Informa

healthcare

New York London

Informa Healthcare USA, Inc. 270 Madison Avenue New York, NY 10016

© 2007 by Informa Healthcare USA, Inc. Informa Healthcare is an Informa business

No claim to original U.S. Government works

Printed in the United States of America on acid-free paper

International Standard Book Number-10: 0-8493-7621-1 (Hardcover) International Standard Book Number-13: 978-0-8493-7621-4 (Hardcover)

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.

No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers.

For permission to photocopy or use material electronically from this work, please access www.copyright. com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC) 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged.

Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe.

Library of Congress Cataloging-in-Publication Data

Handbook of Parkinson's disease / edited by Rajesh Pahwa, Kelly E. Lyons. -- 4th ed. p. cm. -- (Neurological disease and therapy ; 92) Includes bibliographical references and index. ISBN-13: 978-0-8493-7621-4 (alk. paper) ISBN-10: 0-8493-7621-1 (alk. paper)

1. Parkinson's disease—Handbooks, manuals, etc. I. Pahwa, Rajesh. II. Lyons, Kelly

RC382.H36 2007

616.8'33-dc22 2006053095

Visit the Informa Web site at www.informa.com

and the Informa Healthcare Web site at www.informahealthcare.com

Foreword

Parkinson's disease is one of the most common neurodegenerative diseases with a higher prevalence in older adults. It is a slowly progressive condition and has set the standard for research in neurodegeneration throughout the history of medicine. It was the first neurodegenerative disease for which the pathology was discovered, when I. Tretjakov first described the degenerated substantia nigra in 1919. The biochemistry was first described by A. Carlsson, and the transmitter deficit by O. Hornykiewicz. The accidental discovery of the selective neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for neurones of the substantia nigra in the 1980s has been of a similar importance, as it subsequently became possible to study Parkinson's disease in animal models. All these basic research achievements were the basis for groundbreaking progress in the field of therapy. Parkinson's disease was the first neurodegenerative disease for which transmitter replacement therapy was developed; it was the first condition in medical history for which cell-replacement therapy or neurotransplantation was attempted; and it was one of the first conditions for which therapy using electrical brain stimulation was shown to be beneficial.

As we benefit from research advances, the beginner, the experienced neurologist, and the movement disorder specialist need continuous updates. New possibilities for treatment offer new choices for patients and expand the skill set and knowledge base of physicians. This new edition of the Handbook of Parkinson's Disease covers all new aspects of the condition and fills the need for an authoritative and recent update. The editors have put together an excellent group of authors, each of whom is a well-known specialist in their field, and the chapters are scholarly and easy to read.

William Koller, MD, PhD, who was among the editors of the previous editions of this handbook, was one of the founders of the research field of movement disorders in the United States. He was specifically dedicated to excellent clinical research and patient care. Kelly Lyons and Rajesh Pahwa, co-workers of Bill Koller for many years, have edited this handbook in his spirit and have succeeded in maintaining the quality of the previous editions with this fourth edition. The book will serve as an ideal reference for all those who care for patients as well as those who want to enter the field.

Günther Deuschl, MD Professor of Neurology Chairman of the Department of Neurology Christian-Albrechts-University Kiel Universiätsklinikum Schleswig-Holstein

Germany

^ Preface

Parkinson's disease is a progressive neurodegenerative condition with often devastating symptoms. Our knowledge of Parkinson's disease has increased tremendously in recent years. We have achieved a greater understanding of the neurochemistry, neurophysiology, and neuropathology of Parkinson's disease. Genes have been identified that are involved in the pathogenesis of some forms of familial autosomal dominant and recessive Parkinson's disease. Advancements in neuropsychological and neuroimaging techniques have led to improvements in diagnostic accuracy, and therapeutic options have been expanded. In addition, new medications have been approved, new compounds and therapeutic approaches are under investigation, and new surgical procedures and therapies are being explored. In spite of these advances, there continue to be many complications associated with the long-term management of both motor and non-motor symptoms of Parkinson's disease, and treatment remains a challenge.

We present in this edition of the Handbook of Parkinson's Disease the most up-to-date information on the scientific and therapeutic aspects of Parkinson's disease. This fourth edition offers a more integrated approach to managing parkinsonian symptoms and has been expanded to include more in-depth coverage of neuropsychiatric aspects of Parkinson's disease, sleep issues, and non-pharmacological and nontradi-tional therapies. There is comprehensive coverage of the latest pharmacologic and surgical therapeutics as well as the newest basic research. It is our hope that this volume, in the tradition of the first three editions, will serve as a reference source for physicians, researchers, and other health care professionals seeking answers to the many questions related to understanding and treating Parkinson's disease.

We would like to thank each of the authors for their time and commitment in preparing state-of-the-art reviews of the most pertinent aspects of Parkinson's disease.

Rajesh Pahwa Kelly E. Lyons

Contents

Foreword Günther Deuschl . . . . iii Preface . . . . v Contributors .. . . ix

1. Early Iconography of Parkinson's Disease 1

Christopher G. Goetz

2. Epidemiology 19

Michele Rajput, Alex Rajput, and Ali H. Rajput

3. Differential Diagnosis 29

John Morgan and Kapil D. Sethi

4. Pathophysiology and Clinical Assessment 49

Joseph Jankovic

5. Autonomic Dysfunction and Management 77

Richard B. Dewey, Jr.

