ed., Lippincott Williams and Wilkins, Philadelphia, PA., 249, 2003. 130. Davis, J.C., Team management of Parkinson’s disease, Am. J. Occup. Ther., 31:305–308, 1977.

63 Music Therapy for People with Parkinson’s Sandra L.Holten Struthers Parkinson’s Center 0-8493-1590-5/05/$0.00+$1.50 © 2005 by CRC Press

INTRODUCTION Music therapy is an established, allied health profession in which music is used within a therapeutic relationship to address the physical, psychological, cognitive, spiritual, and social needs of individuals with an illness or disability. Music therapists complete a bachelors or masters music therapy degree and a minimum of 1200 hr combined clinical practice and internship. To have board certified credentials, the music therapist is required to pass a certification examination offered by the Certification Board for Music Therapists. Board certified (BC) music therapists must complete 100 continuing music therapy education credits (CMTE) within a five-year cycle to maintain their boardcertified status. Continuing education may include institutes that provide specialized training in a specific area of music therapy. In the United States, music therapy was established as a profession in 1950 as a result of work in which music was used with patients in veteran’s hospitals following World War II. Today, more than 5,000 music therapists are employed throughout the U.S. in settings such as hospitals, clinics, community centers, day care centers, substance abuse facilities, schools, nursing homes, rehabilitation centers, and private practices.1 Recent research has provided evidence that validates music therapy in a way that it has not previously. As a result of research done by the Center for Biomedical Research in Music in Fort Collins, Colorado, music therapy techniques have been more clearly defined and standardized into an approach called neurologic music therapy (NMT). NMT is defined as the therapeutic application of music to cognitive, sensory, and motor dysfunction due to neurologic disease of the human nervous system. It is based on a neuroscience model of music perception and production and the influence of music on functional changes on nonmusical brain and behavior functions. NMT treatment techniques are based on scientific research and are directed toward functional goals. They are standardized and applied to therapy as therapeutic music interventions that are adaptable to the patient’s needs. In addition to music therapy training, a neurologic music therapist is educated in the areas of neuroanatomy/physiology, brain pathologies, medical terminology, and rehabilitation of cognitive and/or motor functions.2 NMT applies directly in addressing the symptoms of Parkinson’s. Within the scope of providing music therapy services, necessary steps are followed in planning and facilitating

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interventions. Music therapists assess patient needs, identify goals, and then translate and apply the qualities of music in a focused, intentional manner to plan and facilitate interventions, which improve the quality of life and optimize the functioning level of the people with whom they work. In the monograph, A Scientific Model of Music in Therapy and Medicine, Michael Thaut discusses an approach called transformational design model (TDM) that “provides a system for the therapist to immediately translate the scientific model into functional clinical practice.”3 He delineates five basic steps of the TDM as follows: 1. Diagnostic and functional assessment of the patient 2. Development of therapeutic goals/objectives 3. Design of functional, nonmusical therapeutic exercises and stimuli 4. Translation of Step 3 into functional, therapeutic music experiences 5. Transfer of therapeutic learning to real-world applications All of the steps, excluding the fourth, are shared by all therapy disciplines. Thaut notes that “the crucial clinical process for music therapists occurs in Step 4. Here, a role for music therapists emerges that is unique to the profession: translating functional and therapeutic exercises and stimuli into functional therapeutic music exercises and stimuli….” The correspondence and translation between the musical and nonmusical elements or exercises is direct. Music therapists providing services for people with Parkinson’s face a unique and rewarding challenge. Parkinson’s is a disease that affects every fiber of a person’s being. The qualities of music have the potential to affect humans by eliciting responses that facilitate change and positively affect rehabilitation and healing process. Music therapy is an exciting, effective modality that holds great promise in improving the quality of life for people with Parkinson’s. This chapter explores the applications and related research for music therapy within the areas of sensorimotor function, speech and cognition, and psychosocial challenges for people with Parkinson’s. NMT TECHNIQUES FOR SENSORIMOTOR TRAINING NMT techniques for sensorimotor training address gait, posture, and arm and trunk training. Three techniques have been developed and standardized based on a body of research. These techniques are rhythmic auditory stimulation (RAS), patterned sensory enhancement (PSE), and therapeutic instrumental music performance (TIMP). RHYTHMIC AUDITORY STIMULATION Rhythmic auditory stimulation is a specific technique of rhythmic motor cueing to facilitate training of movements that are intrinsically and biologically rhythmical. Because the most important type of these movements in humans is gait, RAS is almost exclusively used for gait rehabilitation to aid in the recovery of functional, stable, and adaptive walking patterns in patients with significant gait deficits. The underlying mechanism in RAS is rhythmic entrainment, which enhances gait. In this process, rhythm is an external timekeeper. Through the anticipation of the functional movement patterns,

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rhythmic cues are provided to synchronize and change existing to desired movement frequencies. This entrainment retrains the motor programs through anticipatory cueing of functional movement patterns. Rhythmic cues are provided to synchronize and change existing to desired movement frequencies. “Through frequency entrainment of motor patterns, rhythm stabilizes the timing, kinematic control, and force applications in movement.”2 There are two ways in which RAS can be used. First, it can be used as an immediate entrainment stimulus providing rhythmic cues during the movement.2 Given the difficulties for people with Parkinson’s with “freezing” episodes, this is an effective coping strategy to assist patients in the initiation of movement. Utilization of rhythm through verbalization of a cadence or counting, singing or playing a music that encourages movement, such as a march, provides an excellent compensation strategy. Although people with Parkinson’s or their care partners may already use this method, the music therapist who is trained in using these techniques will be able to go beyond the obvious in the execution of RAS. Therapists will capitalize on and enhance the rhythm with dynamics, force, and pitch as needed specifically by the patient. The second way in which RAS can be employed is as a facilitating stimulus for training where patients train with RAS for a certain period of time so as to achieve more functional gait patterns, which they then transfer to walking without rhythmic facilitation.2 When utilizing RAS in this way, the music therapist will follow a specific treatment protocol. The length of treatment time is determined by the patient needs and may be done in an inpatient setting or with a home program on an outpatient basis. The music therapist may co-treat with a physical therapist. Because their approaches are different, collaboration can help to solidify the patient’s learning and rehabilitation in gait training. Neurologic music therapists specialized training provides them the ability to work with patients in gait assessment and training. From the early 1990s to the present, the body of research that demonstrates the effectiveness of both applications with different gait disorders continues to grow. Thaut et al.4 studied the effect of RAS gait training with people with Parkinson’s. Study participants involved in the RAS program significantly (p1 year

TH±GTPCHI TH staining DA content

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GTPCH1 coexpression Yes, only with GTPCH1 coexpression

Yes, only ND with GTPCH1 coexpression ND ND

NA

Yes, feeding and drinking

NA

Yes, feeding and drinking

This table is intended to compile almost all of the publications using in vivo gene therapy to deliver L-dopa in rodent models of PD. The main point of this table is the same as Table 70.1 (ND=not done). If a measurement was taken and a positive result was found, a ‘yes’ is placed in a cell. If the measurement was taken but a negative result was found, ‘no’ is placed in a cell. The other point is that more of the function of L-dopa in striatum is being elucidated as evidenced by the more sophisticated measurements used by a number of the papers shown toward the bottom of the table (more recent.) † A partial Striatal lesion was used here and very few cells were transduced, therefore, the source of L-dopa might be questionable. *

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FIGURE 70.2 The dopamine biosynthetic pathway and the biosynthetic pathway for the essential cofactor for TH, BH4. Most cells constitutively express 6-pyruvoylneopterin synthase and sepiapterin reductase.233 Therefore, gene expression of the rate-limiting enzyme, GTP-cyclohydrolase 1 is all that is necessary for BH4 production. The dashed arrow indicates that BH4 is needed for TH enzyme activity. BH4 also appears to stabilize the TH protein.131, 213

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apomorphine-induced rotational behavior is a highly confounded behavioral assay.109,147 Any treatment that reduces striatal DA receptors will also inhibit apomorphineinduced rotational behavior (see Mandel et al.147 for review). This effect is clearly demonstrated using rAd-TH by Corti et al.48 Production of BH4 in the striatum requires the expression of a second gene, GTPcyclohydrolase I, the primary synthetic enzyme for BH4233 (GTPCH1, Figure 70.2). When the further requirement for the ability to regulate the levels of striatal L-dopa is added to the probable requirement for the expression of two transgenes (TH and GTPCH1), the complexity of the technical aspects of this strategy can clearly be appreciated. In summary, a major advantage of choosing striatal Ldopa as a gene therapy strategy is that the safety profile of L-dopa is well known. However, durable regulated gene expression that produces levels of striatal L-dopa that are therapeutic must be achieved. In addition, the combination of genes to be used is still controversial. Furthermore, especially because a PD patient may live several decades after the gene therapy procedure, the safety of the chosen gene therapy vector should be established as well as possible in animal models. Clear attainment of some of these goals is hampered by the absence of a truly valid animal model that displays long-term progressive nigrostriatal degeneration that is also L-dopa responsive. This issue is particularly important, because the response to L-dopa therapy wanes over time as the disease progresses in humans. Therapeutic Efficacy of Intrastriatal rAAV-Mediated L-Dopa Delivery Until recently, the apomorphine-induced rotational behavior paradigm was the most accepted test for functional recovery in the rat 6-OHDA PD model. However, several recent nondrug-induced functional tests have been shown to be sensitive to striatal DA depletions and to respond to therapeutic treatments including L-dopa. Thus, stepping behavior, a measure of forelimb akinesia,203 and the cylinder test, a measure of spontaneous forelimb usage,204 are deficient in response to 6-OHDA lesions and respond

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FIGURE 70.3 Intrastriatal Lentiviral vectors expressing L-dopa synthesizing enzymes in the 6-OHDA PD rat model. (A) Apomorphineinduced rotational behavior (0.1 mg/kg i.p.) in complete lesioned (MFB) animals from the experimental groups indicated in the figure legend. There was no significant difference between any of the groups in this test (p>0.05). Each point represents seven to eight animals. Error bars=±1 SEM. (B) Amphetamine-induced rotational behavior (2.5 mg/kg, i.p.) in partial lesioned animals that received identical intrastriatal lentiviral vector injections to that shown in A. Again, there was no significant effect of expressing striatal L-dopa in this group; however, the mixed (1:1 mixture of lenti-hGTPCH1 and lenti-hTH) group’s reduction in rotational behavior approached significance (p=0.07). Each point

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represents five to six animals. (C) Striatal L-dopa levels from striatal punches taken from the animals in A. Detectable L-dopa levels were observable only in the mix vector group. Note that the mean L-dopa was below 1.5 pmole per mg striatal tissue (nd=not detectable). (D) Relative striatal preproenkephalin (PPE) mRNA levels in partial lesioned animals shown in B. Striatal PPE mRNA levels were quantified by densitometry from striatal sections that underwent in situ hybridization. Striatal PPE mRNA levels normally rise in response to DA denervation and have been shown to be reduced after L-dopa treatment.90,173,174,248 Intrastriatal lentiviral mediated L-dopa production had no effect on the 6-OHDA induced increase in PPE mRNA levels. positively to intrastriatal fetal transplants190,116 and L-dopa treatment.116,144 More than doubling the dose of the same vectors used in Mandel et al.148 allowed significantly greater coverage of striatum yet produced no behavioral recovery in either stepping or cylinder tests (Mandel, Björklund, and Kirik, unpublished observations). One obvious hypothesis, given that peripheral L-dopa injections can significantly ameliorate these behaviors, is that insufficient striatal L-dopa levels were being produced. To investigate this issue, rats were administered a peripheral dose of L-dopa known to improve function and their striatal L-dopa tissue levels were determined (Figure 70.4).113 The data indicate that L-dopa levels must be greater than 1.5 pmoles above the DA depleted background levels. New, high-titer rAAV vectors expressing TH and GTPCH1 under the control of a very strong promoter243 were injected in five sites in striatum in order to reach this level of striatal L-dopa (Figure 70.4). Using this injection procedure in both completely DA denervated rats (MFB lesions) or partially DA depleted rats (n. accumbens DA innervated) revealed that, when striatal L-dopa levels exceeded the defined threshold, both partially and complete 6-OHDA lesioned rats significantly

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(E) Striatal TH immunostaining from an animal receiving Lenti-TH alone, scale bar=1 mm. (F) Striatal GTPCH1 immunostaining in an animal that received a mixed vector injection, scale bar=1 mm. Arrow shows area of magnification shown in G. (G) Higher magnification of GTPCH1+cells shown in E. Scale bar=100 µm. These data are in agreement with the idea that subthreshold striatal L-dopa levels do not affect behavior and also suggest that 6-OHDA-induced striatal molecular alterations also require high L-dopa expression levels for functional reversal.

FIGURE 70.4 (A, B) Striatal L-dopa levels after i.p. injection. (A) Two

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groups of partially lesioned animals received injections of benzeraside (benz, 15 mg/kg i.p.) or L-dopa (6.25 mg/kg i.p). In the benz group, low levels of L-dopa were recovered on the lesion or the intact sides. Injection of L-dopa caused accumulation of 1.30 pmol/mg of L-dopa on the lesion side above that of benz alone (arrow). (B) When central decarboxylation is blocked for 30min before killing, 1.2 pmol/mg of L-dopa was recovered on the lesion side (NSD-1015 alone group). L-dopa injection increased striatal L-dopa to 2.75 pmol/mg. Thus, we estimated that accumulation of 1.51 pmol/mg of L-dopa was induced by the injection (arrow). (C, D) Striatal levels of Ldopa and dopamine in completely lesioned animals injected with rAAV vectors. (C) Striatal TH enzyme activity was estimated 30min after NSD-1015 by measuring the accumulation of L-dopa. Increased rAAV-mediated striatal L-dopa in the five-site 1:1 mix group was above the threshold value obtained with peripheral injection (dashed line). In contrast, animals receiving the TH vector alone or the 1:1 mixed vectors in only two sites did not produce this threshold L-dopa level. (D) Dopamine (DA) levels were reduced greatly on the lesioned side in all groups. Striatal dopamine was increased only in the 5×3×3-µl mixed-vector group.

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(E-H) Behavioral effects of L-dopa delivery. (E) Experimental time course. The 1:1 vector mix group showed clear improvements in the cylinder (F) and amphetamine-rotation (G) tests. Reduction in the apomorphine rotation (compared with the fourth pretest; prevalue in H) was observed only in the partially lesioned animals (*=significantly different from the control group and their baseline values before vector injection). (I-N) TH immunohistochemistry in the striatum at three weeks after injection of the 1:1 rAAV-THyrAAV-GCH1 vector mix. In large parts of the striatum (I-L) and globus pallidus (gp, K and L), cell bodies and fibers were TH+. Nearly all infected cells had neuron-like morphology both in

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striatum (M) and globus pallidus (N). There were about 300,000 striatal neurons expressing human TH as estimated by unbiased stereological methods and this number of trangene expressing striatal neurons remained stable over the 15-week period of the experiment (ac=anterior commissure; cc=corpus callosum; lv=lateral ventricle; str=striatum). (The scale bar shown in I=1 mm for I-L; the scale bars in M and N=40 µm). Reprinted from Kirik et al.113 with the permission of the National Academy of Sciences. recovered. Functional recovery, as defined by amphetamine-induced rotational behavior (index of restored striatal DA release227 forelimb akinesia and skilled limb use, was improved in both PD models (Figure 70.4) but, in all cases, partially lesioned rats improved to a greater extent (Figure 70.4). This difference in vector delivered L-dopa efficacy in less severely DA depleted rats can be interpreted to model the situation in PD where L-dopa has a greater therapeutic window earlier in the natural history of the disease in humans.64,65,176 These data are very encouraging, but they do not alone demonstrate any therapeutic advantage over standard L-dopa therapy. Fortunately, a highly reproducible and validated model of L-dopa-induced dyskinesias has been recently developed for the rat.35,36,144,237 rAAV delivered intrastriatal L-dopa in this model produced highly significant reduction in the number of rats that developed dyskinesias by intrastriatal L-dopa delivery.32 Very significantly, molecular changes that occur in striatum in dyskinetic rats such as increased ∆FosB and prodynorphin were also reversed.32 Moreover, extremely long-term expression of L-dopa synthetic enzymes supported by rAAV vectors.148,217 Thus, at least in rodents, several key demonstrations of efficacy have been completed, and marked advantages over standard L-dopa therapy have been observed. Remaining Questions for the L-Dopa Strategy The results reviewed above are extremely encouraging for suggesting that site-specific rAAV-mediated striatal Ldopa delivery might be a useful strategy for treating PD. However, externally regulated L-dopa has not been demonstrated in this model, and this is an absolute requirement considering the different dose levels that are needed for peripheral L-dopa in PD patients and the potential for side effects. Moreover, it would be very prudent to obtain similar positive data in primate models of PD. Primate data will be especially useful in determining if there is a different threshold of striatal L-dopa levels needed to treat the MPTP lesioned monkey as compared to the 6-OHDA lesioned rat. Finally, while wt-AAV is nonpathogenic, and rAAV does not induce significant inflammation in rodents, no significant data regarding rAAV-induced immune response

