Obituary William C. Koller, MD, PhD 1945–2005
William C. Koller died unexpectedly on October 3, 2005, in Chapel Hill, North Carolina, while this volume, which he was co-editing, was in preparation. Bill was born in Milwaukee on July 12, 1945, where he graduated with a BS degree from Marquette University in1968. He went on to Northwestern University in Chicago, where he received a Masters degree in pharmacology in 1971, a PhD in pharmacology in 1974, and an MD in 1976. After completing his internship and residency at Rush Presbyterian St. Luke’s Medical Center in Chicago, he held positions at the Rush Medical College, University of Illinois, Chicago VA, Hines VA, and Loyola University. In 1987, he was appointed Professor and Chairman of Neurology at the University of Kansas Medical Center, where he remained until 1999, when he moved to the University of Miami and became the National Research Director for the National Parkinson Foundation. He subsequently moved on to direct the Movement Disorders clinical program at the Mount Sinai Medical Center in New York, and then to the University of North Carolina, where he laid the foundation for yet another superb clinical and academic program. Bill was a world-renowned neurologist who specialized in Parkinson’s disease, essential tremor and related disorders. He published more than 270 peer-reviewed manuscripts, over 160 review papers and numerous books. His research interests included the epidemiology and experimental therapeutics of parkinsonism and essential tremor, and his work contributed enormously to the current treatment of these disorders. His collaborations were worldwide and many current experts in movement disorders worked with him at one time or another. He was a Fellow of the American Academy of Neurology, Treasurer of the Movement Disorder Society (1999–2000), Executive Board Member of the Parkinson Study Group (1996–1999), President of WE MOVE (2001–2002), a founding member of the Tremor Research Group and founder of the International Tremor Foundation. Dr. Koller will be especially remembered for his humor, warmth and the youthful vigor and enthusiasm that he brought to his work. He was the consummate physician, befriending many of his patients who were encouraged to call him on his cell phone at any time. Whether lecturing in South America, fishing on the boat he shared with several colleagues, traveling with one of his sons to an international meeting or seeing patients in the clinic, Bill’s smile and the sparkle in his eye endeared him to all who knew him. The movement disorders community has lost a valued colleague, mentor and friend. He is survived by his wife and three sons. Kelly Lyons Matthew B. Stern
Photo courtesy of Professor Lindsey and the European Parkinson’s Disease Association.
Foreword
The Handbook of Clinical Neurology was started by Pierre Vinken and George Bruyn in the 1960s and continued under their stewardship until the second series concluded in 2002. This is the fifth volume in the new (third) series, for which we have assumed editorial responsibility. The series covers advances in clinical neurology and the neurosciences and includes a number of new topics. In order to provide insight to physiological and pathogenic mechanisms and a basis for new therapeutic strategies for neurological disorders, we have specifically ensured that the neurobiological aspects of the nervous system in health and disease are covered. During the last quarter-century, dramatic advances in the clinical and basic neurosciences have occurred, and those findings related to the subject matter of individual volumes are emphasized in them. The series will be available electronically on Elsevier’s Science Direct site, as well as in print form. It is our hope that this will make it more accessible to readers and also facilitate searches for specific information. The present volume deals with Parkinson’s disease and related disorders. This group of disorders constitutes one of the most common of neurodegenerative disorders and is assuming even greater importance with the aging of the population in developed countries. The volume has been edited by Professor William Koller (USA) and Professor Eldad Melamed (Israel). It is with particular sadness that we must record the sudden and untimely death of Professor Koller while the volume was coming to fruition. An experienced clinician, neuroscientist, author and editor, he was a friend of many of the contributors to this volume, as well as of the series editors, and we shall greatly miss him. It is our hope that he would have been proud of this volume, which he did so much to craft. As series editors, we reviewed all of the chapters in the volume and made suggestions for improvement, but we were delighted that the volume editors had produced such a scholarly and comprehensive account of the parkinsonian disorders, which should appeal to clinicians and neuroscientists alike. When the Handbook series was initiated in the 1960s, understanding of these disorders was poor, any genetic basis of them was speculative, several of the syndromes described here had not even been recognized, the prognosis was bleak and the therapeutic options were almost unchanged since the late Victorian era. Advances in understanding of the biochemical background of parkinsonism during the 1960s and early 1970s led to dramatic pharmacological advances in the management of Parkinson’s disease and profoundly altered the approach to other degenerative disorders of the nervous system. The pace of advances in the field has continued, and the exciting new insights being gained have mandated a need for a thorough but critical appraisal of recent developments so that future investigative approaches and therapeutic strategies are based on a solid foundation, the limits of our knowledge are clearly defined and an account is provided for practitioners of the clinical features and management of the various neurological disorders that present with parkinsonism. It has been a source of great satisfaction to us that two such eminent colleagues as the late William Koller and Professor Eldad Melamed agreed to serve as volume editors and have produced such an important compendium, and we thank them and the contributing authors for all their efforts. We also thank the editorial staff of the publisher, Elsevier B.V., and especially Ms Lynn Watt and Mr Michael Parkinson in Edinburgh for overseeing all stages in the preparation of this volume. Michael J. Aminoff Franc¸ois Boller Dick F. Swaab
Preface
James Parkinson described Parkinson’s disease in his memorable Essay on the Shaking Palsy in 1817. Since then, and particularly in recent years, there has been tremendous progress in our understanding of this complex and fascinating neurological disorder. Briefly, we have learned that it is not only manifest by motor symptoms but also that there is a whole range of non-motor features, including autonomic, psychiatric, cognitive and sensory impairments. We now know how to distinguish better clinically between Parkinson’s disease and the various parkinsonian syndromes. Likewise, it is now well established that in this disorder not only the substantia nigra but many other central as well as peripheral neuronal cell populations are involved. Novel diagnostic imaging technologies have become available. The nature of the Lewy body, the intracytoplasmic inclusion body that is a characteristic element of Parkinson’s disease pathology, is being unraveled. There are new insights in the etiology and pathogenesis of this illness. Experimental models are now available to understand better modes of neuronal cell death and help develop new therapeutic approaches. There has been dramatic progress in discovering the genetic causes of dominant and recessive forms of hereditary Parkinson’s disease with the identification of mutations in several genes. There is new knowledge in the intricate circuitry of the basal ganglia and the physiology of the connections in the healthy state and in Parkinson’s disease. There is more understanding of the role of dopamine and other neurotransmitters in the control and regulation of movement by the brain. All of the above led to the development of many novel pharmacological treatments to improve the motor as well as non-motor phenomena. There is better understanding of the mechanisms responsible for the complications caused by long-term levodopa administration. Futuristic approaches using deep brain stimulation with electrodes implanted in anatomically strategic central nervous system sites are now in common use to improve basic symptoms and the side-effects of levodopa therapy. Potentially effective neuroprotective strategies are in development to modify and slow disease progression. Likewise, cell replacement therapy with stem cells offers great promise. The best of experts in the field joined in this book and contributed chapters that make up an exciting coverage of all the exhilarating developments in the many aspects of Parkinson’s disease. This volume will certainly expand the current knowledge of its readers and it is also hoped that it will stimulate further research that will eventually lead to finding both the cause and the cure of this common and disabling neurological disorder. William C. Koller Eldad Melamed Dr. William Koller died suddenly, unexpectedly and prematurely on October 3, 2005, before this volume went to press. His loss is painful to all his friends and colleagues. His leadership, wisdom and expertise were the main driving force behind the creation of this very special book. It is the belief of all involved that Dr. Koller would have been pleased and proud of this volume in its final form. We hope it will be a tribute to his memory.
List of contributors
L. Alvarez Movement Disorders Unit, Centro Internacional de Restauracio´n Neurolo´gica (CIREN), La Habana, Cuba M. Baker European Parkinson’s Disease Association (EPDA), Sevenoaks, Kent, UK Y. Balash Movement Disorders Unit, Department of Neurology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel E. R. Bauminger Racah Institute of Physics, Hebrew University, Jerusalem, Israel M. F. Beal Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY, USA P. J. Be´dard Centre de Recherche en Neurosciences, CHUL, Faculte´ de Me´dicine, Universite´ Laval, Quebec, Canada A. Berardelli Department of Neurological Sciences and Neuromed Institute, Universita` La Sapienza, Rome, Italy R. Betarbet Department of Neurology, Emory University, Atlanta, GA, USA K. P. Bhatia Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, London, UK
R. Bhidayasiri The Parkinson’s and Movement Disorder Institute, Fountain Valley, CA, USA R. E. Breeze Department of Neurosurgery, University of Colorado School of Medicine, Denver, CO, USA C. Brefel-Courbon Department of Clinical Pharmacology, Clinical Investigation Centre and Department of Neurosciences, University Hospital, Toulouse, France D. J. Brooks MRC Clinical Sciences Centre and Division of Neuroscience and Mental Health, Imperial College London, Hammersmith Hospital, London, UK R. E. Burke Departments of Neurology and Pathology, Columbia University, New York, NY, USA D. J. Burn Institute of Ageing and Health, University of Newcastle upon Tyne, Newcastle upon Tyne, UK M. G. Cerso´simo Program of Parkinson’s Disease and Other Movement Disorders, Hospital de Clı´nicas, University of Buenos Aires, Buenos Aires, Argentina A. Chade The Parkinson’s Institute, Sunnyvale, CA, USA K. R. Chaudhuri Regional Movement Disorders Unit, King’s College Hospital, London, UK Y. Chen Morris K. Udall Parkinson’s Disease Research Center of Excellence, University of Kentucky College of Medicine, Lexington, KY, USA
xii
LIST OF CONTRIBUTORS
K. L. Chou Department of Clinical Neurosciences, Brown University Medical School and NeuroHealth Parkinson’s Disease and Movement Disorders Center, Warwick, RI, USA C. Colosimo Dipartimento di Scienze Neurologiche, Universita` La Sapienza, Rome, Italy Y. Compta Neurology Service, Hospital Clinic, University of Barcelona, Barcelona, Spain E. Cubo Unit of Neuroepidemiology, National Centre for Epidemiology, Carlos III Institute of Health, Madrid, Spain B. Dass Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA M. R. DeLong Department of Neurology, Emory University, Atlanta, GA, USA G. Deuschl Department of Neurology, Christian-AlbrechtsUniversity, Kiel, Germany V. Dhawan Regional Movement Disorders Unit, King’s College Hospital, London, UK The´re`se Di Paolo Centre de Recherche en Endocrinologie Mole´culaire et Oncologique, CHUL, Faculte´ de Pharmacie, Universite´ Laval, Quebec, Canada R. Djaldetti Department of Neurology, Rabin Medical Center, Petah Tiqva and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel M. Emre Department of Neurology, Behavioral Neurology and Movement Disorders Unit, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey G. Fabbrini Dipartimento di Scienze Neurologiche, Universita` La Sapienza, Rome, Italy
C. Fox National Center for Voice and Speech, Denver, CO, USA S. H. Fox Toronto Western Hospital, Movement Disorders Clinic, Division of Neurology, University of Toronto, Toronto, Ontario, Canada J. Frank Department of Neurology, Mount Sinai Medical Center, New York, NY, USA C. R. Freed University of Colorado School of Medicine, Denver, CO, USA A. Friedman Department of Neurology, Medical University, Warsaw, Poland J. H. Friedman Department of Clinical Neurosciences, Brown University Medical School and NeuroHealth Parkinson’s Disease and Movement Disorders Center, Warwick, RI, USA V. S. C. Fung Department of Neurology, Westmead Hospital, Sydney, NSW, Australia J. Galazka-Friedman Faculty of Physics, Warsaw University of Technology, Warsaw, Poland C. Gallagher Department of Neurobiology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA D. M. Gash Morris K. Udall Parkinson’s Disease Research Center of Excellence, University of Kentucky College of Medicine, Lexington, KY, USA G. Gerhardt Morris K. Udall Parkinson’s Disease Research Center of Excellence, University of Kentucky College of Medicine, Lexington, KY, USA O. S. Gershanik Department of Neurology, Centro Neurolo´gico-Hospital Frances, Laboratory of Experimental Parkinsonism, ININFA-CONICET, Buenos Aires, Argentina
LIST OF CONTRIBUTORS
xiii
C. G. Goetz Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA
J. S. Hui Department of Clinical Neurology, University of Southern California, Los Angeles, CA, USA
J. G. Goldman Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA
J. Jankovic Parkinson’s Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, TX, USA
D. S. Goldstein Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
P. Jenner Neurodegenerative Disease Research Center, School of Health and Biomedical Sciences, King’s College, London, UK
J.-M. Gracies Department of Neurology, Mount Sinai Medical Center, New York, NY, USA
M. Kasten The Parkinson’s Institute, Sunnyvale, CA, USA
J. T. Greenamyre Department of Neurology, Emory University, Atlanta, GA, USA
H. Kaufmann Department of Neurology, Mount Sinai School of Medicine, New York, NY, USA
J. Guridi Department of Neurology and Neurosurgery, University Clinic and Medical School and Neuroscience Division, University of Navarra and CIMA, Pamplona, Spain T. D. Ha¨lbig Department of Neurology, Mount Sinai School of Medicine, New York, NY, USA N. Hattori Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan M. A. Hely Department of Neurology, Westmead Hospital, Sydney, NSW, Australia C. Henchcliffe Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY, USA B. Ho¨gl Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria X. Huang Departments of Neurology and Medicinal Chemistry, University of North Carolina School of Medicine, Chapel Hill, NC, USA
W. C. Kollery Department of Neurology, University of North Carolina, NC, USA A. D. Korczyn Sieratzki Chair of Neurology, Tel-Aviv University Medical School, Ramat-Aviv, Israel J. H. Kordower Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA V. Koukouni Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, London, UK A. E. Lang Toronto Western Hospital, Movement Disorders Clinic, Division of Neurology, University of Toronto, Toronto, Ontario, Canada M. Leehey Department of Neurology, University of Colorado School of Medicine, Denver, CO, USA A. J. Lees Reta Lila Weston Institute of Neurological Studies, University College London, London, UK y
Deceased.
xiv
LIST OF CONTRIBUTORS
F. A. Lenz Department of Neurosurgery, Johns Hopkins Hospital, Baltimore, MD, USA
Y. Mizuno Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan
N. Lev Laboratory of Neuroscience and Department of Neurology, Rabin Medical Center, Petah-Tikva, Tel Aviv University, Tel Aviv, Israel
H. Mochizuki Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan
M. F. Lew Department of Neurology, University of Southern California, Los Angeles, CA, USA M. Lugassy Department of Neurology, Mount Sinai Medical Center, New York, NY, USA R. B. Mailman Departments of Psychiatry, Pharmacology, Neurology and Medicinal Chemistry, University of North Carolina School of Medicine, Chapel Hill, NC, USA C. Marin Laboratori de Neurologia Experimental, Fundacio´ Clı´nic-Hospital Clı´nic, Institut d’Investigacions Biome´diques August Pi i Sunyer (IDIBAPS), Hospital Clinic, Barcelona, Spain P. Martı´nez-Martı´n Unit of Neuroepidemiology, National Centre for Epidemiology, Carlos III Institute of Health, Madrid, Spain I. McKeith Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, UK K. St. P. McNaught Department of Neurology, Mount Sinai School of Medicine, New York, NY, USA E. Melamed Department of Neurology, Rabin Medical Center, Petah Tiqva and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel M. Merello Movement Disorders Section, Raul Carrea Institute for Neurological Research, FLENI, Buenos Aires, Argentina F. E. Micheli Program of Parkinson’s Disease and Other Movement Disorders, Hospital de Clı´nicas, University of Buenos Aires, Buenos Aires, Argentina
J. C. Mo¨ller Department of Neurology, Philipps-Universita¨t Marburg, Marburg, Germany J.-L. Montastruc Department of Clinical Pharmacology, Clinical Investigation Center, University Hospital, Toulouse, France E. B. Montgomery Jr National Primate Research Center, University of Wisconsin-Madison, Madison, WI, USA J. G. L. Morris Department of Neurology, Westmead Hospital, Sydney, NSW, Australia J. A. Obeso Department of Neurology and Neurosurgery, University Clinic and Medical School and Neuroscience Division, University of Navarra and CIMA, Pamplona, Spain W. H. Oertel Department of Neurology, Philipps-Universita¨t Marburg, Marburg, Germany D. Offen Laboratory of Neuroscience and Department of Neurology, Rabin Medical Center, Petah-Tikva, Tel Aviv, University, Tel Aviv, Israel F. Ory-Magne Department of Neurosciences, University Hospital, Toulouse, France B. Owler Department of Neurosurgery, Westmead Hospital, Sydney, NSW, Australia D. P. Perl Mount Sinai School of Medicine, New York, NY, USA R. F. Pfeiffer Department of Neurology, University of Tennessee Health Science Center, Memphis, TN, USA
LIST OF CONTRIBUTORS S. Przedborski Departments of Neurology, Pathology and Cell Biology, Columbia University, New York, NY, USA J. M. Rabey Department of Neurology, Assaf Harofeh Medical Center, Zerifin, Israel A. Rajput Division of Neurology, Department of Medicine, University of Saskatchewan, Saskatoon, SK, Canada A. H. Rajput Division of Neurology, Department of Medicine, University of Saskatchewan, Saskatoon, SK, Canada L. O. Ramig Department of Speech, Language and Hearing Sciences, University of Colorado-Boulder Department of Speech, and National Center for Voice and Speech, Denver, CO, USA J. Rao Department of Neurology, Louisiana State University Health Sciences Center, New Orleans, LA, USA O. Rascol Department of Clinical Pharmacology, Clinical Investigation Centre and Department of Neurosciences, University Hospital, Toulouse, France J. Rasmussen Merstham Clinic, Redhill, Surrey, UK W. Regragui Department of Neurosciences, University Hospital, Toulouse, France P. F. Riederer Clinical Neurochemistry, Department of Psychiatry and Psychotherapy, National Parkinson Foundation (USA) Center of Excellence Research Laboratories, University of Wu¨rzburg, Wu¨rzburg, Germany M. C. Rodrı´guez-Oroz Department of Neurology and Neurosurgery, University Clinic and Medical School and Neuroscience Division, University of Navarra and CIMA, Pamplona, Spain C. Rouillard Centre de Recherche en Neurosciences, CHUL, Faculte´ de Me´dicine, Universite´ Laval, Quebec, Canada
xv
P. Samadi Centre de Recherche en Endocrinologie Mole´culaire et Oncologie, CHUL, Faculte´ de Pharmacie, Universite´ Laval, Quebec, Canada S. Sapir Department of Communication Sciences and Disorder, Faculty of Social Welfare and Health Studies, University of Haifa, Haifa, Israel A. H. V. Schapira University Department of Clinical Neurosciences, Royal Free and University College Medical School, University College London, London, UK J. Shahed Parkinson’s Disease Center and Movement Disorders Clinic, Baylor College of Medicine, Department of Neurology, Houston, TX, USA T. Slaoui Department of Neurosciences, University Hospital, Toulouse, France M. B. Stern Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA F. Stocchi Department of Neurology, IRCCS San Raffaele Pisana, Rome, Italy N. P. Stover Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, USA C. M. Tanner The Parkinson’s Institute, Sunnyvale, CA, USA E. Tolosa Neurology Service, Hospital Clinic, University of Barcelona, Barcelona, Spain C. Trenkwalder Paracelsus Elena-Klinik, Center of Parkinsonism and Movement Disorders, Kassel, and University of Go¨ttingen, Go¨ttingen, Germany D. D. Truong The Parkinson’s and Movement Disorder Institute, Fountain Valley, CA, USA W. Tse Department of Neurology, Mount Sinai Medical Center, New York, NY, USA
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LIST OF CONTRIBUTORS
J. Volkmann Department of Neurology, Christian-AlbrechtsUniversity, Kiel, Germany H. C. Walker Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, USA R. H. Walker Movement Disorders Clinic, Department of Neurology, James J. Peters Veterans Affairs Medical Center, Bronx, and Department of Neurology, Mount Sinai School of Medicine, New York, NY, USA R. L. Watts Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, USA D. Weintraub Departments of Psychiatry and Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
T. Wichmann Department of Neurology and Yerkes National Primate Center, Emory University, Atlanta, GA, USA M. B. H. Youdim Department of Pharmacology, Technion-Bruce Rappaport Faculty of Medicine, Eve Topf and NPF Neurodegenerative Diseases Centers, Rappaport Family Research Institute, Haifa, Israel W. M. Zawada Division of Clinical Pharmacology, Department of Medicine, University of Colorado School of Medicine, Denver, CO, USA W. Zhou Division of Clinical Pharmacology, Department of Medicine, University of Colorado School of Medicine, Denver, CO, USA
Contents of Part II
Obituary vi Foreword vii Preface ix List of contributors xi
SECTION 5 Treatment of Parkinson’s disease 30. Physical therapy in Parkinson’s disease Jean-Michel Gracies, Winona Tse, Mara Lugassy and Judith Frank (New York, NY, USA)
3
31. Neuroprotection in Parkinson’s disease: clinical trials Fabrizio Stocchi (Rome, Italy)
17
32. Levodopa Thomas D. H€ albig and William C. Koller (New York, NY and Chapel Hill, NC, USA)
31
33. Dopamine agonists Olivier Rascol, Tarik Slaoui, Wafa Regragui, Fabiene Ory-Magne, Christine Brefel-Courbon and Jean-Louis Montastruc (Toulouse, France)
73
34. Monoamine oxidase A and B inhibitors in Parkinson’s disease Moussa B. H. Youdim and Peter F. Riederer (Haifa, Israel and W€ urzburg, Germany)
93
35. Anticholinergic medications Yaroslau Compta and Eduardo Tolosa (Barcelona, Spain)
121
36. Antiglutamatergic drugs in the treatment of Parkinson’s disease Marı´a Graciela Cers osimo and Federico Eduardo Micheli (Buenos Aires, Argentina)
127
37. Investigational drugs Carlo Colosimo and Giovanni Fabbrini (Rome, Italy)
137
38. The importance of patient groups and collaboration Mary Baker and Jill Rasmussen (Sevenoaks and Redhill, UK)
151
SECTION 6 Complications of therapy 39. Motor and non-motor fluctuations Susan H. Fox and Anthony E. Lang (Toronto, ON, Canada)
159
xviii
CONTENTS
40. Levodopa-induced dyskinesias in Parkinson’s disease Jose A. Obeso, Marcelo Merello, Maria C. Rodrı´guez-Oroz, Concepci o Marin, Jorge Guridi and Lazaro Alvarez (Pamplona and Barcelona, Spain, Buenos Aires, Argentina and La Habana, Cuba)
185
41. Treatment-induced mental changes in Parkinson’s disease Kelvin L. Chou and Joseph H. Friedman (Warwick, RI, USA)
219
SECTION 7
Surgical treatment
42. Ablative surgery for the treatment of Parkinson’s disease Frederick A. Lenz (Baltimore, MD, USA)
243
43. Deep brain stimulation J. Volkmann and G. Deuschl (Kiel, Germany)
261
44. Transplantation Curt R. Freed, W. Michael Zawada, Maureen Leehey, Wenbo Zhou and Robert E. Breeze (Denver, CO, USA)
279
45. Gene therapy approaches for the treatment of Parkinson’s disease Biplob Dass and Jeffrey H. Kordower (Chicago, IL, USA)
291
SECTION 8
Other parkinsonian syndromes
46. Multiple system atrophy Ronald F. Pfeiffer (Memphis, TN, USA)
307
47. Progressive supranuclear palsy David J. Burn and Andrew J. Lees (Newcastle upon Tyne and London, UK)
327
48. Corticobasal degeneration Natividad P. Stover, Harrison C. Walker and Ray L. Watts (Birmingham, AL, USA)
351
49. Infectious basis to the pathogenesis of Parkinson’s disease V. Dhawan and K. Ray Chaudhuri (London, UK)
373
50. Toxic causes of parkinsonism Nirit Lev, Eldad Melamed and Daniel Offen (Petah-Tikva and Tel-Aviv, Israel)
385
51. Drug-induced parkinsonism Federico Eduardo Micheli and Marı´a Graciela Cers osimo (Buenos Aires, Argentina)
399
52. Vascular parkinsonism Yacov Balash and Amos D. Korczyn (Tel-Aviv and Ramat-Aviv, Israel)
417
53. Old age and Parkinson’s disease Alex Rajput and Ali H. Rajput (Saskatoon, SK, Canada)
427
54. Other degenerative processes J. Carsten Mo¨ller and Wolfgang H. Oertel (Marburg, Germany)
445
55. Hydrocephalus and structural lesions John G. L. Morris, Brian Owler, Mariese A. Hely and Victor S. C. Fung (Sydney, NSW, Australia)
459
CONTENTS
xix
56. Calcification of the basal ganglia Jennifer S. Hui and Mark F. Lew (Los Angeles, CA, USA)
479
57. Trauma and Parkinson’s disease Oscar S. Gershanik (Buenos Aires, Argentina)
487
58. Psychogenic parkinsonism Vasiliki Koukouni and Kailash P. Bhatia (London, UK)
501
59. Parkinsonism and dystonia Ruth H. Walker (Bornx and New York, NY, USA)
507
60. Dementia with Lewy bodies Ian McKeith (Newcastle upon Tyne, UK)
531
61. Myoclonus and parkinsonism Daniel D. Truong and Roongroj Bhidayasiri (Fountain Valley and Los Angeles, CA, USA and Bangkok, Thailand)
549
Subject index Color plate section
561 571
Section 5 Treatment of Parkinson’s disease
Handbook of Clinical Neurology, Vol. 84 (3rd series) Parkinson’s disease and related disorders, Part II W. C. Koller, E. Melamed, Editors # 2007 Elsevier B. V. All rights reserved
Chapter 30
Physical therapy in Parkinson’s disease JEAN-MICHEL GRACIES*, WINONA TSE, MARA LUGASSY AND JUDITH FRANK Department of Neurology, Mount Sinai Medical Center, New York, NY, USA
The movement disturbances characteristic of Parkinson’s disease (PD), such as hypometria, akinesia, rigidity and disturbed postural control, can significantly impact function and quality of life. Typical disabilities resulting from these motor impairments range from dressing or rising from a chair to maintaining balance and initiating gait (Morris et al., 1995, Morris and Iansek, 1996). Since the emergence of levodopa in the late 1960s, pharmacologic therapy has been the primary strategy to manage these symptoms and has been considered the ‘gold-standard’ therapy. However, medication regimens are unable to control the disease satisfactorily in the long term, as dyskinesias, fluctuations of the medication efficacy and cognitive difficulties invariably occur after a number of years (Olanow, 2004). Over the past decades, there has been increasing awareness as to the potential role of physical exercise and investigations have been carried out to evaluate techniques that may alleviate functional disabilities in patients with PD. Despite this rising interest, surveys show that only 3–29% of PD patients regularly consult with a paramedical therapist, such as a physical, occupational or speech therapist (Deane et al., 2002). A large variety of physical therapy methods have been evaluated in PD. The approach to therapy in an individual patient, however, may be governed at the most basic level by the stage of the disease. In individuals with mild to moderate disease, who are ambulatory and have retained a certain degree of physical independence, therapy may focus on the teaching of exercises directly designed to delay or prevent the aggravation of the motor impairment in PD, with the goal of maintaining or even increasing functional capacities. At the other end of the spectrum, in an individual with compromised ambulation and significant disability due to advanced PD, the therapeutic focus may shift from the teaching of exercises to the
teaching of compensation strategies allowing preservation of as much functional independence as possible. These strategies include adaptation of the home environment, both to lessen the effects of motor impairment and to optimize safety.
30.1. Physical exercises in mild to moderate stages of Parkinson’s disease Most studies investigating physical exercises have been carried out in subjects with mild to moderate PD, i.e. up to Hoehn and Yahr stages 3 (Dietz et al., 1990, Kuroda et al., 1992, Comella et al., 1994; Bond and Morris, 2000, Marchese et al., 2000, Hirsch et al., 2003). 30.1.1. Metabolic and neuroprotective effects of physical exercise in Parkinson’s disease Exercise intensity may affect dopaminergic metabolism in PD. In unmedicated PD patients, 1 hour of strenuous walking reduces the dopamine transporter availability in the medial striatum (caudate) and in the mesocortical dopaminergic system as measured using positron emission tomography (PET) scans, which has been considered highly suggestive of increased endogenous dopamine release (Ouchi et al., 2001). In addition, exogenous levodopa seems to be better absorbed during moderate-intensity endurance exercise, as measured using maximal levodopa concentrations in plasma (Reuter et al., 2000; Poulton and Muir, 2005). The beneficial effect of exercise on the dopamine metabolism in PD patients has recently been supported by a number of compelling studies in animal models. Rats exposed to either 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 6-hydroxydopamine (6-OHDA) to induce behavioral and neurochemical loss analogous
*Correspondence to: Jean-Michel Gracies, Department of Neurology, Mount Sinai Medical Center, One Gustave L Levy Place, Annenberg 2/Box 1052, New York, NY 10029-6574, USA. E-mail:
[email protected], Tel: 1-(212)-241-8569, Fax: 1-(212)-987-7363.
4
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to PD lesions that are then exercised show significant sparing of striatal dopamine compared to lesioned animals that remain sedentary (Fisher et al., 2004; Poulton and Muir, 2005). Further, one study showed that exercise after MPTP exposure increases dopamine D2 transcript expression and downregulates the striatal dopamine transporter (Fisher et al., 2004). However, behavioral effects of training were inconsistent in these studies (Tillerson et al., 2003; Mabandla et al., 2004; Poulton and Muir, 2005). Rodents with unilateral depletion of striatal dopamine display a marked preferential use of the ipsilateral forelimb. After casting of the unaffected forelimb in unilaterally 6-OHDA-lesioned rats, the forced use of the affected forelimb spares its function as well as the dopamine remaining in the lesioned striatum (Faherty et al., 2005). There was a negative correlation in this study between the time from lesion to immobilization, i.e. to forced use and the degree of behavioral and neurochemical sparing. This may suggest the importance of initiating an exercise regimen early in the course of PD. Furthermore, two recent studies have shown that exposing animals to an environment prompting exercise and activity prior to MPTP lesion, or to unilateral forced limb use prior to contralateral lesioning with 6-OHDA, may prevent the emergence of the behavioral and neurochemical deficits that normally follow the administration of 6-OHDA (Cohen et al., 2003; Faherty et al., 2005). In one of these studies, animals receiving a unilateral cast had an increase in glial cell-line derived neurotrophic factor (GDNF) protein in the striatum corresponding to the contralateral overused limb. The prevention of parkinsonian deficits by prior exercise was suggested partly to involve GDNF changes in the striatum (Cohen et al., 2003). 30.1.2. Training techniques Several types of exercise techniques have been evaluated with regard to their impact on motor deficits in mild to moderate PD. Few studies have been controlled and much of the evidence is anecdotal or relies on open trials. The strongest line of evidence to date supports the benefit of lower-limb resistance training in PD patients, particularly for balance and gait. 30.1.2.1. Resistance training Major goals of physical therapy in PD should be the reduction of rigidity, the improvement of postural control and the prevention of falls as most PD patients experience balance disturbances and increased risk of falls in the course of their illness (Koller et al., 1989; Pelissier and Perennou, 2000; Ochala et al.,
2005). It has been shown that musculotendinous stiffness decreases following strength training in healthy elderly individuals (Ochala et al., 2005). In a recent open-label study, 40 Hoehn and Yahr III PD patients and 20 healthy age-matched controls underwent a 30-day program comprising a variety of physical therapies including regular physical activity, aerobic strengthening, muscle positioning and lengthening exercises (Stankovic, 2004). Physical therapy resulted in significant improvement in tandem stance, one-leg stance, step test and external perturbation – all tests of balance – in the PD group. Important risk factors for falls in PD are the muscle atrophy and the decrease in physical conditioning that may result from activity reduction (Scandalis et al., 2001). There is a proven relationship between decreased lower-limb muscle strength and impaired balance in PD, as muscle weakness in the lower extremities may limit the ability to mount appropriate postural adjustments when balance is challenged (Toole et al., 1996). A controlled study addressed the effects of lower-limb resistance training in PD, in which patients were randomized to two groups. The first group underwent 30-minute sessions three times a week for 10 weeks of standard balance rehabilitation exercises, including practicing standing on foam and weight-shifting exercises. The second group underwent the same balance training and, in addition, received tri-weekly high-intensity resistance training sessions focusing on plantar flexion, as well as knee extension and flexion. Subjects who received balance training only increased their lower-extremity strength (composite score from knee extensor, flexor and plantar flexor strength) by 9%, whereas subjects who underwent additional resistance training increased their strength by 52%. Balance training only increased the subjects’ ability to maintain balance. This effect was significantly greater and lasted longer in the group undergoing additional lower-limb resistance training (Hirsch et al., 2003). Improvement in lower-limb muscle strength in PD may also improve gait. In an open protocol, 14 PD patients and 6 normal controls underwent an 8-week course of resistance training, twice a week, with exercises including leg press, calf raise, leg curl, leg extension and abdominal crunches. Lower-limb strength and gait were assessed in the practically defined levodopa ‘off’ state (i.e. off medication for at least 12 hours) before and after the training period, showing gains in strength in the PD patients that were similar to those of the control subjects and improvement on quantitative measures of gait such as stride length, gait velocity and postural angles (Scandalis et al., 2001).
PHYSICAL THERAPY IN PARKINSON’S DISEASE 30.1.2.2. Attentional strategies and sensory cueing It is a common clinical observation that increased attention or effort may allow improvements of remarkable magnitude in motor tasks performed by PD patients (Muller et al., 1997). This observation has contributed to the development of cueing, an increasingly prevalent concept in the field of physical therapy in PD, in which external visual or auditory cues are used to enhance attention and thus performance. It has been hypothesized that the basal ganglia, which normally discharge in bursts during the preparation of well-learned motor sequences, provide phasic cues to the supplementary motor area, activating and deactivating the cortical subunits corresponding to a given motor sequence (Morris and Iansek, 1996). In PD however, the internal cues provided by the basal ganglia are no longer appropriately supplied. Thus, restoration of phasic activation of the premotor cortex might be facilitated by external means. 30.1.2.2.1. Auditory cueing Use of auditory cueing has gained popularity over the past decade (Rubinstein et al., 2002). In the upper limb, auditory cues for button-pressing tasks have shown that added external auditory information dramatically reduces initiation and execution time and improves motor sequencing (Georgiou et al., 1993; Kritikos et al., 1995). Another study showed that a single external auditory cue to start a movement was associated with a more forceful, more efficient and more stable movement than if the movement was accomplished only when the patients were ‘ready’ (internal cue) (Ma et al., 2004). Musical beats, metronomes and rhythmic clapping have been used as cueing techniques to improve gait in PD patients (Thaut et al., 1996; McIntosh et al., 1997). The use of metronome stimulation has been shown to reduce acutely the number of steps and the time to complete a walking course, compared to uncued walking in PD patients (Enzensberger et al., 1997). A study of a 3-week home-based gait-training program revealed that PD patients trained with rhythmic auditory stimulation in the form of metronome pulsed patterns embedded into the beat structure of music improved gait velocity, stride length and step cadence compared to subjects receiving gait training without rhythmic auditory stimulation or no gait training at all (Thaut et al., 1996). Additional research further indicated that these gait improvements occur regardless of whether the patient is on or off medication at the time of training (McIntosh et al., 1997). The effects of auditory cueing by metronome on gait may depend on the frequency used for the metronome beat, which may have to be
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slightly faster than the baseline walking cadence to be efficacious. PD patients using such rhythmic cues set at rates of 107.5 and 115% of their baseline walking cadence are able to increase the cadence and mean velocity of their gait correspondingly (Howe et al., 2003; Suteerawattananon et al., 2004). In contrast, Cubo and colleagues (2004) found that the use of the metronome set at the baseline walking cadence slowed ambulation and increased the total walking time without having any significant effect on freezing. However, the latter results were obtained in the ‘on’ state, which does not allow any conclusions as to the effects of such treatment in the off state, when patients typically experience the most slowness and freezing. Another specific situation in which sensory cueing may not be associated with functional improvements is that in which patients initiate walking at their maximal speed. Sensory cueing then interferes with movement speed and performance, which suggests competition between the external and internal signals of movement command in situations in which strong internal signals may be adequate to achieve optimal movement performance (Dibble et al., 2004). In the clinical setting, auditory cueing is most often used in the form of rhythmic auditory stimulation during gait, in which patients pace their walking to either a metronome beat or a rhythmic beat embedded in music. 30.1.2.2.2. Combination of auditory cueing with attentional strategies Auditory cueing may also be involved in attentional strategies such as the use of verbal instruction sets. In one controlled study in PD, gait was analyzed during trials of natural walking interspersed with randomized conditions in which subjects were verbally instructed to increase arm swing, or step size or walking speed. In addition to being able to improve any of these variables in response to specific instructions, hearing only one of these instructions was associated with an improvement in the other gait variables as well (Behrman et al., 1998). Conversely, giving an additional concurrent task (cognitive or an upper-limb motor task) to a walking patient worsens gait in PD as it may distract attention directed towards gait. This is the situation of dual task, which is a classical cause of movement deterioration in PD (Brown et al., 1993) and more specifically of gait deterioration (Bond and Morris, 2000; Hausdorff et al., 2003). Experimental situations combining such dual tasks (reducing attention) with verbal instructions to focus on walking (increasing attention) or on auditory cues tended to reverse the deterioration and restore better walking (Canning, 2005; Rochester et al., 2005).
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30.1.2.2.3. Visual cueing Since classic experiments by Martin (Martin and Hurwitz, 1962), a number of studies have shown that stride length can be improved by visual cueing, in the form of horizontal lines marked on the floor, over which the patient is encouraged to step. In a series of experiments, Morris et al. (1996) demonstrated that PD patients using such horizontal floor markers as visual cues were able to normalize their stride length, velocity and cadence, an effect that persisted for 2 hours after the intervention. It was noted that although transverse lines of a color contrasting with the floor and separated by an appropriate width are effective for this purpose, zigzag lines or lines parallel to the walking direction are not. These visual cues might function by supplying a now deficient well-learned motor program with external visual information on the appropriate stride length (Rubinstein et al., 2002). Similar improvement in stride length and gait velocity is possible using light devices attached to the chest to provide a visual stimulus on the floor over which the patient must step (Lewis et al., 2000). However, such light devices increase attentional demand and perceived effort of walking, which suggests that static cues are more effective in improving gait while minimizing effort. Finally, there are suggestions that benefit from cueing techniques might be optimal in earlier stages of the disease (Lewis et al., 2000). 30.1.2.2.4. Combination of visual cueing with attentional strategies Gait improvement also occurs when, instead of using horizontal markers on the floor, an attentional strategy is used with instructions to visualize the length of stride that subjects should take while walking (Morris et al., 1996). Whether gait is assisted by direct visual cueing or by such attentional visualization strategy, the benefit is reversed when patients are given additional tasks to do while walking, distracting attention from the gait (Morris et al., 1996). Thus, direct visual cues and visualization exercises may both function by focusing attention on the gait, such that walking ceases to be a primarily automatic task delegated to the deficient basal ganglia (Morris et al., 1996). 30.1.2.2.5. Combination of visual and auditory cues Suteerawattananon et al. (2004) have studied the effect of combining visual and auditory cues to determine the effect of such a combination on gait pattern in PD. In this study the auditory cue consisted of a metronome beat 25% faster than the subject’s fastest gait cadence. Brightly colored parallel lines placed along a walkway at intervals equal to 40% of the subject’s height served as the visual cue. The auditory cueing significantly
improved cadence whereas the visual cue improved stride length. However, the simultaneous use of visual and auditory cues did not improve gait significantly more than each cue alone. 30.1.2.3. Active appendicular and axial mobilization, stretch Axial mobility may affect function in PD. There is a significant association between reduced axial rotation and functional reach (maximal reach without taking a step forward) independent of disease state (Schenkman et al., 2000). A controlled study confirmed that physical intervention targeted on improving spinal flexibility improves functional reach in PD (Schenkman et al., 1998). An open study suggested that active mobilization exercises of the trunk and lower limbs improved transfers (from supine to sitting and sitting to supine), supine rolling and rising from a chair (Viliani et al., 1999). It has been hypothesized that muscle stiffness alone may be a factor of functional impairment in PD, particularly in the lower limb with respect to shortened stride length and altered gait pattern (Lewis et al., 2000). Aggressive stretch programs might decrease muscle stiffness. However, stretch alone as a therapy technique has not been systematically evaluated as a method to improve motor function in PD. In one controlled study an improvement in rigidity was observed as compared to baseline after a therapy program involving passive stretch as well as other motor tasks and balance training. This effect had disappeared by 2 months after study completion, which suggests that standard therapy programs should probably be continued in the long term, or at least repeated frequently (Pacchetti et al., 2000). 30.1.2.4. Treadmill training Treadmill training has been increasingly used in the rehabilitation of patients with spinal cord injury, hemiparesis and other gait disorders (Hesse et al., 2003). However, treadmill training may be expensive for some patients and the specific literature on treadmill training in PD must be analyzed with particular caution. Some studies have recently suggested that treadmill training might increase walking speed and stride length in PD (Miyai et al., 2000, 2002; Pohl et al., 2003). However, although these studies compared treadmill with nontreadmill training, they were not controlled for the walking speed used in the training. In particular the non-treadmill training did not involve specific requirements of gait velocity, step cadence or stride length. Under these circumstances, the positive effects seen after treadmill use may have been the effects of higher energy demands, or a higher walking speed used on the treadmill training
PHYSICAL THERAPY IN PARKINSON’S DISEASE (Miyai et al., 2000, 2002; Pohl et al., 2003). In a study which did control for walking speed by having subjects walk first on the ground and then on a treadmill set at the same speed, both PD patients and age-matched controls showed shorter stride lengths and higher stride frequency in the treadmill condition (Zijlstra et al., 1998). These effects were more pronounced in the PD patients. This is consistent with previous findings that, in healthy subjects, walking on a treadmill results in smaller steps than when walking on the ground at the same speed (Murray et al., 1985). This is particularly relevant to the PD patient population, in which decreased stride length and impaired stride length regulation are fundamental characteristics (Morris et al., 1996). Thus, the typical shortening of stride length in PD may in fact be accentuated when walking on a treadmill (Zijlstra et al., 1998). 30.1.3. Long-term effects of physical therapy The exact duration of the effects of programs of physical exercise in PD remains unknown. Most studies on physical therapy in PD have been open and had follow-up periods of less than 8 weeks, making the longterm persistence of beneficial effects difficult to determine (Deane et al., 2001). However, in one recent open-label trial 20 PD patients followed a comprehensive rehabilitation program three times a week for 20 weeks. Following the program, there was a significant improvement in Unified Parkinson’s Disease Rating Scale (UPDRS) activities of daily living and motor sections scores, self-assessment Parkinson’s Disease Disability scale, 10-meter walk test and Zung scale for depression, which was still seen at the 3-month follow-up, suggesting that a sustained motor improvement can be achieved with a long-term rehabilitation program in PD (Pellecchia et al., 2004). A few previous open studies have similarly suggested motor improvements lasting 6 weeks to 6 months after physical therapy was discontinued (Comella et al., 1994; Reuter et al., 1999; Pellecchia et al., 2004). This might underscore the importance of physical therapy not as one event limited in time, but as a continuous or repetitive effort, so that its benefits might be maintained and perhaps strengthened over time. Other long-term benefits from exercise in PD have been suggested, involving in particular an increased sense of well-being and an improved quality of life (Reuter et al., 1999). One observational study reported that mortality was higher by a hazard ratio of 1.8 amongst PD patients who did not exercise regularly compared with patients who did. However, the odds ratios were not adjusted for major health factors, such as cardiovascular disease, lung disease, smoking or obesity.
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In addition to having greater effects on motor function than physical therapy without cueing (Thaut et al., 1996; McIntosh et al., 1997), the use of cueing may extend the duration of the effects of therapy (Rubinstein et al., 2002). In a recent single-blind, prospective study, 20 PD patients were randomized to two physical therapy groups (Marchese et al., 2000). The first group underwent a 6-week program of posture control exercises, passive and active stretch and walking exercises, whereas the second group combined the same regimen with a variety of visual, auditory and proprioceptive cueing techniques. Although both groups showed improvement on activities of daily living and motor ability (UPDRS) at the end of the program, the group without sensory cue training had returned to baseline at a 6-week follow-up, whereas the group trained with cueing techniques was still improved at that visit. Although it remains uncertain whether all the involved types of sensory cueing or only specific types were associated with this benefit, the learning of new motor strategies associated with cueing may have caused the lasting improvement (Marchese et al., 2000).
30.1.4. Emotional arousal, group therapy and use of motivational processes Attempts at increasing cortical excitability in PD have involved, in addition to external sensory inputs, the use of emotional arousal. A recent open-label study suggested improved precision of arm movements as a consequence of exposure to stimulating music (Bernatzky et al., 2004). Pacchetti and colleagues (2000) compared standard physical therapy (passive stretching exercises, motor tasks, gait and balance training) with music therapy, involving choral singing, voice exercises and rhythmic and free body expression, both administered in weekly group sessions in a randomized, prospective controlled study. The improvement of bradykinesia, emotional well-being, activities of daily living and quality of life scores was greater in the music therapy group, whereas rigidity was the only measure that was more improved in the standard physical therapy group. These effects dissipated at a 2-month follow-up. The improvement in bradykinesia associated with music therapy may have resulted from external rhythmic cues or from the affective arousal induced by the music, influencing motivational processes (Pacchetti et al., 2000). It has been theorized that physical therapy in group sessions might enhance socialization and motivation, but group therapy has not been systematically compared with individual therapy and group therapy studies have not been controlled. In their study, Pacchetti and
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colleagues (2000) evaluated training in a group setting, both in the physical therapy and music therapy arms. The authors did not observe any increase in emotional function or quality of life in the physical therapy group. In open label studies of group physical therapy in PD, subjects have reported subjective impressions of benefit in motor symptoms and quality of life, but there was no improvement in quantitative measures of motor function (Pedersen et al., 1990; Lokk, 2000; Deane et al., 2002).
30.2. Recommendations for physical exercise in mild to moderate Parkinson’s disease 30.2.1. Schedule Although most protocols of the literature have involved supervised exercise sessions one to three times per week (Deane et al., 2002), we recommend that the exercise schedule be intensified and expanded from organized physical therapy sessions into a daily event, with a time window (1–1.5 hours) consistently devoted to this activity every day. Controlled studies have
indeed demonstrated that PD patients can improve performance on complex motor tasks with intense repeated practice – an effect that persists days after the practice trials have ended (Soliveri et al., 1992; Behrman et al., 2000). Similar principles of rapid repetition can be applied to daily physical exercise. It has been suggested that such exercises should be performed during the levodopa ‘on’ state, in order to optimize their execution (Koller et al., 1989). However, this is not supported by evidence and the opposite strategy may also be suggested, i.e. the performance of physical exercises during the early morning ‘off’ phase for example, which might improve dopamine availability and possibly delay the need for the first daily pill (Reuter et al., 2000; Ouchi et al., 2001). Finally, for exercises to be effectively replicated at home, it is probably optimal to teach them as early as possible in the course of the disease. 30.2.2. Suggested exercises We recommend alternating between two types of exercises in a practice session (Figs. 30.1 and 30.2). Active
STRETCHES & EXERCISES UPPER BODY
Lift the weight (bag) forward up & down Repeat with each arm until fatigued
Stretch shoulder with hand behind wall (e.g. in a doorway) 5 mins. Each side. Stretch shoulder with elbow leaning against wall as high as possible. 5 mins. Each side Lift the weight (bag) to the side, up & down Repeat with each arm until fatigued
Fig. 30.1. Stretches and exercises for the upper body.
PHYSICAL THERAPY IN PARKINSON’S DISEASE exercises should consist of vigorous series of lightresistance rapid alternating movements focused on strengthening muscles that ‘open’ the body (extensors, abductors, external rotators, supinators and shoulder flexors). Passive exercises should involve limb and trunk posturing focused on lengthening muscles that ‘close’ the body (flexors, adductors, internal rotators, pronators). Following a series of active exercises with passive posturing for a few minutes also allows cardiorespiratory rest. In the upper body, the active resistance exercises may involve light weight-lifting, particularly focusing on active shoulder abductions and shoulder flexions, as these movements are associated with spinal extensor recruitment (Moseley et al., 2002), which should contribute to strengthening these muscles (Fig. 30.1). The spinal extensors are typically hypoactive in PD and strengthening them should improve trunk posture. These exercises should be vigorous so as to provoke a clear sense of fatigue at the end of the series (Rooney et al., 1994). In this population we recommend choosing weights so as to avoid using maximal or near maximal intensity training (Khouw and Herbert, 1998) in order to limit the risk of muscle and tendon strain in
30.2.2.1. Sit-to-stand Patients should repeat a series of sit-to-stand exercises every day, if possible with arms crossed, ideally as many times as possible in a continuous series so as to achieve
STRETCHES & EXERCISES LOWER BODY
Stretch by bending forward 5 mins. on each side Walk the same distance in as few steps as possible.
Stand from sitting position without using hands. Repeat as many times as possible until fatigued.
Fig. 30.2. Stretches and exercises for the lower body.
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elderly patients. Therefore, the weight recommended should cause fatigue optimally after 10–20 repeats as opposed to fewer than 10 repeats. On the contrary, stretching postures should focus on stretching the muscle groups that tend to ‘close’ the body: horizontal and vertical adductors, internal rotators at the shoulder, flexors and pronators at the elbow, flexors at the wrist and fingers. Ideally, each active exercise should be pursued for about a minute whereas each posture of passive stretch should be maintained for about 5 minutes on each side. In the lower body, stretching postures (passive exercises) should again focus on muscles such as the hamstrings and hip adductors that tend to adopt a shortened position in PD because of hypoactivity in their antagonists. The active exercises should primarily focus on sit-to-stand (training trunk and lower-limb extensors) and walking practice (Fig. 30.2).
Stand with support and stretch legs for 5 mins.
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a sense of fatigue in the primary muscles involved (hip, knee and spinal extensors). This should lead to strengthening of these muscles, which should improve sit-to-stand ability and walking balance. 30.2.2.2. Walking Patients should not focus on the speed achieved while walking but on their stride length. Ideally the patient selects a specific distance that should be covered every day and counts the steps taken to walk that distance. Each day, the patient should try to walk the same distance using as few steps as possible (Fig. 30.2). When stride length improvement over that distance is maximized (i.e. the number of steps taken cannot be further decreased), the same process should be repeated on a longer distance. In terms of walking in conditions other than a flat ground, treadmill walking has not been compared to walking in a swimming pool in controlled studies. However, we would hypothesize that walking against the viscous resistance of water should maximize hip flexion and ankle push-off training and thus better improve stride length than treadmill walking, which might lead to opposite results (see above).
30.3. Compensation strategies in advanced stages of Parkinson’s disease 30.3.1. Role of discipline As PD progresses and motor function deteriorates, patients become significantly less mobile and therefore less able to perform daily self-initiated exercises such as active movements against resistance and walking. Although the goal of physical therapy remains to optimize functional independence, the method gradually shifts towards teaching strategies to patients and care-givers to compensate for worsening motor impairments. Omitting some of these strategies may jeopardize activities such as walking or swallowing, with potentially serious consequences. The emphasis on a strict patient discipline and on the importance of its enforcement by the care-giver thus becomes even more important than in the early stages, as the patient must now consistently apply the compensation strategies learned in therapy. One fundamental compensatory strategy in advanced PD involves increasing the amount of attention and effort the patient directs toward any given motor activity. Tasks such as walking, talking, writing and standing up are no longer automatic and should no longer be taken for granted. The individual with advanced PD must learn to want to perform each of these activities and actively concentrate on them,
possibly even to rehearse them mentally as a new task each time, as opposed to just doing them. This corresponds to a major change in the approach to daily activities. Such change can be facilitated through a clear understanding by the therapist and/or the care-giver of: (1) the fundamental difference between automatic and consciously controlled movements; and (2) the need to switch to conscious movement control for virtually all daily motor activities, particularly those that we tend to view as the most natural, such as talking, writing, standing up and walking. We provide examples of these changes in daily strategies below. However, teaching and maintaining such discipline can become a highly challenging proposition in advanced PD, depending on the presence of depression and particularly mental deterioration (impairment in executive functions) and on the degree of patient motivation to improve quality of life (Gracies and Olanow, 2003). Depression is a common feature of PD, particularly in advanced stages (Gracies and Olanow, 2003; McDonald et al., 2003) and is characterized by hopelessness and pessimism, as well as decreased motivation and drive (Brown et al., 1988). This may undermine the motivation to practice or to change daily living strategies. Apathy and abulia (lack of drive and initiative) can also be prominent symptoms in PD, independent of depression, and occur with greater frequency than in patients of similar disability level from other causes (Pluck and Brown, 2002). Most importantly, the gradual emergence of dementia, in particular frontal dysexecutive features (perseverations, impulsivity), may hamper the ability to pursue a strict but slower routine of conscious rehearsal when performing daily activities that used to be automatic. In these cases, the care-giver often becomes the primary focus of the teaching and the person effectively responsible for implementing the discipline of the compensation strategies. 30.3.2. Strategies for freezing episodes In advanced PD, episodes of freezing, characterized by an interruption of motor activity especially when encountering obstacles or constricted spaces, can constitute a significant problem, occurring in up to onethird of patients (Giladi et al., 1992). Management may consist primarily of behavioral strategies. As mentioned in the previous section, one can teach the patient how to substitute external auditory, visual, or proprioceptive cues to replace the deficient internal motor cues normally provided by the basal ganglia (Morris et al., 1995). Specific attentional strategies may also be useful (see below).
PHYSICAL THERAPY IN PARKINSON’S DISEASE 30.3.2.1. Sensory cues for freezing Several techniques have been used to alleviate freezing episodes through external visual input. Visual markers can be placed in the home in areas where freezing episodes are common such as doorways and narrow hallways. These may include horizontal markers on the floor over which the individual is instructed to step, or a dot on the wall on which the patient is instructed to focus in the event of freezing. If the patient is accompanied, the other person may place a foot in front of the patient, which the patient then steps over (Morris et al., 1995). Inverted walking sticks, with the handle used as a horizontal visual cue at the level of the foot, have also been investigated as a potential means of improving freezing (Kompoliti et al., 2000). Results have been inconsistent, with some subjects showing worsening of freezing while using such a walking stick and others showing improvement (Dietz et al., 1990; Kompoliti et al., 2000). Additionally, caution must be used with inverted sticks in PD patients, as these sticks may cause tripping and increase the risk of fall. Acoustic cues can also be used to decrease freezing. PD patients may carry a metronome, which can be switched on during a freezing episode emitting an auditory beat. Such external cues may be sufficient to initiate movement. 30.3.2.2. Attentional strategies for freezing A number of adjustments of motor behavior have been suggested to alleviate freezing episodes when they occur. These include:
Focusing on swaying from side to side, transferring body weight from one leg to the other (Morris et al., 1995) Singing, whistling, loudly saying ‘go’ or ‘left, right, left, right’, clapping or saying a rhyme and stepping off at the last word are behavioral strategies that have the additional advantage of generating acoustic cues (Morris et al., 1995) Cue cards posted on the walls of freezing-prone areas, with instructions such as ‘go’ or ‘large step’ (Morris et al., 1995) The one-step-only technique – strategy of distraction from the functional or social meaning of the action to be accomplished. Success with a method using a deep-breathing relaxation technique has been noted in a patient who had failed several other techniques to reduce freezing episodes (Macht and Ellgring, 1999). It is often noted that during an episode of freezing, the more the patient worries about the functional end-goal of walking (freeing the elevator entry for other people to come out, moving out of a crowded store through
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a narrow exit, entering the doctor’s office), the more difficult the task becomes, particularly as others look on. The emotional stress associated with the social function of walking in these situations makes the freezing episode worse. At the Mount Sinai Movement Disorders Clinic we attempt to have the patient disconnect for a short while from the social and functional implications of walking forward again, and instead to focus analytically on the walking technique. Walking is normally a smooth succession of steps. The patient is asked to focus only on achieving one elementary unit of walking, i.e. one step only. One single step should have minimal social role (since one step is usually not sufficient to enter or exit a crowded place) and thus minimal emotional charge. In practice, the first stage is to stop trying to walk. The patient may then take a deep breath to mark a pause in the effort and achieve better relaxation and spread the feet. Then the patient should concentrate on taking one big step only and specifically on the power of the hip, knee and foot flexor movements required to achieve this one step. Clinical experience shows that when a strong first step is achieved the second and third steps naturally follow. Movement planning and attention – switching back from automatic movements to consciously controlled movements. To enhance movement in advanced PD, patients can be taught – or repeatedly reminded – to rehearse mentally each movement before it is executed and to pay close attention to the movement while it is being performed. For example, in crowded environments where the risk of freezing episodes or tripping increases, the patient should think ahead and plan the most direct route through the obstacles. Turning around is another difficult task in advanced PD, which may be the most common circumstance causing falls in the home setting. Before turning, the patient should rehearse the individual leg movements that are required to turn the body around effectively. Also, it is recommended to accomplish the turn over a wide arc instead of swiveling (Morris et al., 1995).
30.3.3. Strategies to minimize postural instability In general, advanced PD patients have difficulty maintaining balance secondary to slow righting reactions (recruitment of the appropriate axial muscles) in response to a challenge to equilibrium. Therefore, patients should try to apply the above principle of conscious control of
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previously automatic tasks to postural balance. Patients may be taught actively to focus their attention on balance whenever they perform an activity involving standing, similar to what healthy subjects must do when they stand on a small boat in a turbulent sea. The purpose is to be in a state of alertness and readiness to respond to threats of balance and thus promptly implement the necessary actions to restore equilibrium (Morris and Iansek, 1996). A recent open-label study suggested that 14-day repetitive training of compensatory steps might enhance protective postural responses and shorten the period of double support during gait in PD. In addition, significant increases in cadence, step length and gait velocity were observed after such training. These effects were stable for 2 months without additional training (Jobges et al., 2004). 30.3.4. Motor subunits It is beneficial for the PD patient to treat long movement sequences not as a whole, but to break them down as a series of component parts or subunits. With this strategy, each subunit is considered and performed as if it were itself a whole movement. This strategy is partly used in the one-step-only technique to alleviate freezing. Focusing on each subunit of a motor sequence may be particularly effective for multijoint actions such as reaching and grasping, thus facilitating activities such as feeding and dressing, or whole-body activities such as standing up from a bed or a chair (Morris and Iansek, 1996). For example, to stand up from a bed, the patient should first mentally rehearse the entire movement and then break the motor sequence down into a series of subunits, including bending the knees, turning the head, reaching both arms in the desired direction, turning the body, swinging the legs over the bed and then finally sitting up (Morris et al., 1995). A similar strategy can be used for rising from a chair. The patient is encouraged to rehearse the sequence mentally, then to wriggle forward to the front of the seat, make sure the feet are placed back underneath the chair, lean forward, push on the legs and straighten up the back to stand up. In an open study, PD patients trained with these techniques as part of a 6-week physical therapy home regimen showed significant improvement in their ability to transfer in and out of chairs and beds (Nieuwboer et al., 2001). 30.3.5. Avoidance of dual-task performance It has been hypothesized that PD patients may minimize their balance or walking difficulties by using conscious cortically mediated control to overcome
defective automatic basal ganglia activation (Morris et al., 2000). When conscious attention is diverted from the task of maintaining equilibrium, the balancing deficits may be accentuated. The set-shifting difficulties commonly seen in advanced PD prevent efficient and rapid switches in concentration between two motor tasks that must be achieved simultaneously (Gracies and Olanow, 2003). Not surprisingly, studies have shown that it is beneficial in PD to avoid performing two tasks simultaneously. In a study comparing PD patients to agematched healthy controls, subjects performed two walking trials, one freely and one while carrying a tray with four glasses on it. Whereas the gait performance changed only minimally across conditions in controls, the PD patients showed decreased walking speed and stride length while carrying the tray with glasses (Bond and Morris, 2000). In another study, single set instructions to increase walking speed, arm swing or stride length (all contributors to efficient walking) resulted in improvement not only of the specific variable upon which the patient had focused, but in the other gait variables as well. However, when subjects were instructed to count aloud while walking (an activity that is not a direct component of the walking movement), these gait improvements did not occur (Behrman et al., 1998). In this particular paradigm, the acoustic cue provided by the loud counting – that could have been expected to help walking – may have been counteracted by the distraction from the walking movements caused by the additional cognitive task. A more recent study confirms that dual-task performance worsens gait in PD with an equal impairment whether the secondary task is motor or cognitive in nature (O’Shea et al., 2002). Dual-task performance appears to affect standing balance as well, particularly in PD patients with a previous history of falls (Morris et al., 2000; Marchese et al., 2003). In a study comparing PD patients and age-matched controls there were no differences in postural stability between groups when subjects simply stood on a platform, but PD patients showed significantly greater postural instability compared to controls when given additional tasks, either cognitive or motor (Marchese et al., 2003). Therefore PD patients should be instructed to avoid carrying out dual tasks and focus on one task at a time. For example, while walking, patients should be encouraged to avoid carrying objects (the use of backpacks may be recommended), talking or thinking about other matters and instead, focus attention towards each individual step and on increasing the stride length (Morris et al., 1995). To prevent loss of balance and falls, PD patients should avoid standing while performing
PHYSICAL THERAPY IN PARKINSON’S DISEASE complex motor or cognitive tasks such as showering, dressing or conversing (Morris, 2000). 30.3.6. Modification of the home environment In advanced PD, attention should be paid to the home environment, with the goal of maintaining independence and ensuring safety from falls. The ability to transfer self from bed to chair, chair to toilet and to stand up is of primary importance in remaining independent. To assist with difficulties in transferring from a lying or sitting to a standing position, higher chairs, toilet seats and beds can be beneficial as they reduce the energy requirements to raise the center of gravity. In addition, because narrow constricted spaces and obstacles can induce freezing episodes and place individuals at risk for tripping and falling, care should be taken to create clear, wide spaces with a minimum of low-lying obstacles (such as carpets and stools) in the home setting. Finally, to assist with difficulties with turning in bed, sheets made of satin in the upper part (to allow the body to slide) and of cotton in the lower part (to allow the heels to grip on it and initiate the turning movement) may be used. 30.3.7. Ambulation assistive devices Although walkers are meant to improve walking stability and prevent falls in general and particularly in orthopedic conditions, the impact of chronic walker use in PD needs to be critically examined. The arguments for or against a walker should be weighed on a case-by-case basis, as the use of walkers may worsen gait and increase the risk of tripping or falling (Morris et al., 1995; Kompoliti et al., 2000). A recent study evaluated the acute effects of standard walkers and wheeled walkers as compared to unassisted walking in PD (Cubo et al., 2003). Both wheeled and standard walkers significantly slowed gait compared to unassisted walking, and the standard walker also increased freezing. In addition to potentially exacerbating posture and balance difficulties, walkers may also become deleterious in individuals whose steps have become faster and shorter: when the frame advances too far in front of the feet, the person may bend over too far and possibly fall (Morris et al., 1995). However, the main issue with walkers may not be their acute effects on freezing, gait-slowing or the possibility of forward falls, but the possibility of long-standing posture and balance impairment caused by chronic use of these devices. By chronically providing passive forward support, walkers may decondition the forward-righting reactions required
13
during inadvertent backward sways (i.e. appropriately timed rectus femoris and tibialis anterior contractions) and aggravate or even generate a clinical syndrome of retropulsion. This risk has not been measured in a prospective study, but anecdotal evidence has been sufficiently prevalent in our center and others (Morris et al., 1995), that leads us to limit the chronic use of walkers in PD to a minimum in our clinics. The use of a cane without objectively verifying a positive effect on gait parameters and without providing specific training to the patient is also questionable. Patients with PD often handle canes improperly, carrying them around instead of using them as a support. This is particularly problematic in this condition, as the use of a cane becomes a form of dual task performance, involving the simultaneous activities of walking and carrying an object. As described above, performing additional tasks while walking can result in gait deterioration. However, it should be recognized that patients may sometimes feel more comfortable using a cane for walking outdoors or in public places, not for the supposed increase in stability that the cane may provide, but as a social signal helping to be recognized by others as someone walking slowly or with a handicap. Whether a cane or a walker is considered, the indication should be determined objectively and accurately: psychological reassurance, social signal, objective improvement in stability, reduction in energy consumption during gait. Whichever indications are assumed, patients should be tested with and without the assistive device at the clinic to obtain a rigorous assessment of the acute impact of the device on freezing episodes, walking speed and stride length. Finally, regardless of the acute effects observed at the clinic, the potential effects of chronic use of these devices should also be considered, particularly with the use of walkers. An assistive device must not necessarily be used indefinitely. One may consider the temporary use of an assistive device in acute periods such as after deep brain stimulation surgery, during a period of intensive medication adjustments with risks of walking instability due to excess levodopa and dyskinesias, or after an orthopedic injury such as a hip fracture.
30.4. Conclusions Interest in physical therapy for patients with PD has grown over recent years. It should intensify further with the recent evidence of neuroprotective effects of physical exercises in animal models of PD. Although a number of studies have explored specific treatment options, they are complicated by heterogeneous treatment methods, different outcome measures and varying
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timeframes of analysis (Deane et al., 2002). Many studies have also been limited by inadequate randomization methods and lack of convincing sham treatments. The latter two are a particular problem in physical therapy research, since neither the therapist nor the patient can be blinded to the arm of the trial (Deane et al., 2002). In the future, larger, randomized, sham-controlled studies with staged follow-up will be necessary to determine for each program the benefits, the duration and the appropriate frequency of training. However, the limitations of the current literature should not lead neurologists to underestimate the fundamental role of daily physical exercise in PD. To optimize motor function, we provide personal recommendations consisting of strict programs of daily home exercises in the mild to moderate stages of the disease and the teaching – to the patient and then to the care-giver – of compensation strategies in the late stages.
Acknowledgments We are grateful to Jerri Chen and Jonathan Alis for their excellent work in illustrating some of the exercises recommended in this chapter. We also thank Sheree Loftus Fader, MSN, APRN, BC, CRRN for her expert comments.
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Handbook of Clinical Neurology, Vol. 84 (3rd series) Parkinson’s disease and related disorders, Part II W. C. Koller, E. Melamed, Editors # 2007 Elsevier B. V. All rights reserved
Chapter 31
Neuroprotection in Parkinson’s disease: clinical trials FABRIZIO STOCCHI* Department of Neurology, IRCCS San Raffaele Pisana, Roma, Italy
31.1. Introduction Parkinson’s disease (PD) is an age-related neurodegenerative disorder characterized clinically by resting tremor, rigidity, bradykinesia and a gait disorder. Pathologically, there is degeneration of nigrostriatal neurons in the substantia nigra pars compacta (SNpc) and the presence of intracytoplasmic inclusions known as Lewy bodies. Biochemically, degeneration of nigrostriatal neurons is associated with a decline in striatal dopamine and this finding is the basis for the symptomatic treatment of the disorder with the dopamine precursor levodopa. However, in the majority of patients, levodopa treatment is complicated by motor fluctuations, dyskinesia and the development of features that do not respond to the drug (e.g. freezing, dementia, autonomic disturbances and postural instability). Further, levodopa does not stop disease progression. Consequently, despite the major benefits associated with levodopa therapy, the majority of patients with advanced disease suffer unacceptable levels of functional disability that cannot be controlled with existing therapies. Because of these limitations, there has been a concerted effort aimed at designing a neuroprotective therapy for PD (Marsden and Olanow, 1998). Such a treatment can be defined as a treatment or intervention that slows or stops disease progression by protecting, rescuing or restoring the nerve cells that degenerate in PD. Toward this end, an understanding of the etiologic and pathogenetic factors responsible for cell death is of critical importance. Both autosomal-dominant and -recessive gene mutations have been reported to cause PD (see Ch. 9), but these account for only a small number of cases. There is also evidence that environmental factors contribute to the etiology of
PD, as suggested by the association of parkinsonian syndromes with exposure to neurotoxins such as 1methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or hydrocarbons (Langston et al., 1983; Pezzoli et al., 1996). Further, epidemiological studies indicate that rural living, well-water consumption and exposure to pesticides increase the risk of developing PD, whereas there is a decreased risk of PD associated with smoking and coffee consumption (Koller et al., 1990). None of these factors, however, explain the large majority of cases who appear to have a sporadic form of the disease. Indeed, twin studies suggest that genetic factors probably play a dominant role in young-onset cases where environmental factors are likely to be the more important in most older sporadic cases (Tanner et al., 1999). It is likely that sporadic PD is related to a complex interaction between a variety of genetic and environmental factors that may be different in different individuals. This implies that there are many different causes of PD and makes it unlikely that a single neuroprotective treatment aimed at interfering with a single etiologic factor will be effective in the majority of PD patients. Other opportunities for neuroprotection in PD derive from studies on the pathogenesis and mechanism of cell death. Current information suggests that neurodegeneration in PD is associated with a cascade of events including oxidant stress, mitochondrial abnormalities, excitotoxicity and inflammation (Jenner and Olanow, 1998). Based on this evidence, a number of theoretical neuroprotective strategies can be designed. What is not clear, however, is whether these processes are primary or secondary, which if any is the driving force that initiates neurodegeneration and what role each plays in the neurodegenerative process that occurs in an individual patient. In addition, recent
*Correspondence to: Dr Fabrizio Stocchi, Department of Neurology, IRCCS San Raffaele, Via della Pisana 285, 00165 Rome, Italy. E-mail:
[email protected], Tel: þ39-33-690-9255, Fax: þ39-06-678-9158.
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studies suggest that protein aggregation due to failure of the ubiquitin-proteasome system to clear unwanted proteins may be a common theme in PD neurodegeneration, but how to prevent or deal with this problem is presently not known (McNaught et al., 2001; see Ch. 28). Further, considerable evidence supports the notion that cell death in PD, regardless of etiology, occurs by way of signal-mediated apoptosis (Hirsch et al., 1999). The importance of defining a common factor that contributes to neurodegeneration in PD is that it provides an opportunity to develop a single neuroprotective therapy that might interfere with the neurodegenerative process that ensues as a result of many different etiologies and therefore may be of value to a large population of PD patients. This chapter addresses a clinical relevant question regarding the management of PD: are there any therapies that can slow down the progression of PD?
31.2. Trials with antioxidants and monoamine oxidase-B inhibitors Considerable evidence supports the notion that oxidative stress plays a role in the pathogenesis of cell death in PD (see Ch. 24). Postmortem studies in the substantia nigra of PD patients demonstrate increased levels of iron (which promotes oxidative stress) and decreased levels of glutathione (the major brain antioxidant) (Jenner and Olanow, 1998). Further, there is evidence of oxidative damage to carbohydrates, lipids, proteins and DNA in the SNpc of PD patients. Additionally, the oxidative metabolism of levodopa and/or dopamine can generate reactive oxygen species that can induce or aggravate underlying oxidative stress. These considerations formed the basis for initiating clinical trials aimed at obtaining a neuroprotective effect in PD with antioxidant agents. The initial drugs chosen for study were a-tocopherol (vitamin E) and deprenyl (selegiline, eldepryl). a-Tocopherol was selected because it is the most potent lipid-soluble antioxidant in plasma and plasma levels can be increased by dietary augmentation (Ingold et al., 1987). Deprenyl was selected because in doses of 10 mg/day it is a relatively selective inhibitor of monoamine oxidase type B (MAO-B) that avoids the risk of a sympathomimetic crisis (the ‘cheese effect’) associated with non-selective MAO inhibition (Elsworth et al., 1978). Interest in deprenyl as a possible neuroprotective agent in PD was fostered by the observation that MPTP can induce parkinsonism in humans (Langston, 1983) and that MPTP-induced parkinsonism in monkeys can be prevented by deprenyl (Cohen et al., 1985). In this model, deprenyl inhibits the MAO-B oxidation of MPTP to the pyridinium ion 1-methyl-4-phenylpyridinium ion
(MPPþ) which is responsible for MPTP toxicity (Chiba et al., 1984). It was reasoned that if PD were related to an MPTP-like protoxin, MAO-B inhibition with deprenyl might similarly prevent the oxidation of other toxins that contribute to neuronal degeneration. In addition, it was also postulated that deprenyl could block the MAO-Bdependent oxidative metabolism of dopamine and thereby limit free radical damage to SNpc neurons (Cohen and Spina, 1989). A prospective, randomized, double-blind, placebo-controlled study involving 800 patients known as the DATATOP study (Deprenyl And Tocopherol Antioxidant Therapy Of PD) was performed to evaluate deprenyl 10 mg/day and tocopherol 2000 IU (Parkinson Study Group, 1989a, b, 1993). Untreated PD patients were randomly assigned in a 2 2 factorial design to treatment with deprenyl (10 mg/day), tocopherol (2000 IU), the combination of both, or placebo. Patients were followed with no other treatment until they deteriorated to a point that blinded investigators felt that symptomatic therapy in the form of levodopa needed to be introduced (the primary endpoint). In this study, no effect on the primary endpoint was detected with a-tocopherol treatment. In contrast, treatment with selegiline significantly delayed the emergence of disability necessitating treatment with levodopa (P < 0.0001). After 12 months, levodopa treatment was required in 26% of selegiline recipients compared with 47% of those who received placebo. Onset of disability necessitating levodopa therapy occurred after a mean of 26 months in the 375 selegiline recipients compared to 15 months in 377 placebo recipients (with or without tocopherol). Similar results were observed with selegiline in a smaller study involving 54 patients that served as a pilot for the DATATOP study (Tetrud and Langston, 1989). Although these results were impressive and suggested that deprenyl might have a neuroprotective effect, a careful posthoc analysis demonstrated that selegiline was associated with both wash-in and wash-out effects indicative of a symptomatic effect in addition to any putative neuroprotective effect. Thus, although there was no doubt that selegiline delayed the emergence of disability in otherwise untreated PD patients, it was unclear as to the responsible mechanism (Olanow and Calne, 1991). Namely, was the delay in requiring levodopa in selegiline-treated patients due to the drug having a neuroprotective effect on remaining dopamine neurons or was it due to the symptomatic effect of the drug masking ongoing neurodegeneration? This confound remains unresolved, although subsequent clinical trials provide some support for the
NEUROPROTECTION IN PARKINSON’S DISEASE: CLINICAL TRIALS possibility that the drug may have neuroprotective effects in addition to its established symptomatic effects. The SELEDO (selegiline-levodopa) study evaluated 120 early-stage PD patients who received treatment with either levodopa monotherapy or levodopa plus selegiline (Przuntek et al., 1999). The primary endpoint was the need for a 50% increase in baseline levodopa dosage. Selegiline-treated patients were less likely to require this additional increase in levodopa, suggesting the possibility that the disease was progressing at a slower rate. Further, the levodopa plus selegiline group had a lower incidence of motor fluctuations despite comparable clinical control, again suggesting that selegiline influences the natural course of levodopa-treated PD. The SINDEPAR (Sinemet-Deprenyl-Parlodel) was a prospective double-blind study that attempted to define the putative neuroprotective effects of selegiline in a trial that controlled for the drug’s symptomatic effects (Olanow et al., 1995). Patients with untreated PD (n ¼ 100) were randomized to receive treatment with selegiline versus placebo in addition to treatment with either Sinemet or bromocriptine. Thus, patients were randomized to one of four treatment groups; Sinemet plus selegiline, Sinemet plus placebo, bromocriptine plus selegiline, or bromocriptine plus placebo. The primary endpoint of the study was the change in Unified Parkinson’s Disease Rating Scale (UPDRS) motor score between original untreated baseline and final visit performed 2 months after washout of selegiline and 7 days after washout of either the bromocriptine or the Sinemet. This study showed that deterioration in UPDRS score over the course of the study was significantly less in patients randomized to receive selegiline than in those receiving placebo regardless of whether they received symptomatic treatment with levodopa/carbidopa (Sinemet) or bromocriptine (P < 0.0001). To insure adequate drug washout, a subgroup of 23 patients underwent a 14-day washout of their Sinemet or bromocriptine. Even with this small sample size, deprenyl-treated patients had significantly less deterioration from original baseline than did placebo controls. The authors interpreted these findings as being consistent with the hypothesis that selegiline has a neuroprotective effect that could not be accounted for by the symptomatic effect of the drug in view of the fact that patients were washed out of selegiline for a relatively long period of time while receiving powerful symptomatic agents in addition to the study drugs. However, even in this circumstance some doubt remains as it is not possible to state with any certainty that washout was sufficient to rid patients of a long-duration symptomatic effect associated with either selegiline or the symptomatic
19
agents employed. Indeed, Hauser et al. (2000) suggest that even 2 weeks of withdrawal from levodopa or bromocriptine may not be sufficient to eliminate the symptomatic effects associated with their use. Although the debate continues as to whether or not the drug has protective effects, it is clear that selegiline treatment does not stop disease progression (Elizan et al., 1989) and several reports suggest that after many years of treatment patients receiving deprenyl are no less impaired than patients who have not received the drug (Parkinson Disease Research Group in the United Kingdom, 1993; Brannan and Yahr, 1995; Parkinson Study Group, 1996a, b). A long-term follow-up of the DATATOP patients similarly noted no major difference between those originally on selegiline or placebo, but it is perhaps noteworthy that selegiline-treated patients had a reduced frequency of freezing and ‘off’ episodes which are thought to be related to degeneration of non-dopaminergic systems (Shoulson et al., 2002). The problem has been further confused by the report of an open-label long-term study suggesting that selegiline increases the risk of early death in levodopa-treated PD patients (Lees et al., 1995). There were, however, statistical concerns about how this study was performed and analyzed (Olanow et al., 1996a) and similar findings were not observed in an assessment of mortality in the DATATOP cohort (Parkinson Study Group, 1998) or in a large meta-analysis that included all prospective long-term double-blind controlled trials comparing selegiline to placebo (Olanow et al., 1998b). Based on the results of the DATATOP study, trials of other MAO-B inhibitors were initiated as putative neuroprotective agents. Lazabemide is a relatively short-acting, reversible and selective MAO-B inhibitor that is not metabolized to amphetamines or active compounds (Cesura et al., 1989). The ability of lazabemide to influence the progression of disability in untreated PD was assessed in a randomized, multicenter, placebo-controlled, double-blind clinical trial (Parkinson Study Group, 1996c). A group of 321 untreated PD patients were assigned to one of five treatment groups (placebo or lazabemide at a dose of 25, 50, 100 or 200 mg/day) and followed for up to 1 year. The risk of reaching the primary endpoint (the onset of disability sufficient to require levodopa therapy) was reduced by 51% for the patients who received lazabemide compared with placebo-treated subjects (P<0.001). This effect was consistent among all dosages and the magnitude and pattern of benefits seen with lazabemide were similar to those observed with selegiline treatment in the DATATOP clinical trial. However, as with selegiline, lazabemide also has symptomatic effects and there were similar concerns as to whether or not benefits seen with this drug
20
F. STOCCHI Randomize N = 404* intent-to-treat (n = 134)
Rasagiline 1 mg/d
N = 380/382 completers started next phase (n = 124)
9 terminated
4 terminated
(n = 132) Rasagiline 2 mg/d
Open-label Rasagiline 1 mg/d
(n = 124) 6 terminated
8 terminated
(n = 138) Delayed start
N = 306/360 completers elected to continue
(n = 132) Rasagiline 2 mg/d 10 terminated
Placebo 5 terminated 6 mo
6 mo
Double-blind, placebo-controlled
Double-blind, rasagiline early vs delayed
Up to 6.5 y from TEMPO start Ongoing extension
Fig. 31.1. TEMPO trial study design.
were due to neuroprotective or symptomatic effects (Le Witt et al., 1993). This uncertainty caused the sponsor to discontinue further trials in PD with this agent (Youdim and Weinstock, 2001). 31.2.1. Rasagiline Rasagiline is an irreversible and selective MAO-B inhibitor which does not generate amphetamine metabolites. The drug proved to be effective in the symptomatic treatment of early and advanced parkinsonian patients. However, there are some indications that the drug may have disease modification effects. A total of 380 patients from the TEMPO trial (Tvp-1012 (rasagiline) in early monotherapy for Parkinson’s disease outpatients – a randomized, double-blind study versus placebo including 404 patients with early PD placebocontrolled phase) entered a 6-month phase of active treatment, where patients previously receiving placebo were switched to rasagiline 2 mg/day (Fig. 31.1). The aim of this phase of the study was a comparison between those patients who received 12 months’ treatment with rasagiline and those patients, previously on placebo, who had a delayed start and received only 6 months’ treatment with rasagiline. This delayed-start technique is one of several study designs that have been employed to evaluate the disease-modifying potential of antiparkinsonian agents. The theory behind this particular design is that by the end of the full 12 months of study, the symptomatic effects of treatment will be balanced in all groups, leaving any observed differences attributed to disease-modifying effects. Results showed that patients receiving 2 mg/day rasagiline for a 12-month period had a significant
benefit over patients who had their treatment delayed by 6 months, as measured by UPDRS-Total score (–2.29 unit difference, P ¼ 0.01) and UPDRS-ADL (activities of daily living) score (–0.96 unit difference, P < 0.01). Once again, this was supported by a superior responder rate in the 12-month treatment group (P < 0.05). Comparisons of other subscales (UPDRSMotor and -Mental) were not significant. Patients who received 1 mg/day rasagiline for 12 months also showed significant benefits over the 2 mg/day delayedtreatment group in UPDRS-Total score (–1.82 unit difference; P ¼ 0.05). One potential disadvantage of this method of measuring disease modification is that symptomatic effects may be enhanced if treatment is started earlier in the disease course. However, taken as a preliminary indication, this delayed-start study provides promising indications of disease modification that certainly warrant further investigation. To this end, a new controlled study of rasagiline, with disease modification as a primary endpoint, is ongoing ADAGIO-study (Attenuation of disease progression with azilect given once-daily). 31.2.2. Antiexcitotoxic agents There is substantial evidence suggesting that excess glutamatergic stimulation with consequent excitotoxicity contributes to the neurodegenerative process in PD, raising the possibility that antiexcitotoxic drugs might be neuroprotective (Lipton and Rosenberg, 1994). Physiologic and metabolic studies demonstrate that neuronal activity in the subthalamic nucleus (STN) is increased in parkinsonian animals and humans (Obeso et al., 2000). As the STN uses the excitatory
NEUROPROTECTION IN PARKINSON’S DISEASE: CLINICAL TRIALS neurotransmitter glutamate as a neurotransmitter and projects to the internal segment of globus pallidus, the pedunculopontine nucleus and the SNpc, it is reasonable to consider that these targets might be subject to excitotoxic damage (Rodriguez et al., 1998). Nmethyl-D-aspartate (NMDA) receptor antagonists have been reported to protect dopamine neurons from glutamate-mediated toxicity in tissue culture and in rodent and primate models of PD (Turski et al., 1991; Greenamyre et al., 1994; Doble, 1999). Further, there is a retrospective report suggesting that early use of the NMDA receptor antagonist amantadine might slow the rate of PD progression (Uitti et al., 1996). A double-blind placebo-controlled dosing study was performed testing the safety and tolerability of remacemide hydrochloride, a low-affinity NMDA channel blocker (Parkinson Study Group, 2000a). Total daily doses of 150, 300 and 600 mg were not as well tolerated as placebo, but were not associated with serious side-effects and, importantly, symptomatic effects were not detected, although only small numbers of patients were studied. However, the drug failed to provide evidence of a neuroprotective benefit in patients with Huntington’s disease even when combined with coenzyme Q10 and formal tests of neuroprotection in PD have not been carried out (Huntington’s Disease Study Group, 2000). Riluzole is another antiglutamate agent that acts by inhibiting sodium channels and thereby prevents the release of glutamate in overactive glutamatergic neurons. The drug is approved for use in the treatment of amyotrophic lateral sclerosis (Bensimon et al., 1994; Lacomblez et al., 1996) and preclinical studies have demonstrated the capacity of riluzole to protect dopamine neurons in rodent and primate models of PD (Araki et al., 2001; Obinu et al., 2002). A small open-label pilot study in PD patients demonstrated that riluzole is well tolerated at doses of 100 mg/day and does not provide symptomatic benefits (Jankovic and Hunter, 2002). Morover, despite the short duration of the trial and the small sample size (20 patients), there was a trend toward benefit for patients in the riluzole group with riluzole patients remaining unchanged over the course of the study whereas those randomized to placebo seemed to deteriorate. A randomized, double-blind, placebocontrolled trial evaluated riluzole 50 mg b.i.d. compared to placebo with a primary outcome of change in UPDRS. No significant difference was found (Jankovic and Hunter, 2002). 31.2.3. Bioenergetics A body of information suggests that mitochondrial dysfunction plays a role in the pathogenesis of PD
21
(see Ch. 22). Decreased levels of complex I activity and reduced staining are observed in the substantia nigra of PD patients and the selective complex I inhibitor MPTP induces a levodopa-responsive PD syndrome in both animal models and human patients. More recently chronic administration of rotenone, a widely available pesticide which selectively inhibits complex I, has been shown to be capable of inducing a parkinsonian syndrome with selective degeneration of nigral dopaminergic neurons, a reduction in striatal dopamine and intracellular inclusions resembling Lewy bodies (Betarbet et al., 2000). The precise mechanism whereby inhibition of complex I activity leads to a parkinsonian syndrome is not known and reduced adenosine triphosphate formation, free radical generation and reduction in mitochondrial membrane potential have all been implicated. These findings do, however, raise the possibility that bioenergetic agents such as creatine, coenzyme Q10, ginkgo biloba, nicotinamide, riboflavin, acetyl-carnitine or lipoic acid might be neuroprotective in PD. Indeed, creatine and coenzyme Q have been shown to protect dopamine neurons in MPTP-treated rodents (Beal et al., 1998; Matthews et al., 1999). The Parkinson Study Group recently completed a phase II clinical study of coenzyme Q10 in de novo PD patients. The study was double-blind and the patients were randomized to treatment with placebo, 300, 600 or 1200 mg of coenzyme Q10 for 16 months or until disability required levodopa. The primary outcome measure was the change from baseline in the UPDRS. In addition, levels of complex I activity of the mitochondrial electron transport chain and coenzyme Q10 levels were obtained. The study demonstrated a dose-dependent reduction in disease progression as assessed by the UPDRS which correlated with increases in plasma coenzyme Q10 levels. Although the results were not statistically significant, a positive trend was observed. The study was designed to determine safety and tolerability and only a relatively small number of patients were included; therefore a larger phase III study is required. Nonetheless, this study supports the notion that bioenergetic agents such as coenzyme Q10 might offer promise as neuroprotective agents for PD and studies of other such agents are likely to be performed in the near future. 31.2.4. Antiapoptotic agents Although the issue of neuroprotection with deprenyl and other MAO-B inhibitors remains unresolved at the clinical level, in the laboratory the situation has become much clearer. An increasing body of evidence has now accumulated supporting the capacity of deprenyl to
22
F. STOCCHI
provide neuroprotection for dopaminergic and other motoneurons in a variety of in vitro and in vivo studies (Mytilineou and Cohen, 1985; Tatton and Greenwood, 1991; Ansari et al., 1993; Roy and Bedard, 1993; Wu et al., 1993, and reviewed in Olanow et al., 1998c). Further, it has now become clear that MAO-B inhibition is not a prerequisite for these benefits (Mytilineou and Cohen, 1985; Mytilineou et al., 1997a). Indeed, there is evidence indicating that the neuroprotective effects seen with deprenyl are due to its metabolite, desmethyl deprenyl (Mytilineou et al., 1997b, 1998). These benefits are attributed to the propargyl component of the deprenyl molecule and indeed some other drugs that are propargylamines show a similar effect on glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and similar neuroprotective effects (Boulton, 1999; Waldmeir et al., 2000; Youdim and Weinstock, 2001). Data now indicate that neuroprotection associated with deprenyl is due to an antiapoptotic effect related to drug-induced transcriptional events with the synthesis of new proteins (Tatton et al., 1994, 2002). Specifically, deprenyl has been shown to induce altered expression of a number of genes involved in apoptosis, including SOD1 and SOD2, glutathione peroxidase, c-JUN, GAPDH, BCL-2 and BAX. These findings suggest that the antiapoptotic properties of deprenyl relate to their potential to protect the mitochondrial membrane potential and to exert antioxidant effects. More recent findings indicate that GAPDH may be central to these effects. GAPDH is an intermediate in glycogen metabolism and plays an important role in protein translation and synthesis. However, under certain adverse conditions, GAPDH in its tetrameric form translocates to the nucleus where it interferes with BCL-2 upregulation and promotes apoptosis. Desmethyl deprenyl binds to GAPDH and maintains it as a dimmer, in which form it does not translocate to the nucleus and allows the normal antiapoptotic neuroprotective programs to be initiated (Carlile et al., 2000). Other propargylamines can also provide neuroprotective effects in model systems of parkinsonism (Tatton et al., 2000; Waldmeir et al., 2000; Youdim and Weinstock, 2001). Two currently undergoing testing for putative neuroprotective effects in PD are rasagiline (see above) and CGP3466 or TCH346. TCH346 is a more potent neuroprotectant than deprenyl in laboratory models and does not inhibit MAO-B, which may eliminate a symptomatic confound and make detection of a neuroprotective effect easier to detect. In MPTP monkeys, TCH346 prevented neuronal degeneration and led to functional improvement (Waldmeir et al., 2000). Prospective double-blind trials comparing TCH346 with placebo were stopped after an interim analysis for lack of efficacy (Olanow, 2006).
There are several different signaling pathways that can lead to apoptosis depending on the model and toxin that are tested, providing different opportunities for introducing antiapoptotic strategies (Reed, 2002), but none has yet been adequately tested in clinical trials or established to be neuroprotective in PD.
31.3. Restorative therapies Whereas most studies have focused on attempts to alter the natural course of PD through manipulation of factors thought to be involved in the pathogenesis of cell death, other approaches have attempted to restore dopaminergic neuronal function. This has been attempted with transplantation strategies designed to provide new cells to replace those that have undergone neurodegeneration or trophic factors that might restore or enhance function in remaining dopamine neurons. Transplanted fetal nigral cells implanted into the denervated striatum have been demonstrated to survive, manufacture dopamine and provide behavioral effects in rodent and primate models of PD (reviewed by Olanow et al., 1996b). Open-label studies in advanced PD patients have reported clinical benefits, increased fluorodopa uptake on positron emission tomography (PET) and robust survival of implanted dopamine neurons with organotypic reinnervation of the striatum (reviewed by Olanow et al., 1996b). However, these benefits have not yet been reproduced in double-blind, placebo-controlled trials. Freed et al. (2001) randomized 40 advanced PD patients to receive transplantation with embryonic ventromesencephalic cells or sham surgery. The study failed to meet its primary endpoint (a quality-of-life measure). Improvement was observed in UPDRS motor scores, particularly in patients younger than 60 years, but benefits were not of the magnitude reported in open-label studies. Further, some of the patients developed severe off-medication dyskinesia which persisted for days after withdrawal of levodopa. A similar type of dyskinesia has now been reported by the Swedish group (Hagell et al., 2002). The mechanism responsible for this unanticipated side-effect is not known, but it is noteworthy that this type of dyskinesia has not been detected in patients with advanced PD who have not undergone transplantation (Cubo et al., 2001). This study illustrates the importance of placebo-controlled trials (Freeman et al., 1999) and the need to address clinically relevant issues in the laboratory before beginning trials in PD patients in order to minimize the risk of running into unanticipated side-effects. In this regard it should be noted that transplantation has not yet been tested in levodopa-treated parkinsonian
NEUROPROTECTION IN PARKINSON’S DISEASE: CLINICAL TRIALS monkeys to see if they have been primed to develop off-medication dyskinesia. A second double-blind placebo-controlled trial of fetal nigral transplantation has just been completed in which different concentrations of donor tissue were tested, immunosuppression was employed and patients were followed for 2 years (Freeman et al., 1999), but final results are not yet published. The use of human embryonic neural tissue creates logistical and societal problems such as acquiring enough tissue for grafting in a predictable and largescale manner and ethical problems inherent in the use of aborted human fetal tissue. For these reason alternative sources of fetal dopaminergic neurons have been sought. One such approach involves the use of porcine fetal nigral cells. Implanted porcine fetal nigral cells have been shown to survive and to provide some behavioral effects. However, open-label trials showed no benefit for patients with Huntington’s disease and only minimal benefit in PD patients with no increase in striatal fluorodopa uptake on PET and only minimal survival at postmortem (Deacon et al., 1997; Fink et al., 2000; Schumacher et al., 2000). A doubleblind, placebo-controlled study has been performed in patients with advanced PD and demonstrated no benefit in comparison to patients receiving a placebo procedure (unpublished information). In this study the magnitude of the placebo effect was extensive and sustained, emphasizing again the importance of placebo-controlled trials in evaluating new interventions (Freeman et al., 1999). A small open-label trial reported some clinical benefits following transplantation of retinal pigmented epithelial cells (Watts, 2002) and a prospective double-blind placebo-controlled trial has been initiated. Although these studies are not encouraging, it is possible that better results can be obtained with different transplant variables such as increased numbers of cells, continued use of immunosuppression, combined use of antiapoptotic factors and different transplant targets (Barker, 2002). It is also possible that better results can be obtained with stem cells (see Ch. 44). Stem cells are capable of self-renewal and expand after implantation. Neural stem cells are found in the developing brain (embryonic neural stem cells), but also in certain sites within the adult brain (Armstrong and Svendsen, 2000; Gage, 2000). Embryonic neural stem cells can be isolated and grown in culture and made to differentiate into all of the major cell types of the central nervous system, including dopaminergic neurons (Kawasaki et al., 2002). Indeed, initial studies demonstrate that embryonic stem cells can spontaneously differentiate into neurons, with a small percentage being dopaminergic neurons. Further, following
23
transplantation, they can survive and induce behavioral effects in the dopamine-lesioned rodents (Bjorklund et al., 2002). However, these experiments are not without their own problems and, in one study, 5 of 19 transplanted animals developed tumors (Kim et al., 2002). Stem cells have not yet been implanted into PD patients and, although they offer considerable promise, many clinical issues remain to be resolved at the preclinical level before clinical trials in PD patients can be considered. A second restorative approach involves the use of trophic factors. Numerous studies have demonstrated the capacity of a variety of trophic factors to protect dopamine neurons in tissue culture and to restore nigrostriatal function in dopamine-lesioned animals (Collier and Sortwell, 1999). Among these, glialderived neurotrophic factor (GDNF) appears to be the most effective in laboratory models (see Ch. 45). GDNF treatment has been shown to protect cultured dopamine neurons from a variety of toxins (Lin et al., 1993) and to restore function to the nigrostriatal system of the MPTP-lesioned monkey even when treatment is delayed for up to several weeks (reviewed by Hebert et al., 1999). One of the major limitations of trophic factors relates to delivery of the protein to the target site. An open-label trial of intraventricular GDNF did not provide meaningful benefit to advanced PD patients, probably because the protein was not able to gain entry from the cerebrospinal fluid into the brain (Kordower et al., 1999). Side-effects of GDNF delivered in this way were troublesome and included consititutional complaints, pain and Lhermitte’s sign, probably reflecting meningeal irritation. Another open-label study was subsequently performed in advanced PD patients in which GDNF was directly injected into the striatum (Barker, 2006). These researchers claimed to observe antiparkinsonian benefits and direct infusion of GDNF was better tolerated than with the intraventricular approach, although 4 of 5 patients still experienced Lhermitte’s sign. A prospective double-blind placebo-controlled trial testing continuous infusion of GDNF into the striatum of parkinsonian patients, recently conducted, failed to demonstrate efficacy versus placebo (Lang, 2006). An alternate approach utilizes gene therapy to deliver GDNF. Using a modified lentivirus vector to deliver GDNF to the striatum and nigra of MPTP-lesioned monkeys, dramatic histologic and behavioral improvement was observed (Kordower et al., 2000). Further, the protein was well tolerated. Long-term safety studies in nonhuman primates are currently underway and a clinical trial of lentivirus GDNF in PD patients is ongoing. Numerous other preclinical studies have been performed testing different vectors (e.g. adeno-associated virus), different proteins (e.g. AADC or GAD) and
24
F. STOCCHI
different targets (e.g. SNpc or STN) and it is anticipated that favorable behavioral results and safety profiles will lead to clinical trials in PD in the not too distant future. Based on the unanticipated off-medication dyskinesia observed in some patients following transplantation, it remains necessary to demonstrate that GDNF does not induce dyskinesias and debate continues with regard to whether or not to use a regulatable gene therapy system. Nevertheless, based on laboratory studies available to date and the preliminary results with direct infusion in PD patients, GDNF therapy appears to be very promising for PD patients. Immunophilins are partial ligands for the ciclosporin-binding site that, independent of their immunosuppressant properties, provide trophic-like effects for dopamine neurons in tissue culture and animal models (Steiner et al., 1997). Two immunophilin agents have been tested in PD patients, but the results have been disappointing and no evidence of a neuroprotective or restorative effect has been observed (Gold and Nutt, 2002).
31.4. Dopamine agonists There has been considerable interest for more than a decade in the potential of dopamine agonists to provide neuroprotective effects and to alter the natural course of the levodopa-treated PD patient (Olanow, 1992; Stocchi, 2000). In the laboratory, dopamine agonists have been shown to protect dopamine neurons from a variety of toxins in both in vitro and in vivo models (Olanow et al., 1998; see Ch. 22). Various theories have emerged to account for these effects, including levodopa-sparing, stimulation of dopamine autoreceptors, direct free radical scavenging, inhibition of STNmediated excitotoxicity and activation of dopamine receptors with signal-mediated antiapoptotic effects. Two prospective randomized clinical trials have recently been performed in early PD patients to test the putative neuroprotective effects of dopamine agonists. In one study (the Comparison of the agonist pramipexole with levodopa on motor complications of Parkinson’s disease, CALM-PD, study), patients with untreated PD were randomized to initiate therapy with either the dopamine agonist pramipexole or levodopa (Marek et al., 2002). In the second (the Requip as an early therapy versus levodopa PET, REAL-PET, study), patients were randomized to initiate therapy with the agonist ropinirole or levodopa (Whone et al., 2002). Open-label levodopa could be added to the blinded therapy if deemed necessary for patients in both studies. In an attempt to circumvent the problems of detecting a neuroprotective effect with symptomatic agents, both trials utilized a neuroimaging surrogate marker of nigrostriatal
function as a primary endpoint. The REAL-PET study used striatal fluorodopa uptake on PET whereas the CALM-PD study used striatal beta-carbomethoxy-3 beta-(4-iodophenyl)tropane (b-CIT) uptake on singlephoton emission computed tomography (SPECT). The results of two trials have recently been released. In the CALM PD-SPECT study, an estimate of the rate of dopamine neuronal degeneration was assessed by measuring the rate of decline in b-CIT, a marker of the dopamine transporter. This study was performed in a subsection of patients participating in the CALMPD trial (Olanow et al., 1998). A total of 82 patients with early PD requiring dopaminergic therapy to treat emerging disability were enrolled in the study. Patients were randomly assigned to receive pramipexole in a dose of 0.5 mg t.i.d. (n ¼ 42), or carbidopa/levodopa 25/100 mg t.i.d. (n ¼ 40). The primary outcome variable was the percentage change from baseline in striatal b-CIT uptake after 46 months. The mean ( SD) percentage loss in striatal b-CIT uptake between baseline and 46 months was significantly reduced in the pramipexole group compared with the levodopa group (16.0 13.3% versus 25.5 14.1%; P < 0.05). The authors concluded that patients initially treated with pramipexole demonstrated a reduced rate of PD progression, as determined by rate of decline in striatal b-CIT uptake if treatment was initiated with the dopamine agonist. As there was no placebo control group, no comment could be made as to whether the agonist group deteriorated at a slower rate or the levodopa group at a faster rate. Interestingly, there was no clinical correlate of this finding, with patients randomized to initial treatment with levodopa doing as well as or better than agonist-treated patients on the UPDRS scale. The REAL-PET study was designed to compare the rate of PD progression using striatal fluorodopa uptake on PET as a marker of nigrostriatal function. A total of 186 patients with early untreated PD were randomized in a 1:1 ratio to initiate treatment with either the dopamine agonist ropinirole or levodopa. The primary outcome variable was the percentage reduction in putamenal 18F-dopa influx constant (Ki) over the 2-year study in patients with both clinical and PET evidence of PD. Data were collected from six PET centers and centrally transformed at the Hammersmith Hospital (London, UK) so as to standardize brain position and shape and the placement of the regions of interest (ROIs) for calculation of putamen Ki. Parametric images were also interrogated with statistical parametric mapping (SPM) to localize regions of significant within-group and between-group differences in rates of loss of dopaminergic function. Secondary endpoints included the incidence of dyskinesias and clinical efficacy evaluations. The central ROI analysis of putamen
NEUROPROTECTION IN PARKINSON’S DISEASE: CLINICAL TRIALS Ki showed that, over the course of the 2-year study, there was a significantly slower rate of deterioration in the ropinirole group as compared to the levodopa group (–13% versus –20%; P < 0.05). Using the SPM analytic technique, a significantly slower rate of progression for agonist-treated patients was detected in both putamen and nigra (P < 0.05 for both). The authors concluded that the progression of PD, as reflected by loss of putamenal 18F-dopa uptake, was slower in PD patients when treatment was initiated with the dopamine agonist ropinirole as compared to levodopa. Interestingly, this study also found no clinical correlate for the imaging finding, with UPDRS scores being comparable or superior in the levodopa group. Both studies clearly demonstrate a reduced rate of loss of nigrostriatal function, as determined by imaging surrogate markers in patients treated with dopamine agonists compared to levodopa. As previously (Parkinson Study Group, 2000b; Rascol et al., 2000), patients initiated on agonists also had a significantly reduced risk of developing motor complications than did those started on levodopa. Interestingly, neither study demonstrated a clinical correlate to go along with the improvement detected in the imaging studies. In both studies clinical efficacy, as measured by the UPDRS rating scale, favored patients in the levodopa group. This, too, is similar to what was described in other trials comparing initial therapy with dopamine agonists versus levodopa (Parkinson Study Group, 2000b; Rascol et al., 2000). Although the clinical significance of this difference can be debated, as patients in the agonist groups could receive levodopa supplement whenever either the patient or physician deemed it was necessary, it is evident that there is no clear clinical indication of slower disease progression in the agonist groups. These represent the first studies in PD to demonstrate positive results utilizing imaging techniques to seek evidence of neuroprotection. There remain several issues. Firstly, if benefits seen on imaging reflect a change in the rate of disease progression, is this a function of a neuroprotective effect of the agonist or accelerated disease progression due to levodopa? Further studies with a placebo control will be required to address this issue. Secondly, are there pharmacologic effects that interfere with the comparison of levodopa versus a dopamine agonist that give the false impression that agonists have a slower rate of reduction in imaging markers of nigrostriatal function than does levodopa? Here too, further studies should clarify this issue. Preliminary studies have not shown a specific levodopa or dopamine agonist effect on fluorodopa uptake on PET or ß-CIT uptake on SPECT. Finally, if the imaging studies do reflect a neuroprotective effect of agonists, why is there no clinical correlate? Is the
25
benefit so slight at this early time point that it is masked by the symptomatic effects of the drugs and is longer follow-up required? These results are most exciting and, independent of whether or not dopamine agonists prove to be neuroprotective in the long run, neuroimaging offers the potential of establishing a surrogate marker of nigrostriatal function that will enable the assessment of the many putative neuroprotective drugs that are currently or will eventually become available. Toward this end, it is important to perform careful studies to establish that these imaging surrogates do in fact represent accurate markers of the number of dopamine terminals and/ or neurons and to determine the influence on these markers of time, drug therapy and disease progression. A delayed start design trial with pramipexole in early PD patients is ongoing.
31.5. Levodopa A double-blind controlled randomized trial levodopa (150, 300, 600 mg/day) versus placebo including 361 patients was recently conducted. The primary outcome was masked assignment of change in UPDRS from baseline after 40 weeks of treatment and a 2-week washout. In addition SPECT ß-CIT was performed at baseline and week 40 in a subgroup of 116 patients. Patients randomized to all levodopa doses had significantly better UPDRS scores than patients on placebo, with the greatest improvement seen on the highest dose, showing a clear dose–response relationship. After the washout period none of the three treated groups matched the disease severity scored in the placebo group. These data suggested that patients on levodopa had a sustained functional improvement and this was more evident in the higher-dose group. However, it is possible that the washout period was not sufficient to exclude a persistent symptomatic effect (long-duration response). Patients on the highest dose of levodopa developed more dyskinesias and motor complications. This may be due to the dose of levodopa but also to the way levodopa was administered (t.i.d.). There was no significant difference in ß-CIT uptake across the groups. However a greater reduction in ß-CIT uptake was observed in patients taking the higher levodopa dose.
31.6. Conclusion In establishing that an intervention has a neuroprotective effect, it is necessary to choose outcome measures of disease progression that are satisfactory to both clinicians and regulatory authorities. To date, no drug has been established to be neuroprotective in PD (Morrish, 2002) and regulatory agencies have not yet confirmed that any
26
F. STOCCHI
of the outcome measures that have been used are acceptable for purposes of drug approval and labeling. Several clinical trials aimed at detecting a neuroprotective effect have shown positive results, but interpretation has been confounded by the symptomatic effects of the drugs being tested. As a consequence, positive results cannot be interpreted as representing neuroprotection. More recently, clinical trials have attempted to detect neuroprotection by utilizing neuroimaging surrogate markers of nigrostriatal function. However, even though results have been positive, it is not established that these imaging surrogate markers do in fact accurately represent the number of dopamine neurons or terminals and no clinical correlate has been observed in these studies. In the final analysis, it will probably be necessary to provide evidence of improvement in both imaging and clinical markers of disease progression before it can be declared that an intervention is neuroprotective and has a disease-modifying effect.
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Handbook of Clinical Neurology, Vol. 84 (3rd series) Parkinson’s disease and related disorders, Part II W. C. Koller, E. Melamed, Editors # 2007 Elsevier B. V. All rights reserved
Chapter 32
Levodopa ¨ LBIG1* AND WILLIAM C. KOLLER2 THOMAS D. HA 1
Department of Neurology, Mount Sinai School of Medicine, New York, NY, USA 2
Department of Neurology, University of North Carolina, NC, USA
32.1. History The English physician James Parkinson from London first described Parkinson’s disease (PD) in 1817. Since then several different drugs have been employed to treat PD symptomatically. The first therapeutic agents that were proven to be clinically effective were anticholinergics. Charcot and Ordendstein in the early 1860s at the Salpeˆtrie`re in Paris treated patients with belladonna compounds. However, therapeutic efficacy of treatments with potato plant extracts such as belladonna and atropine was disappointing. This changed with the introduction of synthetic anticholinergics in the 1940s, which had fewer side-effects and provided better symptomatic control, in particular of tremor and rigidity. It was only in the mid-1960s that replacement therapy with levodopa was introduced and marked the turning point, eventually leading to a revolution in symptomatic therapy of PD (for review, see Tolosa et al., 1998; Hornykiewicz, 2002). Levodopa treatment became the so-far only true success story in the symptomatic treatment of a neurodegenerative disorder and PD in particular. The key for the establishment of dopaminergic replacement therapy was the hypothesis that dopamine deficiency is the pathophysiological basis of PD. The work of Arvid Carlson in Lund in Sweden paved the ground for the establishment of this assumption. In the late 1950s Carlson observed that reserpine-treated rabbits present a clinical picture with parkinsonian features and that these symptoms could be reversed by injection of the norepinephrine precursor DL-dopa. Carlson furthermore provided experimental evidence for the presence of dopamine in the striatum. In 1960, Ehringer and Hornykiewicz in Vienna finally demonstrated neuropathological evidence for striatal dopamine deficits of PD patients (Ehringer and
Hornykiewicz, 1960). Based on these findings, only 1 year later, Birkmayer and Hornykiewicz administered levodopa in an open trial intravenously in 20 patients and reported marked improvements of all motor symptoms (Birkmayer and Hornykiewicz, 1961). However, several other trials provided conflicting results on the efficacy of levodopa and a double-blind study published in 1966 reported a negative result (Fehling, 1966). The clinical breakthrough in levodopa treatment of PD is grounded on the seminal work of the American Cotzias (Cotzias et al., 1967). In a placebo-controlled trial, he escalated doses of externally administered levodopa up to 16 g and observed marked effects on all cardinal symptoms of PD. Based on several other confirmatory controlled trials, the US Food and Drug Administration (FDA) finally approved levodopa for use in PD in 1970. Since then it has become the ‘gold standard’ in the symptomatic treatment of PD.
32.2. Dopamine pharmacology 32.2.1. Synthesis and storage Dopamine (3,4-dihydroxyphenylethylamine) is a monoamine belonging to the family of catecholamines. In mammalians, it is synthesized in nerve terminals via intermediate products in several steps (Webster, 2001). L-Tyrosine is considered the initial substrate for the synthesis of levodopa (Fig. 32.1). It is synthesized from phenylalanine. L-Tyrosine is hydroxylated by tyrosine hydroxylase (TH) at position 3 of the phenyl ring to L-3,4-dihydroxyphenylalanine (levodopa). Tyrosine is present in all catecholamine-containing neurons and requires tetrahydrobiopterin and oxygen as cofactors. Tyrosine hydroxylase is a rate-limiting enzyme in the synthesis of dopamine and higher concentrations
*Correspondence to: Thomas D. Ha¨lbig, MD, Centre d’Investigation Clinique et Fe´de´ration des Maladies du Syste`me Nerveux, Centre Hospitalier Universitaire Pitie´-Salpeˆtrie`re, 47-83 Boulevard de l’Hoˆpital, 75651 Paris cedex 13, France. E-mail: thomas.
[email protected] &
[email protected], Tel: +33-1-42-16-19-50, Fax: +33-1-42-16-19-58.
¨ LBIG AND W. C. KOLLER T. D. HA
32 NH2
CH2 CH COOH
Phenylalanine
Phenylalanine hydroxylase NH2 CH2 CH COOH
HO
Tyrosine
Tyrosine hydroxylase NH2 CH2 CH COOH
HO
HO
DOPA DOPA decarboxylase
CH2CH2NH2
HO
HO
Dopamine
Fig. 32.1. Synthesis of dopamine from its precursors. Reproduced from von Bohlen und Halbach and Dermietzel (2002) with permission from Wiley-VCH Verlag Gmbh & Co. KG and the authors.
of tyrosine do not increase the amount of hydroxylated levodopa. Levodopa is rapidly decarboxylated to 3,4dihydroxyphenethylamine (dopamine) by the cytosolic aromatic amino acid decarboxylase (AADC) which splits the carbon acid group of the amino acid. AADC is not rate-limiting and higher concentrations of levodopa increase the production of dopamine. Although the highest concentrations of AADC are found in striatal nigrostriatal dopaminergic nerve terminals (Lloyd et al., 1975; Melamed et al., 1980; Trugman et al., 1991), there are other, alternative sites of levodopa decarboxylation. For example, there is also striatal decarboxylase activity in the terminals of serotonergic and noradrenergic neurons and in capillary endothelial or glial cells (Trugman et al., 1991). After dopamine is synthesized in dopaminergic nerve terminals, it is transported through a
specific vesicular transport system and stored in presynaptic vesicles. Calcium-dependent mechanisms mediate the release of dopamine into the synaptic cleft (von Bohlen und Halbach and Dermietzel, 2002). More specifically, action potentials induce calcium influx via voltagedependent channels, eliciting fusion of the storage vesicles with the presynaptic membrane and release of dopamine into the synaptic cleft. After diffusing in the synaptic cleft, the dopamine molecule binds at postsynaptic receptors, triggering a complex cascade of postsynaptic intracellular events and eventually leading to either activation or inhibition of the postsynaptic neuron. Nigrostriatal dopaminergic neurons implicated in motor functions are characterized by continuous firing (DeLong et al., 1983) with intermittent-burst firing (Grace, 1991; Schultz, 1986). However, striatal intrasynaptic dopamine levels are relatively constant and ensure continuous dopaminergic receptor stimulation (DeLong et al., 1983; Moore et al., 1998). The duration of action of dopamine at the postsynaptic receptors is a function of several factors, including the amount of dopamine in the synaptic cleft, activation of presynaptic autoreceptors and active removal from the synaptic cleft. The latter is in part determined by presynaptic reuptake of dopamine by dopamine transporters (DAT). DAT is a glycoprotein of 619 amino acids (70 kDa). This rapid presynaptic reuptake system recaptures about 80% of the released dopamine (Giros and Caron, 1993). Intraneurally, the dopamine that is reuptaken is transported through a specific vesicular transport system and again stored in vesicles until upcoming release into the synaptic cleft. Another important factor determining the amount of dopamine in the synaptic cleft is the activation of dopaminergic autoreceptors located at the presynaptic membrane. These autoreceptors monitor the intrasynaptical dopamine concentration and their activation inhibits the synthesis and release of dopamine, whereas their blockage enhances dopaminergic synthesis and release (von Bohlen und Halbach and Dermietzel, 2002). 32.2.2. Metabolization Dopamine is metabolized via two pathways to homovanillic acid (HVA) (Webster, 2001). Both pathways involve the action of monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT). MAO is located in, or attached to, the intraneural mitochondria. There are two MAO subtypes, A and B. MAO-A is found primarily in the gastrointestinal tract and has stronger affinity to serotonin (5-HT) and norepinephrine. MAO-B, in contrast, has a higher affinity for dopamine. In the brain 80% of MAO is formed by MAO-B (Squires, 1972).
LEVODOPA COMT is a cytoplasmic enzyme present throughout the body (Guldberg and Marsden, 1975; Schultz et al., 1989; Schultz and Nissinen, 1989; Mannisto et al., 1992). Intracerebrally, there is no significant COMT activity in presynaptic dopaminergic terminals, but some activity is present postsynaptically and substantial activity is located in glial cells (Guldberg and Marsden, 1975; Mannisto and Kaakkola, 1999). On the first pathway, MAO intraneurally oxidatively deaminates dopamine to 3,4-dihydroxyphenylacetaldehyde, which in turn is dehydrogenated by aldehyde dehydrogenase to dihydroxyphenylacetic acid (DOPAC) (Fig. 32.2). DOPAC is methylated by COMT to HVA. On the second pathway, COMT O-methylates dopamine to 3-methoxytyramine (3-MT). 3-MT in turn is deaminated by MAO to 3-methoxy-4-hydroxyphenylacetaldehyde, which is dehydrogenated by aldehyde dehydrogenase to HVA (Webster, 2001).
32.3. Pharmacology of orally administered levodopa Dopamine does not penetrate the blood–brain barrier and therefore cannot be used for symptomatic dopaminergic replacement therapy. However, levodopa does cross the blood–brain barrier. Orally administered
33
levodopa is actively resorbed at the level of the small bowel. Resorption is mediated by an active transport system, the energy-dependent large neutral amino acid (LNAA) transport system (Nutt, 1992). Several factors limit the amount of resorbed levodopa. Firstly, the speed of gastric emptying can be decreased by autonomic dysfunctions which have been found to be frequent in PD (Edwards et al., 1992; Hardoff et al., 2001; Pfeiffer, 2003). Transfer of orally administered levodopa can also be delayed by concurrent food intake (Djaldetti et al., 1996), with dietary LNAAs such as lysine or phenylalanine in protein-rich food competing with levodopa for transport across the gut wall via the LNAA transport system. Once absorbed, levodopa is metabolized peripherally by AADC and COMT to dopamine and 3-O-methyldopa (3-OMD), reducing the bioavailability of externally administered levodopa. Peripheral levodopa half-life is thought to be 60–90 minutes (Sasahara et al., 1980; Nutt and Fellman, 1984; Hardie et al., 1986; Fabbrini et al., 1988). Levodopa crosses the blood–brain barrier, again via an LNAA transport system. Since simultaneous intravenous administration of levodopa and intake of protein-rich meals lead to diminished clinical efficacy, it has to be assumed that levodopa transport via the CH2CH2NH2
HO
HO Dopamine
COMT
MAO HO
CH2CHO
HO
HO 3,4-Dihydroxyphenylacetaldehyde
CH3O 3-Methoxytyramine (3-MT)
Aldehydedehydrogenase
HO
MAO
CH2COOH
HO
CH2CHO
CH3O
HO 3,4-Dihydroxyphenylacetic acid (DOPAC)
CH2CH2NH2
3-Methoxy-4-hydroxyphenylacetaldehyde
COMT
Aldehydedehydrogenase
CH3O HO
CH2COOH
HVA
Fig. 32.2. Degradation of dopamine. Reproduced from von Bohlen und Halbach and Dermietzel (2002) with permission from Wiley-VCH Verlag GmbH & Co. KG and the authors.
¨ LBIG AND W. C. KOLLER T. D. HA
34
blood–brain barrier again competes with dietary LNAAs (Nutt et al., 1985). Due to peripheral absorption concurrence, peripheral degradation and competition with LNAA at the blood–brain barrier, only 1% of orally administered levodopa reaches the central nervous system (CNS) (Mannisto et al., 1990). After transfer via the blood–brain barrier, levodopa is decarboxylated by AADC to dopamine. The exact site of decarboxylation of exogenous levodopa to dopamine in the brain is unknown (Lloyd et al., 1975; Melamed et al., 1980; Trugman et al., 1991). Although probably most striatal AADC is located in nigrostriatal dopaminergic nerve terminals, decarboxylase activity in the terminals of serotonergic and noradrenergic neurons and in capillary endothelial cells (Trugman et al., 1991) is likely involved in the decarboxylation of exogenous levodopa. This is important, since nigrostriatal dopaminergic AADC activity diminishes in the course of the progressive dopaminergic nigrostriatal cell degeneration. Based on research using animal models, it has to be assumed that the exogenous dopamine complements remaining endogenous dopamine and is taken up by nigrostriatal nerve terminals, increasing striatal dopamine levels (Hornykiewicz, 1974; Horne et al., 1984). Both the endogenous and exogenous dopamine are presumably stored in storage vesicles and subsequently released into the synaptic cleft in order to mediate its effects via stimulation of postsynaptic dopaminergic receptors as well as presynaptic autoreceptors. Further metabolization underlies the same mechanisms as described for endogenous dopamine.
32.4. Dopa-decarboxylase inhibition Although initial attempts to treat PD using oral levodopa permitted the reduction of symptoms to some extent, the overall outcome was frustrating. In their seminal paper published in the New England Journal of Medicine, Cotzias and colleagues (1967) reported symptom reduction by oral administration of levodopa but also marked side-effects. Since only 1% of administered levodopa eventually reached the CNS, initially used doses had to be very high. Due to peripheral
O
HO
Levodopa
NH
HO
OH NH2
NH2
OH
COOH
HO
HO
decarboxylation of levodopa to dopamine, patients experienced intolerable side-effects, such as nausea or hypotension, resulting from stimulation of peripheral dopamine receptors (see section 32.6). Thus, major problems related to levodopa administration in initial trials were insufficient efficacy related to marked side-effects. In consequence, levodopa-only therapy was not a practical therapeutical option to be used in most patients. This changed dramatically when evidence for the pharmacological and clinical effects of peripheral inhibition of decarboxylase was obtained. For example, Bartholini et al. (1967) demonstrated that the inhibition of peripheral decarboxylase enhanced the concentration of cerebral catecholamines. More importantly, different peripherally acting decarboxylase inhibitors when coadministered with levodopa were shown to allow administration of levodopa doses which were about four times lower than the levodopa-only administration. Compatible with this, combined administration of levodopa and AADC led to diminished dopaminergic side-effects and more efficient and faster symptom control (Birkmayer, 1969; Cotzias et al., 1969; Calne et al., 1971; Yahr et al., 1971; Sweet et al., 1972; Howse and Matthews, 1973; Papavasiliou et al., 1973; Cedarbaum et al., 1986). In 1975, combinations of the AADCs a-methyldopa hydrazine (carbidopa) and RO4–4602 (benserazide) plus levodopa were commercialized as Sinemet and Madopar and since then have been used for symptomatic dopaminergic replacement therapy (Fig. 32.3). The pharmacokinetics of carbidopa and beneserazide differ. Benserazide in conjunction with levodopa leads to earlier and higher peak dopa levels which decline earlier compared to carbidopa. However, pharmacological differences between both AADCs in general are not reflected clinically (Greenacre et al., 1976; Rinne and Molsa, 1979; Lieberman et al., 1984; Troconiz et al., 1998). To ensure therapeutic levodopa efficacy without peripheral side-effects, complete peripheral inhibition of dopa-decarboxylase is desirable. Although it is generally agreed that a daily dose of at least 75 mg is needed to achieve clinically satisfactory inhibition of decarboxylase activity, higher doses of up to 290 mg/day of carbidopa have been shown to increase levodopa
H3C HO
NH2 Carbidopa
Fig. 32.3. Chemical structures of levodopa, carbidopa and benserazide.
OH
NH
NH
O
HO Benserazide
LEVODOPA
32.5. Clinical effects of levodopa on Parkinson’s disease symptoms After initial trials (Birkmayer and Hornykiewicz, 1961; Barbeau et al., 1962) with encouraging yet controversial results, the first study reporting rather consistent beneficial effects of levodopa on PD motor symptoms was published in 1967 (Cotzias et al., 1967). In this ground-breaking report of an open-label study, Cotzias and colleagues were able to show the efficacy of levodopa in 16 PD patients with a mean disease duration of 7.8 years (range 1–32 years). Patients received levodopa (DL-dopa) at a dose of 3–16 g (without AADC) or placebo. The clinical assessment included handwriting, number of steps required to walk 10 meters, grasping objects, drawing, sit-to-stand maneuver, rigidity, tremor, festination, dysarthria and muscle strength. Eight patients showed either complete or marked sustained improvements of symptoms, including tremor, rigidity, festination and hypomimia, and 2 patients showed mild improvements. Cotzias et al. already noted that rigidity decreased or disappeared at low doses whereas improvements in tremor were observed on higher doses. However, it took 5 more years until again Cotzias demonstrated that coadministration of a peripheral dopa-decarboxylase inhibitor reduced the side-effects of levodopa therapy significantly by allowing the use of markedly lower doses of levodopa (Papavasiliou et al., 1972). Since then, levodopa therapy (in the following, ‘levodopa’ denominates levodopa þ AADC) was extensively used and soon became established as the gold standard of symptomatic antiparkinsonian therapy. Interestingly, even though worldwide clinical use supported the view that levodopa is a highly effective agent in the treatment of motor symptoms in PD, it took about 30 years until the first prospective
35
randomized double-blind placebo-controlled trial testing the efficacy of levodopa was initiated in 1999 (Parkinson Study Group, 2004a). The Early Versus Late L-Dopa (ELLDOPA) study tested the effects of levodopa on disease progression in de novo PD patients with a mean age of 64 years and a disease duration of 2 years. Baseline modified Hoehn–Yahr scores (Hoehn and Yahr, 1967; Fahn et al., 1987) were less than 3, total Unified Parkinson’s Disease Rating Scale (UPDRS) score (Fahn et al., 1987) was about 27 and UPDRS III (motor score) was about 19. Subjects were randomly assigned to receive placebo or levodopa/carbidopa at a dose of 50/12.5 mg three times daily, 100/25 mg three times daily or 200/50 mg three times daily, respectively. Doses were increased to the full amount over a period of 9 weeks in a blinded fashion. For clinical evaluation, the UPDRS was used at the screening, baseline and interim visits (at the end of weeks 3, 9, 24 and 40) and during each of the 2 weeks of a subsequent washout phase. During the four interim visits, the evaluations were performed before the administration of the first dose of the study drug. Of a total of 361 subjects enrolled in the study, 317 (88%) took the study medication for 40 weeks. The patients in the placebo group had mild improvement at the week 3 visit, but after that their symptoms worsened steadily throughout the study period, including the 2-week washout phase (Fig. 32.4). In contrast, in patients treated with levodopa, a strong dose–response benefit that persisted through week 40 was detected.
12 Change in Total Score (units)
bioavailability and decrease time to peak plasma concentration (Cedarbaum et al., 1986). It is conceivable that further increase in carbidopa doses may lead to penetration of carbidopa through the blood–brain barrier and consecutive inhibition of levodopa conversion to dopamine. Yet, there are no data at that point to support this conclusion. The administration of AADCs doubles the bioavailability of orally administered levodopa and halves its plasma clearance (Nutt et al., 1985). Administration of standard oral levodopa preparations, including AADC, in general leads to Cmax after 15–45 minutes (Nutt and Fellman, 1984). Plasma half-life is mainly determined by distribution in tissues and hepatic first-pass effects and varies between 1 and 1.5 hours (Nutt and Fellman, 1984; Hardie et al., 1986; Fabbrini et al., 1988).
10 8
Placebo
6 4 150 mg
2 0
300 mg
−2 −4
600 mg
−6 −8 2 6 Baseline
10
14
18
22 26 Week
30
34
38 42 46 Withdrawal of study drug
Fig. 32.4. Early Versus Late L-Dopa (ELLDOPA) study Unified Parkinson’s Disease Rating Scale (UPDRS) changes. Changes in total scores on the UPDRS from baseline through evaluation at week 42. The points on the curves indicate mean changes from baseline in the total scores at each visit. Negative scores on the curves indicate improvement from baseline. The bars indicate the standard error. From Parkinson Study Group (2004a), reproduced with permission. # 2004 Massachusetts Medical Society. All rights reserved.
36
¨ LBIG AND W. C. KOLLER T. D. HA
Improvements in the levodopa-treated patients reached a peak at week 24 in patients receiving the highest dose of 600 mg. At week 24, improvements were found to be dose-dependent with a decrease of 6 points in the 600 mg group, 4 points (300 mg), no change (150 mg) and worsening by 4 points in the placebo group. The scores on the UPDRS in the three levodopa groups worsened during the 2-week washout period, but these groups did not deteriorate to the level observed in the placebo group and the group receiving the highest dose of levodopa had the best result. Compatible with these results are findings from studies assessing the effects of other antiparkinsonian agents such as dopamine agonists (Rinne et al., 1998b; Parkinson Study Group, 2000, 2004b; Rascol et al., 2000) or levodopa slow-release preparations in de novo patients (Dupont et al., 1996; Block et al., 1997; Koller et al., 1999) against levodopa as comparator. These trials assessed de novo patients with a disease duration of approximately 2 years and patients were followed for up to 5 years. In the agonist vs levodopa trials, patients of both treatment conditions usually could receive additional levodopa when study medication did not allow sufficient symptom control. Results obtained in levodopa-only-treated patients consistently showed improvements of motor functions of up to 30% as assessed by the UPDRS at the end of the study periods (Table 32.1). Compared to dopamine agonisttreated patients, studies show significantly greater improvement in patients treated with levodopa only and support the notion that levodopa is the most effective agent in the symptomatic treatment of PD.
32.6. Tolerability and acute non-motor side-effects Apart from the nigrostriatal dopaminergic system which is the target of dopaminergic replacement therapy in PD, there are several other different central and peripheral dopaminergic systems (Webster, 2001). External administration of dopaminergic agents may therefore exert peripheral, central and combined peripheral and central effects and side-effects. As for the motor effects, controlled data on side-effects are mainly obtained from the ELLDOPA study and trials comparing the effects of different dopaminergic agents with levodopa as comparator. The most frequent nonmotor side-effects include nausea, sedation, hypotension and neuropsychiatric symptoms (Table 32.2). 32.6.1. Nausea The most frequent side-effect in levodopa-treated patients is nausea, occurring in up to 30% of patients
during treatment initiation (Rinne et al., 1998b; Parkinson Study Group, 2000, 2004a). Nausea developed in a dose-dependent way and in the ELLDOPA study occurred on daily doses as low as 150 mg in 16%, on 300 mg in 26% and on 600 mg in 31% of patients (Parkinson Study Group, 2004a). Nausea and vomiting are considered peripheral side-effects of levodopa treatment. They are mediated via dopaminergic stimulation of the area postrema which is located at the bottom of the fourth ventricle outside the blood–brain barrier and involved in the regulation of nausea and emesis. In most patients, nausea resolves within days or weeks of continued levodopa treatment without any additional action being taken. When nausea persists, temporary dose reduction and slower levodopa retitration may be tried. Furthermore, several agents are available to prevent or reduce gastrointestinal side-effects. For example, peripherally acting dopamine receptor blockers may be employed in order to avoid dopaminergic receptor stimulation of the area postrema. Domperidone is a peripherally acting dopamine-2 (D2) receptor antagonist that does not penetrate the blood–brain barrier and has a half-life of more than 10 hours. Its time to maximum peak level is about 30–60 minutes (Huang et al., 1986). Domperidone has no significant effect on dopamine pharmacokinetics (Bradbrook et al., 1986). It is administered in a dose of 10–20 mg per dose of levodopa. Domperidone has been shown to be as efficient as carbidopa (see below) in preventing nausea and vomiting as side-effects of levodopa (Langdon et al., 1986; Barone, 1999). Domperidone is approved in Europe (Motilium) and Canada but is unavailable in the USA. Another option is the add-on of trimethobenzamide hydrochloride. Although its mechanism of action is not entirely understood, it may also involve the chemoreceptor trigger zone of the area postrema. There are no controlled studies on the effects of trimethobenzamide hydrochloride in PD; however, the administration of 200 mg three times daily has been recommended for the treatment or prevention of dopaminergically induced nausea and vomiting (Olanow et al., 2001). Trimethobenzamide is marketed in the USA as Tigan and not available in most European countries. Furthermore, additional carbidopa may be added to the levodopa regimen (Markham et al., 1974). Carbidopa alone is available as Lodosyn in the USA. Other agents which may be employed are the 5-HT receptor antagonist (5-HT3) ondansetron (Wilde and Markham, 1996) or the antiemetic diphenidol (Duvoisin, 1972).
Table 32.1 Symptomatic motor effects of long-term levodopa (LD) treatment (2–5 years) reported in phase III studies assessing the effects of dopamine agonists (1, 3, 4, 5) or controlled release LD (2) against LD as comparator in drug-naive Parkinson’s disease (PD) patients
Agents
1
LD (cabergoline) LD (controlled release LD) LD (pramipexole) LD (pramipexole) LD (ropinirole)
2
3 4 5
Age (years)
H&Y stage
PD duration months
UPDRS lll baseline
UPDRS ll baseline
Study duration months
Levodopa mg/day
204 (208) 306 (312)
62.6 (60.5) Range 30–75
1–3
24 (22.8) Overall 27.6
29.1 (27.5) 15.1 (15.4)
NR
48
500
8.7 (9.4)
60
426
150 (151) 150 (151) 89 (179)
60.9 (61.5) 60.9 (61.5) 63.0 (63.0)
1–3
21.6 (18) 21.6 (18) 30 (29)
22 (22.3) 22 (22.3) 21.7 (21.5)
8.3 (9.1) 8.3 (9.1) 8 (8)
23.5
509
48
702
60
753
1–3
1–3 1–3
Change in UPDRS lll at end
Change in UPDRS ll at end
9 (6) 0.4 (1.2)
2.7* (2.4*) þ0.1 (1.0)
7.3 (3.4) 3.4 (þ1.3) 4.8 (0.8)
2.2 (1.1) þ0.5 (þ1.7) 0 (þ1.6)
LEVODOPA
Reference
n at baseline
1, Rinne et al. (1998b); 2, Koller et al. (1999); 3, Parkinson Study Group (2000); 4, Parkinson Study Group (2004b); 5, Rascol et al. (2000). H&Y, Hoehn and Yahr; UPDRS, Unified Parkinson’s Disease Rating Scale; *, % value; NR, not reported.
37
38
Table 32.2 Side-effects of levodopa within up to 5 years of treatment in controlled studies assessing the effects of LD against dopamine agonists (1, 3, 4), controlled release LD (2) and placebo (5) as comparator
48
500
4
LD (LD controlled release) LD (pramipexole)
204 (208) 306 (312)
60
426
150 (151) 89 (179) 92 (90) 88
23.5
509
60
753
10
150
10
300
36.7 (36.4) 49.4 (48.6) 16.3 (13.3) 26.1
91
10
600
31.9
5
13 (16) 9 (7)
17.3 (32.4) 19.1 (27.4) 0 (2.2) 5.7
22.0 (25.8) 23.6 (25.1) 8.7 (10.0) 4.5
3.3 (9.3) 5.6 (17.3) 3.3 (0) 0
10 (6.0) 12.4 (11.7) – –
8.0 (10.6) 33 (27) 2 (3) 2
5.5
5.5
5.5
–
1
Somnolence*
Sleep disturbances*
1, Rinne et al. (1998b); 2, Koller et al. (1999); 3, Parkinson Study Group (2000); 4, Rascol et al. (2000); 5, Parkinson Study Group (2004a). * indicates % of patients; NR, not reported.
5 (4)
¨ LBIG AND W. C. KOLLER T. D. HA
LD (cabergoline)
5
24 (32) 2 (3)
NR
1
5
NR
6 (6)
28 (27) 2 (4)
32 (37) 28 (26)
n
LD (ropinirole) LD (placebo) LD (placebo) LD (placebo)
Withdrawal rate for adverse events*
Nausea/ vomiting*
Agents
3
Orthostatic hypotension*
Mean LD dose (mg)
References
2
Hallucinations (1–4)/abnormal dreaming (5)*
Study duration (months)
LEVODOPA 32.6.2. Hypotension Since the introduction of levodopa as symptomatic PD therapy, orthostatic hypotension has been reported as a side-effect (Calne, 1970; Calne et al., 1970). However, the data on the specific acute and long-term effects of levodopa on hypotension are controversial and vary depending on methodological differences. Orthostatic hypotension occurs in 0–30% of PD patients without major comorbidity during the first 3–5 years of treatment in the early stages of the disease (Rinne et al., 1998b; Parkinson Study Group, 2000, 2004a). Interestingly, the ELLDOPA trial did not report any incidence of orthostatic hypotension. Compatible with this result, several other studies did not find acute effects of levodopa administration (Sachs et al., 1985; Meco et al., 1991; Senard et al., 1995). On the other hand, higher doses of stable levodopa or dopamine agonist regimes or long-term treatment with levodopa may be related to orthostatic hypotension (Camerlingo et al., 1990; Senard et al., 1997). The conflicting data may be explained by the fact that, at least in some PD patients, disease-associated pre-existing cardiovascular dysfunction (Brevetti et al., 1990; Hakamaki et al., 1998), disease duration and levodopa doses are confounded. Compatible with this, a recent study provided evidence that levodopa aggravated pre-existent impairment of the autonomic control of blood pressure and heart rate in de novo patients (Bouhaddi et al., 2004). The mechanisms of orthostatic hypotension induced by levodopa administration are complex and incompletely understood. Lewy body degeneration has been shown to be present in the sympathetic and parasympathetic autonomic nervous system on various levels (Wakabayashi et al., 1993; Kaufmann et al., 2004). Peripherally, the sympathetic ganglions and parasympathetic cardiac, myenteric and submucosal plexi have been shown to be involved. Centrally, structures such as the locus ceruleus, the hypothalamus and the dorsal vagal nucleus are affected (Wakabayashi and Takahashi, 1997). Compatible with these findings, evidence suggests that orthostatic hypotension in PD reflects neurocirculatory failure from generalized sympathetic denervation (Goldstein et al., 2002; Li et al., 2002). Based on these abnormalities, orthostatic hypotension induction by dopaminergic agents might be subserved peripherally by activation of postsynaptic D1-receptors mediating vasodilatation and by activation of sympathetic presynaptic D2-receptors (Langer, 1980; Goldberg and Rajfer, 1985). The latter mechanism induces reduced vasoconstrictor responses via inhibition of norepinephrine release (Bouhaddi et al., 2004). However, peripheral inhibition of decarboxylation of
39
levodopa to dopamine by AADC does not entirely suppress the development of levodopa-induced hypotension. It thus is likely that central mechanisms are also involved (see Ch. 14). Symptomatic orthostatic hypotension may be treated by non-pharmacologic measures such as increased salt and fluid intake, compressive stockings and sleeping with head-up tilt of bed. Pharmacologic treatment includes fludrocortisone acetate 0.05–0.2 mg/day (Hoehn, 1975; Hakamaki et al., 1998), indometacin 50 mg three times daily (Abate et al., 1979), or midodrine hydrochloride, an alpha-adrenergic agonist at a dose of up to 10 mg three times a day (Jankovic et al., 1993; Low et al., 1997). Finally, domperidone may be tried. Yet, although there is a pathophysiologically based rationale for the employment of domperidone, clinical evidence for its beneficial effects on orthostatic hypotension is controversial (Merello et al., 1992; Lang, 2001). Indeed, a recent study, though demonstrating an increase of blood pressure in apomorphine-treated PD patients, failed to show effects on blood pressure drops in the supine position (Sigurdardottir et al., 2001). 32.6.3. Neuropsychiatric side-effects 32.6.3.1. Hallucinations Levodopa treatment in PD may cause a number of neuropsychiatric side-effects. These include hallucinations, paranoid psychosis and, more rarely, impulsive and compulsive behavior. Based on the reported controlled studies (Table 32.2), the incidence of hallucinations is rather low: 3–5% during the first 3–5 years of treatment. However, patients in these trials were a selected population early in the disease. In later stages of the disease with higher daily levodopa doses and in patients with additional risk factors (see below), levodopa-induced hallucinations and other neuropsychiatric side-effects develop in 30–50% of patients (Sanchez-Ramos et al., 1996; Fenelon et al., 2000; de Maindreville et al., 2005). Hallucinations are sensory perceptions without external stimulation of the relevant sensory organ (APA, 2000). They are distinguished from illusions in which objectively present stimuli are perceived and then misinterpreted. Dopaminergically induced hallucinations are most often visual; however, they may also present in other sensory modalities (Holroyd et al., 2001). One study detected auditory hallucinations in 8% of patients who mostly also experienced visual hallucinations (Inzelberg et al., 1998). Olfactory or tactile hallucinations have also been reported to be present; however, data are sparse and prevalence rates have to be assumed to be rather low.
40
¨ LBIG AND W. C. KOLLER T. D. HA
The development of hallucinations is frequently preceded by vivid dreaming which may further develop into illusions (Pappert et al., 1999; Fenelon et al., 2000). Vivid dreaming may lead to sleep fragmentation and daytime sleepiness. Illusions are initially often present during evenings and at night and predominantly in twilight and darkness. Sometimes patients report hallucinations of presence – the physical feeling of the presence of persons or objects near them, usually behind or beside them. Visual phenomena have been described as being simple or complex. Simple elementary hallucinations may be color patches, lightnings or geometrical forms. Most frequently patients visualize figural appearances of persons or animals and less frequently unanimated objects (Barnes and David, 2001). Figural appearances usually appear normal; however, they may also be present as distorted or demonic faces or grimaces. Hallucinations in PD vary on several other characteristics. They may be stationary or moving and may develop at any time of the day but preferentially and with longer episodes in the morning and evening (Barnes and David, 2001). Their duration varies between seconds and hours. The degree of incapacitation due to hallucinations varies considerably between patients. In many patients, hallucinations are benign and patients have insight into the nature of their visual experiences. In these patients, hallucinations may occur sporadically and are often non-threatening. Hallucinations may even be experienced as entertaining and be integrated in artwork production. Although exact data are lacking, patients suffering from benign and infrequent hallucinations may present with a stable clinical manifestation over years. However, in many patients hallucinatory episodes are experienced as frightening. Furthermore, frequently patients demonstrate lack of insight into the nature of their visual experiences. In many patients, hallucinations increase in frequency of occurrence and severity and may eventually develop into full-blown psychosis (Sharf et al., 1978). The presence of hallucinations is an important disease complication and is the most frequent reason for institutionalization of PD patients (Goetz and Stebbins, 1993; Aarsland and Karlsen, 1999; Holroyd et al., 2001). The pathophysiological basis for levodopa-induced hallucinations in PD is complex and likely involves widespread disease-associated neuropathological changes, including Lewy body degeneration and dopaminergic, cholinergic, noradrenergic and serotonergic denervation in association with the effects of levodopa supplementation. More specifically, in PD, it is not only nigrostriatal dopaminergic neurons that degenerate. There is also degeneration of mesolimbic and
mesocortical dopaminergic pathways (Agid et al., 1987). Dopaminergic denervation and chronic levodopa treatment may lead to supersensitization of dopaminergic limbic D3- and D4-receptors. Based on diminished presynaptic buffering capacity, the therapeutic non-physiological administration of levodopa may lead to overstimulation of postsynaptic receptors and induction of hallucinations (Moskovitz et al., 1978). Compatible with the role of levodopa for the induction of hallucinations in PD, dopamine receptorblocking agents have been found to alleviate psychotic symptoms in PD patients (Friedman, 1991; Rabey et al., 1995; Fernandez et al., 1999; French Clozapine Parkinson Study Group, 1999; Parkinson Study Group, 1999). Even though treatment with levodopa and other dopaminergic agents is a contributing factor for the development of hallucinations in PD, not all patients treated with dopaminergic agents develop hallucinations. A recent study identified ‘endogen’ factors rather than the amount of levodopa doses as relevant in the genesis of PD hallucinations (Merims et al., 2004). Compatible with this, there is evidence that the overall dose of dopaminergic drugs does not significantly differ between patients with and without hallucinations (Sanchez-Ramos et al., 1996; Klein et al., 1997; Aarsland and Karlsen, 1999; Merims et al., 2004). Furthermore, in one study, high doses of intravenously administered levodopa did not induce hallucinations in predisposed patients (Goetz et al., 1998). Several cofactors have been discussed that may increase the risk for hallucinations. These include age, cognitive impairment, depression, sleep disorders, PD severity, predominance of axial symptoms, ocular disorders and genetic factors such as the apolipoprotein E e 4 allele (Sanchez-Ramos et al., 1996; Inzelberg et al., 1998; Aarsland and Karlsen, 1999; de la FuenteFernandez et al., 1999; Arnulf et al., 2000; Fenelon et al., 2000; de Maindreville et al., 2005). Furthermore, treatment with other drugs used in PD therapy, including dopamine agonists, dopamine-enhancing agents such as MAO-B and COMT inhibitors, anticholinergic medications and amantadine have been shown to contribute (de Smet et al., 1982; Perry et al., 1990; Steckler and Sahgal, 1995). Furthermore, there is evidence for an involvement of other than dopaminergic transmitter systems in the pathogenesis of hallucinations in levodopa-treated PD patients. It has been suggested that chronic levodopa treatment in conjunction with serotonergic (5-HT) dysregulation contributes to the induction of hallucinations. Neurodegeneration in PD involves brainstem 5-HT neurons associated with diminished central 5-HT levels. Chronic levodopa administration may further lower 5-HT levels via reuptake by 5-HT nerve terminals and conversion to
LEVODOPA dopamine (Markianos et al., 1982; Tohgi et al., 1993). Compatible with this, the administration of the 5-HT precursor L-tryptophan may reduce the frequency and severity of hallucination in PD (Rabey et al., 1977). On the other hand, serotonergic denervation and chronic administration of levodopa have been thought to lead to hypersensitivity of postsynaptic 5-HT receptors (Nausieda et al., 1983). Indeed, blockage of serotonergic receptors using methysergide or the 5-HT3 antagonist ondansetron appears to alleviate psychotic symptoms in PD patients (Nausieda et al., 1983; Zoldan et al., 1995). Treatment of psychosis in PD can be difficult. Although data on empirical validity are lacking, currently established treatment algorithms usually recommend the identification of those agents in the individual treatment schema carrying the biggest potential for the induction of hallucinations. In general, it is thought that agents that are major risk factors for PD psychosis are those with the weakest antiparkinsonian efficacy. If possible, agents should be eliminated in the following order: anticholinergics, amantadine, MAO-B inhibitors, dopamine agonists and finally levodopa (Olanow et al., 2001). Nevertheless, overall reduction of PD medication and in particular of dopaminergic agents is often done at the expense of deterioration of motor functions. In order to prevent worsening of motor functions, the alternative to decreasing dopaminergic medication is the introduction of antipsychotic agents (Merims et al., 2004). In order to avoid extrapyramidal side-effects and worsening of PD symptoms, for the treatment of drug-induced psychosis, only atypical neuroleptics should be used. A variety of atypical neuroleptics are available. Atypical neuroleptics have lower D2 occupancy than typical neuroleptics and block 5-HT2A receptors. The latter mechanism may be responsible for their antipsychotic effects (Meltzer, 1999). The current gold standard for the treatment of psychosis in PD is clozapine. Clozapine has relatively low D2 but strong affinity to 5HT2A receptors, as well as affinity to histamine H1, muscarinergic and cholinergic receptors. Clozapine has a strong antipsychotic effect and does not induce motor side-effects (Friedman and Lannon, 1989a; Kahn et al., 1991; French Clozapine Parkinson Study Group, 1999; Parkinson Study Group, 1999). Clozapine is slowly titrated, starting with 12.5 mg at bedtime and may be increased to 75–100 mg/day, which usually allows psychotic symptoms to be controlled. If necessary, daily doses may be administered spread out throughout the day. Due to its sedating effects, clozapine helps to control psychotic symptoms, agitation and sleep disturbance when given
41
before bedtime. The administration of clozapine, however, is limited for pragmatic reasons due to its potential to induce neutropenia. Patients treated with clozapine require frequent monitoring of white blood counts, particularly during treatment initiation (Dewey and O’Suilleabhain, 2000; Brandstadter and Oertel, 2002; Morgante et al., 2004). Monitoring of white blood cell count and absolute neutrophil count should be based on stage of therapy with monitoring weekly for 6 months, every 2 weeks for 6 months and every 4 weeks ad infinitum (Novartis Pharmaceuticals Corporation, 2005). Alternatively, quetiapine, another atypical neuroleptic can be used. Quetiapine also blocks dopaminergic and serotonergic receptors and has affinity to histamine H1 with only small affinity to muscarinergic and cholinergic receptors (Dewey and O’Suilleabhain, 2000; Ondo et al., 2005). In a randomized, open-label, blinded-rater, parallel-group trial, quetiapine and clozapine demonstrated equal efficacy and side-effect profile in 45 patients with PD with drug-induced psychosis (Morgante et al., 2004). However, a recent, smaller placebo-controlled study failed to demonstrate significant improvement on psychosis rating scales (Ondo et al., 2005). The starting dose for quetiapine is 25–50 mg at bedtime and the dose may be increased about every third day up to 125 mg/day. Another atypical antipsychotic medication with low affinity for D2-receptors is olanzapine. However, double-blind, placebo-controlled evaluations of efficacy and safety profile revealed no significant improvement of hallucinations but worsening of motor function (Breier et al., 2002; Ondo et al., 2002). Recently, a new class of neuroleptics with functionally selective action mechanisms was introduced. For example, aripriprazole has partial D2 dopamine agonistic and antagonistic characteristics as well as partial agonism at 5-HT1A and partial antagonism at 5-HT2A receptors (Naber and Lambert, 2004). Its pharmacological characteristics suggest a low-profile risk of extrapyramidal side-effects. However, since preliminary case studies reported significant motor side-effects, aripriprazole cannot currently be recommended as first-line treatment for drug-induced psychosis in PD (Fernandez et al., 2004; Schonfeldt-Lecuona and Connemann, 2004). 32.6.3.2. Impulse control deficits Recently, it has been appreciated that impulse control deficits may develop in PD associated with dopaminergic therapy (Vogel and Schiffter, 1983; Uitti et al., 1989; Fernandez and Friedman, 1999; Molina et al., 2000; van Deelen et al., 2002; Driver-Dunckley et al., 2003; Kurlan, 2004). Impulsivity is the failure to resist an
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¨ LBIG AND W. C. KOLLER T. D. HA
impulse, drive or temptation that is harmful to oneself or others (Hollander and Evers, 2001). The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV: APA, 2000) classifies conditions such as intermittent explosive disorder (failure to resist aggressive impulses), kleptomania (failure to resist urges to steal items) or pathological gambling (failure to resist the impulse to gamble despite severe personal, family or vocational consequences) as impulse control disorders. Although classified separately, hypersexuality and punding (see below) are other examples of deficits of impulse control. Pathological gambling and hypersexuality have recently been reported to be present in PD (Molina et al., 2000; Seedat et al., 2000; Gschwandtner et al., 2001; Driver-Dunckley et al., 2003; Montastruc et al., 2003; Avanzi et al., 2004; Dodd et al., 2005). For example, Molina et al. presented a series of 12 PD patients (out of a cohort of 250: 4.9%) with pathological gambling. Symptoms in 9 patients developed after initiation of levodopa therapy. Other reports note the first occurrence of pathological gambling in association with a dose increase of dopaminergic drugs (Gschwandtner et al., 2001). One retrospective database study identified 9 out of 1884 patients with pathological gambling (Driver-Dunckley et al., 2003). The study reports an overall incidence of 0.05% and a slightly higher incidence of 1.5% in patients treated with levodopa and a dopamine agonist. Hypersexuality (paraphilia-related disorder) has repeatedly been reported in smaller case series and case studies of PD patients in association with the administration of dopaminergic drugs (Quinn et al., 1983; Vogel and Schiffter, 1983; Uitti et al., 1989; van Deelen et al., 2002; Berger et al., 2003). Compulsive behavior has also been described in PD. Compulsive behavior is characterized by stereotypical motor behavior accompanied by an intense fascination with a particular object. For example, repetitive handling and examining of mechanical objects (punding) have been observed in single cases of PD and could be related to the overall dose of dopaminergic medication (Fernandez and Friedman, 1999; Evans et al., 2004). These observations have raised concern that dopaminergic agents, including levodopa, may be associated with the induction of impulse control deficits. Although the mentioned impulse control deficits differ regarding their phenomenological presentation and neurobiological basis, they have commonalities. For example, compulsive and impulsive control deficits are characterized by the decreased ability of the individual to inhibit motor responses to affective states which might critically depend on dopaminergic neuromodulation. More specifically, animal research and
clinical studies have shown that the monoamines 5-HT and dopamine affect sexual behavior (Melis and Argiolas, 1995; Kafka, 2003). Furthermore, the mesolimbic-mesocortical dopaminergic system presumably has an important role in several aspects of reward mechanisms and behavioral impulse control which have been shown to be dysfunctional in pathological gambling (Fiorillo et al., 2003). The occurrence of impulse control deficits in PD during dopaminergic treatment might therefore be interpreted as behavioral abnormalities induced by overstimulation of dopamine receptors in denervated mesolimbic structures. Genetically determined traits might explain why these problems are induced in only some PD patients (Menza et al., 1993; Noble, 2000). However, for methodological restrictions, the above-cited studies are inconclusive. Furthermore, data on the prevalence of impulse control deficits in the general population are not well established and vary depending on the methods of assessment (Shaffer and Hall, 1996). In summary, due to methodological restrictions and limited data, the implications of these findings are still open. Yet, patients rarely volunteer to report behavioral abnormalities and their assessment is not part of the clinical routine in most movement disorders centers. The prevalence of impulse control deficits induced by dopaminergic agents, including levodopa, therefore may be considerable. 32.6.4. Melanoma Levodopa treatment has been thought to be related to the development of malignant melanoma. Based on several case reports on the co-occurrence of PD and malignant melanoma, the diagnosis of malignant melanoma or the presence of suspicious, undiagnosed skin lesions has been determined as a contraindication for the use of levodopa (Physicians Desk Reference, 2003). The putative causal connection between levodopa treatment and malignant melanoma was based on the fact that levodopa is an important substrate for the formation of melanin. Within the melanocyte, tyrosine is converted to dopa and then to dopaquinone via the bifunctional enzyme tyrosinase. Dopaquinone is further oxidized to form the pigment melanin (Kincannon and Boutzale, 1999). It was hypothesized that exogenous levodopa may increase the production of melanin and promote malignant transformation of the melanocytes. However, there is no experimental evidence for this assumption. In contrast, in experimental tumor systems with human and murine melanoma cells, levodopa and dopamine had antitumor activity (Wick, 1979, 1980, 1987, 1989).
LEVODOPA Since the first report of malignant melanoma in PD in 1972 (Skibba et al., 1972), a total of 54 cases have been reported in the literature (Weiner et al., 1993; Fiala et al., 2003). Interpretation of these rare cases with respect to a causal link of levodopa administration and tumor induction is difficult for a variety of reasons. Firstly, both PD and malignant melanoma are highly prevalent conditions, in particular in the elderly population (Thompson et al., 2005). Based on the small reported numbers and deficient documentation of cases, it is therefore not possible to determine whether co-occurrence of levodopa and malignant melanoma is coincidental or not (Fiala et al., 2003). Secondly, pathogenesis of malignant melanoma and the time gap between exposure to carcinogens and tumor manifestation are thought to take years to decades. Given the variety of risk factors for melanoma, including genetic predisposition with tyrosine kinase gene mutation, family history, sun exposure, skin phenotype and history of skin lesion (Thompson et al., 2005), it is difficult to determine statistical probabilities for the role of exogenous levodopa. In conclusion and despite continued warning, based on experimental and epidemiological data, there is at present no evidence for a causal relation between levodopa therapy and malignant melanoma. 32.6.5. Hyperhomocysteinemia Recently, elevated plasma homocysteine levels have been described in PD patients treated with levodopa (Allain et al., 1995; Kuhn et al., 1998; Muller et al., 1999, 2001; Lamberty and Klitgaard, 2000; Yasui et al., 2000, 2003; Miller, 2002; Miller et al., 2003; Nakaso et al., 2003; Rogers et al., 2003; Genedani et al., 2004; O’Suilleabhain et al., 2004a). These findings raised the question of whether levodopa treatment is a risk factor for hyperhomocysteinemia (Postuma and Lang, 2004). Hyperhomocysteinemia in turn is a risk factor for vascular disease (Perry et al., 1995; Bostom et al., 1999a, b), possibly for dementia (Seshadri et al., 2002; Luchsinger et al., 2004; Wright et al., 2004) and is potentially neurotoxic (Duan et al., 2002). It is thus possible that the risk for these conditions is increased in PD patients receiving levodopa. The mechanisms for increased plasma homocysteine are most likely associated with peripheral metabolization of levodopa and more specifically the O-methylation of levodopa by COMT (see section 32.3) (Postuma and Lang, 2004). O-methylation of levodopa by COMT requires S-adenosylmethionine (SAM) as methyl donor. Demethylation of SAM forms S-adenosylhomocysteine which is converted to homocysteine. Since levodopa administration leads to increased metabolic levodopa
43
turnover and the conjunction with an AADC shifts peripheral levodopa metabolization to the COMT pathway, levodopa therapy may lead to increased plasma homocysteine levels (Morris, 2003). Yet, the clinical importance of elevated plasma homocysteine levels in levodopa-treated PD patients is far from understood. First of all, data on atherosclerosis and PD are controversial. Several studies found an increased risk in PD patients for death from stroke and coronary artery disease (Gorell et al., 1994; BenShlomo and Marmot, 1995) and an increased risk for intima media thickness of the carotid artery in patients undergoing levodopa treatment (Nakaso et al., 2003). These findings were not confirmed by other studies (Struck et al., 1990; Korten et al., 2001; Mastaglia et al., 2002; Jellinger, 2003). A reason for these conflictual findings may be that several other vascular risk factors appear to be less prevalent in PD patients. For example, blood pressure is lower in PD patients (Brevetti et al., 1990; Hakamaki et al., 1998) and smoking is less frequent in PD patients (Hernan et al., 2001). It is therefore conceivable that homocysteine-associated increased risk for stroke and coronary heart disease is outweighed by other diminished vascular risk factors (Postuma and Lang, 2004). It is well established that PD is a risk factor for the development of dementia (Emre, 2003). Elevated plasma homocysteine levels in some, but not all, studies have been found to increase the risk for Alzheimer’s dementia (Seshadri et al., 2002; Luchsinger et al., 2004), possibly independently of vascular factors (Dufouil et al., 2003; den Heijer et al., 2003). One may thus hypothesize that hypercysteinemia in PD may contribute to the development of dementia in PD. Indeed, a recent preliminary study reported that patients with PD and hyperhomocysteinemia are more likely to be depressed and to perform worse on psychometric tasks compared with normohomocysteinemic patients (O’Suilleabhain et al., 2004b). However, further research is needed to see whether hyperhomocysteinemia is a risk factor for neuropsychiatric burden in patients with PD. Experimental and animal research suggested that hyperhomocysteinemia may exert neurotoxic effects on the substantia nigra. More specifically, hyperhomocysteinemia is associated with excitotoxicity via N-methyl-Daspartate (NMDA) activation (Lipton et al., 1997) and free radical formation (Cook et al., 2002; Lawrence de Koning et al., 2003) and also may have proinflammatory effects (Lawrence de Koning et al., 2003). Interestingly, a study using a mouse model of PD demonstrated that when homocysteine is infused directly into either the substantia nigra or striatum, homocysteine exacerbates 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-
¨ LBIG AND W. C. KOLLER T. D. HA
44
induced dopamine depletion, neuronal degeneration and motor dysfunction (Duan et al., 2002). Furthermore, the same authors report that homocysteine exacerbates oxidative stress, mitochondrial dysfunction and apoptosis in human dopaminergic cells exposed to the pesticide rotenone or the pro-oxidant ferrous iron (Fe2þ). However, there are no clinical data on possible neurotoxic effects relevant for the development of PD or hastening of PD progression. Taken together, there is considerable, converging evidence for the potential of levodopa long-term treatment to increase homocysteine plasma levels. The latter has been shown to be a risk factor for vascular disease and possibly cognitive decline in humans and to be neurotoxic in experimental models of PD. Yet, presently, there is no evidence for the clinical relevance of these findings, which certainly merits further investigation. Although it appears rational to screen PD patients presenting with or being at risk for vascular disease and dementia for hyperhomocysteinemia and to supplement vitamin B or COMT inhibitors which have been shown to decrease homocysteine plasma levels (Nissinen et al., 2005; Lamberti et al., 2005), further data are needed before a general guideline regarding screening and prevention should be given.
32.7. Long-term motor effects: motor fluctuations and dyskinesias 32.7.1. Clinical presentation Early during treatment, the response to levodopa is sustained and extends by far the pharmacological half-life of 1.5 hours. This long-duration response
Clinical Effect
Response Threshold
4 Levodopa 2 Time (h)
6
Advanced PD
Dyskinesia Threshold Response Threshold
4 Levodopa 2 Time (h)
6
Smooth, extended duration of target clinical response
Diminished duration of target clinical response
Low incidence of dyskinesias
Increased incidence of dyskinesias
Clinical Effect
Moderate PD Dyskinesia Threshold
Clinical Effect
Early PD
(LDR) is reflected as gradual improvement of motor functions after repeated administration and prolonged wearing-off after cessation of therapy (Muenter and Tyce, 1971). Benefits from this LDR may even be maintained if doses are skipped (Fig. 32.5, early PD). Apart from the LDR, there is a short-duration response which reflects the plasma dopamine concentration and may be present even early in the disease; however, it may be masked by the LDR (Nutt et al., 1995). Evidence suggests that the LDR progressively diminishes within the course of disease progression. Efficacy of levodopa in terms of duration of symptom control decreases and eventually becomes a function of the levodopa plasma concentration with progressively shortened (Fig. 32.5, moderate PD), and eventually even unpredictable, levodopa responses. Moreover, involuntary movements (dyskinesias) may occur associated with levodopa administration (Fig. 32.5, advanced PD). Interestingly, Cotzias et al. (1967), in their seminal early report on the symptomatic effects of levodopa in PD, already described involuntary (athetoid) movements of tongue and extremities in those patients who had an excellent response to levodopa. Motor complications can seriously interfere with activities of daily living and impair quality of life and their treatment is a challenge (Chapuis et al., 2004). From a clinical point of view, hypokinetic symptoms can be distinguished from hyperkinetic manifestations (Table 32.3). The first motor complication that developes in most patients is the wearing-off phenomenon, i.e. patients experience a re-emergence of symptoms before intake of the next dose. The wearing off may present clinically in the morning as early-morning
Dyskinesia Threshold Response Threshold
4 Levodopa 2 Time (h)
6
Short duration of target clinical response "On" time is associated with dyskinesias
Fig. 32.5. Motor complications in early, moderate and advanced Parkinson’s disease (PD). Pharmacologic response to a levodopa dose (arrow) depending on the stage of disease progression. In the early stage, the response is slow in onset, and has a small magnitude and a very long duration. In the intermediate stage, the severity of motor dysfunction in the ‘off’ state has increased and the response is of greater magnitude and shorter duration. Dyskinesias may be elicited at this stage. In the late stage, the motor response is abrupt and has a very large magnitude but the duration of response is short and the threshold for dyskinesia is reduced. Reproduced from Obeso and Olanow (1997), published by Wells Medical, Kent.
LEVODOPA Table 32.3 Motor complications Motor fluctuations End-of-dose worsening or wearing off Re-emergence of symptoms at the end of a dose interval at daytime Nocturnal symptoms Early-morning symptoms Beginning-of-dose worsening Dose failures Unpredictable worsening (‘on/off’) Freezing Rebound worsening Hyperkinetic responses Peak-dose dyskinesias Square-wave dyskenias Diphasic dyskinesias ‘Off’-period dystonia/early-morning dystonia
akinesia, throughout the day (wearing-off) or at night (Fahn, 1974; Marsden et al., 1982; Nutt, 1987). In more advanced stages, drug responses may become more and more unpredictable and patients experience symptomatic periods of varying duration at any time during the dose interval (on–off). Related to this, delayed onset of dose effects as well as complete dose–response failures occur. Furthermore, patients may experience a levodopa intake-related worsening
45
of symptoms before the beneficial effects kick in (beginning-of-dose worsening) (Merello and Lees, 1992). Finally, motor functions at the end of the dose interval may deteriorate below the dose interval baseline level for a prolonged time, before the following dose becomes effective (rebound) (Gancher et al., 1988; Nutt et al., 1988). Related to the on–off motor manifestations, patients may suffer from neuropsychiatric symptoms which are present in particular during off phases. These may include depression, anxiety and panic attacks which may be associated with marked autonomic symptoms (Menza et al., 1990; Siemers et al., 1993). During ‘on’ periods patients may experience hypomania or, less frequently, mania (Giovannoni et al., 2000). Apart from these fluctuations of levodopa response in terms of temporary restoration of motor functions, long-term levodopa treatment may be associated with involuntary movements which most often present as dyskinesias (Nutt, 1990) (Table 32.3). Dyskinesias are usually initially present during on phases. Later on they may occur at virtually any time of the dose interval. Dyskinesias are typically choreiform; they may, however, also resemble dystonia or athetotic movements or akathisia or present as myoclonic jerks or ballism (Nutt, 1990; Comella and Goetz, 1994; Marconi et al., 1994). Dyskinesias can be distinguished regarding their temporal relation with the intake of a levodopa dose (Fig. 32.6). Most frequently, they present as peak-dose dyskinesias. Peak-dose
Dyskinesia
Dyskinesia
"off"
"off" Levodopa
Levodopa
Levodopa
Levodopa
Diphasic dyskinesia
Levodopa
Diphasic dyskinesia "on" dyskinesia
"on" dyskinesia
A
Levodopa
B
"off" dystonia
Fig. 32.6. Motor complications: dyskinesias. (A) Schematic representation of dyskinesias in patients with Parkinson’s disease. Each levodopa dose (arrow) induces a predictable motor improvement lasting for about 3–4 hours. ‘Peak-of-dose’ dyskinesias (open squares) occur at the time of maximal improvement but may also occupy the entire ‘on’ period. Diphasic dyskinesias (black squares) may occur at the beginning and/or the end of the cycle. (B) An example of a patient with an ‘on’ response in which the patient fails to respond to a given dose of levodopa, often associated with ‘off’-period dystonia (hatched rectangles). Failure to respond to a dose of levodopa tends to occur in the afternoon or evening after repeated doses. Reproduced from Obeso et al. (2000), with permission from the American Academy of Neurology.
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dyskinesias tend to occur at the time of peak plasma concentration, usually in the middle between two levodopa doses when patients are without typical parkinsonian features. Dyskinesias may persist during the entire ‘on’ period (square-wave dyskinesias). In contrast, diphasic dyskinesias occur at the beginning or the end of a levodopa dose interval, i.e. when levodopa plasma concentrations begin to rise and fall, but not during peak concentrations (Fig. 32.6). Diphasic dyskinesias more often affect the lower limbs and in particular asymmetrically the side of the body that is more affected by PD. Movements are often stereotypical and may present with dystonic components. In contrast to peak-dose dyskinesias, the presence of diphasic dyskinesias may overlap with parkinsonian features. Diphasic dyskinesias are thought to be associated with rising or falling, yet insufficient levodopa concentrations. Finally, severe off states with marked immobility may be followed by abrupt onset periods of violent dyskinesias (yo-yoing). In contrast, ‘off’-period dystonia develops when levodopa levels are low at the end of a dose interval or when levodopa doses fail to kick in (Fig. 32.6). 32.7.2. Time of onset of motor complications Various studies examined the time of onset of motor complications. Data, however, vary depending on the methods and patient characteristics. Ideally, in order to examine the effects of long-term levodopa treatment for the development of motor complications, prospective long-term studies should compare drug-naive and levodopa-treated de novo patients over long time intervals. Yet, the only study meeting this criterium is the ELLDOPA study (see section 32.5). Results of the ELLDOPA study indicate that motor complications may develop after less than 1 year of levodopa therapy (Parkinson Study Group, 2004a). Within a treatment period of 40 weeks, dyskinesias were significantly more frequent in patients treated with a daily dose of 600 mg levodopa (15/91) as compared to patients on placebo (3/90) or patients receiving 150 mg (3/92) or 300 mg (2/88) per day. Likewise, there was a strong trend for those patients on 600 mg to present with more frequent wearing-off phenomenon compared to all other treatment groups. Other studies allowing conclusions regarding onset of motor complications in levodopa-treated patients compared the effects of levodopa with other antiparkinsonian agents or are based on chart reviews (Table 32.4). It is generally agreed that, after 5 years of treatment, about 50% of patients and after 10 years 80–100% of patients have developed motor complications (Marsden and Parkes, 1977; Burguera et al., 1999; Grandas et al., 1999;
Schrag and Quinn, 2000; Ahlskog and Muenter, 2001; Garcia Ruiz et al., 2004). 32.7.3. Determining factors for motor complications There is substantial evidence that the disease duration is a major factor contributing to the development of motor complications. According to a meta-analysis (Ahlskog and Muenter, 2001), clinical studies on patients with PD onset well before levodopa availability (pre-levodopa era) report high frequencies of dyskinesias early after treatment initiation, with approximately half of patients experiencing dyskinesias after 5–6 months. This complies with the early observations of Cotzias et al. (1967). In contrast, in more recent series, frequencies were minimal until 1–2 years and then amounted up to only 25% through the first 2.5–3.5 years. At 4–6 years of follow-up, modern-era series still had lower median dyskinesia frequencies (36–39%). Several other clinic-based and community studies confirmed that longer disease durations and hence more advanced neurodegenerative changes may play a critical role in the development of levodopa-induced dyskinesias (Lesser et al., 1979; Parkinson Study Group, 1996a; Schrag and Quinn, 2000; Kostic et al., 2002). Furthermore, clinical and experimental evidence suggests that time of onset and severity of dyskinesias are associated with the total exposure to levodopa (Agid et al., 1985; Smith et al., 2002). Another factor determining onset and frequency of motor complications is the age of PD onset. Several studies demonstrated that motor complications and in particular dyskinesias tend to develop earlier in patients with young onset of symptoms and are less likely to occur in patients with onset of symptoms after the age 70 (Golbe, 1991; Kostic et al., 1991; Stern et al., 1991; Schrag and Quinn, 2000). Another controversial factor, however, is gender. Few studies provided evidence for higher frequency of dyskinesias in women (Parkinson Study Group, 1996a; Lyons et al., 1998). 32.7.4. Mechanisms The mechanisms that contribute to the development of motor complications are controversial. Since there is no change in the peripheral pharmacokinetics of levodopa and dopamine during the course of disease progression, the underlying mechanisms have to be assumed to be central. A variety of factors have been discussed. For the maintenance of motor functioning, postsynaptic striatal receptors have to be continuously activated (DeLong et al., 1983). Early in the disease, remaining endogenous dopamine supplemented by
LEVODOPA
47
Table 32.4 Prevalence of levodopa-induced motor complications
Study
Prevalence of complications
Length of study
Method of evaluation
Rajput et al. (1984)
10% fluctuations 25% dyskinesias
5 years
Physician evaluation
Poewe et al. (1986)
52% wearing off 54% dyskinesias
6 years
Webster Scale Modified Columbia Scale
Hely et al. (1994)
41% wearing off 55% dyskinesias
5 years
Modified Columbia Scale Dyskinesia Scale Physician evaluation
Montastruc et al. (1994)
40% wearing off 56% dyskinesias
5 years
Columbia Scale UPDRS
Dupont et al. (1996)
59% fluctuations 41% dyskinesias
5 years
UPDRS, part 4
Parkinson Study Group (1996b)
50% wearing off 30% dyskinesias
2 years
Physician evaluation UPDRS, part 4
Koller et al. (1999)
20% wearing off 20% dyskinesias
5 years
Patient diary Physician-recorded questionnaire/diary
Rascol et al. (2000)
45% dyskinesias
5 years
UPDRS, dyskinesia scale
Parkinson Study Group (2000)
38% wearing off 31% dyskinesias
2 years
Physician determination
Whone et al. (2003)
27% dyskinesias
2 years
Physician evaluation UPDRS, dyskinesia scale
Parkinson Study Group (2004b)
63% wearing off 54% dyskinesias
4 years
Physician evaluation UPDRS, dyskinesia scale
Parkinson Study Group (2004a)
21% wearing off 7% dyskinesias
10 months
Physician evaluation UPDRS, dyskinesia scale
UPDRS, Unified Parkinson’s Disease Rating Scale. Adapted from Olanow et al. (2001) and supplemented.
exogenous levodopa is sufficient for continuous dopaminergic stimulation (CDS). During progressive degeneration and loss of nigrostriatal neurons, the postsynaptically available dopamine depends more and more on externally administered dopamine. One reason for this is the progressive decrease in the production of endogenous dopamine. Furthermore, presynaptical reuptake and storage of intrasynaptical dopamine progressively diminish. Due to this loss of presynaptic buffering, fluctuations in the levodopa plasma levels are reflected as fluctuations in postsynaptic receptor activations which translate in turn into motor fluctuations. This hypothesis is supported by the notion that motor fluctuations develop much faster with severe nigrostriatal degeneration, as demonstrated by the shortened delay between treatment initiation and emergence of motor fluctuations in PD patients with severe disease (Ahlskog and Muenter, 2001) or in
monkeys treated with MPTP, where the cell loss amounts to 90–95% (Clarke et al., 1987). Compatible with this, compared to patients without motor fluctuations, patients experiencing wearing off show more pronounced reduction in striatal levodopa uptake (Leenders et al., 1986). However, motor fluctuations probably also reflect changes of postsynaptic receptor responses to dopaminergic stimulation. The duration of motor improvements due to administration of levodopa or the dopamine agonist apomorphine decreases with disease progression, which cannot be explained by a reduced presynaptic dopamine storage (Fabbrini et al., 1988; Bravi et al., 1994; Verhagen Metman et al., 1997). Apart from the degree of dopaminergic denervation, the manner in which missing dopamine is replaced by dopaminergic agents also appears to contribute to the establishment of motor complications. Dopaminergic agents used for the symptomatic treatment of PD differ
¨ LBIG AND W. C. KOLLER T. D. HA
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regarding their pharmacological half-life. Dopamine metabolized from levodopa has a half-life of about 1.5 hours, whereas dopamine agonists have half-lives of up to 65 hours (see Ch. 33). Due to its short half-life, repeated oral administration of levodopa leads to rapidly changing plasma levels with pulsatile stimulation of postsynaptic receptors. In contrast, continuous levodopa infusions or administration of long-acting dopamine agonists is associated with stable CDS. Converging evidence from animal models (Bedard et al., 1986; Pearce et al., 1998; Maratos et al., 2001) as well as from clinical trials (Rascol et al., 2000; Parkinson Study Group, 2004b) suggests that the short half-life of dopaminergic agents importantly contributes to the development of motor complications and in particular dyskinesias. For example, levodopa and short-acting dopamine agonists are much more likely to induce dyskinesias in MPTP-treated monkeys than dopamine agonists with a long half-life (Bedard et al., 1986; Pearce et al., 1998). Furthermore, there is evidence that the potential of the same dopamine agonist to induce dyskinesias depends on whether it has been administered pulsatile or in a continuous fashion via infusion (Blanchet et al., 1995). Compatible with this are results from several clinical trials comparing the incidence of dyskinesias in patients treated with levodopa and dopamine agonists (Table 32.5). Patients in the dopamine agonist treatment arm in these studies usually received supplementary levodopa if symptoms remained inadequately controlled. Results of these studies consistently demonTable 32.5 Prevalence of dyskinesias in patients treated with either levodopa or dopamine agonists þ levodopa
Study Rascol et al. (2000) Parkinson Study Group (2000) Whone et al. (2003) Parkinson Study Group (2004b) Rinne et al. (1998b)
Length of study (years) 5 2
2 4
4
*Peak-dose dyskinesias.
Agent
Prevalence of dyskinesias (%)
Ropinirole Levodopa Pramipexole Levodopa
20 45 10 30
Ropinirole Levodopa Pramipexole Levodopa
3.4 27 24.5 54
Cabergoline Levodopa
6* 14*
strate that the incidence of dyskinesias is higher in patients treated with levodopa only than in patients treated with a dopamine agonist and hence a dopaminergic agent with a longer half-life. Different postsynaptic changes related to the nigrostriatal degenerative process and associated with external administration of levodopa that may account for motor fluctuations and the establishment of dyskinesias have been identified in experimental models. These include gene changes with upregulation of preproenkephalin mRNA and downregulation of dynorphin and substance P as well as changes of Fos genes and prodynorphin) (Gerfen et al., 1990; Jolkkonen et al., 1995; Duty and Brotchie, 1997; Calon et al., 2000; Zeng et al., 2000; Westin et al., 2001) and GABA-A receptor upregulation of the globus pallidus internus (Calon et al., 1995). Although the exact mechanisms to date are unknown, it is thought, that these gene changes are associated with abnormal firing patterns of the major basal ganglia output nuclei and in particular the globus pallidus internus, as assessed during dyskinetic states (Papa et al., 1999; Lozano et al., 2000).