6. Sleep Dysfunction 91

Laura Nieder and K. Ray Chaudhuri

7. Neuropsychological Aspects 109

Alexander I. Tröster and Steven Paul Woods

8. Management of Anxiety and Depression 133

Jack J. Chen

9. Management of Psychosis and Dementia 155

Kelvin L. Chou and Hubert H. Fernandez

10. Neuroimaging 177

Kenneth Marek, Danna Jennings, and John Seibyl

11. Neuropathology 195

Dennis W. Dickson

12. Neurochemistry of Nigral Degeneration 209

Jayaraman Rao

13. Neurophysiology and Neurocircuitry 223

Erwin B. Montgomery and John T. Gale

14. Animal Models 239

Giselle M. Petzinger and Michael W. Jakowec vii

15. Genetics 269

Akiko Imamura, Matthew J. Farrer, and Zbigniew K. Wszolek

16. Environmental Risk Factors 279

Brad A. Racette

17. Amantadine and Anticholinergics 293

Khashayar Dashtipour, Joseph S. Chung, Allan D. Wu, and Mark F. Lew

18. Levodopa 309

Stewart A. Factor

19. Dopamine Agonists 335

Valerie Street and Mark Stacy

20. Monoamine Oxidase Inhibitors 349

Alex Rajput, Theresa A. Zesiewicz, and Robert A. Hauser

21. Catechol-O-Methyltransferase Inhibitors 365

Ronald F. Pfeiffer

22. Investigational Pharmacological Treatments 379

William G. Ondo

23. Lesion Surgeries 391

Michael Samuel, Keyoumars Ashkan, and Anthony E. Lang

24. Deep Brain Stimulation 409

Kelly E. Lyons and Rajesh Pahwa

25. Investigational Surgical Therapies 423

Joseph S. Neimat, Parag G. Patil, and Andres M. Lozano

26. Physical and Occupational Therapy 441

Atul T. Patel and Sean Shire

27. Voice, Speech, and Swallowing Disorders 451

Shimon Sapir, Lorraine Olson Ramig, and Cynthia Fox

28. Alternative Therapies 475

Jill Marjama-Lyons

Contributors

Keyoumars Ashkan Department of Neurosurgery, National Hospital for Neurology and Neurosurgery, Queen Square, London, U.K.

K. Ray Chaudhuri Movement Disorders Unit, Kings College Hospital, University Hospital Lewisham and Guy's King's and St. Thomas' School of Medicine, London, U.K.

Jack J. Chen Department of Neurology, Schools of Medicine and Pharmacy, Movement Disorders Center, Loma Linda University, Loma Linda, California, U.S.A.

Kelvin L. Chou Department of Clinical Neurosciences, Brown Medical School and NeuroHealth Parkinson's Disease and Movement Disorders Center, Warwick, Rhode Island, U.S.A.

Joseph S. Chung Department of Neurology, Movement Disorders Specialist, Southern California Kaiser Permanente, Los Angeles, California, U.S.A.

Khashayar Dashtipour Division of Movement Disorders, Department of Neurology, Loma Linda University School of Medicine, Loma Linda, California, U.S.A.

Richard B. Dewey, Jr. Department of Neurology, University of Texas Southwestern Medical Center, Dallas, Texas, U.S.A.

Dennis W. Dickson Department of Pathology, Mayo Clinic College of Medicine, Jacksonville, Florida, U.S.A.

Stewart A. Factor Emory University School of Medicine, Department of Neurology, Wesley Woods Health Center, Atlanta, Georgia, U.S.A.

Matthew J. Farrer Mayo Clinic, Jacksonville, Florida, and Mayo School of Graduate Medical Education, Mayo Clinic College of Medicine, Rochester, Minnesota, U.S.A.

Hubert H. Fernandez Movement Disorders Center and Department of Neurology, University of Florida/McKnight Brain Institute, Gainesville, Florida, U.S.A.

Cynthia Fox Tucson, Arizona, National Center for Voice and Speech, Denver, Colorado, U.S.A.

John T. Gale Department of Neurosurgery, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, U.S.A.

Christopher G. Goetz Department of Neurological Sciences, Rush University, Chicago, Illinois, U.S.A.

Robert A. Hauser Parkinson's Disease and Movement Disorders Center, University of South Florida, NPF Center of Excellence, Tampa, Florida, U.S.A.

Akiko Imamura Mayo Clinic, Jacksonville, Florida, and Mayo School of Graduate Medical Education, Mayo Clinic College of Medicine, Rochester, Minnesota, U.S.A.

Michael W. Jakowec Department of Neurology, University of Southern California, Los Angeles, California, U.S.A.

Joseph Jankovic Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, Texas, U.S.A.

Danna Jennings Department of Neurology, The Institute for Neurodegenerative Disorders, New Haven, Connecticut, U.S.A.

Anthony E. Lang Department of Medicine, Division of Neurology, The Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada

Mark F. Lew Division of Movement Disorders, Keck/USC School of Medicine, Los Angeles, California, U.S.A.

Andres M. Lozano Division of Neurosurgery, Toronto Western Hospital, Toronto, Ontario, Canada

Kelly E. Lyons Department of Neurology, University of Kansas Medical Center, Kansas City, Kansas, U.S.A.

Kenneth Marek Department of Neurology, The Institute for Neurodegenerative Disorders, New Haven, Connecticut, U.S.A.

Jill Marjama-Lyons Albuquerque, New Mexico, U.S.A.

Erwin B. Montgomery Department of Neurology, National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin, U.S.A.

John Morgan Department of Neurology, Medical College of Georgia, Augusta, Georgia, U.S.A.

Joseph S. Neimat Department of Neurological Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, U.S.A.

Laura Nieder Neurology Department, Guy's King's and St. Thomas' School of Medicine, London, U.K.

William G. Ondo Department of Neurology, Baylor College of Medicine, Houston, Texas, U.S.A.

Atul T. Patel Department of Rehabilitation, Research Medical Center, Kansas City Bone and Joint Clinic, Overland Park, Kansas, U.S.A.

Parag G. Patil Department of Neurosurgery, University of Michigan, Ann Arbor, Michigan, U.S.A.

Rajesh Pahwa Department of Neurology, University of Kansas Medical Center, Kansas City, Kansas, U.S.A.

Giselle M. Petzinger Department of Neurology, University of Southern California, Los Angeles, California, U.S.A.

Ronald F. Pfeiffer Department of Neurology, University of Tennessee Health Science Center, Memphis, Tennessee, U.S.A.

Brad A. Racette Department of Neurology and American Parkinson Disease Association Advanced Center for Parkinson Research, Washington University School of Medicine, St. Louis, Missouri, U.S.A.

Alex Rajput Division of Neurology, Department of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada

Ali H. Rajput Division of Neurology, Department of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada

Michele Rajput Division of Neurology, Department of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada

Lorraine Olson Ramig Department of Speech, Language, Hearing Sciences, University of Colorado, Boulder, and National Center for Voice and Speech, Denver, Colorado, U.S.A.

Jayaraman Rao Department of Neurology, Parkinson's Disease and Movement Disorders Center, Ochsner Foundation Clinic, New Orleans, Louisiana, U.S.A.

Michael Samuel Department of Neurology, King's College Hospital, Denmark Hill, London, U.K.

Shimon Sapir Department of Communication Sciences and Disorders, University of Haifa, Haifa, Israel

John Seibyl Department of Neurology, The Institute for Neurodegenerative Disorders, New Haven, Connecticut, U.S.A.

Kapil D. Sethi Department of Neurology, Medical College of Georgia, Augusta, Georgia, U.S.A.

Sean Shire Department of Rehabilitation, Research Medical Center, RMC-Brookeside, Kansas City, Missouri, U.S.A.