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are available from primates or from animals preexposed to wt-AAV. As stated above, much of the human population has been exposed to wt-AAV at some point during their life span. Therefore, the effect of circulating anti-AAV antibodies on the immune response to intracerebral administration of rAAV must be investigated prior to the initiation of human trials. Intrastriatal Gene Transfer of AADC as a PD Treatment Rationale for the AADC Strategy As the nigrostriatal pathway continues to degenerate in PD, the therapeutic window for L-dopa narrows. The idea that supplementing striatal levels of AADC, that converts Ldopa to form DA (Figure 70.2), might be therapeutic in PD was first proposed by Kang and colleagues in 1993.108 Increased striatal AADC levels may allow use of lower Ldopa doses that might widen the therapeutic window in late-stage PD patients.108,132 This gene therapy strategy is particularly attractive, because modulation of the peripheral L-dopa dose will control the amount of striatal DA and therefore regulated transgene expression is not necessary. While the rationale for the use of intrastriatal AADC gene transfer is clear and simple, the actual situation in PD is not quite so straightforward. While AADC activity is reduced in both the unilateral 6-OHDA rat model and in PD, there is an unidentified pool of residual AADC activity in the DA depleted striatum.87,88,160–165,181 Moreover, because AADC is a highly active enzyme, even residual striatal AADC levels are capable of efficiently decarboxylating exogenously applied L-dopa. Indeed, it is residual striatal AADC activity that allows L-dopa therapy to be efficacious.31,97 If AADC is rate limiting in the PD striatum, then L-dopa’s conversion to DA would not be therapeutic. While the therapeutic response to L-dopa does wane over the course of PD, a major limitation to Ldopa therapy is largely due to overwhelming L-dopa-induced dyskinetic side effects, and possibly not due to a loss of decarboxylation of L-dopa. Finally, the AADC gene therapy strategy relies on the production of AADC in nondopaminergic striatal neurons. In contrast to the normal situation in the PD striatum, where peripheral L-dopa is decarboxylated in the remaining nigrostriatal DA neurons and DA is released in a physiological manner, AADC-expressing neurons release DA in response to peripheral L-dopa doses in a completely unregulated fashion.200 The therapeutic efficacy of unregulated striatal DA release should be essentially similar to the clinical efficacy of direct DA agonists.81 While DA agonists do abate PD symptoms, they are not as effective as the best response to L-dopa. These caveats raise the possibility that the AADC-based gene therapy strategy may not be better than currently available standard therapy. Gene Transfer Can Restore Striatal AADC Activity Contrary to the situation with L-dopa-based gene therapy strategies, there is little disagreement in the AADC gene therapy literature with regard to the effect of overexpressing striatal AADC on L-dopa decarboxylation. Both intrastriatal transplanted retrovirally transduced AADC-expressing fibroblasts and rAAV mediated striatal transduction have been conclusively shown to functionally increase decarboxylation of peripheral L-dopa.107,132,200,229 In one rAAV study, increased AADC activity was shown

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to last for at least six months.132 Similar results have been achieved using rAAV in rhesus monkeys.7 In an elegant study, Kang and colleagues have shown that AADC expressed along with the vesicular monoamine transporter (VMAT2) overexpression in fibroblasts can prolong the time-course of striatal conversion of L-dopa to DA.130 These experiments show that addition of VMAT2 to AADC in nondopaminergic cells may confer more regulated release of DA. Functional Effects of Intrastriatal AADC Gene Transfer If striatal overexpression of AADC increases the efficiency of decarboxylation of peripheral L-dopa, then lower doses of L-dopa should induce rotational behavior in animal models of PD, i.e., the L-dopa dose response curve should be shifted to the left. At a low dose of peripheral L-dopa, in one study, intrastriatally rAAVAADC transduced 6-OHDA-lesioned rats responded with rotational behavior, whereas control rats did not.200 This is in direct contrast to the behavioral results obtained in an earlier study.132 The behavioral data were not shown in the Leff et al. (132) study, however, they are shown in Figure 70.5. No L-dopa dose, including one that is quite close to the dose used by Sanchez-Pernaute et al.200 (2.5 mg/kg versus 3.0 mg/kg), produced a significant increase in L-dopa-induced rotations in animals that received rAAV-AADC in striatum. AADC Gene Therapy: Conclusion Regardless of the caveats involved with this gene therapy strategy, intrastriatal AADC gene therapy remains a very interesting idea due to its safety profile and the clear ability to overexpress AADC in striatum. In addition, the development of fluoro-meta-tyrosine as a positron emission tomography ligand78,127 enables the detection of the AADC transgene product in vivo.200 The ability to noninvasively monitor the transgene adds to the scientific interest in this strategy. A small carefully designed AADC-based clinical trial might be warranted. Gene Transfer-Mediated DA Synthesis As stated above with regard to the AADC gene therapy strategy, it is unclear whether it will be beneficial to produce unregulated striatal DA as a treatment for PD. However, PD symptoms are probably caused by the specific loss of DA neurons; therefore, it is a simple concept that replacing lost DA might be therapeutic in PD. To synthesize DA, at least three genes are necessary (Figure 70.2)—GTPCH1 to produce BH4, TH to produce L-dopa, and AADC to produce DA. Positive results in animal models of PD have been reported using various vectors to produce striatal DA including rAAV178,207 and lentivirus.6 There are also studies utilizing only TH and AADC that report striatal DA production and behavioral correction in animal models of PD.66,215 However, as reviewed above, it is unclear if there are sufficient striatal BH4 levels to support TH enzyme activity in these animal models. Given the relatively few gene therapy reports available that aim to deliver striatal DA, no firm conclusions can be drawn regarding the potential to treat PD in this manner.

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GENE TRANSFER OF GLUTAMIC ACID DECARBOXYLASE (GAD) TO THE SUBTHALAMIC NUCLEUS (STN) AS A TREATMENT FOR PD Recent phy siological and anatomical analysis of the motor function of basal ganglia circuitry suggested that the STN could be a critical structure for controlling the motor symptoms of PD.11,12,235,236 These data have led to the development of deep brain stimulation (DBS) of the STN as an effective treatment for late-stage PD patients.102,124– 126,137,194 The precise physiological basis for the effectiveness of STN DBS is currently under debate. However, STN lesions improve symptoms and nigral DA neuron survival in animal models of PD.11,22,33,89,159,193 These data have lead to the idea that reduction of activity in STN would be therapeutic in PD. Along these lines, rAAV mediated overexpression of GAD, the synthetic enzyme for gamma-amino-butyric acid (GABA), in the STN has been reported to reduce symptoms in the rat model of PD.145 In further support of this idea, muscimol (a GABA agonist) has been injected into the STN of human PD patients in an area reported to be related to tremor activity.136 Acute muscimol injections were reported to reduce tremor in these patients (n=2).136 These data, have, in turn, lead to the advent of a Phase I clinical trial to test rAAV mediated GAD expression in STN of PD patients.58 While DBS is clearly effective in controlling symptoms of PD, the rAAV vector proposed in the rAAV-GAD clinical trial is not externally regulated. Due to the safety concerns associated with unregulated transgene expression, it is questionable whether this gene transfer strategy will be superior to current version of STN DBS, which has an excellent safety profile. Moreover, chronic stimulation of GABA receptors has been shown to induce tolerance;168,169 however, this phenomenon has not been studied using rAAV-GAD gene delivery. Finally, if symptomatic improvements are observed in this trial, since STN lesions can theoretically improve PD symptoms, there will be no way to determine whether GAD gene expression or toxicity is responsible for the positive results. Indeed, in the human study where STN muscimol injections improved tremor, lidocaine dramatically improved the PD symptoms when injected locally in the STN, indicating that any treatment that reduced STN firing rates should be clinically effective.136 Given the potential hazards and the outstanding conceptual issues associated with this strategy, it would be desirable to expand the current basic research base before proceeding. FUTURE DIRECTIONS: L-DOPA-INDUCED DYSKINESIA The clinical response to L-dopa in PD, even after the “honeymoon” period, is still quite good. One of the main limitations of L-dopa therapy after side effects begin is the onset of peak-dose dyskinesias. Therefore, blockade of the onset of L-dopa-induced dyskinesia would represent a significant advance in PD therapy, and there has been virtually no attention paid to this avenue in the gene therapy field. The mechanisms underlying the development of dyskinesia and motor fluctuations in PD are not fully understood but are believed to depend on the intermittent elevation of brain DA levels caused by pulsatile L-dopa administration in severely DA-denervated subjects.14,38 The consequent intermittent stimulation of brain DA receptors is thought to cause maladaptive plastic changes

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FIGURE 70.5 L-dopa-induced rotational behavior from the animals reported on in Leff et al.132 The animals were tested on Ldopa rotational behavior once per week following a balance Latin square design to control for sensitization

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and/or carryover effect, none of which was observed. (A) Dose-response curve for L-dopa (+25 mg/kg carbidopa in all cases) induced rotational behavior from 6-OHDA lesioned animals expressing 80% of normal levels of striatal AADC after rAAV injections versus control animals expressing about 18% of normal striatal AADC levels. There was no significant differences between controls and rAAV-AADC injected rats. However, the 2.5 mg/kg group approached significance (p=0.06). (B) To rule out the possibility that there was a difference in L-dopa-induced rotational behavior between the vector injected groups at the 2.5 mg/kg dose, the time course of rotational behavior was examined for this dose. There was no time point at which the rotational behavior was statistically different. In a separate experiment, 10 more rAAVAADC transduced animals were tested at the 2.5 mg/kg dose in a crossover experiment with 1.25 mg/kg L-dopa (data not shown). Again, at 2.5 mg/kg L-dopa, there was no significant effect (p>0.05); when both experiments were combined (n=19), the statistical significance remained unchanged. These data indicate that a fourfold increase in striatal AADC activity in the rat 6-OHDA model was insufficient to affect this particular behavior in contrast to the effect reported for 3.0 mg/kg L-dopa.200

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in neurons of the basal ganglia. Current knowledge of such changes has mainly been obtained from studies performed in DA-denervated rodents. Rats that develop dyskinesia in response to chronic L-dopa treatment show exceedingly high levels of ∆FosB-like transcription factors, prodynorphin and glutamic acid decarboxylase (GAD67) mRNA in the striatum, while L-dopa-treated nondyskinetic animals show normal levels of these gene products.4,35 Similar findings have been obtained in non-human primate models of L-dopa-induced dyskinesia24,28,53,218 and postmortem tissue from dyskinetic parkinsonian patients.34 Knowledge of these transcriptional changes in the denervated striatum that only occur in dyskinetic animals suggests a potential therapeutic target for gene therapy. As indicated above, there are methods available to inhibit very specific mRNAs. Thus, blockade of the molecular changes known to be coincident with the expression of peak dose L-dopa-induced dyskinesias may be worth pursuing. CONCLUSION The continued development of viral vectors for gene transfer in the brain has provided the research community with vectors that now transduce a relatively large number of neurons and are capable of supporting very long-term gene expression in the brain. This fact allows the study of various ameliorative gene therapy strategies in animal models of PD. Moreover, especially given the exciting and high profile successes reported in this field,121,145 clinical trials have begun58 and more are being considered. With regard to these “mature” gene therapy strategies, the proteins that are being expressed are secreted, and therefore the viral vectors do not have to transduce every cell in the target population. Indeed, in transmitter replacement gene therapy and GDNF gene therapy, gene transfer is simply providing a technically advanced drug delivery method. In contrast, other gene therapy strategies discussed in this chapter, such as antiapoptotic treatments or the expression of transgenes designed to have molecular effects on target neurons of the striatum, require that very large populations of neurons be transduced by viral vectors. At present, transduction of nearly every neuron in the human neostriatum is probably beyond any vector’s capabilities. However, rapid improvements in viral vector design and production, for example new rAAV serotypes that are far more efficient in the brain52 (Burger, Mandel, and Muzyczka, unpublished data), will eventually enable the consideration of clinical trials using molecular therapeutic strategies. While the technical advances in the development of vectors for use in gene therapy protocols for neurological disorders are encouraging, safety considerations are paramount when considering the use of viral vectors in clinical protocols. The development of regulated vector systems is a prerequisite prior to human use (except in noted cases). Currently, all transcriptional regulation systems require pharmacological agents that may pose additional safety concerns. While promising, these systems have not been validated for clinical use.153,195,232 Moreover, in some cases, most notably with regard to rAAV, the study of the potential immune response in the CNS to viral vectors has not been adequately studied. Certainly, all the technical challenges that remain for the eventual widespread use of gene therapy to treat PD can be resolved; nevertheless, it remains

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important for clinical research only to proceed when all conceivable safety avenues have been proven in animal models. REFERENCES 1. Aboody, K.S., Brown, A., Rainov, N.G., Bower, K.A., Liu, S., Yang, W., Small, J.E., Herrlinger, U., Ourednik, V., Black, P.M., Breakefield, X.O., Snyder, E.Y., From the cover: neural stem cells display extensive tropism for pathology in adult brain: evidence from intracranial gliomas, Proc. Natl. Acad. Sci., U.S.A., 97, 12846–12851, 2000. 2. Aebischer, P., Winn, S.R., Galletti, P.M., Transplantation of neural tissue in polymer capsules, Brain Res., 448, 364, 1988. 3. Akli, S., Caillaud, C, Vigne, E., Stratford-Perricaudet, L.D., Poenaru, L., Perricaudet, M., Kahn, A., Peschanski, M.R., Transfer of a foreign gene into the brain using adenovirus vectors, Nat. Genet., 3, 224, 1993. 4. Andersson, M., Hilbertson, A., Cenci, M.A., Striatal fosB expression is causally linked with 1DOPA-induced abnormal involuntary movements and the associated upregulation of striatal prodynorphin mRNA in a rat model of Parkinson’s disease, Neurobiol. Dis., 6, 461, 1999. 5. Anglade, P., Vyas, S., Javoy-Agid, F., Herrero, M.T., Michel, P., P., Marquez, J., MouattPrigent, A., Ruberg, M., Hirsch, E.C., Agid, Y., Apoptosis and autophagy in nigral neurons of patients with Parkinson’s disease, Histol Histopathol., 12, 25–31, 1997. 6. Azzouz, M., Martin-Rendon, E., Barber, R.D., Mitrophanous, K.A., Carter, E.E., Rohll, J.B., Kingsman, S.M., Kingsman, A.J., Mazarakis, N.D. Multicistronic lentiviral vector-mediated striatal gene transfer of aromatic L-amino acid decarboxylase, tyrosine hydroxylase, and GTP cyclohydrolase I induces sustained transgene expression, dopamine production, and functional improvement in a rat model of Parkinson’s disease, J. Neurosci., 22, 10302, 2002. 7. Bankiewicz, K.S., Eberling, J.L., Kohutnicka, M., Jagust, W., Pivirotto, P., Bringas, J., Cunningham, J., Budinger, T.F., Harvey-White, J., Convection-enhanced delivery of AAV vector in parkinsonian monkeys, in vivo detection of gene expression and restoration of dopaminergic function using pro-drug approach, Exp. Neurol., 164, 2–14, 2000. 8. Bartlett, J.S., Samulski, R.J., McCown, T.J., Selective and rapid uptake of adeno-associated virus type 2 in brain, Hum. Gene Ther., 9, 1181, 1998. 9. Bencsics, C, Wachtel, S.R., Milstien, S., Hatakeyama, K., Becker, J.B., Kang, U.J., Double transduction with GTP cyclohydrolase I and tyrosine hydroxylase is necessary for spontaneous synthesis of L-dopa by primary fibroblasts, J. Neurosci., 16, 4449–4456, 1996. 10. Bensadoun, J.C., Deglon, N., Tseng, J.L., Ridet, J.L., Zurn, A.D., Aebischer, P., Lentiviral vectors as a gene delivery system in the mouse midbrain: cellular and behavioral improvements in a 6-OHDA model of Parkinson’s disease using GDNF, Exp. Neurol, 164, 15, 2000. 11. Bergman, H., Wichmann, T., DeLong, M.R., Reversal of experimental Parkinsonism by lesions of the subthalamic nucleus, Science, 249, 1436–1438, 1990. 12. Bergman, H., Wichmann, T., Karmon, B., DeLong, M. R., The primate subthalamic nucleus.2. neuronal activity in the MPTP model of parkinsonism, J. Neurophysiol., 72, 507–520, 1994. 13. Betz, A.L., Shakui, P., Davidson, B.L., Gene transfer to rodent brain with recombinant adenoviral vectors: effects of infusion parameters, infectious titer, and virus concentration on transduction volume, Exp. Neurol., 150, 136, 1998. 14. Bezard, E., Brotchie, J.M., Gross, C.E., Pathophysiology of levodopa-induced dyskinesia: potential for new therapies, Nat. Rev. Neurosci., 2, 577, 2001. 15. Bilang-Bleuel, A., Revah, F., Colin, P., Locquet, I., Robert, J.J., Mallet, J., Horellou, P., Intrastriatal injection of an adenoviral vector expression glial-cell-linederived neurotrophic factor prevents dopaminergic neuron degeneration and behavioral impairment in a rat model of Parkinson disease, Proc. Natl. Acad. Sci. U.S.A., 94, 8818, 1997.