32.8. Toxicity Though levodopa is considered the gold standard for the sympomatic treatment of PD symptoms, its longterm effects on disease progression are unknown. Different levels of research, including in vitro studies, in vivo animal experiments and clinical and neuroimaging data obtained in humans, raised the possibilities of both neurotoxic and neuroprotective effects of levodopa. There is conclusive evidence that oxidative stress is present in the substantia nigra pars compacta (SNpc) in PD (increased Fe2þ: Dexter et al., 1987, 1989; Sofic et al., 1991; decreased glutathione: Perry et al., 1982; Riederer et al., 1989; decreased mitochondrial complex 1 activity: Parker et al., 1989; Schapira et al., 1990; Tretter et al., 2004). Furthermore, oxidative stress has been shown to impair DNA (Schapira et al., 1990), proteins (Parker et al., 1989; Tretter et al., 2004) and lipids (Emerit et al., 2004). On the other hand, in vitro evidence suggests that under certain conditions both dopamine and levodopa may exert toxic effects on cultured dopaminergic neurons (Mena et al., 1992; Mytilineou et al., 1993) via auto-oxidation, leading to the formation of highly reactive oxygen species (Graham et al., 1978). Compatible with this, high doses of dopamine and levodopa have been shown to decrease TH-positive staining neurons in various dopaminergic cell cultures (Michel and Hefti, 1990; Steece-Collier et al., 1990; Mytilineou et al., 1993), probably via apoptotic mechanisms (Ziv et al., 1997; Corona-Morales
LEVODOPA et al., 2000). Based on these findings, it is reasonable to assume that the increased oxidative stress already present in PD is potentiated by chronic administration of dopaminergic agents. However, for a variety of methodological reasons, the in vitro findings supporting the neurotoxic potential of dopaminergic agents do not simply translate into in vivo effects. For example, the toxic concentration of levodopa used in most studies was much higher than concentrations usually achieved by therapeutic levodopa supplementation. Furthermore, most in vitro studies lack neuroprotective features such as antioxidant ascorbic acid or glial cells which are present in in vivo animal models as well as in humans. Indeed, it has been demonstrated that culture systems that were accommodated for these factors were protected against levodopa toxicity (Kalir and Mytilineou, 1991; Mena et al., 1993, 1997a; Pardo et al., 1993). Interestingly, low-dose levodopa administration may exert neurotrophic effects in in vivo models using other pro-oxidant agents. For example, in cultures using glia-conditioned media, levodopa was shown to enhance neurite outgrowth and to increase cell survival (Mytilineou et al., 1993; Mena et al., 1997a, b). Furthermore, levodopa may protect mesencephalic cultures against oxidative stress, probably via upregulation of glutathione (Han et al., 1996). Taken together, in vitro data are at present inconclusive. In vivo animal studies also tried to assess the putative cell toxic effects of levodopa supplementation in experimental models of PD. One study evaluated the effect of 6-month oral levodopa treatment on several dopaminergic markers in rats with moderate or severe 6-hydroxydopamine (6-OHDA)-induced lesions of mesencephalic dopamine neurons and sham-lesioned animals (Murer et al., 1998). Counts of TH-immunoreactive neurons in the substantia nigra and ventral tegmental area showed no significant difference between levodopatreated and vehicle-treated rats. In addition, for rats of the sham-lesioned and severely lesioned groups, immunoradiolabeling for TH, DAT and vesicular monoamine transporter (VMAT2) at the striatal level was not significantly different between rats treated with levodopa or vehicle. Unexpectedly, quantification of immunoautoradiograms showed a partial recovery of all three dopaminergic markers (TH, DAT and VMAT2) in the denervated territories of the striatum of moderately lesioned rats receiving levodopa. Compatible with these neuroprotective effects, another study, also using a PD rat model with 6-OHDAinduced dopaminergic lesions and chronic levodopa treatment for about 6 months (Datla et al., 2001), also revealed an increased number of dopaminergic neurons. Recently, two prospective randomized clinical trials have compared the effects of levodopa versus the non-ergot derivative D2-binding dopamine agonists pramipexole and ropinirole on disease progression
49
(Parkinson Study Group, 2002a; Whone et al., 2003). As a surrogate marker for disease progression, neuroimaging measures indicative of the functional integrity of the nigrostriatal system were used. For example, in an imaging substudy of the CALM-PD trial (Comparison of the Agonist pramipexole vs. Levodopa on Motor complications in Parkinson’s Disease), 82 de novo PD patients were randomized to receive either 300 mg levodopa or 1.5 mg pramipexole per day (Parkinson Study Group, 2002a). Open-label levodopa could be added, if clinical symptoms could not be sufficiently controlled by the study drug. The main outcome variable was the change of iodine-123-labeled 2-beta-carboxymethoxy-3-beta-(4-iodophenyl)tropane (b-CIT) uptake on single-photon emission computed tomography (SPECT) from baseline to month 46 after trial initiation. Results of the study showed that the 41 patients treated initially with pramipexole had a significantly slower mean decline in striatal b-CIT uptake (16.0%) than the 42 subjects treated initially with levodopa (25.5%). Interestingly, mean total and motor UPDRS scores obtained in the ‘defined off’ state in both the levodopa- and the pramipexole-treated groups did not differ significantly between baseline and assessments at 34 or 46 months. Another prospective, randomized trial, the REALPET study (Requip as Early Therapy versus L-dopa– Positron Emission Tomography) (Whone et al., 2003), assessed the neuroprotective potential of ropinirole using the rate of loss of dopamine-terminal function in 162 de novo patients over 24 months, as assessed by fluoro-dopa-PET as primary outcome measure. Patients were randomized to receive either ropinirole or levodopa. Over the first 4 weeks of the study, doses were escalated to daily regimens of 3 mg ropinirole, or 300 mg levodopa per day. Titration was flexible, based on clinical response and tolerability, to a maximum 24 mg of ropinirole or 1000 mg of levodopa per day. If symptoms were inadequately controlled, titration to the maximum tolerated dose of the assigned medication was encouraged. The primary outcome measure was reduction in putamen 18F-dopa uptake (Ki) between baseline and 2-year PET. Analysis of the putamen as the central region of interest revealed that there was a significantly slower rate of deterioration in the ropinirole group than in the levodopa group (13% versus 20%). Interestingly, UPDRS measures indicated that motor function during treatment at 2 years was superior with levodopa compared with ropinirole. Both the CALM-PD and REAL-PET studies demonstrated a more rapid decline on imaging biomarkers of nigrostriatal functioning in patients treated with levodopa. Since there was no placebo group in both studies, it is not clear whether the different rate of
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¨ LBIG AND W. C. KOLLER T. D. HA
decline reflects toxic effects of levodopa or rather neuroprotective effects of the dopamine agonists. Furthermore, although the same results were seen in both studies despite the use of different agonists, different tracers and different imaging techniques, it is possible that levodopa and dopamine agonists have different pharmacological effects and regulate components of the nigrostriatal system in opposite directions (Ahlskog et al., 1999). In this case, the different SPECT and PET findings would simply reflect these pharmacological differences rather than indicate different rates of disease progression. It is also not clear why the apparently more rapid decline on PET and SPECT in the levodopa groups did not reflect clinically. Indeed, UPDRS motor scores in patients treated with levodopa were equal or superior to scores obtained in patients treated with agonists. The ELLDOPA (see section 32.5) study was the first study ever comparing the effects of levodopa with placebo. The aim of the ELLDOPA study was to determine the effect of levodopa on the rate of progression of PD (Parkinson Study Group, 2004a). The ELLDOPA study evaluated clinical and imaging functions in 361 patients randomized to receive a daily carbidopa-levodopa dose of 37.5 and 150 mg, 75 and 300 mg, or 150 and 600 mg, respectively, or a matching placebo for a period of 40 weeks. Patients then underwent withdrawal of treatment for 2 weeks. The primary outcome was a change in scores on the UPDRS between baseline and 42 weeks. Neuroimaging studies of 142 subjects were performed at baseline and at week 40 to assess striatal dopamine transporter density by measuring bCIT uptake. The clinical component of the study demonstrates that the severity of symptoms increased more in the placebo group than in all the groups receiving levodopa. The mean difference between the total score on the UPDRS at baseline and at 42 weeks was þ7.8 units in the placebo group, þ1.9 units in patients receiving levodopa at a dose of 150 or 300 mg daily and –1.4 in those receiving 600 mg daily. This result is consistent with a protective, not a toxic, effect. However, the possibility of a confounding, long-lasting, symptomatic effect that persists for months after washout cannot be entirely excluded. In contrast, the imaging component of the study demonstrated that, in a subgroup of 116 patients, the mean decline in the b-CIT uptake was significantly greater with levodopa than placebo (–6% among those receiving levodopa at 150 mg daily, –4% in those receiving it at 300 mg daily and –7.2% among those receiving it at 600 mg daily, as compared with –1.4% among those receiving placebo). Again, as in the CALM-PD and REAL-PET studies, the imaging findings suggest either a toxic effect of levodopa or a pharmacologic modification of the
DAT. Thus, the results of the ELLDOPA study with diverging clinical and controversial imaging findings are not conclusive. In summary, even though there is some controversial evidence from laboratory and human imaging studies suggesting a toxic effect of levodopa, in the final analysis it remains unclear whether levodopa is toxic. In contrast, there is no clinical evidence supporting the notion of levodopa toxicity and some data even support the possibility of neuroprotective effects of levodopa.
32.9. Strategies to improve levodopa therapy 32.9.1. Oral formulations aiming at faster onset of symptomatic effects Several different approaches have been developed to face the shortcomings and failures of levodopa therapy. Even in earlier stages of PD, the time to effect of a single dose of levodopa may be delayed for various reasons. The most important factor is usually related to the speed of gastric emptying, which varies and may be prolonged in PD (Edwards et al., 1992; Byrne et al., 1994; Kaneoke et al., 1995; Quigley, 1996; Pfeiffer, 1998, 2003; Hardoff et al., 2001; Goetze et al., 2005). Furthermore, food may delay gastrointestinal transit time and LNAA from protein-rich food may lead to interference and delay of transmucosal and transendothelial levodopa transport (Djaldetti et al., 1996) (see section 32.3). In later stages of the disease, swallowing may also be a problem, further delaying the time until a levodopa dose kicks in. To shorten the time to therapeutic effect, conservative measures such as avoiding food and in particular protein-rich diets 45 minutes before and 90 minutes after intake of a levodopa dose may be helpful. Furthermore, special formulations of levodopa and new forms of administration of levodopa have been developed. In order to speed up levodopa transfer to the jejunum, the major site of resorption, several studies compared the effect of liquefied levodopa with standard oral administration (Kurth et al., 1993; Metman et al., 1994; Pappert et al., 1996; Kurth, 1997). In a doubleblind, cross-over study (Pappert et al., 1996), either liquid levodopa or standard levodopa was administered to 23 PD patients. Liquid levodopa was produced using 10 tablets of levodopa/carbidopa (LD/CD: 100/25 mg) and 1 g of ascorbate dissolved in 1 liter of tap water. Patients were evaluated hourly between 9 a.m. and 4 p.m. for plasma levodopa levels. Furthermore, the UPDRS, a dyskinesia rating scale and ‘on–off’ ratings were employed. Patients receiving liquid LD/CD ingested significantly higher doses and had significantly improved motor function and total ‘on’ time, without an increase in dyskinesia severity. Levodopa levels and
LEVODOPA variability were equivalent with the two formulations. However, overall dosing frequencies in this study were much higher for the liquid preparation (17.22 versus 6.96) and the overall ingested levodopa dose was higher (1321 versus 890 mg). In an open trial comparing a levodopa/carbidopa/ascorbic acid solution (LCAS) and standard levodopa, 4 patients with PD with severe motor fluctuations presented with reduced bradykinesia, decreased dysfunctional dyskinesias and increased functional ‘on’ time when treated with LCAS (Kurth et al., 1993). According to the authors, oral LCAS allowed better titration of levodopa dosage and offered a more predictable response than LD/CD tablets. Compatible with this, in a small double-blind, placebo-controlled, cross-over study in 5 PD patients, orally administered liquid LD/CD led to slightly earlier peak plasma levodopa levels (Metman et al., 1994). A dispersible formulation of levodopa (LD)/benserazide (Madopar LT) is an alternative to the preparations of liquefied levodopa, as described above. Madopar LT can be dissolved in water or taken like a regular tablet and is available in Europe (Contin et al., 1999). It is characterized by earlier release, rapid absorption and shorter time to peak plasma levodopa concentration (Tmax) with no difference in remaining pharmacokinetic and clinical characteristics (Haglund and Hoogkamer, 1995). Several open-label trials have shown its usefulness in the treatment of early-morning akinesia (Steiger et al., 1992) and in patients with swallowing difficulties (Bayer et al., 1988). In summary, even though controlled clinical data are sparse, based on the shorter Tmax, dispersible and liquid formulations may be worthwhile to shorten the delay to effect and may be offered to patients as first dose in the morning, as rescue medication or to shorten diphasic dyskinesias. A dual-release preparation has been developed and is currently marketed in Switzerland. In a double-blind single-dose study 200 mg levodopa (plus 50 mg benserazide) was administered either as dual-release preparation consisting of a three-layer tablet combining immediate and slow-release properties or a conventional slow-release formulation (see section 32.9.3) (Descombes et al., 2001). The cross-over study enrolled 16 fluctuating patients with PD. Compared to the slowrelease formulation, the time to ‘on’ was shown to be shorter with the dual-release formulation (43 31 and 81 39 minutes, respectively), whereas the mean time to relapse to ‘off’ was similar for both formulations. UPDRS improvement and dyskinesias scores were similar for either preparation. There were no differences in tolerability. The dual-release formulation had significantly shorter Tmax and greater maximum concentration (Cmax) and area under the plasma
51
concentration time curve (AUC: 0.5 hours). Apparent elimination half-life was similar for both formulations. Other recent strategies to shorten Tmax used chemically modified levodopa preparations (Stocchi et al., 1994, 1996; Djaldetti et al., 2002, 2003). For example, levodopa ethylester (etilevodopa, LDEE) is a highly soluble prodrug of levodopa passing unchanged through the stomach to the duodenum, where it is rapidly hydrolyzed by local esterases and absorbed as levodopa. In a recent open-label, randomized, fourway cross-over study, different oral preparations of LDEE/carbidopa and LD/CD were compared in 29 PD patients with motor fluctuations (Djaldetti et al., 2002, 2003). Results showed significantly shorter plasma levodopa Tmax, higher AUC and Cmax for LDEE/carbidopa. Compatible with these results, the same authors were able to demonstrate the clinical superiority of LDEE in 62 patients with ‘delayed-on’ and ‘no-on’ subtypes of response fluctuation in a controlled double-blind study (Djaldetti et al., 2002). Results showed that mean latency to turning on was reduced by 21% (morning dose) and 17% (postlunch dose) and percentage of no-on episodes after the postlunch dose was decreased by 21% in the LDEE/CD group but increased by 36% in the LD/CD group. Levodopa methyl ester is another highly water-soluble levodopa derivative that can be administered orally and intravenously and has been shown to decrease latency to on in smaller studies (Juncos et al., 1987; Stocchi et al., 1994, 1996). Recently, an orally disintegrating LD/CD tablet containing phenylalanine has been introduced in the USA (Parcopa) (Nausieda et al., 2005). It rapidly disintegrates on the tongue without chewing and does not require water to aid dissolution. It is available in the USA in dosages corresponding to the usual dosages of standard levodopa preparations. According to an open-label study, the clinical efficacy of orally disintegrating LD/CD tablets is equivalent to standard preparations (Nausieda et al., 2005). This new formulation may be an alternative to standard levodopa for patients who have difficulties swallowing conventional tablets or when water is unavailable or inappropriate. Finally, nasal and transdermal formulations have been evaluated in rats in in vivo and in vitro studies; however, clinical evidence in humans is lacking (Sudo et al., 1998; Kao et al., 2000; Iwase et al., 2000). 32.9.2. Infusions and other non-oral ways of levodopa administration In order to control better motor fluctuations related to the short levodopa half-life, several strategies are available to provide more continous dopaminergic
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¨ LBIG AND W. C. KOLLER T. D. HA
stimulation. For example, constant intravenous infusion of levodopa replacing standard oral levodopa or in addition to standard levodopa has been shown to result in stable plasma dopa concentrations and dramatic improvement of motor fluctuations in patients with predictable wearing off, unpredictable on–off fluctuations and prolonged offs (Shoulson et al., 1975; Quinn et al., 1982). Furthermore, liquid solutions may be used in order to bypass the oral route. Bypassing the oral route may be necessary in patients with swallowing difficulties or in order to smoothen the variable and sometimes erratic time till levodopa kicks in which is often caused by delayed gastric emptying. Liquid solutions have been used in patients with percutaneous endoscopic gastrotomy, with a portable duodenal or jejunal pump or via nasoduodenal catheter (Cedarbaum et al., 1990a; Metman et al., 1994; Syed et al., 1998). For enteral application, a stable gel suspension of LD/CD (20/5 mg/ml) has been developed (Duodopa) (Nilsson et al., 1998, 2001; Nyholm et al., 2003). Continuous intraduodenal infusion has been shown to be associated with stable plasma levodopa concentrations compared to controlled-release (CR) preparations (see section 32.9.3). Compatible with this, ‘on’ time increased and ‘off’ time and dyskinesias decreased (Nyholm et al., 2003, 2005). Long-term evaluations for more than 9 years demonstrated that continuous intraduodenal levodopa infusion may be efficient in patients with advanced disease and severe on–off fluctuations (Nilsson et al., 2001). Patients are usually given a bolus as the first morning dose and then continuous infusion during the day. In addition to decreased motor fluctuations, infusion therapy permits the reduction of the daily overall dose of levodopa. In contrast, rectally administered levodopa was shown to be of no value in patients who are unable to take oral medication. In a series of 12 PD patients postsurgery there was no rise in levodopa plasma levels and no clinical benefit when levodopa was administered rectally (Eisler et al., 1981). 32.9.3. Levodopa slow-release preparations In order to address the fluctuating motor response after long-term treatment with levodopa and in particular the wearing-off phenomenon, controlled/slow-release levodopa preparations have been developed. Their specific aim is to extend the short half-life of levodopa to prolong its clinical effects. CR preparations comprise levodopa/AADC embedded in a slowly eroding matrix (Erni and Held, 1987; LeWitt et al., 1989; Yeh et al., 1989). CR preparations are available in combination with carbidopa or benserazide and mar-
keted as Sinemet CR and Madopar CR (or HBS, or Depot). Madopar CR, when in contact with gastric fluid and after dissolution of the gelatin shell of the capsule, forms a mucous body that continuously releases its contents via a hydrated layer by diffusion over a prolonged period of time (Erni and Held, 1987). Sinemet CR is embedded in an erodible polymeric matrix and dissolves during passage along the duodenal-jejunal mucosa (LeWitt et al., 1989; Yeh et al., 1989). Due to their gradual release, CR preparations are characterized by delayed Tmax by about 45–90 minutes and by prolonged plasma half-life of up to 2 hours. Furthermore, due to variable gastrointestinal transit, less efficient absorption in the distal bowel or greater firstpass systemic metabolism, bioavailability is decreased by about 30% compared to standard levodopa (Yeh et al., 1989). Finally, Cmax is reduced (Grahnen et al., 1992; for Madopar see also Crevoisier et al., 1987; Da Prada et al., 1987; Jensen et al., 1987; Malcolm et al., 1987; Nordera et al., 1987; Poewe et al., 1987; Quinn et al., 1987; for Sinemet see also Cedarbaum et al., 1987; Yeh et al., 1989; Wilding et al., 1991). 32.9.3.1. Effects on motor fluctuations The effects of CR preparations on motor fluctuations are mixed. Overall, there are fewer data available on the effects of CR LD/benserazide than for LD/CD preparations. A double-blind, cross-over study in 14 patients with PD and motor fluctuations examined the effects of Madopar HBS or placebo twice a day in addition to the optimal standard Madopar treatment (De Michele et al., 1989). Clinical response as evaluated by the King’s College Hospital Parkinson’s Disease Rating Scale and the Mobility in Bed Scale improved significantly, whereas evaluation by selfscoring diaries did not show significant changes. Another open-label study on 22 patients reported longer ‘on’ periods, less severe ‘off’ periods and decrease in early-morning akinesia (Chouza et al., 1990). Compatible with the results obtained for LD/benserazide, several double-blind (Hutton et al., 1989; Mark and Sage, 1989a; Lieberman et al., 1990; Wolters et al., 1992; Wolters and Tesselaar, 1996) and open studies (Goetz et al., 1988; Deleu et al., 1989; Rondot et al., 1989; Rodnitzky et al., 1989; Pahwa et al., 1993) demonstrated significant ‘off’-time reduction and improvement of functional clinical abilities for LD/CD CR preparations. In particular, the combined administration of controlled- and immediate-release formulations allowed significant improvement regarding disability from dyskinesias and number of on hours without dyskinesias (Sage and Mark, 1988; Friedman and Lannon, 1989b; Mark and Sage, 1989b; Wolters et al., 1992).
LEVODOPA Other possible advantages of CR preparations are less frequent dose failures (Pahwa et al., 1993) and diminished early-morning dystonia and nocturnal awakenings (Goetz et al., 1989; Pahwa et al., 1993). However, other studies failed to provide evidence for the superior efficacy of slow-release Madopar in improving nocturnal and early-morning disabilities. For example, in a double-blind cross-over study, 103 patients with nocturnal and/or early-morning disabilities received a bedtime dose of either Madopar CR or standard Madopar in addition to their usual daytime levodopa regimen. Both Madopar CR and standard Madopar improved nocturnal and early-morning disability equally (UK Madopar CR Study Group, 1989). Likewise, for LD/CD CR, studies in patients with motor fluctuations were not able to detect significant differences between standard formulation and CR regarding number of off hours (Ahlskog et al., 1988) or effects on wearing off (Feldman et al., 1989). The long-term efficacy of CR preparations is also controversial. Although some studies found efficacy for several months only (Pezzoli et al., 1988; Kleedorfer and Poewe, 1992), other investigators report satisfactory symptom control for more than 2 years with Madopar CR (Siegfried, 1987), in particular for mild to moderate fluctuations or in addition to regular levodopa (Pacchetti et al., 1990). Another controversial issue is the effect of CR preparations on dyskinesias. Although some authors report increase in peak-dose or diphasic dyskinesias for LD/benserazide (Pezzoli et al., 1988; De Michele et al., 1989; Kleedorfer and Poewe, 1992) and LD/ CD (Jankovic et al., 1989; Cedarbaum et al., 1990b; Hutton and Morris, 1991), others report decrease in dyskinesias (Chouza et al., 1990). In summary, evidence for the efficacy of CR preparations to control motor fluctuations is only derived from studies with standard levodopa as comparator and not including comparisons with placebo. In general, studies report a reduction in dose frequency (Hutton et al., 1989; Lieberman et al., 1990). However, most, but not all, studies (Dupont et al., 1996) report an increase of overall doses of levodopa by 30%, which is consistent with the pharmacokinetic profile of CR preparations. Furthermore, efficacy in reducing ‘off’ time, dose failures, nocturnal and early-morning akinesia and rigidity may be transient. A problem related to prolonged on- and offset of clinical effects may be the development or worsening of diphasic dyskinesias. Furthermore, associated with erratic levodopa resorption, levodopa plasma levels may build up unpredictably, with variably high peak dose levels, which may translate into peak-dose dyskinesias. In conclusion, the administration of the CR levodopa formulation of
53
levodopa (plus carbidopa or benserazide) can be transiently useful in moderately advanced stages of PD with motor fluctuations characterized mainly by the wearing-off phenomenon and nocturnal and early-morning motor symptoms. In contrast, in later stages CR preparations may contribute to dopaminergic side-effects such as dyskinesias. 32.9.3.2. Effects in de novo patients and prevention of motor complications According to the concept of CDS, non-physiologic, pulsatile receptor stimulation contributes to the development of motor fluctuations and dyskinesias. Based on this consideration, the administration of levodopa CR preparations has been suggested as pre-emptive strategy to prevent or delay the development of motor complications. Two controlled prospective multicenter trials assessed the potential of CR preparations to reduce the incidence of motor complications compared with immediate-release LD/CD (Block et al., 1997; Koller et al., 1999) or LD/benserazide (Dupont et al., 1996). The primary endpoints of these studies were the incidence of motor fluctuations and dyskinesias after 5 years of treatment. Though both treatment groups responded well to therapy and CR-treated patients were found to score better in terms of measures of activities of daily living (Dupont et al., 1996; Block et al., 1997), there was no significant difference regarding the primary endpoints between both treatment groups: About 20% of patients presented with motor complications after 5 years of continuous treatment. Thus, compared to standard levodopa, CR levodopa has not proven to be efficacious in preventing or delaying the development of motor complications.
32.10. Dopamine-enhancing agents 32.10.1. Monoamine oxidase-B inhibitors To increase central dopaminergic availability and to extend levodopa half-life, different agents that block the breakdown of levodopa and dopamine have been introduced into clinical practice. One therapeutic principle to block the biotransformation of dopamine is the selective inhibition of MAO-B (see section 32.2.2 this chapter and Ch. 34). MAO-B inhibitors block the deamination of residual endogenous dopamine as well as dopamine synthesized from externally administered levodopa. However, several other mechanisms, including reuptake inhibition and action on presynaptic autoreceptors, are involved in the enhancement of dopaminergic neurotransmission by MAO-B inhibitors (Riederer et al., 1978). Selegiline and rasagiline are both irreversible inhibitors of
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MAO-B with mild antiparkinsonian effects when used as monotherapy or in conjunction with levodopa in early PD (Parkinson Study Group, 1989, 2002b; Pahwa et al., 1993; Lees, 1995; Block et al., 1997; Iwase et al., 2000) as well as in fluctuating patients (Rabey et al., 2000; Parkinson Study Group, 2005; Rascol et al., 2005). Furthermore, there is evidence that the use of MAO-B inhibitors may delay the need for dopaminergic therapy (Parkinson Study Group, 1989). Whether this results from mild symptomatic effects of MAO-B inhibition or rather from neuroprotective, PD progression-delaying effects, as suggested by recent studies (Olanow et al., 1995; Parkinson Study Group, 2004c), is debated. For a more indepth evaluation of MAO-B inhibitors in the treatment of PD, see Chapter 34. 32.10.2. Catechol-O-methyltransferase inhibitors Another therapeutic principle that aims at the enhancement of externally administered levodopa is the inhibition of COMT. Levodopa is mainly metabolized by AADC and COMT and, when administered orally, only about 1% reaches the CNS to supplement missing dopamine in PD (see section 32.3). The previous introduction of AADC inhibitors blocked one of the main metabolic pathways, allowing a dramatic levodopa dose reduction of up to 75%. By further blocking the remaining major peripheral metabolic pathway (COMT), central levodopa bioavailability could be significantly further increased. Two different COMT inhibitors, tolcapone and entacapone, have been approved in the 1990s as adjunctive therapy to levodopa. Both agents have been shown to result in more CDS with potentiated and prolonged clinical effects of each single dose of levodopa. 32.10.2.1. Catechol-O-methyltransferase inhibition: pharmacokinetics and dynamics Both COMT inhibitors are rapidly absorbed and their Cmax is reached within less than 2 hours (Keranen et al., 1994; Dingemanse et al., 1995b; Jorga, 1998a). Oral bioavailability is about 60% for tolcapone (Jorga et al., 1998b) and between 30% and 46% for entacapone (Keranen et al., 1994; Heikkinen et al., 2001). Cmax and AUC are higher for tolcapone (Keranen et al., 1994; Dingemanse et al., 1995b). Entacapone and tolcapone are highly protein-bound (98% and 99.9%, respectively). At therapeutic oral doses (see Table 32.6) both COMT inhibitors have an elimination half-life between 1.6 and 3.4 hours (Keranen et al., 1994; Dingemanse et al., 1995b; Jorga et al., 1998b; Heikkinen et al., 2001). Tmax upon oral administration of 100 or 200 mg is 0.6 or 0.7 hours for entacapone
(Keranen et al., 1994; Heikkinen et al., 2001) and 1.7 and 1.8 hours for tolcapone (Dingemanse et al., 1995b; Jorga et al., 1998b). Both agents are highly metabolized and only 0.5% of an oral dose is excreted with the urine. Degradation is primarily via hepatic glucuronidation. Tolcapone is primarily eliminated via the biliary route and about 40% of orally administered doses is excreted in the feces (Wikberg et al., 1993b; Jorga et al., 1999; Heikkinen et al., 2001; Valeant Pharmaceuticals International, 2006). Entacapone is almost entirely glucuronized in the liver and eliminated by the kidneys and via the biliary route, undergoing enterohepatic circulation (Wikberg et al., 1993a; Jorga et al., 1998b; Heikkinen et al., 2001). Pharmacokinetics of both COMT inhibitors is not significantly affected by co-administration of levodopa and AADC inhibitors (Dingemanse et al., 1995b; Smith et al., 1997). There is no difference in pharmacokinetics between healthy young and old subjects and PD patients and no accumulation in plasma takes place during chronic administration of both COMT inhibitors (Dingemanse et al., 1995b; Jorga et al., 1997). Elimination half-life for entacapone is shorter than for tolcapone (0.4–0.7 hours (Keranen et al., 1994; Heikkinen et al., 2001) and 2–3 hours (Jorga, 1998a), respectively). Entacapone is not lipophilic and does not cross the blood–brain barrier. It thus exerts its effects on COMT only peripherally (Nutt, 1998; Troconiz et al., 1998). In contrast, tolcapone is able to penetrate the blood–brain barrier, as shown in rodents and monkeys (Zurcher et al., 1990), as well as by 18F-dopa PET imaging in PD patients (Ceravolo et al., 2002). Nevertheless, the main clinical effects of both drugs are thought to be mediated by peripheral actions (Nutt, 2000). Entacapone and tolcapone inhibit COMT in a dosedependent fashion (Jorga, 1998b). Compatible with their pharmakokinetic differences, COMT inhibition differs between entacapone and tolcapone. As reflected by inhibition of COMT activity in red blood cells, a measure of peripheral COMT inhibition, 200 mg entacapone inhibits COMT by 60% at peak plasma concentration and by 10% 4 hours after administration. In contrast, 200 mg tolcapone inhibits COMT by 80% at peak plasma concentration and by 70% 4 hours after intake (Jorga, 1998b). The effects of both entacapone and tolcapone on COMT are fully reversible, as studied in in vitro models (Lotta et al., 1995; Borges et al., 1997). COMT is recovered within 8 hours (entacapone) and 16 hours (tolcapone), respectively (Keranen et al., 1994; Dingemanse et al., 1995b). COMT-inhibitory effects do not decrease after repeated administration (Dingemanse et al., 1996; Ruottinen and Rinne, 1996a; Jorga et al., 1997) and are maintained independently of PD progression (Ruottinen and Rinne, 1996a).
LEVODOPA 32.10.2.2. Effects of catechol-O-methyltransferase inhibitors on levodopa pharmacokinetics Both COMT inhibitors increase the AUC without increasing Cmax for levodopa, as shown in healthy volunteers when administered as single doses of 100 or 200 mg (Keranen et al., 1993; Dingemanse et al., 1995a; Sedek et al., 1997) and PD patients (Myllyla et al., 1993; Roberts et al., 1993; Nutt et al., 1994; Tohgi et al., 1995; Ruottinen and Rinne, 1996b). Data obtained in healthy volunteers after administration of 200 mg entacapone or tolcapone revealed increases of AUC by 40% or 80%, suggesting better clinical efficacy for tolcapone (Keranen et al., 1993; Jorga et al., 1997; Sedek et al., 1997). Single doses of entacapone and tolcapone prolong levodopa half-life in PD patients by 20–80% (Myllyla et al., 1993; Roberts et al., 1993; Nutt et al., 1994; Tohgi et al., 1995; Ruottinen and Rinne, 1996b; Sedek et al., 1997). Moreover, repeated administration of COMT inhibitors leads to smoothening of levodopa plasma concentration (Rouru et al., 1999). After repeated administration, the AUC of levodopa is increased (by 25–50%) and levodopa trough levels increase (Keranen et al., 1993; Nutt et al., 1994; Dingemanse et al., 1995b; Jorga et al., 1997). Increases of AUC appear to be mildly smaller and elimination half-life shorter after administration of 200 mg entacapone compared to 200 mg tolcapone (Kaakkola, 2000). Long-term treatment of 8 weeks by 600 mg/day of tolcapone and 1200 mg/day of entacapone correspondingly increased the AUC by 33% and 43%, respectively (Nutt et al., 1994; Yamamoto et al., 1997; Kaakkola, 2000). Even though Cmax is not increased after single-dose administration, repeated doses will increase Cmax (Nutt et al., 1994), which may be explained by the fact that levodopa plasma concentrations at the end of each dose interval are higher with COMT inhibition (Nutt, 2000). When entacapone is administered with standard levodopa or CR levodopa, the AUC increased for both formulations (Ahtila et al., 1995; Piccini et al., 2000). Again, when co-administered with CR levodopa, the efficacy of a single dose of 200 mg tolcapone was higher, with an increase of AUC by 70% compared to a 20% increase after 200 mg entacapone (Ahtila et al., 1995; Jorga et al., 1998a). Increased central dopamine availability by COMT inhibition is reflected in studies using fluoro-dopa (FD)-PET. Both entacapone and tolcapone plus fluorodopa in conjunction with an AADC inhibitor increased striatal fluorodopa uptake significantly (Sawle et al., 1994; Routtinen et al. 1995; Ceravolo et al., 2002). This is compatible with an enhancement of striatal dopamine, as shown by microdialysis in rats (for entacapone, see Kaakkola and
55
Wurtman, 1993; Tornwall et al., 1994; for tolcapone, see Acquas et al., 1992; Napolitano et al., 1995). 32.10.2.3. Clinical effects of catechol-Omethyltransferase inhibition 32.10.2.3.1. Effects in patients with motor fluctuations Several prospective, double-blind placebo-controlled clinical trials assessed the effects of the COMT inhibitors tolcapone and entacapone as add-on to levodopa on motor fluctuations (entacapone: Parkinson Study Group, 1997; Rinne et al., 1998a; Myllyla et al., 2001; Poewe et al., 2002a; Brooks et al., 2003; tolcapone: Baas et al., 1997; Kurth et al., 1997; Myllyla et al., 1997; Rajput et al., 1997; Adler et al., 1998). Primary efficacy measures were daily ‘on’ and ‘off’ time. Table 32.6 reports the outcome for treatment with either 100 or 200 mg tolcapone or 200 mg entacapone. ‘On’ time in all studies was significantly increased by 5–15%. Compatible with this, ‘off’ time was reduced between 10 and 22%. Improvements were found to be more profound in patients treated with tolcapone. All studies report that levodopa doses could be decreased by 12–29%, again with higher dose reduction in tolcaponetreated patients. These differences are compatible with the pharmacological properties of both agents. However, based on the differences in observational periods, with longer study durations for entacapone, it cannot be excluded that higher efficacy measures for tolcapone at least partially result from a higher impact of placebo effects early during the trial and loss of efficacy in the entacapone-treated patients who were observed longer (Nutt, 2000). 32.10.2.3.2. Catechol-O-methyltransferase inhibition to prevent dyskinesias Apart from its role as levodopa adjunct in the treatment of motor fluctuations, COMT inhibitors have been implicated in the delay of the development of dyskinesias. Long-term treatment with levodopa has been shown to be associated with motor complications, including wearing off and dyskinesias. Although the pathophysiological basis of these complications is incompletely understood, current pathophysiological and clinical evidence suggests that the half-life of dopaminergic agents substantially contributes to the development of dyskineseas (see section 32.7.4). The administration of levodopa with its short pharmacological half-life of about 1.5 hours and pulsatile receptor stimulation is therefore thought to be a major risk factor for the early development of dyskinesias (Smith et al., 2003). Based on these considerations it has been postulated that more continous dopaminergic stimulation by an extension of the
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Table 32.6 Effects of catechol-O-methyltransferase (COMT) inhibitors on ‘on’ and ‘off’ time in fluctuating patients
Study Entacapone (200 mg with each LD dose) Parkinson Study Group (1997) Rinne et al. (1998) Brooks et al. (2003) Poewe et al. (2002) Tolcapone Adler et al. (1998) (100 mg/200 mg) Rajput et al. (1997) (100 mg/200 mg) Baas et al. (1997) (100 mg/200 mg) Kurth et al. (1997) (50 mg/200 mg)
Number of patients on COMT inhibitor
Study duration (months)
Change in ‘on’ time*
Change in ‘off’ time*
Change in daily levodopa dose
103 85 115 172
6 6 6 6
1.0 1.4 1.3 1.7
NR –1.3 h –1.1 h –1.6 h
–100 mg –87 mg –33 mg –54 mg
69/74
1.5
2.1 h/2.3 h
–2h/–2.5h
–186 mg/–252 mg
69/67
3
NR
–2.3h/–3.2h
–166 mg/–207 mg
60/59
3
2.6 h/2.6 h
–3.0h/–2.4h
–108 mg/–122 mg
41/40
1.5
0.9 h/0.3 h
–1.7h/–1.3h
–139 mg/–200 mg
h h h h
*Change in time as a percent of waking day. NR, not reported.
levodopa half-life by co-administration of COMT inhibition may delay or prevent the development of dyskinesias. Indeed, experimental evidence obtained in MPTP-treated monkeys revealed that the co-adminstration of levodopa and entacapone resulted in significantly less severe dyskinesias compared to levodopa-only treatment (Smith et al., 2005). Interestingly, and in support of the hypothesis that pulsatile stimulation contributes to the establishment of dyskinesias, this effect was only present when the levodopa/entacapone were administered four times daily. When levodopa/entacapone were administered only twice daily, there was no difference in dyskinesia rate compared to levodopa-only treatment. In another study by the same group, the combination of entacapone with levodopa resulted in even more rapid appearance of dyskinesias (Smith et al., 2003) when administered twice daily. Currently, clinical trials in patients with early PD test the notion that more frequent dosing and the coadministration of entacapone may delay the development of dyskinesias. 32.10.2.4. Side-effects of catecholO-methyltransferase inhibitors The side-effect profile of entacapone and tolcapone is in general favorable. Safety data reported here are derived from the mentioned controlled phase III entacapone and tolcapone studies (Table 32.7). Compatible with their levodopa-enhancing effects, side-effects of
both entacapone and tolcapone are primarily associated with dopaminergic overstimulation and may present as dyskinesia, nausea, vomiting and hallucinations. Moreover, non-dopaminergic side-effects such as diarrhea, abdominal pain, constipation, urine discoloration and fatigue have been reported for both agents and liver toxicity for tolcapone only. 32.10.2.4.1. Dopaminergic side-effects Dopaminergic side-effects usually develop early during treatment. The most common dopaminergic sideeffects are dyskinesias, which most often present in the form of peak-dose dyskinesias. Treatment with both COMT inhibitors presented with significantly higher incidence of dyskinesia compared to patients on placebo. Differences in percentage of patients reporting dyskinesias as adverse event varied between 7% and 47% depending on the study. Predictors for the development of dyskinesias are pre-existing dyskinesias and higher doses of levodopa (Poewe et al., 2002a; Reinikainen et al., 2002). Dyskinesias can usually be managed successfully by reducing the amount of levodopa per dose, by increasing the dose intervals or both (Poewe et al., 2002a; Brooks et al., 2003). Nausea has been reported to be the second most important dopaminergic side-effect. It also emerges during the first days of treatment. Nausea developed in about 13–23% of patients treated with entacapone
LEVODOPA
57
Table 32.7 Incidence of the more frequent side-effects in controlled clinical trials assessing the effects of tolcapone1 or entacapone2 against placebo
Agent n Side-effects Dyskinesia Nausea Diarrhea Dizziness Hallucination Vomiting Constipation Fatigue Abdominal pain Urine discoloration
Tolcapone (100 mg t.i.d.)
Tolcapone (200 mg t.i.d.)
Placebo
Entacapone
Placebo
296
298
298
603
400
42 30 16 13 8 8 6 7 5 2
51 35 18 6 10 10 8 3 6 7
20 18 8 10 5 4 5 6 3 1
25 14 10 8 4 4 6 6 8 10
15 8 4 6 4 1 4 4 4 0
Numbers indicate percentage of patients. 1 Valeant Pharmaceuticals International (2006). 2 Novartis Pharmaceuticals Corporation (2000). Adapted from Kaakkola (2000) and modified and updated.
(Parkinson Study Group, 1997; Rinne et al., 1998a; Brooks, 2004) and in about 30% of patients treated with tolcapone (Baas et al., 1997; Kurth et al., 1997; Rajput et al., 1997; Waters et al., 1997; Brooks, 2004). Again, adjustment of the overall levodopa dose usually allows control of this side-effect (Brooks, 2004). Interestingly, the incidence of neuropsychiatric sideeffects after introduction of COMT inhibitors is rather low. However, in an open-label extension study (Larsen et al., 2003), 19 out of 132 patients (14.4%) of patients treated with entacapone developed hallucinations. There is evidence that single patients, in particular elderly patients, may be more vulnerable to confusion and hallucinations when treated with entacapone (Henry and Wilson, 1998). 32.10.2.4.2. Non-dopaminergic effects In contrast to dopaminergic side-effects, non-dopaminergic adverse events were reported to occur throughout the entire study period. The most important non-dopaminergic side-effect is diarrhea. Diarrhea usually did not occur during the first days of treatment. Diarrhea in clinical trials was more frequent in patients receiving tolcapone (16–18%) than in patients treated with entacapone (8–20%). In tolcapone-treated patients, severe explosive diarrhea led to treatment discontinuation in 8–10% of patients (Baas et al., 1997; Kurth et al., 1997; Rajput et al., 1997), whereas only 1–4% receiving entacapone discontinued treatment for diarrhea (Rinne et al., 1998a; Poewe et al., 2002a; Brooks et al., 2003). The underlying pathophysiological mechanism leading to diarrhea is unknown. Even though it appears as if
diarrhea is a class effect of the COMT inhibitors, it is not clear why frequency and severity are clearly more pronounced for tolcapone. However, an association with levodopa/AADC inhibitor treatment seems unlikely, since diarrhea is also induced when tolcapone is administered without levodopa (Hauser et al., 1998). Another frequent side-effect emerging in 7–37% of patients is discoloration of urine to dark yellow or reddish brown, which is harmless but worrisome to patients who were not previously informed about it. A rare but more serious side-effect associated with tolcapone treatment is liver toxicity (Brooks, 2004). Tolcapone-treated patients in phase III trials developed clinically relevant increases of liver enzymes and 3% of patients had to discontinue the study (Brooks, 2004). After tolcapone was approved by regulative authorities, 4 out of 60 000 patients receiving tolcapone developed severe liver dysfunction, which was fatal in 3 patients (Assal et al., 1998; Olanow, 2000). One of these 3 patients died despite adequate liver function laboratory monitoring. In consequence tolcapone was withdrawn from the European and Canadian markets. In the US, the use of tolcapone was restricted to patients who experience motor fluctuations refractory to other treatments and who show no clinical evidence of liver disease or two serum glutamic-pyruvic transaminase (SGPT/ ALT) or serum glutamic-oxaloacetic transaminase (SGOT/AST) values greater than the upper limit of normal. Furthermore, in patients treated with tolcapone, serum SGPT/ALT and SGOT/AST levels should be determined at baseline and periodically (i.e. every 2–4
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weeks) for the first 6 months of therapy. After the first 6 months, periodic monitoring is recommended at intervals deemed clinically relevant. Tolcapone should be discontinued if SGPT/ALT or SGOT/AST levels exceed two times the upper limit of normal or if clinical signs and symptoms suggest the onset of hepatic dysfunction. Finally, patients who fail to show substantial clinical benefit within 3 weeks of initiation of treatment should be withdrawn from tolcapone (Valeant Pharmaceuticals International, 2006). All five mentioned phase III entacapone trials reported occasionally elevations of liver enzymes (Gordin et al., 2003). However, a clear association with entacapone treatment could not be established. Furthermore, these studies did not report instances of serious liver dysfunction. One report, however, describes 3 patients who received entacopone and developed symptopmatic liver dysfunction which improved after withdrawal (Fisher et al., 2002). Interpretation of these cases is complicated by several factors, including poor documentation and lack of rechallenge with tolcapone, multimorbidity of patients and polypharmacy. Thus, the diagnosis of entacapone-induced liver dysfunction is probable, although not proven (Brooks, 2004). Apart from these cases, no further evidence for liver toxicity has been presented and indeed more than 300 000 patient-years of entacapone exposure were not reported to be associated with liver dysfunction. Presently, the liver toxicity seen in COMT inhibitortreated patients may therefore not be interpreted as a COMT inhibitor class effect, but rather a problem associated with tolcapone. Compatible with this view, there are important pharmacological differences between both agents. Tolcapone has a much higher lipid solubility, which may enhance penetration in mitochondrial inner membrane (Nissinen et al., 1997). Furthermore, in contrast to entacapone, tolcapone may uncouple oxidative phosphorylation. On the other hand, entacopone is nearly entirely glucuronized (Wikberg et al., 1993a; Lautala et al., 2000), whereas talcapone is glucuronized but also methylated and oxidized (Jorga et al., 1998c). Both factors may be important for the putative toxicity of tolcapone. In summary, due to its safety profile, entacapone is clearly the first-line COMT inhibitor. However, due to its superior efficacy in the control of motor complications, tolcapone may be considered for selected patients in whom entacapone or other therapeutic measures do not allow sufficient symptom control, provided the required safety monitoring is ensured (Factor et al., 2001; Onofrj et al., 2001).
32.11. Conclusion and practical implications for the use of levodopa Levodopa revolutionized the symptomatic treatment of one of the most prevalent progressive degenerative
diseases. However, since its approval by the FDA in 1970, several other pharmacological compounds mimicking the effects of dopamine or enhancing levodopa availability have been introduced. Compared to newer agents and, in particular, dopamine agonists, levodopa is still the most efficacious drug, as revealed by consistently better symptom control measured by the UPDRS (Rascol et al., 2000; Parkinson Study Group, 2004b). Compatible with this, even though dopamine agonists allow symptoms to be satisfactorily controlled during the first years of disease, eventually nearly all dopamine agonist-treated patients need levodopa supplementation. The particular role of levodopa is further substantiated by its favorable side-effect profile (Table 32.2 and see Ch. 33). Apart from its symptomatic clinical effects and sideeffects, the impact of levodopa therapy on the disease process has been the subject of considerable controversy and neuroprotective effects as well as toxic effects have been examined widely. However, to date, there is no convincing evidence for toxic effects of levodopa in humans. Recent data even show some controversial evidence for mild neuroprotective effects of levodopa therapy (Parkinson Study Group, 2004a). However, after more than 30 years of experience with levodopa, the limitations and shortcomings of levodopa therapy also became evident. A wealth of data indicated that long-term levodopa treatment contributes to the early development of motor complications and in particular dyskinesias (see section 32.7.4 and Tables 32.4 and 32.5). Today it is estimated that, after 5 years of levodopa treatment, between 20 and 50% of patients have developed motor complications, including dyskinesias and on–off fluctuations, whereas the incidence of motor complications in dopamine agonist-treated patients is significantly lower (5–10%). These observations led to a reassessment of the role of levodopa in symptomatic PD therapy and in particular the debate of when and how to initiate dopaminergic therapy. Based on the potential of levodopa to induce longterm motor complications and the lack of evidence for neuroprotection, there is presently no rationale for treating patients with early PD without functional deficits relevant to activities of daily living and quality of life with levodopa. Instead, based on preliminary clinical evidence for their mild neuroprotective potential, MAO-B inhibitors (Ch. 34) or coenzyme Q10 (Ch. 31) may be tried. In patients with minor symptoms and a need for treatment, less potent non-dopaminergic agents such as MAO-B inhibitors or amantadine (Ch. 36) can be tried. In patients with more pronounced symptoms needing symptomatic improvement, dopaminergic agents have to be employed. Based on the potential of levodopa to
LEVODOPA induce motor complications early, current treatment algorithms often recommend that the use of levodopa be spared until necessary to control motor symptoms satisfactorily (Olanow et al., 2001). Instead, dopamine agonists are recommended as initial treatment. However, the question of which is the best strategy to initiate treatment is controversial. There is general agreement that motor complications compromise patients’ functionality and well-being. Nevertheless, in the several controlled studies which compare dopamine agonists and levodopa and which demonstrate superiority of dopamine agonists in terms of delay of motor complications, no difference was found on quality of life and activity of daily living measures (Rinne et al., 1998b; Rascol et al., 2000; Parkinson Study Group, 2004b). Moreover, the use of dopamine agonists may be limited due to their side-effect profile, in particular in vulnerable patients where levodopa, as the generally best tolerated dopaminergic drug, should be considered. Furthermore, dopamine agonists also have the potential to induce motor complications, although precise data on the temporal profile and exact incidence are as yet unknown (Jenner, 2003). Further, there is some evidence that establishment of motor complications is reversible (Jenner, 2002). No controlled study ever assessed whether patients who were initially treated with a dopamine agonist and who received levodopa later on are doing better in terms of motor functions, activities of daily living and quality of life than patients who were initially treated with levodopa and developed motor complications early in the disease and then received a dopamine agonist as add-on in order to control the motor complications via more CDS. Based on these considerations, the more favorable side-effect profile and its higher efficacy, levodopa administration may be also considered a rational choice for individual patients, even in earlier stages of disease progression. This holds in particular for older de novo patients with less risk for the development of motor complications than patients with early onset of PD. In conclusion, although it is now more than 30 years after the introduction of levodopa, pharmacological PD therapy in the beginning of the 21st century involves in most patients who have access to the full armamentarium of PD therapy a complex, growing array of agents that is usually continuously modified in the course of disease progression. For most patients levodopa sooner or later is indispensable for satisfactory symptom control. Finally, apart from new modes of administration, recent conceptual developments may again lead to changes in current therapeutic thinking. For example, based on the concept of CDS, clinical trials currently evaluate whether the combined administration of
59
levodopa and a COMT inhibitor may be able to prevent or delay the development of motor complications. Thus, the development of levodopa therapy in PD as one of the few true success stories in the treatment of a neurodegenerative has by no means come to an end.
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Handbook of Clinical Neurology, Vol. 84 (3rd series) Parkinson’s disease and related disorders, Part II W. C. Koller, E. Melamed, Editors # 2007 Elsevier B. V. All rights reserved
Chapter 33
Dopamine agonists OLIVIER RASCOL1,2*, TARIK SLAOUI2, WAFA REGRAGUI2, FABIENE ORY-MAGNE2, CHRISTINE BREFEL-COURBON1,2 AND JEAN-LOUIS MONTASTRUC1 1
Department of Clinical Pharmacology, Clinical Investigation Center, University Hospital, Toulouse, France 2
Department of Neurosciences, University Hospital, Toulouse, France
The discovery of a dopaminergic deficit in the nigrostriatal pathway of patients with Parkinson’s disease led to the introduction of levodopa therapy (Birkmayer and Hornykiewicz, 1970). After 40 years, levodopa remains the ‘gold-standard’ antiparkinsonian treament. Nevertheless, the initial good therapeutic efficacy of levodopa is often confounded within a few years of the start of treatment by the development of motor complications (fluctuations, abnormal movements) and other problems (Marsden et al., 1987; Nutt, 1990; Rascol et al., 2003). Because of these limitations, the treatment of patients with Parkinson’s disease has expanded to incorporate additional pharmacologic approaches. Among these other therapeutic options, dopaminereceptor agonists are widely used. This chapter will focus on the use of dopamine agonists as antiparkinsonian medications. It will not cover their role in the treatment of other movement disorders, such as the restlesslegs syndrome (Happe and Trenkwalder, 2004; Hening et al., 2004). Bromocriptine was the first agonist to be indicated as an adjunct to levodopa therapy for patients with Parkinson’s disease experiencing motor fluctuations (Calne et al., 1974). There are now nine different dopamine agonists presently approved and marketed for the treatment of Parkinson’s disease: apomorphine, bromocriptine, cabergoline, dihydroergocryptine, lisuride, pergolide, piribedil, pramipexole and ropinirole (alphabetical order). Among these nine dopamine agonists, five are ergot derivatives (bromocriptine, cabergoline, dihydroergocryptine, lisuride and pergolide) whereas the four others are not (apomorphine, piribedil, pramipexole and ropinirole). All are used as oral medications, except apomorphine, *
which is used as subcutaneous injections or infusions. All share the property of binding to the D2-like family of dopamine receptors (D2, D3, D4). All have specific pharmacodynamic and pharmacokinetic profiles (Montastruc et al., 1993; Uitti and Ahlskog, 1996; Deleu et al., 2002). There are many randomized controlled trials (RCTs) and a large body of clinical experience to support the usefulness of dopamine agonists in the treatment of Parkinson’s disease. However several issues remain a matter of controversy. Among these, important ones are the place of the agonists (as a class) in the global strategy of Parkinson’s disease therapy (before or after levodopa) and the potential advantages or disadvantages of a given agonist versus another one.
33.1. Pharmacological properties of dopamine agonists 33.1.1. Pharmacokinetic properties (for review, see Deleu et al., 2002; Tintner and Jankovic, 2003) 33.1.1.1. Absorption and bioavailability Most dopamine agonists, except apomorphine, are absorbed orally. The systemic bioavailability of the ergot agonists is low, due to an extensive first-pass hepatic metabolism. This is also true for piribedil. Because of poor oral absorption and low bioavailability, apomorphine is only used via the subcutaneous route. The second generation of non-ergot agonists, including pramipexole and ropinirole, has a better bioavailability (Table 33.1). The usually recommended range of daily doses for the different dopamine agonists is listed in Table 33.1. Rotigotine, a dopamine agonist designed
Correspondence to: Professor Olivier Rascol, Clinical Investigation Center, Department of Clinical Pharmacology and Department of Neurosciences, Faculty of Medicine, 37 Alle´es Jules Guesde, Toulouse 31073, France. E-mail:
[email protected], Tel: þ33-(0)-5-61-14-5962, Fax: þ33-(0)-5-61-25-5116.
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Table 33.1 Main pharmacokinetic and pharmacodynamic (binding) properties of dopamine agonists Binding affinity Agonists Apomorphine Bromocriptine Cabergoline Dihydroergocryptine Lisuride Pergolide Piribedil Pramipexole Ropinirole
Recommended daily dose (mg)
Times daily
Oral bioavailability (%)
Elimination half-life (h)
D1-like
D2-like
5-HT
a1
a2
* 10–60 2–6
* 3 1
* 6 50
0.5 3–8 65–110
þþ – 0/þ
þþ þþ þþþ
0/þ þþ þþ
0/þ þþ þþ
þþ þþ þþ
30–120 1–5 1.5–4 150–300 1.5–4.5 6–24
3 3 3 3 3 3
5 10–20 20–50 10 >90 50
15 2–3 20 20 8–12 6–8
þ/– 0/þ þ 0/þ 0/þ 0
þþ þþþ þþþ þþþ þþþ þþþ
þþ þþþ þ 0 0/þ 0
þþ þþþ þþ 0/þ 0/þ 0
þþ þþþ þþ þþ þþ 0
*Subcutaneous route. 5-HT, serotonin.
to be administered transdermally rather than orally, is currently under development for the treatment of Parkinson’s disease (Mucke, 2003; Jenner, 2005; Poewe and Lu¨ssi, 2005; Rascol, 2005). This drug is not yet approved for this indication. 33.1.1.2. Elimination half-life Interest has focused recently in Parkinson’s disease on drug plasma elimination half-lives because continuous dopamine stimulation (CDS) is an appealing hypothesis to explain the development of motor complications (fluctuations and abnormal involuntary movements) that are frequently associated with long-term dopatherapy. According to this theory, levodopa, when administrated orally, is supposed to stimulate in a pulsatile nonphysiological way the striatal dopamine receptors. This induces in turn a cascade of molecular and cellular downstream events that change the basal ganglia outflow and lead to abnormal motor programs (Chase, 1998; Olanow et al., 2000). All orally active dopamine agonists have longer elimination half-lives than levodopa. Apomorphine has the shortest one (30 minutes), but this is overcome in clinical practice when the drug is delivered using continuous subcutaneous pumps (Neef and van Laar, 1999; LeWitt, 2004). The shortest half-life for an orally active agonist is that of lisuride (2–6 hours). Cabergoline has the longest one (65–110 hours) (Fariello, 1998), and the other ones have intermediate half-lives, ranging from 6 to 20 hours (Rascol, 1997; Matheson and Spencer, 2000; Di Marco et al., 2002; Biglan and Holloway, 2002; Blin, 2003; Albanese and Colosimo, 2003; Curran and Perry, 2004) (Table 33.1). Globally,
dopamine agonists are thus supposed to offer a more continuous stimulation of dopamine receptors than levodopa. At present, there is however no convincing evidence that this difference in elimination half-lives correlates with specific efficacy or safety clinical parameters. For example, empirical practice does not suggest that cabergoline, with its long elimination half-life, is more efficacious in reducing the risk of long-term motor complications than lisuride, an agonist with a much shorter elimination half life. The sole practical clinical difference that might be related to elimination half-life is that cabergoline is used once daily to treat the patients, whereas the other agonists are generally used on a t.i.d. regimen. In theory, it is also conceivable that cabergoline-induced adverse drug reactions, such as psychosis for example, could persist for longer periods of time than with other agonists when the drug is withdrawn. Conversely, ‘wearing-off’ effects have been observed in some patients on monotherapy with shorter elimination half-life agonists like ropinirole (F. Stocchi, personal communication). 33.1.1.3. Metabolism and drug interactions (for review, see Pfeiffer, 1996) Ergot derivatives as well as ropinirole and piribedil have an extensive hepatic metabolism. Enzymatic inhibitors, like macrolide antibacterials, have been reported to increase some adverse drug reactions induced by ergot agonists like bromocriptine (Montastruc and Rascol, 1984; Periti et al., 1992). Ropinirole is metabolized extensively by the hepatic microsomal enzyme system (CYP1A2, CYP3A4 and CYP2D6)
DOPAMINE AGONISTS (Kaye and Nicholls, 2000). Ciprofloxacin, which is an inhibitor of CYP1A2, can increase the area under the curve of ropinirole plasma levels. In this case, a dose reduction of the agonist might be considered. Estrogens will decrease ropinirole clearance by about 36%. Conversely, pramipexole, which undergoes minimal hepatic biotransformation and is excreted virtually unchanged in the urine by the renal tubular secretion, is not exposed to such interaction. It is devoid of any CYP interaction. On the other hand, this drug can theoretically lead to potential interactions with drugs excreted by renal tubular secretion (H2-antagonists, diuretics, verapamil, quinidine) and this may require dose adjustment. The same is true in patients with impaired renal function. Apomorphine is partly metabolized by the catechol-O-methyltransferase (COMT) enzyme (LeWitt, 2004). However, no relevant interaction has been reported with a COMT inhibitor such as entacapone (Durif et al., 2004). Overall, there is no evidence that the co-prescription of levodopa with any orally active dopamine agonist will modify the pharmacokinetic properties of any of these compounds and vice versa. 33.1.2. Pharmacodynamics and receptor selectivity 33.1.2.1. Binding to non-dopamine receptors The dopamine agonists that belong to the ergot derivative family (bromocriptine, lisuride, pergolide, cabergoline) have high to moderate affinity for a variety of non-dopaminergic receptors such as a-adrenergic (a1 and a2) and serotonergic (5-HT1 and 5-HT2) receptors (Montastruc et al., 1993; Piercey et al., 1996; Fariello, 1998; Piercey, 1998). These compounds, therefore, are less selective than non-ergot agents like ropinirole, pramipexole and piribedil (Tulloch, 1997; Piercey, 1998) (Table 33.1). It is not clear whether such differences influence clinical outcomes. A drug with actions at noradrenergic or serotonergic receptors might theoretically induce better antiparkinsonian efficacy than selective dopaminergic agents, since the transformation of levodopa into norepinephrine and not solely into dopamine could explain why this drug has such potent symptomatic antiparkinsonian effects. However, acting on non-dopamine receptors could also lead to adverse reactions such as psychosis or dysautonomic symptoms. Clinical studies have not yet provided undisputable evidence to support these assumptions. 33.1.2.2. Relative affinity for dopamine-receptor subtypes Dopamine agonists differ in their relative affinities for D1- and D2-like receptors (Table 33.1). Bromocriptine is a D2-agonist and a weak D1-antagonist (partial ago-
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nist). Apomorphine and pergolide are known as mixed D2- and D1-agonists. Other agonists, such as ropinirole and pramipexole, are reported to be selective D2-like (and preferentially D3-) agonists (Piercey, 1998; Tulloch, 1997) (Table 33.1). Such differences could theoretically have clinical correlates, but the literature is quite controversial on that topic. It has been proposed, for example, that a synergistic activation of both D1and D2-receptors may be necessary to induce a full antiparkinsonian effect (Luquin et al., 1992; Robertson, 1992). According to this theory, mixed D1/D2 agents could then be more potent antiparkinsonian medications than the D2-selective ones. An action at D1-receptors has also been implicated in the genesis of adverse drug reactions, like dyskinesias for example. Some authors have proposed that clozapine, an atypical neuroleptic, could exert antidyskinetic properties because of its antagonistic effects at D1-receptors (Bennett et al., 1994). This claim is however incompatible with the observation that selective D2-agonists can induce dyskinesia by themselves, even in nonprimed levodopa-naive monkeys (Gomez-Mancilla and Bedard, 1992; Luquin et al., 1992) and that the selective D1-agonist, A-86929, has a lower propensity than D2-agonists to induce abnormal movements in the primate model of levodopa-induced dyskinesias (Grondin et al., 1997). However the prodrug of this last compound, ABT-431, induced the same amount of dyskinesias as levodopa when tested in dyskinetic patients with Parkinson’s disease (Rascol et al., 2001). Potentially beneficial effects of preferential selectivity for D3-receptors have also been speculated. The highest concentrations of D3-receptor mRNA are found in the mesolimbic pathways, which are thought to be involved in motivation (Wise and Rompre, 1989). Some psychopharmacologic experiments in animals suggest that D3-agonists might have antidepressant properties (Maj et al., 1997). This led to the proposal that drugs like pramipexole and ropinirole could have antidepressant effects, but clinical evidence is still weak to support this assumption. 33.1.2.3. In vivo antiparkinsonian efficacy of dopamine agonists in experimental models of Parkinson’s disease Most D2-agonists have demonstrated that they can reverse the motor deficit that mimics the motor parkinsonian symptoms in different in vivo models of Parkinson’s disease. This is true for the akinetic syndrome induced in the rodent by reserpine, a dopamine-depleting agent, for the abnormal rotational behavior induced by the unilateral striatal injection of 6-hydroxydopamine in the rat and for the parkinsonian-like motor syndrome induced
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by the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication of various species of primates (Eden et al., 1991; Arai et al., 1995; Domino et al., 1998; Pearce et al., 1998). An intriguing finding in these animal models is that most agonists, when used as monotherapy, are as efficacious as levodopa in reversing the symptoms, whereas in clinical practice, it is common observation that orally active agonists have a less potent symptomatic antiparkinsonian activity than levodopa. The reason for this discrepancy and for the non-predictability of the model on this aspect remains unknown. It may be due to tolerability-related dose limitations in humans. Dopamine agonists induce significantly fewer dyskinesias than levodopa in levodopa-naive MPTPintoxicated monkey (Bedard et al., 1986; Grondin et al., 1996; Pearce et al., 1998). This property, which is also observed in patients with Parkinson’s disease, as long as they have not been previously exposed and ‘primed’ by levodopa for dyskinesias, may result from the long elimination half-life of the agonists, but other mechanisms could also be implicated (see section 33.1.1.2). 33.1.2.4. Neuroprotective properties of dopamine agonists in experimental models of neuronal death Current theories on the pathogenesis of Parkinson’s disease have centered for many years on the formation of reactive oxygen species and the onset of oxidative stress, leading to oxidative damage in the substantia nigra pars compacta (Jenner and Olanow, 1996). Dopamine may produce toxic metabolites, via autooxidation to toxic semiquinones, that lead to the production of reactive oxygen species (Olanow, 1990). Levodopa decarboxylation to dopamine may enhance this phenomenon. For this reason, dopamine agonists, which allow delay and reduction of levodopa needs, have been speculated to have a positive impact on the disease progression. However, levodopa toxicity is highly questioned in vivo and there are no clinical data to support the concept that this drug could accelerate the progression of the disease in patients (Olanow et al., 2004). Independent of levodopa toxicity, there are other reasons why a dopamine agonist might be neuroprotective. Activity at presynaptic dopamine autoreceptors might reduce the amount of dopamine released into the synapse, thus reducing the rate of firing and dopamine turnover in the neuron (Sethy et al., 1997). Several dopamine agonists also have free radicalscavenging activity (Yoshikawa et al., 1994; Hall et al., 1996). In addition, they protect cells in vitro and ex vivo from oxidative damage (Iida et al., 1999; Ogawa et al., 1999) and excitotoxicity and demon-
strate antiapoptotic effects in a variety of cell models (Schapira and Olanow, 2003). In the laboratory, dopamine agonists protect dopaminergic and nondopaminergic neurons from a variety of toxins in both in vitro and in vivo models of parkinsonism (Olanow et al., 1998; Le and Jankovic, 2001; Schapira, 2002). However, to date, none of these promising preclinical data have yet translated into undisputable clinical benefit (see below).
33.2. Clinical trials on dopamine agonists: clinical efficacy in the treatment of Parkinson’s disease Under the auspices of the Movement Disorders Society (MDS), a group of experts that included author O. Rascol of the present chapter has performed an evidence-based systematic review to assess all antiparkinsonian therapeutic interventions. The conclusions of this review are based on the robustness of clinical evidence (Goetz et al., 2002; Rascol et al., 2002) and have recently been updated (Goetz et al., 2005). This MDS review includes, among other interventions, the nine dopamine agonists discussed in this chapter. It extensively summarizes the level of evidence supporting the use of each individual agonist according to a number of different clinical objectives: (1) prevention of disease progression; (2) symptomatic control of parkinsonism as monotherapy; (3) symptomatic control of parkinsonism as adjunct to levodopa; (4) prevention of motor complications; (5) control of motor complications; and (6) management of non-motor complications, each drug being rated according to standardized definitions of ‘efficacy’, ‘safety’ and ‘implications for clinical practice’. The present chapter will synthesize the conclusions of this review and the reader is invited to refer to the original documents for a more comprehensive and detailed description of the methods as well as for an extensive description and citation of the level of evidence, agonist by agonist and trial by trial. These data will be presented here according to the use of dopamine agonists in two clinical situations: (1) the early de novo patient not previously exposed to levodopa; and (2) the patient suffering from more advanced disease and already treated with levodopa. 33.2.1. Evidence for the use of dopamine agonists in levodopa-naive patients with early Parkinson’s disease There are generally three main reasons to consider using a dopamine agonist in this situation: (1) to slow down disease progression; (2) to control the parkinsonian symptoms of the patients; and (3) to reduce the
DOPAMINE AGONISTS risk of motor complications associated with the longterm use of levodopa. 33.2.1.1. Dopamine agonists and the prevention of disease progression Our basic understanding of Parkinson’s disease is that the disorder is caused by the progressive death of dopamine nigrostriatal neurons. It is therefore in the earliest stages of the disease that one expects that the largest number of dopamine neurons remain spared by the pathological process and could be available for neuroprotection. Consequently, neuroprotective strategies are often discussed at this stage. The clinical demonstration that a drug could positively influence the progression of Parkinson’s disease is a major therapeutic challenge. This objective remains an unsolved question. Up to now, even the design of the trials assessing the putative disease-modifying effects of a given drug remains a matter of controversies. There is no way to measure directly neuronal loss in vivo and it is unclear how clinical symptoms correlate with neuronal death. Clinical endpoints, such as measuring the hazard function of early untreated patients to reach the need for symptomatic treatment, are biased by the intrinsic symptomatic antiparkinsonian properties of many drugs, including dopamine agonists. The use of imaging biomarkers which quantify for example the amount of dopamine transporters or the production of dopamine in the striatum with single-photon or positron emission tomography does not allow more definite conclusions because of other potential biases. Bromocriptine, pramipexole and ropinirole have been tested in RCTs specifically designed to assess their potential impact on disease progression (Olanow et al., 1995; Parkinson Study Group, 2002a; Whone et al., 2003). Due to methodological shortcomings, none of these studies produced sufficiently convincing evidence to establish that the drugs had a positive effect on disease progression. It has been reported in two long-term (2–4-year) RCTs comparing pramipexole or ropinirole to levodopa that two different neuroimaging biomarkers of striatal dopaminergic function declined more slowly over time in patients treated with an agonist than in those who received levodopa. This can be interpreted as an indirect index of a neuroprotective effect. However, in these trials, the same patients had a better clinical outcome on levodopa than on agonists. Moreover, it was impossible to disentangle in these studies if: (1) the imaging differences were due to a faster decline of the biomarker on levodopa or to a slower one on the agonist; and if (2) the difference was related or not to a more pronounced downregula-
77
tion of the biomarker by levodopa than by the agonists (Schapira and Olanow, 2004). In summary, according to these findings, neuroprotection remains an unmet need in Parkinson’s disease. In spite of a seducing rationale, there is not strong enough evidence definitely to recommend the use of a dopamine agonist for this purpose in clinical practice. This remains an investigational topic. Interestingly, in line with this negative conclusion, the few available controlled data assessing mortality after 10 years of follow-up showed that the early use of an agonist like bromocriptine rather than levodopa in Parkinson’s disease patients did not improve patients’ life expectancy (Hely and Morris, 1999; Lees et al., 2001; Montastruc et al., 2001a). No data are available with other agonists. 33.2.1.2. Dopamine agonists as monotherapy and the symptomatic control of parkinsonian symptoms Parkinsonism (tremor, bradykinesia and rigidity) is the core of the clinical syndrome of Parkinson’s disease. It progressively causes motor disability in patients with early Parkinson’s disease who are not already on levodopa. A dopamine agonist used as initial monotherapy can be proposed to control such symptoms and there are a number of RCTs to support this property. Such RCTs are usually parallel short-term (6-month) comparisons with placebo or an active comparator (levodopa or another agonist). The most widely standardized scale used to assess parkinsonism in these trials is the Unified Parkinson’s Disease Rating Scale (UPDRS) (Fahn et al., 1987). 33.2.1.2.1. Randomized controlled trials comparing agonist monotherapy versus placebo (Table 33.2) There is at least one good-quality RCT and sometimes several to support the efficacy of dihydroergocryptine (Bergamasco et al., 2000), pergolide (Barone et al., 1999), pramipexole (Shannon et al., 1997) and ropinirole (Adler et al., 1997) on parkinsonism in early Parkinson’s disease (for a complete list of references, see the MDS evidence-based review: Goetz et al., 2002, 2005; Rascol et al., 2002). Pergolide is no longer used as a first-line agonist for safety reasons (see section 33.3). There is less convincing but still supportive evidence for bromocriptine. This conclusion is mainly based on levodopa-controlled RCTs showing, as a secondary endpoint, that the drug was as efficacious as levodopa (Riopelle, 1987; Montastruc et al., 1994) (although these studies were not powered to demonstrate non-inferiority) or only slightly less efficacious (in a proportion suggesting that ‘the difference in functional improvement was not important enough to
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Table 33.2 Level of evidence supporting the efficacy of the different dopamine agonists in levodopa-naive patients with early Parkinson’s disease based on the conclusions of the Movement Disorders Society evidence-based review (see Goetz et al., 2002, 2005; Rascol et al., 2002)
Agonists
Disease progression
Symptomatic control of parkinsonism
Prevention of motor complications
Apomorphine* Bromocriptine Cabergoline Dihydroergocryptine Lisuride Pergolide{ Piribedil Pramipexole Ropinirole
Insufficient Insufficient Insufficient
Not used Likely Insufficient
Not used Likely Efficacious
Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient
Efficacious Likely Efficacious Insufficient Efficacious Efficacious
Insufficent Insufficient Insufficient Insufficient Efficacious Efficacious
*Apomorphine is not used in early Parkinson’s disease because it is only active via the subcutaneous route. { Pergolide cannot be recommended as a first-line treatment for early Parkinson’s disease because of the risk of valvular heart disorder. Efficacious, positive effect of the agonists on studied outcomes in at least one high-quality randomized controlled trial (RCT) and no conflicting data from other RCT(s); likely, efficacy likely, i.e. evidence suggests, but is not sufficient to show, that the agonist has a positive effect on studied outcomes, based on any RCT and no conflicting data from other RCTs; insufficient, insufficient evidence, i.e. there are no data or available data do not provide enough evidence either for or against the use of the agonist.
suggest that the choice of the treatment was critical within the first 3 years of follow-up’; Parkinson’s Disease Research Group of the United Kingdom, 1993). The same is true for cabergoline (Rinne et al., 1997, 1998). There are only open-label studies to support the effect of lisuride (Rinne, 1989) and piribedil (Rondot and Ziegler, 1992) in early Parkinson’s disease. Apomorphine, being only used subcutaneously, has never been tested as monotherapy for the treatment of Parkinson’s disease at this early stage. 33.2.1.2.2. Randomized controlled trials comparing agonist monotherapy versus levodopa Levodopa is more efficacious than any orally active dopamine agonist monotherapy. This common clinical practice observation is documented in RCTs assessing agonists like cabergoline (Rinne et al., 1997), pramipexole (Parkinson Study Group, 2000), ropinirole (Rascol et al., 1998) and bromocriptine (Parkinson’s Disease Research Group of the United Kingdom, 1993; Olanow et al., 1995). There are no published levodopa-controlled head-to-head RCTs with the other agonists. The proportion of patients with early Parkinson’s disease capable of remaining on agonist monotherapy falls progressively over years to less than 20% after 5 years of treatment with bromocriptine (Parkinson’s Disease Research Group of the United Kingdom, 1993; Montastruc et al., 1994), cabergoline (Rinne et al., 1998), pramipexole (Parkinson Study Group,
2000) and ropinirole (Rascol et al., 2000). For this reason, after some years of treatment, most patients who start on an agonist will receive levodopa as a replacing or an adjunct treatment to keep control on the motor parkinsonian syndrome. The optimal timing when combining both drugs has never been assessed. In the last decade, the most frequently tested strategy has been to start with an agonist and to postpone the adjunction of levodopa as late as possible as a second step of the therapeutic strategy. However, in the previous decade, it was common practice to combine early an agonist like bromocriptine or lisuride with levodopa within the first months of treatment (early combination strategy) (Przuntek et al., 1996; Allain et al., 2000). There are no data to assess if one strategy is better than the other one. 33.2.1.2.3. Randomized controlled trials comparing an agonist monotherapy versus another agonist There are only few trials comparing the efficacy of a dopamine agonist versus that of another one as monotherapy. When such data are available (bromocriptine versus ropinirole (Korczyn et al., 1998, 1999) and versus pergolide (Mizuno et al., 1995), the clinical relevancy of the reported difference, if any, remains questionable, especially since the exact dose equivalence between the different agonists remains unknown. Such drugs should then be considered from a clinical perspective as having basically a comparable efficacy.
DOPAMINE AGONISTS 33.2.1.2.4. Randomized controlled trials comparing an agonist monotherapy versus another antiparkinsonian medication There are no published direct head-to-head comparisons between any agonist monotherapy and other antiparkinsonian medications in early Parkinson’s disease (monoamine oxidase-B (MAO-B) inhibitors, amantadine, anticholinergics). The changes in UPDRS scores reported in placebo-controlled RCTs are usually greater on agonists than on MAO-B inhibitors (Parkinson Study Group, 1989, 2002b). This could be interpreted as an indirect indication of a greater symptomatic efficacy of the agonists, but one cannot firmly establish if this putative difference is of clinical importance. 33.2.1.3. Prevention of motor complications The incidence of motor complications is 10% per year on levodopa therapy. Over time, they usually become more disabling and difficult to manage. Symptomatic control of symptoms is therefore not the only factor to be considered when initiating an antiparkinsonian treatment and doctors and patients are also often interested in considering the impact of an initial therapeutic strategy on the incidence of long-term motor complications. The strategy of using early a dopamine agonist and to keep levodopa as a second-line rescue medication to delay the problem of motor complication has been a growing matter of interest in the last decade. Several RCTs compared the probability of developing motor complications for up to 5 years in previously untreated patients who received an agonist versus levodopa-treated patients. There was no standardized method used to define when a patient began motor complications and each trial used its own definition, with consequent variable numbers from one study to another. 33.2.1.3.1. Randomized controlled trials comparing an agonist monotherapy versus levodopa (Table 33.2) Prospective RCTs lasting 2–5 years and demonstrating the ability of the early use of an agonist to reduce the incidence of motor complications versus levodopa are available for cabergoline (Rinne et al., 1998), pramipexole (Parkinson Study Group, 2000) and ropinirole (Rascol et al., 2000; Whone et al., 2003). Similar conclusions were reported according to less methodologically convincing trials with bromocriptine (Parkinson Disease’s Research Group of the United Kingdom, 1993; Hely et al., 1994; Montastruc et al., 1994). Conflicting results have been reported with lisuride (Rinne, 1989; Allain et al., 2000) and published controlled data are lacking for other orally active agonists
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(dihydroergocryptine, pergolide, piribedil), apomorphine not having been used and tested in this situation. The ability of several dopamine agonists to reduce or to delay time to motor complications versus levodopa is therefore based on a good level of evidence. However, the clinical importance and usefulness of such results in the global management strategy of patients with early Parkinson’s disease remain a matter of controversy (see section 33.4). 33.2.1.3.2. Randomized controlled trials comparing agonist monotherapy versus another agonist There is no indication that one agonist might be more efficacious than another one in preventing or delaying time to motor complications. The only published headto-head RCT comparing two agonists in this situation (ropinirole versus bromocriptine) (Korczyn et al., 1999) did not show any difference at 3 years in the incidence of dyskinesias. 33.2.1.3.3. Randomized controlled trials with agonist monotherapy versus other antiparkinsonian medications No data are available to assess whether the early use of an agonist could be more efficacious in delaying time to motor complications than other drugs like MAO-B inhibitors, anticholinergics, amantadine or the early combination of a COMT inhibitor with levodopa. Such trials should be performed in the future. 33.2.2. Evidence to use dopamine agonists as adjunct to levodopa in patients with moderate to advanced Parkinson’s disease Adding a dopamine agonist in patients already on levodopa therapy is a strategy that is generally considered and has been assessed for three main reasons: (1) to improve the symptomatic control of parkinsonian motor signs (parkinsonism); (2) to improve motor complications; and (3) to try to improve non-motor signs. 33.2.2.1. Symptomatic control of parkinsonism as adjunct to levodopa The symptomatic efficacy of several agonists has been assessed in RCTs in patients with moderate to severe forms of Parkinson’s disease already treated with levodopa. As for early monotherapy, such RCTs are usually limited to 3–6 months of follow-up and use the UPDRS as an endpoint to assess the symptomatic effect of the drug on the cardinal signs of parkinsonism, in the ‘off’ and/or in the ‘on’ condition if the patients are fluctuating.
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33.2.2.1.1. Randomized controlled trials comparing an agonist versus placebo (Table 33.3) Most agonists have shown to be effective in improving the cardinal motor signs of parkinsonism in patients already treated with levodopa. This is true for apomorphine (Dewey et al., 2001), bromocriptine (Guttman et al., 1997; Mizuno et al., 2003), cabergoline (Hutton et al., 1996), pergolide (Olanow et al., 1994), piribedil (Ziegler et al., 2003) and pramipexole (Pinter et al., 1999; Pogarell et al., 2002). Due to lower-quality trials, the available evidence is less convincing but still supportive for dihydroergocryptine (Martignoni et al., 1991), lisuride (Allain et al., 2000) and ropinirole (Lieberman et al., 1998). Some trials suggested that agonists such as pramipexole and ropinirole might have a special impact on tremor (Pogarell et al., 2002; Schrag et al., 2002), but there is no clear rationale for such a specific effect and this can probably apply to any efficacious symptomatic dopaminergic medication (Navan et al., 2005). 33.2.2.1.2. Randomized controlled trials comparing an agonist versus another agonist There are a number of RCTs of variable methodological quality that compare in cross-over or parallel designs the symptomatic effect of two different dopamine agonists on parkinsonism when adjunct to levodopa. In all these trials, bromocriptine has been used as the reference comparator. Such data cannot have a
strong impact on clinical practice because most studies raised methodological problems (insufficient power, surrogate endpoints, arbitrary definition of dose equivalences) and because they reported only modest intergroup differences, posing the question of their relevance in clinical practice. This applies to trials with cabergoline (Inzelberg et al., 1996), lisuride (LeWitt et al., 1982; Laihinen et al., 1992), pergolide (LeWitt et al., 1983; Pezzoli et al., 1994; Mizuno et al., 1995; Boas et al., 1996), pramipexole (Mizuno et al., 2003) and ropinirole (Brunt et al., 2002). 33.2.2.1.3. Randomized controlled trials comparing an agonist versus other antiparkinsonian medications Bromocriptine (Tolcapone Study Group, 1999) and pergolide (Koller et al., 2001) have been the sole agonists compared to the COMT inhibitor tolcapone in openlabel RCTs. No significant difference was reported in terms of efficacy on the parkinsonian cardinal signs, although the safety profile was somehow different between the drugs. No data are available for other agonists and other antiparkinsonian drugs. 33.2.2.2. Symptomatic treatment of motor complications Motor complications are frequent and can be disabling after several years of treatment with levodopa. They involve fluctuations, erratic or unstable responses to medications, also known as the wearing-off or on–off
Table 33.3 Level of evidence supporting the efficacy of the different dopamine agonists as an adjunct to levodopa in moderate to advanced Parkinson’s disease according to the conclusions of the evidence-based review on antiparkinsonian interventions (Goetz et al., 2002; Rascol et al., 2002)
Agonists
Symptomatic control of parkinsonism
Control of motor fluctuations
Non-motor symptoms
Apomorphine* Bromocriptine Cabergoline Dihydroergocryptine Lisuride Pergolide{ Piribedil Pramipexole Ropinirole
Efficacious Efficacious Efficacious Insufficient Likely Efficacious Efficacious Efficacious Insufficient
Efficacious Likely Likely Insufficient Insufficient Efficacious Insufficient Efficacious Efficacious
Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient
*Apomorphine is used as subcutaneous route. { Pergolide cannot be recommended as a first-line treatment for Parkinson’s disease because of the risk of valvular heart disorder. Efficacious, positive effect of the agonists on studied outcomes in at least one high-quality randomized controlled trial (RCT) and no conflicting data from other RCT(s); likely, efficacy likely, i.e. evidence suggests, but is not sufficient to show, that the agonist has a positive effect on studied outcomes, based on any RCT and no conflicting data from other RCTs; insufficient, insufficient evidence, i.e. there are no data or available data and do not provide enough evidence either for or against the use of the agonist.
DOPAMINE AGONISTS phenomena, and dyskinesias or involuntary movements. Completing dopamine stimulation with drugs like dopamine agonists is expected to be potentially useful for such symptoms. RCTs have thus been implemented to assess the effects of various agonists on motor complications. Such trials were usually short-term (3–6-month) studies using home diaries as an endpoint (Hausser et al., 2000). Because agonists have differing effects on fluctuations and dyskinesias, these behaviors are considered separately. 33.2.2.2.1. Motor fluctuations There are several good-quality RCTs to support the use of a number of dopamine agonists to reduce the duration of off episodes (Table 33.3). This is true for pergolide (Olanow et al., 1994; Clarke and Speller, 2000a), pramipexole (Guttman et al., 1997; Clarke et al., 2000a; Mizuno et al., 2003), ropinirole (Rascol et al., 1996; Lieberman et al., 1998; Clarke and Deane, 2001a) and apomorphine (Ostergaard et al., 1995; Dewey et al., 2001). For safety reasons (see section 33.3), it is not recommended to use pergolide as a first-line agonist. Less convincing RCTs or less consistent results have been reported with bromocriptine (Hoehn and Elton, 1985; Toyokura et al., 1985; Guttman et al., 1997) and cabergoline (Hutton et al., 1996). There are only open-label or anecdotal data to suggest that other agonists like dihydroergocriptine, lisuride or piribedil can also improve motor fluctuations. Comparative trials, when available, did not show major differences between bromocriptine and other agonists such as cabergoline (Inzelberg et al., 1996), lisuride (Laihinen et al., 1992), pergolide (Mizuno et al., 1995; Clarke and Speller, 2000b) ropinirole (Clarke and Deane, 2001b; Brunt et al., 2002) and pramipexole (Clarke et al., 2000b; Mizuno et al., 2003). The same was true when comparing bromocriptine (Tolcapone Study Group, 1999) and pergolide (Koller et al., 2001) with the COMT inhibitor tolcapone. No other comparisons have been published. 33.2.2.2.2. Dyskinesias When levodopa-treated patients with advanced Parkinson’s disease receive an agonist to reduce off episodes, this is usually at the cost of some worsening of dyskinesia. This has been quite constantly observed in any RCT assessing any agonist in this situation (see previous paragraph for references). In clinical practice, the daily dose of levodopa is then partly reduced when the agonist is adjunct in order to minimize this problem. On longer follow-up, in line with the CDS hypothesis, there are theoretical reasons to expect that high doses of dopamine agonists might permit the reduction
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of the duration and severity of levodopa-induced dyskinesias, since agonists could deliver a more stable stimulation than levodopa and therefore reverse the underlying mechanisms causing dyskinesias. There are only few open-label and generally uncontrolled reports in small cohorts of patients to support this practice. The most convincing data have been published with continuous subcutaneous infusions of apomorphine (Colzi et al., 1998; Manson et al., 2002; Katzenschlager et al., 2005). Some positive anecdotal studies have also been presented with oral administration of pergolide (Facca and Sanchez-Ralos, 1996) and ropinirole (Cristina et al., 2003). 33.2.2.3. Symptomatic control of non-motor problems Although Parkinson’s disease is often considered a prototypic movement disorder, most patients have additional non-motor symptoms. These include autonomic dysfunction, depression, cognitive decline, sleep problems, sensory complaints and pain. Available trials on non-motor features of Parkinson’s disease, when available, usually have major methodological limitations. As a result, the evidence is weak in most instances and does not allow the use of an agonist to be supported or recommended in such indications. In RCTs conducted in non-parkinsonian subjects with major or bipolar depression, pramipexole was superior to placebo (Corrigan et al., 2000; Zarate et al., 2004), but convincing data are missing in Parkinson’s disease patients. The only available evidence in Parkinson’s disease is weak, limited to uncontrolled or low-quality RCT trials with agonists like pergolide, pramipexole and ropinirole (Izumi et al., 2000; Perugi et al., 2001; Lattanzi et al., 2002; Rektorova et al., 2003). This does not allow any firm conclusions to be drawn. The same is true for cognition, although it is common empirical knowledge that any agonist can aggravate cognitive and behavioral dysfunction in patients with Parkinson’s disease dementia or Lewy body disease. Agonists are therefore not recommended or should even be withdrawn in such conditions. There is no strong evidence that symptoms like frozen gait, balance problems, anxiety, sleep disturbances or pain are responsive to the effects of dopamine agonists. It is conceivable that such symptoms, if partly dopa-responsive and occurring or worsening during off episodes, might be improved by such drugs as by any other dopaminergic medication. No convincing undisputable clinical data are available however. Conversely, dysautonomic parkinsonian symptoms, like orthostatic hypotension, are often aggravated by dopamine agonist (as by any
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dopaminergic medication), probably through dopaminergic sympatholytic mechanisms.
33.3. Safety issues on dopamine agonists Adverse drug reactions are defined as any appreciably harmful or unpleasant reaction resulting from an intervention related to the use of a medicinal product which predicts hazard from future administration and warrants prevention or specific treatment, or alteration of the dosage regime, or withdrawal of the product (Edwards and Aronson, 2000). They can be classified as type A and type B reactions (Rawlins and Thomson, 1977). Type A reactions are generally expected and predictable, since they are frequently related to the known pharmacological properties of the drug. Their prevalence is relatively high. They are usually nonserious, non-lethal, dose-dependent and can be managed with dose adjustment. Conversely, type B reactions are unexpected, unpredictable, rare, often serious reactions and most of the time they lead to drug withdrawal. 33.3.1. Dopamine agonist type A adverse reactions Such adverse reactions are usually classified as peripheral (gastrointestinal reactions such as nausea and vomiting, cardiovascular reactions such as orthostatic hypotension and leg edema) or central ones (psychiatric reactions and sedative reactions). These type A reactions are shared by other active dopamine-mimetic medications and are generally believed to be the consequence of the stimulation of dopamine receptors out of the basal ganglia. There is no convincing evidence that any agonist is associated with a lower risk than another one for such type A reactions and this is true for peripheral as well as central effects. 33.3.1.1. Peripheral type A adverse reactions Gastrointestinal and cardiovascular adverse reactions are common at the onset of therapy with any dopamine agonist and usually tolerate out over time. They are explained by the agonistic effect of the drugs on dopamine receptors in the gut and in the area postrema (gastrointestinal effects) and at the presynaptic level of the orthosympathetic system (orthostatic hypotension). They can be managed by slow titration. Antiemetics like domperidone, a dopamine-blocker agent that does not cross the blood–brain barrier, help to treat nausea in countries where this drug is available. In large levodopa-controlled double-blind RCTs, gastrointestinal and cardiovascular adverse drug reactions are not necessarily reported to be more frequent on agonists than on levodopa (Rascol et al., 2000),
although it is frequently empirically believed that this is the case in clinical practice. Leg edema is known to be associated with both ergot and non-ergot dopamine agonists. Reported incidences vary widely and this reaction is more frequent on agonists than on levodopa. For example, the incidence of leg edema reported in levodopa-controlled trials was 14% on ropinirole versus 6% on levodopa (Rascol et al., 2000), 42% on pramipexole versus 15% on levodopa (Holloway et al., 2004) and 16% on cabergoline versus 3% on levodopa (Bracco et al., 2004). The mechanism of this side-effect is unknown. This adverse drug reaction is sometimes reported as dose-dependent but can also be idiosyncratic. It is reversible with discontinuation of the agonist and the use of a diuretic therapy should be discouraged because it is not efficacious and can induce or aggravate other problems like orthostatic hypotension. Subcutaneous nodules at the injection site of apomorphine are another type A adverse reaction. This adverse reaction seems unrelated to the dopaminergic effects of the drug but rather to its intrinsic physical properties, since problems of local toxicity have been reported at any site of administration (subcutaneous, sublingual, intranasal). Such subcutaneous nodules are frequent, sometimes painful and may become infected, especially when the drug is delivered by subcutaneous continuous pump. Changing the site of injection every day and careful local hygiene reduce the incidence and severity of such a reaction (Poewe et al., 1993; Bowron, 2004). 33.3.1.2. Central type A adverse reactions Psychiatric symptoms are among the most disabling dopamine agonist-related adverse drug reactions (Factor et al., 1995). This is true for any efficacious dopaminergic medications. The prevalence of these symptoms on agonists varies according to the reports and usually ranges between 5 and 20%. In most levodopa-controlled double-blind trials, psychiatric adverse reactions are reported to be more common on agonists than on levodopa (Rascol et al., 2000; Parkinson Study Group, 2000) and this is also empirically observed in clinical practice. Such psychotic symptoms can present as delusions, usually paranoid, or hallucinations, predominantly visual, though auditory component is common. Abnormal behaviors such as hypersexuality, pathological gambling and other related syndromes have also been reported. Such psychiatric reactions generally develop after a period of treatment and are dose-related. Predisposing factors such as age, individual psychopathological background, cognitive impairment and polytherapy are
DOPAMINE AGONISTS sometimes reported. These adverse reactions are a frequent reason for withdrawing an agonist after some years of therapy. The development of such psychiatric reactions might indeed represent an early indicator of cognitive decline in such a patient, although hallucinations and delusion can occur in cognitively normal subjects. The usual management of such psychiatric adverse reactions is to reduce the dose or even stop the agonist. It may take weeks before the effect clears. If downtitration or withdrawal of the agonist leads to an unacceptable worsening of motor function, the atypical neuroleptic clozapine proved to improve hallucinations without worsening parkinsonism in two short-term placebo-controlled RCTs (French Clozapine Parkinson Study Group, 1999; Parkinson Study Group, 1999). However, due to safety hematological problems, clozapine is not easy to use and other atypical neuroleptics, like quetiapine, for example, are sometimes empirically proposed, although convincing RCTs are not available to provide a good level of evidence to support this practice (Matheson and Lamb, 2000). Abnormal daytime somnolence was not listed among common type A adverse reactions of antiparkinsonian medications like dopamine agonists until the publication in 1999 of cases of ‘sleep attacks’ at the wheel in patients with Parkinson’s disease treated with ropinirole or pramipexole (Frucht et al., 1999). It was thereafter realized that such problems are common with any dopamine agonist, including ergot and non-ergot ones. This is based on postmarketing surveillance case reports with apomorphine (Homann et al., 2000), bromocriptine (Ferreira et al., 2000), cabergoline (Ebersbach et al., 2000), lisuride (Ferreira et al., 2000), pergolide (Ferreira et al., 2000; Schapira, 2000), piribedil (Ferreira et al., 2000; Tan, 2003), pramipexole (Frucht et al., 1999; Ryan et al., 2000), ropinirole (Frucht et al., 1999; Paladini, 2000) and other antiparkinsonian medications than agonists, like entacapone (Ebersbach et al., 2000) and levodopa (Ferreira et al., 2001). Pharmacoepidemiological surveys confirmed that all agonists share the risk of daytime somnolence (Hobson et al., 2002; Paus et al., 2003; Ferreira et al., 2006). In levodopa-controlled double-blind RCTs, the agonists usually induce greater somnolence than levodopa (Etminan et al., 2001). The prevalence of abnormal daytime somnolence varies greatly according to the studies (6% according to Paus et al., 2003; 16%: Tandberg et al., 1999; 18%: Razmy et al., 2004; 27%: Ferreira et al., 2006; 30%: Montastruc et al., 2001b; 32%: Manni et al., 2004; 34%: Schlesinger and Ravin, 2003; 43%: Korner et al., 2004; 76%: Brodsky et al., 2003). This is probably mainly due to different definitions (‘sleep attacks’, ‘sudden onset of sleep’,
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‘unintended sleep episodes’, ‘irresistible sleep episodes’, ‘abnormal daytime sleepiness’, ‘excessive daytime sleepiness’), different populations (nondemented parkinsonians, parkinsonians on agonists only, driving parkinsonians, normal population) and different methods of assessment (questionnaires, scales like the Epworth scale, electrophysiological techniques like the Multiple Sleep Latency Test) according to the studies. Initially, it has been difficult to demonstrate the exact responsibility of the agonists in causing such symptoms because multiple factors can induce daytime somnolence in patients with Parkinson’s disease. These factors are mainly related to the disease itself, comorbidities and comedications. In placebo-controlled RCTs conducted in healthy volunteers, an agonist like ropinirole induced somnolence (Ferreira et al., 2002). This was also true for levodopa (Andreu et al., 1999). These experiments strongly document the link between the drugs and the sedative symptoms, regardless of the disease itself. Risk factors are poorly known and may be related to the patient (age, gender, genetic susceptibility), the disease (severity, duration, associated symptoms such as dysautonomia, dementia, depression) or the drug (dose, duration of exposure, comedications). It must now be recognized that somnolence is a frequent dopaminergic type A adverse reaction, shared by most, if not all, dopaminergic medications (Homann et al., 2002), although dopamine agonists appear to be at greater risk than levodopa (Etminan et al., 2001). Patients should be informed of this potential effect and be advised not to drive if it is present. The practical management of agonist-induced daytime inappropriate sleepiness is poorly known and remains empirical. In some instances, dose reduction is efficacious. Switching from one agonist to another can be proposed, but the same reaction can occur with the other agonist. There are no convincing placebo-controlled RCTs on which to base the prescription of ‘specific’ therapies, such as modafinil for example (Montastruc and Rascol, 2001). 33.3.2. Dopamine agonist type B adverse reactions Examples of rare but potentially severe type B reactions on dopamine agonists are numerous. Fibrosis has been detected in postmarketing surveillance studies with all ergot derivatives, including bromocriptine, lisuride, cabergoline and pergolide. Classically, such fibrotic reactions have been reported as pleuropulmonary, pericardiac and/or retroperitoneal syndromes (Todman et al., 1990; Bhatt et al., 1991; Ling et al., 1999; Shaunak et al., 1999; Ben-Noun, 2000; Mondal and Suri, 2000). These adverse reactions are usually
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considered as rare events, although their exact prevalence is unknown. Their mechanism is possibly related to the dose and duration of exposure to the ergot compounds. Erythrocyte sedimentation and protein Creactive inflammatory markers are usually increased and may be helpful for an early diagnosis. The risk of developing such a fibrosis on non-ergot agonists is much lower, if it exists. These reactions are sometimes life-threatening, although they can be at least partially reversible after withdrawal of the drug. In general, when a patient develops this kind of adverse reaction on an ergot agonist, the strategy is to switch to a non-ergot one. Recently, several cases of another type of fibrotic adverse reaction, severe multivalvular heart disease, have been reported on pergolide and other ergot derivative agonists, namely bromocriptine and cabergoline (Vergeret et al., 1984; Agarwal et al., 2004; Horvath et al., 2004). For the moment, the risk is better documented with pergolide (Van Camp et al., 2004). For this reason, this drug is now generally only used as a second-line alternative option, when other agonists, especially the non-ergot ones, have not provided a satisfying response. Operational definitions (clinical syndrome versus echocardiographic detection), severity grading, prevalence, mechanism of action (related for some authors to 5-HT2B effects), management and reversibility after drug withdrawal of such valvular heart reactions remain a matter of debate and it is too early at this stage to conclude definitely on their true impact on the benefit/risk ratio of the ergot agonists (Rascol et al., 2004a, b). Another example of type B adverse reaction is Coombs-positive hemolytic anemia that has been reported with apomorphine, especially in patients receiving continuous subcutaneous infusions. This is a rare adverse reaction and the usefulness of blood count monitoring for this purpose remains uncertain (Poewe et al., 1993; Pinter et al., 1998). Other examples of type B reactions due to agonists are alopecia, which has been reported with bromocriptine (Fabre et al., 1993), visual cortical disturbances on bromocriptine (Lane and Routledge, 1983), loss of vision color on pramipexole (Muller et al., 2003) and hypersensitivity (allergic reactions) to many agonists (Martindale, 2002). These adverse reactions are rare, but their real prevalence and mechanisms often remain unknown.
33.4. Dopamine agonists in clinical practice and their place in the management of patients with Parkinson’s disease Treatment of Parkinson’s disease has become increasingly complex, due to the growing number of medical
and surgical treatment options that can be offered to patients. There are different ways to introduce and combine antiparkinsonian medications, according to various therapeutic strategies. Regardless of these differences, the global usefulness of dopamine agonists is well established and there is a good level of evidence to document that this class of drugs, as a whole, provides substantial help in the management of patients with Parkinson’s disease. Nevertheless, the exact place of the dopamine agonists, as a class, versus other medications and the best choice among the different agonists within this class (except subcutaneous injections of apomorphine) often remains a matter of empirical preferences that differ according to individual opinions. In de novo patients, the main question is to decide if and when to start levodopa. Should levodopa be used as soon as possible or as a second step, after an initial dopamine agonist early therapy? For each patient, the choice is based on a subtle combination of subjective and objective factors, including concerns related to the drug (efficacy, safety, practicality, cost), the patient (symptoms, age, needs, expectations, experience, comorbidity, socioeconomic level) and his/her environment (variability of drugs availability according to national markets, variability in economical and health care systems). There is thus not a single and unequivocal algorithm applicable to all patients worldwide (Clarke and Guttman, 2002; Ahlskog, 2003; Schwarz, 2003). Starting a patient on one of the available orally active dopamine agonists is now considered as a useful strategy by a growing number of specialists, because agonists are effective antiparkinsonian medications and are associated with a lower risk of motor complications than levodopa. The benefit of this strategy must be balanced however by the fact that: (1) the benefit of the early use of an agonist on motor complications has been assessed only up to 5 years and remains questionable on longer follow-up, especially in terms of quality of life; (2) agonists have a smaller symptomatic effect than levodopa on UPDRS scores according to RCTs (but the difference is only marginal and probably clinically not relevant when small doses of levodopa are allowed as a supplement as soon as the agonist monotherapy becomes insufficient); (3) agonists are more expensive than levodopa; and (4) there is a greater incidence of psychiatric adverse reactions, somnolence and edema on agonists than on levodopa. Patients must be informed of these risks, especially somnolence for drivers. As older patients (70 years of age and above) are less prone to develop motor complications on levodopa and more sensitive to cognitive and psychotic adverse reactions, the
DOPAMINE AGONISTS early use of levodopa rather than that of an agonist is often preferred as first-line therapy in this population. Conversely, as younger patients (< 70 years) are at greater risk for motor complications, this is the population where initial treatment with an agonist is especially considered. In most patients, agonist monotherapy cannot control parkinsonian symptoms for more than a few years, even when increasing the dose over time, and must thereafter be complemented with levodopa. In this case, it is recommended to continue agonist therapy and to supplement it with the lowest possible dose of levodopa rather than to switch to levodopa monotherapy in order to maintain as much as possible the long-term benefit on motor complications. In more advanced levodopa-treated patients, the usefulness of dopamine agonists is established to treat on–off problems. Clinical empirical experience and some comparative studies suggest that the adjunction of an orally active dopamine agonist to levodopa reduces the time spent off in a comparable way than other pharmacological options such as COMT or MAO-B inhibitors. On average, there is a 1–2-hour reduction in time spent off, at the cost of some worsening of dyskinesias that can be managed by adjusting concomitantly the dose of levodopa. Interestingly, the efficacy of the three different types of adjunct medications to levodopa (agonists, MAO-B and COMT inhibitors) does not seem to be mutually exclusive and rather appears to be complementary. Therefore, many patients with advanced Parkinson’s disease will happen to receive a combination of these drugs after some years of management. Starting with one of them first, rather than with one of the others, remains a matter of personal experience and preference. MAO-B inhibitors have the advantage of practicality (no titration, once-daily dose and only one dosage for all patients). COMT inhibitors do not require titration either and are used at a unique dosage. Conversely, dopamine agonists must be titrated but their dosage can then be tailored to individual need. Safety profiles are also different between the three therapeutic classes of complementary drugs to levodopa. A special place must be allocated to apomorphine in the management of advanced patients with Parkinson’s disease (Poewe and Wenning, 2000; Deleu et al., 2004). This is so because of the effect size of apomorphine on parkinsonian symptoms. It is strong, similar to that of levodopa, and this is unique for a dopamine agonist. The group of Lees and coworkers first reported the beneficial effects of apomorphine in patients with advanced Parkinson’s disease (Stibe et al., 1988). As already mentioned, this drug can only be used via subcutaneous route. Intermittent penjet injections can thus be
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proposed to treat off episodes (Factor, 2004). The clinical effect of a single apomorphine injection usually develops within 10 minutes and lasts 45 minutes on average, because of the short elimination half-life of the drug. The concomitant use of domperidone, where available, reduces the risk of gastrointestinal and hypotensive adverse reactions. Apomorphine penjet injections are recommended in patients with severe fluctuations resistant to other medical therapies, on top of the regular oral treatment (including an oral agonist). When the need for apomorphine injections exceeds 8–10 injections per day, or when dyskinesias are too difficult to manage, continuous subcutaneous infusion with apomorphine pumps is then considered. This requires a clinical team with sufficient expertise in order to train the patient and the care-giver correctly to a relatively complex procedure. A proportion of difficult patients who failed on oral medications will profit from this treatment, with a reduction of time spent off, a reduction in dyskinesia and a reduction of the daily dose of oral therapies, including levodopa (Hagell and Odin, 2001). In the centers where deep brain (subthalamic stimulation) surgery is available, these patients are nowadays frequently offered a surgical approach and apomorphine pumps are rather proposed as a second-line alternative option, in cases of surgical contraindication. However, the benefit/risk and cost/effectiveness ratios of both techniques have never been carefully compared in parallel and this should be assessed objectively in the future. Another important matter of interest for clinical practice is to compare the advantages and disadvantages of the different orally active agonists (Tan and Jankovic, 2001). Four aspects can help in comparing drugs: efficacy, safety, practicality and costs. Overall, excluding apomorphine, all orally active dopamine agonists share the same efficacy profile (global class effect) (Bonuccelli, 2003; Inzelberg et al., 2003). However, the level of evidence differs from one drug to the other, because the effect of some agonists has been poorly or never assessed in several indications (Tables 33.2 and 33.3). The best level of evidence is clearly offered by the two most recently marketed agonists, pramipexole and ropinirole. There is however little evidence that an older agonist, like bromocriptine, is less useful than the newer ones. The few trials identified with older medications were conducted in times when technical solutions to plan such trials had not yet been developed. This historical factor explains why such trials are less convincing. Unfortunately, there is no present interest in studying these old drugs again, using modern designs, since their patents have expired and these molecules thus do not offer any more sufficient economical retrieval. As pointed out above, the
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evidence to document a substantial superiority of the new agonists over bromocriptine turns out to be rather weak and poorly convincing. In several countries, bromocriptine is much cheaper than the newer agonists, especially now that generics are available, and this deserves to be considered. Safety is another important matter. Overall, all agonists expose the patients to the same risk of peripheral and central type A adverse reactions. There is no evidence that one of them is safer than another one on these aspects. Conversely, fibrotic type B reactions appear to be more frequent on ergot than non-ergot agonists and this is why pergolide, for example, is no longer considered as a first-line choice when starting a treatment with a dopamine agonist. From a practicality perspective, all orally active agonists are usually administered t.i.d. except cabergoline, which is administrated once daily. All must be titrated over weeks up to the minimal dose that is sufficient to control symptoms. The impracticality of apomorphine subcutaneous injections precludes the use of this drug in patients with early Parkinson’s disease and limits its indications to patients with severe levodopainduced motor complications. Switching from an agonist to another one for efficacy or safety reasons is sometimes considered in clinical practice, although global efficacy and safety profiles (except fibrosis) are similar among the drugs. Most of the available data is based on open-label non-randomized trials with an overnight switch from bromocriptine to the other agonist. An empirical conversion chart of dose equivalence is sometimes proposed with 10 mg bromocriptine ¼ 1 mg pergolide ¼ 1 mg pramipexole ¼ 2 mg cabergoline ¼ 5 mg ropinirole (Reichmann et al., 2003; Grosset et al., 2004; Stewart et al., 2004). Using such equivalent daily doses, some patients appear to enjoy – or not – switching from bromocriptine to another agonist. This might be related to the placebo or nocebo effect, but this strategy is sometimes interesting in the practical management of a given patient. Combining two dopamine agonists is another issue that is sometimes considered in clinical practice. There is no real convincing pharmacological rationale to combine in the same subject two different orally active dopamine agonists, which are supposed to act on the same D2-receptors. However, some movement disorder specialists believe that such a combination regimen (for example, an agonist with a long elimination half-life, like cabergoline þ a non-ergot agonist with a shorter elimination half-life, like ropinirole or pramipexole) is useful in some patients. Such a practice warrants more studies and a more objective evaluation before any conclusions can be drawn. It is common pharmacological observation that combining two compounds belonging to the
same family frequently increases the risk of adverse reactions.
33.5. Conclusions In summary, dopamine agonists are useful medications for the management of patients with Parkinson’s disease in the early stages as well as in more advanced stages of the disorder. Although their symptomatic effect is well established on the cardinal signs of parkinsonism and on motor fluctuations, their clinical impact on disease progression and on non-motor signs such as depression remains to be documented. All orally active dopamine agonists have globally quite a comparable benefit/risk profile, although: (1) cabergoline can be used once daily whereas others are usually prescribed t.i.d.; (2) apomorhine is used subcutaneously in patients with severe refractory motor fluctuation; and (3) ergot compounds are at greater risk than the non-ergot compounds for rare but potentially severe fibrotic complications. Future developments for dopamine agonists in the treatment of Parkinson’s disease might come from new compounds having novel pharmacokinetic profiles, such as the transdermal patch of rotigotine (Rascol, 2005) and the slowrelease formulations of already marketed agonists like ropinirole, or from new agonists with novel pharmacodynamic profiles (more selective on dopamine D1-like or D2-like receptor subtypes) and partial agonists such as SLV 308 (Wolf, 2003). In the next few years, the clinical use of dopamine agonists will extend to novel indications in disorders with greater prevalence than Parkinson’s disease, such as the restless-legs syndrome, for example.
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Rascol O, Brooks DJ, Brunt ER et al. (1998), on behalf of the 056 Study Group. Ropinirole in the treatment of early Parkinson’s disease: a 6-month interim report of a 5-year levodopa-controlled study. Mov Disord 13: 39–45. Rascol O, Brooks DJ, Korczyn AD et al. (2000), for the 056 Study Group. A five-year study of the incidence of dyskinesia in patients with early Parkinson’s disease who were treated with ropinirole or levodopa. N Engl J Med 342: 1484–1491. Rascol O, Nutt JG, Blin O et al. (2001). Induction by dopamine D1 receptor agonist ABT-431 of dyskinesia similar to levodopa in patients with Parkinson’s disease. Arch Neurol 58: 249–254. Rascol O, Goetz C, Koller W et al. (2002). Treatment interventions for Parkinson’s disease: an evidence based assessment. Lancet 359: 1589–1598. Rascol O, Payoux P, Ory F et al. (2003). Limitations of current Parkinson’s disease therapy. Ann Neurol 53 (Suppl 3), S3–S12, discussion S12–S15. Rascol O, Pathak A, Bagheri H et al. (2004a). New concerns about old drugs: valvular heart disease on ergot derivative dopamine agonists as an exemplary situation on pharmacovigilance. Mov Disord 19: 611–613. Rascol O, Pathak A, Bagheri H et al. (2004b). Dopaminagonists and fibrotic valvular heart disease: further considerations. Mov Disord 19: 1524–1525. Rawlins MD, Thomson JW (1977). Pathogenesis of adverse drug reactions. In: DM Daines, (Ed.), Text Book of Adverse Drug Reactions. Oxford University Press, p. 44. Razmy A, Lang AE, Shapiro CM (2004). 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. Reichmann H, Herting B, Mu¨ller A et al. (2003). Switching and combining dopamine agonists. J Neural Transm 110: 1393–1400. Rektorova I, Rektor I, Bares M et al. (2003). Pramipexole and pergolide in the treatment of depression in Parkinson’s disease: a national multicentre prospective randomized study. Eur J Neurol 10: 399–406. Rinne U (1989). Lisuride a dopamine agonist in the treatment of early Parkinson’s disease. Neurology 39: 336–339. Rinne UK, Bracco F, Chouza C (1997), on behalf of the PKD009 Collaborative Study Group. Carbergoline in the treatment of early Parkinson’s disease: results of the first year of treatment in a double-blind comparison of cabergoline and levodopa. Neurology 48: 363–368. Rinne UK, Bracco F, Chouza C et al. (1998), and the PKDS009 Study Group. Early treatment of Parkinson’s disease with cabergoline delays the onset of motor complications. Drugs 55: 23–30. Riopelle RJ (1987). Bromocriptine and the clinical spectrum of Parkinson’s disease. Can J Neurol Sci 14: 455–459. Robertson HA (1992). Dopamine receptor interactions: some implications for the treatment of Parkinson’s disease. Trends Neurosci 15: 201–206.
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Rondot P, Ziegler M (1992). Activity and acceptability of piribedil in Parkinson’s disease: a multicentre study. J Neurol 239 (Suppl 1): 28–34. Ryan M, Slevin JT, Wells A (2000). Non-ergot dopamine agonist-induced sleep attacks. Pharmacotherapy 20: 724–726. Schapira AH (2000). Sleep attacks (sleep episodes) with pergolide. Lancet 355: 1332–1333. Schapira AH (2002). Neuroprotection and dopamine agonists. Neurology 58: S9–S18. Schapira AH, Olanow CW (2003). Rationale for the use of dopamine agonists as neuroprotective agents in Parkinson’s disease. Ann Neurol 53: S149–S159. Schapira AHV, Olanow CW (2004). Neuroprotection in Parkinson’s disease. Mysteries, Myths, and Misconceptions. JAMA 291: 358–364. Schlesinger I, Ravin PD (2003). Dopamine agonist induce episode of irresistible daytime sleepiness. Eur Neurol 49: 30–33. Schrag A, Keens J, Warner J (2002). Ropinirole Study Group. Ropinirole for the treatment of tremor in early Parkinson’s disease. Eur J Neurol 9: 253–257. Schwarz J (2003). Rationale for dopamine agonist use as immunotherapy in Parkinson’s disease. Curr Opin Neurol 16: S27–S33. Sethy VH, Wu H, Oostveen JA et al. (1997). Neuroprotective effects of the dopamine agonists pramipexole and bromocriptine in 3-acetylpyridine-treated rats. Brain Res 754: 181–186. Shannon KM, Bennett JP, Friedman JH (1997). for the Pramipexole Study Group. Efficacy of pramipexole, a novel dopamine agonist, as monotherapy in mild to moderate Parkinson’s disease. Neurology 49: 724–728. Shaunak S, Wilkins A, Pilling JB et al. (1999). Pericardial, retroperitoneal, and pleural fibrosis induced by pergolide. J Neurol Neurosurg Psychiatry 66: 79–81. Stewart D, Morgan E, Burn D et al. (2004). Dopamine agonist switching in Parkinson’s disease. Hosp Med 65: 215–219. Stibe CM, Lees AJ, Kempster PA et al. (1988). Subcutaneous apomorphine in parkinsonian on-off oscillations. Lancet 1: 403–406. Tan EK (2003). Piribedil-induced sleep attacks in Parkinson’s disease. Fundam Clin Pharmacol 17: 117–119. Tan EK, Jankovic J (2001). Choosing dopamine agonists in Parkinson’s disease. Clin Neuropharmacol 24: 247–253. Tandberg E, Larsen JP, Karlsen K (1999). Excessive daytime sleepiness and sleep benefit in Parkinson’s disease: a community-based study. Mov Disord 14: 922–927. Tintner R, Jankovic J (2003). Dopamine agonists in Parkinson’s disease. Expert Opin Investig Drugs 12: 1803–1820.
Todman DH, Oliver WA, Edwards RL (1990). Pleuropulmonary fibrosis due to bromocriptine treatment for Parkinosn’s disease. Clin Exp Neurol 27: 79–82. Tolcapone Study Group (1999). Efficacy and tolerability of tolcapone compared with bromocriptine in levodopa-treated parkinsonian patients. Mov Disord 14: 38–44. Toyokura Y, Mizuno Y, Kase M et al. (1985). Effects of bromocriptine on parkinsonism. A nation-wide collaborative double-blind study. Acta Neurol Scand 72: 157–170. Tulloch IF (1997). Pharmacologic profile of ropinirole: a nonergoline dopamine agonist. Neurology 49: S58–S62. Uitti RJ, Ahlskog JE (1996). Comparative review of dopamine receptor agonist in Parkinson’s disease. CNS Drugs 5: 369–388. Van Camp G, Flamez A, Cosyns B et al. (2004). Treatment of Parkinson’s disease with pergolide and relation to restrictive valvular heart disease. Lancet 363: 1179–1183. Vergeret J, Barat M, Taytard A et al. (1984). Pleuropulmonary fibrosis and bromocriptine. Sem Hop 60: 741–744. Whone AL, Watts RL, Stoessl AJ et al. (2003). REAL-PET Study Group. Slower progression of Parkinson’s disease with ropinirole versus levodopa: the REAL-PET study. Ann Neurol 54: 93–101. Wise RA, Rompre PP (1989). Brain dopamine and reward. Annu Rev Psychol 40: 191–225. Wolf WA (2003). SLV-308. Solvay. Curr Opin Investig Drugs 4: 878–882. Yoshikawa T, Minamiyama Y, Naito Y et al. (1994). Antioxidant properties of bromocriptine, a dopamine agonist. J Neurochem 62: 1034–1038. Zarate CA, Payne JL, Singh J et al. (2004). Pramipexole for bipolar II depression: a placebo-controlled proof of concept study. Biol Psychiatry 56: 54–60. Ziegler M, Castro-Caldas A, Del Signore S et al. (2003). Efficacy of piribedil as early combination to levodopa in patients with stable Parkinson’s disease: a 6-month, randomized placebo-controlled study. Mov Disord 18: 418–425.
Further Reading Etminan M, Gill S, Samii A (2003). Comparison of the risk of adverse events with pramipexole and ropinirole in patients with Parkinson’s disease: a meta-analysis. Drug Saf 26: 439–444. Hunziker T, Bruppacher R, Kuenzi UP et al. (2002). Classification of ADRs: a proposal for harmonization and differentiation based on the experience of the Comprehensive Hospital Drug Monitoring Bern/St. Gallen, 1974–1993. Pharmacoepidemiol Drug Saf 11: 159–163.
Handbook of Clinical Neurology, Vol. 84 (3rd series) Parkinson’s disease and related disorders, Part II W. C. Koller, E. Melamed, Editors # 2007 Elsevier B. V. All rights reserved
Chapter 34
Monoamine oxidase A and B inhibitors in Parkinson’s disease MOUSSA B. H. YOUDIM1* AND PETER F. RIEDERER2 1
Department of Pharmacology, Technion-Bruce Rappaport Faculty of Medicine, Eve Topf and NPF Neurodegenerative Diseases Centers, Rappaport Family Research Institute, Haifa, Israel
2
Clinical Neurochemistry, Department of Psychiatry and Psychotherapy, National Parkinson Foundation (USA) Center of Excellence Research Laboratories, University of Wu¨rzburg, Wu¨rzburg, Germany
34.1. Introduction Monoamine oxidase (MAO), which catalyzes primary, secondary and tertiary amines (Fig. 34.1), was discovered in 1928 by Hare Bernhiem and later identified by Balschko as one of the most important enzymes in neurotransmitter metabolism (Youdim et al., 2005a, 2006). Its physiological roles and inhibitors have played major roles in our understanding of the functional roles of dopamine (DA), norepinephrine and serotonin (5-HT) neurotransmission in the central nervous system (CNS). One of the first psychotropic drugs to be identified was iproniazid, the first MAO inhibitor to be discovered by serendipity and introduced into clinic as an antidepressant. Although this drug and other nonselective MAO inhibitors demonstrated remarkable antidepressant action in the late 1950s and 1960s (Table 34.1), their usefulness as antidepressants was seriously challenged in earlier clinical studies, mainly because of limited dosage employed. In addition some drugs, such as iproniazid, caused liver toxicity and others, such as tranylcypromine, induced what became known as the ‘cheese reaction’. These side-effects seriously hampered the development and assessment of other MAO inhibitors as antidepressants and antiparkinson drugs. Although the problem of hepatotoxicity, which was associated with hydrazine-derived drugs, was resolved with the development of other non-hydrazine MAO inhibitors, the cheese reaction remained the major source of problems. What became known as the cheese reaction is associated with the presence of tyramine and other
indirectly acting sympathomimetic amines, present in food (cheeses and many diverse foodstuffs) and drinks (beer and wine), especially those that are fermented. Most such amines are metabolized by MAO. Tyramine, a substrate of MAO, if present in ingested food cannot be metabolized as a consequence of MAO inhibition. It can gain access to the circulatory system and induce a significant release of norepinephrine from peripheral adrenergic neurons (Fig. 34.2). The consequence of this can be severe cardiovascular response, resulting in hypertensive reaction, and which can be fatal in some cases. The search for an understanding of the mechanism of the cheese reaction by MAO inhibitors and development of inhibitors devoid of this fatal side-effect continued with the identification of multiple forms of MAO with different substrate specificity and inhibitor sensitivity (Youdim and Weinstock, 2001).
34.2. Multiple forms of brain monoamine oxidase The demonstration that MAO was not a single enzyme but existed in several forms in the liver and brain tissues of rats (Youdim and Sourkes, 1965) was strengthened by the observation that the MAO inhibitor clorgyline (Johnston, 1968) could differentiate between two forms of MAO in brain and most tissues of animals and humans. Johnston termed these enzymes type A and type B and where clorgyline (Table 34.1, Fig. 34.3) was a selective irreversible inhibitor of MAO-A, an enzyme responsible for oxidative deamination of norepinephrine and 5-HT. By contrast, MAO-B was
*Correspondence to: Professor Moussa B. H. Youdim, Centers of Excellence for Neurodegenerative Diseases Research, Technion-Rappaport Family Faculty of Medicine and Institute, Efron St., PO Box 9697, Haifa 31096, Israel. Email:
[email protected], Tel: þ972-4-8295-290, Fax: 972-4-8513-145.
94
M. B. H. YOUDIM AND P. F. RIEDERER H2O2
R
N
O2 + H+
FAD R2
FADH2 R
MAO
R1
+ R2 N
R1
OH2
H C R
O +
+ R2 HN
R1
Fig. 34.1. Reaction pathway of monoamine oxidase (MAO) catalyzes oxidative deamination of monoamine neurotransmitters.
Table 34.1 Monoamine oxidase (MAO) inhibitors with application in depression and Parkinson’s disease MAO type AþB Irreversible Iproniazid Phenelzine Isocarboxazid Tranylcypromine Nialamide Pargyline* Clorgyline Deprenyl (selegiline) Rasagiline TV3326
Reversible Moclobemide Brofaromine Caroxazone Toloxatone BW 137OU87 Befloxatone Lazabemide Milacemide Safinamide
þ AD þ AD þ AD þ AD APD? þ AD þ
A
þ AD
B
þ APD þ APD
þ AD, APD? (brainselective, phase II clinical) þ AD, APD þ AD þ þ AD þ þ AD
þ APD þ þ APD
*Shows slight degree of selectivity for MAO-B. AD, antidepressant; APD, antiparkinsonian.
resistant to inhibition by clorgyline and metabolized benzylamine and, as shown later, phenylethylamine. Tyramine and DA were equally well metabolized by both forms of the enzyme (Table 34.2) (Youdim et al., 1988a, 2005; Cesura and Pletscher, 1992). Clorgyline was shown to increase brain levels of norepinephrine and 5-HT and possess antidepressant activity in a series of double-blind clinical trials in depressed patients
(Youdim et al., 1988a). Nevertheless, the consistent cheese reaction observed with this drug in pharmacological and clinical studies led to its abandonment. The reports by Youdim and colleagues (Collins et al., 1970; Youdim et al., 1972) for the presence of MAO-A and B in postmortem human brains led to the suggestion that by mapping human brain MAO and distribution according to its isoenzymes, it would be possible to develop effective selective MAO inhibitors directed at each form for the treatment of depression and other neuropsychiatric diseases, yet without the occasional dangerous side-effects (cheese reaction) inherent with older MAO inhibitors (Youdim et al., 1972). L-Deprenyl (selegiline), the selective irreversible MAO inhibitor was the first such drug to be shown to have MAO inhibitory activities opposite to that of clorgyline, namely being a MAO-B inhibitor that inhibited the metabolism of phenylethylamine, but not 5-HT and norepinephrine, and to be devoid of the cheese reaction in isolated pharmacological preparations and in vivo animal studies (Knoll and Magyar, 1972). The second such inhibitor was AGN1135 and its R-optical isomer, rasagiline (Finberg et al., 1981; Kalir et al., 1981; Youdim et al., 2001a). Since then several other MAO-A and B inhibitors, such as irreversible (rasagiline) and reversible (moclobemide, lazabemide, milacemide and safinamide) inhibitors have also been shown not to induce a cheese reaction in animal and human studies when used at their selective MAO-B-inhibitory dosage (Table 34.1, Fig. 34.3). Yet selective irreversible inhibition of MAO-A is associated with the cheese reaction and studies of Finberg et al. (Finberg et al., 1981; Finberg and Tenne, 1982; Youdim et al., 1988a, b) have clearly illuminated and established that the cheese reaction is the consequence of irreversible MAO-A inhibition by at least 80%, an enzyme predominantly present in the gut, portal system and peripheral and central aminergic neurons (Fig. 34.2). However, selective irreversible MAO-B inhibitors, when used at concentrations that lose their selectivity for MAO-B and inhibit MAO-A, can also initiate such reactions. In vivo inhibition of MAO-A with irreversible non-selective or irreversible selective MAO-A allows the uptake of unmetabolized tyramine into the circulation, which eventually gains access to peripheral adrenergic neurons,
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Fig. 34.2. For full color figure, see plate section. The mechanism of potentiation of cardiovascular effects of tyramine – the cheese reaction. The prevention of metabolism of tyamine by irreversible monoamine oxidase (MAO)-AB or MAO-A inhibitors results in the uptake of dietary tyramine in circulation by cardiovascular adrenergic neurons, which initiates the release of norepinephrine (NA), a substrate for inhibitied MAO-A. L-DOPA, levodopa; COMT, catechol-O-methyltransferase.
thereby releasing norepinephrine (Fig. 34.2). These studies were the impetus for the development of reversible MAO-A inhibitor antidepressants lacking the ability to cause a cheese reaction. The rationale was that in the case of MAO-A inhibition and tyramine ingestion, the latter would displace the reversible inhibitor from the enzyme active site and thus be metabolized itself by the MAO-A (Fig. 34.4). However, reversible MAO-A (moclobemide) and B (lazabemide, milacemide and safinamide) inhibitors are devoid of the cheese reaction by the virtue of the ability of tyramine to displace the inhibitor from its binding site on MAO-A and to be metabolized by it. Indeed, these reversible inhibitors have very high specificity for the enzymes they inhibit and there is little cross-over for inactivation of the other enzyme. Moclobemide, a reversible MAO-A inhibitor, was the first such drug to be developed and introduced into clinics as an antidepressant (Da Prada et al., 1981; Korn et al., 1988; Youdim et al., 1988a, b; Haefely et al., 1992, 1993; Priest, 1992; Paykel and Youdim, 1993; Angst et al., 1995; Youdim, 1995). Several other similar drugs, such as brofaromine and befloxatone (Table 34.1), have undergone preclinical and clinical studies. Their preclinical and clinical pharmacology has shown similar activity to that of moclobemide (Paykel and Youdim, 1993; Youdim, 1995). These drugs, including moclobemide, have a limited cardiovascular tyramine potentiation and do not cause a
cheese reaction, even in excess tyramine ingestion, which is far beyond doses that may be present in food (Bieck et al., 1988; Da Prada et al., 1988). The lack of cheese reaction by these reversible MAO-A inhibitors (Table 34.1) relies on the concept that, during reversible MAO-A inhibition, the presence of tyramine near the active site of the enzyme results in the displacement of the inhibitor, which leads to metabolism of tyramine by this enzyme in the body and, since tyramine does not cross the blood–brain barrier, central MAO-A will continue to be inhibited, thus inducing increased brain levels of MAO-A substrates 5-HT and norepinephrine. The consequence of this is long-term adaptation at postsynaptic sites, leading to alleviation of depression, since these neurotransmitters have been implicated in the pathophysiology of depressive illness and drugs that increase their functional activity induce antidepressant activity.
34.3. Distribution of MAO-A and MAO-B in systemic organs and brain MAO is a ubiquitous enzyme and is found in all tissues in different concentrations and forms. MAO-B is more abundant, accounting for about 80% of total MAO activity in the human basal ganglia, which is in contrast to rat brain, where the ratio is roughly 1:1 (Table 34.3). In the human brain the distribution of MAO-A and
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M. B. H. YOUDIM AND P. F. RIEDERER
CI
CI
CH3 N
CH3 N
O
CH3 H Selegiline
Clorgyline CH3
H3C
N
N CH3 H
CH
H N
H
CH3 H
Methamphetamine
H
Amphetamine O
N N Rasagiline H (Agilect)
O N Ladostigil H
HO NH2 Aminoindane
N
NH2 Hydroxyaminoindane
N OH M30 Brain selective MAO-AB inhibitor
NH2
NH F O
O
Safinamide C17H18N2O2F NW=301
Fig. 34.3. Structures of monoamine oxidase (MAO)-A, B and MAO-AB inhibitors in clinical use or under development. Unlike selegiline, rasagiline is not metabolized to amphetamine or methamphetamine but rather to aminoindane. Ladostigil, a cholinesterase brain-selective MAO-AB inhibitor derivative of rasagiline, is metabolized to hydroxyaminoindane, a consequence of carbamate oxidation. Both ladostigil and M30 are brain-selective MAO-AB inhibitors that do not potentiate the cardiovascular effect of tyramine (cheese effect). Safinamide is a selective reversible MAO-B inhibitor with other pharmacological attributes, including its interaction with Kþ channel.
MAO-B differs in various regions (Collins et al., 1970; O’Carroll et al., 1983). Dopaminergic neurons of the substantia nigra reveal extremely low staining of MAO. This is in contrast to noradrenergic neurons of the locus ceruleus, which stain positively with the MAO-A substrate 5-HT and serotoninergic neurons of the raphe nuclei which stain for MAO-B. Glial cells stain predominantly for MAO-B, whereas astrocytes contain both enzyme forms (Konradi et al., 1989). Nevertheless, non-selective inhibition of MAO results in a highly significant increase of DA in human and rodent brains regions. Furthermore, both reversible and irreversible MAO-A inhibitors increase brain levels of 5-HT and norepinephrine, indicating that, even though the activity of MAO in these neurons may be low, the enzyme has a metabolic regulatory role. An increase in MAO-B with age and in both platelets (Murphy et al., 1976; Bridge et al., 1985) and human brains with Parkinson’s and Alzheimer’s
disease is detected (Adolfsson et al., 1980). Transmitter analyses of three different age groups (0–9.9 years, 10–59.9 years and 60 years and older) defined according to previous studies on ontogenesis and senescence in human brain showed a decrease in the 5-hydroxyindole acetic acid (5-HIAA)/5-HT ratio after the first decade of life. Changes in the dopaminergic system were seen in senescene with decreasing DA levels and an increase in the homovanillic acid/DA ratio, whereas the dihydroxyphenylacetic acid/DA ratio was unaffected. Norepinephrine was not changed over the lifetime (Konradi et al., 1992). In rodents and humans, MAO-A is present in the extraneuronal compartment and within the dopaminergic terminals, where it is involved in the metabolism of intraneuronal and released DA respectively (Fig. 34.5). Its role is to maintain the neurotransmitter concentration low within the neuron (Youdim et al., 1988a, b; Cesura and Pletscher, 1992). However, it should be remembered that DA is equally well metabolized by both MAO-A and B.
MONOAMINE OXIDASE A AND B INHIBITORS IN PARKINSON’S DISEASE
97
Table 34.2
Table 34.3
Some natural and synthetic substrates of monoamine oxidase (MAO)
Distribution of monoamine oxidase (MAO)-A and MAO-B in humans and in the brains of selected species
MAO type AþB Neurotransmitters and metabolites Epinephrine Norepinephrine Dopamine Serotonin (5-HT) Metanephrine Normetanephrine Tele-N-methylhistamine 1-methyl-4phenyl-4-propionoxy -piperidine (MPTP) Milacemide Trace amines, dietary amines, drugs Tyramine Octopamine Phenylethylamine Tryptamine Phenylethanolamine Synephrine Phenylephrine
þ
A
Total activity (%) B
Tissue Brain Human (striatum: all regions) Monkey Guinea pig Cat Pig Rat Mice Aminergic neurons Glia and astrocytes Other tissues Liver (human, rat, rabbit) Small intestine Kidney (rat) Lings (rat) Human platelet Chromaffin cell Pheochromocytoma PC-12 cells
þ þ þ þ þ
þ þ þ
þ
þ þ
þ þ
MAO-A
þ þ
MAO-B
20
80
25 20 25 40 55 50 100 50
75 80 75 60 45 50 0 50
55
45
75 25 55 5 5 95 95
25 75 45 95 95 5 5
Note: The above selectivity for MAO subtypes is based on determination in cell-free preparations.
FAD
SRS
MAO-A
SRS
MAO-A--RIMA
RIMA
SRS
FAD
SRS
Tyramine
SRS
FAD
FAD
FAD
Tyramine displacement of RIMA
SRS
FAD
RIMA and tyramine metabolites
Fig. 34.4. The mechanism of interaction of reversible monoamine oxidase (MAO)-A inhibitor (RIMA, moclobemide) with monoamine oxidase, its displacement by tyramine and their eventual metabolism by MAO and drug-metabolizing enzyme respectively.
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Dopamine receptor D2 agonists
Glia Entacapone MAO-A & B 3OMD
Tyrosine L-DOPA
DDC
Blood−brain barrier
COMT
Selegiline Rasagiline Ladostigil, M30
D2
DT
SV SV L-dopa
DDC
Dopamine DA
SV MAO A
AR
D1
Dopamine
Benzerezide carbidopa
MAO-A & B
Moclobarmide
Presynaptic terminal substantia nigra origin
Astrocyte
Postsynaptic terminal Striatum
Fig. 34.5. The pathway of dopamine (DA) synthesis from tyrosine via hydroxylation by tyrosine hydroxylase to levodopa (L-dopa) and subsequent decarboxylation by dopa decarboxylase (DDC) to DA and its metabolism by interaneuronal monoamine oxidase (MAO)-A and by glia and asotrocyte MAO-A and B extraneuronally. The selective inhibition of MAO by various selective MAO-A (moclobemide) or MAO-B (selegiline, rasagiline) does not alter the steady state of striatal dopamine. On the other hand, non-selective MAO-AB (ladostigil and M30) inhibitors induce highly significant increases in striatal dopamine and in other brain regions. D1 and D2, dopamine receptors; DAT, dopamine transporter; AR, amine reuptake; SV, synaptic vesicle; COMT, catechol-O-methyltransferase; 3OMD, O-methyldopa; DT, dopamine transporter; SV, vesicle.
34.4. MAO-B inhibitors in Parkinson’s disease Selegiline (L-deprenyl), a selective irreversible inhibitor of MAO-B, without the ability to cause a cheese reaction at its selective dosage, was identified for the treatment of PD because of the latter property and prominence of MAO-B in extrapyramidal brain regions of human brain (Birkmayer et al., 1975, 1977; Lees et al., 1977). It has been widely used in the treatment of Parkinson’s disease and has been shown to postpone the need for levodopa in early Parkinson’s disease and to be useful in the management of end-of-dose akinesia in fully developed disease (Birkmayer et al., 1975, 1977; Lees et al., 1977; Parkinson Study Group, 1993; Szeleny, 1993). Since then several other reversible and irreversible MAO-B inhibitors have been developed. The reversible MAO-B inhibitors lazabemide and milacemide, which showed great promise
as antiparkinsonian drugs, had systemic toxicology. However a recent addition is the antiparkinsonian drug rasagiline, a selective potent irreversible MAO-B with more than 10–15-fold the potency of selegiline (Youdim et al., 2001a; Finberg and Youdim, 2002; Parkinson Study Group, 2002, 2004, 2005; Rascol et al., 2005) which, unlike selegiline, does not give rise to methamphetamine metabolites, nor does it have the sympathomimetic activity of selegiline (Finberg et al., 1981; Finberg and Youdim, 2002) or cause cardiovascular complications (Youdim, and Riederer, 1993a; Finberg et al., 1999; Abassi et al., 2004) or orthostatic hypotension observed with selegiline. The orthostatic hypotension of selegiline has now been shown to be related to the methamphetamine metabolite (Abassi et al., 2004). Rasagiline increases the production of DA following levodopa treatment in monkeys, as measured by microdialysis (Finberg et al., 1998a, b) and on
MONOAMINE OXIDASE A AND B INHIBITORS IN PARKINSON’S DISEASE chronic treatment in rats it induced increased release of DA (Lammensdorf et al., 1996). Safinamide is a recently developed reversible selective MAO-B inhibitor with iron channel property that does not induce a cheese reaction (Marzo et al., 2004). This drug has anticonvulsant activity. It improves motor function in early Parkinson’s disease (Stocchi et al., 2004). A median safinamide dose of 70 mg/day (range 40–90 mg/day) has been shown to increase the percentage of parkinsonian patients improving their motor scores by 30% from baseline (responders). In a subgroup of 101 patients under stable treatment with a single DA agonist, the addition of safinamide potentiated the response (47.1% responders, mean 4.7-point motor score decrease; P 0.05). These results suggest that doses of safinamide exerting ion channel block and glutamate release inhibition add to its symptomatic effect and warrant further exploration of this drug in Parkinson’s disease. In parkinsonian brains obtained at autopsy from 2 weeks or 4 years of L-selegiline-treated subjects, a highly significant (>3000%) and moderate (40–70%) increase in phenylethylamine and DA was respectively observed in substantia nigra, caudate nucleus, putamen and globus pallidus, without any changes in 5-HT, norepinephrine or their metabolite contents (Riederer et al., 1986; Riederer and Youdim, 1986; Youdim and Riederer, 1993a). By contrast, clorgyline (an MAO-A inhibitor) increases both norepinephrine and 5-HT highly significantly with a slight increase of DA in human basal ganglia and animal striatum (Youdim et al., 1972). However, tranylcypromine, a non-selective MAO inhibitor, increases the three neurotransmitters in human and rat brain. Indeed, in rat brain clorgyline, selegline and rasagiline are unable to increase striatal DA or alter its metabolism (Finberg and Youdim, 2002). Only when both enzymes are inhibited does striatal DA increase, resulting in DA functional activity potentiation (Green et al., 1977).
34.5. MAO-A inhibitors in Parkinson’s disease Most investigators forget that DA is equally well metabolized by MAO-B and -A and that the latter enzyme is located intraneuronally and regulates the cytoplasmic concentration of DA with neurons and the extend DA is released. Nevertheless, little attention has been paid to MAO-A inhibition by MAO-A inhibitors in the treatment of PD, even though it has clearly been established that DA is equally well metabolized by MAO-A and MAO-B in the striatum (Collins et al., 1970; O’Carroll et al., 1983). There is no indication as to what is the contribution of MAO-A or MAOB inhibition or MAO-A compartmentalization to DA
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metabolism in the human striatum. This is mainly because the effect of L-selegiline or clorgyline on DA elevation in parkinsonian brains and brains obtained at autopsy from depressed subjects on MAO inhibitors (Youdim et al., 1972) is not as profound as the increase in 5-HT and norepinephrine or the selective MAO-B substrate, phenylethylamine, observed respectively with these inhibitors. These data have clearly indicated that when one form of the enzyme is fully inhibited in human basal ganglia, the other MAO can equally metabolize DA and thus its level will not change drastically in the striatum (Youdim and Riederer, 1993a). The major reason why MAO-A inhibitors have not received attention as antiparkinsonian drugs is because its irreversible inhibitors cause the cheese reaction. However, the reversible MAO-A inhibitor antidepressant (RIMA) does not possess this side-effect (Da Prada et al., 1988; Youdim et al., 1988a, b). The antiparkinsonian effects of a RIMA, moclobemide, when added to the standard therapy with levodopa and dopaminergic agonists, on motor performance of patients with idiopathic PD has been studied (Sieradzan et al., 1995). The influence of the drug on the mood and cognitive function of non-depressed parkinsonians has been evaluated. This was also considered valid, since 20–60% of parkinsonian patients suffer from depression and many factors could account for this, including the reported degeneration of raphe nucleus 5-HT and locus ceruleus noradrenergic neurons. Nevertheless, depression has a biological basis and in PD the main monoaminergic systems in the brain are disturbed. Indeed, besides the deficit in striatal DA, significant reductions in locus ceruleus, norepinephrine and raphe nucleus 5-HT have consistently been reported. The involvement of the latter two monoamines in the pathogenesis of depression would suggest that PD may be a useful model for the study of depression. Recent molecular genetic studies demonstrate that polymorphism in the 5-HT transporter, as observed in endogenous depression, is identical to that in parkinsonian patients with severe and frequent episods of depression. It could be shown that the 5-HT transporter gene-linked polymorphic region, but not the MAO-A gene promoter-associated polymorphism, may be a risk factor for depression in parkinsonian patients, whereas neither polymorphism increases the risk for development of Parkinson’s disease itself (Mo¨ssner et al., 2001). However, moclobemide was well tolerated by healthy volunteers when administered with levodopa and benserazide. Its safety and tolerance in parkinsonians treated with levodopa and a peripheral decarboxylase inhibitor were evaluated (Sieradzan et al., 1995). In these studies moclobemide was used as 450 mg
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daily dosage in parkinsonian subjects (Sieradzan et al., 1995). More recent studies indicate that the dosage of moclobemide can be increased to 900 mg, without unwanted side-effects, with a better clinical response in depressed subjects and greater efficacy for MAO-A inhibition, and presumably the same could be true for PD subjects. The low dosage, as used in moclobemidetreated PD studies (Sieradzan et al., 1995), may also explain why a relatively mild symptomatic antiparkinsonian response was obtained. Such a problem does not occur with L-selegiline or rasagiline, since they bind covalently to the enzyme and fully inhibit MAO-B. In this context, treatment with moclobemide and selegiline or rasagiline should be avoided, without application of tyramine restriction. Nevertheless, several studies with such combinations have not shown unwanted side-effects, whereas moclobemide can be safely prescribed to patients on levodopa/decarboxylase inhibitor therapy. A combination of reversible MAO-A (e.g. moclobemide) and reversible MAO-B (e.g. lazabemide) inhibitor may be worth considering as a therapeutic means. However, caution may need to be taken with regard to a combination of MAO inhibitors (even selective ones) with classical antidepressants and especially serotonin selective reuptake inhibitors (SSRIs). Such combined treatment strategies may provoke the ‘serotonin syndrome’, which is a serious adverse reaction in human brains. In the treatment of therapy-resistant depression, MAO inhibitors are an important therapeutic strategy. The combined treatment of MAO inhibitors with tricyclic antidepressants or SSRIs should be avoided (Bijl, 2004; Izumi et al., 2006; Nieuwstraten et al., 2006) due to the possibility of initiating the deleterious serotonin syndrome. The mild antiparkinsonian action of moclobemide (Sieradzan et al., 1995) is matched by its true antidepressant activity in several double-blind studies as compared with other antidepressants such as fluoxetine, imipramine and desimipramine (Bieck et al., 1988; Priest, 1992; Paykel and Youdim, 1993; Angst et al., 1995; Youdim, 1995). Recent studies on moclobemide’s antidepressant action in depressive parkinsonian subjects has shown that the drug can be a useful additional antidepressant and is well tolerated with standard therapy. Thus, the RIMA antidepressant moclobemide could influence the function of the aminergic neurotransmitters, as well as depression in Parkinson’s disease. Moclobemide, originally developed as an antidepressant, is effective in the treatment of depression. A number of studies have assessed its effects on cognition, but the differences in subject samples and experimental designs render their results inconclusive. In major depression, moclobemide was found to improve vigilance, psychomotor speed and
long-term memory. There have also been reports on improvement in memory and choice reaction time in the elderly subjects. In other studies in non-depressed elderly people and in healthy young volunteers, moclobemide had no significant effects on cognitive functions. Most importantly, it does not produce hypertensive reactions due to interaction with dietary tyramine (cheese reaction). Numerous animal (rats and mice) studies have shown that inhibition of MAO-A with either reversible (moclobemide) or irreversible (clorgyline) inhibitors of this enzyme induce little change in DA, suggesting that at first glance DA metabolism does not appear to be affected by this inhibitor. Nevertheless, striatal microdialysis studies in rats have shown that, after moclobemide or clorgyline or rasagiline, the release of DA occurs, and this is highly significant (Haefely et al., 1992, 1993; Lamensdorf et al., 1996; Finberg et al., 1998a). This would indicate that, although MAO-A or B inhibition does affect brain DA steady state, it affects its release. This may explain the antiparkinsonian effects of such drugs. Thus, the increased release of DA during MAO-A inhibition may account for the prolonged duration of motor response to single levodopa challenge in response to moclobemide (Szeleny, 1993; Sieradzan et al., 1995; Sternic et al., 1998). The relatively mild symptomatic effect of moclobemide in PD may be associated with the pharmacokinetic properties of this inhibitor. Moclobemide, being a reversible inhibitor, could be displaced from its binding site on MAO-A present intraneuronally and extraneuronally by DA formed from levodopa. Thus, disinhibition of the enzyme could occur. Haefely et al. (1992, 1993), examining the effect of moclobemide on DA metabolism in microdialysis studies, have indeed shown that DA can displace the inhibitor from its MAO-A binding site. Under such conditions, namely lack of MAO-A inhibition, reductions in DA accumulation and release could occur. Thus, it is evident that special attention needs to be paid to the pharmacokinetics of the ratio of daily dosage of moclobemide or other reversible MAO-A inhibitors to levodopa for a more effective action of moclobemide on DA metabolism and its antiparkinsonian activity. The studies so far done with the MAO-A inhibitor moclobemide have shown it to be well tolerated and safe in levodopa-treated parkinsonians (Sieradzan et al., 1995). The observed shortening of latency and prolonged duration of motor response to single-dose levodopa challenge may be explained by the known effects of moclobemide on the metabolism of exogenous levodopa to DA and oxidative deamination by MAO-A. Moclobemide seems to have a mild symptomatic benefit in PD (Sieradzan et al., 1995; Sternic et al., 1998). In particular, the baseline motor conditions after overnight withdrawal of medication
MONOAMINE OXIDASE A AND B INHIBITORS IN PARKINSON’S DISEASE improved during moclobemide treatment. The results suggest that bradykinesia may be more amenable to moclobemide than other parkinsonian disabilities. In non-depression parkinsonians, moclobemide does not significantly influence cognitive measures of mood. Further controlled studies are required to evaluate the place of moclobemide and other reversible selective MAO-A inhibitors such as brofaromine and befloxatone, which are more powerful inhibitors with greater affinity for MAO-A.
34.6. Selective MAO-B inhibitors in Parkinson’s disease with depressive illness Selegiline was originally developed as a psychoenergizer antidepressant. However, earlier uncontrolled open studies with large doses (100 mg) and later control studies with higher doses (> 15 mg) established a significant antidepressant action. However, in monotherapy and in combination with the 5-HT precursor 5hydroxytryptophan (5-HTP), it had significant antidepressant activity in controlled studies (Mendlewicz and Youdim, 1978, 1979, 1983; Mann and Gershon, 1980; Mann, 1989). An antidepressant activity with a selegiline patch at high doses is reported in recent studies. It is most likely that at high doses, selegiline loses its MAO-B inhibitory selectivity and also inhibits MAO-A, as has been regularly observed in animal studies, but it bypasses system inhibition of MAO-A. However, consideration should be given to a combination of selegiline or rasagiline with 5-HTP as antidepressant since three double-blind studies have shown that the selegiline–5-HTP combination is significantly more effective than 5-HTP alone in bipolar depressed subjects (Mendlewicz and Youdim, 1978, 1979, 1983) and little evidence was obtained for the efficacy of selegiline monotherapy at its selective MAO-B-inhibitory concentrations as antidepressant (Mendlewicz and Youdim, 1978). These studies require confirmation. The highly significant antidepressant action of the combination of 5-HTP plus L-deprenyl (selegiline) has been attributed to its action in human brain on DA metabolism, where selegiline significantly increases DA and phenylethylamine (a releaser of DA) in various regions. It has been shown that the functional activity of 5-HT (i.e behavioral response in rats to increased levels of brain 5-HT) formed from tryptophan or 5-HTP is DA-dependent (Green and Grahame-Smith, 1975; Green and Youdim, 1975; Youdim et al., 1976). This may explain why alpha-methyl-p-tyrosine, an inhibitor of tyrosine hydroxylase, is able to block 5-HT functional activity in response to the 5-HT precursors tryptophan and 5-HTP in rats (Green and Grahame-Smith, 1975).
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Thus, although DA may not be directly involved in the pathophysiology of depression or the mechanism of the action of MAO inhibitors as antidepressants, it may modulate serotonergic activity (Green and Grahame-Smith, 1975, Green and Youdim, 1975; Youdim et al., 1976). Thus, this may be one reason why it has been suggested that a non-selective reversible MAOA-B inhibitor that blocks DA metabolism might be more effective as an antidepressant than a selective reversible MAO-A inhibitor, such as moclobemide, which is thought to be a milder antidepressant and better tolerated by older patients (Sternic et al., 1998; Amrein et al., 1999; Erfurth and Back, 1999; Jansen and Ballering, 1999). Depression has a biological basis of its own, but particularly in Parkinson’s disease, where the main monoaminergic systems are degenerating. It is now well recognized that some 40–60% of parkinsonian subjects suffer from endogenous depression (Bosboom and Wolters, 2004; Lauterbach, 2004; Leentjens, 2004; Rihmer et al., 2004). Most often it is forgotten that, in addition to the deficit in striatal DA, highly significant reductions in locus ceruleus norepinephrine and raphe nucleus 5-HT have consistently been reported in parkinsonian brains. The association of diminished noradrenergic and serotoninergic neurotransmission in the pathogenesis of depressive illness would suggest that: (1) Parkinson’s disease may be an ideal condition for the study of depression and its treatment; and (2) a drug such as moclobemide and other RIMAs could exhibit dual pharmacological activities as antiparkinsonian drug and antidepressant in the same patients suffering from the two diseases. Several studies have shown that in depressed parkinsonian patients moclobemide is a useful antidepressant and it is well tolerated with standard therapy. The fact that RIMA can be safely prescribed to parkinsonian patients on levodopa/decarboxylase inhibitor therapy may be an ideal situation for the symptomatic treatment of parkinsonian subjects with episodes of depression. RIMA are considered to be not as effective antidepressants as the non-selective MAO inhibitors, even though selective inhibition of MAO-A results in increased norepinephrine and 5-HT, with little change in DA. However, non-selective MAO inhibitors induce a much greater increase in brain levels of these neurotransmitters (Green and Youdim, 1975; Green et al., 1977). This has been attributed to the observation that, when MAO-A is selectively inhibited, the intact MAO-B can continue to metabolize these amines, albeit at a slower rate, when their elevated concentrations satisfy the Km (Michaelis constant) of MAO-B for these amines (Green and Youdim, 1975; Green et al., 1977). Since selective MAO-B inhibitors do not increase brain
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levels of the three neurotransmitters, they have limited effect in their full functional neurotransmission. Thus, if we are to understand the contribution of MAO-A and B inhibition to DA metabolism and neurotransmission in PD and the contribution of DA neurotransmission to increased functional activity of 5-HT in the prevention of depression in Parkinson’s disease, there is a need for either non-selective reversible or brain-selective irreversible MAO-A and B inhibitors as antidepressant antiparkinsonian agents, devoid of tyramine potentiation, namely the cheese reaction.
34.7. Novel brain-selective irreversible MAO-AB inhibitors with limited tyramine potentiation in the treatment of Parkinson’s disease comorbid with dementia and depressive illness There are no profound clinical studies for the combined treatment with selective MAO inhibitors and acetylcholine esterase inhibitors in patients with (Alzheimer’s) dementia or parkinsonian patients developing dementia (Lewy body disease). However, recent studies have shown that patients with Lewy body disease on levodopa therapy for their extrapyramidal disorder respond cognitively to anti-Alzheimer acetylcholinesterase inhibitors (Benecke, 2003; Mosimann and McKeith, 2003; Wild et al., 2003) without loss of response to dopaminergic antiparkinsonian drugs. A significant number of these patients, as well as subjects with Alzheimer’s disease and Parkinson’s disease, have a predisposition to depression (Chan-Palay, 1992). To overcome this problem, a series of neuroprotective bifunctional cholinesterase brain-selective MAO-AB inhibitors (Weinstock et al., 2000; Youdim and Buccafesco, 2005a, b) from the pharmacophore of antiparkinsonian drugs selegiline and rasagiline (Sterling et al., 2002) by introducing a carbamate cholinesterase inhibitory moiety in such compounds to increase cholinergic activity (Fig. 34.3). This was done to retain the neuroprotective and antiparkinsonian activities of these compounds. Among the compounds identified, ladostigil ([TV3326 (N-propargyl)-(3R)-aminoindan-5-yl]-ethyl methyl carbamate) (Fig. 34.3) (Weinstock et al., 2000; Sterling et al., 2002), a derivative of rasagiline, is showing remarkable pharmacological activities that may make this compound ideal for the treatment of Parkinson’s disease comorbid with depressive illness and dementia. Ladostigil is a butryl and acetylcholinesterase inhibitor and possesses the anti-Alzheimer drug properties of other cholinesterase inhibitors, such as rivastigmine and galantamine, by attenuating the deficit in spatial learning in rats and monkeys in response to scopolamine (Weinstock et al., 2000; Buccafusco et al.,
2003). Compartive cognitive studies with other cholinesterase inhibitors (galantamine, rivastigmine) in monkey have shown that it is superior to these inhibitors. This may be accounted for by its ability to increase both acetylcholine and DA and cognitive enhancement by the latter neurotransmitter. Being weaker than rivastigmine and galantamine, its toxicity is limited as compared to the latter cholinesterase inhibitors. It retains the neuroprotective antiapoptotic activity of rasagiline (Weinstock et al., 2001; Youdim and Weinstock, 2001; Maruyama et al., 2003). Ladostigil does not exhibit either MAO-A or B inhibition in vitro or in acute in vivo studies. However, on chronic treatment in mice, rats, rabbits and monkeys, it shows remarkable selectivity for the inhibition of both enzymes in the brain, with little effects on MAO-A and B in the liver and small intestine (Weinstock et al., 2000, 2002a, b, 2003). Its in vivo MAO-AB inhibitory activity is explained by the observation that ladostigil acts as a prodrug. The oxidation of its carbamate cholinesterase inhibitory moiety gives rise to hydroxyl rasagiline that inhibits both MAO and B and may be selectively accumulated in the aminergic neurons. This novel property explains its limited tyramine potentiation in rats and rabbits, as compared to tranylcypromine, clorgyline and moclobemide (Weinstock et al., 2002b). It induces highly significant increases in norepinephrine, 5-HT and DA in the hippocampus and striatum of rats and mice (Weinstock et al., 2000; Sagi et al., 2003) and, in the forced-swim test model for antidepressant activity, it is equivalent to amitryptiline, clorgyline, tranylcypromine and moclobemide (Weinstock et al., 2002a). Furthermore, being an MAO-AB inhibitor, similar to MAO-B inhibitors (selegiline, rasagiline and lazabemide), it prevents the striatal dopaminergic neuron degeneration and DA depletion induced by the parkinsonism neurotoxin, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), in the mouse model of Parkinson’s disease (Sagi et al., 2003). And, unlike selegiline and rasagiline, it highly significantly increases brain DA in MPTP-treated mice above the level of control. The fact that it inhibits both forms of MAO is a bonus for preventing metabolism of DA by either form of MAO.
34.8. Combined treatment of MAO inhibitors with COMT inhibitors The combined treatment of MAO inhibitors and the peripherally and centrally acting catechol-O-methyltransferase (COMT) inhibitors entacapone and tolcapone has not been sufficiently evaluated in clinical studies with patients suffering from Parkinson’s disease. However, preclinical data let us assume that such
MONOAMINE OXIDASE A AND B INHIBITORS IN PARKINSON’S DISEASE combined treatment would not be harmful because catecholamines could still be metabolized in the CNS by COMT activity.
34.9. Neuroprotection Selegiline and rasagiline increase neuronal survival in a variety of in vitro and in vivo models of neural insult, often independently of MAO-B inhibition (for review, see Tatton and Chalmers-Redman, 1996; Foley et al., 2000; Youdim et al., 2005, 2006). These results have provoked excitement with respect to their potential as disease-modifying agents. The neurotoxins MPTP and 6-hydroxydopamine (6-OHDA) selectively damage dopaminergic neurons and MPTP elicits parkinsonian syndromes in mice, goldfish and primates, including humans. MPTP is both a substrate and a weak, partially reversible inhibitor of MAO-B, and a reasonably good substrate and potent, reversible inhibitor of MAO-A. The neurotoxic mechanism of MPTP is its conversion by astrocytic MAO-B to the toxin, 1-methyl-4-phenylpyridinium (MPPþ), a reversible inhibitor of both MAO-A and MAO-B (Singer and Ramsay, 1991), which enters the neuron via the DA transporter (for review, see Gerlach et al., 1991). There are also a range of endogenous substances, such as the b-carbolines and tetrahydroisoquinolines, that are metabolized to neurotoxic compounds by MAO-B (Glover and Sandler, 1993). All MAO-B inhibitors protect DA neurons against MPTP and such toxins by inhibiting their activation and, in some cases, neuronal uptake. This has been demonstrated in animal models for selegiline, pargyline and rasagiline at the cellular, neurochemical and behavioral levels (for review, see Glover and Sandler, 1993; Tatton and Chalmers-Redman, 1994). A neuroprotective effect against intrastriatally injected MPPþ has been demonstrated (Wu et al., 1995, 1996). Selegiline antagonizes MPPþ-induced apoptosis in a dopaminergic hybrid cell line, and this protection is independent of MAOB inhibition; higher concentrations (1 mM), however, induced apoptosis (Le et al., 1997), although this could not be confirmed by Vaglini et al. (1996). Sautter et al. (1994) reported that both rasagiline and selegiline protected marmosets against the effects of MPTP. In contrast to MPTP, 6-OHDA must be applied directly to the nigrostriatal system in order to elicit a toxic effect and its neurotoxicity does not require metabolism by MAO-B for its activation. However, rasagiline has been shown to protect against this neurotoxin (Blandini et al., 2004), against spontaneous central adrenergic degeneration in spontaneously hypertensive SHR rats (Eliash et al., 2005) and in cerebellar granule cells (Bonneh-Barkay et al., 2005). The neurotoxic mechan-
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ism of 6-OHDA is believed to be associated with oxidative stress, possibly mediated by release of bound iron (II). A neuroprotective effect of high-dose selegiline and rasagiline is suggested by the normalization of 6OHDA-induced release of acetylcholine from striatal slices and DA neurons (Knoll, 1987). Selegiline, pargyline and 2-hexyl-N-methylpropargylamine (Gibson, 1987; Finnegan et al., 1990; Yu et al., 1994; Zhang et al., 1996) but not mofegiline (Magyar, 1994) or the MAO-A inhibitor clorgyline (Knoll, 1987) protect noradrenergic neurons in rodent hippocampus and locus ceruleus against the toxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4; toxic effect due to its derivative, the aziridinium ion), and selegiline reversibly inhibits DSP-4-stimulated norepinephrine release in rat hippocampus (Magyar et al., 1998). It is not clear whether this capacity depends on inhibition of MAO-B, and inhibition of monoamine transport appears not to be involved (Hallman and Jonsson, 1984; Yu et al., 1994). However, Magyar (1993) attributed the protective effects of selegiline and its p-fluoro-derivative to the prevention of aziridinium ion uptake. Selegiline and mofegiline are also effective against 3,4-methyenedioxymethamphetamine (MDMA)induced serotonergic toxicity in rats (Mytilineou et al., 1997a, b). Both selegiline and rasagiline, but not pargyline, protect cultured mesencephalic dopaminergic neurons against glutamate receptor-mediated toxicity (Sprague and Nichols, 1995; Mytilineou et al., 1997b; Finberg et al., 1996, 1999a, b). For a review on the neuroprotective activity of rasagiline and selegiline in other in vivo models, see Youdim et al., (2003, 2005, 2006). 34.9.1. Neurorescuing effects It is recognized that lesions of the CNS activate a chain of responses which result in greater damage than might be expected from the magnitude of the initial insult. These processes are only incompletely understood, but it is hoped that it might be possible to slow, halt or even reverse such processes after their initiation. Such intervention is the major hope for the more effective management of central neurodegenerative disorders, including Parkinson’s and Alzheimer’s disease. Selegiline has been reported to protect dopaminergic neurons from MPTP-induced cell death, even when applied 3 days after exposure to the toxin, and prevent the neurodegeneration of tyrosine hydroxylase-reactive cells in the rat substantia nigra by subchronic administration of selegiline (Tatton and Wadia, 1991). Tatton coined the term ‘neurorescuing’ to describe this phenomenon, because at the time of selegiline administration, the MAO-B-catalyzed generation of MPPþ is completed
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within 36 hours of exposure to MPTP and neurodegeneration had already commenced. The same laboratory was unable to observe this effect with other MAO-A and B inhibitors (with the possible exception of pargyline and rasagiline (Tatton et al., 1996; Youdim et al., 2006). Both selegiline and rasagiline are able to increase the survival rate of motor neurons following axotomy of the rat facial nerve (Salo and Tatton, 1992) or subjection to spinal cord ischemia (Ravikumar et al., 1998) of rat retinal ganglion cells following damage to the optic nerve (Buys et al., 1995), of cultured mouse mesencephalic cells following withdrawal of growth factors and serum (Roy and Bdard, 1993) and of cultured mesencephalic neurons from rodents (Koutsilieri et al., 1996) and dogs (Schmidt et al., 1997) treated with MPPþ. These effects are seen at concentrations where MAO-B inhibitors do not inhibit the enzyme and PC12 and SHSY-5Y cells contain only MAO-A, and which can be blocked by protein synthesis inhibitors
(Tatton et al., 1994). Their mechanism has been attributable to neurotrophic and antiapoptotic properties of selegiline and rasagiline (Tatton et al., 1996; Paterson and Tatton, 1998; Paterson et al., 1998; Maruyama et al., 2004; Youdim et al., 2005). They noted that the observed neuroprotective action was accompanied by reduced intramitochondrial Ca2þ levels and reduced cytoplasmic radical concentrations, as well as by a decrease in the DNA fragmentation characteristic of apoptotic cell death. The authors also recorded the altered expression of a number of cellular mRNAs and proteins (discussed below), and suggested that the ultimate result of these changes is the prevention of mitochondrial swelling, a stabilization of the mitochondrial membrane potential (cM), thus inhibiting one of the processes thought to be among the earliest events in apoptosis (Figs. 34.6 and 34.7) (Tatton and Chalmers-Redman, 1996; Akao et al., 2002a, b). In a further investigation, they demonstrated that a significant decline in cM could be measured in nerve growth
Fig. 34.6. The mechanism of neurotoxin-induced neuronal death and its prevention by propargylamines. Mitochondria are responsible for cell survival/death via the regulation of Bcl-2 family antiaptotic (Bcl-2) and proapoptotic (Bad, Bax) proteins. Rasagiline, selegiline and propargylamine have been shown to induce cell survival in response to serum withdrawal or neurotoxins in neuronal cell cultures (SHSY-5Y and PC-12) through the activation of Bcl-2 and Bcl-Xl, and the downregulation of Bad and Bax. These propargylamines produce their neuroprotective activity by interacting with the mitochondrial outer membrane. The propargylamine moiety in these inhibitors prevents neurotoxin-induced collapse of mitochondrial membrane potential, mitochondria permeability transition and the opening of the voltage-dependent channel, as a consequence of antiapoptoic Bcl-2 family protein upregulation. The consequence of this is the prevention of ubiquitin-proteasome inhibition, release of cytochrome c and activation of proapoptotic caspases, resulting in cell survival. SOD, superoxide dismutase; PKC, protein kinase; AIF, apoptotic inducing factor; PT, permeability transition.
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Fig. 34.7. For full color figure, see plate section. Mitochondria are responsible for cell survival/death via the regulation of BCl-2 family antiapoptotic (Bcl-2) and proapoptotic (Bad, Bax) family proteins. Rasagiline, selegiline and propargylamine have been shown to induce cell survival in response to serum withdrawal or neurotoxins in neuronal cell cutltures (SHSY-5Y and PC-12) via activation of Bcl-2 and Bcl-Xl and downregulation of Bad and Bax. These propargylamines produce their neuroprotective activity by interaction with the outer-mitochondrial out membrane. They prevent neurotoxins inducing the collapse of mitochondrial membrane potential, mitochondrial permeability transition and the opening of the voltage-dependent channel (VDAC) as a consequence of Bcl-2 and Bcl-Xl activation. OM, outer mitochondria; IM, inner mitochondria; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; ROS, reactive oxygen species; HK, hexokinase; CK, creatine kinase; ANT, adenosine nucleotide translocase; CyD, cyclophilin D; CsA, ciclosporin A; PBR, peripheral benzodiazepine receptor.
factor-deprived PC12 cells 3 hours after the withdrawal of trophic support; this could be reversed by both nerve growth factor restoration and by selegiline and rasagiline (Wadia et al., 1998; Bar-Am et al., 2005). It is suggested that selegiline and rasagiline alter the relationship between Ca2þ levels and cM, perhaps by stimulation of protein synthesis, including that of BCL-2 (Wadia et al., 1998) (Figs. 34.6 and 34.7). Both rasagiline and selegiline prevent the translocation of proapoptic glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in neuronal cells from cytoplasm to the nucleus (Maruyama et al., 2001). Paterson et al. (1990) reported that the R-isomers of selegiline and 2-heptyl-N-methylpropargylamine inhibited cytosine arabinoside (ara C)-induced apoptosis in a primary cerebellar granule neuronal culture, but not that elicited by low Kþ levels. It is perhaps significant that ara C-, but not Kþ-induced apoptosis is associated with impaired mitochondrial function. Rasagiline shares all the properties of selegiline in terms of the molecular mechanisms described for selegiline in its neuroprotection and neurorescue activity (Figs. 34.6 and 34.7: see Youdim et al., 2005 for review). Recent studies have clearly indicated that the neuroprotective neurorescue activity of these propargylamine resides in the propargyl moiety, since propargylamine itself has a similar mechanism of action with almost identical potency (Weinreb et al., 2004; Bar-Am et al., 2005) (Fig. 34.8).
Tatton and Chalmers-Redman (1996) reported that desmethylselegiline (DMS), not selegiline, was responsible for the antiapoptotic effect in their cell culture systems. Given the kinetics of selegiline metabolism and its oral bioavailibility, however, they considered it unlikely that DMS would play a major part in the observed clinical benefits of selegiline, as oral delivery allows it to exhibit only an estimated 5–20% of its antiapoptotic potential. DMS is also an MAO-B inhibitor, but less potent than selegiline (Borbe et al., 1990). It is therefore unlikely that MAO-B inhibition accounts for its actions. In contrast, Magyar et al. (1998) found DMS to be only weakly antiapoptotic in a human melanoma cell line. The amphetamine metabolites of selegiline, on the other hand, antagonize the antiapoptotic effects of selegiline and rasagiline (Bar-Am et al., 2004a) (Fig. 34.9), and at high concentrations are proapoptotic (Tatton and Chalmers-Redman, 1996). Salo and Tatton (1992) compared the rescue phenomena they had observed with those which can be achieved with ciliary neurotrophic factor, and demonstrated that astrocytic ciliary neurotrophic factor mRNA expression is, in fact, upregulated by selegiline (Seniuk et al., 1994). Further, Kragten et al. (1998) reported that the selegiline analog CGP 3466 lacks MAO-B-inhibitory activity but is neuroprotective in a human neuroblastoma cell line; this activity was shown to be dependent on specific binding to the enzyme glyceraldehyde-3-phosphatase. Thiffault
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Fig. 34.8. For full color figure, see plate section. The proposed schematic pathway of the neuroprotective-neurorescue activity of rasagiline and propargylamine and their ability to process amyloid precursor protein (APP) via activation of a-secretase to release the neuroprotective-neurotrophic soluble amyloid protein-alpha (sAPPa). Both propargylamines activate PKC and ERK pathways and the inhibitors of PKC (GF109203X and Calpbestin) and ERK1/2 (PD98059 and UO126) prevent their neuroprotective activity. P-PKC, pan protein kinase C; P-ERK, extracellular signal regulation kinase; BDNF, brainderived neurotrophic factor; GMDF, glia-derived neurotrophic factor.
Cell death (% of control)
1200
1000
* 800
** **
600
*
**
** 400
200
0
C
SF
R
R+A R+AI
S
S+A A+AI
A
AI
Fig. 34.9. Neurorescue of partially differentiated PC-12 cells in serum-free cultures by rasagiline and selegiline and their prevention by methamphetamine metabolites of selegiline. but not by aminoindan. C, control; R, rasagiline; S, selegiline; A, methamphetamine; AI, aminoindan; SF, serum free.
MONOAMINE OXIDASE A AND B INHIBITORS IN PARKINSON’S DISEASE et al. (1997), however, found that no long-term benefit (30 days posttreatment) was affected by either selegiline or mofegiline with respect to MPTP-induced nigral cell loss in mice. A recent similar study with post-MPTP chronic rasagiline treatment has shown neurorescue of DA neurons, which has been attributed to its ability to induce protein kinase C (PKC)-dependent-mitogen-activated protein (MAP) kinase pathway resulting from activation and translocation of PKCa and b and phosphorylation of ERK1/2 (Yogev-Falach et al., 2003; Weinreb et al., 2004; Sagi et al., 2006) (Fig. 34.8). Rasagiline has demonstrated neuroprotective properties in a variety of models of neuroinsult, including closed-head injury in mice and facial nerve axotomy in newborn rats, and in several models of acute druginduced dopaminergic motor and cognition impairment; selegiline was also effective in several of these models, but there was no correlation between the potency of the two inhibitors (Mytilineou et al., 1997a, b; Speiser et al., 1998a, b). In vitro, rasagiline rescued nerve cells and increased the percentage of tyrosine hydroxylase-positive cells in serum deprivation-induced apoptosis (Finberg et al., 1996) and selegiline increased the proportion of tyrosine hydroxylasepositive cells without increasing total cell number, whereas mofegiline and Ro 16–6491 were ineffective in similar experiments (Tatton et al., 1994). Both rasagiline and selegiline were found to promote the survival of rat E14 mesencephalic dopaminergic cells in culture, but not of co-cultured GABAergic cells; rasagiline, but not selegiline, also displayed this effect under serum-free conditions (Finberg et al., 1998a, b). The effects of the rasagiline metabolite L-aminoindane, only observed at high doses, were distinct from those of rasagiline itself (Speiser et al., 1997). L-Aminoindane has no amphetamine-like properties, but its structural similarity to benzylamine suggests that it may be a reversible MAO-B inhibitor (Fowler et al., 1980). Unlike the methamphetamine metabolite of selegiline, which interferes with neuroprotective and neurorescue activity of rasagiline and selegiline, such an effect is not seen with aminoindane and aminoindane may have neuroprotective activity (Bar-Am et al., 2004b). Tatton and Chalmers-Redman (1996) reported that selegiline alters the expression of some 50 or more glial and neuronal proteins whose synthesis is modulated. Of these, 10 have been identified: the levels of both forms of superoxide dismutase, glutathione peroxidase, tyrosine hydroxylase, BCL-2, BCL-XL and c-FOS mitochondrial NADH dehydrogenase were increased; however the levels of BAX and c-JUN, two proteins associated with the initiation of apoptosis, were decreased. Very similar results have also been
107
obtained with rasagiline (Maruyama et al., 2002, 2004; Naoi et al., 2003; Youdim et al., 2003, 2005). These changes were selective and did not represent a general increase in cellular synthetic activity. It was therefore proposed that the propargyl moiety of rasagiline initiates a transcriptional program which removes the cell from the apoptotic pathway, probably by stabilizing the mitochondrial membrane and reducing oxidative stress (Tatton and Chalmers-Redman, 1996). These changes are not attributable to MAO-B inhibition, since propargylamine is a very poor MAO inhibitor. Furthermore, the recent studies with the S-optical isomer of rasagiline, TVP-1022, a drug that is 1000 times less potent than MAO inhibitors, have shown that MAO inhibition is not a prerequisite for neuroprotection. TVP 1022 shares a similar molecular mechanism of neuroprotection (Youdim et al., 2001b). It has now been established that the neuroprotective activity resides in the propargyl moiety, since propargylamine has similar activity, with the same potency in neuronal cell culture studies (Weinreb et al., 2004; Bar-Am et al., 2005). Selegiline increases the number of glial fibrillary acidic protein (GFAP)-immunoreactive astrocytes in rat striatum (Biagini et al., 1993) and subchronic treatment with selegiline lead to an increase in the number of GFAP- and basic fibroblast growth factor (bFGF)positive astrocytes following a mechanical lesion of the rat brain (Biagini et al., 1994). The proliferation of such cells is normally associated with CNS injury, and represents the first stage of the neurotrophinmediated repair process. Revuelta et al. (1997) treated rats with selegiline 3 weeks before and 3 weeks after the unilateral transection of the medial forebrain bundle; although the density of GFAP-positive astrocytes was elevated in the drug-treated animals in both the lesioned and unlesioned substantia nigra (but not striatum), the treatment did not reduce the axotomyinduced degeneration of the nigrostriatal system. In dopaminergic cell cultures exposed to MPPþ, high-dose selegiline (1–10 M), administered on the day following toxin exposure, improved cell survival rate significantly, possibly via stimulation of neurotrophin synthesis (Koutsilieri et al., 1996). Selegiline is also reported to stimulate synthesis of interleukins-1 and -6 in cultured peripheral blood mononuclear cells from healthy volunteers (Wilfried et al., 1997; Mu¨ller et al., 1998). Elevated cerebrospinal fluid levels of these trophins have been reported in untreated de novo Parkinson’s and Alzheimer’s disease patients (BlumDegen et al., 1996), suggesting that their increased synthesis may be an early response to the underlying disease process. Furthermore, selegiline and rasagiline elevated the nerve growth factor GDNF and BDNF
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concentration in an astrocyte and SHSY-5Y cell cultures (Semokova et al., 1996; Maruyama et al., 2004).
34.10. Other properties of MAO-B inhibitors Selegiline suppresses the degradation of putrescine, a key molecule in the regulation of polyamine synthesis. Polyamines, such as spermine and spermidine, are stored and synthesized in brain microglia, and are believed to play a number of roles in the CNS (for review, see Zappia and Pegg, 1988), including the modulation of N-methyl-Daspartate (NMDA) receptor activity (Williams et al., 1991), whose activation plays a central role in excitotoxic damage to the CNS. The N1-acetylated versions of these polyamines are themselves good MAO-B substrates; the suppression of the metabolism of these precursors and of putrescine should therefore lead to diminished sensitivity of the NMDA receptor, and thus offer a direct connection between MAO-B inhibition and neuroprotection by selegiline and rasagiline (Youdim and Riederer, 1993b).
34.11. Clinical aspects of MAO-B inhibitors in Parkinson’s disease The major clinical indications of selective MAO-A inhibitors are for depressive disorders, anxiety disorders and, more recently, Parkinson’s disease. In addition, the selective reversible MAO-A inhibitor moclobemide has shown minor indications for attention-deficit hyperactivity syndrome, smoking cessation and cognitive deficits in dementia. By contrast, selective MAO-B inhibitors have primarily found use in Parkinson’s disease and there may be some indications in Alzheimer’s disease. Nevertheless, high dosage of selegiline, which loses its selectivity and inhibits MAO, has been reported to possess antidepressant activity. The clinical applications of MAOIs in depressive disorders and anxiety disorders have been reviewed in detail by Riederer et al. (2004): the focus here is on the clinical use of the new irreversible type B-MAO inhibitor rasagiline. Also some comparison has been made to selegiline, which has been in clinical use since 1975.
symptomatic control of parkinsonism the safety profile of selegiline (5–10 mg/day) is good and no precaution is necessary at these dosages. Clinical studies designed to identify clinical neuroprotection point to the prevention of disease progression. This conclusion was drawn from an evidence-based review (Goetz et al., 2002) of the Movement Disorder Society, in which levels of therapeutic measures in Parkinson’s disease were analyzed. Tables 34.4–34.6 (from Riederer et al., 2004) give a closer view on prospective, randomized, double-blind and placebo-controlled studies with 5–10 mg/day selegiline monotherapy in Parkinson’s disease (Table 34.4), of selegiline as an adjunct to levodopa (Table 34.5) and selegiline’s efficacy for clinical neuroprotection in Parkinson’s disease (Table 34.6). Forty years of experience with selegiline in the treatment of Parkinson’s disease have indicated that selective inhibition of MAO is a useful therapeutic concept for both the early and advanced phases of this progressive disorder. In addition, basic research points to the efficacy of selegiline as a possible neuroprotective drug. However, this could not be demonstrated by the state-of-the-art clinical trials designed at the Table 34.4 Symptomatic efficacy of selegiline monotherapy in Parkinson’s disease Author (year)
N
Results
Parkinson Study Group (1989)
800
Myllyla¨ et al. (1992)
52
Allain et al. (1993)
93
Mally et al. (1995)
20
Palhagen et al. (1998)
157
Motor UPDRS (1 vs 3 months) Placebo 16.8 / 17.5 Selegiline 15.7 / 15.8 Disability significant less in the selegiline group up to 12 months Significant better motor UPDRS and depression scores at 3 months in the selegiline group Significant change in motor behavior and daily activity (UPDRS) after 3 weeks at 10 mg selegiline. Total UPDRS scores and North Western ratings were changed significantly after 4 weeks. Greatest changes in walking and in hypokinesia, rigidity were not modified by selegiline Change in total UPDRS at 6 weeks and 3 months: Placebo 25.3 / 1.75.4 Selegiline 0.45.0 / 15.3
34.11.1. Selegiline Selegiline’s potential as an antiparkinson drug has been reviewed in numerous studies (Riederer and Lachenmayer, 2003; Riederer et al., 2004). From these clinical studies it has been concluded that selegiline is efficacious as monotherapy and that there is evidence for a symptomatic effect as adjunct therapy (Goetz et al., 2002). There is, however, insufficient evidence for the ability of selegiline to prevent or control motor complications. In the
Prospective, randomized, double-blind, placebo-controlled studies. UPDRS, Unified Parkinson’s Disease Rating Scale. From Riederer et al. (2004).
MONOAMINE OXIDASE A AND B INHIBITORS IN PARKINSON’S DISEASE
109
Table 34.5 Selegiline as adjunct to levodopa (symptomatic efficacy) Author (year)
N
Results
Przuntek and Kuhn (1987) Sivertsen et al. (1989) Larsen et al. (1999)
21 38 163
Przuntek et al. (1999)
116
Shoulson et al. (2002)
368
Significant improvement in CURS and Schoppe motor performance series in 2/3 of cases on adjunct selegiline No significant difference in total CURS and scores for rigidity and funcitonal performance Patients treated with levodopa þ selegiline developed markedly less severe parkinsonism and required lower doses of levodopa during the 5-year study period Over 5 years, only a slight rise of levodopa dose in the selegiline group, but marked rise in the placebo group. Equal therapeutic efficacy in the selegiline group with lower levodopa dose During 2-year follow-up: Selegiline: 34% dyskinesias, 16% freezing, change in total UPDRS 7.0612.7 Placebo: 19% dyskinesia, 29% freezing, change in total UPDRS 1.5110.4
Prospective, randomized, double-blind, placebo-controlled studies. CURS, Columbia University Rating Scale; UPDRS, Unified Parkinson’s Disease Rating Scale. From Riederer et al. (2004).
Table 34.6 Neuroprotection in Parkinson’s disease by selegiline Authors (year)
Name of the study
N
Result
Tetrud and Langston (1990)
Pilot study for DATATOP
54
Parkinson Study Group (1993a, b, 1989)
DATATOP
800
Myllyla¨ et al. (1992)
Finnish trial
47
Allain et al. (1993)
French selegiline multicentre trial
93
Olanow et al. (1995)
SINDEPAR
101
Przuntek et al. (1999)
SELEDO
116
Endpoint (levodopa) Placebo 312. days Selegiline 548.9 days Endpoint (levodopa) After 12 months: Placebo 47% Selegiline 26% Endpoint (levodopa) Placebo 37228 days Selegiline 54590 days Endpoint (levodopa) After 3 months: Placebo 18.4% Selegiline 4.5% Deterioration in UPDRS between baseline and final visit (14 months) Placebo 5.81.4 points Selegiline 0.41.3 points Primary endpoint: need for >50% increase in levodopa dose Placebo 2.6 years Selegiline 4.9 years
UPDRS, Unified Parkinson’s Disease Rating Scale. From Riederer et al. (2004).
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M. B. H. YOUDIM AND P. F. RIEDERER
time selegiline was being studied (Riederer and Lachenmayer, 2003). 34.11.2. Zydis selegiline Zydis selegiline is a new galenic form of selegiline HCl, a freeze-dried product which is taken as a melt tablet (Clarke et al., 2003a). The reason for developing this drug derives from the fact that selegiline is a sympathomimetic agent and it is administered orally. It undergoes a first-pass metabolization in the liver, which leads to 90% breakdown of the parent compound into its metabolites amphetamine and metamphetamine. These metabolites and selegiline itself are thought to be responsible for its side-effects – cardiovascular disturbances (Churchyard et al., 1997). This may not be a selegiline-specific problem according to the numerous clinical publications over the last 40 years (Birkmayer et al., 1985, Gerlach et al., 2003). Nevertheless it is important to avoid amphetamine and metamphetamine cardiovascular effects (Abassi et al., 2004). Zydis selegiline, in a dose of 1.25 mg/ day, avoids the first-pass breakdown and produces a plasma concentration to inhibit irreversibly platelet MAO-B. This inhibition corresponds to the effect of 10 mg selegiline. Zydis selegiline is well tolerated and reduces Unified Parkinson’s Disease Rating Scale (UPDRS) scores significantly within 12 weeks of starting treatment (Clarke et al., 2003b). Double-blind, multicenter trials show that Zydis selegiline significantly reduces daily off time at 4–6 weeks of treatment with 1.25 mg dose by 9.9% (P ¼ 0.003) and at 10–12 weeks with the 2.5 mg dose by 13.2% (P < 0.001). The total number of off hours could be reduced by 2.2 hours/ day at week 12 from baseline, whereas this value was only 0.6 hours/day in the placebo group. Dyskinesiafree time increased by 1.8 hours/day at week 12. There was no difference in adverse reactions between the patient groups receiving Zydis selegiline and placebo (Waters et al., 2004). 34.11.3. Rasagiline (Azilect, Agilect) In a phase II evaluation, rasagiline mesylate has been administered to de novo parkinsonian patients in a 10-week, placebo-controlled and randomized trial using dosages of up to 4 mg/day. Specific attention has been given to cardiovascular parameters, since this inhibitor, unlike selegiline, has no sympathomimetic activity and is metabolized to aminoindan rather than amphetamine derivatives (Abassi et al., 2004). Rasagiline is 10–15 times more active than selegiline and was well tolerated in all doses (0.5–2 mg/day) used. There was no evidence of side-effects like hypertension, brady-
cardia or other cardiovascular adverse reactions (Marek et al., 1997) and side-effects are no more frequent than with placebo. Based on these data, a controlled trial of rasagiline in early Parkinson’s disease, the TEMPO study (Parkinson Study Group, 2002) has been performed. The goal of this clinical examination was to demonstrate the efficacy, safety and tolerability of rasagiline in untreated patients with early Parkinson’s disease by conducting a randomized, placebo-controlled and double-blind trial over 6 months. A first report was published by the Parkinson Study Group in 2002. A total of 138 patients entered the study taking placebo, whereas 134 were receiving 1 mg/day rasagiline and another 132 were receiving 2 mg/day monotherapy respectively. In the placebo group 112 patients completed 26 weeks without additional therapy: this figure was 111 in the group receiving 1 mg/day rasagiline and 105 patients in the group on 2 mg/day rasagiline. The TEMPO study clearly demonstrated that rasagiline monotherapy was effective in this 26-week clinical trial. Table 34.7 shows this significant improvement in UPDRS scores and subscales for rasagiline at 1 and 2 mg/day versus placebo. Table 34.8 gives evidence that there were no adverse events experienced by either treatment group. In a second phase of that trial (Parkinson Study Group, 2004) subjects randomized to 1 or 2 mg/day of rasagiline continued to receive this dosage, whereas patients previously taking placebo received rasagiline at 2 mg/day. This clinical design is named ‘delayedonset clinical trial’ and considers symptomatic efficacy of a drug as well as possible disease-modifying related activity to neuroprotective effect (Leber, 1997). This study demonstrated that rasagiline is effective even 1 year after start of treatment. Subjects treated with rasagiline, 2 and 1 mg/day, for 12 months showed less functional decline than subjects whose treatment was delayed for 6 months, suggesting its possible disease-modifying activity (Table 34.9). Again, there was no evidence for group differences with regard to adverse events (Parkinson Study Group, 2004). In the PRESTO study (Parkinson Study Group, 2005), safety, tolerability and efficacy of rasagiline in levodopa-treated parkinsonian patients and motor fluctuations have been studied. A total of 472 patients were enrolled with at least 2.5 hours off time each day, despite being on optimized antiparkinsonian therapy. In this multicenter, randomized placebo-controlled, double-blind, parallel-group clinical trial, rasagiline was used in doses of 1.0 or 0.5 mg/day in comparison to placebo. Outcome measures were changed from baseline in total daily off time during the 26-week treatment, in the percentage of patients completing the 26-week trial and in adverse event frequency.