Mark Stacy Division of Neurology, Duke University Medical School, Durham, North Carolina, U.S.A.

Valerie Street Division of Neurology, Duke University Medical School, Durham, North Carolina, U.S.A.

Alexander I. Tröster Department of Neurology, University of North Carolina School of Medicine at Chapel Hill, Chapel Hill, North Carolina, U.S.A.

Steven Paul Woods Department of Psychiatry, University of California at San Diego, San Diego, California, U.S.A.

Zbigniew K. Wszolek Mayo Clinic, Jacksonville, Florida, and Mayo School of Graduate Medical Education, Mayo Clinic College of Medicine, Rochester, Minnesota, U.S.A.

Allan D. Wu Division of Movement Disorders, Department of Neurology, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, California, U.S.A.

Theresa A. Zesiewicz Parkinson's Disease and Movement Disorders Center, University of South Florida, NPF Center of Excellence, Tampa, Florida, U.S.A.

Early Iconography of Parkinson's Disease

Christopher G. Goetz

Department of Neurological Sciences, Rush University, Chicago, Illinois, U.S.A.

Parkinson's disease was first described in a medical context in 1817 by James Parkinson, a general practitioner in London. Numerous essays have been written about Parkinson himself and the early history of Parkinson's disease (Paralysis agitans), or the shaking palsy. Rather than repeat or resynthesize such prior studies, this introductory chapter focuses on a number of historical visual documents with descriptive legends. Some of these are available in prior publications, but the entire collection has not been presented before. As a group, they present materials from the 19th century and will serve as a base, on which the subsequent chapters that cover progress of the twentieth and budding twenty-first centuries are built. In 2005, as part of the Movement Disorder Society annual international congress, an extensive history exhibit was developed. Interested readers can access the core of this exhibit (1).

HISTORICAL AND LITERARY PRECEDENTS

FIGURE 1 Franciscus de le Böe (1614-1672). Also known as Sylvius de le Böe, and Francis-cus Sylvius, this early physician was a Professor of Leiden and a celebrated anatomist. In his medical writings, he also described tremors and he may be among the very earliest writers on involuntary movement disorders (2).

FIGURE 1 Franciscus de le Böe (1614-1672). Also known as Sylvius de le Böe, and Francis-cus Sylvius, this early physician was a Professor of Leiden and a celebrated anatomist. In his medical writings, he also described tremors and he may be among the very earliest writers on involuntary movement disorders (2).

FIGURE 2 François Boissier de Sauvages de la Croix (1706-1767). Sauvages was cited by Parkinson himself and described patients with "running disturbances of the limbs," scelotyrbe fes-tinans. Such subjects had difficulty in walking, moving with short and hasty steps. He considered the problem to be due to diminished flexibility of muscle fibers—possibly his manner of describing rigidity (2,3).

FIGURE 2 François Boissier de Sauvages de la Croix (1706-1767). Sauvages was cited by Parkinson himself and described patients with "running disturbances of the limbs," scelotyrbe fes-tinans. Such subjects had difficulty in walking, moving with short and hasty steps. He considered the problem to be due to diminished flexibility of muscle fibers—possibly his manner of describing rigidity (2,3).

FIGURE 3 William Shakespeare. A brilliant medical observer and writer, Shakespeare, described many neurological conditions, including epilepsy, somnambulism, and dementia. In Henry VI, first produced in 1590, the character, Dick, notices that Say is trembling: "Why dost thou quiver, man," he asks, and Say responds, "The palsy and not fear provokes me" (2). Jean-Martin Charcot frequently cited Shakespeare in his medical lectures and classroom presentations and disputed the concept that tremor was a natural accompaniment of normal aging. He rejected "senile tremor" as a separate nosographic entity. After reviewing his data from the Salpetriere service where 2000 elderly inpatients lived, he turned to Shakespeare's renditions of elderly figures: "Do not commit the error that many others do and misrepresent tremor as a natural accompaniment of old age. Remember that our venerated Dean, Dr. Chevreul, today 102 years old, has no tremor whatsoever. And you must remember in his marvelous descriptions of old age (Henry IVand /4s You Like It), the master observer, Shakespeare, never speaks of tremor" (4,5).

FIGURE 3 William Shakespeare. A brilliant medical observer and writer, Shakespeare, described many neurological conditions, including epilepsy, somnambulism, and dementia. In Henry VI, first produced in 1590, the character, Dick, notices that Say is trembling: "Why dost thou quiver, man," he asks, and Say responds, "The palsy and not fear provokes me" (2). Jean-Martin Charcot frequently cited Shakespeare in his medical lectures and classroom presentations and disputed the concept that tremor was a natural accompaniment of normal aging. He rejected "senile tremor" as a separate nosographic entity. After reviewing his data from the Salpetriere service where 2000 elderly inpatients lived, he turned to Shakespeare's renditions of elderly figures: "Do not commit the error that many others do and misrepresent tremor as a natural accompaniment of old age. Remember that our venerated Dean, Dr. Chevreul, today 102 years old, has no tremor whatsoever. And you must remember in his marvelous descriptions of old age (Henry IVand /4s You Like It), the master observer, Shakespeare, never speaks of tremor" (4,5).

FIGURE 4 Wilhelm von Humboldt (1767-1835). The celebrated academic reformer and writer, von Humboldt, lived in the era of Parkinson and described his own neurological condition in a series of letters, analyzed by Horowski (6). The statue by Friedrich Drake shown in the figure captures the hunched, flexed posture of Parkinson's disease, but von Humboldt's own words capture the tremor and bradykinesia of the disease:

FIGURE 4 Wilhelm von Humboldt (1767-1835). The celebrated academic reformer and writer, von Humboldt, lived in the era of Parkinson and described his own neurological condition in a series of letters, analyzed by Horowski (6). The statue by Friedrich Drake shown in the figure captures the hunched, flexed posture of Parkinson's disease, but von Humboldt's own words capture the tremor and bradykinesia of the disease:

Trembling of the hands . . . occurs only when both or one of them is inactive; at this very moment, for example, only the left one is trembling but not the right one that I am using to write If I am using my hands this strange clumsiness starts which is hard to describe. It is obviously weakness as I am unable to carry heavy objects as I did earlier on, but it appears with tasks that do not need strength but consist of quite fine movements, and especially with these. In addition to writing, I can mention rapid opening of books, dividing of fine pages, unbuttoning and buttoning up of clothes. All of these as well as writing proceed with intolerable slowness and clumsiness (7).

JAMES PARKINSON

OH TUB

SHAKING PALSY.