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16. Björklund, A., Kirik, D., Rosenblad, C, Georgievska, B., Lundberg, C., Mandel, R.J., Towards a neuroprotective gene therapy for Parkinson’s disease: use of adenovirus, AAV, and lentivirus vectors for gene transfer of GDNF to the nigrostriatal system in the rat Parkinson model, Brain Res,. 886, 82, 2000. 17. Björklund, A., Lindvall, O., Cell replacement therapies for central nervous system disorders. Nat. Neurosci., 3, 537, 2000. 18. Björklund, A., Lindvall, O., Parkinson disease gene therapy moves toward the clinic, Nat. Med., 6, 1207, 2000. 19. Björklund, A., Rosenblad, C., Winkler, C., Kirik, D., Studies on neuroprotective and regenerative effects of GDNF in a partial lesion model of Parkinson’s disease. Neurobiol. Dis., 4, 186, 1997. 20. Blacklow, N.R., Hoggan, M.D., Rowe, W.P., Serologic evidence for human infection with adenovirus-associated viruses, J. Natl. Cancer Inst., 40, 319, 1968. 21. Blacklow, N.R., Hoggan, M.D., Sereno, M.S., Brandt, C.D., Kim, H.W., Parrott, R.H., Chanock, R.M., A seroepidemiologic study of adenovirus-associated virus infection in infants and children, Am. J. Epidemiol, 94, 359, 1971. 22. Blandini, F., Nappi, G., Greenamyre, J.T., Subthalamic infusion of an NMDA antagonist prevents basal ganglia metabolic changes and nigral degeneration in a rodent model of Parkinson’s disease, Ann. Neurol, 49, 525, 2001. 23. Bowers, W.J., Olschowka, J.A., Federoff, H.J., Immune responses to replication-defective HSV-1 type vectors within the CNS: implications for gene therapy, Gene Ther., 10, 941, 2003. 24. Brotchie, J.M., Henry, B., Hille, C.J., Crossman, A. R., Opioid peptide precursor expression in animal models of dystonia secondary to dopamine-replacement therapy in Parkinson’s disease, Adv. Neurol., 78, 41, 1998. 25. Burazin, T.C., Gundlach, A.L. Localization of GDNF/neurturin receptor (c-ret, GFRalpha-1 and alpha2) mRNAs in postnatal rat brain: differential regional and temporal expression in hippocampus, cortex and cerebellum, Brain Res. Mol. Brain Res., 73, 151, 1999. 26. Burke, R.E., Kholodilov, N.G., Programmed cell death: does it play a role in Parkinson’s disease? Ann. Neurol., 44, S126, 1998. 27. Burton, E.A., Fink, D.J., Glorioso, J.C., Gene delivery using herpes simplex virus vectors, DNA Cell Biol., 21, 915, 2002. 28. Calon, K, Grondin, R., Morissette, M., Goulet, M., Blanchet, P.J., Di Paolo, T., Bedard, P.J., Molecular basis of levodopa-induced dyskinesias, Ann. Neurol., 47, S70, 2000. 29. Cao, L., Zhao, Y.C., Jiang, Z.H., Xu, D.H., Liu, Z.G., Chen, S.D., Liu, X.Y., Zheng, Z.C., Long-term phenotypic correction of rodent hemiparkinsonism by gene therapy using genetically modified myoblasts, Gene Ther., 7, 445, 2000. 30. Cao, L., Zheng, Z.C., Zhao, Y.C., Jiang, Z.H., Liu, Z. G., Chen, S.D., Zhou, C.F., Liu, X.Y., Gene therapy of parkinson disease model rat by direct injection of plasmid DNA-lipofectin complex, Hum. Gene Ther., 6, 1497–1501, 1995. 31. Carlsson, A., Biochemical and pharmacological aspects of Parkinsonism., Acta Neurol. Scand., Suppl. 51, 11–42, 1972. 32. Carlsson, T., Winkler, C., Burger, C., Muzyczka, N., Mandel, R.J., Cenci-Nilsson, M.A., Bjorklund, A., Kirik, D., Reversal of dyskinesias in a rat model of PD by continuous levodopa delivery using AAV vectormediated gene transfer of TH and GTPCH1, Brain (in press). 33. Carvalho, G.A., Nikkhah, G., Subthalamic nucleus lesions are neuroprotective against terminal 6-OHDAinduced striatal lesions and restore postural balancing reactions, Exp. Neurol., 171, 405, 2001. 34. Cenci, M.A., Transcription factors involved in the pathogenesis of L-DOPA-induced dyskinesia in a rat model of Parkinson’s disease, Amino Acids, 23, 105, 2002. 35. Cenci, M.A., Lee, C.S., Björklund, A., L-DOPAinduced dyskinesia in the rat associated with striatal overexpression of prodynorphine-and glutamic acid decarboxylase mRNA, Eur. J. Neurosci., 10, 2694–2706, 1998.

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71 Translating Stem Cell Biology to Regenerative Medicine for Parkinson’s Disease Dennis A.Steindler Departments of Neuroscience and Neurosurgery, McKnight Brain Institute, University of Florida College of Medicine 0-8493-1590-5/05/$0.00+$1.50 © 2005 by CRC Press

INTRODUCTION This chapter is supposed to focus on potential stem cell therapies for Parkinson’s disease (PD). Since there have been only a few such encouraging stem cell studies in animal models of the disease, the preclinical studies are likewise short in number, and, furthermore, there is perhaps only one human PD patient transplanted to date with human stem or progenitor cells, this chapter will instead concentrate on the new field of regenerative medicine as a target for stem cell biology to help translate new approaches for both protecting and replacing the compromised dopaminergic nigrostriatal pathway. There are a plethora of recent reviews on cell replacement therapies for PD, including position papers on the first human transplant trials.1,2 Despite certain drawbacks in the fetal human mesencephalon transplantation trials for PD, there is still hope for transplant and stem cell therapies to help ameliorate symptoms and possibly even cure the disease. That said, learning from past trials and tribulations is also relevant, and the paradigm shifts accompanying the now burgeoning fields of stem cell biology and regenerative medicine have also helped move this tech nology into the forefront of translation and even include potentially ongoing and best-is-yet-to-come clinical trials. For example, there have been reports of autologous transplants of “brain marrow”-derived cells in at least one human PD patient,3 some growth factor/gene therapies (e.g., GDNF4), and possibly by the time this book appears, other cell/molecular therapies may have charted their initial courses toward human clinical protocols. But, without question, the best is yet to come. The enthusiasm for applying the fruits of stem cell biology, including use of the biogenic factors derived from the field (including new in addition to well characterized neurotrophic/tropic growth factors), though justified, still warrants some tempering in light of the need for more understanding of the biology of these cellular and molecular therapeutic reagents. This has been discussed in recent reviews and position papers5 and therefore will not be extensively reiterated here, but includes an ominous, newly discovered connection between stem cell biology and oncology.6–8

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So what are the most promising candidates for regenerative medicine-generated cell/molecular therapies for PD right now? There are many. Some of them are controversial. Governments, ethicists, clergy, and the lay public have begun to voice their opinions on the use of controversial reagents tied to anything to do with human embryos and fetuses. This is perhaps justified to certain degrees, but the emotional, personal, moral, and religious debates must be separate from the science. The science is so promising as to mandate creative applications of the technologies without compromising any of the opinions, not solely relying on animal reagents because they may bypass most of the controversy, but also including use of any postmortem human materials for research that allows the development of new therapeutics for human diseases.9 This is extremely difficult to accomplish if the debates on human embryonic stem (ES) cells, derived from blastocysts, continue on their current course, but the world is beginning to come to grips with this, and it is hopefully generally assumed that science and scientists are sensitive to the issues and the ethical/moral/religious ramifications of all of this work to the point of not conceding any standards of humanity. Unfortunately, the world has become a bit distracted with the debates surrounding stem cell biology, and even the scientific community must get involved, taking stances to try and ensure that the science will not suffer from any guilt by association generated by either the lay press or stated positions of journals and editors. This is exemplified in the following quotes from recent publications. The appropriately honest and accurate response to the false statement that, if adult stem cells could do everything embryonic stem cells can do, then embryonic stem cell research is unnecessary would be that the issue is not a simple “either/or” but instead is more complicated: maximizing the therapeutic potential of either cell population inevitably would require studying both cell populations. Information for making use of one cell population would inevitably be provided by studying the other, and furthermore it was entirely premature to predict which cell population would ultimately produce the most cost-effective therapeutic options. However, the response of the proembryonic stem cell lobby, including scientists, journalists, and politicians, was swift, unequivocal, and unfortunate. Instead of attempting to convey a more complex message, they largely accepted these overly simplistic terms of the debate, responding in kind: embryonic stem cell research must go forward because adult stem cell research is not convincing. Thus, we have evolved to the current state in which support of embryonic stem cell research now requires that adult stem cell plasticity be repeatedly cast in a negative light….10 Drazen, editor of the New England Journal of Medicine, recently wrote, There are two distinct uses of embryonic stem cells. The first, for which there is no support among members of the scientific and medical communities, is the use of stem cells to create a genetically identical person. There is a de facto worldwide ban on such activities, and this ban

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is appropriate. The second use is to develop genetically compatible materials for the replacement of diseases tissues in patients with devastating medical conditions, such as diabetes or Parkinson’s disease. This is important work that must and will move forward….11 At least the author of this chapter has not seen a breach of this in his experiences and interactions with the field. We can therefore assume that all of the debates will lead to guidelines that help to govern an emerging field like regenerative medicine to not enrage patients or the general public, but rather to bring them into the excitement and possibilities the discoveries offer—discoveries that will so change our lives, and those of our children and their children, with the awesome potential of selfrepair.5 Again, the cliché that regenerative medicine offers the potential of immortality can be used in awesome scenarios, but the vision should focus more on longer quality-of-life goals with reducing the human suffering from disease and injury, and fewer examples of outrageous applications (e.g., cloning armies of servants or warriors). Again, this author is tremendously optimistic about applying the many recent examples of stem cell therapies to many debilitating neurological diseases, including PD, multiple sclerosis, and traumatic injuries. This will contribute to true restorative neurology, with attainable rebuilding of any compromised complex central nervous system (CNS) circuit to restore lost function. Such an advance would represent the translation of stem cell biology to regenerative medicine for Parkinson’s disease—the goal being to completely regenerate or reconstitute lost cells and connections, as well as protect cells that are vulnerable in the disease, utilizing stem cell and other technologies in the most powerful of regeneration protocols. Whether it be in toto or partial, topographically appropriate (i.e., replacing cells in the midbrain) or inappropriate (e.g., grafting cells to the striatum), the protection and reconstitution of dopaminergic innervation of the striatum is an attainable goal of both stem cell biology and regenerative medicine for PD. FETAL MIDBRAIN GRAFTS IN PD DID CONTAIN STEM CELLS Among the list of possible explanations for disappointing outcomes from the fetal mesencephalic transplant trials in Parkinson’s disease are poor survival and integration of the grafts; exuberant production of dopamine from the fetal cells; the generation of a supernumerary and possibly unbefitting basal ganglia structure following the intrastriatal rather than intranigral grafting of midbrain cells; and the unintended but difficult to surmount inclusion of non-dopamine neurons from other midbrain structures in the grafts that could contribute to anomalous behaviors, including dyskinesias. Many investigators and studies have suggested that the best approach for treating PD would be to rescue atrisk dopamine neurons and completely reconstitute the dopaminergic nigrostriatal axis. Complexities and problems associated with the human fetal mesencephalic trials, including variance in the different protocols applied at different institutions (e.g., preparation of the grafts, additions of certain growth/survival factors) and differing viewpoints for graft placement, are nicely summarized in a recent review article by Gene Redmond.2 Included within this and many recent review and position papers is the discussion of how stem cell therapy is now a focus of cell replacement therapies because

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of the potential to generate only dopamine neurons using differentiation protocols that nonetheless still represent a great deal of work in progress. Issues in stem cell therapy include which is the best cell, neural versus nonneural stem cell and embryonic versus fetal versus adult sources; and what are the best priming approaches for preparing such cells to generate requisite numbers of dopamine neurons that innervate target striatal cells following grafting? The clinical trials in PD that used fetal tissue did achieve some degree of success, and the tissue that was transplanted did contain neural stem and/or progenitor cells. In animal model studies using grafts of fetal mesencephalon, it was certainly appreciated early on that immature neurons, precursor cells, and even perhaps stem cells were included in the grafts. This is exemplified in one of our early studies12 where very immature cells were meant to be the grafted reagent so they could insinuate themselves in a very complex circuitry because of their youth (e.g., lacking receptors to the hostile environment of even the normal adult CNS, not to mention a compromised circuit as in the case of the PD nigrostriatal pathway). We showed the presence of very immature cells in these fetal mouse nigral grafts, placed either in the midbrain or neostriatum, that expressed markers of primitive radial glia including the RC-2 protein, that we now know can also be expressed by multipotent astrocytic stem cells13 that are present during developmental neurogenesis and secrete developmentally-regulated proteins that support their neuropoiesis.14 It is presumed that stem cells in the tissue grafts would either eventually differentiate into neurons and glia or die as a result of altered molecular environments in the mature brain that are not conducive for stemness. A supportive environment is artificially created in vitro with the addition of certain growth factors including epidermal growth factor (EGF), fibroblast growth factors (FGF), brain derived neurotrophic factor (BDNF), glial cell line derived growth factor (GDNF), serum, and other factors that keep stem/progenitor cells in an immature and roliferative mode.* Regardless of whether stem or progenitor cells had any positive or negative contribution to the results of the fetal midbrain transplant trials, these cells should quickly differentiate or die if they do not get the right combinations of growth factors that are normally present in the developing brain, or that are supplemented in the in vitro experiments that promote expansion of these cells under particular growth conditions. Finally, in other non-PD human fetal tissue transplants, e.g., the trials for syringomyelia performed by a University of Florida team,15 some of the positive outcomes observed in the eight or so patients grafted with fetal human spinal cord might in part relate to the presence of not only young neurons and glia in these grafts, but also the presence of undifferentiated regeneration-friendly cells including stem/progenitor cells that normally reside in the developing CNS. A question arises as to whether the environment of a solid tissue graft or dissociated fetal human ventral mesencephalon was any better or worse for the survival and functional integration of stem and progenitor cells present in those grafts, versus homogeneous primary cells or lines of dopaminergic precursor cells for ameliorating the symptoms of PD. The field is certainly expounding that enriched populations of stem cells and dopaminergic neuron precursors are better for reintroducing dopamine to the depleted basal ganglia than the fetal tissue grafts because of homogeneity (e.g., lack of nondopaminergic nigral neurons, including glia and cells from surrounding midbrain structures that were certainly included in both the animal and human transplant studies1,2), presumed better efficiency, consistency, and maybe even survival and

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dopaminergic innervation compared to the fetal tissue and cell grafts. But at the present time, it is still uncertain as to which stem, stem-like, or progenitor cell will best accomplish cell replacement or circuitry protection in brain injury or neurodegenerative diseases including PD. GRAFTS OF ES, STEM CELL LINES (E.G., THE C17.2 RODENT AND NOW HUMAN IMMORTALIZED NEURAL PRECURSOR LINES), AND OTHER STEM/PROGENITOR CELLS IN ANIMAL MODELS OF PD (FOR RESCUE AND REPLACEMENT) EMBRYONIC STEM (ES) CELLS There are several choices of stem, stem-like, progenitor, and dopaminergic neuron precursor cells for grafting into the striatum or midbrain of PD patients. These include *

It should be defined here that a stem cell is a self-renewing cell that can give rise to different progeny, is able to survive and keep its selfrenewing ability following serial transplantation, and can respond to injury or disease with repopulating prowess. A progenitor cell is a more committed cell that can give rise to more differentiated cells, e.g., neurons or glia, and the term “stem/progenitor cell” is used where the degree of stemness of the cell in question has not been resolved. See Reference 14 for details.