MONOAMINE OXIDASE A AND B INHIBITORS IN PARKINSON’S DISEASE
111
Table 34.7 Primary analysis of changes between baseline and 26 weeks Effect size (95% confidence interval) Characteristic
Rasagiline 1 mg/day groups vs placebo
Rasagiline 2 mg/day group vs placebo
Total UPDRS score UPDRS motor subscale ADL subscale Mental subscale PIGD subscale Rigidity Tremor Bradykinesia Schwab and England ADL stage Hoehn and Yahr stage PDQUALIF scale Beck Depression Inventory Timed motor score
4.20 2.71 1.04 0.14 0.15 0.38 0.63 1.51 0.77 0.04 2.91 0.35 0.55
3.56 1.68 1.22 0.26 0.20 0.39 0.38 0.77 0.39 0.04 2.74 0.21 0.36
(5.66 (3.86 (1.60 (0.44 (0.41 (0.80 (1.03 (2.19 (0.42 (0.13 (5.19 (0.86 (1.19
to to to to to to to to to to to to to
2.73) 1.55) 0.48) 0.15) 0.11) 0.039) 0.23) 0.82) 1.96) 0.04) 0.64) 0.16) 0.08)
(5.04 (2.84 (1.78 (0.56 (0.46 (0.81 (0.78 (1.47 (0.81 (0.13 (5.02 (0.72 (1.00
to to to to to to to to to to to to to
2.08) 0.51) 0.65) 0.04) 0.06) 0.02) 0.02) 0.08) 1.58) 0.04) 0.45) 0.30) 0.28)
UPDRS, Unified Parkinson’s Disease Rating Scale; ADL, activities of daily living; PIGD, postural instability/gait disorder; PDQUALIF, Parkinson’s Disease Quality of Life. Primary outcome variable adjusted according to the primary model. Center-treatment interaction included if significant. Reproduced from Parkinson Study Group (2002), with permission from Archives of Neurology.
Table 34.8 Adverse events by treatment group*
Adverse events Any event Any event (moderate or severe intensity) Infection Headache Accidental injury Dizziness Astheniay Nausea Arthralgia Back pain Pain
Placebo group (n ¼ 138)
Rasagiline 1 mg/day group (n ¼ 134)
Rasagiline 2 mg/day group (n ¼ 132)
Combined rasagiline groups (n ¼ 266)
110 (79.7) 63 (45.7)
109 (81.3) 58 (43.3)
111 (84.1) 60 (45.5)
220 (82.7) 118 (44.4)
22 (15.9) 14 (10.1) 14 (10.1) 15 (10.9) 15 (10.9) 10 (7.2) 6 (4.3) 7 (5.1) 8 (5.8)
20 (14.9) 19 (14.2) 10 (7.5) 9 (6.7) 6 (4.5) 7 (5.2) 5 (3.7) 7 (5.2) 8 (6.0)
21 (15.9) 16 (12.1) 10 (7.6) 10 (7.6) 6 (4.5) 9 (6.8) 14 (10.6) 8 (6.1) 6 (4.5)
41 35 20 19 12 16 19 15 14
(15.4) (13.2) (7.5) (7.1) (4.5) (6.0) (7.1) (5.6) (5.3)
*Data are presented as the number (percentage) of patients. Between-groups differences were not statistically significant, unless otherwise indicated. yP ¼ 0.03 for the difference between placebo and combined treatment groups; P ¼ 0.05, difference between placebo and each of the individual treatment groups. Reproduced from Parkinson Study Group (2002), with permission from Archives of Neurology.
In general, the efficacy of rasagiline at 1 mg/day was greater than within the patient group receiving 0.5 mg/day. However, the primary outcome measure, reduction of daily off time, could be reached in both treatment groups, although it was much better in
the 1 mg/day patient group. UPDRS subscores were significant with respect to improvement of activities of daily living during off time, motor performance during on time, rigidity and tremor in both treatment groups.
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M. B. H. YOUDIM AND P. F. RIEDERER
Table 34.9 Change from baseline in efficacy variables between the 371 subjects receiving 6 months and 1 year of treatment*
Variable
Rasagiline, 1 mg/day vs delayed rasagiline, 2 mg/day
Rasagiline, mg/day, vs delayed rasagiline, 2 mg/day
UPDRS Totaly Motory ADL Mentaly Hoehn and Yahr scale score Schwab and England scale score
1.82 (3.64 to 0.01){ 1.06 (2.47 to 0.34) 0.48 (1.15 to 0.19) 0.16 (0.09 to 0.42) 0.08 (0.01 to 0.17) 0.21 (1.47 to 1.04)
2.29 0.99 0.96 0.07 0.04 0.15
(4.11 (2.39 (2.39 (0.33 (0.05 (1.41
to to to to to to
0.48)} 0.41) 0.29)k 0.19) 0.13) 1.11)
*Data are given as effect size (95% confidence interval). Rasagiline was administered as rasagiline mesylate. yThe model used to determine effect size includes a treatment center interaction. {P ¼ 0.05. }P ¼ 0.01. kP ¼ 0.005. Reproduced from Parkinson Study Group (2004), with permission from Archives of Neurology.
Bradykinesia and dyskinesia improved in only the 1 mg/day group. With regard to side-effects, there was a significant increase at 1 mg/day rasagiline in weight loss, anorexia and vomiting. There were no group differences with regard to blood pressure or pulse rate. The most common serious side-effects in all three groups were related to accidental injury (n ¼ 6), arthritis, worsening Parkinson’s disease, stroke, melanoma (n ¼ 3) and urinary tract infection (n ¼ 3). One patient was identified as having a melanoma before initiating study medication and its occurrence is no more than is seen with levodopa. A further clinical trial was set up to demonstrate the effectiveness of rasagiline as an adjunct to levodopa. The Lasting effect in Adjunct therapy with Rasagiline Given Once daily (LARGO) study was an 18-week, randomized, placebo-controlled, double-blind, doubledummy, parallel-group multicenter trial. A total of 687 outpatients were randomly assigned to oral rasagiline: 231 individuals received 1 mg once daily, 227 received entacapone, a peripheral COMT inhibitor, 200 mg with every levodopa dose and 229 individuals were on placebo. Primary outcomes were change in daily off time, clinical global improvement and UPDRS scores (Rascol et al., 2005). Table 34.10 shows that rasagiline improves daily off time significantly and at the same rate as entacapone. In addition, daily on time without troublesome dyskinesia improved significantly in both groups at similar rates. UPDRS secondary analyses and ancillary study efficacy assessment showed equipotency of rasagiline and entacapone adjunct to levodopa (unpublished data). There were no differences whatsoever between placebo-, rasagiline- and entacapone-treated individuals with regard to adverse events (Rascol et al., 2005). In
addition, rasagiline is well tolerated in patients older than 70 years. There is no evidence for typical sideeffects of dopaminergic treatment such as daytime somnolence, leg edema or nausea. Treatment with rasagiline is simple – once daily without the need for titration. Rasagiline is easy to handle as an adjunct to levodopa. In conclusion, rasagiline may be a relatively ideal drug once a day for the treatment of Parkinson’s disease both in the early stages as monotherapy and in advanced stages in combination with levodopa. Its efficacy is equal to that of entacapone. Rasagiline reduces significantly off-time periods in patients with motor fluctuations and improves daily on time without troublesome dyskinesias. The drug is well tolerated and does not show adverse events, even after longterm treatment. Rasagiline has the potential to demonstrate clinical neuroprotection as assumed from the 1-year delayed-onset clinical trial.
34.12. Conclusion After more than 30 years of experience with MAO and its inhibitors, we are now in a better position to understand the importance of this enzyme in brain function and how MAO inhibitors alter the function of central actions of monoaminergic neurotransmitters norepinephrine, 5-HT and DA. The experiences gained with selegiline (L-deprenyl), rasagiline and moclobemide as antiparkinsonian drugs and other RIMAs have shown that we can synthesize selective MAO-A or MAO-B inhibitors directed at the active sites of each enzyme, and such drugs are devoid of the unwanted hazardous side-effects associated with the earlier MAO inhibitors. The many clinical experiences have
Primary and associated efficacy assessments Adjusted mean change from baseline to treatment (SE) Rasagilin (n ¼ 222)
Entacapone (n ¼ 218)
Placebo (n ¼ 218)
Difference, rasagiline vs placebo (95% CI)
Daily off time (h) 1.18 (0–15) 1.20 (0–15) 0.40 (0–15) 0.78 (1.18 to 0.39) Daily on time without troublesome dyskinesia (h) 0.85 (0.17) 0.85 (0.17) 0.03 (0–17) 0.82 (0.36 to 1.27) Daily on time with troublesome dyskinesia (h) 0.23 (0.13) 0.18 (0.13) 0.14 (0.13) 0.09 (0.28 to 0.46) Responder rate (number [%])* 113 (51%) 99 (45%) 70 (32%) 2.5y (1.62 to 3.85)
P
Difference, entacapone vs placebo (95% CI)
0.0001 0.80 (1.20 to 0.41) 0.0005 0.82 (0.36 to 1.27) 0.6209 0.04 (0.32 to 0.41) < 0.0001 2.0y (1.29 to 3.06)
P < 0.0001 0.0005 0.8157 0.0019
Assessments measured by entries in 24-h diaries. Off-time period of poor overall function (i.e. increasing signs of Parkinson’s disease). On-time period of good overall function and mobility. *Responders were defined as patients showing an improvement of 1 h or more in the change from baseline in mean total daily off time. yOdds ratio. From Rascol et al. (2005).
MONOAMINE OXIDASE A AND B INHIBITORS IN PARKINSON’S DISEASE
Table 34.10
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also educated us how to use these drugs, for an adequate period and with the right dosage – these were the features that contained the inherent problems in earlier studies with non-selective MAO inhibitors. The present experiences with reversible MAO-A inhibitors, especially moclobemide, are demonstrating remarkable activities in different clinical settings. The most prominent aspect of these is that moclobemide is a true antidepressant with few side-effects, is well tolerated and shows clinical antidepressant efficacy and has antiparkinsonian activity. Because reversible MAO-A inhibitors such as moclobemide are showing remarkably safe action and relatively low incidents of side-effects, it is being considered in the treatment of mental functions in Parkinson’s and Alzheimer’s diseases, in which a significant number of these subjects (40–60%) suffer from endogenous depression. However, RIMAs are considered as mild antidepressants and may be useful for the treatment of subtypes of major depressions. The availability of the novel brain-selective MAO-AB inhibitor ladostigil, with limited tyramine potentiation and equivalent or better than RIMA, will indicate whether MAO-AB inhibition would be more effective than antiparkinsonian and antidepressant drugs than the selective MAO-A or B inhibitors so far examined in PD. Furthermore, recent clinical studies with cholinesterase inhibitors have demonstrated that introduction of such drugs in Lewy body disease patients does not interfere with their response to levodopa antiparkinsonian drug therapy. However, the therapeutic effects of MAO-A or B inhibitors in Lewy body disease have not been investigated. Thus, therapeutically there may be a greater advantage with the use of a drug such as ladostigil, which has multiple pharmacological actions, namely the ability to inhibit both forms of MAO and cholinesterase, related to the comorbidity of neurological neurodegenerative diseases with depressive illness.
Acknowledgments This work was supported by National Parkinson Foundation (Miami, USA), Michael J. Fox foundation (New York), Golding Parkinson Research Fund and Eve Topf Neurodegenerative Diseases Center (Technion, Haifa). We are grateful for their support.
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K., Rudolpha A., Parkisnon Study Group. (2002). Impact of sustained deprenyl (selegiline) in levodopa-treated Parkinson’s disease: a randomized placebo-controlled extension of the deprenyl and tocopherol antioxidative therapy of parkinsonism trial. J. Ann. Neurol., 51: 604–612. Sieradzan K, Chanon S, Stern G et al. (1995). The therapeutic potential of moclobemide, a reversible selective monoamine oxidase A inhibitor in Parkinson’s disease. Clin Psychopharmacol 15: 51S–60S. Singer TP, Ramsay RR (1991). The interaction of monoamine oxidases with tertiary amines. Biochem Soc Trans 19: 211–215. Sivertsen B., Dupont E., Mikkelsen B., Mogensen P., Rasmussen C., Boesen F., Heinonen E. (1989). Selegiline and levodopa in early of moderately advanced Parkinson’s disease: a double-blind controlled short- and longterm study. E. Acta Neurol. Scand. 126: 147–152. Speiser Z, Katzir O, Rehavi M et al. (1998a). Sparing by rasagiline (TVP-1012) of cholinergic functions and behavior in the postnatal anoxia rat. Pharmacol Biochem Behav 60: 387–393. Speiser Z, Levy R, Cohen S (1998b). Effects of N-propargyl1-(R)aminoindan (rasagiline) in models of motor and cognition disorders. J Neural Transm Suppl 52: 287–300. Sprague JE, Nichols DE (1995). Inhibition of MAO-B protects against MDMA-induced neurotoxicity in the striatum. Psychopharmacology (Berl) 118: 357–364. Sternic N, Kacar A, Filipovic S et al. (1998). The therapeutic effect of moclobemide, a reversible selective monoamine oxidase A inhibitor, in Parkinson’s disease. Clin Neuropharmacol 21: 93–96. Sterling J, Tamas T, Toth G et al. (2002). Novel dual inhibitors of AChE and MAO derived from hydroxyl aminoindan and phenetylamine as potential treatment for Alzheimer’s disease. J Med Chem 45 (24): 5260–5279. Stocchi F, Arnold G, Onofrj M et al. (2004). Safinamide Parkinson’s Study Group. Improvement of motor function in early Parkinson disease by safinamide. Neurology 63 (4): 746–748. Szeleny I (Ed.) (1993). Inhibitors of Monoamine Oxidase B. Birkha¨user, Boston. Tatton WG, Chalmers-Redman RM (1996). Modulation of gene expression rather than monoamine oxidase inhibition: (–)-deprenyl-related compounds in controlling neurodegeneration. Neurology 47 (Suppl 3): S171–S183. Tatton WG, Ju WY, Holland DP et al. (1994). (–)-Deprenyl reduces PC12 apoptosis by inducing new protein synthesis. J Neurochem 63: 1572–1575. Tatton WG, Wadia JS, Ju WY et al. (1996). ()-Deprenyl reduces neuronal apoptosis and facilitates neuronal outgrowth by altering protein synthesis without inhibiting monoamine oxidase. J Neural Transm 48: 45–59. Tetrud JW, Langston JW. (1990). The effect of deprenyl (selegiline) on the natural history of Parkinson’s disease. J. W. Science, 245: 519–522. Thiffault C, Lamarre-Theroux L, Quirion R et al. (1997). L-deprenyl and MDL72974 do not improve the recovery of dopaminergic cells following systemic administration of MPTP in mouse. Mol Brain Res 44: 238–244.
MONOAMINE OXIDASE A AND B INHIBITORS IN PARKINSON’S DISEASE Vaglini F, Pardini C, Cavalletti M et al. (1996). L-deprenyl fails to protect mesencephalic dopamine neurons and PC12 cells from the neurotoxic effects of 1-methyl-4phenylpyridinium ion. Brain Res 741: 68–74. Wadia JS, Chalmers-Redman RM, Ju WJ et al. (1998). Mitochondrial membrane potential and nuclear changes in apoptosis caused by serum and nerve growth factor withdrawal: time course and modification by ()-deprenyl. J Neurosci 18: 932–947. Waters CH, Sethi KD, Hauser RA et al. (2004). Zydis Selegiline Study Group. Zydis selegiline reduces off time in Parkinson’s disease patients with motor fluctuations: a 3month, randomized, placebo-controlled study. Mov Disord 19: 426–432. Weinreb O, Bar-Am O, Amit T et al. (2004). Neuroprotection via pro-survival protein kinase C isoforms associated with Bcl-2 family members. FASEB J 18 (12): 1471–1473. Weinstock M, Bejar C, Wang RH et al. (2000). TV 3326, a novel neuroprotective drug with cholinesterase and monoamine oxidase inhibitory activities for the treatment of Alzheimer’s disease. J Neural Transm Suppl 60: 157–169. Weinstock M, Kirschbaum-Slager N, Lazarovici P et al. (2001). Neuroprotective effects of novel cholinesterase inhibitors derived from rasagiline as potential anti-Alzheimer drugs. Ann NY Acad Sci 939: 148–161. Weinstock M, Poltyrev T, Bejar C et al. (2002a). Effect of TV 3326, a novel monoamine-oxidase cholinesterase inhibitor, in rat models of anxiety and depression. Psychopharmacology (Berl) 160 (3): 318–324. Weinstock M, Gorodetsky E, Wang RH et al. (2002b). Limited potentiation of blood pressure response to oral tyramine by brain-selective monoamine oxidase A-B inhibitor, TV-3326 in conscious rabbits. Neuropharmacology 43 (6): 999–1005. Weinstock M, Gorodetsky E, Poltyrev T et al. (2003). A novel cholinesterase and brain-selective monoamine oxidase inhibitor for the treatment of dementia comorbid with depression and Parkinson’s disease. Prog Neuropsychopharmacol Biol Psychiatry 27 (4): 555–561. Wild R, Pettit T, Burns A (2003). Cholinesterase inhibitors for dementia with Lewy bodies. Cochrane Database Syst Rev 3: CD003672. Wilfried K, Mu¨ller T, Kruger R et al. (1997). Selegiline stimulates biosynthesis of cytokines interleukin-1 beta and interleukin-6. Neuroreport 7: 2847–2848. Williams K, Romano C, Dichter MA et al. (1991). Modulation of the NMDA receptor by polyamines. Life Sci 48: 469–498. Wu RM, Murphy DL, Chiueh CC (1995). Neuronal protective and rescue effects of deprenyl against MPPþdopaminergic toxicity. J Neural Transm 100: 53–61. Wu RM, Murphy DL and Chiueh CC (1996). Suppression of hydroxyl radical formation and protection of nigral neurons by l-deprenyl (selegiline). Ann NY Acad Sci 786: 379–390. Yogev-Falach M, Amit T, Bar-Am O et al. (2003). The importance of propargylamine moiety in the anti-Parkinson drug rasagiline and its derivatives in MAPK-dependent
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amyloid precursor protein processing. FASEB J 17 (15): 2325–2327. Youdim MBH (Ed.) (1995). Reversible and Selective Inhibitors of Monoamine Oxidase: New Findings. Acta Psyuchiat, Scand 91:1–43. Youdim MB, Buccafusco JJ (2005a). Multi-functional drugs for various CNS targets in the treatment of neurodegenerative disorders. Trends Pharmacol Sci 26 (1): 27–35. Youdim MB, Buccafusco JJ (2005b). CNS Targets for multifunctional drugs in the treatment of Alzheimer’s and Parkinson’s diseases. J Neural Transm 111: 519–537. Youdim MB, Riederer P (1993a). Dopamine metabolism and neurotransmission in primate brain in relationship to monoamine oxidase A and B inhibition. J Neural Transm 91: 181–195. Youdim MB, Riederer P (1993b). The relevance of glial monoamine oxidase-B and polyamines to the action of selegiline in Parkinson’s disease. Mov Disord 8 (Suppl 1): S8–S13. Youdim MB, Weinstock M (2001). Molecular basis of neuroprotective activities of rasagaline and the anti-Alzheimer drug TV3326 [(N-propargyl-(3R)aminoindan-5-YL)-ethyl methyl carbamate.] Cell Mol Neurobiol 21 (6): 555–573. Youdim MBH, Sourkes TL (1965). The effect of heat, pH and riboflavin deficiency on monoamine oxidase activity. Can J Biochem 43: 1305–1318. Youdim MB, Collins GG, Sandler M et al. (1972). Human brain monoamine oxidase, multiple forms and selective inhibitors. Nature 236: 225–228. Youdim MBH, Green AR, Grahame-Smith DG (1976). The role of 5-hydroxytryptamine, dopamine and MAO in the production of hyperactivity. In: W Birkmayer, O Hornykiewicz (Eds.) Advances in Parkinsonism. Editiones Roche, Base, pp. l155–163. Youdim MBH, Finberg JPM, Tipton KF (1988a). Monoamine oxidase. In: U Trendelengurg , U Weiner (Eds.), Catecholamine II. Springer-Verlag, Berlin, pp. 119–192. Youdim MBH, Da Prada M, Amrein R (Eds.) (1988b). The cheese effect and new reversible MAO-A inhibitors. J Neural Transm (Suppl 26). Youdim MB, Gross A, Finberg JP (2001a). Rasagiline [N-propargyl-1R(þ)-aminoindan], a selective and potent inhibitor of mitochondrial monoamine oxidase B. Br J Pharmacol 132 (2): 500–506. Youdim MB, Wadia A, Tatton W et al. (2001b). The anti-Parkinson drug rasagiline and its cholinesterase inhibitor derivatives exert neuroprotection unrelated to MAO inhibition cell culture and in vivo. Ann NY Acad Sci 939: 450–458. Youdim MB, Amit T, Falach-Yogev M (2003). The essentiality of Bcl-2, PKC and proteasome-ubiquitin complex activations in the neuroprotective-antiapoptotic action of the anti-Parkinson drug, rasagiline. Biochem Pharmacol 66 (8): 1635–1641. Youdim MB, Maruyama W, Naoi M (2005). Neuropharmacological, neuroprotective and amyloid precursor processing properties of selective MAO-B inhibitor antiparkinsonian drug, rasagiline. Drugs Today (Barc) 41 (6): 369–391.
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Youdim MBH, Edmondson D, Tipton KF (2006). Monoamine oxidases. Nat Rev Neurosci 7: 295–309. Yu PH, Davis BA, Fang J et al. (1994). Neuroprotective effects of some monoamine oxidase-B inhibitors against DSP-4-induced noradrenaline depletion in the mouse hippocampus. J Neurochem 63: 1820–1828. Zappia V, Pegg AE (Eds.) (1998b). Progress in Polyamine Research. Plenum Press, New York. Zhang X, Zuo DM, Davis BA et al. (1996). Immunohistochemical evidence of neuroprotection by R(-)-deprenyl and N-(2-hexyl)-N-methylpropargylamine on DSP-4-induced degeneration of rat brain noradrenergic axons and terminals. J Neurosci Res 43: 482–489.
Further Reading Bieck PR, Antonin KH, Schmidt E (1993). Clinical pharmacology of reversible monoamine oxidase inhibitors. Clin Neuropharmacol 16 (Suppl 2): S34–S41. Fuller RW, Hemrick-Luecke SK (1985). Inhibition of types A and B monoamine oxidase A and B by 1-methyl4-phenyl-1,2,3,6-dihydropyridine. J Pharmacol Exp Ther 232: 696–701. Gerlach M, Riederer P (1996). Animal models of Parkinson’s disease: an empirical comparison with the phenomenology of the disease in man. J Neural Transm 103: 987–1041. Go¨tz ME, Breithaupt W, Sautter J et al. (1998). Chronic TVP-1012 (rasagiline) dose—activity response of monoa-
mine oxidases A and B in the brain of the common marmoset. J Neural Transm Suppl 52: 271–278. Green AR, Youdim MBH (1976). Use of animal models to study the action of monoamine oxidase inhibitors. In: Monoamine Oxidase and Its Inhibition, Ciba Foundation Symposium No. 39 Elsevier, Amsterdam, pp. 231–246. Lai CT, Yu PH (1997). R()-deprenyl potentiates dopamineinduced cytotoxicity toward catecholaminergic neuroblastoma SH-SY5Y cells. Toxicol Appl Pharmacol 142: 186–191. Larsen JP, Boas J (1997). The effects of early selegiline therapy on long-term levodopa treatment and parkinsonian disability: an interim analysis of a Norwegian—Danish 5-year study. Norwegian-Danish Study Group. J. Movement Disord 12: 175–182. Schmauss M (2002). Kontrolluntersuchungen. In: Riederer P, Laux, G, Po¨ldinger (Hrsg.). Neuro-Psychopharmaka, Band 3: Antidepressiva, Phasenpophylaktika und Stimmungsstabilisierer, 2. neubearbeitete Auflage. Springer, Wien, pp. 538–539. Tatton WG, Greenwood CE (1991). Rescue of dying neurons: a new action for deprenyl in MPTP parkinsonism. J Neurosci Res 30: 666–672. Zreik MJ, Fozard MJR, Dudley MW et al. (1989). MDL 72.974A: a potent and selective enzyme activated irreversible inhibitor of monoamine oxidase type B with potential for use in Parkinson’s disease (Parkinson’s disease and dementia section). J Neural Transm 1: 243–254.
Handbook of Clinical Neurology, Vol. 84 (3rd series) Parkinson’s disease and related disorders, Part II W. C. Koller, E. Melamed, Editors # 2007 Elsevier B. V. All rights reserved
Chapter 35
Anticholinergic medications YAROSLAU COMPTA AND EDUARDO TOLOSA* Neurology Service, Hospital Clinic, University of Barcelona, Barcelona, Spain
35.1. Introduction Ordenstein, following the observations of his professor, Jean-Martin Charcot, first described the beneficial effect of the belladonna alkaloids (mainly containing atropine as active component) on tremor and other Parkinson disease (PD) symptoms (Ordenstein, 1867). Subsequent investigators, such as Gowers (1888) at the end of the 19th century, agreed that other substances like Indian hemp (containing Cannabis sativa), scopolamine (hyoscine) and hyoscyamine (duboisine) were effective in mitigating tremor and muscular rigidity. Ordenstein suggested that parkinsonian symptoms resulted from peripheral parasympathetic overactivity, after the vagolyitic effect exerted by belladonna alkaloids. It was not until 1945 that Feldburg discovered that acetylcholine was also a central neurotransmitter which was abundant in the striatum at the synaptic vesicles of nerve terminals, and suggested a central effect for anticholinergic drugs. A few years later, Barbeau (1962) proposed that an altered dopaminergic–cholinergic balance exists in the striatum in PD with the primary deficit in dopamine leading to a secondary relative overactivity of acetylcholine. Normalization of this striatal imbalance would explain the beneficial effect of anticholinergics in PD. Another proposed mechanism of action for anticholinergics in PD is the inhibition of dopamine reuptake in the striatum (Coyle and Snyder, 1969). For over half a century the belladonna alkaloids formed the mainstay of the medical management of the Parkinson syndrome. These natural products were substituted in the 1960s by a series of synthetic anticholinergics and antihistaminics (Strang, 1965). Synthetic anticholinergic drugs with selective peripheral effects (Duvoisin, 1966, 1967) proved not to have
an antiparkinsonian effect, confirming the aforementioned Feldburg’s (1945) hypothesis.
35.2. Mechanism of action and clinical trials Anticholinergics appear to improve symptoms of PD through a central anticholinergic effect exerted in the striatum. Duvoisin showed that cholinesterase inhibitors, which can penetrate the brain, increase the severity of PD symptoms (Barbeau, 1962; Coyle and Snyder, 1969), an effect that can be reversed by anticholinergics, such as benzotropine. This observation provides a rationale for the use of anticholinergics in PD and supports the notion that a state of striatal cholinergic preponderance exists in PD secondary to the striatal dopamine deficiency (Barbeau, 1962). It is thought that the antimuscarinic properties of the anticholinergics mediate their antiparkinsonian properties. In two studies with direct mesencephalic and pallidal administration of drugs, atropine was found to have an antiparkinsonian action (Nashold, 1959; Velasco et al., 1982). Centrally active anticholinergics (muscarinic receptor antagonists) exert a modest improvement on PD symptoms, but the percentage of patients reported to improve with these drugs has varied greatly, from 40 to 77% in open trials (Corbin, 1949; Strang, 1965) and from 20 to 40% in double-blind studies (Parkes et al., 1974). It is frequently stated that anticholinergics are more effective in alleviating resting tremor and rigidity than akinesia and that the major benefit derived from their use is precisely from their tremorolytic effects (Doshay and Constable, 1957; Burns et al., 1964; Strang, 1965; Ebling, 1971; Obeso and Martı´nez-Lage, 1987). Such affirmation has its origin in the observation that the
*Correspondence to: Professor Eduardo Tolosa, Neurology Service, Hospital Clinic, Esc 8, 4 planta, Villarroel 170, 08036 Barcelona, Spain. E-mail:
[email protected], Tel: þ0034-93-227-5785, Cell: þ0034-227-5783.
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injection of the cholinomimetic drug tremorine elicited tremor and rigidity in animals (Everett et al., 1956), symptoms that improved after the administration of atropine or scopolamine. Reports suggesting that anticholinergics do not have a specific antitremor effect, however, abound in the literature. Thus, Marshall (1968) was of the opinion that anticholinergics had ‘little or no effect upon the tremor’ of PD, and Yahr and Duvoisin (1968), in a review on the subject, concluded that the modest improvement achieved with anticholinergics is ‘derived from a greater effect in relieving muscular rigidity and akinesia rather than tremor’. Still, although a specific tremolytic effect of the anticholinergics in PD has not been well documented, most investigators report improvement in tremor with anticholinergic monotherapy. A double-blind study using objective evaluation of tremor with accelerometry (Koller, 1986) clearly showed a reduction in tremor amplitude of about 60% from baseline in a group of 10 de novo patients with early parkinsonism, after treatment with trihexyphenidyl. However, other studies using quantitative measures of tremor differed in their results, showing both improvement (Agate et al., 1956) and lack of tremolytic effect (Norris and Vas, 1967). The differences described in the effect of anticholinergics on tremor and other symptoms of the PD have been attributed to differences in patient selection, drug dosages, specific drugs studied and on methods of assessment. Whether patients with early mild disease respond better or worse than those with more advanced parkinsonism has not been clarified, and it appears that the use of higher doses of anticholinergics does not yield better results than lower doses. Marsden (1969), in a placebo-controlled study, compared different doses of two anticholinergics and found no evidence of increased benefit from higher doses with either of the two, a failure that did not seem to be related to the appearance of side-effects. Burns et al. (1964) also found no evidence of increasing benefit with increasing dosage of trihexyphenidyl in a carefully controlled clinical trial. Therapeutic differences among the various synthetic anticholinergics are probably minor, but some patients may tolerate one better than the other. Studies of trihexyphenidyl (Martin et al., 1974), benzotropine (Tourtellotte et al., 1982) and bornaprine (Cantello et al., 1986) in levodopa-treated patients, and two reviews indicate that adjunctive anticholinergics have only a minor effect on PD symptoms in patients on levodopa therapy (Goetz et al., 2002; Katzenschlager et al., 2003).
35.3. Adverse effects Peripheral adverse effects of these agents include tachycardia, constipation (rarely leading to paralytic ileus), urinary retention, blurred vision and dry mouth (Duvoisin, 1965; Ebling, 1971). Gingivitis and caries, rarely leading to loss of teeth, may occur (Lang and Blair, 1989) and reduced sweating may interfere with body temperature regulation. These effects are all reversible when diminishing or with discontinuation of the drug, and can even show some tolerance after prolonged exposure. Rarely, some of these side-effects can be beneficial at times, as is the case for dry mouth, which can be advantageous in patients with prominent drooling. Caution must be exercised in elder male patients with comorbid prostate hypertrophy, due to a high risk for urinary retention. Blurred vision is a common side-effect, attributed to reduced accommodation due to parasympathetic blockade. Extremely rare is the occurrence of acute narrow-angle glaucoma, which can be precipitated in predisposed patients. The usefulness of anticholinergics is also limited by central side-effects. These include sedation, confusion and psychiatric disturbances, such as hallucinations and psychosis (Porteous and Ross, 1956; Koller, 1984). Impaired mental function (mainly immediate memory and memory acquisition) is a well-documented central side-effect that resolves after drug withdrawal (van Herwaarden et al., 1993). Anticholinergics can lead to an exacerbation of frontal lobe dysfunction in PD patients (Syndulko et al., 1981; Sadeh et al., 1982; Dubois et al., 1987). An impairment of higher cortical functions has been found in non-demented PD subjects with an acute subclinical dose of scopolamine (Bedard et al., 1998) and impaired neuropsychiatric function has been demonstrated even in patients without cognitive impairment (Syndulko et al., 1981; Sadeh et al., 1982). These central effects are more likely to occur with advanced age and in patients with dementia (De Smet et al., 1982). The marked involvement of the cholinergic system (i.e. nucleus basalis of Meynert) in PD (Forster and Lewy, 1912; Braak and Braak, 2000) and in dementia with Lewy bodies (Tiraboschi et al., 2002) pathology is probably the basis of the cognitive changes induced by anticholinergics.
35.4. Anticholinergic use in clinical practice The anticholinergics currently in use are listed in Table 35.1. One of the first introduced synthetic drugs is a piperidine compound, trihexyphenidyl. It was initially developed as a gastrointestinal antispasmodic agent, shown in trials in the late 1940s to be as effective
ANTICHOLINERGIC MEDICATIONS Table 35.1 Anticholinergic drugs commonly used to treat tremor in Parkinson’s disease Generic name
Daily dose (mg)
Trihexyphenidyl Benztropine Ethopropazine Procyclidine Diphenhydramine Bornaprine
1–20 0.5–6 100–800 7.5–20 25–200 8–8.25
as belladonna alkaloids in the management of PD, with one-half of patients achieving an average of 20% improvement (Rix and Fisher, 1972). The most representative drugs of the antihistamines are diphenhydramine (Montuschi, 1949) and orphenadrine (Strang, 1965); orphenadrine is thought to be more potent because of its more potent anticholinergic activity. Another widely used anticholinergic drug is benztropine, a combination of the atropine molecule and the benzhydryl group of the diphenhydramine molecule (Doshay et al., 1952). Developed in the 1950s, this drug is more potent than trihexyphenidyl and less sedative than antihistaminics. Other less commonly used anticholinergics are phenothiazine derivatives (i.e. ethopropazine), which, despite being neuroleptics, show prominent anticholinergic activity and, hence, some degree of antiparkinsonian effects (Young, 1972). Nowadays, due to the propensity to induce adverse effects, the anticholinergics have been progressively substituted as first-line treatment of the early stages of PD (Yahr, 1990) by other drugs such as the monoamine oxidase-B inhibitors or the modern dopamine agonists, which have better tolerability and have been shown to be associated with fewer motor complications when compared with levodopa (Rascol et al., 2002). However, no trials have directly compared the effects of dopamine agonists with those of the anticholinergics in PD. Despite a lack of definite data to confirm a special role in the management of tremor, anticholinergics are also recommended in patients in whom other therapies such as the agonists amantadine or levodopa have failed to control tremor sufficiently. In patients on long-term levodopa therapy and more advanced disease, e.g. patients with associated motor complications such as fluctuations or dyskinesias, the beneficial effect from adding anticholinergics has been questioned (Martin et al., 1974), but some authors believe that in some instances the addition of anticholinergics may convey some benefit (Parkes
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et al., 1974; Tourtellotte et al., 1982; Yahr et al., 1982; Koller, 1986). Development of tolerance to the effects of beneficial effects of anticholinergics is said to occur frequently. Such loss of therapeutic benefit is indeed a common clinical observation after months of treatment, but should be attributed, at least in part, to disease progression. Withdrawal of anticholinergics, even in patients in whom it is thought that the drugs are no longer effective, invariably results in worsening of the parkinsonian symptoms, at times to a level worse than the patients’ baseline state (Hughes et al., 1971; Horrocks et al., 1973). In PD anticholinergic drugs have been reported to alleviate dystonic spasms resulting from chronic levodopa administration, as is the case in early-morning dystonia (Poewe et al., 1987). In another study by Poewe et al. (1988), challenge with procyclidine in 9 PD patients with foot dystonia resulted in abolition of dystonia in 6, amelioration in 1 and no effect in the remaining 2 patients.
35.5. Summary The anticholinergics have been shown to improve the main symptoms of PD modestly. They are used as initial treatment in the early stages of the disease. Less commonly they are administered as adjuncts to levodopa or other therapeutic agents in more advanced stages. Levodopa-induced dystonia is another situation where anticholinergics could be helpful. In recent years the use of anticholinergics for the symptomatic treatment of PD has decreased significantly, mostly due to the successful introduction into therapy of a variety of new dopamine agonists and enzyme inhibitors that help to control symptoms and have been shown to be efficacious in delaying the introduction of levodopa or minimizing motor complications of chronic levodopa administration. Such studies have not been performed with the anticholinergics. Because of their side-effect profile, with both peripheral and central adverse effects, the anticholinergics should be always started at low doses and upward titration of doses done gradually. Due to their negative effects on memory and cognition, their use should be avoided in elderly patients. Therapeutic differences among the various synthetic anticholinergics are probably minor, but some patients may tolerate one better than another.
References Agate FJ, Dosahy LJ, Curtis FK (1956). Quantitative measurement of therapy in paralysis agitans. JAMA 160: 353–354.
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Barbeau A (1962). The pathogenesis of Parkinson’s disease: a new hypothesis. Can Med Assoc J 87: 802–807. Bedard MA, Lemay S, Gagnon JF et al. (1998). Induction of a transient dysexecutive syndrome in Parkinson’s disease using a subclinical dose of scopolamine. Behav Neurol 11: 187–195. Braak H, Braak E (2000). Pathoanatomy of Parkinson’s disease. J Neurol 247 (Suppl 2): II3–10. Burns D, DeJong D, Solis-Quiroga OH (1964). Effects of trihexyphenidyl hydrochloride (Artane) on Parkinson’s disease. Neurology 14: 13–23. Cantello R, Riccio A, Gilli M (1986). Bornaprine vs placebo in Parkinson disease: double-blind controlled cross-over trial in 30 patients. Ital J Neurol Sci 7 (1): 139–143. Corbin KB (1949). Trihexyphenidyl: evaluation of a new agent in treatment of parkinsonism. JAMA 141: 377–382. Coyle JT, Snyder SH (1969). Antiparkinsonian drugs: inhibition of dopamine uptake in the corpus striatum as a possible mechanism of action. Science 166: 899–901. De Smet Y, Ruberg M, Serdaru M et al. (1982). Confusion, dementia, and anticholinergics in Parkinson’s disease. J Neurol Neurosurg Psychiatry 45: 1161–1164. Doshay LJ, Constable K (1957). Treatment of paralysis agitans with orphenadrine (Disipal) hydrochloride. JAMA 163: 1352–1357. Doshay LJ, Constable K, Fromer S (1952). Preliminary study of a new antiparkinsonian. Neurology 2: 233–243. Dubois B, Danze F, Pillon B et al. (1987). Cholinergicdependent cognitive deficits in Parkinson’s disease. Ann Neurol 22: 26–30. Duvoisin RC (1965). A review of drug therapy in parkinsonism. Bull NY Acad Med 41: 898–910. Duvoisin RC (1966). The mutual antagonism of cholinergic and anticholinergic agents in parkinsonism. Trans Am Neurol Assoc 91: 73–79. Duvoisin RC (1967). Cholinergic-anticholinergic antagonism in parkinsonism. Arch Neurol 17: 124–136. Ebling P (1971). The medical management of Parkinson’s disease before the introduction of L-dopa. Aust N Z J Med 1 (Suppl): 35–38. Everett GM, Blockus LE, Shepperd IM (1956). Tremor induced by tremorine and its antagonism by anti-parkinsonian drugs. Science 124: 79. Feldburg W (1945). Present views on the mode of action of acetylcholine in the central nervous system. Physiol Rev 25: 596–642. Forster E, Lewy FH (1912). Paralysis agitans. In: M Lewandowsky (Ed.), Pathologische Anantomie. Handbuch der Neurologie. Springer Verlag, Berlin, pp. 920–933. Goetz CG, Koller WC, Poewe W et al. (2002). Management of Parkinson’s disease: an evidence-based review. Mov Disord 17 (Suppl 4): S1–S166. Gowers WR (1888). A Manual of Disease of the Nervous System. P. Blakiston’s Sons and Company, Philadelphia. Horrocks PM, Vicary DJ, Rees JE et al. (1973). Anticholinergic withdrawal and benzhexol treatment in Parkinson’s disease. J Neurol Neurosurg Psychiatry 36: 936–941.
Hughes RC, Polgar JG, Weightman D et al. (1971). Levodopa in Parkinsonism: the effects of withdrawal of anticholinergic drugs. Br Med J 2 (760): 487–491. Katzenschlager R, Sampaio C, Costa J et al. (2003). Anticholinergics for symptomatic management of Parkinson’s disease. Cochrane Database Syst Rev. (2): CD003735. Koller WC (1984). Disturbance of recent memory functions in parkinsonian patients on anticholinergic therapy. Cortex 20: 307–311. Koller WC (1986). Pharmacologic treatment of parkinsonian tremor. Arch Neurol 43: 126–127. Lang AE, Blair RDG (1989). Anticholinergic drugs and amantadine in the treatment of Parkinson’s Disease. In: DB Calne, (Ed.), Handbook of Experimental Pharmacology, Vol. 88: Drugs for the Treatment of Parkinson’s Disease. Springer Verlag, Berlin, Heidelberg. Marsden CD (1969). Extending the use of anticholinergic drugs in Parkinson’s disease. In: FJ Gillingham, IM Donaldson (Eds.), Third Symposium on Parkinson’s Disease. E & S Livingstone, Edinburgh, pp. 185–192. Marshall J (1968). Tremor. In: PJ Vinken, GW Bruyn (Eds.), Handbook of Clinical Neurology: Diseases of Basal Ganglia. Elsevier North-Holland, Amsterdam, pp. 809–825. Martin WE, Lowenson RB, Resch JA et al. (1974). A controlled study comparing trihexyphenidyl hydrochloride plus levodopa with placebo plus levodopa in patients with Parkinson’s disease. Neurology 24: 912–919. Montuschi E (1949). Benadryl in parkinsonism. The Lancet 1: 546. Nashold BS (1959). Cholinergic stimulation of globus pallidus in man. Proc Soc Exp Biol Med 101: 68–69. Norris JW, Vas CJ (1967). Mehixene hydrochloride and parkinsonian tremor. Acta Neurol Scand 43: 535–538. Obeso JA, Martı´nez-Lage M (1987). Anticholinergics and amantadine. In: W Koller (Ed.), Handbook of Parkinson’s Disease. Marcel Dekker, New York, pp. 309–316. Ordenstein L (1867). Sur la paralysie et la sclerose en plaque generalise´. Martinet, Paris. Parkes JD, Baxter RC, Marsden CD et al. (1974). Comparative trial of benzhexol, amantadine and levodopa in the treatment of Parkinson disease. J Neurol Neurosurg Psychiatry 37: 422–426. Poewe W, Lees AJ, Steiger D et al. (1987). Foot dystonia in Parkinson’s disease: clinical phenomenology and neuropharmacology. Adv Neurol 45: 357–360. Poewe W, Lees AJ, Stern GM (1988). Dystonia in Parkinson’s disease: clinical and pharmacological features. Ann Neurol 235: 73–78. Porteous HB, Ross DDN (1956). Mental symptoms in parkinsonism following benzhexol hydrochloride therapy. Br Med J 2: 138–140. Rascol O, Goetz C, Koller W et al. (2002). Treatment interventions for Parkinson’s disease: an evidence based assessment. Lancet 359 (9317): 1589–1598. Rix A, Fisher RG (1972). Comparison of trihexyphinidyl and dihydromorphanthridine derivative in control of tremor of parkinsonism. South Med J 65: 1385–1389.
ANTICHOLINERGIC MEDICATIONS Sadeh M, Braham J, Modan M (1982). Effects of anticholinergic drugs on memory in Parkinson’s disease. Arch Neurol 39: 666–667. Strang RR (1965). Orphenadrine (“Disipal”) in the treatment of parkinsonism: a two year study of 150 patients. Med J Aust 2 (11): 448–450. Syndulko K, Gilden ER, Hansch EC et al. (1981). Decreased verbal memory associated with anticholinergic treatment in Parkinson’s disease patients. Int J Neurosci 14: 61–66. Tiraboschi P, Hansen LA, Alford M et al. (2002). Early and widespread cholinergic losses differentiate dementia with Lewy bodies from Alzheimer disease. Arch Gen Psychiatry 59 (10): 946–951. Tourtellotte WW, Potvin AR, Syndulko K et al. (1982). Parkinson’s disease: Congentin with Sinemet, a better response. Prog Neuropsychopharmacol Biol Psychiatry 6: 51–55. van Herwaarden G, Berger HJ, Horstink MW (1993). Shortterm memory in Parkinson’s disease after withdrawal of
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long-term anticholinergic therapy. Clin Neuropharmacol 16 (5): 438–443. Velasco F, Velasco M, Romo R (1982). Effect of carbachol and atropine perfusions in the mesencephalic tegmentum and caudate nucleus of experimental tremor in monkeys. Exp Neurol 78: 450–460. Yahr M (1990). Principles of medical treatment. In: G Stern (Ed.), Parkinson’s disease. Chapman and Hall, Baltimore, pp. 495–508. Yahr M, Duvoisin RC (1968). Medical therapy of parkinsonism. In: PJ Vinken, GW Bruyn (Eds.), Handbook of Clinical Neurology: Diseases of Basal Ganglia. Elsevier North-Holland, Amsterdam, pp. 283–300. Yahr MD, Clough CG, Bergman KJ (1982). Cholinergic and dopaminergic mechanism’s in Parkinson’s disease after long term levodopa administration. Lancet 1: 709–710. Young RR (1972). Treatment of parkinsonism. N Engl J Med 287: 1047–1048.
Handbook of Clinical Neurology, Vol. 84 (3rd series) Parkinson’s disease and related disorders, Part II W. C. Koller, E. Melamed, Editors # 2007 Elsevier B. V. All rights reserved
Chapter 36
Antiglutamatergic drugs in the treatment of Parkinson’s disease ´ SIMO* AND FEDERICO EDUARDO MICHELI MARI´A GRACIELA CERSO Program of Parkinson’s Disease and Other Movement Disorders, Hospital de Clı´nicas, University of Buenos Aires, Buenos Aires, Argentina
36.1. Introduction In the last two decades drugs targeting glutamatergic pathways have been a matter of growing interest for the treatment of a wide variety of neurologic disorders, including Parkinson’s disease (PD) (Lipton and Rosenberg, 1994). In the vertebrate brain glutamate is the main excitatory neurotransmitter and mediates neurotransmission of most excitatory synapses (Miller, 1998; Kemp and Mc Kernan, 2002). Hyperactivity of glutamatergic transmission appears to be involved in different aspects of PD. First, glutamate-mediated excitotoxicity is one of the mechanisms proposed in the cascade of events leading to neuronal cell death (Olney, 1969; Olney and Ho, 1970); therefore, agents capable of avoiding this could be good candidates for neuroprotection (Lange and Riederer, 1994). Second, glutamatergic pathways from the subthalamic nucleus to the globus pallidus pars interna are enhanced in the parkinsonian state, which might contribute in the development of PD symptoms (Nash and Brotchie, 2002). And third, overactivity of the striatal glutamatergic receptors has been implicated as one of the mechanisms underlying levodopa-induced dyskinesias (Chase et al., 1996). There are three types of glutamate ionotropic channels: (1) N-methyl-D-aspartate (NMDA); (2) alphaamino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA); and (3) kainate. The NMDA subtype receptor is composed of two subunits: NR1, whose presence is mandatory, NR2A-D and in some cases NR3A or B subunits (McBain and Mayer, 1994). The functional characteristics of these ionotropic receptors are regulated by their phosphorylation state. In animal models, lesions of the nigrostriatal dopaminergic system are
associated with an increase in the phosphorylation of serine and tyrosine residues of the striatal NMDA receptors (Chase et al., 2000). Glutamate is such a powerful excitatory transmitter that stimulation of the NMDA receptors for prolonged periods of time or in excessive amounts leads to neuronal cell death as a result of a massive calcium influx, overproduction of free radicals, mitochondrial dysfunction and apoptosis (Olney, 1969; Bonfoco et al., 1995). In addition, excitotoxicity can take place in the presence of normal levels of glutamate when the NMDA receptor activity is pathologically increased (Zeevalk and Nicklas, 1992). On the other hand, glutamate-mediated synaptic transmission is essential for the normal functioning of the central nervous system. In fact, compounds with a very strong antiglutamatergic action can also block the normal neuronal function resulting in unacceptable side-effects (Schmidt and Bubser, 1989; Kaur and Starr, 1997). Unfortunately, the clinical use of potent glutamate antagonists, such as MK-801 which has remarkable excitotoxicityblocking properties in experimental models, is limited because of its side-effects (Lipton, 2004). The ideal antiglutamatergic drug should be able to block the NMDA receptor in situations of excessive activation but without altering glutamatergic transmission during normal conditions. It was recently noticed that agents with low affinity for the Mgþ-binding site like the L-aminoadamatane derivatives amantadine and memantine only enter the NMDA channel under conditions of pathological glutamate exposure (Dingledine et al., 1999). At present, the only antiglutamatergic agent used in the management of PD patients is amantadine, an old compound that has proved to be particularly useful for the treatment of levodopa-induced dykinesias.
*Correspondence to: Dr Maria Graciela Cerso´simo, Pen˜a 2225 5 C (CP 1126), Argentina. E-mail:
[email protected]. ar, Tel: 54-11-4806-2217, Fax: 54-11-4811-3076.
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So far, despite the effort in developing new agents with glutamate antagonist properties it has only been possible for a few of them, such as memantine, dextromethorphan, budipine, remacemide and riluzole, to be tried in clinical studies but results were poor.
36.2. Amantadine Amantadine hydrocloride was initially introduced as an antiviral agent effective against A2 influenza (Jackson et al., 1963). Its antiparkinsonian effect was discovered fortuitously in a 58-year-old woman with PD who experienced a remission of her symptoms while taking amantadine to prevent influenza. After this single case, the authors conducted a trial with 163 patients with PD and observed improvement in 66% of them. Since then it has been acknowledged that the beneficial effects on PD are usually short-lived (Schwab et al., 1969). Over the years, the introduction of a number of other different agents, including dopamine agonists, resulted in a more limited use of amantadine in part due to its modest antiparkinsonian action but also because of the short duration of the clinical benefit (Factor and Molho, 1999). Many clinical trials have investigated the efficacy of amantadine and recent reviews on PD treatment placed amantadine as a second-line therapy for PD. The interest in this agent has recently reappeared since Shannon et al. (1987) reported that amantadine improved motor fluctuations and Stoof et al. (1992) demonstrated amantadine’s activity at glutamate receptors, suggesting that its antiparkinsonian effects might be related to NMDA receptor blockade. Factor et al. (1998) reported that amantadine withdrawal in patients treated for longer than 1 year may result in a substantial increase of motor disability or delirium. In addition, several controversial and unresolved issues regarding the mechanism of action of amantadine as well as the duration of the beneficial response are still open questions. 36.2.1. Basic pharmacology and mechanism of action Amantadine hydrocloride is L-amino adamantamine, the salt of a symmetric 10-carbon primary amine. It is a stable, white, crystalline compound that is freely soluble in water (Schwab et al., 1969). In humans, it is well absorbed after oral administration. Blood levels peak 1–4 hours after an oral dose of 2.5 mg/kg. The drug has a plasma half-life of 10–28.5 hours and is excreted largely unmetabolized in the urine. Amanta-
dine hydrocloride is used clinically as 100-mg capsules and recommended doses for PD treatment are 100 mg b.i.d. or t.i.d. (Aoki and Sitar, 1988; Goetz, 1998). Amantadine interacts with several different neurotransmitters systems; however the exact mechanism of action is not established. It is classically described that the drug has dopaminergic and anticholinergic properties and more recently amantadine’s antagonist activity of NMDA glutamatergic receptors has been reported (Stoof et al., 1992). Amantadine exerts its dopaminergic effects, acting at presynaptic and postsynaptic levels. Presynaptically, the drug interacts with dopaminergic neurotransmission in two ways: first, enhancing the release of dopamine and other cathecholamines from dopaminergic terminals and second, inhibiting the reuptake process. Postsynaptically, a direct action of the drug on dopamine receptors has been described, resulting in changes in dopamine receptor affinity. Additionally, studies on the chronic effect of amantadine showed an increased striatal spiroperidol binding, suggesting D2 dopamine receptor blockade (Von Voigtlander and Moore, 1971; Bailey and Stone, 1975; Gianutsos et al., 1985). Stoof and colleagues (1992) reported amantadine’s antiglutamatergic properties as demonstrated by NMDA receptor blockade in the rat neostriatum at therapeutic doses. It has been demonstrated that amantadine acts as a non-competitive NMDA antagonist producing a concentration-, time- and voltage-dependent blockade of open NMDA channels (Kornhuber et al., 1991; Sobolevski et al., 1998). Recently it has been recognized that amantadine belongs to the type of blocker manifesting the so-called ‘trapping block’ of NMDA channels. These drugs enter an open NMDA channel and bind to its blocking site located deep in the pore. The blocking molecules remain in the pore for a relatively long time, being trapped behind the closed activation gate. Agonist reapplication opens the gate and allows the blocker to leave the channel. The molecular mechanisms of the trapping of blockers are at present unclear (Banplied et al., 1997; Sobolevski et al., 1998). Interestingly, despite the many different pharmacological properties attributed to this drug, it is not clear how they contribute to its clinical effect. Furthermore, the classic idea that the antiparkinsonian effect of amantadine is secondary to its dopaminergic or anticholinergic activities is not supported by more recent studies. In fact, therapeutic doses of amantadine in vitro are not associated with increased extracellular brain dopamine levels. Similarly, the presumed anticholinergic effect is also unlikely as amantadine only binds to acetylcholine receptors at very high
ANTIGLUTAMATERGIC DRUGS IN THE TREATMENT OF PARKINSON’S DISEASE concentrations (Brown and Redfern, 1976; Verhagen Metman et al., 1998a). Regarding the antidyskinetic effect of amantadine, compelling data support the hypothesis that it is related to the anti-NMDA properties of the drug. Furthermore, some authors propose NMDA antagonism of amantadine as the mechanism for its antiparkinsonian effect (Stoof et al., 1992). 36.2.2. Symptomatic treatment of parkinsonism Amantadine has a mild antiparkinsonian effect and appears to be more effective in the control of bradykinesia and rigidity and less effective in tremor. Schwab et al. (1969) conducted the first clinical experience to assess the efficacy of amantadine in 163 patients with PD. This was an open-label non-controlled study; patients received a maximum daily dose of 200 mg amantadine in addition to their usual antiparkinsonian medication. The authors found improvement of akinesia, rigidity and tremor in 66% of patients and noted that in 58% the benefit was sustained for a period of 3–8 months. Since that first report, several trials were performed to investigate amantadine’s effectiveness in the treatment of PD as monotherapy or associated with other antiparkinsonian drugs. A double-blind, placebo-controlled cross-over study was performed on 30 PD patients, all but 3 who were on anticholinergic or antihistaminic drugs; patients received amantadine as monotherapy. Clinical assessments included evaluations of tremor, rigidity, all physical signs, daily activities, repetitive motions and an overall average. Amantadine resulted in a statistically significant 12% overall improvement over placebo. Ten patients continued treatment for 10–12 months. Improvements in tremor and rigidity remained relatively constant although there was some apparent loss of efficacy in timed tests (Butzer et al., 1975). Fahn and Isgreen (1975) conducted a randomized double-blind, cross-over, placebo-controlled trial in 23 Parkinson’s disease patients. During the first cross-over period the patients were randomized to placebo or amantadine 200 mg/day. The authors reported a favorable response in 16 patients (70%). The most common adverse reactions were insomnia, anorexia, dizziness, nervousness, irritability, depression and sleepiness. Parkes and colleagues (1974) compared the efficacy of amantadine (200 mg/day) and anticholinergics (benzhexol 8 mg/day) or both in 17 PD patients in a randomized, double-blind cross-over trial. The clinical improvement observed with amantadine or benzhexol as monotherapy was a reduction of 15% in functional disability without significant differences between the
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two drugs: both drugs in combination resulted in a reduction of 40% of total disability. Walker et al. (1972) also showed that amantadine is superior to placebo when administered in patients receiving anticholinergics. In a double-blind, crossover trial in 42 PD patients they found amantadine was 74% superior to placebo. As adjunct therapy of levodopa, amantadine is somewhat efficacious in the symptomatic treatment of PD. In a double-blind, randomized cross-over study, Savery (1977) added amantadine to 42 PD patients treated with levodopa/carbidopa. The clinical evaluation after a period of 9 weeks resulted in a significant improvement in symptoms. Similarly, Fehling (1973) in a double-blind, randomized cross-over study compared the effect of amantadine or placebo in 21 patients receiving levodopa/carbidopa and found amantadine to be significantly more effective than placebo in improving PD symptoms. Nonetheless, these findings could not be confirmed by other authors who found no differences in the evaluation of patients treated with levodopa/carbidopa with and without amantadine (Millac et al., 1970; Callagham et al., 1974). It is generally described that amantadine produces a transient clinical benefit with a loss of efficacy after 6–12 months, probably due to a tachyphylaxis phenomenon (Schwab et al., 1969). Nonetheless, some authors have questioned the validity of this concept. Factor et al. (1998) in a critical review of 22 studies of amantadine found that many of them had included patients with postencephalitic parkinsonism, multiple system atrophy or progressive supranuclear palsy. The length of amantadine therapy ranged from 4 days to 12 months and in 13 studies a decline of efficacy was not mentioned, suggesting there are not enough reliable data to support this notion (Marsden, 1988; Factor and Molho, 1999). Zeldowicz and Huberman (1973) performed a clinical trial on 77 PD patients to evaluate whether there is a decline in efficacy. A total of 19 patients had good to excellent response to amantadine monotherapy and maintained that improvement for an average of 21 months, with the longest duration being 30 months. In addition, a marked deterioration took place when amantadine was switched in a random fashion to placebo. 36.2.3. Treatment of motor complications Amantadine was found to be effective in the treatment of levodopa-induced dyskinesias in patients with PD. Preclinical studies suggest that the development of levodopa-induced motor complications is associated with an increase in phosphorylation state of NMDA
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receptors in striatal medium spiny neurons; as a result, synaptic efficacy is enhanced and corticostriatal glutamatergic input is amplified, affecting striatal GABAergic output and probably leading to motor response complications. Therefore, it is conceivable that amantadine exerts its antidyskinetic effect by normalizing striatal NMDA receptor hyperfunction (Chase et al., 1996; Dunah et al., 2000). Verhagen Metman and colleagues (1998a) conducted the first controlled clinical trial to evaluate the effects of amantadine on levodopa-associated dyskinesias and motor fluctuations in 18 advanced PD patients (average age 60 years, Hoehn and Yahr stage II–V) in a double-blind, cross-over, placebo-controlled study during a 6-week period. All patients received amantadine or placebo for 3 weeks. Amantadine doses ranged from 100 to 400 mg/day depending on age, renal function and tolerance. At the end of each study period the patients received an intravenous levodopa infusion for 7 hours at an individually determined optimal rate, defined as the lowest rate producing the maximal antiparkinsonian effect. The evaluations were performed during the last 2 hours of the levodopa infusion and choreiform dyskinesias and parkinsonian symptoms were scored every 10 minutes. Dyskinesias were also videotaped and subsequently scored by a second blinded neurologist. Parkinsonian symptoms and dyskinesias were assessed using the Unified Parkinson’s Disease Rating Scale (UPDRS) part III, items 20, 22, 23, 26 and 31 and a modified Abnormal Involuntary Movement Scale (AIMS). Motor fluctuations were assessed with the UPDRS part IV, items 32 (duration of dyskinesias), 33 (severity of dyskinesias) and 39 (proportion of the day in the ‘off’ state), as well as patient diaries on the last 2 or 3 days of each study arm. The statistical analysis of measures showed a significant (P < 0.001) reduction in the severity of dyskinesias which was 60% lower with amantadine as compared to placebo. In this study amantadine substantially ameliorated levodopa-induced peak-dose dyskinesias without worsening parkinsonian symptoms. Dysphasic dyskinesias could not be evaluated as they did not occur during optimal levodopa infusion rate. Only 4 patients withdrew from the study because of adverse reactions (confusion 1, hallucinations 1, palpitations 1 and nausea 1) (Verhagen Metman et al., 1998a). One year later Metman et al. (1999) reported the results of a 1-year follow-up of the previously reported study. Of the initial 18 patients, 17 participated in this study with a nonrandomized, double-blind, placebo-controlled design. Ten days prior to the follow-up assessment, amantadine was replaced by capsules containing either amantadine or placebo. On the test day, the patients received an intravenous infusion of levodopa followed by motor
assessments. Results showed that the reduction in dyskinesias severity was 56% compared with 60% 1 year before. The authors conclude that the beneficial effect of amantadine on levodopa-induced dyskinesias is maintained for at least 1 year after treatment initiation (Metman et al., 1999). In the two previous studies amantadine was administrated orally and onset of benefit was observed from days to weeks after treatment initiation. Del Dotto and colleagues (2001) investigated the possible occurrence of an acute effect of amantadine after an intravenous infusion. They conducted a randomized, double-blind, placebo-controlled study including 9 PD patients with peak-dose levodopa-induced choreiform dyskinesias. Their mean age was 59.7 years, disease duration was 8.4 years, Hoehn and Yahr stage III in the ‘off’ condition and the daily dose of levodopa immediately prior to study was 860 mg. All patients were evaluated on 2 different days for 5 hours while taking their usual antiparkinsonian medications. The 9 patients received their first morning levodopa dose, followed by a 2-hour intravenous amantadine (200 mg) or placebo infusion. Parkinsonian symptoms and dyskinesias were assessed every 15 minutes during the infusion and 3 hours postinfusion using the UPDRS scale part III, tapping test and the AIMS. Results showed that the average of dyskinesia scores during amantadine infusion was 50% lower when compared to placebo (P < 0.01). These results indicate that the antidyskinetic effect of amantadine occurs acutely and does not require days or weeks to develop (Del Dotto et al., 2001). The antidyskinetic effect of amantadine was also confirmed by other authors. Snow et al. (2000) performed a double-blind, placebo-controlled, cross-over study to assess the effect of amantadine (200 mg/day oral) versus placebo on levodopa-induced dyskinesias in 24 patients with PD showing a significant (P < 0.004) reduction of 24% in the total dyskinesia score after amantadine administration. 36.2.4. Prevention of disease progression Several recent studies suggest that amantadine has neuroprotective properties in addition to its symptomatic effects. It has been suggested that the enhanced excitatory amino acid neurotransmission may play a role in the pathogenesis of several chronic neurodegenerative diseases, including PD (Kornhuber et al., 1994; Danysz et al., 1997). Studies in monkeys indicate that excitatory amino acids such as glutamate are involved in the pathophysiological cascade of 1-methyl-4-phenyl-1236tetrahydropyridine (MPTP)-induced neuronal cell death. This observation supports the hypothesis that glutamate antagonists such as amantadine may be able to delay
ANTIGLUTAMATERGIC DRUGS IN THE TREATMENT OF PARKINSON’S DISEASE the progression of the disease (Lange et al., 1997). In addition, multiple in vitro studies have recently shown the neuroprotective properties of amantadine and its congener compound memantine at therapeutically used doses (Kornhuber et al., 1994). Uitti and colleagues (1996) studied survival in patients with PD and other parkinsonian syndromes employing standard survival curves and a Cox regression model to identify independent predictive variables for survival. Patients treated with and without amantadine were similar in terms of age, gender, type of parkinsonism, Hoehn and Yahr staging and cognitive status. The authors found that the use of amantadine is an independent predictor of improved survival. Glutamate receptor antagonist drugs appear to be promising agents for the neuroprotective therapy of PD (Kornhuber and Weller, 1996). Several compounds with antiparkinsonian effects, such as amantadine, memantine and budipine, have been shown to be non-competitive NMDA receptor antagonists, are candidates for clinical trials (Lange et al., 1997) and appear to be promising agents for the neuroprotective therapy of PD (Kornhuber and Weller, 1996). 36.2.5. Side-effects Amantadine is usually well tolerated. The more frequent adverse reactions associated with the use of amantadine include: insomnia, anxiety, dizziness, impaired coordination, nervousness, nausea and vomiting. These side-effects are usually mild, although they can be severe in elderly patients. In fewer than 5% of patients, irritability, headaches, depression, ataxia, confusion, hallucinations, nightmares, somnolence, agitation, diarrhea, constipation, livedo reticularis and xerostomia are reported. Dry mouth and blurred vision are considered peripheral anticholinergic side-effects. Livedo reticularis is more often in women and is frequently associated with persistent ankle edema (Loffler et al., 1998). Unusual adverse effects include hyperkinesias, urinary retention, rash and decreased libido whereas toxic manifestations of amantadine include acute psychosis, coma, cardiovascular toxicity and death. More rare adverse reactions have been reported as isolated cases such as vocal myoclonus, heart failure or peripheral neuropathy (Vale and Maclean, 1977; Pfeiffer, 1996). Shulman and colleagues (1999) reported a case of sensory motor peripheral neuropathy secondary to chronic administration of amantadine in a 48-year-old woman where the discontinuation of the drug resulted in the resolution of trophic skin ulcers, paresthesias and distal weakness.
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Amantadine toxicity may be associated with overdose or renal insufficiency as 90% of an oral dose is excreted unchanged in the urine (Macchio et al., 1993). These toxic effects may be exacerbated by the concomitant use of anticholinergic agents. Withdrawal effects of amantadine are not frequent but may be serious. Factor and colleagues (1998) reported 3 PD patients who, after gradually tapering amantadine, experienced acute delirium, paranoia and agitation in addition to worsening of motor symptoms. In all of them the syndrome rapidly resolved after amantadine restitution. Some characteristics were common among the 3 patients. They were elderly and had hallucinations in the past, dementia, advanced PD and a long duration of amantadine therapy, representing possible risk factors for this complication (Factor et al., 1998).
36.3. Other antiglutamatergic drugs 36.3.1. Memantine Memantine (1-amino-3,5-dimethyladamantane) is an L-aminoadamantane derivative first synthesized in 1968. It has been proposed that memantine may be useful for the treatment of PD symptoms (Fischer et al., 1977; Schneider et al., 1984). Also, some case reports have suggested the utility of memantine in levodopa-induced dyskinesia therapy (Hanagasi et al., 2000) However, evidence to conclude about its efficacy in any indication for PD is so far insufficient. Clinical trials have shown that memantine is effective in the treatment of Alzheimer’s disease (Reisberg et al., 2003). Memantine is an uncompetitive and low-affinity NMDA receptor antagonist with voltage-dependent binding (Bormann, 1989). Unlike amantadine, memantine has no dopaminergic or anticholinergic actions. Memantine has a three-ring structure with a bridgehead amine that binds to the Mgþ binding site of the NMDA receptor (Bormann, 1989; Lipton, 1993). Memantine is completely absorbed from gastrointestinal tract with peak blood levels occurring 20–30 minutes after an oral dose of 5 mg/kg. The mean half-life of memantine is 60–100 hours and approximately 80% of the drug circulates unchanged. The usual recommended dose for patients with PD is 10 mg t.i.d. (Jarvis and Figgit, 2003; Lundbeck, 2002). Only a few qualified studies assessing the efficacy of memantine in PD are found in the literature. Merello et al. (1999) performed a randomized, placebo-controlled, cross-over study in 12 PD patients with motor fluctuations to asses the effect of memantine on the cardinal symptoms of PD and levodopa-induced dyskinesias.
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A significant improvement of motor symptoms in the ‘off’ and ‘on’ states evaluated by means of the UPDRS motor scale was observed. No significant effect of memantine on levodopa-induced dyskinesias was reported (Merello et al., 1999). Memantine is usually well tolerated; reported sideeffects included diarrhea, dizziness, headache, hallucinations, agitation, insomnia and urinary incontinence (Jarvis and Figgitt, 2003). There are no data available regarding the utility of memantine in the prevention of PD progression. 36.3.2. Dextromethorphan Dextromethorphan is a widely used and safe antitussive agent with low affinity and uncompetitive antagonist properties of the NMDA receptors. Based on this knowledge, dextromethorphan was tried in PD and a variety of conditions where glutamate overactivity is supposed to play a pathogenic role (Wong et al., 1988; Church et al., 1989). Dextromethorphan is well absorbed in the gastrointestinal tract with peak blood levels occurring 1–4 hours after an oral dose of 2.5 mg/kg and a median half-life of 2 hours. There is genetic polymorphism for the oxidative O-demethylation being both extensive and poor metabolizers. Half-life in poor metabolizers can reach up to 45 hours. Recommended dosage varies between 100 and 200 mg/day (Woodworth et al., 1987; Schadel et al., 1995). Only two open-label and non-controlled studies assessing the efficacy of dextromethorphan for the treatment of motor symptoms of PD in non-fluctuating patients have been carried out. Montastruc et al. (1994) performed a study to investigate the effect of adding dextromethorphan 90 mg/day to the therapy of 13 PD patients. Evaluations with the UPDRS motor scale done at baseline and after 1 month of treatment did not show any change in the scores (Montastruc et al., 1994). Conversely, Bonuccelli et al. (1992) found significant improvement on UPDRS motor scale scores of 6 de novo PD patients and another 6, in which dextromethorphan was added to their previous treatment. In this study doses of 180 mg/day were associated with significant improvement in tremor, rigidity and finger-tapping. Verhagen Metman et al. (1998b) conducted a study with dextromethorphan in patients with levodopainduced dyskinesia and motor fluctuations. Eighteen patients were included to initial open-label dose escalation screening. The dose of dextromethorphan was increased up to 180 mg/day or until side-effects occurred. All patients in addition received quinidine 100 mg b.i.d. to inhibit O-demethylation of dextromethorphan. Pati-
ents reporting subjective improvement were included in a second phase of the study, with a double-blind, placebo-controlled, cross-over design consisting of 2-week arms separated by 1-week washout. Six patients were included in the second part of the study. Although parkinsonian scores were not modified by dextromethorphan, dyskinesias improved by 25 % (P 0.05). The severity of motor fluctuations also improved significantly by 66% (P 0.05), according to the UPDRS part IV-item 39. Adverse events included decreased levodopa efficacy, increased dystonia, increase in pre-existing impotence, nausea, perspiration and drowsiness (Verhagen Metman et al., 1998b). At present data are insufficient to conclude on efficacy and safety of dextromethorphan in any indication of PD. 36.3.3. Budipine Budipine (1-t-butyl-4,4-diphenylpiperidine) has a complex pharmacological profile interacting with different neurotransmitter systems. Besides its NMDA receptor antagonist properties it also influences GABAergic, noradrinergic, serotoninergic and cholinergic transmission (Jackisch et al., 1993; Kolckgether et al., 1996; Eltze, 1999). Up to 2000 budipine was still available in some European countries but cardiac side-effects, including arrhythmias due to an acquired long QT syndrome, led to important restrictions, further limiting its use in clinical practice (Scholz et al., 2003). Przuntek et al. (2002) conducted a multicenter, placebo-controlled, double-blind study in 84 PD patients to assess the efficacy of 20 mg budipine three times a day in addition to a stable optimum dopaminergic regimen. Duration of the study was 4 months and patients were evaluated with the Columbia University Rating Scale (CURS). Budipine significantly (P 0.01) decreased the CURS subscores for rigidity, tremor and akinesia compared with placebo. Adverse events reported in the budipine group were dizziness, dry mouth, loss of appetite, nervousness and visual dysfunction (Przuntek et al., 2002). The usefulness of budipine in the treatment of patients with motor fluctuations was investigated by Spieker et al. (1999) in an open-label study performed in 7 PD patients medicated with budipine at doses of 40 mg/day in addition to their dopaminergic therapy. The duration of the study was 8 weeks and assessments were UPDRS motor section in the ‘on’ state and a diary over 7 days recording hours of ‘on/off’ states, dyskinesias or dystonia. Results showed that time ‘off ‘decreased in 5 of the 7 patients; also motor scores during the ‘on’ period improved. Peak-dose dyskinesias did not occur in any of the patients.
ANTIGLUTAMATERGIC DRUGS IN THE TREATMENT OF PARKINSON’S DISEASE At present there is agreement that the risk-tobenefit ratio for the use of budipine is unfavorable because of the significant increased risk of cardiac arrhythmias. This is the reason why the use of budipine in the treatment of PD is not recommended. 36.3.4. Remacemide Remacemide hydrochloride is a low-affinity, noncompetitive NMDA channel antagonist which has shown antiparkinsonian efficacy in rodent and primate models. The active metabolite of remacemide AR-R 12495 also has a moderate affinity for the NMDA receptor and both interact with voltage-dependent neuronal sodium channels (Greenamyre et al., 1994; Schachter and Tarsy, 2000). A multicenter randomized, placebo-controlled, double-blind, parallel-group, dose-ranging study of remacemide was performed in 200 early PD patients who were not receiving levodopa or dopamine agonists. Subjects were randomized to remacemide 150, 300 or 600 mg daily, or matching placebo for 5 weeks. The study failed to demonstrate any symptomatic effect of remacemide as monotherapy in patients with early PD (Parkinson Study Group, 2000). Shoulson et al. (2001) assessed the safety, tolerability and efficacy of remacemide adjunct treatment in 279 PD patients with motor fluctuations receiving levodopa. The authors conducted a randomized, double-blind, placebo-controlled, parallel-dose-ranging study during a 7-week treatment period. Remacemide doses were 300 mg b.i.d. and 600 mg q.i.d. Results showed that remacemide was safe and well tolerated as adjunct to dopaminergic therapy in patients with PD and motor fluctuations. However, UPDRS motor scores and percentage of ‘on’ time did not show any significant improvement in the remacemide group compared with placebo (Shoulson et al., 2001). The Parkinson Study Group (2001) evaluated the effect of remacemide hydrochloride in the treatment of levodopa-induced dyskinesias. A total of 39 PD subjects with disabling dyskinesias were included in a multicenter, randomized double-blind, placebocontrolled, parallel-group study during a period of 2 weeks. Daily doses of remacemide were 150, 300 or 600 mg or matching placebo. The study failed to demonstrated any significant changes in dyskinesia measures, but a statistically significant improvement in the ‘off’ state UPDRS motor score (P ¼ 0.01) and in the UPDRS part II (P ¼ 0.04) was observed in patients receiving remacemide 150 mg/day. In subjects receiving remacemide 300 mg/day a significant (P ¼ 0.004) improvement in the percentage of ‘on’ state daily hours was found and in the UPDRS part II
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scores in the ‘off’ state (P ¼ 0.04). Finally, the group of remacemide 600 mg/day only showed significant (P ¼ 0.04) improvement in the UPDRS part II scores in the ‘on’ state. The most common dose-related adverse events associated with remacemide were nausea and dizziness (Shoulson et al., 2001). More rarely, headache, abnormal vision, vomiting and hypokinesia can ocur (Clarke et al., 2001). Remacemide appears to be a safe and well-tolerated drug; however, larger trials are required to establish its efficacy in the treatment of levodopa-induced dyskinesias and parkinsonian symptoms. 36.3.5. Riluzole The antiglutamatergic agent riluzole (2-amino-6-trifluoromrthoxy-benzothiazole) is currently the only drug approved for the treatment of amyotrophic lateral sclerosis and its effect can only extend the survival of patients for a few months (Bensimon et al., 1994). Riluzole has multiple mechanisms of action: (1) inactivation of voltage-dependent sodium channels (Benoit and Escande, 1991; Hubert et al., 1994); (2) non-competitive blockade of postsynaptic excitatory amino acid receptors (Benavides et al., 1985; Debono et al., 1993); and (3) presynaptic inhibition of glutamate release (Cheramy et al., 1986, 1992). Preclinical data suggest that riluzole has a neuroprotective effect in animal models of PD (Boireau et al., 1994; Bezard et al., 1998). Jankovic and Hunter (2002) assessed neuroprotective properties of riluzole in a double-blind placebocontrolled study in 20 patients with early PD. Subjects were randomized to 50 mg b.i.d. of riluzole or matching placebo. All patients were evaluated at baseline, 1, 3 and 6 months and following a 6-week washout period. After the washout, all subjects were offered to enroll in a 1-year extension study. Assessments included UPDRS scale, Hoehn and Yahr stage and Schwab and England scale. Results did not show any symptomatic effect of riluzole on the UPDRS score and no changes in the Hoehn and Yahr stage. Among the 17 patients who decided to continue in the extension phase of the study, the deterioration in the UPDRS score was more pronounced in the placebo group but this difference was not significant. The study failed to show evidence of symptomatic or neuroprotective effects of riluzole (Jankovic and Hunter, 2002). The effect of riluzole in PD patients with dyskinesias was investigated by Braz et al. (2004) in a double-blind, placebo-controlled pilot study. A total of 16 patients were randomly treated with riluzole 50 mg b.i.d. or matching placebo during 7 consecutive days. The patients were evaluated at baseline and at
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the end of the treatment period. Assessments included UPDRS part III and IV, Hoehn and Yahr stage and the Larsen scale for dyskinesia. On the day of the evaluations the patients were asked to assist after a washout period of at least 8 hours without taking levodopa or any other antiparkinsonian medication. For the evaluation all subjects were treated with subcutaneous apomorphine 1 mg every 15 minutes until the ‘on’ condition was achieved. No significant differences were found between the two groups. Riluzole was not able to reduce apomorphine-induced dykinesia (Braz et al., 2004).
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Handbook of Clinical Neurology, Vol. 84 (3rd series) Parkinson’s disease and related disorders, Part II W. C. Koller, E. Melamed, Editors # 2007 Elsevier B. V. All rights reserved
Chapter 37
Investigational drugs CARLO COLOSIMO* AND GIOVANNI FABBRINI Dipartimento di Scienze Neurologiche, Universita` La Sapienza, Rome, Italy
37.1. Introduction The introduction of the dopamine precursor levodopa (LD) as the mainstay of treatment of Parkinson’s disease (PD) has provided excellent symptomatic benefit for the majority of patients. However, the effects of dopaminergic therapy are limited by the fact that LD has not been shown to slow the progression of the disease and that PD patients still face major shortcomings in the chronic phase of the disease. Fluctuations and levodopa-induced dyskinesia (LID) are the major complications in the current therapeutic approach to the treatment of PD, deeply affecting patients’ quality of life. More than 50% of all patients treated with LD for 5 years or more develop motor response fluctuations, which are usually associated with the appearance of LID (Nutt and Holford, 1996; Colosimo and De Michele, 1999; Brotchie, 2000). The exact pathophysiology of fluctuations and LID is not fully understood, but they are probably related to striatal dopamine receptor changes following dopaminergic denervation and chronic exposure to LD (Crossman, 1990). These receptor alterations include changes of sensitivity, relative balance between different dopamine receptor subtypes and different translational and neuromodulatory-system responses (Crossman, 1990; Colosimo et al., 1996; Brotchie, 2000; Bezard et al., 2001). Duration of the disease and early initiation of LD therapy are key factors for the development of motor complications, though the poor pharmacokinetics of LD (very short half-life, inconsistent absorption) also plays an important role. As a result, the dopamine agonists, compounds with a better pharmacokinetic profile than LD, were developed. Based on experimental data showing that de novo administration of dopamine agonists to non-human primates rendered parkinsonian
with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced less dyskinesia than LD (Bedard et al., 1992; Pearce et al., 1998), several clinical studies have been conducted, all showing that dopamine agonists can alleviate parkinsonian symptoms in previously untreated patients with a much reduced incidence of fluctuations and dyskinesia (Rascol et al., 2000; Parkinson Study Group, 2004b). Unfortunately, this strategy has its limitations since only approximately 30% of parkinsonian patients show a good and durable response to dopamine agonists as monotherapy. Chronic use of dopamine agonists is also associated with frequent psychiatric side-effects, including visual hallucinations, delusions and paranoid psychosis. Furthermore, dopamine agonists more easily elicit dyskinesia when administered together with LD or following ‘priming’ with LD. Therefore, in the foreseeable future, dopamine replacement in the form of LD is likely to remain the mainstay of therapeutic approaches for PD. Attempts to reduce dyskinesia by means of drug holidays, controlled-release LD preparations, long-acting dopamine agonists (cabergoline), or other adjunct therapies such as monoamine oxidase-B (MAO-B) or catechol-O-methyl-transferase inhibitors, have generally met with limited success in the clinic (Colosimo and De Michele, 1999). Continuous wakingday subcutaneous apomorphine infusion is effective in the long term, though not easily applicable to the majority of patients (Colosimo et al., 1994). As a result, several new treatment strategies for PD are currently being investigated, particularly those targeting non-dopaminergic pathways. Furthermore, in PD there is still no satisfactory approach to the treatment of cognitive disturbances and dementia (Brown and Marsden, 1990), autonomic dysfunction (Senard et al., 2001), balance, walking
*Correspondence to: Carlo Colosimo, Dipartimento di Scienze Neurologiche, Universita` La Sapienza, Viale dell’Universita` 30, I-00185 Rome, Italy, E-mail:
[email protected], Tel: þ39-06-4991-4511, Fax: þ39-06-4991-4700.
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difficulties and the risk of falling (Bloem et al., 2004), speech disorders (Pinto et al., 2004), psychiatric and behavioral symptoms (Wint et al., 2004) and sleep problems (Brotini and Gigli, 2004). Based on all the previous observations, therapeutic research in the future is expected to be moving in several different directions. Among these are: (1) development of socalled neuroprotective drugs, capable of blocking or at least slowing down the degenerative process responsible for neuron death, or even of restorative strategies, which would allow to normal brain function to be regained; (2) further improvement in the replacement of dopaminergic loss; (3) antidyskinetic drugs; and (4) symptomatic drugs acting on neurotransmitters other than dopamine, or which may target the brain in other areas rather than only in the striatum.
37.2. Neuroprotective therapies Interventions that can slow or halt the progression of PD remain a crucial unmet need. Several promising approaches are under development for the potential of neuroprotection in PD. However, the confounding fact of the possible symptomatic effects of the drugs tested, the placebo effect, the choice of optimal endpoint and the need for validated surrogate markers are all significant issues when studying a putative neuroprotective intervention in PD, which have not been completely addressed until now. Neuroprotection strate-
gies will derive directly from studies directed to an understanding of the pathogenesis and mechanisms of cell death. Current information suggests that neurodegeneration in PD is associated with a cascade of events that includes oxidant stress, mitochondrial abnormalities, failure in the ubiquitin-proteasome system to clear unwanted proteins, excitotoxicity, inflammation and possible other still not identified mechanisms (Dawson and Dawson, 2003). Considerable evidence suggests that cell death in PD, regardless of cause, occurs by way of signal-mediated apoptosis (Hirsch et al., 1999). Development of new drugs for neuroprotection is very fast. In a recent survey of potential neuroprotective agents for clinical trials in PD (Ravina et al., 2003), several compounds have been identified as potential effective neuroprotective agents, but only a few are real candidates for phase II or III studies. The development status of these compounds is summarized in Table 37.1. 37.2.1. Monoamine oxidase inhibitors 37.2.1.1. Rasagiline Rasagiline is a propargylamine and is a potent, irreversible, selective inhibitor of MAO-B with no amphetaminelike metabolites and with the capability of increasing DA release. Beside its activity on MAO enzymes, the neuroprotective properties of rasagiline may be linked to other factors, such as the capability of inhibiting apoptosis at three levels: (1) intranuclear translocation of
Table 37.1 Development status of neuroprotective/neurorestorative agents Compound
Company/institution
Class of compound
Phase of development
CEP-1347
Cephalon/H Lundbeck Kyowa Hakko Kogyo Spectrum Pharmaceuticals Vertex Pharmaceuticals Schering Amgen Guildford Pharmaceuticals Panacea Pharmaceuticals
Mixed-lineage kinase inhibitor
Withdrawn
Nerve growth factor agonist Neuroimmunophilin ligand
Phase II
Growth factor agonist Neuroimmunophilin-ligand a-Synuclein oligomerization inhibitors Dopamine modulator
Withdrawn Phase II Preclinical Phase II
GAPDH inhibitor Estrogen analog Hedgehog agonist
Withdrawn Phase I Preclinical
Astrocyte modulator AMPA antagonist
Phase II Phase II
Leteprinim V-10367 Liatermine GPI-1485 PAN-408 PYM-50028 TCH-346 MITO-4509 Sonic hedgehog protein agonist ONO-2506 E-2007
Phytopharm plc/Yamanouchi Pharmaceutical Novartis Mitokor Curis/Wyeth Pharmaceuticals ONO Pharmaceutical Eisai
Adapted with permission from The Thomson Corporation and Johnston and Brotchie (2004). # 2004 The Thomson Corporation. GAPDH, glyceraldehyde-3-phosphate dehydrogenase; AMPA, a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid.
INVESTIGATIONAL DRUGS the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase; (2) induction of bcl-2; and (3) activation of mitochondrial permeability transition. Clinical studies on rasagiline have also confirmed the potential usefulness of this drug in the symptomatic treatment of PD. In early patients (TEMPO study) rasagiline was superior to placebo in improving Unified Parkinson’s Disease Rating Scale (UPDRS) motor and activities of daily living scores. More patients in the placebo group (16.7%) than those in rasagiline treatment (11.2%) needed LD within 12 months of the beginning of the study, although this difference was not significant. This study also included an initial 6-month placebo phase (delayed treatment) which showed that patients treated for 6 months with placebo and then allowed to receive the active drug did not catch up with those patients who were in active treatment since the beginning of the study. These data, although preliminary, suggest a disease-modifying effect rather than symptomatic benefit only (Parkinson Study Group, 2002, 2004a). 37.2.1.2. Zydis selegiline The usefulness of conventional selegiline is confounded by low bioavailability, extensive first-pass metabolism and production of amphetamine metabolites. Zydis selegiline (a rapidly disintegrating tablet) dissolves in the mouth on contact with saliva and undergoes pregastric absorption, providing high plasma levels of selegiline, almost completely avoiding first-pass metabolism and markedly reducing the production of amphetamine metabolites (Seager, 1998). Few studies have shown the potential usefulness of the drug in the treatment of advanced patients with motor fluctuations, increasing the time spent in the on phase. Side-effects more commonly reported were dizziness, dyskinesia, hallucinations, headache and dyspepsia, usually in the first 6 weeks of treatment (Waters et al., 2004). The possible role of zydis selegiline as a neuroprotective agent has not been tested. 37.2.2. Modulators of mitochondrial function Coenzyme Q1 is a ‘health supplement’ which is able to increase the activity of mitochondrial complex I activity and may act as an antioxidant. Preliminary evidence suggests that doses of 1200 mg/day, which are well tolerated, may slow functional decline as measured by UPDRS scores (Shults et al., 2002). Creatine is also a nutritional supplement which is converted to phosphocreatine, a metabolite functioning as an energy buffer able to transfer a phosphoryl group to adenosine diphosphate. Creatine has been shown to be protective in MPTP rodent models (Matthews et al.,
139
1999). A pilot study using creatine and minocycline is under way. 37.2.3. Other mechanisms 37.2.3.1. Estrogens Epidemiological data suggest a reduced incidence of PD in women (Currie et al., 2004) and there are also several animal models in which estrogens appear as promising neuroprotective agents. The mechanism may involve neurotrophic effects as well as antioxidant effects (Dluzen and Horstink, 2003). 37.2.3.2. GM1 ganglioside GM1 ganglioside is a component of neuronal membranes, may facilitate the neurotrophic actions of brain-derived nerve growth factor (BDNF) and glialderived neurotrophic factor (GDNF), may inhibit apoptosis and may protect against excitotoxicity. Some preliminary data in PD have shown that the compound is well tolerated and has short-term symptomatic benefit (Schneider, 1998). However concerns still exist about its immunogenicity and the relationship with Guillain–Barre´ syndrome. 37.2.3.3. Neuroimmunophilin Neuroimmunophilin ligands (NILs) are drugs derived from the immunosuppressant FK506 (tacrolimus) that have been shown to have variable efficacy in reversing neuronal degeneration and preventing cell death (Gold and Nutt, 2002). In animal models mimicking PD they induce resprouting and are neurotrophic. Some evidence suggests that NILs may act through regulation of steroid hormone receptors. Other evidence suggests that NILs may protect neurons by upregulating the antioxidant glutathione and stimulating nerve regrowth by inducing the production of neurotrophic factors. Initial clinical trials have had mixed success. In one, patients with moderately severe PD showed no overall improvement in fine motor skills following 6 months of treatment with the neuroimmunophilin GPI 1485, although there was a decreased loss of dopaminergic nerve terminals or eventually an increase in dopaminergic terminals within 6 months of the higher dose of GPI 1485 drug treatment (Poulter et al., 2004). 37.2.3.4. Inhibitors of microglial inflammation (antiapoptotic kinase inhibitors) The c-Jun NH2-terminal kinase (JNK) signaling pathway is frequently induced by cellular stress and correlated with neuronal death. JNK signaling is therefore a promising target in PD for developing pharmacological intervention. CEP-1347 blocks the activation of
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the c-Jun/JNK apoptotic pathway in neurons exposed to various stressors and attenuates neurodegeneration in animal models of PD, eventually associated with microglial activation. CEP-1347 reduced cytokine production in primary cultures of human and murine microglia and in monocyte/macrophage-derived cell lines, stimulated with various endotoxins or the plaque-forming peptide Abeta1–40. Moreover, CEP-1347 inhibited brain tumor necrosis factor (TNF) production induced by intracerebroventricular injection of lipopolysaccharide in mice. As expected from a mixed linear inhibitor (MLK), CEP-1347 acted upstream of p38 and c-Jun activation in microglia by dampening the activity of both pathways (Lund et al., 2005). These data infer that MLKs may be important, yet unrecognized, modulators of microglial inflammation and demonstrate a novel anti-inflammatory potential of CEP-1347 (Johnston and Brotchie, 2004). The safety and tolerability of CEP-1347 have recently been studied in 30 patients with PD. Overall the drug was well tolerated and had no acute effect on parkinsonian symptoms or LD pharmacokinetics (Parkinson Study Group, 2004c). 37.2.3.5. Minocycline Minocycline is a semisynthetic, second-generation tetracycline derivative which crosses the blood–brain barrier and may inhibit microglial-related inflammatory events and also the apoptotic cascade. Several studies have shown that minocycline is neuroprotective in animal models of central nervous system trauma and neurodegenerative diseases; in particular, this compound has greatly enhanced survival in nigrostriatal dopaminergic neurons in the MPTP model of PD (Du et al., 2001). Minocycline has, therefore, been incorporated into an ongoing clinical investigation in untreated PD patients (Ravina et al., 2003).
37.3. Improvement of dopaminergic drugs Several strategies have been proposed and developed in order to improve the pharmacokinetics and pharmacodynamics of dopaminergic agents used in PD. The development status of all these compounds is summarized in Table 37.2. 37.3.1. Improvement of levodopa bioavailability Absorption of LD is very sensitive and depends on the state of the stomach and gastrointestinal system. Therefore efforts are under way to improve LD absorption. Recent attempts have shown that methylester LD (melevodopa) is effective as standard LD and may have the additional advantage of a faster absorption (Johnston and Brotchie, 2004).
Another approach is currently under investigation through the intraduodenal infusion delivery of LD. Advanced parkinsonian patients may benefit from this form of treatment in order to achieve more stable plasma LD levels (Nyholm et al., 2005). 37.3.2. Increase in the synaptic availability of dopamine Dopamine reuptake blockers, by enhancing and stabilizing intrasynaptic transmitter levels, could help palliate motor dysfunction in PD, in both early and advanced disease. In experimental animals with severe neurotoxin-induced dopaminergic neuron loss mimicking conditions in advanced PD, LD treatment after an effective pharmacologic dopamine transporter (DAT) blockade produces far higher elevations in extracellular DA than normally occur (Pearce et al., 2002). Thus, DAT inhibitors should act clinically to potentiate the antiparkinsonian action of LD. Moreover, because a reduction in DA reuptake prolongs its striatal half-life, motor fluctuations as well as dyskinesia and other adverse consequences of the intermittent stimulation of striatal DA receptors might diminish in the long term (Nutt and Holford, 1996). A randomized, double-blind, placebo-controlled study compared the acute effects of the monoamine uptake inhibitor NS 2330 with those of placebo in 9 fluctuating parkinsonian patients (Bara-Jimenez et al., 2004). Individuals randomly assigned to NS 2330 treatment were given an initial 1-week placebo run-in, followed by a treatment phase consisting of eight doses of 1.5 mg each, administered three times weekly. The cumulative total dose of 12 mg was selected to achieve plasma drug concentrations in therapeutic range, based on preliminary pharmacokinetic data obtained by the drug manufacturer. Remaining patients received placebo throughout the entire study. At the dose administered, no change in parkinsonian scores was found when NS 2330 was given alone or with LD. Moreover, NS 2330 coadministration did not appear to reduce the severity of dyskinesia or the duration of the antiparkinsonian response to LD. Since, under the conditions of this study, results failed to support the usefulness of dopamine reuptake inhibition in the treatment of advanced PD, this compound was withdrawn from clinical trials. 37.3.3. Dopamine agonists There is still work to be done to understand better the effects of selective D1 dopamine agonists in PD (Rascol et al., 1999, 2001a). It is realistic to hope for further innovations through the development of new
INVESTIGATIONAL DRUGS
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Table 37.2 Development status of symptomatic antiparkinsonian agents
Compound
Company/Institution
Class of compound
Dopaminergic Melevodopa
Chiesi Farmaceutici
SR-57667
Sanofi-Synthelabo
Safinamide
Newron Pharmaceuticals
Rasagiline
SLV-308
Teva Pharmaceutical Industries/H Lundbeck/Eisai NeuroSearch/ Boehringer Ingelheim Shire Pharmaceutical Group Pfizer Schwarz Pharma/Otsuka Pharmaceutical Solvay
Methyl-l-dopa/ carbidopa Irreversible MAO-B inhibitor? MAO-B inhibitor Naþ/Caþ channel blocker Irreversible MAO-B inhibitor
Talipexole
Boehringer Ingelheim
DU-127090
Solvay/H Lundbeck/Wyeth Pharmaceuticals BIAL Group
NS-2330 SPD-473 Sumanirole Rotigotine
BIA-3–202 Non-dopaminergic Istradefylline KF-17837 VR-2006 Donepezil
Kyowa Hakko Kogyo Kyowa Hakko Kogyo Vernalis Group Eisai/Pfizer/Wyeth-Ayerst International
Monoamine reuptake inhibitor Monoamine reuptake inhibitor D2-agonist D2-agonist
Phase of development
Other potential actions
Launched
–
Phase IIb
Neuroprotective
Phase III
Neuroprotective
Launched
Neuroprotective
Withdrawn
Withdrawn Launched
Cognitive enhancement Antidepressant Cognitive enhancement Antidepressant – –
Phase II
Antidepressant
Launched
–
Phase II
D2 partial agonist/ 5-HT1A agonist D2-agonist/a2adrenoceptor agonist D2 partial agonist/ 5-HT1A agonist COMT inhibitor
Phase III
–
Phase I
Neuroprotective
A2A antagonist A2A antagonist A2A antagonist AChE inhibitor
Phase III Preclinical Phase I Launched
Neuroprotective Neuroprotective Neuroprotective Cognitive enhancement
Adapted with permission from The Thomson Corporation and Johnston and Brotchie (2004). # 2004 The Thomson Corporation. MAO-B, monoamine oxidase-B; COMT, catechol-O-methyltransferase; AChE, acetylcholinesterase.
dopamine agonists, fully or partially selective or nonselective (Bezard et al., 2003a). D2-selective agonists such as sumanirole were developed based on the concept that the D3 component action of the previous generation of dopamine agonists, such as pramipexole, may be detrimental to the antiparkinsonian effect (Stephenson et al., 2005). The concept of constant dopaminergic stimulation (Chase, 1998) is now leading to the study of new ways of administering dopaminomimetics, such as the transdermal route, for the possibility of giving particularly stable plasma levels (Parkinson Study Group, 2003). Rotigotine is a non-ergot dopamine agonist, acting selectively on D2-receptors, which has been formulated
in a silicone-based transdermal system. The rationale behind this transdermal delivery system is based on the option of having a non-oral DA agonist which may be useful in terms of compliance in patients already assuming many drugs for the oral route and the capability of stable blood levels of a dopamine agonist. Rotigotine patch reaches the steady state in 24 hours and allows stable drug release in the 24-hour period (Metman et al., 2001). Early PD patients (n ¼ 242) were treated in a phase III double-blind, placebo-controlled study against four different doses of rotigotine (4.5, 9.0, 13.5 or 18 mg). The doses of 13.5 and 18.0 mg were superior to placebo at week 11. Side-effects were also more frequent in the active-treatment groups and were qualitatively similar to
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those reported in other studies of dopamine agonists in early PD patients (nausea, application-site reaction, dizziness, somnolence, insomnia, vomiting and fatigue) (Parkinson Study Group, 2003). Local skin reactions were not uncommon (39%), leading to early withdrawal in a few cases. Preliminary positive data are also available for the transdermal delivery of lisuride (Woitalla et al., 2004). 37.3.3.1. Slv-308 SLV-308 is a partial D2D3 agonist and an agonist of 5HT1A receptors, a profile which suggests a good antiparkinsonian action with reduced capability of inducing dyskinesia. Phase II trials in the treatment of PD are under way (Wolf, 2003). 37.3.3.2. Safinamide This is a novel experimental drug combining several pharmacological properties that are potentially useful in the treatment of PD. This drug has the capability of blocking voltage-dependent sodium and N-type calcium channel, therefore inhibiting glutamate release. Safinamide is also a highly selective and reversible inhibitor of MAO-B, decreasing dopamine breakdown and the production of toxic free radicals (Fariello et al., 1998). The peculiarity of this dual mechanism of action offers the possibility that safinamide might be used in PD, but also in the treatment of epilepsy. A recent double-blind trial has shown that safinamide increased in respect to placebo (37.5 versus 21.4%) the percentage of early PD patients improving their motor score by >30% and also improved the motor scores in a subgroup of patients under stable treatment with dopamine agonists (Stocchi et al., 2004).
37.4. Antidyskinetic drugs The pathophysiology underlying treatment-related dyskinesia is not well known and cannot easily be fitted into current models of basal ganglia dysfunction in PD. It may involve altered activity in the projection pathways from the striatum to the globus pallidus, resulting in reduced activity in the output regions of the basal ganglia, i.e. the internal segment of the globus pallidus and the substantia nigra pars reticulata (Papa et al., 1999). Several experimental and clinical studies in parkinsonism have shown that motor fluctuations and LID can be modulated by drugs acting on neurotransmitters other than dopamine, including glutamate, g-aminobutyric acid, norepinephrine, acetylcholine, serotonin, adenosine and cholecystokinin. In numerous cases, the prospect of using specific drugs
to counteract LID was raised by the previously shown efficacy of such compounds in the treatment of other types of dyskinesia. 37.4.1. Glutamatergic drugs Amantadine is an antiviral compound, which has been widely used as a first-line antiparkinsonian drug since 1969, but has only recently been found to act as a noncompetitive N-methyl-D-aspartate (NMDA) glutamatergic antagonist (Chase et al., 2000). Findings from basic science suggesting that NMDA receptor blockade may improve the dyskinetic complications of LD therapy have thus prompted the use of this compound as a specific antidyskinetic drug (Metman et al., 1998a). Following pilot studies showing that amantadine has a favorable effect on LID in a significant percentage of patients with PD, further work has confirmed the beneficial effects of amantadine on motor response complications (Pourcher et al., 1989; Metman et al., 1999; Luginger et al., 2000; Snow et al., 2000; Del Dotto et al., 2001), although some authors have shown that benefit may be short-lived (Thomas et al., 2004). The hope of better-tolerated glutamate antagonists is driving the development of the non-competitive a-amino-3-hydroxy-5-methylisoazole4-propionate (AMPA) antagonists, for example talampanel. Since AMPA antagonists may also have neuroprotective actions, some of the companies now appear to be developing AMPA antagonists for this use, rather than as antidyskinetic drugs (Johnston and Brotchie, 2004). The results of other trials in which familiar drugs have been used in LID are less convincing. For instance, the efficacy of a combination of LD and anticholinergic drugs in parkinsonian patients to reduce both parkinsonian symptoms and biphasic dyskinesia was only demonstrated in a single trial (Pourcher et al., 1989). The addition of 5-methoxy 5-N, N-dimethyl-tryptamine, a non-selective serotonin agonist, slightly reduced dyskinesia but also reduced the antiparkinsonian benefit of LD (Gomez-Mancilla and Bedard, 1993). More recently, alleviation of parkinsonian symptoms without the development of dyskinesia has been reported in both MPTP-lesioned monkeys and other experimental animals by using adenosine A2A receptor antagonists and NR2B-selective NMDA glutamatergic antagonists (Kanda et al., 1998, 2000; Grondin et al., 1999; Steece-Collier et al., 2000; Bibbiani et al., 2002; Lundblad et al., 2003). The potential symptomatic use in PD of drugs acting on serotonergic and adenosine receptors will be discussed in more detail in the next part of this chapter.
INVESTIGATIONAL DRUGS A summary of the various drugs which have been successfully tested in LID in controlled trials on humans is shown in Table 37.3 (Colosimo and Craus, 2003). Data for this synopsis were identified by means
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of searches, using the search terms ‘Parkinson’s disease’, ‘levodopa’ and ‘dyskinesia’ on Medline and references from relevant articles; numerous articles were also identified through searches in the authors’
Table 37.3 Symptomatic drugs for LID as proven by controlled trials Compound
Mechanism of action
Reference and study design
Dose*
Ritanserin
Selective serotonergic 5-HT2 antagonist
Meco et al. (1988): Single-blind, placebo-controlled, cross-over study
Buspirone
Serotonergic 5-HT1A-agonist
Fluoxetine
Selective serotonin reuptake inhibitor b-Adrenergic blocker
Bonifati et al. (1994): Double-blind, placebo-controlled, cross-over study Durif et al. (1995): Videotape randomized evaluation Carpentier et al. (1996): Videotape randomized evaluation Durif et al. (1997): Videotape randomized evaluation Durif et al. (2004): Double-blind, parallel-group, placebo-controlled, multicenter trial Metman et al. (1998a): Double-blind, placebo-controlled, cross-over study Metman et al. (1999): Double-blind, placebo-controlled, cross-over study Luginger et al. (2000): Double-blind, placebo-controlled, cross-over trial Snow et al. (2000): Double-blind, placebo-controlled, cross-over trial Del Dotto et al. (2001): Acute doubleblind, placebo-controlled study Metman et al. (1998b): Double-blind, placebo-controlled, cross-over study Metman et al. (1998c): Double-blind, placebo-controlled, cross-over study Manson et al. (2000a): Randomized, placebo-controlled, double-blind, cross-over trial Rascol et al. (2001b): Randomized, double-blind, placebo-controlled study Sieradzan et al. (2001): Randomized, double-blind, placebo-controlled, cross-over trial Olanow et al. (2004): Prospective, 6month multicenter open-label doserising study and videotape evaluation Fox et al. (2004): Randomized, doubleblind, placebo-controlled, cross-over, acute-challenge study
Mean dosage of 21.4 mg (range 10–30 mg), 3 a day 10 mg, 2 a day
Propranolol Clozapine
Amantadine
Dextromethorphan
Dopaminergic D4/D1antagonist, serotonergic 5-HT2 antagonist, anticholinergic?
Non-competitive NMDA glutamatergic antagonist
NMDA glutamatergic antagonist
Olanzapine
Dopaminergic D1/D2/D4antagonist
Idazoxan
a2-Adrenergic antagonist
Nabilone
Cannabinoid receptor agonist
Sarizotan
Serotonergic 5-HT1A full agonist, dopaminergic D2/D3/D4 weak antagonist? Opioid antagonist
Naloxone
*Unless indicated, the dose was given orally; when available, the number of doses per day was given. Adapted with permission from Colosimo and Craus (2003). NMDA, N-methyl-d-aspartate.
20 mg, 2 a day Up to 60 mg a day 50 mg/day Up to 50 mg a day
100 mg, 3–4 a day 100 mg, 3–4 a day 100 mg, 3 a day 100 mg, 2 a day 200 mg in a 2-hour intravenous infusion Range, 60–120 mg/day Up to 180 mg a day Up to 7. 5 mg/day
10, 20, 40 mg, in single dose 0.03 mg/kg in two doses Up to 10 mg/day
0.4 mg/kg per min in intravenous infusion
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extensive files. Abstracts and reports from meetings were also included. Several other drugs have been reported to improve LID in case series or uncontrolled trials, e.g. methysergide (Gomez-Mancilla and Bedard, 1993), physostigmine (Tarsy et al., 1974; Gomez-Mancilla and Bedard, 1993), estrogens (Gomez-Mancilla and Bedard, 1992), progesterone (Gomez-Mancilla and Bedard, 1992), riluzole (Merims et al., 1999), mirtazapine (Meco et al., 2003), quetiapine (Oh et al., 2002), magnesium sulfate (Chassain et al., 2002), alpha-amino-3hydroxy-5-methyl-4-isoxazole (a propionic acid receptor antagonist) (Silverdale et al., 2002), 3,4-methylenedioxymethamphetamine (ecstasy) (Iravani et al., 2003) and cannabis (Venderova et al., 2004). These pilot studies should encourage, when appropriate, larger double-blind controlled trials. 37.4.2. Noradrenergic drugs A key abnormality most likely underlying LID is the overactivity of the direct striatal output pathway connecting the striatum with the output regions of the basal ganglia. Adrenergic a2-receptors are present in the basal ganglia and several experimental studies have shown that they occur in high density in the rat and mouse striatum, in a position likely to influence the direct or indirect striatal motor outputs (Scheinin et al., 1994; Holmberg et al., 1999; Papa et al., 1999; Bezard et al., 2001; Zhang and Ordway, 2003). As it has also been suggested that activation of a2adrenergic receptors can facilitate movements produced by activation of the direct pathway, it is possible that enhanced a2-adrenergic receptor stimulation may contribute to the pathophysiology of LID (Hill and Brotchie, 1999). Other studies have indicated that dopaminergic transmission in the striatum can also be influenced by ß-adrenergic activity; the density of ßadrenergic receptors is one of the highest in the striatum and the local release of dopamine is increased by isoproterenol when applied in vivo into the caudate nucleus or in vitro on rat striatal slices, an effect that is prevented by propranolol (Reisine et al., 1982). In addition, motor behavior studies in animals on dopamine–norepinephrine interactions have shown that the noradrenergic systems in PD are impaired and this probably contributes to both motor and affective symptoms observed in this condition (Burn, 2002). These observations have encouraged studies on drugs acting on the noradrenergic system. Ever since the 1980s, the coadministration of yohimbine and LD to MPTP-treated primates has been known to reduce LID without influencing the antiparkinsonian efficacy of this compound (Chopin et al., 1986). Yohimbine
reduces the dyskinetic effect produced by LD, whereas the antiparkinsonian effect is not altered regardless of the dosage. Yohimbine has a variety of pharmacological properties: it is mainly an a-adrenergic receptor antagonist with low selectivity between a1 and a2 subtypes, but also acts as an antagonist at dopamine D2, 5HT1A and peripheral 5-HT2B receptors and as an agonist at 5-HT1D receptors. On the other hand the combination of LD with clonidine, an a2-adrenoreceptor agonist, also reduced LID, whereas at higher doses clonidine blocked both the antiparkinsonian and the dyskinetic effects of LD (Nishikawa et al., 1984; Gomez-Mancilla and Bedard, 1993; Hill and Brotchie, 1999). More recent are the data concerning fipamezole (JP-1730), a 2-indane imidazole a2-adrenergic receptor antagonist which was also able to reduce LID in the MPTP-lesioned marmoset model of PD (Savola et al., 2003): this compound is currently in phase III clinical trials (Peltonen et al., 2002). Besides, in a single clinical trial it has been suggested that administration of low doses of propranolol, a non-selective ßadrenergic blocker, may improve LID in patients with advanced PD (Carpentier et al., 1996). On the basis of these data, idazoxan, a new selective a2-adrenoreceptor antagonist, was developed and tested in animals with experimental parkinsonism and subsequently in patients with LID. Two reports, one experimental and the other clinical, have confirmed that idazoxan has an interesting pharmacological profile, improving LID without a return to parkinsonian symptoms (Fox et al., 2001; Rascol et al., 2001b). Previous experimental data in animals have suggested that, although idazoxan as a monotherapy displays no antiparkinsonian effect, when given in combination with LD it not only reduces the dyskinetic side-effects of LD, but may even extend the antiparkinsonian action of this compound (Henry et al., 1999). The purpose of the experimental study by Fox and coworkers (2001) was to compare the effect of idazoxan on dyskinesia produced by both LD and apomorphine in the MPTP experimental model of PD. The marmosets were treated with MPTP to induce a parkinsonian syndrome. In the first part of the study, only LD (8 mg/kg) or apomorphine (0.075–0.3 mg/kg) was administered in order to establish the severity of the dyskinesia each drug produced. In the second part of the study, doses of apomorphine and LD were individually administered along with either idazoxan (2.5 mg/kg) or vehicle. A neurologist with clinical experience in movement disorders who was blinded to the animals’ treatment then analyzed the videotapes. Part one of the study demonstrated that both apomorphine and LD increased mobility and improved
INVESTIGATIONAL DRUGS bradykinesia and posture scores, when compared with vehicle-treated marmosets. Administration with either apomorphine or LD resulted in a dose-dependent increase in dyskinesia, with dyskinesia present for the entire period of maximal antiparkinsonian action. When idazoxan was coadministered with LD, the median peak-dose dyskinesia score was significantly lower than that observed with LD alone (4 versus 16; P < 0.05), whereas peak posture, bradykinesia or mobility scores were not significantly different. There were no significant differences between LD/idazoxan versus LD alone in the duration of dyskinesia, nor were there any significant differences between the coadministration of idazoxan and apomorphine and apomorphine alone in the median peak-dose dyskinesia score. Idazoxan had no effect on the antiparkinsonian action of apomorphine or in the duration of dyskinesia induced by this compound. By contrast, the action of LD, following the coadministration of idazoxan and LD, lasted longer than when LD was administered alone (250 20 minutes on time versus 130 10 minutes on time; P < 0.05). The authors concluded that the dyskinesia resulting from LD involves adrenoreceptor activation, whereas dyskinesia resulting from apomorphine does not. Indeed, the action of a2-adrenergic antagonists may involve the blockade of the action of norepinephrine synthesized from LD; the hypothesis is that, since dopamine agonists are not metabolized to norepinephrine, idazoxan does not reduce dyskinesia produced by such agents. This should be taken into consideration when trials with new antidyskinetic agents based on acute challenges with apomorphine are planned. In a clinical study, Rascol and coworkers (2001b) assessed the effects of idazoxan on LID in patients with advanced PD. A total of 18 patients were enrolled in this single-oral-dose randomized double-blind placebo-controlled study. The study tested three different idazoxan doses (10, 20 and 40 mg) and placebo. Assessment consisted of a single oral dose of either idazoxan or placebo, followed an hour later by the patient’s usual first morning dose of LD plus an additional 50 mg. A trained physician used the UPDRS to monitor the treatment effect. Patients were videotaped for the assessment of dyskinesia and were identified as either peak-dose or biphasic. Data were analyzed by means of three different measurements: (1) calculation of the area under the curve (AUC) of the changes from baseline in the dyskinesia and UPRDS scores; (2) calculation of the score distribution; and (3) an analysis of the peak-dose and biphasic dyskinesia scores. The AUC analysis revealed a statistically insignificant dose-related reduction for the mean dyskinesia
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AUC in the 10- and 20-mg idazoxan treatment groups (–20 and –40%) as compared to the placebo group. No AUC trend was found in the 40-mg idazoxan treatment group. The severity score distribution indicated a statistically significant treatment effect in favor of idazoxan (20 mg) when compared with placebo (P ¼ 0.01). No significant treatment effects were found in the biphasic and dyskinesia distribution analysis. The antiparkinsonian effects of LD were similar in both the idazoxan and the placebo groups, whereas adverse events were more frequent with idazoxan than with placebo. The results of this study seem to indicate that idazoxan, by blocking a2-receptors, may reduce levels of dyskinesia in PD patients without affecting the antiparkinsonian efficacy of LD treatment. Although the data obtained in these two studies are consistent with each other, they are in contrast with the only other available clinical trial, which recently reported that idazoxan was not beneficial for LID in 8 PD patients (Manson et al., 2000b). Moreover, although not published, a subsequent multi-institutional trial investigating idazoxan as a treatment for LID was negative. The reasons for the negative results were complex and at least partly due to the capacity of trial centers to comply with the protocol and to the safety profile of the drug (early drop-outs), maybe due to inadequate titration (O. Rascol, personal communication). These studies with idazoxan are of theoretical and clinical interest, but they do have several drawbacks: the results of the clinical trial, in particular, are based on a relatively small number of PD patients and only following an acute oral challenge of LD. Moreover, since idazoxan may induce several adverse events, such as hypertension, tachycardia, flushing and headache, it is difficult to ascertain what are the usefulness and benefit-to-risk ratio of idazoxan in the long-term management of dyskinetic parkinsonian patients. In summary, it seems that, though the mechanisms underlying the manifestations and the priming process for dyskinesia have yet to be fully elucidated, nondopaminergic compounds may provide an effective way of limiting the expression of involuntary movements in PD.
37.5. Symptomatic non-dopaminergic drugs Dopamine replacement therapy effectively treats the early motor symptoms of PD. However, its association with the development of motor complications limits its usefulness in late stages of the disease (Nutt and Holford, 1996; Colosimo and De Michele, 1999) and
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a non-dopaminergic approach to therapy might thus provide an effective way of preventing the development of these complications in PD. 37.5.1. Drugs acting at adenosine receptors Adenosine A2A receptors are localized to the indirect striatal output function and control motor behavior. They are active in predictive experimental models of PD and appear to be promising as the first major non-dopaminergic therapy for PD (Johnston and Brotchie, 2004). The initial results from a controlled clinical trial of an adenosine A2A antagonist, theophylline, conducted on 10 patients with PD, have been contrasting (longer beneficial response on akinesia without significant changes in the other clinical parameters of the disease) (Kulisevsky et al., 2002). Istradefylline (KW-6002) is a novel adenosine A2A receptor antagonist designed to treat patients with motor fluctuations and dyskinesias (Jenner, 2005). Istradefylline is currently in phase III clinical trials for efficacy in patients with PD; results from phase II clinical trials demonstrated that it provides a significant reduction in ‘off’ time and increased ‘on’ time with non-troublesome dyskinesia in LD-treated patients with established motor complications and is safe and well tolerated. In a 12-week, double-blind, randomized, placebo-controlled, exploratory study (Hauser et al., 2003), patients with motor fluctuations and peak-dose dyskinesias were randomly assigned to placebo (n ¼ 29), istradefylline (maximum of 20 mg/ day: n ¼ 26), or istradefylline (maximum 40 mg/day: n ¼ 28). As assessed by patient home diary, off time was reduced and severity of dyskinesia was unchanged, whereas the on time with dyskinesia increased. In addition, there is increasing preclinical evidence that A2A receptor antagonists may also have neuroprotective properties (Johnston and Brotchie, 2004). Thus, their eventual use as symptomatic therapy may lead to the identification of disease-modifying properties. 37.5.2. Serotonergic drugs With progressive degeneration of dopaminergic neurons in PD, dopamine formation from exogenous LD increasingly takes place in striatal serotonergic nerve terminals (Bezard et al., 2003b). It is thus not surprising that pharmacologic agents affecting serotonergic nerve impulse activity, by interacting with 5-HT1A autoreceptors, can regulate serotonin release under normal conditions and dopamine release in LD-treated parkinsonian animals. In the latter circumstances, drugs that stimulate these autoreceptors tend to attenuate peak striatal concentrations of dopamine and
prolong its half-life. If 5-HT1A agonists produce the same pharmacologic effects in PD patients, then a reduction in peak-dose dyskinesias and wearing-off fluctuations might be expected. Recent observations in parkinsonian animals support this possibility (Bibbiani et al., 2001). To evaluate this hypothesis, the effects of a selective 5-HT1A agonist, sarizotan, given orally at 2 and 5 mg twice daily to 18 relatively advanced parkinsonian patients, were recently compared with baseline placebo function during a 3-week, double-blind, placebocontrolled, proof-of-concept study (Bara-Jimenez et al., 2005). Sarizotan alone or with intravenous LD had no effect on parkinsonian severity. But at safe and tolerable doses, sarizotan coadministration reduced LID and prolonged its antiparkinsonian response (P < 0.05). The findings suggest that 5HT1A receptor stimulation in LD-treated parkinsonian patients can modulate striatal dopaminergic function and that 5-HT1A agonists may be useful as LD adjuvants in the treatment of advanced PD. In another open-label trial on 64 patients with advanced PD, sarizotan treatment induced a significant reduction in dyskinesia and particularly in troublesome dyskinesia (Olanow et al., 2004). These benefits were obtained without change in total off time or change in UPDRS or activities of daily living scores. Unfortunately, this compound was recently withdrawn from clinical trials. 37.5.3. Drugs acting at synaptic vesicular proteins Levetiracetam (LEV; (S)-alpha-ethyl-2-oxo-1-pyrrolidine acetamide) is an antiepileptic drug that is approved as add-on therapy in the treatment of partial-onset seizures (Kumar and Smith, 2004). LEV has been shown to reduce LID in preclinical studies of animal models of PD (Bezard et al., 2003c). Furthermore, a few case reports and small open-label studies indicate that LEV may reduce various abnormal involuntary movements, including myoclonus, paroxysmal kinesiogenic choreoathetosis and Meige’s syndrome. The tolerability and preliminary efficacy of LEV in reducing LID in PD patients were evaluated in a prospective open-label pilot study (Zesiewicz et al., 2005). Nine PD patients who were experiencing peak-dose dyskinesias for at least 25% of the awake day and were at least moderately disabled were treated with LEV in doses up to 3000 mg for up to 60 days. The primary outcome measure was the percentage of the awake day that patients spent on without dyskinesia or with non-troublesome dyskinesia (good on time). The mean dose of LEV at endpoint was 625 277 mg/day. LEV significantly
INVESTIGATIONAL DRUGS improved the percentage of the awake day on without dyskinesia or with non-troublesome dyskinesia at endpoint compared to baseline (43 12% versus 61 17%; P ¼ 0.02). Percentage on time with troublesome dyskinesia decreased from 23 10% at baseline to 11 6% at endpoint, although not significantly. There was no significant increase in off time from baseline to endpoint. There was a 56% drop-out rate, in most of the cases due to somnolence. These preliminary data suggest that LEV is a promising drug in PD patients who experience severe peak-dose dyskinesia; as a result, LEV is currently in phase III clinical trials.
37.6. Conclusions Future developments in drug therapy of PD appear to be exciting and it is likely that PD will remain one of the most active areas of drug development in neurology for many years to come. In the near future it will probably be feasible to demonstrate in vivo if drugs act as neuroprotective or even restorative. It is also very likely that there will be improvements in the way physicians may be able to replace dopaminergic loss and more and more attention is expected on new ways of treating non-dopaminergic symptoms. Efforts are expected too in a better characterization and treatment of cognitive disturbances which frequently accompany PD. This chapter is by definition a section which must be intended in evolution. It is possible that by the time of publication some studies will have appeared showing the efficacy or the failure of a certain treatment. We have tried to give an overview of the closest prospective in the new pharmacological strategies in PD.
Acknowledgments The authors thank W. Poewe and O. Rascol for their data on ongoing trials in Parkinson’s disease. M. Bologna and C. Aurilia helped with the manuscript preparation.
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Savola JM, Hill M, Engstrom M et al. (2003). Fipamezole (JP-1730) is a potent alpha2 adrenergic receptor antagonist that reduces levodopa-induced dyskinesia in the MPTPlesioned primate model of Parkinson’s disease. Mov Disord 18: 872–883. Scheinin M, Lomasney JW, Hayden-Hixson DM et al. (1994). Distribution of alpha2-adrenergic receptor subtype gene expression in rat brain. Brain Res Mol Brain Res 21: 133–149. Schneider JS (1998). GM1 ganglioside in the treatment of Parkinson’s disease. Ann NY Acad Sci 845: 363–373. Seager H (1998). Drug-delivery products and the Zydis fastdissolving dosage form. J Pharm Pharmacol 50: 375–382. Senard JM, Brefel-Courbon C, Rascol O et al. (2001). Orthostatic hypotension in patients with Parkinson’s disease: pathophysiology and management. Drugs Aging 18: 495–505. Shults CW, Oakes D, Kieburtz K et al. (2002). Parkinson study group. Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing of the functional decline. Arch Neurol 59: 1541–1550. Sieradzan KA, Fox SH, Hill M et al. (2001). Cannabinoids reduce levodopa-induced dyskinesia in Parkinson’s disease: a pilot study. Neurology 57: 2108–2111. Silverdale MA, Nicholson SL, Crossman AR et al. (2002). Anti-dyskinetic actions of AMPA receptor antagonists in the MPTP-lesioned marmoset model of Parkinson’s disease. Mov Disord 17 (Suppl 5): S41. Snow BJ, Macdonald L, Mcauley D et al. (2000). The effect of amantadine on levodopa-induced dyskinesias in Parkinson’s disease: a double-blind, placebo-controlled study. Clin Neuropharmacol 23: 82–85. Steece-Collier K, Chambers LK, Jaw-Tsai SS et al. (2000). Antiparkinsonian actions of CP-101,606, an antagonist of NR2B subunit-containing N-methyl-d-aspartate receptors. Exp Neurol 163: 239–243. Stephenson DT, Meglasson MD, Connell MA et al. (2005). The effects of a selective D2 receptor agonist on behavioral and pathological outcome in 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine-treated squirrel monkeys. J Pharmacol Exp Ther 314 (3): 1257–1266.
Stocchi F, Arnold G, Onofrj M et al. (2004). Improvement of motor function in early Parkinson disease by safinamide. Neurology 63: 746–748. Tarsy D, Leopold N, Sax DS (1974). Physostigmine in choreiform movement disorders. Neurology 24: 28–33. Thomas A, Iacono D, Luciano AL et al. (2004). Duration of amantadine benefit on dyskinesia of severe Parkinson’s disease. J Neurol Neurosurg Psychiatry 75: 141–143. Venderova K, Ruzicka E, Vorisek V et al. (2004). Survey on cannabis use in Parkinson’s disease: subjective improvement of motor symptoms. Mov Disord 19: 1102–1106. Waters CH, Sethi KD, Hauser RA et al. (2004). Zydis selegiline reduces off time in Parkinson’s disease with motor fluctuations: a 3-month, randomized, placebo-controlled study. Mov Disord 19: 426–432. Wint DP, Okun MS, Fernandez HH (2004). Psychosis in Parkinson’s disease. J Geriatr Psychiatry Neurol 17: 127–136. Woitalla D, Muller T, Benz S et al. (2004). Transdermal lisuride delivery in the treatment of Parkinson’s disease. J Neural Transm Suppl 68: 89–95. Wolf WA (2003). SLV-308. Solvay. Curr Opin Investig Drugs 4: 878–882. Zesiewicz TA, Sullivan KL, Maldonado JL et al. (2005). Open-label pilot study of levetiracetam (Keppra) for the treatment of levodopa-induced dyskinesias in Parkinson’s disease. Mov Disord 20 (9): 1205–1209. Zhang W, Ordway GA (2003). The alpha2C-adrenoceptor modulates GABA release in mouse striatum. Brain Res Mol Brain Res 112: 24–32.
Further Reading Holloway RG, Shoulson I, Fahn S et al. (2004). Parkinson Study Group. Pramipexole vs levodopa as initial treatment for Parkinson disease: a 4-year randomized controlled trial. Arch Neurol 61: 1044–1053. Parkes JD, Debono AG, Marsden CD (1976). Bromocriptine in parkinsonism: long-term treatment dose response, and comparison with levodopa. J Neurol Neurosurg Psychiatry 39: 1101–1108.
Handbook of Clinical Neurology, Vol. 84 (3rd series) Parkinson’s disease and related disorders, Part II W. C. Koller, E. Melamed, Editors # 2007 Elsevier B. V. All rights reserved
Chapter 38
The importance of patient groups and collaboration MARY BAKER1* AND JILL RASMUSSEN2 1
European Parkinson’s Disease Association (EPDA), Sevenoaks, Kent, UK 2
Merstham Clinic, Redhill, Surrey, UK
38.1. Introduction Historically, patient groups (PGs) were formed to offer mutual support, not only for patients with serious or chronic debilitating disorders, but also for their relatives and friends, who in many cases undertook primary responsibility for day-to-day care. As these groups expanded, they focused first on access to professional and institutional care as needed and to improving insofar as possible patients’ quality of life and a dignified and peaceful end. The next logical step soon followed when PGs became legal charities to raise funds to increase public awareness of particular diseases, to lobby policymakers to direct public attention and resources to obtain better access to treatment and to promote the search for more effective remedies. In essence, they became patient advocacy groups (PAGs) providing a public voice for patients and lobbying for their particular interests. There is little doubt that PAGs have made major contributions to patients’ well-being and quality of life. In some cases, PAGs have developed resources of their own that have made material contributions to the discovery of more effective treatments and sometimes to cures. However, the majority of such development has depended and continues to depend upon commercial interests, academic institutions or publicly funded resources. Not only because both charitable and public financial resources are limited, but also because the research infrastructure required for both fundamental and applied research into complex disorders, often with poorly understood etiology, is equally limited, there is competition for the available resources. This occurs against a background where worldwide expenditure on health care falls well short of demand and, in many cases,
short of actual need as well. For the general well-being, it is essential that the economic, social and policy issues that arise are settled in such ways that deliver an optimal balance between patients’ needs and available resources. PAGs hold the keys to this balance, but if these are to be properly applied, PAGs must broaden their perspectives to consider a patient’s general welfare, not just that related to a specific disease that, in many cases, will be complicated by comorbid or consequential disorders.
38.2. The burden of diseases The World Health Organization (WHO) has developed methods to assess generally the burden of disease on societies (Murray and Lopez, 1996). The diseases underlying this burden vary significantly from region to region, with the burden in developing countries arising mainly from perinatal disorders, malnutrition, communicable disease and violence, whereas in developed areas the burden arises mainly from non-communicable diseases (Murray and Lopez, 1996). The WHO summarizes the burden of disease in terms of disability-adjusted life-years (DALYs) which, in turn, is the sum of years of life lost (YLL) and years of life with disability (YLD). YLL represents the reduction in life expectancy whereas YLD represents the number of years lived with disability adjusted for the incidence of disease and the severity of associated disability, a factor ranging from none (0) to death (1) (Olesen and Leonardi, 2003). Considering the European region (roughly, all European countries west of Russia plus a few others), Olesen and Leonardi (2003) using the WHO data have
*Correspondence to: Dr. Mary Baker, c/o Lizzie Graham, European Parkinson’s Disease Association (EPDA), 4 Golding Road, Sevenoaks, Kent TN13 3NJ, UK. E-mail:
[email protected], Tel/Fax: þ44-(0)-1732-457-683, Cell: þ44-(0)-7787-554856, Website: http://www.epda.eu.com
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calculated that ‘brain diseases’ are responsible for 23% of the years of healthy life lost and 50% of YLDs. In this context, ‘brain disease’ included neurological, neurosurgical and psychiatric disorders together with half of the burden of injuries and congenital problems. Considering the key summary measure of lost health, DALY, 35% was related to brain diseases (Olesen and Leonardi, 2003). Based on these data, these authors suggested that a third of the curriculum at medical school should deal with the brain and that a like proportion of life-science funding should go to basic and clinical neuroscience and that overall a third of health care expenditure should be allocated to the prevention, diagnosis and treatment of brain disease. Given that brain disease underlies a significant proportion of health care costs in Europe, a proportion probably similar in other developed areas of the world, it will be incumbent upon PAGs to prioritize the actual needs rather than the demands of patients so that resources that may be available are applied most effectively. In this respect, all PAGs, not just those representing neuroscience, hold the key to resolving insofar as possible the resource/demand dilemma.
38.3. Responsible advocacy In representing patients, PAGs have a duty to listen to their patients’ wants, to filter out trivial wants and to translate the remainder into prioritized needs considering in that process what is most probably achievable in the short, medium and longer term. For such an assessment, scientific and medical expertise will be required and for this most PAGs will require collaborators. Having established a set of priorities that is scientifically, clinically and financially credible in terms of a specific disease, a PAG has an equal duty to consider whether the resource demands of its priorities are not disproportionate in light of the burden of disease. Whereas PAGs naturally have a self-centered focus on specific diseases, this must necessarily be tempered by a wider social responsibility to share equitably the limited resource pool. PAGs must share with governments, policy-makers as well as with medical and scientific communities the responsibility for achieving an optimum balance between resources and the needs of all patients, not just the few. Even though brain disorders underlie more than a third of DALYs, they remain rather a ‘poor relation’ when it comes to research. If health care is to have any hope of efficient delivery, public policy and research must target ‘big ticket’ issues such as brain disease. Although a policy change of this sort would constitute something of a paradigm shift, especially in Europe, it requires no less a shift in the perspectives
of the PAGs whose ‘principal goals of health care advocacy are to raise awareness of specific issues and make them national priorities’ (Carroll, 2004). Instead of competing with one another for scarce resources, PAGs must recognize that many specific disorders have important – perhaps critical – features in common and that synergy, especially at the level of fundamental science, is very likely. Rather than competing on narrowly defined disease entities, the PAGs must coalesce in broadly based consortia that have a much greater opportunity to influence public policy and to define the objectives of basic research that is certainly necessary to achieve breakthrough therapies for many, if not most, brain diseases. Application to specific disorders could then follow.
38.4. Need for collaboration and partnerships PAGs must recognize that their roles and responsibilities, if first to their members, are not just for this particular group of patients, but also for society – for intelligent and equitable policy, for politics, friends, families, supporters, employers, scientists, health care professionals, and no less for those who produce and supply pharmaceuticals and devices. We are all fellow travelers on a challenging journey. And we will all be patients. If PAGs are to fulfill their wider responsibilities to public welfare, they must achieve a difficult balance between representing the needs of their patient ‘constituency’ and the needs of the wider community of patients and society generally. There can be no doubt that the primary objective for any PAG is to listen to and recognize the needs of its members. There is otherwise no point in its existence. However, the needs of patients and their best interests are unlikely to be most effectively served by a narrow focus that excludes the interests of other patients or those of the larger society. Although its member patients may applaud such an exclusive focus simply because their own disorder looms largest in the framework of scientific or medical issues that urgently require resolution, such resolution is most likely to be achieved not only through collaboration with the whole range of individuals and organizations with specific expertise, but also with other PAGs and groups that share similar representative and advocacy objectives.
38.5. Need for research partnerships and coalitions Because PAGs in general have neither the expertise nor the financial resources to conduct primary research themselves, when representing the interests of patients, PAGs
THE IMPORTANCE OF PATIENT GROUPS AND COLLABORATION must seek and facilitate collaboration. Although PAGs have recognized this, collaborations are usually limited to individuals or entities that are able and willing to focus narrowly on the particular disease entity the PAG represents. For example, in a workshop for PAGs sponsored by the American Society for Experimental Neuro Therapeutics, a speaker suggesting ways of engaging academic partners (Benderly, 2004) recommended that PAGs should try to attract promising young academic researchers who were just starting their careers. A small grant might be used to direct their attention toward areas specific to the PG. Having thus ‘captured’ an academic, the PAG could encourage continued loyalty by contributing to the individual’s professional career by supporting grant applications to other funding bodies, by offering opportunities to publish and by other similar means. However, such methods are inherently competitive, pitting PAGs against one another in the attempt to harness the next generation of scientific and clinical expertise. Rather than competing, albeit with the best of motives, greater progress is likely to arise from collaboration between PAGs. In many chronic, disabling conditions and certainly in neurology and psychiatry the disparate disease states as defined in the current nosology have more in common than not and separating one from another can be very problematic in vivo. On this basis, common pathological mechanisms and perhaps of etiology seem likely and the diseasefocused PAGs should join forces to support the search for those underlying mechanisms that could allow earlier identification of risk or that may be interrupted or modified before irreversible damage has finally overwhelmed the compensating resources of the brain. For example, a number of neurodegenerative disorders associated with dementia (Alzheimer’s disease, dementia of the Lewy body type, frontotemporal dementia, prion disease) have a different predominant pathology, but share a common mechanism of production of the hallmark pathology, namely protein misfolding (Hammarstrom et al., 2001; Hardy, 2003). What distinguishes their specific development is unclear, but is probably important in the search for therapies or prevention. Coalitions of all PAGs representing the disparate diseases should be formed to support research in such cases. It would also be reasonable to expect that an alliance of PAGs representing disparate diseases with some common features could encourage ‘thinking outside the box’ that often seems to produce breakthrough concepts.
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38.6. Partnerships for policy change Beyond partnerships of PAGs to promote progress on issues of common interest, even wider alliances with other professional organizations undoubtedly improve both credibility and leverage when advancing the social and economic justifications for directing public policy and resources. Whether or not within an alliance, PAGs must be effective at enabling, at bringing people of disparate interests together to spawn original thinking and to induce change. When attempting to influence both public perception and by extension public policy, the size of the problem obviously matters. Groups representing a large patient population with significant demands on state or other resources will have greater success in getting their message across. They will be more able to highlight the burden of illness substantiated by economic evidence, including both direct and indirect personal, financial and societal costs. Having got the attention of the public and policymakers, the PAGs must mediate between conflicting interests and perspectives. For example, they need to engage clinicians and health economists (who are not natural bedfellows) with patients who have a sharp focus on their distress, but very little idea of the cost. Such engagement presents real potential for conflict, as the various interests are not easily reconciled. Even apart from economics, patients and doctors have different perspectives and priorities. PAGs have an important mediating role in listening to patients and helping them to express their needs clearly and to encourage partnership in their care. Doctors typically focus on the specific disease, the site of pathology and upon symptomatology. They measure illness, its progression and response to treatment, for example, according to neurological parameters. Patients, by contrast, focus on the effect of the illness and its treatment on their daily lives (mood, pain, sleep, bodily function, disability). Patients look at things in terms of their self-respect (work, independence) and relationships with others. From that highly personalized perspective, specialized clinical assessments are largely meaningless and the primary debilitating effects often arise not from the underlying disease, but from such comorbid conditions as depression or anxiety, from employment or financial concerns, or from sensitivity to public stigma. To insure that patients have access to management of all of their problems, not simply access to specialized care, important as that is, PAGs need on the one hand to engender evidence-based policies, treatment guidelines and management practices based on
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mass statistics whilst on the other hand representing the spectrum of disease and the real problems that particular cohorts experience. These problems often cross specialist boundaries.
38.7. Advocacy is not enough Although advocacy is a necessary, important and challenging function, it is not in itself sufficient. It is equally important that PAGs also take responsibility to inform and educate their members. They must provide their members not only with encouragement and support, but also with realistic expectations. Patients have a right to see a doctor who understands their disease, but also a team that can recognize associated problems and address them. Patients have a right to expect continuity of care, that is, to see the same doctor and team at successive visits. But patients also have a duty to educate themselves about their disease, to recognize and understand its possible complications and to have reasonable expectations concerning their care and to be prepared to participate fully and effectively in their own treatment. It is a prime responsibility of the PAGs to provide and deliver this sort of patient education. As part of this educational responsibility, PAGs need to make it clear to their members that there is fierce competition for health care resources and that patients with a particular disorder have no intrinsic right to a disproportionate share of the limited resources. Distribution of available resources is inherently political. As such, politicians and policy-makers are tempted to respond to the views of the much larger population of the generally healthy who tend to consider most serious those disorders that they believe present the greatest immediate risk to them personally. PAGs representing patients with disorders that predominantly affect the elderly, including most of the degenerative neurological diseases, are disadvantaged in the competition for resources simply because the general public consider these to be remote risks. Neurological disorders are often considered a threat only to the old and victims are largely hidden from society, whereas psychiatric disorders are associated with public stigma and likewise hidden or denied wherever possible. PAGs representing these patients must strive to illustrate the burden of these disorders and to raise their profile in public perception. In terms of DALYs and consequent direct and indirect costs to society, brain diseases are very important. In the past, spouses or other members of the immediate family have absorbed much of this personal as well as financial cost. However, increasing dispersion of the extended family as well as dissolution of the
nuclear family coupled with increasing full-time employment for both sexes results in an increasing responsibility of the state to provide care. This is inherently expensive and exacerbated by the demographic reality of an increasing proportion of older people in the population. It is perhaps natural and certainly understandable that diseases that lead to premature death are frightening for most people. Understanding the personal impact of an illness that gradually erodes the senses, intellectual function or the ability to perform simple motor tasks is much harder for healthy people to imagine. It therefore devolves to the PAGs to use every possible tool at their disposal to educate the healthy not only to recognize their personal risk, but more importantly, to gain some concept of the impact of living with a disability that will only become more severe. It must be obvious that the risk of a single disorder such as Parkinson’s disease is small compared to the risk of one of the range of equally or more debilitating degenerative neurological conditions. Again, fragmenting the message among many specific disorders, each equally devastating, can hardly be as effective as a coordinated message. The PAGs have a duty to their members, if not to society generally, to collaborate in the effort to educate the public, the politicians and the policy-makers.
38.8. Research and development issues In the same way, the PAGs have a duty to collaborate when representing their members in the many areas of common interest such as the ethical dimensions of stem cell or animal research. The effort to relieve the suffering of patients should not be compromised by the fact that some necessary aspects of scientific and clinical research may offend the sensibilities of those with dogmatic views, however fervently held. Collaboration of PAGs is also necessary if a uniform standard of care is to be accessible to members regardless of their disease, their station in life or where they live. There are, for example, significant differences in reimbursement and in the time lags for access to new treatments. Regulatory requirements and the associated timecosts of drug development coupled with a high risk of failure and short patent terms constrain the development of new drugs. In particular, development for relatively rare conditions is unlikely. In addition, the cost of new drugs is necessarily high to recoup development costs not only for the one registered drug, but also for the three or four that failed in development. Short patent terms mean that most cost recovery has to be achieved before the patent expires and manufacturers
THE IMPORTANCE OF PATIENT GROUPS AND COLLABORATION of generics who contribute nothing to research or development flood the market. If the PAGs wish to encourage new therapies, they need to collaborate to lobby for regulatory changes that will encourage rather than stifle research and development.
38.9. What next for patient advocacy? Finally, although there is no doubt that PAGs have made major contributions to the well-being of their patients and that continuing such contributions will be required in future, changing times now require that the PAGs should seriously consider altering their operating methods in areas of mutual interest. In the encouragement and/or sponsorship of research into the underlying mechanisms of neurological disorders, a broader scope of enquiry that could promote lateral thinking should prove more productive than one based upon a narrow focus on a single disease entity. Close collaboration of several PAGs would be most appropriate and perhaps necessary to engender such research. In particular, there is compelling evidence from the WHO for the importance of brain disorders, mainly neurological and psychiatric, among the diseases contributing most significantly to the global burden of disease. Fragmenting the voice of all affected patients along disease-specific lines is counterproductive in
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the competition for an equitable distribution of limited research, development and care-centered resources. Although it may well be desirable that diseasecentered PAGs should retain a measure of individual identity and autonomy, a much greater measure of association and collaboration among the PAGs dealing with brain-related diseases will be necessary if they are to serve most effectively the needs of patients and to achieve a share of resources commensurate with the impact of brain diseases on individuals, society and the health care systems.
References Benderly BL (2004). Advocacy groups are crucial players in developing new neurotherapeutics. NeuroRx 1: 500–502. Carroll PR (2004). The impact of patient advocacy: the University of California-San Francisco experience. J Urol 172 (5 Pt 2): S58–S61. Hammarstrom P, Schneider F, Kelly JW (2001). Transsuppression of misfolding in an amyloid disease. Science 293: 2459–2462. Hardy J (2003). Impact of genetic analysis on Parkinson’s disease research. Mov Disord 18 (Suppl 6): S96–S98. Murray CJ, Lopez AD (1996). Evidence-based health policy— lessons from the Global Burden of Disease Study. Science 274: 740–743. Olesen J, Leonardi M (2003). The burden of brain diseases in Europe. Eur J Neurol 10: 471–477.
Section 6 Complications of therapy
Handbook of Clinical Neurology, Vol. 84 (3rd series) Parkinson’s disease and related disorders, Part II W. C. Koller, E. Melamed, Editors # 2007 Elsevier B. V. All rights reserved
Chapter 39
Motor and non-motor fluctuations SUSAN H. FOX* AND ANTHONY E. LANG Division of Neurology, University of Toronto, Toronto, ON, Canada
39.1. Introduction The cardinal symptoms of Parkinson’s disease (PD), bradykinesia, rigidity and tremor, occur in large part secondary to progressive degeneration of the dopaminergic neurons within the substantia nigra pars compacta of the midbrain. Treatment of PD is therefore based on dopamine replacement, either in the form of the dopamine precursor, levodopa (co-administered with a peripheral dopa-decarboxylase inhibitor) or via directly acting dopamine receptor agonists. Early treatment of PD with these agents results in effective and sustained control of motor symptoms which may last for several years. With the progression of the disease and the requirement for higher doses of levodopa, the vast majority of patients start to experience a reduced and variable benefit from medication. At this stage, patients often experience fluctuations in response to medication in both the motor symptoms (motor fluctuations), but also in non-motor symptoms (non-motor fluctuations), such as psychiatric/behavioral problems, autonomic dysfunction and sensory/pain symptoms. In addition, PD patients may also experience spontaneous fluctuations in symptoms, unrelated to levodopa dosing. The presence of fluctuations in motor and nonmotor symptoms is almost invariable in PD patients and as such the absence of fluctuations may suggest that a patient does not have idiopathic PD (Quinn, 1998).
39.2. Levodopa-induced motor fluctuations 39.2.1. Definitions The commonest fluctuations to emerge in advancing PD are the variable and often unpredictable benefits on the motor symptoms of bradykinesia, rigidity, tremor and
gait seen in response to a dose of levodopa (Table 39.1). A PD patient exhibiting parkinsonian symptoms is described as being ‘off’ and an improvement in symptoms after dopaminergic medication is termed ‘on’. The dose–response to levodopa is often divided into three timeframes: (1) the initial improvement or beginning of dose, when the patient first begins to notice an improvement in symptoms and ‘switches on’; (2) the maximal time of improvement in parkinsonian symptoms, called ‘peak dose’; and (3) the beginning of loss of benefit and re-emergence of parkinsonian symptoms or ‘end of dose’. Motor fluctuations can affect all or part of these levodopa dose-related timeframes. Thus a careful history of the patient’s problems in relation to the timing of a dose of levodopa is critical to management and treatment of motor fluctuations. Measurement of motor fluctuations in response to medication is incorporated into the Unified Parkinson’s Disease Rating Scale (UPDRS). 39.2.1.1. Predictable wearing-off Motor fluctuations tend to begin with a predictable shortening in the duration of response to levodopa with gradual emergence of parkinsonian symptoms, called ‘wearing-off’. This is usually apparent when the duration of levodopa benefit is 4 hours or less (Muenter and Tyce, 1971; Shoulson et al., 1975; Fahn, 1982). The earliest manifestation of this is usually morning akinesia, since the time between doses is generally longest overnight before the morning dose. 39.2.1.2. Unpredictable, sudden offs Patients can also experience wearing-off that is fast, random and unrelated to the timing of the last dose of levodopa, called ‘unpredictable offs’. Such patients
*Correspondence to: Susan H. Fox, Toronto Western Hospital, Movement Disorders Clinic, Division of Neurology, University of Toronto, 399 Bathurst Street MCL7–412, Toronto, ON M5T 2S8, Canada. E-mail:
[email protected], Tel: þ1-416-6035383, Fax: þ1-416-603-5004.
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Table 39.1 Levodopa-induced motor fluctuations in Parkinson’s disease Predictable wearing-off Unpredictable, sudden offs Dose failure, delayed or partial on response Beginning-of-dose worsening End-of-dose rebound On- and off-period freezing (motor blocks) Tachyphemia and running gait Dyskinesia Peak dose/square-wave dyskinesia Wearing-off/off-period dystonia Diphasic dyskinesia On–off fluctuations/‘yo-yoing’
can suffer off-periods that come on over a few seconds with resultant severe akinesia, called a ‘sudden off’ (Fahn, 1974). 39.2.1.3. Dose failure, beginning-of-dose worsening, end-of-dose rebound Patients may also experience delay in benefit (‘delayed on’) or absence of benefit from a dose of levodopa, called ‘dose failure’ (Melamed and Bitton, 1984). Some patients can experience a transient worsening of symptoms at the beginning of dose, often as an increase in tremor (beginning-of-dose worsening) (Merello and Lees, 1992). In some cases, the off state may be worse than in the untreated state or after longer periods of drug withdrawal (‘super off’) and these patients may experience an exacerbation or rebound in their symptoms at the end of dose (endof-dose rebound) (Nutt et al., 1988). 39.2.1.4. On- and off-period freezing (motor blocks) One particular problem that can occur is a transient difficulty initiating a movement – a sudden transient freezing (also called motor blocks) that may occur when starting to walk (start hesitation), while turning (turning hesitation) or going through a narrow doorway (Giladi et al., 1992; Fahn, 1995). Once the block is overcome then the activity can be completed smoothly. In addition, freezing can occur during other activities such as speech and writing (Fahn, 1995). Motor blocks can also occur due to sudden stress or anxiety (startle hesitation). Such freezing episodes most commonly occur when the patient is in the off state but may also occur in the on state (‘on-period freezing’). 39.2.1.5. Tachykinetic problems Some patients with PD may experience increased speed of speaking (tachyphemia) that also becomes
lower-volume and increasingly inaudible; this is often associated with high doses of levodopa and is an onperiod phenomenon. Tachyphemia is often associated with a similar phenomenon in walking: an increasing speed of walking even to the point of running, with smaller steps, which may lead to falls (Giladi et al., 1997). 39.2.1.6. Dyskinesia At the same time as the above fluctuations start to occur, patients often experience involuntary movements or dyskinesia. Dyskinesia can occur at variable times in response to levodopa. Thus dyskinesia most commonly occurs at the peak dose of levodopa action (peak-dose dyskinesia) or throughout the duration of the on-period (square-wave dyskinesia) and can be a mixture of chorea, ballism and dystonia and to a lesser extent myoclonus (Nutt, 1990). Choreiform movements in the limbs are most common but dystonic posturing in the limbs and craniocervical dystonia and chorea are also common (Luquin et al., 1992). Off-period or wearing-off-period dyskinesia is predominantly dystonic and tends to affect the limbs, particularly the legs and feet (Poewe et al., 1988; Bravi et al., 1993). Patients often experience a more fixed posture (e.g. ankle intorsion with toe flexion or extension), especially early morning, often associated with pain (early-morning dystonia) (Melamed, 1979). Less common is dyskinesia occurring at the beginning and end of dose, when the levels of levodopa are rising and falling, respectively. This is known as diphasic dyskinesia, or beginning-of-dose and end-of-dose dyskinesia. This has also been referred to as dystonia– improvement–dystonia or DID pattern (Muenter et al., 1977). Diphasic dyskinesia tends to affect the legs predominantly (Marsden et al., 1982) and can involve stereotypical rapid alternating leg movements, as well as unusual ballistic kicking or dystonia (Luquin et al., 1992). 39.2.1.7. On–off fluctuations With further disease progression and levodopa treatment, patients can experience predictable or unpredictable switching from being ‘on’ and mobile with dyskinesia to being ‘off’ and immobile, known as ‘on–off fluctuations’ (Duvoisin, 1974; Fahn, 1974). The term ‘on–off’ implies a transition from one state to the other akin to switching on and off a light. Patients with advanced PD can develop a ‘yo-yoing’ effect where they rapidly, unpredictably and repeatedly switch from being on with dyskinesia to off and then on again (Fahn 1974, 1982; Marsden and Parkes, 1976).
MOTOR AND NON-MOTOR FLUCTUATIONS
39.3. Spontaneous motor fluctuations Motor fluctuations can also occur spontaneously as part of the disease and not necessarily related to long-term levodopa therapy. There is often a diurnal variation in symptoms with improvement in the morning and deterioration through the day (Struck et al., 1990; Nutt and Holford, 1996). Marked diurnal variation is seen in young-onset PD patients with mutations in the parkin gene (Khan et al., 2003). Another spontaneous motor fluctuation, first observed in the prelevodopa era, is paradoxical kinesia. This was particularly apparent in postencephalitic parkinsonism. Paradoxical kinesia is a sudden improvement in motor activity in response to a mental stress, e.g. a fire alarm or as a reflex response to being thrown a ball (Quinn, 1998). Although some fluctuations mentioned earlier can be exacerbated by levodopa, they can also be a feature of the underlying disease; these include motor blocks and tachykinetic symptoms.
39.4. Epidemiology of motor fluctuations The incidence of motor fluctuations in PD has been consistently shown to increase with both duration of levodopa therapy and duration of disease. The earliest reports estimated that 10% of patients per year developed motor fluctuations after the initiation of levodopa therapy (Marsden and Parkes, 1977). The frequency of wearing-off/on–off motor fluctuations and dyskinesia has been estimated from a cumulative literature review (between 1966 and 2000) to be 40% and 50%, respectively, after 4–6 years of levodopa treatment (Ahlskog and Muenter, 2001). In recent prospective randomized clinical trials comparing initiation of levodopa with a dopamine agonist, where the development of motor fluctuations was the primary endpoint of the study, 40–54% experienced dyskinesia and 34–62.7% wearing-off after 4–5.5 years of follow-up (Rascol et al., 2000; Parkinson Study Group, 2004). Accurate measurement of the current prevalence of motor fluctuations experienced by PD patients, however, is marred by variability in ascertainment (Marras and Lang, 2003) and the effect of changes in treatment practice over the past two decades. A community-based study of 124 PD patients found that 20% were experiencing dyskinesia and 30% response fluctuations after a mean disease duration of 6 (4.3) years (Schrag et al., 2002).
39.5. Pathophysiology of motor fluctuations Motor fluctuations are due to a combination of pre- and postsynaptic changes in the nigrostriatal dopaminergic
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system and possibly other dopamine pathways, e.g. the nigropallidal pathway, together with peripheral pharmacokinetic factors. Disease progression with loss of nigrostriatal dopaminergic terminals results in altered central pharmacokinetics of levodopa (presynaptic changes); peripheral pharmacokinetics of levodopa and the duration and dose of levodopa therapy result in changes to postsynaptic dopamine receptor signaling (central pharmacodynamic or postsynaptic changes). These factors result in abnormal intrasynaptic dopamine concentration with loss of normal constant stimulation of postsynaptic dopamine receptors. 39.5.1. Central pharmacokinetics of levodopa In early PD, the clinical response to a single dose of levodopa is stable and lasts for several hours, despite the half-life of levodopa being only 60–90 minutes (Muenter and Tyce, 1971). Thus if a patient misses a dose of levodopa, there is no recurrence of symptoms. This is called the long-duration response (LDR) to levodopa (Nutt and Holford, 1996; Obeso et al., 2000a). The duration of the LDR, i.e. the time to complete loss of drug effect after stopping levodopa, is thought to last 1–2 weeks (Olanow et al., 1995; Hauser et al., 2000), but recent studies have suggested that this may extend for up to 4 weeks (Hauser and Holford, 2002; Fahn et al., 2004) or even longer. The exact origin of this LDR is unknown but it may be partly due to levodopa conversion to dopamine in remaining nigrostriatal terminals and storage in synaptic vesicles for release as required, thus mimicking the normal physiological function of the dopamine terminals (Quattrone et al., 1995; Zappia et al., 1999). The LDR may also be due to postsynaptic changes in dopamine receptor pharmacology and second-messenger systems, as the LDR is similar in dopa-responsive dystonia where there is no presynaptic loss of dopamine terminals (Nutt and Nygaard, 2001) (see below). In PD patients with motor fluctuations, the duration of the LDR shortens and the rate of decline in LDR after stopping levodopa is greatest in more severely affected patients (Quattrone et al., 1995; Zappia et al., 1999; Nutt et al., 2002). In advanced PD, the response to levodopa is dominated by a short-duration response (SDR), which is the loss of benefit, typically less than 4 hours following a dose of levodopa. At this stage, patients start to experience fluctuations in their response to levodopa with wearing-off and thus become more dependent on the timing of each levodopa dose. These wearing-off symptoms are probably due to a progressive loss of presynaptic dopaminergic terminals with a loss of dopamine storage (Fabbrini et al., 1988; Chase et al., 1993;
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Verhagen Metman et al., 2000). Loss of dopaminergic terminals means levodopa is converted to dopamine in other aromatic acid-decarboxylase-containing cells, such as serotonergic and endothelial cells (Ng et al., 1971; Melamed et al., 1980). These cells lack the ability to store dopamine and thus non-regulated release of dopamine into the synaptic space may cause fluctuations. In patients with motor fluctuations, compared to those without, there is decrease in the latency to onset and peak response of levodopa (Nutt et al., 1992, 2002; Colosimo et al., 1996). In early PD there is a linear relationship between dose of levodopa and response; however, in advanced PD with motor fluctuations, this dose–response switches to a sigmoid curve; thus patients switch on at a critical level, below which they are off and above which they are essentially ‘fully on’ (Mouradian et al., 1988). Altered synaptic dopamine turnover has also been suggested to underlie motor fluctuations (Torstenson et al., 1997). [11C]Raclopride positron emission tomography (PET) studies have shown that PD patients who subsequently develop motor fluctuations, even before these occur, have three times greater levels of synaptic dopamine 1 hour after levodopa administration compared to non-fluctuators and, after 4 hours, only the non-fluctuators were able to maintain a stable level of synaptic dopamine (de la Fuente-Fernandez et al., 2001). However, in PD patients experiencing peak-dose dyskinesia, synaptic dopamine levels were higher 1 hour post-levodopa but there was no difference after 4 hours with non-dyskinetic patients (de la Fuente-Fernandez et al., 2004). Thus, it is unclear if levodopa-induced changes in synaptic dopamine are compensatory to underlying disease or a cause of motor fluctuations. 39.5.2. Peripheral pharmacokinetics of levodopa Gastrointestinal factors may also play an important role in motor fluctuations due to variability of levodopa delivery to the brain. Levodopa crosses the wall of the small intestine and the blood–brain barrier via a saturable carrier-mediated transporter. Competition for this transporter between dietary amino acids and levodopa can result in delayed switching on or failure of a dose of levodopa to have any benefit (Nutt et al., 1984). Other factors that affect levodopa absorption include slow or erratic gastric emptying, which may occur secondary to concurrently used anticholinergics and food (Nutt and Fellman, 1984), as well as to age and PD itself (see section 39.6.2.2). All of these factors combined can result in an important contribution of peripheral pharmacokinetics to the chance of erratic and unpredictable responses to levodopa.
39.5.3. Central pharmacodynamics Central pharmacodynamics or postsynaptic mechanisms are probably the most important factor in the development of motor fluctuations. Thus, wearing-off and dose failures also occur following long-term levodopa therapy in animal models of parkinsonism, where there is no progressive loss of nigrostriatal terminals (Papa et al., 1994; Chase, 1998a). In normal primates, long-term treatment with levodopa can induce dyskinesia which is dose-dependent; thus nigrostriatal degeneration is not a prerequisite for motor fluctuations to develop (Pearce et al., 2001; Togasaki et al., 2001). (However, fluctuations will develop quicker with a greater loss of nigrostriatal terminals: see below.) In addition, the shortening of the LDR as measured by the rate of antiparkinsonian response decline following withdrawal of medication (turning off a constant intravenous infusion of levodopa), which becomes increasingly faster from mild, untreated PD patients to those with severe on–off fluctuations, is also seen using infusions of the dopamine agonists apomorphine and lisuride, which act predominantly on postsynaptic dopamine receptors, independent of presynaptic terminals (Bravi et al., 1994; Verhagen Metman et al., 1997; Stocchi et al., 2001a). In addition, eliminating variability in synaptic dopamine levels with a constant infusion of levodopa still results in fluctuations as measured by changes in tapping speed as an indicator of bradykinesia (Nutt et al., 1997). Thus central pharmacokinetics of levodopa is not the only factor in the development of a fluctuating response. This implies that the basis for the development of motor fluctuations is probably due to erratic or pulsatile stimulation of the postsynaptic dopamine receptor and consequent downstream processes. However, the extent of presynaptic denervation clearly contributes by altering the frequency of dopamine receptor stimulation, which then sets up changes within the postsynaptic signaling pathways. Thus in PD patients, dyskinesia occurs earlier and is more severe on the most affected side (Horstink et al., 1990). In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) parkinsonism, with a greater degree of dopaminergic denervation than idiopathic PD, dyskinesia occurs earlier, on average 6 months, after initiation of levodopa (Ballard et al., 1985). The exact postsynaptic mechanisms responsible for inducing motor fluctuations are unclear but probably consist of multiple changes to neurotransmitter signaling pathways within the basal ganglia (Crossman, 1990; Obeso et al., 2000b; Bezard et al., 2001). To date, most investigations into postsynaptic mechanisms have evaluated levodopa-induced dyskinesia specifically.
MOTOR AND NON-MOTOR FLUCTUATIONS On the other hand, animal models of PD with levodopainduced dyskinesia also exhibit wearing-off fluctuations (Papa et al., 1994) and, in advanced PD, patients with dyskinesia invariably exhibit other types of motor fluctuations, thus the neural mechanisms underlying dyskinesia may be similar to those underlying other motor fluctuations. However, postmortem studies have suggested that some differences exist between PD patients who experience dyskinesia only compared to those with wearing-off only. For example, in patients with wearing-off only, putaminal dopamine was mainly metabolized intraneuronally whereas in patients with dyskinesia only, the dopamine was mainly extraneuronal (Rajput et al., 2004). In addition, increased GABAA receptors in the putamen have been linked to the pathophysiology of wearing-off but not to dyskinesia (Calon et al., 2003). To date, however, the exact distinction, if any, between the neural mechanisms underlying dyskinesia, wearing-off and other on/off fluctuations (that are unrelated solely to the peripheral pharmacokinetics of levodopa, such as delayed-on) is unknown. The phasic stimulation of postsynaptic dopamine receptors by repeated doses of levodopa is clearly a factor in the development of motor fluctuations. Consistent with this is the observation in animal models of PD that de novo treatment with chronic continuous levodopa results in fewer or no motor fluctuations compared to repeat dosing with intermittent levodopa (Engber et al., 1989; Blanchet et al., 1995). In PD patients, de novo therapy with long-acting dopamine agonists reduces motor fluctuations compared to short-acting levodopa (Rascol et al., 2000; Parkinson Study Group, 2004). Thus, less pulsatile dopaminergic stimulation reduces the risk of developing motor fluctuations by preventing postsynaptic changes that occur with intermittent stimulation. To date, no consistent changes have been demonstrated in dopamine D1-, D2- or D3-receptor subtype number or affinity in levodopa-treated PD patients to account for the development of motor fluctuations (Rinne et al., 1991; Turjanski et al., 1997). The old explanation of dopamine receptor ‘supersensitivity’, as a consequence of dopamine depletion, causing motor fluctuations and particularly dyskinesia, is unlikely, as dyskinesia rarely appears with the first doses of levodopa, even in severely affected patients, or in MPTP-lesioned primates with profound dopamine terminal loss. Some recent evidence suggests that there may be increased signaling downstream of striatal dopamine D1-receptors in MPTP-lesioned primates with dyskinesia compared to non-dyskinetic animals, despite the absence of receptor number changes (Aubert et al., 2005). As dopamine D1-receptor signaling regulates the activity of the so-called direct
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pathway, which is an inhibitory GABAergic pathway from the caudate putamen (striatum) to the internal segment of the globus pallidus, this may lead to increased activation of this pathway, which is thought to underlie levodopa-induced dyskinesia (Bezard et al., 2001) (see Ch. 40). Non-dopaminergic neurotransmitter systems have also been shown to be associated with the development of motor fluctuations. In animal models of PD with motor fluctuations, activation of the dopamine D1-receptor results in enhanced phosphorylation of N-methyl-d-aspartate (NMDA) glutamate receptor subunits within the striatum (Oh et al., 1999; Dunah and Standaert, 2001; Calon et al., 2002a). NMDA receptor antagonists will reduce motor fluctuations in animal models of PD (Papa et al., 1995; Papa and Chase, 1996) and the non-selective NMDA receptor antagonist amantadine is effective in reducing the severity of dyskinesia in clinical practice (VerhagenMetman et al., 1998). The NMDA receptor is critical to synaptic plasticity and in levodopa-induced dyskinesia it appears that stimulation of striatal dopaminergic receptors functionally linked to NMDA neurotransmission may lead to a form of synaptic plasticity similar to long-term potentiation (LTP) in the hippocampus involved in memory and learning. Thus in the striatum in levodopa-induced dyskinesia, excessive LTP may contribute to the development of motor fluctuations (Calabresi et al., 2000, Picconi et al., 2003). Increases in the opioid peptides within the striatum may also be associated with motor fluctuations, as shown by evidence from animal models (Henry and Brotchie, 1996; Andersson et al., 1999; Henry et al., 1999; Klinteberg et al., 2002), human postmortem studies (Calon et al., 2002b; Henry et al., 2003) and PET studies (Piccini et al., 1997). In PD patients with motor fluctuations, non-selective opioid receptor antagonists extend on-time (Fox et al., 2004) but have no effect on established dyskinesia (Rascol et al., 1994; Manson et al., 2001; Fox et al., 2004). The exact role of opioids in dyskinesia is unclear, as recent studies in MPTPlesioned primates have shown that opioid antagonists can increase dyskinesia (Samadi et al., 2003). Evidence that other non-dopaminergic neurotransmitter systems are involved in motor fluctuations comes from preclinical studies in animal models of PD (Brotchie et al., 2005) and from clinical studies (Silverdale et al., 2003) using selective a2-adrenoceptor antagonists (Bara Jimenez et al., 2004); 5HT1A-receptor agonists (Olanow et al., 2004) and cannabinoids (Sieradzan et al., 2001). Thus a range of non-dopaminergic neurotransmitter systems are probably involved in the pathophysiology of motor fluctuations.
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39.6. Treatment of levodopa-induced motor fluctuations 39.6.1. Predictable wearing-off 39.6.1.1. Alter dose interval or preparation of levodopa End-of-dose or wearing-off phenomenon, if mild, can be initially treated by decreasing the time interval between dosing of levodopa to give the next dose just before the beneficial effects have worn off. Alternatively or in addition, if the patient is not experiencing dyskinesia and off-periods predominate, then the dose of levodopa can be increased. As discussed earlier, because of the change in the dose–response curve to levodopa in advanced PD, increasing individual doses of levodopa will not improve the quality of the onperiod, but will simply increase the duration (Marsden, 1994). Longer-acting levodopa preparations such as Sinemet CR or Madopar CR may help improve on-time by 1–1.5 hours (Ahlskog et al., 1988; MacMahon et al., 1990). However, the bioavailability of these longer-acting preparations is 20–30% less than standard-release preparations and patients usually end up on higher overall daily doses of levodopa, with a risk of exacerbating dyskinesia, particularly later in the day (Lieberman et al., 1990). In addition, these preparations also typically have a longer latency to benefit so patients may experience ‘delayed-on’ problems; especially if doses are not overlapping (i.e. the patient wears off before the next dose). The problem with all the above strategies is that, because the dose of levodopa is increased, there is a risk of exacerbating motor fluctuations in the future. 39.6.1.2. Add a dopamine receptor agonist Adding an oral dopamine receptor agonist is a better option as it minimizes the need to increase the dose of levodopa. All dopamine agonists in clinical practice, such as bromocriptine, ropinirole, pergolide, pramipexole and cabergoline, reduce off-time and improve the duration of on-time when combined with levodopa (Hoehn and Elton, 1985; Lieberman et al., 1993; Olanow et al., 1994; Rascol et al., 1996; Pinter et al., 1999). In addition, it may be possible to reduce the dose of levodopa. Systematic review and analysis of clinical trials comparing bromocriptine with ropinirole, cabergoline and pramipexole as add-on therapy have shown no significant differences in efficacy (Clarke et al., 2000; Clarke and Deane, 2001a, b; Goetz, 2003). In two trials, pergolide was more efficacious at reducing motor impairment and disability compared to bromocripine (Clarke and Speller,
2000). A new patch formulation of the dopamine agonist rotigotine is in clinical development (Parkinson Study Group, 2003). To date, there are no comparisons of efficacy between the newer dopamine agonists. Side-effects of dopamine agonists have been discussed earlier (see Ch. 33). 39.6.1.3. Add a catechol-O -methytransferase (COMT) inhibitor COMT is an enzyme involved in the breakdown of levodopa and dopamine to methylated derivatives. Inhibition of this enzyme therefore increases the elimination half-life of levodopa, thus increasing bioavailability (Ruottinen and Rinne, 1996a). The other pharmacological effect of repeated dosing with COMT inhibitors is a reduction in the usual peaks and troughs of levodopa levels, i.e. a smoothing-out of levodopa levels through the course of the day, resulting in an increase in mean daily plasma levodopa levels (Nutt et al., 1994). There are currently two COMT inhibitors available, entacapone and tolcapone. However, tolcapone is unavailable in many European countries and Canada due to concerns regarding liver toxicity and, in those countries where available, restrictions apply to its use. Tolcapone is administered three times daily, usually in 100-mg doses, irrespective of levodopa dosing. The shorter half-life of entacapone (1 hour) means that each 200-mg dose has to be co-administered with levodopa. A combined preparation of levodopa/carbidopa and entacapone (Stalevo) in a single tablet is now available and is undergoing clinical trials (Koller et al., 2005). Many clinical trials have demonstrated improved on-time with the addition of entacapone (Ruottinen and Rinne, 1996b; Parkinson Study Group, 1997) or tolcapone (Kurth et al., 1997; Rajput et al., 1997) to levodopa, on average by 1–2 hours. There are no differences in the responses obtained using levodopa/carbidopa, levodopa/benserazide preparations or with controlled-release preparations of levodopa (Poewe et al., 2002). Although randomized comparative studies have not been performed, it is common clinical impression that tolcapone may be more efficacious than entacapone in controlling motor fluctuations (Factor et al., 2001). This may relate to the purely peripheral effects of entacapone on degradation of levodopa as compared to the additional central effects of tolcapone on dopamine metabolism (Kaakkola et al., 1994; Forsberg et al., 2003). Early side-effects of COMT inhibitors include prolongation of existing on-period dyskinesia, usually without an increase in severity, as there is no change in peak levodopa level after a single dose. However,
MOTOR AND NON-MOTOR FLUCTUATIONS as the level of levodopa may accumulate following repeated dosing, then severity of dyskinesia may also increase (Ruottinen and Rinne, 1996a; Kurth et al., 1997; Muller et al., 2000). The dyskinesia can be improved by reducing the dose of levodopa (Myllyla et al., 2001). Later side-effects include abdominal pain and severe diarrhea that can occur after a few weeks of treatment and may lead to discontinuation in 5–10% of patients (Rajput et al., 1997; Myllyla et al., 2001). Tolcapone requires liver enzyme monitoring; significant elevation of transaminases can occur in about 3% of patients and 3 unmonitored patients died of acute hepatic failure before this complication was recognized (Rajput et al., 1997; Assal et al., 1998). Entacapone does not cause elevation of liver enzymes (Myllyla et al., 2001). The difference between tolcapone and entacapone in inducing liver enzymes does not relate to the COMT inhibition per se but rather to an effect on other metabolic pathways, possibly via inhibition of mitochondrial adenosine triphosphate synthesis (Korlipara et al., 2004) (see Ch. 32). 39.6.1.4. Add a monoamine oxidase B inhibitor Monoamine oxidase B (MAO-B) inhibition can extend the duration of action of levodopa by inhibiting the metabolism of dopamine and increasing dopamine levels by up to 70% in the brain (Riederer and Youdim, 1986). Several early clinical studies demonstrated that the MAO-B inhibitor, selegiline (5–10 mg/day) had a mild effect on PD patients with wearing-off motor fluctuations (Lees et al., 1977; Golbe et al., 1988). There was no benefit in patients with marked, disabling on– off fluctuations and the main side-effects related to increased dopamine levels, such as nausea and dyskinesia, which improved on reduction of levodopa dose. A new transmucosal preparation of selegiline (Zydis selegiline) is now available. This is placed on the tongue and is rapidly absorbed directly into the systemic circulation, resulting in more reliable and higher blood levels of selegiline (Seager, 1997; Clarke et al., 2003). This bypasses first-pass hepatic metabolism and reduces production of theoretically toxic amphetamine-like metabolites (Clarke et al., 2003). A single double-blind, randomized, placebo-controlled trial (RCT) has shown that Zydis selegiline (2.5 mg/ day) significantly reduced total daily off-time in PD patients, with predictable wearing-off, by 2.2 hours compared to 0.6 hours for placebo (Waters et al., 2004). The main side-effects were dizziness, hallucinations, headache and dyskinesia, although there was no significant difference in on-time with dyskinesia between placebo and Zydis selegiline. Levodopa doses were reduced by 20% with Zydis selegiline, although
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not specifically due to worsening of dyskinesia (Tetrud and Koller, 2004). To date, no comparisons have been made with conventional selegiline in terms of improving wearing-off symptoms. Rasagiline, a newly developed irreversible MAO-B inhibitor, is 10–15 times more potent than selegiline and is not associated with amphetamine metabolites (Finberg et al., 1999). A double-blind RCT showed that in PD patients with on–off fluctuations, rasagiline up to 2 mg/day improved motor and activities of daily living on-period UPDRS scores compared to placebo, but there was no significant decrease in off-periods (Rabey et al., 2000). However, a more recent study found that rasagiline 0.5 and 1 mg/day reduced total daily off-time by 1.41 and 1.85 hours, respectively (Parkinson Study Group, 2005) (see Ch. 34). 39.6.2. Dose failure, delayed or partial ‘On’ 39.6.2.1. Improve gastric emptying by taking levodopa on an empty stomach Impaired absorption of levodopa in the small intestine may cause either a delayed or partial improvement of parkinsonian symptoms or result in no benefit – a dose failure or ‘no-on’. Levodopa absorption may be impaired by delay in gastric emptying secondary to the presence of food (Fahn, 1977; Baruzzi et al., 1987). Initially patients are advised to take levodopa with food to prevent nausea but with time this requirement diminishes. Thus advising a patient to take levodopa on an empty stomach will improve absorption and reduce dose failures (Contin et al., 1998). 39.6.2.2. Improve gastric emptying by stopping anticholinergics and treating constipation Gastric emptying is also erratic and slow in PD due to the underlying disease per se as well as secondary to dopaminergic and anticholinergic medications (Evans et al., 1981; Edwards et al., 1992). In addition, constipation via a cologastric reflex leads to delayed gastric emptying (Bojo and Cassuto, 1992). A slower speed of gastric emptying has been demonstrated to correlate with the presence of motor fluctuations (Djaldetti et al., 1996). 39.6.2.3. Liquid/soluble levodopa preparations Soluble levodopa preparations are more rapidly and reliably absorbed compared with conventional levodopa (Stocchi et al., 1994). Preparations that exist include levodopa/benserazide (Madopar dispersible), levodopa methyl ester and levodopa/carbidopa (Parcopa). Alternatively, patients can crush oral levodopa preparations and take them with a carbonated beverage. Patients
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requiring frequent smaller doses to control complicated fluctuations and disabling dyskinesias can take liquid levodopa preparations by crushing tablets in water combined with ascorbic acid; however, the solutions are unstable after 24 hours (Kurth et al., 1993a). Such soluble preparations of levodopa are more rapidly and reliably absorbed than conventional tablets but have a shorter duration of action – 1–1.5 hours. 39.6.2.4. Bypass gastric problems There have been several attempts at delivering levodopa, in various preparations, directly into the duodenum as a way of circumventing the stomach and so improving absorption (Kurlan et al., 1986; Kurth et al., 1993b; Nyholm et al., 2005). One preparation of levodopa used is Duodopa, a stable suspension of levodopa and carbidopa in methylcellulose, which improves levodopa solubility (Nyholm et al., 2005). These studies have been performed in small numbers of patients and have not been double-blind or placebo-controlled, so the true efficacy is unclear. However, these studies have shown improved on-time without an increase in dyskinesia in advanced PD patients (see later). One study followed patients for 10 years and noted particular benefit in reducing dyskinesia (Syed et al., 1998). In all cases, however, technical and mechanical issues may limit widespread use. 39.6.2.5. Take levodopa when still in ‘On’ state Occasionally patients with advanced PD experiencing motor fluctuations may report that the first dose of the day is less effective (Melamed and Bitton, 1984) (in general, however, PD patients tend to notice that their response to medication is usually better in the morning and deteriorates over the course of the day). Some patients need a larger dose to ‘kick in’; or if they become very parkinsonian or ‘super off’, then a usually effective dose of levodopa does not switch them on. This can often be observed when performing acute levodopa challenges in the practically defined off-state after an overnight withdrawal of PD medications. Studies have shown that patients taking Sinemet CR have a better response to the second dose compared to the first morning dose, suggesting there is a delay in absorption in the off-state (Yeh et al., 1989). One explanation for these observations has been that PD patients with fluctuations have an increase in gastric emptying in the on-state but decreased gastric emptying in the off-state (Hardoff et al., 2001). The authors suggest that taking the next dose of levodopa while still partly on may reduce dose failures as the increased gastric emptying will improve absorption via the small intestine.
39.6.3. Unpredictable ‘On–Off’ fluctuations Unpredictable ‘on–off’ fluctuations appear in more advanced disease and are more resistant to treatment than predictable wearing-off. Patients are unable to correlate on- and off-periods with their levodopa dosing schedule and they may suddenly switch from one to the other over a few seconds. Such fluctuations are typically associated with concurrent dyskinesia, thus pharmacological treatment is difficult and often such patients will require surgical intervention to allow a reduction in levodopa dosage. 39.6.3.1. Increase oral dopaminergic agents (as for predictable wearing-off) Increasing dopaminergic stimulation with increased frequency and/or dosing of levodopa may reduce sudden on–off fluctuations by smoothing out dopamine levels. However, these unpredictable on–off fluctuations do not appear to correlate with levodopa timing or levels. Patients often have associated on-period choreiform dyskinesia and so this regime can exacerbate involuntary movements. Specific therapies to reduce on- and off-period dyskinesias are discussed in Chapter 40. Increasing the dose of a dopamine agonist is a better option as this may permit a reduction in the levodopa dose. The addition of entacapone is less helpful for unpredictable sudden offs compared to predictable wearing-off (Gordin et al., 2003). Whatever approach is taken, PD patients with advanced disease often cannot tolerate even small increases in dopaminergic stimulation because of a disabling increase in dyskinesia or the development of behavioral and psychiatric problems. At this stage, the response to intermittent oral medication becomes brittle and unpredictable. More frequent, smaller doses attempting to address the shortening response without aggravating dyskinesias sometimes result in a more unpredictable response pattern with a greater number of dose failures. At this stage many patients seem to have an all-or-none response to levodopa that requires a threshold level of dopaminergic stimulation to obtain (see section 39.5.1). Frequent small doses may undershoot this threshold. In such patients with very complicated, unpredictable fluctuations, simplifying the dosage schedule using fewer but larger doses will often result in a return to a more predictable response pattern. 39.6.3.2. Use liquid/soluble preparations The more rapidly absorbed, fast-acting soluble levodopa preparations may be helpful for rapid reversal of off-periods (see above).
MOTOR AND NON-MOTOR FLUCTUATIONS 39.6.3.3. Modify dietary protein On–off fluctuations have been suggested to be secondary to impaired absorption of levodopa across the gut and blood–brain barrier due to competition with large neutral amino acids found in dietary protein (Nutt et al., 1984; Leenders et al., 1986; Alexander et al., 1994). As such, either reducing protein intake or leaving large protein meals to the end of the day may reduce on–off fluctuations (Pincus and Barry, 1987; Karstaedt and Pincus, 1992). This effect is probably not at the level of the gut as the neutral amino acid transporter capacity is unlikely to become saturated and there is no difference in plasma levodopa kinetics following administration of levodopa after a lowprotein meal compared to a normal-protein meal in advanced PD patients (Carter et al., 1989; Simon et al., 2004). 39.6.3.4. Add apomorphine The injectable mixed dopamine D1/D2-receptor agonist, apomorphine, has been used in Europe for many years as a treatment for on–off motor fluctuations (Stibe et al., 1988; Stocchi et al., 2001b) and has recently been approved for use in the USA. Due to the proemetic action of apomorphine, prior treatment for 2–3 days and continued treatment using the oral antiemetics domperidone (20 mg t.i.d.) or trimethobenzamide hydrochloride (300 mg t.i.d.) is required. Some patients can discontinue the antiemetic after a few weeks. A single subcutaneous injection of apomorphine alleviates parkinsonian symptoms within 5–15 minutes for 60–90 minutes and so can be used as a ‘rescue’ for off-period disability (Chaudhuri et al., 1988; Frankel et al., 1990; Dewey et al., 2001). Apomorphine can be used either as intermittent subcutaneous injections (2–8 mg per injection, average daily total dose approximately100 mg/day) and/or as an infusion (20–160 mg) ranging over 10–24 hours (Manson et al., 2002; Tyne et al., 2004). The antiparkinsonian actions of apomorphine and levodopa are equivalent (Cotzias et al., 1970). Long-term use of apomorphine does not result in loss of benefit (Hughes et al., 1993; Gancher et al., 1995). For patients with frequent off-periods, infusion of apomorphine is useful. This is more practical when patients are requiring several injections per day. Continuous infusion of apomorphine not only markedly reduces off-time but also reduces on-period dyskinesia. This reduction in dyskinesia is partly due to a concomitant reduction in levodopa dose (Colzi et al., 1998; Manson et al., 2002). However, continuous dopaminergic stimulation of striatal dopamine receptors in animal models of established motor fluctuations and
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dyskinesia also results in changes within neurotransmitter signaling pathways in the basal ganglia circuitry (Chase, 1998b; Hadj Tahar et al., 2000; Bezard et al., 2001). In effect this results in a ‘depriming’ of the system with a reduction in motor fluctuations and dyskinesia. In clinical studies, continuous dopaminergic stimulation using infusions of levodopa (Sage et al., 1988; Kurth et al., 1993b; Nutt et al., 2000) or lisuride (Stocchi et al., 2002) can also reduce established on– off fluctuations and dyskinesia. However, in terms of ease of use and tolerability, infusion of apomorphine subcutaneously is a better option. Unfortunately, this depriming is short-lived and patients who have to stop the infusions and return to intermittent doses of oral medication often experience a rapid return to their motor complications. Thus such patients may need to be considered for surgery to treat motor fluctuations (see later). The main side-effect of apomorphine is formation of skin nodules. These can occur in 20–78% of patients (Colzi et al., 1998; Tyne et al., 2004) but are only bothersome in about a third of these patients (Manson et al., 2002). Management includes rotating the injection site, ensuring strict aseptic technique; diluting the apomorphine 1:1 with normal saline, massage or local skin ultrasound. Neuropsychiatric side-effects appear to be less common than with oral dopamine agonists but hallucinations and confusion can occur at high doses. In a small proportion of patients with PD, addictive behaviors develop and include excessive use of their dopaminergic medications (see later). Escalating doses of apomorphine and levodopa in such patients may result in major behavioral and psychiatric side-effects such as hypersexuality and gambling, termed ‘hedonistic homeostatic dysregulation’ (Giovannoni et al., 2000). Management of this may require hospitalization and an aggressive reduction in medication doses. On the other hand, in some cases, a reduction in neuropsychiatric problems, such as depression, occurs with apomorphine (Manson et al., 2002). New methods of administering apomorphine are being developed in an attempt to reduce the problems associated with injections. To date, sublingual (Montastruc et al., 1991), intranasal (Kapoor et al., 1990) and rectal administration (Hughes et al., 1991) have all been tried but with suboptimal absorption and tolerability. A recent epicutaneous transdermal (ApoMTD) route has been developed and a preliminary study has shown improved off-periods with mild side-effects, including some transient skin erythema (Priano et al., 2004). In all cases, however, the rate of absorption of apomorphine is much slower than via an injection and as such limits use as a rescue therapy for off-periods.