JAM£S PARKINSON,

Hint* or na kjval cmjjgc or undEOH*

FOR 5HEBVOOO, N EEL Y, AfiD JONES-MIt«»MIt!l ÄOW-

1817.

FIGURE 5 Front piece of James Parkinson's An Essay on the Shaking Palsy. This short monograph is extremely difficult to find in its original 1817 version, but has been reproduced many times. In the essay, Parkinson describes a small series of subjects with a distinctive constellation of features. Although he had the opportunity to examine a few of the subjects, some of his reflections were based solely on observation (8).

FIGURE 6 St. Leonard's Church. The Shoreditch parish church was closely associated with James Parkinson's life, as he was baptized, married, and buried there (9).

HUNTERIAN REMINISCENCES ;

HIM mi HWlHI i

COURSE OP IjECTURES PRINCIPLES AND PRACTICE OF SURGERY, MR. JOHN HUNTER,

IS Tilt YEAR Ifflii »KB IN Slt01tT>IIANDr AXD AFTB*WAM» FA1HLV T1UWSCMSKB. HV TUB UTK

MR. JAMES PARKIN SON,

HUNTERIAN REMINISCENCES ;

HIM mi HWlHI i

COURSE OP IjECTURES PRINCIPLES AND PRACTICE OF SURGERY, MR. JOHN HUNTER,

IS Tilt YEAR Ifflii »KB IN Slt01tT>IIANDr AXD AFTB*WAM» FA1HLV T1UWSCMSKB. HV TUB UTK

ILLUSTRATIVE NOTES.

LONDON;

SHERWOOD, OILHEHT, ASH UK«, fATEiKOiTM »O»-. 1833,

FIGURE 7 John Hunter. The celebrated physician, Hunter [painted by J. Reynolds (10)], was admired by Parkinson, who transcribed the surgeon's lectures in his 1833 publication called Hunter-ian Reminiscences (11). In these lectures, Hunter offered observations on tremor.The last sentence of Parkinson's Essay reads:

... but how few can estimate the benefits bestowed on mankind by the labours of Morgagni, Hunter or Baillie (8).

Currier has posited that Parkinson's own interest in tremor was first developed under the direct influence of Hunter (12).

FIGURE 8 James Parkinson's home. No. 1 Hoxton Square, London, formerly Shoreditch, today carries a plaque, honoring the birthplace of James Parkinson (13). The plaque that hangs by the entrance is shown close-up.
FIGURE 9 James Parkinson as paleontologist. An avid geologist and paleontologist, Parkinson, published numerous works on fossils, rocks, and minerals (14). He was an honorary member of the Wernerian Society of Natural History of Edinburgh and the Imperial Society of Naturalists of Moscow.

MEDICAL

CLASSICS

BMRMON GKOMV JCKt.LY. M.D.,

1(t WILLIAMS ik WII.XISI COMFANY

FIGURE 10 Counterfeit portrait of James Parkinson. To date, no portrait is known to exist of James Parkinson. This photograph of a dentist by the same name was erroneously published and widely circulated in 1938, as part of a Medical Classics edition of Parkinson's Essay (15). Because Parkinson died prior to the first daguerreotypes, if a portrait is found, it will be a line drawing, painting, or print. A written description does however exist. The paleontologist, Mantell wrote:

Mr. Parkinson was rather below middle stature, with an energetic intellect, and pleasing expression of countenance and of mild and courteous manners; readily imparting information, either on his favourite science or on professional subjects (9).

FIGURE 11 One of Parkinson's medical pamphlets. As an avid writer, Parkinson compiled many books and brochures that were widely circulated on basic hygiene and health. His Medical Admonitions to Families and The Villager's Friend and Physician were among the most successful, although he also wrote a children's book on safety entitled Dangerous Sports, in which he traced the mishaps of a careless child and lessons he learns through injury (13).

JEAN-MARTIN CHARCOT AND THE SALPETRIERE SCHOOL

JEAN-MARTIN CHARCOT AND THE SALPETRIERE SCHOOL

FIGURE 12 Jean-Martin Charcot. Working in Paris, in the second half of the 19th century, Charcot knew of Parkinson's description and studied the disorder in the large Salpetriere hospital that housed elderly and destitute women. He identified the cardinal features of Parkinson's disease and specifically separated bradykinesia from rigidity (5,16):

FIGURE 12 Jean-Martin Charcot. Working in Paris, in the second half of the 19th century, Charcot knew of Parkinson's description and studied the disorder in the large Salpetriere hospital that housed elderly and destitute women. He identified the cardinal features of Parkinson's disease and specifically separated bradykinesia from rigidity (5,16):

Long before rigidity actually develops, patients have significant difficulty performing ordinary activities: this problem relates to another cause. In some of the various patients I showed you, you can easily recognize how difficult it is for them to do things even though rigidity or tremor is not the limiting features. Instead, even a cursory exam demonstrates that their problem relates more to slowness in execution of movement rather than to real weakness. In spite of tremor, a patient is still able to do most things, but he performs them with remarkable slowness. Between the thought and the action there is a considerable time lapse. One would think neural activity can only be affected after remarkable effort.

FIGURE 13 Statue of a parkinsonian woman by Paul Richer. Richer worked with Charcot, and, as an artist and sculptor, produced several works that depicted the habitus, joint deformities and postural abnormalities of patients with Parkinson's disease (14,17).
FIGURE 14 Evolution of parkinsonian disability. These figures, drawn by Charcot's student, Paul Richer, capture the deforming posture and progression of untreated Parkinson's disease over a decade (15,18).

Parkinson's disease, he showed two subjects, one with the typical or archetypal form of the disorder with hunched posture and flexion (/eft), and another case with atypical parkinsonism, showing an extended posture (right).The latter habitus is more characteristic of the entity progressive supranuclear palsy, although this disorder was not specifically recognized or labeled by Charcot outside of the term "parkinsonism without tremor" (5).

Parkinson's disease, he showed two subjects, one with the typical or archetypal form of the disorder with hunched posture and flexion (/eft), and another case with atypical parkinsonism, showing an extended posture (right).The latter habitus is more characteristic of the entity progressive supranuclear palsy, although this disorder was not specifically recognized or labeled by Charcot outside of the term "parkinsonism without tremor" (5).

FIGURE 16 Charcot's early tremor recordings. Charcot adapted the sphygmograph, an instrument originally used for recording arterial pulsation, to record tremors and movements of the wrist. His resultant tremor recordings (lower right), conducted at rest (A-B) and during activity (B-C), differentiated multiple sclerosis (top recording) from the pure rest tremor (lower recording) or mixed tremor (middle recording) of Parkinson's disease (19).