adult “brain marrow” (see below, but defined as those periventricular regions of the adult brain that exhibit persistent expression of developmentally regulated proteins including extracellular matrix, and the presence of cycling, neurogenic stem, and progenitor cells; this includes the periventricular subependymal zone, SEZ, of the forebrain lateral ventricle, its migratory extension into the olfactory bulb termed the rostral migratory stream, RMS, and the hippocampus, see Figure 71.1), fetal sources, bone marrow, cord blood or mesenchymalderived cells, cell lines including those derived from human cancers, indigenous cycling precursor cells that do inhabit the nigra (see below), and embryonic stem cells. ES cells are controversial for a variety of reasons, as already mentioned, but they offer potential for combining cell and gene therapies for a variety of neurological and other disorders. The advantages of ES cells as donors for replacement or rescue therapies include their pluripotency, defined by their ability to generate cells exhibiting the phenotype of most or all tissues in the body; the potential for unrestricted proliferation; their amenability to genetic modification; and, finally, the possibility for controlled fate choice and differentiation such that it might be possible to obtain highly purified neural cell populations.16–18 ES cell-derived neural precursor cells have been efficiently derived from both rodent and human ES cells. Upon transplantation, these cells incorporate widely throughout the CNS and differentiate into neurons, astrocytes, and oligodendrocytes. Transplantation of neural precursor cells represents an alternative route to replace lost or damaged neurons in the adult CNS. Although this approach can be developed to a clinical scale,19 it is currently complicated by its dependency on donor tissue, e.g., from in vitro fertilization clinics. Transplanted neural precursors derived from primary CNS tissue or cultured ES cells can integrate into the developing brain and

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differentiate into mature neurons and glia. The successful integration of these cells can be established using morphological and immunophenotypic labeling methods. There is a paucity of electrophysiological data on the functional integration of embryonic stem cell derived neural precursors following transplantation, although very recent studies16,18 have shown functional integration of neuronal precursor cells that were derived from ES cells. One might suggest that complete functional integration may be mandatory for complete functional restoration of the dopaminergic nigrostriatal pathway. There is some possibility that dopamine-replacement alone from these cells might be therapeutic, much like L-dopa is. One would assume that reconstitution of the cell replacement topography and precise afferent and efferent innervation patterns is likewise important for complete functional reconstitution. These ultimate goals fall on one end of a spectrum of emerging palliative as well as cure—attempting protocols that use dopamine and nondopamine cells

FIGURE 71.1 Sites of persistent neurogenesis, or neuropoiesis, within the adult human brain. Neural stem cells (NSCs), and a potentially heterogeneous population thereof, reside within adult “brain marrow”— the periventricular subependymal zone (SEZ, “long arrow”) and the hippocampus (arrowhead). In addition, there are small numbers of cycling cells found throughout the neuraxis (e.g., asterisk in the cerebral cortex) that could exhibit stem cell-like behaviors under certain conditions. Adult NSCs are clonogenic and

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multipotent, able to give rise to all three types of CNS cells (also see Figures 71.2 and 71.3). It is still not clear that these cells can give rise to all types of neurons and glia of the CNS (they may have a propensity to generate local circuit cells). We do not understand why cells persist in the senescent and even cadaveric brain, but their position may indicate something about their nature. Most proliferative or clonogenic cells appear to reside within the periventricular SEZ and hippocampus, but recent evidence indicates the possibility for dedifferentiating glial cells to exhibit stem cell-like behaviors, suggesting the possibility that other areas besides the SEZ and hippocampus may be neurogenic. The SEZ and hippocampal cells may be involved in steady-state neurogenesis for the replacement of cells in the constantly remodeling olfactory bulb, and in the hippocampus. In the latter, the functional implications of new granule cells in the dentate gyrus have not been clearly elucidated, although recent reports indicate a loss of these cells in experimental animal models impacts short term memory. One possibility is that a small stem cell population within the SEZ (a vestigial remnant of the proliferative germinal matrix of the embryonic forebrain) represents “leftover bricks at a construction site”; this should not imply that the cells that inhabit the SEZ are the same cells that built the brain during development,

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rather, they should be considered nonprogrammed neural cells that can be induced to exhibit stem cell-like behaviors. (Adapted from Steindler and Pincus, Reference 5. With permission.) derived from ES, fetal, neural, and nonneural stem/progenitor cell graft therapies. These cells might supply dopamine or other sustaining neurotrophic factors that help to promote survival of at-risk nigral dopamine neurons as well as attempt cell replacement. New designer therapies might combine a variety of cellular and genetic therapies in combinations to generate cells that will

FIGURE 71.2 Neurosphere clones of cells derived from mouse neural stem/progenitor cells. Neurospheres reflect the ability to expand small numbers of neural stem/progenitor cells into large numbers of these densely packed cellular aggregates that contain neuronal, in addition to the

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clonogenic stem cell, glial progenitor cells, neurons, and glia in different states of differentiation. The neurons in these clones are stained with a red fluorescent neuronal marker, the glia are green, and the neurospheres were counterstained with a blue fluorescent nuclear marker. The diameter of the neurospheres is approximately 150 µm. (A color version of this figure follows page 518.) accomplish both of the aforementioned goals, but there will be chaperone and replacement cell therapies for PDthat owe their development to evolving understandings of the molecular cell biology of dopaminergic precursor cells. Two studies in particular show the promise as well as the uncertainty of using ES cells as PD therapeutics at this point in the time. Lars Bjorklund with the Isacson group, and Ron McKay and collaborators16,17 transplanted low doses of undifferentiated ES cells into the normal and 6-hydroxydopamine (OHDA)-lesioned adult rat striatum. Following an injection of 1 to 2000 mouse ES cells, with cyclosporine A immunosuppression, after 14 to 16 weeks, 2059±626 tyrosine hydroxylase positive cells were identified in the graft site, and these cells expressed other markers of midbrain dopamine cells including aromatic amino acid decarboxylase and calretinin. The Isacson lab has been a very strong proponent of ES cell therapies for PD, and at the same time has cautioned the field about the need for precise molecular differentiation protocols (see Figure 71.4 and Reference 1), and proper assessment of differentiated cell phenotype that matches the desired neuron fate choice (e.g., A9 versus A10 dopamine groups, Vental Tegmental Area phenotypy that can be resolved using the appropriate molecular markers and fingerprinting; the list of both neuralization and dopaminization factors, often requiring presentation in combinations and at particular stages of the neuron and dopamine neuron generating protocols, reads like a list of morphogenetic genes used to build a fruit fly, e.g., sonic hedgehog, Pax’s, Lmx, Smad4, neurogenin, noggin, chordin, FGFs, Wnts, and on and on, see Reference 1). In their study of undifferentiated ES cell grafts in the normal and lesioned striatum, in addition to the very positive outcomes of apparent ventral mesencephalon dopamine neuron differentiation and improved “behavioral restoration of dopamine-mediated motor asymmetry,” some astrocyte differentiation, and some apparent generation of mesodermal cells (via the observed expression of desmin/myosin and keratin), 5 of the 25 ES cell-injected animals also became severely ill and had developed “teratoma-like structures” at the graft site. This should not be surprising in light of their choice of undifferentiated ES cells, but their positive outcomes were quite impressive and supported the notion that ES cells can generate dopamine neurons that release dopamine and improve motor behaviors in the 6-OHDA-lesioned rat (see Figure 71.5).

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FIGURE 71.3 Human neurosphere clones, and cells derived from them, grown in tissue culture from stem/progenitor cells cultivated from adult human brain biopsy and autopsy specimens. A neurosphere is a tissue culture-generated clone of cells that are in different states of differentiation (e.g., maturing glia and neurons), all presumed to arise from a single multipotent stem/progenitor cell. Phase (a) and immunocytochemical (b–g) images of differentiated human neurospheres after plating on laminin.

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(a) Phase microscopy of a neurosphere plated on laminin shows how the sphere begins to differentiate following plating, and cells migrate out from the sphere. Scale bar=100 µm. (b) Immunofluorescence for the intermediate filament protein nestin in a single sphere, showing many large nestinlabeled cells, in addition to small cells (arrow). Inset shows a cluster of nestin-positive cells (arrowhead) that have migrated from a neurosphere (asterisks), as well as a labeled long process projecting from the sphere (arrow). Scale bar=50 µm in (b) and 10 µm in the inset. (c) Immunolabeling of a sphere (asterisk) shows dense vimentin expression by neurosphere cells, including those and their processes that have emigrated from the sphere (e.g., arrow). Scale=50 µm. (d) GFAP immunolabeling of astrocytes within a neurosphere, and processes emanating from the neurosphere. Arrows in (d) and (e) point to the same landmark in this neurosphere stained with GFAP vs. beta III tubulin markers. Inset in (d) shows a cluster of vimentin positive radial-like glia and immature astrocytes that have migrated away from a neurosphere. Scale=50 µm for (d) and (e). (e) Neuronal beta III tubulin immunolabeling of the neurosphere shows many labeled neurons. (f) Double labeling for GFAP (blue) and beta III tubulin (green) shows both astrocytes and neurons residing within a plated sphere. Scale bar=50 µm. (g) De novo generated

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neurons, with distinct morphologies, that have grown out from a plated neurosphere stained for beta III tubulin (brown, peroxidase in the inset) and using immunofluorescence (g). Scale bar= 25 µm in (g), 100 µm in the inset. (Adapted from References 5 and 22. With permission.) (A color version of this figure follows page 518.) Another ES cell-Parkinson’s rat model grafting study published in 2002 from Ron McKay’s lab16 utilized thefive-stage method of ES cell differentiation into neurons, and also exploited a well appreciated dopaminization factor, Nurr1, and manipulating exposure of the cells to the fibroblast growth factors (FGFs), Leukemia Inhibitory Factor, and sonic hedgehog (SHH) to attempt enrichment of the tyrosine hydroxylase (TH)expressing population.

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FIGURE 71.4 Midbrain dopamine neuronal development from embryonic stem (ES) cells. Schematic illustration of known developmental factors involved in the identification and generation of midbrain dopamine (DA) neurons from mouse ES cells. ES cells

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can be identified by expression of embryonic markers such as stage specific embryonic antigen 1 (SSEA1)or OCT-4. ES cells can adopt neuroectodermal fate through a “default” mechanism involving inhibition of transforming growth factor (TGF)-related molecules such as activin and bone morphogenetic proteins (BMPs) as well as TGF-beta downstream targets like smad4. Factors known to be of importance for “default” neuralization are the socalled “BMP inhibitors,” Noggin, Chordin, Follistatin, Cerberus, and Xnr3 as well as culturing or transplanting ES cell in low density to avoid autocrine and paracrine TGFsignaling. Cells of neuroectodermal lineage are believed to adopt a neuronal fate under the influence of basic helix-loop-helix (bHLH) factors such as NeuroDs and Neurogenins or other factors such as Musashi 1 and 2. Neuronal phenotype can be identified by expression of Beta III tubulin, neuronal nuclear antigen (NeuN), A2B5 antigen, or microtubuleassociated protein 2 (MAP-2). Midbrain DA neurons are generated at the intersection between midbrain and hindbrain in response to a ventraldorsal gradient of floor plate-derived sonic hedgehog (SHH) and a anteriorposterior gradient of fibroblast growth factor 8 (FGF-8). Factors known to be of importance for proper development of midbrain DA neurons are Gbx-2, Otx-2, Pax 2, 5, 8, Wnt-1,

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Nurr1, Pitx-3, and Lmxlb. Midbrain DA neurons that express tyrosine hydroxylase (TH), L-aromatic amino acid decarboxylase (AADC), the dopamine transporter (DAT), and the vesicular monoamine transporter 2 (Vmat-2) will, through yet unknown mechanisms, develop into functionally and anatomically distinct subpopulations such as the A9 (aldehyde dehydrogenase 2, also known as retinaldehyde 1 [Raldh1] expressing) and A10 (calbindin and cholecystokinin [CCK]) expressing cells. (Adapted from Reference 1. With permission.) (A color version of this figure follows page 518.)

FIGURE 71.5 In vivo imaging of dopamine neurons after transplantation of mouse embryonic stem cells to the

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adult dopamine denervated rat striatum. (A) positron emission tomography (PET) imaging using the specific dopamine transporter (DAT) ligand carbon-11-labeled 2carbomethoxy-3-(4fluorophenyl)tropane (11 C-CFT) showing specific binding in the right grafted striatum, as shown in this brain slice (A, left panel) acquired 26 min after tail vein injection of the ligand. Color-coded (activity) PET images were overlaid with magnetic resonance imaging images for anatomical localization. The increased 11 C-CFT binding in the right striatum correlated with postmortem presence of THimmunoreactive (IR) neurons in the graft (A, right panel). (B) Animals receiving embryonic stem (ES) grafts showed restored DA release mediated neuronal activation in response to amphetamine (2 mg/kg). Colorcoded maps (percentage change) in relative cerebral blood volume (rCBV)in an animal with an ES cell-derived DA graft are shown in three slices spanning the striatum. Only ES cellgrafted animals showed recovery of signal change in motor and somatosensorial cortex (arrows), and this was also seen, although to a minor extent, in the striatum. (C) Graphic representation of signal changes over time in the same animal as shown in (B.) The response in grafted (red line) and normal (blue line) striata was similar in magnitude and time course, whereas no changes were observed in

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sham-grafted dopamine-lesioned animals (green line). Baseline was collected for 10 min before and 10 min after MION injection, and amphetamine was injected at time 0. cc=corpus callosum. (Adapted from References 1 and 17. With permission.) (A color version of this figure follows page 518.) It was found that SHH and FGF8 further enhanced the production of TH-expressing cells from the Nurr1 overexpressing ES cells to almost 80% of the neurons generated. Furthermore, when slice electrophysiological studies were performed, it was found that the “…ES-derived neurons develop functional synapses and show electrophysiological properties expected of mesencephalic neurons…,” including those of TH+ and TH– mesencephalic neurons (see Figure 71.6). These animals, in behavioral studies, also showed significant improvement in rotational, adjusting step, cylinder and paw-reaching tests. This prompted McKay and collaborators to say, “Our results encourage the use of ES cells in cell-replacement therapy for Parkinson’s Disease….”16 It is at this point that, in light of the Isacson and McKay group ES cell transplant findings, that stem cell tumorigenesis and incomplete neuronal differentiation18 issues should be addressed, since Isacson’s group reported the generation of tumors following their undifferentiated ES cell grafts, and the McKay group reported apparently normal synaptic activities of their Nurr1 overexpressing ES-derived midbrain-dopamine-like neurons. Of course, the world has appreciated the roles of hematopoietic stem cells in the leukemias (see Reference 5 for review), but it has only been recently that three studies have shed a great deal of light on the potential roles of stem/progenitor cells in solid tumorigenesis in the brain6 and breast.8 In both of these studies, the behaviors of abnormal stem-like cells associated with neoplasia and the generation of diverse progeny have been noted, with the suggestion that a primitive cell that normally gives rise to limited numbers of progeny with characteristic lineage diversity now gives rise, due to genetic and/or epigenetic anomalies, to a diverse set of abnormal progeny that constitute gliomas and other solid tumor types. Thus, the existence of a “cancer stem cell”7 suggests that we need to

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FIGURE 71.6 Electrophysiological properties of TH+ neurons. Simultaneous recordings were performed from neurons in the graft located on the graft-host border and neurons in the host striatum. (a) Representative current-voltage relationship for a host striatal TH− neuron and a TH+ neuron in the graft. The TH+ neurons display the timedependent anomalous rectifier characteristic of dopaminesynthesizing cells after a hyperpolarizing pulse. Circles, the full extent of the immediate reduction in the membrane potential; triangles, the sustained membrane potential. (b) Spike train profiles of a host striatal neuron and a graft-derived TH+ neuron. TH+ neurons fired broader action potentials at a lower frequency than TH- neurons. (c) ES-derived TH+ neurons in the graft displayed a unique evoked IPSP mediated by activation of the metabotropic glutamate receptors.