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Despite the obvious advantages, there has been a general underusage of apomorphine (Chaudhuri and Clough, 1998). In many countries, this has been because of a lack of a peripheral dopamine receptor antagonist such as domperidone. Another common reason also relates to the practicalities of using apomorphine as most patients will need support from family and specialist PD nurses (Manson et al., 2002; Tyne et al., 2004). The efficacy of bilateral subthalamic nucleus deep brain stimulation (STN DBS) for motor fluctuations has resulted in this becoming the preferred option, particularly since doses of dopaminergic medication can often be substantially reduced (Moro et al.,1999), with resultant reduced risk of, or an improvement in, other adverse side-effects (see later). However, in elderly patients where the risks of surgery are thought too great, apomorphine infusion for treatment of motor fluctuations is a viable option. To date, no direct comparison of apomorphine infusion with bilateral STN DBS has been made. 39.6.3.5. Bilateral Subthalamic Nucleus Deep Brain Stimulation In patients with advanced PD, bilateral STN DBS is currently the most effective treatment for all motor fluctuations (Limousin et al., 1998; Kumar et al., 1998; Lagrange et al., 2002; see Ch. 43). In particular, predictable and unpredictable on–off motor fluctuations, as measured by the UPDRS part IV subscale, are significantly reduced by about 50% and on-period dyskinesia is reduced by > 50 % (Kumar et al., 1998; Limousin et al., 1998; Moro et al., 1999). As discussed in the next section, due to the profound reduction in off-periods, patients may also experience significant benefit in other non-motor off-period symptoms, such as pain and autonomic symptoms. Long-term follow-up to 5 years has demonstrated that patients continue to have fewer motor fluctuations (Krack et al., 2003). In most patients, there is a reduction in dopaminergic medication of about 50% and in rare instances no dopaminergic drugs are required after surgery (Kumar et al., 1998; Limousin et al., 1998; Moro et al., 1999; Molinuevo et al., 2000). This in part accounts for the reduction in on-period dyskinesia. However, even when challenged with the same preoperative dose of levodopa, patients will have significantly less levodopa-induced dyskinesia, thus suggesting that continuous STN DBS has a depriming effect on the basal ganglia circuitry in a similar fashion to continuous dopaminergic stimulation (Bejjani et al., 2000; Moro et al., 2002; Varma et al., 2003). Bilateral internal globus pallidus (GPi) DBS is also effective at improving off-periods and especially in lessening dyskinesia, even without a concurrent reduction
in dopaminergic medication (Kumar et al., 2000; Loher et al., 2002; Volkmann et al., 2004). Although there have been no large RCTs comparing STN to GPi DBS, there is a general belief that the benefit obtained with STN DBS is on the whole greater and more sustained than that obtained with GPi DBS (Deep-Brain Stimulation for Parkinson’s Disease Study Group, 2001; Boucai et al., 2004; Peppe et al., 2004). 39.6.4. Treatment of sudden transient motor blocks PD patients with off-period freezing may respond to various approaches designed to reduce the off-periods, as outlined above. However, freezing of gait is often more resistant to increasing dopaminergic stimulation compared to other parkinsonian symptoms. In addition, freezing can occur during on-periods (on-period freezing) and this can be extremely difficult to treat. At times this on-period freezing worsens in response to increasing the dose of dopaminergic drugs. Bilateral STN DBS may have no effect on on-period freezing (Stolze et al., 2001). Reductions in dopaminergic agents may help the problem but can also result in an increase in other parkinsonian symptoms. Such patients may respond by developing tricks that utilize a variety of sensory cues, such as having to step over an object, whether the foot of another person, lines drawn on the floor, a specifically designed cane or walker with either a laser or modified lower part of the cane at right angles, or other cues such as playing music, marching in time or counting that can then trigger a movement (Quinn, 1998; Kompoliti et al., 2000).
39.7. Non-motor fluctuations 39.7.1. Definitions In addition to fluctuations in the motor symptoms of parkinsonism, patients can also experience fluctuations in non-motor symptoms, which may be as debilitating, or more so, than immobility and akinesia (Lang and Lozano, 1998). These fluctuations have been classed into three groups of symptoms: neuropsychiatric, autonomic and sensory/pain (Riley and Lang, 1993; Hillen and Sage, 1996) (Table 39.2). These non-motor symptoms appear to follow a similar pattern to the wearingoff phenomena seen in parkinsonian symptoms and may appear during wearing-off and off-periods and improve after taking levodopa or dopaminergic drugs. In addition, some symptoms may be associated with elevated levels of levodopa and so appear during the on-periods.
MOTOR AND NON-MOTOR FLUCTUATIONS Table 39.2 Non-motor fluctuations 1. Neuropsychiatric (a) Mood Anxiety, depression, irritability, panic attacks, screaming Apathy Fatigue (b) Psychotic symptoms Euphoria, agitation, dopamine dysregulation syndrome Visual hallucinations, delusion, paranoia (c) Cognitive functions 2. Autonomic (a) Thermoregulation: sweating, facial flushing, pallor, hyperthermia (b) Sphincter function: urinary disturbances, bloating, abdominal discomfort, constipation (c) Dysphagia and drooling of saliva; dry mouth (d) Orthostatic hypotension, tachycardia (e) Dyspnea (f) Peripheral edema 3. Sensory (a) Pain (b) Numbness, paresthesia (c) Restless-legs syndrome; akathisia
39.7.2. Epidemiology The epidemiology of these non-motor fluctuations is not well defined. On the current UPDRS scale, Activities of Daily Living part II subscale, only three questions specifically address non-motor symptoms related to on- and off-periods: sensory symptoms, swallowing and drooling saliva. Attempts have been made to determine the extent of non-motor symptoms with questionnaires (Riley and Lang, 1993; Hillen and Sage, 1996; Gunal et al., 2002; Witjas et al., 2002). These studies have shown that fluctuations in neuropsychiatric symptoms are probably the most common, with mood fluctuations, especially off-period anxiety, occurring in up to 75% of patients (Quinn, 1998; Witjas et al., 2002). PD patients with non-motor fluctuations usually experience more than one symptom and often have multiple symptoms (Shulman et al., 2001). However, the exact incidence and prevalence are not known. To try and address this problem, the new UPDRS rating scale currently under development has incorporated more non-motor aspects, such as apathy, sleep patterns and various autonomic functions (Movement Disorder Society Task Force, 2003). New non-motor questionnaires are also being developed (Gulati et al., 2004; Brown et al., 2005; Stacy et al., 2005). These tools require clinimetric testing but represent an increased
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awareness of the non-motor complications and fluctuations experienced by PD patients. 39.7.3. Neuropsychiatric fluctuations 39.7.3.1. Mood fluctuations 39.7.3.1.1. Anxiety/depression PD patients commonly experience fluctuations in mood, generally with worsening in the off-periods and improvement in the on-periods (Brown et al., 1984; Cantello et al., 1986; Nissenbaum et al., 1987; Menza et al., 1990). The commonest symptoms experienced are off-period anxiety, irritability and depression (Menza et al., 1990; Riley and Lang, 1993; Siemers et al., 1993; Witjas et al., 2002). PD patients can also have panic attacks (Vazquez et al., 1993) and off-period moaning and screaming episodes have been reported (Steiger et al., 1991). 39.7.3.1.2. Apathy Apathy is a distinct neurobehavioral syndrome experienced by PD patients that consists of reduced interest and motivation, behavioral changes with reduced initiative and decreased spontaneous action and emotional changes with a flattened affect (Pluck and Brown, 2002). PD patients may experience fluctuations in apathy with worsening in off-periods (Witjas et al., 2002). Apathy is thought to involve limbic basal ganglia – anterior cingulate cortical loops (Isella et al., 2002). Patients who have undergone STN DBS and have a reduction in their levodopa dose are reported to develop apathy, suggesting a dopaminergic etiology (Funkiewiez et al., 2004). 39.7.3.1.3. Fatigue Fatigue is a common symptom in PD patients, and is defined according to the patient’s own perceived state of lack of energy (Krupp and Pollina, 1996; Herlofson and Larsen, 2002). The cause is unclear but fatigue is usually distinct from depression or sleepiness, not associated with disease severity (Friedman and Friedman, 1993; van Hilten et al., 1993; Alves et al., 2004) and is probably an independent symptom of PD (Herlofson and Larsen, 2002). Single-photon emission computed tomography (SPECT) studies have suggested that PD patients with fatigue have impaired frontal-lobe perfusion (Abe et al., 2000). In questionnaire studies, the frequency of fatigue in PD patients is over 50% and fluctuates through the day, and is predominantly worse in off-periods (Witjas et al., 2002; Zenzola et al., 2003). 39.7.3.1.4. Pathophysiology As outlined in the sections above, the origin of mood symptomatology varies and includes frontal, basal
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ganglia and limbic circuits as well as brainstem bioamine nuclei and their projections. The pathophysiology underlying fluctuations of these mood disorders is unclear. Improvements in mood have been demonstrated to be proportional to levodopa dose, suggesting a relationship to brain dopamine concentration (Maricle et al., 1995). In addition, the improvements in mood with infusion of levodopa precede the improvement in motor function, suggesting that patients do not simply feel better because they are more mobile (Maricle et al., 1995). Mood fluctuations have also been shown to be associated with a longer disease duration and younger age at onset, as well as with the presence and severity of motor fluctuations (Cantello et al., 1986; Vazquez et al., 1993; Racette et al., 2002; Witjas et al., 2002; Richard et al., 2004), thus the underlying pathophysiology may be similar to that causing fluctuations in parkinsonian symptoms. However, there is not always a consistent relationship between motor and mood fluctuations (Richard et al., 2004). In addition it is not entirely clear whether fluctuations in mood are related to an underlying persistent, comorbid mood disorder. The limited conflicting available evidence derives from case reports or small series (Menza et al., 1990; Racette et al., 2002; Richard et al., 2004). 39.7.3.1.5. Management Mood deterioration, which is a wearing-off or offperiod phenomenon, may respond to treatment of the off-periods. There have been no clinical trials formally assessing treatment of fluctuations in anxiety or depression. Patients with persistent anxiety and depression despite reduced off-periods may benefit from specific anxiolytic or antidepressant therapy. However, the influence of this treatment on off-period-related exacerbations of mood is unknown. 39.7.3.2. Fluctuations in psychotic symptoms 39.7.3.2.1. Euphoria, agitation, dopamine dysregulation syndrome In the on-periods, PD patients can experience an elevation in mood that may be associated with alertness and euphoria (Keshavan et al., 1986; Nissenbaum et al., 1987; Lees, 1989). Some patients report a feeling of euphoria that just precedes the motor on-state (Witjas et al., 2002). An extreme form of mood elevation associated with on-periods may result in psychomotor agitation and hyperactivity, increased excitability and even a hypomanic or true manic state. This has been described in a small number of patients, predominantly male, and has been termed the ‘dopamine dysregulation syndrome’ (Giovanni et al., 2000; Lawrence
et al., 2003). These patients consume much larger doses of levodopa and other dopaminergic drugs than they require to maintain a good on-state, and can experience a range of symptoms that occur with onperiods, including hypersexuality, pathological gambling and shopping, aggression and compulsive eating (Molina et al., 2000; Lawrence et al., 2003; Kurlan, 2004). In addition to or separate from the dopamine dysregulation syndrome, patients may demonstrate stereotypical behavior termed ‘punding’. Here patients will perform the same, meaningless, seemingly purposeless task over and over again (Friedman, 1994; Evans et al., 2004). These behaviors, usually related to a prior trade or hobby, occur at the expense of sleep and patients may spend hours with a single purposeless activity followed by severe exhaustion and fatigue. 39.7.3.2.2. Visual hallucinations, delusions, paranoia Psychotic symptoms of illusions, well-formed visual hallucinations, paranoia and delusions are often reported in PD and are associated with disease severity, age, depression and cognitive impairment (Goetz and Stebbins, 1993; Factor et al., 2003). Visual hallucinations will fluctuate through the day and are most commonly reported in the evening and overnight (Sanchez-Ramos et al., 1996; Fenelon et al., 2000). In questionnaire studies of prevalence of non-motor fluctuations, patients have reported hallucinations specifically related to on-periods (Witjas et al., 2002) but others experience them specifically related to off-periods (Nissenbaum et al., 1987; Witjas et al., 2002). 39.7.3.2.3. Pathophysiology The underlying pathophysiology of psychotic symptoms in PD may relate to alterations in neurotransmitter pathways, particularly involving mesolimbic dopamine and serotonin (Meltzer, 1992; Breier, 1995). Pathological studies have suggested that the inferotemporal cortex may be implicated as Lewy bodies are increased in the amygdala and parahippocampus of the temporal lobe in PD patients with hallucinations compared to those without (Harding et al., 2002). The cause of fluctuations in psychotic symptoms, however, is unclear, although it may relate to changes in mesolimbic dopaminergic stimulation as all dopaminergic agents can cause psychosis and reducing or discontinuing dopaminergic medication can resolve the symptoms (Friedman and Sienkiewicz, 1991; Poewe, 2003). However, psychotic symptoms such as hallucinations are not always related to the level of dopaminergic stimulation, since infusion of levodopa in hallucinating patients did not trigger hallucinations in one study (Goetz et al., 1998) and several reports have
MOTOR AND NON-MOTOR FLUCTUATIONS found no relationship between either type or dose of dopaminergic drug and psychosis (Sanchez-Ramos et al., 1996; Graham et al., 1997; Fenelon et al., 2000; Merims et al., 2004). Disturbances in the sleep–wake cycle are often found in patients with psychotic symptoms and may account for fluctuations in these symptoms. Thus, patients with psychotic symptoms have more daytime somnolence and have vivid dreams or nightmares (Moskovitz et al., 1978; Nausieda et al., 1982; Pappert et al., 1999; Fenelon et al., 2000), although the exact nature of this relationship is not entirely clear (Goetz et al., 2005). In addition, there is a disturbance in rapid-eye movement (REM) sleep pattern in PD patients with hallucinations (Comella et al., 1993; Arnulf et al., 2000). Indeed, in some patients hallucinations may relate to intrusions of REM sleep into wakefulness comparable to hypnagogic hallucinations in narcolepsy. Thus pathology in brainstem structures controlling sleep may also cause fluctuating hallucinations in PD (Manford and Andermann, 1998). 39.7.3.2.4. Management On-period elevations in mood and psychotic symptoms may resolve with reduction in levodopa or dopamine agonist dose. Some studies have suggested that dopamine agonists are more likely to be associated with psychotic symptoms than levodopa (Saint Cyr et al., 1993), but the relationship to dopaminergic stimulation is not entirely clear (see above). In the case of the dopamine dysregulation syndrome, patients benefit from a reduction and rationing of levodopa and dopamine agonists (Lawrence et al., 2003; Evans et al., 2004). In general, psychotic symptoms usually require specific treatment with atypical neuroleptics such as quetiapine or clozapine. Other patients may have coexistent depression and sleep disturbances which will require specific treatment (Lawrence et al., 2003; Evans et al., 2004). 39.7.3.3. Fluctuations in cognitive function Cognitive problems ranging from mild cognitive impairment to dementia are common in advanced PD (Aarsland et al., 1996; see Ch. 18). Patients with dementia with Lewy bodies often demonstrate quite prominent fluctuations in cognition and alertness (McKeith et al., 1996; see Ch. 60). However, fluctuations in cognition can also occur in PD patients without dementia (Delis et al., 1982; Girotti et al., 1986; Cooper et al., 1991; Meco et al., 1991). Thus some patients report on-period slowing of thoughts or bradyphrenia and difficulty or delay in memory retrieval, sometimes referred to as the ‘tip of the tongue’
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phenomenon (Brown et al., 1984; Poewe et al., 1991; Green et al., 2002). Other patients report slowing of thoughts predominantly in the off-periods (Matison et al., 1982; Witjas et al., 2002). Indeed, in our experience, patients complain of cognitive slowing and difficulty concentrating more often related to the offperiods. Some patients show reduction in selective areas of cognitive function in off-periods such as delayed recall of complex verbal material (Mohr et al., 1989) and verbal fluency (Gotham et al., 1988). However, this has been suggested to be more related to a reduction in attention/arousal than a true cognitive effect (Brown et al., 1984). 39.7.3.3.1. Pathophysiology Patients with fluctuating cognition and no dementia often have dysfunctions in frontal lobe function, suggesting impaired basal ganglia–prefrontal cortical loops (Gotham et al., 1988; Green et al., 2002). The exact circuitry involved or underlying mechanisms, however, remain unclear. Memory function in PD has been shown to correlate with changes in dopamine levels, rather than with a constant high or low level (Huber et al., 1987, 1989), suggesting that fluctuations in cognitive function may relate to levodopa dosing. 39.7.4. Autonomic symptoms Patients with PD develop a variety of symptoms of dysautonomia as part of the underlying disease process (Koike and Takahashi, 1997; see Ch. 14). These commonly include sweating and thermoregulatory dysfunction, sphincter disturbances, abdominal bloating and discomfort, drooling, dry mouth, orthostatic hypotension, peripheral edema and a range of other rarer symptoms. Many patients report fluctuations in these symptoms predominantly occurring with off-periods (Riley and Lang, 1993; Hillen and Sage, 1996). However, in other studies, many autonomic symptoms were independent of on- or off-periods (Gunal et al., 2002; Witjas et al., 2002). Patients with fluctuations in autonomic symptoms usually have a collection of symptoms that occur together consistently, usually in the off-periods (Raudino, 2001; Swinn et al., 2003). 39.7.4.1. Disturbances of thermoregulation One of the commonest types of non-motor fluctuation reported by patients is off-period sweats, which can be sudden and drenching, sometimes referred to as ‘sweating crises’ (Sage and Mark, 1995; Raudino, 2001; Gunal et al., 2002). In one study, 64% of patients experienced sweating in the off-period, whereas 16% reported symptoms when on with dyskinesia (Witjas
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et al., 2002). In a cohort of PD patients all reporting sweating, 35% had sweating episodes in the off-period, 18% when on with dyskinesia but 39% apparently unrelated to their motor state (Swinn et al., 2003). Patients also often complain of facial flushing or a sensation of feeling hot occurring during the off-periods (Hillen and Sage, 1996; Gunal et al., 2002; Witjas et al., 2002). During formal autonomic function testing in the off-state, PD patients have increased sweating and lower skin temperatures to a heat stimulus which reverses with levodopa therapy (Goetz et al., 1986a). There have been rare reports of severe hyperthermia induced by off-periods in patients with motor fluctuations, similar to the neuroleptic malignant syndrome-like state that may occur in response to sudden withdrawal of levodopa (Pfeiffer and Sucha, 1989; Keyser and Rodnitzky, 1991). 39.7.4.2. Disturbance of sphincter function Off-period urinary urgency is a common problem (Riley and Lang, 1993; Raudino, 2001; Gunal et al., 2002). Urodynamic studies in the on- and off-state have shown that apomorphine will improve voiding by decreasing bladder outflow resistance (Christmas et al., 1988), whereas levodopa gives inconsistent results (Fitzmaurice et al., 1985; Uchiyama et al., 2003; Winge et al., 2004). Another sphincter problem occurring predominantly in the off-period is constipation (Witjas et al., 2002), rarely to the extent of anismus. Apomorphine has been demonstrated to relieve paradoxical striated muscle contraction during defecation (Mathers et al., 1989). Some patients report fluctuating abdominal discomfort and bloating due to suppression of peristalsis that occurs during offperiods (Hillen and Sage, 1996; Raudino, 2001; Gunal et al., 2002; Witjas et al., 2002). 39.7.4.3. Dysphagia and drooling of saliva Swallowing difficulties with choking on food can occur in PD in the off-periods (Bushmann et al., 1989; Witjas et al., 2002). Some patients experience an improvement in symptoms with levodopa, although it is not consistent. Barium studies before and after administration of levodopa have demonstrated that about 50% of PD patients experience improved oropharyngeal or esophageal function (Bushmann et al., 1989). Off-period belching secondary to esophageal motility dysfunction, relieved by apomorphine, has also been reported (Kempster et al., 1989). PD patients often report drooling of saliva secondary to dysphagia, which can range from mild to severe with a constantly wet face and clothes (Bateson et al., 1973). Patients often report fluctuations in salivation with worsening in the off-periods (Raudino, 2001; Gunal et al.,
2002). Alternatively some patients report a dry mouth during off-periods (Witjas et al., 2002), possibly related to breathing through a persistently open mouth. 39.7.4.4. Orthostatic hypotension PD patients can experience a symptomatic postural fall in blood pressure (BP) which may cause a range of symptoms, including dizziness, fainting, fatigue, sleepiness, shoulder pain or falls (Senard et al., 1997; Mathias and Kimber, 1998). Generally this is secondary to pathological involvement of the sympathetic nervous system but also occurs de novo or is aggravated by dopaminergic medication since all such agents are capable of lowering BP (Wakabayashi et al., 1993; Korchounov et al., 2004). However, the presence of motor fluctuations appears to be an additional independent risk factor for fluctuations in BP control. In one study, PD patients with wearing-off fluctuations compared to a group without motor fluctuations had significantly higher supine and erect BP during the off-phase as compared to the on-phase (Baratti and Calzetti, 1984). 39.7.4.5. Dyspnea Dyspnea occurring as an off-period phenomenon has been reported in PD patients with fluctuations (Hillen and Sage, 1996; Raudino. 2001; Gunal et al., 2002; Witjas et al., 2002) and may be accompanied by a bothersome, subjective sense of ‘air hunger’. Alternatively, some patients may demonstrate tachypnea without much in the way of accompanying complaints, although the care-giver may express concerns about the symptoms. These symptoms may occur due to upper-airway obstruction (Vincken et al., 1984). However, a study by Weiner et al. (2002) has shown that patients’ perception of dyspnea is improved by levodopa without any objective change in pulmonary function. In addition, off-period dystonia of the cervical or laryngeal musculature can also induce stridor (Corbin and Williams, 1987). Breathing difficulties can also occur as an on-period problem and may be a form of respiratory dyskinesia (De Keyser and Vincken, 1985; Jankovic and Nour, 1986). 39.7.4.6. Pathophysiology Dysautonomic features in PD are related to pathological involvement of the peripheral and central sympathetic and parasympathetic nervous systems that occurs with advancing disease (Edwards et al., 1992; Wakabayashi et al., 1993). Fluctuations in autonomic function have been shown to correlate with both disease duration and severity of disease (Gunal et al., 2002; Witjas et al., 2002). Patients with fluctuating
MOTOR AND NON-MOTOR FLUCTUATIONS autonomic symptoms tend to have higher daily levodopa doses compared to non-fluctuators (Gunal et al., 2002). Fluctuations in these autonomic functions may relate to fluctuating peripheral dopaminergic stimulation (Goetz et al., 1986a). Dopamine D1- and D2receptor agonists can reduce the bladder threshold for the micturition reflex in the MPTP-lesioned primate (Yoshimura et al., 1993, 1998), suggesting improved bladder function in the on-state. Dopamine plays a role in the regulation of BP by inhibition of sodium transport in renal proximal tubules and relaxation of vascular smooth muscles (Velasco and Luchsinger, 1998), thus accounting for fluctuating orthostatic and cardiovascular symptoms. However, some symptoms, such as sweating, are not related to disease severity or duration or to levodopa dose. In these cases the pathophysiology is less clear but may relate to disease involvement of more central autonomic stuctures such as the hypothalamus (Langston and Forno, 1978; Braak et al., 2004). 39.7.4.7. Management In general, off-period autonomic dysfunction will respond to treatment of the off-periods (Sage and Mark, 1995; Olanow and Koller, 1998). Urinary dysfunction related to a hyperactive bladder may be helped with anticholinergic medications such as oxybutinin or tolteradine. Bilateral STN DBS is also effective at reducing urinary symptoms due to detrusor hyperreflexia (Seif et al., 2004). Sweating episodes may respond to beta-blockers (Stocchi et al., 1997; Olanow and Koller, 1998). Sialorrhea may respond to botulinum toxin injections into the salivary glands (Mancini et al., 2003; Ondo et al., 2004). 39.7.5. Sensory PD patients can experience a number of fluctuating symptoms that have been loosely termed ‘sensory’ to distinguish them from symptoms that may occur due to the motor features of parkinsonism. Such symptoms may include pain, numbness and paresthesias, akathisia and restless-legs syndrome. These symptoms can fluctuate and are either most often experienced exclusively during off-periods or are accentuated during these times. Such symptoms are often the most distressing to patients and in some cases become more disabling and bothersome than the motor fluctuations. 39.7.5.1. Pain Pain is a common symptom in PD and fluctuations in pain are reported in 23–46% of PD patients (Goetz et al., 1986b; Quinn et al., 1986; Gunal et al., 2002;
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Witjas et al., 2002). Fluctuations in pain are due to a number of factors. One important cause is the presence of dystonia and rigidity associated with off-periods. Pain associated with dystonia most commonly occurs accompanying early-morning dystonia, typically affecting the feet and toes, and improving when the patient switches on (Melamed, 1979; Currie et al., 1998). Painful dystonic spasms may also occur as an end-of-dose or off-period pattern (Ilson et al., 1984) or in a diphasic pattern (Luquin et al., 1992). Patients also report painful sensations without evidence of dystonia, most often associated with offperiods (Quinn et al., 1986). Such pain can be severe and have a burning, aching or stabbing quality. Often the symptoms are diffuse and poorly localized, but may be more severe on the more affected parkinsonian side. Non-specific oral and genital pain related to offperiods has also been reported, in all cases responding to treatment with levodopa (Ford et al., 1996). Onperiod pain is also a recognized problem and may be secondary to peak-dose dyskinesia; however, it has not been well characterized (Goetz et al., 1986b; Quinn, 1998). In some patients, this may simply relate to a combination of a musculoskeletal cause (e.g. arthritis) with prominent choreoathetoid involuntary movements. 39.7.5.2. Numbness/dysesthesia PD patients with motor fluctuations can also experience fluctuating sensory symptoms without objective sensory loss. These symptoms include numbness, coldness, tightening or paresthesia that is most often associated with off-periods (Snider et al., 1976; Koller, 1984). Patients are reported to experience symptoms more in the legs than the arms, with the neck and face being rarely affected (Snider et al., 1976). 39.7.5.3. Restless-legs syndrome/akathisia Restlessness is a common complaint among patients with PD; however, it may be difficult to distinguish restlessness due to leg pain or discomfort as a wearingoff phenomenon from true restless-legs syndrome and akathisia (Poewe and Hogl, 2004). Fluctuations in symptoms of restlessness, with a predominantly off-period distribution, have been reported in a number of case series; however, the term was often not clearly defined (Gunal et al., 2002; Witjas et al., 2002). Akathisia is a sensation of inner restlessness and inability to sit still that has been reported to occur in 26% of PD patients, when underlying factors such as discomfort due to parkinsonism-related symptoms are excluded (Lang and Johnson, 1987). Fluctuations in akathisia are common among PD patients with motor
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fluctuations (Witjas et al., 2002). The relationship to the motor state is not consistent: some patients report akathisia related to off-periods but also when switching on or in an end-of-dose pattern (Lang and Johnson, 1987; Comella and Goetz, 1994; Witjas et al., 2002). 39.7.5.4. Pathophysiology Fluctuating pain and other sensory symptoms in PD may be secondary to peripheral mechanisms associated with sustained muscle contraction in dystonia, rigidity or musculoskeletal problems as well as to primary central mechanisms, the nature of which remains unclear. Off-period fluctuating pain and other sensory symptoms are often dramatically alleviated by dopaminergic medication, suggesting that the pathophysiology is associated with the neural mechanisms generating the underlying parkinsonian symptoms and dystonic symptoms. In addition, pain, which may or may not be associated with dystonia, can be a presenting feature of untreated PD (LeWitt et al., 1986). The basal ganglia are involved in pain processing, via the ventral anterior and ventrolateral thalamic nuclei (Chudler and Dong, 1995; Tracey et al., 2000). The pathways involved in primary parkinsonian pain are unknown; however a PET study has shown that increased pain perception correlates with lower numbers of striatal dopamine D2-receptors (Hagelberg et al., 2002), suggesting a link between the dopaminergic system and pain processing. Spinal cord dopaminergic pathways have also been suggested to play a role in fluctuating pain, since spinal anesthesia but not sympathetic or epidural block effectively alleviated diphasic leg pain in one PD patient (Sage et al., 1990). More recently it has been demonstrated that, in PD, there is increased sensitivity to some painful stimuli such as heat threshold; however, this did not change between the on- and off-state in PD patients with motor fluctuations (Djaldetti et al., 2004). This suggests that some painful sensory symptoms may be secondary to involvement of non-dopaminergic systems such as noradrenergic structures (Buzas and Max, 2004). 39.7.5.5. Management Sensory symptoms clearly related to off-periods, or low levels of levodopa as in diphasic dyskinesia, will improve with increased dopaminergic medication and treatment of on–off fluctuations (Sage, 2004). Early-morning off-period dystonia will respond to the use of long-acting dopamine agonists or controlledrelease levodopa prior to bedtime (Lees, 1987). Rescue medication for severe off-period pain includes soluble levodopa preparations or apomorphine (Lees, 1993;
Factor et al., 2000). Severe nocturnal pain may be helped by apomorphine infusion (Reuter et al., 1999). Bilateral STN DBS and pallidotomy are also an effective therapy for fluctuating off-period sensory symptoms (Honey et al., 1999; Krack et al., 1999; Loher et al., 2002). Other treatment options for off-period dystonia include specifically targeted botulinum toxin injections ((Pacchetti et al., 1995), baclofen (Lees et al., 1978) and lithium (Quinn and Marsden, 1986). On-period pain and sensory symptoms may respond to a reduction in dopaminergic mediation. Sensory symptoms unrelated to dystonia and unresponsive to manipulations in dopaminergic therapy are often intractable and difficult to treat. There are no published clinical trials to date and thus treatment options are based on case reports and include opiates (Stein and Read, 1997) and clozapine (Factor and Freidman, 1997; Trosch et al., 1998). It should be noted that, although bilateral STN DBS is extremely effective at treating motor fluctuations in PD and thus reducing many off-period-related non-motor symptoms (Funkiewiez et al., 2004), the concomitant reduction in dopaminergic medications can often induce or unmask new non-motor symptoms that were not present prior to the surgery, such as restless-legs syndrome (Kedia et al., 2004). The short- and long-term influence of bilateral STN DBS on the broad spectrum of non-motor fluctuations outlined above is at present unknown.
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Handbook of Clinical Neurology, Vol. 84 (3rd series) Parkinson’s disease and related disorders, Part II W. C. Koller, E. Melamed, Editors # 2007 Elsevier B. V. All rights reserved
Chapter 40
Levodopa-induced dyskinesias in Parkinson’s disease ´ MARIN3, JOSE A. OBESO1*, MARCELO MERELLO2, MARIA C. RODRI´GUEZ-OROZ1, CONCEPCIO 1 4 JORGE GURIDI AND LAZARO ALVAREZ 1
Department of Neurology and Neurosurgery, University Clinic and Medical School and Neuroscience Division, University of Navarra and CIMA, Pamplona, Spain
2
Movement Disorders Section, Raul Carrea Institute for Neurological Research, FLENI, Buenos Aires, Argentina
3
Laboratori de Neurologia Experimental, Fundacio´ Clı´nic-Hospital Clı´nic, Institut d’Investigacions Biome´diques August Pi i Sunyer (IDIBAPS), Hospital Clı´nic, Barcelona, Spain 4
Movement Disorders Unit, Centro Internacional de Restauracio´n Neurolo´gica (CIREN), La Habana, Cuba
40.1. Introduction Hyperkinetic or dyskinetic disorders are characterized by excessive motor activity that interferes with normal motor control mechanism. The early literature during the 1950s and 1960s used the term ‘hyperkinesia’ to designate wild involuntary movements like chorea, ballism, choreoathetosis or action tremor, all of which are currently embraced under the global denomination of dyskinesias This comprises chorea and ballism, dystonic movements and postures, myoclonus, tics and tremor. The capacity for levodopa to induce involuntary movements (i.e. levodopa-induced dyskinesias or LID) never witnessed before in Parkinson’s disease (PD) patients was established soon after its introduction in the early 1970s (Cotzias et al., 1969; Barbeau, 1976). LID are associated with several molecular, biochemical and physiological changes in the basal ganglia (BG). Among these, molecular and neuronal firing are the ones that have been studied in greater depth. It has not yet been possible to decipher which changes are compensatory, causally linked to LID or induced as a consequence of the involuntary movements. Animal models of PD, mainly the 6-hydroxydopamine (6-OHDA) lesioned rat and the 1-methyl-4-phenyl1,2,3,6-tetrayhydropyridine (MPTP)-intoxicated monkey, have been used to elicit LID, allowing the study of biochemical changes and modifications of neuronal firing activity in the BG. More recently, a few
biochemical studies have been conducted with tissue derived from well-characterized PD patients and the revitalization of surgery has permitted the recording of BG activity in vivo. Thus, a wealth of information is now available to put together findings in animal models and in patients, leading to a more comprehensive understanding of LID. This review will generically concentrate on LID but dopamine agonists are also capable per se of inducing dyskinesias, as shown in MPTP monkeys and de novo PD patients.
40.2. Clinical presentation LID generally occur in patients with motor fluctuations (i.e. ‘wearing-off’ or ‘end-of-dose deterioration’) and are therefore better described in relation to the motor state achieved in response to levodopa (Marsden and Parkes, 1977; Marsden et al., 1981; Obeso et al., 1989; Fahn, 2000). Accordingly, LID may be divided into three main groups: (1) peak-dose choreic or dystonic movements; (2) diphasic dyskinesias; and (3) ‘off’-period dystonia. This is a convenient classification that relates phenomenology (i.e. type of dyskinesia) and temporal onset with the degree of dopaminergic activity and motor state (Fig. 40.1), thus allowing the characterization of the underlying pharmacological origin of the dyskinesia by clinical inspection. Admittedly, in a large proportion of patients, more than one type of LID is
*Correspondence to: Jose A. Obeso, Neurologia, Clinica Universitaria, Avenida Pio XII 36, Pamplona 31180, Spain. E-mail:
[email protected], Tel: þ34-948-255400, Fax: +34-948-194700.
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Fig. 40.1. Relationship between onset and type of levodopa-induced dyskinesia and the dopaminergic response. ‘Off’-period dystonia and diphasic dyskinesias occur while dopaminergic activity is low and should, therefore, disappear when higher levels are reached. In contrast, peak-dose chorea is related to excessive dopaminergic stimulation.
present and the assessment and pharmacological solution are more problematic. 40.2.1. Choreic and dystonic movements Choreic and dystonic movements occur during the period of peak plasma level and maximal clinical benefit (‘on’ dyskinesias or peak-dose dyskinesias). On-period dyskinesias are associated with levodopa in a doserelated manner. Typically, movements are choreiform and involve the face, neck and proximal upper limbs. A smaller proportion of patients exhibit other movement disorders such as ballism, myoclonic jerks and tic-like movements. Involuntary upward saccadic eye movements are seen in a minority of patients. 40.2.2. Diphasic dyskinesias These are repetitive movements, usually of the legs, that occur at the beginning and end of the levodopa dose effect (diphasic) and disappear or transform into a choreic (peak-dose) pattern during the on period (Muenter et al., 1977). Diphasic dyskinesias are associated with low or intermediate levodopa plasma levels that are insufficient to achieve a full ‘on’ antiparkinonian effect. Labeling and classifying diphasic dyskinesias have been permanent sources of confusion. Muenter et al., (1977) applied the term
DID for ‘dystonia–improvement–dystonia’ but the movements are also frequently labeled as ballistic or choreic. In reality, they typically consist of repetitive stereotypic flexor and extensor movements of the lower limbs (Fig. 40.2) due to alternating contractions of agonist and antagonist muscles (Obeso et al., 1989; Luquin et al., 1992b). This well-established pattern is incompatible with the definitions of chorea or dystonia. In severe patients, the repetitive pattern of muscle contraction may become disrupted and reach large amplitude, giving rise to a more disorganized movement, resembling ballism. 40.2.3. ‘Off’-period dystonia Dystonic postures are due to sustained co-contraction of agonist and antagonist muscles, twisting the body into fixed postures. Off-period dystonia commonly consists of focal dystonic postures of a limb, such as extension of the foot and big toe or flexion of the toes, but may also be generalized. Dystonic postures may also have a diphasic evolution (Luquin et al., 1992b) and may be the initial manifestation of PD, before treatment is introduced. In fact, dystonic postures in PD were well recognized before levodopa became available. Nowadays, however, they are more frequently seen and characteristic of ‘off’ periods and therefore readily subside when the ‘on’ response ensues.
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Fig. 40.2 Phenomenology of diphasic dyskinesias. Movements typically consist of repetitive, kicking of the leg (left). The characteristic electromyogram pattern, recorded with surface electromyographic electrodes, consists of alternating contraction of antagonist muscles of the lower limb (right). Note the typical 5 Hz resting tremor in the upper limb. ff, finger flexors; fe, finger extensors; quad, quadriceps; ham, hamstrings; gastroc, gastronemius; tib ant, tibialis anterior muscles. Modified from Obeso et al. (1989) and Luquin et al. (1992).
40.2.4. Special presentations There are some special circumstances when the clinical presentation of LID does not follow the typical patterns described above (see below). 40.2.4.1. Nocturnal myoclonus Spontaneous myoclonic jerking of the leg at night occurs in the normal population but more frequently in patients with PD treated with dopaminergic drugs and usually coincides with nightmares and other parasomnias. The importance of nocturnal myoclonus, besides its potential inconvenience for the spouse, is that it generally heralds the beginning of psychiatric complications. It therefore demands early recognition and treatment. 40.2.4.2. Dyskinesias–parkinsonism In patients with severe PD who require large doses of levodopa, motor fluctuations and dyskinesias may not strictly follow the typical patterns described above. The combination of one body part exhibiting dyskinesias while the other half is ‘off’ is one of the most troublesome presentations. Typically, the upper half of the body exhibits dyskinesias and coincidentally the patient is incapable of walking due to severe freezing of gait.
40.2.4.3. Dyskinesias without benefit Dyskinesias without benefit were described in the 1970s and early 1980s but are not so frequently encountered nowadays. In this situation patients suffer dyskinetic movements without having the antiparkinsonian benefit of levodopa, similar to ‘off’ dyskinesias. However, we believe from our experience with chronic infusion of dopamine agonists that such presentation mainly corresponds to diphasic dyskinesias without the characteristic short-lasting and beginning and end-of-dose dual presentation. 40.2.4.4. Graft-induced ‘off’ dyskinesias This is a new problem in the field of dyskinesias in PD. Focal or segmental dyskinesias similar to typical LID have now been reported in two transplantation studies and were not observed in any of the placebotreated patients (Freed et al., 2001; Olanow et al., 2003). These dyskinesias thus appear to be specifically related to the grafted cells. Dyskinesias can persist for days or even weeks following withdrawal of dopaminergic medication, hence the use of the term ‘offmedication’ dyskinesias. However, careful evaluation indicates that in fact patients are not really ‘off’ as compared to their baseline (pregrafting) state. Indeed, in the
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study by Freed et al. (2001), those patients who developed dyskinesias after transplantation greatly improved, reaching motor scores comparable to those present during ‘on’ dyskinesia. On the other hand, patients in the study by Olanow et al. (2003) showed a very modest improvement and the clinical features and evolution of the dyskinesias were more compatible with a diphasic-like pattern.
40.3. Biochemical and molecular characteristics Striatal dopaminergic depletion and the discontinuous or pulsatile activation associated with levodopa therapy are the two major factors determining the development of dyskinesias. Together they induce alterations in the expression of dopamine receptors and in the vast majority of neurotransmission systems acting at the striatal level. The following section summarizes the major findings. 40.3.1. Dopaminergic receptors There are five subtypes of dopaminergic receptors grouped into two main families. D1 and D5 subtypes constitute the D1 family of dopaminergic receptors and D2, D3 and D4 subtypes form the D2 family. Many studies have been focused on possible changes in the dopaminergic receptors in the striatum of parkinsonian and dyskinetic PD patients and in a possible differential role of these receptor subtypes in the genesis of LID. It has been proposed that LID surges as an imbalance in activity of the two striatal output pathways, possibly through activation of D1 and inhibition of D2-receptors on the direct and indirect pathways, respectively (Obeso et al., 2000b; Bezard et al., 2001). Despite numerous experimental investigations, however, a clear relationship between dyskinesia and D1- or D2-receptor expression is not established. Numerous studies have shown that dopamine denervation causes an increase in striatal D2-receptors in the postmortem tissue of untreated PD patients and animal models of parkinsonism (Lee et al., 1978; Bezard et al., 2001; Aubert et al., 2005; Guigoni et al., 2005a). Chronic levodopa treatment induces a normalization of the D2-receptor in patients with PD, as assessed in postmortem tissue (Lee et al., 1978) and by positron emission tomography (PET) (Brooks et al., 1992; Shinotoh et al., 1993) and in MPTP monkeys (Graham et al., 1993; Herrero et al., 1996a). However, no difference in the expression of D2-receptors was observed between non-dyskinetic and dyskinetic groups of MPTP-treated monkeys (Aubert et al., 2005; Guigoni et al., 2005a).
The D1 subtype of dopamine receptor was found to be increased in the 6-OHDA rat model (Gerfen et al., 1990). However, no marked changes induced by levodopa were encountered in MPTP monkeys and PD patients (Lee et al., 1978; Graham et al., 1993). Recent findings suggest that LID may be more related to changes at the level of D1-receptor transmission. There is now evidence that downstream D1-mediated signal transduction cascade (Gerfen, 1995) is abnormal in LID. These include increased phosphorylation of cyclic adenosine monophosphate-regulated phosphoprotein of 32 kDa (DARPP-32) (Picconi et al., 2003), an increase in D1-agonist-induced G-protein-coupled receptor kinases and high levels of cyclin-dependent kinase-5 (Cdk5) (Aubert et al., 2005; Guigoni et al., 2005a). These data suggest that LID are closely related to augmented D1-receptor-mediated transmission at the level of the direct pathway. In addition, D3-receptors may play a role in LID. This was initially proposed based on the observation that striatal expression of this receptor is highly dependent on afferent dopamine innervation (Sokoloff et al., 1990; Levesque et al., 1995). Thus, D3-receptor expression is reduced in the striatum of parkinsonian rats and in the caudate nucleus of MPTP monkeys (Levesque et al., 1995; Bordet et al., 1997). Levodopa compensates for this reduction (Morissette et al., 1998; Quik et al., 2000, Bezard et al., 2003) but D3 putaminal receptors are only increased in animals that developed LID (Bordet et al., 2000; Bezard et al., 2003). Importantly, the overexpression of D3-receptor was confined to medium spiny striatal neurons, giving rise to the direct striatopallidal projection (Bordet et al., 2000). These findings have led to suggest an important role of D3 activation and the direct pathway in the pathophysiology of dyskinesias. On the other hand, other studies have failed to define significant abnormalities of D3-receptors in LID in both the MPTP monkey model (Hurley et al., 1996a) and PD patients (Hurley et al., 1996b) and pharmacological studies using the partial D3-agonist BP 897 induced reduction of LID, but at the expense of increased parkinsonism (Hsu et al., 2004). 40.3.2. Glutamatergic receptors Striatal medium spiny output neurons receive massive glutamatergic inputs from the cerebral cortex and the thalamus and are the site of close interaction between dopamine and glutamate receptors (Calabresi et al., 2000). Accordingly, striatal glutamate receptors have been suspected to be implicated in the development of LID (Chase and Oh, 2000; Calabresi et al., 2000; Calon et al., 2002). The actions of glutamate on target neurons are mediated by four classes of receptors: three types
LEVODOPA-INDUCED DYSKINESIAS IN PARKINSON’S DISEASE of channel-forming ionotropic receptors and one group of metabotropic, or G-protein-coupled, glutamate receptors (Hollmann and Heinemann, 1994; Dingledine et al., 1999). 40.3.2.1. Glutamatergic ionotropic receptors In the striatum, the majority of fast excitatory synaptic transmission is mediated by ionotropic glutamate receptors, which are ligand-gated ion channels. These receptors are named according to the synthetic agonists that are most effective in activating them and classified into N-methyl-D-aspartate (NMDA), a-amino-3-hydroxy-5methylisoxasole-4-propionate (AMPA) and kainate receptors (Dingledine et al., 1999). Striatal dopamine depletion increases the concentration and release of glutamate from corticostriatal terminals (Lindefors and Ungerstedt, 1990) but neither intrinsic membrane properties nor the response to exogenous application of glutamate agonists are altered in medium spiny neurons (Calabresi et al., 1993, 2000). 40.3.2.1.1. NMDA receptors NMDA receptors are the more densely expressed subtype in the striatum and their synaptic localization appears to be exclusively on the dendritic spines of the medium spiny gamma-aminobutyric acid (GABA)ergic neurons. The NMDA receptor is a heterodimeric protein essentially composed of two distinct subunits, namely NR1 and NR2 (Monyer et al., 1992). The expression of at least one NR1 subunit is required to form a functional channel and the combinations of distinct NR1 and NR2 subunits confer diversity of NMDA receptors. In the striatum, the NMDA receptor subtype containing NR2B is predominantly present (Standaert et al., 1994). Dopamine depletion in animal models (6-OHDA and MPTP monkeys) induces a redistribution of NMDA receptor subunits in two biochemical separate compartments. Thus, in unfractionated homogenates prepared from striatal tissue, the abundance of NR1, NR2A and NR2B subunit proteins was unchanged (Menegoz et al., 1995; Dunah et al., 2000; Calon et al., 2002) or minimally increased for the NR2A subunit proteins (Oh et al., 1997). In contrast, in striatal synaptosomal membrane fractions, dopamine depletion results in decreased NR1 and NR2B subunits (Dunah et al., 2000; Hallett et al., 2005) and no change in the NR2A subunit. It has been suggested that an underlying mechanism for this distribution may be a rapid D1-receptor- and tyrosine kinase-dependent trafficking system, which regulates delivery of NMDA receptor to synaptic sites in striatal neurons (Dunah et al., 2004).
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Chronic levodopa treatment in 6-OHDA-lesioned rats, eliciting behavioral sensitization, increases NR1, NR2A and NR2B subunits in homogenate and synaptosomal membrane fractions (Oh et al., 1997; Dunah et al., 2000; Dunah and Standaert, 2001). In MPTP monkeys, levodopa treatment causing dyskinesias restored or increased the NR2B levels in synaptosomal membranes but in addition increased the abundance of the NR2A subunit (Calon et al., 2002; Hallett et al., 2005). Similar studies from postmortem tissue of patients (treated chronically with levodopa) showed unchanged (Calon et al., 2003a) or increased (Lange et al., 1997) NR2A binding and increased NR2B binding (Calon et al., 2003a). Phosphorylation of ion channels plays a role in mediating synaptic plasticity and serves to increase molecular and functional heterogeneity of NMDA receptors (Betarbet et al., 2004). In animal studies there is a controversy over the phosphorylation state of these receptors either in the parkinsonian state or in the levodopa-treated condition. Thus, a number of changes in the rat parkinsonian model, such as increase in the proportion of NR2B subunits that are tyrosine-phosphorylated (Menegoz et al., 1995; Oh et al., 1997), reduced serine phosphorylation of NR1 subunit (Dunah et al., 2000) or increased serine phosphorylation of NR2A but not NR2B receptor subunit (Oh et al., 1997), have been described. Chronic levodopa treatment enhanced serine phosphorylation of NR1 and NR2A subunits and increasing tyrosine phosphorylation of NR2A and NR2B subunits (Oh et al., 1997; Dunah et al., 2000). However, these alterations have not been confirmed in parkinsonian MPTP and dyskinetic monkeys (Hallett et al., 2005). The efficacy of antagonists of the NMDA receptors in animal models of PD has been widely examined. These studies have revealed the ability of NMDAreceptor blockade to alleviate the symptoms of parkinsonism and augment the effectiveness of dopaminergic therapy preventing or reversing the induction of LID. For example, the competitive antagonist LY345959 and the NR2B-selective antagonists Co101244 and CI-1041 administered as coadjutants to levodopa diminished LID (Papa and Chase, 1996; Blanchet et al., 1999; Had Tahar et al., 2004) and CI-1041 prevented the development of LID in MPTP monkeys (Morissette et al., 2006). In summary, NMDA receptor subunit expression is altered in both the parkinsonian and dyskinetic states in the MPTP monkey model and PD patients. These changes may mediate a putative deregulation of corticostriatal activity underlying LID. The involvement of D1 dopamine receptor activation in the cascade of intracellular changes summarized above and the fact
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that the NR2A subtype of receptor is mostly expressed in striatal neurons projecting to the substantia nigra pars reticulata (SNpr) in the rat are in keeping with the suggested pivotal role of the direct pathway in the pathophysiology of LID (Bezard et al., 2003; Aubert et al., 2005). 40.3.2.1.2. AMPA receptors The role of AMPA receptors in LID is still controversial. AMPA receptors in the striatum of MPTP monkeys with LID have been reported as normal (Silverdale et al., 2002) or moderately increased (Calon et al., 2002). No alterations were found in the abundance of striatal GluR2/3 AMPA receptor subunits in synaptosomal membrane fractions following MPTP lesion and repeated levodopa treatment (Hallett et al., 2005). The absence of changes in AMPA receptor subunit proteins in monkeys confirmed previous studies in 6-OHDAlesioned rats (Dunah et al., 2000; Picconi et al., 2004). In postmortem tissue from levodopa-treated parkinsonian patients, no change of AMPA binding was observed (Ulas et al., 1994) but recently, a small elevation in AMPA receptors restricted to the lateral putamen has been reported (Calon et al., 2003a). The notion that AMPA receptor-mediated mechanisms are involved in LID is further suggested by the observation that AMPA-receptor antagonists can reduce the expression of LID when administered as an adjuvant to levodopa in the MPTP monkeys (Konitsiotis et al., 2000). 40.3.2.2. Glutamatergic metabotropic receptors In contrast to ionotropic glutamate receptors, the metabotropic glutamate receptors (mGluRs) are coupled to second-messenger systems through G-proteins. They have been classified into three groups: group I (mGluR1 and mGluR5), group II (mGluR2 and mGluR3) and group III (mGluR4, 6, 7 and 8) and have been identified in the striatum. In particular, group I mGluRs have been localized throughout the whole striatum at postsynaptic level, whereas group II and III mGluRs have been found at presynaptic level of corticostriatal terminals (Pisani et al., 2002). Indeed, induction of plastic changes in corticostriatal synapse depends upon activation of metabotropic receptors. In particular, long-term potentiation (LTP) is partially mediated by mGluR1 and mGluR5 (Gubellini et al., 2004) and the activation of mGluR2/ 3 is required for inducing long-term depression (LTD) (Sung et al., 2001). The meaning of these physiological changes with respect to LID is discussed in more detail in section 40.4 below. The experimental evidence suggests that metabotropic receptors represent another important point in the regulation of the excessive corticostriatal glutamatergic
transmission in PD (Gubellini et al., 2004). Modulation of these receptors can alleviate some parkinsonian motor features in the 6-OHDA rat (Murray et al., 2002; Picconi et al., 2002). However, there are no direct data at present regarding the possible involvement of these receptors in the pathophysiology of LID. Future research on the possible role of mGluR on the development of dyskinesias is clearly warranted. 40.3.3. Neuropeptides and adenosine receptors 40.3.3.1. Enkephalin, dynorphin and substantia P Enkephalin, dynorphin and substantia P are opiod peptides acting as cotransmitters in the striatopallidal system. The striatal GABAergic projection neurons are segregated with respect to the opioid peptides used as cotransmitters. Thus, striatal neurons projecting to the globus pallidum externa (GPe) in the indirect pathway express enkephalin derived from the precursor preproenkephalin A (PPE-A), whereas striatal neurons projecting to the globus pallidum interna (GPi) and SNpr in the direct pathway express dynorphin derived from PPE-B (Henry et al., 1999; Steiner and Gerfen, 1999) (Fig. 40.3). Dopamine modulates the activity of striatal neurons and the expression of these neuropeptides. Dopamine depletion increases PPE-A mRNA and enkephalin peptide levels and reduces PPE-B mRNA and dynorphin. These findings have been well established in rat and monkey models as well as in tissue from patients with PD (Augood et al., 1989; Gerfen et al., 1990; Asselin et al., 1994; Herrero et al., 1995; Nisbet et al., 1995). Chronic treatment with levodopa increases PPE-B mRNA over basal levels but has little or no effect on the elevated levels of PPE-A mRNA expression (Herrero et al., 1995; Nisbet et al., 1995; Cenci et al., 1998; Henry et al., 1999; Tel et al., 2002). In LID, PPE-A is either unchanged or further increased whereas PPE-B is increased (Herrero et al., 1995; Morissette et al., 1997; Henry et al., 1999; Calon et al., 2000; Zeng et al., 2000; Tel et al., 2002; Henry et al., 2003). Interestingly, increase of PPE-A mRNA expression in dyskinetic patients appears restricted to the lateral part of the putamen, which receives dense projections from the sensorimotor cortex. In humans, Piccini et al. (1997) found significantly reduced striatal and thalamic opioid binding in dyskinetic but not in non-dyskinetic PD patients. Unexpectedly, there has been no follow-up study to gain further understanding of these findings. Opioid receptor antagonists were shown to reduce LID in MPTP monkeys (Henry et al., 2001) but clinical studies have produced controversial results. Two studies have reported an antidyskinetic action of the
LEVODOPA-INDUCED DYSKINESIAS IN PARKINSON’S DISEASE non-selective opioid receptor antagonist naloxone (Trabucchi et al., 1982; Sandyk and Snider, 1986), whereas oral administration of naltrexone, a longeracting analog of naloxone, was ineffective in alleviating levodopa or apomorphine-induced dyskinesias (Rascol et al., 1994; Manson et al., 2001). None of these studies were placebo-controlled.
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variable and may not even be present in some instances (Bove et al., 2005). A2A-receptor blockade did not attenuate or prevent LID in 6-OHDA-lesioned rats (Lundblad et al., 2003). Similarly, it did not modify the upregulation in prodynorphin elicited by chronic levodopa treatment in rodents (Lundblad et al., 2003). 40.3.3.3. Early genes
40.3.3.2. Adenosine receptors The adenosinergic activity in the striatum has also been investigated in PD and LID. The A2A subtype of adenosine receptor is abundantly expressed in the medium spiny neurons of the striatum (Martinez-Mir et al., 1991), particularly in dendrites, and appears to signal, in part, through activation of serine/threonine kinases known to modulate the phosphorylation state of ionotropic glutamate receptors (Swope et al., 1999; Carvalho et al., 2000). Adenosine receptors are mainly expressed in GABAergic neurons projecting to the GPe (indirect pathway) and that also coexpress PPE-A and D2-receptors (Svenningsson et al., 1998). Dopaminergic lesion in the 6-OHDA rat model produces either no change or 20% increase of A2A receptor in the striatum (Kaelin-Lang et al., 2000; Pinna et al., 2002). In a recent study, enhancement of striatal A2A adenosine receptors was shown in 6-OHDA-lesioned rats and also in MPTP monkeys with LID (Zeng et al., 2000; Tekumalla et al., 2001), although the finding could not be replicated in squirrel monkeys (Quik et al., 2002). In human studies, adenosine A2A receptors are increased in the lateral putamen, without changes in the caudate nucleus, of dyskinetic PD patients compared with non-dyskinetic patients. A2A receptors are also increased in the GPe of parkinsonian patients with and without dyskinesia (Calon et al., 2004). There was a positive correlation between the expression of PPE-A and A2A receptors in the putamen of these patients, which represents the motor region of the striatum (Calon et al., 2004). It is known that PPEA is regulated by A2A receptor activity. Thus, A2Areceptor antagonists reverse the PPE-A increment induced in the rat striatum by 6-OHDA lesions and dopaminergic drugs (Carta et al., 2002; Lundblad et al., 2003). This has led to the suggestion that A2Areceptor activation could precede PPE-A increment and play a prominent causative role in the origin of LID. Pharmacological studies in animal models suggest that the A2A-antagonist KW-6002 has antiparkinsonian activity and potentates the action of levodopa (Kanda et al., 1998, 2000; Grondin et al., 1999; Lundblad et al., 2003; Pinna et al., 2005). A2A antagonism attenuates the overactivity of the striatopallidal pathway in the parkinsonian rat, but this effect is
Early genes and transcription factors that regulate the expression of other genes could also be involved in the increment of PPE and A2A-receptor (Calon et al., 2000). PPE and A2A gene expression in LID may be amplified by a common transcription factor such as fosB, one of the most thoroughly studied factors. In the striatum of the MPTP monkey there is an increment in fosB not seen after chronic treatment with very long-acting D2-agonists such as cabergoline or continuous administration of the D1-agonist SKF-82958, which provided sustained antiparkinsonian efficacy without dyskinesias (Doucet et al., 1996). In animals receiving pulsatile stimulation with the D1-agonist SKF-82958, dyskinesias appeared in 2 out of 3 monkeys within 1 week of administration along with a marked induction of fosB in the striatum of dyskinetic animals. Thus, fosB is found to be increased in the striatum of dyskinetic monkeys (Doucet et al., 1996; Calon et al., 2000) and rats (Cenci, 2002), suggesting it could be a key factor in the development of LID. Interestingly, administration of an antisense directed to fosB blocked LID in the rat (Andersson et al., 1999). However, no differences in fosB expression have been found between dyskinetic and non-dyskinetic PD patients (Tekumalla et al., 2001). Clearly, the meaning and functional changes of transcription factors in LID are not fully understood at present. 40.3.4. GABA receptors GABA is the major neurotransmitter of the BG. GABA receptors are classified into two major subtypes: ionotropic (GABAA and GABAC) and metabotropic. GABAergic neurons are abundantly present in the BG, including striatal interneurons, medium spiny neurons, pallidal and SNpr efferent neurons. They are enriched by GABAA and GABAB receptor subtypes. GABAA receptors are increased in the GPi of dyskinetic MPTP monkeys and in PD patients with LID (Calon et al., 1995, 1999, 2003b; Calon and Di Paulo, 2002). GABAA receptor upregulation in GPi correlates with the development of dyskinesias induced by D1and D2-agonists in MPTP monkeys (Calon et al., 1995, 1999). This was not the case in MPTP monkeys chronically treated with dopamine agonists which did
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Fig. 40.3. Schematic representation of the main basal ganglia circuits. (A) Normal state; (B) Parkinsonian state due to dopaminergic striatal depletion. Dopamine depletion induces a dual, opposite effect, on medium spiny neurons. D1-expressing neurons are inhibited whereas D2-containing neurons are overactive. (C) Levodopa-induced dyskinetic state in Parkinson’s disease. This represents the changes elicited by levodopa on a denervated striatum (summarized in B). SNpc-DA, substantia nigra pars compacta–dopamine; NMDA, N-methyl-D-aspartate; SP, substance P.
not induce dyskinesias. The main changes in the expression of GABAA receptors occurred in the motor (posteroventral) region of the GPi (Calon et al., 2002). On the other hand, no significant change was found in GABAA receptors in the putamen of dyskinetic PD patients. Patients with LID had increased expression of GABAB receptors in the ventral GPe compared with non-dyskinetic patients, but in absolute terms there was no difference from control values (Calon et al., 2003b). Overall, these data suggest abnormal deviation of GABA receptors in the motor area of both segments of the GP but the precise relationship with the parkinsonian and dyskinetic states is not well depicted. 40.3.5. Serotoninergic receptors The BG receive a rich serotoninergic innervation from the dorsal and medial raphe nuclei which could play a role in their motor and behavioral functions (Jacobs and Fornal, 1993). The action of serotonin (5-hydroxytryptamine: 5-HT) is mediated by a variety of 5-HTreceptors, including G-protein-coupled subtypes (5-HT1, 5-HT2, 5HT4–7) and a ligand-gated ion channel (5-HT3) (Hoyer et al., 2002).
Under normal circumstances levodopa is decarboxylated to dopamine in the striatal terminals of nigrostriatal dopaminegic neurons. However, the site of levodopa decarboxylation in parkinsonism remains obscure, as most dopamine terminals have degenerated. There is now evidence that 5-HT neurons are primarily responsible for the storage and release of levodopa-derived dopamine into the striatum where dopaminergic terminals are lost (Tanaka et al., 1999; Kannari et al., 2001). In animal models and in patients with PD striatal dopaminergic mechanisms can be influenced by drugs that selectively interact with serotoninergic neurons, including those that stimulate 5-HT1A receptors (Santiago et al., 1998). Interestingly, it has been shown that in 6-OHDA-lesioned rats, pretreatment with the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) attenuates the excessively high extracellular dopamine levels that occur in the dopamine-denervated striatum after levodopa treatment (Kannari et al., 2001). This effect was mediated by stimulation of 5-HT1A-receptors since the co-administration of WAY-100635, a 5-HT1A-receptor antagonist, attenuated the effect of 8-OH-DPAT on dopamine levels (Kannari et al., 2001).
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Based on these observations, it has been suggested that the administration of 5-HT1A-receptor agonists with levodopa may prevent the deleterious effects of pulsatile stimulation of dopamine receptors associated with levodopa treatment and reverse LID. Recent results have shown that the co-administration of 8-OH-DPAT prevents behavioral sensitization to levodopa in the 6-OHDA model (Tomiyama et al., 2005), in association with a decrease in the striatal expression of mRNA coding for dynorphin and acid decarboxylase, both of which are established markers of levodopainduced motor complications (Tomiyama et al., 2005). Moreover, the 5-HT1A agonists buspiron and sarizotan have been found to reduce LID in two open trials with PD patients (Bonifati et al., 1994; Bara-Jimenez et al., 2005) and MPTP monkeys (Bibbiani et al., 2001). This therapeutic effect was not associated with a reduction of levodopa efficacy. Moreover, in 6-OHDA-lesioned rats, sarizotan reversed the shortening in motor response duration induced by intermittent administration of levodopa (Bibbiani et al., 2001). The clinical effects observed with sarizotan are most likely related to the potent ability of the drug to activate 5-HT1A-receptors since its effects disappeared when the 5-HT1A antagonist WAY-100635 was co-administered in rat and monkey models (Bibbiani et al., 2001). Other potential mechanisms for the antidyskinetic effect of sarizotan may also be taken into account. In principle, sarizotan’s ability to diminish dyskinesias does not seem to be related to its capability to block D2, D3 or D4 dopaminergic receptors (Rabiner et al., 2002; Bartoszyk et al., 2004). Recently, the effects of sarizotan on the corticostriatal glutamate pathways have been investigated and the results indicate that sarizotan produces a reduction in cortical and striatal glutamate levels when systemically administered or perfused into the motor cortex (Antonelli et al., 2005). Of particular interest are recent reports that indicate the influence of 5-HT-receptors on subthalamic nucleus (STN) activity. The intrasubthalamic administration of 5-HT-induced contralateral rotational behavior suggests an inhibitory effect of 5-HT on STN neurons (Bellforte and Pazo, 2004). Furthermore, extracellular single-unit recordings in mouse brain slices demonstrates that 5-HT elicits two distinct effects in STN neurons, the first being an excitation and the second an inhibition; the latter effect is attenuated by the administration of WAY-100635, indicating a 5-HT1A-receptormediated inhibition (Stanford et al., 2005).
40.4. Pathophysiology 40.4.1. The classic model In the late 1980s a pathophysiological model of the BG was established (Figure 40.3) based on observa-
tions in animal models of PD and dyskinesias (Crossman, 1987; Albin et al., 1989; DeLong, 1990). The main idea underlying the model is that corticostriatal afferent activity influences the output of the BG, the GPi and SNpr, by two relatively segregated striopallidal projections: the indirect pathway and the direct pathway. The indirect pathway or circuit consists of GABA medium spiny striatal neurons expressing D2 and enkephalin and inhibiting the GPe, which in turn inhibits the STN. The STN projection is excitatory, i.e. glutamatergic, onto the GPi and SNpr. The direct pathway also arises from GABA striatal neurons bearing D1-receptors and expressing substance P and dynorphin and projecting monosynaptically to the GPi/SNpr. These functional arrangements sustain a dual functional effect of dopamine on striatal medium spiny neurons and on the output of the BG (Fig. 40.3A). Thus, increased activity in the direct pathway and indirect pathway produces inhibition and excitation respectively of GPi/SNpr neurons. Pauses of neuronal activity in the GPi/SNpr are associated with movement facilitation (Hikosaka and Wurtz, 1983; DeLong, 1990) whereas firing is more related to the end and halting of movement (Brotchie et al., 1991; Mink and Thach, 1991). Dopamine striatal deficiency secondary to loss of the nigrostriatal projection leads to increased activity in GABA medium spiny neurons expressing D2 and enkephalin and overinhibition of the GPe, resulting in exaggerated activity of the STN in the indirect pathway (Fig. 40.3B). In the direct pathway dopamine deficiency induces a reduction of activity in GABAergic neurons bearing D1-receptors and expressing substance P and dynorphin (Gerfen et al., 1990). Together, these changes in the indirect and direct pathways combine to produce a state of abnormally increased activity in the inhibitory output of the BG (Fig. 40.3B), which is a main pathophysiological feature of the parkinsonian state. The opposite functional picture (Fig. 40.3C), on the other hand, characterizes dyskinesias. Initial evidence indicated a paramount role of the indirect pathway in the induction of dyskinesias. In normal monkeys, choreic dyskinesias are produced by disinhibition of the GPe and blockade or lesion of the STN (Carpenter et al., 1950; Crossman et al., 1988; Hamada and DeLong, 1992). Thus, blockade of the striato-GPe inhibitory projection (with bicuculline) leads to increased GPe efferent activity, which results in overinhibition of the STN (Crossman et al., 1988; Mitchell et al., 1989, Grably et al., 2004), and reduction in STN glutamatergic efferent activity induces hypoactivity of the GPi, both causing dyskinesias (Mitchell et al., 1989; Robertson et al., 1989; Hamada and DeLong, 1992). Hypoactivity of the GPi may also occur by increased GABAergic input from the GPe and the direct
LEVODOPA-INDUCED DYSKINESIAS IN PARKINSON’S DISEASE striatopallidal pathway. Direct administration of the GABA agonist muscimol into the GPi has mainly been associated with dystonic co-contraction of antagonist muscles and secondary slowness of movement initiation (Mink and Thach, 1991; Kato and Kimura, 1992; Inase et al., 1996). There is only one report of choreic dyskinesias of the contralateral limbs provoked by overinhibition (with muscimol) of the GPi (Burbaud et al., 1998). In addition, permanent lesion of the GPi (Horak and Anderson, 1984; Mink and Thach, 1991) is not associated with any dyskinetic movement; on the contrary (see below) it eliminates dyskinesias. Hypoactivity of the GPi leads to disinhibition of the thalamocortical projection in the motor circuit, releasing the motor thalamic nuclei and thereby facilitating the abnormal recruitment of cortical motor areas and the development of involuntary movements (Crossman, 1987; Albin et al., 1989; DeLong, 1990; Obeso et al., 2000b). This summary reflects the underlying notion of the classic model. A similar sequence of events is supposed to take place due to excessive striatal dopaminergic stimulation in the levodopa-treated parkinsonian state (Crossman, 1990; Obeso et al., 2000b). In recent years, newer evidence has arisen which has forced the revision and adaptation of several assumptions of the original model. We discuss in detail all these different developments in the subsections below. 40.4.2. Synaptic plasticity LTP and LTD are forms of synaptic plasticity that may be critically involved in learning and memory processes and are mediated by glutamatergic NMDA receptors. In addition to the hippocampus, where it was described for the first time, this phenomenon is also present in a variety of brain structures, including the striatum. Repetitive stimulation of the corticostriatal pathway can induce both LTP (in response to high-frequency stimulation) and LTD (in response to low-frequency stimulation) of synaptic transmission in the striatum. Glutamatate released by corticostriatal stimulation excites striatal medium spiny neurons, which are modulated by the nigrostriatal dopaminergic projection. Dendritic spines of striatal neurons are the anatomical locus of interaction between glutamate and dopamine with the dopaminergic terminal localized at the necks and the glutamatergic terminals at the head of the spines respectively (Smith et al., 1996). LID exhibit some features that are highly suggestive of plastic changes. The gradual development, persistency and dependence of glutamate receptor mechanism suggest that LID may be aberrant forms of motor learning (Centonze et al., 1999). Accord-
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ingly, abnormal synaptic plasticity at corticostriatal synapses may play a role in the pathophysiology of parkinsonism and LID (Calabresi et al., 1996, 2000; Picconi et al., 2003; Pisani et al., 2005). In parkinsonian rats after dopaminergic denervation with 6-OHDA or in animals treated with a D1-selective antagonist, LTP is blocked (Calabresi et al., 2000; Pisani et al., 2005). Chronic levodopa treatment restores this response in dyskinetic and non-dyskinetic animals. After induction of LTP, the delivery of low-frequency stimulation in normal rats produces a reversal of synaptic strength to pre-LTP levels, named ‘depotentiation’. Parkinsonian rats chronically treated with levodopa but without dyskinesias exhibited the same response as normal rats, whereas dyskinetic rats did not show the depotentiation response (Picconi et al., 2003). Thus, LTP cannot be reversed by low-frequency stimulation in the 6-OHDA animals that developed LID after chronic treatment, in contrast to levodopa-treated rats without LID. Synaptic depotentiation is thought to increase the efficiency of information storage in neuronal networks and may play a prominent role in eliminating irrelevant information underlying the process of forgetting. Thus, the lack of depotentiation in the dyskinetic animals can represent a failure in erasing inadequate motor information, leading to the development of abnormal involuntary movements (Picconi et al., 2003). Striatal LTP mainly depends on activation of NMDA and D1-receptors (Calabresi et al., 1996) but it is also modulated by mGluR2/3 metabotropic receptors and endocannainoids (Genderman et al., 2002). As already indicated in section 40.3 above, NR2A receptors are overexpressed in the striatum of MPTP monkeys with LID (Calon et al., 2002; Hallett et al., 2005) whereas NR1 and NR2B are normalized by levodopa treatment. This set of changes could be responsible for a reinforcement of LTP leading to augmented threshold for its reversion, or depotentiation, in the dyskinetic animals. Dendritic spines are the locus of the interaction between glutamate and dopamine responsible for the LTP and LTD. It could be that dopaminergic depletion induces a redistribution of the subtypes of NMDA receptors, along the cellular membrane, that might cause an impairment of corticostriatal synaptic plasticity. An increase in the percentage of glutamatergic synapses has been found (Anglade et al., 1996) in the striatum of rats with 6-OHDA-induced lesion and in PD patients. Moreover, the same studies have shown that dendritic spines of striatal neurons are reduced numerically and show abnormal length, size and shape (Anglade et al., 1996; Meshul et al., 1999; Stephens et al., 2005). At present, there are no data either in the MPTP monkey model or in PD
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patients regarding the synaptic or extrasynaptic allocation of the NR2A and NR2B subtypes of NMDA receptors in the dyskinetic state. The exact meaning of the changes so far encountered needs further studies. In perirhinal cortex, the NR2B NMDA receptors responsible for LTD are allocated extrasynaptically, whereas NR2A NMDA receptors, responsible for LTP and depotentiation, are located synaptically (Massey et al., 2004). Thus, it is possible that LID in PD could similarly involve relocation of NR2 receptors underlying the formation of abnormal changes in synaptic plasticity. This could be a prominent feature of striatal physiology and LID. 40.4.3. Neurophysiology: neuronal firing The parkinsonian state is associated with increased firing rate in the STN and GPi (Filion and Tremblay, 1991; Bergman et al., 1994; Merello et al., 1999a; Vitek and Giroux, 2000). LID are associated with reduction in the STN and GPi firing rate in the MPTP monkey model (Filion et al., 1991; Papa et al., 1999) and in patients with PD (Merello et al., 1999a; Lozano et al., 2000; Boraud et al., 2001; Levy et al., 2001). Levodopa treatment is associated with an increment in the firing rate of GPe neurons (Filion et al., 1991; Boraud et al., 1998). However, precise data regarding
GPe neuronal activity and the presence of LID are strikingly limited (Filion et al., 1991). Firing rate in the STN and GPi is therefore, apparently well correlated with the parkinsonian and dyskinetic motor states (Fig. 40.4). At odds with the model is the fact that the lesion of the GPi (pallidotomy), instead of aggravating LID, is associated with the suppression of these undesired movements. A more detailed analysis of neuronal activity in the GPi during LID has shown that not every single neuron decreased its firing rate during LID (Filion et al., 1991; Boraud et al., 2001; Levy et al., 2001). Similarly, in the STN (Levy et al., 2001), there was a reduction in the overall firing rate of the nucleus but a proportion of neurons had no change. Importantly, the proportion of neurons discharging in bursts and irregularly is increased in the STN and GPi during LID (Filion et al., 1991; Merello et al., 1999a; Lozano et al., 2000; Boraud et al., 2001). Accordingly, the averaged firing frequency is not the only physiological determinant of the dyskinetic state with respect to the parkinsonian motor condition. Thus, it is now believed that it is the pattern of neuronal activity in the output of the BG that is relevant to the development of dyskinesias (Vitek et al., 1999; Vitek and Giroux, 2000; Obeso et al., 2000b; Bezard et al., 2001; Boraud et al., 2001).
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Fig. 40.4. Recording of neuronal extracellular activity in the globus pallidus internal segment of one representative 1-methyl4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkey. In the ‘off’ state there is increased firing rate, which is reduced when the animal turns ‘on’ after administration of a dopaminergic drug. The rate decreases to near zero, coinciding with the ensuing of dyskinesias. Reproduced from Papa et al. (1999) with permission from the American Neurological Association.
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Fig. 40.5. Recording oscillatory activity in the subthalamic nucleus of a patient with Parkinson’s disease through implanted electrodes. In the ‘off’ state there is a predominant peak of activity in the beta band. The onset of diphasic dyskinesias (left vertical line) is associated with drastic attenuation of beta activity and onset of theta activity (upper row). At the time of ‘on’ dyskinesias (right vertical line), there is an additional peak in the gamma band.
The importance of oscillations and patterns of neuronal activity in LID is starting to be clarified (Fig. 40.5). In patients submitted to surgery for deep brain stimulation (DBS) it is possible to record local field potentials (LFP) from the implanted electrodes in the STN or GPi. Typically, in the ‘off’ state there is a predominant peak in the 11–30 Hz (beta) band and, when patients are treated with dopaminergic drugs, the beta rhythm is drastically attenuated and activity in the 60–80 Hz gamma band predominates (Levy et al., 2002; Brown, 2003). A recent study has shown that the dyskinetic state is associated with a predominant oscillatory activity at 4–10 Hz in the STN of PD patients who developed LID (Alonso-Frech et al., 2006) and that such theta/alpha peaks are absent in patients without dyskinesias. Indeed, stimulating the STN at this 4–8 Hz frequency in patients treated with DBS in the STN elicited dyskinesias (Liu et al., 2002). In the 6-OHDA rat with LID the Bordeaux group (Meissner et al., 2006) recorded from the SNpr
and found precisely the same correlation between dyskinesias and slow oscillations. The peak activity in the theta/alpha band coincided with a reduction in neuronal firing rate in the SNpr and increased dopamine levels in the striatum. It appears, therefore, that reduction in single-cell neuronal activity allows synchronization at around 4–8 Hz, which facilitates the onset of dyskinesias. Interestingly, a similar predominance around 4–8 Hz coinciding with LID has been recorded in the GPi in 1 patient with PD (Foffani et al., 2005) and in a group of patients with torsion dystonia (Silberstein et al., 2003). How this pattern of activity in the output nuclei of the BG releases involuntary movements is not understood. 40.4.4. Anatomofunctional basis Loss of nigrostriatal terminals is associated with large and uncontrolled oscillations in dopamine levels after exogenous administration of levodopa (Miller and
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Abercrombie, 1999; Brotchie et al., 2005), which increases with disease progression (De la FuenteFernandez et al., 2004; Obeso et al., 2004). The striatum has been classically assumed to be the site where abnormal dopaminergic activation takes place in patients chronically treated with levodopa, but direct evidence had not existed until recently. This has come from experience regarding fetal mesencephalic transplants in patients with PD. Two double-blind studies have conclusively shown that increasing dopaminergic levels in the putamen (revealed by PET) is associated with dyskinesias, which are otherwise identical to the ones provoked by levodopa (Ma et al., 2002; Olanow et al., 2003). In line with the prevailing pathophysiological explanation for LID discussed in the previous section, excessively large amounts of dopamine induce plastic changes in medium spiny striatal (i.e. putaminal) neurons, giving rise to the indirect and direct pathways. The relative importance of either striatopallidal projection is not well defined and, in fact, it has changed over the years. Direct data for the participation of the indirect pathway in LID are relatively scarce. In normal primates dyskinesias are evoked by reducing STN activity (see above) and 2-deoxyglucose uptake is increased in the STN and GPi of MPTP monkeys with LID (Mitchell et al., 1992). Neuronal activity in the STN from PD patients with dyskinesias elicited by apomorphine during surgery is reduced compared with the ‘off’ parkinsonian state (Lozano et al., 2000; Vitek and Giroux, 2000). Interestingly, the distribution of the 4–10 Hz oscillatory activity recently associated with LID in PD patients (Alonso-Frech et al., 2006) and the increment in glucose uptake in dyskinetic MPTP monkeys predominate over the ventral region of the STN (Mitchell et al., 1992; Guigoni et al., 2005b). These results are in keeping with the classic model and the role of the indirect pathway in the pathophysiology of LID. However, there is controversy over the functional state of the GPe and its role in the reduction of STN activity that mediates dyskinesias (Obeso et al., 1997). On the one hand, recording neuronal activity in the GPe of dyskinetic animals has shown increased firing rate (Filion et al., 1991; Boraud et al., 2001). However, metabolic markers are not in keeping with such findings. Expression of mRNA for striatal met-enkephalin remains increased (Herrero et al., 1995) and expression of glutamic acid decarboxylase (GAD) mRNA (an index of GABA activity) and cytochrome oxidase mRNA (an index of cellular activation) were not above normal in the GPe of dyskinetic monkeys (Vila et al., 1997; Herrero et al., 1996b). Importantly, lesions of the GPe did not block
previously installed LID in MPTP monkeys who actually deteriorated further (Blanchet et al., 1994). Thus, the prediction of the model whereby levodopa induces hyperactivity of the GPe leading to the expected overinhibition of the STN is not supported by metabolic data. In this regard, it is worth noticing that there is a direct dopaminergic innervation of the STN, GPe and GPi (Hedreen, 1999) which is impaired in animal models and patients with PD (Francois et al., 2000; Jan et al., 2000). It is therefore possible that modulation of STN output activity occurs not only from the GPe but also by a direct effect of dopaminergic drugs. The involvement of the direct pathway in the development of LID has been substantiated in recent years, particularly by studies related with modifications of D1 striatal receptors’ signal transduction, as discussed in section 40.3 above. Animal models gave variable results regarding the expression of D1-receptors in the striatum but importantly, no modification was present in PD patients (Lee et al., 1978). A recent study concluded that the expression of D1 striatal receptors is unchanged in relation to LID in MPTP monkeys but recognized an increment in binding of [(35)S] GTP gamma, indicating functionally active receptors. Moreover, levels of Cdk5 and DARPP-32, two pivotal players in the D1 signal transduction pathway, are increased in the striatum of dyskinetic monkeys (Aubert et al., 2005). These findings were not present in monkeys with a similar degree of parkinsonism and dopaminergic depletion and without dyskinesias, despite the fact that they received the same regimen of levodopa treatment. The severity of LID also correlated linearly with D3-receptor binding levels. Thus, two markers of the medium spiny neurons at the origin of the direct pathway, such as D1- and D3-receptors, indicate a prominent role of the direct pathway in LID. In contrast, levodopa treatment reduced and normalized the increased expression of D2-receptors in MPTP monkeys with and without dyskinesias (Herrero et al., 1996a; Bezard et al., 2001). PET studies in PD patients showed a similar pattern of striatal D2-receptor after receiving levodopa treatment (Brooks et al., 1992). We believe that the dichotomy between the direct and indirect pathways in the pathophysiology of LID is fruitless and unrealistic. Manipulation of either pathway at the level of the GPi can induce dyskinesias. Thus, in normal monkeys dyskinesias can be elicited either by injection of glutamatergic antagonists into the GPi, blocking the STN glutamatergic excitation (Robertson et al., 1989), or by local injection of the GABAergic agonist muscimol (Burbaud et al., 1998), mimicking inhibition from the GPe and the direct pathway. There are several other sources of evidence indicating participation of both striatopallidal projections in the 6-OHDA rat and MPTP
LEVODOPA-INDUCED DYSKINESIAS IN PARKINSON’S DISEASE monkeys. For instance, to restore striatal LTP in the denervated striatum activation of both D1- and D2-receptors is necessary (Calabresi et al., 2000). Dyskinesias may be elicited by a D2-agonist (i.e. þPHNO, 4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho(1,2-b)(1,4) oxazin-9-ol) after co-administration of a D1-antagonist (i.e. SCH-233390) and vice versa, a D1-agonist may evoke dyskinesias in the presence of a D2antagonist (Luquin et al., 1992a). Finally, and more importantly, administration of a D1-agonist in the primed MPTP monkey induces dyskinesias and causes changes in neuronal activity in the GPi which are the same as those caused by a D2-agonist that also provokes dyskinesias (Boraud et al., 2001). This suggests that reduction of GPi firing frequency and slow oscillatory synchronization responsible for LID may occur through functional changes in several circuits influencing GPi output activity. In fact, recent anatomical data strongly indicate that the concept of the direct or indirect pathways cannot be sustained based on connectivity among the different BG nuclei (Levesque and Parent, 2005). Our own view is, therefore, that the available data do not suggest the exclusive participation of a given striatopallidal pathway in the pathophysiology of LID. More likely, changes in afferent activity to the GPi from the GPe, STN and putamen are all involved in setting the firing patterns and oscillatory activity that give rise to LID. Lesions of the GPi and the pallidal receiving area of the thalamus may eradicate LID. This conclusively indicates that the abnormal signals are conveyed through the pallidothalamic projection to the cortical motor areas. Indeed, regional cerebral blood flow measured by PET or single-photon emission computed tomography (SPECT) was increased in the motor thalamus in patients with LID (Hershey et al., 1998) or hemichorea (Kim et al., 2002), indicating increased input, presumably from the GPi. Two other studies compared regional activation during the performance of manual activity. A PET study with O15–H2O compared levodopa-treated PD patients with and without dyskinesia and found increased activation of the BG, area 4, area 6, supplementary motor area and dorsolateral prefrontal cortex at rest and during a joystick task coinciding with ‘on’ dyskinesias (Brooks et al., 2000). Using 133Xe SPECT to measure blood flow during a finger movement task, Rascol et al. (1998) described similar findings at the cortical level. In conclusion, it appears that LID depend upon uncontrolled dopaminergic signaling at the putaminal level, leading to abnormal generation of firing patterns and oscillations in the output of the BG, which is conveyed via the thalamus to the cortical motor areas. LID may represent the dysfunction of primary BG mechan-
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isms involved in the suppression of unwanted actions and the running of automatic movements (Marsden and Obeso, 1994; Obeso et al., 2000a). Normally, actions are limited to a few movements at a time. The motor apparatus guarantees that other body segments are not recruited. The BG are thought to contribute fundamentally to this operation by setting the right balance between movement facilitation and inhibition (Mink and Thach, 1991; Marsden and Obeso, 1994; Obeso et al., 2000a; Mink, 2003). Dyskinesias represent a deviation of this essential mechanism whereby voluntary motor acts are performed with relative accuracy, but unwanted, involuntary fragments of movements are also simultaneously recruited. It is as if the motor system has lost the capacity to focus and appropriately select just the correct and desired movement pattern, a typical function of the BG (DennyBrown and Yanagisawa, 1976; Marsden, 1982).
40.5. Treatment LID are highly prevalent in the overall PD population and may be very disabling, interfering with quality of life (Chapuis et al., 2005). This is especially relevant in patients with younger age at disease onset. For example, in PD beginning before the age of 45 years old, LID are severe and present in almost all patients after 5 years of treatment. The optimal therapeutic approach for LID is to avoid their development. Advances in such an approach have been gained over the last few years but the outcome is still quite limited. This is due to the fact that LID are directly related to disease progression, a problem that has no realistic therapy yet and the inevitable need to use levodopa during the evolution of PD. 40.5.1. Pharmacological treatments Three main therapeutic strategies are used to manage LID in parkinsonian patients: (1) prevention of the sensitization or priming phenomenon by early use of a dopamine agonist; (2) symptomatic treatment, once LID have developed, with putative antidyskinetic interventions; and (3) continuous dopaminergic stimulation to reverse the functional changes underlying dyskinesias. 40.5.1.1. Prevention of priming The use of neuroprotective drugs to slow disease progression has been extensively explored. L-deprenyl (in an extension of the Deprenyl and Tocopherol Antioxidative Therapy of Parkinson’s disease (DATATOP) study) failed to produce a significant reduction in the incidence of dyskinesias (Shoulson, 1998).
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The only group of drugs that has convincingly demonstrated a reduction in the risk of developing dyskinesias is the dopamine agonists. Three placebo-controlled studies comparing the evolution of patients initiated with a dopamine agonist (ropinirol, pramipexol and cabergoline) and standard levodopa have shown that the former provided significant symptomatic relief, although slightly less than levodopa, with less risk for developing dyskinesia after a follow-up period of 2–5 years. Rascol et al. (2000), in a comprehensive, doubleblind parallel study, compared the efficacy of ropinirol and levodopa over a period of 5 years in 268 patients with early PD. The analysis of the time to onset of dyskinesia showed a significant difference in favor of ropinirol. At 5 years, the cumulative incidence of dyskinesia, regardless of levodopa supplementation, was 20% in the ropinirol group and 45% in the levodopa group. This confirmed clinically experimental data in the MPTP monkey (Maratos et al., 2001), showing that ropinirol alone or in combination with low-dose levodopa delayed dyskinesia onset while improving motor performance. The mean daily dose of ropinirol was 15 mg but the majority of patients enrolled in that arm required supplementary treatment with levodopa (Rascol et al., 2000). Holloway et al. (2004) compared the incidence of motor complications between pramipexole and levodopa as initial treatment in early PD. Patients allocated to pramipexole treatment showed a significant reduction in the risk of developing dyskinesias (24.5% versus 54%; P < 0.001). Cabergoline is an ergoline derivative with a very long half-life ( 72 hours) that can therefore be administered once daily. In a double-blind multicenter trial on 419 patients naive to treatment, comparing cabergoline and levodopa as initial therapy for PD, motor complications were significantly delayed and occurred less frequently in cabergoline-treated patients compared to levodopa-treated patients (Bracco et al., 2004). An evidence-based review (Inzelberg et al., 2003) compared the results of studies published on early treatment of PD with dopamine agonists (cabergoline, ropinirol or pramipexole) with similar studies using levodopa. Cabergoline, pramipexole and ropinirol were similarly effective in reducing the risk for dyskinesia relative to levodopa. Dyskinesia risk reduction was slightly greater for pramipexole and ropinirol than for cabergoline. A concern encountered in the three studies was that, whereas treatment with a dopamine agonist reduced the risk of dyskinesia, this was associated with less antiparkinsonian benefit. It remains open to future analysis if the initial benefit on LID of treatment with a dopamine agonist is carried forward over the long-term evolution, once
levodopa is added to the regimen. In addition, several issues related to the design of the studies have been raised by critical voices. Our own view is that the severity of LID observed in clinical practice has been considerably reduced in the last decade or so, coinciding with the earlier use of dopamine agonist and the associated possibility of reducing levodopa daily dose. In addition, neuroimaging studies with PET and SPECT suggested that dopamine agonists may be associated with a reduction in the decline of dopaminergic striatal terminals when used in the early stages of the disease, raising the possibility of a neuroprotective effect (Marek et al., 2002; Whone et al., 2003). Thus, while sufficient and definitive data are being compiled, we favor the prevailing concept of starting therapy with a dopamine agonist, particularly in patients who are 65 years old or younger, at the time of diagnosis. 40.5.1.2. Dyskinesias in patients already primed: symptomatic treatments This is the commonest clinical scenario. Patients have already developed LID and the clinician has to attempt to control the dyskinesias by adjusting the antiparkinsonian drugs or adding agents capable of reducing LID without increasing motor disability. The difficulty in achieving therapeutic efficacy is directly related to the severity and complexity of PD in each individual subject. Thus, LID are relatively easy to control when they are mild and occur in patients with a wide therapeutic window but may be very difficult (or impossible) to treat pharmacologically in severe patients who exhibit all forms of LID and fall into severe ‘off’ episodes when they are not dyskinetic. We shall review here the different individual pharmacological approaches available to treat LID but, in many instances of clinical practice, one needs to combine several options. 40.5.1.2.1. Dopamine agonists A dopamine agonist is added with the intention of reducing levodopa dose and avoiding peak of dose on-dyskinesias associated with high levodopa plasma levels. Belanger et al. (2003) examined the possibility of reducing LID by using a small dose of cabergoline. During treatment, they observed LID in the levodopa group but not in the levodopa þ cabergoline group, which suggests that a small dose of a long-acting D2agonist combined with low doses of levodopa could reduce the incidence of LID in patients with PD. This study supports a commonly applied clinical strategy. Another approach is to achieve an antidyskinetic effect with a partial dopamine agonist. These drugs,
LEVODOPA-INDUCED DYSKINESIAS IN PARKINSON’S DISEASE characterized by having lower intrinsic activity at the receptor level than full agonists, act as either functional agonist or antagonist, depending on the levels of endogenous dopamine. A partial D2-receptor agonist may represent an interesting alternative for the treatment of PD and dyskinesias. Preclamol, the (–)enantiomer of 3(3-hydroxyphenyl)N-n-propyl piperidine (3-PPP), has a selective dopamine mixed agonist–antagonist profile for both pre and postsynaptic receptors. Its action in patients with disabling ‘on–off’ fluctuations was compared against placebo and subcutaneous apomorphine (Pirtosek et al., 1993). Preclamol had a mild but unequivocal antiakinetic effect, less than that achieved with subcutaneous apomorphine, but caused less dyskinesia. Aripiprazole is a new antipsychotic drug showing partial agonist activity for D2 and 5-HT1A-receptors and antagonist activity for 5-HT2A-receptors. Lieberman (2004) postulated that this drug may be able to reduce dyskinesias without producing akinesia, but further studies are required to investigate its antidyskinetic capacity. 40.5.1.2.2. Dopamine antagonists The use of drugs that block the dopaminergic system has been a classical approach for the treatment of dyskinesias in general. D2-antagonists, like haloperidol, tiapride and sulpiride, and presynaptic dopamine-depleting drugs, like reserpine and tetrabenazine, have all proven useful in the management of hemichorea-ballism (HCB), tardive dyskinesias and tics. These same drugs are also effective in reducing or stopping LID in PD, but this effect is invariably associated with marked motor worsening after a variable period (ranging from hours to weeks). In clinical practice, therefore, they are not useful. Recent observations increasingly suggest that atypical neuroleptic drugs, which are able to block D3receptors preferentially, can be beneficial for patients with movement disorders. Oh et al. (2002) evaluated the effects of quetiapine, an atypical antipsychotic with 5-HT2A/C and D2/3-antagonistic activity, on motor behavior in the 6-OHDA-lesioned rat and in MPTP monkeys. In unilaterally lesioned rats, quetiapine (5 mg/kg p.o.) reversed the shortening of the motor response to levodopa challenge produced by treatment during 3 weeks with levodopa twice daily. Quetiapine (5 mg/kg p.o.) also normalized the short-duration response to acute injection of either a D1-receptor agonist (SKF-38392) or a D2-agonist (quinpirole) in rats that had received chronic levodopa treatment. Quetiapine had no effect on parkinsonian manifestations when given alone to 6-OHDA-lesioned rats or MPTP monkeys but did substantially reduce LID when administered together with levodopa.
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Katzenschlager et al. (2005) assessed the effect of quetiapine on dyskinesias in a double-blind placebocontrolled cross-over study in 9 patients with PD, receiving 25 mg quetiapine or placebo at night, for 2 weeks, in prerandomized fashion, with a 1-week washout between treatment periods. Patients subsequently went on open-label quetiapine at 50 mg/day for a mean duration of 30 days. During the double-blind phase, dyskinesias remained unmodified with either 25 mg quetiapine or with placebo. On 50 mg/day quetiapine, a slight reduction in dyskinesia severity was observed on a visual analog scale. This improvement was not reflected in the patients’ overall impression of treatment effect. Thus, no antidyskinetic effect was perceived with the low dose (25 mg) of quetiapine, but a possible antidyskinetic effect was described with higher doses. Durif et al. (2004) investigated the efficacy and safety of clozapine in the treatment of LID in 50 patients during a 10-week, double-blind, parallelgroup, placebo-controlled, multicenter trial. Mean clozapine dose was 39.4 4.5 mg/day. The maximal LID score at rest during the levodopa challenge was significantly decreased in the clozapine group. The authors concluded that clozapine is effective in the treatment of LID in severe PD. In another study, Manson et al. (2000) assessed the usefulness of 2.5–7.5 mg/day of olanzapine versus placebo for LID in 10 patients with PD during a 2-week course. There was a 41% dyskinesia reduction in the olanzapine-treated group compared to placebo as measured by objective dyskinesia rating, but it resulted in a significant increment in ‘off’ time as measured by patient diaries (30% versus 2%) and increased parkinsonism. These authors therefore concluded that olanzapine is effective in reducing dyskinesias in PD but, even at a very low dose, it may lead to unacceptable increases in parkinsonism and ‘off’ time. 40.5.1.2.3. Drugs acting on the opioid system The opioid striatal neurons may play a role in the induction of dyskinesias. Samadi et al. (2004) investigated the effect of different doses of the opioid receptor antagonists naloxone and naltrexone on the dyskinetic response to the D1-agonist SKF-82958, the D2-agonist quinpirole and levodopa in MPTP cynomolgus monkeys. They found that conjunct administration of naloxone or naltrexone together with dopaminergic agents led to a significant reduction in the severity of dyskinesias without losing antiparkinsonian efficacy. Carroll et al. (2004) conducted a randomized, double-blind, placebo-controlled cross-over trial to examine the hypothesis that cannabis may have
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a beneficial effect on dyskinesias in PD. Seventeen patients completed the trial and cannabis was well tolerated with no pro- or antiparkinsonian action, but no evidence of a treatment effect on LID as assessed by Unified Parkinson’s Disease Rating Scale (UPDRS) or any secondary outcome measurements. Thus, despite many experimental suggestions, there is no drug currently employed clinically to manipulate the opioid system for the treatment of LID (Manson et al., 2001). 40.5.1.2.4. Glutamatergic antagonists The use of NMDA antagonists in humans has been generally limited because of adverse effects associated with non-selective NMDA receptor blockade. Verhagen Metman et al. (1998b) in a double-blind cross-over study showed that 3 weeks’ treatment with dextrometorphan was able to reduce dyskinesias by 30–40% while maintaining the response to levodopa. In recent years, amantadine has become popular as a possible antidyskinetic drug based on its putative anti-NMDA action (Verhagen Metman et al., 1998a). However, it is worth noticing that there is no definitive evidence indicating such a mechanism of action. Del Dotto et al. (2001) evaluated the effect of a 2-hour intravenous amantadine (200 mg) or placebo infusion against LID in 9 PD patients with motor fluctuations and severely disabling peak-dose dyskinesias. Intravenous amantadine acutely improved LID by 50%, without losing the antiparkinsonian benefit of levodopa in a 5-week, double-blind cross-over trial. In another study Luginger et al. (2000) assessed dyskinetic severity following oral levodopa challenges as well as with self-scoring dyskinesia diaries and found them to be reduced by approximately 50% after amantadine treatment compared with baseline or placebo control. Snow et al. (2000) evaluated the effect of amantadine on LID in a double-blind, placebo-controlled study and found a 24% reduction in the total dyskinesia score. The above clinical data indicate that amantadine is an effective treatment for LID. However, the duration and magnitude of its antidyskinetic effect remain to be established. Thomas et al. (2004) performed a 12-month double-blind study including 40 patients suffering peakdose and diphasic dyskinesias in an attempt to elucidate the duration of the antidyskinetic effect. After 15 days of amantadine treatment, a reduction of 45% in the total dyskinesia scores was detected, but the benefit lasted less than 8 months. Moreover, in a systematic review on the efficacy and safety of amantadine for LID treatment, Crosby et al. (2003) concluded that there was not enough evidence to determine whether amantadine was effective. Our view is that, on an individual basis, amantandine may result in a drastic amelioration of
LID and is therefore worth trying in the absence of contraindications. The antidyskinetic effect is probably exerted at the level of the STN as amantandine failed to control dyskinesias evoked by subthalamotomy in patients who had previously responded markedly well (Merello et al., 2006). Merello et al. (1999b) evaluated the efficacy of memantine (1-amino 3,5-dimethyl-adamantane hydrochloride) on cardinal symptoms of PD, the pharmacological response to levodopa (latency, duration and magnitude) and the induction of dyskinesias. In 12 patients and contrary to recent findings with amantadine, no effect on LID was observed. However, in a recent report by Lokk (2004), memantine was given to 3 PD patients with cognitive impairment and LID and 2 of them benefited with regard to dyskinesia control. Riluzole is an inhibitor of glutamatergic transmission in the central nervous system currently given to patients with lateral amyotrophic sclerosis in an attempt to improve prognosis. Braz et al. (2004) evaluated the effect of riluzole on dyskinesia in 16 patients with PD and found no effect against apomorphineinduced dyskinesias. In general, the high expectations (Chase et al., 2000) that were raised with the potential therapeutic impact of antiglutamatergic drugs for PD have failed to become a reality. 40.5.1.2.5. Drugs acting on the serotoninergic system The serotoninergic system projects quite profusely to the striatum and also to other key BG nuclei (i.e. STN, GPe, GPi) and exerts an inhibitory control on dopamine striatal transmission. Durif et al. (1995) found a 47% improvement in the severity of dyskinesias evoked by apomorphine in 7 patients with PD treated with fluoxetine. There was no reduction in levodopa antiparkinsonian benefit. Buspirone has a complex mechanism of action, which aside from its 5-HT1A properties includes partial dopamine agonism and mild opiate and noradrenergic antagonism (Kleedorfer et al., 1991). Bonifati et al. (1994), in a double-blind, placebo-controlled, cross-over study, found that buspirone (20 mg) significantly lessened the severity of LID in 5 out of 7 patients. Mirtazapine is an a2-antagonist, 5-HT1A agonist and 5-HT2 antagonist, potentially useful for LID. Meco et al. (2003) found in an open-label study including 20 parkinsonian patients that mirtazapine may be effective in reducing LID. 40.5.1.2.6. Noradrenergic drugs The close relationship between the dopaminergic, adrenergic and noradrenergic systems has led to the
LEVODOPA-INDUCED DYSKINESIAS IN PARKINSON’S DISEASE assessment of a possible antidyskinetic effect of a few drugs acting on those systems. Two studies have shown how the a2-adrenoreceptor antagonist idazoxan can significantly reduce LID in MPTP monkeys as well as in patients with advanced PD (Grondin et al., 2000). Rascol et al. (2001) reported improvement of LID without reappearance of parkinsonian symptoms in 18 patients treated with idazoxan. Carpentier et al. (1996) found a significant 40% improvement in dyskinesia scores in PD patients treated with a low dose of propranolol (10–20 mg/day). 40.5.1.2.7. Practical considerations There appear to be many drugs that are capable of reducing the severity of LID. In some occasional patients, the therapeutic impact of any one of the treatments summarized above may be strikingly positive, but in the majority it is limited to mild or short-lasting improvement. Nevertheless, they are generally well tolerated and worth trying in patients in whom other therapeutic measurements cannot be afforded. In our experience, the degree of symptomatic control of LID mainly depends upon the complexity of dyskinesias and severity of ‘off’ periods. This may be schematically summarized as follows: (1) in patients with mild but bothersome peak-dose dyskinesias, readjust the levodopa schedule, and consider adding a dopamine agonist and any one of the drugs discussed above; (2) for patients with severe peak-dose dyskinesias, consider switching treatment to provide continuous dopaminergic stimulation; and (3) patients with severe peak-dose dyskinesias and diphasic dyskinesias probably require surgical treatment. 40.5.1.3. Reversing priming: continuous dopaminergic stimulation Since the introduction of the concept of continuous dopaminergic stimulation in the 1980s (Horowski et al., 1988; Chase et al., 1989; Obeso et al., 1989, 1994), it was realized that constant delivery of dopaminergic drugs was associated with a reduction in the severity of LID. Over the past decade, further evidence has accumulated to support the notion that continuous stimulation of dopamine receptors may even reverse part of the changes induced by chronic pulsatile levodopa administration. The initial pivotal study in this regard was conducted by Mouradian et al. (1990), who continuously delivered levodopa intravenously for 7–12 days to a small group (n ¼ 12) of patients with severe PD. They found a progressive attenuation of LID and amelioration of the ‘on–off’ fluctuations. More recently, 24 patients with motor fluctuations and dyskinesia were randomized in a cross-over design to compare conventional oral treatments and intraduodenal
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infusion of a levodopa/carbidopa gel (Nyholm et al., 2005). The time spent in the ‘on’ state was increased 81–100% by infusion therapy with no increase in dyskinesias. This was associated with improvement in quality-of-life scores. This approach is now commercially available and may be a valid option for some patients, despite the obvious practical limitations. Similarly, continuous delivery of dopamine agonists by the subcutaneous route, such as lisuride and apomorphine, is associated with a reduction in LID. The majority of trials used infusions during the daytime but stopped at nighttime to reduce the risk of severe psychiatric complications. Manson et al. (2002) reviewed their experience in 64 patients treated with apomorphine infusions. Forty-five patients were successfully converted to monotherapy and discontinued all other dopaminergic drugs during the daytime treatment period with apomorphine. Patients were followed for a mean of 33.8 months, with a mean maintenance dose of apomorphine of 98 mg/day. Dyskinesias were reduced by 64% in the monotherapy group compared to 30% in those on polytherapy. These results confirmed that subcutaneous apomorphine monotherapy can reset peak-dose dyskinesia threshold in levodopa-treated patients, while further reducing off-period disability. Katzenschlager et al. (2005) prospectively assessed the antidyskinetic effect of continuous subcutaneous apomorphine using subjective and objective measures and the response to a levodopa challenge. At 6 months, the mean levodopa dose had been reduced by 55% and the daily ‘off’ time in patients’ diaries was reduced by 38%. Levodopa challenge showed a reduction of 40–44% in the dyskinesia scores. Patients’ self-assessment scores reflected these significant changes. The improvement correlated with a reduction in oral drug therapy and with final apomorphine dose. This prospective study confirmed a marked reduction in dyskinesia with continuous subcutaneous apomorphine therapy, paralleled by reduced dyskinesias during dopaminergic challenge tests. Similarly, Stocchi et al. (2002) compared the long-term incidence of dyskinesias in patients treated with subcutaneous infusion of lisuride (plus supplementary oral levodopa as needed) versus patients treated with standard levodopa orally and showed that patients receiving lisuride infusions experienced a significant reduction in the incidence of both motor fluctuations and dyskinesia, compared with patients receiving standard dopaminergic therapies. Benefits persisted for the 4-year duration of the study. This study also confirmed earlier results indicating that continuous lisuride infusion can be fairly well tolerated and beneficial for patients’ motor complications (Obeso et al., 1986), provided they have not previously
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developed severe psychiatric complications (Vaamonde et al., 1991). Overall, these results support the concept that replacement of short-acting oral antiparkinsonian medication with drugs capable of providing a more continuous dopamine receptor stimulation may at least partially avoid or reverse the sensitization process believed to mediate the development of LID. In theory, therefore, therapy with infusions capable of providing continuous dopaminergic stimulation might be the pharmacological treatment of choice for advanced PD patients. Nevertheless, the degree of control of LID achieved with infusions is not complete in many patients. Pharmacological tolerance appears in a large proportion after some time on treatment. It occurs more readily the more severe the underlying disease is, leading to ‘off’ episodes or exacerbation of diphasic dyskinesias. The latter may cause a very troublesome dyskinetic status (Vaamonde et al., 1991). Thus, surgery may still be the only and best therapeutic option for a proportion of patients with severe LID. 40.5.2. Surgery Early surgical procedures to treat hyperkinesias, such as choreoathetosis or hemiballism, were aimed to interrupt the peripheral and spinal motor pathways, the cerebral peduncles and cerebral cortex with subpial extirpations of motor areas. Subsequently, during the early 1950s, the GPi became the target of choice for the surgical treatment of any movement disorder, whether bradykinetic or hyperkinetic. The introduction of levodopa modified the need for the surgical treatment of PD. For many years thalamotomy was the only surgical procedure performed in patients with PD. Failure to control appropriately the tremor or levodopa-induced side-effects were the principal reasons for elective surgery during the 1970s and up to the early 1990s. In the last decade, there has been a revitalization of surgery for PD in the light of the newer pathophysiological concepts (DeLong 1990; Obeso et al., 1997), described in section 40.4 above. 40.5.2.1. Surgery of the globus pallidum Unilateral pallidotomy induces a significant alleviation of the cardinal motor features of PD in the side contralateral to the surgery, reducing the severity of disability in the ‘off’ motor state and the UPDRS motor score. Alkhani and Lozano (2001) encountered 1735 pallidotomies in 85 papers published between1992 and 1999 from 40 different centers. The UPDRS motor score improved by about 40–45% at 6 and 12 months after pallidotomy, the benefit being mainly contralateral to the lesion (Alkhani and Lozano, 2001).
Motor function and UPDRS motor score are not improved in the ‘on’ medication condition following pallidotomy (Bronstein et al., 1999; Alkhani and Lozano, 2001). Pallidotomy conveys a marked and permanent benefit against LID. The lesion practically abolishes peak-dose dyskinesias, diphasic dyskinesias and ‘off’-period dystonia on the contralateral side to the lesion. This effect is permanent, in our experience lasting 10 years postoperatively, and has been shown to remain stable between 1 and 4 years after surgery by controlled studies (Baron et al., 2000). A beneficial effect in the ipsilateral side of the surgery has also been reported but became not significant after 1–2 years (Lang et al., 1997; Baron et al., 2000). The meta-analysis of Alkhani and Lozano (2001) found 71 patients properly assessed 1 year after pallidotomy. In such a selected patient population, LID were reduced by 73.5% and 86.4% at 6 months and 12 months respectively postsurgery. Bilateral pallidotomy is, despite its potentially larger antiparkinsonian effect, a procedure with high risk of speech (Favre et al., 2000), gait and cognitive deterioration (Intemann et al., 2001; Merello et al., 2001). Thus, it is not particularly indicated nowadays when deep brain stimulation (DBS) is available throughout the world. DBS of the GPi (GPi DBS) has a significant antidyskinetic effect, about 70–80% reduction, which is associated with improvement in activities of daily living (ADL) score. The effect of GPi DBS against LID appears stable after several years in spite of maintaining levodopa daily dosage unchanged. A recent study showed a reduction in LID severity of 76% (P < 0.0001) with no change in the levodopa dose equivalents in 20 patients with severe PD followed by 3–4 years in the Cooperative Study of DBS for advanced PD (Rodriguez-Oroz et al., 2005). Volkmann et al. (2004) followed 11 patients for 5 years after bilateral GPi DBS and reported that LID remained significantly reduced (58% at 1 year, 63% at 3 and 64% at 5 years) in parallel with a worsening in the degree of benefit in the UPDRS motor scale (56% at 1 year, 43% at 3 and 24% improvement at 5 years). This study therefore showed a differentiated response, being therapeutically very positive against LID but showing no sustained benefit against the parkinsonian condition, similar to what occurs with pallidotomy (Volkmann et al., 2004). Two studies described that GPi DBS may have both a prodyskinetic and an antidyskinetic effect depending upon electrode placement, suggesting two different targets for parkinsonism and LID in the same anatomical structure (Bejjani et al., 1997; Krack et al., 1998). The dorsal contacts of the GPi conveyed the prodyskinetic effect whereas the antidyskinetic action was due to activation of the ventral contacts. Yelnik et al.,
LEVODOPA-INDUCED DYSKINESIAS IN PARKINSON’S DISEASE (2003) described that dyskinesias induced by stimulation in the GPi may be correlated with the placement of the dorsal contacts within or near the GPe. In monkeys, inactivation of the motor region of the GPe (by local administration of bicuculline) is associated with choreatic movements (Crossman et al., 1988; Grabli et al., 2004). It is possible therefore that activation of GABAergic fibers from the GPe or blockade of the GPe itself from dorsal contacts is responsible for the reported induction of dyskinesias. Interestingly, we never encountered this problem with GPi DBS (Obeso et al., 2001) and it has not been reported after longterm follow-up of 20 patients from eight centers (Rodriguez-Oroz et al., 2005). 40.5.2.2. Surgery of the subthalamic nucleus Nowadays, bilateral stimulation of the STN (STN DBS) is the surgical procedure most often used for
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PD by its striking capacity to reduce ‘off’ medication severity and disability and because it is usually associated with a 30–60% reduction of levodopa daily dose, unlike pallidal surgery. The experience regarding the effect of STN DBS on LID is relatively homogeneous in different studies. Most surgical groups have reported a significant antidyskinetic effect, closely correlated with reduction in daily levodopa dose (Table 40.1) (Krack et al., 2003; Moro et al., 1999; Molinuevo et al., 2000; Obeso et al., 2001; Simuni et al., 2002). Subthalamic stimulation appears to improve the whole spectrum of LID, namely peak dose, diphasic dyskinesias and off-dystonia (Krack et al., 1999). Two independent studies summing together 98 patients reported a significant reduction of LID severity after 4–5 years of follow-up (Krack et al., 2003; Rodriguez-Oroz et al., 2005) (Table 40.1). Levodopa was reduced from a mean of 1309 to 859
Table 40.1 Efficacy of bilateral deep brain stimulation (DBS) of the globus pallidum pars interna (GPi) and the subthalamic nucleus (STN) against levodopa-induced dyskinesias in Parkinson’s disease: summary of the literature
Reference
Patients
Surgery
Dyskinesia reduction
Levodopa reduction
Ghika et al. (1998) Houeto et al. (2000) DBSPDSG
6 23 36 96 16 (6 unilateral) 16
GPi DBS STN DBS GPi DBS STN DBS
P < 0.01 77% (P < 0.001) P < 0.01 P < 0.001
Unchanged 61% (P < 0.001) Unchanged (P < 0.001)
6 months 6 months 6 months
GPi DBS STN DBS
Unchanged 48% (P < 0.002)
12 months 12 months
12 25 30 6 12
STN STN STN STN STN
71% Duration (P < 0.002) Disability (P < 0.01) 64% 50% P < 0.001 67% (P < 0.003) 83% (P < 0.05)
55% 50% 22% 51% (P < 0.03) 70% (P < 0.05)
12 12 12 12 12
25 48
STN DBS STN DBS
46.4% (P < 0.007) 85%
38% (P < 0.001) 67.8%
24 months 24 months
11
STN DBS
53% (P < 0.01)
50% (P < 0.01)
4 years
20 49
GPi DBS STN DBS
Unchanged (P < 0.001)
4 years
Visser-Vanderwalle et al. (2003)
26 unilateral
GPi DBS
Volkman et al. (2004) Krack et al. (2003)
11 49
GPi DBS STN DBS
76% (P < 0.0001) 59% (P < 0001) 75% (P < 0.001)3 months 28% (P < 0.03)15 months 64% (P < 0.05) Duration (P < 0.001) Disability (P < 0.001)
Loher et al. (2002) Patel et al. (2003) Simuni et al. (2002) Hamel et al. (2003) Ford et al. (2004) Burchiel et al. (1999) Bejjani et al. (2000) Kleiner-Fisman et al. (2003) Herzog et al. (2003) Rodriguez-Oroz et al. (2005) Rodriguez-Oroz et al. (2005)
DBS DBS DBS DBS DBS
Follow-up
months months months months months
53% increased
4 years and 3 months
Unchanged 74% (P < 0.001)
5 years 5 years
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mg/day (P < 0.001) and in 6 patients levodopa was stopped altogether (Rodriguez-Oroz et al., 2005). Hamani et al. (2005) in a recent survey encountered 38 studies from 34 neurosurgical centers with 737 patients involved. They found reduction of LID (UPDRS dyskinesias’ scores) by 73% and 94% at 6 and 12 months in the on-stimulation ‘on’ medication compared with preoperative ‘on’ medication scores. For a large majority of authors the LID response to STN DBS is directly related to a reduction of dopaminergic drugs (Molinuevo et al., 2000; Moro et al., 2002; Vingerhoets et al., 2002). Recently, a study separated patients into two groups after STN DBS according to the possibility of reducing levodopa. The group that required medication after surgery had a moderate alleviation in LID (47% reduction) and the group that did not receive levodopa after surgery had a dramatic reduction in LID (90%; P < 0.003) (Vingerhoets et al., 2002). On the other hand, some authors have suggested that the antidyskinetic response after STN DBS could be due to a direct effect of continuous high-frequency electrical stimulation in the target (Krack et al., 1999). Another possible mechanism could be that stimulation of fibers running above the dorsal border of the STN (fasciculus lenticularis and zona incerta) would block impulse transmission in the GPi-thalamic projection. This would be in agreement with the findings that the STN target for stimulation is dorsal to the upper border of the nucleus and therefore the electrical current may spread to fibers in the fasciculus lenticularis passing through the Forel field. In such instances, the mechanism would be similar to a pallidotomy-like effect. Lesion of the STN, i.e. subthalamotomy, as a surgical approach for PD was first considered in the early 1990s (Guridi et al., 1993). This relied on the striking improvement induced in the MPTP monkey model by unilateral ablation of the STN. However, the fear of inducing hemiballism moved attention towards pallidotomy, despite the fact that there was no experimental basis, because of the important surgical experience accumulated in patients by Laitinen et al. (1992). Currently, subthalamotomy is performed by only a few teams, around the world. Probably, this is due to the greater methodological difficulty, in comparison with DBS surgery, in establishing a lesion large enough to have a permanent and marked benefit without side-effects. The largest published experience corresponds to the Centro Internacional Restauracio´n Neurolo´gica (CIREN) in La Habana (Cuba) as part of an international collaborative effort (Alvarez et al., 2001, 2005). Subthalamotomy is associated with a significant and maintained improvement in all cardinal features
of PD on the side contralateral to the surgery and on axial features up to 7 years postoperatively (Alvarez et al., 2001, 2005). Immediately after surgery, the great majority of patients exhibit dyskinesias on the operated side but these are transient and self-resolving in most instances, mimicking what happened after pallidotomy (Merello et al., 1997). The incidence of symptomatic, i.e. severe, HCB secondary to lesion of the STN is not as large as expected by classic neurosurgical concepts. A review of the literature looking for HCB in PD secondary to mistargeting during thalamotomy in the pre-levodopa era indicated a low incidence of cases (Guridi and Obeso, 2001). In fact, we have observed symptomatic HCB in 7% of 170 consecutive patients with unilateral STN lesions operated in the CIREN. In such instances, pharmacological management of the HCB is not simple. Stopping all antiparkinsonian drugs does not immediately abolish the dyskinesias and may result in worsening of the non-operated side (Su et al., 2002; Alvarez et al., 2005). Amantandine is not useful either, even in patients in whom this drug has been previously useful for LID (Merello et al., 2005). Pallidotomy is higly efficacious in eliminating the HCB in those few patients in whom the dyskinesia persists and is disabling. This corroborates the principle established in the monkey by Carpenter et al. (1950) and recently applied in patients with HCB of vascular origin (Vitek et al., 1999). In our experience, pallidotomy abolishes the HCB secondary to subthalamotomy without aggravation of parkinsonian features or indeed any other neurological complication. Experience with bilateral, simultaneous subthalamotomy is much more limited but it seems that HCB may be more frequent with such an approach, which requires further evaluation before being recommended for routine application (Alvarez et al., 2005). The factors governing the onset and persistence of severe HCB after subthalamotomy are not yet well defined. Extension of the lesion dorsally to interrupt the fasciculus lenticularis, producing a pallidotomylike effect, has been suggested as an explanation of the low incidence of HCB after a lesion of the STN (Lozano, 2001; Guridi and Obeso, 2001; Chen et al., 2002). However, almost all instances of severe HCB have been associated with dorsal lesions, usually large enough to extend well within the zona incerta, which should have also lesioned the pallidothalamic projection. Guridi and Obeso (2001) suggested, based on their experience with lesions of the STN in MPTP monkeys and the organization of the BG, that the dyskinetic threshold is increased in the parkinsonian state, thus reducing the probability of developing severe HCB after interrupting the STN efferent activity.
LEVODOPA-INDUCED DYSKINESIAS IN PARKINSON’S DISEASE The striking antiparkinsonian effect of subthalamotomy per se or the presence of HCB has resulted in a drastic reduction in levodopa daily dose in most reported studies, making assessment of the impact on LID almost impossible. However, Alvarez et al. (2001) kept the levodopa dose unchanged up to a year after unilateral subthalamotomy and found a significant reduction in LID. Those patients nevertheless were chosen for surgery precisely because of the absence of severe LID preoperatively. Su et al. (2002) also reported that LID were reduced by 75% at 18 months postoperatively in 3 out of 4 patients who suffered severe bilateral LID before surgery, even though the levodopa dose was unchanged during the initial 3 months. Recently, Alvarez et al. (2005) reported the effects of bilateral subthalamotomy in 18 patients, 7 staged lesions and 11 simultaneous surgery, followed for a minimum period of 3 years and up to 7 years. In both groups, the reduction in LID was significant after subthalamotomy together with a reduction in daily levodopa dose. 40.5.2.3. Thalamic surgery Hassler and Riechert in 1954 pioneered thalamotomy to improve tremor control in PD. The optimal region within the thalamus was later defined by Ohye et al. (1976) as the ventralis intermedius (Vim) and became the established surgical target for tremor up to the 1970s, when levodopa was introduced as the treatment of choice for PD. Subsequently, a few papers described a possible preventive effect on the development of LID in patients with a prior thalamotomy (Narabayashi et al., 1984; Derome et al., 1986; Tasker, 1990) or the successful amelioration of LID after surgery (Kelly and Gillingham, 1980; Fox et al., 1991; Jankovic et al., 1995). However, there is no consistent report in the literature truly assessing the impact of Vim-thalamotomy against LID, with the exception of the work of Narabayashi et al. (1984). This report described that patients with surgical lesions in Voa/Vop-thalamotomy (ventralis oralis anterior and posterior, which are the pallidal receiving territory in the thalamus) prior to the introduction of levodopa did not develop LID. On the other hand, patients with Vim-thalamotomy for tremor developed dyskinesias when levodopa was introduced for PD (Narabayashi et al., 1984). They concluded that the GPi-Voa/Vop pathway mediated LID, in agreement with Hassler’s previous concept about the origin of hyperkinesias (Hassler, 1978). Page et al. (1993) reported similar results in MPTP monkeys with LID in whom a lesion in the pallidal territory of the thalamus abolished dyskinesias but lesion of the nigral or cerebellar terminal territories had no benefit.
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Benabid in Grenoble introduced DBS for PD for the treatment of tremor instead of thalamotomy (Benabid et al., 1989, 1996). Generally, it is agreed that the effect of Vim-DBS on LID is minor or nil. Limousin et al. (1999) reported 73 patients enrolled in a multicenter cooperative study for the treatment of tremor and described that LID were slightly, but not significantly decreased by DBS at 12 months postoperatively. Similarly, Tasker et al. (1997) found no significant difference between Vim-thalamotomy and Vim-DBS regarding LID. On the other hand, the Lille group described in 12 parkinsonian patients LID abolition after Vim-DBS. They suggested that electrodes placed near the centromedian-parafascicular nucleus of the thalamus may have a more marked effect against LID, but this has not been further substantiated (Caparros-Lefebre et al., 1999). 40.5.2.4. Mechanism of action of surgery against LID Hassler in Freiburg and a few years later Cooper in New York considered that hyperkinesias were associated with uncontrolled discharges in the GPi, leading to excessive impulses in the pallidal projection to the Voa of the thalamus (Hassler et al., 1960; Cooper, 1969). Hassler reported that hyperkinesias of various etiologies and in particular HCB following surgery for PD could be abolished by a lesion placed in the GPi, by coagulation of the Forel H2 field or by an extensive lesion performed in the Voa/Vop of the thalamus. This approach was supported by earlier work in the monkey performed by Mettler’s group (Whittier and Mettler, 1949; Carpenter et al., 1950). They described the induction of HCB by destruction of the STN (at least 20% of its volume) and how a second lesion placed in the globus pallidum or the lenticular fasciculus abolished the choreoballic movements (Carpenter et al., 1950). According to current pathophysiological concepts of PD, surgical destruction or inactivation of pallidal neuronal activity reduces excessive inhibitory output to the thalamus (DeLong, 1990; Obeso et al., 1997). Pallidotomy has been shown by PET, functional magnetic resonance imaging and physiological studies to restore thalamocortical excitability functionally (Bakay et al., 1992; Eidelberg et al., 1996; Samuel et al., 1997). On the other hand, reduction of GPi output activity is the essential physiological hallmark of LID (Filion and Tremblay, 1991; Papa et al., 1999; Boraud et al., 2001), which is superficially in contradiction with the profound antidyskinetic effect of pallidotomy. In other words, according to the classic pathophysiological model of the BG, pallidotomy
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should induce a worsening rather than amelioration of LID. Recent findings may shed some light on this seemingly paradoxical finding. In the rat with unilateral lesion of the nigrostriatal pathway by 6-OHDA, LID are associated with a reduction in neuronal firing rate in the SNpr, the main BG output in rodents. Simultaneously, the same animals exhibited a peak in the theta/alpha band (4–10 Hz) recorded from the SNpr by LFPs. Thus, reduced firing rate of single neuronal activity and oscillatory activity in the theta band in the SNpr coincided with excessive striatal dopamine release (Meissner et al., 2006). Moreover, recording of LFP from the GPi and STN of PD patients who were implanted with electrodes for DBS have shown that LID are associated with a specific oscillatory activity at around 4–8 Hz (Brown, 2003; Foffani et al., 2005; Alonso-Frech et al., 2006). These two complementary experimental and clinical studies strongly suggest that LID coincides with an abnormally slow synchronization of neuronal activity in the output of the BG, which is the code or signal conveyed to the cortex via the thalamus. Indeed, neuroimaging studies using PET and SPECT data showed increased activity and regional blood flow in the supplementary motor area, premotor area and ipsilateral and contralateral primary motor areas (Rascol et al., 1998). Accordingly, pallidotomy and Voa/Vop-thalamotomy would remove the effect of slow oscillatory activity on the thalamocortical motor projection, stopping the delivery of ‘wrong signals’ or ‘noisy patterns’ to the cortex. Whether GPi-DBS acts by a similar mechanism is unknown at present. It seems likely that GPi-DBS will interfere with the theta rhythm associated with LID, either by blocking GPi neuronal activity or by driving it into a different (i.e. non-prodyskinetic) oscillatory activity. The improvement of LID in patients treated with STN surgery may have a more complex interpretation. Reduction of levodopa daily dose is not the sole explanation, as a proportion of patients treated with STN surgery clearly had an improvement in LID despite maintaining levodopa dose unchanged. A pallidotomy-like effect, by dorsal extension of the lesion or the electrical field, to block pallidothalamic transmission does not seem to account for all observations. We may suggest here that blockade of STN activity may have by itself an anti-LID effect. This could take place through two principal mechanisms:
the BG through its dense glutamatergic innervation of the GPi, GPe and SNpr and, to a lesser extent, of the substantia nigra pars compacta and striatum. It could be that a given subregion of the STN is required to maintain synchrony in the BG at 4–8 Hz. Consequently, blockade of the STN removes an essential component of the network engaged in the generation of the abnormal signals, leading to LID. In this regard, it is noteworthy that LID in the MPTP monkey model is associated with a significant increase in 2-deoxyglucose uptake in the ventromedial region of the STN (Mitchell et al., 1992; Guigoni et al., 2005b). 2. STN blockade functionally restores the BG, making it relatively insensible to the prodyskinetic effects of levodopa. Reduction of STN efferent activity, immediately after a lesion or at the beginning of DBS treatment, may be associated with dyskinesias because of drastic reduction in excitatory drive on to the GPi. However, this gives way over the following weeks to a functional restoration of output (Hirsch et al., 2000). Thus, molecular markers such as mRNA expression of cytocrome oxidase and succinate dehydrogenase (as an index of cellular activation) or mRNA expression of GAD become reduced or even normalized in the output BG after subthalamotomoty in the rat and monkey (Guridi et al., 1996; Blandini et al., 1997). Moreover, subthalamotomy reverses the increase in corticostriatal glutamatergic activity and increased GAD mRNA expression in entopeduncular nucleus (GPi equivalent in the rat) associated with dopamine depletion, reverses the abnormalities in striatal excitatory synaptic transmission (Delfs et al., 1995; Touchon et al., 2004; Centonze et al., 2005) and ameliorates the ‘wearing-off’ response (Marin et al., 2004). It appears therefore that STN surgery leads to functional normalization of the BG output nuclei. This in turn could reduce the sensitivity of the BG network to pulsatile dopaminergic stimulation with standard levodopa (Obeso et al., 2004), thus increasing the threshold for dyskinesias. We envisage that STN blockade stabilizes the BG network, removing the generation of abnormal signals in the parkinsonian ‘off’ state and in response to levodopa.
40.6. Conclusions 1. The abnormal rhythms and oscillation patterns associated with LID represent neuronal firing synchrony in various nuclei of the BG and possibly elsewhere. The STN is the major driving force of
The origin of LID in PD is mainly related to the impact on striatal physiology of nigrostriatal dopaminergic depletion and discontinuous levodopa replacement ther-
LEVODOPA-INDUCED DYSKINESIAS IN PARKINSON’S DISEASE apy. These combine to induce abnormal expression of dopamine-receptor signaling and neuropeptides, leading to deranged corticostriatal plasticity. Avoiding pulsatile dopaminergic stimulation (i.e. high dose of standard levodopa administration) has already resulted in a reduction in the incidence and severity of LID in the general PD population. Treatment of severe LID requires continuous dopaminergic stimulation by means of infusions. Nevertheless, it is worth trying simpler and more conventional treatments as a first approach. Pallidotomy is radically useful against LID but nowadays rarely indicated because of the limited unilateral effect. DBS of the GPi or the STN is also highly efficacious in the treatment of LID, perhaps through different mechanisms than simple blockade of BG output. In patients with very severe and complex LID, GPi-DBS may be a safer indication, even when pallidal surgery is not associated with a significant reduction in daily levodopa intake. Advances in neuroprotection and better means of replacing the dopaminergic striatal deficit should lead to a gradual reduction of LID in PD in the near future. Eventually, LID will become an obsolete neurological complication.
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Handbook of Clinical Neurology, Vol. 84 (3rd series) Parkinson’s disease and related disorders, Part II W. C. Koller, E. Melamed, Editors # 2007 Elsevier B. V. All rights reserved
Chapter 41
Treatment-induced mental changes in Parkinson’s disease KELVIN L. CHOU AND JOSEPH H. FRIEDMAN* Department of Clinical Neurosciences, Brown University Medical School and NeuroHealth Parkinson’s Disease and Movement Disorders Center, Warwick, RI, USA
41.1. Introduction Although Parkinson’s disease (PD) is defined by the presence of its motor features alone, it has become increasingly clear that PD is not just a neurological disorder, but a neurobehavioral syndrome with welldocumented mood, cognitive and behavioral symptoms. Unfortunately, many of the behavioral abnormalities associated with PD are due to or exacerbated by the medications used to treat the myriad symptoms of the disease. In addition, evidence is accumulating to show that surgical therapies may worsen or even cause behavioral or cognitive decline in patients with PD. Because these mental changes may occur late in the course of the illness, long after antiparkinsonian medications have been started, it can be difficult to determine whether these changes are treatment-induced, treatment-exacerbated or intrinsic to the disease process. Further complicating the problem is the issue of dementia with Lewy bodies (DLB) and our limited understanding of the dementia syndrome that often occurs in PD (see Ch. 60). Whereas the presence of visual hallucinations in an untreated state is one of the clinical hallmarks of DLB, visual hallucinations in DLB are indistinguishable from drug-induced hallucinosis in PD. Moreover, DLB is diagnosed clinically when the dementia occurs before or soon after the onset of parkinsonism (McKeith et al., 1996), yet it has become clear that the dementing aspect may develop years later (Apaydin et al., 2002). Finally, all of the dementing disorders, including the dementia of PD and DLB, are associated with a variety of psychotic and other behavioral symptoms (Cahn-Weiner et al., 2002). These overlapping clinical symptoms make it challenging to distinguish between the different disorders.
This chapter provides an overview of the various adverse behavioral and cognitive changes seen as a result of the pharmacological and surgical treatment of PD. The phenomenology and treatment of druginduced psychosis will be discussed in detail, and mood fluctuations, as well as repetitive and compulsive behaviors due to dopaminergic medications, will be reviewed. Recent literature highlighting the negative behavioral and cognitive changes from ablative surgeries and deep brain stimulation (DBS) for PD will also be covered.
41.2. Mental changes due to pharmacologic treatment of Parkinson’s disease 41.2.1. Drug-induced psychosis Although psychosis used to be defined as a major mental disorder in which reality testing is impaired, the current definition describes psychosis as a disorder characterized by hallucinations, delusions or disorganized thinking (American Psychiatric Association, 1994). Hallucinations are perceptions without any basis in reality, i.e. seeing, hearing, smelling, tasting or feeling things that are not present. These need to be distinguished from illusions, which are distorted perceptions, such as seeing an animal in a shadow, mistaking a distant tree for a person, seeing faces in flowers or misperceiving a motor sound for a voice. A delusion is a false and irrational belief that has no foundation. Common examples include believing that strangers are living in or moving objects around the house, thinking that family members have been replaced by imposters and believing that one is being investigated by the Federal Bureau of Investigation.
*Correspondence to: Joseph H. Friedman, NeuroHealth Parkinson’s Disease and Movement Disorders Center, 227 Centerville Road, Warwick, RI 02886, USA. E-mail:
[email protected], Tel: þ1-401-732-3332, Fax: þ1-401-737-3623.
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Psychosis is not a feature of untreated PD. Whereas visual hallucinations are typical of untreated DLB and delusions may occur in demented PD patients who are not taking medication, the vast majority of PD patients who develop psychotic symptoms do so on PD medications and return to their non-psychotic baseline if the PD medications are discontinued (Kofman, 1984; Friedman, 1985). Psychosis affects 5–10% of drug-treated PD patients (Dewey and O’Suilleabhain, 2000). There are three explanations for the occurrence of psychosis in this population. Most commonly, the medications themselves are responsible. However, many psychoses also undoubtedly occur because of the presence of dementia, whether due to PD dementia, DLB or some other pathology (see Ch. 60). Additionally, a tiny percentage of patients have a premorbid primary psychosis, such as schizophrenia, and later develop PD. The importance of recognizing and treating psychosis in PD is illustrated by studies which have shown that psychosis, not motor dysfunction, is the single greatest precipitant for nursing-home placement in PD patients (Goetz and Stebbins, 1993; Aarsland et al., 2000). As might be deduced from this observation, the single greatest stress for care-takers is also psychosis (Aarsland et al., 1999). In addition, the appearance of psychosis markedly increases the risk of mortality (Goetz and Stebbins, 1995; Factor et al., 2003). In one double-blind, placebo-controlled treatment trial of psychosis in PD, 10% of the subjects died during or shortly after completing a 3-month trial (Parkinson Study Group, 1999). In another, 5% of the subjects died (Pollak et al., 2004). The clinical scenario for psychosis in PD is fairly stereotypic and can be divided into two major categories: psychosis with a clear sensorium and psychosis with a clouded sensorium. In both conditions patients typically develop hallucinations. The latter condition is often termed an ‘encephalopathy’ by neurologists and a ‘delirium’ by psychiatrists. 41.2.1.1. Psychosis with a clear sensorium These patients are much more like the primary psychiatric patient in that they will have a normal attention span, memory and cognition. The psychosis is manifest primarily by hallucinations and, to a lesser extent, by delusions, which are generally of a paranoid nature. The most common delusion in a descriptive analysis of two double-blind, placebo-controlled antipsychotic trials (Table 41.1) was stealing (Friedman et al., 2002). However, not all patients have delusions. When the hallucinations are so severe that they are believed to be real, then the patient is considered psychotic. At this point, food may be set out for the
Table 41.1 Types of delusions in 160 Parkinson’s disease patients with drug-induced psychosis Type of delusion
Number of patients
Stealing Not my house Abandonment Spouse imposter Infidelity Other
53 46 41 32 26 38 paranoid þ 21 non-paranoid
imagined guests and water and food bowls are placed for dog and cat visitors. The police may be called to catch ‘burglars’. The phenomenology of the delusions overlaps with those seen in other dementing illnesses (Cahn-Weiner et al., 2002), as assessed in the Neuropsychiatric Inventory (Cummings, 1997). Family members or other people may be stealing money or discussing things about the patient, strangers may be living in the house, patients may accuse the spouse of being an imposter, trips are supposedly being taken without the patient and nursing-home placement is planned – none of which is true. Another common delusion is the accusation of spousal infidelity, which affects both men and women and is even more difficult to manage. 41.2.1.2. Psychosis with an impaired sensorium or dementia Unlike psychosis in patients with a clear sensorium, these patients are delirious or demented and, as a result, manifest psychotic features. Delirious and demented patients with psychosis do less well, in all respects. They are less responsive to and less tolerant of antipsychotic drugs. The common antipsychotics used in managing PD patients with psychosis, clozapine and quetiapine, are sedating. Whereas this side-effect is beneficial in helping the patient sleep at night, it may increase the confusion that occurs when the patient awakens during the night, as well as produce a ‘hangover’ state in the morning. In a demented or delirious patient, this increased daytime somnolence contributes to the delirium. In some cases, we believe this worsened sleepiness may also blunt the response to the anti-PD medications, resulting in worsened motor function. Since both drugs may also cause or worsen orthostatic hypotension, precautions to prevent fainting, especially after lying supine at night, must be maintained. 41.2.1.3. Hallucinations Hallucinations are not part of the untreated state of idiopathic PD but were described with postencephalitic
TREATMENT-INDUCED MENTAL CHANGES IN PARKINSON’S DISEASE parkinsonism (de Ajuriaguerra, 1972) and constitute a cardinal feature of untreated DLB (McKeith et al., 1996). In terms of frequency, visual hallucinations are most commonly reported (Fenelon et al., 2000; Holroyd et al., 2001). We analyzed baseline data regarding hallucinations (Table 41.2) on 160 subjects from two identical antipsychotic studies performed simultaneously in Europe and the USA (Friedman et al., 2002). DLB patients were excluded, but 58 patients were demented (defined as Mini-Mental State Examination (MMSE) < 24). Visual hallucinations were the most prevalent, followed by auditory, olfactory and then tactile hallucinations. These data were from subjects enrolled in double-blind placebo-controlled trials and are therefore not representative of the general PD population, but are probably representative of mild to moderately psychotic PD patients with drug-induced psychosis. There are marked differences between the hallucinations encountered in treated PD and those reported with primary psychiatric disorders such as schizophrenia (Table 41.3). Primary psychiatric hallucinations are usually auditory and ego-syntonic, whereas druginduced hallucinations in PD are generally visual and without emotional content. This is true even when the hallucinated image should have some emotional content, such as a deceased spouse, a deceased pet or a long-unseen loved one. In PD, most patients recognize that the hallucinations are not real, but in primary Table 41.2 Types of hallucinations in 160 Parkinson’s disease patients with drug-induced psychosis Type of hallucination
No. of patients
Visual Auditory Olfactory
155 76 25
Table 41.3 Differences in the hallucinations of schizophrenia and Parkinson’s disease Schizophrenia
Drug-induced Parkinson’s disease
Auditory Poor insight Demeaning/nasty Present for long periods Ego-syntonic Interact with patient
Visual Preserved insight Benign Usually under 5 minutes Unrelated to emotional state Ignore patient
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psychotic conditions, they are perceived as real. Auditory hallucinations frequently make demeaning comments in schizophrenia whereas the drug-induced PD hallucinations are not bothersome and may even be entertaining. Visual hallucinations occur in 9–44% of drugtreated patients, depending on the survey (Meco et al., 1990; Haeske-Derwick, 1995; Sanchez-Ramos et al., 1996; Graham et al., 1997; McDowell and Harris, 1997; Fenelon et al., 2000; Barnes and David, 2001; Holroyd et al., 2001). The hallucinations may occur at any time and with any type of lighting. Fenelon and colleagues (2000) included the term ‘presence’ hallucinations to denote ‘the vivid sensation of the presence of somebody either somewhere in the room or . . . behind him’. This ‘presence’ was usually that of a person, but occasionally was an animal and, in one case, the patient felt a ‘guardian angel’. They also described ‘passage’ hallucinations, which were brief visions that were seen in the periphery of the visual field. These so-called minor hallucinations occurred slightly more frequently than formed visual hallucinations, which were usually of non-threatening people, animals or objects. The hallucinations usually last under 5 minutes and many last for seconds only. They usually occur a few times a week, but are rarely omnipresent. The hallucinations may look clear and real or hazy and out of focus. Occasional patients will report using their spectacles to see the hallucinations more clearly. They may be in color or black and white. Sometimes the hallucinations are in the house, but frequently are outdoors, i.e. workers digging up the garden, checking the telephone lines or playing in the street. One of the most interesting aspects of the hallucinations is their consistency. A patient who hallucinates children wearing ‘funny clothes’ tends to see the same children wearing the same clothing each time, often sitting in the same chairs in the house doing the same things. This type of stereotyped hallucination is therefore quite different from a dream. The hallucinated figures typically ignore the patient but may talk or gesture among themselves without sound. The hallucinations may get up and walk out of the door, but the closing door makes no noise. Less frequently, the hallucination may be inanimate, like a statue or plant. Visual hallucinations are more frequent in the evening but may occur during the day as well. Some patients only see hallucinations in the light. The hallucinations may be Lilliputian (i.e. small people living in a houseplant) or of normal size. Giant people are generally not part of the phenomenology, although enlarged animals, like large rats or cats, may be.
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Auditory hallucinations, on the other hand, are usually quite different from the visual. Auditory hallucinations occur primarily in people who already have visual hallucinations (Inzelberg et al., 1998). In these cases, the visual hallucinations may talk to the patient and carry on interactive conversations. When auditory hallucinations occur without visual hallucinations, the sounds tend to be indistinct, such as party noises coming from another room or voices talking outside, but without individual words being heard. The hallucinations almost always occur when the patient is otherwise unstimulated. The patient is usually alone, either reading or watching television, when he/she notices the hallucinated people watching him/her. Major risk factors for visual hallucinations include impaired vision, disease duration, dementia, depression, sleep disorders and recent medication changes (Nausieda et al., 1982; Comella et al., 1993; Pappert et al., 1999; Arnulf et al., 2000; Barnes and David, 2001), but many patients have no risk factors. Most hallucinating patients have no premorbid psychiatric history. A common misconception is that the hallucinations only arise when medications have been increased. Although this is frequently true, it is not always the case. Patients commonly develop hallucinations on doses of drugs that have not been changed in several years. The association of diminished vision with visual hallucinations brings to mind Bonnet’s syndrome, in which elderly people with severe visual dysfunction but normal cognition develop visual hallucinations. Since PD patients may have impaired vision that is unrelated to their PD, they are subject to Bonnet’s hallucinations (Matsui et al., 2004). However, the statistical association between visual dysfunction and hallucinations is loose, with hallucinators performing only slightly worse on eyechart testing (mean visual acuity 20/44.6) than non-hallucinators (20/32.8) (Holroyd et al., 2001). Dementia has been clearly documented as a risk factor, which brings up the possible alternative diagnosis of DLB. A prominent expert has opined that most cases of drug-induced hallucinations represent the premature unmasking of DLB by use of dopaminergic drugs (McKeith, personal communication), but no data exist to support this claim. It is interesting that all of the PD medications (anticholinergics, dopaminergics and amantadine) have been found to induce very similar hallucinations (Goetz et al., 1982b) despite their different mechanisms of action. Yet certain drugs are more likely than others to induce these problems. For example, the dopaminomimetics, such as pramipexole, ropinirole and pergolide (Parkinson Study Group, 2000; Rascol
et al., 2000), are more likely to induce visual hallucinations than levodopa. Drug doses are also important risk factors. The higher the dose, the higher the risk. Yet the occurrence of hallucinations is only partly related to the serum or brain level of the drug. One study infused high-dose levodopa intravenously into PD patients who suffered from visual hallucinations at home (Goetz et al., 1998a). Despite receiving much higher levels of drug than they did at home, none of them hallucinated in the hospital research setting, indicating that there is a combined effect of the drug and the patient’s mental state at the time. It is believed, but without supportive data, that polypharmacy also increases risk. Some experts believe that there is more risk from low levels of multiple psychoactive drugs than higher levels of a single or few numbers of other drugs. Tactile, olfactory and gustatory hallucinations tend to be considerably less common in PD patients with drug-induced psychosis, but occur more than rarely (Friedman et al., 2002). One report described tactile hallucinations as affecting about 7% of hallucinators (Goetz et al., 1998b). As with auditory hallucinations, these non-visual hallucinations occur almost exclusively in people who already suffer from visual ones (Fenelon et al., 2002; Tousi and Frankel, 2004). The tactile hallucinations tend to be animals, worms, bugs and other generally unpleasant things that are also seen (Fenelon et al., 2002). The recognition of hallucinations is usually quite simple. Nevertheless, when the patient is too demented to produce a reliable history or when the hallucinations take place around sleep, it can be challenging. It is unknown whether PD patients experience an increase in hypnagogic or hypnopompic hallucinations. A variant of these conditions, the ‘rapid-eye movement (REM) intrusion’, occurs when a patient may experience a dream intruding into consciousness while sleepy but not actually asleep. It has become clear in recent years that patients frequently do not recognize their sleepiness and may suffer from ‘sleep attacks’ (Olanow et al., 2000), suggesting that a patient suffering a REM intrusion may not recognize it as a dream, but rather remember it later as a hallucination. However, the most likely confusion arises in distinguishing nocturnal hallucinations from vivid dreams and REM sleep behavior disorder. In the former the patient experiences realistic dreams whereas in the latter the dream is acted out, typically of fighting or running away from a threat. 41.2.1.4. Treatment The management of the psychotic PD patient is similar in delirious and non-delirious patients. Most importantly,
TREATMENT-INDUCED MENTAL CHANGES IN PARKINSON’S DISEASE the possibility of triggering factors should be considered. The most likely triggers are infection or drug toxicity. Although infections generally produce fever and other systemic symptoms, this is not always the case. Therefore, urinary tract infections and pneumonias should always be considered as possible underlying explanations for the onset of psychosis. PD drug overdoses may produce psychotic symptoms with or without delirium. Of all the PD medications, only amantadine is cleared by the kidney, so that a degree of renal failure which would produce no encephalopathic features in a typical PD patient may produce a toxic delirium in one taking amantadine. Other common drugs taken by PD patients that may cause or exacerbate psychosis include pain or sleeping medications. However, digitalis toxicity as well as other drug toxicities may be contributory. Occasionally other metabolic explanations are found, such as isolated renal or hepatic impairment or hypoxia. Structural brain lesions are virtually never explanations. Although a patient may have fallen and sustained a subdural hematoma or intraparenchymal hemorrhage, these are exceedingly uncommon and, when found, are usually the result, not the cause, of the psychiatric decline. When possible, the patient is best managed at home, in a secure, comforting, familiar environment. It is common for PD patients who had no psychotic or delirious behavior at home to decompensate simply upon moving into the hospital environment. We strongly recommend that, whenever possible, the neurologist develop a working relationship with a limited number of psychiatric inpatient units, so that their PD patients can be referred to these units. This allows the clinical staff in such units to gain more experience with management of psychosis in this population, which ultimately results in better care for the patient. The approach to treatment in patients with PD is different than in other conditions where the drug causing the side-effect is discontinued. First of all, all antiparkinsonian medications can produce mental disturbances, making it difficult to know which drug is responsible or contributing to the psychosis. Secondly, reductions in these PD medications may cause intolerable motor decline. We therefore recommend the following approach. First, we suggest discontinuing medications used to treat other conditions, such as pain and insomnia, before reducing the anti-PD medications. We would then discontinue, in the following order, anticholinergics, selegiline and amantadine, because these medications have such mild antiparkinsonian effects that they can usually be discontinued without difficulty. If the patient remains psychotic, the next step is to reduce or stop the dopamine agonists, since studies comparing the benefits of levodopa to dopamine
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agonists in previously untreated PD patients have demonstrated that the agonists are more likely than levodopa to induce psychotic symptoms (Parkinson Study Group, 2000; Rascol et al., 2000). We would reduce COMT inhibitors and levodopa last. If psychosis persists despite the fact that anti-PD medications have been reduced to their lowest level consistent with tolerable motor function, then an antipsychotic medication should be started. Other approaches to reducing the psychosis have included ‘drug holidays’ (Friedman, 1991) and electroconvulsive therapy (ECT) (Hurwitz et al., 1988; Factor et al., 1995). The data on ‘drug holidays’ are scanty and were accumulated primarily as a treatment of clinical fluctuations, not psychosis or delirium (Goetz et al., 1982a). These data suggest that it is not helpful and often harmful. The use of ECT is supported by isolated case reports and appears to work even in cases not diagnosed with psychotic depressions. We consider ECT a treatment of last resort, although psychiatrists with an interest in ECT think this is a major and biased oversight. The atypical antipsychotic drugs (AA) represent the newest generation of antipsychotic drugs used primarily in the treatment of schizophrenia but also the other psychotic disorders (primarily schizoaffective, bipolar and psychotic depressive disorders). Clozapine was the first such drug, followed shortly thereafter by risperidone, olanzapine, quetiapine, ziprasidone and most recently aripiprazole. Unfortunately there is no consensus definition of ‘atypicality’. Although several different suggestions have been entertained, the most commonly accepted definition is ‘relative’ freedom from extrapyramidal side-effects at the usual antipsychotic doses. What ‘relative’ means however has never been addressed and for patients with PD or DLB, who are the most sensitive populations to the extrapyramidal effects of these drugs, the issue is of great importance. Data now exist on the effects of each of the AAs, with the exception of ziprasidone. Although ziprasidone is not the most recently released AA, it alone carries a warning about a prolonged QT interval on the electrocardiogram, making it an unpopular drug to try on the elderly frail. There are double-blind placebo-controlled data on clozapine and olanzapine in the treatment of drug-induced psychosis in PD (Parkinson Study Group, 1999; Breier et al., 2002; Pollak et al., 2004). Prior to the first randomized trial of clozapine there was a wealth of open-label data indicating that the drug, at very low doses in comparison to the doses used in schizophrenia, was extremely effective in treating the psychosis without worsening of motor function (Friedman and Factor, 2000). In fact, several reports have demonstrated that clozapine
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has antitremor efficacy that rivals that of levodopa and benztropine (Friedman and Lannon, 1990; Jansen, 1994; Friedman et al., 1997). In schizophrenia, clozapine was started at 25 mg/day and increased by 25 mg each day on a t.i.d. regimen to a dose total of 300–900 mg/day (Kane et al., 1988). For schizophrenics with ‘fixed’ delusions, that is, delusions that had been present and unchanged for several months, the improvement was generally only partial and usually took several weeks or months. In PD patients, fixed delusions sometimes resolved overnight even when the delusions had been present for many months. In addition, the dose required was often as low as 6.25 mg/day. Before this was recognized, a doubleblind placebo-controlled trial was instituted using the schizophrenia titration schedule, resulting in the only negative study ever reported on the efficacy of clozapine in PD (Wolters et al., 1990). In 1999 the only two randomized, double-blind placebo-controlled trials of low-dose clozapine were published (Parkinson Study Group, 1999; French Clozapine Parkinson Study Group, 1999). Both designs were almost identical and the results were very close. Both showed that low-dose clozapine, with doses held between 6.25 and 50 mg/ day, resulted in clinically and statistically significant benefit in all measures of psychosis employed and that motor function did not decline. In fact there was a non-statistically significant motor benefit of clozapine due to its antitremor effect. (The tremor benefit was statistically significant.) In the American study, the most commonly used dose, chosen in a double-blinded fashion, was only 6.25 mg/day and the mean dose required was 25 mg/day (Parkinson Study Group, 1999). In the French study, the mean dose was 35 mg/day (Pollak et al., 2004). Interestingly, the schizophrenic dosing is t.i.d. whereas the PD dosing is generally limited to a single dose, given at bedtime. These different responses again underscore the major differences between schizophrenic psychosis and drug-induced psychosis in PD. The clozapine data from the double-blinded trials support the way clozapine was used prior to the two trials. Generally clozapine is started at 6.25 mg at bedtime and increased, based on response and tolerance, by 6.25 mg to 12.5 mg each night, as needed. We recommend increasing the dose daily until the patient sleeps through the night, at which point the dose should be increased more slowly, based on whether the patient is oversedated in the morning. Despite the low dosing, weekly white blood cell counts must be monitored as the agranulocytosis side-effect is not dose-dependent and appears to be mildly more common in the elderly (Alvir et al., 1993), affecting between 1 and 2% within the first 3 months. It becomes
increasingly less likely thereafter but, in the USA, biweekly monitoring is required as long as the patient takes the clozapine. The Food and Drug Administration, in order to secure the blood count monitoring, has required the blood count result before dispensing the clozapine. Only enough pills are dispensed to last until the next blood draw, thus guaranteeing compliance while on the clozapine. In Europe the monitoring is reduced to monthly after the first 6 months. There have been no deaths attributed to clozapine among PD patients in the USA. The monitoring requirement has made alternatives to clozapine very attractive. The second AA, risperidone, unfortunately failed to preserve motor function. Risperidone has all the side-effects of a low-potency neuroleptic. It causes dose-dependent parkinsonism, acute dystonic reactions, akathisia and increases in prolactin secretion. It also induces tardive dyskinesia, but at a considerably lower rate than the historical controls to which it has been compared (Jeste, 2004). The data on risperidone in PD are actually quite mixed, with some reports describing the complete absence of motor side-effects (Meco et al., 1994; Allen et al., 1995; Workman et al., 1997) whereas others reported severe motor worsening in each patient who took the drug (Ford et al., 1994; McKeith et al., 1995). No double-blinded trial has been published and it is unlikely that any will be performed, given the mixed results. Olanzapine was the subject of four double-blinded trials, three of which were placebo-controlled and one actively controlled, comparing the risperidone to clozapine (Goetz et al., 2000; Breier et al., 2002; Ondo et al., 2002). The clozapine trial was halted prematurely due to intervention by the Safety Monitoring Board on behalf of the olanzapine-treated patients. The Safety Monitoring Board declared that olanzapine was unsafe for use in PD because of worsened motor function, despite mean dosages of about 5 mg/day. The three other trials used placebo controls and all were completed. All three had similar results. Olanzapine was ineffective as an antipsychotic and worsened motor function. This was in direct contrast to the first prospective study, in which PD patients had dramatic improvement in their psychosis without any decline in motor function (Wolters et al., 1996). Two of these negative studies were identical and performed in the USA and Europe simultaneously (Breier et al., 2002). Each of the studies involved 80 subjects, the most ever in any study of a treatment for a behavioral abnormality in PD. Thus 160 subjects were enrolled. Both studies had very similar negative outcomes. Since olanzapine does not increase prolactin levels and does not cause acute dystonic reactions, the sensitivity of
TREATMENT-INDUCED MENTAL CHANGES IN PARKINSON’S DISEASE PD patients is surprising. It is also surprising that the drug did not improve the psychosis. The mean doses in these studies were about one-third to one-half of the doses used in primary psychoses, in contrast to the relatively much smaller doses of clozapine and risperidone, which were effective in drug-induced psychosis in PD. These discrepancies remain unexplained. The third drug, quetiapine, has been subject only to a single double-blinded placebo-controlled trial (Ondo et al., 2005). This trial was powered to determine whether the drug interfered with motor function, not to prove that it was an effective treatment. The study confirmed the safety of the drug and did not worsen motor function, but there was no statistically significant improvement in psychosis. In addition, a doubleblinded comparison trial found no differences between clozapine and quetiapine, but the number of subjects was small (Morgante et al., 2004). The open-label reports, involving over 400 patients, indicate that quetiapine, although somewhat less potent and less effective than clozapine and without the benefit on tremor, is nevertheless an effective drug for treating the psychosis. The mean dose of quetiapine for treating this condition is about 65 mg/day, in contrast to the 25–35 mg/day of clozapine. Like clozapine, quetiapine is sedating and may contribute to orthostatic hypotension. The most recent AA is aripiprazole. This drug has partial dopamine agonist properties despite being an effective antipsychotic. There was hope that aripiprazole may improve both the psychosis and the motor dysfunction, but early reports suggest that this is not the case (Fernandez et al., 2004b; Friedman et al., 2005). At very low doses, even under 5 mg, aripiprazole worsened motor function in some PD patients. Since the smallest commercially available dose is 5 mg and since the lower doses were not effective in treating the psychosis, it is unlikely that this drug will prove helpful. 41.2.1.5. Long-term outcome Little data exist on this topic. The first report described a small nursing-home cohort of PD patients with hallucinations, all of whom died within 2 years (Goetz and Stebbins, 1995). This was in the era before treatment with AAs was initiated. After clozapine found widespread use, a study of the long-term outcome of patients who had participated in the American double-blind trial of clozapine (all of whom participated in an open-label safety extension) found that 25% of completers were dead, that 42% were in nursing homes, 68% were demented and 69% were still psychotic (Factor et al., 2003). Another study,
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reflecting a retrospective outcome analysis of 39 parkinsonian, not necessarily PD, patients who had been treated with clozapine for psychosis found that 15% had died by 5 years and 33% had been admitted to nursing homes (Fernandez et al., 2004a). Few were off antipsychotic treatment, although an Israeli group (Klein et al., 2003) reported that 9 of 32 clozapinetreated patients no longer required the clozapine. In contrast, another report on only 6 patients who had been on either quetiapine or clozapine for a mean duration of 20 months had their antipsychotic slowly tapered and discontinued (Fernandez et al., 2004c). Five of the 6 suffered worsened psychosis and 3 of these had a more severe psychosis than at baseline, suggesting the possibility of a ‘rebound psychosis’. Compared to the one historical report involving a small number of patients (Goetz and Stebbins, 1995), these data suggest a somber but marked improved outcome with quetiapine and clozapine. It is likely that most psychotic patients will require their antipsychotic for life if the medications responsible are not dramatically altered. However, it is always appropriate to consider the possibility of tapering and stopping an antipsychotic to determine if it is still required. Since the recurrent psychosis can be treated very early, it is unlikely to become severe and hard to control, even if the concept of a rebound psychosis turns out to be true. 41.2.2. Mood and anxiety fluctuations associated with motor fluctuations It is well known that some patients who exhibit motor fluctuations also experience associated mood fluctuations. In general, ‘off’ periods are associated with depressed mood and increased anxiety, whereas ‘on’ periods are associated with normal or elevated moods (Hardie et al., 1984; Cantello et al., 1986; Friedenberg and Cummings, 1989). In addition, some patients experience ‘off’ states as relatively pure sensory or mood experiences and others report mood swings preceding the changes in motor function. These observations imply that mood changes in fluctuating patients are not simply a reaction to the motor changes. It may be that mood is directly affected by changing drug levels, with anxiety and depression having somewhat different temporal relationships to serum drug levels than motor responses (Maricle et al., 1995b). In one study, two-thirds of patients with motor fluctuations also suffered from mood fluctuations (Nissenbaum et al., 1987); however, these data were obtained by post hoc questioning of patients. Overall, only a small number of PD patients have actually been
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studied during their motor fluctuations to determine mood and anxiety changes (Menza et al., 1990; Maricle et al., 1995a, b). The results so far have been difficult to interpret due to the small numbers of subjects as well as different techniques for assessment and, perhaps most importantly, possibly different patient populations. In a double-blind placebo-controlled trial of 2-hour levodopa infusions in the ‘off’ state in 8 PD patients with clinical fluctuations, Maricle et al. (1995b) demonstrated that mean depression and anxiety scores improved in a dose-related manner to levodopa infusions, although finger-tapping rate, the sole measure of motor function, did not differ much with the two different infusion rates. Six of the 8 subjects noted an improvement in mood and anxiety with high-dose levodopa. Four had a response to low-dose infusion and 2 responded to placebo. Anxiety scores appeared to have a different time response to the infusions than either the depression or the motor score, but the numbers of subjects were too small for statistical significance. Menza and colleagues (1990) reported that, in 10 consecutive, non-demented, non-depressed PD patients with ‘on’, ‘off’ and ‘on with dyskinesia’ periods, mood and anxiety fluctuated with the ‘on–off’ status, but, interestingly, and in contrast to the report by Maricle et al. (1995b), worsened when the patients suffered from their dyskinesias. These authors described improvement of mood and anxiety as the patient went from ‘off’ to ‘on’, then worsening from ‘on’ to ‘on with dyskinesias’. This important observation suggests that the mood change is not a function of dopamine brain release, since that hypothesis would predict either stability of mood or further enhancement of mood as dopamine responsiveness increased. It is commonly observed that PD patients do, in fact, sometimes become hypomanic when they become dyskinetic (Giovannoni et al., 2000); however that did not occur in this report. The decline in mood and worsening anxiety in this case may simply have been due to the fact that dyskinesias were bothersome, which would suggest that mood is a reflection of changes in motor responses rather than biochemical changes in the brain or serum. One study of 16 PD patients with motor fluctuations found that the correlation between motor state and either mood or anxiety was not very strong over a 1-week period (Richard et al., 2001). In this study, 7 patients experienced daily mood fluctuations and 7 patients reported daily anxiety fluctuations. However, these were not necessarily the same patients. Some patients had mood fluctuations without anxiety fluctuations, whereas in others, the opposite was true.
Only one subject had positive correlations between mood and motor function each day. The investigators concluded that ‘a consistent relationship between anxiety and motor states is not the rule’. Furthermore, the study ‘failed to confirm a consistent temporal relationship between mood and motor states’. Perhaps most surprising was this study’s observation that mood was sometimes negatively correlated with motor function. Another study reported that 22 out of 47 PD patients experienced non-motor symptoms associated with their motor fluctuations whereas only 16 had purely motor changes (Raudino, 2001). The non-motor symptoms reported in this study were autonomic symptoms, pain, mood changes and anxiety. Other reports have described patients with mood or other non-motor fluctuations during the day that are independent of motor changes (Nissenbaum et al., 1987). The fact that some patients become hypomanic in the ‘on with dyskinesia’ state, whereas others are euthymic, remains difficult to explain (Nissenbaum et al., 1987), but no more so than the wide phenomenological spectrum of non-motor fluctuations that have been reported, which include pain, irritability, cognitive slowing, racing thoughts, sweating, belching, constipation, respiratory dysfunction, akathisia, restless legs, cough, hunger, limb edema, nausea and temperature (Hillen and Sage, 1996; Quinn, 1998). It must be noted that mood and anxiety may fluctuate in response to many of these very uncomfortable sensations, producing the usual conundrum of whether certain symptoms are causal, related or merely coincidental. Clearly, more research needs to be performed in order to understand better the phenomenology of mood and anxiety fluctuations in patients with PD. Although the general impression is that in fluctuators mood and motor function go hand in hand, some studies indicate that this is frequently not the case. Simple explanations for mood and anxiety changes will probably never be adequate. 41.2.3. Repetitive or compulsive behaviors Although there is a relationship between abnormal repetitive or obsessive-compulsive behaviors and PD, its nature is far from clear (Evans et al., 2004; Kurlan, 2004; Voon, 2004). Even the terminology is somewhat confusing. Obsessive-compulsive disorder (OCD) is described as ‘intrusive cognitive events (obsessions), which result in intentional repetitive behaviors (compulsions) designed to neutralize both the cognitive intrusions and associated anxiety’ (Voon, 2004). This is in contrast to the obsessive-compulsive spectrum disorders (OCSD),
TREATMENT-INDUCED MENTAL CHANGES IN PARKINSON’S DISEASE which are ‘intrusive events with associated repetitive behaviors’ (Voon, 2004), the difference being that cognitive intrusions are absent from OCSD. These two categories are thought to have different underlying mechanisms, but overlapping phenomenologies, sowing confusion in our clinical understanding. Tics and behaviors such as hair-pulling, nail-biting and foottapping fall into the OCSD category, whereas ritual behaviors and checking are considered OCD. In addition, OCD is classified as an anxiety disorder, which the OCSD syndrome is not. There are also non-pathological obsessive-compulsive personality traits that have sometimes been considered to be part of the PD ‘character’, such as inflexibility, neatness, punctuality, obeying rules, following commands and a decrease in novelty-seeking behavior (Menza et al., 1993). Studies of such character attributes have been contradictory, leading to the conclusion that such associations are still highly speculative. Although the possibility of an obsessive-compulsive personality being ‘part of’ PD has been hypothesized for a long time, the occurrence of abnormal repetitive behaviors in the setting of PD has been recognized only recently (Friedman, 1994; Fernandez and Friedman, 1999) and its relationship to the drug treatment of PD versus being intrinsic to the disease itself is unclear (Evans et al., 2004; Kurlan, 2004; Voon, 2004; Friedman, 2005). Although certain pathological non-psychotic behaviors have been attributed to levodopa, such as hypersexuality, other compulsive behaviors such as punding (see below), pathological gambling, compulsive shopping and levodopa drug abuse (or the dopamine dysregulation syndrome) also occur in PD patients. Furthermore, the absence of studies looking at control populations makes interpretation of these reports somewhat tenuous in arguing the connection between either disease state or drug treatment. The main observations concerning these behaviors are that they developed while on dopaminergic therapy and thus likely result from alterations of either dopamine or serotonin. However, the small number of patients involved and the variability of responses to interventions make it quite difficult to infer much from these reports. 41.2.3.1. Dopamine dysregulation syndrome It has become increasingly apparent that a small number of PD patients, mostly treated with levodopa, begin to take increasing amounts of their medication, despite the fact that their motor symptoms are well controlled with lower doses. This compulsive drug use pattern has been variably described in the litera-
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ture as levodopa dependence or abuse, hedonistic homeostatic dysregulation and, most commonly, the dopamine dysregulation syndrome (Priebe, 1984; Nausieda, 1985; Giovannoni et al., 2000; Lawrence et al., 2003; Evans et al., 2004). The patients who develop this syndrome tend to be male with a young onset of their PD. Past drug abuse, heavy alcohol use or a history of mood disorders may be predisposing factors (Giovannoni et al., 2000; Lawrence et al., 2003). The rapid titration to high levels of levodopa use occurs relatively early in the disease, often in excess of 2000 mg/day. Consequently, these patients often have severe, violent dyskinesias and display aggressive and devious tendencies when physicians attempt to curb their levodopa use. The extra levodopa results in enhanced mood, vigor and productivity and patients often base their increase in medications not on the control of motor symptoms, but on somatic cues (Evans et al., 2004). Apomorphine, a short-acting dopamine agonist, may exacerbate or even initiate the symptoms of this disorder (Giovannoni et al., 2000). It may be debated whether dopamine dysregulation syndrome represents a true addiction to levodopa, but many physicians acknowledge that patients become psychologically dependent on levodopa. Such a definition requires a pattern of excessive and inappropriate use that results in impairment of social functioning and causes withdrawal when the drug is discontinued. In the PD population, it may be difficult to tell whether there is excessive use of levodopa, particularly because the medication alleviates motor symptoms. Yet a case report of a PD patient who needed his levodopa dose despite being quadriplegic from Guillain–Barre´ syndrome suggests that patients can develop a pattern of excessive and inappropriate use (Merims et al., 2000). There is no doubt that patients with dopamine dysregulation syndrome display behaviors that are detrimental to normal social functioning and, when limiting levodopa use, develop dysphoria and other symptoms consistent with withdrawal. Additionally, central dopaminergic pathways, specifically the mesolimbic dopaminergic projections to the nucleus accumbens, have been implicated in models of drug abuse and dependence (Koob and Le Moal, 1997; Sanchez-Ramos, 2002), so it is no surprise that patients have the potential to develop dependence on levodopa. Other abnormal behaviors can be seen with this syndrome, including mania, psychosis, aggression, drug hoarding, punding (see below), hypersexuality, compulsive shopping and pathological gambling. Management of this disorder can be difficult, but it is essential to decrease and ration dopaminergic medications. Atypical antipsychotics such as quetiapine or clozapine can
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be used to treat the behavioral manifestations (Giovannoni et al., 2000). 41.2.3.2. Punding Punding refers to a repetitive behavior first described in amphetamine addicts who developed an endless fascination with taking objects such as flashlights and small electrical gadgets apart, then trying, usually unsuccessfully, to put them back together (Rylander, 1972). This type of repetitive behavior was calming to the patient and considered pleasurable. Several PD patients have been described with similar behavior, all developing while under dopaminergic drug treatment, although in 2 patients, the punding appeared after the initiation of quetiapine and decreased or resolved when the quetiapine dose was reduced (Miwa et al., 2004). The different punding behaviors that have been described include cataloging a small, inexpensive jewelry collection, repetitively adding tables of sums, endlessly rearranging a collection of buttons, taking apart and putting together flashlights, examining television and other electrical cords and repeatedly reading the labels on cans in a supermarket (Friedman, 1994; Fernandez and Friedman, 1999; Evans et al., 2004; Miwa et al., 2004). These behaviors are often connected to the patient’s occupation and the patients themselves realize that the time spent on their punding tasks is excessive (Friedman, 1994; Evans et al., 2004). In contrast to the punding of amphetamine users, PD patients often feel irritable or anxious when distracted from or stopping their behaviors, although most report no compulsion to pund (Fernandez and Friedman, 1999; Evans et al., 2004). Although punding is hypothesized to be due to excessive dopaminergic stimulation (Ridley and Baker, 1982) and some patients have improved with decreased doses of dopaminergic medications (Fernandez and Friedman, 1999), one report describes similar stereotyped behaviors in PD patients that were unresponsive to reductions in antiparkinsonian therapy (Kurlan, 2004). As mentioned before, 2 other PD patients have been reported where punding began after the administration of quetiapine (Miwa et al., 2004). These reports suggest that a simple hyperdopaminergic state is not enough to account for these stereotyped behaviors. Hypomanic symptoms have occurred in conjunction with repetitive behaviors in some cases, implying that the underlying pathophysiology is complex and may involve a combination of dopaminergic, serotonergic and other neurotransmitter systems (Kurlan, 2004). Other repetitive behaviors have been reported, including 1 patient who made annoying sucking sounds which bothered his friends. This developed after many
years of PD and was unrelated to medications or his clinical condition. Another patient hummed, but only as an ‘off’ phenomenon (Friedman, 2005). 41.2.3.3. Pathological gambling Although pathological gambling can be seen as part of the dopamine dysregulation syndrome or mania, it has been reported in patients with PD without other symptoms of the above disorders. Pathological gambling is characterized by a failure to resist the impulse to gamble despite severe consequences, whether personal, financial or vocational. It is considered an impulse control disorder in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) (American Psychiatric Association, 1994). This phenomenon was first reported in 12 patients with PD, 9 of whom began gambling after initiating levodopa therapy (Molina et al., 2000). One patient, who gambled prior to levodopa therapy, reported that his gambling behavior worsened after starting treatment. The authors of this paper noted that their patients were relatively young and 5 of them had alcohol use or dependence. Since this initial report, pathologic gambling has been observed in other patients on levodopa therapy (Gschwandtner et al., 2001; Avanzi et al., 2004) and in patients on dopamine agonist therapy alone (Seedat et al., 2000; Driver-Dunckley et al., 2003). The patients on dopamine agonists alone were on pramipexole or pergolide and, for many, their gambling behavior resolved when switched to ropinirole. Others noted improvement with reductions in total dopaminergic medication, the addition of antipsychotic therapy, antidepressant therapy, family control or DBS (Molina et al., 2000; Seedat et al., 2000; Avanzi et al., 2004). Most did not respond to standard therapies for pathological gambling, such as behavioral or cognitive therapy (Molina et al., 2000; Avanzi et al., 2004). Although these reports suggest that pathologic gambling is linked to dopaminergic medications in PD, it should be noted that no report has specifically assessed the prevalence of pathologic gambling in the general population and compared it to the prevalence in patients with PD.
41.3. Mental changes due to surgical treatments for Parkinson’s disease 41.3.1. Overview of surgical treatments for Parkinson’s disease The surgical approach to PD has evolved dramatically since the pre-levodopa era. Early attempts at treating PD surgically were highly variable, partly due to an
TREATMENT-INDUCED MENTAL CHANGES IN PARKINSON’S DISEASE incomplete understanding of basal ganglia pathophysiology, but mostly because of poor techniques for targeting brain structures. Target localization improved dramatically with the advent of stereotactic techniques (Spiegel et al., 1947), but unfortunately, surgical treatments for PD were abandoned after the introduction of levodopa in the 1960s. It wasn’t until the medical community realized that long-term levodopa therapy severely restricted PD patients’ daily functioning due to the development of motor fluctuations and dyskinesias that there was a resurgence of interest in surgical therapies for PD. Over the last two decades, major progress has been made in the field of movement disorders surgery, from the refinement of ablative techniques to the development of new alternatives, such as DBS (Benabid et al., 1991), and surgery is now an accepted form of therapy for advanced PD. The thalamus was originally the preferred target for PD. However, because thalamic lesions improve only the tremor in PD and because bilateral lesions were associated with a high incidence of speech problems (Kelly and Gillingham, 1980), the thalamus has fallen out of favor as a target. The internal segment of the globus pallidus (GPi) and the subthalamic nucleus (STN) are much more commonly targeted now because a lesion in either structure reduces all three of the cardinal motor manifestations in PD, but because no double-blind, randomized, head-to-head trials have been conducted between the two sites, it is unclear which target is better. There are also minimal data comparing the two different surgical techniques in use for PD surgery today: ablation and DBS. Nevertheless, most surgical centers are now performing DBS. This is largely because DBS offers several advantages over ablative therapy, including: (1) ‘reversibility’, meaning there is no permanent destructive lesion made in the brain and likely will not hamper future PD therapies; (2) DBS can be performed bilaterally with relatively few adverse effects; and (3) stimulation parameters can adjusted to decrease adverse effects and increase clinical effect as the disease progresses. Despite the controversy regarding which surgical target or technique is clinically superior in PD, it is abundantly clear that both ablation and stimulation of either target can provide significant relief of many parkinsonian motor symptoms and reduce the severity of long-term motor complications from levodopa therapy. Unfortunately, as neurologists and neurosurgeons have slowly accumulated more experience with these procedures, especially DBS, it has been recognized that patients sometimes experience declines in mood and cognition. Despite the fact that most movement disorders surgical centers actively screen potential
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candidates for psychiatric and cognitive disorders, we still have limited knowledge of who is subject to these adverse effects. Possible explanations include interruption of fibers controlling mood and cognition, natural progression of the neurobehavioral features of PD, dopaminergic medication withdrawal or a combination of the above. Hopefully, as the cognitive and psychiatric morbidities associated with ablation and DBS are studied more systematically, we will be able to understand the underlying etiologies better. 41.3.2. Adverse psychiatric effects of surgical treatments for Parkinson’s disease Although cognitive side-effects have been reported with thalamotomy in PD, this section will focus on adverse psychiatric and cognitive effects from the most common surgical procedures currently performed for advanced PD: pallidotomy, GPi DBS and STN DBS. Table 41.4 shows the common psychiatric changes seen with surgery. It is important to keep in mind that most surgical studies of PD patients have not used psychiatric scales to assess behavior. Thus, most of the data on adverse psychiatric effects of PD surgery consist of descriptive case reports or case series. The cognitive consequences of PD surgery have been better studied, but are also limited because of small sample sizes and short-term follow-up. 41.3.2.1. Psychosis Despite being the most common neuropsychiatric complication of pharmacologic therapy in PD, psychosis is a relatively rare occurrence after ablation or DBS surgery and, in fact, has only been reported after STN DBS. In one study, 4 out of 77 PD patients
Table 41.4 Adverse psychiatric effects reported with surgical treatments in Parkinson’s disease Pallidotomy Depression Hypomania Globus pallidus internal segment stimulation Mania Subthalamic nucleus stimulation Apathy Anxiety Depression Hypomania Mania Mirthful laughter Psychosis
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undergoing STN DBS surgery and evaluated up to 3 years postoperatively suffered from psychosis (Funkiewiez et al., 2004). One of these patients reportedly had a transient psychosis that occurred 6 weeks after electrode implantation. The other 3 had permanent psychoses, although 2 were demented. In another study examining 48 PD patients following bilateral STN DBS surgery, 2 had psychotic syndromes that resolved without any specific therapy (Herzog et al., 2003b). The Grenoble group (Krack et al., 2003) reported 1 case of transient psychosis in a 5-year follow-up study of 49 STN DBS patients. Unfortunately none of these studies reported the specifics of the psychotic episodes, so it is unknown whether they had hallucinations, delusions or both. Furthermore, it is unclear if these patients had psychosis prior to surgery, a factor that could predispose them to develop psychosis after implantation. In another study of 24 DBS patients (Houeto et al., 2002), 1 patient with drug-induced psychosis prior to surgery developed a ‘florid psychosis with mystic delusions’ a few weeks postoperatively. However, another patient with druginduced psychosis prior to surgery did not manifest psychotic symptoms afterwards. One patient has been reported as having developed delusions subsequent to STN DBS surgery (Herzog et al., 2003a). This patient had no psychiatric history. Her delusions occurred concurrently with manic symptoms, including euphoria, loosened associations, flight of ideas and hyperactivity. The mania and the delusions eventually needed to be controlled with a combination of carbamazepine and clozapine. A few patients have experienced isolated visual hallucinations after DBS surgery of the STN. One patient, off all dopaminergic medications after bilateral STN DBS surgery, experienced formed visual hallucinations only when the stimulators were turned on (Diederich et al., 2000). Because the visual hallucinations responded to clozapine therapy, the authors concluded that electrical stimulation physiologically mimicked drug-induced visual hallucinations and suggested that there may be a connection between the STN and limbic pathways. However, not all cases of visual hallucinations after surgery are induced by stimulation. Some are related to the development of dementia (Krack et al., 2003; Rodriguez-Oroz et al., 2004), whereas in others, the etiology is less clear (Varma et al., 2003). 41.3.2.2. Mania Although manic symptoms have been known to occur with pallidal lesions (Turecki et al., 1993), mania or hypomania hardly ever occurs after pallidotomy. This is largely because most neurosurgeons specifi-
cally target the posterior ventral pallidum in PD, which contains purely sensorimotor fibers, making it the most effective target for ameliorating parkinsonian symptoms (Bakay et al., 1997). Lesions restricted to this area do not result in mood disorders, whereas lesions outside this area may affect the non-motor basal ganglia circuits responsible for cognitive and mood changes (Lombardi et al., 2000). Two patients were recently reported to have transient hypomania subsequent to pallidotomy (Okun et al., 2003). It was discovered that both of these patients had lesions involving the anteromedial (non-motor) portion of the GPi, which was believed to be responsible for their mood changes. Mania has also been reported as a result of pallidal stimulation (Miyawaki et al., 2000). In this case report, the patient had recurrent mania which always occurred temporally after his stimulators were turned on. When the stimulators were off, he never went into a manic state. His mood eventually stabilized in the ‘on’ stimulation state with the reduction of dopaminergic therapy, leading the authors to suspect that stimulation altered his sensitivity level to the mood-altering effects of levodopa. In contrast to pallidotomy or pallidal stimulation, mania has frequently been observed with STN stimulation. As mentioned above, 1 patient experienced mania with delusions after STN DBS surgery (Herzog et al., 2003a). Another study reported manic symptoms occurring in 3 out of 15 STN stimulation patients (Kulisevsky et al., 2002), including elation, inflated self-esteem, overactivity and sexual indiscretion. None had previous psychiatric episodes and in all 3 patients, manic symptoms began shortly after stimulation was turned on. Interestingly enough, stimulation was switched from the lowest contacts to higher ones in all 3 patients a week after surgery because of better motor responses and the symptoms resolved. In 1 patient, restimulating the lowest contact on the right side caused the mania to recur. Because the lowest contacts were located caudally to the substantia nigra in all 3 patients, the authors speculated that stimulation may have affected limbic projections from the midbrain. Romito and colleagues (2002), among their first 30 STN DBS patients, described 2 who met DSM-IV diagnostic criteria for mania postoperatively. One developed manic symptoms prior to the initial programming session, whereas the other developed symptoms a few hours after the stimulators were turned on. The mania persisted even after discontinuation of all antiparkinsonian medications. Similar to the patients reported by Kulisevsky et al. (2002), the lower contacts were stimulated in both of these patients. However, in contrast, Romito and colleagues (2002) did not change the contacts in their patients and the
TREATMENT-INDUCED MENTAL CHANGES IN PARKINSON’S DISEASE mania resolved spontaneously over the ensuing months without therapy. In addition to mania, hypomania has also been commonly described after placement of bilateral STN electrodes (Houeto et al., 2002; Herzog et al., 2003b; Krack et al., 2003; Funkiewiez et al., 2004). Nearly all of the episodes reported occurred within the first 3 months of surgery and resolved spontaneously. Moreover, 2 cases of mirthful laughter due to STN stimulation have been described (Krack et al., 2001). The laughter seen in these patients was acutely induced by stimulation increases in voltage or pulse width. It remains unclear, however, whether the STN itself is involved in regulating affect and behavior or whether diffusion of the stimulation to limbic-related structures adjacent to the STN is responsible for these changes in mood. 41.3.2.3. Depression Although the strong association between depression and PD had been recognized for some time, investigators did not pay close attention to depression following surgical interventions in PD until 1999, when a case report of stimulation-induced depression following bilateral STN electrode implantation was published (Bejjani et al., 1999). In this patient, electrical stimulation through the lowest contact (0) of the left STN electrode elicited symptoms of depression that disappeared immediately when stimulation was turned off. Although this particular contact was estimated to lie in the left substantia nigra rather than the STN, this observation shattered the concept that depression in PD was mainly a reaction to the parkinsonian symptoms experienced by the patient and suggested that depression could be ‘hard-wired’ in the brain. A number of reports from different surgical centers have since reported the development of depression following STN DBS surgery in patients with PD (Krack et al., 1997; Volkmann et al., 2001; Berney et al., 2002; Doshi et al., 2002; Thobois et al., 2002; Herzog et al., 2003b; Kleiner-Fisman et al., 2003; Funkiewiez et al., 2004), with a frequency ranging from 10% to 30%, but none has been so clearly induced by stimulation. Although PD patients undergoing STN DBS seem to show mild improvement overall when evaluated with depression rating scales at baseline and postoperatively (Ardouin et al., 1999; Daniele et al., 2003; Troster et al., 2003), certain individuals seem to be susceptible to severe mood changes after surgery, with some even attempting suicide (Krack et al., 1997; Berney et al., 2002; Doshi et al., 2002; Houeto et al., 2002; Kleiner-Fisman et al., 2003). It is still difficult at this time, however, to predict which patients are at the greatest risk.