FIGURE 16 Charcot's early tremor recordings. Charcot adapted the sphygmograph, an instrument originally used for recording arterial pulsation, to record tremors and movements of the wrist. His resultant tremor recordings (lower right), conducted at rest (A-B) and during activity (B-C), differentiated multiple sclerosis (top recording) from the pure rest tremor (lower recording) or mixed tremor (middle recording) of Parkinson's disease (19).

FIGURE 17 Charcot's sketch of parkinsonian subject. Pencil sketch of a man with Parkinson's disease drawn by Charcot during a trip to Morocco in 1889 (20). Referring to the highly stereotyped clinical presentation of Parkinson's disease patients, Charcot told his students:

I have seen such patients everywhere, in Rome, Amsterdam, Spain, always the same picture. They can be identified from afar.You do not need a medical history (4,5).

Charcot's medical drawings form a large collection, which is housed at the Bibliothèque Charcot at the Hôpital de la Salpêtrière, Paris.

FIGURE 18 Treatment of Parkinson's disease. Prescription dated 1877 (21). In treating Parkinson's disease, Charcot used belladonna alkaloids (agents with potent anticholinergic properties) as well as rye-based products that had ergot activity, a feature of some currently available dopamine agonists (21). Charcot's advice was empiric and preceded the recognition of the well-known dopaminergic/cholinergic balance that is implicit to normal striatal neurochemical activity.

FIGURE 18 Treatment of Parkinson's disease. Prescription dated 1877 (21). In treating Parkinson's disease, Charcot used belladonna alkaloids (agents with potent anticholinergic properties) as well as rye-based products that had ergot activity, a feature of some currently available dopamine agonists (21). Charcot's advice was empiric and preceded the recognition of the well-known dopaminergic/cholinergic balance that is implicit to normal striatal neurochemical activity.

FIGURE 19 Vibratory therapy. Charcot observed that patients with Parkinson's disease experienced a reduction in their rest tremor, after taking a carriage ride or after horseback riding. He developed a therapeutic vibratory chair that simulated the rhythmic shaking of a carriage (18). A vibratory helmet to shake the head and brain was later developed. Such therapies were not utilized widely and have not been studied in modern times.

FIGURE 19 Vibratory therapy. Charcot observed that patients with Parkinson's disease experienced a reduction in their rest tremor, after taking a carriage ride or after horseback riding. He developed a therapeutic vibratory chair that simulated the rhythmic shaking of a carriage (18). A vibratory helmet to shake the head and brain was later developed. Such therapies were not utilized widely and have not been studied in modern times.

OTHER NINETEENTH CENTURY CONTRIBUTIONS

FIGURE 20 Dysautonomia in Parkinson's disease. This drawing by Daniel Vierge (1851-1904) shows the Salpetriere inpatient wards with a single central furnace for heat (18). In this context, Charcot recognized the distinctive dysautonomia of Parkinson's disease, noting how patients experienced a sense of hyperthermia even in the drafty, cold wards of the French hospitals:

FIGURE 20 Dysautonomia in Parkinson's disease. This drawing by Daniel Vierge (1851-1904) shows the Salpetriere inpatient wards with a single central furnace for heat (18). In this context, Charcot recognized the distinctive dysautonomia of Parkinson's disease, noting how patients experienced a sense of hyperthermia even in the drafty, cold wards of the French hospitals:

In the midst of winter (everyone on my service will substantiate this), you can see the parkinsonian patients with no blankets covering them and with only the lightest of clothes on . . . they feel hot especially around the epigastrium and back, although the face and extremities can also be the focus of their discomfort. When this heated sensation occurs, it is often accompanied by such severe sweating that the sheets and pajamas may need changing. I assure you that regardless of how hot these patients feel or how much they shake, their temperature remains normal (18).

FIGURE 21 Micrographia and tremorous handwriting. Charcot recognized that one characteristic feature of Parkinson's disease was the handwriting impairment that included tremorous and tiny script. Charcot collected handwriting samples in his patients' charts and used them as part of his diagnostic criteria, thereby separating the large and sloppy script of patients with action tremor from the micrographia of Parkinson's disease (16).

FIGURE 21 Micrographia and tremorous handwriting. Charcot recognized that one characteristic feature of Parkinson's disease was the handwriting impairment that included tremorous and tiny script. Charcot collected handwriting samples in his patients' charts and used them as part of his diagnostic criteria, thereby separating the large and sloppy script of patients with action tremor from the micrographia of Parkinson's disease (16).

FIGURE 22 William Gowers' work. William Gowers' A Manual of Diseases of the Nervous System shows sketches of patients with Parkinson's disease (left) and diagrams of joint deformities (right) (22). More known for written descriptions than visual images, Gowers offered one of the most memorable similes regarding parkinsonian tremor:

FIGURE 22 William Gowers' work. William Gowers' A Manual of Diseases of the Nervous System shows sketches of patients with Parkinson's disease (left) and diagrams of joint deformities (right) (22). More known for written descriptions than visual images, Gowers offered one of the most memorable similes regarding parkinsonian tremor:

the movement of the fingers at the metacarpal-phalangeal joints is similar to that by which Orientals beat their small drums (22).

FIGURE 23 William Osler. Osler published his celebrated Principles and Practice of Medicine in 1982, one year before Charcot's death. As an internist always resistant to the concept of medical specialization, Osler was influential in propagating information to generalists on many neurological conditions, including Parkinson's disease. Osler was less forthcoming than Charcot in appreciating the distinction between bradykinesia and weakness, and sided with Parkinson in maintaining that mental function was unaltered. Osler was particularly interested in pathological studies and alluded to the concept of Parkinson's disease as a state of accelerated aging (23).

FIGURE 23 William Osler. Osler published his celebrated Principles and Practice of Medicine in 1982, one year before Charcot's death. As an internist always resistant to the concept of medical specialization, Osler was influential in propagating information to generalists on many neurological conditions, including Parkinson's disease. Osler was less forthcoming than Charcot in appreciating the distinction between bradykinesia and weakness, and sided with Parkinson in maintaining that mental function was unaltered. Osler was particularly interested in pathological studies and alluded to the concept of Parkinson's disease as a state of accelerated aging (23).