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(d) Extracellular stimulation in the center of the graft resulted in an EPSP in both a graft-derived TH+ neuron and a host striatal neuron, indicating the presence of graft-to-host and graftto-graft synapses. (e) Confocal micrograph illustrating a biocytinfilled (green) TH+ neuron in the graft in close proximity to other nonfilled, graft-derived TH+ neurons (red). The neuron was filled during recording. The filled neuron extends processes well into the host striatum. The dotted line shows the host-graft interface. Scale bar, 50 mm. (Adapted from Reference 16. With permission.) be cautious before transplanting any potent cell into the nervous system, and this is further reinforced by the recent study from our group that showed transplantation of an indigenous stem cell population from the postnatal and adult mouse brain, the SEZ multipotent astrocytic stem cell, back into the vicinity of brain marrow can give rise to hyperplasias that have attributes of tumors.20 Whether the ex vivo manipulations of the clonogenic cells, supporting dedifferentiation programs and possibly making these cells susceptible to genetic malformations during the excessive growth factor exposures, or other factors or conditions contributed to the potential for hyperplasia, the potential for neoplasia must be studied further before pronouncing a stem or progenitor cell population ready for human use. Likewise, pronouncing any stem cell, including ES, as giving rise to a completely differentiated and “normal” populations of desired neurons (e.g., dopamine neurons for PD), based on electrophysiological and molecular phenotyping, also requires a fair amount of diligence, since it is possible that we might miss incomplete differentiation as well as the retention of subtle attributes of the starting cell population (e.g., in the case of ES cells, undifferentiated or non-neural differentiated states), since our protocols for characterizing phenotype and differentiation are not yet perfect. Most groups admit that certainly less than 100% of their populations, even following the best neuralization protocols, are neural; we probably do not want to graft these non-neural and undifferentiated non-neural cells into the brain along with the neuronal precursors of choice. Even the best of differentiation protocols of ES-derived neuronal progenitors still give rise to populations of cells that do not express the full repertoires of neurotransmitter-related receptors and channels (e.g., see Benninger et al.,18 who elegantly showed many normal neurophysiological behaviors of their ES-derived neurons, but they appear to lack NMDA currents that are so rudimentary to the functions of the hippocampal neurons they were studying). It is certainly possible that a cell that does not grow up in the nervous system does not have all of the appropriate programs for

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generating molecular and behavioral hallmarks of fullydifferentiated neurons. We must therefore devise protocols and assays to test for this and surmount this. Perhaps exposing such primitive cells in search of identity to morphogenetic factors and conditions that might favor full differentiation sequalae can compensate for the lack of exposure to critical and sequential morphogenetic programs and factors that are normally present in situ. ADULT NEURAL STEM CELLS Adult human brain neuropoiesis5 supports suggestions that adult brain-derived stem cells21,22 might also see a place in PD transplant therapies, especially if we might be able to modify their maturation with factors including telomerase.23 At the end of a neurodevelopmental critical period (roughly the second postnatal week in rodents), extracellular matrix (ECM) and other developmentally regulated “recognition” molecules are down-regulated to negligible levels, except for in a few brain areas including the periventricular subpendymal zone (SEZ).14,22 The presence of developmentally regulated ECM and other molecules in the SEZ, along with cycling cells as seen using tritiated thymidine- or bromodeoxyuridine-labeling, suggested the possibility of persistent neurogenesis, or “neuropoiesis” throughout life in the mammalian forebrain, and also prompted comparisons of this neurogenic region to hematopoietic bone marrow (thus, “neuropoietic brain marrow”5,14). The long-standing axiom within neuroscience that, with few exceptions, the postnatal mammalian CNS is capable of little or no de novo neurogenesis, includes now the well accepted findings of newly generated neurons in the periventricular SEZ as well as other CNS regions in rodents and primates. In addition to in vivo demonstrations of neurogenesis, cells have also been isolated from postnatal and adult CNS that can grow as proliferative clones, termed “neurospheres” (see Figure 71.2), that are multipotent, since they can give rise to the three major classes of neural cells: neurons, astrocytes, and oligodendrocytes from a variety of fetal, postnatal, and adult mammalian (including human, see Figure 71.3) brain marrow sources. Neurospheregenerating cells, or the tissue-specific “neural stem cell” have been isolated from the SEZ24 and other regions, including spinal cord, of rodents as well as from adult human SEZ and hippocampus.22 When fetal human neural stem cells were transplanted into the neostriatum of rats with unilateral dopaminergic lesions, even after 20 weeks, there were surviving cells in the grafts, and some of these cells expressed tyrosine hydroxylase and seemed to attempt innervation of the host striatum.25 The fetal and adult human neural stem cell studies obviously drove the first autologous stem cell transplants for human PD by Levesque and colleagues who have described in lay press publications3 the grafting of a PD patient’s own “neural stem cell population,” obtained from a brain biopsy, into their neostriatum. Despite the apparent initial expression of dopamine in these grafts, they reported that, after one year, these levels returned to presurgery levels, but “…an 83% reduction in symptoms, such as tremor, has inexplicably persisted…. may be due to other cells in the transplanted mixture….” It would seem reasonable to further explore the proof of principle of autologous stem/progenitor cell grafts in animal models before taking these cells to additional human trials. The ability to purify NSC populations from postnatal and adult CNS is particularly important for studies attempting to characterize, expand, and use these cells in cell-

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replacement therapies. Not surprisingly, the search for the NSC has concentrated on the periventricular SEZ of the rostral forebrain. The adult SEZ seems to be a special region, since it represents the vestigial embryonic germinal zone, displays a high level of constitutive proliferation, and is likely to contain the greatest density of putative NSCs. Work from our laboratory13 has shown that a cell exhibiting characteristics of an astrocyte, from the developing brain until the end of the second postnatal week, and from the SEZ throughout life, is a multipotent stem cell that can give rise to neuropsheres containing both glia and neurons. Detailed ultrastructural analyses of this cells has also been performed by Alvarez-Buylla’s group.26 Studies recently conducted in our laboratory have shown that neurospheres derived from multipotent SEZ astrocytes (the type “B” cell of Alvarez-Buylla’s group), in the presence of epidermal growth factor (EGF) and FGF -2, can differentiate into cells with antigenic profiles of neurons, astrocytes, and oligodendrocytes. These studies support a notion of dedifferentiation ability of mature, differentiated populations of neural cells (e.g., a subclass of the pervasive astrocyte population), and also support recent observations of a potential lack of replicative senescence (the possible overturning of the “Hayflick limit,” whereby it was suggested that cells can undergo only so many population doublings, e.g., 50 divisions, before “aging”27) of these clonogenic, multipotent cells (see Reference 5 for review). Despite holes in our understanding of the nature of adult neural stem cells, they do offer a potential source of cells for transplantation in PD. The finding that both adult mouse and human neural stem cells can survive with rather protracted postmortem intervals28 even suggests that the cadaveric human brain is a source of cells that could be manipulated for therapeutic applications in diseases including PD. HEMATOPOIETIC STEM CELLS In addition to the neuropoietic sources in brain, the hematopoietic system is another potential source of mul-tipotent cells that might be able to be coaxed into neuronal and glial differentiation. Hematopoietic stem cells (HSCs), including the highly touted, presumably extremely potent umbilical cord blood stem cells, retain their pleuripotent differentiative capacity throughout the life span of an organism, and homeostasis is maintained by a constant, ordered, and tightly regulated developmental cascade. HSCs differentiate through a hierarchical array of multipotent and monopotent progenitor cells to form all blood cell types, including lymphocytes, granulocytes, monocytes, erythrocytes, and megakaryocytes. The regulatory pathways that control hematopoiesis consist of several interconnected mechanisms. One level of regulation is the transcriptional control of hematopoieticspecific gene expression. A second mechanism involves the interaction of hematopoietic growth factors with their cognate cell-surface receptors. Cell-cell signaling mediated by adhesion molecules also plays an important role in regulating hematopoiesis. The hematopoietic system also offers a well characterized, adult model of reconstitution following ablation. Despite a recent study by our collaborators here at the University of Florida,29 raising the question of “cell fusion” involved in the so-called recent stem cell plasticity studies, there is a considerable body of literature regarding the possible ability of hematopoietic cells to participate in the formation of neural tissue. In vitro studies indicate that conditions can be found to coax hematopoietic cells to express neural characteristics. For

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example, Sanchez-Ramos and collaborators, and Black and collaborators30,31 showed that bone marrow stromal cells in culture can express neural markers of astrocytes and neurons when exposed to particular growth conditions and factors. It also has been shown that bone marrow stromal cells, injected into neonatal mouse ventricles, could adopt neural fates as evidenced by their expression of glial fibrillary acidic protein (GFAP, an intermediate filament protein specific to astrocytes) and a neuron-specific neurofilament protein.32 When Mezey and colleagues33 transplanted bone marrow from male wildtype mice into hematopoietically compromised PU.1 null female neonatal mice, they found that numerous cells containing the Y-chromosome were present in the brain, and some of these expressed antigens specific for mature neurons. Finally, Brazelton and colleagues34 transplanted adult-derived bone marrow from green fluorescent protein (GFP) transgenic mice into lethally irradiated adult wildtype mice, and found that GFP-expressing cells entered numerous brain regions, and some of the grafted cells coexpressed neuronal, but not glial, antigens. However, both of these latter studies failed to show complete differentiation and integration of donor cells in the host brain, as would be typified by elaboration of extensive neuritic arbors and the generation of synapses, and the yield of donor cells that exhibited transdifferentiation was quite low. The goal of rebuilding functional brain tissue following injury or disease could be achieved through the directed homing of bone marrow-derived stem cells to the injured brain. This would certainly overcome the many obstacles of trying to access, isolate, and expand one’s neural stem cell population for cell replacement therapies in neurological disease. There is very little known about potential homing and trafficking factors (see Figure 71.9) involved in CNS stem cell recruitment, unlike our increasing knowledge of “Homing and Trafficking of Hemopoietic Progenitor Cells.”35 It is interesting that we have recently found, looking at postmortem brain specimens from patients receiving bone marrow transplants, that chimerism can occur in the hippocampus, with bone marrow-derived cells apparently homing to the possibly radiation/chemotherapy-affected forebrain whereby they transdifferentiated into neurons and glia without cell fusion involved.36 IMMORTALIZED NEURAL PRECURSOR CELLS As recently reviewed,37 the year 1992 was an important year for restorative neuroscience with the discovery of clonogenic stem cells in the adult brain by Reynolds and Weiss, Bartlett and colleagues, and the report of an immortalized neural stem cell line able to participate in mouse cerebellar development by Evan Snyder and the Cepko lab. The most utilized cell line, the C17.2 cell line, has demonstrated extreme potential and plasticity, and these “stem-like” cells exhibit a remarkable ability to insinuate themselves within established and compromised rodent central nervous system CNS structures and circuits, home to injured areas, migrate, exhibit diverse lineage potential, release neurohumoral factors, and overall offer the possibility of reconstituting neural circuitry in a variety of models of neurological disease (see Figure 71.7). These cells are “stem-like” cells because the starting cell population (neonatal mouse cerebellar external granular layer cells) was immortalized by retrovirus-mediated transduction of avian myc (V-myc) that produced a clonal multipotent progenitor cell line. These cells are therefore somewhat “transformed,” which probably helps contribute to their impressive plasticity.

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Nonetheless, the cells offer insights into the control of fate and integration of cells as therapeutics for a variety of neurological disorders.

FIGURE 71.7 Immortalized cerebellar precursor cells for dopamine neuron rescue. The C17.2 cell line was generated by V-myc immortalization

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of neonatal mouse cerebellar precursor cells. This cell line has been used in previous studies to “chase” tumor cells, replace lost cells in the injured cerebral cortex, help ameliorate some of the behavioral deficits following spinal cord injury, and replace lost cerebellar neurons in a mutant mouse. Grafts of C17.2 cells within the dopamine neuron-injured midbrain of adult mice that have a “chaperone” effect on the rescuing of dopamine neurons in a rodent MPTP model of Parkinson’s disease. In addition to an apparent neurotrophic rescue of the injured dopaminergic neurons and their nigrostriatal axonal projections, C17.2 cells also gave rise to small numbers of newly generated dopamine neurons, and they also were found to migrate to disparate CNS sites. These grafts also appeared to improve motor behaviors of the MPTP-injured animals. (Adapted from Reference 37. With permission.) This cell line has been used to generate an interesting chaperone effect for rescuing TH expression by injured cells in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-injured midbrain substantia nigra of aged mice (see Figure 71.7). Transplantation of the C17.2 cells in the vicinity of the MPTP-injured dopamine neurons in the midbrain resulted in some new dopamine neurons being generated, but in addition, it was found that most of the TH (the rate-limiting enzyme in dopamine synthesis) expression was associated with rescued host cells. In this study,38 in addition to the C17.2 cells rescuing midbrain dopamine neurons in the MPTP-lesioned animals (as seen using immunocytochemical and biochemical assays), in a functional assay D-amphetamineevoked rotational behavior also regressed. In addition to this immortalized mouse neural precursor cell line seeming to offer another potential source of cells for protection and replacement of dopamine neurons in rodent PD models, a human neural precursor cell line has been generated with the help of Evan Snyder and Angelo Vescovi,39 again using a v-myc immortalization protocol and human fetal neural stem cells. Even though all examples of the immortalized precursor and stem celllike lines indicate a strong propensity to protect and rebuild damaged brains,

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their zealous ability to migrate, and their potential for harboring an abnormal genome that could conceivably generate neoplastic transformation, must make us take pause when considering the use of such cells for human transplantation therapeutics in diseases including PD without exhaustive analyses in animal models. OTHER CELLS AND MORPHOGENETIC FACTORS AS POTENTIAL THERAPEUTICS FOR PD A paper was published in 2001 using Evan Snyder’s C17.2 immortalized neural precursor cell line to provide the potent dopaminergic neuron growth/protective factor glial-cell line-derived neurotrophic factor (GDNF) to at risk neurons in the 6-hyrdroxydopamine mouse model of PD.40 This built on numerous previous observations of the potential of GDNF in gene therapy protocols from Ron Mandel, Jeff Kordower, Marty Bohn, and many others, showing that this growth factor could be used to protect and rescue at risk dopamine neurons in these lesion models. In addition to the GDNF-expressing C17.2 cells insinuating themselves into the compromised striatum and generating neurons and glia, including neurons with dopaminergic traits, they “…gave rise to therapeutic levels of GDNF in vivo, suggesting a use for NSCs engineered to release neuroprotective molecules in the treatment of neurodegenerative disorders, including Parkinson’s disease….” Thus, as depicted in Figure 71.7, in addition to stem cells being used to replace lost dopaminergic neurons in models of PD, they hold the potential to act as sources of neurotrophic, neuroprotective molecules to be released to possibly rescue atrisk cells during the course of disease. Clive Svendsen and collaborators41 also showed that genetically modified neurospheres, engineered to release GDNF using lentiviral constructs, when cotransplanted with primary dopamine neurons in 6-OHDA-lesioned animals, seemed to support the survival of these cografted cells. Obviously, some of this work, along with the pre vious GDNF successes in rodent and primate models by other investigators, led to the recent human trials by Svendsen and collaborators.4 Perhaps one of the most exciting therapeutic approaches for PD will utilize the findings of a pervasive network of multipotent glial cells that exist into adulthood in the CNS, even in the substantia nigra. Such cycling glial cells, which we originally described as being able to generate both glia and neurons throughout the neuraxis during a critical period in postnatal development,13 have now been described as cells that persist in the adult rodent and have many attributes of “satellite” cells whose potency and repopulation prowess have been studied in other tissues including muscle and vasculature (e.g., the elusive pericyte). The cycling glial stem cell data from the Gage group (see Figure 71.8 and Reference 42), and the neurogenesis findings of nigral glial cells by the Gallo lab,43 suggest that certain substantia nigra glia may be capable of sustaining and/or making dopamine neurons. With the idea being set forth that glial cells can exhibit stem cell-like behaviors (e.g., Reference 44), a goal now is to establish how to get cells like the one recently discovered in the adult rodent substantia nigra to be neurogenic in vivo, as it has been demonstrated in vitro,42 since it has been shown to only give rise to glial cells in vivo even when manipulated using a variety of approaches. If what appears to be a truly mutlipotent, cycling glial cell does inhabit the human substantia nigra, and if the rodent data is also extended to the human, and this cell can only generate neurons when

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manipulated ex vivo (or following grafting into forebrain brain marrow or hippocampal42 structures), then we must figure out ways to encourage true stem cell abilities of such cells so they can attempt neuronal, e.g., dopaminergic neuronal, repopulation in PD.