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It may be that targeting the STN itself predisposes patients to the development of postoperative depression. It is of particular interest that depressive symptomatology has been reported more often after bilateral STN DBS surgery than after pallidotomy or GPi stimulation. In fact, most studies report that severity of depression is either unchanged (Vingerhoets et al., 1999; Baron et al., 2000; Favre et al., 2000) or mildly improved (Troster et al., 1997; Masterman et al., 1998; Martinez-Martin et al., 2000; Straits-Troster et al., 2000) after pallidotomy or GPi stimulation, whereas only a few have reported otherwise. One group noted that 12% of their pallidotomy patients developed depression after surgery (Bezerra et al., 1999). Interestingly, all of them had undergone left-sided unilateral ablation. Another group conducted a randomized trial of bilateral pallidotomy versus a combination of unilateral pallidotomy plus contralateral GPi stimulation, but had to discontinue the study early when the 3 patients undergoing bilateral pallidotomy displayed a significant deterioration on the Hamilton depression and apathy scores (Merello et al., 2001). A third study reported that 2 out of 4 bilateral pallidotomy patients experienced postoperative depression (Ghika et al., 1999). The reasons for a greater incidence of depression after STN DBS remain unclear. Several possibilities exist, however. More attention has recently been focused on non-motor symptoms in PD, such as depression and dementia, than in the past. It may be that this spotlight on cognitive and behavioral issues has caused investigators to recognize psychiatric side-effects more readily. The discrepancy between a patient’s expectations from surgery and the actual result may be a contributing factor. Furthermore, the STN is a small target, making it more likely for the electrode to be misplaced. It is also probable that electrical stimulation in this area may activate limbic fibers traveling from the STN through the striatum to the prefrontal cortex, pathways that have been implicated in the neurobiology of depression (Groenewegen and Berendse, 1990; Drevets, 2003). Finally, because STN stimulation allows patients to reduce their medications, generally by approximately 50% (Thobois et al., 2002; Kleiner-Fisman et al., 2003; Krack et al., 2003), patients may experience a depressed mood because of the withdrawal of levodopa or other PD medication. The existing literature suggests that those who develop a depressed mood postoperatively often have a prior psychiatric history. Of the 5 patients with depression after STN surgery in the group reported by Houeto and colleagues (2002), 4 had a previous history of depression, whereas 2 of 6 patients with
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postoperative depression in a separate series had depression preoperatively (Berney et al., 2002). However, 15 other patients in these two studies had depressive symptomatology prior to DBS, yet did not experience a depressed mood afterwards. Therefore, although a past psychiatric history may predispose patients to postsurgical depression, it is clearly not the only factor. Fortunately, it seems that most postoperative depressive episodes are transient. If treatment is necessary, an increase in dopaminergic medication or the addition of an antidepressant, such as a serotonin uptake inhibitor, is usually sufficient (Doshi et al., 2002; Thobois et al., 2002; Krack et al., 2003; Funkiewiez et al., 2004). 41.3.2.4. Apathy Apathy as a sequela of surgical procedures in PD has been reported specifically with bilateral STN DBS (Trepanier et al., 2000; Daniele et al., 2003; Krack et al., 2003; Funkiewiez et al., 2004). These patients are generally not depressed or demented and typically sit in a chair for most of the day (Funkiewiez et al., 2004). The pathophysiology is unknown. Although an increase in dopaminergic agents or antidepressant therapy may help apathy in PD, most of the patients with post-DBS apathy did not respond to dopaminergic therapy. Nevertheless, signs of apathy should be sought in patients following STN stimulation surgery and treatment should be attempted. 41.3.2.5. Anxiety Anxiety disorders are commonly seen in patients with PD. However, they do not seem to develop after surgical procedures for PD. In fact, symptoms of anxiety generally improve in PD patients after pallidotomy, pallidal stimulation and STN stimulation (Fields et al., 1999; Straits-Troster et al., 2000; Higginson et al., 2001; Martinez-Martin et al., 2002; Daniele et al., 2003). Only one study reported a decompensation of anxiety symptoms after surgery in PD patients (Houeto et al., 2002). In this study, 24 PD patients undergoing STN DBS were evaluated for behavioral disorders before and after surgery. Seventeen (71%) were diagnosed with generalized anxiety and 4 (17%) were diagnosed with agoraphobia before the DBS procedure. Unfortunately, in all 17 of the anxiety patients and 2 of the agoraphobic patients, symptoms worsened after surgery. One patient without psychiatric symptoms prior to surgery was discovered to have anxiety postoperatively, but the reasons for this decompensation remain unclear. Given such sparse data, it is obvious that more studies need to be conducted in order to determine how anxiety symptoms respond to surgery in PD.
41.3.3. Adverse cognitive effects of surgical treatments for Parkinson’s disease As with psychiatric symptoms, STN DBS procedures are generally associated with more declines in cognitive function than with procedures involving GPi, although long-term postoperative assessments in these patients remain limited. Although most patients remain cognitively stable after surgery overall, there are reports of PD patients with dementia or borderline cognitive function who worsen irreversibly postoperatively (Limousin et al., 1998; Hariz et al., 2000). Furthermore, patients of advanced age and increased PD severity may have worse cognitive outcomes after surgery for PD (Vingerhoets et al., 1999; Baron et al., 2000; Kubu et al., 2000; Saint-Cyr et al., 2000). As a result, it is essential to screen potential surgical candidates for the presence of a dementing illness with preoperative neuropsychological testing. Such testing ensures that only the most optimal candidates are selected and also provides a baseline for comparison of postsurgical changes in cognition. 41.3.3.1. Neuropsychological assessment Preoperative neuropsychological testing involves the assessment of multiple cognitive domains. These are generally grouped into five categories: (1) general cognitive or intellectual ability; (2) language; (3) learning and memory; (4) executive function; and (5) visuospatial function. Common neuropsychological tests used to evaluate these different domains are listed in Table 41.5. Loss of general intellectual ability is one of the hallmarks of a dementing illness (Saint-Cyr and Trepanier, 2000). Because the main purpose of neuropsychological testing prior to surgery is to rule out dementia, evaluation of intellectual ability is essential. The common neuropsychological tests that are utilized (Table 41.5) can estimate current intellectual ability and premorbid intellectual level and provide a global cognitive screen. PD patients with evidence of borderline or impaired cognitive function based on these tests are not considered good surgical candidates. Evaluation of the domain of language involves examining the ability to comprehend and produce verbal language easily and fluently. Future long-term follow-up studies assessing language ability after surgery for PD will be important because decreased verbal fluency has been the most consistent change reported postoperatively (see section 41.3.3.3 below). Memory disturbance can be another sign of dementia. In PD, free recall is typically impaired, whereas cued recall is preserved (Pillon et al., 1994). This is in contrast to other
TREATMENT-INDUCED MENTAL CHANGES IN PARKINSON’S DISEASE Table 41.5 Common neuropsychological tests used in the evaluation of Parkinson’s disease patients before and after surgery General cognitive/intellectual ability Wechsler Adult Intelligence Scale-III (WAIS-III) American New Adult Reading Test (ANART) Mattis Dementia Rating Scale (DRS) Mini-Mental State Examination (MMSE) Language Subsets of the WAIS-III Boston Naming Test Category Fluency (Animals trial) Controlled Oral Word Association Test Learning and memory Wechsler Memory Scale-III (WMS-III) Hopkins Verbal Learning Test California Verbal Learning Test Executive function Digit span and digit span backwards Wisconsin Card Sorting Test (WCST) Trail Making Test Stroop Color-Word Test Visuospatial function Construction subscore of the DRS Hooper Visual Organization Test Benton Judgment of Line Orientation
dementing illnesses such as Alzheimer’s disease where both free and cued recall is disrupted. Thus, a deficit in cued recall in a PD patient prior to surgery may imply a memory disorder more severe than what would be expected. The domain of executive function allows patients to formulate, plan and execute actions. Problems in this domain generally suggest frontal lobe dysfunction (Lezak, 1995), a finding commonly seen in PD and thus important to evaluate. The presence and extent of visuospatial deficits in PD remain debatable (Pillon et al., 2001). Because of this, visuospatial function has not been consistently assessed pre- and postsurgery in PD patients. 41.3.3.2. Global cognitive and intellectual ability It is important to make sure that PD patients are not demented prior to surgery. Therefore, testing for intellectual function and global cognitive ability is always performed preoperatively. However, most centers do not routinely test intellectual function after surgery. The Mattis Dementia Rating Scale (DRS) has emerged as a popular test of global cognitive ability, but only a few studies have examined changes in the DRS before and after surgery. Most of the early pallidotomy literature did not routinely employ neuropsychological tests to assess
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cognitive decline (Laitinen, 2000) and among the early pioneers of pallidotomy, only Leksell’s group reported general postoperative cognitive decline (Svennilson et al., 1960). This decline was a permanent deficit that occurred in 4 of 81 patients. More recently, Baron and colleagues reported that, of 9 patients undergoing pallidotomy, 3 showed significant declines in DRS scores over 4 years (Baron et al., 2000). However, these 3 patients were older at the time of surgery and it is unclear if the cognitive decline was due to the pallidotomy or because their older age put them at greater risk of developing dementia. In contrast, a study of 43 patients undergoing unilateral pallidotomy showed no significant changes in the DRS scores at 3 and 12 months, respectively (Obwegeser et al., 2000). In general, DRS scales show no significant deterioration with either GPi (Troster et al., 1997; Ardouin et al., 1999; Fields et al., 1999) or STN DBS (Ardouin et al., 1999; Pillon et al., 2000; Funkiewiez et al., 2004). However, one small study found a small but statistically significant improvement (6.7%) in the MMSE after 12 months of STN stimulation (Daniele et al., 2003). 41.3.3.3. Language No studies have reported an improvement in language function postoperatively. On the contrary, declines in language function have been consistently reported after surgical procedures for PD. Specifically, reductions in verbal fluency have been observed after pallidotomy (Uitti et al., 1997; Ghika et al., 1999; Kubu et al., 2000; Lacritz et al., 2000; Obwegeser et al., 2000; Trepanier et al., 2000), pallidal stimulation (Troster et al., 1997; Ghika et al., 1998) and STN stimulation (Ardouin et al., 1999; Pillon et al., 2000; Saint-Cyr et al., 2000; Trepanier et al., 2000; Alegret et al., 2001; Gironell et al., 2003; Funkiewiez et al., 2004). Although there are studies that have reported no change in verbal fluency after pallidotomy (Soukup et al., 1997; Turner et al., 2002; Gironell et al., 2003), these are clearly in the minority. Even more interesting is the fact that this decrease in fluency seems to occur with left-sided pallidotomy, but not right pallidotomy (Uitti et al., 1997; Kubu et al., 2000; Lacritz et al., 2000; Obwegeser et al., 2000; Trepanier et al., 2000). These differential findings are not found with unilateral GPi stimulation (Troster et al., 1997; Vingerhoets et al., 1999), although the number of patients studied so far has been small. Ghika and colleagues (1998) reported that 2 of 6 patients undergoing bilateral GPi DBS had decreased verbal fluency postoperatively, but most others have reported no significant change (Ardouin et al., 1999; Fields et al., 1999; Trepanier et al., 2000).
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A recent review of neuropsychological consequences following STN DBS found that 69% of the studies reported significant declines in measures of phonemic fluency, category fluency or both (Woods et al., 2002). These deficits continue to be present in long-term studies of STN DBS that have followed patients anywhere from 12 to 36 months postoperatively (Saint-Cyr et al., 2000; Daniele et al., 2003; Funkiewiez et al., 2004). It is unclear why these reductions in verbal fluency tests occur. It does not seem to be related to the stimulation itself, given that, in one study, verbal fluency deficits were present at 3 and 12 months after STN surgery, regardless of stimulation status (Pillon et al., 2000). 41.3.3.4. Learning and memory Changes in learning and memory have been variable following pallidotomy. Whereas many studies showed either no change or an improvement on memory testing postpallidotomy (Uitti et al., 1997; Lacritz et al., 2000; Obwegeser et al., 2000; Turner et al., 2002; Gironell et al., 2003), others have shown a decline in memory (Ghika et al., 1999; Trepanier et al., 2000). In one of these studies, free recall worsened in patients with a left-sided pallidotomy as opposed to patients who underwent right-sided pallidotomy (Trepanier et al., 2000), a pattern similar to that observed with verbal fluency. Interestingly enough, another study observed an improvement in memory in patients who had a pallidotomy on the right side (Obwegeser et al., 2000). However, the data remain too limited to draw any conclusions. Thus far pallidal DBS has not been shown to worsen performance on learning and memory testing. A few studies examining both unilateral (Troster et al., 1997; Vingerhoets et al., 1999) and bilateral GPi stimulation (Ardouin et al., 1999; Burchiel et al., 1999) reported no change in learning or memory, whereas a separate study showed that bilateral GPi stimulation actually improved free recall, as assessed by the California Verbal Learning Test in 6 patients (Fields et al., 1999). Most studies following STN electrode implantation have demonstrated no change on measures of learning and memory (Ardouin et al., 1999; Burchiel et al., 1999; Moro et al., 1999; Alegret et al., 2001; Perozzo et al., 2001; Gironell et al., 2003). One study observed a decline in immediate and delayed recall on Rey’s auditory verbal learning test 3 months postoperatively, but this decline returned to baseline at both the 6- and 12-month follow-up visit (Daniele et al., 2003). In contrast, another study found significant declines in longdelay free recall and long-delay cued recall at both
the 3- and 6-month postoperative visits (Trepanier et al., 2000). 41.3.3.5. Executive function Executive function is generally unchanged after pallidotomy and GPi stimulation (Troster et al., 1997; Ardouin et al., 1999; Burchiel et al., 1999; Fields et al., 1999; Ghika et al., 1999; Vingerhoets et al., 1999; Trepanier et al., 2000; Gironell et al., 2003). However, one group demonstrated greater perseveration on the Wisconsin Card Sorting Test in PD patients tested 3 months after a right pallidotomy (Lacritz et al., 2000), whereas another found that performance declined after pallidotomy on the Tower of London Test, a finding that suggests reduced planning ability (Turner et al., 2002). Similarly, most groups have found no significant changes in attention or executive function after STN DBS surgery (Ardouin et al., 1999; Burchiel et al., 1999; Pillon et al., 2000; Trepanier et al., 2000; Perozzo et al., 2001; Daniele et al., 2003; Gironell et al., 2003), with only a couple of studies showing improvement (Alegret et al., 2001; Daniele et al., 2003). Although the surgery itself does not seem to have much of an effect on this domain overall, some recent studies have suggested that stimulation itself may have a positive effect on frontal lobe function. One study reported the results of both STN and GPi stimulation on neuropsychological measures in the stimulator ‘on’ and ‘off’ states and discovered that, when stimulation was ‘on’, both STN and GPi groups improved on various measures of executive function, including the Trail Making Test (parts A and B) and the interference task on the Stroop test (Jahanshahi et al., 2000). Pillon and colleagues (2000) reported similar findings on the Stroop and Trail Making Tests with stimulators turned ‘on’ and ‘off’ in a group of 48 STN DBS patients. 41.3.3.6. Visuospatial function Only a few studies have looked at measures of visuospatial function. One pallidotomy study showed no significant changes in this domain, as assessed by the Wechsler Adult Intelligence Scale-Revised Block Design and the Benton Judgment of Line Orientation (Obwegeser et al., 2000). Another pallidotomy study showed a transient decrease in visuoconstructional ability, as assessed by copying the Rey-Osterrieth Complex Figure, although the effects were transient and had disappeared by 1 year (Trepanier et al., 1998). It was also unclear whether the difficulty in copying the figure was due solely to a visuospatial deficit, as reduced planning ability may also cause patients to have problems with
TREATMENT-INDUCED MENTAL CHANGES IN PARKINSON’S DISEASE this test. Pallidal DBS overall seems to have no effect on visuospatial function (Troster et al., 1997; Ardouin et al., 1999; Vingerhoets et al., 1999), but one study reported that bilateral GPi DBS caused a decline in the construction subscore on the DRS (Fields et al., 1999). Likewise, STN stimulation appears not to affect significantly cognitive function in this domain, with only one study reporting a negative effect (assessed with the Judgment of Line Orientation test) (Alegret et al., 2001).
41.4. Conclusions In order to provide quality care to the PD patient, we can no longer be content with just treating the motor symptoms because the cognitive and behavioral manifestations that result from PD treatment are just as disabling, if not more so. This is true not only of the pharmacologic treatments currently available, but also of the various surgical options. Future research focusing on understanding the underlying mechanisms of drug-induced psychosis and its relation to PD and DLB should enable us to develop better treatments and perhaps alter the long-term outcome of PD patients with psychosis. Elucidating why dopaminergic treatment causes abnormal behaviors in certain patients and not others should help us in that regard, but discovering how DBS can induce or exacerbate these symptoms may be the key to unlocking how cognition and behavior are hard-wired in the brain.
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Section 7 Surgical treatment
Handbook of Clinical Neurology, Vol. 84 (3rd series) Parkinson’s disease and related disorders, Part II W. C. Koller, E. Melamed, Editors # 2007 Elsevier B. V. All rights reserved
Chapter 42
Ablative surgery for the treatment of Parkinson’s disease FREDERICK A. LENZ* Department of Neurosurgery, Johns Hopkins Hospital, Baltimore, MD, USA
42.1. Introduction Spiegel and Wycis (1954; Cooper, 1954; Spiegel et al., 1958) pioneered stereotactic surgery for the treatment of Parkinson’s disease (PD) by introducing coagulation of the globus pallidus – stereotactic pallidotomy. (Hassler et al., 1979), introduced ablation of the ventral oral nucleus of thalamus (Vo, consisting of Voa and Vop, anterior and posterior subnuclei), the terminus for pallidal afferents to the thalamus. Microelectrode recordings demonstrated that the area posterior to Vop, i.e. the terminus of cerebellar afferents (ventral intermediate: Vim), was later found to have rhythmic bursting activity close to the frequency of tremor (Guiot et al., 1962). Vim then became the target of choice for tremor of all types. The introduction of levodopa in the early 1970s led to a dramatic decrease in the number of stereotactic surgeries for movement disorders (Levy, 1992). Two decades later, drug-related complications of medical treatment, including dyskinesias and fluctuations, had proven intractable (Marsden and Parkes, 1977; Marsden and Fahn, 1987). Neurophysiologic studies in the realistic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD had demonstrated increased activity in the subthalamic nucleus (STN) and the internal segment of the globus pallidus (GPi) (Bergmam et al., 1990). Finally, the demonstration that posteroventral GPi pallidotomy was effective for advanced PD (Laitinen et al., 1992) led to a resurgence in ablative approaches for the treatment of PD. The introduction of stimulation techniques led to decreased frequency of ablative approaches to the movement disorders (Siegfried and Lippitz, 1994; Benabid et al., 1996; Clatterbuck et al., 2000).
42.2. Mechanisms of parkinsonian motor symptoms PD affects approximately 1% of the population over 65 years (Adams et al., 1996). The three cardinal signs of PD are resting tremor, cogwheel rigidity and bradykinesia (Paulson and Stern, 1997). After years of treatment with levodopa, patients with PD often develop intractable complications of this therapy, including dyskinesias and fluctuations (Marsden and Parkes, 1977; Marsden and Fahn, 1987). The forebrain mechanisms of some of these symptoms have recently been clarified, leading to a rationale for effective targets for treatment of PD. 42.2.1. Bradykinesia The motor circuit of the basal ganglia includes a direct inhibitory pathway from the putamen to the internal segment of the GPi and an indirect, excitatory pathway from the putamen to GPi via the STN (see Ch. 1). In monkeys, GPi-inhibitory (GABAergic) efferents in the motor loop project to neurons of the monkey thalamic nucleus ventral lateral pars oralis (VLo) (Penney and Young, 1981; Young and Penney, 1984), corresponding to human Vop. Cortical projections activate these pathways, with a resultant reduction in inhibitory GPi activity via the direct pathway and an increase in inhibitory GPi activity via the indirect pathway. The motor manifestations of parkinsonism are seen with dysfunction of the nigrostriatal dopaminergic pathway (Hornykiewicz, 1974). Dopaminergic projections from the substantia nigra tend to activate the direct pathway (D1 dopamine receptor-mediated) and decrease the
*Correspondence to: Professor F. A. Lenz, Department of Neurosurgery, Meyer Building 8-181, Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, MD 21287-7713, USA. E-mail:
[email protected], Tel: þ1-410-955-2257, Fax:þ1- 410614-9877.
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activity of the indirect pathway (D2-receptor-mediated). Therefore, in PD there is decreased inhibition of GPi through the direct pathway and increased excitation though the indirect pathway. As a result of these effects of dopamine deficiency there is increased GPi activity leading to inhibition of Vop (Vitek et al., 1993). Thus thalamocortical and corticothalamic motor circuits might be inhibited, leading to slowing of movement initiation and of movement itself, i.e. bradykinesia (Penney and Young, 1981; Young and Penney, 1984; DeLong, 1990). 42.2.2. Tremor In the case of Parkinson’s tremor the most current hypothesis is a thalamic oscillator activated by hyperpolarization of the thalamocortical cells in VLo/Vop due to increased inhibitory input from the pallidum in PD (Bergman et al., 1990; Pare et al., 1990; see also Lamarre and Joffroy, 1979; Marsden, 1984; Elble and Koller, 1990). When inhibited, these cells generate a somatic calcium spike which produces an action potential burst (LTS bursts, low-threshold spike bursts) with a following inhibition, leading to recurrent oscillations (Filion et al., 1988; Buzsaki et al., 1990; Pare et al., 1990). However such bursts are rarely found in recordings from Vim and Vop of parkinsonian patients undergoing thalamotomy (Zirh et al., 1998; Magnin et al., 2000). Another proposed central generator is GPi, specifically neurons that project to and inhibit Vop neurons. This hypothesis is inconsistent with higher rates of tremor-related activity in a cerebellar relay (Vim: 25%) than a pallidal relay of patients with PD (Vop: 21%) (Lenz et al., 1994; Hua et al., 1998). Furthermore, GPi activity at tremor frequency is rarely correlated with tremor in PD (Hutchison et al., 1997b; Lemstra et al., 1999) or in monkey models of parkinsonism (Raz et al., 2000). Therefore, the activity of cells in thalamus and pallidum is not consistent with a pallidal generator for parkinsonian tremor. Another proposed mechanism of parkinsonian tremor is the peripheral-feedback hypothesis. This hypothesis proposes that tremor is the oscillation of unstable stretch reflex arcs (long-loop reflex arc) which may traverse motor cortex in much the same way tendon tap reflexes traverse the spinal cord (Desmedt, 1978; Lenz et al., 1983a, b). The increased gain of these reflexes may cause parkinsonian rigidity and tremor, in much the same way as increased spinal reflexes cause spasticity and clonus (Stein and Lee, 1981). This hypothesis has been supported by the finding that thalamic neuronal activity precedes tremor in the case of thalamic neurons with sensory inputs, but not those without (Strick, 1976; Lenz et al., 1990, 1994; Vitek
et al., 1994). Therefore sensory cells participating in a reflex or feedback loop might cause tremor. Finally, a transfer function analysis has demonstrated a feedback loop in > 90% of cells in the Vim and Vop (Schnider et al., 1989). 42.2.3. Dyskinesias The current model of hyperkinetic disorders (DeLong, 1990) suggests that a decrease in pallidal activity disinhibits the pallidal relays, VLo/Vop, by decreased inhibitory input to the thalamus from the pallidum (Penney and Young, 1981). In hemiballism the activity of neurons in GPi is characterized by firing rates which are lower and more irregular than parkinonsian patients ‘off’ or ‘on’ medications (intravenous apomorphine) (Suarez et al., 1997; Vitek et al., 1999), consistent with studies in monkeys (Nini et al., 1995). The pauses and grouped discharges of GPi neurons may be related to the random bursts of electromyogram (EMG) activity hemiballistic movements (Vitek et al., 1999). The importance of patterned GPi activity in hemiballismus is consistent with the efficacy of pallidotomy since pallidotomy will interrupt activity but not decreased pallidal firing (DeLong, 1990). A similar mechanism seems to be involved in drug (apomorphine)-related dyskinesias (Hutchison et al., 1997a; Merello et al., 1999). 42.2.4. Dystonia Dystonia is a common feature of PD. During dystonia of multiple etiologies, firing rates of cells in GPi are patterned and are intermediate between those in hemiballismus and normal monkeys (Vitek et al., 1995, 1998b; Suarez et al., 1997). However, ‘normal’ firing rates can occur with mild dystonia whereas decreased firing rates develop with repeated active movements which also exacerbate dystonia (Lenz et al., 1998). Thus the inverse relationship between GPi cellular firing and dystonia may be the result of cortically mediated, activity-dependent changes in striatal activity transmitted to GPi and then to Vop through the direct pathway (Albin et al., 1989; Carlson and Carlson, 1990). Decreased patterned firing of GPi neurons in patients with dystonia should produce an increased patterned firing in the monkey/human thalamic pallidal relay VLo/Vop. However, decreased, patterned firing was reported in Vop more than Vim during dystonia (Lenz et al., 1999), perhaps related to the dystonia-related plasticity of firing in GPi (Lenz et al., 1998). Thalamic dystonia frequency activity correlated with and leading dystonia is significantly more common in Vop than Vim. Lesions of GPi
ABLATIVE SURGERY FOR THE TREATMENT OF PARKINSON’S DISEASE (Vitek and Lenz, 1998) and presumed Vop (Andrew et al., 1983; Tasker et al., 1988; Cardoso et al., 1995; Lenz et al., 1999) can relieve dystonia, which suggests that, for neurons in Vop, patterned activity is more important than decreased firing rates in the mechanism of dystonia (Lenz et al., 1999). Therefore, there is reasonable rationale for lesions of the pallidum and Vop as treatment for the dystonia of PD.
42.3. Stereotactic surgical technique Radiologic and physiologic landmarks are usually used to localize accurately the target for ablative procedures (Bakay et al., 1992; Lozano et al., 1996; Garonzik et al., 2002; Patel et al., 2003). Many surgeons employ radiologic localization of the anterior (AC) and posterior commissure (PC) and of the border between the capsule and thalamus using computed tomography (CT) or magnetic resonance imaging (MRI) scans. The radiologic estimate of location is refined physiologically by microelectrode recording before radiofrequency lesioning (Mandir et al., 1997; Garonzik et al., 2002; Hua et al., 2004). Alternative approaches are to localize radiologically using ventriculography or CT/MR fusion techniques (Carlson and Iacono, 1999) and to localize physiologically using semimicroelectrode recording or macrostimulation (Burchiel, 1995) and to lesion using radiosurgery (Friedman et al., 1996; Kondziolka, 2002). The relative efficacy and safety of these different techniques have not been examined systematically.
42.4. Radiologic localization Ventriculography can still be used as a means of locating the ACPC line (Diederich et al., 1992; Schuurman et al., 2000), although it has largely been replaced by CT and MRI scanning. Computerized imaging is as accurate as ventriculography (Tasker et al., 1991) and does not carry the risks of ventricular puncture and instillation of contrast media into the ventricles. MRI scanning is slightly less accurate than CT scanning, with errors of approximately 2 mm on average and 4 mm at maximum (Kondziolka et al., 1992; Gerdes et al., 1994; Holtzheimer et al., 1999). This error is due to artifacts related to inhomogeneities and non-linearities in the gradient field – the positiondependent strength in the magnetic field (Hardy and Barnett, 1998). Artifacts can be induced by metal or magnetic suseptibility artifacts, produced at the interface between materials (e.g. air and bone) which have different tendencies to affect the magnetic field in a region.
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Attempts to decrease errors in MRI scan due to these artifacts include software modifications and overlapping (fusion) of the three-dimensional MRI database with the CT database which is not prone to these types of artifacts (Alexander et al., 1995). These databases can then be merged with atlas maps of anatomy to estimate the location of nuclei relative to the radiologic anatomy. These atlas maps may be transformed either to match the ACPC line in isolation or to match the ACPC line and other structures, such as the margins of the third ventricle or the internal capsule (Kelly et al., 1987; Dostrovsky, 1998). Another approach is to estimate the target directly from the AC–PC line as determined radiologically. The target for Vim is 3 mm anterior and 14 mm lateral to PC and 2 mm above the ACPC line. Alternatively, the target in Vim can be estimated in the lateral plane midway between the internal capsule and the lateral edge of the T2 intense medial dorsal nucleus of the thalamus (Hua et al., 2004). GPi can be estimated 3 mm anterior, 3 mm inferior and 20–22 mm lateral to the mid commissural point. Direct targeting can be carried out on axial and coronal inversion recovery series. On an axial cut through the ACPC line at the anterior posterior coordinate is the mid commissural point and the medial lateral coordinate is 4 mm medial to the external lamina separating the internal from the external pallidal segment. The vertical axis was targeted from the location of the optic tract and GPi on the coronal cut through the mid commissural point (Starr et al., 1999). The location of STN can be estimated at 4 mm posterior, 4 mm inferior and 12 mm lateral to the midpoint of ACPC (Guridi et al., 1999; Patel et al., 2003). STN can be directly localized using 2 mm, T2-weighted spin-echo sequence axial and coronal scans through the thalamus and midbrain. On such a series STN can also be localized 7 mm lateral and 4 mm anterior to the center of the red nucleus (Starr et al., 2002). Fusion of other MR series, such as gradient echo T2 and fast spin-echo series or CT can be used to localize STN and target the dorsal part of the posterior third of STN (Patel et al., 2003). Physiological confirmation of the radiologic estimate is carried out by stimulation or recording at and around the target.
42.5. Physiologic localization Radiologic targeting should be verified by identifying the different nuclei (GPi, STN and Vim) on the basis of properties such as spontaneous activity and neuronal firing related to the movement disorders and to passive and active movements. Nuclear properties are also defined by microstimulation (< 100 mA)-evoked
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sensations and motor effects such as alteration in the movement disorder, e.g. decreased tone or tremor. Physiologic localization can be carried out by stimulation using a macroelectrode (impedance < 1000 ohms) or by stimulation and recording using a semimicroelectrode (impedance < 100 kohms) or a microelectrode (impedance > 500 kohms). In our institution a map of physiologic results is made to the same scale as a set of transparent atlas maps from the sagittal sections of the Schaltenbrand and Bailey atlas (1959) parasagittal sections for different targets as follows: 13.5 mm lateral atlas map for Vim, 21 mm for GPi and 11 mm for the STN. The fusion and fitting of the imaging studies to the physiologic and atlas maps can also be accomplished through a number of commercially available surgical navigation systems.
stimulation determines the amount of local current spread (Ranck, 1975). Semimicroelectode recordings are carried out using low-impedance microelectrodes with an impedance of less than 100 kohms. The semimicroelectrode signal is often amplified against a concentric ring electrode which is located on a radius of 0.4 mm around the microelectrode (Taren et al., 1968; Burchiel, 1995; Ohye, 1998). Recordings through a semimicroelectrode will yield recordings of local field potentials (slow waves) or multiunit activity. Bipolar stimulation through a concentric ring electrode can be used alone or in combination with recording through a semimicroelectrode (Ojemann and Ward, 1982; Tasker et al., 1982; Laitinen and Hariz, 1996).
42.5.1. Microelectrode localization
42.6.1. Radiofrequency
Microelectrodes for physiologic monitoring and recording are designed to isolate single action potentials (Hubel, 1957; Jasper and Bertrand, 1966; Lenz et al., 1988a) and to withstand microstimulation which degrades the electrode. Typically these characteristics are achieved by constructing electrodes from a platinum-iridium alloy or from tungsten, producing a tapered tip and insulating with glass (Hubel, 1957; Wolbarsht et al., 1960; Umbach and Ehrhardt, 1965; Albe-Fessard, 1973; Ohye, 1982; Lenz et al., 1988a). The electrode impedance is usually (Lozano et al., 1996) greater than 500 kohms (Jasper and Bertrand, 1966; Lenz et al., 1988a). A highimpedance microelectrode is required to isolate single units (Lenz et al., 1988a). The assembled electrode is attached to a hydraulic or piezoelectric microdrive and mounted on the stereotaxic frame. Some microdrive systems incorporate a coarse drive so that overlying structures can be traversed quickly. The tip is then retracted into a protective cylindrical housing while the whole assembly is advanced to a new depth (Vitek et al., 1998a). The microdrive may then be employed from this new depth for detailed exploration of deeper structures. Another option is to use the microdrive throughout the trajectory by advancing it each time it reaches the end of its traverse (Lenz et al., 1988a). The signal from the microelectrode is amplified and filtered. Multiple neuronal discharges of varying sizes may be seen on an oscilloscope and heard by use of an audio monitor. In addition to recording, microstimulation of subcortical structures may be delivered. We employ biphasic, square-wave pulse trains of 0.1–0.3 ms pulses for up to 10 seconds at a frequency of 300 Hz (Lenz et al., 1993). The current used in
One or two lesions are then made at the target defined by the above techniques. Lesions are made by the technique of radiofrequency coagulation using an electrode with a 1.1 mm outer diameter and a 3 mm exposed tip and a thermister at the tip of the electrode (TM electrode: Radionics, Burlington, MA). Temperature is held constant at 60 C over a 1-minute interval. The temperature is increased in 5–10 C steps during subsequent 1-minute intervals to a level of approximately 80 C. Since temperature is increased in steps of about 10 C, the average length of time to make the lesion is 4 minutes. Neurologic examination stresses the function of structures adjacent to the target so that during GPi coagulation motor strength and visual fields are stressed. In the case of Vim, the examination stresses cutaneous sensory, pyramidal and cerebellar function, plus speech. These abbreviated exams should be carried out before, during and after each stage of lesion-making. The coagulum of each such separate lesion made by this technique is approximated to a cylinder with a diameter of 3 mm and a length of 5 mm (Cosman and Cosman, 1985; Lenz et al., 1995).
42.6. Stereotactic lesioning technique
42.6.2. Localization of Vim Sensory cells responding to sensory stimulation in small, well-defined, receptive fields are found in the ventral caudal thalamic nucleus (Vc), posterior to Vim (Lenz et al., 1988c). There is a well-described mediolateral somatotopy within Vc (Jasper and Bertrand, 1966; Lenz et al., 1988c) proceeding from representation of oral structures medially to leg laterally. In anterior Vc and further anterior in Vim, neuronal firing is related to passive joint movement (deep sensory cells) or to active
ABLATIVE SURGERY FOR THE TREATMENT OF PARKINSON’S DISEASE movement (voluntary cells) (Raeva, 1986; Lenz et al., 1990). Some neurons respond to both active movement and to sensory stimulation such as joint movement (combined cells) (Lenz et al., 1990, 1994). Deep sensory, combined and voluntary cells have activity correlated with EMG activity during tremor (Lenz et al., 1985, 1988b; Hua et al., 1998a) and have a somatotopy parallel to that in Vc. Stimulation in Vc will evoke somatic sensations (Lenz et al., 1993). Stimulation in Vim may produce brief movements or alter ongoing tremor or dystonia (Lenz et al., 1999). Thalamic semimicroelectrode recordings (Ohye, 1982, 1998; Burchiel, 1995) reveal patterns of neuronal activity parallel to those of microelectrode recordings. Macrostimulation through a low-impedance electrode (impedance often less than 1000 kohms) can reliably identify Vim by alterations in the movement disorder (Tasker et al., 1982) and capsule by stimulation-evoked tetanic contraction of skeletal muscle at low threshold (Ojemann and Ward, 1982; Tasker et al., 1982). Stimulation of intralaminar nuclei medial to Vc or Vim may evoke the recruiting response – long-latency, high-voltage, negative waves occurring over much of the cortex at the frequency of stimulation (usually less than 10 Hz) (Jones, 1985; Fisher et al., 1996). An analysis of the locations of tremor cells suggests that the optimal target for thalamotomy is located 2 mm anterior to Vc and 3 mm above the ACPC line (Lenz et al., 1995). Alternatively, targets in thalamotomy have been placed anterior to the site at which evoked potentials can be recorded in response to cutaneous stimulation of the fingers (Guiot et al., 1973; Kelly et al., 1978; Fox et al., 1991). Lesions have been made in the region where electrical stimulation produces effects on tremor and anterior to the region where electrical stimulation evokes sensations (Tasker et al., 1982). Lesions have also been made in the region where cells respond to somatosensory stimulation of muscle, joint and tendon and where electrical stimulation affects tremor (Ohye and Narabayashi, 1979). 42.6.3. Localization of target within the internal segment of the globus pallidus During pallidotomy, microelectrode penetrations toward the radiologic target are made from a coronal burrhole about 25 mm from the midline. Striatum, globus pallidus external segment (GPe) and GPi each have a characteristic pattern of neural activity (DeLong, 1971; Lozano et al., 1996; Mandir et al., 1997; Vitek et al., 1998a). Striatal cells are characterized by broad action potentials and a slow firing rate (approximately 1 Hz), often with long silent periods.
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Cells in GPe have narrower action potentials and fire either at high frequency (approximately 50 Hz) with intermittent pauses (pause cells) or at lower frequency (approximately 20 Hz) with intermittent bursts (burst cells). Cells in GPi fire tonically at high rates (60–80 Hz). Cellular activity is also recorded during passive movements of upper and lower extremities both ipsilateral and contralateral to the recording site to identify the cellular receptive field. Cells in GPi of PD patients often respond to movement of multiple joints. At the target the optic tract is about 1 mm below the lower border of GPi. The optic tract can be identified by the hissing sound resulting from the firing of multiple myelinated axons which increases in response to a flashing light (visual-evoked potentials). Microstimulation in the optic tract evokes multiple colored sparkles of light. The internal capsule behind GPi can be identified by the same hissing sound plus microstimulation-evoked muscle twitches. These data are used to generate a functional map of the target zone in sagittal section. Two lesions are made within the part of GPi where cells respond to movements of the extremities (Lozano et al., 1996; Mandir et al., 1997; Vitek et al., 1998a). Each lesion is made to 70 with the tip of the electrode 2 mm above the optic tract and to 80 with the tip 3–4 mm above the optic tract and in front of the internal capsule. Alternately, the lateral extend to the target may be estimated by lateral microelectrode trajectories and multiple small lesions (1–3 per trajectory) can be used to fit the lesion to the contours of GPi (Bakay et al., 1992; Vitek et al., 1998a). The value of microelectrode-guided lesion location in pallidotomy has often been debated. In one report microelectrode recording led to a change in final location for lesion placement in 14/20 (70%) cases (Hiner et al., 1997) with an average change of 3.5 mm. In another, 75% of cases were within 3 1 mm of the final lesion site, whereas 25% (4/10) were > 5 mm away (Azizi et al., 1996). Another study reported an incidence of correction of the radiologic target by microelectrode recording which was too high to justify pallidotomy without microelectrode recording (Taha et al., 1996). Although these results suggest that microelectrode recording increases the accuracy of pallidotomy, this position has not been proven (Hariz, 2002). 42.6.4. Localization of the subthalamic nucleus lesions During the subthalamic explorations, trajectories are made from a coronal burrhole about 25 mm from the midline. Striatum and Voa thalamus each have a
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characteristic pattern of neural activity (Hutchison et al., 1998). As the electrode approaches the STN from anterior and dorsal directions, striatal cells are often encountered and are characterized by broad action potentials and a slow firing rate (approximately 1 Hz), often with long silent periods. When the thalamus is entered the action potentials become narrower and often occur in bursts of the LTS type (see above). LTS bursts are preceded by a silent period of 20–100 ms and consist of a interspike interval of less than 6 ms followed by interspike intervals of less than 16 ms (Zirh et al., 1998; Ramcharan et al., 2000). A relatively acellular gap of 1–6 mm is observed below the thalamus and above the STN, depending upon the anterior–posterior location of the trajectory. The STN is characterized by multiple spike trains recorded from closely packed neurons, each with a mean rate of about 20 ms. Microstimulation evokes paresthesias posterior to STN, muscle contractions lateral to STN and decreases in tremor or tone within STN. The single lesion may be made dorsolateral to STN (Patel et al., 2003) or two lesions may be made within STN but located 3 mm apart in the medial lateral plane (Lopez-Flores et al., 2003), with much different results (see below).
42.7. Results In this section we will consider the indications, efficacy, complications/safety for pallidotomy, thalamotomy and subthalamotomy. The analysis of efficacy and safety was based on the comprehensive assessment of lesioning procedures for the treatment of PD. This assessment by the Therapeutics and Technology Assessment Committee of the American Academy of Neurology (TTA-AAN) led to a position paper on surgery for PD based on a systematic evaluation of the literature (Hallett and Litvan, 1999). This paper was subsequently updated and endorsed in a scientific position paper by the Movement Disorder Society (MDS) (Hallett and Litvan, 2000). The literature searches were based on papers identified in four databases for the medical literature which were searched for terms related to surgical treatment of PD. All papers included in the analysis had to meet the minimum standard of class III evidence as follows: non-randomized, retrospective studies with historical controls which were peer-reviewed, used validated methods of assessment and provided consistent, clinical (rather than technical) data. Although most studies considered were prospective, a few included a concurrent control group, a requirement necessary to meet class II evidence, and fewer still were randomized, controlled studies.
For each procedure this review considered the following subjects: (1) indications prior to the TTAAAN/MDS position papers; (2) randomized controlled studies of the procedures; (3) studies included in the position papers and then the final ATT-AAN/MDS recommendation. 42.7.1. General comments on all procedures Across all procedures the TTA-AAN/MDS position papers made a number of general comments, as follows. The publications included in these position papers were carried out by groups having neurosurgeons and neurophysiologists with particular expertise in functional stereotactic procedures, as well as neurologists with expertise in movement disorders. Inexperienced centers had less success and more complications in all surgical procedures. Cognitive impairment was a predictor of poor outcome and patients with advanced age derived less benefit. Contraindications were medical or psychiatric conditions and abnormal imaging studies, including focal lesions or atrophy greater than expected for age (Hallett and Litvan, 1999). Many of the complications of ablative stereotactic surgery are common to all procedures. Complications from lesion-making can arise from infection or intracranial hemorrhage. Hemorrhages comprise a significant percentage of operative mortalities in stereotactic surgery, occurring in 1–6% of procedures (Louw and Burchiel, 1998). Hemorrhages may occur at the lesion site or at cortical sites, resulting in intracerebral or subdural hematomas. The risk of radiologically defined hemorrhage during functional stereotactic procedures employing coagulation is 9/57 overall (16%; Vim 5/ 23: 22%; GPi 4/34: 12%) and the risk of symptomatic bleeding is 4/57 (7%) (Terao et al., 2003). This is greater than the risk of deep brain stimulation (DBS) surgery (3%: 2/59). Following stereotactic biopsy, radiologically defined bleeds occurred in 40/500 (8%); delayed hemorrhages as defined by CT and symptoms occurred rarely, but always occurred within 48 hours of the procedure (0.4%, 2/500) (Kondziolka et al., 1998). Overall 12 patients were symptomatic (1.2%) and 1 died (0.2%). In that study platelet counts of less than 150 000 were identified as a risk of bleeding in comparison with higher counts. 42.7.2. Pallidotomy for Parkinson’s disease At the time of rebirth of surgical approaches to the treatment of PD, pallidotomy was considered an option for treatment of patients with advanced PD who have motor drug-related complications, particularly
ABLATIVE SURGERY FOR THE TREATMENT OF PARKINSON’S DISEASE dyskinesias and fluctuations (Laitinen et al., 1992; Krack et al., 2000). These symptoms should be disabling and unresponsive to optimal medical therapy if they are to be considered as indications for pallidotomy. Patients with relatively less advanced disease but who are disabled by tremor or dystonia are also candidates for these procedures. 42.7.2.1. Randomized, controlled studies of pallidotomy There are two randomized, controlled studies of pallidotomy for the treatment of PD (de Bie et al., 1999; Vitek et al., 2003). In the most recent study 18 patients were randomized each to best medical therapy and to unilateral pallidotomy (Vitek et al., 2003). The change in the Unified Parkinson’s Disease Rating Scale (UPDRS) scale at 6 months demonstrated that the pallidotomy group had significant improvement whereas the medical arm was slightly worse (overall 35% versus –5%, ‘off’ motor 32% versus –3%). In the surgical patients improvements were most significant in the symptoms of contralateral tremor, rigidity and dyskinesia. Improvements in postural stability, gait and bradykinesia were less significant (Vitek et al., 2003). Improvements during the ‘off’ periods were always larger than those in the ‘on’ periods, which were often insignificant. Patients in the medical arm were given the option of surgery at 6-month follow-up and all patients opted for surgery. Follow-up in 20 of the 36 patients was obtained at 2 years postoperative and showed highly significant (P < 0.00001) improvements in the UPDRS overall (21%), in the ‘off’ motor subscale (26%) and in the drug-related complications subscale (fluctuations and dyskinesias, 58%). Sustained improvements in tremor, rigidity, bradykinesia, percentage on time and drug-related dyskinesias were also observed. There was a highly significant relationship between UPDRS score at 2 years and age. Patients who were aged 50 or less had twice the reduction in the UPDRS score of those greater than 60 years of age. There were some significant complications (6/36: 17%). Two patients had seizures intraoperatively, delaying the completion of the procedure by weeks. Four patients had hemorrhages, 1 of whom had ‘worsening of speech’, which resolved by 6 months postoperatively. Similar results were obtained in an earlier randomized, controlled, single-blind, multicenter trial of pallidotomy versus best medical therapy (de Bie et al., 1999). At 6 months the ‘off’ condition of the UPDRS motor subscale improved (44%) significantly in the surgical group whereas it decreased in medical controls (–7%). The ‘on’-phase motor UPDRS improved by 50% in the surgical group but was
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unchanged in the medical group. The UPDRS-2 activities of daily living subscale improved by 23% in the surgical group and diminished by 16% in the medical group. All but 2 of the patients in the medical arm crossed over but results were not reported. In the surgical group of 19 there were 6 patients (32%) with persistent complications, including: psychosis and dysarthria/imbalance (one each) and 4 with minor complications including dysarthria, facial weakness, urinary incontinence and mental status change. Therefore, controlled randomized trials have shown consistent benefit for motor function as measured by the UPDRS motor scale. Complications in pallidotomy ranged from 17% to 57%, suggesting technical differences between centers. 42.7.2.2. Prospective uncontrolled studies A review combining results of unilateral pallidotomy examined all original studies of surgical outcome with or without validated measures of clinical PD status or a control group (Alkhani and Lozano, 2001). Those studied using the validated UPDRS scores at 1 year reported 45% improvement in ‘off’ UPDRS motor subscale and 35% improvement in the combined motor and activities of daily living subscales. In addition, there was a 41% improvement in the Schwab and England activities of daily living scale (Alkhani and Lozano, 2001). Contralateral ‘on’-period dyskinesias improved by 86%. The beneficial effect on ipsilateral dyskinesias was lost by 1 year whereas the effect on gait and balance was lost by 3–6 months. Greater than 50% improvements at 1 year were observed in tremor and rigidity scales. This is consistent with another review of studies of unilateral pallidotomy which showed a 30% improvement in the UPDRS motor subscale and in the UPDRS overall (Okun and Vitek, 2004). Levodopa-equivalent dose was not decreased postoperatively (Alkhani and Lozano, 2001; Okun and Vitek, 2004). Continued benefit has been documented up to 2 years postoperatively (Lang et al., 1997). Complications were common. Overall there was a hemorrhage rate of 1.7%, resulting in a mortality rate of 0.4% (Alkhani and Lozano, 2001). The incidence of visual field defects was variable, as a function of institution, with permanent deficits in 1.5%. Persistent facial and limb weakness was observed in 1.3% and 0.9%, respectively. Persistent dysarthria, hypophonia and dysphagia were reported in 1.6%, 1.3% and 0.5%, respectively. Postoperative confusion, which was usually transient, occurred in about 10% of patients. Overall, the morbidity rate was 23%, of which 14% were permanent, as assessed by summing all complications across and within patients and dividing by the total
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number of patients. Older patients were more likely to have cognitive problems and left-sided lesions were associated with persistent verbal deficits (Saint-Cyr et al., 1996). 42.7.2.3. Bilateral pallidotomy A small, multicenter prospective study of staged bilateral pallidotomy controlled the second side against the first and found significant differences between the two pallidotomies (Parkin et al., 2002). Three months after the first pallidotomy there was a significant decrease in the off UPDRS motor score (mean 27%, P < 0.05) and dyskinesias were completely abolished in 40%. After the second side these figures were 31% and 63%. At 1 year after the second side the improvement in the motor scales diminished but the effect on activities of daily living scales and dyskinesias was maintained. Persistent complications were reported in 4%, much less than the average for unilateral pallidotomies (Saint-Cyr et al., 1996). An earlier retrospective study of 25 patients reported efficacy for simultaneous, bilateral pallidotomy in the treatment of bilateral symptoms and dyskinesias without surgical complications (Iacono et al., 1997). A prospective study compared the efficacy of the second staged side of a bilateral pallidotomy with the first side (de Bie et al., 2002). Clinical ratings after the first surgery were significantly improved for the ‘off’ UPDRS motor and activities of daily living scales and the Schwab and England scales. There was a trend toward improvement in the first two of these scales for the second as compared to the first procedure. Three out of 10 patients had persistent complications following the first pallidotomy whereas 8/10 had such complications after the second, including dysarthria (n ¼ 7), hypothonia (n ¼ 1), hemiplegia (n ¼ 1) and visual field defect (n ¼ 1). Thus, the pallidotomy is associated with an incremental improvement of more than the improvement after the first side with a variable rate of complications. 42.7.2.4. TTA-AAN/MDS recommendation regarding pallidotomy Forty studies of pallidotomy were found in the position papers, of which approximately one-half met the criteria listed above (Laitinen et al., 1992; Dogali et al., 1995; Lozano et al., 1995; Baron et al., 1996; Fazzini et al., 1997; Hariz and De Salles, 1997; Kazumata et al., 1997; Kishore et al., 1997; Krauss et al., 1997; Lang et al., 1997; Soukup et al., 1997; Uitti et al., 1997; Biousse et al., 1998; Cahn et al., 1998; Giller et al., 1998; Lozano et al., 1998; Masterman et al., 1998; Ondo et al., 1998; Shannon et al., 1998; Samuel
et al., 1998; Scott et al., 1998; Trepanier et al., 1998). Unilateral pallidotomy was recommended as effective and safe based on class III evidence. Unilateral pallidotomy was thought to be indicated for patients with PD with fluctuations, bradykinesia, tremor and rigidity and particularly for those with dyskinesias. The benefit for gait and postural disturbances was judged to be less pronounced. Based on the unreliable, contradictory data and reports of speech complications, bilateral pallidotomy was given a type D negative recommendation. 42.7.3. Thalamotomy for Parkinson’s disease Studies published prior to the mid-1980s established thalamotomy as an option for patients with PD who are disabled by tremor and who have not responded to medication, including levodopa-carbidopa and anticholinergics (Narabayashi, 1982; Nagaseki et al., 1986). Contraindications to thalamotomy include patients who have dementia, significant medical illness or Parkinson’s plus syndromes (e.g. Shy–Drager, multisystem atrophy). 42.7.3.1. Randomized, controlled trial of Vim thalamotomy versus Vim-DBS A recent trial compared Vim thalamotomy versus DBS in 68 patients with PT (n ¼ 45), as well as patients with essential tremor (n ¼ 13) and intention tremor (n ¼ 10) (Schuurman et al., 2000). Among patients with parkinsonian tremor, abolition or slight residual tremor was seen post-Vim-DBS 21/21 (100%) and in 21/23 (93%) of patients postthalamotomy. Overall, types of tremor functional scales (Schuling et al., 1993) demonstrated a significantly greater increase in functional ability for Vim-DBS (16%) versus thalamotomy (2%). Functional status was improved in significantly more patients following Vim-DBS (54%, 18/33) than thalamotomy (24%, 8/34). Overall, tremor was abolished or minimal residual in 30/33 (90%) of patients treated with Vim-DBS and 27/34 (79%) of patients treated with thalamotomy (Schuurman et al., 2000). The only death, secondary to intracerebral hematoma, occurred in the Vim-DBS group. Nevertheless, complications overall were more common in the thalamotomy group. In PT patients at 6 months postoperatively cognitive deterioration was found in 1 patient postthalamotomy versus none post-Vim-DBS, mild dysarthria in 3 versus 1, severe dysarthria in 3 versus 1, gait and balance disturbance was mild in 3 versus 0 and severe in 4 versus 0 and there was arm ataxia in 1 versus 0. Overall, significantly more patients (16/ 34) had complications postthalamotomy than patients following Vim-DBS stimulation (6/33).
ABLATIVE SURGERY FOR THE TREATMENT OF PARKINSON’S DISEASE 42.7.3.2. Prospective, uncontrolled studies of thalamotomy for Parkinson’s disease Vim thalamotomies have been performed for PT over five decades and advances in technology during this period have improved the accuracy and safety of this operation. CT or MR imaging as well as microelectrode recording has advanced the technical standards of thalamotomy. Tasker (1990) reported that good results from thalamotomy increased from 45% for surgeries performed before 1967 to 86–96% for surgeries carried out during the 1970s. Reports of thalamotomies performed from 1980 to 1990 reveal good results in 86–94% of cases (Fox et al., 1991; Jankovic et al., 1995). One such study reported the results of Vim thalamotomy performed between 1982 and 1994 in 42 patients with severe, asymmetric, medically intractable parkinsonian tremor (Jankovic et al., 1995). Thalamotomies were guided by CT or ventriculographic localization and microelectrode recording. Treating physicians performed outcome assessments using the UPDRS and a global tremor-rating scale. Tremor was completely abolished in 72% (31/42) of cases, whereas an additional 14% (6/42) showed significant improvement in tremor and functional ability. None of the patients who were tremor-free after surgery experienced a recurrence of the tremor at long-term follow-up (60–158 months). Similar efficacy rates were reported in another study, in which 37 Vim thalamotomies were performed between 1984 and 1989 for medically refractory parkinsonian tremor (Fox et al., 1991). CT localization and microelectrode guidance were used. At the time of discharge, complete abolition of contralateral tremor was seen in 94% (34/36), which was maintained in 81% (13/16) at 3 years. All recurrences occurred within 3 months of surgery. In a third study ventriculography and macrostimulation were used to localize the lesion site, which was thought to be in Vop, a thalamic pallidal relay nucleus (Wester and Hauglie-Hanssen, 1990), unlike the Vim target chosen in other studies reviewed here. Good to moderate improvement was achieved in 82% (27/33) of patients with Parkinson’s tremor, as assessed by the referring neurologists. One blinded, long-term assessment of the efficacy of thalamotomy compared tremor in the arm contralateral to thalamotomy versus the ipsilateral arm (Diederich et al., 1992). The potentially confounding effect of asymmetry in tremor was not considered. Thalamotomies were performed between 1976 and 1985 and patients were followed for a mean of 10 years. A significant concordance for UPDRS score
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was demonstrated between blinded raters and tremor severity scores were consistently better contralateral to surgery. This study suggests that thalamotomy can abolish tremor. Tasker (1998) has reported that tremor which was completely abolished contralateral to a thalamic lesion for 3 months never recurred. Such results have prompted some to propose that thalamotomy may actually alter the course of PD (Matsumoto et al., 1984). An investigation into this issue has revealed three subgroups of PD in which the disease progresses so slowly that elimination of the major symptoms may appear to have altered the progression of the disease. PD of the young-onset, postencephalitis type and a subset of patients with idiopathic parkinsonism all seem to have very slow progression of their parkinsonian symptoms (Tasker, 1998). Thus elimination of tremor in these patients might give the appearance of a long-term ‘cure’. 42.7.3.3. Thalamotomy for dyskinesias in Parkinson’s disease In addition to the reduction of tremor symptoms, several studies have shown that patients require less or no levodopa after thalamotomy (Fox et al., 1991; Jankovic et al., 1995). This decreased requirement for levodopa helps to reduce the drug-related complications of PD (e.g. dyskinesias). Independent of this reduction of levodopa, thalamotomy has been shown to reduce levodopa-induced dyskinesias (Jankovic et al., 1995). Narabayashi et al. (1984) reported that, although levodopa dyskinesias are ameliorated by Vim thalamotomy, the optimal site for a lesion to relieve dyskinesias may be Vop, just anterior to Vim. Such reduction in dyskinesia and increased tolerance of levodopa is important for patients who have other parkinsonian symptoms in addition to tremor, such as bradykinesia and rigidity (Poewe and Granata, 1997). 42.7.3.4. Complications of thalamotomy Neurological complications specific to thalamotomy can be explained by lesion-induced disruption of the cerebellothalamocortical pathway or damage to thalamic and nearby structures. In a series of 60 patients with essential, parkinsonian or cerebellar tremor, functional deficits in the immediate postoperative period were reported in 58% of patients (Jankovic et al., 1995). These transient deficits included weakness (34%), dysarthria (29%), ataxia (8%), dystonia (5%) and sensory deficits (3%). Cognitive deficits were seen, including disorientation and somnolence, as well as speech and language deficits, including
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hypophonia. Functional deficits persisted in 23% but were generally mild and did not increase disability (Jankovic et al., 1995). In a series of 34 patients operated on for parkinsonian tremor, there were permanent complications in 14% (5), including apraxia (1), dysarthria (2), dysphasia (1) and abulia (1) (Fox et al., 1991). Transient complications in 61% included cognitive decline (5), central facial (10) or hand weakness (7) and hand numbness (2). Half of the transient deficits resolved by 1 week and most deficits, including transient and permanent, had resolved at the 3-month follow-up visit. Parkinsonian patients in the study of Wester and Hauglie-Hassen (1990) had mild complications, ‘not yielding invalidity’, in 36% (12/33), including: mild mental status changes in 4, mild contralateral weakness in 3, dysphasia in 4 and dysarthia in 1. Significant complications occurred in 18% (6/33), including: mental status change in 3, dysphasia in 1 and dysarthia in 2. Thus, significant or permanent side-effects were often observed in patients with PD, as in essential and intention tremor. Therefore, the best available evidence supports a rate of transient complications in approximately 60% of patients and persistent complications in the range of 15–20%. 42.7.3.5 TTA-AAN/MDS recommendation regarding thalamotomy For thalamotomy, 18 articles were found in the TTAAAN study, but only the four studies cited above met the TTAS-AAN criteria (Wester and Hauglie-Hanssen, 1990; Fox et al., 1991; Diederich et al., 1992; Jankovic et al., 1995). Thalamotomy was recommended as effective and safe for asymmetric, severe, medically intractable tremor, particularly for the tremor variant of PD. This was a positive recommendation based on results of prospective studies with historical controls. It was judged to be possibly effective for the treatment of dyskinesias and rigidity. Thalamotomy was not thought to be effective for micrographia, bradykinesia or difficulties of gait or speech. Thalamotomy on the second side was felt to be effective for the treatment of tremor but to be associated with a high incidence of speech and swallowing difficulty. Therefore a class D negative recommendation was made for bilateral thalamotomy; Vim-DBS was recommended on the second side. 42.7.4. Subthalamotomy There are no historical studies of subthalamotomy for the treatment of PD so that indications for surgery were based upon general principles. The first study
of subthalmotomy included patients with relatively early PD characterized by hemiparkinsonism (‘off’ Hoehn and Yahr scale 3.1) (Patel et al., 2003). In this study many patients were disabled by tremor but not other parkinsonian symptoms, i.e. the tremor variant of PD. In the other study subthalamotomy was carried out in patients (n ¼ 18) with bilateral involvement indicating more advanced disease, as reflected in the ‘off’ Hoehn and Yahr grade of III in 22% and of IV in 78% (Alvarez et al., 2005). These two studies of subthalamotomy for PD were also much different with respect to techniques and results. In the first, unilateral single lesions of the dorsolateral STN were made to 80 C for 60 seconds with an electrode having a 2 mm exposed tip. Postoperative MRIs demonstrated extension of the lesions dorsal to STN, i.e. zona incerta, in 19 of 21 cases. At 6 months there was an improvement in total UPDRS of 22% ‘off’ and 24% ‘on’, both of which were maintained at 24 months, 18% and 11% respectively. There was a significant improvement in ‘off’ UPDRS activities of daily living scale at 6 (19%) but not 24 months. UPDRS III (motor) ‘off’ was significantly improved at 6 months contralateral to the lesion (36%) and overall (19%) and at 24 months (16% contralateral and 38% overall). There were also significant improvements in tremor, rigidity and bradykinesia in all patients followed for 12 and 24 months. Levodopaequivalent doses were approximately halved postoperatively. Neuropsychological tests revealed mild cognitive deficits of verbal function observed on tests such as the Rey auditory verbal learning test. Intractable dyskinesias occurred in 1 patient but responded to implantation of a DBS electrode into the zona incerta. The technique and results of the second study of subthalamotomy for PD (Alvarez et al., 2005) were much different from the first. Lesions were made to a temperature of 70 C for 60 seconds with an electrode having a 2 mm exposed tip. Two of these lesions were made centered in the STN and located 3 mm apart in the medial–lateral plane. UPDRS motor scores were improved by 50% in the ‘off’ state and 38% in the ‘on’ state, measured at the time of last assessment, a minimum of 3 years postoperatively. Tremor, rigidity, bradykinesia, activities of daily living and dyskinesias were all significantly improved at the time of the last assessment. Three patients had severe postoperative dyskinesias which resolved over 3–6 months. Two of these patients developed severe persistent gait instability. Two of these and 1 other patient had severe persistent postoperative dysharthria. These 4 patients had lesion temperatures of 80 C for 1 minute and had large
ABLATIVE SURGERY FOR THE TREATMENT OF PARKINSON’S DISEASE lesions that were 30–40% larger than the average for the rest of the population. Two of the patients with severe dyskinesias and 1 other developed severe ataxia and broad-based gait which ‘improved substantially’ by 1 year. Severe ataxia occurred in a third patient who also had a larger than expected lesion. Thus there were significant, persistent complications in 26% of patients in this study. Therefore, both studies demonstrated significant long-term improvements at 2 years postoperatively. The first had relatively limited morbidity, whereas the second had significant, persistent morbidity, perhaps related to inclusion of patients with more advanced PD or to the bilateral, large lesions. Subthalamotomy was not included in the TTC-AAC/MDS review. The results reviewed here suggest that both unilateral and bilateral subthalamotomy may be effective procedures. The safety of these procedures is in doubt because of inconsistent reports of significant persistent complications, possibly related to surgical technique and the extent of the lesions. Since there is only one report each for unilateral and bilateral subthalamotomy, it is not possible at present to assess the consistency of these results or to make a recommendation. 42.7.5. Radiosurgery for the treatment of movement disorders The use of MRI to provide radiologic localization has led to the development of stereotactic radiosurgical ablation. The majority of stereotactic gamma-knife procedures are carried out with an 50% isodose plan (Kondziolka, 2002) using 4 mm collimators, sometimes located on a secondary collimator helmet (Young et al., 1998) and sometimes on the standard 201 cobalt source helmet. Maximal doses of 120–160 Gy are usually used (Niranjan et al., 1999), although doses of approximately 180 Gy (Friedman et al., 1996; Pan et al., 1996) or 200 Gy have also been reported (Friehs et al., 1997). Lesions with a volume of approximately 250 mm3 are created (Duma et al., 1998; Young et al., 1998). The lesion placement is estimated from the usual location of Vim in relation to the AC and PC and the internal capsule (Duma et al., 1998; Young et al., 1998). In the largest of these series, MRI-guided gammaknife procedures (4 mm collimator, 110–165 Gy, 50% isodose line at the medial edge of the internal capsule) were carried out in 34 patients with Parkinson’s tremor at high risk for standard stereotactic procedures (Duma et al., 1998). Patients and their physicians rated the outcome using the UPDRS tremor scale. Retrospectively, the groups were stratified by radiation dose into
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110–135 Gy and 140–165 Gy groups. A good to excellent result (increase of 2–3 UPDRS grades at three evaluations) was significantly more common in the high- (78%) than the low-dose group (56%), which was less than their success with standard stereotactic procedures. No complications were reported at minimum follow-up of 5 months (median 28 months). Another series of MRI-guided gamma-knife radiosurgery reported complete to nearly complete relief of tremor in 88% of cases (n ¼ 27) (Young et al., 1998). An older series of patients with intention, parkinsonian and undefined tremor reported good outcome of MRIguided gamma-knife thalamotomy in 66% of cases (n ¼ 9) (Rand et al., 1992). No complications were reported to occur in these latter two series. Linear accelerator thalamotomy targeting the central median and parafascicular nuclei for the treatment of neuropathic and central pain has been reported in 3 cases (Frighetto et al., 2004). The lesion (75–100 Gy) was made 4 mm anterior to PC and 10 mm lateral to the ACPC line using a 5 mm collimator along 5–8 non-coplanar arcs separated by 20 . Postoperatively immediate pain relief was reported in all 3 cases based on the assessment of the treating physician. Post-MRIs showed lesions 7 8 mm in the posterior ventral medial thalamus and 3.5 5 mm in the posterior ventral thalamus. No complications were reported. In contrast to these series is a report of 9 complications encountered at Emory University Altanta, GA, from a series of gamma-knife ablations for movement disorders carried out at a nearby medical center (Okun et al., 2001, 2002). These complications occurred among an estimated total of 118 patients, including PD in 96: 7 had the tremor-predominant variant and there was essential tremor in 22 (Okun et al., 2001, 2002). In this series, patients were found to have onset of benefit from the radiation never to 6 months and onset of complications from 5 to 10 months. Complications included weakness or paresis (n ¼ 3), visual loss, speech/bulbar symptoms (n ¼ 3), dysphagia/ aspiration pneumonia/death (n ¼ 1). This report resulted in a debate centered on technique (Kondziolka, 2002), interpretation of the accuracy of these lesions (De Salles et al., 2003) and the complications of gamma-knife versus open procedures (Kondziolka, 2002). The conservative interpretation of this debate is that gamma-knife (4 mm collimator, 120–40 Gy, targeting with a 50% isodose line) is indicated for thalamotomy, but not pallidotomy, in patients whose high surgical risk precludes a microelectrode-guided, radiofrequency procedure (Kondziolka, 2002). The need for a consensus and for prospective or controlled studies of gamma-knife movement disorder surgery is clear (Okun et al., 2002).
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42.7.6. Lesions versus stimulation for treatment of Parkinson’s disease 42.7.6.1. Pallidotomy As a way of evaluating ablative versus stimulation procedures we now compare the best data for ablative procedures with that for stimulation of the same anatomic locus. In the two randomized, controlled trials of pallidotomy for the treatment of PD there was a significant improvement in ‘off’ motor UPDRS score of 35–44% versus slight deterioration in the medical group (–5% and –7%) at 6 months (de Bie et al., 1999; Vitek et al., 2003). Results of the surgical group at 6 months were preserved at 2 years in the whole cohort following cross-over (Vitek et al., 2003). Two patients had seizures intraoperatively which delayed the pallidotomy. There were 4 hemorrhages, 1 with temporary ‘worsening of speech’, which resolved by 6 months postoperatively (17%). Similar results were obtained in an earlier randomized, controlled, single-blind, multicenter trial of pallidotomy versus best medical therapy (de Bie et al., 1999). At 6 months the ‘off’ condition of the UPDRS motor subscale improved (44%) significantly in the surgical group whereas it decreased in medical controls (–7%). The ‘on’ motor UPDRS and activities of daily living subscale were both improved in comparison with the medical group. In the surgical group of 19 there were 2 patients with major complications and 4 patients with minor but persistent side-effects (32%). Pallidal stimulation in patients with advanced PD (n ¼ 38) in a prospective trial with a non-randomized control group of patients with subthalamic stimulators showed a UPDRS motor score improvement of 49% and an increase in ‘on’ time without dyskinesias from 24 to 64% of the day at 3 months. In the total study (n ¼ 140) there were 7 hemorrhages (5%), 6 with neurologic deficits, of which 4 were persistent (3%). Thus the results of a controlled prospective study for GPi-DBS are similar to those of the randomized controlled study of pallidotomy with higher rates of surgical complications in the pallidotomy group. A small randomized, controlled, multicenter trial of unilateral pallidotomy versus bilateral STN stimulation has been reported; the latter is often considered to be the best surgical treatment for advanced PD. Patients had advanced PD (n ¼ 34, Hoehn and Yahr > 4 in 20/34) (Esselink et al., 2004) and both surgical groups were improved by off UPDRS motor scale; the primary outcome was variable. The improvement was less in the pallidotomy group (15%) than in the subthalamic stimulation group (37%). Dyskinesias improved in both groups; the duration but not severity
of dyskinesias was significantly better in the subthalamic stimulation group. Pallidotomy patients had persistent complications in 9/14 (64%) whereas the stimulation patients had complications in 8/20 (40%). This study demonstrated significantly greater benefit for bilateral subthalamic stimulation than unilateral pallidotomy with numerous significant complications of both procedures. 42.7.6.2. Thalamotomy The primary alternative to Vim thalamotomy for tremor has been implantation of DBS electrodes into the VIM. The two have recently been compared in a recent trial of surgery for parkinsonian, essential and intention tremor (Schuurman et al., 2000). Among patients with parkinsonian tremor (PT), abolition or slight residual tremor was seen post-Vim-DBS in 21/21 (100%) and 21/23 (93%) of patients postthalamotomy. Functional status was reported to be improved in significantly more patients following Vim-DBS (18/33, 54%) than in patients with thalamotomy (24%, 8/34). Although the only death occurred in the DBS group, there were significantly more complications in the group undergoing thalamotomy (16/34, P < 0.05) than in those undergoing Vim-DBS (6/33). Thus Vim-DBS was safer and more effective than thalamotomy in PD. 42.7.6.3. Subthalamotomy The subthalamotomy study with bilateral surgery in patients with more advanced disease is more comparable to a study of STN-DBS (Alvarez et al., 2005). UPDRS motor scores were improved by 50% in the ‘off’ state at a minimum of 3 years postoperatively. Tremor, rigidity, bradykinesia activities of daily living and dyskinesias were all significantly decreased at the time of the last assessment. Severe persistent complications, including imbalance, dyskinesias and ataxia, occurred in 28% of these patients. On the contrary, no severe persistent complications were encountered in a study of subthalamotomy in patients with less advanced PD, with unilateral lesions (Patel et al., 2003). A prospective, uncontrolled study of bilateral STN-DBS in patients with advanced PD with 5-year follow-up (n ¼ 42) had UPDRS motor scale (54%) and activities of daily living (49%) improvements in comparison with preoperative baseline (Krack et al., 2003). All subscales except speech were improved with respect to baseline. Levodopa equivalents were decreased in comparison with baseline, as was the amount of drug-related dyskinesia. Surgical complications were limited to death secondary to an intracerebral hematoma and suicide (1 each). Thus the efficacy is similar for STN-DBS and subthalamotomy.
ABLATIVE SURGERY FOR THE TREATMENT OF PARKINSON’S DISEASE However, the risks are higher for bilateral, but not unilateral, subthalamotomy. Therefore, the efficacy is similar for ablative and stimulation procedures in the subthalamus and pallidum. The efficacy of Vim-thalamotomy is less than that for Vim-DBS. The rate of complications, both transient and permanent, is much higher for ablative procedures. Thus, lesions of the subthalamus, thalamus and pallidum are indicated when stimulation is contraindicated by the particular circumstances of an individual patient. Acknowledgments Some of the studies described in this chapter were supported by grants to FAL from the National Institutes of Health (RO1:NS38493, RO1:NS40059).
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Handbook of Clinical Neurology, Vol. 84 (3rd series) Parkinson’s disease and related disorders, Part II W. C. Koller, E. Melamed, Editors # 2007 Elsevier B. V. All rights reserved
Chapter 43
Deep brain stimulation J. VOLKMANN* AND G. DEUSCHL Department of Neurology, Christian-Albrechts-University, Kiel, Germany
43.1. Introduction Deep brain stimulation (DBS) is an alternative to ablative stereotaxy, which was first introduced in the 1970s but has not been routinely used for the treatment of movement disorders until the pioneering work of Benabid and colleagues in Grenoble became public in the late 1980s. The subthalamic nucleus (STN), which was introduced as a target for DBS in 1993, quickly changed the scope of DBS from a symptomatic treatment of tremor to a highly effective therapy for all cardinal symptoms of Parkinson’s disease (PD) and levodopa-induced motor complications. DBS is based on the empirical observation that high-frequency electrical stimulation of specific brain targets can mimic the effect of a lesion without the need for destroying brain tissue. DBS is accomplished by permanently implanting an electrode into the target area and connecting it to an internal pulse generator. The stimulator settings can be adjusted telemetrically with respect to electrode configuration, current amplitude, pulse width and pulse frequency. DBS has rapidly replaced ablative stereotactic surgery in movement disorders with several advantages: (1) DBS does not require a destructive lesion to be made in the brain; (2) it can be performed bilaterally with relative safety, in contrast to most lesioning procedures; (3) stimulation parameters can be adjusted postoperatively to improve efficacy, to reduce adverse effects and to adapt DBS to the course of disease; and (4) DBS is in principle reversible and does not preclude the use of possible future therapies in PD requiring integrity of the basal ganglia circuitry. The number of DBS procedures for PD has been steadily increasing over the past decade and has reached a cumulative number of approximately 22 000 patients
worldwide in the year 2005, which may underline the importance of this therapy in the treatment algorithm of PD. In 2004 sufficient scientific evidence had accumulated for the Movement Disorder Society to conclude in its evidence-based medical review update that DBS of the STN was efficacious for the symptomatic control of parkinsonism. Although the status of DBS has changed from an investigational therapy to an evidence-based routine treatment, a number of issues still need to be addressed in controlled clinical trials, such as the target selection and the safety in subgroups of patients or the timing of DBS within the course of disease.
43.2. Physiological mechanisms Despite the clinical success of DBS and the rapidly expanding application for different neuropsychiatric disorders, its mechanism of action is still poorly understood. DBS mimics the clinical effects of lesioning in all three target structures currently used for the treatment of PD (ventrolateral thalamus, internal pallidum and STN), when high-frequency (> 100 Hz) stimulation (HFS) is applied. Stimulation at lower frequencies (< 50 Hz) results in little or no clinical benefit or may even aggravate parkinsonian symptoms (Moro et al., 2000; Fogelson et al., 2005). When stimulating the central nervous tissue, the electrode is placed within a complex volume conductor containing three main elements, which could be affected by stimulation: (1) local cells, that have their cell body close to the stimulating electrode; (2) afferent fibers making synaptic contact to the local cells; and (3) fibers of passage, where both the cell body and axon terminal are far from the stimulating electrode. Given the stimulation parameters and electrode configurations presently used, it is likely that DBS directly affects all
*Correspondence to: Dr Jens Volkmann, Department of Neurology, Christian-Albrechts-University, Schittenhelmstr. 10, 24105 Kiel, Germany. E-mail:
[email protected], Tel: þ49-431-597-8509, Fax: þ49-431-597-8506.
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three elements. The inability to stimulate a single element selectively complicates our ability to understand the contribution of each of these elements to the final behavioral effect of DBS. Electrical stimulation of nervous tissue, in general, is more likely to activate large myelinated fibers before small axons or cell bodies, axons near the cathode before those near the anode and axons oriented parallel to the electrode before axons oriented transversely (Ranck, 1975). Presently, there exist five principal hypotheses to explain the therapeutic mechanism of DBS, that have derived from in vitro and in vivo experiments in animals or intraoperative recordings in humans: (1) non-synaptic blocking of neural output through inactivation of voltage-dependent ion channels near the stimulating electrode (Benazzouz et al., 1995; Beurrier et al., 2001); (2) antidromic stimulation of inhibitory afferents to the target nucleus and local release of gamma-aminobutyric acid (GABA) (Dostrovsky et al., 2000); (3) driving of efferents and masking (or jamming) of pathological network activity (Montgomery and Baker, 2000; Hashimoto et al., 2003); (4) modulation of afferent input to the target nucleus (Strafella et al., 1997; Anderson et al., 2006); and (5) synaptic transmission failure of the efferent output of stimulated neurons as a result of synaptic depletion (synaptic depression) (Brock et al., 1952; Urbano et al., 2002). Which of these mechanisms alone or in combination is involved in the behavioral effect of DBS is unknown and may depend on the anatomy of the target structure (e.g. the thalamic target contains a local inhibitory circuitry of interneurons and projections from reticular thalamic nuclei, which does not exist in the pallidal and subthalamic target) and the exact location of the stimulating electrode. First clinical evidence in line with the mechanisms proposed above suggests that the optimal target point for DBS may not be within the target nuclei themselves but rather at entry or exit sites of fiber tracts or adjacent crossings of large fiber bundles (Velasco et al., 2001; Saint-Cyr et al., 2002; Voges et al., 2002; Hamel et al., 2003; Murata et al., 2003; Herzog et al., 2004; Plaha et al., 2004; Kitagawa et al., 2005). These preliminary results, however, await further confirmation in larger series and for other target sites. For this reason, the exact documentation of the final electrode location postoperatively and the corresponding clinical effects not only serves for internal quality control but is also essential to create a sufficiently large database to address the important controversy about DBS mechanisms and the optimal electrode location. 43.2.1. Systemic effects of thalamic DBS Two studies using positron emission tomography (PET) to reveal the cerebral activity changes associated with
thalamic DBS in parkinsonian tremor have revealed conflicting results. Parker et al. (1992) could demonstrate that suppression of parkinsonian tremor by thalamic DBS was associated with significant reduction of regional cerebral blood flow (rCBF) in the ipsilateral putamen, sensorimotor cortex, supplementary motor area (SMA) and contralateral cerebellum. They argued that DBS could inactivate the involuntary running of a central motor program for alternating movements involving the basal ganglia–thalamocortical loop and that cerebellar deactivation might be secondary to reduced proprioceptive input. In contrast, Deiber et al. (1993) found reduced cerebellar activity exclusively during thalamic DBS and therefore assumed a tremor generator within the cerebellothalamic network. Tremor-locked neuronal discharges have been found in the internal pallidum and STN (RodriguezOroz et al., 2001) during stereotactic surgery, but most prominently in areas of the ventrolateral thalamus receiving cerebellar input (Lenz et al., 1994). Tremor in PD, however, is unlikely to originate from the olivocerebellar loop, because cerebellectomy does not abolish resting tremor, but rather transforms it into a slow resting, postural and intention tremor (Deuschl et al., 1999). Nevertheless, most neurosurgeons believe that the cerebellar relay nucleus, ventrointermediate nucleus (VIM), represents the optimal site for thalamic lesioning or stimulation in various types of tremor, including parkinsonian tremor. The regional anatomy, however, is complex and pallidothalamic afferents to the adjacent nucleus ventrooralis anterior (Voa) receiving pallidal input cross at the base of the VIM or even pass through (Krack et al., 2002), such that this site may rather reflect a strategic anatomical ‘bottleneck’ where interventions may affect either loop of the extrapyramidal motor system. Because postmortem studies are rare and inconclusive, it is difficult to discern currently whether thalamotomy or DBS effects in the various types of tremors are mediated by inhibition of abnormal activity originating from the basal ganglia, cerebellum or both. 43.2.2. Systemic effects of pallidal or subthalamic DBS The pathophysiological hallmarks of the parkinsonian state in animal models of PD are abnormally increased neuronal discharge rates in the STN and globus pallidus internal segment (GPi). Lesioning or HFS of these structures reverses the symptoms of 1-methyl4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism, thus supporting the functional significance of these changes. The increased output activity
DEEP BRAIN STIMULATION of the basal ganglia results from opposite effects of the striatal dopaminergic depletion on the direct and indirect basal ganglia pathway according to the current model of basal ganglia circuitry: The activity of the direct basal ganglia pathway is reduced, resulting in decreased inhibition of the GPi. Along the indirect basal ganglia pathway excitatory afferents from STN are driving GPi neurons to be overactive as a result of decreased inhibitory input to the STN from globus pallidus external segment (GPe) (DeLong, 1990). The hyperactive inhibitory influence of the GPi on thalamic nuclei and via this path on cortical motor areas linked with the corresponding thalamic areas is thought to cause bradykinesia and other PD symptoms. Pallidotomy can restore a normal level of activity in the thalamocortical motor pathways by decreasing the excessive inhibitory drive from the GPi to the ventrolateral thalamus. PET studies after successful pallidotomy showed increased rCBF and metabolism in ipsilateral SMA and dorsolateral prefrontal cortex of parkinsonian patients (Eidelberg et al., 1996; Samuel et al., 1997; Ceballos Baumann et al., 1999). Similar reversible changes of rCBF in SMA and dorsolateral prefrontal cortex were described after HFS of the internal pallidum (Davis et al., 1997) or STN (Ceballos Baumann et al., 1999). Although these observations may explain the alleviation of akinesia, they provide little insight into the mechanisms by which tremor, rigidity or dyskinesias might be improved. The simple ‘rate model’ of abnormal neuronal activity in PD would predict reduced pallidal discharge rates in hyperkinetic states and thus a further worsening with pallidal lesioning or DBS (Marsden and Obeso, 1994). Clinically, however, the most consistent effect of pallidal surgery is a marked reduction of contralateral hyperkinesias (Volkmann et al., 2004). It has therefore been suggested that pallidal or STN surgery in more general terms is effective by removing the disturbing influence of a ‘noisy’ basal ganglia operator on to thalamocortical motor areas (Marsden and Obeso, 1994). ‘Noisy’ or unphysiological basal ganglia activity could result not only from changes in discharge rate but also from abnormal patterning, oscillation or synchronization of neuronal firing (Bergman and Deuschl, 2002; McIntyre et al., 2004b; Brown and Williams, 2005). Furthermore, descending projections from the basal ganglia to the brainstem nuclei and spinal cord are often neglected and may also play an important role in the pathophysiology of rigidity, postural instability and gait disorder of PD (Delwaide et al., 2000; Pahapill and Lozano, 2000; Nandi et al., 2002a, b; Potter et al., 2004).
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Fig. 43.1. Axial (A) and coronal section (B) of a T2-weighted magnetic resonance imaging scan at the level of the subthalamic nucleus (STN). On the upper images the STN is visible preoperatively in relation to the red nucleus (RN) and substantia nigra (SN). The lower rows depict the artifact caused by the deep brain stimulation electrode implanted bilaterally within the STN.
43.3. Methods 43.3.1. Surgical procedure Accurate electrode placement requires the use of a stereotactic head frame. Imaging is one of the most critical aspects of the stereotactic procedure and generally includes ventriculography, computed tomography (CT) and/or magnetic resonance imaging (MRI). Historically, ventriculography had been the radiological ‘gold standard’ for a reliable identification of the anterior and posterior commissure (AC, PC) and landmarkbased, indirect stereotactic targeting, but today it has largely been replaced by CT and MRI. The advantage of MRI lies in the direct visualization of the target (STN, GPi) and neighboring structures (Fig. 43.1). Moreover, three-dimensional reconstructions from MRI or CT allow coronal, axial and sagittal determination of the AC and PC, planning of the entry point and a control of the entire trajectory for possible conflicts with deep and superficial vessels. The radiologically derived target is further refined intraoperatively by neurophysiological techniques. Intraoperative stimulation predicts the effect of chronic stimulation and is crucial to determine the final site of electrode implantation. To allow for clinical evaluation of the
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stimulation response, the implantation is usually performed under local anesthesia in awake patients. Microelectrode recordings may provide additional information on the nuclear boundaries and allow mapping of the target area along several passes (Fig. 43.2). Microelectrode mapping is particularly useful when clinical testing is difficult or inconclusive due to a microlesioning effect or in uncooperative patients. There is some debate on whether microelectrode mapping increases the surgical bleeding risk (Hariz and Fodstad, 1999). However, leading centers in the field routinely explore multiple microelectrode trajectories and have reported low complication rates along with excellent clinical results in DBS (Krack et al., 2003; Lyons et al., 2004; Mehdorn et al., 2005; Schupbach et al., 2005; Goodman et al., 2006). After insertion of the permanent DBS electrode and attachment of the extension cable, the system is connected to the internal pulse generator. This is either done immediately or in a staged fashion. 43.3.2. Target location Optimal targeting is the prerequisite for clinical success in DBS. Clinically effective stimulation is most commonly directed at the anterior segment of the
dorsolateral STN (Saint-Cyr et al., 2002; Voges et al., 2002; Herzog et al., 2004; Zonenshayn et al., 2004). This target corresponds to the sensorimotor territory of the nucleus, which may be identified by the presence of movement-responsive cells in microelectrode recordings (Rodriguez-Oroz et al., 2001). In this location the electrode also passes Forels’s field H and the zona incerta, which are dorsally adjacent to the STN. Whether current spread into the subthalamic white matter is necessary for optimal clinical success is a matter of debate. However, exclusive stimulation of subthalamic white matter by placing the electrode dorsal to the STN boundary results in an unfavorable relation between clinical improvement and current consumption (Herzog et al., 2004). The usual coordinates for pallidotomy are 20–21 mm lateral to the intercommissural line (AC–PC line), 5–6 mm below and 3 mm anterior to the mid commissural point (Laitinen et al., 1992). This corresponds to the ventrolateral aspect of the GPi, where microelectrode recordings demonstrate movement-related cells (Iacono et al., 1997; Lozano et al., 1997). To what extent the topography of pallidal stimulation effects is related to the anatomical subdivision of GPi or the anatomy of pallidal fiber tracts remains a matter of speculation. Neither is it known whether the optimal
Zona Incerta (−4.3 mm)
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Fig. 43.2. Typical traces of microelectrode recordings along a trajectory to the subthalamic nucleus (STN) are displayed in relation to the recording site. Proximal to the STN sparse neuronal activity can be found in the zona incerta alternating with traces of white-matter noise, when the electrode passes fiber tracts. STN is identified by a marked increase in background noise and large-amplitude, burst-like spike discharges. This pattern changes to tonic, high-frequency discharges when the microelectrode enters substantia nigra (SNr). The characteristic difference in neuronal discharge patterns of STN and SNr may help to refine the anatomical target, because the ventral border of STN is difficult to delineate on magnetic resonance images, as it was in this case, where the anatomical target was chosen too deep.
DEEP BRAIN STIMULATION sites for pallidal lesioning and stimulation are identical. Two independent studies on the acute effects of pallidal stimulation have found a better reduction of parkinsonian symptoms by stimulating the distal contacts of the quadrupolar stimulating electrode (Bejjani et al., 1997; Krack et al., 1998b), which were located in the dorsolateral aspect of GPi, closely neighboring GPe. Stimulation of the ventromedial GPi, in contrast, was antidyskinetic but also blocked the beneficial effect of levodopa on akinesia. In our own experience, the position of the most beneficial electrode pole used for chronic pallidal stimulation was on average slightly more lateral and dorsal than the standard pallidotomy target (Volkmann et al., 1998). This corresponds to a location lateral and dorsal to the optic tract in postoperative MRI controls. Given a current spread of approximately 3 mm around the cathode, based on average electrical parameters for pallidal stimulation (Ranck, 1975; McIntyre et al., 2004a), it is likely that stimulation at these coordinates will not remain restricted to the sensorimotor region of GPi, but may spread to the efferent fiber tracts of GPi and medial regions of GPe. A reduction of parkinsonian tremor may be achieved by stimulation within a rather larger volume encompassing the ventrolateral thalamus and subthalamic areas. There is no consensus in the literature regarding the clinically most effective site. Most neurosurgeons favor the thalamic VIM as the optimal site for thalamic lesioning or stimulation in various types of tremor, including parkinsonian tremor. Others have reported excellent outcome with DBS of the subthalamic white matter, including the prelemniscal radiation and zona incerta (Velasco et al., 2001; Plaha et al., 2004; Kitagawa et al., 2005). These clinical observations are complemented by recent physiological data suggesting that DBS might be effective for tremor by blocking afferent synaptic input to thalamic tremor cells, thereby stopping propagation of abnormal oscillations beyond the thalamus (Anderson et al., 2006). Finally, DBS of the STN is considered an alternative to thalamic surgery and reduces the tremor score by approximately 80% even in PD patients with severe high-amplitude tremor (Krack et al., 1998a; Rodriguez et al., 1998). Because no comparative trials exist, it is difficult to conclude on a better efficacy of either target. 43.3.3. Safety Adverse events associated with DBS must be divided into those related to the surgical procedure, to the implanted device, to stimulation and to medication changes necessitated by DBS. In this section the safety of the operative procedure and hardware-associated problems are discussed. Therapy-related adverse
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events (induced by stimulation or medication changes) depend on the stimulated area and will be discussed with the clinical results of each target. 43.3.3.1. Surgery-related adverse events DBS requires a craniotomy and one or several needle passes through the brain, carrying with it the risks of intracranial hemorrhage and damage to adjacent brain structures. The risk of unintended injury to adjacent brain structures, however, is much smaller than in ablative procedures, where the exact size of the final therapeutic lesion may be difficult to predict. In the only prospective controlled study randomizing patients to either thalamic stimulation or lesioning for the treatment of tremor, the cumulative rate of neurological adverse events was 47% in the thalamotomy group and 16% in the DBS group. All adverse events in the DBS group were reversible when stimulation was turned off. One death related to an intracranial hemorrhage in the DBS group, however, cautions about the inherent risk of any stereotactic intervention (Schuurman et al., 2001). In the literature intracranial hemorrhages are reported in 1–4% of patients undergoing functional stereotactic procedures (Favre et al., 2002; Binder et al., 2003; Terao et al., 2003). The proportion of asymptomatic and symptomatic bleedings within this percentage is unclear, but the prevalence of persistent neurological deficits seems to be considerably lower compared with the total sum of hemorrhagic complications. Transient postoperative confusion is present in up to 20% of the patients after implantation of STN leads. This proportion is higher than the rate of confusion previously reported for other targets and may be related to the usual STN trajectory, which passes the head of the caudate on both sides (Woods et al., 2002). An additional source of surgeryrelated morbidity is infection with an incidence of 3–4% (Lyons et al., 2004; Goodman et al., 2006). 43.3.3.2. Device-related adverse events The reported rate of hardware-related problems (e.g. lead dislocation, lead breakage, internal pulse generator dysfunction, skin erosion) varies between different centers in the range of 5–30% (Hariz et al., 1999; Oh et al., 2001; Lyons et al., 2004; Goodman et al., 2006) and must not be underestimated. Most hardware-related problems, however, occurred in the first patients of a series and were less frequent afterwards. This sheds light on the sophisticated nature of the procedure, which requires extensive neurosurgical skill learning before getting into a routine with DBS surgery. Device-related complications are usually manageable, but often require an additional surgical intervention. The permanent morbidity associated with these problems is low.
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43.3.3.3. Summary The risk of permanent neurological deficits associated with DBS is lower than in lesional stereotaxy. Most larger controlled series report permanent neurological morbidity in the region of 2–3%. Mortality is extremely rare. Therefore, the benefit-to-risk ratio of the DBS procedure seems favorable, at least in severely disabled patients. A careful selection of candidates for increased neurosurgical risks should help to maintain a relatively low level of morbidity.
(2000, 2001) demonstrated after 2 years of follow-up that both procedures resulted in about equal symptomatic relief of tremor, but that functional outcome according to the Frenchay activity index was significantly better in the DBS group. The authors related this difference to permanent mild neurological sequelae of thalamotomy such as impairment of fine motor skills due to lesions encroaching upon the internal capsule. 43.4.2. Pallidal deep brain stimulation
43.4. Clinical efficacy 43.4.1. Thalamic deep brain stimulation Experience with DBS in the thalamus for the treatment of parkinsonian tremor has been generally safe and effective. Clinical success is usually defined as a complete abolition or a reduction of contralateral tremor to grade 1 on the tremor-rating scale (mild and intermittent tremor) with chronic stimulation. The success rates of DBS in the following paragraph relate to this definition. For tremor in PD, Benabid et al. (1991) reported a success rate of 88% in 26 patients and very low morbidity even after bilateral surgery. These findings were confirmed in a European multicenter study with 74 patients and a follow-up of 1 year (Limousin et al., 1999). The tremor reduction is sustained in the long term for up to 7 years, but thalamic DBS does not improve other symptoms of PD, nor does it alleviate long-term complications of levodopa treatment. Akinesia, rigidity, gait and postural problems may progress despite successful treatment of tremor and can cause new therapeutic difficulties (Rehncrona et al., 2003). In a double-blind randomized study comparison of thalamotomy and thalamic DBS Schuurman et al.
The consistent effect of pallidal stimulation in all current reports is a marked reduction of contralateral levodopainduced dyskinesias. Improvement of ‘off-period’ symptoms of parkinsonism is more variable but significant in most studies. Figure 43.3. summarizes the results of 15 studies in the literature, including a total of 276 patients (Gross et al., 1997; Pahwa et al., 1997; Tronnier et al., 1997; Ghika et al., 1998; Krack et al., 1998c; Kumar et al., 1998; Burchiel et al., 1999; Merello et al., 1999; The Deep-Brain Stimulation for Parkinson’s Disease Study Group, 2001; Volkmann et al., 2001; Durif et al., 2002; Loher et al., 2002; Ogura et al., 2004; Peppe et al., 2004; Anderson et al., 2005). In these studies the median improvement of off-period motor symptoms induced by pallidal stimulation was 36% (lower quartile 31%, upper quartile 43.1%) and the median reduction of dyskinesias in the on-state 71% (lower quartile 52.5%, upper quartile 78.5%). These data leave little doubt about the clinical efficacy of palllidal DBS. In our own experience bilateral GPi stimulation (n ¼ 11) led to a 54 33.1% improvement of the ‘off’-period Unified Parkinson’s Disease Rating Scale (UPDRS) motor score at 1-year follow-up (Volkmann et al., 1998, 2001). In UPDRS subscores we found
Fig. 43.3. Summary of results of pallidal deep brain stimulation (DBS) in the literature: 15 publications from 1997 to 2005: 276 patients, 54 unilateral. For each study the average reduction of off-period motor symptoms by levodopa before surgery (levodopa response in %), by DBS at the final visit, the reduction of dyskinesias and the reduction of the levodopa-equivalent daily dose (LEDD) are represented by a symbol. Horizontal lines denote the median of all studies. STIM, stimulation.
DEEP BRAIN STIMULATION significant improvements for bradykinesia, tremor and posture and gait and a tendency towards improvement of rigidity. ‘On’-period motor symptoms did not significantly change after surgery except for dyskinesias, which were reduced by 83% at 1-year follow-up. The alleviation of dyskinesias and the reduction of ‘off’period motor symptoms in combination led to a significant reduction of self-perceived motor fluctuations in our patients. Unfortunately, the initial benefit on offperiod symptoms of PD tended to decrease in the long term, whereas the antidyskinetic effect remained stable for up to 5 years. The worsening of akinetic-rigid symptoms of PD had to be compensated for by increases in dopaminergic medication (Volkmann et al., 2004), which kept the total duration of off-time after surgery at a stable level. As a result, both hyperand hypokinetic motor fluctuations were still reduced after 5 years but the increases in dopaminergic medication caused additional problems in some patients, such as delusions or gambling. Interestingly, one group reported, in contrast to all other available studies, a reduction of dyskinesias but a worsening of motor function during the medication ‘on’ period (Tronnier et al., 1997) after bilateral pallidal stimulation. Because the exact position of the stimulating electrodes is uncertain in this and most other studies, it is difficult to discern how much of the variable effect of pallidal stimulation results from different target locations within GPi. Two studies (Bejjani et al., 1997; Krack et al., 1998b) claim, based on the observation of acute stimulation effects, that DBS of the ventral GPi may block dyskinesias but aggravate akinesia, whereas dorsal GPi stimulation ameliorates akinesia on account of being prodyskinetic. The importance of these experimental observa-
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tions for therapeutic long-term stimulation can only be determined in future studies carefully relating the efficacy of chronic pallidal stimulation to the exact target location within GPi determined by neuroimaging techniques and microelectrode recordings. Despite the common assumption that DBS is equally effective but safer than lesioning techniques, there is only one clinical trial currently available addressing this issue. In a group of 13 patients randomized to either unilateral pallidal DBS or radiofrequency lesioning of the GPi, Merello and colleagues (1999) found about equal improvement of the UPDRS motor score after 3-month follow-up. There was greater reduction of contralateral dyskinesias after pallidotomy, whereas bilateral hand-tapping scores improved more with DBS. 43.4.3. Subthalamic nucleus deep brain stimulation DBS of the STN has replaced pallidal DBS in most centers for the treatment of advanced PD. This preference for the subthalamic target is rarely based on own comparative experience. Centers that started a surgical program for advanced PD with STN DBS have little incentive to explore another target, if they obtain good results in the STN. For this reason, there is a reporting bias in the literature in favor of STN DBS in recent years. Figure 43.4. summarizes 39 clinical studies of STN DBS in advanced PD, reporting on a total of 1129 patients (Moro et al., 1999; Pinter et al., 1999; Houeto et al., 2000; Molinuevo et al., 2000; Broggi et al., 2001; Katayama et al., 2001; Krause et al., 2001; Lopiano et al., 2001; The Deep-Brain Stimulation for Parkinson’s Disease Study Group, 2001; Volkmann et al., 2001; Doshi et al., 2002; Figueiras-Mendez et al., 2002; Iansek et al., 2002; Kleiner-Fisman et al., 2002; Lanotte et al.,
Fig. 43.4. Summary of results of subthalamic nucleus deep brain stimulation (DBS) in the literature: 39 publications, from 2000 to 2005: 1129 patients. For each study, the average reduction of off-period motor symptoms by levodopa before surgery (levodopa response in %), by DBS at the final visit, the reduction of dyskinesias and the reduction of the levodopa-equivalent dose (LEED) are represented by a symbol. Horizontal lines denote the median of all studies. STIM, stimulation.
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2002; Martinez-Martin et al., 2002; Ostergaard et al., 2002; Romito et al., 2002b; Simuni et al., 2002; Tavella et al., 2002; Thobois et al., 2002; Valldeoriola et al., 2002; Vesper et al., 2002; Vingerhoets et al., 2002; Herzog et al., 2003b; Krack et al., 2003; Landi et al., 2003; Pahwa et al., 2003; Tamma et al., 2003; Varma et al., 2003; Esselink et al., 2004; Ford et al., 2004; Jaggi et al., 2004; Peppe et al., 2004; Capecci et al., 2005; Lyons and Pahwa, 2005; Minguez-Castellanos et al., 2005; Rodriguez-Oroz et al., 2005; Visser-Vandewalle et al., 2005). The median improvement in the UPDRS motor score in the off-period was 50.2% (lower quartile 42%, upper quartile 60.8%) More specifically, improvement is seen in off-phase akinesia, rigidity, tremor (Krack et al., 1998c; Rodriguez et al., 1998), gait (Allert et al., 2001; Faist et al., 2001; Stolze et al., 2001) and balance. Bilateral STN stimulation improves most axial features of PD that responded to levodopa before surgery (Bejjani et al., 2000b). Hypokinetic motor fluctuations tend to disappear and patients show marked improvement in the activities of daily living (median improvement 37.5%). Off-period dystonia is immediately alleviated, synchronously with stimulation (Krack et al., 1999). The on-period dyskinesias are reduced in parallel with a marked reduction of the equivalent daily levodopa dose (LEED). The median reduction of dyskinesias was 73% (lower quartile 64%, upper quartile 91%) in our survey and the median reduction of the LEED 54% (lower quartile 40%, upper quartile 66%). In the long term, the antidyskinetic effect of STN stimulation may be equivalent to or superior to that of GPi stimulation if the levodopa dose remains reduced. Whereas STN stimulation has a direct effect on off-period dystonia, on-period dyskinesias are decreased by a more complex mechanism, involving the decrease in levodopa dosage and possibly adaptive neuronal changes induced by continuous HFS. Bejjani et al. (2000a) demonstrated that the sensitization phenomenon resulting from longterm intermittent levodopa administration presumably causing dyskinesias is partially reversible with STN DBS. His group used a challenging dose to induce dyskinesias before surgery and, after 6 months of continuous STN DBS, found that in the stimulation offcondition, the severity of levodopa-induced dyskinesias was greatly reduced compared to baseline. The motor changes after STN DBS can have a significant impact on patient’s quality of life (Just and Ostergaard, 2002; Lagrange et al., 2002; Martinez-Martin et al., 2002; Spottke et al., 2002; Tamma et al., 2003; Troster et al., 2003; Esselink et al., 2004; Lezcano et al., 2004; Drapier et al., 2005; Lyons and Pahwa, 2005). In studies using the Parkinson’s Disease Questionnaire PDQ-39, an average improvement of the summary index of approximately 35% was reported. PDQ-39 dimensions
that significantly improved were stigma (54.4 18.1%), activities of daily living (51.6 18.2%), mobility (38.5 18.2%), bodily discomfort (35.8 15.4%) and emotional well-being (32.1 18.1%). Dimensions with modest benefit included social support (17.0 19.1%), cognition (16.5 15.0%) and communication (13.0 26.9%). 43.4.4. Comparison of the different targets Few studies have compared the effect of STN and GPi DBS. Most of them are parallel-group comparisons, except for one randomized but underpowered clinical trial (Burchiel et al., 1999; Anderson et al., 2005). Krack et al. (1998c) reported a 71% improvement of the ‘off’-period UPDRS motor score with STN stimulation but only 39% with GPi stimulation in a group of 13 patients with young-onset PD. This significant difference resulted from a greater reduction of akinesia in the STN-stimulated group, whereas other parkinsonian symptoms showed about equal improvement. In contrast, Burchiel and colleagues (Burchiel et al., 1999; Anderson et al., 2005) found no difference in reduction of akinetic-rigid symptoms of PD or dyskinesias between STN- and GPi-stimulated patients in a well-designed, randomized prospective trial. In our own retrospective analysis of the initial 11 patients implanted within GPi and 16 patients implanted within STN, the main finding was a 54 33.1% improvement of ‘off’-period motor symptoms in the first and 67 22.6% improvement in the later group after 1 year of follow-up (Volkmann et al., 2001). The 10– 15% difference between both groups was not significant and power analysis suggested that, based on the group variances, a much larger trial including a minimum of 135 patients in each arm would have been needed to prove significance of this possible small difference in favor of STN stimulation. A non-randomized multicenter study enrolled 96 patients with STN DBS and 38 with GPi DBS (The Deep-Brain Stimulation for Parkinson’s Disease Study Group, 2001). Except for levodopa-induced dyskinesias, which were greatly alleviated in both groups, all other outcome variables favored the STN group, although some of the differences were small. At 3-month follow-up, double-blind, cross-over evaluations demonstrated that STN stimulation was associated with a median improvement in the motor score (as compared with no stimulation) of 49% and GPi stimulation with a median improvement of 37%. Between the preoperative and 6-month visits, the percentage of time during the day that patients had good mobility without involuntary movements increased from 27 to 74% with STN stimulation and from 28 to 64% with GPi stimulation. Interestingly, these differences in the severity of
DEEP BRAIN STIMULATION off-period symptoms did not affect the total on-time after surgery, which was still significantly increased 3–4 years after surgery to an identical extent after DBS of the STN or GPi (Rodriguez-Oroz et al., 2005). In a small group of PD patients that had simultaneous bilateral electrode implants in the STN and the GPi, Peppe et al. (2004) recently confirmed the slightly better efficacy of STN DBS in reducing off-period symptoms. They found a larger decrease in off-period UPDRS III scores with DBS of the STN (54.5%) than during DBS in the GPi (43.1%), when either target was stimulated separately. The additive effect of stimulation in both targets was small (54.5%) and not significant. The available data, therefore, suggest a better efficacy of STN DBS in reducing off-period motor symptoms, but formal confirmation in a larger prospective randomized trial has to be awaited (Follett et al., 2005). Other consistent differences between pallidal and STN stimulation concern medication requirements and stimulation parameters. Patients with pallidal stimulation continue to require preoperative anti-PD medication doses and in some cases even higher doses are introduced postoperatively. In contrast, STN stimulation allows an average reduction of dopaminergic medication in the range of 50–60% and approximately 10% of patients are able to discontinue all dopaminergic drugs (Moro et al., 1999). This gives STN DBS a favorable benefit-to-cost ratio, but these advantages contrast with a need for more intensive postoperative monitoring and a higher incidence of adverse events (Volkmann et al., 2001; Rodriguez-Oroz et al., 2005). In summary, no general advice can be given yet about the optimal target for the treatment of advanced PD. The STN will be the preferred choice for younger patients in most centers based on the expected levodopa savings and the lower energy expenditure. Pallidal stimulation, however, is an effective procedure and may still be considered in older patients, who may not tolerate levodopa withdrawal or timeconsuming programming of STN-DBS. Mild cognitive impairment or a history of depression (as outlined in section 43.3.3.1) could also be arguments in favor of GPi DBS. 43.4.5. Therapy-related adverse effects Optimal surgical positioning of the stimulating electrode helps to reduce the risk of stimulation-induced side-effects which mostly result from unintended current spread to adjacent fiber tracts or nuclei. Stimulation-induced side-effects are fully reversible when stimulation is stopped and can be improved in most cases by changing stimulation parameters or electrode configuration. If sufficient control of motor symptoms
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is not achieved without side-effects, patient and physician may deliberately accept a certain degree of stimulationinduced adverse effects. In thalamic DBS, paresthesias and dysarthria are among the most common stimulation-induced sideeffects. Especially with bilateral DBS some dysarthria will have to be accepted in up to 10% of cases if optimal tremor control is desired. Less frequent are real dystonia or pseudodystonia’ resulting from costimulation of the pyramidal tract (Limousin et al., 1999; Schuurman et al., 2000, 2001; Rehncrona et al., 2003). Stimulation-induced side-effects in pallidal DBS are rare and mostly transient during the immediate postoperative adaptation of stimulation parameters. They include visual field disturbances from current spread to the optic tract, tetanic muscle contractions (pseudodystonia) from costimulation of the pyramidal tract and nausea or dizziness. Possible therapeutic problems with DBS of the STN result from the complex interactions of medical therapy and electrical stimulation. One of the challenges in follow-up treatment is to distinguish between ‘genuine’ stimulation-induced side-effects and pre-existing symptoms of the disease that are uncovered by a combination of reduced dopaminergic therapy and inadequate stimulation effects. Postoperative speech, gait and balance problems fall within this particular category. Stimulation-induced dyskinesias are one of the most frequent and important specific side-effects of STN stimulation. The appearance of dyskinesias indicates correct lead placement and an additive effect has been observed in bilateral stimulation. Stimulation-induced dyskinesias are worsened by levodopa. Therefore initial programming should always be done early in the morning when the patient is off medication. Stimulation is continuously increased over a period of days or weeks until a satisfactory effect on bradykinesia in the off-phase is achieved and at the same time the levodopa dosage is lowered (Volkmann et al., 2000). Either current diffusion due to excessive stimulation parameters or incorrect lead placement may result in reversible stimulation-induced side-effects, such as tonic muscle contractions, dysarthria, eyelid-opening apraxia, ocular deviation, ipsilateral mydriasis, flushing, unilateral (ipsilateral) perspiration (contralateral) paresthesias, worsening of akinesia and a reversal of the levodopa effect. These reversible side-effects may help to define the optimal target intraoperatively or to track the deviation of a misplaced electrode after surgery (Volkmann et al., 2000). Despite the theoretical concern that pallidal or STN stimulation could interfere with the functioning of cognitive basal ganglia loops, most studies found no
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or clinically insignificant changes in neuropsychological functioning after DBS (Ardouin et al., 1999; Jahanshahi et al., 2000; Pillon et al., 2000; Trepanier et al., 2000; Alegret et al., 2001). Some reports, however, have warned that STN DBS has a risk of inducing cognitive decline with a frontal executive dysfunction similar to progressive supranuclear palsy in older patients (above 70 years) or those with minimal cognitive dysfunction prior to surgery (Saint-Cyr et al., 2000; Dujardin et al., 2001). Mood disorders are among the most frequently observed postoperative side-effects in STN stimulation (Limousin et al., 1998; Volkmann et al., 2001; Rodriguez-Oroz et al., 2005) but the true prevalence is still difficult to estimate due to small sample sizes and possible biases in reporting on adverse events. The incidence of depression in the first postoperative months has been up to 25% in some reports (Volkmann et al., 2001; Berney et al., 2002), but there may be a considerable overlap with apathy, that can present after surgery as reduced drive without sadness. Depression was associated with suicidal ideation in some patients (Berney et al., 2002; Doshi et al., 2002). One center described a suicide rate of 4% following DBS for PD, which is probably not representative for the therapy in general. More recently, Foncke et al. (2006) reported on 2 suicides out of 16 patients that were included in a clinical trial for pallidal DBS for dystonia. This observation indicates that suicide risk after DBS may not be associated with specific targets or indications, but rather with more general characteristics of the patient group suffering from long-standing and severe motor disability and often regarding DBS as a last-resort treatment. Manic disorders are less frequent, somewhere around 2–5% (Kulisevsky et al., 2002; Romito et al., 2002a; Daniele et al., 2003; Herzog et al., 2003a) after STN DBS. Other reports about behavioral abnormalities after DBS of the STN include hypersexuality, gambling or aggressive–impulsive behavior in individual patients (Houeto et al., 2002). Many of the patients with behavioral abnormalities after surgery had a pre-existing psychiatric condition (Houeto et al., 2002). Therefore, careful preoperative psychiatric assessment is indicated to identify patients at risk and to follow these patients closely after DBS. The high incidence of psychiatric problems after STN DBS is most likely multifactorial, but the relevance of the individual factors still needs to be determined: 1. PD is a neuropsychiatric disease most frequently associated with depression and anxiety. Mood and behavioral abnormalities after surgery often reflect a reactivation of a pre-existing psychiatric condition (Houeto et al., 2002).
2. Levodopa has psychotropic effects in addition to the well-known motor effects. Patients describe the action of levodopa as pleasantly euphoriaand drive-enhancing. In extreme cases, mania and hypersexuality may be affective and behavioral side-effects of dopaminergic therapy. The medication reduction after STN stimulation may, therefore, cause withdrawal phenomena with an impact on mood and drive. 3. The basal ganglia are integrated into associativecognitive and limbic regulatory systems, so that psychiatric symptoms could also result as a direct side-effect of stimulation. However, the acute emotional effect of STN DBS is mood-enhancing (Funkiewiez et al., 2003; Schneider et al., 2003) and high stimulation amplitudes may cause laughing spells (Krack et al., 2001; Funkiewiez et al., 2003; Schneider et al., 2003). There is currently no evidence for other emotional or behavioral effects of HFS within STN. The two spectacular cases of stimulation-induced depression and aggressive behavior resulted from misplaced electrodes (Bejjani et al., 1999, 2002) within the substantia nigra pars reticulata and the triangle of Sano. 4. Successful surgery reduces disability and may enable the patient to regain independence. This may affect partnership, social bonds and professional life and, at the same time, cause a loss of primary and secondary gains from the illness (Perozzo et al., 2001). The psychological and behavioral consequences of social readaptation have been extensively studied in patients undergoing epilepsy surgery. The term ‘burden of normality’ describes a syndrome of social maladjustment causing most of the psychiatric problems after successful treatment (Wilson et al., 2001). Whether a similar concept applies to movement disorder surgery remains to be determined.
43.5. Patient selection DBS has not been evaluated for other forms of parkinsonism than idiopathic PD. From the experience in few patients with progressive supranuclear palsy, multiple system atrophy or other atypical parkinsonian syndroms who underwent DBS, one can conclude that the overall progression of these disorders rapidly counteracts a possible transient benefit from surgery. Up to 10% of the therapeutic failures after DBS may result from an inappropriate diagnosis of PD (Okun et al., 2005), which underlines the importance of involving movement disorder specialists in the selection process.
DEEP BRAIN STIMULATION The objective of the selection process in general is to identify those individuals in whom the expected benefit will outlast the inherent risks of the surgical procedure. Functional stereotactic surgery strives to improve motor function and to reduce disability by alleviating symptoms of a movement disorder. Benefit in the context of movement disorder surgery is therefore a complex variable, addressing the multidimensional components of health and health-related well-being in an individual. In the World Health Organization (2005) WHO International Classification of Functioning, Disability and Health (ICF), these health-related domains are described from the perspective of the body, the individual and society. Disability is used as an umbrella term for impairments of body structure or function, resulting activity limitations and participation restrictions (social handicap). The degree of activity limitations and social handicap a patient may experience from a physical impairment is influenced by individual factors (such as profession and family status) within this framework. The challenge that any neurologist or neurosurgeon is facing in the selection process for movement disorder surgery is: 1. to determine whether the target symptom for surgery is the predominant source of disability in this patient, 2. to identify other potential sources of disability, 3. to estimate the likelihood of improving the target symptom by surgery, 4. to estimate the individual risk of suffering from complications, 5. to formulate realistic goals for the rehabilitation of the patient on the different levels of functioning, 6. to relate the patient’s own expectation from surgery to these goals and to correct unrealistic expectations. Patients need to be informed about their individual risk/benefit analysis and possible alternative treatments. 43.5.1. Tremor Tremor is seldom the most incapacitating symptom in PD. Social embarrassment may be the driving force for patients seeking surgical treatment rather than functional impairment. In our view, the involved risks do not justify surgery in these cases unless the patient is experiencing relevant disability from the social restrictions implied by tremor. Before advising surgery, the following medical therapies should have been tried: levodopa with a sufficiently high daily dose (1000– 1500 mg/day) for a period of at least 4 weeks to observe the long-term levodopa effect, a dopamine
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agonist, clozapine up to 75 mg/day and propanolol or primidone in cases of predominant action tremor (Deuschl and Volkmann, 2002). Thalamic DBS is effective in reducing tremor, but does not improve other symptoms of PD. As an alternative, STN DBS should be advised in younger patients who are at risk of developing akinesia and levodopa-related motor complications in the further course of disease or in patients already suffering from these symptoms. Older patients (> 70 years) with tremor-dominant PD are less likely to progress and may undergo thalamic DBS with good benefit. The advantage of thalamic DBS in these cases lies in a more rapid and predictable therapeutic response and the less complicated adjustment of stimulation and medication compared to STN DBS. 43.5.2. Advanced Parkinson’s disease Pallidal or subthalamic DBS are symptomatic treatments for motor fluctuations and dyskinesias in advanced PD. Levodopa-resistant symptoms of PD do not respond to DBS either. Hence, ideal candidates should suffer from idiopathic PD with an excellent levodopa response but side-effects of long-term medical treatment. Dementia, acute psychosis and major depression are usually exclusion criteria. The general health condition of the patient needs to be good enough to withstand the operation and to maintain cooperation during prolonged awake-surgery. The presurgical levodopa test helps to predict the individual response profile of a patient to bilateral STN or GPi stimulation (Welter et al., 2002). Symptoms other than dyskinesias or tremor which persist during ‘best on’ after taking a challenging dose of levodopa (1–1.5 times the equivalent of the regular antiparkinsonian morning medication in the form of short-acting, soluble levodopa) are less likely to benefit from DBS. Most centers have operated primarily on patients suffering from young-onset PD, because they fulfill these criteria best. Older patients may also benefit from surgery, but levodopa-resistant symptoms are more often encountered in this group; axial symptoms may respond less to DBS than in younger patients (Russmann et al., 2004), surgical adverse events are more frequent, motor rehabilitation is slower and comorbidities (such as orthopedic problems secondary to a parkinsonian postural or gait disorder) may limit the degree of functional restitution. The treating physician should be informed about the patient’s personal expectations about surgery and correct unrealistic perspectives. Finally, the patient needs to understand that the therapeutic benefits of DBS for advanced PD are not immediately obtained after
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surgery. Programming the device and adjusting medication may be time-consuming and tedious and the patient must be ready to cooperate during this process.
43.6. Conclusion DBS is one of the most promising new therapies for the treatment of PD. There is sufficient evidence in the literature that DBS of the STN is an effective and relatively safe therapy for all cardinal symptoms of PD and levodopa-induced motor complications. The improvements in motor symptoms are so profound that quality of life is significantly improved by STN DBS. With respect to possible side-effects of DBS, especially behavioral and psychiatric adverse events, larger registries or multicenter trials are needed, because single centers would take several years to recruit sufficient data for a safety evaluation. Finally, future trials have to clarify the differential indications for the three targets in which DBS can be applied for treating PD (Follett et al., 2005).
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Handbook of Clinical Neurology, Vol. 84 (3rd series) Parkinson’s disease and related disorders, Part II W. C. Koller, E. Melamed, Editors # 2007 Elsevier B. V. All rights reserved
Chapter 44
Transplantation CURT R. FREED*, W. MICHAEL ZAWADA, MAUREEN LEEHEY, WENBO ZHOU AND ROBERT E. BREEZE University of Colorado School of Medicine, Denver, CO, USA
44.1. Introduction Neurotransplantation offers a novel treatment strategy for Parkinson’s disease (PD), replacing lost dopamine neurons with new cells. The fact that there are so many successful therapies for PD is extraordinary. This book has summarized both pharmacologic and neurosurgical procedures, including lesions and deep brain stimulation. Neurotransplantation is fundamentally different from these strategies, because only neurotransplantation repairs a primary defect of PD, the loss of dopamine neurons. Transplantation of dopamine neurons into humans has developed from a comprehensive series of experiments in animal models of PD, particularly rats. Most principles established in the rat have proven applicable to humans. In the rat, embryonic dopamine neurons from a narrow window of development, 13–15 days after conception, are suitable for transplantation. For human transplantation, the equivalent stage of embryonic development is 6–8 weeks after conception. All successful allografts of human embryonic tissue into patients with PD have come from tissue in this developmental window (for reviews, see Clarkson and Freed, 1999; Bjo¨rklund et al., 2003; Lang and Obeso, 2004). Tissues other than fetal dopamine neurons have been transplanted into PD patients. Autotransplants of adrenal chromaffin cells were pursued intensively in the late 1980s, without success. Because the supply of human fetal tissue is limited and variable in quality, some researchers looked to other species as a source of fetal dopamine neurons. Ventral mesencephalon from fetal pig was transplanted into patients who were immunosuppressed with ciclosporin and prednisone. Despite efforts to prevent rejection, porcine cells failed
to survive in large numbers because of the insurmountable problem of xenograft rejection. In the USA, during the presidency of Bill Clinton, there was a window of federal funding to test systematically the value of embryonic dopamine cell transplants. Two double-blind studies were performed (Freed et al., 2001; Olanow et al., 2003). Although neither study achieved significance in primary outcome variables, both showed long-term survival of embryonic dopamine cells. In the first of these, we found that transplants significantly improved Unified Parkinson’s Disease Rating Scale (UPDRS) and Schwab and England ‘off’ scores in patients under age 60 (Freed et al., 2001). A proportion of patients in our study as well as the later study by Olanow et al. (2003) developed persistent dyskinesias in a pattern similar to that seen after levodopa therapy in the same patients. Thus, transplants replicated the effects of levodopa, including the tendency to produce dyskinesias in patients with an earlier history of drug-induced dyskinesias. To explore the value of dopamine cell transplantation for PD comprehensively, a more reliable tissue source must be found. Efforts to produce dopamine neurons from human embryonic stem cells are promising (Buytaert-Hoefen et al., 2004; Perrier et al., 2004; Yan et al., 2005). If a homogeneous supply of dopamine neurons can be generated, cell replacement can be systematically studied in large groups of patients, better defining the potential of this therapeutic strategy.
44.2. Experimental basis for neurotransplantation Developing a good rodent model of PD was critical to the development of neurotransplantation. Ungerstedt
*Correspondence to: Curt R. Freed, University of Colorado Health Sciences Center, Box C237, 4200 E. Ninth Avenue, Denver, CO 80262, USA. E-mail:
[email protected], Tel: þ1-303-315-8455, Fax: þ1-303-315-3272.
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and Arbuthnott (1970) demonstrated that unilateral injection of the neurotoxin 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle of rat brain can destroy dopamine neurons in the substantia nigra pars compacta with loss of dopamine nerve terminals in the striatum. Nearly complete destruction of dopamine neurons can be achieved on one side of the brain without damaging other neural systems or dopamine neurons on the contralateral side. Animals maintain nearly normal eating, drinking and grooming behaviors. When doses of methamphetamine are administered that ordinarily produce stereotypic behavior (5 mg/kg subcutaneously), the unilaterally lesioned animals will begin circling toward their lesioned side at rates as high as 10 rpm. Dopamine released asymmetrically from the intact side of striatum drives the circling behavior. Only rats with >95% unilateral dopamine depletion will circle at these high rates. By contrast, the dopamine agonist apomorphine stimulates the supersensitive dopamine receptors in the denervated striatum and leads to circling in the direction contralateral to the lesion. This rat model made it possible to explore cell replacement therapies for PD. Cells from a wide developmental range from early embryonic to adult tissue were tested for their ability to survive in brain. Critical experiments by Bjorklund and Stenevi (1979) and Perlow et al. (1979) were the first to show that rat mesencephalic dopamine cells transplanted into the denervated striatum could survive, extend neurites and stop the circling response to amphetamine as dopamine concentrations were restored. These early experiments were followed by others that showed that dopamine neurite outgrowth occurred in response to factors produced by the dopamine denervated striatum. Only mesencephalic dopamine neurons will reinnervate the striatum and transplant growth occurs only after striatum has been denervated. The behavioral effects of transplantation in rats are specific to mesencephalic dopamine cells. Rats transplanted with serotonergic neurons from mesencephalic raphe or dopamine neurons from hypothalamus have no improvement in behavior (Dunnett et al., 1988; Hudson et al., 1994). These experiments showed that innervation of the target is a specific interaction between the appropriate dopamine neuron and factors released from the denervated striatum. This important principle provides an argument for the safety of dopamine cell transplants, suggesting that a wide range of tissue doses could produce an acceptable behavioral response since the host striatum would secrete neurotrophic factors until appropriate dopaminergic input was achieved. Because this response is likely to be very local, even confined to individual or
small groups of striatal neurons, the model does not assure homogeneous reinnervation by dopamine neurons. Since the grafted dopamine neurons are ectopically placed in the striatum and do not have normal afferents, the dopamine neurons do not receive normal inputs regulating their own firing rates. If those inputs are needed for fully normal control of movement, dopamine cell transplants will be limited in value. Based on current results in humans, as described below, fetal cell transplants into putamen appear to mimic all of the effects of levodopa. At the present time, transplants can be viewed as equivalent to a continuous infusion of levodopa. This outcome is quite remarkable, given the fact that dopamine is being made available only to putamen. Ultrastructural studies have shown that fetal grafts reinnervate denervated striatum with both host-to-graft and graft-to-host synapses (Mahalik et al., 1985). Dopaminergic nerve terminals synapse on dendritic spines of medium spiny neurons. Transplanted cells synthesize and release dopamine (Schmidt et al., 1982). Grafted dopamine neurons exhibit electrical firing patterns and pharmacologic responses to dopamine agonists similar to the intrinsic dopamine cells of the substantia nigra pars compacta of adult animals (Wuerthele et al., 1981). Prior to transplanting human embryonic dopamine neurons into patients, human cells were transplanted into the rat model of PD. In ciclosporin-immunosuppressed rats, human fetal dopamine neurons were shown to survive and produce behavioral effects equivalent to rat dopamine cells, albeit with a time course delayed to 8–20 weeks compared to the 4–6 weeks seen with the faster-developing rat neurites (Brundin et al., 1986; Stromberg et al., 1986). Xenograft transplants of human to rat predicted the future difficulty of xenograft transplants in humans. Although allografts of human embryonic dopamine neurons are not rejected following transplant, even with no immunosuppression (Freed et al., 2001), xenograft transplants of human into rat require continuous treatment with ciclosporin. In the search for alternatives to mesencephalic dopamine neurons, cells from the adrenal medulla were harvested and transplanted into the rat model of PD (Freed et al., 1981; Freed, 1983; Stromberg et al., 1985). Ordinarily, these cells produce norepinephrine and epinephrine, not dopamine. Separated from adrenal cortex, adrenal medullary tissue generates a substantial amount of dopamine. Although these cells usually secrete neurotransmitters directly into the circulation and do not resemble neurons, isolated adrenal medulla cells adopt a neuronal morphology, particularly when exposed to a source of nerve growth factor
TRANSPLANTATION (NGF) (Freed, 1983; Stromberg et al., 1985). Survival of cells in striatum was much better with a source of NGF or equivalent neurotrophic factor. Behavioral effects were not as robust as seen with mesencephalic dopamine neurons (Freed, 1983). Humans and monkeys were shown to be at risk for chemically induced PD after catastrophic incidents in drug addicts. Initially, a young man who tried to produce synthetic narcotics inadvertently injected himself with a mixture that was subsequently shown to include the neurotoxin 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) (Davis et al., 1979). Shortly thereafter, he developed bradykinetic signs that were initially diagnosed as catatonic schizophrenia but later rediagnosed as parkinsonism. Because he was a single case and the phenomenon could not be reproduced in rats, the report gained little attention. Had the investigators picked any other mammal, such as mouse, cat, dog or monkey, they would have seen a parkinsonian syndrome. Instead, this critical observation had to be rediscovered after a group of drug addicts obtained MPTP from a single dealer (Langston et al., 1983). From these unfortunate events came a non-human primate model of PD (Burns et al., 1983). Monkeys lesioned by MPTP showed signs of bradykinesia, rigidity and tremor with dopamine depletion in the caudate and putamen. Levodopa improved these signs. Although the systemically lesioned monkey closely resembled idiopathic PD, the condition was highly variable. Some animals recovered to normal, making it difficult to distinguish a therapeutic intervention from spontaneous improvement. Others, unable to feed themselves or maintain an upright posture, died of the complications of immobility. A more predictable lesioning method was developed by Bankiewicz et al. (1986). By unilaterally infusing MPTP into the internal carotid artery, dopamine neurons on one side of the brain could be destroyed, leading to contralateral signs of parkinsonism. As with the 6-OHDA-lesioned rat, these animals could care for themselves. Transplanting fetal dopamine neurons into denervated striatum reduced the parkinsonian signs in both systemically and unilaterally lesioned monkeys, if the embryonic dopamine cells were obtained from early in embryogenesis at a developmental stage equivalent to days 13–16 in the embryonic rat (Bakay et al., 1985; Freed et al., 1988; Annett et al., 1994, 1997). By contrast, if mesencephalic tissue from later fetal stages was transplanted, cells failed to survive and animals did not improve (Redmond et al., 1986; Freed et al., 1988). Monkey experiments were valuable for showing that the principles established in rats also applied to primates. Because embryonic monkey tissue of the appropriate early gestational stage is even more
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difficult to obtain than human fetal tissue, the number of monkey transplants reported in the literature has been relatively small. The question of targeting transplants to putamen, caudate or both is based on electrophysiological and transplant studies in monkeys. Alexander and DeLong (1985) used microstimulation of the caudate and putamen to show that the putamen had motor responses specific to parts of the body with a homonculus that resembled that of motor and sensorimotor cortex. Leg and trunk movements were dorsolateral, arm movements intermediate and orofacial movements ventromedial. By contrast, microstimulation of caudate produced no limb movements. Hikosaka and colleagues (1989a) performed a series of experiments in monkeys showing that caudate controls saccadic eye movements. They also showed that caudate has a role in more complex behavioral responses to reward, perhaps reflecting its connections with prefrontal cortex (Hikosaka et al., 1989b). The same group has found that monkeys with dopamine depletion of caudate show impaired eye movements, similar to PD patients, but no abnormalities of limb movement (Kori et al., 1995). Only one study in monkeys has directly compared transplants into caudate versus putamen. In the marmoset, dopamine neurons placed in caudate reversed amphetamine-induced circling, whereas transplants introduced into putamen improved motor function of the contralateral limb (Annett et al., 1995). Taken together, these experiments in monkeys indicate that dopamine replacement in the putamen will directly improve movement of the limbs, whereas dopamine cell transplants into the caudate may have effects on eye movements and complex motor behaviors.
44.3. Clinical experience with adrenal medulla transplantation In 1987, an article by Madrazo et al. described a remarkable improvement in 2 patients after transplantation of adrenal medulla fragments recovered from the patients’ own adrenals and placed into the head of the caudate on one side of the brain. Although the clinical improvement was confounded by also initiating levodopa treatment, the fact that the report appeared in the New England Journal of Medicine brought a great deal of attention. Immediately, many groups began performing transplants of adrenal medulla, with more than 200 patients receiving surgery over the next 2 years. Although these open clinical trials reported some improvement for up to 6 months, there were no sustained effects of transplant. The morbidity of the surgery was significant. During recovery from the abdominal surgery on the adrenal
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gland, patients were often unable to take their oral antiparkinsonian medications. Typically, patients spent 10 days in the intensive care unit and up to 30 days in hospital. One-year mortality was 10% and 2-year mortality was 20%. In a registry of 61 patients, only 19% were judged improved 2 years after transplant (Goetz et al., 1991). Autopsy revealed few surviving adrenal chromaffin cells (Hurtig et al., 1989). Since no source of NGF had been provided, significant cell survival was improbable. Adrenal medulla transplants using cografts of peripheral nerve as a source of trophic factors have been conducted with reportedly better cell survival and longer duration of clinical effects (Date et al., 1996; Watts et al., 1997). Nonetheless, enthusiasm based on flawed case reports turned to disappointment. Grafting of cells from the adrenal medulla was abandoned because of the lack of efficacy and the significant morbidity associated with the surgical procedure itself.
44.4. Clinical experience with human fetal dopamine cell transplantation Since transplantation of human fetal tissue was first undertaken in the late 1980s, several groups have reported results using a variety of methods (Freed et al., 1990, 1992, 1995, 2001; Langston et al., 1992; Spencer et al., 1992; Widner et al., 1992; Peschanski et al., 1994; Freeman et al., 1995a; Kordower et al., 1995; Kopyov et al., 1996; Lindvall et al., 2001; Olanow et al., 2003). Comparisons among studies have been difficult because technical strategies and clinical evaluations have differed so widely. Tissue has been placed in putamen as well as caudate and unilaterally as well as bilaterally. It has been transplanted as solid tissue fragments as well as suspensions. Because transplants of allografts in outbred rats and in monkeys are not rejected even without immunosuppression, the need for immunosuppressants was uncertain. Therefore, some groups used immunosuppression, some did not and others compromised with short-term antirejection regimens. Patients with parkinsonism provide additional variability. Age is an important variable, as is the specific disease in the individual patient. To define patients as having idiopathic PD, most investigators have chosen patients who were responsive to levodopa. Some investigators have used fluorodopa positron emission tomography (FDOPA PET) to image the characteristic pattern of dopamine depletion in putamen with relative sparing in the caudate nucleus. No single clinical rating scale has been used, though there was an effort to define an evaluation strategy using a combination of the UPDRS scale and timed tests called Core
Assessment Program for Intracerebral Transplantations (Langston et al., 1992). Kordower and colleagues (1995), who did bilateral transplants of fragments of embryonic mesencephalon into postcommissural putamen, were the first to demonstrate surviving dopamine cells postmortem. The patient was immunosuppressed with ciclosporin for 6 months and died 18 months after transplant. Large numbers of surviving dopamine neurons were seen in the transplant tracks. The biggest problems with most clinical efforts were that patient numbers were small and trials uncontrolled. Therefore, statistically valid group comparisons could not be made. Results were anecdotal assertions rather than statistically valid evaluations. Only the two clinical trials sponsored by the National Institutes of Health have had experimental designs with enough patients, consistent methodology and control groups to make it possible to draw conclusions. Our double-blind, placebo-controlled trial transplanted dopamine neurons from ventral mesencephalon recovered from four embryos 7–8 weeks postconception and transplanted into four sites in the putamen, bilaterally under stereotaxic control. Tissue had been kept as strands in culture for up to 4 weeks prior to transplant. A 3–4-cm-long column of cells was placed in a dorsal and a ventral site in putamen on each side of the brain via twist drill holes in the forehead under local anesthesia. Sham surgery patients received the identical procedure except there was no needle penetration of the brain and no tissue was deposited. All patients gave informed consent to receive either tissue transplants or sham surgery. All recovery of embryonic tissue from elective abortions was done only after women had consented to the abortion and after they had given a second consent to donate fetal tissue per federal law and Institutional Review Board (IRB) requirements. There were no surgical complications that led to breaking the blind. There were no infections. We found that, 12 months after surgery, transplant subjects showed improvements in UPDRS motor ‘off’ scores for the group as a whole and for the subgroup under age 60 compared to the sham surgery controls (Fig. 44.1) (Freed et al., 2001). As shown in Figure 44.2, transplants were detectable in 85% of patients by blind scoring of FDOPA PET scans and grew equally well in younger and older patients (Nakamura et al., 2001). Patients under the age of 60 were most likely to benefit and changes in the UPDRS correlated with changes in PET signal. The signs that improved were bradykinesia and rigidity. Although tremor showed a trend for improvement, statistical significance was not reached. For each patient, the ‘best on’ state was carefully determined after the first
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Fig. 44.1. Changes in Unified Parkinson’s Disease Rating Scale motor ‘off’ scores in the first 12 months after transplant during the double-blind phase. Results show significant improvement for the transplant group as a whole and for the younger transplant patients, compared to the sham surgery group.
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Fig. 44.2. For full color figure, see plate section. Fluorodopa positron emission tomography (FDOPA PET) scans before and after transplantation. The left-hand panel shows the FDOPA PET signal of a normal person scanned in a horizontal plane that includes caudate and putamen. Stored F-dopamine is shown in false color red. The two right upper panels show PET scans in a patient before and 12 months after implantation with embryonic dopamine neurons. The preoperative panel demonstrates the profound depletion of putamenal signal. Caudate signal is relatively higher. Twelve months after transplant, the FDOPA PET signal in putamen has increased toward the normal range. The two right lower panels show PET signals in a sham-surgery patient before and 12 months after transplant. As shown, there is no improvement in putamenal dopamine. The caudate dopamine is further depleted. Reproduced from Freed et al. (2001), by permission of the New England Journal of Medicine. Copyright # 2001 Massachusetts Medical Society. All rights reserved.
morning dose of levodopa. After transplant, there was no change in the ‘best on’ state. The sham surgery group had no changes in UPDRS or Schwab and England scores after surgery (Freed et al., 2001). In patients with the best clinical responses, transplants could equal but not exceed the best effect of levodopa seen preoperatively. Therefore, transplants generate a purely dopaminergic effect. Just as with deep brain stimulation, parkinsonian signs not improved by
levodopa cannot be altered with transplants. Because transplants were placed only into putamen, we can say with some confidence that the motor effects of levodopa are mediated through actions on the putamen. The primary outcome variable in our study, a global rating scale, proved to be an unreliable measure of patient outcome. While still blinded at 12 months posttransplant, patients were asked to pick terms that described their current state compared to 1 year before.
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Those descriptors were then assigned whole-number values and averaged as though they were continuous variables. Scores were recorded. Patients were then shown videos of themselves 1 year before and all groups changed their ratings to more positive values. Our study demonstrated that a global rating scale cannot provide reliable assessments of long-term outcome in PD patients. Because some subjects are now more than 10 years posttransplant, long-term analysis is possible. As noted above, the most important predictor of response to transplant was the magnitude of the preoperative response to levodopa. Patients who had less than 50% improvement after the first morning dose of levodopa were unlikely to respond to transplant. In our group of subjects, levodopa had a much broader range of effects in those over age 60 compared to younger. Some older patients had only the minimal 30% improvement in UPDRS scores required to enter the study whereas others had up to 90% improvement. All subjects under age 60 had greater than 50% improvement after levodopa. Transplant results showed that only patients with greater than 50% levodopa response had improvement after surgery. When corrected for levodopa responsiveness, the older and younger patients had similar transplant outcomes. By 2 or 3 years after transplantation, UPDRS motor ‘off’ scores showed an average improvement of 50% of the best response to levodopa seen before transplant, regardless of age. At the current stage of development, the average response to transplant is equivalent to about half of the levodopa effect. These long-term changes are similar to what we first described in 1992 (Freed et al., 1992) and they are similar to what other groups have subsequently reported. One could argue that a transplant which produces at least 50% of the best levodopa effect is an appropriate target response. This effect is large enough to prevent severe ‘off’ symptoms while still not leading to dyskinetic movements (Freed et al., 2001). With the transplant producing 50% of the needed dopamine, the optimum clinical response in the individual patient can be achieved by administration of levodopa and other dopamine agonists. Individual variability of transplants has been a problem. Using tissue obtained from elective abortion, transplant outcome has varied from no effect to complete replacement of the need for levodopa. If stem cell research leads to a source of authentic midbrain dopamine neurons with more predictable growth and survival characteristics, then outcome might become more uniform. If cell transplantation could reliably replace 50–80% of the levodopa requirement in the individual patient, then transplantation could become an important component of the management of PD.
Dyskinesias have appeared in some transplant recipients who had levodopa-induced dyskinesias prior to transplant (Freed et al., 1990, 1992, 2001; Hagell et al., 2002; Olanow et al., 2003). In nearly all patients who respond to transplants, there is an initial period of increased dyskinesias which resolve as drug doses are reduced. In some patients, dyskinetic responses persisted even after substantial reduction or even elimination of levodopa and other dopamine agonist therapy. In our double-blind study, all patients who developed persistent ‘off’ dyskinesias were from the younger transplant group and all had had levodopa-induced dyskinesias prior to transplantation. It appears that the transplantation of tissue from four embryos provided enough dopamine to trigger dyskinesias. In the first year after transplant, these patients had had remarkable resolution of their parkinsonian signs. FDOPA PET scans showed some asymmetry of dopamine fiber outgrowth in these patients, with greater signal in left ventral putamen than was seen in other patients who did not develop dyskinesias (Ma et al., 2002). Patients did not show supranormal concentrations of dopamine. Although asymmetric transplant growth may be an explanation for dyskinesias, it is also possible that the dyskinetic response has its origin in other brain structures such as the subthalamic nucleus, the pallidum or the pars reticulata of the substantia nigra. An imbalance between the restored dopamine innervation of putamen and the persistent denervation of other brain regions may be responsible for the dyskinetic responses. We reported a tendency toward dyskinetic movements in our first transplant recipient in 1990 (Freed et al., 1990), as well as in 6 of 7 patients described in 1992 (Freed et al., 1992). In most of these patients, dyskinesias were controlled by reductions in drug doses. Neurophysiologic and cognitive effects of transplant were evaluated during the double-blind phase. Results showed significant improvement in reaction plus movement times (Gordon et al., 2004). This benefit was seen in both younger and older subjects. Cognitive performance showed no change in any measure 1 year after transplant (Trott et al., 2003). In the second double-blind clinical trial, the goal of the study was to compare placebo surgery with two doses of tissue, a low dose of cells from two embryos and a high dose of tissue from up to eight embryos transplanted into putamen, bilaterally (Olanow et al., 2003). The primary outcome variable was the UPDRS motor ‘off’ score, which had shown significant changes in our earlier study. Surprisingly, at the 2-year endpoint, there were no differences in the transplant groups compared to the placebo surgery controls. FDOPA PET scans showed greater reinnervation of
TRANSPLANTATION the putamen with the higher tissue dose at 1 year after transplant but similar reinnervation at 2 years after transplant. This result is compatible with animal studies which indicate that transplant growth occurs in response to signals generated by denervated striatum (Dunnett et al., 1988). Presumably, the transplants from the low-dose group continued to have axon arborization between year 1 and year 2 in order to supply portions of putamen inadequately innervated in the first year. By this mechanism, the FDOPA PET scans of the low-dose group caught up with the high-dose group by the second year. The authors could not account for the failure of the transplants to have effects on UPDRS scores. Because immunosuppression was instituted for only 6 months, they speculated that transplants might have been rejected after drugs were stopped. This conjecture is unlikely, since this same group has shown transplant survival at 18 months after transplant (Kordower et al., 1995) and FDOPA PET scan signals did not fall as they would if transplant rejection had occurred. They did find that patients with more severe baseline signs (higher UPDRS ‘off’ scores) failed to improve after transplant (Olanow et al., 2003). Olanow et al. did note dyskinesias present in the ‘off’ state in a large proportion of their transplant subjects and in none of the sham-surgery patients. Although the dyskinesias were of minor significance in most, some patients required the placement of deep brain stimulating electrodes in the subthalamic nucleus to control excess movements. 44.4.1. Unilateral versus bilateral transplantation Unilateral transplantation of fetal tissue was used in the first clinical PD transplant trials (Lindvall et al., 1989, 1990; Freed et al., 1990). Typically, implants were made into the side of the brain contralateral to the side of the body with the worse parkinsonian symptoms. In an attempt to provide more symmetric innervation and with the goal of improving axial functions such as walking, we and others began transplanting fetal tissue bilaterally in the early 1990s (Freed et al., 1992). 44.4.2. Solid versus suspension graft Fetal mesencephalic tissue can be transplanted either as a suspension of dissociated mesencephalon or as a solid graft. In some studies, human fetal tissue transplanted into immunosuppressed 6-OHDA-lesioned rats showed comparable survival of both solid and suspension grafts (Freeman et al., 1995b). However, our studies showed that rat mesencephalon transplanted
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in the form of a strand (made by extruding mesencephalic tissue through a tapered glass cannula with a 0.2-mm bore) into 6-OHDA-lesioned rats produced greater behavioral improvement and better dopamine neuron survival than transplants of dissociated mesencephalon (Clarkson et al., 1998b). 44.4.3. Age as a predictor of transplant outcome Although PD is primarily a disease of elderly people, some researchers have been hesitant to perform transplantation in older patients. In our 1999 review, we noted that the average age at the time of transplantation was 54 years, with average disease duration of about 13 years (Clarkson and Freed, 1999). Because in PD, the average age of onset is 55 years and the average patient with PD is estimated to be 67, clinical trials have been biased toward younger patients. Our double-blind study specifically addressed the issue of age with half of recruited patients 60 or over and half younger than 60. As noted above, it was not age per se but the preoperative response to levodopa that correlated with transplant outcome. In the aging brain, the symptoms of PD are likely to be one manifestation of a more global neuropathologic process. 44.4.4. Number of donors The number of surviving dopaminergic neurons needed to improve motor function significantly in a patient with PD is unknown. The normal adult human substantia nigra contains approximately 500 000 dopamine-producing neurons (Pakkenberg et al., 1991). Unfortunately, about 95% of dopamine neurons die after transplantation of rat or human tissue. In human patients, no more than 20 000–25 000 dopamine cells survive from each embryo transplanted (Kordower et al., 1995; Freed et al., 2001). Some investigators have argued that such a high rate of cell death requires that tissue from six or more donors be transplanted into each putamen to restore a complete complement of dopamine-producing neurons. Studies examining the ideal volume of grafted tissue in patients with PD are limited (Kopyov et al., 1997; Olanow et al., 2003) and the issue is still widely debated. Because PD symptoms only develop after a 50% loss of nigral neurons and a 60–80% reduction in striatal dopamine (Bernheimer et al., 1973; Kish et al., 1988), complete replacement of dopamine-producing neurons may not be required to improve motor skills and to reduce the need for levodopa. We have counted the dopamine neurons that have survived in transplant tracks in postmortem brain. In patients with bilateral putamenal implants who had
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clinical improvement sufficient to discontinue all levodopa, the total number of surviving dopamine neurons was 30 000–40 000 (Freed et al., 2005). The two individuals had received tissue from two and four embryos, respectively. Figure 44.3 shows transplanted dopamine neurons in a subject who received cells from two embryos via the frontal surgery approach. He discontinued all levodopa 15 months after transplant. He was never immunosuppressed. He died 10 years after surgery. These data provide experimental rather than hypothetical evidence for the amount of embryonic tissue and the number of surviving cells needed to have maximum clinical effect.
44.5. Alternative tissue sources In addition to the scientific controversies about techniques for transplantation of human fetal tissue, ethical concerns remain about the use of fetal tissue. There are logistical problems to recovering tissue after elective abortion. With the demonstration that a few fetal pig neural cells can survive transplantation into a patient with PD (Deacon et al., 1997), xenografts have been proposed as an alternative to human cell transplants, although the immunologic hurdles are enormous and unresolved. We reported that cloned transgenic cow embryos could survive transplantation in immunosuppressed rat and improve circling beha-
vior (Zawada et al., 1998a). Immortalized dopaminergic cell lines that do not generate tumors can reduce behavioral deficits and may offer an additional alternative to human fetal tissue (Clarkson et al., 1998a). Because xenograft rejection remains an unsolved problem, aggressive immunosuppression is required for transplantation of all non-human tissue. Efforts to blunt the immune response by methods such as using fragments of a monoclonal antibody to major histocompatibility complex class I (Palzaban et al., 1995) or class II antigens may reduce xenograft rejection. Encapsulating dopamine-producing xenografts may also prevent rejection, although such anatomically isolated grafts have no capacity to reinnervate the host brain (Emerich et al., 1992). Xenografts carry the potential risk of animal virus transmission to humans. With the concern about Creutzfeldt–Jakob disease, special efforts to monitor and control this risk are required. Non-neuronal dopamine cells from retinal pigment epithelium have been proposed and are under clinical evaluation (Stover et al., 2005). This biotechnology approach has expanded dopamine-producing retinal pigment epithelial cells and made them adhere to microspheres which have then been transplanted into PD patient striatum. An open clinical trial has suggested some clinical benefits from this approach and a doubleblind study is underway.
Dopamine neurons-10 yrs after transplant
Fig. 44.3. Surviving dopamine neurons in a putamenal transplant track of a patient who died 10 years after implant. This patient received dopamine neurons from two embryos via four needle passes in the putamen using a frontal surgical approach. He received no immunosuppression. The left-hand panel shows a low-power view of one of the transplant tracks with large numbers of dopamine neurons in the field (35). The right-hand panel shows a high-power view of the same transplant with profiles of individual tyrosine hydroxylase-positive dopamine neurons evident (400). Cell counts revealed nearly 40 000 surviving dopamine neurons from the two embryos. Cells and processes are immunostained with antibody to tyrosine hydroxylase (Pel Freez) followed by a secondary antibody with peroxidase diaminobenzidine visualization.
TRANSPLANTATION The most promising source of an unlimited supply of dopamine neurons is from differentiated human embryonic stem cells. Since 2000, mouse and non-human primate embryonic stem cells have been successfully converted to neurons with some dopaminergic characteristics and transplanted into experimental animals (Kawasaki et al., 2000; Lee et al., 2000; Kim et al., 2002; Shim et al., 2004; Takagi et al., 2005). Although strategies have differed in details, the basic concept has been to differentiate embryonic stem cells from neuroprogenitor cells, then expand that cell population and finally guide differentiation to dopamine neurons using known differentiation factors such as sonic hedgehog and fibroblast growth factor 8 (FGF8). The same principles have been applied to human embryonic stem cells with similar results, although with a slower timeline because of the longer cell cycle of human cells (Buytaert-Hoefen et al., 2004; Perrier et al., 2004; Yan et al., 2005). For reasons that remain uncertain, transplant survival of dopamine neurons derived from embryonic stem cells has been even worse than from fetal mesencephalon. Some success has been achieved by transplanting small numbers of mouse embryonic stem cells into immunosuppressed rat models of PD, though teratomas inevitably form in a proportion of the animals (Bjorklund et al., 2002). Selecting only neural progenitors at an earlier stage of differentiation may eliminate the teratoma risk (Chung et al., 2006). Interest has also focused on the delivery of neurotrophic factors to help reduce the number of dopamine neurons that die after transplantation. Cotransplantation of fibroblasts infected to produce basic fibroblast growth factor with mesencephalic grafts increased the number of dopamine neurons in these transplants (Takayama et al., 1995). Other survival factors, including insulin-like growth factor I and glial cell linederived neurotrophic factor and caspase inhibitors, can protect transplanted cells from apoptotic cell death (Clarkson et al., 1995; Zawada et al., 1996, 1998b; Schierle et al., 1999). Inhibitors of lipid peroxidation have been tested in humans and may promote improved dopamine cell survival (Brundin et al., 2000).
44.6. Summary Since 1988, neurotransplantation with embryonic mesencephalic dopamine neurons has been tried as a treatment for patients with advanced PD. Although transplant methods have differed substantially among centers, most reports have found some value to implants made into putamen. Open clinical trials of small numbers of patients have shown benefit from transplantation in most patients reported. Reduction of levodopa dose is frequently
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reported. Several principles have emerged. Mesencephalic tissue must be from early in embryonic development, typically 7–8 weeks after conception. Bilateral transplantation into putamen can be done safely during a single operation. Unilateral transplantation leads to asymmetric transplant effects. Immunosuppression is not required. Two double-blind studies have shown that transplants can survive and improve FDOPA PET scans in most subjects. One has shown that UPDRS motor scores (bradykinesia and rigidity) can significantly improve in transplant patients compared to placebo controls (Freed et al., 2001). Well-controlled doubleblind studies must be used to compare the outcome of the transplant strategies yet to be tested. Although the clinical benefit in individual patients has made drug elimination possible, there is substantial variability in outcome. Contributing to this variability are differences in pathologic processes in individual patients and in dopamine neuron survival and outgrowth. The best predictor of transplant outcome is the preoperative response to levodopa (Freed et al., 2004). Transplantation can duplicate but cannot exceed the best preoperative response to levodopa. Some patients with a prior history of levodopa-induced dyskinesias may have persistent dyskinesias even after the reduction or elimination of levodopa. These dyskinesias respond to inhibitors of dopamine synthesis such as metyrosine or to deep brain stimulation of pallidum or subthalamic nucleus.
44.7. Future prospects for neural transplantation Where shall human transplant research go from here? To evaluate fully the effectiveness of dopamine cell transplants for PD, a uniform source of dopamine neurons must be developed. Differentiation of embryonic stem cells from dopamine neurons may produce an unlimited number of dopamine neurons for transplant. Unlike most somatic tissue transplants, allografts of human fetal neural tissue are not rejected. Therefore, donor-specific embryonic stem cells will probably not be required. Although less likely, some of the other cell sources described in this chapter may prove useful. Because of immunologic barriers, successful xenografts are improbable. Results of the double-blind studies indicate that transplants only into the putamen can produce beneficial motor effects. On the other hand, clinical benefits have been incomplete in most patients. Many PD patients have cognitive deterioration either early or late in their disease. In an effort to improve the outcome of neurotransplantation, we are obliged to consider new targets for transplantation. Because the region of dopamine cell loss, the substantia nigra pars compacta, has
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important regional connections with the pars reticulata, the subthalamic nucleus and the pallidum, dual tranplants into putamen and substantia nigra should be considered. Because the caudate nucleus has a role in cognitive function and eye movements, comparison of dual transplants into caudate and putamen could be compared to putamen alone. Since dyskinesias in both experimental animals and in humans are most often seen after priming with levodopa, a clinical trial of transplantation early in PD may show that transplantation prevents the development of levodopa-induced dyskinesias. Although restoring uniform anatomic integrity of the nigrostriatal dopamine system is a daunting challenge, transplantation has already demonstrated successful repair of the human PD brain. Nonetheless, transplant effects are limited to the replacement of dopamine. There is no treatment for the progressive, non-dopaminergic signs of PD. The ideal treatment for PD would stop the loss of dopamine neurons and other affected cell types at the earliest stage of the disease.
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Lindvall O, Brundin P, Widner H et al. (1990). Grafts of fetal dopamine neurons survive and improve motor function in Parkinson’s disease. Science 247: 574–577. Ma Y, Feigin A, Dhawan V et al. (2002). Dyskinesia after fetal cell transplantation for parkinsonism: a PET study. Ann Neurol 52: 628–634. Madrazo I, Drucker-Colin T, Daiz V et al. (1987). Open microsurgical autograft of adrenal medulla to the right caudate nucleus in two patients with intractable Parkinson’s disease. N Eng J Med 316: 831–833. Mahalik TJ, Finger TE, Stromberg I et al. (1985). Subsranria nigra transplants into denervated srriatum of the rat ultrastrucrure of graft and host interconnections. J Comp Neurol 240: 60–70. Nakamura T, Dhawan V, Chaly T et al. (2001). Blinded positron emission tomography study of dopamine cell implantation for Parkinson’s disease. Ann Neurol 50: 181–187. Olanow CW, Goetz CG, Kordower JH et al. (2003). A doubleblind controlled trial of bilateral fetal nigral transplantation in Parkinson’s disease. Ann Neurol 54: 403–414. Pakkenberg B, Moller A, Cundersen HJ et al. (1991). The absolute number of nerve cells in substantia nigra in normal subjects and in patients with Parkinson’s disease estimated with unbi-based stereological method. J Neurol Neurosurg Psychiatry 54: 30–33. Palzaban P, Deacon TW, Burns LH et al. (1995). A novel mode of immunoprotection of neural xenotransplants: masking of donor major histocompatibility complex class I enhances transplant survival in the central nervous system. Neuroscience 65: 983–996. Perlow MJ, Freed WJ, Hoffer BJ et al. (1979). Brain grafts reduce motor abnormalities produced by destruction of nigrosttiatal dopamine system. Science 204: 555–560. Perrier AL, Tabar V, Barberi T et al. (2004). Derivation of midbrain dopamine neurons from human embryonic stem cells. Proc Natl Acad Sci USA 101: 12543–12548. Peschanski M, Defer C, N’Guyen JP et al. (1994). Bilateral motor improvement and lateralization of L-dopa effect in two patients with Parkinson’s disease following intrastriatal transplantation of foetal ventral mesencephalon. Brain 117: 487–499. Redmond DE, Sladek JR Jr, Roth RH et al. (1986). Fetal neuronal grafts in monkeys given methylphenyltetrahydropyridine. Lancet 8490: 1125–1127. Schierle GS, Hansson O, Leist M et al. (1999). Caspase inhibition reduces apoptosis and increases survival of nigral transplants. Nat Med 5: 97–100. Schmidt RH, Ingvar M, Lindvall O et al. (1982). Functional activity of substantia nigra grafts reinnervating the striatum: neurotransmitter metabolism and (14C)-2-deoxy-Dglucose autoradiography. J Neurochem 38: 737–748. Shim JW, Koh HC, Chang MY et al. (2004). Enhanced in vitro midbrain dopamine neuron differentiation, dopaminergic function, neurite outgrowth, and 1-methyl-4-phenylpyridium resistance in mouse embryonic stem cells overexpressing Bcl-XL. J Neurosci 24: 843–852.
Spencer DD, Robbins RJ, Naftojin F et al. (1992). Unilateral transplantation of human fetal mesencephalic tissue into the caudate nucleus of patients with Parkinson’s disease. N Engl J Med 327: 1541–1548. Stover NP, Bakay RA, Subramanian T et al. (2005). Intrastriatal implantation of human retinal pigment epithelial cells attached to microcarriers in advanced Parkinson disease. Arch Neurol 62: 1833–1837. Stromberg I, Herrera-Marschitz M, Ungerstedt U et al. (1985). Chronic implants of chromaffin tissue into the dopamine-denervated striatum. Effects of NGF on graft survival, fiber growth and rotational behavior. Exp Brain Res 60: 335–349. Stromberg I, Bygdeman M, Goldstein M et al. (1986). Human fetal substantia nigra grafted to the dopamine-denervated striatum of immunosuppressed rats: evidence for functional reinnervation. Neurosci Lett 71: 271–276. Takagi Y, Takahashi J, Saiki H et al. (2005). Dopaminergic neurons generated from monkey embryonic stem cells function in a Parkinson primate model. J Clin Invest 115: 102–109. Takayama H, Ray J, Raymon HK et al. (1995). Basic fibroblasts growth factor increases dopaminergic graft survival and function in a rat model of Parkinson’s disease. Nat Med 1: 53–58. Trott CT, Fahn S, Greene P et al. (2003). Cognition following bilateral implants of embryonic dopamine neurons in PD: a double blind study. Neurology 60: 1938–1943. Ungerstedt U, Arbuthoott CW (1970). Quantitative recording of rotational behavior in rats after 6-hydroxy-dopamine lesions of the nigrostriatal dopamine system. Brain Res 24: 485–493. Watts RL, Subramanian T, Freeman A et al. (1997). Effect of stereotaxic intrastriatal cografts of autologous adrenal medulla and peripheral nerve in Parkinson’s disease: two-year follow-up study. Exp Neurol 147: 510–517. Widner H, Tetrud J, Rehncrona S et al. (1992). Bilateral fetal mesencephalic grafting in two patients with Parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). N Engl J Med 327: 1556–1563. Wuerthele SM, Freed WJ, Olson L et al. (1981). Effect of dopamine agonists and antagonists on the electrical activity of substantia nigra neurons transplanted into the lateral ventricle of the rat. Exp Brain Res 44: 1–10. Yan Y, Yang D, Zarnowska ED et al. (2005). Directed differentiation of dopaminergic neuronal subtypes from human embryonic stem cells. Stem Cells 23: 781–790. Zawada WM, Kirschman DL, Cohen JJ et al. (1996). Growth factors rescue embryonic dopamine neurons from programmed cell death. Exp Neurol 140: 60–67. Zawada WM, Cibelli JB, Choi PK et al. (1998a). Somatic cell cloned transgenic bovine neurons for transplantation in parkinsonian rats. Nat Med 4: 569–574. Zawada WM, Zastrow DJ, Clarkson ED et al. (1998b). Growth factors improve immediate survival of embryonic dopamine neurons after transplantation into rats. Brain Res 786: 96–103.
Handbook of Clinical Neurology, Vol. 84 (3rd series) Parkinson’s disease and related disorders, Part II W. C. Koller, E. Melamed, Editors # 2007 Elsevier B. V. All rights reserved
Chapter 45
Gene therapy approaches for the treatment of Parkinson’s disease BIPLOB DASS AND JEFFREY H. KORDOWER* Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA
Parkinson’s disease (PD) is the second most common neurodegenerative disease, with over 1 million Americans suffering from this disorder. The cardinal symptoms of PD are rigidity of the cogwheel type, resting tremor, bradykinesia and postural instability (Marsden, (1990)). These symptoms result from striatal dopamine insufficiency secondary to degeneration of dopaminergic neurons in the substantia nigra (SN) pars compacta (Ehringer and Hornykiewicz, 1960). Although it has been over 50 years since its discovery, levodopa remains the gold-standard treatment by which all other therapies are compared. Despite being an outstanding therapy, levodopa ultimately loses its usefulness, not because it can no longer provide benefit, but because benefit is accompanied by debilitating side-effects that limit its utility (Marsden and Parkes, 1977; Curtis et al., 1984). Therefore novel therapeutic strategies are needed for the long-term treatment of PD patients. Towards this end, a myriad of pharmacological therapies have comprised the armament of treatment strategies for PD. These have been reviewed elsewhere in this volume. Furthermore, a variety of surgical treatments have been tested clinically, such as adrenal cell transplants, adrenal cell/peripheral nerve cografts, human fetal nigral transplantation and porcine fetal transplantation (Madrazo et al., 1987; Lindvall et al., 1989; Quinn, (1990); Kordower et al., 1995; Date et al., 1996; Deacon et al., 1997; Wenning et al., 1997; Schumacher et al., 2000; Freed et al., 2001). Out of all the surgical interventions tested to date, only deep brain stimulation has emerged as a genuinely useful treatment strategy (Figueiras-Mendez et al., 1999). Recently, preclinical studies delivering therapeutic genes have shown such promise that three strategies have already begun clinical trials (Neurologix: adeno-associated
virus-glutamic acid decarboxylase (AAV-GAD), Avigen: AAV-aromatic acid decarboxylase (AADC) and Ceregene: adeno-associated virus-neurturin (AAV-NTN)). There are a number of reasons to suspect that delivery of therapeutic genes would be superior to the delivery of pharmacological agents. The first reason is site specificity. When delivering therapeutic drugs peripherally, you are often dose-limited because the drug usually acts in a nonspecific manner and activates unintended systems. For example, administration of levodopa in high enough doses can lead to hallucinations due to increasing dopaminergic neurotransmission in the mesolimbic system. The mesolimbic system emanates from the ventral tegmental area, a region adjacent to the SN. Axons from the ventral tegmental area do not terminate in the striatum but rather in the nucleus accumbens and medial prefrontal cortex. When this occurs, the dose of levodopa needs to be lowered, thereby minimizing the therapeutic efficacy of this powerful compound. In contrast, novel therapeutic strategies such as gene therapy can drive the dose of the therapeutic molecule by placing the vectors in site-specific loci and, with care, this delivery method should not affect unintended brain regions. For prodopaminergic gene therapy approaches (see below), it is thought that the postcommissural putamen is the most critical site. This choice has been based upon a number of factors. First, the loss of dopamine in PD is greatest in the postcommissural putamen. Second, this region of the striatum is intimately connected with motor cortex. In contrast, the caudate nucleus and anterior putamen are similar embryologically, have dense interconnections with association cortices and are linked to higher-order functions such as cognition rather than motor function. Based upon this logic and
*Corresponding author: Jeffrey H. Kordower, Department of Neurological Sciences, Cohn Building, Rush University Medical Center Chicago, IL 60612, USA. E-mail:
[email protected], Tel: 312-563-3570, Fax: 312-563-3571.
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due to the limited availability of donor material, doubleblinded clinical trials testing human and porcine fetal transplantation strategies have grafted cells exclusively to the postcommissural putamen that were based upon successful open-label studies (Lindvall et al., 1989; Kordower et al., 1995; Deacon et al., 1997; Wenning et al., 1997; Schumacher et al., 2000; Freed et al., 2001). Similarly, Amgen sponsored a double-blind trial in which catheters were placed in the postcommissural putamen to deliver the trophic factor glial-derived neurotrophic factor that were also based upon successful open-label studies (GDNF, Gill et al., 2003; Slevin et al., 2005). It is notable that all of these double-blind trials have failed to meet their primary endpoints. There are a number of explanations for the failure of these trials, for instance, cells not surviving in the porcine transplantation study, immune issues may have influenced the human embryonic transplantation experiments and dose and catheter design issues may have influenced the outcome of the GDNF trial. However, it remains troubling that this dogmatic view that the postcommissural putamen is the essential region for dopaminergic reinnervation has yet to be sustained in any double-blinded clinical trial in PD.
45.1. Drug development strategy Because PD is a long-term degenerative disorder and the gene delivery itself will require neurosurgery, a single surgical procedure that results in long-term or permanent therapy will be required to make this therapeutic option practical. This means that the gene transfer should lead to very long-term or permanent gene expression. The issue of which vector would be ideal for use in the treatment was initially a problem, since each virus has strengths and drawbacks. Adenovirus and herpes simplex virus (HSV) administrations were initially shown to induce strong immunogenic responses and be short-acting and were therefore nonstarters for clinical application in PD. AAV has a low level of transgene expression and lentivirus has a fairly small capacity and the stigma of being associated with human immunodeficiency virus (HIV). However there has been remarkable improvement in the safety and expression of many of these vectors. The use of gutless adenovirus has minimized its immunogenicity. The creation and characterization of novel AAV serotypes have resulted in robust long-term gene expression in rats and monkeys. For a while, empirical evidence favored lentivirus as the vector of choice as studies progressed towards clinical trials. However, AAV now appears equal to lentivirus with regard to many of the characteristics deemed important for gene delivery, such as longterm expression, infectivity of neurons and the absence of immunogenicity and inflammation. In fact, the one
clear empirical difference between AAV and lentivirus is that the former is retrogradely transported whereas the latter is not. The functional relevance of this difference, if any, is unclear. Given their safety profile and scientific advantages, only AAVs have currently been approved for clinical trials in PD.
45.2. Gene therapy for Parkinson’s disease: delivery of therapeutic enzymes The first strategy proposed as a gene therapeutic treatment for PD was striatal levodopa delivery by ex vivo expression of tyrosine hydroxylase (TH) (Wolff et al., 1989). The initial basis for the ex vivo delivery of TH was the known efficacy of peripheral levodopa treatment combined with the neurosurgical safety demonstrated by fetal ventral mesencephalic dopamine grafting in rodents and humans (Brundin et al., 1986; Lindvall et al., 1989). These studies failed due to the inability of ex vivo gene therapy approaches at that time to provide high-titer long-term gene expression, as well as having issues with inflammation. Indeed, shutdown of the transgene and only transient and low-level functional recovery was seen using this approach. Although the rationale for proceeding with enzyme gene delivery was logical, the tools at that time to elicit long-term high-titer gene expression were unavailable. To expand upon this initial study, a serotype 2 AAV encoding TH was utilized in 6hydroxydopamine (6-OHDA)-lesioned rats. The use of stably lesioned animals facilitated the investigation of the reversal of deficits induced by neurotoxin treatment. TH immunoreactivity was detectable in the striata up to 4 months after vector administration and resulted in a persistent reduction of apomorphineinduced rotational behavior for the duration of the experiment (Kaplitt et al., 1994). Following this, vectors encoding for combinations of genes involved in the synthesis of levodopa were injected into the denervated striata of rats using separate AAVs. Thus, double or triple transfections of TH, AADC and guanosine triphosphate-cyclohydrolase-1 (GCH-1) were shown to be effective at producing levodopa in the 6-OHDAlesioned striatum, as measured by microdialysis (Mandel et al., 1998; Shen et al., 2000; Kirik et al., 2002). The success of this approach was also determined by the PD model that was employed. In fully lesioned animals, gene delivery of TH and GCH-1 did not alter apomorphine-induced rotational behavior, but rotational deficits were attenuated in rats with a partial lesion of the nigrostriatal pathway (Kirik et al., 2002). When three genes were delivered (TH, GTPCH1 and AADC), behavioral recovery, as measured by apomorphine-induced rotational behavior, could be observed in rats with complete nigrostriatal
GENE THERAPY APPROACHES FOR THE TREATMENT OF PARKINSON’S DISEASE lesions. The increase in striatal dopamine content was modest in these animals, although the effects of the gene delivery could be demonstrated for 12 months (Kirik et al., 2002). Using a lentivirus gene delivery system based on equine infectious anemia virus, Azzouz and coworkers (2002) performed similar experiments. A non-human lentivirus was employed as a safety measure as it is less likely to recombine and form HIV if used clinically. It is critical to note, however, that there is currently no empirical evidence that lentivirus could recombine to form a pathogenic HIV particle and there is also no proof that non-human forms of HIV would pose a lesser risk. Rotational behavior induced by apomorphine administration was partially reversed by treatment with the tricistronic (TH, GTPCH1 and AADC) vector, although turning behavior was still greater than 5 per minute in these rats. Striatal dopamine content was also partially elevated by the gene delivery, but levels were still less than 10% of the intact hemisphere. Since the symptoms of PD only arise after a threshold of approximately 70% striatal dopamine depletion occurs, a small increase in dopamine levels could result in significant improvements in motor function. Thus, these strategies were investigated in primates with stable lesions. When administered to 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP)-treated primates, AAV-mediated gene delivery of TH and AADC was successful up to 10 weeks (During et al. (1998)). No inflammation or other adverse effects were noted after AAV administration. However, no behavioral recovery was observed in these monkeys and postmortem
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dopamine concentrations were only modestly raised in the lesioned striata. In contrast, triple transfection in the putamen of TH, AADC and GCH-1 did result in behavioral recovery of 40–60% in 4 MPTP-treated primates (Muramatsu et al., 2002). Dopamine synthesis in the striatum was also increased approximately fivefold, although this increase was still very low. Long-term studies examining bi- and tricistronic delivery of therapeutic enzymes are still needed prior to the initiation of clinical trials. As an alternative to expressing the enzymes required for the production of levodopa and dopamine, the Bankiewicz group has used viral vectors (see Table 45.1) to express solely AADC in the striatum to enhance the production of dopamine following the administration of levodopa. This approach is hoped to reduce levodopa requirements and provide a more stable level of conversion to dopamine in the striatum and therefore help avoid the incidences of levodopainduced dyskinesias. In their initial experiments, they injected AAV-AADC into the striata of MPTPlesioned monkeys and were able to observe increased AADC activity in vivo, coupled with increased dopamine metabolite production (Bankiewicz et al., 2000). Convection-enhanced delivery was used as the infusion method and resulted in a high density of AADC immunoreactive cells throughout the striatum. Most transfected cells had a NeuN-positive, medium spiny neuron-type morphology and there were very few glial fibrillary acid protein and AADC co-positive cells. In a subsequent experiment in 6-OHDA-lesioned rats, the gene transfer of AADC also resulted in
Table 45.1 Characteristics and uses of viral vectors in animal models of Parkinson’s disease
Vector
Neuronal preference
Maximum insert
Strength of expression
Duration of expression
Immunogenic response
Current uses in models of PD
Adenovirus
þ
7.5 kb
þþ
Weeks
þþþ
Adeno– associated virus
þþþþ (type 2) þ (type 5)
4 kb
þ (type 2) þþ (type 5)
>2 years
þ
Herpes simplex virus Lentivirus
þþþþ
30–150 kb
þþ
Weeks
þþþ
TH, GDNF, XIAP, JBD, Calpastatin, Cu/Zn SOD, TH, AADC, GTPcyclohydrolase, BDNF, GDNF, NTN, SHH, GAD TH, Bcl-2, GDNF
þþþ
9 kb
þþþ
>1 year
þ
GDNF, TH, AADC, GTP–cyclohydrolase
TH, tyrosine hydroxylase; GDNF, glial-derived neurotrophic factor; XIAP, X chromosome-linked inhibitor of apoptosis; JBD, JNK binding domain; SOD, superoxide dismutase; AADC, aromatic acid decarboxylase; GTP, guanosine triphosphate; NTN, neurturin; SHH, sonic hedgehog; GAD, glutamic acid decarboxylase.
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enhanced conversion of levodopa to dopamine, but the dopamine was not stored within the neurons and seemed to be released continuously (Sanchez-Pernaute et al., 2001). Theoretically, uncontrolled and increased dopamine release in the striatum might exacerbate levodopa-induced dyskinesias. However, a reduction in the required dose of levodopa might lead to fewer treatment-related side-effects. Interestingly, when AAV-AADC was delivered without using convectionenhanced delivery at three focal points in the striatum of MPTP-lesioned monkeys, dyskinesias were observed, suggesting that the creation of a hotspot of dopamine activity is key to the generation of levodopa-related side-effects (Bankiewicz et al., 2006). This corroborates previous work with cell grafts, suggesting that focal hotspots rather than widespread grafts can cause dyskinesias (Steece-Collier et al., 2003). In further studies with MPTP-lesioned monkeys infused with AAV-AADC throughout the striatum using convection-enhanced delivery, no dyskinesia was observed over a 5-year time period, although behavior in response to levodopa treatment was improved in these animals (personal communications from Dr. Bankiewicz). As a result of the preclinical work performed in the Bankiewicz laboratory using MPTP-lesioned monkeys and 6-OHDA-lesioned rats, a clinical trial was initiated by Avigen in December of 2004 using an AAV to deliver the DNA for AADC into the human putamen. At the time of writing, the trial is still under way and no peer review data are available for assessment. However, a press release suggested that AAV-AADC was well tolerated and resulted in the production of AADC (Avigen press release, 18 July 2005). Currently, a phase I clinical trial utilizing an AAV expressing GAD in PD patients is under way in New York (During et al., 2001). The rationale behind this study is that the overactivity of the excitatory subthalamic nucleus (STN) in PD patients might be reduced by the transfer of the GAD gene into this nucleus and so provide relief from thalamic inhibition. Previously, this group had shown that AAV-GAD transfection into the STN of fully 6-OHDA-lesioned rats could induce a phenotypic change in these nuclei, causing them to release gamma-aminobutyric acid (GABA) in addition to glutamate (Luo et al., 2002). Injection of an AAVGAD65 vector 3 weeks before a nigrostriatal lesion resulted in a 35% protection of nigral TH-positive cells and decreased rotational behavior and behavioral asymmetries. As with other studies utilizing AAVs, no inflammation was found 4–5 months after administration and no antibodies against the viral capsid were detected in the sera of these animals (Luo et al., 2002). Thus, the basis for further studies utilizing AAV-GAD
has been set and currently patients enrolled in the phase I trial that have received unilateral AAV-GAD into the STN are reported to have improved 27% on the Unified Parkinson’s Disease Rating Scale and have significant decreases in fluorodeoxyglucose utilization on the side contralateral to the injection (Neurologix press release, 25 September 2005).
45.3. Delivery of trophic molecules Although the striatal delivery of genes encoding for dopaminergic enzymes or STN delivery of inhibitory enzymes might provide substantial therapeutic benefit, none of these approaches has a compelling basis for altering the underlying disease. An alternative approach, which theoretically could alter the natural history of PD, is the delivery of genes encoding for neuron-saving trophic factors. In addition to providing neuroprotection, gene delivery of trophic factors has the added advantage of enhancing the function of cells and inducing cells to produce greater amounts of relevant neurotransmitters (i.e. dopamine). A wealth of data has been amassed on the efficacy of many dopaminergic trophic molecules, such as epidermal growth factor, basic fibroblast growth factor, brain-derived neurotrophic factor (BDNF), sonic hedgehog and GDNF to prevent degeneration following bolus administrations in models of nigrostriatal degeneration (Gash et al., 1996; Pearce et al., 1996, 1999; Svendsen et al., 1996; Dass et al., 2002; for review, see Collier and Sortwell, 1999). In particular, GDNF is a particularly promising candidate for clinical use, based on a series of studies in animal models of PD. Initial open-label and doubleblind studies examining the safety and efficacy of monthly intraventricular injections GDNF failed. No efficacy was seen and serious side-effects were observed (Kordower et al., 1999; Nutt et al., 2003). However this result was to be expected, since vulnerable neurons are not exposed to GDNF via this delivery method. Indeed, even chronic intraventricular infusions of GDNF demonstrated trivial immunoreactivity to GDNF protein beyond the ventricular ependyma. These initial studies demonstrated that, even if GDNF is the correct protein, it would be unsuccessful if delivered in an ineffective manner. In an attempt to improve delivery parameters, two open-label trials delivered GDNF chronically into the postcommissural putamen of PD patients (Gill et al., 2003; Amgen press releases, June 2004, February 2005; Slevin et al., 2005). Both studies reported sustained functional benefit. One trial (Gill et al., 2003) also reported increases in fluorodopa uptake on positron emission tomography (PET) scan, an effect that increased from 6 months to 1 year. Disappointingly, the 1 patient who has currently come
GENE THERAPY APPROACHES FOR THE TREATMENT OF PARKINSON’S DISEASE to autopsy showed only marginal changes in TH, an effect that was dwarfed by other procedures such as fetal transplants that have yet to be proved efficacious. As a follow-up to these open-label studies, Amgen sponsored a multicenter double-blind trial examining the safety and efficacy of bilateral intraputamenal GDNF in patients with PD. This trial failed to demonstrate efficacy. At first glance, one has to consider strongly that placebo effects and experimenter bias, phenomena that are inherent to all open-label trials and particularly those in PD (de la Fuente-Fernandez et al., 2001), resulted in the positive clinical effects seen in the Bristol and Kentucky studies and when they were controlled for by the enhanced rigor associated with a double-blind trial, these reported effects could not be substantiated. However, equally strongly, it needs to be noted that there were substantial and potentially critical differences in technique between the open-label trials and the double-blind trial. These differences included dosage (higher dosages ultimately used in the open-label trials), catheter design (a thicker catheter (Bristol) and multiport catheter (Kentucky) in the open-label studies) and rate of trophic factor delivery (convection-enhanced delivery in the open-label trials and non-convection enhanced delivery in the doubleblind trial). Therefore it is very possible that delivery methods in the double-blind procedure were inferior to those in the open-label trial and this critical aspect of the study prevented the induction of functional benefit. In addition to the absence of clinical benefit, the Amgen trial was stopped prematurely due to the presence of side-effects. Neutralizing antibodies against GDNF were observed in approximately 10% of patients and some monkeys treated with high-dose GDNF displayed profound cerebellar degeneration. The origin of the antibody response is unclear and has been seen in all infusion trials. It could be due to leakage of protein into the abdomen during refilling of the pump. It also could be due to the use of glycosylated, rather than native, GDNF. It is unclear what side-effects antibodies to GDNF might cause in adult humans and, to date, no side-effects have been reported in patients who received GDNF. With regard to the cerebellar damage, it is possible that, due to the thin catheter and non-convection delivery method, the GDNF backed up the catheter and GDNF flowed over the brain convexities to the cerebellum. Two aspects of this phenomenon are notable. It never happens when GDNF or GDNF family members are delivered via viral vectors to monkeys directly to the striatum. Second, no patients who have received intraputamenal GDNF have been reported to have signs of cerebellar degeneration. The only thing at this point that is perfectly clear is that nothing is perfectly clear. The safety and delivery issues surrounding intraputame-
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nal infusions of GDNF need to be addressed and once further information is gathered, a new double-blind trial using more optimal dosing and delivery parameters should be initiated.