FIGURE 24 Eduard Brissaud. Brissaud was a close associate of Charcot and contributed several important clinical observations on Parkinson's disease in the late 19th century. Most importantly, however, he brought neuropathological attention to the substantia nigra as the potential cite of disease origin. In discussing a case of a tuberculoma that destroyed the substantia nigra and in association with contralateral hemiparkinsonism, he considered the currently vague knowledge of the nucleus and its putative involvement in volitional and reflex motor control. Extending his thoughts, he hypothesized that, "a lesion of the locus niger could reasonably be the anatomic basis of Parkinson's disease" (24).

FIGURE 24 Eduard Brissaud. Brissaud was a close associate of Charcot and contributed several important clinical observations on Parkinson's disease in the late 19th century. Most importantly, however, he brought neuropathological attention to the substantia nigra as the potential cite of disease origin. In discussing a case of a tuberculoma that destroyed the substantia nigra and in association with contralateral hemiparkinsonism, he considered the currently vague knowledge of the nucleus and its putative involvement in volitional and reflex motor control. Extending his thoughts, he hypothesized that, "a lesion of the locus niger could reasonably be the anatomic basis of Parkinson's disease" (24).

REFERENCES

1. www.movementdisorders.org

2. Finger S. Origins of Neuroscience. New York, Oxford University Press, 1994.

S. Sauvages de la Croix FB. Nosología methodica. Amstelodami: Sumptibus Fratrum de Tournes, 176S.

4. Charcot J-M. Leçons du Mardi: Policlinique: 1887-1888. Paris: Bureaux du Progrès Médical, 1888.

5. Goetz CG. Charcot, the Clinician: The Tuesday Lessons. New York: Raven Press, 1987.

6. Horowski R, Horowski L, Vogel S, Poewe W, Kielhorn F-W. An essay on Wilhelm von Humboldt and the shaking palsy. Neurology 199S; 45:565-568.

7. Leitzmann A. Briefe von Wilhelm von Humboldt an Eine Freundin. Leipzig: Inselverlag, 1909.

8. Parkinson J. Essay on the Shaking Palsy. London: Whittingham and Rowland for Sherwood, Neeley and Jones. 1817.

9. Morris AD, Rose FC. James Parkinson: His Life and Times. Boston: Birkhauser, 1989.

10. Allen E, Turk JL, Murley R. The Case Books of John Hunter FRS. London: Royal Society of Medicine, 1993.

11. Parkinson J. Hunterian Reminiscences. London: Sherwood, Gilbert and Piper, 1833.

12. Currier RD. Did John Hunter give James Parkinson an idea? Arch Neurol 1996; 53:377-378.

13. Robert D. Currier Parkinson Archives legged to Christopher G. Goetz.

14. Parkinson, J. Organic Remains of a Former World (three volumes). London: Whittingham and Rowland for Sherwood, Neeley and Jones, 1804-1811.

15. Kelly EC. Annotated reprinting: Essay on the Shaking Palsy by James Parkinson. Medical Classics 1938; 2:957-998.

16. Charcot J-M. De la paralysie agitante (leçon 5). Oeuvres Complètes 1869; 1:161-188 (Paris, Bureaux du Progrès Médical). In English: On paralysis agitans (Lecture 5). Lectures on the Diseases of the Nervous System. Translated by G. Sigurson. Philadelphia: HC Lea and Company, 1879:105-107.

17. Historical art and document collection, Christopher G. Goetz.

18. Goetz CG, Bonduelle M, Gelfand T. Charcot: Constructing Neurology. New York: Oxford University Press, 1995.

19. Charcot J-M. Tremblements et mouvements choreiforms (leçon 15). Oeuvres Complètes 1888; 9:215-228 (Paris, Bureaux du Progrès Médical). In English: Choreiform Movements and Tremblings. Clinical Lectures on Diseases of the Nervous System. Translated by EF Hurd. Detroit: GS Davis, 1888:208-221.

20. Meige H. Charcot Artiste. Nouvelle Iconographie de la Salpêtrière 1898; 11:489-516.

21. Philadelphia College of Physicians, Original manuscript and document collection, Philadelphia, PA.

22. Gowers WR. A Manual of Diseases of the Nervous System. London: Churchill, 1886-1888.

23. Osler W. The Principles and Practice of Medicine. New York: Appleton and Company, 1892.

24. Brissaud E. Nature et pathogénie de la maladie de Parkinson (leçon 23:488-501). Leçons sur les maladies nerveuses: la Salpêtrière, 1893-1894; Paris: Masson, 1895.

Epidemiology

Michele Rajput, Alex Rajput, and Ali H. Rajput

Division of Neurology, Department of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada

Epidemiology is "the study of distribution and determinants of health-related states in specified populations"(1). This chapter will focus on the distribution of parkinsonism. Unlike laboratory studies where the experimental conditions can be controlled, epidemiology examines natural events occurring in human populations that are influenced by characteristics of the individuals studied as well as by outside forces including medical, economic, and social factors. For these reasons, care must be taken when conducting and reviewing epidemiological studies. No two epidemiological studies are identical. For many reasons, the methods utilized at one location or at one time may not be possible at another and populations vary by time and place. Two primary factors must be considered in studying the epidemiology of parkinsonism, the case definitions used and the population studied.

INCLUSION CRITERIA FOR PARKINSON EPIDEMIOLOGY

The two major considerations for inclusion in parkinsonism epidemiology are:

1. Does this individual have parkinsonism, normal aging, or another disorder?

2. Does this person have idiopathic Parkinson's disease (PD) or another variant of parkinsonism?

Primitive reflexes, slowed motor functions, flexed posture, and impaired postural reflexes characteristic of parkinsonism are also a part of normal aging (2). In general, age-related abnormalities are symmetrical while parkinsonism is often asymmetrical. Rest tremor, a common early feature of parkinsonism, is not part of normal aging and hence is the single most reliable feature of this disorder (3).

The most common tremor disorder misdiagnosed as PD is essential tremor (ET). Typically, ET is present on positioning a limb against gravity and during activity. ET is usually restricted to the upper limbs and/or head. By contrast, resting tremor is characteristic of parkinsonism and may involve the upper and lower limbs. Nearly one-third of ET patients may develop rest tremor after many years and may be mistaken as having parkinsonism; however, the risk of PD does not appear to be greater in patients with ET (4).

For epidemiological surveys, the diagnostic criteria should be simple, consistent through the study interval, and easy to apply. For example, after careful consideration of different diagnostic criteria utilized in epidemiological studies, de Rijk et al. (5) concluded that the most suitable for PD is the presence of two of at least three criteria—bradykinesia, rigidity, and resting tremor. In individuals with preexisting ET, the additional diagnosis of parkinsonism should be made only when all three criteria are present (6).