FIGURE 71.8 Phenotype of BrdUpositive cells (a thymidine analogue that marks newly-generated cells) in

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the substantia nigra after a 10d BrdU pulse. (A) One-half of the BrdUpositive cells (green) express the glial progenitor marker NG2 (blue). (B) Some BrdU-positive cells (blue) that are not associated with blood vessels express the multipotent progenitor marker nestin (green). TH is shown in red. (Adapted from Reference 42. With permission.) (A color version of this figure follows page 518.) The potential for dedifferentiation of cycling glial cells in the mature and compromised brain offers numerous repair possibilities and is now being considered by the field.44 It is also possible that these cells could be exploited in novel protocols that combine stem cell therapy with gene therapy to attempt protection and replacement of atrisk populations of dopamine neurons in both early and late stages of PD. Most genetic therapy protocols have concentrated on growth factor, e.g., GDNF, rescue approaches,45 but these technologies could be combined with stem cell grafting or recruitment approaches in PD. Recent advances in identifying new factors for controlled expansion of dopaminergic neurons, as well as fate control of non-neural cells (e.g., pigmented epithelia, see Reference 46), support optimism for the discovery of new factors that could be targets of novel combined gene therapy-stem cell approaches. Finally, although somewhat controversial, it might also be possible to use nonhuman sources of stem/progenitor cells as starting populations for xenografting in circuit reconstruction paradigms for PD.47 HOPES FOR NEW REGENERATIVE MEDICINE DESIGNER THERAPIES FOR PD Based on accumulating evidence in support of stem cell therapies for PD, one can envision a variety of dream scenarios for new therapeutic approaches that might evolve with increased therapeutic options for both early and late stage PD neuron rescue and replacement. Basic mechanisms of cellular de- and transdifferentiation must continue to be studied, with the idea that old brain cells might be coaxed into young, repair-interested cells, 13,44 and nonneural (e.g., bone marrow stem cells) ones could be readily harvested from the patient and gene therapy applied, ex vivo if necessary, and reintroduced into the patient via either intracerebral or systemic injections to seek out the damaged basal ganglia circuitry (Figure 71.9). In addition to the cells mentioned above, there is evidence that skin and fat cells might be able to be neuralized, and some of these other epithelial and mesenchymal cell sources may also provide significant growth and survival

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FIGURE 71.9 Once the choice of source (e.g., bone vs. brain marrow) has been made, and particular stem/progenitor cells have been characterized (e.g., phenotypy issues have been resolved), one can imagine several scenarios for the eventual use of the cells deemed best suited for neurorepair. With the scenario of allografting of donor stem/progenitor cells, large-scale expansion of the select population, enrichment, purification, and resolution of pathogen-free cells (good medical practice issues), the best root of introduction must be determined (stereotaxic placement vs. systemic administration to reach the compromised regions). Precise image-

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guided approaches are required for discrete and specific circuitry repair. The use of microcarriers and degradable biomatrices will also be used to support the initial survival and integration of intracerebral grafts. Whether stem/progenitor cell homing occurs, or the possibility of undesired migration might take place once in the adult CNS, might determine which “root of entry” strategy is the best. Stem/progenitor cells must then make short and long distance axonal connections. There is right now only limited evidence of long distance connections of newly generated neurons in the injured adult rodent CNS. There may be the need to simultaneously encourage axon growth with growth promoting factors and inhibit the growth-inhibiting molecules known to be upregulated in injured brain areas so as to facilitate axon growth and synaptogenesis. These events may also require adjunctive behavioral modification and therapies to help recapitulate particular ontogenetic events involved in circuitry formation. Self-repair also could be induced or augmented with “poietins,” small, selective growth factors that trigger repair processes by one’s own indigenous populations of stem/progenitor cells. Such a CNS regeneration dream scenario might utilize systemic administration of such factors that specifically home to or selectively affect areas of the damaged CNS where normally quiescent

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stem/progenitor cells reside. These factors might also induce dedifferentiation of mature cells that could then replace cells lost to disease or injury. Until this is possible, functional microrepair approaches are needed to provide new cells and support circuit repair. It is reasonable to predict that all of these scenarios are possible, in light of rapid breakthroughs in functional genomics and proteomics that should lead to the discovery of new factors that induce neuro- and synaptogenesis. (Adapted from Reference 5. With permission.) factors as well. Of course, as previously described,5 we need much better and efficient methods for the isolation and purification of different stem cell populations on the way to producing higher yields of dopaminergic neural precursors (e.g., immunopanning, gradient centrifugation, fluorescence activated cell sorting), but other methods must be developed to generate highly enriched populations of specific stem/progenitor cell populations for massive expansion and specific neuronal fate determination and differentiation. Furthermore, we need to determine why there seems to be a poor ability of SEZ, hippocampal, and nigral stem/progenitor cells to proliferate, migrate, and home to areas of injury and depletion in the adult CNS. Even if ES cell-derived, fetal, or adult brain stem/progenitor cell populations exhibit the propensity to integrate within neurogenic migratory pathways as well as established circuitries in the adult brain, there is still a great deal of information needed on the potential establishment of long-distance axonal projections from newly generated neurons in the mature brain. We must be able to place dopaminergic neuron precursors in a hostile environment of the injured nigrostriatal pathway, either in the midbrain (optimal, for appropriate afferent and efferent driving of their biochemical, physiological, and behavioral phenotypes) or in the dopamine-depleted neostriatum, have them survive and functionally integrate, and achieve the ability to innervate their distant target structures in the same topographic patterns as that achieved originally during development. This may require conjunctive neuritegrowth support presented in distinct spatial and temporal sequences and patterns as that seen during normal ontogeny. This is an extremely daunting possibility and suggests that achieving dopamine neuron repopulation in the PD brain is but the first “obstacle” in the process of rebuilding a functional nigrostriatal dopaminergic pathway. There is still limited evidence for long distance axonal growth and reestablishment of circuits even after possibly successful integration of the progeny of a grafted or indigenous stem/progenitor cell population.

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It is worth reiterating (see Reference 5 for review) that stem cells have already been used as experimental therapeutics for various rodent models of human disease, including metabolic disorders, muscular dystrophy, global CNS cell replacement, spinal cord repair, and brain tumors, but, in light of their potential for overproduction, hyperplasia, we must be cautious to not underestimate the abilities of a prolific population of cells to generate brain tumors. Ideally, one would like to understand the biology of fetal and adult stem cells a bit more before translating them into therapeutics; yet, morbidity and mortality associated with devastating human diseases and injuries argue for exploiting stem cell therapeutics without clearly understanding their nature….”5 Furthermore, if autologous repair is not possible, and heterologous stem/progenitor cells must be supplied from donor sources, immunorejection must be considered2 with the need for haplotype-matching or immunosuppressants, although a very recent report suggests the possibility that, unlike stem cells from other sources (e.g., blood), neural stem cells do not usually express MHC class I and II, therefore lacking immunogenecity and possessing resistance to destruction as allografts.48 Figure 71.9 provides a summary of some scenarios for PD repair that may be on the horizon. Indigenous and poised-for-repair stem/progenitor cells attempt repair following injury or disease. If, for example, indigenous cycling stem cell populations in and around the substantia nigra are not able to meet the demands for rescue or replacement, cells from other “poietic regions” (e.g., brain marrow or bone marrow cells) might be able to home to the midbrain via cues provided by sick and dying cells. The release of trophic and guidance factors following injury might contribute to the reestablishment of both short and long distance axonal connections that lead to functional and behavioral recovery, but other growth and guidance factors may have to be introduced, along with cellular and/or biomatrix support systems to help rebuild connections within an already complex and growth-inhibitory neuraxis that is well respected for its inability to support growth compared to the more compact and regeneration-friendly developing brain. Thus, self-repair might also be augmented through noncellular, e.g., drug therapies, since there are studies that show peripheral growth factor injections can expand indigenous neural stem cell populations. “Neuropoietins” and guidance molecules that help support proliferation, fate choice, and neurite growth are clearly important elements to be further studied in nigrostriatal circuitry rebuilding paradigms. To quote one of our recent position papers, Despite potential rapid progress from the bench to the bedside for restorative neurology and neurosurgery, we must still employ a tremendous amount of caution in applying exciting new stem cell findings to human therapeutics. Continued progress is dependent upon the prudent use of new technologies in justifiably highly scrutinized new therapeutic approaches. There are still examples of an impressive ability of different stem cells and immortalized stem cell lines to survive, release neurotransmitters, and other factors to overcome various molecular

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deficiencies, and perhaps even integrate in different and compromised mature brain circuits. But as of right now, we are not certain which potent cell population, either indigenous or donor derived, will safely and efficiently protect and replace vulnerable and lost neurons; we are also not certain that molecular therapeutics developed with insights gained from stem cell biology and regenerative neuroscience, might augment or even act on their own to achieve a cure in PD. Nonetheless, we might take one lesson from the hematopoietic stem cell field where their concern over the use of immortalized, transformed stem/progenitor cells stems from their comprehensive knowledge of the leukemias, and another lesson from the Parkinson’s disease cell-replacement field which early on called for “patience rather than patients.”5

ACKNOWLEDGMENTS The author is supported by NIH grants NS37556 and HL70143. REFERENCES 1. Isacson, O., Bjorklund, L.M., and Schumacher, J.M., Toward full restoration of synaptic and terminal function of the dopaminergic system in Parkinson’s disease by stem cells, Ann. Neurol., 2003, 53, S135, 2003. 2. Redmond, D.E. Jr., Cellular therapy for Parkinson’s disease: Where are we today? The Neuroscientist, 8, 457, 2002. 3. Weiss, R., Stem cell transplant works in a California Case; Parkinson’s Traits Largely Disappear,” Washington Post, p. A8, April 9, 2002 (in referring to work by Dr. M.Levesque). 4. Gill, S.S., et al., Direct brain infusion of glial cell linederived neurotrophic factor in Parkinson disease, Nat Med. 9, 589, 2003. 5. Steindler, D.A. and Pincus, D., Stem cells and neuropoiesis in the adult human brain, Lancet, 359, 1047, 2002. 6. Ignatova, T., et al., Human cortical glial tumors contain stem-like cells expressing astroglial and neuronal markers in vitro, GLIA, 39, 193, 2002. 7. Reya, T., et al., Stem cells, cancer, and cancer stem cells, Nature, 414:105, 2001. 8. Al-Hajj, M. et al., Prospective identification of tumorigenic breast cancer cells, Proc. Natl. Acad. Sci. U.S.A., 100:3983, 2003. 9. Capron, A.M., Stem cells: Ethics, law, and politics, Biotech Law Report, 20, 678, 2001. 10. Theise, N.D., Stem cell research: Elephants in the room, Mayo Clin. Proc. 78, 1004, 2003. 11. Drazen, J.M., Legislative myopia on stem cells, N. Engl. J. Med., 349:300, 2003. 12. Gates, M.A., Laywell, E.D., Fillmore, H., and Steindler, D.A., Astrocytes and extracellular matrix in adult mice following intracerebral transplantation of embryonic ventral mesencephalon or lateral ganglionic eminence, Neuroscience, 74, 579, 1996. 13. Laywell, E.D. et al., Identification of a multipotent astrocytic stem cell in the immature and adult mouse brain, Proc. Natl. Acad. Sci. U.S.A., 97, 13883, 2000. 14. Scheffler, B., et al, Marrow-mindedness: a perspective on neuropoiesis, Trends in Neurosciences, 22, 348, 1999. 15. Wirth, E.D. 3rd et al., Feasibility and safety of neural tissue transplantation in patients with syringomyelia, J. Neurotrauma, 18, 911, 2001.

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16. Kim, J.H. et al., Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson’s disease, Nature, 418, 50, 2002. 17. Bjorklund, L.M. et al., Embryonic stem cells develop into functional dopaminergic neurons after transplantation in a Parkinson rat model, Proc. Natl. Acad. Sci. U.S.A., 99, 2344, 2002. 18. Benninger, F. et al., Functional integration of embryonic stem cell-derived neurons in hippocampal slice cultures, J. Neurosci., 23, 7075, 2003. 19. Bjorklund A., Lindvall, O., Cell replacement therapies for central nervous system disorders, Nat. Neurosci., 3, 537, 2000. 20. Zheng, T., Steindler, D.A., and Laywell, E.D., Transplantation of an indigenous neural stem cell population leading to hyperplasia and atypical integration, Cloning and Stem Cells, 4, 3, 2002. 21. Kirschenbaum, B. et al., In vitro neuronal production and differentiation by precursor cells derived from the adult human forebrain, Cereb. Cortex. 4, 576, 1994. 22. Kukekov, V.G. et al., Multipotent stem/progenitor cells with similar properties arise from two neurogenic regions of adult human brain, Experimental Neurology 156, 333, 1999. 23. Ostenfeld, T. et al., Human neural precursor cells express low levels of telomerase in vitro and show diminishing cell proliferation with extensive axonal outgrowth following transplantation, Exp. Neurol., 164, 215, 2000. 24. Reynolds, B.A., and Weiss, S., Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system, Science, 255, 1707, 1992. 25. Svendsen, C.N., et al., Long-term survival of human central nervous system progenitor cells transplanted into a rat model of Parkinson’s disease, Exp. Neurol., 135, 1997. 26. Doetsch, F., et al., Subventricular zone astrocytes are neural stem cells in the adult mammalian brain, Cell 97, 703, 1999. 27. Brautbar, C., Payne, R., and Hayflick, L., Fate of HL-A antigens in aging cultured human diploid cell strains, Exp. Cell Res., 75:31, 1972. 28. Laywell, E.D., Kukekov, V.G., and Steindler, D.A., Multipotent neurospheres can be derived from forebrain subependymal zone and spinal cord of adult mice after protracted post-mortem intervals, Experimental Neurology 156, 430, 1999. 29. Terada, N. et al., Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion, Nature, 416, 542, 2002. 30. Sanchez-Ramos, J. et al., Adult bone marrow stromal cells differentiate into neural cells in vitro, Exp. Neurol., 164, 247, 2000. 31. Woodbury, D. et al., Adult rat and human bone marrow stromal cells differentiate into neurons, J. Neurosci. Res., 61, 364, 2000. 32. Kopen, G.C., Prockop, D.J., and Phinney, D.G., Marrow stromal cells migrate throughout forebrain and cerebellum, and they differentiate into astrocytes after injection into neonatal mouse brains, Proc. Natl. Acad. Sci. U.S.A., 96, 10711, 1999. 33. Mezey, E. et al., Turning blood into brain: cells bearing neuronal antigens generated in vivo from bone marrow, Science, 290, 1779, 2000. 34. Brazelton T.R. et al., From marrow to brain: expression of neuronal phenotype in adult mice, Science, 290, 1775, 2000. 35. Papayannopoulou, T., and Craddock, C., Homing and trafficking of hemopoietic progenitor cells, Acta Haematol., 97, 97, 1997. 36. Cogle, C. et al., Bone marrow transdifferentiation in the brain following transplantation, The Lancet, 363: 1432–1437, 2004. 37. Steindler, D.A., Neural stem cells, scaffolds, and chaperones, Nature Biotechnol, 20, 1091, 2002. 38. Ourednik, J. et al., Neural stem cells display an inherent mechanism for rescuing dysfunctional neurons, Nat. Biotechnol., 20, 1103, 2002. 39. Villa, A., et al., Establishment and properties of a growth factor-dependent, perpetual neural stem cell line from the human CNS, Exp. Neurol., 161, 67, 2000.

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40. Akerud, P. et al., Neuroprotection through delivery of glial cell line-derived neurotrophic factor by neural stem cells in a mouse model of Parkinson’s disease, J. Neurosci., 21, 8108, 2001. 41. Ostenfeld, T. et al., Neurospheres modified to produce glial cell line-derived neurotrophic factor increase the survival of transplanted dopamine neurons, J. Neurosci. Res., 69, 955, 2002. 42. Lie, D.C., et al., The adult substantia nigra contains progenitor cells with neurogenic potential, J. Neurosci., 22, 6639, 2002. 43. Belachew, S. et al., Postnatal NG2 proteoglycanexpressing progenitor cells are intrinsically multipotent and generate functional neurons. J. Cell Biol.,161, 169, 2003. 44. Steindler, D.A., and Laywell E.D., Astrocytes as stem cells: nomenclature, phenotype, and translation, Glia, 43, 62, 2003. 45. Kirik, D. et al., Long-term rAAV-mediated gene transfer of GDNF in the rat Parkinson’s model: intrastriatal but not intranigral transduction promotes functional regeneration in the lesioned nigrostriatal system, J. Neurosci., 20, 4686, 2000. 46. Kawasaki, H. et al., Generation of dopaminergic neurons and pigmented epithelia from primate ES cells by stromal cell-derived inducing activity, Proc. Natl. Acad. Sci. U.S.A., 99, 1580, 2002. 47. Armstrong, R.J., The potential for circuit reconstruction by expanded neural precursor cells explored through porcine xenografts in a rat model of Parkinson’s disease, Exp. Neurol., 175, 98, 2002. 48. Hori, J. et al., Neural progenitor cells lack immunogenicity and resist destruction as allografts, Stem Cells, 21, 405, 2003.