45.4. Gene delivery of glial-derived neurotrophic factor in rodents before lesioning A superior approach to trophic factor infusion may be gene therapy. Gene therapy does not have the hardware issues associated with the implantation of catheters and pumps, nor does it have the issue of numerous pump refills over long periods of time. In this regard, numerous studies have created a body of evidence indicating that gene delivery of GDNF and GDNF-like molecules may be a powerful therapeutic tool to provide neuroprotection and neuroaugmentation for degenerating SN neurons. Martha Bohn and colleagues deserve credit for performing the first experiments examining gene delivery of GDNF in animal models of PD. Initial studies used an adenovirus to deliver GDNF before 6-OHDA lesioning in rats and so examined the neuroprotective potential of this therapeutic strategy (Bilang-Bleuel et al., 1997; Choi-Lundberg et al., 1997; Lapchak et al., 1997). In Choi-Lundberg’s study, supranigral administration of Ad-GDNF (AD, adenovirus) 7 days before the initiation of a striatal 6-OHDA lesion in rats resulted in a 75% protection of nigral fluorogold-positive dopaminergic neurons, but the size of the striatal lesion was unchanged in these animals, compared to controls. Horellou’s group injected Ad-GDNF into the rat striatum 6 days before the initiation of a striatal 6-OHDA partial lesion (Bilang-Bleuel et al., 1997). The number of TH-IR (IR, immunoreactivity) cells in the SN was significantly greater than in control animals, although again complete protection of the SN was not achieved. In the striatum, TH immunoreactivity was increased following striatal Ad-GDNF administration and amphetamine-induced rotational asymmetry was attenuated. Thus, the site of administration of GDNF is critical to the protection of the nigrostriatal pathway following a neurotoxic insult. Using GDNF protein, similar results have been obtained when comparing the protective effects of intrastriatal, intranigral and intraventricular administration (Kirik et al., 2000a). Accordingly, GDNF was only able to protect the anatomy and function of the nigrostriatal pathway following an intrastriatal injection of Ad-GDNF and, if a viral vector encoding a trophic molecule was considered for use in PD patients, it is more likely to be efficacious to administer the vector into the caudate and putamen. Choi-Lundberg and colleagues (1998) repeated the administration of Ad-GDNF, but injected the vector intrastriatally before creating a partial 6-OHDA lesion.
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No improvement in the density of TH-IR fibers in the striatum was observed, but behavioral asymmetry was reduced and nigral TH-IR cell numbers were protected. This result might be mediated by the retrograde transport of GDNF itself or Ad-GDNF into the SN and the subsequent trophic support that GDNF could provide to the functionality of the cell body. GDNF was detectable at nanogram levels in the striatum and picogram levels in the nigra. Since GDNF can undergo retrograde transportation along the nigrostriatal tract, it was unclear if this finding was as a result of the actions on GDNF or a function of the adenovirus (Tomac et al., 1995; Lapchak et al., 1997; Mufson et al., 1999). Following this study, the same group pretreated aged rats with Ad-GDNF before initiating a striatal 6-OHDA lesion (Connor et al., 1999). GDNF increased TH-IR optical density in the striatum, indicating the potent phenotypic upregulation GDNF can provide in addition to its neuroprotective properties. It is likely that the actions of GDNF transfected by an adenovirus not only protects cells from 6-OHDAmediated cell death but also from the toxicity induced by the virus itself, highlighting the reason to use less immunogenic vectors such as AAV or lentivirus in the brain. As an example of this, in the studies by Choi-Lundberg et al. (1997) and Bilang-Bleuel et al. (1997), both groups reported adverse cellular reactions to the administration of ‘first-generation’ adenovirus, regardless of the particular gene sequence transfected by the vector. Choi-Lundberg et al. reported that 12 out of 14 rats injected with adenovirus possessed a mild to moderate reaction in the SN, whereas Bilang-Bleuel and colleagues found that the size of the striatum was reduced and that Ad-b-Gal (Gal, galactosidase) administration alone reduced the number of TH-IR cells by 37%. To circumvent the adenovirus-mediated immunogenic response, the use of AAVs has markedly increased in the last few years. GDNF, when expressed following transfection by an AAV, has been very successful at preventing dopaminergic cell death in the SN pars compacta and reducing behavioral deficits in 6-OHDA-lesioned rats (Mandel et al., 1997; Kirik et al., 2000b; Wang et al., 2002). In the study by Mandel et al., the authors injected AAV-GDNF 3 weeks before initiating a partial 6-OHDA lesion, resulting in protection of fluorogold-labeled neurons in the SN. Kirik and colleagues (2000b) found that the expression of GDNF was stable for over 6 months when AAV-GDNF was injected into the SN, but no protection of the striatal dopaminergic immunoreactive terminals was observed and behavioral recovery did not occur following striatal 6-OHDA treatment (Kirik et al., 2000b). In contrast, when AAV-GDNF was administered into the striatum of rats prior to a
6-OHDA lesion, the dopaminergic nigrostriatal pathway was completely protected and this was accompanied by a reduction in (þ)-amphetamine-induced asymmetry (Kirik et al., 2000b). This landmark study indicates that the site of GDNF delivery and the reinstatement of striatal dopamine are critical if functional effects are to be observed. Another alternative vector to adenovirus that induces little inflammation is lentivirus and this has also been used in the rat 6-OHDA model of nigrostriatal degeneration. Georgievska and coworkers (2002a) demonstrated that GDNF administered 3 weeks before a striatal injection of 6-OHDA can preserve nigral neurons relative to rats receiving a control vector in a dosedependent manner. In this regard, animals treated with a lower titer of vector preserved 65% of TH-IR neurons whereas animals administered with a higher concentration of lenti-GDNF preserved 77% of TH-positive cells. Interestingly, intense sprouting of fibers was observed in the medial parts of the striatum, globus pallidus and entopeduncular nucleus and this corresponded to the presence of GDNF immunoreactivity, indicating that GDNF was transported and had effects away from the injection site. The same group repeated this experiment with a single titer of lenti-GDNF administered into the striatum (Georgievska et al., 2002b). As before, THpositive cell numbers in the nigra were preserved by lenti-GDNF treatment and deficits in amphetamineinduced rotational behavior were prevented. Tracing the nigrostriatal pathway using fluorogold retrograde labeling from the striatum or AAV-GFP (GFP, green fluorescent protein) anterograde marking from the nigra showed that lenti-GDNF administration also protected the axonal projections of the SN pars compacta into the striatum. However TH fiber immunoreactivity was downregulated in the striatum: the authors speculated that this was due to a downregulation of TH following high levels of GDNF expression. Also, nondrug-induced motor asymmetry was unchanged by lenti-GDNF administration and this was attributed to the aberrant sprouting of TH-positive fibers from the striatum projecting to the globus pallidus, entopenduncular nucleus and the SN. GDNF gene therapy has been successful at protecting dopamine neurons in other models of PD, including mice receiving MPTP. MPTP, after metabolism to 1-methyl-4-phenylpyridinium ion (MPPþ), selectively kills dopaminergic neurons by inhibiting complex I in the electron transport chain and thereby stopping cellular respiration. GDNF delivered into the striatum using an adenovirus, 2 days prior to the administration of MPTP in mice, elevated striatal dopamine levels in comparison to lesioned control mice, although the dopamine content was still severely
GENE THERAPY APPROACHES FOR THE TREATMENT OF PARKINSON’S DISEASE reduced compared to naive animals (Kojima et al., 1997). In another interesting study, Ad-GDNF was concurrently administered into the striatum with an adenovirus encoding the protein caspase inhibitor, Xchromosome-linked inhibitor of apoptosis (XIAP) (Eberhardt et al., 2000). Treatment of the mice with Ad-GDNF alone, followed by a chronic lesioning paradigm with MPTP injections over 5 days, resulted in no protection of TH-IR neurons in the SN and no elevation of striatal dopamine, or dopamine metabolites levels. However, when Ad-XIAP and Ad-GDNF treatments were administered in combination, a synergistic elevation in both nigral TH-IR cell numbers and protection of the catecholamine content of the striatum from MPTP treatment occurred. GDNF has also been transfected in combination with the antiapoptotic molecule Bcl-2, using HSV vectors (Natsume et al., 2001). When administered to 6OHDA-lesioned rats amphetamine-induced rotational behavior was significantly reduced by the administration of either HSV-GDNF or HSV-Bcl-2 or an injection of both combined. Cell survival was enhanced by either vector and there was an additive effect of the two when co-administered. It is unclear however if this effect would be replicated in parkinsonian patients, since so little is known about the etiology of the disease and this approach is primarily oriented towards neuroprotection. Also, in a previous experiment, the administration of either HSV-Bcl-2 or a control virus resulted in a 40% reduction in fluorogold and TH-positive cells, in the absence of 6-OHDA lesioning, and so the use of HSV as a vector for gene transfer in humans is unlikely (Yamada et al., 1999). It is important to note that gene delivery of GDNF is not effective in all models of PD. Lo Bianco et al. (2004) administered lenti-GDNF to the supranigral region of rats 2 weeks prior to an intranigral lentiviral injection of the A30P mutant human a-synuclein. Although excellent expression of GDNF was observed, gene delivery of this trophic factor was unable to prevent the loss of nigrostriatal neurons. Two other trophic molecules have been tested in animal models of PD. BDNF has been delivered into the SN pars compacta of rats using a recombinant AAV, which also encoded green fluorescent protein (Klein et al., 1999). Expression of the green fluorescent protein was observed at 9 months after the administration of the viral vector. Six months after gene transfection, the animals were partially lesioned with 6-OHDA and rotational behavior in response to amphetamine was reduced in the AAV-BDNF-treated animals in comparison to controls. However, no protection from 6-OHDA-induced dopaminergic cell death in the SNpc was found and so this neurotrophin
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has not been considered further (Klein et al., 1999). Sonic hedgehog has also been shown by two groups to protect cells in vivo from 6-OHDA lesioning. Using an adenoviral construct, Hurtado-Lorenzo and colleagues (2004) protected dopaminergic cells at the nigral level from 6-OHDA lesioning, but could not protect the striatal axonal terminals. In an alternative study, the administration of sonic hedgehog delivered using an AAV 3 weeks before striatal 6-OHDA treatment reduced amphetamine-induced rotational behavior and protected striatal dopamine levels and nigral TH-positive cell counts (Dass et al., 2005b).
45.5. Neuroprotection in a primate model of Parkinson’s disease Primate studies are essential prerequisites for determining whether novel therapies for PD are ready for clinical trials. Primarily, primate studies employ MPTP to induce a lesion and often repeated administrations are required to induce a stable lesion. Using this method, the extent of the MPTP-induced lesion cannot be predicted before degeneration, making neuroprotective effects difficult to interpret. Thus, some investigators have used sterotaxic administrations of 6-OHDA in smaller primates, such as marmosets, to guarantee destruction of the nigrostriatal pathway. AAV-GDNF administered into the striatum and SN of marmosets, before an injection of 6-OHDA into the medial forebrain bundle (MFB), only provided a modest protection of dopaminergic cells in the SN. However, motor function assessed by a modified clinical rating scale was reversed to pre-lesion levels 5 weeks after 6-OHDA (Eslamboli et al., 2003). Also (þ)-amphetamine induced rotational behavior and head positional bias were attenuated at all time points after lesioning, indicating that AAV-transfected GDNF protected motor function in the primates.
45.6. Neurorestoration following 6-hydroxydopamine lesioning Of equal importance to the protection of the nigrostriatal system from the unknown degenerative processes of PD is the ability to restore dopaminergic transmission using trophic factors. Lapchak and colleagues (1997) attempted to use Ad-GDNF to restore the dopaminergic function of the nigrostriatal pathway of rats with an established 6-OHDA lesion. Their 6-OHDA administration paradigm resulted in a 73% loss of dopamine in the SN and a 99% reduction in the striatum. In animals injected with Ad-GDNF into the SN, the nigral dopamine content was elevated to 44% of the levels on the intact side, whereas dopamine levels
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in the striatum were increased to 4% of the contralateral side. These neurochemical improvements in the nigrostriatal system were reflected in a moderate reduction in apomorphine-induced asymmetry and an improvement in locomotor activity. In a recent similar study, the administration of Ad-GDNF, 7 days after the initiation of a striatal 6-OHDA lesion, protected basal, potassium chloride and amphetamine-evoked extracellular dopamine levels in the striatum measured by mcirodialysis, such that the basal level of dopamine was 65% of intact animal levels and the drug-induced levels were 35–40% (Smith et al., 2005). Another group investigated the effect of administration of AAV-GDNF after the initiation of a striatal 6OHDA partial lesion in rats and examined effects of gene therapy over a longer term. Delayed delivery of AAV-GDNF prevented nigral cell death, when administered 4 weeks following the initiation of a 6-OHDA lesion. Behavioral recovery, assessed by apomorphineinduced rotations and contralateral limb use, was also improved following AAV-GDNF treatment and these changes were maintained for 20 weeks (Wang et al., 2002). Thus, the use of AAV offers a mechanism for the expression of molecules in the striatum over a long period of time, whilst inducing minimal side-effects, such as inflammation, and so could be used to achieve a long-term administration of trophic factors.
45.7. Neurorestoration following MPTP treatment Our group generated a GDNF-expressing lentivirus and injected it into the striatum and nigra of young adult rhesus monkeys 1 week after MPTP lesioning, or unlesioned aged monkeys (Kordower et al., 2000). In all monkeys, strong GDNF immunoreactivity was observed and this was coupled with increased striatal fluorodopa uptake, TH immunoreactivity, dopamine and HVA content. Interestingly, GDNF immunoreactivity was also observed in the globus pallidus and SN pars reticulata, indicating anterograde transport of the transgene. MPTP-lesioned animals displayed clear motor disability, as measured by a clinical rating scale, but the administration of lenti-GDNF resulted in a reduction over the following 3 months. Dexterity, as measured by a hand-reach task, was also improved in lentiGDNF-administered monkeys compared to the lenti-bGal-treated animals. Lenti-GDNF-treated animals had a 300% increase in fluorodopa uptake seen in PET scans taken at 3 months postvector injection compared to control monkeys, although this was limited to the putamen only. Striatal TH immunoreactivity was enhanced by lenti-GDNF treatment in a manner that correlated with
the individual dexterity levels of MPTP-lesioned monkeys. Overall, TH immunoreactivity in the striatum was significantly greater in lenti-GDNF-treated monkeys compared to control animals. In the SN, an increase in TH-positive cell numbers and cell density compared to the untreated hemisphere was observed following lenti-GDNF administration, whereas lentib-Gal-treated animals had large decreases in cell counts and density on the MPTP-lesioned side. Immunohistochemistry for CD45, CD3 and CD8 resulted in negligible levels of positive cells, indicating that the lentivirus caused no immunogenicity. Two young unlesioned rhesus monkeys were also administered with lenti-GDNF into the right caudate and putamen and left SN pars compacta and examined 8 months later for gene expression. Enzyme-linked immunosorbent assay analysis found 2.5–3.5ng/mg tissue of GDNF in the caudate and putamen, whereas in the SN there were many GDNF immunoreactive cells, proving long-term transgene expression. In a subsequent study, the effect of lenti-GDNF was examined stereologically in the striatum of aged monkeys and unilaterally MPTP-lesioned monkeys (Palfi et al., 2002). MPTP treatment alone increased the numbers of intrinsic dopamine neurons in the striatum and lenti-GDNF administration further increased the striatal TH immunoreactive cell counts sevenfold. In aged monkeys, there was also a large increase in TH and dopamine transporter immunoreactivity in the striatum and this correlated with GDNF expression, indicating an autotrophic effect. The coupling of the two results suggests that lenti-GDNF is effective, regardless of the level of downregulation of the dopaminergic phenotype (Figs. 45.1 and 45.2).
45.8. Effect of glial-derived neurotrophic factor in an intact system Following 6-OHDA lesioning in rats, it was noticed by Georgievska and colleagues (2002b) that in areas of strong lentivirally mediated overexpression of GNDF in the striatum, the expression of TH was reduced. The authors then checked to see if this phenomenon was replicated in naive rats and observed that treatment with lenti-GDNF into either the striatum or nigra resulted in 60–70% decreases in TH expression and TH mRNA levels. Levodopa production remained at normal levels, indicating that GDNF increased the activity of TH (Georgievska et al., 2004). However, when GDNF is delivered using a viral vector in primates, TH expression has only been observed to increase in naive animals, indicating that the phenotypic downregulation only occurs in rodents (Kordower et al., 2000; Eslamboli et al., 2005).
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GDNF Immunoreactivity
TH Immunoreactivity
Fig 45.1. Bilateral lentiviral delivery of glial-derived neurotrophic factor (GDNF) into the caudate and putamen improves (TH-IR) in aged rhesus monkeys.
45.9. Neurturin: An alternative to glial-derived neurotrophic factor Neurturin is a protein that was discovered by Milbrandt and coworkers (Kotzbauer et al., 1996) and is the second trophic factor identified in the GDNF family of ligands. The amino acid sequence of neurturin has a high sequence homology to GDNF. Although both GDNF and neurturin signal through the RET receptor, they physiologically bind to two separate receptors; GDNF uses GFRa1 whereas neurturin prefers GFRa2. There are no GFRa2 receptors in the striatum, suggesting that the delivery of neurturin would not be effective. However, at the levels achieved following gene delivery, neurturin can bind to GFRa1 and, like GDNF, provide potent neuroprotection for degenerating nigrostriatal neurons. In this regard, neurturin has recently been delivered to four sites in the rat striatum via a lentivirus, 2 weeks before a 6-OHDA lesion. Lenti-neurturin was shown to protect over 90% of the nigral TH immunoreactive cells. Unfortunately, striatal innervation was not spared and amphetamine-induced rotational behavior was not ameliorated (Fjord-Larsen et al., 2005). Our lab, in collaboration with Ceregene Inc., has performed a series of experiments in rats and monkeys
that indicate that neurturin can provide structural and functional protection of nigrostriatal neurons (Dass et al., 2004, 2005a; Bartus et al., 2005; Herzog et al., 2005). These studies have led to the initiation of a phase I clinical trial.
45.10. Conclusions When considering a gene therapy strategy to treat any human disease, there are two major unknowns that must be conquered. These are: (1) the safety of the gene transfer itself; and (2) the efficacy of the transgene product. In addition, any new treatment, especially a highly experimental strategy such as gene therapy, must be shown to be superior to the current gold-standard therapy of levodopa. The most important issue to be addressed, if gene therapy is to be utilized clinically, is safety. Previously, in 2002, a gene therapy trial involving patients with severe combined immune deficiency using a retrovirus was halted after 1 out of the 11 trial subjects developed leukemia (Hacein-Bey-Abina et al., 2003). Analysis of this patient revealed that the retrovirus had integrated into the host genome at 40 different sites, including one, LMO-2, which was related to oncogenesis and
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GDNF Immunoreactivity
TH Immunoreactivity
Fig. 45.2. Unilateral lentiviral delivery of GDNF into the caudate and putamen increases (TH-IR) in 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP)-lesioned rhesus monkeys. No GDNF-IR or increases in TH-IR are observed in the untreated hemisphere (left side).
this contributed to the abnormal growth of a T cell. Insertational mutagenesis is therefore a concern with the use of integrating viral vectors, especially those such as serotype 5 AAV or lentivirus, which are capable of infecting glial cells. Also, Nakai and colleagues (2003) showed in mice that AAV serotype 2 integrates its DNA more frequently into active genes rather than quiescent ones. More seriously, a patient suffering from ornithine transcarbamylase (OTC) deficiency was infused into the right hepatic artery with an adenovirus encoding the human OTC gene, as part of a phase I trial (Raper et al., 2003). Unfortunately, the patient suffered from a severe immune reaction to the adenovirus and died 5 days after treatment. The reason for this may have been that the patient was previously exposed to adenovirus and this may have contributed towards an increased autoimmune response to the vector. Most of the other patients in this trial, who all received lower titers of adenovirus, also rapidly developed fever, supporting the theory that previous exposure to adenovirus followed by a second administration of the virus could cause greater inflammation. Therefore
rigorous screening of patients must be conducted before the commencement of gene therapy. To gain the greatest efficacy when treating PD, the best site for administration of a viral vector must be ascertained. AAV, but not lentivirus, has shown a capability for retrograde transport. Anterograde transport can also occur with trophic factors such as GDNF. This could cause problems of unwanted expression of transgenes in other areas of the brain if the site of administration was the striatum. Currently this is just a theoretical concept as no adverse reactions have been demonstrated as a result of such transport. Thus, although it would be favorable to have transport of a trophic factor or dopamine-synthesizing enzyme into the SN pars compacta, it is unclear whether transport to the pallidum, thalamus or the neocortex would be beneficial, harmful or inconsequential. Diffusion, following an injection of a vector into the nigral region, equally could result in major problems with alterations in the firing of ventral tegmental area neurons. Thus, the preferential site of injection and the expression level of transgenes away from the administration location need to be fully investigated. One possibility to
GENE THERAPY APPROACHES FOR THE TREATMENT OF PARKINSON’S DISEASE limit the expression of a transgene is to infect cells with a viral vector and then transplant them into the brain, but currently this strategy has had mixed results in promoting behavioral recovery in 6-OHDA-lesioned rats (Ostenfeld et al., 2002; Park et al., 2003). The ideal candidate for gene therapy in PD is another question that needs more study. Trophic factors, dopamine-synthesizing enzymes and basal ganglia modulation therapies have been outlined here. The transfection of trophic factors promises the greatest benefit, in that it could prevent the progressive degeneration of the dopaminergic nigrostriatal system, whilst enhancing the function of surviving neurons. The problems encountered following the administration of GDNF protein should not discourage the site-specific gene delivery of trophic molecules. Consideration must be made about whether the gene therapy treatments in development today for PD are truly being tested in conditions and models that reflect the clinical scenario in which they would actually be employed. The etiology of the disease remains unknown and therefore the neuroprotective elements of trophic factor therapy may become ineffectual, but the well-characterized restorative effects should still provide benefit. Other strategies for the treatment of PD may also provide benefit for patients, by reducing their levodopa requirements and so ameliorate the development of levodopa-induced side-effects. Site-specific intrastriatal delivery of the enzymes involved in the production of levodopa is expected to obviate side-effects resulting from global decarboxylation of levodopa in non-therapeutic brain compartments, as occurs with Sinemet treatment. Thus, future research into gene therapy is promising with regard to the development of prospective treatments for PD.
References Amgen Press Release 28th June 2004. Amgen’s Phase 2 Study of GDNF for Advanced Parkinson’s Disease Fails to Meet Primary Endpoint; Six Months of Treatment Showed Biological Effect But No Clinical Improvement. http://wwwext.amgen.com/media/media_pr_detail.jsp? year¼2004&releaseID¼585632 Amgen Press Release 11th Feb 2005. Following Complete Review of Phase 2 Trial Data Amgen Confirms Decision to Halt GDNF Study; Comprehensive Review of Scientific Findings, Patient Safety, Drove Decision. http://wwwext. amgen. com/media/media_pr_detail.jsp?year¼2005&releaseID¼ 673490 Avigen Press Release 18th July 2005. Avigen Announces Encouraging Early Data from Parkinson’s Disease Clinical Trial. Evidence for First Successful Gene Transfer of AADC Gene in Humans. http://www.avigen.com/non_ financial_release/2005/2005_Avigen_EarlyData_PDClinicalTrial_071805.htm
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Gash DM, Zhang Z, Ovadia A et al. (1996). Functional recovery in parkinsonian monkeys treated with GDNF. Nature 380 (6571): 252–255. Georgievska B, Kirik D, Rosenblad C et al. (2002a). Neuroprotection in the rat Parkinson model by intrastriatal GDNF gene transfer using a lentiviral vector. Neuroreport 13 (1): 75–82. Georgievska B, Kirik D, Bjorklund A (2002b). Aberrant sprouting and downregulation of tyrosine hydroxylase in lesioned nigrostriatal dopamine neurons induced by longlasting overexpression of glial cell line derived neurotrophic factor in the striatum by lentiviral gene transfer. Exp Neurol 177 (2): 461–474. Georgievska B, Kirik D, Bjorklund A (2004). Overexpression of glial cell line-derived neurotrophic factor using a lentiviral vector induces time- and dose-dependent downregulation of tyrosine hydroxylase in the intact nigrostriatal dopamine system. J Neurosci 24 (29): 6437–6445. Gill SS, Patel NK, Hotton GR et al. (2003). Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease. Nat Med 9 (5): 589–595. Hacein-Bey-Abina S, von Kalle C, Schmidt M et al. (2003). A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. N Engl J Med 348 (3): 255–256. Herzog CD, Holden JE, Bakay RA et al. (2005). Enhanced 18F–dopa uptake in the striatum of aged rhesus monkeys following striatal delivery of CERE–120, an AAV2 vector encoding human neurturin. J Neurosci #545.7. Hurtado-Lorenzo A, Millan E, Gonzalez-Nicolini V et al. (2004). Differentiation and transcription factor gene therapy in experimental Parkinson’s disease: Sonic Hedgehog and Gli-1, but not Nurr-1, protect nigrostriatal cell bodies from 6-OHDA-induced neurodegeneration. Mol Ther 10 (3): 507–524. Kaplitt MG, Leone P, Samulski RJ et al. (1994). Long-term gene expression and phenotypic correction using adenoassociated virus vectors in the mammalian brain. Nat Genet 8 (2): 148–154. Kirik D, Rosenblad C, Bjorklund A (2000a). Preservation of a functional nigrostriatal dopamine pathway by GDNF in the intrastriatal 6-OHDA lesion model depends on the site of administration of the trophic factor. Eur J Neurosci 12 (11): 3871–3882. Kirik D, Rosenblad C, Bjorklund A et al. (2000b). Longterm 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 (12): 4686–4700. Kirik D, Georgievska B, Burger C et al. (2002). Reversal of motor impairments in parkinsonian rats by continuous intrastriatal delivery of L-DOPA using rAAV-mediated gene transfer. Proc Natl Acad Sci USA 99 (7): 4708–4713. [Epub 2002 Mar 26]. Klein RL, Lewis MH, Muzyczka N et al. (1999). Prevention of 6-hydroxydopamine-induced rotational behavior by BDNF somatic gene transfer. Brain Res 847 (2): 314–320. Kojima H, Abiru Y, Sakajiri K et al. (1997). Adenovirusmediated transduction with human glial cell line-derived
GENE THERAPY APPROACHES FOR THE TREATMENT OF PARKINSON’S DISEASE neurotrophic factor gene prevents 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine-induced dopamine depletion in striatum of mouse brain. Biochem Biophys Res Commun 238 (2): 569–573. Kordower JH, Freeman TB, Snow BJ et al. (1995). 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 (17): 1118–1124. Kordower JH, Palfi S, Chen EY et al. (1999). Clinicopathological findings following intraventricular glial-derived neurotrophic factor treatment in a patient with Parkinson’s disease. Ann Neurol 46 (3): 419–424. Kordower JH, Emborg ME, Bloch J et al. (2000). Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson’s disease. Science 290 (5492): 767–773. Kotzbauer PT, Lampe BA, Heuckeroth RO et al. (1996). Neurturin, a relative of glial-cell-line-derived neurotrophic factor. Nature 384: 467–470. Lapchak PA, Araujo DM, Hilt DC et al. (1997). Adenoviral vector-mediated GDNF gene therapy in a rodent lesion model of late stage Parkinson’s disease. Brain Res 777 (1-2): 153–160. Lindvall O, Rehncrona S, Brundin P et al. (1989). Human fetal dopamine neurons grafted into the striatum in two patients with severe Parkinson’s disease. A detailed account of methodology and a 6-month follow-up. Arch Neurol 46 (6): 615–631. Lo Bianco C, Deglon N, Pralong W et al. (2004). Lentiviral nigral delivery of GDNF does not prevent neurodegeneration in a genetic rat model of Parkinson’s disease. Neurobiol Dis 17 (2): 283–289. Luo J, Kaplitt MG, Fitzsimons HL et al. (2002). Subthalamic GAD gene therapy in a Parkinson’s disease rat model. Science 298 (5592): 425–429. Madrazo I, Drucker-Colin R, Diaz V et al. (1987). Open microsurgical autograft of adrenal medulla to the right caudate nucleus in two patients with intractable Parkinson’s disease. N Engl J Med 316 (14): 831–834. Mandel RJ, Spratt SK, Snyder RO et al. (1997). Midbrain injection of recombinant adeno-associated virus encoding rat glial cell line-derived neurotrophic factor protects nigral neurons in a progressive 6-hydroxydopamineinduced degeneration model of Parkinson’s disease in rats. Proc Natl Acad Sci USA 94 (25): 14083–14088. Mandel RJ, Rendahl KG, Spratt SK et al. (1998). Characterization of intrastriatal recombinant adeno-associated virusmediated gene transfer of human tyrosine hydroxylase and human GTP-cyclohydrolase I in a rat model of Parkinson’s disease. J Neurosci 18 (11): 4271–4284. Marsden CD (1990). Parkinson’s disease. Lancet 335 (8695): 948–952. Marsden CD, Parkes JD (1977). Success and problems of long-term levodopa therapy in Parkinson’s disease. Lancet 1 (8007): 345–349. Mufson EJ, Kroin JS, Sendera TJ et al. (1999). Distribution and retrograde transport of trophic factors in the central nervous system: functional implications for the treatment
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Shen Y, Muramatsu SI, Ikeguchi K et al. (2000). Triple transduction with adeno-associated virus vectors expressing tyrosine hydroxylase, aromatic-L-amino-acid decarboxylase, and GTP cyclohydrolase I for gene therapy of Parkinson’s disease. Hum Gene Ther 11 (11): 1509–1519. Slevin JT, Gerhardt GA, Smith CD et al. (2005). Improvement of bilateral motor functions in patients with Parkinson disease through the unilateral intraputaminal infusion of glial cell line-derived neurotrophic factor. J Neurosurg 102 (2): 216–222. Smith AD, Kozlowski DA, Bohn MC et al. (2005). Effect of AdGDNF on dopaminergic neurotransmission in the striatum of 6-OHDA-treated rats. Exp Neurol 193 (2): 420–426. Steece-Collier K, Collier TJ, Danielson PD et al. (2003). Embryonic mesencephalic grafts increase levodopainduced forelimb hyperkinesia in parkinsonian rats. Mov Disord 18: 1442–1454. Svendsen CN, Clarke DJ, Rosser AE et al. (1996). Survival and differentiation of rat and human epidermal growth factor-responsive precursor cells following grafting into the lesioned adult central nervous system. Exp Neurol 137 (2): 376–388. Tomac A, Widenfalk J, Lin LF et al. (1995). Retrograde axonal transport of glial cell line-derived neurotrophic
factor in the adult nigrostriatal system suggests a trophic role in the adult. Proc Natl Acad Sci USA 92 (18): 8274–8278. Wang L, Muramatsu S, Lu Y et al. (2002). Delayed delivery of AAV-GDNF prevents nigral neurodegeneration and promotes functional recovery in a rat model of Parkinson’s disease. Gene Ther 9 (6): 381–389. Wenning GK, Odin P, Morrish P et al. (1997). Short- and long-term survival and function of unilateral intrastriatal dopaminergic grafts in Parkinson’s disease. Ann Neurol 42 (1): 95–107. Wolff JA, Fisher LJ, Xu L et al. (1989). Grafting fibroblasts genetically modified to produce L-DOPA in a rat model of Parkinson disease. Proc Natl Acad Sci USA 86 (22): 9011–9014. Yamada M, Oligino T, Mata M et al. (1999). Herpes simplex virus vector-mediated expression of Bcl-2 prevents 6hydroxydopamine-induced degeneration of neurons in the substantia nigra in vivo. Proc Natl Acad Sci USA 96 (7): 4078–4083.
Further Reading Maries E, Kordower JH, Chu Y et al. (2006). Focal not widespread grafts induce novel dyskinetic behavior in parkinsonian rats. Neurobiol Dis 21 (1): 165–180. [Epub 2005 Aug 10].
Section 8 Other parkinsonian syndromes
Handbook of Clinical Neurology, Vol. 84 (3rd series) Parkinson’s disease and related disorders, Part II W. C. Koller, E. Melamed, Editors # 2007 Elsevier B. V. All rights reserved
Chapter 46
Multiple system atrophy RONALD F. PFEIFFER* University of Tennessee Health Science Center, Memphis, TN, USA
46.1. Introduction The nosological history of what is now known as multiple system atrophy (MSA) brings to mind the wellknown ancient Buddhist parable of the blind men examining an elephant. In the parable, each of the blind men feels a different part of the elephant and then, unable to visualize the entire beast, describes the elephant in strikingly different terms. MSA might be considered the movement disorders elephant. Descriptions of the three parts of the MSA elephant date back to the end of the 19th century, when Dejerine and Thomas (1900) described two individuals with a sporadic, adult-onset syndrome characterized primarily by ataxia, but also displaying parkinsonism, brisk reflexes and incontinence. The autopsy findings of atrophy in the inferior olives, pons, middle cerebellar peduncles and cerebellum led them to apply the label of olivopontocerebellar atrophy (OPCA) to the condition. Wenning and colleagues (1997) in their review of 203 cases of pathologically proven cases of MSA document even earlier descriptions by Schultze (1887) and Arndt (1894) of individuals with cerebellar syndromes that would now be called MSA. In 1960, two additional conditions that would later be recognized as MSA were described. Shy and Drager (1960) reported two individuals with progressive autonomic failure accompanied by parkinsonism, dysarthria, ataxia, pyramidal signs, distal muscle wasting and extraocular muscle weakness. Autopsy in one of the cases demonstrated degenerative changes in the caudate, substantia nigra, cerebellum, inferior olives, locus ceruleus and intermediolateral cell columns. In the same year, van der Eecken and colleagues (1960) detailed unique pathological findings in 3 patients with predominantly rigid-akinetic parkinsonism. Atrophy
with neuronal loss and gliosis in the putamen and caudate and loss of pigmented neurons in the substantia nigra were evident, but Lewy bodies were conspicuously absent. Described in more detail 1 year later (Adams et al., 1961), cerebellar dysfunction, pyramidal tract abnormalities and autonomic impairment were also present in these individuals. Although the original authors applied the appellation striopallidonigral degeneration to the condition, the abbreviated label of striatonigral degeneration (SND) was subsequently employed. Thus, it came to be that three syndromes – sporadic OPCA with predominantly cerebellar dysfunction, Shy–Drager syndrome (SDS) with striking autonomic impairment and SND with rigid-akinetic parkinsonism – existed side by side in the neurological nomenclature as three distinct entities. The conceptual synthesis of these three entities into a single pathological process was initiated by Graham and Oppenheimer in 1969, when they described an individual with progressive autonomic failure and ataxia. In discussing the case, they noted the clinical and pathological similarities between OPCA, SDS and SND and suggested that the term ‘multiple system atrophy’ be used for them all. This suggestion did not meet with immediate or universal acceptance and employment of the older three terms in publications continued for many years. However, the discovery of a distinctive pathological marker, glial cytoplasmic inclusions (GCI), by Papp and colleagues in 1989 finally provided a firm basis for the designation of MSA as a distinct disease process with a complex combination of clinical presentations (Papp et al., 1989). The subsequent identification of a-synuclein as a major component of GCI has established MSA as a member of the family of synucleinopathies (Gai et al., 1998; Wakabayashi et al., 1998; Dickson et al., 1999a).
*Correspondence to: Ronald F. Pfeiffer, Department of Neurology, University of Tennessee Health Science Center, 855 Monroe Avenue, Memphis TN 38163, USA. E-mail:
[email protected], Tel: þ1-901-448-5209, Fax: þ1-901-448-7440.
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The confusing clinical picture of MSA, with its diversity of clinical presentations and the absence of any unequivocally diagnostic clinical feature or definitive laboratory test, has prompted formation of clinical diagnostic criteria to aid in diagnosis. The first effort was undertaken by Quinn in 1989 (Quinn, 1989a), followed a decade later by the development of the currently employed Consensus Criteria assembled by Gilman and colleagues (1998, 1999). This chapter will address the epidemiology, clinical features, pathological characteristics, diagnostic evaluation and treatment approaches for MSA.
46.2. Epidemiology 46.2.1. Descriptive epidemiology MSA is a rare disease and relatively few formal studies of its prevalence have been completed. In two studies reported by the same group of investigators, the prevalence rate of MSA was approximately 1.9 per 100 000 (Tison et al., 2000; Chrysostome et al., 2004). In a report by another group of investigators, the crude prevalence (including probable and possible cases) was 3.3 per 100 000 and the age-adjusted prevalence 4.4 per 100 000 (Schrag et al., 1999). Schrag and colleagues (1999) also extrapolated MSA prevalence rates of 2.3 per 100 000 (Wermuth et al., 1997) and 4.9 per 100 000 (Chio` et al., 1998) from two studies that were primarily investigating the prevalence of Parkinson’s disease in the Faroe Islands and in northwest Italy respectively. Not all studies have arrived at rates this low. Trenkwalder and colleagues (1995) investigated the prevalence of different types of parkinsonism in individuals over age 65 by performing a door-to-door survey in two Bavarian villages and found a markedly higher prevalence of MSA, with a rate over 300 per 100 000. Whether this difference is due to the age limitation employed in this study, its door-to-door design leading to improved ascertainment, or simple chance is unclear. Studies of annual incidence of MSA are equally scarce. Bower and colleagues (1997) employed the medical records linkage system of the Rochester Epidemiology Project to estimate an overall annual incidence rate of 0.6 per 100 000; in their study no patient developed MSA prior to age 50, whereas between ages 50 and 99 incidence was 3.0 per 100 000. Schrag and colleagues (1999) obtained a similar figure (approximately 0.5 per 100 000) when they indirectly measured MSA annual incidence. Although MSA affects both sexes, studies seem to indicate that men are at somewhat higher risk than women. Wenning and colleagues (1997) reported a
male-to-female ratio of 1.3:1 in their 203 cases of MSA; Bower and colleagues (1997) a ratio of 2:1 in 9 patients. The mean age of onset of symptoms of MSA is somewhat younger than that of Parkinson’s disease. In most studies, the mean age of onset of symptoms has hovered between 53 and 56, with a range of 31–78 years (Saito et al., 1994; Wenning et al., 1994, 1997; Ben-Shlomo et al., 1997; Testa et al., 2001; Watanabe et al., 2002). Quinn (2005) has made the point that there has never been a case of pathologically proven MSA with onset of symptoms before age 30. Although there is a case report of an individual with very slowly progressive probable MSA who experienced the onset of symptoms at age 18 (Schatz, (2003)), the accuracy of the clinical diagnosis is thrown into some doubt by the unusually prolonged survival (40 years) of that patient. The report of Bower and colleagues (1997) stands somewhat apart from the other studies, with a more advanced median age of symptom onset of 66, with a range of 51–82 years. In addition to earlier age of onset, individuals with MSA possess a considerably poorer prognosis than persons with Parkinson’s disease, with more rapid deterioration in neurological function. The mean survival time for someone with MSA is only 6–7 years (BenShlomo et al., 1997; Wenning et al., 1997; Kurisaki, 1999). Viewed from another standpoint, survival rates of 90% at 3 years, 83.5% at 5 years, 54% at 6 years and 29–39.9% at 10 years have been documented (Saito et al., 1994; Testa et al., 2001; Watanabe et al., 2002). Watanabe and colleagues (2002) also reported median intervals from disease onset until requiring aids for walking to be 3 years, to wheelchair requirement 5 years and to being bed-ridden 8 years. 46.2.2. Analytical epidemiology MSA is generally considered a sporadic disease. According to the Consensus Criteria formulated for the diagnosis of MSA (Gilman et al., 1998, 1999; Quinn, 2005), a family history of a similar disorder is considered an exclusion criterion. Nevertheless, some reports have suggested the possibility of a genetic component to MSA. Nee and colleagues (1991) completed a case-control study of 60 patients with MSA and 60 control subjects and noted that first-degree relatives of persons with MSA were more likely to report clinical symptoms of MSA than were relatives of the control subjects. There have also been several descriptions of families with possible autosomal-dominant MSA. Lewis (1964) reported a kindred with ‘familial orthostatic hypotension’ (the term ‘multiple system atrophy’
MULTIPLE SYSTEM ATROPHY had not yet been created) involving six family members over three generations. However, the accuracy of the portrayal of this family as having MSA has recently been questioned (Berciano and Wenning, 2005). More recently, another family with an autosomal-dominant disorder possessing the clinical phenotype of MSA has been reported (Wu¨llner et al., 2004). Although no pathological confirmation of the diagnosis of MSA is yet available in this family, extensive clinical testing that has included autonomic function testing, magnetic resonance imaging (MRI) and even singlephoton emission computed tomography (SPECT) in several affected individuals has been consistent with a diagnosis of MSA. The possibility that genetic polymorphisms might play a role in the development of MSA has received considerable attention in recent years but the search thus far has been largely fruitless. Multiple studies, looking at multiple genes (cytochrome P450–2D6, cytochrome P450–1A1, N-acetyltransferase 2, dopamine transporter, glutathione S-transferase M1, ciliary neurotrophic factor, insulin-like growth factor-1, hiGIRK2, HLA-A32, a-synuclein, apolipoprotein E, synphilin, tau, alcohol dehydrogenase 7, UCHL-1) have not demonstrated any association with the development of MSA (Plante´-Bordeneuve et al., 1995; Bandmann et al., 1997; Cairns et al., 1997; Nicholl et al., 1999; Morris et al., 2000; Kim and Lee, 2003; Healy et al., 2005). However, Combarros and colleagues (2003) have reported that individuals homozygous for interleukin-1A (IL-1A) allele 2 in the regulatory region of the IL-1A gene have a fivefold (odds ratio (OR) ¼ 5.1) increased risk of developing MSA; persons with only one copy of the allele also have an increased risk (OR ¼ 1.6), but considerably less than those with two copies. Even more recently, the same group of investigators has provided evidence that the IL-8 and intercellular adhesion molecule-1 (ICAM-1) genes may also be susceptibility genes for MSA (Infante et al., 2005). The presence of two copies of the IL-8 T allele increased the risk of MSA over threefold (OR ¼ 3.89). Polymorphism of the ICAM-1 gene did not independently affect the risk of MSA, but individuals carrying two copies of the ICAM-1 K allele and two copies of the IL-8 T allele had an even higher risk of MSA (OR ¼ 11.0). Since both studies involved relatively small numbers of MSA patients (30 and 41 respectively), the authors point out that further studies, both to confirm their findings and to investigate the potential mechanisms by which these polymorphisms might act to increase risk of MSA, need to be undertaken. Possible environmental risk factors for MSA have also received some attention. Nee and colleagues
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(1991) performed a case-control study of 60 individuals with MSA and 60 controls, using a self-administered questionnaire and found statistically significant increased exposure to metal dusts and fumes (OR ¼ 14.75), pesticides (OR ¼ 5.8), plastic monomers and additives (OR ¼ 5.25) and organic solvents (OR ¼ 2.41) in the MSA group. A more recent case-control study, using the Consensus Criteria for the diagnosis of MSA, has been carried out by the European Study Group for Atypical Parkinsonism (Vanacore et al., 2001, 2005). A total of 73 patients with MSA, 73 population controls and 146 hospital controls with non-neurodegenerative neurological diseases were enrolled. A statistically significant difference between the MSA group and both the population and hospital control groups was uncovered for an occupational history of farming (adjusted OR ¼ 2.52 versus hospital controls; adjusted OR ¼ 4.53 versus population controls). Additionally, a dose–response effect was demonstrable with regard to duration of farming exposure. The specific component(s) of farming exposure responsible for the increased risk could not be determined from this study, but the authors nominated pesticides, solvents and mycotoxins as candidate risk factors for MSA. In the same study, increased but not statistically significant ORs for several other occupational categories (iron and steel, textile and clothing, leather and shoe) were also documented. In another investigation in which medical records of 100 patients with MSA were reviewed, significant environmental toxin exposure was documented in 11 individuals (Hanna et al., 1999). No single suspect toxin was again identified, but a history of significant exposure to pesticides was documented in 6 of the 11 individuals, and exposure to a variety of other chemicals in the other 5. Prolonged occupational exposure to carbon disulfide in a person with MSA has also been reported (Frumkin, 1998). In contrast, Chrysostome and colleagues (2004) did not find any relationship between occupational exposure to pesticides and MSA in their study of 50 MSA patients, 50 Parkinson’s disease patients and 50 healthy controls. As has been reported with Parkinson’s disease, an inverse association between MSA and smoking has been identified by several groups of investigators (Vanacore et al., 2000; Chrysostome et al., 2004). The mechanism by which smoking might reduce the risk of MSA is not known. One patient has been reported in whom the symptoms of MSA were exacerbated by cigarette smoking (Johnsen and Miller, 1986), but this phenomenon could not account for the higher numbers of ‘never-smokers’ in the ranks of MSA patients.
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46.3.1.1. Parkinsonism
tremor does not occur in MSA. It does. In fact, tremor of some type develops in the majority of patients; even rest tremor is seen in 29–40% of cases, although a classic pill-rolling tremor is evident in only 7–9% (Colosimo et al., 2005a). What has been branded tremor in MSA, however, may not always actually be so. The term ‘jerky tremor’ is sometimes used to describe postural tremor in MSA (Gouider-Khouja et al., 1995; Bower, 2000), but accelerometric and electromyographic recordings of such small-amplitude, non-rhythmic movements of the fingers that occur when holding a posture or initiating movement demonstrate that they are actually a form of postural and action myoclonus (labeled minipolymyoclonus by the authors) rather than tremor (Salazar et al., 2000). Several other misconceptions have crept into the neurological mindset regarding the parkinsonian features of MSA. Recognition that asymmetric onset of symptoms or signs is more common in Parkinson’s disease than in the atypical parkinsonian disorders (Hughes et al., 1992a) has sometimes been misconstrued to mean that the atypical syndromes, such as MSA, never present asymmetrically. In fact, bilateral symmetric onset of motor dysfunction actually occurs in only a minority of MSA patients (Colosimo et al., 1995, 2005a). The idea that MSA is invariably levodopa-unresponsive is also incorrect. Response to levodopa, occasionally good or even excellent, but often suboptimal and fleeting, is evident in approximately 30–60% of patients (Parati et al., 1993; Boesch et al., 2002; Wenning et al., 2003a; Christine and Aminoff, 2004). The experience of Tison and colleagues (2002), however, stands in some contrast in that they noted a subjective impression of greater than 50% improvement in motor function in fewer than 10% of their MSA subjects. Balance impairment with postural instability and frequent falling occur earlier and with greater frequency in MSA than in Parkinson’s disease. Tison and colleagues (2002) elicited a history of falling at symptom onset in 20% of the 50 MSA patients they studied, compared with 2% of the 50 individuals with Parkinson’s disease; postural instability was present on testing in 10% of the MSA patients at the initial exam, but in only 2% of the Parkinson’s disease subjects. With disease progression over 70% of MSA patients develop postural instability (Tison et al., 2002).
Parkinsonism is by far the most common extrapyramidal feature of MSA. Most frequently, it is characterized by rigidity and bradykinesia/akinesia. In the literature series of Wenning and colleagues (1997), akinesia was noted to be present in 83% of patients and rigidity in 63%. It is a common misconception that
46.3.1.2. Dystonia Dystonia is another facet of extrapyramidal dysfunction that surfaces in MSA. Although reported to be present relatively infrequently by some investigators
46.3. Primary clinical features The pleomorphic propensity of MSA produces a potentially confusing picture for the clinician, who can be faced with a bewildering array of symptoms and signs in the patient with MSA. The difficulty in diagnosing MSA was amply illustrated in a study carried out by Litvan and colleagues (1997), in which the diagnostic accuracy of the treating neurologist in 16 patients with autopsy-proven MSA had been only 25% at the first clinic visit and 50% at the final visit. In this and another series, however, the diagnostic accuracy of movement disorders specialists was considerably higher (Hughes et al., 2002). The clinical features of MSA generally fall into four categories: extrapyramidal, cerebellar, autonomic and pyramidal. Individuals may display any combination of these features and do not necessarily develop all of them during the course of their illness. In a study of 203 cases of autopsy-proven MSA drawn from published literature, Wenning and colleagues (1997) found that parkinsonism was present in 87% of patients during the course of their illness, autonomic failure in 74%, cerebellar signs in 54% and pyramidal signs in 49%. In the same study, parkinsonism was the initial motor disturbance in 58% of the patients, cerebellar ataxia in 29% and a mixture of the two in 9%; pyramidal signs were the initial motor feature in only 3% of individuals. In an earlier analysis of 100 MSA cases, autonomic symptoms were the initial clinical feature in 41% of patients, parkinsonism in 46% and cerebellar symptoms or signs in only 5% (Wenning et al., 1994). Gilman (2002) observes, however, that the predominance of parkinsonism in the latter series may have reflected sampling bias since the patients were derived from a movement disorders clinic. The proclivity of MSA to present with predominantly parkinsonian or predominantly cerebellar motor features has led to the convention of classifying MSA as being of either the MSA-P or MSA-C type (Quinn, 1989a, 2005). The distinction is somewhat artificial, however, since most patients eventually acquire both extrapyramidal and cerebellar dysfunction. Autonomic features eventually develop in both groups. 46.3.1. Extrapyramidal features
MULTIPLE SYSTEM ATROPHY (Rivest et al., 1990; Wenning et al., 1997) and not at all by others (Adams and Salam-Adams, 1986), Boesch and colleagues (2002), in a prospective study of 24 individuals with MSA followed for up to 10 years, documented the development of dystonia prior to any levodopa exposure in 46%. In individuals with MSA who responded to levodopa, the emergence of levodopa-induced dystonic dyskinesia was also frequent. In an accompanying editorial, Riley (2002) made the point that, ‘if actively sought’, dystonia may actually be one of the most common features of MSA. Head and neck are the most common sites for dystonia development in MSA, in both levodopa-naive and levodopa-induced settings, but limb involvement also occurs. Several patterns of dystonia are particularly notable in MSA. Dystonia involving orofacial and platysma muscles may produce a tetanus-like facial distortion that has been christened the risus sardonicus of MSA (Wenning et al., 2003b). Two additional phenomena have generated some controversy as to whether they represent dystonic phenomena or not: stridor and disproportionate antecollis. Inspiratory stridor, typically occurring at night, develops in 13–34% of patients with MSA (Wenning et al., 1994, 1997). Although most often considered a later manifestation, one group of investigators noted stridor to be the initial clinical feature in 4% of 200 consecutive patients with probable MSA (Uzawa et al., 2005) and in another study 69% of individuals who developed stridor did so within the first 4 years of disease diagnosis (Yamaguchi et al., 2003). Conflicting opinions exist regarding the genesis of stridor in MSA. Some investigators attribute it to laryngeal abductor paralysis (Bannister et al., 1981; Iranzo et al., 2000, 2004; Uzawa et al., 2005), whereas others maintain, and provide electromyographic documentation, that stridor is a dystonic phenomenon, with sustained contraction of vocal cord adductors (Simpson et al., 1992; Merlo et al., 2002). Regardless of its etiology, the presence of stridor in an individual with MSA should be interpreted as a danger signal. Persons with stridor have an increased mortality risk, which has led to the suggestion that tracheostomy be considered in all individuals in whom stridor develops (Silber and Levine, 2000). Unusually prominent neck flexion resulting in a ‘dropped-head syndrome,’ or disproportionate antecollis, has been widely recognized as a feature suggestive of, though not unique to, MSA (Quinn, 1989b, 2005). Disproportionate antecollis is uncomfortable for patients; it may also interfere with eating and speaking and even effectively impair vision (Colosimo et al., 2005a). As with stridor, the etiology of disproportionate antecollis in MSA has been the source of controversy.
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Although most often considered a dystonic phenomenon, some have suggested that antecollis in MSA may sometimes be a manifestation of neck extensor myopathy (Askmark et al., 2001). Extreme forward flexion of the spine that appears or increases when the individual is walking and disappears when supine (camptocormia) and laterally oriented trunk flexion (Pisa syndrome) may also develop in the setting of MSA (Slawek et al., 2006). It is also unsettled whether these phenomena represent axial dystonia or axial myopathy. 46.3.2. Autonomic dysfunction Impairment of autonomic function eventually develops in the vast majority of individuals with MSA. As noted earlier, autonomic symptoms were the presenting clinical feature in 41% of 100 patients with clinically probable MSA and they ultimately developed in 97% (Wenning et al., 1994). Similarly, in an analysis of 35 subjects with pathologically proven MSA, autonomic failure had been present in 97% (Wenning et al., 1995a). Among 75 persons with MSA followed at the Mayo Clinic, severe autonomic dysfunction developed in 97% also (Sandroni et al., 1991). Genitourinary, cardiovascular, gastrointestinal (GI) and thermoregulatory autonomic dysfunction may all appear in the setting of MSA. 46.3.2.1. Genital dysfunction Erectile dysfunction is almost universal in men with MSA. It ultimately develops in 96% and is the initial clinical feature in 37% (Beck et al., 1994). It typically precedes the development of both urinary dysfunction and orthostatic hypotension (Kirchhof et al., 2003). Oertel and colleagues (2003) studied genital sensation (as a possible equivalent of erectile dysfunction) in 17 women with MSA and found reduced genital sensitivity in 47%, compared with only 4% of 27 women with Parkinson’s disease and 4% of 26 normal controls. In most of the women with MSA, the reduced genital sensitivity had preceded the onset of motor dysfunction and in many it had developed subacutely over a period of several months. 46.3.2.2. Urinary dysfunction Disordered bladder function is also common in MSA. It may be the initial clinical feature (Sakakibara et al., 1993) and routinely is one of the earliest autonomic features to emerge (Mabuchi et al., 2005). Over 90% of individuals with MSA develop micturition disturbances during the course of the disease (Sakakibara et al., 1993, 2000). Both urinary retention and incontinence
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may occur. The most frequent urinary symptom in persons with MSA is difficulty voiding, which Sakakibara and colleagues (2000) catalogued in 79% of the 121 patients they studied. In the same study, nocturnal urinary frequency was present in 74%, urgency in 63%, urge incontinence in 63% and urinary retention in 8%. Others have described urinary incontinence in 55–71% and urinary retention in 18–27% of individuals with MSA (Wenning et al., 1994, 1997). Urodynamic and neurophysiological testing also presents a diverse picture; both hyperactive and hypoactive bladder dysfunction occur. Sakakibara and colleagues (2000) documented detrusor hyperreflexia in 56% of the MSA patients they studied. In contrast, some other investigators have found detrusor hyporeflexia to be more frequent (Bonnet et al., 1997). Sakakibara and colleagues (2000, 2001) also reported the presence of a low-compliance bladder in 31%, an atonic curve in 5% and detrusor-sphincter dyssynergia in 45% of the persons with MSA they studied. Increased postmicturition residual urine (>30 ml) was evident in 74% of patients and residual urine of over 100 ml was noted in 52%. In MSA, urinary disturbances typically develop earlier and are more severe than those seen in Parkinson’s disease. 46.3.2.3. Cardiovascular dysfunction Cardiovascular dysfunction in the form of orthostatic hypotension is the autonomic feature that has attracted the most attention in MSA, but it actually occurs less frequently than urogenital dysfunction. Symptoms of orthostatic hypotension develop in 43–68% of individuals with MSA (Wenning et al., 1994, 1997; Sakakibara et al., 2000). Postural lightheadedness is the most frequently experienced symptom of orthostatic hypotension, but individuals may instead experience blurred vision, clouded cognition, head and neck pain in a ‘coat-hanger’ distribution, lower back or buttock pain, a sense of weakness or fatigue, tremulousness, or simply an ill-defined feeling of dizziness (Mathias et al., 1999; Bower, 2000; Mathias, 2005). Syncope occurs in 15–19% of MSA patients with orthostatic hypotension (Wenning et al., 1994, 1997; Sakakibara et al., 2000). Orthostatic hypotension may be present and become symptomatic early in the course of MSA, a characteristic that provides some contrast with Parkinson’s disease (Wenning et al., 1999). A variety of factors can accentuate and magnify orthostatic hypotension. Symptoms upon first arising in the morning can be prominent, consequent to prolonged recumbency. Postprandial hypotension, especially following a large, carbohydrate-heavy meal, may also occur, due to impairment of compensatory
autonomic responses normally triggered by increased superior mesenteric artery blood flow (Mathias, 2005) and is more prominent in MSA than in Parkinson’s disease (Thomaides et al., 1993). 46.3.2.4. Gastrointestinal dysfunction Although considerable ink has flowed concerning electromyographic abnormalities of the anal sphincter in MSA (discussed below), relatively little has been written about clinical GI dysfunction. Nevertheless, both upper and lower GI disturbances occur frequently in MSA. Dysphagia is common in MSA and tends to develop earlier than in Parkinson’s disease. In one study, the median latency to the onset of dysphagia in 15 patients with MSA was 24 months (Muller et al., 2001). Higo and colleagues (2003) documented reduced oropharyngeal and hypopharyngeal swallowing pressures in 29 persons with MSA and incomplete relaxation of the upper esophageal sphincter was present in 23%. Gastric emptying may also be delayed in individuals with MSA, comparable to that seen in Parkinson’s disease (Thomaides et al., 2005). Bowel dysfunction, including both decreased bowel movement frequency and difficulty with the act of defecation itself, is another aspect of GI dysfunction in MSA. In one study, decreased bowel movement frequency (fewer than 3/week) was present in 60% of participating MSA patients, and 67% experienced difficulty with defecation (Sakakibara et al., 2004a). In another study of 16 persons with MSA experiencing GI symptoms, 87% were having fewer than 3 bowel movements per week and 69% were experiencing difficulty with defecation (Stocchi et al., 2000). Decreased bowel movement frequency in MSA is due to slowed colon transit time. Sakakibara and colleagues (2004a) documented a mean total colon transit time of 71.8 hours in 15 individuals with MSA, compared with 39 hours in 10 age-matched controls. Disturbances in anorectal function, leading to increased straining and incomplete evacuation during defecation, are also present in many patients with MSA. Manometric and electromyographic recordings of anorectal function demonstrate a plethora of abnormalities that suggests these disturbances are due to either paradoxical contraction or insufficient inhibition of the anal musculature during straining, along with weakness of associated abdominal muscle contraction (Stocchi et al., 2000; Sakakibara et al., 2004a). Fecal incontinence, especially following laxative ingestion, may also occur in 12–31% of patients with MSA (Wenning et al., 1997; Stocchi et al., 2000; Sakakibara et al., 2004a). Denervation, with consequent weakness of the external anal sphincter, is probably responsible.
MULTIPLE SYSTEM ATROPHY 46.3.2.5. Thermoregulatory dysfunction A number of features indicative of thermoregulatory and sudomotor dysfunction have been identified in MSA. Reduced sweating is common and may be severe (Cohen et al., 1987; Kumazawa et al., 1989). Individuals with MSA demonstrate impaired heat tolerance (Colosimo et al., 2005a) and may be at risk for increased morbidity due to worsened orthostatic hypotension during heat exposure (Pathak et al., 2005). Reduced skin temperature may also be present in persons with MSA, along with a more profound reduction in skin temperature when exposed to cold (Klein et al., 1997). These abnormalities may, in turn, account for the presence of cold, blue or purple hands (and feet) that has been christened as one of the ‘red flags’ of MSA (Klein et al., 1997). Raynaud’s phenomenon, with painful, pale fingers and hands due to vasospasm, induced by cold or by ergot drugs, may also afflict individuals with MSA (Kaufmann and Biaggioni, 2003; Geser and Wenning, 2005). One further reflection of impaired thermoregulatory control in MSA is the blunting of the physiological fall in body temperature that normally occurs at night (Pierangeli et al., 2001). 46.3.3. Cerebellar dysfunction In patients evaluated in movement disorders clinics, cerebellar dysfunction is only rarely the presenting clinical feature of MSA, accounting for only 5% in one study (Wenning et al., 1994). Gilman (2002) points out, however, that this may reflect a sampling bias and implies that the percentage might be greater in a general neurology clinic. With disease progression, the percentage of individuals displaying cerebellar dysfunction expands considerably. Gait ataxia eventually becomes evident in almost 50% of individuals and dysarthria in almost everyone (Wenning et al., 1997; Shulman et al., 2004). A quintet of abnormalities characterizes cerebellar dysfunction in MSA: gait ataxia, limb ataxia, kinetic tremor, oculomotor dysfunction and dysarthria (Wenning et al., 1997, 2004; Shulman et al., 2004; Colosimo et al., 2005a). Not all of the features develop in each individual and any combination of them may occur. In one study, gait ataxia eventually became evident in 49% of subjects, limb ataxia in 47%, intention tremor in 24% and nystagmus in 23% (Wenning et al., 1997). In addition to nystagmus, other oculomotor abnormalities seen in MSA include ocular dysmetria, impaired smooth pursuit and square-wave jerks (Bower, 2000). 46.3.4. Pyramidal signs Clinically apparent pyramidal tract dysfunction, such as spastic paraparesis, is unusual in MSA. Signs of
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pyramidal tract dysfunction on neurological examination, in contrast, are quite frequently present. In the series of 203 MSA patients assembled from the literature by Wenning and colleagues (1997), hyperreflexia was present in 46% and Babinski responses in 41%, but spasticity in only 10%. Although the clinical consequences of pyramidal tract dysfunction in MSA are not striking, the presence of unequivocal pyramidal tract signs in an individual with parkinsonism and autonomic dysfunction is of diagnostic utility in that it points toward a diagnosis of MSA rather than Parkinson’s disease.
46.4. Other clinical features 46.4.1. Disordered sleep Recognition is growing that a variety of sleep disorders may emerge during the course of MSA. In a questionnaire study involving 57 patients with MSA, 70% voiced complaints of sleep impairment (Ghorayeb et al., 2002). In the study, 60% were aware of nighttime vocalizations, 52.5% experienced sleep fragmentation, 47.5% described symptoms of rapid-eye movement (REM) sleep behavior disorder, 32.5% were troubled by early awakening, 20% by insomnia, 19% experienced stridor and 12.5% were kept awake by symptoms of restless-legs syndrome. Snoring was also acknowledged by 72.5%. Persons with MSA are also more likely to experience excessive daytime sleepiness than individuals with Parkinson’s disease (Ghorayeb et al., 2002). Video-polysomnographic recordings confirm and expand the information gathered from questionnaire studies. In a study of 19 MSA patients who were not selected on the basis of any sleep or respiratory problems, inspiratory noise was documented in every participant, with stridor in 42% and snoring in 100% (Vetrugno et al., 2004). In fact, subjects in this study spent 50% of their sleep time either snoring or with stridor. Abnormal sleep structure, with reduced non-REM deep sleep and decreased sleep efficiency but normal amounts of REM sleep, were also evident. REM sleep behavior disorder is now recognized as a feature of a-synucleinopathies such as MSA, Parkinson’s disease and dementia with Lewy bodies (Boeve et al., 2001), but it appears to develop earlier and with greater severity in individuals with MSA (Iranzo et al., 2005). Manifestations of REM sleep behavior disorder can be present early in the course of MSA, prior to institution of any antiparkinson medication (Wetter et al., 2000) and may even antedate the appearance of motor and autonomic features (Tison et al., 1995; Boeve et al., 2001). In one study, 44% of the MSA
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patients experienced the symptoms of REM sleep behavior disorder more than 1 year before the onset of motor features (Plazzi et al., 1997). Polysomnographic recordings can be very useful in establishing the presence of REM sleep behavior disorder in MSA patients and have revealed a considerably higher frequency of the abnormality than subjective questionnaire studies. In a study of 39 consecutive MSA patients reported by Plazzi and colleagues (1997), polysomnographic evidence of REM sleep behavior disorder was present in 90%. It has been suggested that increased or excessive sleep talking may be an early manifestation of REM sleep behavior disorder in MSA (Tachibana et al., 1997). 46.4.2. Behavioral disorders Frank dementia is not a feature of MSA and, in fact, is one of the exclusionary criteria for the diagnosis (Gilman et al., 1998, 1999). However, behavioral changes do occur in the setting of MSA and may actually be quite common. Executive dysfunction, similar to but more severe than that seen in Parkinson’s disease, has been documented in MSA (Dujardin et al., 2003; Lange et al., 2003). Persons with MSA frequently suffer from depression. In a study of 99 individuals with MSA, Benrud-Larson and colleagues (2005) documented symptoms of at least mild depression in 80%, with moderate to severe depression in 39%. Emotional blunting or apathy has also been described in persons with MSA. In one small study, this was evident in 92% of 12 individuals evaluated (Fetoni et al., 1999).
with head turning, distinct from orthostatic lightheadedness, has been described in individuals with the cerebellar form of MSA (Sakakibara et al., 2004b).
46.5. Consensus criteria The diversity of clinical features of MSA, their variable mode of presentation and the absence of any unequivocal diagnostic test for MSA combine to make the clinical diagnosis of MSA a difficult, even treacherous exercise. In response to this diagnostic quicksand, a conference was convened in 1998, in which guidelines for the diagnosis were developed (Gilman et al., 1998, 1999). The Consensus Criteria are detailed in Tables 46.1–46.3. Three diagnostic categories are employed: possible MSA, probable MSA and definite MSA (Table 46.1). Pathological confirmation is required for a diagnosis of definite MSA. Therefore, in the clinical setting the only possible diagnoses are possible or probable MSA and determination between these two categories is dependent upon the number of features within the four clinical domains that are met (Table 46.2). The third component of the consensus criteria is a list of exclusion criteria; the presence of any feature listed therein prohibits a diagnosis of MSA (Table 46.3).
46.6. Neuropathology 46.6.1. Macroscopic pathology Involvement of both basal ganglia and cerebellum may be evident on gross examination of the brain in MSA.
46.4.3. Other features A number of other clinical features have been described in persons with MSA, although they have not received extensive scrutiny. Although impairment of olfaction is often present in patients with MSA, it is typically mild compared with the deficits characteristic of Parkinson’s disease (Nee et al., 1993; Wenning et al., 1995b; Muller et al., 2001). Pramstaller and colleagues (1995) documented electromyographic abnormalities consistent with peripheral neuropathy in 40% of the 74 patients with MSA they studied. In a single case report, sensory polyneuropathy was the initial neurological abnormality in an individual who later developed MSA (Wu et al., 2004). Pain has been reported to be the initial clinical manifestation of MSA in 6% of patients (Pezzoli et al., 2004). Anisocoria was present in 8% of the 203 cases of MSA described by Wenning and colleagues (1997); in 5%, it was associated with Horner’s syndrome. Dizziness or vertigo
Table 46.1 Diagnostic categories of multiple system atrophy (MSA) I. Possible MSA One criterion plus two features from separate other domains When the criterion is parkinsonism, a poor levodopa response qualifies as one feature (hence only one additional feature is required) II. Probable MSA Criterion for autonomic failure/urinary dysfunction plus poorly levodopa-responsive parkinsonism or cerebellar dysfunction III. Definite MSA Pathologically confirmed by the presence of a high density of glial cytoplasmic inclusions in association with a combination of degenerative changes in the nigrostriatal and olivopontocerebellar pathways Adapted from Gilman et al. (1999) with permission.
MULTIPLE SYSTEM ATROPHY
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Table 46.2
Table 46.3
Clinical domains, features and criteria used in the diagnosis of multiple system atrophy
Exclusion criteria for the diagnosis of multiple system atrophy
Domain I: Autonomic and urinary dysfunction A. Features: 1. Orthostatic hypotension (20 mmHg systolic or 10 mmHg diastolic) 2. Urinary incontinence or incomplete bladder emptying B. Criterion: Orthostatic fall in blood pressure (30 mmHg systolic or 15 mmHg diastolic) or Urinary incontinence (persistent, involuntary partial or total bladder emptying, accompanied by erectile dysfunction in men) or Both Domain II: Parkinsonism A. Features: 1. Bradykinesia (slowness of voluntary movement with progressive reduction in speed and amplitude during repetitive actions) 2. Rigidity 3. Postural instability (not caused by primary visual, vestibular, cerebellar or proprioceptive dysfunction) 4. Tremor (postural, resting or both) B. Criterion: Bradykinesia plus at least one of items 2 through 4 Domain III: Cerebellar dysfunction A. Features: 1. Gait ataxia (wide-based stance with steps of irregular length and direction) 2. Ataxic dysarthria 3. Limb ataxia 4. Sustained gaze-evoked nystagmus B. Criterion: Gait ataxia plus at least one of items 2 through 4 Domain IV: Corticospinal tract dysfunction A. Features: 1. Extensor plantar responses with hyperreflexia B. Criterion: No corticospinal features are used
I. History A. Symptomatic onset under 30 years of age B. Family history of a similar disorder C. Systemic diseases or other identifiable causes for features listed in Table 2 D. Hallucinations unrelated to medication II. Physical examination A. DSM criteria for dementia B. Prominent slowing of vertical saccades or vertical supranuclear gaze palsy C. Evidence of focal cortical dysfunction: aphasia, alien-limb syndrome, parietal dysfunction III. Laboratory investigation A. Metabolic, molecular genetic and imaging evidence of an alternative cause of features listed in Table 46.2
Adapted from Gilman et al. (1999) with permission.
The putamen may be shrunken and display grayish discoloration due to iron deposition, whereas involvement of the caudate and globus pallidus is less noticeable (Dickson et al., 1999b; Colosimo et al., 2005a; Jellinger et al., 2005). Loss of pigmentation of the substantia nigra pars compacta and locus ceruleus is also characteristic. Cerebellar atrophy, along with atrophy of pons, inferior olives and the inferior and middle cerebellar peduncles may also be present (Burn and Jaros, 2001; Jellinger et al., 2005).
Adapted from Gilman et al. (1999) with permission. DSM, Diagnostic and Statistical Manual of Mental Disorders.
46.6.2. Microscopic pathology On a microscopic level, MSA is characterized by neuronal loss and gliosis involving multiple areas of the brain, brainstem and spinal cord. The most prominent neurodegenerative changes occur in putamen, globus pallidus, substantia nigra, locus ceruleus, cerebellar cortex, inferior olive, pontine nuclei, dorsal motor nucleus of the vagus and in the intermediolateral columns and Onuf’s nucleus in the spinal cord (Lantos and Papp, 1994; Wenning et al., 1997; Burn and Jaros, 2001; Gilman, 2002). Neuronal loss may also involve catecholaminergic neurons in the ventrolateral medulla (Benarroch et al., 1998), neurons in the Edinger–Westphal nucleus and in the hypothalamus (Shy and Drager, 1960). White-matter pathology, with myelin degeneration, is also present in MSA (Matsuo et al., 1998). As noted earlier, the discovery by Papp et al., (1989) of argyrophilic inclusions within the cytoplasm of oligodendroglia in the brains of MSA patients has provided the pathological hallmark of MSA (Fig. 46.1). In fact, MSA is the only neurodegenerative disease in which oligodendroglial pathology is predominant (Jellinger et al., 2005). These inclusions, now labeled GCI, are composed of loosely aggregated, multilayered, tubular filaments that are immunoreactive for ubiquitin and a-synuclein, along with a number of additional cytoskeletal proteins (Wakabayashi et al., 1998; Dickson et al., 1999a; Gai et al., 1999, 2003; Burn and Jaros, 2001). a-Synuclein is normally expressed in only low levels in oligodendrocytes and
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Fig. 46.1. Glial cytoplasmic inclusions. a-Synuclein staining. Courtesy of Dr. Dennis Dickson, Mayo Clinic-Jacksonville.
it is uncertain whether in MSA there is impaired ability to degrade a-synuclein or whether increased amounts are being formed (Wenning et al., 2003a). Pountney and colleagues (2005a) have recently identified aB-crystallin, a chaperone protein that binds to unfolded proteins and inhibits aggregation, in GCIs in MSA and have suggested that it may play an important role in the development of the GCIs. They have also demonstrated the presence of SUMO-1, a small ubiquitin-like modifier protein, within 10–30% of GCIs and speculate that SUMO-1 may be playing a role in the formation of GCIs and reflect dysfunction of the proteasomal machinery (Pountney et al., 2005b). GCIs primarily reside in what has been termed a ‘system-bound’ distribution within the suprasegmental motor systems (primary and supplementary motor cortex, basal ganglia, corticocerebellar system) and supraspinal autonomic systems and their targets (Papp and Lantos, 1994; Burn and Jaros, 2001). In addition to GCIs, oligodendroglial nuclear inclusions have been identified in MSA, as have neuronal cytoplasmic and nuclear inclusions (Papp and Lantos, 1992).
46.7. Diagnostic evaluation Although no single diagnostic study is capable of providing incontrovertible proof of the diagnosis of MSA, useful information that may help to include or exclude the diagnosis can sometimes be derived from a variety of examinations. 46.7.1. Structural neuroimaging Although MRI has uncovered no features that are pathognomonic for MSA, several abnormalities have been identified that, if present, increase the probability
of the diagnosis. A band-like rim of hyperintense signal may be present at the lateral putamenal border on T2-weighted images. Konagaya and colleagues (1994) identified this abnormality in 17 of 28 patients with clinically diagnosed MSA. Some investigators have suggested that the hyperintensity is due to reactive microgliosis or iron deposition (Schwarz et al., 1996), whereas others have attributed it to widened intertissue space produced by putamenal shrinkage (Konagaya et al., 1998). Hypointensity within the putamen itself on T2-weighted images may also be seen in MSA. Hypointensity of the dorsolateral putamen coupled with hyperintensity of the putamenal rim on T2-weighted images is highly specific for MSA, but its absence does not exclude the diagnosis (Schrag et al., 1998; Kraft et al., 1999). Increased signal involving the pyramidal tracts from the cortex down to the cerebral peduncles has recently been described on T2-weighted fluid-attenuated inversion recovery (FLAIR) images, but is not specific for MSA (Limberg et al., 2005). MRI abnormalities within the posterior fossa may also be evident in MSA. Atrophy of the cerebellar vermis, pons, middle cerebellar peduncles and the cerebellar hemispheres is often present, primarily in patients presenting with predominantly cerebellar clinical findings (MSA-C). Degeneration of pontocerebellar fibers in the pons and middle cerebellar peduncles sometimes produces hyperintensity within the pons on T2-weighted images in a cross-like pattern that has been labeled the ‘hot-cross bun’ sign (Schrag et al., 1998). More sophisticated MRI techniques, such as diffusion-weighted imaging, proton magnetic resonance spectroscopy, magnetization transfer imaging and magnetic resonance volumetry may prove to be of value in the diagnosis of MSA, but are not used in routine clinical care at this time (Seppi et al., 2005). 46.7.2. Functional neuroimaging Functional neuroimaging procedures, such as positron emission tomography (PET) and SPECT, have been extensively evaluated for potential utility in the diagnosis of MSA. However, neither ligands that are presynaptic dopaminergic markers nor dopamine receptor ligands can consistently and reliably differentiate MSA from other parkinsonian disorders in individual patients (Quinn, 2005). PET imaging with 18F-deoxyglucose may do somewhat better, especially if computer-assisted interpretation using statistical parametric mapping is employed (Eckert et al., 2005; Juh et al., 2005), but is also still not fully adequate (Quinn, 2005). Moreover, since neither PET nor SPECT imaging with these ligands is widely available,
MULTIPLE SYSTEM ATROPHY use of functional imaging in the diagnosis of MSA is currently confined to the research setting. Multiple studies employing either 6-[18F]fluorodopamine PET or 123I-metaiodobenzylguanidine (MIBG) scintigraphy to image the sympathetic innervation of the heart have demonstrated marked denervation in Parkinson’s disease, in contrast to intact innervation in MSA (Goldstein, 2005; Mathias, 2005). A meta-analysis of studies involving 245 patients with Parkinson’s disease and 45 with MSA who underwent cardiac MIBG scintigraphy demonstrated a specificity of 94.6% in discriminating between the two conditions (Braune, 2001). The commercial availability of MIBG and scintigraphy may encourage more extensive use of this technique in the future in differentiating MSA from Parkinson’s disease. 46.7.3. Autonomic function tests Autonomic function testing can be valuable both in the diagnosis of MSA and in the formulation of treatment plans. Virtually all aspects of autonomic function are amenable to testing that can illuminate both the character and severity of any autonomic deficit. Tests of cardiovascular and urinary function are most frequently employed in evaluation of the MSA patient, but examination of GI and thermoregulatory function is also available and can be very useful. The mere presence of abnormalities on autonomic function testing, however, does not clinch a diagnosis of MSA; similar, though typically less severe, abnormalities can also be present in other conditions, especially Parkinson’s disease. Tilt-table testing, in which heart rate and blood pressure are continuously monitored, is a sensitive and non-invasive method by which the presence of orthostatic hypotension can be documented. Orthostatic hypotension has been defined as a drop of 20 mmHg or greater in systolic pressure or a drop of 10 mmHg or greater in diastolic pressure within 3 minutes of standing or head-up tilt (Consensus statement on the definition of orthostatic hypotension, pure autonomic failure and multiple system atrophy, 1996; Goldstein et al., 2002). An array of additional tests of cardiovascular function is available and may be part of the testing battery in the autonomic function laboratory. Plasma norepinephrine levels are often normal or near normal when measured in the supine position in persons with MSA, but levels do not rise appropriately with standing (Mathias, 2005). Reversal of the circadian change in blood pressure, assessed by 24-hour blood pressure and heart rate monitoring, may also be present in MSA (Mathias, 2005). Tests assessing parasympathetic cardiovascular function, such as the
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heart rate response to deep breathing and the Valsalva maneuver, are also abnormal in MSA (Khurana, 1994). Assessment of bladder function, with measurement of postvoid residual urine volume, can be performed by either bladder sonography or catheterization. Catheterization is simple and requires no special equipment, but sonography is non-invasive and can even be performed at bedside (Hahn and Ebersbach, 2005). Videourodynamic testing is a more elegant procedure that provides a more expansive picture of bladder function (Sakakibara et al., 2001). Erectile function is most often evaluated simply by questionnaire; specialized objective testing, such as nocturnal penile tumescence and rigidity assessment, is not usually necessary (Montorsi, 2005). A variety of tests is available for assessment of GI dysfunction in MSA. The modified barium swallow test is widely employed for evaluation of dysphagia. Gastric emptying time can be measured by scinitigraphic means (Thomaides et al., 2005). In evaluating bowel function, colon transit time is most often assessed by the repetitive ingestion method (Sakakibara et al., 2004a), and anorectal manometry can be used to examine anorectal function (Stocchi et al., 2000). Tests of thermoregulatory function that have been employed in MSA include the thermoregulatory sweat test and the quantitative sudomotor axon reflex test (Kihara et al., 1991). However, these tests are not always readily available and have not been extensively employed in patients with MSA. 46.7.4. Neurophysiological testing The ability of external anal and urethral sphincter electromyography (EMG) to distinguish MSA from Parkinson’s disease and other parkinsonian disorders has been the subject of considerable controversy. Electromyographic evidence of denervation, due to anterior horn cell loss in the nucleus of Onufrowicz (Onuf’s nucleus) in the sacral spinal cord, is present in over 80% of individuals with MSA (Wenning et al., 2004). However, similar abnormalities may be present in persons with other parkinsonian disorders, such as Parkinson’s disease and progressive supranuclear palsy (Valldeoriola et al., 1995; Colosimo et al., 2000). In light of this, the idea has emerged that a normal sphincter EMG renders a diagnosis of MSA very unlikely, especially if disease symptoms have been present for more than 5 years, whereas an abnormal EMG cannot be considered as confirmation of a diagnosis of MSA (Nahm and Freeman, 2003; Paviour et al., 2005).
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A number of other neurophysiologic studies may demonstrate abnormalities in patients with MSA. Various varieties of evoked potentials – somatosensory, visual and auditory – may be abnormal in a minority of persons (Abele et al., 2000b), but these are not of any genuine diagnostic utility. Evidence of peripheral neuropathy on nerve conduction velocity testing has been noted in 24% of 42 subjects with MSA (Abele et al., 2000a), but this is also a non-specific finding that has no diagnostic usefulness. 46.7.5. Other examinations Kimber and colleagues (1997) reported that patients with MSA do not display a rise in serum growth hormone in response to administration of the a2-adrenoreceptor agonist clonidine, whereas individuals with Parkinson’s disease do. However, other investigators have found that the test does not reliably distinguish the two disease processes (Tranchant et al., 2000; Pellecchia et al., 2001; Strijks et al., 2002). The use of brain parenchyma sonography (transcranial ultrasound) to differentiate Parkinson’s disease from MSA and other atypical parkinsonian disorders has also been advocated (Benecke, 2002; Walter et al., 2003). In preliminary studies, hyperechogenicity of the substantia nigra was present in 96% of individuals with Parkinson’s disease but in only 9% of patients with atypical parkinsonian syndromes, whereas lentiform nucleus hyperechogenicity was evident in 77% of persons with atypical parkinsonism and in only 23% of those with Parkinson’s disease (Walter et al., 2003). Investigations that are more recent have reinforced these findings (Behnke et al., 2005). Although the non-invasive nature of sonography is appealing, the practical utility of this procedure in individual patients, especially those with suspected MSA, remains to be determined.
46.8. Treatment There has been a general perception that MSA is rapidly and relentlessly progressive and completely refractory to any treatment measures. Although it is certainly correct that no treatment modality has demonstrated an ability to alter the progression of the underlying disease process itself, it is incorrect to conclude that there are no useful symptomatic treatment measures that may be marshaled in the management of MSA. In fact, it is often possible to ameliorate the non-motor features of MSA and even the motor features may at least transiently demonstrate some response to treatment. However, the relative rarity of MSA has rendered it exceedingly difficult to mount
controlled trials of targeted treatment modalities. Thus, the available evidence of efficacy for various agents is largely empiric. 46.8.1. Motor features The parkinsonian features of MSA are treated with the same medications that are invoked in the treatment of Parkinson’s disease. A clinically meaningful, though typically suboptimal, response to levodopa is evident in 33–65% of patients with MSA (Rajput et al., 1990; Hughes et al., 1992b; Parati et al., 1993; Wenning et al., 1994; Colosimo and Pezzella, 2002; Colosimo et al., 2005b; Gilman et al., 2005). Individuals with MSA may require larger levodopa doses than individuals with Parkinson’s disease to generate a recognizable response. Therefore, a therapeutic trial of levodopa should not be abandoned until a levodopa dose of at least 1000 mg/day is reached (Gilman et al., 1998, 1999), although adverse effects such as orthostatic hypotension may prohibit titration to such levels. Wenning and colleagues (2005a) recently reported that 41% of 337 patients with MSA experienced a beneficial response to levodopa at a mean daily dose of 686 mg, with the response lasting for an average of 4 years. Although the initial improvement diminishes with the passage of time in most individuals, Hughes and colleagues (1992b) reported that over 50% of the MSA patients they studied who initially experienced improvement with levodopa remained partially responsive until death. Levodopa-induced dyskinesia develops in approximately 50% of responders and, in contrast to Parkinson’s disease, is often dystonic in character, preferentially involving the face and neck (Boesch et al., 2002). The experience with other antiparkinsonian agents has been more discouraging. Although an occasional patient will derive some benefit from a dopamine agonist, most do not and tolerance of these agents is generally poor. Conflicting reports regarding the effectiveness of amantadine have been published. Rajput and colleagues (1998) noted improvement on amantadine in over 60% of the 13 MSA patients they studied, but in a recent double-blind, placebo-controlled, cross-over trial involving 8 subjects, no statistically significant improvement with amantadine could be documented (Wenning, 2005). However, the investigators did note a trend toward improvement with amantadine and commented that the small sample size may have obscured mild amantadine-related benefit. Anticholinergic drugs are generally ineffective in alleviating parkinsonism in individuals with MSA, but an occasional patient may benefit (Polinsky, 1984; Wenning et al., 2005). Botulinum toxin A
MULTIPLE SYSTEM ATROPHY injections may be effective in reducing blepharospasm and limb dystonia, but some investigators caution against using it to treat cervical dystonia or antecollis because of the risk of inducing severe dysphagia (Thobois et al., 2001; Wenning et al., 2005). Stereotactic and deep brain stimulation surgery has generally been considered ineffective in the treatment of MSA. However, investigators have described sustained improvement in 4 individuals who underwent bilateral high-frequency stimulation of the subthalamic nuclei and recommended a larger prospective study (Visser-Vandewalle et al., 2003). In contrast, the same procedure has been reported to aggravate dysarthria, dysphagia and gait impairment in MSA (Tarsy et al., 2003). There is no proven effective treatment for the cerebellar dysfunction that develops in MSA. 46.8.2. Autonomic features 46.8.2.1. Genital dysfunction Although erectile dysfunction in MSA responds to cyclic guanosine monophosphate phosphodiesterase inhibitors such as sildenafil and its relatives, these drugs have also demonstrated a predilection to produce plummeting blood pressure with severe symptoms of orthostatic hypotension, especially in men with pre-existent orthostatic hypotension (Hussain et al., 2001). It thus seems wise to avoid these drugs in men with MSA. Other treatment modalities for erectile dysfunction are available. Intracavernosal injections of alprostadil are effective, but the necessity for and discomfort with the injections deters many from this treatment modality. Priapism and the formation of fibrotic nodules within the corpora are other potential complications (Hatzichristou, 1999). Alprostadil can also be administered by intraurethral instillation. Vacuum devices, used in conjunction with constrictor bands, are also effective, but patient acceptance of the devices is low. 46.8.2.2. Urinary dysfunction Appropriate treatment of bladder dysfunction depends on the specific type of impairment present. The approach to treatment of an overactive bladder is very different from that toward an underactive or areflexic bladder. Because both types of bladder dysfunction may occur in MSA, use of appropriate urodynamic and neurophysiologic testing is of immense value in setting the treatment course. For detrusor overactivity with urinary frequency and urgency, peripherally acting anticholinergic drugs are the treatment of choice. Oxybutynin has been the standard-bearer for many years, but the recent introduction of several newer, more selective anticholinergic drugs (trospium,
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solifenacin, darifenacin) with a better therapeutic index holds the promise of reduced toxicity. For individuals who cannot tolerate anticholinergic drugs, other treatment approaches are available. Gabapentin has been reported to improve symptoms of overactive bladder (Kim et al., 2004), although it has not been specifically tested in MSA. Desmopressin, administered at bedtime, can be used to reduce nocturia (Dasgupta and Haslam, 1999; Fowler, 1999). For individuals with an underactive or hypotonic bladder, anticholinergic drugs are contraindicated. Instead, methods to promote bladder emptying are needed. Unfortunately, the treatment choices for this dysfunction are more limited. If an element of prostatic hypertrophy is present, a-blocking agents such as tamsulosin are appropriate, but if the problem is strictly due to a hypocontractile detrusor muscle, intermittent catheterization is the best treatment option (Fowler, 1999). For those individuals with detrusor-sphincter dyssynergia, anticholinergic drugs will diminish detrusor overactivity but intermittent catheterization may be necessary to deal with the failure of the urethral sphincter to relax. Botulinum toxin A injections into the urethral sphincter have also been used successfully on an experimental basis in this regard, though not in individuals with MSA (Smith et al., 2005). 46.8.2.3. Cardiovascular dysfunction Management of orthostatic hypotension in persons with MSA can be very challenging. Both pharmacologic and non-pharmacologic treatment approaches may be necessary. Non-pharmacologic measures are often overlooked by physicians, but are simple, inexpensive and often effective. Avoidance of high environmental temperature, large meals, alcohol, prolonged recumbency, straining during voiding or defecation, excessive exercise and sudden changes in position can reduce the risk of serious postural hypotension (Mathias, 2003, 2005). Sleeping with the head of the bed elevated will reduce the supine hypertension that often occurs in MSA (Mathias, (2005)). The mechanism for this nocturnal blood pressure increase is not entirely clear, but may involve baroreflex abnormalities or shifting of fluid into the central vascular compartment, producing an effective increase in blood volume (Goldstein et al., 2003; Mathias, 2005). Elevating the head of the bed may also diminish orthostatic hypotension upon getting out of bed in the morning, possibly by reducing nocturnal sodium loss that occurs because of increased renal glomerular filtration prompted by the effective increase in blood volume (Pechere-Bertschi et al., 1998). Increased salt
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intake can also diminish orthostatic symptoms by increasing intravascular volume. The most effective non-pharmacologic measure for reducing orthostatic symptoms, however, may be the use of individually measured and fitted waist-high support stockings. Unfortunately, the stockings are difficult to don and very uncomfortable to wear, thus patients often resist wearing them. An abdominal binder also reduces venous pooling and is often better tolerated than the stockings (Mathias, 2003). The initial step in medical management of orthostatic hypotension is usually administration of the mineralocorticoid fludrocortisone (Mathias, 2005; Wenning et al., 2005). If this is insufficiently effective, midodrine can be added to the treatment regimen. In a double-blind study of 171 patients (40 with MSA), Low and colleagues (1997) reported that midodrine, an a-adrenergic agonist, was both effective and safe in reducing symptomatic orthostatic hypotension. The authors cautioned that midodrine should be avoided after 6 p.m. in order to reduce the risk of inducing nocturnal supine hypertension. Other drugs that may be directly helpful in alleviating orthostatic hypotension include ephedrine, indometacin, yohimbine and L-threo-dihidroxy-phenylserine. Octreotide, a somatostatin analog, ameliorates postprandial hypotension by inhibiting release of vasodilatory GI peptides (Mathias, 2003). Desmopressin can diminish orthostatic hypotension in the morning by reducing nocturnal diuresis (Mathias, 2003). Increasing red cell mass by means of erythropoietin administration has also been reported to improve orthostatic hypotension (Winkler et al., 2002).
be helpful if patients are experiencing dysphagia with aspiration, but percutaneous endoscopic gastrostomy tube placement is sometimes necessary. Domperidone, where available, is effective in accelerating gastric emptying in persons with Parkinson’s disease and, presumably, would also do so in the setting of MSA, although no specific information is available. Tegaserod has been reported to improve gastric emptying in normal volunteers and in critically ill patients in intensive care units (Degen et al., 2001; Banh et al., 2005). Whether it might do so in individuals with MSA or Parkinson’s disease is unknown. Management of constipation due to slowed colonic transit in MSA can be patterned after that practiced for Parkinson’s disease (Pfeiffer, 2005a, b). Increased fiber and fluid should be the first step, along with a stool softener if necessary. If that does not suffice, lactulose can be added to the treatment regimen. The next rung up the treatment ladder is the use of polyethylene glycol electrolyte balanced solutions, which have specifically been studied in patients with MSA and found to be effective (Eichhorn and Oertel, 2001). Finally, enemas are available, if needed. The value of prokinetic agents in treating colonic dysmotility is uncertain. The other component of bowel dysfunction in MSA, defecatory dysfunction due to disturbed function of the anorectal musculature, presents a much more difficult management problem. In patients with Parkinson’s disease, subcutaneous apomorphine injections and botulinum toxin A injections into the external anal sphincter have been employed with benefit (Mathers et al., 1989; Edwards et al., 1993), but there is no experience with these treatment modalities in MSA.
46.8.2.4. Gastrointestinal dysfunction Very little has been written specifically to address treatment of GI dysfunction in MSA. However, measures that have been successfully employed in the management of GI problems in Parkinson’s disease (Pfeiffer, 2005a) are likely to be useful in MSA also. Anticholinergic drugs have traditionally been used to alleviate drooling, but adverse effects are sometimes problematic. An approach that may limit the potential for toxicity while still reducing saliva production is the employment of one drop of 1% atropine ophthalmic solution sublingually twice daily (Hyson et al., 2002). Salivary gland injections of both botulinum toxin A and B have also been successfully employed to reduce saliva production in persons with parkinsonism, including some individuals with MSA (Mancini et al., 2003; Racette et al., 2003). Although antiparkinson medications sometimes improve dysphagia in Parkinson’s disease, no similar information exists regarding MSA. Swallowing therapy techniques may
46.9. Conclusion In the almost four decades since Graham and Oppenheimer first recognized MSA as a distinct disease process, awareness and knowledge concerning the clinical features and pathophysiology of MSA have soared. However, progress in discovering effective treatment has languished behind the scientific advances. Strides have been made, but there is still a tremendously long way to travel. Our blindness has been cured and we recognize the elephant. The daunting task that still faces us is taming the beast.
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Handbook of Clinical Neurology, Vol. 84 (3rd series) Parkinson’s disease and related disorders, Part II W. C. Koller, E. Melamed, Editors # 2007 Elsevier B. V. All rights reserved
Chapter 47
Progressive supranuclear palsy DAVID J. BURN1* AND ANDREW J. LEES2 1
Institute of Ageing and Health, University of Newcastle upon Tyne, Newcastle upon Tyne, UK 2
Reta Lila Weston Institute of Neurological Studies, University College London, London, UK
47.1. Introduction In its full-blown form, the clinical picture of progressive supranuclear palsy (PSP, or Steele–Richardson– Olszewski syndrome) is both arresting and highly characteristic. The patient has a fixed ‘Mona Lisa’ stare, with a markedly reduced blink frequency (0–4 blinks/minute). The head is retracted and the voice is reduced to a distinctive slurred growl. The sufferer walks clumsily and unsteadily (like a drunken sailor), with a notable tendency to topple backwards. Motor recklessness is a common early feature, leading to the highly distinctive ‘rocket sign’ on rising from a chair. Clothes are soiled with spilled food, due an inability to look down at the plate and difficulties swallowing (the ‘messy-tie’ sign). The time taken to respond to a question is prolonged, because of slow cognitive processing (bradyphrenia). Recent clinical and molecular genetic studies suggest that PSP should be considered a relatively common, discrete neurodegenerative disorder with a number of different clinical presentations but a distinctive neuropathological signature. This chapter will include important recent developments in PSP, including the association of the disease with an H1 haplotype, an altered tau isoform ratio, evidence for mitochondrial dysfunction and oxidative stress in the pathogenesis and the discovery of a cluster of a PSP-like syndrome on Guadeloupe.
47.2. Historical perspective The intriguing suggestion has been made that Charles Dickens may have been first to describe a subject with classical PSP in 1857 in his novel The Lazy Tour of Two Idle Apprentices (Larner, 2002):
. . . chilled, slow, earthy, fixed old man. A cadaverous man of measured speech. An old man who seemed as unable to wink, as if his eyelids had been nailed to his forehead. An old man whose eyes – two spots of fire – had no more motion that [sic] if they had been connected with the back of his skull by screws driven through it and riveted and bolted outside, among his grey hair. He had come in and shut the door and he now sat down. He did not bend himself to sit, as other people do, but seemed to sink bolt upright, as if in water, until the chair stopped him. The late 19th century was a productive time for seminal descriptions of neurological disorders. Charcot encouraged the use of medical photography and drawings to document the physical signs of the patients under his care and from two daguerreotypes published in 1889 in the Nouvelle Iconographie de la Salpeˆtrie`re by Dutil, one of his interns, a case of PSP may have been described as a ‘hemiplegic paralysis agitans with unusual postures of the trunk and head’ (Goetz, 1996). Retrocollis and an eye movement disorder were prominent components of the clinical picture. Charcot’s celebrated case history and sketches of Bachere, reported as a case of Parkinson’s in extension, may be another missed early example. A recent review of 2000 studies on Parkinson’s disease (PD) between 1861 and 1963 found 9 cases with possible PSP in the pre-encephalitis lethargica (von Economo’s disease) era (1861–1920) (Brusa et al., 2004). The authors felt it could therefore be assumed that PSP is neither a ‘new’ disease, nor a variant of postencephalitic parkinsonism (PEP).
*Correspondence to: Prof. David J. Burn, Regional Neurosciences Centre, Newcastle General Hospital, Westgate Road, Newcastle upon Tyne NE4 6BE, UK. E-mail:
[email protected], Tel: þ44-(0)-191-256-3425, Fax: þ44-(0)-191-256-3534.
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It is of note that, although motor neuron disease and PSP were described within 20 years of each other, the former condition, with its accompanying distinctive pathology, was rapidly accepted by neurologists as a discrete morbid entity, whereas a full clinicopathological description of PSP had to wait almost another century. Misdiagnosis of many cases of PSP as PEP or inappropriate lumping with other atypical causes of parkinsonism such as arteriosclerotic Parkinson’s syndrome may be a partial explanation for this paradox. In 1963, Dr. J. Clifford Richardson described 8 patients with ‘a common syndrome of ocular, motor and mental symptoms’ at the American Neurological Association in Atlantic City. Richardson drew an analogy between this seemingly new condition and Von Economo’s disease and Asao Hirano, one of the discussants, was struck by its similarity to a new disorder being found amongst the indigenous Chamorros on the Mariana Islands (lytico-bodig).
the likeliest explanation for the apparent variation. For instance, the incidence of 0.4 per 100 000 per year from the study of Mastaglia et al. is derived from 8 cases seen in Perth, Western Australia over a 2-year period, ‘population approximately one million’. Their study was primarily clinical and electrophysiological, not epidemiological in nature (Mastaglia et al., 1973). In contrast, Bower and colleagues (1997) studied the incidence of PSP over a 14-year period in Olmsted County, Minnesota. Sixteen incident cases were identified and none had an age of onset before 50 years of age. The average annual incidence rate for ages 50–99 years was 5.3 per 100 000. This study was specifically designed to measure incidence and utilized the records linkage system of the Rochester Epidemiology Project. The authors suggested that increased awareness of PSP by physicians could have contributed toward the higher incidence figure.
47.3. Epidemiology
PSP comprises 2–6% of parkinsonian patients seen in movement disorder clinics in Europe and the USA (Jackson et al., 1983; Katzenschlager et al., 2003). Extrapolation of population prevalence from such data is, however, misleading as atypical cases or patients responding poorly to treatment are more likely to be referred to these clinics. Similarly, the use of so-called necroepidemiological data may also be skewed towards more atypical parkinsonian cases, including PSP, as these patients are more likely to undergo postmortem (Maraganore et al., 1998). Only four studies have directly addressed the prevalence of PSP (Golbe et al., 1988; Schrag et al., 1999; Nath et al., 2001; Kawashima et al., 2004). Table 47.2 summarizes these studies, together with other estimates of the prevalence of PSP. In the latter, standard diagnostic criteria were not used and the primary aim of the work was to determine the prevalence of PD. Golbe et al. (1988), based in New Jersey, USA, first addressed the population prevalence of PSP. Neurologists were the only physicians approached, so underascertainment would have occurred if PSP cases were being managed by other specialists. The authors had to use their own definition of PSP, since standardized criteria were unavailable at the time. Despite potential criticisms, this study established that PSP was not as rare as had previously been supposed. Golbe (1992) later suggested that the true prevalence of symptomatic cases could be at least twice that of diagnosed cases, since the average delay from symptom onset to diagnosis is approximately 50% of the disease course.
47.3.1. Incidence Table 47.1 summarizes available incidence data for PSP (Mastaglia et al., 1973; Rajput et al., 1984; Radhakrishnan et al., 1988; Bower et al., 1997). The figure from the study of Golbe et al. (1988) was obtained indirectly, using prevalence and survival data. The incidence of PSP ranges from 0.3 to 1.1 per 100 000 per year, with differences in study design being Table 47.1 Incidence studies for progressive supranuclear palsy
Author
Year of report
Mastaglia et al. Rajput et al.
1973
Radhakrishnan et al. Golbe et al.
1988
Bower et al.
1997
1984
1988
Geographical area covered Perth, Australia Minnesota, USA Benghazi, Libya New Jersey, USA Minnesota, USA
Incidence (cases per 100 000 per year) 0.4* 0.3 0.3 0.5y 1.1
*Figure derived from number of cases seen in 2 years with illdefined population denominator. y Figure estimated from prevalence and survival data. Modified from Nath and Burn (2000).
47.3.2. Prevalence
PROGRESSIVE SUPRANUCLEAR PALSY
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Table 47.2 Prevalence studies for progressive supranuclear palsy (PSP)
Author
Year of report
PSP prevalence primary
Geographical area studied
Population denominator
Crude prevalence (per 100 000)
Golbe et al. De Rijk Wermuth Chio` Schrag et al. Nath et al. Kawashima et al.
1988 1995 1997 1998 1999 2001 2004
Yes No No No Yes Yes Yes
New Jersey, USA Rotterdam, Netherlands Faroe Islands North-west Italy London and Kent, UK Newcastle, UK Yonago, Japan
799 022 6969 43 709 61 830 121 608 259 998 137 420
1.39 14.3* 4.6 3.2 4.9 6.5 5.82
*Only persons aged 55 years of age or older were included. Modified from Nath and Burn (2000).
Seventeen cases of PSP were identified within the community study (population 259 998) of Nath et al., yielding an age-adjusted prevalence figure of 5.0 (95% confidence interval (CI) 2.5–7.5) per 100 000, standardized to the hypothetical European population. When the Schrag data are standardized to the same population, an identical prevalence figure of 5.0 is obtained. The most recent study, undertaken in Japan, also found a similar crude prevalence for PSP of 5.82 (95% CI 1.78–9.86) per 100 000 (Kawashima et al., 2004). There is a high prevalence of PSP in the French Antilles, with a minimum prevalence of 14 per 100 000 on the island of Guadeloupe (Caparros-Lefebvre et al., 2002). Of 220 consecutive patients with Parkinson’s syndrome examined, 58 had probable PSP, a further 96 had undetermined parkinsonism (many of whom closely resembled the incomplete or a typical bradykinetic presentation of PSP), 50 had PD and 15 had an amyotrophic lateral sclerosis–parkinsonian syndrome. Pathological confirmation of PSP, with a major doublet of pathological tau at 64 and 69 kDa in brain tissue homogenates (see below), has been found in all three of the probable PSP cases coming to postmortem. 47.3.3. Age of onset and sex ratio Table 47.3 summarizes the sex ratio and age of onset of PSP in published series to date (Kristensen, 1985; Frasca et al., 1991; De Bruin and Lees, 1994; Collins et al., 1995; Litvan et al., 1996c; Verny et al., 1996; Santacruz et al., 1998). One must be cautious in the interpretation of cases where no pathological confirmation is available. In one review, the lower end of the range for age at onset was reported as 12 years –
an improbably early age and incompatible with PSP according to current diagnostic criteria (Kristensen, 1985). There is a remarkably consistent median age of disease onset in the different series, between 60 and 66 years. With the exception of Kristensen’s review, no case has been reported with a disease onset below the age of 40. The upper limit of the age range for Table 47.3 Sex ratio and age at disease onset of progressive supranuclear palsy from published series
Author Kristensen* Maher and Lees Golbe et al. Frasca et al. De Bruin and Lees* Collins et al. Litvan et al. Verny et al. Santacruz et al.
Year of report
No. of cases
Median age at Sex ratio disease onset (M:F) (range) years
1985 1986
325y 52
1.5:1 0.7:1
60.0 (12–80) 63.5 (50–77)
1988 1991 1994
50 26 90{
1.4:1 1:1 1.5:1
62.9 (44–75) 63.1 (43–76) 62.0 (47–78)
1995
12{
3:1
66.0 (48–77)
1996c 1996 1998
24{ 21{ 437}
1.6:1 0.4:1 1.1:1
63.0 (45–73) 62.0 (43–70) 66.0 (41–87)
*Review of published cases. y Sex and disease onset specified in 302 and 202 cases, respectively. { All cases pathologically confirmed. } Admixture of living and deceased patients, surveyed by postal questionnaire. Median age at disease onset is approximated from data given in paper. Modified from Nath and Burn (2000).
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PSP must also be viewed cautiously, as clinicopathological series are prone to bias and older cases are less likely to undergo postmortem (Maraganore et al., 1998). Men may be diagnosed later than women following symptom onset (33.4 versus 24.1 months), but die earlier following the diagnosis (37.0 versus 47.6 months) (Santacruz et al., 1998). Regarding the sex ratio of PSP, six series have found a male predominance, two a female predominance and one an even ratio (Table 47.3). The most parsimonious explanation is that there is no significant difference in the sex ratio.
47.4. Classical progressive supranuclear palsy (Richardson’s syndrome) 47.4.1. Clinical features Poor mobility and slowness of movement are the most commonly occurring symptoms at disease onset, occurring in nearly 70% of cases, followed by cognitive problems (15%) and bulbar dysfunction (14%) (Nath et al., 2003). Falls occur in the majority of patients and are typically backwards (Maher and Lees, 1986). In the National Institute of Neurological Disorders (NINDS) study, 83% of 24 PSP patients had a history of falls (Litvan et al., 1996c), whereas 88% reported this problem out of 187 cases studied by Nath and coworkers (2003). The supranuclear gaze paresis characteristic of PSP is in the vertical plane, with non-targeted saccadic movements first affected. As the clinical picture evolves, slow pursuit eye movements are involved and eventually there may be complete vertical and horizontal gaze ophthalmoparesis. Electro-oculographic studies confirm early and persistent saccadic slowing in PSP compared to other parkinsonian syndromes whereas, unlike corticobasal degeneration (CBD), saccadic latency is normal (Vidailhet et al., 1994; Rottach et al., 1996; Rivaud-Pechoux et al., 2000). The percentage of errors in an antisaccade task, an index of prefrontal dysfunction, is markedly increased in PSP (Vidailhet et al., 1994). Square-wave jerks are common in PSP. Vertical optokinetic nystagmus in PSP has an impaired slow-phase response and slowed quick phases, combined with frequent small, paired, horizontal saccadic intrusions (Garbutt et al., 2004). Eyelid and corneal problems are common, including vague ‘grittiness’, corneal ulceration, photophobia and apraxia of eyelid opening. The latter, occurring in 43% of 49 PSP patients undergoing a standardized clinical assessment, may be severe enough to cause functional blindness (Nath et al., 2003).
Bradykinesia affects nearly half the patients by the time of diagnosis and up to 95% of PSP patients during the course of their illness (Maher and Lees, 1986; Verny et al., 1996). Bilateral bradykinesia was reported in 88% of the NINDS series (Litvan et al., 1996c). Axial and nuchal rigidity, in particular, may also be marked but disproportionate retrocollis, although thought to be characteristic of PSP, is usually a late and relatively infrequent sign (Litvan, 2001). Generalized hyperreflexia is common, but of limited diagnostic help. Tremor may be reported in up to 20% of cases; this is usually postural in type (Nath et al., 2003). A classic pill-rolling tremor is atypical for PSP (Quinn, 1997). The profoundly reduced blink frequency, facial dystonia and gaze abnormalities produce an unnervingly impassive face (so-called ‘reptilian’ stare). Dystonic vertical wrinkles in the glabellar region and bridge of the nose have been termed the ‘procerus sign’ (Romano and Colosimo, 2001), although the use of this term has been questioned by others (Lepore and Moudgil, 2002). Glabellar and palmomental reflexes are present in 92% and 25% of PSP, respectively, but do not correlate with cognition, as assessed using the Mini-Mental State Examination (MMSE) (Brodsky et al., 2004). Early bulbar dysfunction is notable, with a peculiar ‘growling’ dysarthrophonia (Litvan et al., 1996c). Swallowing difficulties, reported in 60% of patients, may be severe enough to warrant insertion of a percutaneous endoscopic gastrostomy feeding system in up to 10% (Nath et al., 2003). Vague changes in personality may be amongst the earliest signs of PSP, at a time when the diagnosis cannot be made with any degree of certainty. These changes include forgetfulness, anhedonia, irritability, depressed mood and impaired concentration. The cognitive problems may worsen with disease progression and ultimately conform to a pattern of subcorticofrontal dementia, characterized by a slowing of thought processes and impaired executive functions with recall deficit improved by cueing, recognition and preservation of instrumental activities (Grafman et al., 1995; Aarsland et al., 2003). Patients with PSP may also show behavioral changes, exhibiting apathy and disinhibition, together with prehension, initiation and utilization behaviors (Pillon et al., 1991). These behavioral and cognitive problems are a source of considerable distress to the patients and their carers. Depression has not been well studied in PSP but may occur in up to 20% of patients (Aarsland et al., 2003). Sometimes it may be difficult to discriminate mood disorder from apathy. Rapid-eye movement (REM) sleep behavior disorder is rare in PSP, when compared with ‘synucleinopathic’ disorders
PROGRESSIVE SUPRANUCLEAR PALSY (PD, multiple system atrophy (MSA) and dementia with Lewy bodies) (Boeve et al., 2003). The MMSE is relatively insensitive to frontal dysfunction and either the Dementia Rating Scale or the Addenbrooke’s Cognitive Examination-Revised (ACE-R) may be more useful for assessing global cognition in PSP (Aarsland et al., 2003). The Frontal Assessment Battery (FAB) is a short bedside cognitive and behavioral battery, comprising six subtests exploring the following: conceptualization, mental flexibility, motor programming, sensitivity to interference, inhibitory control and environmental autonomy (Dubois et al., 2000). The FAB is sensitive to the frontal lobe dysfunction of PSP, takes about 10 minutes to administer and has good discriminant validity. Motor perseveration is also detected by showing, then asking, the patient to clap three times only. PSP sufferers commonly continue to clap in excess of three times (the ‘signe d’applause’). The combination of subcorticofrontal disturbance and postural instability may lead to the so-called rocket sign, whereby the patient jumps up impulsively from a seated position, only to fall back immediately into the chair. Sitting ‘en bloc’ is also a common sign, with both feet coming up off the floor as the patient falls backwards into their chair when asked to sit down (Litvan, 2001). 47.4.2. Natural history Classic PSP is a rapidly progressive neurodegenerative illness. The median duration from disease onset to death is 5.8–5.9 years (Maher and Lees, 1986). Mean interval from symptom onset to diagnosis ranges from 3.6 to 4.9 years, indicating that many patients with PSP may remain misdiagnosed for much of their disease course (Golbe et al., 1988). Onset of falls (hazard ratio (HR) 3.28, 95% CI 1.17–9.13), speech problems (HR 4.74, 95% CI 1.10–20.4) or diplopia (HR 4.23, 95% CI 1.23–14.6) within 1 year and swallowing problems within 2 years (HR 3.91, 95% CI 1.39–11.0) were associated with a worse prognosis in one study of 187 PSP cases (Nath et al., 2003). Goetz and colleagues (2003) approached the natural history in a different way, defining key motor impairments in PSP as unintelligible speech, no independent walking, inability to stand unassisted, wheelchair-bound or recommendation for feeding tube placement. Median time from disease onset to the first key motor impairment in a sample of 50 subjects was 48 months, 24 months after the first consultation. The three gait items occurred temporally closely together and, when considered as a single milestone, occurred at a median disease duration of only 57 months.
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An analysis of International Classification of Diseases, version 9 (ICD-9)-coded deaths obtained through the UK Office of National Statistics over an 8-year period yielded a crude annual mortality rate for PSP of 1.77 (95% CI 1.64–1.90) cases per million (Nath et al., 2005). In this study, the annual mortality rate increased over time, possibly as a result of increased incidence or increased awareness of the disorder. The commonest proximate cause of death in PSP is pneumonia, as cited in 45–65% of death certificates (Maher and Lees, 1986; Nath et al., 2005).
47.5. Misdiagnosis and diagnostic criteria Primary care diagnoses on hospital referral are protean and include PD (30%), ‘balance disorders’ (20%), stroke (10%) and depression (7%) (Nath et al., 2003). Combining the prevalence studies of Schrag et al. (1999) and the methodologically similar communitybased component of the Nath et al. (2001) study, a total of 23 PSP cases were identified. Of these, 10 patients (43%) carried a primary referral diagnosis of PSP. In the remainder, PD and cerebrovascular disease accounted for all but one of the misdiagnosed cases. In a clinicopathological study, based in a specialist movement disorders service, 19 of 143 cases of parkinsonism were pathologically confirmed as PSP (Hughes et al., 2002). Antemortem clinical diagnosis was correct in 16 of these 19 cases: MSA, PD and ‘parkinsonism undetermined’ constituted the three misdiagnoses (Hughes et al., 2002). Utilizing the Society for PSP brain bank, Josephs and Dickson (2003) found that, of 180 cases referred with a clinical diagnosis of PSP, 137 had this diagnosis confirmed pathologically. CBD, MSA and dementia with Lewy bodies accounted for 70% of the 43 misdiagnosed cases. A history of tremor, psychosis, dementia and asymmetric findings was more frequent in misdiagnosed cases. Using the Queen Square Brain Bank for Neurological Disorders, Osaki and colleagues (2003) found that the clinical diagnosis of PSP was confirmed pathologically in 78% of 60 cases, a remarkably similar positive predictive value to that obtained by Josephs and Dickson. False-positive diagnoses included PD with significant cortical Lewy body (n ¼ 3) or Alzheimer (n ¼ 1) pathology and MSA (n ¼ 4). At the first consultation, only 17% of the 47 ‘true’ PSP cases, 6 of which had been seen by consultant neurologists, were diagnosed as PSP. Postural instability, leading to falls (typically backwards) within the first year of disease onset, coupled with a vertical supranuclear gaze paresis have good discriminatory diagnostic value when PSP is compared with other degenerative parkinsonian syndromes (Litvan et al., 1997).
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47.5.1. Diagnostic criteria Seven different sets of diagnostic criteria have been proposed for PSP (Table 47.4) (Lees, 1987; Blin et al., 1990; Duvoisin, 1992; Golbe, 1993; Tolosa et al., 1994; Collins et al., 1995; Litvan et al., 1996a). In the majority, the criteria were not derived in a systematic fashion, but were mainly compiled from the extensive clinical experience of the authors. There is considerable overlap between the different sets of criteria, with disease onset over the age of 40 or 45 and supranuclear gaze palsy common to all. The most rigorous approach to date led to the formulation of the National Institute of NeurologiTable 47.4 Published diagnostic criteria for progressive supranuclear palsy Author (year)
Derivation and use
Lees (1987)
Not explicitly stated; defined as progressive non-familial disorder beginning in middle or old age with SNO and 2 of 5 further cardinal features Not explicitly stated; defined as ‘probable’ if all of 9 criteria met or ‘possible’ if 7 out of 9 criteria fulfilled Not explicitly stated; criteria divided into four sections – essential for diagnosis, confirmatory manifestations, manifestations consistent with but not diagnostic of PSP and features inconsistent with PSP Not explicitly stated; defined as onset after age 40, progressive course bradykinesia and SNO, plus 3 of 6 further features, plus absence of 3 ‘inconsistent’ clinical features Not explicitly stated; defined as a nonfamilial disorder of onset after age 40, progressive course and SNO, plus 3 of 5 further features for ‘probable’ and 2 of 5 for ‘possible’, plus absence of 5 ‘inconsistent’ clinical features Retrospectively from review of 12 pathologically confirmed cases; algorithm-based, including prerequisites and exclusionary criteria; SNO and/or prominent postural instability, plus a number of other specified signs Systematic literature review, logistic regression and CART analysis; validated using data from postmortem confirmed cases; ‘definite’, ‘probable’ and ‘possible’ categories described (see Table 47.5 and text)
Blin et al. (1990) Duvoisin (1992)
Golbe (1993)
Tolosa et al. (1994)
Collins et al. (1995)
Litvan et al. (1996a)
SNO, supranuclear ophthalmoparesis; CART, classification and regression tree analysis.
cal Disorders and Stroke and Society for Progressive Supranuclear Palsy (NINDS-SPSP) diagnostic criteria (Table 47.5) (Litvan et al., 1996a, 2003). When applied retrospectively to a case mix comprising various parkinsonian syndromes, the NINDS-SPSP criteria have high diagnostic sensitivity and specificity (Litvan et al., 2003). These parameters have not, however, yet been determined for prospective series with pathological correlation, nor have they been applied retrospectively to an independent clinicopathological series. The accuracy of the NINDS-SPSP clinical diagnostic criteria has also been evaluated along with existing criteria for three other dementing disorders by a different group of raters in an independent sample of pathologically confirmed cases (Lopez et al., 1999). This study confirmed that both probable and possible NINDS-SPSP diagnostic categories for PSP had excellent specificity. One area where the NINDS-SPSP criteria would be predicted to have lower sensitivity is when the development of core diagnostic features is delayed. Application of the NINDS-SPSP criteria marginally improved the accuracy of initial clinical diagnosis in one retrospective clinicopathological series (Osaki et al., 2003), but did not improve accuracy of the final clinical diagnosis. Diagnostic sensitivity, using the ‘possible PSP’ category of these criteria, was still only 21%, compared with 17% for initial clinical diagnosis.
47.6. Clinical heterogeneity ‘Atypical’ phenotypic variants of PSP add to the difficulty of accurate diagnosis. Pathologically confirmed cases of PSP have been reported in which there was pure akinesia, whereas others have documented early and severe dementia (Davis et al., 1985; Matsuo et al., 1991). Additional reports have described features that would conventionally be considered unusual for PSP, including unilateral limb dystonia or apraxia, prominent tremor, palatal myoclonus and cricopharyngeal dysfunction (Schleider and Nagurney, 1977; Masucci and Kurtzke, 1989; Barclay and Lang, 1997; Pharr et al., 1999). Conversely, cases of frontotemporal lobar degeneration with ubiquitinonly-immunoreactive neuronal changes (including the frontotemporal lobar degeneration with motor neuron disease (FTLD-MND) variant) (Paviour et al., 2004), frontotemporal dementia linked to chromosome 17 (tau exon 10 þ 16 mutation) (Morris et al., 2003), Whipple’s disease (Averbuch-Heller et al., 1999), neurosyphilis (Murialdo et al., 2000), cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) (Van Gerpen et al., 2003), primary antiphospholipid antibody syndrome (Reitblat et al., 2003), Creutzfeldt– Jakob disease (Josephs et al., 2004), clebopride
PROGRESSIVE SUPRANUCLEAR PALSY
333
Table 47.5 NINDS-SPSP diagnostic criteria for progressive supranuclear palsy (PSP)
PSP
Mandatory inclusion criteria
Possible
Gradually progressive disorder Onset age 40 or later
Either vertical supranuclear palsy or both slowing of vertical saccades and postural instability with falls < 1 year after disease onset No evidence of other diseases that could explain the foregoing features, as indicated by exclusion criteria
Probable
Definite
Mandatory exclusion criteria Recent history of encephalitis Alien-limb syndrome, cortical sensory deficits, focal frontal or temporoparietal atrophy Hallucinations or delusions unrelated to dopaminergic therapy Cortical dementia of Alzheimer type Prominent, early cerebellar symptoms or unexplained autonomic dysautonomia
Supportive criteria Symmetric akinesia or rigidity, proximal more than distal Abnormal neck posture, especially retrocollis. Poor or absent response of parkinsonism to levodopa. Early dysphagia and dysarthria. Early onset of cognitive impairment including > 2 of: apathy, impairment in abstract thought, decreased verbal fluency, utilization or imitation behavior or frontal release signs
Gradually progressive disorder Onset age 40 or later Vertical supranuclear palsy and prominent postural instability with falls < 1 year after disease onset No evidence of other diseases that could explain the foregoing features, as indicated by exclusion criteria Clinically probable or possible PSP and histopathological evidence of typical PSP
NINDS-SPSP, National Institute of Neurological Disorders and Stroke and Society for Progressive Supranuclear Palsy. Modified from Litvan et al. (1996a).
exposure (Campdelacreu et al., 2004) and postsurgical repair of ascending aortic dissection or aneurysm (Mokri et al., 2004) have been reported with a PSP phenotype. Morris and colleagues (2002a) have drawn attention to a clinically atypical form of PSP, in which a classical distribution of PSP pathology occurs, but with the deposition of Alzheimer disease-type tau protein rather than PSP-type tau (see below). Four of these 15 atypical cases had PD-like presentations with an asymmetrical onset and good levodopa response and 3 of the 4 were documented to have normal eye movements. Another case had asymmetrical dystonia and apraxia, suggestive of CBD. Using factor analysis, Williams and colleagues (2004) identified two distinct groups amongst 107 consecutive cases of pathologically confirmed PSP. Fifty-three percent of cases had features compatible with the classic clinical description outlined above. A second group of 32% cases, however, were characterized by asymmetric onset, tremor and response to levodopa. Mean disease duration in this group
was, at 9.2 years, significantly longer than the ‘classic cases’ (5.9 years). It was suggested that the first group of cases might be named ‘Richardson’s syndrome’ and the second group ‘PSP-parkinsonism’ (PSP-P) (Williams et al., 2004).
47.7. Investigations The diagnosis of PSP still rests on the clinical history and examination. Attempts have been made, however, to improve diagnostic accuracy through cerebrospinal fluid (CSF) analysis and protein biomarkers, structural and functional imaging and neurophysiological techniques. 47.7.1. Neuropsychological assessment Neuropsychological assessment in the early stages may assist the accurate clinical diagnosis of a parkinsonian disorder, as may the time course and pattern of progression of cognitive and behavioral decline (Soliveri et al., 2000).
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Patients with PSP show a greater decline in attention, set-shifting and categorization abilities, compared with PD and MSA. Patients with PSP also show greater impairment in both phonemic and semantic fluency than patients with MSA or PD. Using discriminant function analysis, variables derived from four verbal fluency tasks (simple and alternate semantic and phonemic fluency) were able to classify correctly over 90% of PSP patients (Lange et al., 2003). The Katz Adjustment Scale-Relatives (KAS-R) may be sensitive to changes in apathy, social withdrawal and independence in PSP (Millar et al., 2006). Comparative studies are required, however, to assess the sensitivity and specificity of this profile in differentiating PSP from other parkinsonian conditions. 47.7.2. Cerebrospinal fluid analysis Studies have attempted to identify biomarkers in the CSF to achieve early and accurate diagnosis, as well as monitoring response to treatment. CSF amyloid A-b42 levels are normal in PSP and do not discriminate this condition from PD (Holmberg et al., 2003). Tau has potential as a candidate protein, although it may lack specificity unless isoform analysis can also be performed (see below). Significantly higher tau protein levels in CSF have been reported in CBD, compared with PSP, yielding sensitivities and specificities of 100% and 87.5%, respectively (Urakami et al., 2001). Other proteins in the CSF, including neurofilament protein (NFL) and glial fibrillary acidic protein (GFAP), have also been studied. Whereas no difference was found in CSF GFAP levels between PD, MSA and PSP, high NFL concentrations seemed to differentiate typical from atypical parkinsonian disorders (Holmberg et al., 1998). The overlap in ranges, however, limits the sensitivity of this technique and it was not possible to differentiate MSA from PSP cases. More recently, Holmberg and colleagues (2001) suggested that the concomitant use of a levodopa test in combination with CSF NFL assay could improve diagnostic accuracy for atypical parkinsonism to 90%. Major products of lipid peroxidation are selectively increased in PSP midbrain tissue, suggesting that a CSF assay for these products could provide a specific biomarker. Since the clinical phenotype of Whipple’s disease may resemble PSP, investigators have examined CSF from PSP patients for Tropheryma whippelii DNA (Pezzella et al., 2004). Polymerase chain reaction for T. whippelii was negative in all samples tested, indicating that this pathogen is not involved in the etiopathogenesis of PSP, nor is it a useful biomarker for the disease.
47.7.3. Magnetic resonance imaging (MRI) Over 70% of patients with clinically diagnosed PSP may be correctly classified on the basis of 0.5 T or 1.5 T MRI brain scanning (Schrag et al., 2000). Criteria used for the diagnosis of PSP include midbrain diameter on axial scans of less than 17 mm, signal increase in the midbrain, atrophy or signal increase of the red nucleus and signal increase in the globus pallidus. Other studies have also suggested that reduced midbrain diameter on routine MRI may be of value in discriminating PSP from PD and MSA-P, although values may overlap and do not clearly correlate with disease duration or severity (Warmuth-Metz et al., 2001; Righini et al., 2004). Atrophy or abnormal signal of the superior cerebellar peduncle on proton density-weighted MRI, postulated to represent demyelination and gliosis, may also be of help in differentiating PSP from PD (Oka et al., 2001). Pathological data indicate that atrophy of this structure is a relatively early feature of PSP and correlates with disease duration (Tsuboi et al., 2003). Tegmental T2 hyperintensity has poor sensitivity for the diagnosis of PSP (Righini et al., 2004). In all radiological studies, clinically ‘typical’ PSP cases were selected, rendering the discriminatory value of MRI something of a tautology. The value of routine MRI scanning in longitudinal clinicopathological studies, particularly of early indeterminate cases, has not been investigated. MRI-based volumetry (MRV) has also been used to differentiate PSP from other parkinsonian syndromes, by examining atrophy of the caudate nucleus, putamen, brainstem and cerebellum (Schulz et al., 1999). Although significant group differences were found in mean striatal and brainstem volumes, on an individual patient basis this technique could still not reliably separate PSP from MSA-P. Voxel-based morphometry, an observer-independent MRV technique, has demonstrated atrophy in PSP, predominantly involving mesiofrontal targets of striatal projections (Brenneis et al., 2004). This study did not compare PSP with other parkinsonian syndromes, however, so the diagnostic value of these observations is unknown. More elaborate mathematical modeling has also been applied in an attempt to discriminate PSP from CBD using MRV (Groschel et al., 2004). As for MRI, the potential utility of MRV remains to be established in prospective studies, including subjects with early ‘indeterminate’ parkinsonism. Proton magnetic resonance spectroscopy may provide an indirect measure of neuronal loss in vivo. There have been a number of reports of the use of this technique in PSP, concentrating mainly upon spectral changes in the lentiform nucleus. In general,
PROGRESSIVE SUPRANUCLEAR PALSY although lentiform N-acetylaspartate/choline and/or Nacetylaspartate/creatine ratios may be reduced in PSP, the discriminatory value of this technique on an individual basis remains questionable. A systematic review of proton magnetic resonance spectroscopy in parkinsonian syndromes concluded that the heterogeneity of the results to date precludes the use of any of these findings in differential diagnosis at the present time (Clarke and Lowry, 2001). Apparent diffusion coefficient measurements using diffusion-weighted MRI (DWI) may discriminate PSP from PD with a sensitivity of 90% and a positive predictive value of 100%; significant increases in regional apparent diffusion coefficients have been noted in striatum and globus pallidus in PSP cases (Seppi et al., 2003). Importantly, however, DWI could not discriminate PSP from MSA-C in this study. Magnetization transfer imaging, a measure that correlates with myelination and axonal density, has revealed changes in magnetization transfer ratios corresponding with known sites of pathological predilection in PSP, MSA and PD (Eckert et al., 2004). The same study showed ‘fairly good’ discrimination of PD from control subjects and of MSA from PSP. 47.7.4. Brain parenchyma sonography (BPS) BPS is a new ultrasound technique capable of displaying tissue echogenicity of the brain through an intact skull. Information may be obtained from key brain structures that may be of value in differentiating PSP from other parkinsonian syndromes. BPS can be useful in discriminating typical from atypical parkinsonism (MSA and PSP) (Walter et al., 2003). Marked hyperechogenicity of the substantia nigra has been reported in CBD but not in PSP, whereas dilatation of the third ventricle is common in PSP, but not in CBD. The presence of at least one of the BPS findings, marked nigral hyperechogenicity and third ventricle width <10 mm, indicated CBD with sensitivity of 100%, a specificity of 83% and a positive predictive value of 80% in one small cross-sectional study (Walter et al., 2004). 47.7.5. Functional imaging Blood flow and oxygen or glucose metabolism positron emission tomography (PET) studies in PSP subjects have demonstrated relative frontal lobe hypometabolism, although bifrontal hypoperfusion using more widely available 99mTc-HMPAO (99mTc-hexamethylpropylene amine oxime) single-photon emission computed tomography technique (SPECT) is not a robust finding in PSP. [18F]-Fluorodeoxyglucose PET
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and statistical parametric mapping highlights hypometabolism in cingulate gyrus, caudate nucleus, thalamus and midbrain in PSP (Juh et al., 2004), compared to normal controls, PD and MSA patients, whereas midbrain hypometabolism may be an early diagnostic marker for PSP (Mishina et al., 2004). Both findings require validation in independent, prospective series. Evaluation of the nigrostriatal dopaminergic system using cocaine analogs and functional imaging (PET or SPECT) reliably shows presynaptic dopaminergic degeneration in PSP and can also demonstrate progression of this degeneration. The pattern of abnormality is, however, non-specific and cannot differentiate PSP from other parkinsonian syndromes (Pirker et al., 2002), even when used in combination with a dopamine D2-receptor ligand (Kim et al., 2002; Plotkin et al., 2005). A newly developed PET ligand, the dopamine D2-receptor antagonist, [18F]-desmethoxyfallypride, can discriminate between typical and atypical parkinsonism with high specificity (100%) and sensitivity (76%), but cannot reliably differentiate PSP from MSA, limiting its use in clinical practice (Schreckenberger et al., 2004). The lack of specificity in functional imaging of the dopaminergic system has led to the study of other neurotransmitter systems in PSP. Thus, significant reductions in both caudate and putamen opioid receptor binding were seen in PSP using [11C]-diprenorphine PET, compared with PD, MSA and controls (Burn et al., 1995). [11C]-flumazenil and PET, used to image benzodiazepine receptors, demonstrated a modest reduction in binding in the anterior cingulate gyrus when compared with normal controls, but no other regional abnormality (Foster et al., 2000). Although benzodiazepine binding is reduced in the globus pallidus of autopsy tissue from PSP patients and preserved in the striatum, the low level of the receptors in the pallidum and the proximity of the putamen indicate functional imaging of the benzodiazepine receptor is too insensitive to detect these differences. Ligands for the cholinergic system may offer more hope in improving diagnostic accuracy for PSP. Analogs of vesamicol, an inhibitor of the acetylcholine vesicular transporter, demonstrate loss of intrinsic striatal cholinergic neurons (Eidelberg and Dhawan, 2002). N-methyl-4-[11C]piperidyl acetate and PET reflect acetylcholinesterase activity and indicate preferential loss of cholinergic innervation to the thalamus in PSP, compared with PD and controls (Shinotoh et al., 1999). In vivo imaging of activated microglia, using [11C] PK11195 and PET, revealed increased binding in the lentiform nucleus and pons, in particular, although dorsolateral prefrontal cortex, caudate, substantia nigra and thalamus were also involved (Gerhard et al., 2001).
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The significance of this preliminary finding (in only 2 PSP patients) is uncertain. 47.7.6. Neurophysiological techniques A variety of neurophysiological techniques have been used to study PSP, both with the aim of improving diagnostic accuracy and also improving understanding of the underlying pathophysiological process. A longitudinal oculomotor study of patients with PSP and other parkinsonian syndromes has suggested that electrooculography may help diagnose PSP earlier. PSP patients are characterized by decreased saccadic velocity throughout their disease course, as well as having less specific findings of frequent square-wave jerks and increased error rate on antisaccade tasks (RivaudPechoux et al., 2000). Significant orthostatic hypotension is rare in PSP, in contrast to MSA, with only minor and inconsistent abnormalities on formal assessment of sympathetic and parasympathetic functions. Furthermore, there is a normal rise in growth hormone following clonidine administration in PSP patients (Kimber et al., 2000). Sphincter electromyography may differentiate atypical akinetic-rigid syndromes from PD, but fails to discriminate reliably between PSP and MSA (Vodusek, 2001). Neuronal loss in Onuf’s nucleus of the sacral spinal cord in PSP could explain this lack of specificity (Scaravilli et al., 2000). The auditory startle response is delayed or absent in PSP and without habituation, although there is overlap with values obtained from other akinetic-rigid syndromes. A combination of abnormalities on acoustic blink reflex, acoustic startle reflex and electro-oculography may have high specificity (95%) and sensitivity (100%) for an early diagnosis of PSP, according to one prospective study of 41 atypical parkinsonian patients with mean 26-month clinical follow-up (Gironell et al., 2003). Abnormalities in visual event-related potentials (P300 amplitude and reaction times to rare target stimuli), somatosensory evoked potentials (enlarged cortical somatosensory evoked potentials) and pattern of facial reflexes (electromyogram activity in mentalis but not orbicularis oculi muscles following electrical stimulation of the median nerve at the wrist) have all been reported in PSP patients. Transcranial magnetic stimulation reveals disinhibition of the motor cortex in PSP, with enlarged response amplitudes at rest, reduced intracortical inhibition and prolonged ipsi- and contralateral silent periods (Kuhn et al., 2004; Wolters et al., 2004). The clinical utility of these investigations remains uncertain, as does their pathophysiological significance. Computerized posturography testing may differentiate early PSP from early PD and age-matched controls (Ondo et al., 2000). Seventy-five percent of the 20 PSP patients met ‘all
optimal criteria’ for PSP, according to the NINDS-SPSP criteria, implying early postural instability and falls within the first year of disease onset. The sensitivity and specificity of this and several of the other techniques described above in prospectively followed ‘indeterminate parkinsonian’ cases would be of interest. Sleep architecture studies in PSP patients are characterized by almost complete absence of REM sleep, reduction of total sleep time and sleep spindles, atonic slow-wave sleep and fragmentation with disrupted sleep pattern (Montplaisir et al., 1997; Brotini and Gigli, 2004). Cell loss in the pedunculopontine tegmentum may be the pathophysiological basis for the absence of REM sleep.
47.8. Pathology The majority of PSP cases have little or no visible atrophy macroscopically, distinguishing it from other tauopathies (Schofield et al., 2004). PSP is characterized by the destruction of a number of subcortical structures, including the substantia nigra, globus pallidus, subthalamic nucleus and midbrain and pontine reticular formation (Jellinger and Blancher, 1992). Deeper cortical layers, especially around the precentral gyrus, may also be affected to a lesser degree. Large numbers of neurofibrillary tangles (NFTs, made up of ultramicroscopic straight filaments), neuropil threads and tufted astrocytes are also found in these brain regions. These distinctive histopathological inclusions are made up of insoluble aggregates of tau phosphoprotein. ‘Coiled bodies’ are small round cells of oligodendrocytic origin found in white matter, underlining the widespread nature of the pathology in PSP. Tau-positive glial inclusions are also positively stained with antibodies against ubiquitin, DJ-1 (Neumann et al., 2004) and heat shock protein (HSP) ab-crystallin (but not HSP70) (Richter-Landsberg and Bauer, 2004). In contrast to CBD, ballooned neurons are sparse in PSP and limited to the limbic system (Wakabayashi and Takahashi, 2004). 47.8.1. Neuropathological diagnostic criteria and differential diagnosis There are a number of clinical and pathological similarities between PSP, PEP and the parkinsonism–dementia complex of Guam (PDCG) (Geddes et al., 1993). When no clinical information is given, the neuropathologist may have difficulty in differentiating PSP from PEP and PDCG. The sensitivity and reliability of the diagnosis of PEP improve significantly when clinical data are available (Litvan et al., 1996b). NFTs in subcortical and cortical areas are found in all three
PROGRESSIVE SUPRANUCLEAR PALSY conditions. PSP may also be difficult to discriminate from CBD, where NFTs also occur and where the basophilic inclusions of CBD are not always readily distinguished from the tangle pathology. Standardized neuropathological criteria have been developed for PSP. An early version divided the neuropathology of PSP into typical, atypical and combined types, although the value of the atypical category was controversial (Hauw et al., 1994). Revised criteria subsequently omitted this category, leaving typical and combined PSP, with the latter associated with infarcts in the brainstem, basal ganglia, or both sites (Table 47.6) (Litvan et al., 1996b). A clinical history compatible with PSP is mandatory when defining typical PSP, according to these criteria. 47.8.2. Tau aggregation and cell death Tau is critically important for the dynamic behavior and stabilization of microtubules in the cytoskeleton. In normal neurons, tau is soluble, unfolded and binds reversibly to microtubules, enhanced by chaperone activity of HSPs. In PSP the protein loses its affinity for microtubules and excess free tau accumulates into Table 47.6 NINDS-SPSP neuropathological criteria for the diagnosis of typical progressive supranuclear palsy (PSP)
Typical PSP
Inclusion criteria
Exclusion criteria
A high density of neurofibrillary tangles and neuropil threads in > 3 of: pallidum, subthalamic nucleus, substantia nigra or pons and a low-tohigh density of neurofibrillary tangles or neuropil threads in > 3 of: striatum, oculomotor complex, medulla, or dentate nucleus* and clinical history compatible with PSP
Large or numerous infarcts; marked diffuse or focal atrophy; Lewy bodies; changes diagnostic of Alzheimer’s disease; oligodendroglial argyrophilic inclusions, Pick bodies; diffuse spongiosis; prion P-positive amyloid plaques
*Tau-positive astrocyte processes or astrocyte cell bodies in the areas of neurofibrillary tangles and neuropil threads confirm the diagnosis; other lesions include various degrees of neuronal loss and gliosis in affected areas. NINDS-SPSP, National Institute of Neurological Disorders and Stroke and Society for Progressive Supranuclear Palsy. Modified from Litvan et al. (1996b).
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fibrillar aggregates that are resistant to proteolysis. A number of posttranslational processes may be involved in the aggregation of tau in PSP, but hyperphosphorylation, glycation and transglutamination have been principally implicated. Glycation leads to the formation of advanced glycation end-products (AGEs), detected histochemically in NFTs (Sasaki et al., 1998). The tau in these aggregates is abnormally hyperphosphorylated and in turn this may lead to tau release from microtubules. Tissue transglutaminase (TGase) is a calcium-activated enzyme which cross-links substrate proteins into insoluble, proteaseresistant complexes, potentially initiating NFT formation. By altering the conformation of tau, TGase may render digestion sites inaccessible to proteases. In support of a pathogenic role for TGase, high levels of epsilon-(gamma-glutamyl) lysine cross-linked tau, together with increased TGase and mRNA levels for TGase 1 and 2 have been found in the pallidum and pons in PSP (Zemaitaitis et al., 2003). Antibodies capable of detecting nitrated tau have also shown labeling in the glial and neuronal tau of PSP, in addition to other tauopathies, implying that nitrative injury might also be involved (Horiguchi et al., 2003). In addition to pathogenic mechanisms leading to tau hyperphosphorylation, proteasomal inhibition may also be necessary to produce the stable fibrillary deposits of tau found in PSP, as indicated by results from an in vitro oligodendroglial cell model (OLN-t40) (Goldbaum et al., 2003). Indirect evidence for proteasome inhibition in PSP is derived from immunohistochemical and immunoblotting studies, demonstrating an aberrant ubiquitin protein (UBBþ1) in human pons tissue (Hope et al., 2004). UBBþ1 is regarded as a reporter for proteasomal dysfunction. Interestingly, the presence of UBBþ1 was not associated with an HSP response. Since HSPs are linked to normal tau function and also act as a rescue response to UBBþ1 expression, this could explain both tau dysfunction and tau accumulation in PSP (Hope et al., 2004). The mechanism leading to cell death in PSP is unknown but is likely to be multifactorial, with both environmental (toxic) and genetic influences playing a role. Microglial activation is greater in PSP than in control brains and correlates with tau burden in most areas. There is also accumulating evidence for oxidative stress and mitochondrial dysfunction in PSP (Albers and Augood, 2001). Complex I activity is significantly reduced compared with controls in transmitochondrial cytoplasmic hybrid (cybrid) cell lines, expressing mitochondrial genes from subjects with PSP. The mitochondrial dysfunction may be of toxic or genetic origin. In addition, tau-positive astrocytes may exert neurotoxicity through the overproduction
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of nitric oxide, in excess of the detoxification capacity of superoxide dismutase. The formation of AGE-tau, detectable in NFTs, is also associated with the generation of oxygen free radicals and the induction of oxidative stress. Phosphorylation of tau in PSP and Pick’s disease may be a direct consequence of the oxidative stress-induced activation of mitogen-activated protein kinases, including the p38 pathway (phosphor-MKK6 and phosph-p38) (Hartzler et al., 2002). The consumption of tropical plants and herbal teas has been linked with an abnormally high frequency of a levodopa-resistant form of parkinsonism, clinically and pathologically resembling PSP, in Guadeloupe (French West Indies) (Caparros-Lefebvre et al., 1999). Stabilization or even improvement in some symptoms has been reported after cessation of consumption of these fruits and infusions. Moreover, when mesencephalic dopaminergic neurons are exposed in culture to corexime and reticuline, the most abundant subfractions of Annona muricata (corossol, soursop), apoptotic cell death occurs (Lannuzel et al., 2002). Cell death in these cultures seems independent of excitotoxic mechanisms, although energy depletion has been implicated. Lowmolecular weight benzylisoquinoline derives of the Annonaceae family (reticuline and N-methylcoculaurine) are toxic to SH-SY5Y neuroblastoma cells and can inhibit mitochondrial complex I in vitro (Kotake et al., 2004). 47.8.3. Familial progressive supranuclear palsy Although PSP is considered to be a late-onset, sporadic neurodegenerative disease, a number of families with sometimes heterogeneous clinical presentation have been described. Postmortem confirmation of diagnosis in one or more cases has been obtained in many of these reports. In a report of 12 pedigrees, the presence of affected members in at least two generations in eight of the families and the absence of consanguinity suggested autosomal-dominant transmission with incomplete penetrance (Rojo et al., 1999). A clinical study yielded the intriguing observation that 39% of 23 asymptomatic first-degree relatives of patients with PSP scored abnormally on a PD test battery, compared with none of 23 age-matched normal controls (Baker and Montgomery, 2001). The authors suggested that the test battery could have detected an asymptomatic carrier state or risk for PSP, or a subclinical effect of a shared environmental exposure. Further evidence for subclinical cases comes from PET studies using 18F-dopa and 18fluorodeoxyglucose (Piccini et al., 2001). Four of 15 asymptomatic relatives scanned from two families with PSP had abnormal striatal 18F-dopa uptake and a fifth subject
showed significant reduction in cortical and striatal glucose metabolism. The relative rarity of familial PSP cases may be due to a failure to recognize atypical cases, other diagnostic problems or death of the carriers before the appearance of clinical symptoms. The use of neurophysiological and/or imaging techniques to detect presymptomatic cases could assist in linkage analysis of potential PSP families, with a view to identifying causative genes. Conversely, families with phenotypically ‘characteristic’ PSP may have been reported where molecular pathology would be indicative of another neurodegenerative condition. Frontotemporal dementiaparkinsonism (FTDP-17), for example, is clearly linked to mutations in the tau gene (see below) and may mimic PSP clinically. 47.8.4. Molecular pathology The human tau gene (MAPT) is located on chromosome 17q21 and contains 16 exons. Six different isoforms of tau are found in the human brain, generated by alternate splicing of exons 2, 3 and 10. These isoforms can be divided into two groups of three, differing in the presence of three or four repeated microtubulebinding domains (three-repeat or four-repeat tau). The isoform is determined by whether the exon 10 coding for one of the four microtubule-binding repeat domains, a 31-amino-acid repeat located in the C-terminal part, is spliced in or out of the final tau protein product. In normal brain, there is a slight preponderance of threerepeat tau, whereas in PSP the ratio is at least 3:1 in favor of four-repeat tau. This isoform ratio contrasts with Alzheimer’s disease, in which the paired helical filaments contain both three- and four-repeat tau, and also with Pick’s disease where three-repeat tau is the major component (van Slegtenhorst et al., 2000). Bodig (PDCG) has tau inclusions with an isoform composition similar to Alzheimer’s disease but very few studies have been reported so far. Tau isoform composition varies markedly within PSP, without a simple relationship between isoform composition and the pattern of insoluble tau before dephosphorylation (Gibb et al., 2004). Some of the clinically ‘atypical PSP’ cases reported by Morris and colleagues (2002a) were also found to have a triplet band, raising the possibility that bodig may not be a disorder restricted to a few geographic isolates. These differences may help the neuropathologist to categorize and distinguish the tauopathies, since electrophoresis reveals two main protein bands of 64 and 68kDa in PSP and CBD, whereas Pick’s disease has two lighter bands of 55 and 64 kDa. Furthermore, PSP and CBD may be distinguishable on immunoblots of sarkosyl-insoluble brain extracts by different patterns of amino-terminally
PROGRESSIVE SUPRANUCLEAR PALSY cleaved tau fragments, with a 33-kDa band predominating in PSP, compared with two closely related bands of approximately 37 kDa in CBD (Arai et al., 2004). The discovery of mutations in MAPT in some families with FTDP-17 confirmed that tau dysfunction can lead to neurodegeneration. In some of these families, the three- to four-repeat tau ratio is similar to that found in PSP. A number of different MAPT mutations have now been found in FTDP-17 families, in and near the 50 splice site, downstream of exon 10 (Hutton, 2000). Through disruption of a stem-loop structure formed in pre-mRNA, 50 splice site mutations increase recognition of exon 10 by U1 snRNP splicing factor, increasing the proportion of exon 10þ mRNA and thus four-repeat tau. Analysis of FTDP-17 families would support this ‘stem-loop hypothesis’ and its pathogenicity, in that mutations with the greatest effect on splicing in vitro cause an earlier age of disease onset. Disruption of the stem-loop structure need not, of course be only genetic in origin and toxic causes could also be involved. There is some evidence from analysis of tau mRNA in affected brain regions in PSP that selective fourrepeat tau deposition in PSP may also involve disruption of exon 10 alternative splicing. Furthermore, there have now been two reported families with a clinical syndrome resembling PSP where mutations in MAPT have been detected (Stanford et al., 2000; Pastor et al., 2001). In the first, Australian kindred, a ‘silent’ mutation (S305S) was identified in the stem-loop structure. Although not producing an amino acid substitution (hence ‘silent’), functional exon-trapping experiments suggested that the mutation caused up to a fivefold increase in splicing of exon 10, resulting in overexpression of four-repeat tau. In the second, Spanish kindred, two brothers born from a third-degree consanguineous marriage were both affected by clinically atypical PSP. Both cases had an age of disease onset below the age of 40, a history of cocaine-abuse asymmetric parkinsonism and reduced saccadic speed, whereas neither had an ophthalmoparesis. In 1 of the 2 cases, a homozygous deletion at codon 296 (delN296) was identified, lying within the sequence corresponding to the second tubulin repeat of tau protein. The clinical phenotype of these siblings closely resembled that described in a familial tauopathy with a N279K mutation, where cases developed parkinsonism, supranuclear gaze paresis and dementia in their fifth decade (Delisle et al., 1999). The nosology of these ‘familial PSP’ mutations remains a matter of debate and at this point it may be better to classify them as familial tauopathies. It is likely that further sporadic cases clinically resembling young-onset PSP will be found to have tau
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mutations. However, a sequence analysis of MAPT exons 9–13 in two small families with PSP and 7 clinically typical and atypical sporadic PSP cases with pathological confirmation of diagnosis has not identified coding or splice site mutations, suggesting that PSP or typical PSP-like syndromes are not due to mutations in MAPT (Morris et al., 2002b). A recent study concluded that screening for MAPT gene mutations in sporadic cases is unlikely to identify pathogenic mutations (Stanford et al., 2004). However, based on association studies, it is possible that pathogenic variation in non-coding regions (e.g. introns and promoter and 30 or 50 UTR) could be involved in influencing expression levels of mRNA. Conrad and colleagues (1997) first reported a polymorphic dinucleotide repeat sequence in intron 9 (between exons 9 and 10) of MAPT in which the A0 allele (TG repeat number of 11) and in particular the A0/A0 genotype were overrepresented in PSP cases compared with controls in the white population. These data were later extended to a haplotype, H1, including several polymorphisms in linkage disequilibrium with A0, spanning MAPT (Baker et al., 1999). During evolution of the two human tau haplotypes, H1 and H2, almost no recombination has occurred between the two alleles. Although the H1 allele has a frequency approaching 100% in pathologically confirmed patients with PSP, it is also found in about 70% of controls. It is not known at the present time whether there is a rarer mutation on the H1 haplotype predisposing to PSP, or whether it is the haplotype itself. The presence of an H1 haplotype or H1/H1 genotype may therefore be regarded as no more than a modest genetic predisposition towards developing PSP. Furthermore, almost all normal Japanese people carry the H1/H1 genotype. The H1 haplotype seems to have no effect upon the tau or amyloid burden in the lentiform nucleus of PSP cases. Furthermore, the H1/H1 genotype does not influence age at disease onset, severity or survival of patients with PSP. Recently, the Saitohin gene (STH) Q7R polymorphism, nested within intron 9 of MAPT, has been shown to be in complete linkage disequilibrium with the extended H1/H2 haplotype (de Silva et al., 2003; Ezquerra et al., 2004). This implicates the Q allele of this non-silent STH polymorphism as a potentially important candidate pathogenic variant in PSP. STH codes for a protein of unknown homologies and function that may play an important role in tau regulation. Further studies using 19 single nucleotide polymorphisms (SNPs) have identified specific subhaplotypes in 17q21 that modify risk for PSP and CBD (Pastor et al., 2004). A subhaplotype, H10 A, was present in 16% of PSP patients but not observed in
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controls, whereas the H2E0 A subhaplotype was rarely present in the disease group, suggesting that it might have a protective role. Again, using SNPs, linkage disequilibrium in the regions flanking MAPT was mapped to establish the maximum extent of the haplotype block on chromosome 17q21.31 as a region covering approximately 2 Mb (Pittman et al., 2004). The entire fully extended H1 haplotype was associated with PSP, implicating several other genes in addition to MAPT as candidate pathogenic loci. Additional intriguing findings are of significant associations between the A0 polymorphism of tau and both PD and CBD and between the extended tau gene haplotype H1 and CBD and clinically defined non-demented PD cases (Houlden et al., 2001; Maraganore et al., 2001). For PD, it has been postulated that the H1 haplotype might interact with a-synuclein, thereby influencing the propensity of a-synuclein to aggregate. This would imply potential pathogenic synergism between ‘synucleinopathies’ and ‘tauopathies’. A study of pathologically confirmed PD cases did not, however, confirm any association with the H1 haplotype (de Silva et al., 2002). However, in the genetically more homogeneous Norwegian population, Farrer and colleagues (2002) showed a significant association of tau with sporadic PD. At present, the association of MAPT with PD therefore remains controversial and requires further study. To date, no linkage has been found between PSP and the candidate genes for PD synuclein, synphilin or parkin, nor the ApoE4 allele, a risk factor for late-onset Alzheimer’s disease. In addition, no association with polymorphisms in the CYP2D6 (which encodes for debrisoquine 4-hydroxylase cytochrome P450), CYP1A1, N-acetyltransferase 2, dopamine transporter and glutathione S-transferase M1 genes has been found for PSP.
walking aids, such as weighted walkers and exercises (Sosner et al., 1993). Severe postural instability, coupled with the inability of the patient to recognize the balance problem because of frontal lobe dysfunction, may mean that a wheelchair is the safest option when falling becomes a frequent occurrence. Expert nursing support and lay associations are invaluable for carers and families. Such support can also provide important advice with regard to future care planning, legal options of power of attorney, trusteeship, advance directives and consideration for brain donation (Rohs, 1996). Table 47.7, modified from a review by Litvan (2001), summarizes palliative treatments that may be considered for PSP. 47.9.2. Neurotransmitter replacement strategies No drug tested to date has had a major symptomatic benefit in PSP. Minor benefits could have been missed, since small trial sizes may have introduced a type II error.
Table 47.7 Palliative treatments for progressive supranuclear palsy (PSP) Feature
Palliative approach
Gait instability Dysphagia
Weighted walkers; physiotherapy Thickeners; dietician, speech and language input; percutaneous endoscopic gastrostomy Speech therapy; communication aids Artificial tears (to avoid exposure keratitis); dark glasses (to reduce photophobia) Prism glasses; talking books
Dysarthria Decreased rate of eye blink
47.9. Management 47.9.1. General considerations A multidisciplinary approach is essential for the management of PSP. Speech and language therapists and dieticians can advise to improve dysphagia and communication difficulties, although severe dysphagia may warrant insertion of a percutaneous gastrostomy feeding system. Mirror prism spectacles can make it possible for patients with severe down-gaze limitation to read and feed themselves. Eyelid crutches, sometimes combined with botulinum toxin therapy, may be useful for apraxia of eyelid opening (Krack and Marion, 1994). Botulinum toxin injections may also be helpful in improving blepharospasm, retrocollis and orofacial dystonia (Polo and Jabbari, 1994; Piccione et al., 1997; Muller et al., 2002). A physiotherapist can advise on
Vertical ophthalmoplegia Blepharospasm and apraxia of eyelid opening Depression Emotional incontinence Drooling Patient and family support
Modified from Litvan (2001).
Eyelid crutches; botulinum toxin
Antidepressants; supportive therapy Tricyclic antidepressants Anticholinergics (topical or oral) – use cautiously Social services; two lay associations: PSP (Europe) Association (http://www.pspeur.org) Society for PSP (http://www.psp.org)
PROGRESSIVE SUPRANUCLEAR PALSY The response to a variety of medications, usually administered in a non-systematic and unblinded fashion and without the use of standardized assessment scales has been documented (Jackson et al., 1983; Jankovic, 1984; Maher and Lees, 1986; Nieforth and Golbe, 1993; Kompoliti et al., 1998; Birdi et al., 2002). 47.9.2.1. Dopaminergic agents Intravenous levodopa fails to elicit the increases in cerebral blood flow in PSP observed in PD (Kobari et al., 1992), whereas PSP patients rarely show a clinically significant response to apomorphine testing (D’Costa et al., 1991; Bonuccelli et al., 1992). Therapeutic trials of levodopa noted benefit in 51% (Jankovic, 1984), 54% (Golbe et al., 1990) and 38% (Nieforth and Golbe, 1993) of patients. In a more recent study, only 4 out of 12 postmortem confirmed PSP cases showed a ‘modest improvement’ whilst receiving levodopa that was not sustained (Kompoliti et al., 1998). Adverse effects occurred in over half of the patients. Birdi and colleagues (2002) reported that in 15 of their postmortem-confirmed patients receiving levodopa either alone or in combination with an anticholinergic, dopamine agonist, selegiline or amantadine, 9 had shown ‘some benefit’. Consistent with the recent observations by Williams and colleagues (2004), none of the 7 cases with supranuclear ophthalmoplegia responded to levodopa, whereas 5 of 8 patients without ophthalmoplegia improved (although the magnitude and duration of the improvement were not documented). Bromocriptine is generally ineffective in doses up to 70 mg/day (Williams et al., 1979). A controlled study of lisuride, a relatively selective dopamine D2receptor agonist, in daily doses of up to 5 mg in 7 patients did not yield any positive results whereas 3 patients developed hallucinations (Neophytides et al., 1982). Pergolide at a daily dose of 4 mg improved parkinsonian and/or pseudobulbar signs in 2 out of 3 PSP patients (Jackson et al., 1983). Pramipexole, a nonergot dopamine agonist with high affinity for the dopamine D3-receptor, failed to show any benefit in 6 PSP patients, in a daily dose of up to 4.5 mg (Weiner et al., 1999). Two patients reported visual hallucinations and 1 a worsening of motor symptoms. Selegiline, a monoamine oxidase type B inhibitor, has not shown any significant therapeutic effect in PSP (Golbe et al., 1990). Amantadine, a drug with multiple actions, including increasing the synthesis, release and reuptake of dopamine, as well as potent N-methyl-D-aspartate antagonist properties, can provide a transient therapeutic benefit in up to 15% of cases (Litvan and Chase, 1992).
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47.9.2.2. Cholinergic agents PSP is characterized by a loss of cholinergic neurons, particularly in the striatum, thalamus, pedunculopontine nucleus and nucleus basalis of Meynert. Cholinergic blockade using scopolamine worsens memory and gait in PSP (Litvan et al., 1994). Cholinomimetic drugs have thus been explored for their therapeutic potential in PSP. Physostigmine, a centrally acting cholinesterase inhibitor, improved long-term memory and visuospatial function in 8 PSP patients in a double-blind, placebo-controlled cross-over study, but no benefits were reported for extraocular, parkinsonian or pseudobulbar features (Litvan et al., 1989; Kertzman et al., 1990). The same drug had no effect upon swallowing or oral motor function in a 10-day cross-over placebo-controlled double-blind trial (Frattali et al., 1999). Direct stimulation of postsynaptic cholinergic receptors with the non-selective M1 and M2 muscarinic agonist, RS-86, did not produce any beneficial effects in motor function, eye movements or cognitive performance in 10 PSP patients in a 9-week doubleblind, placebo-controlled cross-over trial, despite electroencephalographic evidence of enhanced central cholinergic activity upon sleep architecture (Foster et al., 1989). The effects of the cholinesterase inhibitor donepezil upon cognitive function, motor skills and activities of daily living (ADL) were assessed in 6 PSP patients at baseline and after 3 months of treatment. There was no change from baseline in any of the parameters measured (Fabbrini et al., 2001). Litvan used the same dose of donepezil (10 mg) in 21 patients in a doubleblind, placebo-controlled, randomized, cross-over trial (Litvan et al., 2001). There was a modest improvement in one of the memory tests but a significant worsening in motor and ADL scores. 47.9.2.3. Adrenergic agents A placebo-controlled, double-blind, cross-over study of idazoxan in 9 PSP patients showed a significant decrease in the Unified Parkinson’s Disease Rating Scale (UPDRS), corresponding to an improvement in mobility, balance and dexterity (Ghika et al., 1991). In contrast, the potent a2-antagonist efaroxan did not significantly improve motor impairments in 14 PSP patients using a double-blind, placebo-controlled, cross-over study design (Rascol et al., 1998). 47.9.2.4. Other drugs Nortriptyline may be useful for the management of depression in PSP (Tamai and Almeida, 1997). Amitriptyline has been produced with variable results.
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Three of 4 patients showed ‘moderate to definite’ improvement in one study, whereas postural instability worsened in the fourth (Newman, 1985). A retrospective analysis of 28 PSP patients, treated with doses of amitriptyline ranging from 50 to 200 mg, indicated an improvement in gait or dysphagia in 9 patients, but moderate to severe side-effects, particularly anticholinergic-related, occurred in 14. Other case reports have demonstrated moderate improvement in motor scores at low doses (20–80 mg/day), with cognitive and behavioral problems only emerging at higher doses (Engel, 1996). A double-blind, placebo-controlled, cross-over study of the GABAergic drug zolpidem in 10 PSP patients revealed significant improvements in motor function and saccadic eye movements (Daniele et al., 1999). Adverse effects were drowsiness and increased postural instability. A further case report highlighted a non-sustained improvement in gaze palsy and parkinsonism in a patient taking 5 mg zolpidem at night, with benefit lasting 4 weeks (Mayr et al., 2002). Methysergide was associated with clinical improvement in 1 of 3 PSP patients and with deterioration of symptoms in another (Kompoliti et al., 1998). One of 2 patients experienced modest improvement with 5-hydroxytryptophan. Fluoxetine, mianserin and biperiden hydrochloride have all been used in single patients with no observed improvement (Kompoliti et al., 1998). 47.9.3. Non-pharmacological interventions Barclay et al. (1996) reported 5 patients with PSP who each received 9 electroconvulsive therapy (ECT) treatments, over 3 weeks. One patient showed a ‘dramatic improvement’ in mobility, although no long-term data were available, whereas 2 experienced a mild benefit and a further 2 did not change. There were transient side-effects in all patients, including confusion and bulbar dysfunction. An apomorphine challenge carried out pre- and post-ECT did not show any change in motor improvement, suggesting that ECT did not induce dopamine receptor sensitization. ECT may improve severe depression in PSP without beneficial or deleterious effects on motor function (Netzel and Sutor, 2001), although adverse effects of ECT on motor function have also been reported (Hauser and Trehan, 1994). Other non-drug treatments include transcranial alternate current pulsed electromagnetic fields, which apparently reduced the frequency of freezing by 50% and falls by 90% in 1 patient (Sandyk, 1998). Autologous adrenal medullary transplantation into the caudate nucleus of 3 PSP patients had limited efficacy and
was associated with a number of transient postoperative complications (Koller et al., 1989; Ward-Smith and Berry, 1990). A small number of PSP patients have also undergone pallidotomy without significant benefit (Litvan, 2001). 47.9.4. Future directions More radical advances in PSP therapeutics will come from a greater understanding of the pathophysiology of the condition and the development of animal models in which to test new disease-modifying treatments (Golbe, 2000). Regarding the latter, transgenic mice, Drosophila and zebrafish models have biological similarities with a number of tauopathies, including PSP (Lewis et al., 2000; Wittman et al., 2001; Tomasiewicz et al., 2002). One example of the use of such models comes from a report of the inhibition of glycogen synthase 3 kinase (GSK-3b), an enzyme believed to be important in tau phosphorylation, leading to functional improvement in transgenic Drosophila (Mudher et al., 2004). Lithium is an inhibitor of GSK-3b and trials are already planned for Alzheimer’s disease (Mudher et al., 2004), although preliminary studies using human tissue have suggested that GSK-3b levels are unchanged in PSP, compared with age-matched controls (Borghi et al., 2004). Other approaches to disease modification in PSP could involve the manipulation of splicing regulation by RNA stem-loops, with the aim of reducing fourrepeat tau production (Golbe, 2000). This could be achieved, for example, by the use of RNA interference to inhibit the translation of E10þ messenger RNA (Litvan, 2001; Davidson and Paulson, 2004). A number of posttranslational processes may be involved in the aggregation of tau in PSP, but glycation and transglutamination have been principally implicated (see above). Targeted inhibition of TGase might be capable of reducing tau aggregation. The formation of AGE-tau is also associated with the generation of oxygen free radicals and the induction of oxidative stress. Phosphorylation of tau in PSP may be a direct consequence of oxidative stress-induced activation of mitogen-activated protein kinases, including the p38 pathway, thus opening up further therapeutic potential through manipulation of this pathway (Hartzler et al., 2002). Microglial activation is greater in PSP than in control brains and microglial activation correlates with tau burden in most areas. The use of anti-inflammatory agents could therefore be considered, although from trials of these drugs in Alzheimer’s disease and the size of effect, the feasibility of similar studies for PSP must be questionable. Finally, the use of trophic
PROGRESSIVE SUPRANUCLEAR PALSY factors could be a promising therapeutic approach for PSP, although there would be considerable technical issues to overcome (Litvan, 2001).
47.10. Conclusions Despite greater awareness in recent years, many patients with PSP remain undiagnosed or misdiagnosed for much of their disease duration. The role of tau protein in the pathophysiological process, together with the establishment of a modest genetic predisposition has stimulated research. At the same time, studies on a cluster of a PSP-like condition in Guadeloupe have produced new clues for potential environmental toxins. If the fundamental pathophysiological process in PSP turns out to be an overproduction of four-repeat tau, it will be crucial to determine how the function of the RNA stem-loop structure, a key regulator in the alternate splicing process, may be affected by various genetic influences and toxins. As disease-modifying therapies emerge it will be vital to intervene as early in the pathological process as possible. There is therefore a need for a greater awareness of PSP and the development of robust diagnostic clinical and investigational markers that predict whether an individual with suspicious, but not ‘typical classical’ features, will go on to develop PSP. Physicians should consider PSP when rigidity and bradykinesia coexist with early falls. The patient should be examined carefully for slowing of downward saccadic eye movements and the presence of square-wave jerks. The presence of frank vertical ophthalmoparesis is of significant diagnostic help but it should also be borne in mind that this physical sign might take several years to develop in some patients.
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Handbook of Clinical Neurology, Vol. 84 (3rd series) Parkinson’s disease and related disorders, Part II W. C. Koller, E. Melamed, Editors # 2007 Elsevier B. V. All rights reserved
Chapter 48
Corticobasal degeneration NATIVIDAD P. STOVER*, HARRISON C. WALKER AND RAY L. WATTS University of Alabama at Birmingham, Birmingham, AL, USA
48.1. Historical aspects Corticobasal degeneration (CBD) is a neurodegenerative disorder that has gained the interest of clinicians and scientists, especially over the last two decades. The typical clinical presentation of CBD is one of an atypical parkinsonian syndrome with cerebral cortical signs such as apraxia or cortical sensory loss, similar to the 3 cases described originally (Rebeiz et al., 1967). The disorder was initially called corticodentatonigral degeneration with neuronal achromasia, based on the pathological findings in the first cases. Other names used include corticonigral degeneration with neuronal achromasia, corticobasal ganglionic degeneration and myoclonic dystonia. The term ‘corticobasal degeneration’ was initially used in 1989 (Gibb et al., 1989) and more recently the term corticobasal syndrome or complex has also been proposed to characterize better the heterogeneity and overlap of the clinical features and neuropathologic findings in cases of CBD (Kertesz et al., 2000). The observation that the aggregation of tau, a microtubule-associated protein, is involved in the pathology of several neurologic disorders has revolutionized our understanding of CBD and its relationship to other neurodegenerative diseases that are collectively called tauopathies (Litvan, 1999; Goedert et al., 2000; Tolnay and Probst, 2003; Cairns et al., 2004). The identification of mutations in the tau gene on chromosome 17 in familial cases of frontotemporal dementia with parkinsonism (FTDP-17) (Verin et al., 1997) and the overlapping clinical and pathological features of CBD with other tauopathies emphasized the importance of tau proteins in this group of disorders: Pick’s disease, primary progressive aphasia (PPA), progressive supranuclear palsy (PSP) (Steele
et al., 1964; Litvan et al., 1996), amyotrophic lateral sclerosis–parkinsonism–dementia complex and argyrophilic grain disease (AGD) (Tolnay and Clavaguera, 2004). In parallel, it has been discovered that abnormalities of the vesicle-associated protein a-synuclein underlie the pathology of Parkinson’s disease (PD), Lewy body dementia (LBD) and multiple system atrophy (MSA) (Wenning et al., 1994) and thus they comprise the synucleinopathies (Dickson, 1999b; Arai et al., 2001b). Cases of CBD have clinical features that also overlap with the synucleinopathies. It is still debated whether CBD is a distinctive nosological entity or a syndrome. Currently, we recognize two clinical phenotypes of CBD: the first is a classic motor presentation with asymmetric parkinsonian symptoms and apraxia and/or cortical sensory loss and the second is a presentation of dementia often with focal cortical signs with or without parkinsonian features (Hachinski, 1997; Kertesz and Munoz, 2004).
48.2. Description of the initial cases James Parkinson described PD in 1817 and Jean-Martin Charcot and his disciples drew emphasis to the cardinal features of the disease in the last years of the 19th century. They also described a number of parkinsonian variants with atypical jerking movements and abnormal posture in the limbs, described originally as ‘hemiplegic parkinsonism’ (Charcot and Vulpian, 1861–1862; Charcot, 1887–1888). It is possible that some of these patients had CBD. In 1925 J. Lhermitte described a clinical case suggestive of CBD to the French Neurological Society: ‘A carpenter retired at age 67 because of progressive right hand clumsiness. At age 72, he could no longer walk independently and ambulated with a wide-based,
* Correspondence to: Natividad P. Stover, Department of Neurology, University of Alabama at Birmingham, 360 Sparks Center, 1720 7th Avenue South, Birmingham, AL 35294-0017, USA. E-mail:
[email protected], Tel: þ1-205-934-0683, Fax: þ1-205-996-4039.
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shuffling gait with the right arm ‘flexed.’ In addition, his right arm moved involuntarily ‘like a foreign body.’ In spite of normal primary sensation, he could not recognize objects placed in his right hand’ (Ballan and Tison, 1997). The initial three cases described by Rebeiz et al. at the Massachusetts General Hospital (1967, 1968) presented a unique pattern of progressive neurological disorder with motor impairment, affecting mainly the left side of the body and characterized by stiffness, slowness, clumsiness, numbness or ‘deadness’ and awkward movements of the left arm and leg as initial symptoms. In 2 patients the leg was affected first with progressive gait impairment. As the disease progressed, involuntary movements became prominent with elevation and abduction of the limbs that came on during attempted motor activity and when the affected arm was being used the opposite limb exhibited involuntary synkinesias. Each of the 3 cases had some tremor, even if it was not the prominent feature. There was progressive impairment in the use of affected limbs without motor weakness except late in the course of the disease. In 1 case, there was impaired position sense, tactile localization, two-point discrimination and ability to recognize objects by touch and another patient had impaired position sense. In all cases there were increased tendon reflexes and increased resistance to passive movements of the affected limbs and severe finger contractures. With time the 3 patients developed impairment of speech and dysphagia. Cognitive dysfunction was not a remarkable feature in the clinical picture until later in the disease. The symptoms in the 3 patients started in late middle age and they died 6–8 years after diagnosis. Radiographic contrast studies showed cerebral atrophy in the 3 patients, more pronounced on the right than on the left. None of the patients had seizures or myoclonus. Electroencephalograms (EEG) showed slow- and sharp-wave activity without specific changes. The rest of the laboratory investigations were normal. Postmortem examination of the brains revealed asymmetric frontoparietal cortical atrophy. On microscopic examination the most severe changes were in the superomedial frontoparietal and Rolandic regions with severe neuronal loss and disappearance of the cells in the outer three cortical layers with astrocytic gliosis and little microglial activation. Many neurons in the deep cortical layers showed swelling of the cell bodies frequently accompanied by vacuolization. The swollen neurons often had eccentric nuclei without Nissl substance in the cytoplasm that prompted the terms ‘achromatic’ and ‘ballooned’ as descriptors and these histological abnormalities colocalized with the distribution of the neuronal loss. The white-matter
regions corresponding with areas of cortical atrophy showed considerable demyelination and fibrous gliosis. The hippocampus, inferior and medial temporal cortex and occipital regions were spared in the original cases. Considerable loss of pigmented neurons in the substantia nigra (SN) was observed in 2 of the cases and was less marked in the third, mainly in the lateral two-thirds. The subthalamic nucleus contained a few swollen neurons and gliosis and in 2 of the cases there was significant loss and swelling of nerve cells in the central nuclei of the cerebellum with retrogade atrophy of the superior cerebellar peduncles, as well as gliosis of the red nuclei and the ventrolateral portion of the thalamus. Those 2 cases also showed degeneration of the corticospinal tracts in the brainstem and spinal cord, most likely secondary to neuronal loss in the cerebral cortex. The characteristic pathological findings seen in other neurodegenerative diseases, such as Lewy bodies, Pick bodies and amyloid plaques, were not observed in the initial cases. A case described initially as myoclonic dystonia was reported by Obeso et al. in 1983; the patient was followed until death and the pathology was characteristic for CBD. This patient had clinical features resembling PSP but pathological findings similar to Pick’s disease. The patient had focal dystonia and myoclonus of an arm, alien-hand phenomenon and an akinetic-rigid syndrome and he developed supranuclear gaze palsy, parkinsonism and mild cerebellar signs. The pathology showed frontoparietal atrophy with cortical cell loss, Pick’s disease cells with gliosis in the basal ganglia, midbrain tegmentun, SN and locus ceruleus. The pathological examination also showed inclusions in the SN that were called corticobasal inclusions, similar to the globose neurofibrillary tangles (NFT) of PSP. Some of the nigral inclusions were similar to those seen in Pick’s disease (Obeso et al., 1985). Watts et al. (1985) described a case with pathologic correlation of CBD. The patient presented with stiffness of the right arm and leg followed by progression of the symptoms to the left side. There was a rapid, irregular action tremor and impairment of balance that progressed to inability to walk without assistance. During the third year of disease, he developed dysarthria and poor semantic content in his language. He had hypomimia, blepharospasm and saccadic breakdown of smooth pursuit eye movements. The right arm and leg had severely increased tone and dystonic posturing of the fingers. The patient lost the ability to perform motor tasks previously learned like using a toothbrush and saluting with the right arm. Fasciculations were seen in several muscle groups of the upper and lower limbs. There was no family history of
CORTICOBASAL DEGENERATION neurologic disease. Electrophysiologic and laboratory evaluations were normal. Imaging studies showed peri-Rolandic cortical atrophy and signal attenuation of the white matter beneath the left central sulcus. Neuropathological examination revealed asymmetrical cerebral cortical atrophy, worse on the left with neuronal loss and reactive gliosis in all layers of the premotor, anterior cingulate, inferior parietal, insula and anterior temporal regions. White-matter changes consisted of extensive loss of myelinated axons and gliosis. Occasional neuritic plaques were noted, but there were no NFT. In areas not so severely affected there were swollen neurons with achromasia. There was neuronal loss in the SN bilaterally, but no Lewy bodies were seen. No abnormalities were observed in the striatum, globus pallidus, substantia innominata, amygdala, hypothalamus, cerebellum, brainstem or spinal cord. The peripheral nerves showed demyelination and there were denervation changes in skeletal muscles. Therapeutic trials with multiple agents were ineffective. Several other authors have contributed clinical and pathological descriptions of cases consistent with CBD and the use of modern laboratory techniques in recent years has helped to characterize the disease and its relationship with the other neurodegenerative disorders better. In recent years a number of patients with atypical parkinsonian syndromes and a predominance of dementia have turned out to have the classical pathologic picture of CBD (Grimes et al., 1999; Graham et al., 2003a; Kurz, 2005). There are also reports of cases presenting with clinical features of CBD that lack specific pathological features (Lerner et al., 1992; Maraganore et al., 1992; Giannakopoulos et al., 1995; Brown et al., 1998).
48.3. Epidemiology Epidemiologic studies in CBD are difficult because of clinical diagnostic uncertainties and the lack of a biological marker. The incidence and prevalence of CBD increase if the different clinical and pathological phenotypes are considered as part of a syndrome or complex. The incidence of non-Alzheimer and nonvascular dementia cases is around 10% in cases from brain banks (DLB, Pick’s disease and FTDP-17) and this percentage may increase to 20% if CBD and PSP are included (Tanner, 1996). The age of onset of CBD is usually in later adult life with a mean onset of symptoms at 63 (7.7) years. The youngest case with pathological confirmation was 34 years old. Some authors have suggested a predominance in women but both sexes are affected. There is no clear ethnic preponderance and most of the
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described cases are Caucasian. Most of the patients reported have been sporadic, but some studies do suggest a familial tendency. One of the original cases described had a history of similar neurologic disorders in several family members, possibly representing a case of FTDP-17. There is no evidence at present that any CBD cases are related to a toxic exposure or to an infectious agent (Di Maria et al., 2000; DePold Hohler et al., 2003).