The second major consideration is to classify parkinsonism cases into different variants. Most neurologists use the term PD for Lewy body disease but this diagnosis

cannot be made definitively before death (7,8). Distinction between different parkinsonism variants is difficult, especially during the early stages of disease. Even in a clinical setting where patients are repeatedly evaluated by experts, accurate clinical diagnosis may not be possible as the telltale features that distinguish other variants from PD may evolve late or never (8-10). Classification into possible, probable, and definite PD has limited value in epidemiological studies that are primarily aimed at measuring the magnitude of the disorder in the population. Response to levodopa, though valuable, does not always distinguish between different variants of parkin-sonism (12).

The classification of parkinsonism has been evolving with time. Following the first description in 1817 by James Parkinson (13) and the discovery of the substantia nigra neuronal loss and Lewy body inclusions, parkinsonism was regarded as a single clinicopathological entity. This concept changed in the 1920s and 1930s after von Economo encephalitis from which an estimated 60% of the patients developed postencephalitic parkinsonism (14). At one time, these patients constituted a large proportion of the parkinsonism cases in the general population, but no new posten-cephalitic parkinsonism cases have been reported since the mid-1950s. Arteriosclerosis was once reported as a common cause of parkinsonism (15,16), but this diagnosis is now rare (17,18). This change in diagnostic classification reflects changes in autopsy studies and the determination of underlying pathology rather than a dramatic decline in arteriosclerosis in the general population.

Neuroleptic induced parkinsonism was first recognized in the late 1950s and is now a common parkinsonism variant ranging between 7% (17) and 20% of all cases (18,19). Drug-induced parkinsonism is now second only to PD and is more common in women than men (18).

Large clinicopathological studies of Shy-Drager syndrome (SDS) (20), striaton-igral degeneration (SND) (21), and progressive supranuclear palsy (PSP) (22) were first reported in the 1960s. The current classification includes SND, SDS, and olivopontocerebellar atrophy under the common heading of multiple system atrophy (MSA). Prominent dysautonomia in SDS and akinetic rigid parkinsonian features in SND were not fully recognized until 1960 and 1964, respectively, and in all likelihood, such cases prior to that were classified as postencephalitic or atypical parkinsonism, as they occurred at a relatively young age and had widespread nervous system involvement.

In spite of the improved understanding of these uncommon parkinsonism variants, the diagnosis is not always possible clinically. Autopsy series may be biased as the families of those suffering from the unusual variants may have heightened interest in finding out the nature of the disease and therefore consent to autopsy. The accurate frequency of these variants in the general population is, therefore, not possible to determine. In one epidemiological study, 2.5% of all parkinsonian patients were classified as MSA and 4.3% as PSP (18). A previous study from the same community reported a diagnosis of PSP in 1.4% and MSA in 2.1% of parkinsonian cases (17). Thus MSA and PSP each represent less than 5% of the contemporary parkinsonian cases in North America.

The most common parkinsonism in epidemiological studies is idiopathic PD. The proportion of those with PD, however, varies widely in different studies from 42% (18) to 85% (17). Preponderance of PD is also noted in autopsy studies of unselected parkinsonian cases (12,23,24).

The clinical and pathological classification of different parkinsonism variants continues to evolve. Classification into different variants is valuable, but it should be recognized that this only provides approximate estimates. Autopsy studies to confirm the diagnosis are not possible in epidemiological surveys; therefore, for descriptive epidemiological studies, all parkinsonian variants should be considered. Further classification may then be made based on the best clinical evidence.

INCIDENCE OF PARKINSONISM

Incidence is defined as the number of new cases per year and is usually described per 100,000 people. Conducting an incidence study requires not only defining cases but also determining which are the new cases. Some new onset cases that ought to be included may not be recognized until sometime later. As well, the number of new cases in a community may vary from one year to the next. Consequently, incidence studies require a long period of observations in the same community using consistent case finding methods and case definitions.

The reported incidence rates of PD vary widely. The lowest PD incidence in Western countries was reported from Sardinia at 4.9/105 (25). A systematic review of 25 European studies identified five well-designed, similar studies of PD incidence (26). Four studies reported similar incidence of 16 to 19/105 but one Italian study reported a much lower incidence of 8.4/105, and age-adjusted PD incidence in Taiwan (Republic of China) is 10.4/105 (27).

In the Western countries, some of the most reliable incidence studies are those from Rochester Minnesota using the record system of the Mayo Clinic, which combines case ascertainment with diagnosis by neurologists. Four different incidence reports based on the Rochester population have been published (15-18). Since drug-induced parkinsonism was not recognized until the early 1960s (28), we excluded drug-induced parkinsonism from each study for the purpose of comparison. The rates for 1945-1954 (15), 1935-1966 (16), 1967-1979 (17), and 1976-1990 (18) were 20.5, 18.5, 18.2, and 20.5/105, respectively. There was no significant change in incidence over 55 years. The latest study (18) revealed overall incidence of parkinsonism of 25.6/105, including drug-induced parkinsonism.

Incidence increases with increasing age. The incidence of parkinsonism was 0.8/105 in those aged 0 to 29 years, 25.6/105 in those 50 to 59 years and, more than 11 times higher (304.8/105) in the 80- to 99-year age group (18). There has been no significant change in the age-specific incidence rates during the 55-year interval of these studies (29). Slightly higher overall incidence of parkinsonism in recent reports likely reflects longer life expectancy in the general population, more frequent use of neuroleptics and improved diagnosis (18,29).

Pathological studies (30,31) show a progressive increase in the rate of incidental Lewy body inclusions with advancing age. These cases are regarded as having preclinical PD. With every decade of life, there is a doubling of incidental Lewy bodies (31). The decline of parkinsonism and PD specifically, in the very old observed in some studies, is attributed to difficulty in ascertaining cases in the presence of comor-bid disorders (18). Age remains the single most important risk factor for parkinsonism. An Italian study noted a 9% increase in risk for every increasing year of age (i.e., a 60-year-old has a 90% greater risk than a 50-year-old), and men had higher risk than women (19). The current lifetime risk of parkinsonism from birth is estimated at 4.4% for men and 3.7% for women (32).

LIFE EXPECTANCY IN PARKINSONISM

All of the parkinsonism variants limit mobility, and the increased tendency for falls and dysphagia predisposes these patients to life-threatening complications (33,34). Life expectancy prior to the widespread use of levodopa was significantly reduced.