72 Alternative Drug Delivery in the Treatment of Parkinson’s Disease Pierre J.Blanchet Department of Stomatology, University of Montreal and University of Montreal Hospital Center 0–8493–1590–5/05/$0.00+$1.50 © 2005 by CRC Press

INTRODUCTION Even though oral levodopa (combined with a peripheral dopa decarboxylase inhibitor) remains the most efficacious symptomatic drug treatment for Parkinson’s disease (PD), it is not devoid of problems. The emergence of motor-response complications in levodopatreated PD patients has puzzled and fascinated neurologists for over 30 years. Sooner or later, most patients eventually experience a predictable (so-called “wearing-off” effect) and less often unpredictable return in parkinsonian disability during the day, associated with nonmotor symptoms (neuropsychiatric, cognitive, or dysautonomic) and various dyskinesias, for reasons that remain elusive. The very short plasma half-life, poor bioavailability, and erratic absorption of oral levodopa are consistently present throughout the illness, and unequivocal changes in the peripheral pharmacokinetic handling of levodopa have never been demonstrated. Thus, attention shifted toward acquired changes in central pharmacokinetic properties (so-called “buffering capacity”) and additional pharmacodynamic factors to explain and eventually correct the fluctuations of the levodopa motor response. Experimental attempts have tried to match the fairly good correlation between stable plasma levels of levodopa and sustained motor response with ways to continuously supply the dopamine precursor by bypassing the oral route. The proof of concept of the remarkable efficacy of constant intravenous infusions of levodopa to sustain stable and adequate plasma levodopa levels and rapidly maintain fluctuating patients in the “on” state was made by Woods et al.1 and Shoulson et al.,2 and later confirmed and extended by Quinn et al.3 Initially, the duration of levodopa infusions lasted up to 8 hr, and hourly infusion rates were from 70 to 143 mg (mean, 109 mg/hr) in most subjects.4 Patients with biphasic dyskinesias also improved but experienced “breakthrough” dyskinesias during intravenous levodopa, transiently responding to a further increase in the rate of infusion. The clinical results of more sustained infusions were initially thought to be less satisfactory, with reduced mobility and severe dyskinesias reported.5–6 However, repeated but interrupted daytime infusion for 12 to 14 hr for 5 consecutive days in three patients with the “on-off” phenomenon was shown to

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be an effective strategy.7 In two cases, motor benefit was sustained during the day without severe dyskinesias or a need to modify the rate of infusion. The third patient also had a favorable, albeit less stable, response, with daily “on” time increasing from 42% on oral treatment to 82% during the infusion. A consistent threshold of plasma levodopa level to maintain the “on” state could not be determined. The importance of the infusion paradigm and necessity to keep drug-free nights to maintain the clinical response and avoid severe dyskinesias were highlighted. Nonetheless, continuous, around-the-clock intravenous infusions of levodopa gradually lessened the fluctuations in motor status during the day over 10 days and raised the antiparkinsonian and dyskinetic threshold plasma levodopa levels, and the severity of the complications typical of the oral treatment only progressively returned to baseline after the end of the infusion.8 This response profile highlighted the importance of the continuous mode of dopamine receptor occupancy as a more physiological therapeutic strategy in PD, and the potential reversibility of the “priming” process underlying motor response complications provided dopamine receptors are stimulated correctly. The distinct behavioral effects resulting from the pulsatile and continuous delivery of levodopa and dopamine agonists have been studied in animal models of PD in the last decade, using subcutaneous osmotic minipumps. In one experiment, the rotational response to the nonselective dopamine agonist apomorphine was clearly enhanced following intermittent but not continuous levodopa administration in hemiparkinsonian rats.9 Non-oral drug administration has several potential advantages (Table 72.1). Constant, rate-controlled drug delivery through the subcutaneous or transdermal route is expected to reduce drug toxicity and fluctuations in clinical status during the day attended by the excessive maximal plasma concentrations (Cmax) and variations around the mean plasma concentration observed with oral dosing. Sustained relief of parkinsonian symptoms during sleep may also desirable, particularly in more advanced stages of the illness. Moreover, the delay of onset of response to standard oral dopaminergic drugs represents a serious limitation when emergency rescue therapy is required to quickly reverse an akinetic crisis. A peripheral route of delivery is also impractical for drugs unable to cross the blood-brain barrier. The experience with the alternative routes of drug administration explored over the years (Table 72.2) to obviate such problems is reviewed.

TABLE 72.1 Advantages of Non-Oral Drug Delivery • Constancy of drug delivery • Avoidance of first-pass effect • Rapid drug delivery for emergency use (subcutaneous) • Lesser toxicity (lower peak levels) • Rate-controlled delivery (patch, pump infusion) • Targeting of central nervous system (intracranial) • Avoidance of blood-brain barrier (intracranial) • Good patient acceptability (patch)

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TABLE 72.2 Alternative Modes of Drug Delivery Studies in Parkinson’s Disease Intravenous • Bolus injections • Continuous pump perfusion Subcutaneous • Bolus injections • Continuous pump perfusion Enteric • Nasoduodenal • Nasojejunal • Duodenal (gastrostomy) Intranasal Sublingual • Passive Rectal • Enhanced (chemical, iontophoretic) Transdermal Intracranial • Ventricular • Site-specific

ENTERIC INFUSION Since the mid 1980s, a number of clinical investigators have attempted to lessen fluctuations in levodopa plasma levels and motor status by infusing levodopa continuously beyond the pylorus. Open-label observations on the effects of continuous daytime nasoduodenal delivery of levodopa at an hourly rate between 10 and 96 mg greatly improved mobility in three patients with the “on-off” phenomenon, and, in one of these to a greater extent than intermittent infusion.10 On occasion, a transient loss of motor benefit was recorded when the distal end of the tube in the proximal duodenum slipped back into the stomach. Further work revealed that continuous duodenal delivery was comparatively more beneficial than intermittent duodenal and continuous gastric infusions in improving motor ratings and fluctuations in a different set of patients.11 The longterm experience of two patients under daytime continuous duodenal levodopa infusions via a gastrostomy for 145 and 240 days was also favorable.12 The rate of infusion adjusted to keep patients mobile gradually diminished over the first two months and remained constant thereafter. The daily levodopa intake rapidly declined initially, then more gradually during the first two months before it stabilized. Motor fluctuations virtually disappeared, and dyskinesias decreased in severity. Plasma levodopa levels just sufficient to maintain the “on” state dropped from 5.6± 1.2 µg/ml (on oral tablets) to 3.5±0.6 µg/ml on infusion day 63. Thus, erratic gastric emptying may contribute to fluctuating plasma levels and motor response complica-tions. Single nasoduodenal dosing has also been shown to shorten the time to normalize motor function and time to reach maximal plasma levels (0.5 hr in both instances) compared to oral dosing (1.71 and 2.0

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hr, respectively), and to prolong the mean duration of clinical benefit from 1.2 hr (oral dosing) to 3.2 hr (duodenal dosing).13 The acute benefit of continuous duodenal infusion compared to intermittent oral levodopa treatment was subsequently evaluated in a double-blind, placebo-controlled, crossover trial.14 Ten patients were randomly assigned to one of six four-day protocols alternating between continuous duodenal delivery for eight hours daily and standard intermittent oral therapy. The daily amount of levodopa used during the seven-hour observation period was comparatively higher on the infusion than on oral therapy (501±253 mg versus 420±205 mg). The variability or deviation from the daily mean plasma levodopa levels decreased by 47% on infusion days, from 38 ±11% on oral therapy to 17±9% on duodenal infusion. Seven patients showed improved “on” time, increasing on average from 2.88±1.43 hr to 4.51±2.06 hr. The number of “off” episodes declined in five subjects, from 3.8±1.4 to 2.7±1.6. The patients primarily experiencing dyskinesia reduced their total intake of levodopa while on duodenal infusion. In contrast, those with the “wearing-off” phenomenon increased their total dose during the infusion without worsening dyskinesia. Five patients elected to continue daily duodenal infusion therapy for at least one year after completing the study, and four of these eventually consented to a jejunostomy. Some investigators have suggested that the problem with duodenal infusion levodopa therapy lies in its low water solubility. In one experiment,15 oral levodopa/carbidopa tablets were milled and dispersed in a 1.8% aqueous methylcellulose solution (20 mg/ml). The solution is stable for one week, requires no added antioxidants, and can be kept refrigerated overnight and redispersed in the morning. It was delivered continuously during daytime through a nasoduodenal tube. The effects of this duodenal dispersion were tested on two nonconsecutive days in five patients with advanced PD and compared six weeks apart to their usual oral treatment. The intra-individual variation in levodopa plasma concentrations declined from three- to tenfold on oral therapy to twofold at the most on the duodenal dispersion, with parallel reductions in motor response fluctuations. The highly soluble methylester of levodopa has also been used to reduce the volume of solution necessary for daytime infusions. At a dilution of 250 mg/ml, one patient showed dramatic motor improvement following continuous daytime nasoduodenal and jejunal administration of a solution of methylester at a rate of 180 mg/hr through a micropump with a 10-ml capacity.16 An oral peripheral dopa decarboxylase inhibitor was co-administered. This approach kept him “on” throughout the day and improved dyskinesias, enabling him to lower the infusion rate to 140 mg/hr. Thus, continuous enteric infusion, albeit impractical for long-term use, produced gradual changes in clinical response and in levodopa dose requirements, suggestive of an inducible shift in sensitivity by the mode of receptor occupancy. Support for this hypothesis can be found in the experience of one parkinsonian patient receiving continuous nighttime jejunal infusions, who noticed some carryover benefit on daytime fluctuations and dyskinesias in spite of the maintenance of a standard oral levodopa regimen during the day.17 In another single case report,18 continuous around-the-clock enteric infusions failed to improve motor status in spite of increases in the infusion rate. Nighttime interruptions of the infusion to “reset” the receptors led to a gradual and considerable improvement of the situation. This apparent dopamine receptor downregulation with raised motor response threshold induced by the constant supply of

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the dopamine precursor should be borne in mind in the design of experimental therapies aiming to provide continuous dopamine receptor stimulation. Receptor internalization or uncoupling may be at play. SUBCUTANEOUS BOLUS INJECTIONS By virtue of the rapid onset of action it provides and bioavailability of certain dopamine agonists, the subcutaneous route of drug administration has been the main alternative route tested. In addition to the usual pharmacokinetic, pharmacodynamic, and safety issues that are part of any experimental drug development, practical issues related to handling and local skin tolerability must also be carefully addressed. For over half a century now, the nonselective, direct-acting dopamine agonist apomorphine has been the gold standard for this route of delivery. It is almost completely bioavailable and has shown efficacy in the treatment of PD following subcutaneous dosing.19 In fact, it is equipotent to levodopa and produces virtually identical motor and dyskinetic responses.20 The therapeutic benefit is of rapid onset (5 to 15 min) with Tmax averaging 16±11 min.21 The mean duration of motor response to a single suprathreshold injection is 60 min (range, 20 to 120).22 In view of this short duration of action, frequent adverse effects (including nausea, vomiting, hypotension and sedation), poor oral bioavailability, and dose-dependent, reversible uremia when effective oral doses up to 1500 mg per day were used,23–24 it fell in disrespect for years. The use of domperidone to improve the tolerability of apomorphine25 led to renewed interest for apomorphine as a rescue drug in levodopa-responsive parkinsonian patients with resistant response fluctuations.6,26–27 Since the individual standard levodopa dosage is not predictive of apomorphine dose requirements,28 the opti-mal effective dose must be titrated and adjusted for each patient. The threshold dose is predetermined with incremental test doses under domperidone and a standard dose (e.g., double threshold dose) given subcutaneously in the abdomen or thigh using an insulin syringe mounted in a “penject” system.22 The goal of this add-on approach is to help reducing the severity and duration of “off” periods during daytime, not to eradicate them. Patients are instructed to inject apomorphine as soon as the “off” period has set in. Single doses average 40 to 50 µg/kg (between 1 and 3 mg), and the protocol may be repeated 3 to 8 times during the day. Benefit usually lasts between 40 and 90 min.27,29 A reduction in daily “off” time of approximately 50% is often reported with intermittent apomorphine add-on therapy, usually with maintenance of the same daily levodopa dose.22,27,30–32 Some patients have used apomorphine at night to rapidly improve nocturnal akinesia or other unpleasant, sleep-disrupting “off” period disabilities.22 Single apomorphine injections can also quickly relieve unusual and intractable “off” period symptoms such as pain,22,33 panic symptoms,33 freezing,34 functional bladder outlet obstruction,35 anismus,36 and impotence.37 This strategy has also been used successfully in the perioperative management of PD patients undergoing abdominal surgery.38 In spite of its clinical efficacy, subcutaneous apomorphine is felt to be underused.39–40 The reasons for this include the following: 1. Perception that the technique is too cumbersome and that the patient will be unable to learn how to self-inject and overcome the technical demands

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2. Fear that apomorphine frequently causes severe abdominal wall panniculitis 3. Misconception that neuropsychiatric and dyskinetic complications worsen and constitute contraindications to this strategy 4. Ambiguity regarding long-term efficacy These sources of concern are only partly justified. Stibe and colleagues27 commented on the easy use and acceptability of penjects by patients who are able to predict impending “off” periods. In 14 out of 22 PD patients evaluated in a double-blind, placebo-controlled study,31 13 were able to self-inject apomorphine by the end of the maintenance phase of 8 weeks, and 11 found this easy to handle. Rare patients develop an aversion for selfinjection.30 Supervision and support by a dedicated nurse practitioner and neurologist help solve most technical issues in motivated patients. In some countries, easy-to-use, prefilled single-use pen injectors are also commercially available.31 Advanced patients with profound “off” episodes who cannot selfinject apomorphine for rescue may also benefit from daytime continuous apomorphine infusion (see below). The treatment is well tolerated by most patients, and the adverse event profile is considered favorable with coadministration of oral domperidone.27 Intermittent injections cause minor local skin reactions with small itchy nodules at some of the injection sites, which usually disappear within 48 hr.30 Patients with advanced PD are at risk to experience neuropsychiatric complications with any dopaminergic drug, and apomorphine is no exception. However, under chronic intermittent apomorphine injections, psychotic features have been conspicuously absent27 or have occurred in 12% (3 out of 24)32 and up to 22% (11 out of 49) of individuals,30 but their intensity was usually insufficient to require discontinuation of treatment. Since intermittent apomorphine is used as add-on therapy in patients with motor response complications, it is not surprising that almost 50% of patients maintained on long-term bolus apomorphine as part of a polypharmacy displayed a gradual worsening in peak dose dyskinesias,30 representing a 67% increase in the mean daily duration of involuntary movements.31 In another study, dyskinesias worsened in only 12% (3 out of 24) of subjects.32 Adjustment of the antiparkinsonian co-medications may help solve the problem. The use of apomorphine injections to counteract biphasic dyskinesias is more controversial. Some case reports suggest that intermittent subcutaneous apomorphine is antidyskinetic in such cases22,33,41–42 but eventually becomes a much less effective modality22,43 in spite of upward dose titration. However, tachyphylaxis to the usual peripheral adverse effects of apomorphine (nausea, vomiting, postural hypotension, sedation) is normally seen over time, and only a few patients require long-term domperidone administration. CONTINUOUS SUBCUTANEOUS INFUSION These results have encouraged several groups, mainly in Europe, to infuse apomorphine continuously during the daytime through a needle inserted subcutaneously into the abdominal wall and connected to a portable minipump automated system. This strategy produces striking improvement in motor function in many PD patients with severe motor complications. The first study by Stibe and colleagues27 showed great improvement in 11 severely disabled patients using an apomorphine pump for several months at a mean hourly infusion rate of 40 µg/kg (range, 20 to 70) during waking hours (mean daily dose

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of 77 mg). The quality of the motor benefit was comparable to that seen with oral levodopa, and two patients reported a greater sense of well-being on apomorphine. Mean reductions in daily “off” time (by 62%) and levodopa dose (by 19.5% or 209 mg) were more significant than those resulting from apomorphine injections. Residual “off” episodes were also less severe. A confirmatory account of the expe-rience of 7 patients also infused for several months was soon published,44 in which a lower mean daily apomorphine dose of 29.7 mg (range, 15 to 55) produced even more dramatic reductions in mean daily “off” time (by 85%) and levodopa dose (by 39% or 348 mg). The mean infusion rate is 3.3mg/hr or 0.05 mg/kg/hr (range, 1.25 to 5.5 mg/hr or 0.02–0.08 mg/kg/hr), the majority of patients requiring between 2–4 mg/hr.22 In a cohort of 17 patients with severe motor fluctuations switched to continuous apomorphine infusion, the mean hourly infusion rate was 97±44 µg/kg during daytime, and 39µg/kg overnight in six patients.45 Marked motor improvement was observed with reductions in mean “off” time (by 61%) and mean daily levodopa dose (by 53% or 420 mg). Residual “off” episodes still occurred but were felt to be less severe in some cases. Additional 3-mg boluses (4 on average) of apomorphine were used during the day and cotreatment with oral levodopa was necessary in all but one patient. Overall, the infusion program was maintained beyond one year in 41% (7/17) of patients. Eleven open-label long-term infusion studies with follow-up extending between 1 and 8 years published since 1990 were reviewed.22,30,32,45–52 Collectively, the experience of these 263 patients indicates highly favorable motor benefit (Figure 72.1). The mean daily apomorphine dose was 114±33 mg, with a range extending from 31.4 mg up to 162 mg due to different treatment approaches regarding attempts to lessen cutaneous complications or wean patients off oral levodopa, or maintenance of the infusion during waking hours only or around the clock. While low infusional rates of apomorphine (70 mg/day) allow the discontinuation of oral levodopa which was achieved in 30% of cases. The global reduction of apomorphine infusion on mean daily “off” time and oral levodopa dose was 60± 11% and 47±24%, respectively (Figure 72.1). These figures are in many instances superior to those resulting from the combination of levodopa with oral dopamine agonists40 that only exceptionally allow patients to discontinue levodopa treatment completely. The short-term replacement of continuous subcutaneous apomorphine for levodopa has shown efficacy in advanced patients following major surgery.53 Nocturnal apomorphine infusion also constitutes a sensible alternative for patients with refractory severe sleep fragmentation due to motor symptoms or restless legs manifestations.54 The outcome of levodopa-induced dyskinesias under continuous apomorphine infusion is variable. In one study, the severity of dyskinesias was either spared, decreased in 4 out of 11 subjects, or initially increased in 2 others.27 However, the cumulative experience of 234 chronically infused patients reveals a favorable antidyskinetic effect contrasting with the impact of add-on intermittent injections. Over half of the patients with peak dose dyskinesias have noticeably improved, with striking benefit in some cases in spite of the improvement in “on” time. Some authors expressed less consistent improvement in those with severe dyskinesias.55 The initial reduction in peak-dose dyskinesia intensity generally paralleled the decrease in daily levodopa dose.45,51–52 However, the observation of a more gradual and sustained antidyskinetic benefit taking