48.4. Diagnosis There have been several attempts to establish diagnostic criteria for CBD, but a formal validation has not been performed. Most of the cases diagnosed with CBD in movement disorder clinics focus primarily on motor symptoms. Signs of cortical impairment such as apraxia or cortical sensory loss usually develop within 1–3 years of onset, but in some series dementia was the most frequent initial symptom in patients with pathologically confirmed CBD (Bergeron et al., 1998; Litvan et al., 2003). Riley and Lang (1993) proposed a set of clinical characteristics of CBD based on the review of 12 cases, 9 with pathological confirmation of CBD. The clinical manifestations were divided as related to basal ganglia dysfunction (bradykinesia/akinesia, rigidity, dystonia, postural instability, falls, athetosis and orolingual dyskinesias), cerebral cortical signs (cortical sensory loss, apraxia, alien-limb phenomenon, dementia, frontal-release signs and dysphasia) and other manifestations (postural/action tremor, hyperreflexia, impaired ocular motility, dysarthria, focal reflex myoclonus, impaired eyelid motion and dysphagia). The authors proposed inclusion and exclusion features for the diagnosis of CBD to establish research criteria. The inclusion criteria were defined as the presence of rigidity plus one cortical sign (apraxia, cortical sensory loss or alien limb) or asymmetric rigidity, dystonia and focal reflex myoclonus. Other authors (Kumar et al., 1998) also included as inclusion criteria an asymmetric, progressive course, presence of higher cortical dysfunction and a movement disorder consisting of an akinetic-rigid syndrome, levodopa resistance, prominent limb dystonia and reflex or focal myoclonus. Exclusion criteria were defined as early dementia, early vertical gaze palsy, rest tremor, severe autonomic dysfunction, sustained responsiveness to levodopa and lesions or imaging studies suggesting a different diagnosis. Watts et al. (1994) proposed major and minor criteria to be used in the clinical diagnosis of CBD. The major criteria were defined as akinesia, rigidity, postural/gait disturbance, action/postural tremor,
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alien-limb phenomenon, dystonia, myoclonus and cortical signs. Minor criteria were described as choreoathetosis, dementia, cerebellar signs, supranuclear gaze abnormalities, frontal-release signs and blepharospasm. A strong degree of asymmetry was also necessary for the diagnosis of CBD. Another study presented the description of 105 patients with different neurodegenerative diseases and known pathologic correlation to a group of movement disorders specialists, to investigate the accuracy of the clinical diagnosis of CBD. The study evaluated 10 autopsy-proven cases of CBD from a movement disorder center and found that specificity of the diagnosis of CBD cases using the clinical features was high but the sensitivity was low, particularly in the first 3 years of the disease. This finding suggests that CBD is most likely underdiagnosed. In this study, the best initial clinical predictors for the diagnosis of CBD included limb dystonia, asymmetric parkinsonism, apraxia and absence of balance or gait disturbances. There were some cases with pathology consistent with PSP that had limb dystonia as the predominant presenting sign and most of the cases with an initial gait disorder actually had pathology indicative of PSP. Other clinical motor features commonly seen in CBD are alien-limb phenomenon, choreoathetoid movements, blepharospasm, eye movement abnormalities, myoclonus and speech and swallowing problems. This study also mentioned cognitive and neuropsychiatric symptoms among the frequent manifestations (Litvan et al., 1997). The statistical analyses in the study with 24 patients pathologically diagnosed with PSP and 27 cases with CBD identified two predictor models for CBD patients. Patients with CBD presented with lateralized motor and cognitive signs, whereas PSP patients often had severe postural instability at onset, symmetric parkinsonism, vertical supranuclear gaze palsy and speech problems and CBD patients with a non-motor phenotype had early frontal dementia and eventually bilateral parkinsonism (Litvan et al., 1999). Rinne et al. (1994) reported that the most common motor presentation in a series of 36 patients with pathologically proven or clinically probable diagnosis of CBD was a useless arm due to any combination of rigidity, akinesia, dystonia, apraxia or alien-limb phenomena, with or without myoclonus. Of those patients, 20 presented with symptoms beginning in the upper extremities and 10 in the lower extremities. Other less common presentations of CBD include combined arm and leg involvement with motor dysfunction, unilateral painful paresthesias and orofacial dyskinesias. The gradual extension of the symptoms to the contralateral limbs, facial hypomimia, dysphagia,
dysarthria and postural instability often develop over the ensuing years (Wenning et al., 1998). 48.4.1. Motor symptoms The so-called ‘typical’ cases of motor presentation in CBD consist of limb clumsiness or difficulty using the limb, with or without rigidity and difficulty coordinating small, precise movements. An asymmetric, insidiously progressive parkinsonism, usually of the bradykinetic or akinetic-rigid type, with or without tremor, is typical (Schneider et al., 1997). The symptoms respond poorly to levodopa treatment, although onethird of patients may have some initial response, making the diagnosis challenging before other signs and symptoms appear. Akinesia, rigidity and apraxia are the most common motor findings during the course of the disease, occurring in over 90% of motor cases within the first 3 years of illness. Postural instability, gait disorder and speech disorder early in the course of CBD are also frequent clinical features (Lang et al., 1994a). Rigidity in one arm is probably the most common parkinsonian feature documented in motor CBD cases and this symptom alone can be severe and very debilitating (Lang, 2000). There are also cases reported with symptoms affecting the lower limbs initially (Lalive et al., 2000). The tremor in CBD differs from the typical resting or postural tremor seen in PD. It is a faster (6 – 8 Hz) tremor with action and postural components and it has a more irregular, jerky quality. Myoclonic movements are most frequently reported in the upper extremities and they are usually superimposed on the tremor. Myoclonus develops in approximately half of patients with CBD during the course of the illness (Chen et al., 1992; Thompson et al., 1994). Myoclonus may be preceded by a jerky tremor and it manifests itself in the most affected limb early in the disease. Myoclonus is most evident in distal muscles and it may coexist with dystonia in the most affected limbs as well (Brunt et al., 1995; Mima et al., 1998). The myoclonus in CBD is best seen during action or maintenance of a posture; however, it can also be elicited by other stimuli, including cutaneous or auditory stimuli. The myoclonus may be masked by the presence of increased muscle tone (Thompson and Shibasaki, 2000; Lleo et al., 2002; Caviness, 2003). Electrophysiologic studies show that the myoclonus is mainly an action or reflex myoclonus, preceded by a short-duration muscle discharge with simultaneous activation of antagonistic muscles (Carella et al., 1991, 1997). Brief trains of high-frequency myoclonic discharges happen in clusters of 2–3 Hz and in action
CORTICOBASAL DEGENERATION myoclonus this activity occurs throughout the period of voluntary muscle activation and in a pattern consistent with corticospinal activation. The intracortical component of the long latency in reflex myoclonus in CBD is shorter than the intracortical processing of sensory input in typical cortical reflex myoclonus. Cortical hyperexcitability was demonstrated in some cases of CBD with myoclonus, consistent with impaired cortical inhibitory systems. Although myoclonus is commonly seen in CBD, it is also described in later stages of Alzheimer’s disease and in Creutzfeldt–Jakob disease (CJD), MSA, Huntington’s disease and cerebellar degeneration (Shibasaki, 1995; Thompson, 1995). Dystonia is frequently observed in patients with CBD and it has not been possible to differentiate historically the onset of dystonia from the onset of other features of CBD (Vanek and Jankovic, 2000). Dystonia was described in the initial cases and other studies reported the presence of dystonia in 40–70% of cases (with pathologic confirmation of CBD in a small number of these cases). Initial presentation with dystonia in one arm has been reported in a majority of motor cases of CBD. The dystonia is usually asymmetric and the arm is the most frequently affected region. Usually the hand and forearm are flexed and the arm is adducted at the shoulder area. The fingers are typically flexed at the metacarpophalangeal joints, extended or flexed at the proximal and distal interphalangeal joints and show variable degrees of fixed postures with or without associated contractures. Head, neck, leg, knee, foot (mainly inversion), trunk and toe (flexed or extended) dystonia are less frequently observed (Oide et al., 2002). Some patients have thumb, index and middle fingers extended and fourth and fifth fingers flexed. Axial dystonia (head, neck, trunk) is less frequent and may include retrocollis, anterocollis or torticollis (Vanek and Jankovic, 2001). Oromandibular dystonia, orofacial dyskinesias and blepharospasm have been reported. Pain accompanying dystonia is described in over 40% of cases; it can be very intense and is usually associated with contractures (Stover and Watts, 2001). Rigidity and bradykinesia are more evident in the dystonic limbs. Spontaneous onset of choreoathetoid movements in patients with and without dystonia involving the limbs and facial muscles may be present, usually associated with the dystonic extremity (Riley and Lang, 2000). Eye movement abnormalities in CBD are distinctive from other movement disorders frequently misdiagnosed as CBD, such as PSP, and ocular findings may therefore help to improve diagnostic accuracy in the early stages of the disease (Pierrot-Deseilligny et al., 1989; Pierrot-Deseilligny, 1994; Vidailhet et al., 1994). In patients with CBD there is a significantly
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increased latency of horizontal saccades bilaterally compared with controls and patients with PSP. Vertical saccades may be slightly impaired in patients with CBD compared with PSP patients (except for upgaze in elderly patients) (Rottach et al., 1996). In early stages of CBD smooth pursuit may be slow and exhibit saccadic breakdown, but the range of movements is generally full (Hamilton, 2000; Rivaud-Pechoux et al., 2000; Vidailhet and Rivaud-Pechoux, 2000). As the illness progresses, patients with CBD gradually lose the ability to initiate rapid saccades in response to verbal commands; however, they retain both spontaneous saccades and optokinetic nystagmus. Asymmetry of saccade latency is also a helpful and persistent abnormality characteristic of CBD cases. Consecutive evaluation of eye movements separated by several months may therefore help to differentiate among CBD, PSP and other atypical parkinsonian syndromes. Visuospatial dysfunction has been described as the presenting symptom in CBD (Tang-Wai et al., 2003). Upper motor neuron syndromes and corticospinal signs may be present in CBD patients and were described in the early cases by several authors. Speech problems and dysphagia are frequently reported in patients with CBD, especially in later phases of the disease as cortical and subcortical pathways become involved (Frattali and Sonies, 2000). Motor speech problems can range from monotonous voice, dysphonia, echolalia or pallilalia to dysarthria or even anarthria (Lang, 1992). Dysphagia usually appears at later stages of the disease (Muller et al., 2001). 48.4.2. Cortical symptoms The most frequent cortical symptoms are apraxia, cortical sensory abnormalities, aphasia, alien-limb phenomenon and frontal-release reflexes. Apraxia is considered to be a hallmark of CBD early in the disease and raises the possibility of a diagnosis if seen as part of the motor presentation. Different types of apraxia can be seen in patients with CBD depending not only on the area of cortex affected initially but also on the timeframe of disease progression in which the apraxia is evaluated (Jacobs et al., 1994; Okuda and Tachibana, 1994; Soliveri et al., 2003, 2005; Zadikoff and Lang, 2005). Ideomotor apraxia has been the most frequent form of apraxia in patients with CBD in several studies. Ideomotor apraxia is manifested by impairment of timing, sequencing, spatial organization and mimicking of movements. Patients with ideomotor apraxia commit mainly temporal (irregular speed and sequencing) and spatial errors (abnormal amplitude, orientation of objects and movements and abnormal use of body
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parts as objects). Ideomotor apraxia is associated with damage to the parietal association areas, premotor cortex and interhemispheric white-matter bundles that connect them, as well as basal ganglia and thalamus (Jacobs et al., 1999; Leiguarda et al., 2000). Patients with CBD may also demonstrate ideational and ‘limb kinetic’ apraxia (Otsuki et al., 1997; Okuma et al., 2000). Fingers and hand movements are more commonly affected and the movements are awkward, amorphous and contaminated with movements unnecessary to perform a task. This form of apraxia is mainly seen with lesions of the premotor cortex with or without associated parietal cortex or basal ganglia involvement. Ideomotor and limb kinetic apraxia may coexist in the same patient. Limb kinetic apraxia is most frequently described in patients with mild dystonia or rigidity (Merians et al., 1999; Ishiwata et al., 2000; Leiguarda et al., 2003; Salter et al., 2004). Ideational apraxia is a dysfunction of the praxis conceptual system. It is an inability to sequence correctly different movements needed to perform a specific task (Poeck, 1983). The performance in ideational apraxia is abnormal in the content and tool selection (including perseverations and pantomime-related errors) and it may be observed in later stages of the disease or in patients with dementia and language dysfunction at presentation (De Renzi and Lucchelli, 1988). In limb kinetic apraxia the manipulative behavior is affected by a decrease in dexterity and fine movements in the affected limb (Peigneux et al., 2001). More advanced cases of CBD make it more difficult to appreciate apraxia due to the severe bradykinesia, rigidity and dystonia in the same limb (Caselli et al., 1999). Speech apraxia was described in 2 patients (1 with pathological confirmation of CBD) as a presenting sign in the evolution of the classical clinical motor syndrome (Rosenfield et al., 1991). Orofacial apraxia with dysarthria has been reported in CBD patients (Ozsancak et al., 2000). Apraxia has been described in PSP cases as well (Pharr et al., 2001; Denes, 2002). Language disorders are frequently seen during the course of CBD (Frattali et al., 2000; Graham et al., 2003b) and most of the cases initially diagnosed with PPA were shown to have pathological changes consistent with FTDP-17 and CBD/PSP in the pathologic evaluation (Black, 2000). Involuntary synkinesias of the less affected limb are seen in CBD patients when they attempt complex movements with the more affected, contralateral limb. Abnormalities of two-point discrimination and somatosensory extinction to double simultaneous stimulation may be present several years before apraxia and other cortical symptoms become evident. In this
way, a focal sensory complaint in the setting of atypical parkinsonism should raise the question of CBD. The alien-limb phenomenon is a failure to recognize ownership of an extremity in the absence of visual cues, accompanied by observable involuntary motor activity. It is associated with autonomous activity of the affected extremity, which may be perceived by the subject as outside his or her control (Goldberg and Bloom, 1990; Fisher, 2000). Up to half of patients with CBD may develop the alien-limb phenomenon, often with coexisting dystonia (Banks et al., 1989; Ball et al., 1993), myoclonus, apraxia, athetosis, pseudoathetosis and signs of cortical sensory loss dysfunction such as sensory neglect, astereognosis and agraphesthesia (Doody and Jankovic, 1992). If the dystonia or rigidity is severe enough to cause contractures, these autonomous movements may be limited. Most patients exhibit intermanual conflict, mirror movements and difficulties with bimanual coordination with compulsive synkinesias in the opposite limb. Posturing and levitation are associated with alien-limb phenomenon in CBD more commonly than in other etiologies. Olfaction is not affected in CBD (Wenning et al., 1995; Muller et al., 2002a; Hawkes, 2003). Eventually, many patients exhibit signs of corticospinal dysfunction, with extensor plantar responses and hyperreflexia. The differentiation of spasticity from rigidity in these patients is clinically very difficult, but the loss of voluntary movement is almost certainly related in part to degeneration of primary and secondary cortical motor regions that contribute to the corticospinal tracts. In fairly advanced stages of CBD, frontal-release signs (grasp, glabellar and exaggerated facial and palmomental reflexes) may become prominent. Urinary symptoms, mainly consisting of decreased bladder capacity and detrusor overactivity, are frequently seen in patients with CBD, especially in more advanced stages (Sakakibara et al., 2004). 48.4.3. Cognitive and neuropsychiatric symptoms Although many of the early CBD case reports described little cognitive dysfunction, it is now accepted that this may be the presenting and predominant feature in many patients. Patients with CBD frequently show abnormal cognitive and neuropsychological profiles in association with motor and praxis disorders. A spectrum of different degrees of intellectual, memory and language impairment may develop (Cummings et al., 1994). Storage and recall information and temporospatial orientation are usually preserved in early stages of CBD where motor symptoms predominate (Pillon
CORTICOBASAL DEGENERATION et al., 1995; Levy et al., 1996). In one study with 11 cases of neuropathologically confirmed CBD, all patients eventually developed cognitive deficits; the onset, nature and severity of the impairment, however, varied widely. Cognitive disturbances preceded or accompanied the onset of the movement disorder in 4 patients; an additional 3 patients developed memory loss, progressing to more global dementia within 2–3 years prior to the onset of motor symptoms. Another patient displayed mild early memory impairment and, in 3 individuals, dementia was a late feature (Litvan et al., 1998). The memory disorders in CBD patients without significant pathology in the temporal lobes and hippocampus may be related to disruption of subcorticofrontal circuits. This may explain the dysexecutive syndrome with abnormalities of dynamic motor control and execution similar to those described in other neurodegenerative diseases related to CBD, most notably PSP (Bak et al., 2005). Those patients also have difficulties with motor programming, manifested by deficits in temporal organization, bimanual coordination and inhibition of interfering motor activities, word fluency and switching between different task sets and activities (Cummings and Litvan, 2000; Green, 2000; Pillon and Dubois, 2000). Those changes contrast with the findings in Alzheimer’s disease, characterized by a true amnesic syndrome and linguistic disorders. CBD patients perform worse on unimanual and bimanual dexterity compared with PSP patients. Verbal fluency and evocation of verbal series are also impaired in CBD patients and there is a tendency to lower scores in patients with initial right-sided symptoms (Monza et al., 2003). The neuropsychological features most frequently described in patients with CBD include depression, apathy, irritability, anxiety, disinhibition, agitation, disorders of sleep and high incidence of somatic pain. It has been demonstrated that CBD patients with left-sided symptoms (as a result of right hemisphere involvement) manifested greater disinhibition, apathy, irritability and lower depression scores than patients with predominantly right-sided symptoms (Moretti et al., 2005). Manifestations of obsessive-compulsive disorder, including recurrent thoughts, repetitive acts, indecisiveness, checking behaviors and preoccupation with perfectionism, are also included in the neuropsychological profile and they are described in both motor and cognitive presentations of CBD. Contrasting the neuropsychiatric findings in CBD with those found in other neurodegenerative disorders is helpful in establishing a differential diagnosis. Compared with Alzheimer’s disease patients, CBD patients have less apathy, agitation, anxiety and delusions. Patients with FTDP-17 usually manifest more disinhibition and euphoria. CBD patients manifest similar
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Table 48.1 Clinical manifestations of corticobasal degeneration Motor signs and symptoms Rigidity Bradykinesia/akinesia Dystonia (focal limb and blepharospasm) Tremor: postural and action tremor Gait disorders/postural instability Dysarthria Dysphagia Myoclonus Choreoathetosis Orofacial dyskinesias Hyperreflexia Impaired ocular movements Impaired eyelid motion Involuntary synkinesias Cortical signs and symptoms Apraxia Cortical sensory loss: abnormalities of two-point discrimination, somatosensory extinction to double simultaneous stimulation, astereognosis, agraphesthesia Alien-limb phenomenon Dysphasia/aphasia Frontal-release signs: grasp, glabellar, palmomental reflexes Cognitive and neuropsychiatric signs and symptoms Dementia Apathy Depression Irritability/agitation Disinhibition Illusions Delusions Obsessive-compulsive behavior Sleep disorders Somatic pain
rates of depression to PD but lower rates of anxiety (Hargrave and Rafal, 1998). LBD has a high rate of visual hallucinations, a phenomenon not described in pathologically confirmed CBD cases. Rapid-eye movement (REM) sleep behavior disorder has been associated with the synucleinopathies (Kimura et al., 1997; Boeve et al., 2001), but it has also been reported in patients with CBD (Wetter et al., 2002). Unilateral periodic limb movements of sleep have been seen in CBD as well (Iriarte et al., 2001) (Table 48.1).
48.5. Pathology CBD as a distinctive pathological condition may have several clinical presentations: on the other hand, a variety of pathologies can cause the classical syndrome that
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was initially thought to be specific to the pathology of CBD. This may be better understood if the different pathological findings are considered as part of a broader syndrome. Bearing this in mind, we can describe the typical pathological hallmarks of the CBD syndrome. In addition to the morphologic examination, immunohistochemical stains and biochemical and genetic analyses are directed to identify tau pathology and to rule out other neurodegenerative processes (Feany et al., 1996; Litvan, 1997; Mirra and Hyman, 2002). 48.5.1. Macroscopic findings Asymmetric atrophy of the frontoparietal cortex is the finding most consistently seen in typical cases of CBD. Atrophy is usually more evident in the superior peri-Rolandic frontal gyrus, the pre- and postcentral parasagittal gyri and the superior part of the parietal lobe. The asymmetry of the atrophy usually correlates with the laterality of the clinical manifestations. However, cases have been described with asymmetric symptoms and the pathological exam showed no significant asymmetry with bilateral atrophy of the precentral gyrus and other cortical regions variably affected. This lack of asymmetry is usually seen late in patients with severe symptoms. Cortical atrophy may be more generalized and include the inferior frontal and temporal lobes in cases that mainly present with cognitive problems and/or PPA. The occipital lobe, hippocampus and parahippocampal gyrus are usually spared. Of note, asymmetric parietal lobe atrophy has been described in cases with pathology consistent with Alzheimer’s disease (Kaida et al., 1998). As a consequence of the cortical atrophy, the ventricles and cerebral aqueduct may be enlarged. If the atrophy is significant, changes in the white matter may be seen as well. The corpus callosum may be atrophic (Yamauchi et al., 1998) and the anterior limb of the internal capsule, corticospinal fascicles within the base of the pons and the medullary pyramids may show attenuation, in part related to retrograde cortical atrophy. Other white-matter pathways, such as the optic tract, anterior commissure and fornix, are usually unaffected in the gross evaluation of CBD patients. Involvement of subcortical gray matter varies widely from case to case, but it is usually less severe and variable than the cortical atrophy. The head of the caudate nucleus may have a flattened appearance and the thalamus in CBD cases tends to be smaller than normal. Transverse sections of the brainstem show severe loss of neuromelanin pigment in the SN; however, neuromelanin within the locus ceruleus is usually preserved. Marked atrophy of the pons,
inferior olivary nuclei and cerebellar dentate nucleus suggests an alternative diagnosis such as MSA. 48.5.2. Microscopic and biochemical findings The microscopic examination of cortical sections stained with hematoxylin and eosin shows neuronal loss and gliosis associated with vacuolar or spongiform change of the upper cortical layers. The characteristic cortical finding in CBD is the ballooned neuron (BN), achromatic cells with swollen perikarya and eccentrically displaced nuclei without Nissl substance. These neurons have a pale and ballooned appearance (Mackenzie and Hudson, 1995) and they can be seen in other tauopathies (Mori et al., 1996), Alzheimer’s disease (Fujino et al., 2004), CJD (Nakazato et al., 1990) and amyotrophic lateral sclerosis. The presence of BN in the peri-Rolandic region, however, is characteristic of CBD. Immunocytochemical staining of the BN is positive for phosphorylated neurofilament proteins, a-ßcrystallin and sometimes ubiquitin (Castellani et al., 1995; Halliday et al., 1995). Notably, tau and a-synuclein immunoreactivity are negative in BN (Fig. 48.1).
Fig. 48.1. A hematoxylin and eosin-stained section of frontal cortex from the brain of a patient with corticobasal degeneration shows a large “ballooned” neuron (large arrow) and another neuron with a cytoplasmic inclusion body (small arrow). Courtesy of Dr. K.A. Roth, UAB Division of Neuropathology.
CORTICOBASAL DEGENERATION Astrocytic plaques carry significant diagnostic value and are considered the most specific histopathologic features in CBD by some authors (Ishizawa and Dickson, 2001). They are mainly located in the neocortex, appearing as an annular cluster of short processes that resemble the neuritic plaque of Alzheimer’s disease; however, these astrocytic plaques do not contain amyloid. Tau positivity in these lesions is derived from astrocytes as demonstrated by double immunostaining for tau and the astrocytic marker glial fibrillary acidic protein. Other less characteristic tau-immunoareactive astrocytic lesions are described in CBD, including thorn-shaped astrocytes, which are found in all tauopathies (Armstrong et al., 2001; Dickson, 2003). Glial threads, which indicate dystrophic axonal and glial processes in the gray and white matter, are described in CBD (Komori et al., 1997; Richter-Landsberg and Bauer, 2004). Neuritic threads are less common than in Alzheimer’s disease. A key feature that distinguishes CBD from Alzheimer’s disease is the lack of both neuritic plaques and diffuse plaques in silver-stained material. Conversely, Alzheimer’s disease does not exhibit the tau-positive glial inclusions observed in CBD (Ikeda et al. 1994; Horoupian and Wasserstein, 1999). Silver stain preparations typically show the presence of NFT in affected areas. The tangles vary in configuration from delicate thread-like structures to compact globoid morphologies. The typical flameshaped appearance of NFT seen in Alzheimer’s disease is less frequent in CBD (Ikeda et al., 1995; Dickson et al., 1996; Dickson and Litvan, 2003). The ultrastructure of tangles in CBD consists of paired helical filaments or ‘twisted filaments’ with a wider diameter and longer periodicity than the filaments present in Alzheimer’s disease. The tangles in PSP are more uniform, compact and globoid in shape and they consist of straight filaments at the ultrastructural level (Collins et al., 1995; Dickson, 1999a). Cell loss in the SN is usually severe with extraneuronal neuromelanin in phagocytes (melanophagia) and residual neurons typically contain NFT. Lewy bodies are not seen in CBD. The locus ceruleus, raphe nuclei, tegmental gray matter, the subthalamic nuclei and the ventrolateral nucleus of the thalamus may also contain NFT. The cerebellar dentate nucleus, inferior olivary nuclei, red nucleus, oculomotor complex and colliculi are relatively spared but may show a variable degree of neuronal loss and gliosis. The cerebellar cortex may also show focal Purkinje cell axonal torpedoes and Bergmann gliosis (Su et al., 2000; Piao et al., 2002). Apolipoprotein E epsilon 4 (APOE4) is a risk factor for Alzheimer’s disease pathology in all neurodegen-
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erative disorders, including synucleinopathies and tauopathies; however, Alzheimer’s disease-type pathologic features are more likely to coexist with synucleinopathies (Ingelson et al., 2001; Josephs et al., 2004b). Cholinergic neuronal loss has been described in patients with CBD and PSP pathological findings (Kasashima and Oda, 2003). Spinal cord involvement with the presence of neuropil threads and neuronal inclusions has been described in CBD (Iwasaki et al., 2005) and PSP patients as well (Kikuchi et al., 1999). 48.5.3. Tau pathology Tau is a structural microtubule-associated phosphoprotein that stabilizes microtubules and promotes tubulin polymerization, playing an important role in maintaining neuronal integrity and axoplasmic transport (Mirra et al., 1999; Forman et al., 2000). Tau undergoes selective phosphorylation that determines its functional state (Hanger et al., 2002). Normal tau is soluble and heat-stable, but under pathological conditions it becomes insoluble and forms aggregates as the result of abnormal phosphorylation or abnormal ratios of different isoforms (Buee and Delacourte, 1999). The most important diagnostic finding in CBD and tauopathies in general is the presence of abnormal taupositive deposits (Lee et al., 2001). The tau pathology is extensive in CBD and is present within neurons and glial cells of the cortex, subcortical nuclei and brainstem (Cordato et al., 2001). In most affected neurons, abnormal tau immunoreactivity is present as diffuse or granular cytoplasmic deposits, called pretangles (Komori, 1999). A characteristic feature of CBD and other tauopathies that distinguishes them from Alzheimer’s disease is the presence of tau-immunoreactive glial inclusions in cell bodies and processes. The so-called astrocytic plaques are the most characteristic astrocytic lesion in CBD and there are mainly located in the neocortex. The astrocytic plaques resemble the neuritic plaques of Alzheimer’s disease; however, they do not contain amyloid or dystrophic neurites. Another lesion, the ‘tufted astrocyte’, consists of fibrillary accumulation of tau within cell bodies and processes; it is believed to be more characteristic of PSP than of CBD (Komori et al., 1998). The tau-positive inclusions in oligodendroglia, known as ‘coiled bodies’, are argyrophilic structures that are frequently present in the tauopathies. These inclusions are distinct from the ‘glial cytoplasmic inclusions’, considered the hallmark of MSA, which are immunoreactive for ubiquitin and a-synuclein, but negative for tau (Feany and Dickson, 1996; Rademakers et al., 2004).
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The caudate, putamen and globus pallidus may contain tau-immunoreactive lesions, most frequently pretangles, variable nerve cell depletion, gliosis and NFT. The ventrolateral nucleus of the thalamus, subthalamic nucleus, red nucleus, raphe nuclei and tegmental gray matter may have similar lesions but are usually less severely involved. NFT are common in the locus ceruleus and SN. The latter structure and the basal nucleus of Meynert may contain tauimmunoreactive pre-tangles (Sergeant et al., 1999). White-matter areas not contiguous with cortical atrophy may also contain tau-immunoreactive threadlike lesions and coiled bodies. The internal capsule and thalamic fasciculus often have many thread-like processes (Forman et al., 2002). The minimal criteria for the pathologic diagnosis of CBD are cortical and striatal tau-positive neuronal and glial lesions, especially astrocytic plaques and threadlike lesions in white and gray matter and neuronal loss in cortical regions and in the SN (Lantos, 2000; Dickson et al., 2002) (Fig. 48.2).
Fig. 48.2. Immunohistochemical staining for phosphorylated tau shows a rim of cytoplasmic reactivity in a ballooned neuron (large arrow) and more diffuse staining of another neuron (small arrow). Numerous thread-like tau-immunoreactive processes are seen in the surrounding neuropil. Courtesy of Dr. K.A. Roth, UAB Division of Neuropathology.
48.5.4. Tau mutations and ultrastructure Tau is the major component of the intracellular filamentous deposits in the tauopathies. Tau pathology in Alzheimer’s disease is thought to arise secondary to b-amyloid pathology (Bancher et al., 1989; Goedert and Jakes, 2005). Some of the tau mutations have their primary effect at the protein level, reducing the ability of the tau protein to interact with microtubules (Stanford et al., 2004). Other mutations have their effect at the RNA level, modifying the normal ratio of tau isoforms. The splicing of mRNA transcripts from a single gene on chromosome 17 generates a total of six isoforms in adult human brain, with either three- or four-repeat (3R or 4R) domains, depending upon whether exon 10 is expressed or not. Three of these isoforms contain three microtubule-binding domains (3R) and three contain four microtubule-binding domains (4R) (Delacourte, 1999). Abnormal protein aggregates in the brain can be isolated as insoluble tau fractions and analyzed for isoform composition and phosphorylation state. Insoluble tau from CBD, PSP and AGD show elevated 4R/3R ratios relative to Alzheimer’s disease and controls (Togo et al., 2002; Tolnay et al., 2002; de Silva et al., 2003; Katsuse et al., 2003; Miserez et al., 2003). The tau protein may be hyperphosphorylated or abnormally phosphorylated (Arai et al., 2001a). The mechanisms that lead to these tau abnormalities in Alzheimer’s disease are still not well understood (Ishizawa et al., 2002). In contrast, tau aggregates in Pick’s disease consist of elevated levels of 3R tau. Therefore, in these disorders there may be a fundamentally different abnormality in tau processing, leading to abnormal isoform composition, hyperphosphorylation and protein aggregation. In FTDP-17 two major types of mutation may occur: missense mutations of exon 10 may lead to mutant proteins that exhibit diminished affinity for microtubules; alternatively, intronic mutations (and some exon 10 mutations) stabilize the splicing site so that higher levels of 4R tau are generated. This latter situation is similar to what occurs in PSP, CBD and AGD. Recently, a selective loss or reduction in the levels of all six brain tau isoforms has been described in a subset of sporadic cases with frontotemporal dementia and those cases are classified as ‘tau-deficiency’ tauopathies (Kawasaki et al., 1996; Ksiezak-Reding et al., 1998; Godbolt et al., 2005). Other genes and/or factors may also be essential for the neurodegenerative process to occur, as shown by FTDP-17 cases without tau mutation or deposition and with ubiquitin-positive inclusions (van Swieten et al., 2004).
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Genetic analysis of tau has revealed several polymorphisms in the coding and non-coding regions that represent two ancestral haplotypes, referred to as H1 and H2. In PSP and CBD, H1 homozygosity (H1/H1) is overexpressed and found in close to 90% of patients (Houlden et al., 2001), as opposed to only 60% of normal controls. These findings suggest that genetic polymorphisms of the tau gene somehow influence the risk for developing the sporadic 4R diseases, CBD and PSP (Oliveira et al., 2004; Pittman et al., 2005; Tuite et al., 2005). H1/H1 genotype has also been associated with PPA (Sobrido et al., 2003). Tau epitopes are similar in CBD and PSP but different from those in Alzheimer’s disease (Berry et al., 2004). Molecular heterogeneity and posttranslational modifications may influence the morphology and stability of the abnormal filaments. Electron microscopy of the paired helical filaments show that they are wider in CBD cases and have a longer periodicity of the helical twist, compared with filaments found in Alzheimer’s disease. CBD filaments are primarily composed of single- or double-stranded, highly phosphorylated polypeptides (15 or 29 nm wide and 62 or 133 kDa mass per unit length). Additionally, CBD filaments have a less stable ultrastructure because they are composed of two distinct protofilaments. In contrast, Alzheimer’s disease has three highly phosphorylated polypeptides of tau (Ksiezak-Reding et al., 1996) (Table 48.2).
Table 48.2
48.6. Imaging studies
MRI in FTDP-17 and Pick’s disease patients typically demonstrates marked brain atrophy in the frontal and temporal regions, usually in a symmetrical fashion. Widening of the interpeduncular fossa secondary to degeneration of frontopontine fibers is another imaging finding frequently seen in the different neurodegenerative diseases that have prominent cerebral cortical atrophy (Hosaka et al., 2002). The MRI of patients with PSP shows atrophy in the midbrain and brainstem without asymmetrical cortical atrophy. Patients with Alzheimer’s disease have diffuse temporal and hippocampal atrophy and in MSA of the olivopontocerebellar atrophy type the atrophy is more evident in the pons and cerebellum (Savoiardo et al., 2000). Asymmetric atrophy of the corpus callosum in the most affected side with correspondent ventricular dilatation is frequently seen in confirmed cases of CBD. Significant loss of callosal volume may appear in Alzheimer’s disease, PSP and FTD compared to controls. This morphologic change has a strong correlation with the degree of cognitive impairment in patients with Alzheimer’s disease and CBD, but not in PD and PD with dementia cases. Neither the cortical
An important characteristic to be considered when evaluating the brain imaging of patients with suspected CBD is asymmetric cortical atrophy, a feature that is quite distinctive from other neurodegenerative syndromes in the differential diagnosis of CBD (Gimenez-Roldan et al., 1994; Savoiardo, 2003). Serial evaluation of brain computed tomography (CT) or magnetic resonance imaging (MRI) scans over 6–12-month intervals is generally more useful than an isolated study. The abnormalities are best detected with MRI, particularly in the fluid attenuated inversion recovery (FLAIR) sequences. Volumetric studies of the cortex and hemispheric surface show that the more atrophic areas in CBD are the parietal lobe and the anterior, middle and posteroinferior frontal lobe. Asymmetric cortical atrophy is frequently seen, contralateral to the most affected side of the body in asymmetric presentations (Blin et al., 1992; Hu et al., 2005). The subcortical white matter underlying the atrophic cortex also exhibits decreased volume (Doi et al., 1999; Groschel et al., 2004). See Fig. 48.3.
Pathologic findings of corticobasal degeneration Macroscopic Asymmetric atrophy: frontoparietal and parasagittal Enlarged ventricles Corpus callosum atrophy Variable atrophy of subcortical structures (basal ganglia, thalamus) Pallor in substantia nigra Atrophy of white matter Microscopic Neuronal loss and gliosis Ballooned, achromatic neurons Astrocytic plaques, mainly in the cortex Glial threads in the cerebral cortex, white matter, striatum, thalamus, cerebral peduncles, cerebellar dentate nucleus and pons Neurofibrillary tangles Substantia nigra cell loss Immunocytochemical Tau pathology Neurons: granular cytoplasmic deposits (pretangles) or diffuse aggregates. Tau pathology in basal ganglia Glia Astrocytic plaques Tufted astrocytes Coiled bodies in oligodendroglia Tau pathology in white matter
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or corpus callosum atrophy or subcortical and periventricular white-matter signal changes on MRI are specific to CBD (Laureys et al., 1999; Josephs et al., 2004a). Functional imaging with positron emission tomography (PET), single-photon emission computed tomography (SPECT) and proton magnetic resonance spectroscopy (PMRS) in suspected CBD cases can provide a sensitive way to study changes in regional cerebral blood flow (CBF), cerebral metabolism (oxygen or glucose) and dopamine receptor binding. SPECT study findings in CBD are variable and include asymmetric frontotemporal perfusion and a wide range of prefrontal abnormalities. Other cases show bifrontal hypoperfusion with varying degrees of temporal and/or parietal involvement (Eidelberg et al., 1991; Brooks, 2000). The presence of isolated, asymmetrical hypoperfusion contralateral to the most affected side of the body is highly suggestive of CBD. PET studies demonstrate asymmetrical cortical and basal ganglia metabolism in patients clinically diagnosed with CBD. Cases of MSA show decreased metabolism in the basal ganglia and cerebellum and in PSP there is decreased medial frontal metabolism and increased metabolism of the lentiform nucleus in relation to that of patients with PD. This study created a template to serve as a statistical aid in diagnosing different neurodegenerative disorders based upon imaging findings. Studies of CBD show a relative reduction in both metabolic rate and glucose radiotracer uptake in several cortical areas, as well as the basal ganglia and the insula, contralateral to the most affected side (Eckert et al., 2005). 18 Fluorodopa (18F-dopa) PET and SPECT labeling of the dopamine transporter by 2ß-carboxymethoxy 3ß(4-odophenyl)-tropane [123I] ß-CIT have demonstrated homogeneous reduction in caudate and putamen signal to as low as 25% of normal values in clinically diagnosed CBD, PSP and MSA, compared with the asymmetric reduction in PD where binding is selectively reduced in the putamen. The characteristic pattern of asymmetrically reduced frontoparietal cerebral cortical metabolism and/or CBF coupled with equal reduction of 18F-dopa uptake in the caudate and putamen provides strong supportive evidence in a patient with a clinical diagnosis of CBD (Sawle et al., 1989; Kreisler et al., 2005; Plotkin et al., 2005). A PET study using a marker for peripheral benzodiazepine-binding sites which are expressed by activated microglia addressed the role of microglial inflammatory responses in neurodegenerative disorders. This study located the changes in the caudate nucleus, the putamen, the SN, the pons, the pre- and postcentral gyri and the frontal lobe. There was a broad heterogeneity within individual patients, especially in the basal
ganglia, that may represent overlap with other disorders (Gerhard et al., 2004; Henkel et al., 2004). Brain parenchyma sonography is a relatively new technique using ultrasound to display tissue echogenicity of the brain through the skull. The results of these studies need to be interpreted with caution, since the cases do not have neuropathological confirmation. Sonography has proved to be reliable and sensitive to determine basal ganglia abnormalities in several pathologies, including the SN in PD, the caudate nucleus in Huntington’s disease and the lenticular nuclei in dystonia. A study attempted to discriminate between CBD and PSP with ultrasound, but the cases did not have pathologic confirmation and the results were inconclusive. CBD exhibits marked bilateral SN hyperechogenicity; this is reported as the characteristic finding in PD. According to some authors, cases of PSP or MSA have normal echogenicity in the SN (Walter et al., 2004). Studies using proton magnetic resonance neurospectroscopy correlated with EEG cartography confirmed the asymmetrical features of CBD cases with only clinical diagnosis (Vion-Dury et al., 2004).
48.7. Electrophysiological studies Electrophysiological studies may support the diagnosis of CBD and give us information about asymmetrical dysfunction. The EEG is usually normal during the initial stages of the disease and may reveal non-specific asymmetric slowing in the more affected side in later stages. The non-specific diffuse slowing can be bilateral in advanced cases or in cases with predominant cognitive dysfunction at presentation. Electrophysiological studies of the tremor with accelerometry and electromyography (EMG) have distinguished tremor of CBD from the parkinsonian tremor: it is faster, more irregular, more variable in amplitude, more evident during action and has a myoclonic component. The myoclonus seen in CBD is a reflex myoclonus but the cortical spike is not always recognized. Results from studies of somatosensory evoked potentials have not been conclusive in CBD. The N30 frontal component has been found to be absent unilaterally, bilaterally and with increased latency in patients with clinically probable CBD. Motor evoked potentials are reported as being prolonged in patients with CBD (Okuda et al., 1998). The P100 wave of the visual evoked potentials has been reported to not differ significantly between different types of dementia and age-matched control subjects. Brainstem auditory evoked potentials are reported to be abnormal with prolonged P300 and N200 latencies in CBD (Homma et al., 1996; Lu et al., 1998). Routine
CORTICOBASAL DEGENERATION EMG is normal in early stages or may show changes consistent with dystonia in the affected limbs. Nerve conduction studies may show focal or generalized neuropathy that is usually subclinical.
48.8. Laboratory studies Serum copper and ceruloplasmin levels and heavymetal screens in blood and urine are normal in CBD patients. Cerebrospinal fluid (CSF) analysis in patients with CBD, PSP and Alzheimer’s disease show reduced levels of b-amyloid peptide compared with control subjects. Total tau protein levels are increased in Alzheimer’s disease and the rest of the tauopathies and may help to differentiate them from normal aging, depression, synucleinopathies and vascular dementia. However, the tau level in the CSF is inadequate to differentiate among the different tauopathies (Arai et al., 1997; Mitani et al., 1998; Paraskevas et al., 2005). Levels of somatostatin were reported to be decreased in some patients with autopsy confirmation of CBD.
48.9. Differential diagnosis and heterogeneity The typical motor presentation of CBD is usually sufficiently distinctive to allow a confident clinical diagnosis. PD is the most common misdiagnosis early in the course of the disease (Boeve et al., 2002; Doran et al., 2003; Kertesz et al., 2005). The best early clues that can help to distinguish CBD from idiopathic PD are the lack of sustained beneficial response to dopaminergic medication and signs of cortical dysfunction, most notably apraxia and/or cortical sensory impairment. Based on pathological findings of cases diagnosed as CBD, the differential diagnosis needs to include Pick’s disease (Lang et al., 1994b), PSP (Wakabayashi and Takahashi, 2004), dementia lacking distinctive histology or taunegative inclusions of the motor neuron disease type, FTDP-17 (Reed et al., 2001) and PPA (Ferrer et al., 2003). Primary dementing disorders should also be included in the differential diagnosis of CBD. Other diagnoses to consider are MSA, including olivopontocerebellar atrophy and striatonigral degeneration (Adams et al., 1964), diffuse Lewy body disease, Alzheimer’s disease with extrapyramidal features, AGD (Jellinger, 1998), parkinsonism–dementia–amyotrophic lateral sclerosis complex, widespread cerebrovascular disease, variants of Binswanger’s disease, progressive multifocal leukodystrophies (Bhatia et al., 1996; Van Zanducke and Dehaene, 2000), variants of Azorean disease (Nakano et al., 1972; Sachdev et al., 1982) and hemiparkinsonism–hemiatrophy (Giladi and Fahn, 1992). CBD has presented as a Balint’s syndrome (Mendez, 2000). A case of neurosyphilis resembling
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CBD has been described as well (Benito-Leon et al., 2004). If a patient presents with a rapidly progressive CBD-like picture, prion-related disease should be considered (Cannard et al., 1998; Kovacs et al., 2002; Josephs et al., 2004c; Kleiner-Fisman et al., 2004; Moreaud et al., 2005). PSP is the disorder most likely to be confused with the motor presentation of CBD. PSP classically presents with prominent axial rigidity, postural instability with early falls and abnormal vertical eye movements. Atypical features such as asymmetric onset, oculomotor impairment that is only mild, focal dystonia and involuntary limb levitation resembling the alien-limb phenomenon are the most frequent features that may cause confusion with CBD (Table 48.3).
48.10. Therapy Pharmacotherapy for CBD is currently of limited benefit. This may be explained by the widespread pathological involvement of cortical and subcortical systems and the lack of biochemical and molecular explanations for the pathophysiology of the disease. New therapeutic approaches will be directed towards the development of compounds that modify, correct or block the underlying pathological mechanisms of CBD. Some cases may show initial benefit with levodopa or with dopamine agonists, but this benefit is usually temporary. The primary treatment is symptomatic, focused on alleviating the rigidity, dystonia, tremor, myoclonus, neuropsychologic manifestations and other symptoms (Lang, 2005). 48.10.1. Treatment of motor symptoms Improvement was reported in only 24% of clinically diagnosed CBD patients with carbidopa/levodopa treatment. The rest of the dopaminergic agents (bromocriptine, pergolide, pramipexole, ropinirole) may produce more side-effects with less clinical benefit in this group of patients. Clonazepam and other benzodiazepines have been the most beneficial agents for action tremor and myoclonus. Baclofen and tizanidine may improve rigidity. Anticholinergics have not been beneficial and they have been poorly tolerated due to cognitive side-effects and amantadine is of little or no benefit (Kompoliti et al., 1998). Botulinum toxin injections may be useful in the treatment of painful focal limb dystonias, as well as in blepharospasm (Cordivari et al., 2001; Muller et al., 2002b). Stereotactic surgery for relief of severe painful limb dystonia and parkinsonism has little or no benefit and is not indicated in the treatment of atypical parkinsonian syndromes (Fazzini et al., 1995).
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Table 48.3 Differential diagnosis of patients with neurodegenerative diseases with motor and cognitive dysfunction Diagnosis
Clinical features
Features which suggest an alternative diagnosis
CBD
Asymmetric bradykinetic/akinetic parkinsonism with lack of response to dopaminergic treatment, dystonia, cortical sensory loss, apraxia, asymmetric dystonia or rigidity, alien-limb phenomenon, myoclonus, cognitive dysfunction Behavioral disturbances and problems with interpersonal interactions, disinhibition, hyperorality, personality changes, dietary changes, speech and language symptoms, word-finding difficulties, memory loss Ophthalmoplegia (particularly vertical gaze paresis), early gait impairment, frequent falls, axial rigidity, dysarthria, dysphagia, suboptimal response to levodopa therapy Symmetric rigidity, absence of rest tremor, cerebellar and autonomic dysfunction, rapid course, suboptimal response to levodopa therapy, gait disorder Asymmetric rest tremor, bradykinesia and rigidity with dementia, memory loss, responsive to levodopa therapy
Prominent ocular involvement, axial dystonia, aphasia, autonomic dysfunction, rest tremor
FTD/PPA/PiD
PSP
MSA
PD with dementia
AD with parkinsonism
Early cognitive dysfunction (especially memory loss), cortical dysfunction (visuospatial deficits, aphasia, apraxia), mild bradykinesia and rigidity
DLB
Fluctuating symptoms, cognitive dysfunction, psychosis induced or worsened by dopaminergic therapy, parkinsonism, gait disorder Rapid course of dementia, personality changes, myoclonus, upper motor neuron signs, cerebellar or extrapyramidal signs
CJD
Gait disorder, early ocular involvement, hallucinations, prominent extrapyramidal symptoms, levodopa responsiveness, progressive apraxia without dementia Lack of ocular involvement, apraxia, cortical sensory loss, prominent autonomic dysfunction Early ocular involvement, apraxia, cortical signs, dementia
Symmetric rigidity, early ocular involvement, suboptimal response to levodopa therapy, apraxia, cortical sensory loss, prominent autonomic dysfunction Parkinsonism present prior to onset of dementia, aphasia or apraxia without significant memory loss, early gait impairment, axial rigidity, ophthalmoplegia, alien-limb phenomenon Axial rigidity or dystonia, early ocular involvement
Protracted course, isolated parkinsonism or cortical dysfunction, levodopa responsiveness
CBD, corticobasal degeneration; FTD, frontotemporal dementia; PPA, primary progressive aphasia; PiD, Pick’s disease; PSP, progressive supranuclear palsy; MSA, multiple system atrophy; PD, Parkinson’s disease; AD, Alzheimer’s disease; DLB, dementia with Lewy bodies; CJD, Creutzfeldt–Jakob disease.
48.10.2. Treatment of cognitive and neuropsychiatric symptoms There is no clear evidence that treatment of cognitive dysfunction with medications that enhance cholinergic neurotransmission has much benefit; however, they may be considered in early stages of the disease. Depression and obsessive-compulsive symptomatology may be treated effectively with selective serotonin reuptake inhibitors (SSRIs), but cautious titration and low doses are recommended because these medications can exacerbate agitation. Antidepressants with anticholinergic side-effects,
including tricyclic compounds, may exacerbate confusion. Small doses of atypical neuroleptic medications such as quetiapine, olanzapine or clozapine may be helpful for paranoid delusions, psychotic behavior, agitation, irritability and sleep problems. The use of typical antipsychotic medications such as haloperidol may worsen motor symptoms of CBD and are not recommended. Small doses of sedative hypnotic agents may be helpful for insomnia, but they may also exacerbate confusion and agitation. Clonazepam is usually helpful and agents such as diphenhydramine, chloral hydrate and zolpidem may be useful as well, but they should be used cautiously.
CORTICOBASAL DEGENERATION 48.10.3. Treatment of other symptoms Gastrointestinal symptoms in CBD patients include hypersalivation, dysphagia, nausea and constipation. Excessive salivation may respond to small doses of anticholinergic therapy, but side-effects are a limiting factor in most cases. The goal of treatment of the dysphagia is to maintain safe and efficient nutrition and hydration. Evaluation with a barium swallow study may be necessary. Treatment includes dietary modifications, positional changes, swallowing maneuvers and exercises and surgical interventions. Selection of foods with a consistency that facilitates swallowing is critical. If patients are not able to ingest enough food to meet nutritional requirements, percutaneous feeding gastrostomy tube placement may be necessary. The decision to place a gastrostomy in a patient with a chronically progressive neurodegenerative disease must be handled on an individual basis, keeping in mind the wishes of the patient or the patient’s surrogate. Constipation in parkinsonism is due to colonic hypomotility, colonic outlet dysfunction or both. Constipation has also been associated with pelvic floor dystonia. The use of stool softeners, increased fluid intake, foods rich in fiber and laxatives may be beneficial. Polyethylene glycol is another alternative for the treatment of severe constipation.
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The urinary symptoms of CBD include urgency and frequency and they may improve with the use of hyoscyamine, tolterodine or oxybutynin. Close observation for central and peripheral side-effects is warranted when using these or related medications. Symptomatic orthostatic hypotension, although more frequently seen in MSA, may be treated with fludrocortisone or midodrine. Other aspects of patient care, not involving pharmacotherapy, can be of special importance for these patients and their families (Litvan, 2001). Physiotherapy is very helpful for maintenance of mobility and prevention of contractures. Pain related to dystonic posturing can be lessened by maintenance of good range of motion and occasionally splinting can be helpful. Occupational therapy can help patients maintain some degree of functional independence by providing specially made devices such as eating utensils with large handles. Speech therapy may offer practical suggestions and exercises to optimize speech function and guard against aspiration secondary to swallowing difficulty. Good home care assistance can help prolong the time a patient remains at home before requiring nursing-home placement. Despite our best therapeutic efforts, regardless of whether it presents with motor or cognitive symptoms, CBD generally progresses to a state of bilateral rigid immobility due to increased tone or apraxia and patients usually die from aspiration pneumonia or urosepsis.
Fig. 48.3. (A) and (B) T1 and T2-weighted brain images of a patient with corticobasal degeneration showing the asymmetric cortical atrophy, contralateral to the most affected side
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Handbook of Clinical Neurology, Vol. 84 (3rd series) Parkinson’s disease and related disorders, Part II W. C. Koller, E. Melamed, Editors # 2007 Elsevier B. V. All rights reserved
Chapter 49
Infectious basis to the pathogenesis of Parkinson’s disease V. DHAWAN1,2 AND K. RAY CHAUDHURI1–3* 1
Regional Movement Disorders Unit, King’s College Hospital, London, UK 2
University Hospital Lewisham, London, UK
3
Guy’s, King’s and St. Thomas’ School of Biomedical Medicine and King’s College, London, UK
49.1. Introduction The etiology of Parkinson’s disease (PD) is unknown but a considerable body of research suggests that a variety of occupational, environmental and genetic factors may play an important role (Ben-Shlomo, 1997). Infections have also been suggested as a cause of PD both directly and indirectly (through occupational exposure), stemming from the observation that development of parkinsonism often followed the influenza pandemic of the 1910s and encephalitis lethargica (von Economo’s disease) often preceded it (Ben-Shlomo, 1997; Lai et al., 2002). Since then, several other possibilities of an infective basis to PD and parkinsonism have been put forward and this review examines the basis behind these observations. PD occurs throughout the world across all races and increases exponentially with age. The late onset and slow-progressing nature of the disease have prompted the consideration of environmental exposure to agrochemicals, including pesticides, as a risk factor. Moreover, increasing evidence suggests that early-life occurrence of inflammation in the brain, as a consequence of either brain injury or exposure to infectious agents, may play a role in the pathogenesis of PD. Most importantly, there may be a selfpropelling cycle of inflammatory process involving brain immune cells (microglia and astrocytes) that drives the slow yet progressive neurodegenerative process. Differences in prevalence between identical ethnic groups in different countries support the role of an environmental factor, including an infectious basis (Richards and Chaudhuri, 1996; Stoessl, 1999; Chaudhuri et al., 2000).
49.2. A Possible immunological basis and a link with infection Several studies have displayed evidence of immune abnormalities in PD. These include the occurrence of antineuronal antibodies, increases in human leukocyte antigen-DR (HLA)-DR expression on cerebrospinal fluid (CSF) monocytes and increases in HLA-DRþ activated microglia in substantia nigra (SN). In one study examining immune mediators in peripheral lymphocytes of patients with PD, patients with PD displayed a significantly greater population of circulating CD3þ CD4 brightþ CD8 dullþ lymphocytes than age-matched control subjects (Hisanaga et al., 2001). These cells are known to increase after some specific viral infections, hence raising the possibility of an association between postinfectious immune abnormalities and pathogenesis of PD. CD8dullþ and CD4brightþ T cells have been associated with Epstein–Barr virus (EBV), cytomegalovirus, human herpes 6, human T-cell leukemia virus type-1 and human immunodeficiency virus (HIV). However, these have also been demonstrated in patients with neoplasms as well as in small populations of healthy adults and in patients with multiple sclerosis, myasthenia gravis and during rejection of renal transplants. The precise reasons behind why CD4þ and CD8þ T cells increase in PD and whether these circulating lymphocytes contribute to the pathogenesis of neuronal death in PD remain inconclusive and require further investigation. Salman and colleagues (1999) reported decreased phagocytic function exhibited by peripheral blood polymorphonuclears of PD patients, as shown by their
*Correspondence to: Dr. K. Ray Chaudhuri, 9th floor, Ruskin Wing, King’s College Hospital, Denmark Hill, London SE5 9RS, UK. E-mail:
[email protected], Tel: þ44-(0)208-333-3030, Ext. 6184, Fax: þ44-(0)208-333-3093.
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impaired ability to engulf latex particles. Function of phagocytes is significant in trying to combat bacterial invasion or destruction of any foreign material, thereby increasing the susceptibility of PD patients to infection, but could be secondary to the disease rather than playing a direct causative role in its pathogenesis. Other immune abnormalities described in PD include the occurrence of autoantibodies against neuronal structures and an elevated number of microglia cells expressing the histocompatibility glycoprotein HLA-DR in the SN. An increased gamma delta (þ) T-cell population and immunoglobulin G immunity in CSF to heat shock proteins has been found in PD (Fiszer, 2001). Impaired cytokine production by the peripheral immune system in PD patients with a significant decrease in the production of tumor necrosis factor-a (TNF-a), interleukin (IL)-1a, IL-1b and IL-6 by peripheral blood mononuclear cells and TNF-a by peripheral blood macrophages was demonstrated by Hasegawa et al. (2000). Rats with nigral injection of immunoglobulin G (IgG) purified from the serum of 5 patients with PD and 10 disease control patients suggested that PD IgG can initiate a relatively specific inflammatory destruction of SN pars compacta neurons in vivo (Chen et al., 1998). A cytokine/CD23-dependent activation pathway of inducible nitric oxide synthase, toxic oxidative species and of proinflammatory mediators in glial cells and their involvement in the pathophysiology of PD has been suggested in a study by Hunot et al. (1999). Also in a study in 1999, Linda et al. demonstrated that motor neurons and nigral dopaminergic neurons (i.e. those neurons that are susceptible to neurodegeneration in diseases such as PD and amyotrophic lateral sclerosis), in the brainstem of the adult rat, displayed high levels of both major histocompatibility complex (MHC) class I heavy-chain and b2-microglobulin mRNAs. A deficiency in expression of MHC class I is thought to impede CD8 T-cell recognition and target cell killing. These mechanisms may protect neurons and other cells with low regenerative capacity from destruction by T cells. Antibodies raised against viral determinants sometimes cross-react with host proteins in immunohistochemical studies and such cross-reacting antibodies may thereby play a role in disease pathogenesis. a-Synuclein, a neuronal protein, is reported to be a major component of Lewy bodies (LBs) in PD, dementia with LBs and common variants of Alzheimer’s disease. Giasson et al. (2000) developed a panel of antisynuclein antibodies and performed immunohistochemical studies showing that these antibodies label numerous LBs in the SN of PD, thereby suggesting a role of pathological
forms of this protein in PD and related neurodegenerative synucleinopathies. It is possible that similar cross-reacting immune responses are generated as part of the immune response to natural infection with a virus. The cross-reactivity between a virus and protein may bear important implications in elucidating infectious mechanisms in the pathogenesis of PD. More specifically, studies have focused on the possible role of the following organisms in the pathogenesis of PD and related syndromes (Fig. 49.1):
HIV Prion protein Nocardia asteroides Japanese encephalitis virus Influenza A virus Helicobacter pylori Toxoplasma gondii
49.3. Review of clinical case reports 49.3.1. HIV spontaneous-onset extrapyramidal symptoms in patients with HIV/AIDS Movement disorders are recognized as a complication of HIV/acquired immune deficiency syndrome (AIDS) and may be both hypo- and hyperkinetic in nature. Opportunistic infections or, occasionally, drug therapies may be responsible, although in some cases there may be no identifiable precipitant. Estimates of prevalence of movement disorders in HIV-seropositive patients range between 0.006 and 14%, depending on concurrent pharmacological therapy and the method of analysis employed (Nath et al., 1987; Mirsattari et al., 1998; De Mattos et al., 2002; Tse et al., 2004). Cardoso (2002) proposed that clinically relevant movement disorders are identified in 3% of patients with HIV infection seen at tertiary referral centers and prospective followup shows that 50% of patients with AIDS develop tremor, parkinsonism or other extrapyramidal features. Parkinsonism has been described in several cases with HIV infection and AIDS, which result from lesions caused by opportunistic infections such as toxoplasmosis, which damage the basal ganglia connections (Table 49.1). Parkinsonism, tremor and dystonia can also result from dopaminergic dysfunction caused by cellular action of dopamine-blocking agents (Table 49.2). Extrapyramidal symptoms associated with HIV/ AIDS were described by Berger et al. (1984), who noted the presence of tremor in 3 out of 165 patients (0.02%) recently diagnosed with AIDS in Florida, USA. Three years later Nath et al. (1987) published a case report of 2 patients with AIDS and rest tremor. The patients were both male, aged 57 and 37 years, and had been diagnosed with AIDS 17 and 22 months
INFECTIOUS BASIS TO THE PATHOGENESIS OF PARKINSON’S DISEASE
A
B
C
D
375
Fig. 49.1. Possible infectious organisms implicated in cause of Parkinson’s disease and parkinsonism. (A) Human immunodeficiency virus; (B) influenza; (C) Helicobacter pylori; (D) CJD (prion particles); (E) Toxoplasma; (F) Nocardia asteroides.
previously. Serological investigations and neuroimaging failed to identify obvious causes of parkinsonism in these patients and a direct effect of HIV-1 on the basal ganglia was hypothesized. Brain biopsy later revealed cerebral Whipple’s disease in 1 of the patients and it was suggested this may have contributed to the clinical presentation.
In 1989 Carrazana et al. published a case report of acute-onset parkinsonism associated with AIDS in a 66-year-old female. The patient presented with a 2-week history of lethargy, tremor and slow, shuffling gait and a 2-day history of fever. Her family had noted her facial expression was reduced. Examination revealed bilateral cogwheel rigidity, infrequent
376
V. DHAWAN AND K. R. CHAUDHURI
E
F
Fig. 49.1. (Continued)
blinking, drooling, right pronator drift, right-sided hyperreflexia and an extensor plantar response on the right. Serum and CSF toxoplasma titers were elevated and computed tomographic (CT) neuroimaging revealed bilateral ring-enhancing lesions in the anterior limb of the internal capsule, suggestive of cerebral toxoplasmosis. HIV-1 in serum was positive. There was a poor clinical response to levodopa and pyrimethamine and sulfadiazine therapy were discontinued following the development of pancytopenia. The patient died secondary to septicemia within 5 months of the onset of parkinsonian symptoms. Tolge and Factor (1991) reported a case of isolated focal dystonia in the left hand and arm of a 29-year-old male, 5 months after having received the diagnosis of HIV-1 infection. Serum toxoplasma titer was elevated and a CT scan revealed ring-enhancing lesions, typical of Toxoplasma abscesses, in the right lenticular nucleus and right thalamus (Fig. 49.2). Maggi et al. (2000) reported an AIDS patient who developed cerebral opportunistic granulomatous lesions and, subsequently, a parkinsonian akineticrigid syndrome. The parkinsonian syndrome only developed when the lesions involved basal ganglia bilaterally. Werring and Chaudhuri (1996) also described a rapidly developing akinetic-rigid syndrome progressing to akinetic mutism and death in a patient with recently acquired HIV.
Parkinsonian symptoms of tremor, hypomimia and gait disturbance caused by mesencephalic cryptococcal abscesses in a 63-year-old man with AIDS have also been reported (Bouffard et al., 2003). The patient’s symptoms were initially attributed to early PD; diagnoses of AIDS and cryptococcal infection were made following his death due to cardiac arrest 8 months after the onset of his neurological symptoms. Autopsy revealed bilateral cryptococcal abscesses in the SN without any characteristic changes of cerebral HIV infection or other obvious underlying pathology (Bouffard et al., 2003). Bradykinesia and rigidity were also reported in association with central nervous system (CNS) tuberculosis in a 49-year-old male, as the presenting manifestation of HIV infection (de La Fuente-Aguado et al., 1996). The diagnosis of CNS tuberculosis was made on the basis of neuroimaging appearances (Fig. 49.3) and the growth of acid-fast bacilli on a CSF smear. CD4 count at diagnosis was 133 cells/mm3. The case is interesting as parkinsonian features resolved fully following 12 days of antituberculosis therapy plus intravenous dexamethasone. 49.3.2. Postencephalitic parkinsonism (PEP) 49.3.2.1. Epidemiological aspects A pandemic of encephalitis lethargica occurred between 1919 and 1926, resulting in the emergence of the syndrome of PEP. A younger age of onset of
Summary of case reports of spontaneous-onset parkinsonism in patients with human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS)
Case reports of parkinsonism Male Female Mean age (years) Latency between Dx HIV/AIDS and onset of EPS (months) Baseline CD4 count (cells/mm3) EPS attributed to toxoplasmosis EPS attributed to cryptococcosis EPS attributed to CNS tuberculosis EPS attributed to PML No cause found to explain EPS Improvement with antitoxoplasmosis Tx Improvement with anti-TB Tx Improvement with levodopa Improvement with HAART Deaths Latency between onset of EPS and death (months)
Berger et al. (1984)
Nath et al. (1987)
3
2 47 þ17 to22
Carrazana et al. (1989)
Werring and Chaudhuri (1996)
De la Fuente-Aguado et al. (1996 )
Hersh et al. (2001)
De Mattos et al. (2002)
Bouffard et al. (2003)
10 3 37
1
1
1
1
1 66
38
49
37
0.5 1/1
1 110
0
4 438
þ5
63 0 133
1/14 1/1 1/1 1/1 No
12/13
No
5
No
1
1
Yes Yes
1 8
6
Yes–5/9 8
5
227 2/23 1/23
0/2 1/1 6/12 1/1 11
1/1 No
19 4 44.1
1/23 1/1 15/23
1/1 2/2
Total
Dx, diagnosis; EPS, extrapyramidal symptoms; CNS, central nervous system; PML, progressive multifocal leukoencephalopathy; Tx, treatment; TB, tuberculosis; HAART, highly active antiretroviral treatment; þ implies EPS began after diagnosis of HIV/AIDS; – implies EPS began before HIV diagnosis.
INFECTIOUS BASIS TO THE PATHOGENESIS OF PARKINSON’S DISEASE
Table 49.1
377
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V. DHAWAN AND K. R. CHAUDHURI
Table 49.2 Summary of case reports of dystonia in patients with human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS)
Case reports of dystonia Right-sided Male Right-sided Female Left-sided Male Left-sided Female Bilateral Male Bilateral Female Mean age (years) Mean time between diagnosis of HIV/AIDS and onset of EPS EPS attributed to basal ganglia toxoplasmosis No cause found to explain EPS Clinical improvement with antitoxoplasmosis treatment Deaths
Nath et al. (1987)
Tolge and Factor (1991)
De Mattos et al. (2002)
Total
1
1
1
1
1 35 þ 4 months
1 29 þ 5 months 1/1
28
30.7
1/1
No
No
2/3 1/3 0/2 0
1/1
EPS, extrapyramidal symptoms. þ implies EPS began after diagnosis of HIV/AIDS; – implies EPS began before HIV diagnosis.
Fig. 49.2. Contrasted computed tomographic image in a patient presenting with focal dystonia. Cerebral toxoplasmosis abscess in right lenticular nucleus and left temporal cortex (A) and right thalamus (B). Reproduced from Tolge and Factor (1991), with permission.
disease (36.8 years) was reported from a group of London hospitals compared to an age of onset of 54.7 years between 1900 and 1920 (Duvoisin et al., 1963) At this time the age of onset of PEP (between 1921 and 1942) was 27.4 years. Studies from the USA (Massachusetts General Hospital) also suggest that age of diagnosis of parkinsonism between 1920 and 1924 was 27 years less than those diagnosed between 1919 and 1926 (Poskanzer and Schwab, 1963), suggesting
that the pandemic of 1919–1926 may have influenced the earlier onset of disease in this group of patients. Mortality data from England and Wales related to PD showed that, although there is a fivefold increase in death rates among people over 80 years of age, younger people with PD had a lower mortality rate (Martyn, 1997). Although the possibility of a birth cohort rate cannot be excluded, these data provide indirect evidence that people born at the beginning of the
INFECTIOUS BASIS TO THE PATHOGENESIS OF PARKINSON’S DISEASE
Fig. 49.3. Computed tomography image in a patient presenting with parkinsonism. Hypodense cerebral lesion affecting left external capsule, posterior limb of internal capsule and lower region of left lenticular nuclei. The lesion did not show enhancement to the intravenous contrast and was diagnosed as central nervous system tuberculosis on the basis of cerebrospinal fluid analysis. Reproduced from de La FuenteAguado et al. (1996), with permission.
20th century suffered from an unusually high rate of parkinsonism, thus supporting the notion that encephalitis lethargica could have been implicated. Reports from a recent study on 22 patients with an encephalitis lethargica-like phenotype advocate that it is still prevalent and is a postinfectious autoimmune CNS disorder with autoantibody targeting of basal ganglia and SN neurons (Dale et al., 2002). 49.3.2.2. Case report-related observations The Japanese B encephalitis virus is the first demonstrated virus capable of producing nigral lesions and causing parkinsonism. Pradhan et al. (1999) selected 5 patients from 52 patients with Japanese B encephalitis seen in an endemic zone, on the basis of isolated lesions in the SN (revealed on imaging with magnetic resonance imaging (MRI)) and performed detailed clinical and laboratory evaluations. Examination during acute illness revealed restricted eye movements, opsoclonus, upbeating nystagmus and cogwheel rigidity with reversal of consciousness and eye signs after the acute illness. Parkinsonian features, such as positive glabellar tap, facial impassivity, bradykinesia, tremors and postural instability, became apparent as
379
these patients improved and were able to mobilize and walk. Reversible mutism was observed in 3 patients during the acute phase. Response to levodopa, amantadine and trihexiphenedyl was partial. All 5 patients were followed for more than 1 year, during which time the parkinsonian features recovered substantially. Peatfield (1987) described 2 patients with a chronic non-progressive illness beginning with excessive sleepiness and personality change. Both had an atypical movement disorder, clearly distinct from PD, with impairment of memory and learning and relative preservation of arithmetical, language and visuospatial tasks, suggesting parkinsonism with a subcortical dementia. CT scans of the brain showed atrophy of deep structures and elevated Coxsackievirus antibody titers. The author speculated that insidious viral encephalitis (perhaps these cases would previously have been described as encephalitis lethargica) could lead to subcortical dementia. Calne and Lees (1988) performed a detailed retrospective analysis of 11 long-standing (greater than 40 years) inmates in a hospital with neurological deficits due to encephalitis lethargica. Retrospective information was gathered from physicians’ and nurses’ records, photographs, published narrative and hospital charts dating back as far as 1931. They concluded that neurological disabilities attributable to basal ganglia damage frequently increase in late life, with deterioration being most marked in motor function and largely sparing the intellect, special senses and somatosensory system. Picard et al. (1996) described a patient who went on to develop a severe parkinsonian syndrome a few years after being diagnosed with an encephalitic syndrome associated with a prolonged lethargic state in his childhood. He presented with axial dystonia and stereotyped abnormal movements of the upper limbs, with normal brain imaging. Fluorodopa positron emission tomography (PET) showed a significant bilateral reduction of tracer accumulation in both putamens, similar to that observed in patients with idiopathic PD, and treatment with levodopa suppressed akinetic, dystonic and dyskinetic symptoms in this patient. These symptoms appeared to be related to a limited lesion of the dopaminergic neurons of the zona compacta of the SN. Ghaemi et al. (2000) reported another case of a 74-year-old woman who developed an akinetic-rigid Parkinson syndrome with tremor, hypokinesia, hypomimia, rigidity and cogwheel phenomenon in all four extremities following viral encephalitis. The diagnosis was supported by a reactive CSF assay and a positive influenza A IgA antibody titer (1:>160). PET studies
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V. DHAWAN AND K. R. CHAUDHURI
showed an altered pattern of glucose and dopa metabolism, clearly distinguishing it from idiopathic Parkinson syndrome. 49.3.2.3. Clinical features Litvan and colleagues (1998) reported results of a retrospective clinicopathologic study to determine the validity of the clinical diagnosis of PEP by presenting 105 records with neuropathologic diagnoses of PEP (n ¼ 7), progressive supranuclear palsy (n ¼ 24), PD (n ¼ 15), dementia with LBs (n ¼ 14), multiple system atrophy (n ¼ 16), corticobasal degeneration (n ¼ 10), Creutzfeldt–Jakob disease (CJD: n ¼ 4) and other dementia disorders (n ¼ 15) as clinical vignettes to six neurologists who were unaware of the autopsy findings. The neurologists’ own clinical diagnoses, when compared with neuropathologic diagnoses, displayed high reliability, sensitivity and positive predictive values for the clinical diagnosis of PEP. According to their data set, the best predictors for the diagnosis of PEP included: 1. Onset below middle age 2. Symptom duration lasting more than 10 years 3. Presence of oculogyric crisis A relevant history of encephalitis lethargica, present in most PEP cases, was an important individual diagnostic predictor. Other reported features include: 1. Sleep disturbances 2. Excessive daytime sleepiness However, as the reported case histories suggest, there is a wide phenotypic variation in cases labelled as PEP, ranging from a levodopa-responsive syndrome with PET appearances of idiopathic PD to a syndrome of parkinsonism with early dementia. 49.3.3. Nocardia asteroides Nocardia is a genus of aerobic Gram-positive bacteria which forms filamentous cells that fragment into rodshaped or coccoid elements or L-forms (see Fig. 49.1). It is found in soil, stagnant water and farming areas. The link between Nocardia infection and parkinsonism was suggested by Beaman, a leading worker in this field based on work in animal models (see section 49.4, below). Kohbata and Shimokawa (1993) detected antibodies to coccoid and rod-shaped cells of Nocardia in the serum of patients with PD. The antibodies were demonstrated in all the 20/20 patients with PD at a titer greater than 1:10 and 10 out of 14 controls. The results suggested that PD patients amid agematched healthy volunteers are routinely exposed to and naturally infected with Nocardia-related microor-
ganisms and thus disputed the link of parkinsonism with Nocardia. Subsequently, Hubble et al. (1995) used a serodiagnostic panel to determine antibodies specific for Nocardia in PD patients by comparing sera from healthy volunteers and from patients with cultureproven nocardiosis. No difference in seropositivity was found when PD patients were compared with their age- and gender-matched controls (n ¼ 140). The results reveal a high exposure rate of humans to nocardial antigens, especially among men and older individuals, and do not confirm the hypothesis that nocardiosis may cause PD or parkinsonism, although the authors acknowledge that serological testing may not be optimal for the detection of Nocardia-related CNS infection (Hubble et al., 1995). N. asteroides are composed of both filamentous and filterable forms. In a further study, Kohbata et al. (1998) investigated the presence of acid-fast spherical structures similar to filterable Nocardia at the midbrain nigral lesions of 3 patients with PD. Many clusters of acid-fast lipochrome bodies were present in the vicinity of melanin-pigmented neurons in the 3 PD patients studied and none were observed in 3 control patients. Examination of adjacent hematoxylin and eosin-stained sections indicated that they consisted of yellow-green granules, bodies and aggregates in ballooned glial cells. However, the results do not confirm or refute the proposed link between Nocardia and Parkinson’s disease, and they suggest that the immunological and genetic relationship between the acid-fast lipochrome bodies and filterable Nocardia should be investigated. In another experiment with the midbrain sections of PD patients and controls, acid-fast stain and antifilterable Nocardia antiserum were used and confirmed the presence of filterable forms of N. asteroides in the midbrain nigral lesions that occur with PD (Kohbata et al., 2002). Recently LeWitt and colleagues (2004) reliably verified that, in mica models, prior infection with certain strains of N. asteroides or, possibly, other neurotoxic microorganisms in the environment caused neuronal degeneration and various levodoparesponsive and persisting motor disorders resembling parkinsonism. They postulated that this might be an etiological basis for this or for other neurodegenerative disorders. 49.3.4. Helicobactor pylori Altschuler (1996) suggested that gastric Helicobacter pylori infection might be a cause for both idiopathic PD and non-arteritic anterior optic ischemic neuropathy, given the higher prevalence of gastrointestinal
INFECTIOUS BASIS TO THE PATHOGENESIS OF PARKINSON’S DISEASE
381
ulcers in both these diseases than reported in age- and sex-matched controls or in the general population. Charlett et al. (1999) investigated the role of H. pylori of PD and the issue of cross-infection in familial aggregation by checking H. pylori seropositivity in 33 elderly subjects with idiopathic parkinsonism and 39 siblings and controls). They found that both parkinsonians and siblings differed from controls in the odds of being H. pylori-seropositive (odds ratios 3.04 (95% confidence interval: 1.22, 7.63) and 2.94 (1.26, 6.86) respectively, P < 0.02); seropositivity was present in 0.70 of sufferers. Familial transmission of chronic infection was linked with causality. H. pylori is one of the commonest of known bacterial infections linked with peptic ulcer/non-ulcer dyspepsia, immunosuppression and autoimmunity. Dobbs et al. (2000) challenged the conventional concept of a role of a neurotoxin as an environmental cause of idiopathic parkinsonism by suggesting that H. pylori-related acquired immunosuppression, predisposing to autoimmunity, could serve as a model for the pathogenesis of parkinsonism and eradication of H. pylori has the potential to change the approach to parkinsonism. The theory remains controversial, and a study conducted by Wlodarek et al. (2003) found no relation between PD and H. pylori infection. Another issue is that H. pylori infection positivity affects levodopa pharmacokinetics in PD, through direct degradation of the drug or changes of gastroduodenal environment (Brusa et al., 2004).
a patient with histopathologically verified sporadic CJD presented initially with diplopia, sleep disturbances and levodopa-responsive parkinsonism. Unusually, he did not dement and initially failed to fulfill the clinical criteria for possible CJD after more than a year of slow progression. It was proposed that CJD should be included in the differential diagnosis of ‘parkinson plus’ syndromes until a different etiology has been found or a histopathologic examination performed. Nitrini et al. (2001) presented the clinical features of 12 patients from a family with CJD associated with a point mutation at codon 183 of the prion protein gene. The duration of the symptoms until death ranged from 2 to 9 years. Nine patients were first seen by psychiatrists for behavioral disturbances. Eight patients manifested parkinsonian signs. The authors concluded that these clinical features bear a considerable resemblance to those described in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), not usually considered in the differential diagnosis of prion diseases. A Japanese case of sporadic CJD presenting as progressive supranuclear palsy with slowly progressing neurological deficits for 2 years after onset was reported in 2003 (Shimamura et al., 2003). Needle biopsy revealed deposition of prion protein of a patchy/ perivacuolar type with spongiform degeneration. Of late, 2 further cases of CJD presenting with a progressive supranuclear palsy-like syndrome and autopsy confirmation have been reported from the USA (Josephs et al., 2004).
49.3.5. Epstein–Barr virus
49.3.7. Leprosy
Woulfe et al. (2000) suggested cross-reactivity between monoclonal antibodies against EBV and asynuclein in the human brain. a-Synuclein has been reported to be a major component of LBs in PD, dementia with LBs and common variants of Alzheimer’s disease. However, in continuation of the study, similar experiments in 2002 failed to demonstrate elevated anti-a-synuclein and anti-EBV latent membrane protein antibodies in PD, thus refuting the association between the virus and PD (Woulfe et al., 2002).
In early 2003, an international team of scientists conducted a genome scan in Vietnamese multiplex leprosy families and found that susceptibility to leprosy was significantly linked to region q25 on the long arm of chromosome 6 (Buschman and Skamene, 2004). In a continuation of these findings, the team has pinpointed the chromosome 6 susceptibility locus to the 5 regulatory promoter region shared by both the PD gene PARK2 and its co-regulated gene PACRG. The surprising discovery has important implications for the understanding of leprosy pathogenesis and for the strategy of genetic analysis of infectious diseases.
49.3.6. Transmissible spongiform encephalopathy (prion protein-related disorders)
49.4. Animal studies There are reports of parkinsonism developing in the context of CJD. A case of coexistent clinical findings of idiopathic PD and CJD was described in 1985 and confirmed at autopsy (Ezrin-Waters et al., 1985). An unusual case of CJD was identified in 1998, in Geneva, Switzerland (Vingerhoets et al., 1998), where
Potential associations between PD or parkinsonismlike disease and exposure to various infectious agents have been demonstrated in some animal studies. The development of a rhythmic, uncontrolled vertical shake of the head (4–5/second), tremulous
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movement, stooped posture and restlessness in female BALB/c mice (head shakes were temporarily stopped by treatment with levodopa) following intravenous injection of various doses of log-phase Nocardia asteroides GUH-2 has been reported (Kohbata and Beaman, 1991). Studies show localization and growth of nocardial cells within the brains and loss of Nissl substance and tyrosine hydroxylase immunoreactivity in the neurons of SN. Therefore, the authors speculate that mice infected with N. asteroides may serve as a model for studying parkinsonian signs and other degenerative diseases involving extrapyramidal and pyramidal systems. In another study, in vivo and in vitro models were utilized to measure the ability of N. asteroides GUH-2, a neuroinvasive strain, to induce the apoptotic death of dopaminergic cells (Tam et al., 2002). Apoptosis has been implicated in dopaminergic neuronal dropout in Parkinson’s patients, causing a levodopa-responsive movement disorder resembling parkinsonism. Following infection with GUH-2, dopaminergic apoptotic cells were identified in the SN of animals by in situ end-labeling, which detects DNA fragmentation, combined with fluorescent immunolabeling of tyrosine hydroxylase-positive cells. Nocardia otitidiscaviarum (GAM-5), isolated from a patient with an actinomycetoma, produced signs similar to PD following a non-lethal dose of intravenous injection into Naval Medical Research Institute (NMRI) mice (Diaz-Corrales et al., 2004). Fourteen days after bacterial infection, most of the 60 mice injected exhibited parkinsonian features characterized by vertical head tremor, akinesia/bradykinesia, flexed posture and postural instability. Dopamine levels were reduced from 110 32.5 to 58 16.5 ng/mg protein (47.2% reduction) in brain from infected mice exhibiting impaired movements, whereas serotonin levels were unchanged (191 44 ng/mg protein in control and 175 39 ng/mg protein in injected mice). Chapman et al. (2003) developed an in situ hybridization technique to detect nocardial 16S ribosomal RNA, using a Nocardia-specific probe (B77) in the cerebral cortical specimens from cynomolgus monkeys at 48 hours, 3.5 months and 1 year after experimental infection with N. asteroides. This in situ hybridization procedure, applied in a blinded fashion to human SN specimens with LBs, detected similar reactivity in inclusions with the appearance of LBs, suggesting a possible association between Nocardia and neurodegenerative disorders in which LBs are present. In 2004 a German study measured levels of dopamine and its metabolites, homovanillic acid and 3,4dihydroxyphenylacetic acid, in brains of uninfected and simian immunodeficiency virus (SIV)-infected
rhesus monkeys during the asymptomatic stage of the infection (Jenuwein et al., 2004). Changes in cyclic adenosine monophosphate (cAMP) and cAMP response element-binding protein (CREB), two factors involved in the signaling pathway of dopamine, were also investigated. The brain regions examined were the nucleus accumbens and the corpus amygdaloideum, which are limbic structures of the basal ganglia that are involved in the pathophysiology of psychiatric disorders and substance abuse. Dopamine content was reduced in both regions, nucleus accumbens and the corpus amygdaloideum (limbic structures of the basal ganglia that are involved in the pathophysiology of psychiatric disorders) of SIV-infected monkeys compared to uninfected animals. Moreover, dopamine deficits were associated with a decrease in the expression of total CREB. Changes in dopamine signaling were not related to pathology or viral load of the investigated animals.
49.5. Conclusion The precise cause of PD remains unknown. Environmental factors, with their possible effects on genetic susceptibility, are possible causal mechanisms. Infections may form part of the environmental insult which may predispose to PD or parkinsonism. However, the evidence is weak and largely based on anecdotal reports. The most robust causative link of PD/parkinsonism and infection is the emergence of PEP, although the current rates of prevalence and incidence of PD do not suggest a stray/infective encephalopathic basis.
Acknowledgments We acknowledge the contribution of the following fourth-year medical students, Gillian Lapthorn and Yolanda Sydney Augustin, who performed their study modules based on the theme of this article at Guy’s, King’s and St. Thomas’s School of Medicine, London, UK.
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Maggi P, De Mari M, Moramarco A et al. (2000). Parkinsonism in a patient with AIDS and cerebral opportunistic granulomatous lesions. Neurol Sci 21: 173–176. Martyn CN (1997). Infection in childhood and neurological diseases in adult life. Br Med Bull 53: 24–39. Mirsattari SM, Power C, Nath A (1998). Parkinsonism with HIV infection. Mov Disord 13: 684–689. Nath A, Jankovic J, Pettigrew LC (1987). Movement disorders and AIDS. Neurology 37: 37–41. Nitrini R, Teixeira da Silva LS, Rosemberg S et al. (2001). Prion disease resembling frontotemporal dementia and parkinsonism linked to chromosome 17. Arq Neuropsiquiatr 59: 161–164. Peatfield RC (1987). Basal ganglia damage and subcortical dementia after possible insidious Coxsackie virus encephalitis. Acta Neurol Scand 76: 340–345. Picard F, de Saint-Martin A, Salmon E et al. (1996). Postencephalitic stereotyped involuntary movements responsive to L-Dopa. Mov Disord 11: 567–570. Poskanzer DC, Schwab RS (1963). Cohort analysis of Parkinson’s disease: Evidence for a single etiology related to subclinical infection about 1920. J Chronic Dis 16: 961–973. Pradhan S, Pandey N, Shashank S et al. (1999). Parkinsonism due to predominant involvement of substantia nigra in Japanese encephalitis. Neurology 53: 1781–1786. Richards M, Chaudhuri KR (1996). Parkinson’s disease in populations of African origin. Neuroepidemiology 15: 214–221. Salman H, Bergman M, Djaldetti R et al. (1999). Decreased phagocytic function in patients with Parkinson’s disease. Biomed Pharmacother 53: 146–148.
Shimamura M, Uyama E, Hirano T et al. (2003). A unique case of sporadic Creutzfeldt-Jacob disease presenting as progressive supranuclear palsy. Intern Med 42: 195–198. Stoessl AJ (1999). Etiology of Parkinson’s disease. Can J Neurol Sci 26 (Suppl 2), S5–S12. Tam S, Barry DP, Beaman L et al. (2002). Neuroinvasive Nocardia asteroides GUH-2 induces apoptosis in the substantia nigra in vivo and dopaminergic cells in vitro. Exp Neurol 177: 453–460. Tolge CF, Factor SA (1991). Focal dystonia secondary to cerebral toxoplasmosis in a patient with acquired immue deficiency syndrome. Mov disord 6: 69–72. Tse W, Cersosimo M, Gracies J et al. (2004). Movement disorders and AIDS: A review. Parkinsonism Relat Disord 10: 323–334. Vingerhoets FJ, Hegyi I, Aguzzi A et al. (1998). An unusual case of Creutzfeldt-Jakob disease. Neurology 51: 617–619. Werring DJ, Chaudhuri KR (1996). Human Immunodeficiency virus-related progressive multifocal leukoencephalopathy presenting with an akinetic rigid syndrome. Mov Disord 11: 758–761. Wlodarek D, Pakszys W, Bujko J (2003). Helicobacter pylori infection and its influence on Parkinson’s disease. Pol Merkuriusz Lek 15: 428–431. Woulfe J, Hoogendoorn H, Tarnopolsky M et al. (2000). Monoclonal antibodies against Epstein-Barr virus crossreact with alpha-synuclein in human brain. Neurology 55: 1398–1401. Woulfe JM, Duke R, Middeldorp JM et al. (2002). Absence of elevated anti-alpha-synuclein and anti-EBV latent membrane protein antibodies in PD. Neurology 58: 1435–1436.
Handbook of Clinical Neurology, Vol. 84 (3rd series) Parkinson’s disease and related disorders, Part II W. C. Koller, E. Melamed, Editors # 2007 Elsevier B. V. All rights reserved
Chapter 50
Toxic causes of parkinsonism NIRIT LEV*, ELDAD MELAMED AND DANIEL OFFEN Laboratory of Neuroscience and Department of Neurology, Rabin Medical Center, Petah-Tikva, Tel Aviv University, Tel Aviv, Israel
50.1. Introduction Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, affecting 1% of the population over 65 years of age. Clinically, most patients present with a motor disorder and suffer from bradykinesia, resting tremor, rigidity and postural instability. Other manifestations include behavioral, cognitive and autonomic disturbances. Pathologically, PD is characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta. However, PD is a widespread neurodegenerative disease, which affects multiple areas in the central as well as the peripheral nervous systems. The pathologic hallmark of PD is the appearance of cytoplasmic inclusions, named Lewy bodies. Lewy bodies contain a heterogeneous mixture of insoluble, filamentous proteins and lipids, including a-synuclein, ubiquitin, neurofilaments and oxidized/nitrated proteins (Betarbet et al., 2002). Nigral pathology in parkinsonian patients has been shown to be associated with oxidative stress, mitochondrial dysfunction, excitotoxicity and inflammation. Oxidative stress-related changes, including oxidative damage to proteins, lipids and DNA, as well as decreased levels of reduced glutathione, have been detected in PD brains (Jenner, 1998; Sherer et al., 2003). Reactive oxygen species (ROS) are generated during dopamine metabolism and by mitochondrial respiration (Bahat-Stroomza et al., 2005). Within complex I there is a site of electron leakage that produces ROS (Kushnareva et al., 2002) and impaired complex I activity enhances ROS formation (Betarbet et al., 2002; Kushnareva et al., 2002). Failure of another system, the ubiquitin-proteasome system (UPS), to clear
unwanted proteins leading to the accumulation and aggregation of cytotoxic proteins, has recently been shown to play a major role in the pathogenesis of both familial and sporadic forms of PD (McNaught et al., 2002; Elkon et al., 2004). PD is a multifactorial disease caused by both genetic and environmental factors. However, most PD patients suffer from a sporadic disease. The etiology of sporadic PD is largely unknown and epidemiological studies are conducted in order to define factors increasing the risk for developing PD. Factors that may predispose to dopaminergic cell loss, including mitochondrial dysfunction and oxidative damage, could be common to separate genetic and environmental etiologies. Several studies were conducted in order to assess the influence of hereditary factors of PD by studying monozygotic (MZ) and dizygotic (DZ) twin pairs. These studies, relying on [18F]-dopa positron emission tomography (PET) findings, did find higher concordance for subclinical striatal dopaminergic dysfunction in twins (Burn et al., 1992; Holthoff et al., 1994; Piccini et al., 1999; Laihinen et al., 2000). However, several large studies based on clinical evaluation of PD found low concordance rates for twins, emphasizing environmental factors as the major risk factors for PD (Duvoisin et al., 1981; Ward et al., 1983; Marttila et al., 1988; Vieregge et al., 1992, 1999; Tanner et al., 1999; Wirdefeldt et al., 2004, 2005). These findings indicate that genetic factors do not play a major role in causing typical PD (when the disease begins after the age of 50 years). The search for environmental risk factors for PD revealed several risk factors as well as protective factors associated with PD. An inverse association
*Correspondence to: Dr. Nirit Lev, Laboratory of Neuroscience and Department of Neurology, Rabin Medical Center, Petah-Tikva 49100, Israel. E-mail:
[email protected], Tel: 972-3-937-6276, Fax: 972-3-937-6277.
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between smoking and PD was reported in many studies (Grandinetti et al., 1994; Hernan et al., 2001; Wirdefeldt et al., 2005). Nevertheless, the presence of a confounder has not been ruled out. A recent study found an increased risk for PD with several occupations: farming, health care and teaching (Goldman et al., 2005). There is a growing body of evidence implicating rural living, consumption of well water, farming and pesticide exposure as environmental risk factors for PD (Liou et al., 1997; Priyadarshi et al., 2001). A meta-analysis of 22 epidemiologic studies done by Priyadarshi et al. (2001) found that the odds ratio (OR) for rural living is 1.56 (95% confidence interval (CI) 1.17–2.07) and that the highest risk was 4.9 (95% CI 1.4–18.2) for living in a rural area for more than 40 years. Exposure to well water and the risk of contracting PD yielded a combined OR of 1.26 (95% CI 0.96–1.64), increasing to 3.28 (95% CI 0.93–11.51) for exposure to well water for at least 1 year (Priyadarshi et al., 2001). Farming was also associated with an increased risk of getting PD, with combined OR of 1.42 (95% CI 1.05–1.91), (OR 5.2, 95% CI 1.6–17.7, for farming over 20 years) (Priyadarshi et al., 2001). The association of rural living, farming and well-water drinking with PD may be related to exposure to potential neurotoxins present in these areas, such as pesticides. In contrast, Tanner et al. (1989) found that in China, living in a village was associated with a decreased risk for PD, whereas occupational or residential exposure to industrial chemicals, printing plants or quarries was associated with an increased risk of developing PD. These findings are consistent with the hypothesis that environmental exposure to certain agricultural or industrial chemicals may be related to the development of PD. The concept of ‘silent neurotoxicity’ suggests that a developmental exposure to a toxin may significantly increase the vulnerability of the dopaminergic system, which is unmasked by later challenges to the dopamine system (Thiruchelvam et al., 2002; Uversky, 2004; Cory-Slechta et al., 2005). Exposure to pesticides during the postnatal period can produce permanent and progressive lesions of the nigrostriatal dopamine system and enhanced adult susceptibility to these pesticides. Inflammation of the brain in early life caused by exposure to infectious agents, toxicants or environmental factors has been suggested as a possible cause or contributor to the later development of PD (Liu et al., 2003). The inflammatory process in such cases may involve activation of brain immune cells (microglia and astrocytes), which release inflammatory and neurotoxic factors that in turn produce neurodegeneration (Liu and Hong, 2003). The finding of toxic causes of PD had a tremendous importance on the scientific study of PD since it
helped develop animal models for this disease. The two most common, classic animal models of PD rely on toxic-induced parkinsonism induced by 1-methyl4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA) (Schober, 2004). Other animal models were generated following the discovery that agricultural chemicals, such as rotenone, maneb and paraquat, when administered systemically, can also induce specific features of PD (Betarbet et al., 2002). In this chapter, we describe the current knowledge of PD induced by neurotoxic compounds.
50.2. Agricultural chemicals Several clinical and epidemiologic studies have demonstrated that exposures to certain chemicals are associated with increased incidence of PD (Landrigan et al., 2005). Exposure to pesticides yielded an increased risk for getting PD with combined OR of 1.85 (95% CI 1.31–2.60), with exposure for over 10 years increasing the risk to 5.81 (95% CI 1.99–16.97) (Priyadarshi et al., 2001). Baldi et al. (2003) found an association between past occupational exposure to pesticides, low cognitive performance and an increased risk of developing PD. Levels of organochlorines have been found to be elevated in the brains of persons with PD (Fleming et al., 1994; Corrigan et al., 2000). Epidemiologic data suggest a positive dose–response relationship between lifetime cumulative exposure to paraquat and risk of PD (Liou et al., 1997). 50.2.1. Rotenone Rotenone (Fig. 50.1A) is a natural compound, used as an insecticide and a herbicide. Rotenone is a naturally occurring complex ketone, derived from the roots of Lonchocarpus species (Uversky, 2004). It is a commonly used pesticide and is also used in lakes and reservoirs to kill fish that are perceived as pests. Gardeners commonly use it as the active ingredient of derris dust or liquid preparations of derris, described as ‘natural herbicide’, which are commonly found on the shelves of garden centers (Jenner, 2001). Rotenone is a highly lipophilic compound and readily crosses the blood– brain barrier (Betarbet et al., 2002; Uversky, 2004). Rotenone is a highly selective inhibitor of complex I of the mitochondrial respiratory chain (Sherer et al., 2003). Sherer et al. (2003) demonstrated that rotenone toxicity involved an oxidative mechanism. In neuroblastoma cells and a chronic midbrain slice model, rotenone toxicity depended on an interaction with complex I and was attenuated by antioxidants, suggesting a causal role for oxidative damage. Rotenone
TOXIC CAUSES OF PARKINSONISM
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Fig. 50.1. Pesticides and herbicides: chemical structure of (A) rotenone, (B) paraquat, (C) maneb and (D) atrazine.
toxicity depended on a direct interaction with complex I, because cells expressing the rotenone-insensitive, single-subunit NADH dehydrogenase of yeast, NDI1, were resistant to rotenone toxicity. In this system, electrons from complex I substrates are shunted through NDI1 into downstream portions of the electron transport chain, thereby allowing mitochondrial respiration. Rotenone toxicity does not result solely from a bioenergetic defect since brain levels of rotenone after chronic exposure are not sufficient to alter mitochondrial respiration in isolated brain mitochondria (Betarbet et al., 2000). In addition, Sherer et al. (2003) found that similar adenosine triphosphate depletion induced by 2-deoxyglucose was not toxic as rotenone exposure. Panov et al. (2005) recently demonstrated that it is not the primary inhibitory effect of rotenone on the electron transport activity of complex I, but the resulting secondary mechanism, increased superoxide radical production, that is responsible for the development of further structural and functional damages to the mitochondria. They also found that in vivo rotenone toxicity results in a substantial loss of activity not only of complex I, but also of complex II, probably mediated by ROS (Panov et al., 2005). The animal model induced by chronic systemic rotenone administration includes clinical and pathologic features similar to those of human PD, including selective chronic and progressive degeneration of the nigrostriatal system and the formation of inclusion
bodies similar to Lewy bodies (Betarbet et al., 2002). It also induces oxidative stress and mitochondrial complex I inhibition, found in human patients (Betarbet et al., 2000, 2002; Liu et al., 2003; Sherer et al., 2003). Rotenone infusion by osmotic pumps can induce a chronically progressive degeneration of dopaminergic and of some non-dopaminergic neurons in both the basal ganglia and the brainstem (Hirsch et al., 2003). Behaviorally, rotenone induces hypokinesia, flexed posture and, in some rats, rigidity and paw shaking, clinical findings that are similar to PD (Betarbet et al., 2002). The rotenone-induced degeneration of dopaminergic neurons may not be solely attributable to an impairment of neuronal mitochondrial complex I activity but may also involve the activation of microglia (Gao et al., 2002, 2003b). In vitro, rotenone-induced microglial activation occurs before apparent neurodegeneration (Gao et al., 2002). Activated microglia upregulate cell surface markers such as the macrophage antigen complex I and produce a variety of proinflammatory cytokines, leading to ROS production. Synergistic dopaminergic neurotoxicity was found with combined exposure to rotenone and the inflammogen lipopolysaccharide (Gao et al., 2003a). Therefore, the rotenone-induced animal model for PD recapitulates most of the pathological and clinical features of PD, as well as central pathophysiological mechanisms of the disease, strengthening the environmental hypothesis of PD.
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50.2.2. Paraquat
50.2.4. Atrazine
An etiologic link has been suggested between PD and the herbicide paraquat (1,10 -dimethyl-4,40 -bipyridinium) (Fig. 50.1B) (Brooks, 1999; McCormack et al., 2002). Paraquat is structurally similar to 1methyl-4-phenylpyridinium ion (MPPþ), the active metabolite of MPTP (Uversky, 2004). The major neurotoxic effect of paraquat is through the production of ROS (Uversky, 2004). Paraquat crosses the blood–brain barrier slowly, inefficiently and to a limited extent. However, detectable levels of the herbicide have been measured in the central nervous system after its systemic injection into rodents (Corasaniti et al., 1998). In experimental studies in which paraquat has been administered to animals, researchers have observed loss of substantia nigra dopaminergic neurons, depletion of dopamine, reduced ambulatory activity and apoptotic cell death (Liu and Hong, 2003; Liu et al., 2003). Subchronic exposure to paraquat causes a dose-dependent decrease in substantia nigra dopaminergic neurons, some decrease in striatal dopamine nerve terminal density and also induces neurobehavioral syndrome characterized by reduced ambulatory activity (Brooks et al., 1999; Di Monte, 2001). The exposure of mice to paraquat leads to a significant increase in brain levels of a-synuclein and accumulation of a-synuclein-containing inclusions within neurons of the substantia nigra pars compacta, similar to Lewy bodies (Manning-Bog et al., 2002).
Atrazine (2-chloro-4-ethylamino-6-isopropylamino-Striazine) (Fig. 50.1D), a chlorinated member of the family of S-substituted triazines, is one of the most widely employed herbicides in the world. It acts to suppress photosynthesis by inhibiting electron transfer at the reducing site of chloroplast complex II (Rodriguez et al., 2005). Although it has limited solubility in water, atrazine is frequently detected in ground and surface waters in agricultural regions (Rodriguez et al., 2005). Rodriguez et al. (2005) demonstrated that sustained low-level atrazine exposure in the diet can adversely affect dopaminergic tracts of the central nervous system, resulting in persistent increases in locomotor activity, alterations in responsivity to the indirect dopamine agonist amphetamine, changes in monoamine levels and loss of neurons in the midbrain. Chronic atrazine exposure caused cell loss of both tyrosine hydroxylase (TH)-immunoreactive cells and TH-negative cells in the ventral tegmental area and substantia nigra (Rodriguez et al., 2005).
50.2.3. Maneb The organomanganese fungicide maneb (Fig. 50.1C), which is largely used in agricultural regions for the control of field crop pathologies, has been implicated in PD. Maneb contains a major active fungicidal component, manganese ethylene-bis-dithiocarbamate (MnEBDC) and belongs to the dithiocarbamate fungicide family. Permanent parkinsonism has been reported in a man with chronic exposure to maneb (Meco et al., 1994). Administration of maneb to experimental animal models has a depressant-like effect on the central nervous system, involving the dopaminergic systems (Uversky, 2004). In animal studies, early-life exposure to a combination of paraquat and maneb produced destructive effects on the nigrostriatal dopaminergic system and abnormalities in motor response that were more severe than those produced by either agent alone (Thiruchelvam et al., 2000). These effects were escalated by aging (McCormack et al., 2002; Thiruchelvam et al., 2003). Exposure to maneb was also reported to enhance MPTP uptake and to amplify its neurotoxicity (Uversky, 2004).
50.2.5. Organochlorine compounds High levels of organochlorine compounds in the substantia nigra of PD brains were found, as compared to the levels in cortical Lewy body dementia, Alzheimer’s disease and non-demented non-parkinsonian controls (Corrigan et al., 2000). The levels of the gamma isomer of hexachlorocyclohexane (gamma-HCH, lindane; Fig. 50.2A) were significantly higher in PD tissues than in the other three groups (P < 0 .05). Dieldrin (HEOD) was higher in PD brain than in Alzheimer’s disease or control brain, whereas 1,10 -(2,2-dichloroethenyl diene)-bis(4-chlorobenzene) ( p, p-DDE; Fig. 50.2B) and total Aroclor-matched polychlorinated biphenyls were
Cl
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Fig. 50.2. Organochlorine compounds: chemical structure of (A) gamma-hexachlorocyclohexane (lindane) and (B) 1,10 (2,2-dichloroethenyl diene)-bis(4-chlorobenzene ( p,p-DDE).
TOXIC CAUSES OF PARKINSONISM higher in PD compared with cortical Lewy body dementia. Bhatt et al. (1999) described 5 patients who developed acute reversible parkinsonism following organophosphate pesticide exposure. Three of these patients were family-related, therefore a genetic susceptibility to organochlorine pesticide-induced parkinsonism may account for susceptibility for developing this syndrome. These findings support the hypothesis derived from epidemiological work and animal studies that organochlorine insecticides produce a direct toxic action on the dopaminergic tracts of the substantia nigra and may contribute to the development of PD.
50.3. Metals The possible involvement of heavy metals in the etiology of PD follows primarily from the results of epidemiological studies. In particular, exposure to manganese, copper, lead, iron, mercury, zinc and aluminum appears to be a risk factor for PD (Uversky et al., 2001). Long-term occupational exposure to copper and manganese individually, as well as to dual combinations of lead, copper and iron, were found to indicate a significant risk for PD (Gorell et al., 1997, 1999, 2004). Analysis of the PD mortality rates in Michigan (1986–1988) with respect to potential heavy-metal exposure revealed that counties with an industry in the paper, chemicals, iron or copper-related categories had significantly higher PD death rates than counties without these industries (Rybicki et al., 1993). Another epidemiological study established an increased risk for PD with occupational exposure to manganese, iron and aluminum, especially when the duration of exposure is longer than 30 years (Zayed et al., 1990). Quantifications of aluminum, calcium, copper, iron, magnesium, manganese, silicon and zinc were performed in urine, serum, blood and cerebrospinal fluid (CSF) of 26 PD patients (Forte et al., 2004). The results indicate the involvement of iron and zinc (increased concentration in blood) as well as of copper (decreased serum level) in PD (Forte et al., 2004). Postmortem analysis of brain tissues from patients with PD revealed an increase in total iron and zinc content of the parkinsonian substantia nigra, whereas copper levels were reduced and manganese levels were unchanged (Dexter et al., 1991, 1992). Moreover, several di- and trivalent metal ions caused significant acceleration in the rate of a-synuclein fibril formation (Uversky et al., 2001). Aluminum was the most effective, along with copper, iron, cobalt and manganese. The effectiveness correlated with increasing ion charge density (Uversky et al., 2001).
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50.3.1. Iron A central role of iron in the pathogenesis of PD, due to its increased levels in substantia nigra pars compacta dopaminergic neurons (Dexter et al., 1991, 1992; Double et al., 2000) and reactive microglia and its capacity to enhance production of ROS, has been discussed for many years. Moreover, analysis of Lewy bodies in the parkinsonian substantia nigra revealed high levels of iron and the presence of aluminum (Hirsch et al., 1991). Besides the accumulation of iron in the substantia nigra of PD brains, derangements in iron metabolism were identified. The substantia nigra of the PD brain is characterized by a shift in the Fe2þ/Fe3þ ratio in favor of Fe3þ (Berg et al., 2001). Furthermore, mutated iron metabolism genes have now been shown to be involved in neurodegeneration (Felletschin et al., 2003; Grunblatt et al., 2004). The observations of the ability of iron to induce aggregation and toxicity of a-synuclein have reinforced the critical role of iron in the pathogenesis of nigrostriatal injury (Berg et al., 2001). Thus, iron redox state constitutes a pivotal factor contributing to the extent of protein misfolding and aggregation in the substantia nigra of PD patients. Unilateral injection of FeCl3 into the substantia nigra of adult rats resulted in a substantial selective decrease of striatal dopamine (95%) (Ben-Shachar and Youdim, 1991). Dopamine-related behavioral responses, such as spontaneous movements in a novel space and rearing, were significantly impaired, whereas amphetamine administration induced ipsilateral rotation in the iron-treated rats (Ben-Shachar and Youdim, 1991). Wesemann et al. (1994) found that intranigral-injected iron progressively reduces striatal dopamine metabolism. Neuromelanin has the ability to bind a variety of metals and up to 20% of the total iron contained in the substantia nigra from normal subjects is bound within neuromelanin. Increased tissue iron found in the parkinsonian substantia nigra may saturate iron-chelating sites on neuromelanin (Gerlach et al., 2003). It is hypothesized that this redox-active iron could be released and involved in a Fenton-like reaction, leading to an increased production of oxidative radicals. The resultant radical-mediated cytotoxicity may contribute to cellular damage observed in PD. These studies indicate that the nigrostriatal dopaminergic neurons are susceptible to the presence of ionic iron and support the assumption that iron causes dopaminergic neurodegeneration in PD. 50.3.2. Manganese Manganese, an essential trace element, is one of the most used metals in the industry. It is employed in
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the manufacture of steel and batteries, in water purification, in bactericidal and fungicide agents and as an antiknock agent in gasoline. Recently, several new manganese compounds have been introduced as fungicide, as antiknock agent in petrol (Mn tricarbonyl, MMT) and as contrasting agent in nuclear magnetic resonance tomography (MnDPDP) (Gerber et al., 2002). Manganese is relatively non-toxic to the adult organism, except to the brain, where it causes Parkinson-like symptoms when it is chronically inhaled, even at moderate amounts (Gerber et al., 2002). Manganism was reported in manganese miners (Mergler and Baldwin, 1997). Hudnell (1999) found that the risk of a Parkinson-like syndrome diagnosis is increased with continued manganese exposure and aging. Chronic exposure to high levels of this metal causes accumulation in the basal ganglia, resulting in manganism, characterized by tremors, rigidity and psychosis. A cohort of patients who worked in a manganesesmelting plant in Taiwan developed parkinsonism that was almost certainly due to manganese intoxication. Six of 13 individuals chronically exposed to a very high ambient concentration of manganese developed basal ganglia syndrome, characterized by gait dysfunction, with particular difficulty walking backwards, bradykinesia, micrographia and hypophonia (Olanow, 2004). Some of the patients also had dystonia and intermittent tremor (Olanow, 2004). Patients with manganeseinduced parkinsonism were reported to have a normal striatal fluorodopa uptake on PET (Olanow, 2004). However, a recent study reported decreased putamenal fluorodopa uptake on PET (Racette et al., 2005). Dopamine transporter (DAT) scan showed a slight decrease in the putamen of manganism patients as compared with that of the normal controls. It seems, then, that the presynaptic dopaminergic terminals are not the main targets of chronic manganese intoxication (Huang et al., 2003). Exposure of dopaminergic cells to an organic form of manganese compound, methylcyclopentadienyl manganese tricarbonyl (MMT), resulted in a rapid increase in the generation of ROS, followed by the release of mitochondrial cytochrome c into the cytoplasm and
subsequent activation of caspase-9 and caspase-3. Caspase-3-dependent proteolytic activation of protein kinase C (PKC) delta was demonstrated to play a role in oxidative stress-mediated apoptosis in dopaminergic cells after exposure to manganese (Anantharam et al., 2002). 50.3.3. Copper Copper(II) was found to be the most effective metal ion affecting a-synuclein to form oligomers (Paik et al., 1999). Copper was recently found to promote a-synuclein aggregation at physiologically relevant concentrations by binding to the N-terminus (for which copper has the highest affinity) (Rasia et al., 2005). These findings support the notion of PD as a metalassociated neurodegenerative disorder.
50.4. MPTP In 1982 severe Parkinson-like symptoms were described among a group of drug users in northern California who had taken synthetic heroin contaminated with MPTP (Fig. 50.3A) (Davis et al., 1979; Langston et al., 1983, 1999; Ballard et al., 1985). Exposure to MPTP produced bradykinesia and rigidity almost identical to those of idiopathic PD and severe loss of dopaminergic neurons in the substantia nigra (Davis et al., 1979; Langston et al., 1999). These patients responded to treatment with levodopa or bromocriptine, but rapidly developed treatment-related complications, including fluctuations and dyskinesias (Ballard et al., 1985; Langston et al., 1999). In some patients, MPTP-induced PD appeared almost immediately after exposure, whereas in others, onset became evident only months or years later, reflecting a progressive neurodegenerative process. MPTP was shown to act selectively, specifically injuring dopaminergic neurons in the nigrostriatal system in humans as well as in experimental animals (Langston et al., 1999). Evidence was also found for ongoing dopaminergic nerve cell loss without Lewy body formation in these patients (Langston et al., 1999). Many years
NH2 HO N
CH3 OH
A
B
OH
Fig. 50.3. Chemical structure of (A) 1-methyl-4-phenylpyridinium ion (MPPþ) and (B) 6-hydroxydopmaine.
TOXIC CAUSES OF PARKINSONISM later, postmortem examination of brains from persons exposed to MPTP showed a marked microglial proliferation in the substantia nigra pars compacta (Orr et al., 2002). MPTP is highly lipophilic and after systemic administration rapidly crosses the blood–brain barrier. Subsequently, the protoxin MPTP is converted to 1-methyl-4-phenyl-2,3-dihydropyridium (MPDP) exclusively in non-dopaminergic cells (especially in astrocytes and serotonergic neurons) by monoamine oxidase B (MAO-B) and then spontaneously oxidizes to MPPþ and is released into the extracellular space (Nicklas et al., 1987; Przedborski et al., 2001; Przedborski and Vila, 2003). MPPþ enters the dopaminergic neurons through DAT, as well as via the norepinephrine and serotonin transporters (Javitch et al. 1985; Mayer et al., 1986). Inside dopaminergic neurons, MPPþ can bind to the vesicular monoamine transporter, which is associated with an incorporation of MPPþ into synaptic vesicles containing dopamine (Del Zompo et al., 1993). In addition, MPPþ can accumulate within mitochondria, where it inhibits complex I (Nicklas et al., 1987; Mizuno et al., 1987), or it can remain inside the cytoplasm and interact with cytosolic enzymes (Klaidman et al., 1993). Since MPPþ is selectively taken up into dopaminergic neurons through the DAT and acts as a potent inhibitor of mitochondrial complex I, it selectively poisons the dopaminergic neurons. Surprisingly, Smeyne et al. (2005) found that the susceptibility of substantia nigra dopaminergic neurons to MPTP was inversely related to the number of astrocytes. They also found that Swiss Webster (MPTP-resistant) mice have a greater number of astrocytes and a lower number of microglia than C57Bl/6J (MPTP-sensitive) mice. Astrocytes appear to provide protection to neurons against ROSmediated toxicity by multidimensional mechanisms involving glutathione, phase II detoxifying enzymes and neuronal growth factors (Smeyne et al., 2005). One of the major implications of the discovery of MPTP was the production of an effective experimental model of PD by systemic toxin administration (Jenner, 2003). When injected into mice, MPTP causes a PDlike syndrome with massive loss of nigral dopaminergic neurons and striatal dopamine. MPTP injections do not induce neuronal inclusions characteristic of PD even after repeated injections (Vila et al., 2000). Fornai et al. (2005) have recently developed a mouse PD model that is based on continuous MPTP administration with an osmotic minipump that produced progressive behavioral changes and triggered severe striatal dopamine depletion with the formation of nigral inclusions immunoreactive for ubiquitin and a-synuclein. This continuous MPTP administration also led to the inhibition of the UPS (Fornai et al., 2005). The toxic
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effects of MPTP on nigral dopaminergic cells were most evident in primates, therefore MPTP-lesioned monkeys were developed and have now become the most relevant and extensively used animal model of PD (Burns et al., 1983; Stern, 1990). However, the MPTP-treated primate is a model of selective nigral destruction and does not reflect other pathological features of PD. MPTP is mainly used in non-human primates and in mice but also in several other species, such as dogs, cats, sheep, rats and goldfish (Schober, 2004). Biochemical and histological investigations have demonstrated that MPTP-induced parkinsonism reflects the human disease and has been important for understanding the pathophysiology of PD as well as for the evaluation of the effects of various drug therapies and efficacy of new surgical techniques such as fetal grafts, pallidotomy and deep brain stimulation (Jenner, 2003).
50.5. Isoquinoline derivatives Various isoquinoline derivatives were found in the brain and are considered to be the endogenous neurotoxins with neurochemical properties similar to those of MPTP (Nagatsu, 1997; Antkiewicz-Michaluk, 2002; Naoi et al., 2002; Storch et al., 2002). Among them, 1,2,3,4-tetrahydroisoquinoline (TIQ), 1-benzyl-TIQ and 1-methyl-5, 6-dihydroxy-TIQ (salsolinol) have the most potent neurotoxic action (Nagatsu, 1997; Antkiewicz-Michaluk, 2002). N-methyl-(R)-salsolinol, a dopamine-derived alkaloid, selectively occurs in human brains and accumulates in the nigrostriatal system (Naoi et al., 2002). N-methyl-(R)-salsolinol is synthesized in the human brain by two enzymes, an (R)-salsolinol synthase and an N-methyltransferase, and accumulates in the nigrostriatum in human brains (Maruyama et al., 2000). The activity of a neutral N-methyltransferase in the striatum was found to determine the level of MPPþ-like 1,2-dimethyl-6,7-dihydroxyisoquinolinium ion, an oxidation product of N-methyl(R)-salsolinol in the substantia nigra (Maruyama et al., 2000). N-methyl-(R)-salsolinol is increased in the CSF of PD patients (Maruyama et al., 1999) and the activity of (R)-salsolinol N-methyltransferase is increased in lymphocytes from PD patients (Maruyama et al., 2000; Naoi et al., 2002). The studies of animal and cellular models of PD proved that salsolinol is selectively cytotoxic to dopamine neurons. Exposure of human dopaminergic neuroblastoma cells to salsolinol-induced apoptosis by the activation of the apoptotic cascade initiated in the mitochondria (Akao et al., 1999; Naoi et al., 2000). 2[N]-methylated isoquinoline derivatives structurally related to MPTP/MPPþ are selectively toxic to
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dopaminergic cells via uptake by the DAT and therefore may play a role in the pathogenesis of PD (Storch et al., 2002). Cell death induced by salsolinol is due to impairment of cellular energy supply, caused in particular by inhibition of mitochondrial complex II (succinate Q reductase) (Storch et al., 2000). On the other hand, (R)-salsolinol proved to scavenge hydroxyl radical produced by oxidation of dopamine (Naoi et al., 1998). The neurotoxicity and neuroprotection of catechol isoquinolines may be ascribed to their oxidation and scavenging of radicals. Since PD is a slowly progressing neurodegenerative disease, longterm neurotoxic effects of isoquinolines may have a central role in its progression.
50.6. 6-hydroxydopamine 6-OHDA (Fig. 50.3B)-induced nigrostriatal damage is today one of the most common animal models used in the research of PD. 6-OHDA is a hydroxylated analog of the natural neurotransmitter dopamine (Schober, 2004). 6-OHDA-induced toxicity is relatively selective for catecholaminergic neurons, resulting from a preferential uptake of 6-OHDA by dopamine and noradrenergic transporters (Schober, 2004). The mechanisms involved in 6-OHDA toxicity include respiratory inhibition and oxidative stress, induced by free radical formation. It is toxic to mitochondrial complex I (Betarbet et al., 2002) and leads to the formation of superoxide free radicals (Schober, 2004). Furthermore, it has been shown that 6-OHDA treatment reduces striatal glutathione and superoxide dismutase enzyme activity (Schober, 2004). Several studies have reported the presence of 6-OHDA in both rat and human brains as well as in the urine of levodopa-treated PD patients (Curtius et al., 1974; Andrew et al., 1993; Liao et al., 2003; Maharaj et al., 2005). Dopamine chemically reacts with iron and ascorbate, resulting in hydroxylated forms of dopamine products, such as 6-OHDA (Maharaj et al., 2005). 6-OHDA is easily oxidized and can also take part in free radical-forming reactions, such as the metabolic monoamine oxidation. Due to the high content of dopamine, hydrogen peroxide and free iron in dopaminergic neurons, a non-enzymatic reaction between these elements may possibly lead to the endogenous 6-OHDA formation (Jellinger et al., 1995; Linert et al., 1996). Animal models based on 6-OHDA toxicity are commonly used in the study of PD. Since systemically administered 6-OHDA fails to cross the blood–brain barrier, 6-OHDA has to be injected stereotactically into the brain. Preferred injection sites are the substantia nigra, medial forebrain bundle and striatum (Perese et al., 1989; Przedborski et al., 1995). In the unilateral
6-OHDA models, also known as ‘hemiparkinson model’, the intact hemisphere serves as internal control structure (Perese et al., 1989). Unilateral 6-OHDA injection causes an asymmetric and quantifiable motor behavior (rotations) induced by systemic administration of dopaminergic receptor agonists (e.g. apomorphine), levodopa or dopamine-releasing drugs (e.g. amphetamine).
50.7. Cycad (amyotrophic lateral sclerosis– parkinsonism dementia complex of Guam) The Chamorro people of Guam have been afflicted with a complex of neurodegenerative diseases known as amyotrophic lateral sclerosis–parkinsonism dementia complex (ALS-PDC) with similarities to ALS, Alzheimer’s disease and PD at a far higher rate than other populations throughout the world. Several other foci of endemic ALS-PDC were found in Asia and Oceania. Epidemiologic study has shown that preference for traditional Chamorro food is significantly associated with an increased risk for PD (Durlach et al., 1997). The toxic cycad seed that was used in traditional food and medicine was found to contain various toxins and particularly have an excitotoxic amino acid beta-Nmethylamino-L-alanine (L-BMAA) (Fig. 50.4) (Durlach
A H2N
B
CH2NHCH3 COOH
Fig. 50.4. Cycad toxin. (A) Cycad tree; (B) chemical structure of beta-methylaminoalanine (BMAA).
TOXIC CAUSES OF PARKINSONISM et al., 1997; Spencer et al., 2005). Traditional feasting on flying foxes may be related to the prevalence of neuropathologic disease in Guam, since consumption of a single flying fox may have resulted in an equivalent BMAA dose obtained from eating 174–1014 kg of processed cycad flour, sufficiently high to result in ALS-PDC neuropathologies (Cox and Sacks, 2002; Banack and Cox, 2003). Therefore, cycad neurotoxins are biomagnified within the Guam ecosystem. Apoptosis was identified in histological sections of brain and gut tissue of adult mice fed with seed preparations of cycad (Gobe, 1994). Shaw and Wilson (2003) developed an animal model of ALS-PDC which mimics all the essential features of the disease by feeding the animals with washed cycad seeds.
50.8. Annonacin An unusually high percentage of atypical forms of parkinsonism were discovered in Guadeloupe (French West Indies). The patients are characterized by levodopa-resistant symmetrical bradykinesia and rigidity, postural instability, dementia and, after 2–5 years, pseudobulbar palsy. The early occurrence of postural instability followed by vertical supranuclear palsy supported the diagnosis of progressive supranuclear palsy (PSP) in one-third of patients (Caparros-Lefebvre et al., 1999, 2002). The neurological syndrome was linked to regular consumption of tropical plants of the Annonaceae family, in particular Annona muricata (synonyms: corossol, soursop, guanabana, graviola), used for alimentary and medicinal purposes (Lannuzel et al., 2003). A similar clinical syndrome has also been reported in Afro-Caribbean and Indian immigrants in England who regularly consumed imported annonacea products (Chaudhuri et al., 2000). The validity of this association was strengthened by the partial regression of symptoms in young patients who stopped consuming these plants (Caparros-Lefebvre et al., 1999). Annonacin (Fig. 50.5) is highly toxic to dopaminergic and other mesencephalic neurons via a mechanism that is not excitotoxic and occurs independently of ROS (Lannuzel et al., 2003). Some of the compounds found in A. muricata are potent complex I inhibitors (Lannuzel et al., 2003). Annonacin was approximately
OH
50.9. Methanol Several case reports describe the development of parkinsonism as an acute or delayed toxic effect of exposure to vapors of methanol (McLean et al., 1980; Ley and Gali, 1983; Verslegers et al., 1988; Indakoetxea et al., 1990; Davis and Adair, 1999; Hageman et al., 1999; Finkelstein and Vardi, 2002). Methanol intoxication caused development of permanent parkinsonism (McLean et al., 1980; Ley and Gali, 1983; Verslegers et al., 1988; Indakoetxea et al., 1990). Chronic exposure, even without episodes of acute intoxication, caused parkinsonism, pyramidal signs, cognitive decline and unresponsiveness to levodopa (Hageman et al., 1999; Finkelstein and Vardi, 2002). The setting of prolonged exposure to methanol vapors may exist in research laboratories and other environments and pose the risk of similar delayed toxic influences.
50.10. Carbon monoxide poisoning Carbon monoxide (CO) exposure is a common cause of toxic brain damage and its effects range from transient neurological dysfunction to coma and death (Prockop, 2005). Parkinsonism is a common sequel of CO poisoning (Lee and Marsden, 1994; Choi and Cheon, 1999; Prockop, 2005). Choi and Cheon (1999) followed 242 patients with CO poisoning. Delayed movement disorder affected 13.2% of these patients, of whom 71.9% suffered from parkinsonism (9.5% of all patients with CO poisoning) (Choi and Cheon, 1999). Other movement disorders described after CO poisoning include dystonia, chorea, athetosis, tremor and myoclonus (Choi and Cheon, 1999). Movement disorders can develop during or immediately after acute CO poisoning, but are usually delayed for weeks after acute anoxia. The median latency between CO poisoning and the onset of parkinsonism was 4 weeks (Choi and Cheon, 1999). Most patients suffering from parkinsonism recovered gradually within 6 months (Choi and Cheon, 1999).
OH
O OH
OH
O H3C
(H2C)10
Fig. 50.5. Chemical structure of annonacin.
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as effective as rotenone but 50-fold more potent than the prototypical dopaminergic neurotoxin MPPþ (Lannuzel et al., 2003).
(H2C)4
(H2C)5
O
CH3
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Brain computed tomography findings of patients with parkinsonism after CO poisoning shows lowdensity lesions bilaterally in the white matter of the cerebral cortex and in the globus pallidus, which can also be seen in non-parkinsonian patients with CO poisoning (Lee and Marsden, 1994; Choi and Cheon, 1999). A spectrum of severity of magnetic resonance imaging (MRI) findings after CO poisoning was described, including globus pallidus and white-matter lesions (Sohn et al., 2000; Parkinson et al., 2002; Prockop, 2005). MR spectroscopy (MRS) shows decreased n-acetyl aspartase in the white matter and basal ganglia in some of the patients (Sohn et al., 2000; Prockop, 2005). Hara et al. (2002) studied the effects of CO exposure on the dopaminergic system in rats by in vivo brain microdialysis. Exposure of rats to CO (up to 0.3%) caused a marked increase in extracellular dopamine in the striatum, probably through stimulation of sodium-dependent dopamine release in addition to suppressing dopamine metabolism. CO withdrawal and subsequent reoxygenation enhanced the oxidative metabolism of the increased extracellular dopamine, preferentially mediated by MAO-A (Hara et al., 2002). These findings might imply that CO toxicity to the dopaminergic system is mediated, at least partially, through the toxicity of dopamine and its reactive substances, such as quinones and activated oxygen species, generated via dopamine oxidation.
50.11. Conclusions PD is a common and mostly sporadic disease. The pathogenesis of PD is likely multifactorial and involves genetic and environmental interactions. The discovery that MPTP could induce parkinsonism was the first substantial evidence that this complex disease could result from a single toxin. Evidence from multiple epidemiological studies emphasizes the roles of environmental risk factors. New findings arising from toxin-induced animal models of PD highlight the possibility that selective injury to the striatonigral dopaminergic system may arise not only from the distinctive properties of the toxin, but also from intrinsic susceptibility of the dopaminergic neurons. The dopaminergic neurons are more vulnerable than other cell populations to mitochondrial complex I inhibition and oxidative stress and several toxins implicated in PD were demonstrated to act through these mechanisms. These two mechanisms may be interrelated, since inhibition of complex I results in augmented production of ROS. Combinations of environmental risk factors may result in more profound nigrostriatal damage, as was shown in animal and in vitro studies. Early-life
exposure to toxins may also induce an increased vulnerability and enhanced adult susceptibility to toxins. These models of synergistic toxicity, as well as chemical-induced inflammatory response, may underlie the effects of environmental agents on the pathogenesis of PD. Another important factor is the individual susceptibility to a certain toxin defined by susceptibility genes in PD, therefore a combination of genetic and environmental factors is needed to produce the disease. Revelation of the environmental factors that lead to PD enabled the development of toxin-induced animal models for PD. These models have a critical role in the research of PD and enable the development and assessment of new therapeutic strategies.
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Further Reading Di Monte DA (2003). The environment and Parkinson’s disease: is the nigrostriatal system preferentially targeted by neurotoxins? Lancet Neurol 2: 531–538.
Handbook of Clinical Neurology, Vol. 84 (3rd series) Parkinson’s disease and related disorders, Part II W. C. Koller, E. Melamed, Editors # 2007 Elsevier B. V. All rights reserved
Chapter 51
Drug-induced parkinsonism ´ SIMO FEDERICO EDUARDO MICHELI* AND MARI´A GRACIELA CERSO University of Buenos Aires, Buenos Aires, Argentina
51.1. Introduction Parkinsonism encompasses a heterogeneous group of movement disorders, featuring resting tremor, rigidity, bradykinesia and postural instability (Quinn, 1995), which have a significant impact on an individual’s quality of life (Marinus et al., 2002). Whereas primary parkinsonism includes progressive, neurodegenerative disorders, Parkinson’s disease (PD) being the most common, it is known that secondary parkinsonism can be induced by drugs or caused by toxins or metabolic disorders. Drug-induced movement disorders (DIMD), most of them induced by antidopaminergic drugs, are some of the most frequent causes of secondary movement disorders, often causing severe psychosocial disturbance in both non-psychotic patients and patients with schizophrenia (Caligiuri et al., 2000). In addition, DIMD are a major cause of poor compliance with treatment, which in turn is associated with relapses, hospitalization and morbidity (Casey, 1991). DIMD encompasses a broad spectrum of syndromes, diverse in time of onset and in their clinical manifestations. Acute-onset syndromes develop in hours to days and include acute akathisia, acute dystonic reactions and neuroleptic malignant syndrome; parkinsonism develops over weeks and the tardive syndromes typically develop after months or even years of exposure to neuroleptic or other antidopaminergic drugs. Although some types of DIMD can be successfully treated, at present, no consistently effective treatment is available for others which may become irreversible even if the causative drug is discontinued, highlighting that certain drugs are apt to cause persisting, if not permanent, central nervous system (CNS) changes. Thus, attention should focus on close monitoring and prevention.
Interestingly enough, despite the wide interest neurologists have shown in this subject in the last 15 years, the cause of these movement disorders is apt to be overlooked, unless the physician has a good understanding of the possible offending medications. Therefore, the risks and benefits of drug therapy need to be known and carefully considered by physicians. Patients and their families should be duly informed about them.
51.2. History The modern history of DIMD starts in the early 1950s when chlorpromazine was developed in France and acknowledged as a breakthrough in the treatment of psychosis (Delay et al., 1952; Delay and Deniker, 1956). However, initial enthusiasm was soon tempered by its side-effects, including acute reactions such as akathisia, dystonia and drug-induced parkinsonism (DIP), which were soon documented (Steck, 1954; Ayd, 1961). The psychomotor apathy syndrome was described after initial clinical trials with chlorpromazine in psychiatric patients and was thought to be specific for this drug. Later on, this finding was related to the akinesia syndrome without hypertonia which had been previously described as the sequelae of encephalitis lethargica by Lhermitte in 1923. At that time reserpine, a dopamine-depleting drug, known to induce an akinetic state in animals (Carlsson, 1959) was noted to cause a parkinsonian state in humans. This observations, coupled with the known histopathology of PD, led to the discovery that dopamine is severely depleted in PD (Ehringer and Hornykiewicz, 1960). In 1954 Steck reported parkinsonism in patients treated with chlorpromazine and reserpine. He highlighted
*Correspondence to: Professor Federico Micheli, University of Buenos Aires, Hospital de Clı´nicas Jose´ de San Martı´n, Buenos Aires, Argentina. E-mail:
[email protected]
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that these manifestations were reversible and that they rather resembled postencephalitic parkinsonism, but not PD. He also reported akathisia, a common feature in postencephalitic parkinsonism but not in PD, in his cases. More persistent or even permanent dyskinesias were first recognized in the late 1960s (Uhnbrand and Faurbye, 1969). Currently, it is widely acknowledged that all dopamine antagonists as well as other drugs that interfere with the synthesis or release of dopamine have the potential to produce DIP in predisposed individuals. As DIP was initially recognized as secondary to neuroleptics (from the Greek: ‘which grip the nerves’), it almost became synonymous with neurolepticinduced parkinsonism. The use of antipsychotic drugs in the treatment of psychosis led to the common occurrence of DIP in this population (Freyhan, 1959), which was most likely underestimated in clinical practice (Marti Masso et al., 1993). For some time, it was suggested that appropriate control of psychosis could only be accomplished when DIP occurred, but this has been clearly shown to be false, leaving DIP as an unwanted adverse effect of neuroleptic drugs. The new class of antipsychotics, denominated ‘atypical neuroleptics’, is at least as effective as the older antipsychotics but is much less likely to cause movement disorders. Among the various types of DIMD secondary to neuroleptics, DIP is one of the most frequent but is often poorly recognized, and is frequently indistinguishable from idiopathic PD which purportedly results from the blockade of striatal dopamine receptors. It is now well known that drugs, with a wide range of applications in medicine, beyond the treatment of psychiatric illnesses and of diverse chemical nature, may induce or exacerbate parkinsonism. In addition to neuroleptics, selective serotonin reuptake inhibitors (SSRIs), lithium, valproic acid, calcium channel blockers, antiarrhythmics, cholinergics, chemotherapeutics, amphotericin B, estrogens and others have been implicated and it seems that an ever-growing list will add new potential causes for DIP. Currently, neuroleptic drugs, including substituted benzamides and calcium channel blockers, not always used as antipsychotics, are probably the drugs most commonly involved in DIP. It is known that the elderly population is at an increased risk of DIMD, including DIP, due to intrinsic factors and because such patients are often treated with several drugs, including those from self-medication (Gershanik, 1994). Psychiatric patients treated with typical neurolepics are well known to be at risk to develop DIP; however, non-psychotic outpatients developing parkinsonism
often pose a dilemma as to the cause of their movement disorder and drug therapy must always be considered in the differential diagnosis. Which particular patient with parkinsonism will turn to be a case of DIP or even PD aggravated or unmasked by drugs? Clinicians need to answer these questions as accurately as possible since a mistaken diagnosis may lead to unnecessary therapies, often associated with unwanted effects and an emotional and economic burden for patients and their families. In brief, the wide range and increasing list of drugs implicated in the production of DIP pose a challenging task for the clinician (Friedman, 1989).
51.3. Prevalence DIP has been claimed to represent one of the most frequent causes of secondary parkinsonism in clinical practice (Teive et al., 2004), if not the most frequent cause (Nguyen et al., 2004) in several countries, to the point that many authors have suggested that DIP should always be suspected when parkinsonian symptoms rapidly develop or worsen in a patient treated with certain medications, particularly those with antidopaminergic properties. The estimates for DIP differ widely among different series. Whereas PD is likely to account for up to 60% of patients with parkinsonism, the second leading cause is DIP, detected in 20% of patients (Cardoso, 1995). However, regional estimates are extremely variable. A study of a population of 208 000 in a district located in the English Midlands showed a PD prevalence of 108.4 per 100 000, which is roughly comparable with figures from Carlisle, England; Rochester, Minnesota; and south-west Finland. In this population, DIP was very uncommon (Aronson, 1985). Conversely, a door-to-door, two-phase approach study of parkinsonism prevalence in three elderly (over 65 years of age) population groups of central Spain showed that, out of 118 subjects with parkinsonism, 81 had PD (68.6%), 26 DIP (22.0%), 6 parkinsonism/ dementia (5.1%), 3 vascular parkinsonism (2.5%) and 2 unspecified parkinsonism (1.7%). The prevalence was 2.2% (95% confidence interval (CI), 1.8–2.6) for all types of parkinsonism and 1.5% (95% CI, 1.2–1.8) for PD (Benito-Leon et al., 1998). To support the above, DIP has also been considered the second leading cause of parkinsonism, only after PD, and representing 10–30% of all patients with parkinsonism in Spain (Errea-Abad et al., 1998). The incidence of parkinsonism and its specific types was studied among residents of Olmsted County, USA, between 1976 and 1990. They found 364 incident cases
DRUG-INDUCED PARKINSONISM of parkinsonism: 154 with PD (42%), 72 with DIP (20%), 61 unspecified (17%), 51 with parkinsonism in dementia (14%) and 26 with other causes (7%). PD was the most common type of parkinsonism, followed by parkinsonism in dementia in men and DIP in women (Bower et al., 1999). Similar findings have been reported in Japan, where DIP is currently the second leading cause of parkinsonism together with idiopathic PD. The ratio of the incidence of DIP to PD has been reported to be between 1:2 and 1:5 (Kuzuhara, 1997). In Italy the figures for DIP seem to be lower. A population-based survey performed in eight Italian municipalities detected 42 PD (62%), 8 parkinsonism/dementia (12%), 8 vascular parkinsonism (12%), 7 DIP (10%) and 3 cases of unclassified parkinsonism (5.8%) (Baldereschi et al., 2000).
51.4. Symptoms The differential diagnosis from PD on clinical grounds is often troublesome as the clinical features of DIP mimic those of PD, except for the rather rapid progression of symptoms in the latter (Kuzuhara, 1997). Bradykinesia, rigidity, impaired postural reflexes and tremor may occur. However, some subtle differences may be observed (Table 51.1): for example, DIP is often associated with tardive dyskinesias (TDKs) and involvement may be symmetrical. Rigidity and impaired arm-swing are the most common early signs, with tremor marking the onset in only about one-third of cases (Ayd, 1961). The latter is often not relevant and may even be absent (Akbostanci et al., 1999). This could be due to either the younger age of most patients with DIP or to differences between the two conditions.
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Bradykinesia is often the initial, most frequent and often the only manifestation of DIP, featuring hypomimia, loss of associated movements and speech disturbances. Symmetric clinical signs are felt to be the rule in PD and often a clue to a correct diagnosis. However, this may not always be the case and, as in PD, subgroups seem to exist. Caligiuri et al. (1989) studied 26 treated schizophrenic patients and 14 normal controls for the presence and asymmetry of neurolepticinduced rigidity, to evaluate the sensitivity, reliability and validity of a quantitative procedure, showing that 65% of the patients exhibited pathological rigidity. Moreover, 76% of these patients displayed asymmetric rigidity, and the remaining 24% exhibited bilateral symptoms. Newly treated patients exhibited greater rigidity on the right side as compared to patients who had been consistently treated for at least 3 months. They speculated that striatal dopaminergic activity may be asymmetric and more marked in the right striatum among recently treated patients (Caligiuri et al., 1989). Even though this is a drug-induced syndrome, signs may be asymmetric in half of the patients, as illustrated by findings in a small number of patients (Hardie and Lees, 1988; Sethi and Zamrini, 1990). In addition PD may present a symmetrical onset in 4% of cases (Rajput et al., 1993). The complete triad of tremor, rigidity and bradykinesia is only seen in a limited number of cases, as illustrated by the 25% observed in the series from Llau et al. (1994). Gait abnormalities are frequent manifestations of DIP (Akbostanci et al., 1999) but a very uncommon initial manifestation of PD. Interestingly enough, freezing is frequently observed in patients with vascular parkinsonism (57%), normal-pressure hydrocephalus (56%) and generally in patients with neurodegenerative
Table 51.1 Features that characterize drug-induced parkinsonism and Parkinson’s disease
Symptoms at onset Onset Course with appropriate treatment Response to anticholinergic drugs Response to levodopa Akathisia Other associated features Incidence of rest tremor Gender Freezing Seborrheic dermatitis
Drug-induced parkinsonism
Parkinson’s disease
Bilateral and symmetric or asymmetric Acute or subacute Regressive Evident Poor Present Orobuccal dyskinesia and other choreic manifestations, rabbit syndrome < > Females Uncommon >
Unilateral or asymmetric Chronic Progressive Mild to moderate Marked Absent – > > Males Common <
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parkinsonism, including progressive supranuclear palsy, multiple system atrophy and corticobasal ganglionic degeneration (45%). However, freezing seems to be rare in patients with DIP who have a very low risk for developing freezing (P < 0.00001; OR, 0.1) compared to patients with other types of parkinsonism (Giladi et al., 1997). A significant number of patients treated with phenothiazine or butyrophenone neuroleptic drugs with no previous movement disorders develop abnormally low tremor frequencies. As low-frequency tremors are often associated with PD, it has been speculated that they probably represent early signs of DIP (Arblaster et al., 1993). An increased prevalence of seborrheic dermatitis is a well-known feature of idiopathic PD and postencephalitic parkinsonism. Evaluation of 42 hospitalized patients with DIP and 47 hospitalized psychiatric patients with movement disorders showed a statistically significant higher prevalence of clinically diagnosed seborrheic dermatitis in the DIP group (59.5% versus 15%) (Binder and Jonelis, 1983). As in PD, dysphagia may be a prominent and even an early sign of DIP. A 74-year-old woman, without prior symptoms of parkinsonism or dysphagia, presented the association of both after the administration of trifluoperazine hydrochloride (Bashford and Bradd, 1996). Another patient complained of difficulty chewing and swallowing as the initial manifestation of DIP. The evaluation of dysphagia demonstrated abnormalities during all stages of ingestion. However, the prepharyngeal stages were disproportionately affected when compared with those patients with PD and similar levels of parkinsonian functional disability (Leopold, 1996). Dysphagia is a potentially lifethreatening complication of DIP. Its early recognition is of paramount importance as it enables treatment by simple medical, physical and dietary manipulations.
51.5. Associated features DIP can be associated with other movement disorders which are known to be typically induced by drugs. Quite often such movements require therapeutic approaches which are different from, if not opposed to, those needed for the treatment of parkinsonism. Nevertheless, the presence of such movements is a clue to the correct diagnosis of DIP. Although some of them are acute (akathisia), tardive movement disorders appear after long-term treatment with the causative drug and moreover treatment poses a real challenge. Akathisia is a complex syndrome featuring a subjective sense of inner restlessness with a compul-
sive need to move and objective motor manifestations such as shifting of the body weight from foot to foot while standing or crossing and uncrossing the legs when sitting. It is a typical side-effect of neuroleptics and often coexists with DIP (Kim and Byun, 2003). Akathisia is extremely uncommon in PD, although it has been documented in parkinsonian patients treated with neuroleptics (Prueter et al., 2003). Rabbit syndrome features a rapid orofacial tremor, frequently occurring as a long-term side-effect of neuroleptic treatment. However, response to anticholinergic medication and the frequent association with DIP suggest that the underlying mechanism of rabbit syndrome is similar to that of acute forms of DIP (Wada and Yamaguchi, 1992). Tardive tremor is defined according to Jankovic (1995) as a high-amplitude, 4–8 Hz rest and postural tremor developing after prolonged exposure to a drug. Tardive tremor has been associated with neuroleptics (Stacy and Jankovic, 1992) and other drugs, including calcium channel blockers (Garcia-Ruiz et al., 1992). Tardive dyskinesia (TDK) comprises hyperkinetic involuntary movements, varying in localization and appearance. The most common presentation involves the oral and facial regions and is called bucco-linguomasticatory syndrome; however, in many cases finger– arm or toe–leg movements are evident. Thoracic movements (respiratory dyskinesias) and pelvic involvement are also frequent. TD and DIP have been hypothesized to reflect opposing states of dopamine function as DIP TD occurs more frequently in the elderly population (Crane and Smeets, 1974). Tardive dystonia (TD) features sustained involuntary contractions of antagonist muscles causing slow twisting movements or sustained postures. Dystonia is more often localized in the oral region, causing oromandibular involvement with either forced jaw opening and tongue protrusion or diurnal bruxism (Micheli et al., 1993); in the facial areas, producing blepharospasm; in the neck, with several types of cervical dystonia; and in the trunk, among others.
51.6. Course DIP usually develops gradually within the first 3 months after the patient is exposed to the causative drug (Friedman, 1989), although it may take several months for the full-blown picture to manifest. On rare occasions DIP can be caused by neuroleptic withdrawal and has been labeled as ‘withdrawal emergent parkinsonism’ (Inoue and Janikowski, 1981), but no adequate explanation for this phenomenon has been provided. A possible clue, in some cases treated concomitantly with neuroleptics and
DRUG-INDUCED PARKINSONISM anticholinergics, where both drugs are discontinued at the same time, could be the different half-lives of these drugs as well as the dissimilar duration of their action on the CNS. It is commonly acknowledged that DIP is usually a benign condition that resolves rapidly after the causative drug is withdrawn. Usually parkinsonian symptoms begin to improve in several weeks and patients are relieved from the symptoms usually within several months (Kuzuhara, 1997), although complete resolution may take over a year (Marti-Masso and Poza, 1996, 1998). Occasional cases with extremely unusual duration of symptoms after discontinuance of the offending drug have been described (Klawans et al., 1973). Physicians should be acquainted with the potential long duration of DIP in order to avoid diagnostic errors. Despite the lack of clear-cut evidence, it is often acknowledged that tolerance develops to DIP. This assumption is supported by the observation that withdrawal of anticholinergics co-administered with neuroleptics is followed by rare cases of DIP. Conversely, Kennedy et al. (1971) reported that 27 out of 63 patients treated with trifluoperazine for more than 3 years continued to have tremor and 24 had rigidity. However, a small number of patients may have persistent parkinsonism. Whether this is an agingrelated effect remains unclear (Jeste et al., 1998). DIP is reversible, with the possible exception of a small percentage of elderly patients. Melamed et al. (1991) described 2 young patients who developed DIP during chronic treatment with neuroleptics for a psychotic disorder. Parkinsonism not only persisted but even progressed after discontinuation of the antipsychotic drugs. One patient experienced tremor-predominant parkinsonism whereas the other presented an akineticrigid syndrome. Neither had TDK and they both benefited from levodopa therapy. Such persistent DIP cases have been interpreted as pre-existent subclinical PD cases, uncovered by drug therapy. In theory, these drugs may precipitate the degeneration of vulnerable, nigrostriatal neurons by generating cytotoxic free radicals or by attrition, due to accelerated neuronal firing rates. Total disappearance of the clinical signs occurred in 74% of the patients, whereas, in 15% of cases, DIP led to the diagnosis of underlying idiopathic PD in the series of Llau et al. (1994). This study showed that almost 80% of DIP cases are due to two pharmacological classes of agents: antidopaminergic agents and calcium channel blockers.
51.7. Diagnosis In the setting of a psychiatric patient receiving neuroleptic drugs, the appearance of parkinsonian symptoms
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should immediately alert the physician to consider DIP as the first possible diagnosis. However, in nonpsychotic patients, the awareness of the clinician of the harmful effects of the offending drugs is often insufficient to lead to a correct diagnosis, which is then unfortunately delayed. Frequently DIMD, including DIP, are misdiagnosed (Weiden et al., 1987). Symptoms may be misleading as illustrated by Hansen et al. (1992), who reported on the occurrence of TDK and DIP in 101 inpatients, documenting misrecognition of both disorders by resident physicians, that determined a DIP prevalence of 11% versus a 26% rate found by the researchers. Residents tended to miss DIP in younger patients and in patients with affective disorders in whom a differential diagnosis with DIP may be troublesome. Although radiological procedures, including positron emission tomography (PET) scans, have proven abnormal in PD, they are not commercially available and the diagnosis is currently based on clinical evaluation. Functional neuroimaging using (123I) beta-carboxymethyoxy-3-beta-(4-iodophenyl) tropane (CIT) and single-photon emission computed tomography (SPECT) provide information on the integrity of the dopaminergic system in vivo and are promising diagnostic tools in early PD, and particularly in the differential diagnosis between parkinsonism and non-organic causes of similar symptoms. Performing (123I) beta-CIT and SPECT imaging at baseline appears to be a useful diagnostic approach to detect patients thought to have parkinsonism at baseline but who, after follow-up, do not have parkinsonism (Jennings et al., 2004). These findings may be particularly useful in the differential diagnosis of negative symptoms of psychotic patients mimicking parkinsonism. Other symptoms present in PD, such as depression, asthenia, sense of weakness, sedation and effects of understimulation, as have been reported in patients institutionalized for long periods of time (Fleischhacker, 2000), may overlap with the underlying psychiatric illness. There may also be drug-related side-effects that are unrelated to the parkinsonism. The striking similarity between the pattern of visual contrast sensitivity loss in DIP and that in PD suggests that a widespread dopaminergic deficiency, regardless of the cause, may similarly affect vision (Bulens et al., 1989).
51.8. Pathology Postmortem reports of DIP cases are limited and the results are at odds. Bathia et al. (1993) reported a patient with cranial dystonia who also had rest tremor in one arm and who developed DIP while under treatment. The patient’s brain was normal on autopsy.
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Brown et al. (1996) examined caudate nuclei areas in 10 schizophrenic subjects with DIP and 25 schizophrenic subjects without parkinsonian symptoms. The subjects with parkinsonian symptoms were found to have statistically significant smaller right caudate nuclei and a trend towards smaller left caudates. Cortical measurements did not differ between the groups. The authors conclude that the results support the contention that antipsychotic drugs exert some CNS neurotoxic effects. Rajput et al. (1982) reported 2 patients who developed parkinsonism after treatment with neuroleptic drugs. Clinical manifestations remitted completely when the offending drugs were discontinued. Surprisingly, when these cases came to autopsy, histological examination in each patient disclosed abnormalities characteristic of PD. Levels of homovanillic acid were low in both cases and dopamine levels were reduced in the striatum in 1 case. It is postulated that these 2 patients had subclinical PD that was unmasked by neuroleptics. Bower et al. (2002) correlated the clinical features with pathological findings in an autopsy series of cases of parkinsonism in Olmsted County, MN, for the years 1976–1990. They came across 364 incidental cases of parkinsonism, of which 235 were deceased at the time of the study; 39 autopsied brains were available for analysis (17% of deceased cases). Of the 8 cases given the clinical diagnosis of DIP, 6 were found to have basal ganglia pathology.
51.9. Differential diagnosis A comprehensive drug history is essential when evaluating a patient with parkinsonian signs. Very few disorders can mimic DIP, and when the features of parkinsonism and a drug history are clear, the diagnosis of DIP is straightforward and the most troublesome question that arises is whether the patient has DIP only or subclinical PD uncovered by drug exposure. Answering this question is of paramount importance to both patients and doctors as the prognosis of these disorders is quite different. Unfortunately, a definitive diagnosis is often delayed; meanwhile the patient is under careful observation. Functional imaging of the dopamine transporter (DAT) is useful to check the integrity of the dopaminergic system and is apt to be used in patients with mild, incomplete or uncertain parkinsonism. Imaging with various specific SPECT ligands for DAT (N-omega-fluoropropyl-2-beta-carbomethoxy-3 beta(4-iodophenyl)nortropane, FP-CIT; 2-beta-carbomethoxy-3 beta-(4-iodophenyl)tropane [123I], beta-CIT; N-((E)-3-iodopropen-2-yl)-2 beta-carbomethoxy-3 beta-(4-chlorophenyl)tropane [123I], IPT; [2-[[2[[[3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3,2,1] oct-2-yl]methyl](2-mercaptoethyl)amino]ethyl]amino]
ethanethiolato(3-)-N2,N20 ,S2,S20 ]oxo-[1R-(exo-exo)], TRODAT) may give a measure of presynaptic neuronal degeneration. Striatal uptake has been shown to correlate with disease severity, in particular with bradykinesia and rigidity, and could be useful to monitor disease progression in PD. Dopamine deficiency largely antedates clinical manifestations and is always present, even in the earliest clinical presentations of PD; a normal scan suggests an alternative diagnosis such as DIP or essential tremor, vascular parkinsonism (unless there is focal basal ganglia infarction) or psychogenic parkinsonism. Additional applications of this method include characterizing dementia with parkinsonian features (abnormal results in dementia with Lewy bodies, common in Alzheimer’s disease); and differentiating juvenile-onset PD (abnormal DAT) from dopa-responsive dystonia (normal DAT) (Marshall and Grosset, 2003). Recently it has been shown that striatal morphology on a three-dimensional display of 123I-beta-CIT SPECT data provides information that is of diagnostic significance for PD. This morphometry can be done without technically demanding region of interest analysis and thus this technique may be suitable for routine clinical use to study the integrity of the dopaminergic nigrostriatal system (Ichise et al., 1999). Moreover, it has been reported to characterize the different types of parkinsonism (Lorenzo Bosquet et al., 2004). Negative symptoms in psychotic patients have been correlated with parkinsonian symptoms, some vegetative features of depression and with anticholinergic doses, but not with negative symptoms and cognitive features of depression or neuroleptic drugs. These findings suggest that the assessment criteria for negative symptoms, depression and DIP overlap in treated schizophrenic patients (Prosser et al., 1987). A retrospective evaluation of the premorbid status of patients within their first episode of psychosis showed that lower sociability and withdrawal scores correlated with increased time to treatment response, more severe negative symptoms, deterioration of premorbid functioning and increased DIP. These findings suggest that, prior to acute psychosis onset, certain behavioral precursors reflecting premorbid functioning may predict subsequent illness manifestations (Strous et al., 2004). Psychogenic parkinsonism is extremely rare in clinical practice. Tolosa et al. (2003) reviewed the clinical features and results of DAT imaging in DIP and psychogenic parkinsonism. These two conditions normally give normal striatal DAT imaging results; an abnormal result in either case could rule out both conditions, corroborating a diagnosis of organic parkinsonism in uncertain cases. Severe DIP cases should also be differentiated from catatonia, a probably underdiagnosed disorder (Van der Heijden et al., 2005) in which tremor is absent.
DRUG-INDUCED PARKINSONISM Unfortunately the two conditions may coexist as some patients with catatonia can be under treatment with neuroleptics. Assessment of the patient’s mental state can make the difference clear. Symptoms like waxy flexibility and muteness are clues for the diagnosis of catatonia. As lorazepam and electroconvulsive therapy (ECT) are effective in treating catatonia, an early diagnosis is required (Huang, 2005). Among the various causes of parkinsonism other than PD that must be considered in the differential diagnosis of DIP, those degenerative, toxic, tumors or hydrocephalus that combine mental changes, often requiring drug therapy and movement disorders, are on the first line. In young patients, both Wilson’s and Huntington’s disease cause parkinsonism and psychosis. Wilson’s disease typically causes a prominent resting and postural tremor as well as dysarthria. The peculiar dystonic facies of Wilson’s disease are strongly suggestive of this disorder. Huntington’s disease usually causes chorea in adults and parkinsonism in children, but a parkinsonian (Westphal) variant can occur in young adults. In this case a positive family history for chorea is a rule. Parkinsonism can also be a feature of normalpressure hydrocephalus, often associated with a gait disorder that is rather atypical for DIP, urinary incontinence and cognitive imapirment. Brain computed tomography (CT) scans or magnetic resonance imaging (MRI) scans are useful when considering this diagnosis. In the last few years brain imaging has emerged as a potentially useful tool to study the activity of the basal ganglia as well as help in the diagnosis of different types of movement disorder. Unfortunately they are not yet widely available in clinical practice.
51.10. Magnetic resonance spectroscopy MR spectroscopy has been described as a useful tool to monitor the neurobiological correlates of DIP and other DIMD. The severity of DIP assessed by the Simpson–Angus Scale significantly correlates with the higher choline (Cho) concentration and moreover tends to correlate with the higher N-acetyl-aspartate (NAA) concentration in a group of patients (Yamasue et al., 2003).
51.11. Positron emission tomography Putamen 18F-dopa uptake of PD patients is reduced by at least 35% at onset of symptoms; therefore, PET scans can be used to detect preclinical disease in clinically unaffected twins and relatives of patients with PD. PET scans can be used to detect underlying nigral pathology in patients with isolated tremor and patients taking dopamine receptor-blocking agents who
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become rigid. Patients with familial essential tremor have normal, whereas those with isolated rest tremor have consistently low, putamen 18F-dopa uptake. DIP is infrequently associated with underlying nigral pathology (Brooks, 1991).
51.12. Transcranial ultrasound (TCS) Applying TCS, Berg et al. (1999) found that approximately 9% of healthy individuals exhibit an increased substantia nigra (SN) echogenicity, a sonographic feature that is often found in PD (Becker et al., 1995). PET studies in 10 of these otherwise healthy subjects with hyperechogenicity of the SN showed reduced [18F]-dopa uptake of the striatum, suggesting that elevated echogenicity of the SN in healthy adults can be associated with subclinical dysfunction of the dopaminergic nigrostriatal system (Berg et al., 1999). As these patients could be at increased risk of developing DIP, Berg et al. (2001) compared the echo pattern of patients on neuroleptics who developed DIP with those who did not show evidence of parkinsonian symptoms. In a second study they compared the echo pattern with the severity of the parkinsonian signs. Findings demonstrated that patients with more extended hyperechogenic areas at the SN were more susceptible to DIP, which was more severe contralateral to the side of the more echogenic SN (Berg et al., 2001).
51.13. Risk factors Studies addressing the identification of risk factors for the development of DIP highlighted the noteworthy individual susceptibility to develop DIP. It has been accepted that both the drug potency and dose play a role in the development of DIP, but this may not always be the case. Although not all risk factors have been universally accepted and some have even been challenged, we list here the most frequently cited. 51.13.1. Age/dementia Elderly patients and particularly those with associated dementia are at greater risk than patients without dementia for persistent drug-induced extrapyramidal side-effects (Marti Masso and Poza, 1996; Caligiuri et al., 2000). Moghal et al. (1995) reported the presence of movement disorders in an institutionalized elderly population of Saskatchewan. Movement disorder was detected in 19% of cases. Most of these cases (16%) were female; 10% had essential tremor, 6% PD and 2.3% had DIP. In a community incidence study, 7.2% had DIP (Rajput et al., 1984) and a prevalence study reported 8.8% cases of parkinsonism being DIP (Bharucha et al,. 1988).
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To examine the natural history and pathogenesis of parkinsonism in Alzheimer’s disease, 44 subjects with clearly established senile dementia of the Alzheimer type were studied for 66 months. Sixteen subjects (36%) developed idiopathic parkinsonism and 12 subjects (27%) developed DIP; the chief clinical features of both types were bradykinesia and rigidity, but not resting tremor. The presence of parkinsonism was associated with global (rather than selective) cognitive impairment, as determined by psychometric testing and with a more rapid progression to advanced stages of dementia (Morris et al., 1989). The association between parkinsonism and Alzheimer’s disease has received great attention in recent years. It has been speculated that the occurrence of parkinsonism and Alzheimer’s disease is not a chance association. The pathological correlates of parkinsonism were found to be heterogeneous in the postmortem examination of subjects with Alzheimer’s disease. Some of them exhibited pathological features of PD, whereas others had non-specific nigral lesions; and even in some cases neither histological changes nor reduced neuronal densities in the SN were observed (Morris et al., 1989). The incidence and prevalence of DIP and TD are significantly greater among elderly patients, whereas akathisia seems to occur evenly across the age range and dystonia is more common among younger patients (Errea-Abad et al., 1998; Caligiuri et al., 2000). Neuroleptic use is a common cause of DIP among the elderly and this side-effect is frequently treated by adding an anticholinergic or dopaminergic drug to the regimen. The use of anticholinergic drugs presents risks of additional drug side-effects; the use of dopaminergic drugs, generally not appropriate for DIP, suggests that extrapyramidal neuroleptic side-effects may often be mistaken for idiopathic PD in older patients (Avorn et al., 1995). 51.13.2. Pre-existing movement disorders There is general agreement that pre-existing extrapyramidal signs increase the patient’s vulnerability to develop significant DIMD (Caligiuri et al., 2000). To support this, previous studies suggest that many untreated schizophrenic patients exhibit motor disturbances. On the basis of these findings, the authors hypothesized that pre-existing extrapyramidal movement disorders may increase the risk of developing DIP. A number of studies have shown that in a variable number of cases DIP is only the expression of subclinical PD unmasked by the action of neuroleptics, calcium channel blockers or other drugs known to
cause DIP. Several authors have shown that findings suggest that DIP is associated with an increased risk for PD (Chabolla et al., 1998). 51.13.3. Cigarette smoking Several studies have shown that cigarette smoking may have a protective effect as regards the risk for PD (Allam et al., 2004). Similarly, according to one study, schizophrenic patients who smoke have significantly less cognitive impairment (P < 0.02) and a lower prevalence of DIP as compared to non-smokers (Sandyk, 1993). Based on these findings, the author suggests that cigarette smoking may protect against the development of dementia and DIP in schizophrenia. 51.13.4. Genetics The results of epidemiological studies indicate that there is a hereditary predisposition to developing DIP. Metzer et al. (1989) investigated the human leukocyte antigen (HLA) antigen prevalence rates in patients with neuroleptic DIP. They evaluated neuroleptic-treated, chronic inpatients with Diagnostic and Statistical Manual of Mental Disorders III (DSM-III)-diagnosed schizophrenia, 29 with DIP and 23 without parkinsonian signs. They were tested for 23 type A, 43 type B, 4 type C and 10 type DR HLA antigens and it was found that, in DIP patients, HLA-B44 was significantly more prevalent, suggesting that this HLA antigen could play a role in genetic or immunologic susceptibility to develop DIP in some patients. A higher occurrence of a positive family history of PD and/or essential tremor and of higher frequency of secondary cases with PD and/or essential tremor among close relatives of patients with parkinsonism induced by cinnarizine and flunarizine as compared to age-matched controls suggests the involvement of a genetic susceptibility in developing this druginduced disorder. DIP could be regarded as a multifactorial disease process resulting from potential neurotoxicity of drugs on a background of inherited predisposition (Negrotti et al., 1992). 51.13.5. Gender The fact that women are at increased risk of developing DIP has been consistently reported by many investigators (Klawans et al., 1973; Llau et al., 1994; Marti Masso and Poza, 1996; Errea-Abad et al., 1998). In this regard a retrospective study carried out by Llau et al. (1994) investigated the characteristics of DIP
DRUG-INDUCED PARKINSONISM notified to the Midi-Pyre´ne´es Pharmacovigilance Centre, France between 1983 and 1992 found that, among 3923 side-effects spontaneously reported between 1983 and 1992 to the center, 53 (1.4%) were DIP cases. Mean age was 65 2 (sem) years (range 21–88 years). DIP appeared after a mean treatment duration of 473 142 days (range 1 day to 15 years) and occurred most frequently in women (63%) (Llau et al., 1994). Estrogenrelated dopamine receptor blockade has been suggested as a possible explanation for female preponderance (Glazer et al., 1983). However, others have not found a gender preponderance (Moleman et al., 1982). 51.13.6. Schizophrenia subtype It is possible that DIP may relate to negative symptoms, whereas TDK in schizophrenia may be a covariate of positive symptoms. Sandyk and Kay (1992) studied the relationship of TDK and DIP with psychopathology clusters rated on the Positive and Negative Syndrome Scale in schizophrenic patients and found that involuntary movements of TDK were significantly associated with the activation cluster (P < 0.01), whereas DIP was significantly associated with the anergia cluster (P < 0.01). However, it has been speculated that the positive correlation of DIP and negative symptoms stems from the similarity between masked facies of DIP and blunted affect of schizophrenics (Hoffman et al., 1991). 51.13.7. Ventricular/brain ratio It has been shown that the magnitude of DIP is positively correlated with ventricular/brain ratio and the severity of negative symptoms of schizophrenia (Hoffman et al., 1991). On the basis of these findings it is suggested that a large lateral ventricular size may be associated with increased vulnerability to develop DIP (Luchins et al., 1983). 51.13.8. Human immunodeficiency virus (HIV) HIV infection is a risk factor for developing DIP and acquired immunodeficiency syndrome (AIDS) patients are more prone to develop this side-effect when exposed to drugs liable to induce movement disorders. Pita´goras de Mattos et al. (2002) reported on their 14 years’ experience (1986–1999) treating 2460 HIV-positive inpatients; 1053 (42.8%) presented at least one neurological manifestation and 28 (2.7%) had involuntary movements. Half of them had parkinsonism and, surprisingly, 7 had enlarged ventricles, confirmed on CT scans. One patient had a hypodense area with mass effect, suggestive of toxoplasmosis of the right basal ganglia. One
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had an enhancing lesion in the midbrain at the T1weighted MRI, which correlated with a homolateral ophthalmoplegia and contralateral parkinsonism. The authors concluded that parkinsonism was probably secondary to HIV in 12, to metoclopramide in 1 and to neurotoxoplasmosis in another 1, and that a diagnosis of HIV should always be considered in young patients with secondary parkinsonism: By using stereological techniques, Reyes et al. (1991) estimated the volume density of melanin and counted the number of pigmented and non-pigmented neuronal cell bodies in the pars compacta of the SN of autopsied AIDS cases without any evidence of PD or inflammation or necrosis of the midbrain. They found that the total number of neuronal cell bodies was 25% lower in AIDS patients than in age-matched controls. The histopathological examination showed nigral degeneration with neuronal loss, small neuronal cell bodies packed with melanin, reactive astrocytosis and extracellular melanin in the AIDS patients but not in the controls, showing that a subclinical nigral degeneration is common in AIDS and could possibly explain the higher susceptibility of some patients to DIP. 51.13.9. Drugs that may cause drug-induced parkinsonism It is accepted that roughly half of the parkinsonism cases seen in a neurology practice are drug-induced or aggravated, generally by psychotropic drugs (Marti Masso and Poza, 1996). Llau et al. (1995) reported on the characteristics and drugs inducing unwanted movement disorders notified to a Regional Drug Surveillance Centre between 1989 and 1993. Of a total of 4000 general side-effects, 122 were movement disorders, the most common of which was DIP (40% of cases). They were mostly caused by neuroleptics, followed by antiemetics and calcium channel blockers. In this regard flunarizine and cinnarizine are some of the most common drugs causing DIP in the countries where they are available (Teive et al., 2004). This is probably the rule in most countries, although there may be some intracountry regional variations over time. Marti Masso and Poza (1996) performed a retrospective study of DIP patients seen between January 1981 and December 1993 in Spain. Of the 306 cases of parkinsonism seen, 56.8% were induced or aggravated by drugs. The drugs implicated most often were cinnarizine, sulpiride and flupentixol. Some patients were on two of these drugs and a minority on three. The number of DIP cases seen increased after 1986 and then remained stable through 1993. Between 1981 and 1988, the most often implicated drug in
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DIP was cinnarizine, though its relative impact decreased in later years (Errea-Abad et al., 1998). This is most likely due to the better knowledge of the profile of side-effects of these drugs. Nevertheless, the list
of drugs capable of inducing DIP is growing rapidly and seems to be endless (Marti Masso et al., 1993). Table 51.2 lists drugs known to induce or aggravate parkinsonian symptoms.
Table 51.2 Drugs that may induce or aggravate parkinsonism Acetophenazine Alcohol withdrawal Alizapride Alpha-methyldopa Amiodarone Amoxapine Amphotericin b Antiacids Aprindine Bethanechol Bupivacaine Bupropion Buspirone Captopril Carboplatin Cephaloridine Ciclosporin Cimetidine Citalopram Cyclophosphamide Cytosine arabinoside Chloroquine Chlorpromazine Chlorprothixene Cinnarizine Cisapride Clebopride Diazepam Diltiazem Disulfiram Domperidone Droperidol Ecstasy Estrogen and oral contraceptives Ethinyl Fentanyl Flunarizine Fluoxetine Flupentixol Fluphenazine Flurbiprofen Gemcitabine Gold Haloperidol Halothane Isoflurane Levopromazine Lithium Lorazepam Loxapine
Meperidine Mesoridazine 3,4-Methylenedioxymethamphetamine Metoclopramide Mexiletine Molindone Naproxen Nefazodone Nifedipine Olanzapine Paclitaxel Papaverine Paroxetine Pentoxifylline Perfenazine Perhexiline Perphenazine Pethidine Phenobarbital Phenytoin Pimozide Piperazine Pirlindol Procainamide Procaine Prochlorperazine Promethazine Propiverine Pyridoxine Remoxipride Reserpine Risperidone Sertraline Sodium valproate Sufentanil Sulindac Sulpiride Tacrina Tetrabenazine Thiethylperazine Tiapride Trifluoperazine Triflupromazine Trimeprazine Thioridazine Thiothixene Triperidol Veralipride Verapamil Ziprasidone
DRUG-INDUCED PARKINSONISM 51.13.10. Neuroleptics Neuroleptics are at present the most effective treatment for schizophrenia (Lyne et al., 2004), but noncompliance is a major problem, contributing to the discontinuation of therapy and leading to relapses. Though several factors play a role in this regard, one of the most common side-effects is the development of movement disorders induced by these drugs (Borison et al., 1983). These unwanted effects led to the development of a new generation of neuroleptics devoid of extrapyramidal side-effects, also known as atypical neuroleptics, the prototype of which is clozapine (Awad and Voruganti, 2004). The majority of prescriptions for antipsychotics in developed countries in the past years have been for atypical drugs and the tendency shows a progressive increment. However, although most atypical neuroleptics rarely induce movement disorders in young patients, most are liable to cause them in susceptible populations, including elderly patients or those with previous movement disorders, including subclinical PD. In addition, most cause akathisia (Kurz et al., 1995). Even though investigators agree on the clinical manifestations and diagnosis of DIP, the mechanism by which drugs induce symptoms and the identification of the individuals at risk are still a matter of conjecture. Since the description of the first cases, it has been obvious that a clear dose–response correlation was absent and a discrepancy between the amount of neuroleptics taken and the development of parkinsonism was evident (Hall et al., 1956) suggesting that simply the blockade of dopamine receptors was not the cause of DIP. Neuroimaging studies have suggested that parkinsonism occurs after D2-receptor occupancy exceeds 80% (Farde et al., 1992). However, the observation of parkinsonism at or above 60% occupancy levels is very consistent with prior pathological (Jellinger, 1986; Gibb, 1992) and neuroimaging studies (Frost et al., 1993; Marek et al., 1996) of patients with PD that suggest symptoms become clinically manifest following the loss of as little as 50% of nigrostriatal neurons. In addition, plasma neuroleptic levels fail to correlate with DIP severity. The possibility that the neurotoxic activity of neuroleptics is related to their induced movement disorders has been previously suggested. In two in vivo studies, Ben Shachar et al. (1993, 1994) found that haloperidol and phenotiazines induced a marked increase in iron transport across the blood–brain barrier in rats and mice, resulting in increased concentration of iron in basal ganglia, which in turn triggers in vivo generation of hydroxyl radicals and oxidative stress.
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Consistent with the suggested oxidative stress activity of haloperidol, chronic treatment with the drug is accompanied by the formation of a neurotoxic pyridinium metabolite (high-performance planar chromatography HPPC), a tetra hydropyridine analog resembling those of the pyridinium metabolite 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP), which induces parkinsonian symptoms (Bloomquist et al., 1994; Rollema et al., 1994). Gil-ad et al. (2001) studied the neurotoxic activity of different neuroleptics (typical and atypical) in order to correlate these effects with DIMD. With the exception of clozapine, a correlation was observed between the drug-induced neurotoxicity and its known associated movement disorders, suggesting a possible functional relationship between the two phenomena. Neurotoxic activity of neuroleptics was found in both the NB cell line and the primary mouse embryo-selected neuronal culture. Their results suggest that neurolepticinduced neurotoxicity is independent of dopamine. Previous studies (Chiueh et al., 1993; Offen et al., 1995; Ziv et al., 1995) have shown that dopamine alone possesses a neurotoxic and apoptotic activity at high concentrations in different neuronal cultures. This effect was attenuated by inhibitors of apoptosis and by some antioxidants (vitamin E and N-acetylcysteine), suggesting an oxidative stress mechanism in the drug-induced toxicity which leads to apoptotic cell death. The expression of c-fos, an immediate early gene, correlates with neuronal activation. Thus, Fos immunohistochemistry has turned out to be a valuable method for mapping pathways of the CNS (Curran and Morgan, 1995). It has been reported that acute administration of a typical neuroleptic, haloperidol, produces a large increase in the number of Fos-positive neurons in the striatum, the nucleus accumbens and the lateral septal nucleus in the brain of rats (Robertson and Fibiger, 1992). By contrast, compounds that are not likely to cause movement disorders fail to increase Fos in the dorsolateral striatum or produce only minor elevations (Robertson and Fibiger, 1992). Propranolol has been reported to attenuate Fos expression in regions of the rat brain that are likely to be responsible for akathisia (Ohashi et al., 1998). Benzamide derivatives, including sulpiride and metoclopramide, have been the main cause of DIP in recent years in Japan (Kuzuhara, 2000; Naito and Kuzuhara, 2004). 51.13.11. Flunarizine and cinnarizine Both drugs are calcium channel blockers but flunarizine is 2.5–15 times more potent. Cinnarizine was developed first and flunarizine is a cinnarizine derivative and differs since it includes a piperazine
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derivative in its molecule, like some neuroleptics and antihistamine drugs (Chouza et al., 1986; Micheli et al., 1987, 1989; Fernandez Pardal et al., 1988; Negrotti and Calzetti, 1997; Teive et al., 2004). These drugs have been widely employed in Spain and Latin America in the treatment of dizziness, cerebrovascular disorders and cognitive impairment. More recently, they have also been used in the prevention of migraine attacks (Lucetti et al., 1998) and as adjunctive treatment for epilepsy (Chaisewikul et al., 2001). Movement disorders secondary to these calcium antagonists were first recognized by De Melo-Souza in Brazil and reported at the IX Brazilian Congress of Neurology. Subsequently they were widely recognized in most of the countries where these drugs are available (Chouza et al., 1986; Micheli et al., 1987, 1989; Fernandez Pardal et al., 1988; Marti Masso and Poza, 1996; Negrotti and Calzetti, 1997; Teive et al., 2004). Curiously, most of the reported cases have involved elderly women and many of them showed depression as a prominent feature. Recovery after withdrawal of flunarizine or cinnarizine usually takes several months to complete (Marti Masso and Poza, 1998). The mechanism by which flunarizine and cinnarizine cause DIP and other movement disorders is not completely understood but it is plausible that a presynaptic as well as a postsynaptic mechanism contribute to the dopaminergic dysfunction. Mena et al. (1995) investigated the effects of calcium channel antagonists on the pharmacology of dopamine systems in vivo and in vitro and demonstrated that flunarizine, cinnarizine and diltiazem reduce the viability of dopamine-rich human neuroblastoma cells in vitro. They concluded that all calcium channel antagonists tested reduced dopamine neurotransmission in vitro and in vivo, but the evidence of toxicity for dopamine cells in vitro is restricted to flunarizine, cinnarizine and diltiazem, the latter only seldom associated with DIP (Dick and Barold, 1989). Based on animal models and laboratory studies, flunarizine and cinnarizine have been shown to inhibit the energy-dependent vesicular dopamine uptake (Terland and Flatmark, 1999), block dopamine D2receptor (Brucke et al., 1995) and inhibit cathecolamine transport (Vaccari, 1993) and mitochondrial complexes I and II (Veitch and Hue, 1994). 51.13.12. Selective serotonin reuptake inhibitors Regardless of the general claim that SSRIs do not induce or worsen parkinsonism (Dell’Agnello et al., 2001), in recent years several cases have been reported of movement disorders as a result of treatment with
selective SSRIs. Symptoms include dystonia, akathisia and parkinsonism (Leo, 1996; Spigset, 1999; Pina Latorre et al., 2001). Serotonin modulates dopamine in the basal ganglia by inhibiting its production and release. Thus, an increase in serotonergic transmission may cause parkinsonism, particularly in susceptible patients, including those with subclinical PD and elderly patients. Ectasy and related derivatives which share a basic amphetamine structure and exert stimulatory effects in humans have been found to have a possible antiparkinsonian effect in animal experimental models (Schmidt et al., 2002). Curiously, ecstasy has recently been suspected to cause DIP (O’Suilleabhain and Giller, 2003). For the last 20 years 3,4-methylenedioxymethamphetamine (MDMA: also known as ecstasy) has become a widely used recreational drug. Methamphetamine binds to the DAT in presynaptic terminals and reverses dopamine transport (Sulzer et al., 1993). Loss of dopaminergic neuronal terminals in human postmortem tissue has been documented in chronic methamphetamine users and in experimental animals treated with methamphetamine. Based on such evidence, there is concern that loss of neuronal markers may represent terminal degeneration, predisposing to parkinsonism as the individual becomes older. Recent studies suggest that MDMA can cause toxicity to dopamine-containing neurons in monkeys (O’Shea and Colado, 2003).
51.14. Treatment Particular care should be taken in treating patients who are at risk of developing DIP or other DIMD with drugs that are known to cause such side-effects. Neuroleptic drugs should be used according to strict criteria and during the period when they are necessary. The benefit should be weighed against the possible side-effects before the decision to treat a patient with a potential harmful drug is reached. When more than one drug is apt to benefit the patient, the less harmful drug obviously has to be prescribed. When the offending drug is required, as in the case of a psychotic patient, the antipsychotic should be replaced by an atypical neuroleptic. If prevention fails, the most effective therapy for DIP is cessation of the offending drug. Most patients will become symptom-free after 1–2 months off the causative drug but occasional patients require up to a year or even longer for complete resolution to occur. A small number of patients never recover completely or partially recover and after some time exhibit signs of parkinsonism again, raising the question as to
DRUG-INDUCED PARKINSONISM whether they had subclinical PD that was unmasked by the administration of the drug. The autopsy findings of typical histologic features of PD in patients who had DIP during life supports this notion (Rajput et al., 1982). Medical therapy is indicated when discontinuance of the offending drug does not result in improvement or if the patient requires therapy with the causative drug. DIP may improve with the use of anticholinergics (Saltz et al., 2000) and there seems to be no difference between the efficacy of the two most popular anticholinergics. A single-blind study compared the clinical efficacy of biperiden hydrochloride and benzhexol in the treatment of neuroleptic-induced parkinsonism. Both drugs were highly effective and all patients responded to medication. No significant difference was observed between the two treatment groups when individual symptoms were examined (Rosen, 1963; Jensen and Amdisen, 1964; Magnus, 1980). However, this therapy should be avoided in the elderly or demented patients or those with concurrent TD. Side-effects, including mouth dryness, constipation, blurred vision and essentially memory disturbances and delirium, are more prevalent in the elderly. On the other hand, TD symptoms worsen on anticholinergic therapy. Amantadine, a putative dopaminergic compound known to be therapeutically effective in idiopathic and postencephalitic parkinsonism, is an alternative to anticholinergic drugs (Kelly and Abuzzahab, 1971; Kelly et al., 1974). In a double-blind placebo-controlled cross-over study of 39 psychiatric inpatients, amantadine and trihexyphenidyl were equally effective in treating DIP, and amantadine produced fewer and less severe side-effects. The authors suggest that amantadine is an effective alternative to atropine-like agents, with fewer implications for long-term risk of tardive TD (Fann and Lake, 1976). After a few months, most cases of DIP subside and for that reason a practical approach should include tapering of these drugs after 2–3 months to evaluate spontaneous improvement (Horiguchi and Nishimatsu, 1992). An alternative, and practical, approach is to use ECT when appropriate, which transiently ameliorates parkinsonism and treats psychosis (Goswami et al., 1989). ECT has been claimed to produce some benefit in occasional patients with DIP. A patient with schizoaffective disorder and anticholinergic refractory neuroleptic-induced parkinsonism manifested a marked increase of parkinsonian symptoms and dystonia after ECT (Hanin et al., 1995). As DIP, TD and TDK have also been shown to improve with ECT administration (Ananth et al., 1979), whereas tic syndromes have achieved mixed results. In animals, ECT
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enhances dopamine-mediated effects and increases gamma-aminobutyric acid concentrations in the CNS. Optimal parameters relevant to the antiparkinsonism effects of ECT require further study (Faber and Trimble, 1991). Previous investigations reported in the literature have found propranolol to attenuate tremor in PD, but no significant differences in attenuation of DIP tremor by propranolol and placebo could be documented (Metzer et al., 1993). The results of a preliminary study suggest that, in schizophrenic patients with acute psychosis, the addition of vitamin E to neuroleptic medication at the initiation of treatment shows a trend towards a decrease in the severity of acute DIMD. Unfortunately, it does not, however, affect the severity of acute akathisia. Vitamin E did not interfere with the antipsychotic effect of the neuroleptic medication (Dorfman-Etrog et al., 1999). The association between DIP and other movement disorders, especially TD, poses a challenge as they are responsive to pharmacological agents with antagonistic properties. Unfortunately, there is no adequate answer to this question and results are often poor. It has been proposed that dopamine-depleting drugs like reserpine and tetrabenazine may be of benefit in some cases, improving TD without worsening parkinsonism (Fahn and Mayeux, 1980). The issue as to whether treatment should be used to treat symptoms of parkinsonism or used prophylactically to prevent the development of DIP has been a matter of conjecture. In clinical practice many psychiatrists initiate treatment with neuroleptics and anticholinergics concomitantly. Currently the routine use of prophylactic anticholinergics is not recommended and is clearly contraindicated in the elderly. An individualized risk–benefit assessment is necessary for the younger patient in whom prophylactic use of anticholinergic drugs is considered (Mamo et al., 1999).
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Further Reading Bhatia K, Daniel SE, Marsden CD (1993). Orofacial dystonia and rest tremor in a patient with normal brain pathology. Mov Disord 8 (3): 361–362.
Handbook of Clinical Neurology, Vol. 84 (3rd series) Parkinson’s disease and related disorders, Part II W. C. Koller, E. Melamed, Editors # 2007 Elsevier B. V. All rights reserved
Chapter 52
Vascular parkinsonism YACOV BALASH1 AND AMOS D. KORCZYN2* 1
Movement Disorders Unit, Department of Neurology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel 2
Sieratzki Chair of Neurology, Tel-Aviv University Medical School, Ramat-Aviv, Israel
Parkinson’s disease (PD) is a degenerative brain disease consisting of a progressive loss of dopaminergic neurons in the substantia nigra (SN) and other neuronal systems in certain brain areas. A loss of 60–70% of the nearly 450 000 dopamine-producing neurons of the SN pars compacta and related decrease of the dopamine level at the striatum must occur before PD symptoms will take place. Several other diseases share some clinical features of PD, like tremor, muscle rigidity, hypokinesia and bradykinesia, gait instability and freezing of gait. These disorders, collectively called parkinsonian, can sometimes be clearly distinguished from PD, although on other occasions the distinction is difficult. Neuroimaging data (e.g. single-photon emission computed tomography, SPECT), drug response or the pathological demonstration of specific changes in the SN or elsewhere can help in such cases. The present review will discuss one of these entities, called vascular parkinsonism (VP). In 1929 Critchley, after analysis of the literature, described five types of parkinsonism induced, according to his opinion, by cerebrovascular diseases in elderly patients. He identified the first (commonest) type as ‘rigidity, fixed facies and short-stepping gait’ with absence of rest tremor; the second type is similar but with the addition of pseudobulbar manifestations; the third type has the addition of dementia and incontinence; the fourth type shows signs of pyramidal disease; and the fifth has superimposition of a cerebellar syndrome. Critchley suggested that VP is a spectrum of heterogeneous syndromes resulting from multiple vascular (arteriosclerotic or syphilitic) lesions in the basal ganglia (BG), rather than a certain idiopathic disease.
This concept was criticized by Schwab and England (1968) and Parkes et al. (1974), who claimed that a coincidence or superposition of vascular changes in some patients with PD could account for this overlap. Many years later Critchley himself corrected his basic idea of arteriosclerosis as a possible cause of PD and termed the condition ‘arteriosclerotic pseudoparkinsonism’, considered as alien to PD both clinically and pathogenetically (Critchley, 1981). Nevertheless, the neurological entity of VP remains a matter of debate ever since. Up to now, VP and PD are not clearly separated clinically and for example are lumped together in the Ninth Revision of the International Classification of Diseases (ICD-9) as item 332.0 without any differentiation between arteriosclerotic and idiopathic, primary parkinsonism (ICD-9-CM International Classification of Diseases, 2005). Until recently, VP remained a poorly defined clinicopathological entity, which overlaps with other diagnoses. There are few pathologically verified cases with suitable clinical correlation. The clinical diagnosis of VP may be difficult and sometimes its confirmation is only possible by neuropathological examination, which is still considered the gold standard for making the definite diagnosis of VP (Jellinger, 2002). However, pathological diagnosis of VP is non-specific and the changes are largely those of small-vessel disease. Because of this fact there are doubts whether VP should be regarded as a clinical entity or, more correctly, whether VP is a variant of small-vessel brain disease, manifested neurologically by parkinsonian-like features, usually accompanied by additional neurological signs (Zijlmans et al., 2004).
*Correspondence to: Professor Amos D. Korczyn, Tel-Aviv University Medical School, Sieratzki Chair of Neurology, Ramat-Aviv 69978, Israel. Email:
[email protected], Tel: þ972-3-697-4229, Fax: þ972-3-640-9113.