In one hospital based parkinsonism series during the 1950s and 1960s, the mean survival after onset was 10.8 years (35). Excluding postencephalitic parkinsonism, the mean survival was 9.42 years, which is frequently cited as the yardstick for the prelevodopa era life expectancy (35). Mean survival in the contemporary parkinsonism cases cannot be compared with that study. There have been significant social and health care advances leading to longer life in the general population, and one would expect that parkinsonism patients would share these survival gains. Comparisons for survival should be made matching for year of birth, gender, and region/country.

Kurtzke et al. (36) noted that patients in the 1980s were, on an average, five years older at death than those who died in the 1970s—implying that life expectancy since the widespread use of levodopa has increased by five years. Several other studies (37-40) have also reported longer life expectancy, but it is still lower than expected. At the other extreme are studies (41,42) that suggest that current parkinsonism cases survive longer than the general population. It is difficult to reconcile that individuals suffering from a progressively disabling disorder would live longer than the matched general population. The most common error in the better than expected survival studies is measuring survival from the date of onset assigned several years retrospectively. During that period, the general population would have suffered some death. That gives the parkinsonism group an artificial advantage since they survived at least to diagnosis (41). When we assessed our patients using the date of onset, the parkin-sonian patients had greater survival than the general population (40). The other reason for this error is inclusion of only the levodopa-treated cases (42). For any number of reasons, some patients may not be treated with levodopa, and those destined for longer survival may be treated with levodopa introducing significant bias. Researchers noted that survival is greater if only the levodopa-treated cases were considered (17). Restricting a study to only clinically diagnosed PD and excluding other variants introduces another source of bias as the inaccuracy of clinical diagnosis is well known (8,9) and survival is shorter in non-PD variants (10,43,44).

Ablinded study withholding modern drugs from one group of matched patients is unethical and therefore not possible. In our clinic-based study of 934 parkinson-ian cases seen between 1968 and 1990, survival measured from the date of first assessment was significantly reduced (P< 0.0001) (45). As of 1974, patients in this clinic had widespread and easy access to levodopa. Prelevodopa era reduction in survival was even more pronounced. Taken together, these indicate that widespread use of lev-odopa has improved survival. The timing of treatment with levodopa indicates that survival benefit is achieved only when the patients are treated prior to the loss of postural reflexes—Hoehn and Yahr stage III (35). Others reported similar observations of longer survival in patients with early levodopa treatment (38). It is evident that the survival gap between the current parkinsonian cases and the general population has narrowed. This gain in life expectancy is attributable exclusively to the better symptomatic control with levodopa that reduces disability and life-threatening complications (33,34). We estimate that an average patient with PD onset at age 62 now lives for approximately 20 years.

PREVALENCE OF PARKINSONISM

The prevalence rate is defined as the number of patients in the population at a given time. This can be difficult to ascertain, as approximately 15% of people in the community self-reporting a PD diagnosis do not actually have PD and 20% of people with PD have not been diagnosed (46). The two main factors that determine the prevalence rate are the incidence of new cases and life expectancy. Crude prevalence rates are greatly affected by the age distribution of the source population; age-adjusted rates are one way to permit comparisons between different populations but crude rates are most often reported.

Prevalence rates can be estimated by multiplying incidence rate and the mean survival. Most observers regard Rochester, Minnesota, incidence rates as representative for North America. The latest annual incidence of parkinsonism in Rochester is 25.6/105 (18). The survival in parkinsonism has increased substantially during the last three decades. A conservative estimate of mean survival in contemporary parkinsonism is 15 years, though an average PD case would survive longer. Thus, the minimum prevalence rate in the North American general population is estimated at 384/105.

Other methods have been used to determine prevalence rates for parkinson-ism. A state registry in Nebraska reported a prevalence of 329.3/105 (47). Some studies have used consumption of antiparkinsonian drugs as a surrogate for a diagnosis of parkinsonism (48,49), but these underestimate prevalence since many people with parkinsonism are untreated and the medications can be used for other diagnoses.

In the Caucasian population, the crude prevalence ratios vary from 84/105 to 775/105 population (50,51). Prevalence rates based on door-to-door surveys include 57/105 in China (People's Republic of China) (52), 371.5/105 in Sicily (53), and 775/105 in Australia (51). In a Parsi community from Mumbai, India, the prevalence rate was 328/105 (54). In a U.S. community-based study of Copiah County residents that included only persons over the age of 40 years, the prevalence rate was 347/105 (55). A Dutch study in the early 1990s found a prevalence rate of 1400/105 in those aged 55 to 64 years and 4300/105 in the 85 to 94 years age group (56).

In two Canadian studies using representative samples of residents aged 65 years and older, the prevalence rate in community residents was 3% (57) while in institutionalized persons the rate was 9% (58). Somewhat comparable figures were reported from Australia (51). Including only PD cases in persons aged 55 years and older, the prevalence rate of PD was 3600/105 in the community and 4900/105 in institutionalized persons. As discussed previously, incidence has remained relatively constant but life expectancy has increased; one would then expect overall crude prevalence rates to have increased over time.

GENDER AND PARKINSONISM

The available evidence indicates that men have a slightly higher risk of parkinson-ism than women, with the exception of drug-induced parkinsonism (59,60). According to a meta-analysis, relative risk of parkinsonism for men compared to women is 1.5% (61). Suggested reasons for this risk included differential exposure to external risk factors, an X-linked genetic factor, and mitochondrial dysfunction. The lifetime risk of parkinsonism is greater in men than in women (4.4% vs. 3.7%) (32). In older patients, 65 to 84 years, the male to female incidence ratio was 1.66 for parkinsonism and 2.13 for PD (19). Interestingly, although women have a longer life expectancy than men, women with PD have the same mortality rates as men with PD (60).

GEOGRAPHY, ETHNICITY, RACE, AND PARKINSONISM

Parkinsonism has been reported in all countries and in all races. In most countries, geography, ethnicity, and race are intertwined. Comparing immigrants to residents of their homeland is one way to evaluate the associations with the risk of parkinsonism.

The only reported large geographic cluster of well-documented parkinsonism is the Parkinson-dementia-amyotrophic lateral sclerosis (ALS) complex of Guam, and this may be related to consumption of Cycad sp. seeds (62).

Although several studies have suggested that those with darker skin have a reduced risk of PD compared to lighter skin individuals (25,63), a review of 20 studies of PD in African-Americans found no consistent evidence to support this theory (64). The authors believed that ascertainment bias compromised the studies they reviewed. Studies that included communities with a mixed population did not observe any racial differences (55,65). Two studies conducted by the same investigator using similar methodology showed that the prevalence rate in African-Americans was five times higher than in the Nigerians who presumably share a common genetic background (55,66). This difference remained

Was this article helpful?

0 0

Post a comment