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place over a mean interval of six months47 or longer52 following the onset of apomorphine infusion argued in favor of the development of a genuine “depriming” effect. Few studies have quantified this antidyskinetic effect. Some patients able to achieve apomorphine monotherapy have obtained better results, with 65% reduction in peak-dose dyskinesia severity reported in two studies.47,52 Those treated with apomorphine infusion as part of a polypharmacy showed a mean reduction in peak-dose dyskinesia severity of 30%52 and reduction in the duration of dyskinetic periods averaging 61%.51 In these patients, dyskinesias may gradually return over time, the mean antidyskinetic benefit decreasing from 45% at one year to a respectable 27% at five years in a long-term study.50 The presence of biphasic dyskinesias is not an absolute contraindication to apomorphine infusion since they worsened in six cases22,45 but disappeared in four others.46 The main limitation with long-term continuous apomorphine infusions is the consistent development of local cutaneous reactions with bruises, rash, or nodules occurring in virtually all cases. However, the nodules are often small and not problematic in up to 62% of cases.52 Nodular formation may be minimized by a combination of standard approaches such as aseptic, frequent rotation of the infusion sites, dilution of the apomorphine solution with saline from 10 to 5 mg/ml, restricting infusion times, and use of silicone gel patches or of ultrasound on indurated areas. Nonetheless, moderate to severe skin reactions have occurred in one-third of the 263 patients maintained on longterm infusions, and are more likely to manifest during the second and third year of treatment.30 The nodules can bleed or get infected, forming abscesses that may require surgical debridement and antibiotics, and the abdominal wall skin can become necrotic and fibrotic to produce large indurated areas conceivably affecting drug absorption. A biopsy of a nodule revealed subepidermal edema, mild dermal perivascular inflammation, and patchy inflammation with an eosinophil response extending into subcutaneous fat, compatible with panniculitis.27 Various neuropsychiatric disorders can arise de novo or worsen under apomorphine infusion. Such complications have collectively affected 21% of the 263 infused patients, but these have generally been mild and rarely constituted a cause for concern and discontinuation of the therapy. These have included visual illusions and hallucinations, nightmares, mild confusion, diurnal agitation, and frank paranoid psychosis. In one study,52 apomorphine demonstrated the potential to alleviate neuropsychiatric problems, patients under apomorphine infusion monotherapy improving by 40% and those in the polypharmacy group by 16%. One can only speculate about the reasons underlying this effect, which may be similar to those underlying the reported antidyskinetic effect, including reduction in daily levodopa dose, sustained dopamine receptor occupancy responsible for a new functional state, or direct specific pharmacodynamic properties of the drug through its piperidine moiety.56 Sedation and hyperlibidinous behavior have also occurred. Weight gain was documented in 60% of patients in one series,52 perhaps secondary to improvement in dyskinesias or some other pharmacological effects.

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FIGURE 72.1 Benefit of long-term continuous subcutaneous apomorphine infusions (≥1 year) in patients with Parkinson’s disease. Data concerning the percentage reduction in mean daily “off” time (top histogram) and daily levodopa dose (bottom histogram) compared to baseline are provided. One study compared subjects who achieved apomorphine monotherapy (n=45) or polytherapy (n=19).52 The number of subjects (within bars) and

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the reference numbers (in parentheses under bars) are indicated. Peripheral blood eosinophilia, often transient, has been documented in a total of 27 patients with abdominal nodules.22,46,48 A positive Coombs test,52 associated with an autoimmune hemolytic anemia in eight subjects,22,46,49,52 has also been reported. An early transient elevation in pancreatic enzymes has been documented in 5 out of 29 subjects in a single study.48 Tachyphylaxis to the peripheral adverse effects of apomorphine (nausea, vomiting, orthostatic hypotension) often develops to eventually allow the discontinuation of domperidone in most cases.57 Some patients also withdraw treatment prematurely due to practical technical issues. The penject needle may break and remain in subcutaneous tissue.27 Lisuride [N-(D-6-methyl-8-isoergolenyl)-N’,N’-diethylcarbamide hydrogen maleate] is another water-soluble ergoline derivative that has been administered to patients with PD. Single intravenous doses between 0.1 and 0.2 mg produced motor benefit within 5min and improved motor scores by 40%, comparable to oral levodopa.58 Tremor appeared particularly sensitive. The effect was maximal for 10 to 30 min and disability gradually returned to baseline after 120 to 180 min. All subjects were given domperidone 50 mg orally one hour prior to lisuride dosing. Adverse effects included yawning, hiccups, nausea and vomiting, hypotension, and dyskinesias. In another experiment,59 intravenous lisuride was continuously infused at a mean rate of 76±31 Hg/hr (range, 33 to 125) for a maximum of 12 hr as co-treatment with the usual oral antiparkinsonian regimen in 10 patients with advanced disease and severe motor fluctuations. Domperidone was administered intravenously 30 min prior to the infusion. This drug combination greatly improved daily “off” time and strikingly reduced dyskinesias in five patients. Only one subject showed worsening in dyskinesias during lisuride infusion. Oral levodopa could not be discontinued with the dose of lisuride selected. Hypotension, nausea, sweating, and malaise were reported in onehalf of the subjects. Similar results were obtained in three patients maintained on subcutaneous lisuride infusion for 4 to 7 months administered as co-treatment at a rate of 83 to 129 Hg/hr through a thin needle rotated every 5 days and connected to a portable minipump.60 Cutaneous and systemic tolerability was excellent. Biphasic dyskinesias were abolished, but peak-dose dyskinesias became apparent by the second or third month, requiring a reduction in daily levodopa dose. One patient developed transient hallucinosis. Few studies have addressed the long-term efficacy and adverse event profile of lisuride infusions. Long-term experience with 12- or 24-hr subcutaneous lisuride infusion in advanced PD confirmed its favorable impact on motor response fluctuations and severe nocturnal akinesia.61–62 Daytime infusions (rate, 55 to 80 µg/hr) for 3 to 14 months allowed 6 patients to stop levodopa completely and to remain “on” most of the time with less dyskinesias; 6 others required supplemental levodopa and 24-hour lisuride infusion to achieve similar control of fluctuations, but dyskinesias persisted at a lesser intensity and hallucinosis became apparent after five months in one patient.61 The daytime infusion protocol was felt to be better tolerated. No tolerance occurred. All patients showed local red nodules that spontaneously recovered within days and never justified withdraw from the protocol. In another study of 38 patients infused at a mean hourly rate of 111.3 ±29.5 µg together with supplemental oral levodopa (729.6±452.1 mg/day), three were withdrawn due to psychiatric complications, and one more patient could not pursue the

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protocol for technical reasons.62 The others were infused for a mean period of 21 months (range, 6 to 45) at a mean daily dose of 2.6 mg or 109±26.5 µg/hr. Two portable, batterydriven, infusion pumps were used. The 22-gauge needle was replaced every two days by the majority of patients. Eleven of 34 patients showed an excellent response, with minimal “off” time and no worsening in dyskinesias. The mean daily dose of levodopa was reduced by 47% in that group. In another subgroup of 18 subjects, “off” periods were reduced and the mean daily dose of oral levodopa decreased by 32%, but dyskinesia intensity increased by more than 50%. A last subgroup of 5 patients were considered therapeutic failures due to loss of benefit within 15 months and side effects. Twenty-six patients dropped out of the protocol during the first 2 years for various reasons, most frequently because of psychiatric reactions (16 cases). Under lisuride, daily “off” time fell from 4 to 12 hr to 1 hr or less, and the severity of “off” periods was greatly ameliorated to maintain 50% of these patients fully independent throughout the day. An unstable response was still observed in eight patients, with a partial “off” state often emerging in the early afternoon perhaps due to pharmacokinetic problems. A mean reduction in daily levodopa dose by 37% was possible, and while 2 patients almost achieved levodopa withdrawal, none of the 24 subjects was able to stop levodopa completely. Biphasic dyskinesia and “off” period dystonia largely resolved. However, problematic beginning-of-dose choreic dyskinesia increased or emerged in five patients. Neuropsychiatric complications developed in over one-third of the subjects, including visual and/or auditory hallucinosis (nine), confusional state (six), paranoia (five), and constituted the main reason for permanent withdrawal in five patients. Subcutaneous nodules developed in all patients, enough to interfere with lisuride absorption in five patients. Stocchi and colleagues63 reported their observations in 13 patients, 10 of whom were kept under a 12-hr lisuride infusion regimen for 3 to 15 months. Four patients were able to stop levodopa (mean infusion rate of 0.064 mg/hr, range, 0.06 to 0.08) and the mean daily dose of oral levodopa was reduced by 45% in the others (mean infusion rate of 0.08 mg/hr, range, 0.05 to 0.12). The amount of “off” time fell under one hour in most cases. Three patients required nocturnal infusion at a lower rate to reduce adverse effects. A single patient under a 24-hr infusion experienced hallucinosis and progressed to a frank paranoid state even after the infusion regimen was converted back to 12 hr. Red nodules were observed to regress spontaneously. In another report, 10 out of 12 patients, known for mental side effects with prior antiparkinsonian medications, displayed psychotic features and stopped lisuride infusion.64 The serotonin effects of the ergot drug were thought to be involved. Bittkau and Przuntek65 documented the possibility to infuse lisuride in parkinsonian patients with previous psychiatric disturbances with a low-dose regimen (mean dose of 0.94± 0.65 mg/day) in five cases, yet producing improvement in motor scores, a mean reduction in daily levodopa dosing by 74%, and reduction in daily “off” time by 54%. Interestingly, this treatment combination completely alleviated dyskinesias. Nodule formation greatly improved in two patients after replacing metal needles by plastic catheters. Thus, treatment with constant subcutaneous lisuride pump infusion provides good motor benefit, but dose-limiting and troublesome psychotic features may develop. In another report,66 29 patients with severe and often unpredictable fluctuations were studied prospectively in an open-label trial for periods extending up to 36 months. Lisuride was infused at a mean daily dose of 1 mg (range, 0.3 to 2). The hourly rate was

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either kept constant for 24 hr (8 patients) or reduced by 30% overnight (21 patients). The mean daily levodopa dose (512±249 mg) administered at baseline did not change appreciably. Thirteen patients pursued the protocol, while 16 others abandoned treatment after 0.5 to 30 months. Motor scores improved, and 11 of 17 disabled patients regained the ability to walk during “off” periods. The amount of daily “off” time improved by 35% at 3 months. Only 7 subjects were available for assessment at 12 months of treatment. The assessment of peak-dose dyskinesias at 3 months revealed improvement in 11, no change in 2, worsening in 4, and de novo dyskinesias in 4 patients. Biphasic dyskinesias were abolished in one patient and persisted in two others. Psychiatric disturbances, often benign, occurred in 11 out of 13 patients maintained on protocol, leading to a reduction in lisuride dose (in 10) and addition of promethazine (in 3). Only one patient stopped lisuride because of psychosis. Painless nodules were observed in all cases, but two patients required surgical drainage for abscess formation. A recent prospective, randomized open-label trial in 40 fluctuating PD patients compared the clinical efficacy of subcutaneous lisuride infusion (with supplemental oral levodopa) to standard oral antiparkinsonian regimens over a 4-year period.67 Only two lisuride patients withdrew early during the study due to compliance difficulties. The mean hourly infusion rate of lisuride was 0.91± 0.17 µg/hr maintained for 12hr during the daytime. The patients were instructed to rotate needle sites every 2 to 5 days, but many preferred to remove the needle every night. After four years, mean daily “off” time showed a persistent drop by 59% from baseline to 1.2±0.7 hr in the lisuride group, compared to a 21% increase to 5.1±0.7 hr in the levodopa group. The outcome on the Abnormal Involuntary Movements Scale scores strikingly differed between the groups, with a sustained improvement by 49% in the lisuride group and worsening by 59% in the levodopa group. The mean daily levodopa dose was decreased by half (from 688.2±133.4 mg to 333.3± 89.9 mg) in the lisuride group, and increased by half (from 675±180.6 mg to 1032.5±144.4 mg) in the levodopa group. The alleviation of dyskinesias was not felt to be the result of this reduction in daily levodopa dose, since this reduction took place prior to lisuride infusion, while dyskinesias gradually lessened over weeks to months. The results support the view that continuous dopamine receptor stimulation is more physiological and produces less functional anomalies in the basal ganglia than the repeated, short-lived, “pulsatile” stimulation attended by standard oral levodopa treatment. No patient withdrew because of adverse effects. Eleven out of 18 patients under lisuride showed generally mild skin nodules, 3 had psychiatric complications, and 3 experienced hypersexuality. According to these authors, the patients under lisuride infusions showed almost normal daily functioning, with minimal motor complications. The absence of problematic psychiatric reactions and skin nodules was attributed to the 12-hr infusion schedule. Skin nodules are also reduced by removal of the needle at night and infusion of a small volume of fluid made possible with lisuride. No fibrotic complications occurred. In three patients comparing the effects of apomorphine (0.04 to 0.06 mg/kg/hr) and lisuride (1.79 to 2.5 µg/kg/hr) infusions at least 72 hr apart, the mean daily “off” time was 2.8±0.3 hr with apomorphine and 7.6± 2.6 hr with lisuride.68 In addition, the side-effect profile was less favorable with lisuride, including nightmares, depression, and vomiting. The patients continued to receive apomorphine for up to five months with sustained benefit and no evidence of tolerance. The comparative efficacy of continuous

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subcutaneous 24-hr infusions of apomorphine and lisuride was also evaluated at 6, 12, and 24 months in 20 patients with PD randomly assigned to one treatment arm.69 Patients under lisuride infusion at a mean rate of 84 µg/hr required additional oral levodopa at a mean dose of 297±193 mg/day; those under apomorphine required a mean rate of 3.2 mg/hr with supplemental oral levodopa at a mean dose of 327±324 mg/day. The reduction in mean daily oral levodopa requirements compared to baseline was equivalent (46 and 47.5% with lisuride and apomorphine co-treatment, respectively). No upward titration in infusional rate was necessary over two

TABLE 72.3 Experimental Nonsubcutaneous Routes of Administration of Apomorphine in Parkinson’s Disease Route

N

Dose (mg)

Nasal

8

6 mg 8.9 (6– (0.6 ml) 15) 4.3 mg 5–15 (2–6)

44 (36–55)

7

1–10 (1– 8.8 (5– 2 mg in 15) 4)

49 (26-90)

7

5.3

18.1

61.0

11

2–5

7.5

60 (–90)

9

4.1

11

50

9

3

11.3

50.5

5

Delay of Duration Onset (min) (min) 30–60

Motor Response

Adverse Effects

Ref.

Off score ↓ None 73 50% Off time ↓ 24% • Transient nasal 74 congestion or burning sensation • Vestibulitis requiring discontinuation (N=2) • Hypotension (N=4) • Mild vestibulitis Magnitude 71 (congestion, crusting) equal to s.c. (N=3) dosing • Severe vestibulitis “On” response with 10 mg (N=1) n/a 75 achieved Similar to oral • Vomiting (N=2) 145 levodopa • Nausea (N=3) • Hypotension • Yawning • Bitter taste • Dyskinesia Off time ↓ 19% • Dyskinesia (N=4) 146 • Nausea (N=2) • Yawning (N=2) • Hypotension (N=3) • Nasal irritation, severe (N=3); mild (N=2) Off time ↓, • Nasal crusting 72

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45%

(chronic dosing)

Sublingual 9

8

10×3 mg 43 (30– tab. 55) single dose

3×3 mg 20-40 tab t.i.d.

(chronic to 10×3 dosing) mg tab t.i.d. 7 0.5–3×6 20-40 mg tab

10

57 mg

25(12– 53)

(N=5) within 4–6 weeks No tolerance • Severe nasal crusting with pain and bleeding (N=3) • Infection (N=1) 73 (30–110) Comparable to • Mild sedation (N=6) 147 s.c.

60–90

15–100 (no response in 2)

APO and oral • Nausea (N=2) levodopa • Yawning (N=2) • Hypotension (N=1) Off time ↓ 56% • Stomatitis with 79 ulcers and loss of taste (N=4)

Off time ↓ 45% • Yawning (N=2) (one patient)

118(60–200) Full

(acute dosing)

• Flushing, diaphoresis, nausea (N=1) • Nausea (N=2)

77

81

• Sedation (N=2) • Unpleasant taste (N=8)

Route

N

Sublingual 3 (chronic dosing) 10

Dose (mg) Delay of Duration Onset (min) (min)

Motor Response

Adverse Effects Ref.

57, 114, or 228 mg up to t.i.d. 40 mg t.i.d.