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52.1. Parkinsonism associated with brainstem lesions Vascular lesions to the brain can cause almost any constellation of neurological symptoms, depending on the site of the lesions and other factors, and parkinsonism cannot be assumed to be as exception. Thus, focal hemorrhagic and ischemic brainstem strokes were shown to produce contralateral parkinsonian signs. To illustrate the point we can discuss a case of a patient in whom right hemiparkinsonism was diagnosed following hemorrhage into the left SN. Technetium-99m hexamethylpropylene amine oxime (99mTc-HMPAO) single photon emission computed tomography (SPECT) showed reduced uptake in the left putamen, globus pallidus (GP) and thalamus (Abe and Yanagihara, 1996). The SPECT abnormalities were assumed to be the result of the stroke, rather than a coincidental abnormality. In another report, a patient developed right-sided cogwheel rigidity and resting tremor. In this case the magnetic resonance imaging (MRI) scan showed a contralateral midbrain hemorrhage affecting the SN and n-isopropyl-p-123I iodoamphetamine (123I-IMP) SPECT images showed reduced radioisotope uptake in the left striatum, thalamus and frontal lobe (Inoue et al., 1997). These cases had in common an apoplectic appearance of unilateral parkinsonian signs, which are the logical result of an ischemic or hemorrhagic lesion of the SN or the nigrostriatal tract and therefore constitute the most straightforward examples of VP. Such cases should have an acute onset, be non-progressive and even improve spontaneously over time and respond to levodopa. However, such cases are extremely rare. Microscopically such cases should not contain Lewy bodies. The etiology of vascular damage should not necessarily be atherosclerotic. Unilateral rest tremor associated with bilateral extrapyramidal syndrome responsive to levodopa was seen in a 25-year-old man 7 months after subarachnoid hemorrhage due to rupture of a peduncular subthalamic arteriovenous malformation (Defer et al., 1994). Parkinsonism has been described in patients with central nervous system vasculitis (Fabiani et al., 2002), rheumatoid arthritis (Ertan et al., 1999; Hrycaj et al., 2003), systemic lupus erythematosus (Tan et al., 2001; Garcia-Moreno and Chacon, 2002), antiphospholipid syndrome (Milanov and Bogdanova, 2001; Adhiyaman et al., 2002; Huang et al., 2002), disseminated intravascular coagulation (Yoritaka et al., 1997) and some neuroinfections like syphilis (Critchley, 1929; Sandyk, 1983; Pineda et al., 2000). Not unexpectedly, most patients had additional manifestations, consistent with the damaged area. Of
course, more extensive lesions due to basilar occlusion will also affect the SN but the extrapyramidal signs will be overshadowed by other manifestations of brainstem dysfunction. Acute or subacute parkinsonism was also observed as a result of tentorial herniations with brainstem compression in patients with subdural hematomas of traumatic or hypertensive etiology or as a result of rupture of arterial aneurysms (Cosi and Tonali, 1964; Pau et al., 1989; Trosch and Ransom, 1990; Turjanski et al., 1997). In some of these cases parkinsonism improved following removal of the hematoma (Sunada et al., 1996), but in others it persisted and usually responded to levodopa (Trosch and Ransom, 1990). Sudden onset of small-stepping gait with stooped posture, severe akinesia and freezing of gait and increased muscle tone with bilateral cogwheel phenomenon in the arms was seen in a patient with a small highdensity lesion in the medial side of the right cerebral peduncle and a lens-shaped low-density lesion in the left putamen. On T1- and T2-weighted MRI images a low signal was seen in a right peduncular lesion extending to the SN, which was also partially destroyed. The parkinsonism rapidly improved and completely disappeared within 2 weeks. The highdensity lesion of the right peduncle also disappeared on CT (Miyagi et al., 1992). Interestingly, destruction of the left subthalamic nucleus by hematoma can improve contralateral parkinsonian rigidity after extinction of the ballistic movement phase (Yamada et al., 1992). Kim (2001) reported patients with (hemi)parkinsonism after infarction in the territory of the anterior cerebral artery. Parkinsonism was usually related to large lesions involving the supplementary motor area and observed after the motor dysfunction improved in patients with initially severe limb weakness. In patients with clinically suspected VP, the comparison of levodopa response with the pathologically confirmed presence of macroscopic vascular damage in the nigrostriatal pathway and cell loss in the SN showed that the majority of patients with good or excellent response to levodopa had infarcts or lacunae in the SN in the absence of Lewy bodies (Zijlmans et al., 2004). These anecdotal cases of vascular lesions of the SN or nigrostriatal pathway had features resembling PD, including responsiveness to levodopa. However, the follow-up, long-term prognosis and special features of the dopaminergic treatment in relation to PD are unknown. Motor fluctuations, so common in advanced PD (Korczyn, 1972), have not so far been described in cases such as these. Neither had a gradual increase in dose over the years been documented. These cases
VASCULAR PARKINSONISM then typically consist of a non-progressive, levodoparesponsive (hemi)parkinsonism of acute onset.
52.2. Parkinsonism associated with basal ganglia lesions Ischemic infarcts in the territory of the lenticulostriate arteries were said to be the most frequent cause of unilateral parkinsonism (Friedman et al., 1986; Kulisevsky et al., 1996; Fenelon and Houeto, 1997; Sibon et al., 2004a). In these cases, there was an acute onset of the disorder with supportive imaging data to suggest the vascular etiology. A lateralized subacute parkinsonism with CT evidence of a single lacunar infarct in the contralateral BG was described by Lazzarino et al. (1990). A clinical syndrome indistinguishable from PD, in which postmortem examination revealed extensive lacunar infarctions of the BG without evidence of coexistent PD, was also reported (Murrow et al., 1990). However, subdivision of parkinsonian patients with lacunar infarcts in the BG into those with lacunes in the caudate nucleus, lentiform nucleus or both did not correlate with the clinical presentation (Reider-Groswasser et al., 1995). Lacunar infarctions in the BG are frequently observed in patients without parkinsonism and even in completely asymptomatic cases. The extrapyramidal signs, if present, can be asymmetrical without consistent relationship to the side of the lacuna (Inzelberg et al., 1994). Specific regions of the brain, such as central white matter, GP and hippocampus, are selectively vulnerable to carbon monoxide (CO) (Koehler and Traystman, 2002). Parkinsonism after CO poisoning could be seen in 10% of sufferers from CO encephalopathy (Choi, 2002). The most frequent signs are symmetric rigidity, hypokinesia, masked face, glabellar sign, grasping, short-step gait and retropulsion. Rest tremor has not been observed but intentional tremor may occasionally be found. The latency before the appearance of parkinsonism varies from 2 weeks to 6 months, but most frequently occurs within 1 month of CO exposure. Together with the parkinsonism, all patients have mild to severely impaired cognitive functions. Other common symptoms are mutism, gait disturbances and urinary incontinence. Extreme cases manifest a general akinetic-mute state up to bed-bound (Lee and Marsden, 1994). Neither levodopa nor anticholinergic drugs were shown to be effective. However, nearly 80% of patients improved or recovered spontaneously within 6 months (Choi, 2002). Abnormally high signal bilaterally in the GP on T1weighted MRI images was observed in patients
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following short terms after exposure to CO (Silverman et al., 1993). MRI abnormalities augmented with CT findings that revealed bilateral lucencies of the GP suggested that their damage is of vascular origin, probably hemorrhagic infarction (Bianco and Floris, 1996). Old necrotic lesions of the GP were earlier found on CT scans (Klawans et al., 1982). No correlation between the neuroimaging findings and the development of parkinsonism has, however, been demonstrated (Choi, 2002). The damage in CO poisoning, however, is not restricted to the BG and the direct role of the BG damage is unknown in these cases.
52.3. Parkinsonism with white-matter lesions A more common picture is that of short-stepped gait with or without freezing (Giladi et al., 1997), lead-pipe rigidity, no or mild upper-limb involvement, absence of rest tremor, which develops insidiously, and negative response to levodopa (FitzGerald and Jankovic, 1989; Chang et al., 1992; Yamanouchi and Nagura, 1995; van Zagten et al., 1998; Winikates and Jankovic, 1999). Pseudobulbar palsy is observed in nearly half of the patients (Yamanouchi and Nagura, 1995). The patients frequently have cognitive decline and detrusor overactivity (Cummings, 1994; Holstein et al., 1994). Long tract signs in the limbs, indicating damage to the corticospinal tracts, are found in more then half of patients (Yamanouchi and Nagura, 1997). Many of these patients have vascular risk factors and particularly hypertension. The evolution of this disease is typically slow, occurring over several month or even years (Inzelberg et al., 1994), an evolution similar to that seen in PD. Brain imaging shows diffuse subcortical white-matter damage, not unlike that seen in patients with Binswanger’s disease, sometimes accompanied by unilateral or bilateral BG infarcts (Demirkiran et al., 2001). Loss of postural reflexes and gait abnormalities seen in these cases may indicate extrapyramidal features, but are difficult to disassociate from coexisting spasticity and the slowness may also reflect pyramidal, rather than extrapyramidal, damage. Comparing the brain pathology in these patients with that in matched patients with Binswanger’s disease who had no parkinsonism according to clinical records failed to reveal any significant differences in the extent of BG damage (Yamanouchi and Nagura, 1997), thus pointing to the central role of white-matter damage. The number of oligodendrocytes in the frontal white matter of VP patients was significantly less than in age-matched normal control subjects, but significantly more than in those with Binswanger’s disease. Widespread lesions in the frontal white matter
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with only meager lesions in the BG were the main pathological features of VP. The extent of frontal white-matter pallor tended to be less broad in VP than in Binswanger’s disease without parkinsonism (Yamanouchi and Nagura, 1997). Marked atrophy in the frontal cortex as well as lacunar lesions around the lateral ventricles in VP were previously shown by Grundl et al. (1991). The exact pathogenesis of these white-matter changes is debated and likely heterogeneous, but generally thought to represent areas of chronic or recurrent partial ischemia. Although patients with BG lacunar infarct could recover spontaneously, those with frontal lobe infarcts could remain static and those with periventricular and deep subcortical white-matter lesions usually had progressive deterioration (Chang et al., 1992). From the clinical and pathological data presented so far, it seems that VP can occur as an acute syndrome, resulting from lesions of the SN or the nigrostriatal tract. These cases would be unilateral, non-progressive and respond well to levodopa. Diffuse white-matter damage, resulting from microvascular lesions, typically manifests as a combination of extrapyramidal, pyramidal and sometimes vascular changes, frequently with cognitive decline (Fig. 52.1). These cases would not typically respond to levodopa, because the lesions involve the ascending loop of the BG–thalamic–cortical loop (Bergman and Deuschl, 2002), distal to the striatal site of action of dopamine. Such cases are best described as pseudoparkinsonian because the extrapyramidal features are only part of a more extensive clinical picture and because of a lack of response to dopaminergic drugs.
BG lacunae are quite common in the elderly, frequently without parkinsonian signs. If parkinsonian signs do exist they do not bear a clear relationship to the side of the lesion. The etiology of most BG lesions is microvascular and in fact many, perhaps most, cases with BG lacunae also have white-matter lesions and it is best to look at these cases as reflecting an incidental manifestation of BG lesions, whereas the principal changes responsible for the motor dysfunction occur in the white matter.
52.3.1. Brain imaging The integrity of the nigrostriatal pathway can be inferred from radioligand studies, in which the chemicals used have affinity to the dopamine transporter molecules at the terminals of the dopaminergic synapses in the BG. Small studies failed to find specific changes in VP patients and indeed were not significantly different from those in healthy individuals. The characteristic reduction of the uptake is pronounced in the contralateral putamen of PD patients with unilateral symptoms, but not in VP (Tzen et al., 2001). Normal striatal 123I-FPCIT binding with no significant differences in striatal or subregional binding ratios compared with those of the controls was seen in patients with VP. PD patients had significantly diminished striatal binding compared with that of controls (Lorberboym et al., 2004). As compared to normal controls, patients with VP had significant reduction of the ratio between N-acetylaspartate and creatine plus phosphocreatine in the frontal cortex
Fig. 52.1. T1 and T2 magnetic resonance images of a 73-year-old patient with severe parkinsonism resistant to levodopa, gait disorders, freezing of gait, recurrent falls and urinary urgency. Multiple infarcts are seen in the basal ganglia and brain white matter as well as periventricular white-matter changes (own observation).
VASCULAR PARKINSONISM (Abe et al., 2000), suggesting a lesion beyond the classical extrapyramidal system. 52.3.2. Transcranial ultrasonography The structurally normal SN could be visualized using ultrasound waves delivered through a cranial ‘window’, similar to that when flow in the middle cerebral arteries is examined (Fig 52.2). This method can distinguish between lesions affecting the SN directly, such as PD and other disorders causing extrapyramidal features (Berg et al., 1999). This effect is based on the high iron level in the SN, thought to promote generation of reactive oxygen species (Berg et al., 2002) and has been shown to be specific to PD (Berg et al., 2005). Thus, if all PD patients show a bilateral SN hyperechogenicity, a low echogenic SN, particularly combined with hyperechogenic lentiform nuclei, could suggest other kinds of parkinsonism (Walter et al., 2002; Behnke et al., 2005). 52.3.3. Additional methods of diagnosis of vascular parkinsonism Non-motor differences between VP and PD could be used in the differential diagnosis: 1. Measurement of myocardial innervation may contribute to the differential diagnosis of parkinsonism
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(Berding et al., 2003; Goldstein, 2004). In patients with PD, even without clinical evidence of autonomic failure, reduction in iodine-123-metaiodobenzylguanidine (123I-MIBG) uptake on scintigraphy occurs in the heart. This is considered to be a specific finding for PD and useful for the differential diagnosis from other parkinsonian syndromes, occurring even in the earliest stage of the disease (Taki et al., 2000). Parkinsonian syndromes other than PD did not demonstrate reduction in MIBG uptake. 2. Testing olfactory function could be helpful in differentiating VP from PD (Katzenschlager et al., 2004). For example, olfactory function, diagnosed according to the Pennsylvania smell identification test, was significantly better in VP patients than in PD and did not differ from normal controls. 3. Colonic transit time measured in VP patients was normal (about 59 hours), as opposed to PD (Hardoff et al., 2001), where markedly slow transit is observed (Jost et al., 1994). 52.3.4. Parkinson’s disease versus vascular parkinsonism: comparison of pathophysiology PD results from the slowly progressive death of selected populations of neurons, including the neuromelanin-containing dopaminergic neurons of the pars
Fig. 52.2. Sonographic image of the midbrain axial section in a patient with PD. The butterfly-shaped midbrain section of low echogenicity is surrounded by the hyperchogenic basal cisterns (encircled area, centre of fig.). Note the marked hyperechogenicity of the left SN. This area is encircled for computerized measurement. Courtesy of Prof. Heinz Reichmann from the Department of Neurology, Technical University of Dresden, Germany.
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compacta of the SN, some other catecholaminergic and serotoninergic brainstem nuclei, the cholinergic nucleus basalis of Meynert, hypothalamic neurons and small cortical neurons (particularly in the cingulate gyrus and entorhinal cortex), as well as the olfactory bulb, sympathetic ganglia and parasympathetic neurons in the gut (Korczyn, 1993; Braak and Braak, 2000). According to the accepted model, dopamine loss increases the activity of the indirect pathway and reduces the activity of the direct pathway (Wichmann and DeLong, 2003). The final result of these changes is an overexcitation of the main output nuclei of the BG, GP interna and SN pars reticulata, leading to inhibition of the thalamocortical motor system. If the latter is essentially important in the pathogenesis of rigidity, bradykinesia and loss of postural reflexes, the white-matter lesions affecting the latter pathway should result in a similar phenotype. However, these should not respond to levodopa since there is no dopamine loss and in any case the site of action of dopamine, the BG, is disconnected from the motor cortex. Thompson and Marsden (1987) suggested that the gait disorder of Binswanger’s disease is probably due to diffuse vascular lesions disrupting the interconnecting fiber tracts between the BG and the motor cortex. Multiple lacunar subcortical infarcts interrupting thalamocortical drive are critical for the development of VP (Bhatia and Marsden, 1994; van Zagten et al., 1998; Peralta et al., 2004). Three characteristic features of presynaptic process affecting the dopaminergic system in PD are:
Thus, PD is a neurodegenerative disease, which selectively affects certain categories of neurons, chiefly manifests as a progressive diminution of dopamine level in the nigrostriatal system, induces an overactivation of the output nuclei of the BG and STN and inhibits the thalamocortical motor system. VP is a clinical syndrome that may have similarities to the cardinal motor manifestations of PD. Approximately 10% of cases of parkinsonism clinically recognized as PD could pathologically be the result of cerebrovascular disease and, in contrast, the emergence of one or more clinical signs of parkinsonism was revealed in 30% patients after stroke (Sibon et al., 2004b). As distinct from PD, however, VP is the result of endothelial dysfunction and arteriolosclerosis causing lacunar strokes or punctate hemorrhages, disseminated mainly in the centrum semiovale and/or BG. Risk factors of cerebrovascular disease, like hypertension, diabetes mellitus type 2, hyper-/dyslipidemia, hyperhomocysteinemia, previous stroke history and genetic predisposition are usually present (Keskin and Yurdakul, 1996; Ekinci et al., 2004). In the pathogenesis of VP without a direct lesion affecting the SN, the dopamine level and its metabolites in the cerebrospinal fluid should be normal (Loeffler et al., 1995). Thus, the accepted explanation is that the clinical symptoms in VP are related to postsynaptic lesions of the nigrostriatal system mainly as a result of a patchy destruction of neurons or axons at the putamen, GP and probably the cerebral white matter.
1. A major reduction of striatal levodopa uptake of the nigrostriatal pathways (Leenders, 1997; Broussolle et al., 1999; Brooks, 2004; Thobois et al., 2004) which is correlated with degeneration of the SN neurons found by pathological studies (Jellinger, 2002; Snow, 2003). This process may be accompanied by increased raclopride binding of postsynaptic dopamine receptors in the putamen as a sign of postsynaptic hypersensitivity in de novo, drug-naive PD patients (Antonini et al., 1994; Kaasinen et al., 2000). 2. An obvious effect of levodopa, which can be seen particularly at the early stages of PD (Hornykiewicz, 2002). 3. Presence of pathologic hallmarks – degenerating ubiquitin-positive neuronal processes or neurites (Lewy neurites), which have been found in all affected brainstem regions and especially at the dorsal motor nucleus of the vagus and later in the SN (Braak et al., 1999; Gai et al., 2000).
52.4. Conclusions VP is not a homogenous syndrome. Its etiology may be atherosclerotic in many cases, but it could result from embolic, arteritic or hemorrhagic processes. Pathophysiologically, two forms of VP should be considered: the first affects the nigrostriatal system unilaterally. A discrete lesion of the SN or the nigrostriatal pathway should be seen in imaging. These patients should have an acute onset, should not progress and should respond to levodopa. The other, much more common group, consists of patients presenting at more advanced age and with predominantly lower-body involvement and gait abnormalities rather than tremor. A history of stroke, heart disease, arterial hypertension and other risk factors for stroke support a vascular origin of these symptoms. Usually, these patients do not have the typical parkinsonian rest tremor. In these cases imaging demonstrates an extensive white-matter disease.
VASCULAR PARKINSONISM BG lesions are frequently seen in patients with parkinsonian symptoms, but their relationship to the pathology is unclear since the onset of parkinsonism is rarely acute and not strictly contralateral to the damage (typically, a small lacuna). Moreover, some people with similar lacunae do not demonstrate any clinical manifestations. Probably, this VP syndrome is the result of coexistent white-matter changes. These cases are most likely to represent the entity of ‘pseudoparkinsonism’, as defined by Critchley. The extensive damage ensures that a patient suffers not only from increased muscle tone and bradykinesia, but typically also from cognitive decline, pseudobulbar syndrome, posture and gait instability and urinary incontinence. Obviously these patients will respond poorly to levodopa and there is an urgent need to develop drugs that could help these patients.
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Handbook of Clinical Neurology, Vol. 84 (3rd series) Parkinson’s disease and related disorders, Part II W. C. Koller, E. Melamed, Editors # 2007 Elsevier B. V. All rights reserved
Chapter 53
Old age and Parkinson’s disease ALEX RAJPUT AND ALI H. RAJPUT* University of Saskatchewan, Saskatoon, SK, Canada
53.1. Introduction There is no uniformly agreed definition of old age. For the purpose of this chapter, we will use the commonly utilized employment-related retirement age of 65 as the start of old age (Desai et al., 1990; Canadian Study of Health and Aging Working Group, 1994; Moghal et al., 1994, 1995). The proportion of the elderly has been steadily rising for several decades in western countries (Rowe, 1988). Therefore, the frequency of those disorders that are concentrated in old age is progressively increasing. The motor manifestations of Parkinson’s disease (PD) include bradykinesia, rigidity, tremor, postural abnormality, gait abnormality, impaired postural reflexes, extraocular movement abnormality, presence of primitive reflexes and reduced facial expression. Some similar features also seen in the normal elderly. The most common variant of Parkinson syndrome (PS: parkinsonism) is the Lewy body disease also known as PD or idiopathic PD (Jellinger, 1987; Duvoisin and Golbe, 1989; Rajput et al., 1991c; Bower et al., 1999; Robinson and Rajput, 2005). The primary focus of this chapter will be on aging and PD, with brief consideration of the less common variants of PS and of other disorders that may mimic PD. Normal posture and gait depend on vestibular, visual, proprioceptive and motor functions and an ability to adjust to the postural sway. There is a decline in vestibular (Parker, 1994), visual (Kline et al., 1982; Matjucha and Katz, 1994), proprioceptive (Drachman et al., 1994) and motor functions (Drachman et al., 1994), as well as reduced muscle mass (Lexell et al., 1988) in old age. In addition, there is increased postural sway (Maki et al., 1990; Baloh et al., 1994), postural instability (Weiner et al., 1984; Ross et al., 2004), stooped posture (Ross et al., 2004) and reduced range
of vertical gaze (Jenkyn et al., 1985) with aging. These age-related anatomical and physiological changes lead to a slowed motor function (bradykinesia) and alterations in station, posture, gait and postural reflexes, all of which are well-known features of PD. Therefore, normal changes of aging need to be distinguished from PD in elderly persons. Most PS, including PD, are concentrated in later age. Thus, the incidence of PS and PD rises sharply with advancing age. The pathological hallmark of PD is a marked loss of substantia nigra pigmented neurons and neuronal Lewy body inclusions (Jellinger, 1987; Duvoisin and Golbe, 1989; Rajput et al., 1991c). Autopsy studies show that a significant proportion of the elderly with no clinical features of PS have incidental Lewy body inclusions in the brain. The frequency of incidental Lewy body inclusions in autopsy brains rises with age, reaching 13% in the ninth decade (Graybiel et al., 1990; Fearnley and Lees, 1991; Gibb, 1991; Ross et al., 2004). The incidental Lewy body cases are believed to represent a preclinical stage of PD (Fearnley and Lees, 1991; Gibb, 1991; Ross et al., 2004) who would develop clinical features of PD with time or with an added stress of neuroleptic use (Rajput et al., 1982). The elderly have a disproportionately large number of other diseases (Rowe, 1988). They receive more prescription and non-prescription drugs compared to the younger population and have a higher incidence of drug adverse effects, including parkinsonism (Blaschke et al., 1985; Rowe, 1988; Desai et al., 1990). Other disorders which are common in old age, notably stroke and Alzheimer’s disease, may be associated with clinical features of parkinsonism. When all these factors are considered together, the elderly represent a large segment of the population with an increased risk of developing parkinsonism or PD.
*Correspondence to: Professor Ali H. Rajput, University of Saskatchewan, Royal University Hospital, 103 Hospital Drive, Saskatoon, SK S7N OW8, Canada. E-mail:
[email protected], Tel: (306) 966-8009, Fax: (306) 966-8030.
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The onset of PS is very rare before age 30 years (Rajput et al., 1984a; Marttila, 1987; Bower et al., 1999) and the incidence and prevalence rates rise with age. Whereas there were 0.8/105 new cases of PS before age 30 years and 26.5/105 new cases per year between ages 50 and 59 years, the annual incidence rose to 211.6 between ages 70 and 79 and was 304.8/ 105 for those aged 80–99 years in one community (Bower et al., 1999). Assuming no competing cause of death, the risk of developing PS was estimated at 0.7% by age 60 and 7.5% by age 90 years (Bower et al., 1999). The other major consideration is the survival after onset of disease, as that would impact the number of PS cases in old age. Levodopa is the most widely used drug for PD in industrialized countries (Global Parkinson’s Disease Survey (GPDS) Steering Committee, 2002). Patients treated with levodopa have a significantly longer survival after onset of illness (Rajput, 2001) compared to untreated cases and that observed in the past (Hoehn and Yahr, 1967). Higher incidence and prolonged survival result in higher prevalence rates in the elderly population. Bennett et al. (1996) studied the prevalence of parkinsonism in community residents 65 years and older. The overall prevalence of PS between age 65 and 74 years was 14.9%, between 75 and 85 years it was 29.5% and in those over age 85 years the prevalence rate was 52.4%. In another community-based study, Schoenberg et al. (1985) reported that the prevalence rate of PS in those over 75 years was more than seven times higher compared to those aged 40–60 years. Because of the similarities between normal aging and PD motor features, the first question the neurologist must answer is whether the clinical features are an indication of old age or of PD.
53.2. Normal aging and Parkinson’s disease As noted above, some of the motor manifestations of aging resemble PS. Because there are no readily available biological markers to distinguish between normal aging and parkinsonism, the best tool is careful clinical assessment (Weiner et al., 1984; Jenkyn et al., 1985; Sudarsky, 1990, 1994; Rajput, 1993c). The presence of two of the three cardinal features of bradykinesia, rigidity and resting tremor are needed for a clinical diagnosis of PS (Rajput et al., 1991a, 2002; Rajput, 1994a; de Rijk et al., 1997). Impaired postural reflexes are not used as additional evidence for PS diagnosis in the elderly (Rajput et al., 1991c; Rajput, 1994a), as they are also seen in a large proportion of the normal elderly (Weiner et al., 1984; Ross et al., 2004).
Impaired postural reflexes evolve relatively late in younger cases and are used to classify the clinical severity of the disease (Hoehn and Yahr, 1967; Fahn et al., 1987). 53.2.1. Bradykinesia of old age and parkinsonism The akinesia–hypokinesia–bradykinesia complex implies slowed motor function. Akinesia is the inability to initiate movement, hypokinesia indicates reduced amplitude of movement and bradykinesia implies slowed speed of movement (Marsden, 1989). In clinical practice, these three features are collectively referred to as bradykinesia. Bradykinesia is the cardinal feature of PD and other variants of PS (Webster, 1968; Fahn et al., 1987; Marsden, 1989; Rajput et al., 1991c; Rajput, 1994a). The clinical manifestations of bradykinesia are similar in all variants of parkinsonism, though there may be different anatomical sites of involvement. Slowed motor function is also a part of normal aging (Duncan and Wilson, 1989; Drachman et al., 1994; Bennett et al., 1996; Ross et al., 2004). Distinction between the normal age-related slowing and bradykinesia of parkinsonism is therefore important. Table 53.1 summarizes features that are helpful in distinguishing between age-related slowing, PS and some other neurological and focal abnormalities which may cause motor slowing. Bradykinesia as a symptom reported by PD patients depends on the lifestyle. In general, the motor activities that require repeated change in direction are impaired early. Someone who jogs or walks for exercise may note a foot dragging when tired, a piano player may report being unable to play certain notes and a writer would find slowed and smaller handwriting. Slowing of other activities, e.g. walking, easing gracefully into a chair and difficulty turning in bed are other common complaints. In clinical practice, bradykinesia is tested by observing the patient as he/she sits, talks, walks and when asked to perform certain motor tasks. The normal automatic arm-swing with walking, hand gestures during conversation and facial expression are all reduced in parkinsonism. Simons et al. (2004) studied 19 PD patients and 26 healthy controls for emotional expression during conversation and while watching videos and for the ability to use an emotional facial gesture or imitate facial movements. All these factors were reduced in PD cases compared to controls (Simons et al., 2004). In a microcomputerbased observation, Katsikitis (1988) noted that, when watching funny cartoons, parkinsonian patients smiled less frequently than the controls.
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Table 53.1 Motor slowing in aging, parkinsonism and some other disorders
Symmetry of findings Focal examination Tone
Sensory function Reflexes
Muscle strength
Rest tremor Facial expression Handwriting Speech
Normal age-related slowing
Parkinsonism bradykinesia
Focal pathology emulating slowing
Other nervous system pathology – (central or peripheral) causing slowing
Symmetrical
Often asymmetrical Normal
Asymmetrical
Frequently asymmetrical
Abnormal
Normal
Normal (if pain and joint movement restriction discounted). Test at unaffected joint helpful to identify normal tone As in normal aging
May have paratonia in demented cases Spasticity if corticospinal involvement Decreased if lower motor neuron pathology
Normal Normal
Increased – rigidity
Normal (except vibration reduction in feet) Normal symmetrical (ankle jerks may be hypoactive) Plantars flexor Normal
As in normal aging As in normal aging
Normal
Absent Normal Normal Normal
As in normal aging
May be impaired depending on the nature of lesion Hyperactive with extensor plantar or hypoactive depending on site of lesion. Frequently asymmetrical Reduced or inconsistent
Usually present Reduced
Normal, but patient unable to exert fully due to pain or joint restriction Absent Normal
Absent Normal
Micrographia Low volume
Normal Normal
Normal Normal
The smooth face of young age becomes wrinkled in the elderly. Facial immobility in PD results in a masklike face and prolonged facial immobility leads to a smoother and younger-looking face. Since the facial wrinkles develop over many years, the reduced facial expression must exist for a long time before parkinsonism is clinically evident. Depression, which is common in PD, adds to the reduced facial expression. Motor slowing is most pronounced in those activities that require repetitive, simultaneous or sequential movements. Repetitive movements of finger/thumbtapping, forearm pronation/supination, fist-opening/ closing and foot-tapping are common clinical maneuvers utilized to assess bradykinesia (Fahn et al., 1987). With repeated movements, the amplitude of the movement declines and the movement may arrest. The total slowing of an activity is more pronounced than the sum total of the slowing of each component of the complex movement (Marsden, 1989).
In most PD patients, the bradykinesia and rigidity are of comparable severity when the standardized assessments are done (Webster, 1968; Fahn et al., 1987). However, the pathophysiology of bradykinesia and rigidity may not be the same in elderly cases. Levodopa which relieves rigidity may not improve bradykinesia in advanced PD (Marsden, 1989). Asymmetry of bradykinesia without any other focal or neurological cause is a strong indication of PD. That should, however, be assessed with more than one activity. We have observed asymmetrically reduced arm-swing without any other features of PS in several otherwise neurologically normal members of one family. It is not uncommon for the elderly to have a shoulder problem which restricts movements. When there is evidence of localized motor function slowing, ask the patient if there is pain associated with the movement and evaluate the area for any mechanical or pain-related passive movement restriction at the
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joint. Detailed assessment of sensory function, motor strength, tone and reflexes, as noted in Table 53.1, is a valuable adjunct to distinguish parkinsonism from age-related slowing and other disorders. The age-related slowing is typically symmetrical and generalized. Although bradykinesia due to PD is often asymmetrical, it is more often symmetrical in multiple system atrophy and in progressive supranuclear palsy. The severity of bradykinesia in PD is reported to correlate with the degree of striatal dopamine loss (Ehringer and Hornykiewicz, 1960b, 1998; Hornykiewicz and Kish, 1986; Agid et al., 1987, 1989; Agid, 1991). We investigated the relationship between Unified Parkinson’s Disease Rating Scale (UPDRS)-based bradykinesia (Fahn et al., 1987) and the striatal dopamine levels in PD. The striatal dopamine loss and the severity of bradykinesia revealed a correlation in the akinetic-rigid PD cases but not in the tremor-dominant or the mixed clinical picture cases (unpublished observations). 53.2.2. Tone change in old age, parkinsonism and some other disorders The major tone abnormality in PS is rigidity. It is clinically similar in different variants of PS. Some PS patients may also manifest dystonia. Tone is defined as involuntary resistance to passive movement. In testing tone, one depends on patient cooperation. The patient is asked to relax: neither to assist nor resist the passive movement attempted by the examiner. In the normal elderly, there is no change in tone. Rigidity may manifest as continued smooth resistance to passive movement through the entire range of movement. That is known as lead-pipe rigidity. More often in rigidity, the increased tone is associated with recurring interruptions–a ratchety quality known as cogwheel rigidity. When asked to relax, most patients do so and allow satisfactory assessment of tone. The instructions may need to be repeated to ensure patient cooperation during the passive movement. Rigidity in PD patients is predictably reproducible and is approximately equal in the muscles with opposite mode of action (Findley and Koller, 1995). Cogwheel rigidity is usually observed in patients who have hypertonicity as well as tremor. However, some patients with no visible tremor may also manifest cogwheel rigidity. The patient may try to cooperate and actively move the body part in the same direction as the examiner moves it. In such case, the passive movement should be performed irregularly so that the patient cannot predict and oppose or facilitate the movement. Distracting the patient by asking a question may be helpful in the evaluation.
Cognition and language impairment are more common in the elderly and impact their ability to cooperate for adequate assessment. They may resist passive movement proportional to the force applied by the examiner. Alternatively, the patient may oppose the passive movement intermittently, giving it a feeling of cogwheel rigidity. This is known as paratonia or gegenhalten (Klawans, 1981; Jenkyn et al., 1985; Rajput, 1993c). Such tone abnormality is not reproducible in a predictable fashion (Jenkyn et al., 1985; de la Monte et al., 1989; Rajput, 1993c). Dystonia is characterized by co-contraction of agonist and antagonist muscles. The force of muscle contraction is, however, unequal in the opposing muscle groups. On passive movement, there is greater resistance when the part is moved away from the dystonic posture compared to when the movement is attempted in the same direction as the dystonic posture. Dystonia may be associated with intermittent tremor mainly when the body part is moved away from the dystonic position. This is known as dystonic tremor. The increased tone with corticospinal tract lesions is known as spasticity. It is characterized by a velocity -dependent ‘catch’ which is followed by a release without further resistance, as seen in opening or closing a pocket knife. It is, therefore, called clasp-knife hypertonicity. Although spasticity and rigidity are easy to distinguish in most cases, in cases with mild spasticity the distinction from rigidity may be difficult. The following maneuver may be helpful: Have the patient lie on his/her back, lift one leg with one hand under the heel and put your other arm under the extended knee of the patient. Now suddenly release the heel grip and allow the leg to flex at the knee, falling towards the examining table. In case of spasticity, there will be an initial catch and then the leg will drop to the table rapidly. In the case of rigidity, the leg falls down at a steady speed throughout the downward movement. An additional distinguishing feature is the change in reflexes. Muscle stretch reflexes are hyperactive in corticospinal lesions but there is little, if any, change in PD. The plantar response is extensor in corticospinal tract lesions whereas in PD the plantar reflex is flexor or equivocal. In some PS patients, there is spontaneous or ambulation-related dorsiflexion of the big toe. This dystonic posture is called ‘striatal toe’ (Duvoisin, 1990). When the plantar reflex is performed, the big toe does not extend further but may flex. 53.2.3. Tone testing and tremor disorders The presence of medium- or large-amplitude tremor may produce rhythmic interruption of the passive movement known as cogwheeling phenomenon (Findley
OLD AGE AND PARKINSON’S DISEASE et al., 1981; Findley and Koller, 1995). In such cases increased tone on reinforcement is known as Froment’s phenomenon. During examination, when the ratchety feeling first emerges, stop further movement and gently hold the body part still. In Froment’s phenomenon, the rhythmic movement continues. If, on the other hand, there is cogwheel rigidity related to PD, there would be no continuation of the rhythmic movement. In patients with head tremor, when the passive movement is performed in the direction of the tremor, there may be cogwheeling and on reinforcement Froment’s phenomenon. Passive movement in the direction where there is no tremor will help determine the tone more accurately. In PD-related neck rigidity, there will be resistance in all directions of neck movements – lateral flexion and turning the head from side to side. Special attention should be paid to the elderly
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who are likely to have degenerative cervical spine changes. If there is still a doubt about the nature of the cogwheeling at a joint, e.g. at wrist, the tone should be tested at another joint where there is no tremor, such as the shoulder. Table 53.2 summarizes the tone change in the normal elderly, parkinsonism and selected disorders. 53.2.4. Station, posture and postural reflexes in old age and Parkinson’s disease The manner or attitude of standing is known as station and the position of the whole body and its different parts indicates the posture. Visual, vestibular and proprioceptive functions, which are critical for maintaining normal posture, all decline with normal aging (Kline et al., 1982; Drachman et al., 1994; Matjucha
Table 53.2 Tone changes in elderly Parkinson’s disease and selected conditions
Normal elderly
Parkinson’s disease rigidity
Spasticity (mild)
Paratonia (gegenhalten)
Cogwheeling phenomenon (Froment’s phenomenon)
Characteristic
Equal and normal resistance in all directions of movement
Resistance sustained and equal in opposite directions of movement. Reproducible
Increased tone Velocitydependent catch – ‘clasp-knife’
Irregular, intermittently increased tone or progressively greater resistance on attempted movement Unpredictable
Symmetry
Symmetrical
Usually asymmetrical
Frequently asymmetrical
Usually symmetrical
Reflexes
Normal Reduced at ankles Plantars flexor
Normal. May have striatal toe
Usually normal
Tremor
Absent
Absent
Prominent feature
Reinforcementrelated tone increase
No significant change. Minimal, if any, and is symmetrical
Frequently part of Parkinson’s disease Usually asymmetrical increase
Exaggerated and extensor plantar response Absent
Rhythmic Interruption of passive movement coinciding with tremor. Rhythmic resistance to passive movement only seen on reinforcement in tremor-producing conditions – Froment’s phenomenon May be symmetrical or asymmetrical depending on tremor location Normal
May increase slightly
Unpredictable change
Rhythmic symmetrical increase (Froment’s phenomenon)
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and Katz, 1994; Parker, 1994). There is normally swaying of the body while in the standing position; this increases with advancing age (Maki et al., 1990; Baloh et al., 1994; Bennett et al., 1996; Du Pasquier et al., 2003; Fransson et al., 2004). Dizziness is the subjective sensation of instability. By the age of 65 years, 30%, and by age 80 years, 66% of the general population would have experienced dizziness at some time (Luxon, 1984). This subjective feeling adds to postural instability in older individuals. Normal elderly people have a slightly wide base when standing and walking (Drachman et al., 1994). The body becomes flexed at the neck and trunk (Ross et al., 2004) but the knees and elbows remain straight in old age. By contrast, in PD patients, there is flexion at the neck, trunk, hips, knees and elbows. Those changes are more pronounced in multiple system atrophy. In progressive supranuclear palsy, the posture is erect, with the neck in a normal or even extended position. When asked to stand erect, advanced PD patients have difficulty maintaining the erect posture for several seconds, whereas the normal elderly can do that easily. The ability to regain balance after spontaneous sway or when the body is actively perturbed from standing position depends on the integrity of the postural reflexes. Maki et al. (1990) noted that both spontaneous and induced sway of balance are exaggerated in old age, regardless of whether the eyes are open or closed. Increased anteroposterior displacement velocity in the elderly has been reported in other studies (Du Pasquier et al., 2003; Fransson et al., 2004). The most pronounced velocity change is seen in those who have a fear of falling. With vibratory perturbation applied to the gastrocnemius muscle, the elderly used higher-frequency motion and complex dynamics to adjust compared to younger persons (Fransson et al., 2004). The elderly also have a reduced capability to use visual information to adjust to perturbation. In general, the elderly have more difficulty in compensating for balance perturbation (Fransson et al., 2004). In the clinical setting, postural stability is tested as follows: The patient is asked to stand with eyes open and feet approximately shoulderwidth apart. He/she is asked to resist a sudden pull by the examiner. The patient is advised to take one step if necessary to regain balance and is assured that the examiner will not allow him/her to fall. Depending on the size and agility of the patient, there will be a different degree of force required to displace. The force of the pull should be such as would reasonably displace the person so the capability to regain balance can be assessed. Initially, the examiner applies a pull in the forward direction. Following that, the same maneuver is
repeated in the backward direction (Weiner et al., 1984; Fahn et al., 1987; Sudarsky, 1990). This is known as the pull test. If the patient takes no or one step, that is considered normal. When there are two to three steps it is considered as slight impairment of postural reflexes. Four or more steps on pull or when the patient would fall if not prevented is definitely abnormal (Fahn et al., 1987). The global clinical severity of PD is measured using the pull test as a major parameter (Hoehn and Yahr, 1967; Fahn et al., 1987). Impaired postural reflexes are part of normal aging (Tinetti et al., 1988; Rajput, 1993c; Ross et al., 2004). Postural reflexes were impaired in 43% between age 60 and 69 years and in 70% of individuals between ages 80 and 89 in persons who had no neurological or other identifiable cause (Weiner et al., 1984). Progressive decline of postural reflexes was reported in a longitudinal study of normal elderly people (Wilson et al., 2002). Thus, the postural instability as tested in the clinical setting is also a part of the normal aging process. It can not be utilized therefore as a requirement for the diagnosis of PD in the elderly. However it can be used as an adjunct when the other cardinal features of PD – bradykinesia, rigidity and tremor – are evident, especially if those abnormalities are asymmetrical (Tinetti et al., 1988; Rajput et al., 1991c; Rajput, 1993a, b, c). Although the PD-related loss of postural reflexes may improve with levodopa, the age-related abnormality does not benefit from medical therapy. 53.2.5. Gait abnormality in old age and Parkinson’s disease In normal elderly people, the gait is slightly widebased, slow and the strides are shorter compared to younger individuals but the heel strike and the armswing are normal (Rajput, 1993c; Drachman et al., 1994). In normal elderly people, the stride velocity declines by 10–20% by age 80 years (Sudarsky, 1990; Winter et al., 1990) and they adopt a more conservative gait to reduce the risk of falling (Menz et al., 2003). Individuals who have an exceptionally slow or abnormal pattern of ambulation are classified as having a gait disorder. It is estimated that 15% of persons 60 years and older have a gait abnormality (Sudarsky, 1990). Sudarsky and Ronthal (1983) assessed 50 individuals who had a mean 1-year duration of gait difficulty. They found that 10% of those cases had other features of parkinsonism and improved on levodopa. In approximately 15% of elderly gait disorder cases, no cause is discovered despite extensive investigations (Sudarsky and Ronthal, 1983; Sudarsky, 1990).
OLD AGE AND PARKINSON’S DISEASE Such cases are classified as having idiopathic (Sudarsky and Ronthal, 1983) or senile gait disorder (Koller et al., 1983). Senile gait is characterized by stooped posture, broad base, reduced arm-swing, stiff turns and a tendency to fall (Koller et al., 1983). Gait and balance abnormalities with no identifiable neurological disease were evaluated prospectively in 70 healthy ambulatory elderly subjects (mean 79 years, range 74–88) (Whitman et al., 2001). Brain magnetic resonance imaging (MRI) studies were performed at baseline and 4 years later. Those who developed gait and balance problems had a significantly greater mean increase in volume of T2-weighted white-matter hyperintensities on brain MRI (Whitman et al., 2001). PD is the most common movement disorder resulting in gait abnormality in the elderly. The gait is characterized by flexed posture, narrow base, slow and short shuffling steps, slow multistep turning, loss of heel strike, reduced toe elevation, reversal of ankle flexion/extension movement, reduced movement at the knee joints, loss of dynamic vertical force and loss of backward-directed sheer force resulting in a tendency to propulsion (Forssberg et al., 1984). A Parkinson patient may break into an uncontrollable forward run, known as festination. Because of the impaired postural reflexes, any perturbation may result in involuntarily walking forward (propulsion) or walking backward (retropulsion). Freezing of gait may be evident as start hesitation on approaching an obstacle or on attempts to change direction – ambulatory efforts needed to overcome a block (Bloem et al., 2004). Abnormal gait, freezing of gait and impaired postural reflexes are all major problems at advanced stages of PD (Hoehn and Yahr, 1967; Fahn et al., 1987; Bloem et al., 2004) and lead to significant functional handicap and falls. One study noted that, compared to healthy controls, the relative risk of recurrent falls in PD cases over a period of 6 months was nine times greater (Bloem et al., 2004). In moderately advanced PD patients, the gait may improve with visual guided patterns (Forssberg et al., 1984; Suteerawattananon et al., 2004) and with auditory cues (Suteerawattananon et al., 2004). Prior to the advent of levodopa therapy, no drug reversed the impaired postural reflexes and gait abnormality in PD significantly. On modern drugs, some patients may regain those functions. Freezing of gait is difficult to treat. Response to treatment is less than satisfactory during advanced stages of PD, but some improvement may be seen on dopaminergic drugs and on selegiline (Bloem et al., 2004). Freezing of gait during the ‘off’ period may improve on levodopa (Schaafsma et al., 2003). Freezing of gait is more common in older PD
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patients. However, freezing of gait as an initial manifestation of PD is not different in young- and oldage-onset cases (Bloem et al., 2004). On the other hand, postural instability and gait disturbance with PD onset are more common in old age (Bloem et al., 2004). In the parkinsonian variant of multiple system atrophy, the gait abnormality is similar to PD, but it manifests early and the decline is more rapid than in PD (Rajput et al., 1972, 1993a). In progressive supranuclear palsy cases, the posture is erect and the gait is characterized by a high-stepping and ‘robotic’ quality. Progressive supranuclear palsy cases have predominantly axial akinetic-rigid features and supranuclear ophthalmoplegia. Nearly one-half of the autopsy-confirmed cases were reported without ophthalmoplegia in one study (Birdi et al., 2002). Most progressive supranuclear palsy cases show no significant improvement on levodopa (Birdi et al., 2002). 53.2.6. Gait apraxia In gait apraxia cases, the functional abnormality is restricted to walking and there is no motor weakness, sensory loss or cerebellar dysfunction in the lower limbs to account for the gait difficulty. Typically, these patients have an erect posture, slightly broad base, difficulty initiating gait, reduced cadence (steps per minute) and short shuffling and hesitating steps, as if ‘glued’ to the floor (Estanol, 1981; Fisher, 1982; Sudarsky and Ronthal, 1983; Forssberg et al., 1984; Sudarsky, 1990). Unlike the PD cases, the gait apraxia patients do not improve with visual or auditory cues and are unable to mimic a normal gait (Forssberg et al., 1984; Suteerawattananon et al., 2004). There is a marked dissociation between the leg functions in the supine and sitting positions compared to that during walking. Gait apraxia patients are able to use the lower limbs for activities such as writing on the floor with a foot while in the sitting position, kicking an imaginary ball and emulating bicycle riding in the supine position. However, in the weight-bearing position, the execution of the lower-limb motor activity required for walking is markedly impaired. By contrast, in mild to moderate PD cases, the impairment of lower-limb function during non-weight-bearing and the weightbearing activities is similar. Della Sala et al. (2002) reported a case of gait apraxia due to a stroke affecting bilateral supplementary motor areas. In normalpressure hydrocephalus, the exact site pathology is not known (Fisher, 1982; Sudarsky and Simon, 1987). The normal-pressure hydrocephalus patients often manifest dementia, frontal-release signs and bladder incontinence (Estanol, 1981). In some of those
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cases, the gait abnormality may be the only manifestation (Fisher, 1982; Sudarsky and Simon, 1987). Rare patients with gait apraxia may have extensor plantar responses. Resting tremor, which is a common feature of PD, is not seen with gait apraxia. Limb bradykinesia and rigidity, the other major features of PD, are not seen in either the upper or the lower limbs when assessed in the sitting or supine position. The gait apraxia patients do not improve on levodopa. Table 53.3 summarizes gait in the normal elderly, PD and gait apraxia patients. 53.2.7. Eye movements in the elderly and in Parkinson’s disease Voluntary and pursuit upward gaze movement of 5 mm or less and downward gaze deviation of 7 mm or less are considered abnormal (Jenkyn et al., 1985). In a study of more than 2000 normal volunteers 50– 93 years old, impairment of upward and downward
gaze increased with age. The frequencies for upgaze and downgaze impairments, respectively, were 6% and 8% for those aged 65–69 years, increasing to 29% and 34% for those 80 years and older (Jenkyn et al., 1985). Gaze impairment is characteristic of progressive supranuclear palsy (Steele et al., 1964; Jackson et al., 1983; Birdi et al., 2002). It is also seen in rare multiple system atrophy patients (Jankovic et al., 1993) and we have observed it in an autopsy confirmed PD cases. Oculogyric crisis was a feature of postencephalitic parkinsonism but is also seen in some cases of druginduced parkinsonism (DIP) and in dopa-responsive dystonia (Rajput, 1973). 53.2.8. Primitive reflexes in the elderly and in Parkinson’s disease Grasp and other primitive reflexes seen in childhood are suppressed during development but may re-emerge
Table 53.3 Posture and gait in normal elderly, Parkinson’s disease and gait apraxia Clinical features
Normal elderly
Parkinson’s disease
Gait apraxia
Base (distance between feet)
Slightly wider than at younger age Symmetrical Normal and symmetrical
Narrow
Broad
Usually asymmetrical Impaired regardless of weight-bearing or not (no dissociation)
Symmetrical Impaired only when weight-bearing but normal when not weightbearing (dissociation pronounced and early) Normal Normal As in normal elderly
Symmetry of abnormality Functions in the involved lower limb
Upper-limb motor function Arm-swing Posture Postural reflexes Foot-tapping in sitting or lying position Gait abnormality Visual and auditory cue Tremor Dementia Reflexes
Normal Normal Erect or neck and trunk flexion May be normal or impaired Normal Uncommon – increases with age No change in gait Absent
Grasp reflex Bladder function
Absent Normal (may be reduced at ankles) Normal Normal
Levodopa response
None
Impaired on the involved side Reduced on involved side Generalized flexion – neck, trunk, hip, knee, elbow Impaired in moderately advanced disease Affected side slow and progressively slower Late manifestation usually Improve gait Frequently seen – typically resting In about one-third of cases As in normal (may have striatal toe) Usually negative Normal or hypertonic or hypotonic bladder Improvement
Impaired early As in normal elderly Major problem – early manifestation No improvement in gait As in normal elderly Common but not invariable May be brisk – may have Babinski sign Usually positive Incontinence common None
OLD AGE AND PARKINSON’S DISEASE in old age (Bennett et al., 1996; Schott and Rossor, 2003). Typically, PD patients have a reduced rate of eye-blinking, resulting in a ‘reptilian stare’. Normally, the glabellar reflex habituates after 2–4 taps. Sustained glabellar reflex was observed in 10% of normal volunteers ages 65–69 years and in 37% of those aged 80 years and older (Jenkyn et al., 1985). In PD, this reflex may persist and in rare cases it may produce blepharospasm. Spontaneous blepharospasm is rare in PD but is more common in progressive supranuclear palsy cases. Repeated blinking after a tap at the bridge of the nose (Myerson’s sign) is common in PD. A positive snout reflex correlates with advancing age (Koller et al., 1982). As the primitive reflexes are common in the normal elderly, their presence cannot be used as evidence of PD.
53.3. Pathophysiological consideration of motor abnormalities in the elderly The presence of some parkinson-like motor features in the elderly suggests that PD and old age may share pathophysiological mechanisms. The most consistent pathology in PD is a marked loss of substantia nigra pigmented neurons and Lewy body inclusions (Jellinger, 1987; Gibb and Lees, 1988b; Duvoisin and Golbe, 1989; Gibb, 1991; Rajput et al., 1991c; Robinson and Rajput, 2005). The characteristic biochemical finding in PD is a marked striatal dopamine loss (Ehringer and Hornykiewicz, 1960a; Rajput, 2002) and an uneven subregional pattern of dopamine decline (Kish et al., 1988). Improvement of PD motor symptoms is almost universal in those patients who can tolerate an adequate dose of levodopa (Birkmayer and Hornykiewicz, 1961, 1998; Cotzias et al., 1967; Rajput et al., 1990c). Several studies have compared the pathological and biochemical findings of PD with the normal elderly population who may manifest some parkinsonian-like features. One study (Ross et al., 2004) observed that the elderly who had a stooped posture, postural instability or undue motor slowing had significantly reduced neuronal cell counts in the dorsolateral quadrant of the substantia nigra pars compacta. The counts were lowest when all three signs were present (Ross et al., 2004). A detailed study (Fearnley and Lees, 1991) revealed that the regional pattern of substantia nigra loss in normal aging (dorsal tier) is different from PD (ventral tier). They concluded that age-related loss of dorsal tier substantia nigra pars compacta neurons is not important in the pathogenesis of PD (Fearnley and Lees, 1991). Resting tremor has not been observed in elderly individuals without clinical PD, nor in cases with incidental Lewy body inclusions only (Ross et al., 2004). This indicates that resting tremor is not a feature
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of normal aging and is a major distinguishing feature between PD and normal elderly. Striatal dopaminergic denervation has been reported in normal aging. Positron emission tomography (PET) studies revealed reduced dopaminergic functions in grandparents compared to their grandchildren (Cordes et al., 1994). Reduced striatal dopamine levels are reported in normal elderly autopsy brains (Kish et al., 1992). However, the pattern of the brain regional dopamine loss is different in normal aging (Kish et al., 1992) and PD (Kish et al., 1988). The rate of dopaminergic denervation was estimated to be twice as high in PD compared to normal aging (Scherman et al., 1989). It was concluded that dopamine deficiency does not play a role in normal aging (Scherman et al., 1989). Unlike PD, age-related slowing does not improve on levodopa. It is therefore concluded that the substantia nigra loss and the associated dopamine loss characteristic of PD do not account for the Parkinson-like features of normal aging.
53.4. Tremor disorders in old age Tremor is the most common movement disorder in human adults (Jankovic and Fahn, 1980; Findley and Gresty, 1981; Rautakorpi et al., 1982a, b; Louis et al., 1995). The two most common tremor disorders are PD and essential tremor (ET) (Haerer et al., 1982; Rautakorpi et al., 1982a; Moghal et al., 1994; Salemi et al., 1994; Mayeux et al., 1995; Louis et al., 1996). Both PD and ET are concentrated in old age (Haerer et al., 1982; Rautakorpi et al., 1982b; Rajput et al., 1984a, b; Schoenberg et al., 1985; Bharucha et al., 1988; Bergareche et al., 2001). There is no literature evidence that postural/kinetic tremor is part of the normal aging process and rest tremor is never a part of normal aging. There is clinical overlap between PD and ET-associated tremors. The characteristic tremor of PD is at rest, but these cases may also have postural/kinetic tremor. Rest tremor is not a feature of normal aging (Rajput, 1994a; Bennett et al., 1996; Ross et al., 2004), although it is seen in nearly every PD case (Rajput et al., 1990a, 1991a), and in some ET patients (Rajput et al., 2004b). The elderly more often use medications that enhance the physiological tremor, making it clinically evident. This makes it difficult to distinguish drug-induced tremor from pathological tremor, including ET. Medications that may cause or worsen underlying tremor include tricyclics, monoamine oxidase inhibitors, valproic acid, corticosteroids, calcium channel blockers, amiodarone, sympathomimetics and rugs for asthma, including theophylline (Desai et al., 1990; Koller et al., 1994; Kelly et al., 1995; LeWitt, 1995).
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53.5.1. Parkinsonian tremor The characteristic parkinsonian tremor is resting tremor, i.e. when the body part is fully supported against gravity to prevent muscle activity. The postural and kinetic tremor that is characteristic of ET is also seen in a significant proportion of PD patients (Jankovic et al., 1995, 1999). Tremor is the most common initial symptom reported by PD patients (Hoehn and Yahr, 1967; Martin et al., 1973; Gibb and Lees, 1988a; Rajput et al., 1991a). The upper-limb tremor onset was noted 13 times more frequently compared to the lower-limb rest tremor onset in an autopsy study of PD (Rajput et al., 1993a). James Parkinson was so impressed with the tremor in PD that he called the disorder ‘shaking palsy’. The PD tremor is usually intermittent at the start and appears under stress. Progressively lower-level stress triggers tremor and eventually the tremor may become persistent (Hallett, 1986). We observed 1 patient who had a 33-year history of intermittent upper-limb tremor which only appeared under stress before the other classical features of PD appeared. Putting the patient under stress is helpful in establishing the presence of rest tremor. It can be done by having the patient perform one or multiple tasks simultaneously. While the patient is lying on the examining table, ask him/her to squeeze your finger with one hand, close the eyes tightly while you try to open them and have the patient count backwards from 100 by 7s. This maneuver would bring out resting tremor in the opposite upper limb and both lower limbs. Upper-limb resting tremor on both sides can be simultaneously evaluated as follows: in the supine position, the patient is asked to close his/her eyes tightly, count backwards from 100 by 7s and forcefully dorsiflex both ankles against resistance (with the examiner opposing the dorsiflexion). In most patients, the parkinsonian resting tremor produces limited or no functional disability as it improves with activity. After reaching the peak severity (amplitude and persistence), the tremor may become less pronounced or cease altogether (Stern, 1987; Birdi et al., 2002). When tremor is only present in the resting position but in no other situation, it is a sign of PS (Rajput, 1994b; Bennett et al., 1996; Rajput et al., 2004b; Rajput and Rajput, 2004; Ross et al., 2004). 53.5.2. Essential tremor ET can manifest at any age, from childhood to old age (Haerer et al., 1982; Rajput et al., 1984b; Koller et al., 1994). The incidence and the prevalence rates of ET increase markedly in old age (Haerer et al., 1982; Rautakorpi et al., 1982a, b; Rajput et al., 1984b; Bain
et al., 1994; Salemi et al., 1994). In a population study using door-to-door interviews and neurological exams in Turkey, 4% of those aged 40 years and older had ET (Dogu et al., 2003). In a Finnish study, 5.6% of the population over age 40 years had ET (Rautakorpi et al., 1982b) whereas 13% of those between the ages of 70 and 79 years had ET. We found ET prevalence rates of 14% in the community (Moghal et al., 1994) and 10% in the chronic care institution population (Moghal et al., 1995) aged 65 years and older. Life expectancy in ET is normal (Rajput et al., 1984b). The tremor frequency in ET changes with time. The tremor in young ET cases has a higher frequency (8–10 Hz) than PD tremor (4–6 Hz). ET tremor frequency deceases by 0.06–0.08 Hz/year (Elble, 2000). Therefore, with time, ET tremor frequency may become indistinguishable from PD. The tremor amplitude progressively increases in ET (Stiles, 1976; Elble, 1986; Calzetti et al., 1987) and becomes more widespread throughout the body (Rajput et al., 2004b). Classical ET is kinetic and/or postural (Louis, 2001), but nearly one-third of the autopsy-verified ET patients developed resting tremor in the upper or lower limbs, without bradykinesia or rigidity (Rajput et al., 2004b). In the past, such cases were classified as ‘senile’ tremor (Koller et al., 1994; Kelly et al., 1995). Autopsy studies revealed similar brain histology in classical ET and those with additional resting tremor (Rajput et al., 2004b). Therefore, the term ‘senile tremor’ is no longer justified. Coarse tremor can produce cogwheeling and Froment’s phenomenon, which may be misinterpreted as a sign of parkinsonism. Clinical distinction between that and the rigidity of PS has been discussed above. In a large series of pathologically verified ET patients, 15% subsequently developed dopa-responsive parkinsonism (Rajput et al., 2004b): 5% had Lewy body disease and 10% progressive supranuclear palsy that was undiagnosed during life. Making a distinction between ET cases that develop resting tremor alone and those with additional PS can be challenging. If a known ET patient develops unilateral resting tremor, rigidity and bradykinesia, a second diagnosis of PS is justified (Rajput et al., 1991a, b, 1993b, 2004b). Most ET patients developing resting tremor in old age. However, when the ET first manifests in childhood, such evolution may occur at a younger age, indicating that rest tremor evolution is related to the duration of the ET. We have observed an accelerated emergence of rest tremor in ET patients when both parents had ET, suggesting that a higher degree of genetic abnormality increases the risk of rest tremor. The beneficial effect of alcohol on tremor is not specific to distinguish ET from parkinsonian tremor
OLD AGE AND PARKINSON’S DISEASE or other causes of action tremor, as each may or may not improve with alcohol (Rajput et al., 1975; Koller and Biary, 1984). The available literature indicates that ET and PD are two different disorders and the risk of developing PD in ET cases is comparable to that in the general population (Rajput et al., 2004b). Since there are no biological markers specific for ET or PD, in the event of clinical uncertainty, a therapeutic trial on levodopa for up to 8 weeks is justified. Whereas PD patients improve, there is no benefit to ET.
53.6. Parkinson’s disease in old age Epidemiology, major clinical features, non-motor manifestations of PD, other parkinsonian syndromes and details of treatment are covered in the appropriate chapters of this volume. We will focus on those features that have special significance for PD in old age. PD in elderly patients can be divided into two main categories: (1) those with an early age at onset and surviving to old age; and (2) patients in whom the PD first manifests in old age. When the disease begins at a younger age, nearly all patients in the industrialized countries would have received levodopa (Global Parkinson’s Disease Survey (GPDS) Steering Committee, 2002) before reaching old age. Most of those patients are likely to have motor response fluctuations and/or dyskinesia (Rajput et al., 2002), freezing of gait (Bloem et al., 2004) and a reduced therapeutic benefit (Rajput et al., 1984c, 2002). Such patients are most likely to have been previously treated with dopamine agonists and the other currently available agents. The treatment options in such cases are limited. Levodopa and adjunct catecholamine-O-methyltransferase inhibitors, entacapone or tolcapone (where available) are probably the safest options for this group of patients. If a patient is well controlled and has stage 2 (Hoehn and Yahr, 1967; Fahn et al., 1987) disability, there is no need to change the drugs. 53.6.1. Parkinson’s disease beginning in old age In one community study (Bower et al., 1999), the incidence of PS rose sharply with age. In the same community (Rocca et al., 2001), the age-specific incidence was unchanged over several decades but there was an increased incidence of DIP in those aged 70 years and older (Rocca et al., 2001). In a study of 65–84-year-old population, the annual incidence of PS was 529.7/105 whereas it was 326.3/105 for clinically diagnosed PD (Baldereschi et al., 2000). Thus the incidence of PD continues to rise with advancing age (Mayeux et al., 1995; Bower et al., 1999; Rocca et al., 2001).
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The diagnosis of PD in the elderly needs careful consideration of the age-related motor changes which may be mistaken for PD and vice versa, as discussed above. Community-based surveys indicate that between 35 and 41% of parkinsonian cases (mostly the elderly) remain undiagnosed (Schoenberg et al., 1985; Morgante et al., 1992). In a survey of community residents 65 years and older, we observed that 50% of parkinsonian cases were undiagnosed (Moghal et al., 1994). The undiagnosed patients are usually those who do not have prominent tremor or those in whom the tremor is erroneously interpreted as a manifestation of aging. A patient who is not diagnosed remains untreated and, therefore, will suffer unnecessarily. In one case, a 60-year-old mother of seven children (including one nurse) noted that she could not look after her household. The children concluded that she was getting ‘old’ and was, therefore, placed in a private care-home where she was expected to go to the dining area to eat. However, she could not do that and her condition deteriorated. At that point, she was hospitalized. Neurological exam revealed stage 4 (Hoehn and Yahr, 1967; Fahn et al., 1987) akineticrigid PD which improved on levodopa. Another example is that of an elderly man who had been in a nursing home for several years. With an impending influenza season, he was prescribed amantadine. The attending physician was surprised to see that the patient improved remarkably to the point that he could be discharged from the nursing home. Since the diagnosis of PD is based on clinical observations alone, a trial of levodopa is justified when in doubt. Tremor is the most common first manifestation of PD, ranging from 41% (Gibb and Lees, 1988a) to 70.5% (Hoehn and Yahr, 1967) in different studies. In autopsy-verified cases, we noted that tremor alone was the first manifestation in 49% of PS cases (Rajput et al., 1993a). The first symptom was upper-limb tremor alone in 41% and lower-limb tremor alone in 3% of PS cases. Tremor in conjunction with other parkinsonian motor features was the first manifestation in 53% of PS cases (Rajput et al., 1993a). Postural instability and gait difficulty (PIGD) at onset are reported to be more common among the elderly (Zetusky et al., 1985; Jankovic et al., 1990). Whereas 56% of the tremor-onset parkinsonian cases had only Lewy body PD pathology, 27% of the PIGD cases had similar pathology (Rajput et al., 1993a). Clinical studies (Zetusky et al., 1985; Jankovic et al., 1990) and clinicopathological studies (Rajput et al., 1993a) indicate that the PIGD onset cases have a less favorable prognosis. Such cases are more likely to suffer from other variants of PS than PD (Rajput et al., 1993a), which accounts for some unfavorable outcomes. Since tremor is not a feature of
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normal aging, new-onset tremor should arouse the suspicion of PD. Rest tremor is the most reliable distinguishing feature between normal aging and PS (Rajput et al., 1991a, 1993a; Brooks et al., 1992; Rajput, 1994a; Kelly et al., 1995). Isolated lower-limb rest tremor onset has even higher diagnostic value in PD (Rajput et al., 1990b, 1993a). The most common variant of PS is the Lewy body disease (Rajput et al., 1984a, 1991c; Jellinger, 1987; Duvoisin and Golbe, 1989; Gibb, 1991; Hughes et al., 1992), also known as idiopathic PD. There are other uncommon variants, such as neurofibrillary tangle pathology, which is focused on the substantia nigra (Rajput et al., 1989). Clinical distinction between PD and other variants of PS is not always possible (Rajput et al., 1991c; Hughes et al., 2002). However, parkinsonism, when the pathology is focused on the substantia nigra, can be clinically recognized accurately in 85% of cases (Rajput et al., 1991c). The multiple system atrophy Parkinson subtype (Rajput et al., 1972, 1991c; Quinn, 1989; Rajput, 1994a, b) has a younger age at onset, but in rare autopsy cases we have observed it to begin in old age. The most prominent clinical features are symmetrical bradykinesia and rigidity but very little tremor. The presence of early autonomic dysfunction and corticospinal tract or cerebellar dysfunction is helpful in distinguishing multiple system atrophy from PD. The progression of disability in the multiple system atrophy cases is more rapid and the response to levodopa is less favorable than in PD (Quinn, 1989; Rajput et al., 1990c, 1991c, 1993a). Progressive supranuclear palsy, on the other hand, has similar age of onset as PD. The motor manifestations are symmetrical with predominant axial involvement. The posture is erect, tremor is not a prominent feature (Birdi et al., 2002) and supranuclear ophthalmoplegia is a characteristic manifestation. Levodopa is the drug of first choice in PD cases with onset at 75 years or older. In the 65–75-year age group, depending on health status, one may use amantadine or a dopamine agonist initially. Though selegiline is generally well tolerated, it has only a mild symptomatic benefit and we do not use it often. Anticholinergics frequently cause adverse effects and we avoid using them in the elderly. The response to levodopa therapy is most favorable in PD. Response to levodopa treatment is not diagnostic of the underlying pathology, as other PS variants of parkinsonism may also improve (though the response is less robust and of shorter duration) (Rajput et al., 1990c; Birdi et al., 2002). The functional decline in patients with late-age PD onset is more rapid compared to younger-age-onset cases (Gibb and Lees, 1988a; Goetz et al., 1988; Hietanen and Teravainen, 1988;
Jankovic et al., 1990). Late-onset age by itself does not unduly shorten survival when the age and sex are taken into account (Rajput et al., 1997). The accelerated disability in the old-age-onset PD cases may be due in part to aging or concurrent senile gait (Koller et al., 1983) or gait apraxia (Sudarsky and Simon, 1987). At any given time, approximately one-third of PD cases have dementia (Rajput and Rozdilsky, 1975; Marttila and Rinne, 1976; Rajput et al., 1987, 1997; Mayeux et al., 1988; Rajput, 1992; Uitti et al., 1993, 1996) and over 5 years new cases of dementia emerged 3–5 times more commonly in PD compared to age-matched controls (Mindham et al., 1982; Rajput et al., 1987; Mayeux et al., 1988; Marder et al., 1991; Rajput, 1992; Aarsland et al., 2003). When compared with the early-onset cases, dementia was reported to be nearly 10 times more common in the old-age-onset PD cases (Hietanen and Teravainen, 1988; Mayeux et al., 1988, 1990; Hobson and Meara, 2004). Compared to the non-demented cases, demented PD cases have a shortened survival (Uitti et al., 1996; Rajput et al., 1997) compared to non-demented cases. (See Ch. 18 for further discussion of dementia in PD.) Dyskinesia is a common adverse effect of levodopa therapy. It has been suggested that the incidence of dyskinesia is different among young- and old-ageonset cases. Kostic et al. (1991) compared 25 PD cases with onset before age 40 years (mean 33.5 years) with 25 PD patients who had onset at a later age (mean 55.8 years). After 3 years of levodopa therapy there was a significantly higher (72% versus 28%) incidence of dyskinesia in the early-onset cases. Gibb and Lees (1988a) compared PD patients with mean onset at 38 years with those at mean onset at 73 years. They detected no difference in the duration of levodopa exposure before dyskinesia onset. We have observed levodopa-induced dyskinesia emerging early and on a small dose in some old-age-onset cases. The age-related difference with respect to levodopa-induced dyskinesia was not evident in our PD autopsy series (Rajput et al., 2002). The dyskinesia and wearing-off phenomena represent opposite ends of the spectrum for motor response complications. Dyskinesia is most common at the peak plasma level of levodopa, whereas the wearing off coincides with the lowest plasma level. As expected, dopamine metabolism in the autopsy brains was found to be accelerated in the wearing-off compared to dyskinesia cases (Rajput et al., 2004a). Similar observations were reported on PET scanning in PD wearing-off cases (Fuente-Ferna´ndez et al., 2001). DIP is a well-known complication of dopaminedepleting and receptor-blocking agents that was first recognized in the 1960s (Ayd, 1961; Delay and Deniker, 1968; Friedman, 1992). The DIP incidence is second
OLD AGE AND PARKINSON’S DISEASE only to PD in community studies of PS (Rajput et al., 1984a; Bower et al., 1999). The elderly take a large number of drugs, have age-related striatal dopamine loss (Kish et al., 1992) and up to 13% have preclinical pathology of PD, known as incidental Lewy body disease (Ross et al., 2004). DIP is, therefore, more common in older individuals (Rajput, 1984, 1986; Friedman, 1992; Bower et al., 1999) and that incidence increases with age (Bower et al., 1999). In more than 90% of these cases, the parkinsonism emerges within 90 days of neuroleptic initiation (Friedman, 1992). Some such patients have no known pathology, whereas others with a preclinical PD pathology would develop parkinsonian features on a modest neuroleptic dose (Rajput et al., 1982). Although akinesia appears early in the DIP cases, that is due in part to the tranquilizing effect of the neuroleptics. The drug-induced patients do not always present an akinetic-rigid picture and may have clinical features that are indistinguishable from idiopathic PD (Rajput et al., 1982, 1991c; Hardie and Lees, 1988; Burn and Brooks, 1993). We have observed reversible druginduced tremor-dominant parkinsonism in an individual who had a strong family history of PD. Theoretically, the DIP should be symmetrical, but that is not always the case. Parkinsonism due to dopamine-depleting or receptor-blocking drugs improves when the offending agent is discontinued (Friedman, 1992); however, it may take several months to resolve. The best treatment option for such cases is discontinuing the offending agent. A careful history of drug intake is, therefore, important in elderly parkinsonian cases. Anticholinergics are theoretically the best agents for the symptomatic treatment of DIP. However, the elderly do not tolerate these drugs well. Amantadine and levodopa can be tried for symptomatic control. The use of prophylactic anticholinergics in subjects treated with neuroleptics is not recommended, as only a small proportion would develop DIP. Additionally, cholinergic-blocking agents produce significant adverse effects in the elderly. If the neuroleptics cannot be discontinued, atypical antipsychotic agents such as olanzapine, clozapine or quetiapine should be substituted to reduce the possibility of DIP (Friedman, 1992).
53.7. Parkinsonism in other diseases of old age 53.7.1. Stroke and parkinsonism Stroke and parkinsonism are covered in detail in Chapter 52. Although both stroke and PS are concentrated in old age, there is no evidence that stroke produces Lewy body PD. In a recent report of 1500
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stroke patients, 6 (0.4%) developed parkinsonism (Alarcon et al., 2004). The onset of PS was rapid after approximately 4 months of stroke. Five of the 6 cases had persistent parkinsonian features with initial improvement on levodopa. The lesions were located in the midbrain/pons, caudate/internal capsule, lentiform nucleus, the frontal cortex or frontal subcortex. 53.7.2. Alzheimer’s disease and parkinsonism Alzheimer’s disease, a common disorder in the elderly, may be associated with parkinsonian features in some patients (Molsa et al., 1984; Bennett et al., 1989; Morris et al., 1989; Tyrrell and Rossor, 1989; Soininen et al., 1992). Longer reaction time (bradykinesia) and increased muscle tone (rigidity) are significantly more common in Alzheimer’s disease patients compared to normal controls (Kischka et al., 1993). In a longitudinal study, the bradykinesia rate nearly doubled and rigidity frequency multiplied by nearly six times after 3 years in Alzheimer’s disease cases (Soininen et al., 1992). When the Alzheimer’s disease patients were treated with neuroleptics, nearly everyone developed bradykinesia and rigidity (Soininen et al., 1992), but tremor was not a prominent feature in these cases. Morris et al. (1989) followed 44 clinically diagnosed Alzheimer’s disease patients and 58 controls. At baseline, neither group had parkinsonian features. At the end of 66 months, at least one of the three clinical features of parkinsonism – resting tremor, bradykinesia and rigidity – was detected in 36% of Alzheimer’s cases compared to 5% in the control subjects. An additional 27% of Alzheimer’s cases developed at least one cardinal feature of parkinsonism within 6 months of exposure to neuroleptics (Morris et al., 1989). In a pathological study, histological findings were such that a diagnosis of Alzheimer’s disease and of Lewy body PD each could be made (Rajput et al., 1993c). Two clinical patterns were detected. One group presented with PS and dementia developed several years later. In the other group, the dementia and parkinsonism onset were simultaneous (Rajput et al., 1993c). Those with PD at onset improved on levodopa until the onset of dementia, when they developed small-amplitude irregular jerky postural and kinetic tremor and the levodopa response declined. In those who manifested PD and Alzheimer’s disease simultaneously, the typical resting tremor of PD was not a prominent feature and the response to levodopa was poor, producing major psychiatric side-effects (Rajput et al., 1993c). Alzheimer’s disease, dementia and PD overlap will be discussed in detail in Chapters 18 and 60.
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Handbook of Clinical Neurology, Vol. 84 (3rd series) Parkinson’s disease and related disorders, Part II W. C. Koller, E. Melamed, Editors # 2007 Elsevier B. V. All rights reserved
Chapter 54
Other degenerative processes ¨ LLER* AND WOLFGANG H. OERTEL J. CARSTEN MO Department of Neurology, Philipps-University Marburg, Marburg, Germany
54.1. Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) and related disorders Previously, several familial parkinsonism–dementia syndromes, such as disinhibition–dementia–parkinsonism– amyotrophy complex and autosomal-dominant parkinsonism and dementia with pallidopontonigral degeneration, were distinguished (Wszolek et al., 1992; Lynch et al., 1994). Subsequently, according to a consensus conference, these syndromes were summarized and termed FTDP-17 (Foster et al., 1997). In 1998 this disease was found to be caused by mutations in the tau gene in several affected families (Hutton et al., 1998). At least 26 different mutations are known, with the exon-10 P301L missense mutation being most prevalent (Wszolek et al., 2003). Subsequently, several transgenic mouse models of FTDP-17 have been developed based on these mutations (Lewis et al., 2000). Tau is an intracellular protein that promotes the assembly and stabilization of microtubules. Mutations in the tau gene can be distinguished into two types (Rosso and van Swieten, 2002): 1. The first type of (missense) mutations reduces the ability of the tau protein to bind to microtubules. 2. The second type of mutation results in a change in the ratio (and subsequent accumulation) of tau isoforms with three amino acid repeats to those with four amino acid repeats. Neuropathologically, frontotemporal and basal ganglia atrophy and substantia nigra depigmentation are usually found. Microscopic examination reveals neuronal loss and gliosis of variable intensity, taupositive intraneuronal (and glial) inclusions without the characteristics of Pick bodies and ballooned neurons (Foster et al., 1997). The estimated total number
of affected patients from 62 known families was 470 in 2003 (Wszolek et al., 2003). The mean age at disease onset is 49 years and the average disease duration is 8.5 years (Wszolek et al., 2003). The principal central nervous system (CNS) manifestations consist of motor, cognitive and behavioral disturbances (Foster et al., 1997). Motor symptoms include:
akinetic-rigid parkinsonian resting tremor dystonia spasticity supranuclear gaze palsy occasionally amyotrophy
features
without
The cognitive disturbances comprise impaired executive functions: visuospatial orientation and common memory functions are relatively preserved until later stages of the disease. The behavioral symptoms include:
impaired social conduct hyperorality hyperphagia obsessive stereotyped behavior psychosis
Most patients harboring exon-10 missense and intronic mutations in the tau gene develop a parkinsonism-predominant phenotype (Wszolek et al., 2003). However, FTDP-17 features a wide range of phenotypic variations between kindreds with different tau mutations but also among family members from the same kindred. This issue has recently been confirmed by a prospective study in two siblings carrying the S305N tau mutation, in whom different rates of change in whole-brain and ventricular volume as measured by magnetic resonance imaging (MRI) were found
*Correspondence to: PD Dr. med. Jens Carsten Mo¨ller, Klinik fu¨r Neurologie, Philipps-Universita¨t Marburg, Rudolf-Bultmann-Str. 8, 35039 Marburg, Germany. E-mail:
[email protected], Tel: þ49-6421-286-5200, Fax: þ49-6421-286-7055.
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(Boeve et al., 2005). Useful diagnostic criteria are in general: (1) age at disease onset between the third and the fifth decade; (2) rapid disease progression; (3) parkinsonism-plus symptoms (i.e. akinetic-rigid features associated with early falls, supranuclear gaze palsy, apraxia, dystonia and lateralization); (4) frontotemporal dementia; and (5) personality and behavioral abnormalities (Wszolek et al., 2003). The diagnosis can be confirmed by genetic testing, if available. Structural and functional imaging often reveals frontotemporal atrophy and/or hypometabolism. There is a wide range of possible differential diagnoses, including sporadic tauopathies such as progressive supranuclear palsy, corticobasal ganglionic degeneration and Pick’s disease. Apart from FTDP-17, there are also other types of familial frontotemporal dementia (FTD), i.e. ubiquitin-positive FTD and dementia lacking distinctive histology (Morris et al., 2001). Ubiquitin-positive FTD can be accompanied by histological features of (clinically often inapparent) motor neurone disease (Paviour et al., 2004). Ubiquitin-positive FTD is possibly caused by mutations in the valosincontaining protein and may overlap with dementia lacking distinctive histology (Josephs et al., 2004; Watts et al., 2004; Schroder et al., 2005). Parkinson’s disease (PD) with dementia, dementia with Lewy bodies and Alzheimer’s disease represent further differential diagnoses of FTDP-17. A specific therapy is not known. Paients usually show poor response to levodopa. Psychiatric treatment is usually necessary and often proves challenging despite pharmacological and behavioral therapies.
54.2. Neurodegeneration with brain iron acculumation (NBIA) This disorder was first reported in 1922 in a sibship characterized by gait impairment resulting from rigidity of legs and feet deformity and mental deterioration with juvenile onset. The condition was subsequently named Hallervorden–Spatz syndrome (HSS) (Hallervorden and Spatz, 1922). In response to the unethical activities of Hallervorden and Spatz during World War II, it has been suggested that the name HSS is replaced by the term NBIA. Recently, it has been shown that this disorder can be due to mutations in the gene for pantothenate kinase 2 (PANK2) (Taylor et al., 1996; Zhou et al., 2001). This type of NBIA is known as pantothenate kinaseassociated neurodegeneration (PKAN). It is usually an autosomal-recessive disorder, although in some cases the PANK2 mutation was suggested to be semidominant. In one study, PANK2 mutations were found in all patients with classic NBIA and in one-third of
those with so-called atypical disease (Hayflick et al., 2003). Classic NBIA was assumed in patients with disease onset during the first two decades, dystonia and high globus pallidus iron with characteristic radiographic appearance. The term ‘atypical disease’ was applied to individuals not fitting the above criteria but with radiographic evidence of increased basal ganglia iron (Zhou et al., 2001). Patients with the classic variant of the disease were usually shown to have mutations resulting in predicted protein truncation (Hayflick et al., 2003). The precise pathophysiology of PKAN is still unknown. PANK2 catalyzes the initial step in coenzyme A synthesis. It has thus been suggested that the PANK2 mutations lead to coenzyme A depletion associated with defective membrane biosynthesis (Zhou et al., 2001). Accordingly, it has been shown that some point mutations indeed result in a reduced catalytic activity during coenzyme A synthesis and that the most common mutation (G521R) is associated with a decreased production of mature PANK2 (Kotzbauer et al., 2005). Besides accumulated cysteine, which would normally condense with phosphopantothenate, may form complexes with iron and cause oxidative damage in the brain (Hayflick et al., 2003). Neuropathologically, the most striking feature of NBIA is the rust-brown pigmentation of the globus pallidus and pars reticulata of substantia nigra. On the microscopic level, iron granules were found in neurons, microglial cells and astrocytes. Some iron was also localized extracellularly. Furthermore, ‘mulberry’ concretions were observed in tissue and regarded as so-called pseudocalcium. A further prominent finding of the disease is a widely distributed distal axonal swelling. These swellings may be surrounded by glial cells and contain pigment granules, particularly when located in globus pallidus or pars reticulata of substantia nigra. These structures are known as spheroid bodies (Hallervorden and Spatz, 1922; Swaiman, 1991) and resemble those found in neuroaxonal dystrophy (Seitelberger, 1957), but in the latter the spheroids in the pallidum store fatty material and not pigments. These neuropathological alterations are accompanied by some loss of neurons and myelinated fibers as well as by gliosis. In analogy to PD, Lewy body-like intraneuronal inclusions containing a-synuclein were also observed in NBIA (Galvin et al., 2000). No sufficient epidemiological data of this group of rare disorders are available. Dooling et al. (1974) examined 42 patients who fulfilled both clinical and neuropathological criteria for NBIA. Onset of disease occurred in 24 patients before the age of 10 and 39 patients were ill before age 22. The mean duration of disease was 11 years. Gait difficulty and postural impairment were noted as
OTHER DEGENERATIVE PROCESSES initial symptoms in 37 patients. This may have been the result of spasticity, whereas symptoms of extrapyramidal dysfunction could be delayed by 1 year to several years. However, the usual course included progression of rigidity and presence of posture abnormalities. Other basal ganglia signs were observed, including dystonia in 23 patients, choreoathethosis in 19 patients and tremor without any distinctive character in 15 patients. Additionally, cognitive impairment was common and, in 9 out of 42 patients, seizures occurred (Dooling et al., 1974). Besides personality changes such as impulsivity and violent outbursts, depression and emotional lability were observed in patients with atypical disease and PANK2 mutations (Hayflick et al., 2003). In general, there was a wide spectrum of variation in the clinical manifestations of NBIA. It is noteworthy that 1 case of late-onset PKAN presenting as familial parkinsonism was reported (Jankovic et al., 1985). Apart from the CNS manifestations, foot deformities were frequently observed and skin pigmentation was noted in some cases (Wigboldus and Bruyn, 1968). A summary of the clinical presentation of NBIA based on a genotype–phenotype analysis is provided below. Several obligatory and corroborative symptoms for the diagnosis of NBIA were defined in 1991 (Swaiman, 1991). The obligatory symptoms were: 1. onset during the first two decades of life 2. a progressive course 3. evidence of extrapyramidal dysfunction The corroborative symptoms included: 1. 2. 3. 4. 5.
pyramidal tract signs progressive mental deterioration, hypodensities in basal ganglia on MRI occurrence of seizures ophthalmological symptoms, such as retinitis pigmentosa or optic atrophy 6. positive family history 7. abnormal cytosomes in circulating lymphocytes and sea-blue histiocytes in bone marrow A recent genotype–phenotype analysis provided a novel concept of the clinical presentation of NBIA: patients with classic NBIA and PANK2 mutations had a mean age of onset of 3.4 years; usually presented with gait or postural symptoms; featured dystonia, dysarthria, rigidity and choreoathetosis; and frequently developed spasticity and cognitive decline, whereas atypical NBIA patients with PANK2 mutations had a mean age of onset of 13.7 years and featured less severe and more slowly progressive extrapyramidal symptoms. Furthermore, patients with classic disease
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more often suffered from retinopathy. Conversely, atypical patients more frequently presented with speech problems as part of the early disease (Hayflick et al., 2003). Besides, patients with a younger age of onset (< 20 years) may have a higher frequency of dystonia, gait disturbance and tremor, whereas parkinsonism seems more common in late-onset disease ( 20 years) (Thomas et al., 2004). Possible differential diagnoses of PKAN include Wilson’s disease, Huntington’s disease, chorea acanthocytosis (CHAC), neurometabolic disorders and other types of NBIA such as NBIA without PANK2 mutations, neuroferritinopathy and aceruloplasmenia. Neuroferritinopathy is a recently recognized, dominantly inherited movement disorder caused by a mutation of the ferritin light-chain gene (Curtis et al., 2001). The clinical phenotype of this disorder is highly variable, with symptoms beginning in the third to sixth decade. Chorea, dystonia or an akinetic-rigid syndrome can predominate (Crompton et al., 2005). Aceruloplasmenia is an autosomalrecessive disorder of iron metabolism characterized by diabetes, retinal degeneration and progressive neurodegeneration with extrapyramidal disorders, ataxia and dementia (Gitlin, 1998). In addition, HARP syndrome (hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, pallidal degeneration) was shown to be allelic with PKAN (Ching et al., 2002). Clinical diagnosis of NBIA can be confirmed by MRI and genetic testing, if available. Laboratory investigations do not normally reveal any distinctive abnormalities, except that some patients feature vacuolated circulating lymphocytes containing abnormal cytosomes and sea-blue histiocytes in bone marrow (Swaiman et al., 1983). Computed tomography (CT) in patients with NBIA has been reported to show atrophy and low-density lesions in basal ganglia (Dooling et al., 1980). MRI using a high-field-strength unit (1.5 Tesla) showed decreased signal intensity in the globus pallidus and pars reticulata of substantia nigra in T2-weighted images, which is compatible with heavymetal (iron) deposits and a small area of hyperintensity in the internal segment of pallidum, constituting the socalled ‘eye of the tiger’ sign (Rutledge et al., 1987; Sethi et al., 1988). In all (homozygous and heterozygous) PKAN patients, whether classic or atypical, MRI showed the ‘eye of the tiger’ sign, whereas this pattern was not seen in atypical patients without PANK2 mutations (Hayflick et al., 2003). There is no specific therapy for NBIA. Symptomatic management, such as using levodopa and dopamine agonists, may be beneficial to patients (Swaiman, 1991). Hypothetically, supplementation of panthothenate could ameliorate the symptoms in patients with
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PANK2 mutations (Hayflick et al., 2003). Simple case reports in the media described a dramatic improvement with pantothenate, but no studies have been performed yet.
54.3. Hemiparkinson–hemiatrophy (HPHA) syndrome HPHA is defined by the occurrence of a body hemiatrophy with features of a highly asymmetric, often levodopa-responsive parkinsonism more prominent on the side of the hemiatrophy (Klawans, 1981; Buchman et al., 1988). An association with contralateral brain atrophy was also shown (Giladi et al., 1990). Although no systematic genetic studies have yet been performed, parkin mutations were found in 1 patient with HPHA (Pramstaller et al., 2002). It has been reported that lesions of the postcentral gyrus before the age of 3 are associated with a relative smallness of the contralateral parts of the body (Penfield and Robertson, 1943). Accordingly, it was suggested that the occurrence of parkinsonism in HPHA patients is related to an additional subcortical lesion (Klawans, 1981). Supporting this point of view, Giladi et al. (1990) presented neuroradiological evidence of a contralateral brain hemiatrophy in 64% of their patients. Since an association between perinatal asphyxia, brain hemiatrophy and delayed-onset hemidystonia has been shown, HPHA could represent an example of a movement disorder with delayed onset as a consequence of neonatal brain injury (Giladi et al., 1990). Other authors reported 4 patients with dopa-responsive dystonia and hemiatrophy (Greene et al., 2000). Since dopa-responsive dystonia results from a purely biochemical deficit in the brain, these authors suggested that a deficiency of the nigrostriatal dopamine system may by itself be sufficient to cause body hemiatrophy. However, neonatal ablation of the nigrostriatal pathway did not influence limb development in rats (Hebb et al., 2002). A variable response to levodopa and striatal hypometabolism, as shown by 18Ffluorodeoxyglucose and positron emission tomography (PET), suggests that both pre- and postsynaptic mechanisms contribute to HPHA. No postmortem analysis has been performed. So far reports on a total of 42 patients have been published. Patients suffer from a body hemiatrophy with small and narrow extremities on one side. There is a wide variation in the degree of hemiatrophy: in some patients the face, arm and a leg were affected, whereas in other patients only the hand seemed to be affected. The most likely part of the hand to demonstrate hemiatrophy was the thumb. It has to be kept in mind that there is ‘normal’ asymmetry of the two halves of the
human body. The term ‘normal’ asymmetry should only be applied to differences in opposite limb length that are not visually apparent in the absence of measurements (Halperin, 1931). Interestingly, 1 probable patient showed no hemiatrophy, but an enlarged lateral ventricle as a sign of brain hemiatrophy (Giladi et al., 1990). With respect to the CNS manifestations, Buchman et al. (1988) reported that the mean age of onset of parkinsonism was 43.7 years. The course of the disease was slowly progressive, i.e. the mean duration of disease until initiation of levodopa therapy was 14.2 years. In contrast, in patients suffering from idiopathic PD, levodopa treatment was started after 4.1 years (Buchman et al., 1988). Furthermore, no progression to a Hoehn and Yahr stage greater than III was observed (Buchman et al., 1988). Eight out of 15 patients remained asymmetric after the development of bilateral disease. Giladi et al. (1990) found a more variable clinical course; for instance, one patient progressed from Hoehn and Yahr stage I to V during ‘off’ periods within 2.5 years. Ipsilateral dystonic movements, sometimes presenting as the first symptom, often occur early in the course of the disease before exposure to levodopa. A total of 10 out of 15 patients showed tremor as their initial symptom. Apart from the parkinsonian features, pyramidal tract dysfunction ipsilateral to the side of HPHA was present in 8 out of 15 patients (Buchman et al., 1988). Psychiatric symptoms are not usually a major feature of this syndrome. In the differential diagnosis earlyonset PD has to be considered. Common features are early age of onset and unilateral symptoms with mild progression. The main differences are the evidence of ipsilateral hemiatrophy and the prominence of early dystonia in HPHA patients. Therefore, the diagnosis depends on a thorough physical examination. Moreover, in the beginning the differential diagnosis may include corticobasal ganglionic degeneration, since HPHA may mimic its early stage (Giladi and Fahn, 1992). Due to the involvement of the nigrostriatal dopaminergic system, the level of homovanillic acid in the cerebrospinal fluid can be reduced. Central motor conduction time as measured by transcranial magnetic stimulation was normal in 2 HPHA patients (Nardone et al., 2003). CT and MRI showed contralateral brain asymmetry in 64% of investigated patients (Giladi et al., 1990). However, Buchman et al. (1988) found no evidence of cerebral hemiatrophy (cortical or ventricular asymmetry) in 11 out of 12 patients. Studies using 18F-fluorodeoxyglucose and PET showed a focal hypometabolism in the basal ganglia and the medial frontal cortex of the contralateral side, whereas 18F-fluorodopa and PET revealed a reduction in the striatal 18F-fluorodopa uptake. Hence the former
OTHER DEGENERATIVE PROCESSES examination might be useful to distinguish HPHA from typical unilateral PD (Przedborski et al., 1993, 1994). This observation was not confirmed by other authors (Pramstaller et al., 2002). Seven out of 9 investigated patients showed a good response to levodopa therapy and 7 out of 8 patients responded well to a combination of amantadine and anticholinergics (Buchman et al., 1988). Other investigators found a good response to levodopa treatment in 7 out of 11 patients (Giladi et al., 1990). One patient showed a dramatic improvement after subthalamic nucleus stimulation (Giladi et al., 1990).
54.4. Chorea acanthocytosis Acanthocytes are erythrocytes with changed morphology bearing spicules of variable length and breadth (Brecher and Bessis, 1972). If they occur in association with neurological symptoms, the term ‘neuroacanthocytosis’ is used. Four different types of neuroacanthocytosis are known: acanthocytes are observed in abetalipoproteinemia, the so-called Bassen–Kornzweig syndrome and in familial hypobetalipoproteinemia (Kornzweig and Bassen, 1957; Young et al., 1987). Furthermore, they are detectable in CHAC (Critchley et al., 1968; Levine et al., 1968). Finally, the McLeod syndrome represents a clinical entity that is characterized by the occurrence of acanthocytes and neurological symptoms (Allen et al., 1961; Swash et al., 1983). In addition there are some other conditions in which a sporadic association with acanthocytes has been described, i.e. PKAN and mitochondrial encephalomyopathies (Hardie, 1989). In adults CHAC is probably the most important disease. CHAC patients usually feature chorea, oromandibular dyskinesias, dementia, seizures and peripheral neuropathy. Additionally, parkinsonism may occur either with chorea or as a subsequent feature, when the hyperkinetic movement disorder subsides (Yamamoto et al., 1982; Spitz et al., 1985). CHAC is an autosomal-recessive disorder. The disease gene on chromosome 9q21 has been identified and named chorein (Rampoldi et al., 2001; Ueno et al., 2001). In 43 CHAC patients, 57 different chorein mutations were found, indicating a strong allelic heterogeneity with no single mutation causing the majority of cases (Dobson-Stone et al., 2002). Most mutations, however, lead to premature termination codons and therefore predict the absence or marked reduction of chorein. A transgenic mouse model featuring a mild phenotype and a late-adult onset has recently been established (Tomemori et al., 2005). The function of chorein is not known. Due to homology studies it has been hypothesized that the
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gene product could be involved in intracellular protein cycling. Absence of chorein may therefore lead to destabilization of the plasma membrane structure and hence acanthocytosis (Rampoldi et al., 2001). The suggested occurrence of CHAC without acanthocytes may indicate that the gene can be variably expressed in different tissues and may cause neurological abnormalities alone. In a family with CHAC featuring an autosomal-dominant transmission and polyglutamine-containing neuronal inclusions abnormalities of the membrane protein band 3 were demonstrated by gel electrophoresis of red blood cell membranes (Walker et al., 2002). Neuropathologically, the brains of CHAC patients showed enlargement of the ventricles, particularly of the frontal horns. Caudate and putamen were the most severely affected brain areas showing atrophy, neuronal loss and gliosis. Depletion of small- and medium-sized striatal neurons was most apparent. Involvement of globus pallidus was also present and in some cases thalamus and the anterior horns of spinal cord showed neuronal loss and mild gliosis (Rinne et al., 1994b). The substantia nigra of 3 CHAC patients was investigated in more detail (Rinne et al., 1994a): in CHAC with parkinsonism a reduced neuronal density (particularly in the ventrolateral region) of the substantia nigra was determined, whereas in 1 CHAC patient without parkinsonian features the number of neurons was at the lower limit of the control range. Epidemiological data for this rare disease are not available. The mean age of onset of CHAC was 32 years, ranging from 8 to 62 years. The most striking symptoms were involuntary movements affecting the orofacial region and the limbs, presenting as orofacial dyskinesias and limb chorea (Sakai et al., 1981). The former can cause tongue- and lip-biting and very often interferes with speech and swallowing. Accordingly, involuntary vocalizations were frequently observed. In some cases, the predominant manifestation was dystonia rather than chorea. Furthermore, Yamamoto et al. (1982) and Hardie (1989) described the occurrence of akinetic-rigid features simultaneously with the appearance of hyperkinetic disorders in 2 out of 2 and 5 out of 19 cases, respectively. Spitz et al. (1985) reported 2 CHAC cases presenting as tics, that were progressively replaced or masked by progressive parkinsonism. In 2 out of 19 patients, no movement disorder could be established, indicating that this might not be a necessary condition (Hardie et al., 1991). Additionally, hypo- or areflexia was repeatedly found. In many cases muscle wasting occurred and axonal neuropathy was demonstrated (Serra et al., 1987). Moreover, one-third of patients suffered from seizures and in more than half of the cases cognitive
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impairment, psychiatric features and personality change were seen (Hardie, 1989; Hardie et al., 1991). The most frequent psychiatric symptoms were impulsive and distractable behavior, apathy and loss of insight. Additionally, depression, anxiety, paranoid delusions and obsessive-compulsive features were observed. The correct diagnosis depends on the combination of significant acanthocytosis with normal plasma lipoproteins and neurological abnormalities. In this context the clinical picture of CHAC with a predominantly hyperkinetic movement disorder, personality change and cognitive impairment may resemble that of Huntington’s disease. Therefore, in any suspected case of Huntington’s disease acanthocytosis should be excluded. Usually diagnosis of Huntington’s disease will be confirmed by neurogenetic methods. This may be the case for CHAC in the future as well, but at present its genetic diagnosis is costly and time-consuming due to its genetic heterogeneity. Several methods are known to prove significant acanthocytosis. The most efficient method is probably the examination of a wet preparation of isotonically diluted blood samples (Storch et al., 2005). The normal range of acanthocytes in this kind of preparation is < 6.3%. Scanning electron microscopy may be helpful in measuring the extent of the erythrocyte morphological abnormalities in some cases (Hardie et al., 1991). Apart from acanthocytosis, modestly elevated creatine kinase levels have been reported (Sakai et al., 1981). Other laboratory parameters show no abnormalities. In contrast to Bassen–Kornzweig syndrome and to familial hypobetalipoproteinemia, decreased serum lipid levels are not found in CHAC. Western blotting of patient erythrocyte membranes in order to assess the expression level of chorein may soon become available (Dobson-Stone et al., 2004). CT revealed cortical or occasional caudate atrophy as significant features (Serra et al., 1987; Hardie et al., 1991). MRI showed focal and symmetric signal abnormalities in the caudate and lentiform nuclei in 3 out of 4 cases (Hardie et al., 1991). In another study increased signal intensity accompanied by scattered bright spots in the striatum in T2-weighted images was observed (Tanaka et al., 1998). PET revealed the following alterations: mean posterior putamen 18Ffluorodopa uptake was reduced to 42% of normal; depressed frontal and striatal blood flow was seen; and a loss of caudate and putamen D2-receptors was observed (Brooks et al., 1991; Tanaka et al., 1998). Because there is no specific treatment known, therapy remains symptomatic. However, parkinsonian symptoms did not respond to high dosages of levodopa (Spitz et al., 1985) and the response of the involuntary
movements to drug treatment was generally poor (Hardie, 1989). Severe trunk spasms were improved by bilateral thalamic stimulation in 1 case (Burbaud et al., 2002).
54.5. Pallidonigroluysian degeneration The pallidal, pallidonigral, pallidoluysian and pallidonigroluysian degenerations (PNLD) include a number of familial or sporadically occurring movement disorders, clinically defined by a slowly progressive course and a wide variety of extrapyramidal symptoms. This category of disorders has previously been classified into four distinct groups: 1. pure pallidal atrophy, 2. pure pallidoluysian atrophy 3. extended forms of pallidal degeneration, i.e. pallidonigral and pallidoluysionigral atrophy 4. variable forms of these subtypes with other cerebrospinal degenerations (Jellinger, 1986). For instance, the separately described pallidopyramidal disease (see section 54.6, below) could be considered a member of this group (Jellinger, 1986). Furthermore, the relation of the familial pallidonigral system degeneration with cystic damage reported by McCormick and Lemmi (1965) to PNLD is not known. Finally, in a small number of cases there is evidence of a possibly different movement disorder, characterized by the isolated degeneration of the external pallidum or status marmoratus of the basal ganglia in association with the occurrence of intraneuronal polyglucosan (Bielschowsky) bodies (Yagishita et al., 1983). In this section we focus on PNLD. In most of the reported families this condition appears to be of autosomal-recessive inheritance (Jellinger, 1986). Recently, a mutation in the microtubule-associated protein tau, i.e. a substitution at codon 279, has been found in a PNLD case (Yasuda et al., 1999; Wszolek et al., 2000). This observation and the histopathological demonstration of hyperphosphorylated tau in 1 PLND case indicate that this disorder may be a tauopathy (Mori et al., 2001). It is not clear whether pallidal, pallidoluysian and pallidonigral degeneration are possibly tauopathies as well. Neuropathologically, a degeneration of the pallidum alone or in association with the substantia nigra and/or the nucleus subthalamicus (of Luys) is found. A progressive loss of nerve cells and fibers accompanied by proportional gliosis has been found in these areas (Jellinger, 1986). The changes may vary in their extent. In rare instances they might be associated with further degenerative lesions in other extrapyramidal, motor neuron or
OTHER DEGENERATIVE PROCESSES spinocerebellar systems. A pure pallidal atrophy with gliosis and locally differing neuronal loss was reported by Lange et al. (1970). In another case of pure pallidal atrophy, morphometric analysis revealed a shrinkage of the globus pallidus externus to 59% and the globus pallidus internus to 37% of normal, but the neuron density did not seem to be affected (Aizawa et al., 1991). Bilateral symmetrical loss of neurons and myelin with gliosis mainly in the outer pallidum was combined with pallor of the ansa lenticularis and atrophy of subthalamic nucleus in a case of pallidoluysian degeneration (van Bogaert, 1947). These changes are consistent with the findings observed in the various (extended) forms of this group of neurodegenerative disorders. Other observations include the occurrence of corpora amylacea throughout the CNS and brown granular deposits showing a positive reaction to iron in the degenerated nuclei and the striatum in PNLD (Kosaka et al., 1981; Kawai et al., 1993). Furthermore, hyperphosphorylated tau was observed in 1 patient with PNLD (Mori et al., 2001). No epidemiological data are available due to the small number of investigated cases. Nosologically, PNLD and its related disorders should be distinguished from autosomal-dominant striatal degeneration (ADSD), another rare basal ganglia disease (Kuhlenbaumer et al., 2004). ADSD is characterized by onset in the fourth or fifth decade, slow progression and prominent dysarthria with mild hypokinesia, manifesting mainly as gait disturbance. MRI usually shows a signal increase in the striatum in T2-weighted images. PNLD and its related disorders demonstrate an insidious onset and a slowly progressive course. Onset of illness in familial cases was between ages 5 and 40 and in sporadic cases between ages 30 and 64. Depending on the variable pattern of morphological alterations, there may be distinct predominant symptoms. In pure pallidal degeneration the clinical picture is characterized by the development of progressive choreoathetotic hyperkinesias with axial dystonia, followed by the appearance of progressive rigidity. Finally, the involuntary movements are overcome by permanent rigidity and the patients become bed-ridden (Jellinger, 1986). In contrast, Aizawa et al. (1991) reported a case of pallidal degeneration with an extreme slowness of movements without rigidity as the main symptom. In pallidoluysian degeneration, additional symptoms are torticollis, head tremor and distal movements with or without a ballistic component (Jellinger, 1986). Another case of pallidoluysian degeneration presented with 20 years of progressive generalized dystonia, dysarthria, gait disorder, verti-
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cal gaze palsy and bradykinesia (Wooten et al., 1993). In PNLD the most apparent symptoms are progressive akinesia and rigidity with little or no tremor (Jellinger, 1986). Additionally, upward gaze palsy or Parinaud’s syndrome has been observed. A PNLD case with rapidly progressive hemidystonia has been reported (Vercueil et al., 2000). In conclusion, a wide spectrum of different clinical manifestations exists, depending on the spatial and temporal pattern of effect of the distinct brain areas. Consequently, because of their rarity, the clinical correlates of the distinct forms are still not well described. Familial occurrence of the combination of progressive rigidity and choreoathethosis or torsion dystonia with an early onset may suggest one of these disorders. The disorders may be accompanied by mental deterioration, but intellectual impairment may be absent, even in advanced disease stages (Jellinger, 1986). A history of psychosis was reported in several cases (Klawans, 1981; Kawai et al., 1993). The PNLD patient with the mutation in the tau gene featured dementia whereas no dementia was observed in the case with the accumulation of hyperphosphorylated tau (Yasuda et al., 1999; Mori et al., 2001). Except for the CNS symptoms, no other clinical manifestations are known. The diagnosis of these rare conditions can only be proven by means of postmortem examination. Possible differential diagnoses include juvenile parkinsonism, idiopathic torsion dystonia, PKAN, dentatorubralpallidoluysian atrophy, progressive supranuclear palsy, multiple system atrophy, corticobasal ganglionic degeneration and others. Sequencing of the tau gene, if available, should be performed. Routine laboratory data are unremarkable. CT in younger patients was normal (Jellinger, 1986); minimal atrophy of the brainstem and dilatation of the sylvian fissure were seen in a single case (Aizawa et al., 1991). MRI of the brain in a patient with pallidoluysian degeneration showed no abnormalities (Wooten et al., 1993). T2-weighted MRI demonstrated increased signal intensity in pallidum and substantia nigra in a PNLD patient with hemidystonia (Vercueil et al., 2000). Furthermore, contralateral cortical hyperperfusion was observed in this patient. Treatment with levodopa has produced only equivocal improvement of the movement disorder (Aizawa et al., 1991; Yamamoto et al., 1991). However, 1 patient with dystonic symptoms was reported to benefit from baclofen (Wooten et al., 1993).
54.6. Pallidopyramidal disease Pallidopyramidal disease is thought to be an autosomalrecessive disorder with onset in the second or early third
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decade, with a clinical picture consisting of parkinsonism and pyramidal tract signs (Davison, 1954; Horowitz and Greenberg, 1975; Tranchant et al., 1991; Nisipeanu et al., 1994). Furthermore, a syndrome was reported that is closely related but not identical to pallidopyramidal disease. It is called Kufor–Rakeb syndrome and additionally characterized by supranuclear upgaze paresis and dementia (Najim al-Din et al., 1994). The disease locus for Kufor–Rakeb syndrome has been mapped to chromosome 1p36 (Hampshire et al., 2001). The pathogenesis of pallidopyramidal disease is unknown. Until now only one autopsy in a non-familial patient 50 years after onset has been performed (Davison, 1954). A pallor of the pallidal segments, slight shrinkage and cellular change of the substantia nigra, a thinning of the ansa lenticularis and early demyelination of the pyramids and crossed pyramidal tracts were observed. The latter extended from the lower parts of the medulla oblongata into the spinal cord. Until now 11 familial and 4 nonfamilial cases of pallidopyramidal disease have been described. Pallidopyramidal disease is characterized by its CNS symptoms. In general, disease onset occurred during the second or the early third decade. The two siblings reported by Horowitz and Greenberg (1975) developed their first symptoms in the first decade of life. The classical parkinsonian features were observed in all cases. Pyramidal tract signs, consisting of hyperreflexia, spastic muscle tone and bilateral extensor plantar responses, were also found. In the patients described by Nisipeanu et al. (1994) the occurrence of pyramidal tract signs preceded the appearance of extrapyramidal symptoms. Only a slow progression of the disorder was noted: the 2 patients investigated by Horowitz and Greenberg (1975) were still ambulatory after 10–13 years of disease. No diurnal variation was observed. Some patients examined by Davison (1954) showed additional symptoms such as horizontal nystagmus, intention tremor, poor memory and impaired intelligence. Psychiatric symptoms have not been observed in this syndrome. However, 1 patient reported by Davison had impaired intelligence. Furthermore, 3 out of the 5 patients with Kufor–Rakeb syndrome were demented (Najim al-Din et al., 1994). The diagnostic possibilities are limited. Evidence of isolated extrapyramidal and pyramidal signs and normal laboratory and neuroradiologic investigations in a young adult are suggestive of pallidopyramidal disease. Possible differential diagnoses are juvenile parkinsonism and levodopa-responsive dystonia. No biochemical criteria for diagnosis are known. Three out of the 4 patients examined by Nisipeanu et al. (1994) were subjected to cranial CT and MRI. No abnormalities were found. Patients suffering from
Kufor–Rakeb syndrome showed, in contrast, generalized atrophy on MRI with pronounced atrophy of the lentiform nuclei and the pyramids (Najim al-Din et al., 1994). PET with 18F-fluorodopa was performed in 2 patients with pallidopyramidal disease and showed marked dopaminergic denervation of the striatum (Remy et al., 1995). PET with 11C-flumazenil demonstrated a marked decrease in benzodiazepinereceptor density in the precentral gyrus and the mesial frontal cortex (Pradat et al., 2001). Extrapyramidal symptoms improved with levodopa therapy. Typically, the pyramidal symptoms were not influenced by this treatment. However, Tranchant et al. (1991) reported a worsening of pyramidal tract signs due to the medication regimen. Response to levodopa was somewhat variable; most patients responded rapidly to low doses, with improvement persisting for a long period. After many years of treatment, ‘wearing-off’ phenomena occurred. The daily dose of levodopa used in the patients reported by Nisipeanu et al. (1994) was 500–1000 mg.
54.7. Rett syndrome Rett syndrome is a progressive neurodegenerative disorder which is reported almost exclusively in females and characterized by a wide spectrum of motor and behavioral abnormalities. It was first described by Rett (1966, 1977) and subsequently investigated by other authors (Hagberg et al., 1983; Hagberg and Witt-Engerstrom, 1986). It has been proposed that Rett syndrome is the result of an X-linked-dominant mutation with mortality for hemizygous males, with each case representing a new mutation (Comings, 1986). De novo mutations, possibly in a particular open reading frame, of the gene encoding X-linked methyl-CpG-binding protein 2 (MeCP2) have been identified as a cause of Rett syndrome (Amir et al., 1999; Mnatzakanian et al., 2004). Methylation of CpG dinucleotides in genomic DNA represents a fundamental epigenetic mechanism of gene expression control. MeCP2 likely causes transcriptional repression through an interaction with core histones since the MeCP2-binding domain was shown to associate with histone deacetylases. Mutations in the MeCP2 gene have been identified in 75–90% of sporadic cases and approximately 50% of the rare familial cases (Shahbazian and Zoghbi, 2001). However, MECP2 mutations can also be found in individuals lacking the clinical features of Rett syndrome (Hagberg et al., 2002). Genotype–phenotype studies suggest that the pattern of X-chromosome inactivation has a more prominent effect on clinical severity than the type of mutation (Shahbazian and Zoghbi, 2001). It still
OTHER DEGENERATIVE PROCESSES remains to be determined why mutations of the widely expressed MECP2 gene give rise to a predominantly neuronal phenotype. Recently, DLX5 was identified as one of the genes probably targeted by MECP2 (Horike et al., 2005). Loss of MECP2 caused overexpression of this transcription factor important for GABAergic neurons. Autopsy studies showed diffuse cerebral atrophy with a decrease in brain weight of 14–34% compared to that of age-matched controls with increased amounts of lipofuscin and, occasionally, mild astrocytosis. Moreover, mild but inconsistent spongy changes of white matter were found. Most apparent was a low level of pigmentation of the substantia nigra, whereas the number of nigral neurons was normal (Jellinger and Seitelberger, 1986). In addition, selective dendritic alterations in the cortex of patients with Rett syndrome were reported (Armstrong et al., 1995). The prevalence of Rett syndrome is estimated to be about 0.44/ 10 000 (Kozinetz et al., 1993). The most typical symptoms are stereotyped movements and gait disturbance. A four-stage model for the description of Rett syndrome was proposed (Hagberg and Witt-Engerstrom, 1986). Stage 1 is defined by developmental stagnation, hypotonia and deceleration of head growth (onset 6 months to 1.5 years). Stage 2 is characterized by loss of functional hand use, stereotypic hand-wringing, loss of expressive language, rapid developmental regression and occasional seizures (onset 1–3 or 4 years). Stage 3 is termed a pseudostationary period because of some restitution of communication, but increasing ataxia, hyperreflexia and rigidity, as well as breathing dysfunction and bruxism, are observed. After several years stage 4 develops with the so-called late motor deterioration and growth retardation. With respect to extrapyramidal dysfunction, bruxism (97%), oculogyric crises (63%) and parkinsonism and dystonia (59%) are common features (FitzGerald et al., 1990). Myoclonus and choreoatheosis were seen only infrequently. In younger patients (i.e. < 4 years) hyperkinetic disorders were more evident, whereas in older patients (i.e. > 8 years) the bradykinetic syndrome tended to predominate. Drooling (75%), rigidity (44%) and bradykinesia (41%) were the most often observed parkinsonian symptoms. Sleep disturbances, mainly in the early stages, are frequently present in Rett syndrome. They are characterized by an overall increase in daytime sleep and a delayed sleep onset at night. Despite their mental retardation and their loss of expressive language, these patients tend to appear happy and enjoy close physical contact. Rett syndrome leads not only to neurological abnormalities, but also to dysfunction of other organs
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(Braddock et al., 1993). Gastrointestinal complaints include constipation and weight loss. Swallowing difficulties are also common. Furthermore, an unusual breathing pattern with central apnea intermixed with hyperventilation is frequently observed. Scoliosis often occurs. Patients with Rett syndrome have significantly longer corrected QT intervals and T-wave abnormalities on electrocardiograms that might explain sudden death in Rett syndrome (Sekul et al., 1994). Criteria for the diagnosis of Rett syndrome were initially developed by The Rett Syndrome Diagnostic Criteria Work Group (1988). These criteria have been revised in the light of the recent advances in the understanding of the molecular biology of Rett syndrome (Hagberg et al., 2002). Necessary criteria for the diagnosis of Rett syndrome are apparently normal prenatal and perinatal history; a largely normal (or delayed) psychomotor development through the first 6 months; normal head circumference at birth; postnatal deceleration of head growth in the majority; loss of purposeful hand skills at the age of 0.5–2.5 years; stereotypic hand movements; emerging social withdrawal, communication dysfunction, loss of learned words and cognitive impairment; and impaired or failing locomotion. Supportive criteria include awake disturbances of breathing; bruxism; impaired sleep pattern from early infancy; abnormal muscle tone; peripheral vasomotor disturbances; scoliosis/kyphosis progressing through childhood; growth retardation; and small hands and feet. Diagnostic criteria for variant Rett syndrome have also been developed (Hagberg and Skjeldal, 1994). Parkinsonism has not so far been included among the diagnostic criteria of Rett syndrome or variant Rett syndrome. Infantile autism is one of the most important differential diagnoses. Further differential diagnoses include other neurodevelopmental disorders with mental retardation and motor impairment. Sequencing of the MECP2 gene, if available, is advisable. It was proposed that hyperammonemia could be an essential sign of this condition (Rett, 1966, 1977), but further investigations did not reproduce the findings of hyperammonemia in most patients (Hagberg et al., 1983). Significant reductions in the metabolites of norepinephrine, dopamine and serotonin, as well as an elevation of biopterin in the cerebrospinal fluid, constituted the first detected biochemical alterations (Zoghbi et al., 1989). Additionally, there is evidence of elevation of lactate, pyruvate, alpha-ketoglutarate, malate and glutamate in the cerebrospinal fluid (Hamberger et al., 1992; Matsuishi et al., 1994). MRI indicated a global hypoplasia of the brain and progressive cerebellar atrophy increasing with age (Murakami et al., 1992). An increased density of D2-receptors in
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the striatum of patients suffering from Rett syndrome using single-photon emission spectroscopy (SPECT) imaging was found (Chiron et al., 1993). 18F-fluorodeoxyglucose PET showed several areas of hypometabolism with markedly lower metabolism in the occipital lobes (Naidu et al., 1992). Furthermore, a mild presynaptic deficit of nigrostriatal activity was demonstrated by 18F-fluorodopa and PET (Dunn et al., 2002). There is no specific treatment. Naltrexone appears to provide clinical benefit in the treatment of breathing dysfunction and cognitive impairment (Percy et al., 1994). Furthermore, bromocriptine and l-carnitine can be tried to improve certain disease symptoms (Zappella et al., 1990; Plioplys and Kasnicka, 1993). Lamotrigine and topiramate have been used for seizure control (Kumandas et al., 2001; Goyal et al., 2004). Symptomatic therapeutic approaches also include physiotherapy and music therapy (Armstrong et al., 1995).
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Handbook of Clinical Neurology, Vol. 84 (3rd series) Parkinson’s disease and related disorders, Part II W. C. Koller, E. Melamed, Editors # 2007 Elsevier B. V. All rights reserved
Chapter 55
Hydrocephalus and structural lesions JOHN G. L. MORRIS1*, BRIAN OWLER2, MARIESE A. HELY1 AND VICTOR S. C. FUNG1 1
Department of Neurology, 2Department of Neurosurgery, Westmead Hospital, Sydney, NSW, Australia
55.1. Introduction One of the first clues implicating the substantia nigra in the pathogenesis of parkinsonism was the finding by Blocq and Marinesco (1894) of a mass in that part of the midbrain in a patient with contralateral hemiparkinsonism. Yet structural lesions of the brain are rarely associated with parkinsonism. The clinical presentation of such lesions may however mimic those of parkinsonism, leading to diagnostic confusion. In this chapter, we discuss the syndrome of normal-pressure hydrocephalus (NPH) and how it relates to parkinsonism. We also discuss parkinsonism in the setting of structural lesions such as arteriovenous malformations (AVMs) and brain tumors.
55.2. Normal-pressure hydrocephalus To most neurologists, the syndrome of NPH is hard to understand and disappointing to treat. This is a paradoxical disorder: the ventricles of the brain enlarge, yet the pressure within is not increased. Lowering the (normal) pressure in the ventricles by inserting a shunt may improve symptoms, yet the size of the ventricles is usually unchanged (Meier and Mutze, 2004). To understand this curious disorder it is useful to start with the seminal descriptions written over 40 years ago. 55.2.1. Historical aspects In 1965, Hakim and Adams described 3 patients with hydrocephalus associated with normal cerebrospinal fluid (CSF) pressure. The first patient was a 16-year-old with communicating hydrocephalus (demonstrated on air encephalography) following a severe head injury
and subdural hematoma. He had impaired consciousness which worsened after this procedure and improved with drainage of the lateral ventricles. CSF pressure by lumbar puncture (LP) remained normal (< 200 mm of water) throughout his hospital stay. The second patient was a 52-year-old trombone player with a 1-year history of progressive apathy, slowness of thinking, unsteadiness of gait and incontinence of urine. CSF pressure was normal and it was noted that the patient improved transiently after lumbar puncture. A lumbar air encephalogram and right occipital ventriculogram showed generalized enlargement of the ventricular system. Following the insertion of a ventriculoatrial shunt, his clinical state again improved and this was sustained. The third case was a 43-year-old man with fluctuating conscious level associated with communicating hydrocephalus complicating a major head injury. CSF pressures were normal but he was noted to improve after lumbar puncture. He eventually showed gradual improvement following ventriculoatriostomy. The authors addressed the question of why the ventricles were enlarged in the face of normal CSF pressure and suggested that the hydrocephalus was due to a transient period of raised ventricular pressure and that, once expanded, the size of the ventricles was maintained by CSF pressures lower than that which caused the dilatation in the first place. This has been explained by invoking the laws of physics propounded by the French mathematicians Blaise Pascal (1623– 1662) and Pierre Simon de la Place (1749–1827). According to Pascal’s law, the pressure applied to an
*Correspondence to: Professor John Morris, Department of Neurology, Westmead Hospital, Sydney, NSW 2145, Australia. E-mail:
[email protected], Tel: þ61 02-9845-6793, Fax: +61 02-9635-6684.
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enclosed fluid is transmitted undiminished to every portion of the fluid and to the walls of the containing vessel and, according to LaPlace’s law, the larger the vessel radius, the larger the wall tension required to withstand a given internal pressure. The force exerted on the wall of a fluid-containing vessel represents the product of pressure times surface area. This explains the everyday experience that, when blowing up a child’s balloon, inflation occurs maximally in the body of the balloon rather than the neck. Thus, a given pressure of CSF would be expected to have a greater force when applied to the walls of enlarged ventricles than smaller ones. A pressure of 180 mm of water could be regarded as ‘pathological’ in the presence of dilated ventricles and lowering the pressure might have a beneficial effect. As we will discuss later, there are reasons for not accepting this approach as it applies to the ventricles of the brain. In a second paper in the same year (Adams et al., 1965), the authors described a further 3 cases who ‘having become helplessly demented . . . regained full mental function as a result of a shunt that reduced the “normal” pressure to even lower levels’. Case 1 was a 60-year-old woman with a 6-month history of forgetfulness, unsteadiness of gait and urinary incontinence. She was noted on examination to be ‘gay and witty’ but her history was rambling, her stride was shortened and the tendon reflexes, particularly in her legs, were brisk. Her CSF pressure was 175 mm. Following a lumbar air encephalogram, which showed massive enlargement of the entire ventricular system, she developed akinetic mutism. Her CSF pressures now rose to 300 mm water. She remained in this state for several weeks and then improved greatly after insertion of a ventriculoatrial shunt. That this improvement was related to the shunt was supported by a marked deterioration which followed blockage of the shunt after a fall. Case 2 was a 66-year-old woman with a history of forgetfulness and falls over a period of a few months. She was ‘pleasant and gracious’ on examination but her memory was poor. Reflexes were brisk and her stride length was reduced. Following an air encephalogram, which showed gross dilatation of the entire ventricular system, she became drowsy, incontinent, unable to walk and mute. CSF pressure was 200 mm. She remained in this state for some weeks but improved greatly after insertion of a ventriculoatrial shunt. Case 3 was a 62-year-old man with slowness of thought, unsteadiness of gait and incontinence from
obstructive hydrocephalus due to a cyst of the third ventricle. Lumbar CSF pressures were normal. He recovered after a Torkildsen (ventriculocisternostomy) shunting procedure. It is important to note that the cognitive impairment in cases 1 and 2 was mild until they had air encephalograms. The benefit of withdrawing spinal fluid on the clinical state before embarking on shunting was again recorded. The authors contrasted their cases, who had early loss of balance, with patients with Alzheimer’s disease, where disturbance of gait is a late feature. They noted that the ventricles also enlarge in Alzheimer’s disease due to wasting of brain tissue (hydrocephalus ex vacuo) and correctly anticipated that ‘differentiation of Alzheimer’s disease and “normal-pressure hydrocephalus” is a problem that will recur’. They noted that raised intracranial pressure, even up to 700 mm of water, is often well tolerated in conditions, such as pseudotumor cerebri (idiopathic/benign intracranial hypertension), where the ventricles are small, and suggested that the triad of features which they described – slowness of thought, incontinence of the bladder and gait disturbance – were due to compression of the frontal lobes by the anterior horns of the lateral ventricles. Concerning the lower-limb hyperreflexia, they noted that the long fibers from the leg area of the primary motor cortex descend around the dilated ventricle and undergo the greatest stretching (Yakovlev, 1947). That enlargement was maximal in the lateral ventricles was attributed to this being the largest part of the ventricular system. These two papers aroused great interest, not least because here was another possibly treatable cause of dementia. Experience, however, has modified this view. 55.2.2. Clinical features Hakim and Adams’ papers encouraged neurologists to look for hydrocephalus in patients with the triad of cognitive impairment, incontinence and gait disturbance, particularly when the hazardous procedure of air encephalography was replaced by computed tomography (CT) and magnetic resonance imaging (MRI) scanning. Results of shunting were often disappointing. Numerous papers have been written and opposing positions taken (Bret et al., 2002). Editorials abound (Vanneste, 1994; Bradley, 2001; Silverberg, 2004). In one review, 535 articles were retrieved from Medline (Hebb and Cusimano, 2001). As a result of these studies, there is now a much greater understanding of the sort of patient who is likely to benefit from shunting. The syndrome of NPH now refers to patients with a characteristic disturbance of gait and balance
HYDROCEPHALUS AND STRUCTURAL LESIONS (Fisher, 1982) which is improved by shunting of an acquired, usually communicating, hydrocephalus. Impairment of cognition and incontinence of urine may also be present. Most importantly, and contrary to the interpretation widely placed on the original two publications, NPH is not a treatable cause of dementia where this is the major, sole or initial presenting problem (Vanneste, 1994). Idiopathic and secondary forms of NPH are recognized. About half the cases are idiopathic with onset most commonly in the sixth decade of life or later. Symptomatic NPH, due to prior subarachnoid hemorrhage, meningitis or head trauma, presents at a younger age (Bradley, 2000). NPH must be differentiated from chronic or arrested hydrocephalus, which is often non-communicating, develops early in life but may not present until adulthood. It is not uncommonly picked up as an incidental finding in a patient being investigated for unrelated symptoms. Here the hydrocephalus is compensated. The head is large and, on imaging, the cerebral mantle attenuated (Fig. 55.1.) and the CSF pressure is usually normal. These patients can decline, usually in their 40s and 50s, probably due to the effect of aging in a brain with decreased neuronal reserve. It is important to measure the diameter of the skull in
Fig. 55.1. Computed tomography scan showing a cortical rim with gross enlargement of the lateral ventricles in a 28-year-old female with a greatly enlarged head.
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hydrocephalus as these patients may present with similar problems of gait, balance and cognition as those with NPH but their underlying pathophysiology and management are different. For completeness, mention should also be made of acute/obstructive hydrocephalus where the main presenting features of headache, nausea, vomiting and visual disturbance relate to raised intracranial pressure. The main clinical features are discussed below. 55.2.2.1. Gait Disturbance of gait is the principal symptom of NPH (Fisher, 1982). Of 30 patients studied by Miller Fisher (Fisher, 1982), all of whom had responded to shunting or CSF removal, gait disturbance was the only manifestation of the disorder in 14. Ten patients also had cognitive impairment but in no case did this precede the gait disturbance. Features of the gait included staggering, falls, shuffling and slow, multistepped, precarious turning. Although weakness which worsened on exercise was a common symptom, there was no weakness on formal examination and movement of the legs on the bed was normal. Fisher regarded it as a ‘frontal gait apraxia’. Eleven patients had grasp or sucking reflexes. Estanol (1981), in a study of 6 patients with communicating hydrocephalus, noted that patients, who could readily make cycling movements with their legs on the bed, ‘locked’ and were barely able to walk as soon as they bore weight on their legs. He described the patient with this disorder as ‘hopelessly glued to the floor, unable to take a step. In attempting to walk he might shuffle with short steps. His equilibrium was poor and he might fall while attempting to move’. Estanol viewed the gait disturbance as a limb-kinetic apraxia of gait induced by proprioceptive stimuli to the feet on standing. He also noted that, although these patients had signs of frontal lobe dysfunction such as grasp reflexes and perseveration in the Luria ‘fist, edge and palm test’, they did not have ideomotor apraxia in the upper limbs. Vanneste (1994) took issue with the term ‘gait apraxia’, as it applies to NPH, on the grounds that patients with this disorder ‘execute nearly intact walking movements when minimally supported or lying down’ (though the ability to perform a motor sequence in one setting but not another is surely one of the hallmarks of apraxia). Features of the gait which he emphasized included difficulty in initiating gait, postural instability and shuffling. Hyperreflexia and extensor plantar responses were often present. A similarity with the gait seen in subcortical arteriosclerotic encephalopathy (Thompson and Marsden, 1987) was commented upon. In a definitive review, Nutt et al. (1993) discussed the gait, which has variously been called frontal gait
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disorder, gait apraxia, frontal ataxia, marche petit pas, senile gait, lower-half parkinsonism and arteriosclerotic parkinsonism. They characterized the frontal gait disorder as follows: ‘variable base (narrow to wide), short steps, shuffling, start and turn hesitation, and . . . disequilibrium’. Widening of the base, upright posture and preservation of arm-swing were features, when present, which helped to distinguish it from a parkinsonian gait. Festination, retropulsion and propulsion were more suggestive of parkinsonism than a frontal gait disorder. The authors also disliked the term ‘apraxia’, noting that these patients usually have little evidence of apraxia in the upper limbs. Invoking Hughlings Jackson’s sensorimotor hierarchy, they preferred the designation ‘frontal gait disorder’ under the general heading of ‘highest-level equilibrium and locomotor disturbance’. (The other types of ‘highest-level’ gait disturbance listed by Nutt and colleagues are cautious gait, subcortical disequilibrium, frontal disequilibrium and isolated gait ignition failure.) Whatever label is applied, this type of gait disturbance is most commonly associated with lesions of the frontal lobes, particularly the mesial parts (Ahlberg et al. 1988). Liston and colleagues (2003) reviewed the role of the frontal lobe in movement, dividing it into three main anatomical components: (1) primary motor cortex, which controls muscle force and direction of movement; (2) premotor area (PMA), which couples motor acts to environmental (external) cues; and (3) supplementary motor area (SMA), which is involved in motor preparation and the execution of complex voluntary movements and is internally cued by output from the basal ganglia. In parkinsonism, it is postulated that gait ignition failure, bradykinesia and freezing result from disordered internal cueing of the SMA by the basal ganglia. Movement may be initiated or improved by external cues. Patients with vascular highest-level gait disorders may have three types of gait abnormality: 1. Ignition apraxia, characterized by gait ignition failure, difficulty with turns and freezing, is associated with infarcts in the basal ganglia/thalamus/ SMA connections in the periventricular white matter. These patients have a failure of internal cueing and are helped by external cues, as with Parkinson’s disease (PD). 2. Equilibrium apraxia, where the main problem is loss of balance, is associated with infarcts in the sensory/PMA pathways or in their connections in the periventricular white matter. Such patients are not helped by external cues. 3. Mixed-gait apraxia, characterized by gait ignition failure and disequilibrium, is associated with lesions affecting the connections of both SMA and PMA.
Clues as to where NPH fits into this scheme are provided by a study comparing the gait disorder of NPH with that of PD (Stolze et al., 2001). In both disorders, gait velocity was reduced due to a diminished and variable stride length. In NPH, unlike PD, the gait was broad-based and arm-swing relatively preserved. Although gait was markedly improved in PD by external cues such as a metronome and floor stripes, this was less apparent in NPH. The gait of NPH conforms with the equilibrium apraxia designation of Liston and colleagues (2003), perhaps reflecting disconnection of the PMA in the periventricular white matter, though there are other possibilities (see below). 55.2.2.2. Incontinence Urinary incontinence is a late sign of NPH (Vanneste, 1994). In Miller Fisher’s series (Fisher, 1982) of 30 patients, bladder symptoms were present in 12. Urgency and frequency were the early features leading to incontinence in 8 patients. Cystometrograms showed strong contractions to increments in volume as small as 20 ml. In no patient was incontinence the only manifestation of NPH. Urodynamic studies in another series (Ahlberg et al., 1988) also found hyperreflexia and detrusor instability but without evidence of defective sphincter control. ‘Incontinence sans geˆne’ (unembarrassed incontinence), where there is a lack of concern at incontinence due to frontal dementia, is not a feature of NPH (Vanneste, 1994). Urinary symptoms in NPH are attributed to damage to the periventricular pathways to the sacral bladder center (Ahlberg et al., 1988). 55.2.2.3. Cognitive changes In Miller Fisher’s series (Fisher, 1982), ‘the changes in mentation were usually difficult to separate from the changes that might occur in anyone in their seventies or eighties’. In one patient, there was profound memory disturbance (but this was in the era before MRI, so there may have been other reasons for this). Cognitive impairment is usually mild, with forgetfulness, apathy, inattention, decreased speed of information-processing and impaired ability to manipulate acquired knowledge (Thomsen et al., 1986; Vanneste, 1994). Features of cortical impairment, such as aphasia, apraxia and agnosia, are absent. In further contradistinction to Alzheimer’s disease, but similar to PD, delayed recall may be markedly impaired whereas delayed recognition is preserved (Vanneste, 1994). Iddon and colleagues (1999) noted impairment in executive function involving reasoning, anticipation, goal establishment, strategy formation, shifting mental set and error monitoring in patients with NPH. These pointed to impaired function of the prefrontal cortex. Although improvement was noted in some
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aspects of cognition following shunting, patients who fulfilled the criteria of dementia remained significantly impaired after shunting. In summary, where dementia is the major problem, causes other than NPH need to be considered, and the benefits to the patient from shunting are disappointing (Iddon et al., 1999; Savolainen et al., 2002). 55.2.2.4. Investigations 55.2.2.4.1. Computed tomography/magnetic resonance imaging The diagnosis of NPH hinges upon finding ventricular enlargement out of proportion to cerebral atrophy (Vanneste, 1994) in the appropriate clinical setting. On CT scanning there is enlargement of the ventricular system without significant gyral atrophy (Fig. 55.2). This is in contrast to the ventricular enlargement seen in cerebral atrophy associated with degenerative disease such as Alzheimer’s disease (Fig. 55.3). In NPH there is rounding of the frontal horns and enlargement of the temporal horns without hippocampal atrophy, as shown by dilatation of the perihippocampal fissures (Silverberg, 2004). In Alzheimer’s disease, the perihippocampal fissures are typically markedly dilated (Figs. 55.4 and 55.5). Measurement of the cross-sectional volume of the hippocampus on MRI may be useful in further distinguishing NPH from Alzheimer’s disease (Golomb et al., 1994).
Fig. 55.2. Enlargement of the ventricular system without gyral atrophy.
Fig. 55.3. Computed tomography scan showing ventricular enlargement with frontal and perisylvian atrophy.
Fig. 55.4. Axial magnetic resonance imaging scan (flare sequence) showing ventricular enlargement and perisylvian atrophy, with frontal and occipital periventricular lucencies (ependymitis granularis – a normal finding).
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Fig. 55.5. Coronal magnetic resonance imaging scan (T2weighted) showing ventricular dilatation, perisylvian atrophy and dilatation of the perihippocampal fissures.
Periventricular lucencies on CT are a normal finding around the frontal and occipital horns but are accentuated in NPH (Figure 55.4). On MRI fluid-attenuated inversion recovery (FLAIR) sequences, these findings are more marked and in NPH may extend around the entire perimeter of the lateral ventricles. These changes are thought to result from transependymal CSF leakage. Deep white-matter lesions, which are discontinuous with the ventricular wall, are usually due to infarcts (Fig. 55.6) or perivascular (Virchow– Robin) spaces. Small white-matter infarcts are very common in the elderly and even more common in the setting of NPH (Bradley et al., 1991), where their presence may predispose to ventricular dilatation by softening the brain parenchyma (see below) (Bradley, 2001). The dilemma for the clinician is that, if the patient’s symptoms are due to white-matter infarcts, shunting would not be expected to improve matters. On the other hand, patients with such lesions may still benefit from the procedure (Tullberg et al., 2002), suggesting that there is a reversible component in the pathophysiology of their symptoms (see below).
Fig. 55.6. (A) Axial magnetic resonance imaging (MRI) scan (fluid-attenuated inversion recovery (FLAIR) sequence), showing enlarged lateral ventricles and perisylvian fissures, frontal and occipital periventricular lucencies, high signal intensity lesions (due to probable gliosis – not Virchow–Robin spaces) and a low signal intensity lesion in the periventricular white matter but not contiguous with the ventricular wall. (B) Axial MRI scan (T2-weighted), a little lower, in the same patient as in (A).
HYDROCEPHALUS AND STRUCTURAL LESIONS T2-weighted images may show a CSF flow void sign (Bradley et al., 1986) due to increased CSF flow velocity in the aqueduct in NPH, but the value of this sign is disputed (Vanneste, 1994). 55.2.2.4.2. Cerebrospinal fluid tap test A test for NPH that is available to all clinicians is the CSF tap test. A lumbar puncture is performed using a largecaliber spinal needle, and, after measuring CSF pressure, 20–40 ml of CSF is removed. If the pressure is high and the patient is relaxed, this might be considered enough evidence to undertake shunting. If the pressure is normal, the decision regarding inserting a shunt is determined by the clinical response to the tap. If the patient’s gait improves then the test is positive and the patient should undergo shunting. A negative result does not preclude a possible benefit, since, even after implantation of a shunt, there may be a delay of some days or even a week or two. Thus, although a positive response is useful, the falsenegative rate is high (Haan and Thomeer, 1988). 55.2.2.4.3. Pressure-monitoring and infusion studies In specialized centers, overnight CSF pressure monitoring may be done using an Ommaya or Rickham reservoir connected to the lateral ventricle, or a parenchymal intracranial pressure monitor. In normal subjects, waves of increased pressure may be seen, particularly during sleep. In NPH, these so-called Lundberg B waves occur with increased amplitude, duration and frequency. Frequent B waves of > 9 mmHg amplitude are thought to predict a successful response to CSF shunting (Crockard et al., 1977; Borgesen et al., 1979; Reilly, 2001). However their absence does not exclude a diagnosis of NPH or beneficial response to shunting. CSF dynamics can also be investigated with CSF infusion or perfusion studies. A number of different methods have been described, including constant-rate, constant-pressure and bolus methods. We (BO) have used the constant-rate CSF infusion study, as described by Czosnyka et al. (1996). This test can be performed via the lumbar route or via a CSF reservoir. Two needles are used, one through which CSF pressure is recorded and another through which normal saline is infused at a rate of 1.0–1.5 ml/min. After a period of 10 minutes, during which the baseline CSF pressure is recorded, the CSF infusion is started. CSF pressure rises until it reaches a new equilibrium pressure. The CSF pulse pressure is noted to rise as the mean CSF pressure rises. Once a stable equilibrium CSF pressure has been established, CSF infusion ceases and CSF pressure is noted to return to its baseline. The difference between equilibrium and baseline pressure divided by the infusion rate provides a value for the resistance to CSF absorption (Rcsf). In addition, a number of other parameters can be calculated, including elastance and the pressure volume index.
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Rcsf represents the CSF pressure that must be applied to the CSF system to produce an absorption rate of 1 ml of CSF per minute at equilibrium. The normal Rcsf is < 10 mmHg/ml per min (Albeck et al., 1991) but is usually raised in NPH. The Copenhagen Symposium on NPH in 1990 concluded that an Rcsf > 11 mmHg/ ml per min was suggestive of NPH. Gjerris and Borgesen (1992), using the lumbar-ventricular CSF infusion method, found that, of 271 patients shunted for NPH, no patient with an Rcsf < 12 mmHg/ml per min responded to CSF shunting whereas 80% with Rcsf >12.5 mmHg/ml per min did. Similar findings have been reported by Lundar and Nornes (1990). In a more recent study (Boon et al., 2000) involving 95 patients followed for 1 year, it was suggested that the best strategy for management of patients thought to have NPH was to shunt only those patients with a Rcsf >18 mmHg/ml per min, or if the Rcsf was lower, only those with objective clinical evidence and CT evidence of NPH. 55.2.3. Mechanisms 55.2.3.1. Hydrocephalus Hakim and Adams’ explanation of ventricular enlargement in the face of normal CSF pressure is no longer accepted. An initial period of raised CSF pressure may occur in some cases of secondary NPH but there is very little evidence for this in idiopathic NPH. The laws of Pascal and LaPlace, although relevant to a balloon blown up in air, are less applicable to the cerebral ventricles which, as they enlarge, compress the parenchyma of the brain against the skull wall, increasing rather than decreasing resistance to further expansion. Could enlargement of the ventricles be due to the intermittent rise in pressure that occurs with B waves? Probably not, for these reflect alterations in cerebral blood volume within the brain. There is an increase in the resistance to CSF outflow or absorption in NPH. In secondary NPH this is due to obstruction of arachnoid villi or arachnoid adhesions resulting from previous subarachnoid hemorrhage or meningitis. In idiopathic NPH, chronic meningeal thickening has been described at autopsy (DeLand et al., 1972; Akai et al., 1987). Patients with NPH often also exhibit a ‘convexity block’ when air, contrast or radiographic tracers is injected into the subarachnoid space. Chronic disease and involution of the arachnoid granulations may be seen in NPH (Gilles and Davidson, 1971). Akai et al. (1987) noted that the numbers of arachnoid villi were decreased in the lateral lacunae of patients with NPH. It is likely that the disorder of CSF circulation in secondary and idiopathic NPH is similar, although in idiopathic NPH it is more gradual in onset. Impairment of CSF reabsorption however, would not explain why the ventricles enlarge when the pressure
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inside is not increased. There is increasing evidence that it is changes in the viscoelastic properties of brain tissue with age and disease that predispose to ventricular enlargement (Earnest et al., 1974). Hypertension is a known risk factor for NPH. Akai et al. (1987) found that patients with NPH demonstrated marked sclerosis of the small arteries and arterioles of the subependymal region, deep white matter, thalamus and basal ganglia. Small lacunae were frequent in these regions with focal softening of the tissue. Significant vascular changes have also been reported at autopsy in patients with shunt-responsive NPH who died from other causes (Lorenzo et al., 1974; Newton et al., 1989). 55.2.3.2. Neurological features It is not established how chronic hydrocephalus causes the associated neurological features. Expansion of the ventricular system could impact on the function of a number of structures. Hakim and Adams proposed that
Fig. 55.7. For full color figure, see plate section. Coronal section of the brain showing proximity of the fibers arising from the mesial part of the motor cortex to the lateral ventricle. Adapted from Figure 10.178, page 725, Romanes (1981).
the gait disturbance resulted from stretching of axons in the periventricular white matter. As shown in Figures 55.7 and 55.8, the pyramidal fibers closest to the ventricles in the corona radiata are those arising from the leg area of the motor cortex. Although this might account for the hyperreflexia of the lower limbs, it would not explain the gait disturbance which, as described above, has the features of a higher-order gait disturbance usually associated with lesions of the mesial frontal lobes. Also in close proximity to the lateral ventricles is the anterior cerebral artery (Fig. 55.9A). Stretching of this artery (Fig. 55.9B) may cause frontal lobe ischemia, but no evidence has been found for this from PET studies (Brooks et al., 1986). Cerebral blood flow (CBF) is maximally impaired in the tissue adjacent to the ventricles, improving progressively with distance from the ventricles (Momjian et al., 2004). Ischemia of the basal ganglia interfering with the cortico-striato-pallido-thalamo-cortical motor loop has been proposed (Curran and Lang, 1994) but this might be expected to produce a gait similar to parkinsonism with improvement with cues, which is not the case (Stolze et al., 2000). Disconnection of the frontal lobes by ischemia of the medial nuclei of the thalami (Owler et al., 2004) would account for both the gait and frontal pattern of cognitive impairment (Fung et al., 1997) in NPH. Another structure implicated in the neurological features of NPH is the posterior corpus callosum, which is compressed against the falx cerebri as the ventricles enlarge (Jinkins, 1991). The posterior region of the
Fig. 55.8. The motor homunculus. Reproduced from Penfield and Rasmussen (1950), with permission from Macmillan.
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Fig. 55.9. For full color figure, see plate section. (A) Proximity of the anterior cerebral artery to the lateral ventricle. Adapted from Duus (1989). (B). Sagittal magnetic resonance imaging scan showing relationship of the anterior cerebral artery to the enlarged lateral ventricle in normal-pressure hydrocephalus.
corpus callosum contains crossed corticostriate fibers and association fibers between the vestibular cortical areas. Similarly, involvement of the medial and lateral striae as well as the fornix is proposed as a mechanism for disturbance of memory (Del Bigio, 1993). 55.2.4. Treatment 55.2.4.1. Some observations The identification and treatment of NPH by shunting can be one of the most rewarding in neurological practice: A 74-year-old man presented with a 6–7-year history of difficulty in walking and stooped posture, for which he had been taking levodopa, without benefit. There were occasional spells where his feet got stuck and he had fallen on a number of occasions. His wife reported a decline in memory commensurate with her own. For 2 years he had had urge incontinence. On examination, his face lacked expression and he walked with a festinating gait on a broadened base and with preserved (rapid) arm-swing. He turned en bloc. There was mild cogwheel rigidity in the upper limbs but no bradykinesia. Tendon reflexes were present but reduced. Plantars were flexor. CT scan showed enlarged ventricles without cortical atrophy (Fig. 55.10A). Following insertion of a ventriculoperitoneal (VP) shunt, the ventricles reduced in size (Figure 55.10B, postshunt) but there was only minimal initial improvement in his gait. Over the next few months his gait improved and when videoed 7
months after surgery it had returned to normal, the difference between the pre- and postshunt videos being most striking. It is of interest that, although the ultimate result in this patient was most gratifying, the improvement after shunting was not immediate, causing the treating neurologist to wonder in the immediate postoperative period whether he had made the right decision in referring the patient for surgery. This delay in improvement may reflect recovery of stretched axons in the vicinity of the ventricles. Harder to explain is the improvement which follows shunting when the ventricular size remains unchanged: A 73-year-old man presented with progressive difficulty in walking for a year. Prior to that he had been able to ski. There was urge incontinence and no evidence of cognitive impairment. On examination, he struggled to get out of the chair and walked very slowly on a broad base and with a tendency to shuffle. He was able to rise from a crouching position and could stand on his toes and heels. Power in the limbs was normal. The reflexes were all hard to elicit. Tone was not increased. There was no sensory loss. The arms were normal. An MRI scan showed marked dilatation of the ventricles without gyral atrophy (Fig. 55.11). Following ventriculostomy, he became confused, incontinent of urine and bedbound for several days. Over the next month, he slowly improved to the point where he could walk
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Fig. 55.10. Computed tomography scan: dilated ventricles: (A) preshunt; (B) postshunt.
Fig. 55.11. Axial magnetic resonance imaging scan (T1-weighted) showing enlargement of the lateral ventricles: (A) preshunt; (B) sagittal view.
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Fig. 55.12. Axial magnetic resonance imaging (T1-weighted) showing enlargement of the lateral ventricles: (A) postshunt; (B) sagittal view.
unsupported. A postshunt MRI showed no change in ventricular size (Fig. 55.12). Over the next few months he continued to improve and, when reviewed and revideoed after 7 months, he was walking normally. Improvement was also delayed in this patient and no less impressive than the previous patient, yet the ventricular size looks much the same. This finding is the rule rather than the exception (Meier and Mutze, 2004). This may reflect the fact that current VP shunts have valves in them which prevent the pressure falling so low as to cause the hemispheres to collapse and invite the formation of subdural hematomas. In Meier and Mutze’s study, 80% of 80 patients shunted for NPH had no change in ventricular size, yet 59% of these were judged to have made a good to excellent improvement and a further 17% a satisfactory improvement. Such findings lend support to the hypothesis that shunting produces its benefit by means other than relieving stretch on axons adjacent to the ventricles. One such mechanism is improved blood flow to the brain parenchyma. The response of CBF to shunting has been studied using a variety of techniques. Although some investigators found an increase in CBF after shunting (Tanaka et al., 1997), it was often not sustained (Graff-Radford et al., 1987). Other investigators reported no change in CBF after shunting (Meixensberger et al., 1989) and that there was no relationship to outcome (Klinge
et al., 1999). Others reported that, although global CBF was not improved, the pattern of CBF was improved in shunt-responders (Waldemar et al., 1993). More recently (Silverberg et al., 2003; Silverberg, 2004), it has been proposed that changes in the normal circulation of CSF in NPH may result in a failure to clear toxic molecules such as amyloid-ß-peptide, predisposing to the development of Alzheimer’s disease, which has an increased incidence in biopsy-studied cases of NPH (Golomb et al., 2000). A trial of CSF shunting to slow the progression of Alzheimer’s disease is currently underway. 55.2.4.2. Shunting Shunting is the treatment of choice in NPH. As originally suggested by Adams et al. (1965), the aim is to decrease CSF pressure to even less than normal. The response to shunting varies widely between studies: 25–80%, with a mean of 50% (Vanneste et al., 1992). Of 1047 patients included in this review, the response to shunting was notably better in secondary NPH (64%) compared to idiopathic NPH (50%). Marked improvement was noted in 46% of patients with secondary NPH compared to 33% with idiopathic NPH. The most common form of CSF shunt used in NPH is a VP shunt, although ventriculoatrial shunting is also popular. Both are generally favored over lumboperitoneal shunting, which often poses problems in the elderly.
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55.2.4.2.1. Complications of shunting The most common complications of shunting are infection and blockage. Less common complications include subdural hematoma, stroke, shunt disconnection, erosion of the distal catheter through the skin or internal viscus, thrombosis around atrial catheters and shunt nephritis. Vanneste et al. (1992) performed a risk/benefit study of idiopathic NPH using 1047 patients obtained from 19 studies from the literature. The benefit/harm ratio in patients with idiopathic NPH was 1.7 and increased to 6 if high-risk patients with significant comorbidity were excluded. This is not a procedure to be undertaken lightly. A complication of shunting that deserves special attention is that of subdural hematoma. This occurs in patients with large ventricles with relatively thin cortical mantles when there is overdrainage of CSF. The cortical mantle collapses, separating away from the dura and tearing overstretched subdural veins. NPH patients are particularly prone to this complication (Symon et al., 1972). 55.2.4.2.2. Reasons for shunt failure As discussed previously, clinical improvement in patients with NPH after CSF shunting is usually not immediate. Gait disorder and urinary incontinence are the first symptoms to improve and may do so within days but often take several weeks. Improvement in mental function is less predictable and is usually the last symptom to improve; it may take several months. Failure of the shunt to provide worthwhile benefit can be due to a number of factors: (1) technical problems with the pump itself; (2) complications of shunting, such as subdural hematoma; (3) irreversible pathophysiological changes in the brain parenchyma relating to coexisting disease, such as hypertensive small-vessel disease or Alzheimer’s disease. 55.2.4.3. Drugs and other treatments Drugs have little place in the management of NPH. There is no evidence that reducing CSF production with drugs such as acetazolamide is beneficial. From the preceding discussions, it might be anticipated that control of hypertension may lessen the predisposition to developing NPH. 55.2.5. Association between parkinsonism and hydrocephalus Curran and Lang (1994) have drawn attention to cases of levodopa-responsive parkinsonism associated with hydrocephalus. It is helpful to consider these: Patient 1 was a 16-year-old boy with headaches and papilledema secondary to aqueduct stenosis.
He improved with VP shunting but later became drowsy when the shunt blocked. After shunt revision, he was noted to have tremor, rigidity and akinesia and Parinaud’s syndrome. The parkinsonian features persisted and were markedly improved by levodopa. Patient 2 was a 16-year-old man with headache, bilateral sixth-nerve palsies and papilledema from hydrocephalus secondary to a pineal mass. A VP shunt was inserted and he was given radiotherapy. After repeated episodes of shunt obstruction requiring revisions, he became bradykinetic and rigid. These features improved markedly with levodopa. Patient 3, aged 7, developed tremor, unsteadiness of gait, headache, vomiting and listlessness associated with aqueduct stenosis. He improved with a VP shunt. Again, after periods of repeated shunt obstructions, he became parkinsonian with tremor and rigidity. This too improved with levodopa. After some months the levodopa was withdrawn without return of his parkinsonism. Patient 4 presented at age 9 with headache, papilledema and Parinaud’s syndrome due to aqueduct stenosis. Her symptoms improved with a Torkildsen ventriculocisternal shunt. At age 26, she presented again with personality change and generalized bradykinesia. The ventricles were not enlarged but the shunt was noted to be wrapped around the brainstem and was replaced with a VP shunt. Her parkinsonism persisted and was not improved by levodopa. Later a CT scan revealed a small left thalamic bleed. An 18F-dopa PET scan was normal, suggesting that her parkinsonism was postsynaptic. Patient 5 was a 69-year-old man who developed parkinsonism, shown at postmortem to be due to progressive supranuclear palsy in the setting of NPH and diffuse cerebrovascular disease. Patient 6, aged 72, was similar in presentation to case 5, but with no pathological study. Patient 7, aged 72, presented with a 10-year history of asymmetrical limb slowing, gait disturbance and incontinence associated with hydrocephalus. He improved with shunting but later developed progressive parkinsonism with tremor and bradykinesia. This partially improved with levodopa. Later he developed a vertical supranuclear gaze palsy. At pathology he was found to have typical features of advanced idiopathic PD. Patient 8, aged 68, presented with gait instability, generalized rigidity and right-arm resting tremor. Within a year he was incontinent and had
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cognitive changes. A CT scan showed hydrocephalus and all his symptoms resolved with a VP shunt. Three months later his symptoms returned and he was found to have small bilateral resolving subdural hematomas. He initially improved with levodopa but his parkinsonism and dementia continued to decline over the next 2 years. An MRI scan showed multiple areas of subcortical high signal change. An 18F-dopa PET scan showed decreased fluorine accumulation in the putamen but not the caudate. Patient 9, aged 67, with a previous history of severe head injury, presented with parkinsonism which responded to levodopa. Five years later she had an episode of confusion and a CT scan showed enlarged ventricles. Over the next 2 years she became progressively more demented and parkinsonian. 55.2.5.1. Comment Cases 1–3, all young, show that parkinsonism can occur subacutely as a complication of obstructive hydrocephalus involving the aqueduct. In these patients, the clinical picture was very different from the cases of NPH described above: they had symptoms and signs of raised intracranial pressure with headache, drowsiness and papilledema. Their parkinsonism may have resulted from direct injury to the substantia nigra, as there was evidence of midbrain damage (patient 1 had Parinaud’s syndrome and patient 2 compression of the midbrain by a pineal tumor) and they responded to levodopa. Cases 5–9, all aged 67 or older, illustrate that Occam’s razor – whereby, in a medical context, an attempt should be made to explain all symptoms on the basis of a single disease – is often not a useful exercise in the elderly, where degenerative parkinsonian syndromes such as idiopathic PD and progressive supranuclear palsy may coexist with cerebrovascular disease and NPH.
55.3. Other structural lesions Dopa-responsive parkinsonism is described below in association with a number of structural lesions. 55.3.1. Arteriovenous malformation 55.3.1.1. Intracerebral hemorrhage Our colleague Aggarwal (Ling et al., 2002) reported a case of dopa-responsive parkinsonism following a hemorrhage into the right temporal lobe from an AVM: A 46-year-old man developed a symmetrical parkinsonian syndrome 7 weeks after presenting
Fig. 55.13. Axial T2-weighted magnetic resonance imaging scan showing high signal intensity changes in the right temporal lobe.
with a seizure, decreased level of consciousness, a dilated right pupil and left hemiparesis from a large right temporal intracerebral hemorrhage. The hemorrhage was evacuated together with a small AVM. His signs included bradykinesia, rigidity, start hesitation and poor postural reflexes, without a resting tremor. He also had signs of a Parinaud’s syndrome. CT and MRI of the brain demonstrated changes in the right temporal lobe associated with the hemorrhage but no abnormality of the basal ganglia or midbrain (Fig. 55.13). Levodopa therapy produced a dramatic improvement within a few days of commencement. He still required this treatment 2 years after the bleed. Three years after the event he died from heat stroke after jogging. At postmortem, marked neuronal loss with gliosis was observed in the substantia nigra and superior colliculi. There were no areas of infarction. No Lewy bodies, neurofibrillary tangles or glial cytoplasmic inclusion bodies were seen (M Rodrigues, personal communication). Like cases 1–3 of Curran and Lang (1994), it seems likely that the parkinsonism in this case was the result of damage to the nigrostriatal tract in the midbrain by compression, in this case from an expanded temporal lobe. Similar cases have been described in association with subdural hematoma (Trosch and Ransom, 1990).
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55.3.1.2. Midbrain cavernoma We have had a patient with dopa-responsive parkinsonism associated with a cavernoma involving one substantia nigra: She presented in 1975 at the age of 34 with tremor of the left hand. She was put on levodopa, which abolished her symptoms. When reviewed in 1991, she had a coarse resting tremor and mild akinesia confined to the left arm. In follow-up since that time, she has reported that the effect of each dose
of levodopa wears off after about 2 hours. When she is ‘on’ she has no tremor and her Unified Parkinson’s Disease Rating Scale (UPDRS) score is 5; when she is ‘off’ it is 30. She has never had dyskinesia and never had signs on the other side. MRI scans (Fig. 55.14) showed an area of increased signal in the right cerebral peduncle with some surrounding low signal on T2-weighted images, suggesting the presence of hemosiderin. No abnormal feeding vessels were seen on magnetic resonance angiography. The features were of
Fig. 55.14. (A) T1-weighted magnetic resonance imaging (MRI) scan showing hypointense lesion in the pars compacta of the right cerebral peduncle. (B) T2-weighted MRI scan showing low signal area (hemosiderin) around a small high signal area (methemoglobin)in the right midbrain. (C) Coronal view of (B).
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is on the appropriate side of the midbrain to produce hemiparkinsonism. It seems likely that the right nigrostriatal tract has been damaged by pressure from the cavernoma or associated bleeding. 55.3.2. Tumor Fig. 55.15. For full color figure, see plate section. b-Carbomethoxy-3b-(4-iodophenyl)tropane (b-CIT) single-photon emission computed tomography (SPECT) scan showing reduced formation of dopamine transporter in the right caudate nucleus.
a cavernoma. SPECT images (Fig. 55.15) were obtained using [123I]2b-carboxymethoxy-3biodophenyl tropane (beta-CIT) which labels presynaptic dopamine transporter (DAT) and [123I] iodobenzamide (IBZM), which labels the postsynaptic D2-receptors. There was a dramatic reduction in presynaptic dopaminergic binding ipsilateral to the lesion (Fig. 55.15) that was more marked in the caudate than putamen, the opposite of the putamen–caudate gradient that is found in idiopathic PD. Ipsilateral postsynaptic and contralateral pre- and postsynaptic dopaminergic uptakes were normal. It is unlikely that this patient has unrelated idiopathic PD, as there has been almost no progression in her disability over a period of 30 years. The cavernoma
Tumors rarely, if ever, cause parkinsonism. Sometimes, however, the clinical features produced by a tumor may be mistaken for PD: A 52-year-old right-handed man presented with a 6-month history of difficulty using his right hand. His writing had lost fluency and become small. He had difficulty doing up buttons and getting his wallet out of his pocket. He had a tendency to trip with the right foot. On examination, he did not swing the right arm when he walked. There was minimal lag in the right arm compared with the left when he raised them and there was no weakness. Tone was increased on the right side. He had difficulty performing piano-playing movements with the right hand. Reflexes were brisker on the right side. The plantars were flexor. A scan was done because of the hyperreflexia. This showed a 7 5 4 cm meningioma indenting the left cerebral hemisphere maximally over the motor strip (Fig. 55.16).
Fig. 55.16. (A) Axial postgadolinium T1-weighted magnetic resonance imaging scan showing a large meningioma indenting the left cerebral hemiphere; (B) T2-weighted, coronal view.
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55.3.2.1. Comment Both neurologists who examined this patient at presentation were impressed by the abnormality of finger movement of the right side which was interpreted, in the absence of weakness, as akinesia due to PD. The increase in tone and loss of arm-swing lent support to this. It seems likely that abnormality of finger movement was due to a limb-kinetic apraxia, which may present in a very similar manner to akinesia. 55.3.3. Lesions of the striatum/globus pallidus/thalamus In Bhatia and Marsden’s (1994) extensive review, isolated lesions of the striatum/globus pallidus rarely, and of the thalamus never, caused pure parkinsonism. Parkinsonism occurred in 9% of 240 cases, all associated with bilateral lesions and only rarely with rest tremor. Most cases followed toxic/metabolic lesions, making strict exclusion of nigrostriatal pathology difficult. 55.3.4. Supplementary motor area resection Patients undergoing surgery involving the motor pathways can provide insights into the mechanism of the motor deficit in parkinsonism: A 24-year-old man with a history of intractable seizures had the left SMA resected (Fig. 55.16). There were no clinical signs before surgery. Following surgery, he was initially mute and had right-side weakness. An MRI scan shows the extent of the resection (Fig. 55.17). Over the next few
days his speech improved, as did the power on the right side. There was reduction in amplitude of right-hand movements involving opening and closing the fingers and difficulty in making piano-playing movements involving the index and middle fingers, similar to what is seen in parkinsonism. Most striking, however, was the inability to coordinate the movement of the two hands. He could clap with one hand or the other but not both simultaneously. All of these features gradually disappeared over the next few weeks, leaving him with normal hand function. 55.3.4.1. Comment The relationship between the SMA and akinesia in parkinsonism has been reviewed by Williams et al. (2002): Activity in the SMA is a major contributor to the Bereitschaftspotential that precedes self-generated movements and this potential is reduced in PD. Imaging studies confirm impaired activation of SMA during some movements in untreated PD; this is reversible using the dopaminergic agonist apomorphine. It is of interest therefore that our patient showed features similar to the akinesia of parkinsonism following SMA resection, though the more striking abnormality was in loss of bimanual coordination.
55.4. Incidence of structural lesions in parkinsonism Most reports of structural lesions associated with parkinsonism are of single cases or of retrospective
Fig. 55.17. (A) T1-weighted magnetic resonance imaging scan: sagittal view showing high signal changes (due to blood products) over the mesial surface of the left cerebral hemisphere; (B) coronal view.
HYDROCEPHALUS AND STRUCTURAL LESIONS studies of hospital records. Some information on the incidence of structural lesions in patients presenting with parkinsonism is provided by the long-term Sydney Multicenter study of PD (Hely et al., 1994). Of 149 de novo patients diagnosed as having PD by 26 Sydney neurologists and followed by author MAH for up to 20 years, 13 were found in the first 2 years to be atypical, of which structural lesions relevant to the parkinsonism were seen in 2: A 60-year-old man who had presented with features of a mixed resting and postural tremor, mild but definite rigidity and bradykinesia, developed a wide-based gait soon after presentation. He was found to have a pinealoma compressing the midbrain and causing hydrocephalus (Fig. 55.18). He responded to shunting and did not continue with parkinsonian medication. 55.4.1. Comment There were changes in the midbrain on CT scanning and it seems likely that his transient parkinsonian features were due to compression of the substantia nigra or nigrostriatal tract by the pinealoma. A 37-year-old man presented with a 3-year history of resting tremor, bradykinesia and rigidity
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confined to the right side of his body. He was found to have a cystic lesion in the contralateral thalamus and lentiform nucleus (Fig. 55.19), probably secondary to a severe head injury at age 13 (for which he underwent bilateral burrhole evacuation of subdural hematomas). He responded well to levodopa 300 mg/day and benztropine 15 mg/day and his symptoms remained confined to the right side over 10 years of follow-up. 55.4.2. Comment It seems likely that his hemiparkinsonism was related to the previous head injury, though it began 21 years after the injury. The symptoms were non-progressive and contralateral to the lesion, which probably represented a cavity from an old hematoma. The response to levodopa was surprising and suggests that the lesion also involved the nigrostriatal tract.
55.5. Summary and conclusions Structural pathology of the brain can mimic the clinical features of parkinsonism. Those involving the substantia nigra or the nigrostriatal tract can lead to the classical features associated with idiopathic PD,
Fig. 55.18. (A) Non-contrast computed tomopgraphy (CT) scan showing a calcified mass in the pineal gland. (B) Non-contrast CT scan in the same patient showing low-density change in the region of the aqueduct.
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Fig. 55.20. For full color figure, see plate section. Diffusion tensor magnetic resonance imaging scan of a patient with normal-pressure hydrocephalus showing thinning of the forceps minor (red), forceps major (green) and compression of the corona radiata (blue). Fig. 55.19. Non-contrast computed tomography scan showing hypodense area in the left thalamus.
including asymmetry, rest tremor, akinesia, rigidity and, most importantly, responsiveness to levodopa. Lesions of the striatum/globus pallidus/thalamus rarely cause pure parkinsonism. When it does occur, such postsynaptic parkinsonism is not usually levodoparesponsive. Data from patients with parkinsonism secondary to structural lesions lead to the conclusion that the parkinsonism results from loss of dopaminergic modulation of striatal activity, not from loss of function due to lesions of the striatum itself. NPH produces a clinical picture that is very different from PD (Fig. 55.20). The major motor impairment is gait disturbance, which most closely resembles that seen in multilacunar states or frontal-lobe syndromes. As softening of the brain parenchyma by multiple infarcts predisposes to ventricular enlargement, there is considerable overlap between NPH and the multilacunar state. Where most of the neurological deficit relates to infarction, the response to shunting is likely to be poor. Finally, cortical lesions involving the motor and premotor cortex can cause alterations in fine finger movements similar to what is seen in parkinsonism. These are best considered as limb-kinetic apraxia rather than akinesia as there are no associated signs such as rigidity or rest tremor.
Acknowledgments We thank Drs Somerville, Aggarwal, Bleasel and Duggins for permission to describe their patients and Dr Lavier Gomes for his help with the scans.
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Handbook of Clinical Neurology, Vol. 84 (3rd series) Parkinson’s disease and related disorders, Part II W. C. Koller, E. Melamed, Editors # 2007 Elsevier B. V. All rights reserved
Chapter 56
Calcification of the basal ganglia JENNIFER S. HUI* AND MARK F. LEW University of Southern California, Los Angeles, CA, USA
56.1. Introduction Calcification of the basal ganglia (BG) has been known and described since 1850 by Delacour, and histologically defined as cerebral blood vessel calcifications by Bamberger in 1855. The observations of these scientists, however, are rarely credited today. In 1930, the German pathologist Fahr described a case of calcification in the cerebral vessels in a patient with likely hypoparathyroidism (HP). ‘Fahr’s disease’ has since become a disputed term and a relative misnomer, given that calcifications in his case occurred in predominantly white matter, sparing the BG (Klein and Vieregge, 1998). Confusion regarding the nomenclature and classification of BG calcifications persists, with ‘Fahr’s disease’ used in varying contexts encompassing BG calcinosis of differing etiologies, symptoms and clinical significance. To clarify, the descriptive term ‘bilateral striopallidodentate calcinosis’ (BSPDC) has been proposed to describe idiopathic, symmetric calcifications of the BG resulting in characteristic clinical features and will be used throughout this chapter (Manyam, 1990; Manyam et al., 2001b).
56.2. Epidemiology 56.2.1. Incidental calcifications of the basal ganglia Epidemiologic studies expanded rapidly with the widespread use of computed tomography (CT) in the 1970s, resulting in increased sensitivity of detecting BG calcifications over skull plain films (Fig. 56.1). Nevertheless, prevalence estimates of BG calcifications in the general population have varied widely due to non-standardized radiographic and clinical criteria. Authors have generally agreed that incidental
calcifications of the BG are found in approximately 0.3–1.2% of all subjects undergoing routine brain CT examination (Koller et al., 1979; Murphy, 1979; Sachs et al., 1979; Brannan et al., 1980; Cohen et al., 1980; Fenelon et al., 1993). When found, these calcifications are usually punctate and restricted to the globus pallidus, although few studies report consistent symptoms related to dysfunction of BG pathways. Harrington et al. (1981) reviewed the CT scans of 7000 patients and found 42 patients (0.6%) with BG calcifications and normal serum electrolytes, calcium and phosphate levels. Clinical correlations of these patients included epilepsy, headache, stroke or dementia, but no symptoms related to BG involvement. Likewise, Sachs et al. (1979) found 14 patients out of 3800 CT examinations (0.4%) with bilateral BG calcifications, the majority having seizures or psychic symptoms. Finally, the diversity of symptoms found in a series of 14 of 4219 (0.3 %) consecutive patients with calcifications and normal metabolic profiles led to the conclusion that further diagnostic procedures were not warranted if symmetric BG lesions were incidentally found on brain CT (Koller et al., 1979). Other authors, however, have advocated an evaluation of calcium metabolism in cases of incidental BG calcifications. In particular, Sachs et al. (1982) reported that 10% (2/20) of incidentally revealed BG calcifications revealed a diagnosis of primary HP. However, these cases were specifically referred for evaluation of neurologic symptoms, comprising a potentially higher-risk group than found with other, consecutively derived CT series. In most reported cases of incidental BG calcinosis, serum calcium and phosphorus levels are normal, as seen in a collective total of 88 subjects reported by Koller et al. (1979),
*Correspondence to: Dr. Jennifer S. Hui, University of Southern California, 1520 San Pablo St., Suite 3000, Los Angeles, CA 90033, USA. E-mail:
[email protected]
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J. S. HUI AND M. F. LEW Table 56.1 Etiology of basal ganglia calcifications Idiopathic Incidental calcifications (“physiologic”) BSPDC Familial Autosomal dominant/ recessive Sporadic
Fig. 56.1. Skull film demonstrating basal ganglia calcifications in a patient with hypoparathyroidism. Courtesy of University of Southern California Department of Radiology.
Cohen et al. (1980) and Brannan et al. (1980), except for 2 cases of previously known HP. Given the relative scarcity of pathologic conditions associated with incidental BG calcifications, most have concluded that the radiologic finding can be regarded as a manifestation of physiologic senescence (Murphy, 1979; Brannan et al., 1980; Cohen et al., 1980). This concept is supported by a population-based study showing a relatively high prevalence (18.6%) of BG calcifications in healthy elderly subjects aged 85 years, suggesting that this finding is more common in older persons (Ostling et al., 2003). Similarly, Cohen et al. (1980) found that, among 32 patients with incidental BG calcifications, 25 were above the age of 60 years. Together, these epidemiologic findings suggest that it is reasonable to evaluate further patients with incidental BG calcifications who are younger than age 40 years, those with symptoms related to BG dysfunction or HP (such as tetany) or those with dense or multiple areas of cerebral calcification outside the globus pallidus. 56.2.2. Symptomatic calcifications of the basal ganglia A subset of BG calcifications exists for which there are identifiable metabolic or degenerative causes (Table 56.1). In contrast to those incidental cases without a known etiology, these symptomatic calcifications are often associated with a progressive syndrome of parkinsonism, dystonia, chorea and tremor. Although milder forms of symptomatic cases may occur, those who are clinically affected share a radiographic presentation of massive calcification of the striatum, cerebellum and
Endocrine disorders Hypoparathyroidism Pseudohypoparathyroidism Pseudopseudohypoparathyroidism Hyperparathyroidism Hypothyroidism Infectious Toxoplasmosis Cystercercosis HIV/AIDS Tuberculosis Viral encephalitis
Congenital Cockayne’s syndrome Mitochondrial myopathies Tuberous sclerosis Neurofibromatosis Down’s syndrome Hallervorden-Spatz syndrome Methemoglobinopathies Toxic/anoxic Lead intoxication Carbon monoxide intoxication Radiation therapy Methotrexate Long-term antiepileptics Autoimmune Systemic lupus erythematosus
HIV, human immunodeficiency virus; AIDS, acquired immunodeficiency syndrome.
subcortical white matter, as distinguished by large, confluent areas of hyperdense signal on brain CT (Fig. 56.2). Conditions associated with symptomatic BG calcifications can be classified into idiopathic or secondary causes (Table 56.1). Of the secondary causes, primary HP is the most common, with estimates of BG calcification occurring in 69–93% of those with the disorder, as identified on brain CT imaging (Sachs et al., 1982; Illum and Dupont, 1985). Illum and Dupont (1985) found that 69% (11/16) of subjects with primary HP and 100% (8/8) of those with pseudo-HP showed calcification in the BG. Distribution of the lesions included the globus pallidus in all cases, with most subjects demonstrating additional deposits in the striatum, thalamus, dentate and centrum semiovale. Sachs et al. (1982) surveyed 14 patients with primary HP, 13 of which demonstrated bilateral intracerebral calcifications (93%), 9 located in the BG. In both studies, patients had been diagnosed with HP for over 10 years, with symptoms of tetany or seizures starting in childhood. Parkinsonian signs of hypokinesia, rigidity or tremor were present in only 3 of 12 subjects in the series of Sachs et al. (1982).
CALCIFICATION OF THE BASAL GANGLIA
A
481
B
C Fig. 56.2. (A) Mild, (B) moderate and (C) severe forms of bilateral striopallidodentate calcinosis (BSPDC). Courtesy of University of Southern California Department of Radiology.
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56.3. Bilateral striopallidodentate calcinosis Although reports of parkinsonian syndromes have been relatively rare in association with HP and other secondary causes of BG calcinosis, parkinsonism is a frequent presentation of idiopathic familial cases of massive BG calcification, popularly known as Fahr’s disease (Lowenthal, 1986). Endocrinologic evaluations in these cases do not reveal abnormalities in calcium or phosphorus metabolism. Now termed BSPDC, the disorder can be seen in familial, autosomal-dominant, autosomal-recessive or, less commonly, sporadic patterns (Manyam, 1990; Manyam et al., 2001a). Unlike incidental or some secondary causes of BG calcinosis, familial BSPDC carries a poor prognosis. The true prevalence of the disorder remains unknown due to the evolving clinical and radiographic diagnostic criteria and its predominantly case-report description in the literature. In all likelihood BSPDC is rare, although cases with lesser calcification appearing in routine CT imaging cannot be excluded as early presentations of BSPDC without a detailed family history, including radiographic evidence. 56.3.1. Clinical features Among multiple reports of BSPDC, a fairly uniform clinical presentation has emerged, featuring a progressive syndrome with varying symptoms of dementia, dysarthria, parkinsonism, pyramidal and cerebellar signs (Ellie et al., 1989; Manyam et al., 1992, 2001a, b; Kobari et al., 1997; Warren et al., 2002). Onset of symptoms typically occurs between 30 and 50 years and cognitive symptoms are not uncommon. Given the relative uniformity of features distinct to BSPDC, Manyam et al. (2001b) established the ‘Fahr’s disease registry’, retaining the popular name for sake of familiarity. Inclusion criteria included: (1) radiologic evidence of bilateral, symmetric calcifications in the BG, dentate, thalamus or cerebral white matter; (2) normal childhood development; and (3) absence of parathyroid disorder. All subjects were examined clinically and provided a detailed family history. Cases reported in the literature that met inclusion criteria were also included (n ¼ 61). In the combined registry and literature cases (n ¼ 99), 67 were symptomatic and 32 were asymptomatic. The symptomatic group demonstrated a significantly higher mean age ( sd) (47 15) compared to the asymptomatic group (32 20) and were more than twice as likely to be men (45:22). Men were also more likely to have intracranial calcifications compared to women (57:42, P < 0.01). This predominance of
men in the symptomatic group has been suggested in other reviews of the literature (Ellie et al., 1989; Kobari et al., 1997). Kobari et al. (1997) found a similar ratio, in which over half of symptomatic cases of brain calcification were men (21:11). Ellie et al. (1989) reported a more conservative male-to-female ratio (11:13) in the symptomatic group, but, like the registry, noted that older patients (> 45 years) were more likely to be clinically affected. The clinical features of patients in the registry were separated into 11 categories, the most common symptom being movement disorders (55%), with over half of these cases manifesting parkinsonism (57%), followed by chorea, tremor and dystonia (Manyam et al., 2001b). Cognitive impairment was the second most commonly observed symptom (39%), along with cerebellar (36%) and speech (36%) disorders. Unlike cases of HP-associated calcifications, seizures were relatively uncommon, accounting for 9% of all symptoms. There was considerable overlap of symptoms, although the number of subjects displaying more than one symptom was not specified. Families can demonstrate interfamilial heterogeneity. The cognitive aspects of BSPDC have been well documented and anatomically supported by previously described frontal–subcortical circuits (Cummings et al., 1983; Alexander et al., 1986). Lopez-Villegas et al. (1996) published a case-control study of the neuropsychological symptoms of subjects with BG calcinosis > 5 mm, illustrating significant executive and visuospatial dysfunction, a similar pattern to other disorders affecting deep gray-matter structures (e.g. Parkinson’s disease, Huntington’s disease, progressive supranuclear palsy). Psychiatric symptoms were also more common in those with calcification compared to controls, with 22.2% meeting criteria for mood disorder and 33.3% for obsessive-compulsive disorder (n ¼ 18). In addition, frank psychosis in BSPDC has been seen alone or in conjunction with other movement disorders (Cummings et al., 1983; Rosenberg et al., 1991; Lauterbach et al., 1994), with one report of three siblings, each with BG calcifications and symptoms of schizophrenia, making the likelihood of coincidental diagnoses unlikely (Rosenberg et al., 1991). Finally, Cummings et al. (1983) even suggested that BSPDC presents with two distinct clinical patterns: an early-onset psychotic syndrome and a late-onset group with motor and cognitive symptoms, although delayed tardive effects from early pharmacologic treatment of psychosis could not be discounted. Several variations of the BSPDC clinical syndrome have been published in case-report format, including a patient with subacute dementia occurring over 6
CALCIFICATION OF THE BASAL GANGLIA months affecting memory, executive functioning and mood without motor impairment (Benke et al., 2004). Warren et al. (2002) reported a patient with corticobasal degeneration manifesting as left-sided rigidity and apraxia, a left extensor plantar response and startle myoclonus. Finally, a particularly unique case of a 12-year-old girl with transient parkinsonism lasting 10 days was found after she had drunk a cup of tea, associated with multiple gray- and white-matter calcifications on brain CT (Yoshikawa and Abe, 2003). 56.3.2. Radiography and clinical correlations In virtually all reported cases of incidental, secondary and idiopathic causes of BG calcinosis, calcification in the brain is nearly symmetrical and, in BSPDC, restricted to the central nervous system (Lowenthal, 1986). In cases meeting criteria for the Fahr’s disease registry, calcification was mainly seen in the dentate nucleus, BG, thalamus and centrum semiovale with varying severity (Figs. 56.2 and 56.3) (Manyam et al., 2001b). There were no consistent patterns of calcification within families. Symptomatic patients showed a significantly greater amount of calcification compared to asymptomatic individuals, suggesting a dose–response relationship. Longitudinal changes
483
were documented in 1 subject over a decade with serial CT scans, showing a progressive increase in total calcium deposits from age 50 to 57, then a decrease corresponding to cerebral atrophy at age 60. This pattern of progressive calcification correlating with worsening symptoms over time has been crosssectionally observed in other studies, suggesting a cumulative pathologic effect. In multigenerational families with BSPDC, for instance, younger generations are often asymptomatic with milder degrees of calcification, whereas older relatives present with the progressive clinical syndrome. In a father-and-son series by Ellie et al. (1989), a 48-year-old man presented with progressive speech impairment and cerebellar ataxia with multiple areas of dense cerebral calcification, with his asymptomatic 22-year-old son demonstrating less extensive calcifications of the globus pallidus. In another familial report, Moskowitz et al. (1971) reported 5 patients in one family with BG calcifications. Of the 5 subjects, the two eldest (ages 47 and 58 years) presented with parkinsonism, whereas the younger individuals (aged 13–30 years) were asymptomatic. The severity of calcifications was not measured. Alternatively, other familial reports of BSPDC have found that younger generations were more severely affected, both clinically and radiographically, suggesting a possible role for genetic anticipation (Kobari et al., 1997). This observation has been supported by the recent identification of a chromosomal locus for BG calcification, showing a younger age of onset with each genetic transmission (see below) (Geschwind et al., 1999). As a result of these varying opinions regarding the individual prognosis of BG calcinosis, it is difficult to predict who will become symptomatic from BSPDC, although it appears that more extensive calcifications correlate with increasing severity of symptoms. 56.3.3. Genetics of BSPDC
Fig. 56.3. Dentate calcification in bilateral striopallidodentate calcinosis (BSPDC). Courtesy of University of Southern California Department of Radiology.
Variations in familial expression have revealed several inheritance patterns of BSPDC, the most common of which is an autosomal-dominant pattern. Autosomalrecessive (Smits et al., 1983) and X-linked (Naderi et al., 1993) inheritance patterns of BG calcinosis have also been described, although these cases are often associated with endocrine disorders such as HP or have inadequate pedigrees consisting of only one affected generation, limiting the certainty of genetic transmission patterns. Of the 99 patients included in the Fahr’s disease registry, 73 patients belonged to 14 families, demonstrating a clear autosomal-dominant inheritance of BSPDC. Of the remaining patients, 12
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were grouped as ‘familial’ without a clear pattern of inheritance and 14 were sporadic cases. Moskowitz et al. (1971) were among the first to report an entire family with autosomal-dominant BSPDC, examining 15 members spanning at least two generations, with documented male-to-male transmission. Five subjects had BG calcification and 10 did not have calcification, as detected on skull films rather than CT, perhaps underestimating its prevalence. In another extensive familial study, Manyam et al. (2001a) evaluated 27 members of a family over four generations, with 18 showing radiographic evidence of brain calcifications in an autosomal-dominant pattern. Three patients were symptomatic with parkinsonism, one, interestingly, with autopsy-confirmed Parkinson’s disease and another without Lewy bodies on autopsy. The chromosomal locus for one family with idiopathic BG calcifications has been localized to chromosome 14q (Geschwind et al., 1999). Geschwind et al. clinically and genetically examined 28 members of a multigenerational family using linkage analysis, of which 12 had BG calcifications. The family demonstrated autosomal-dominant inheritance patterns over four generations, with symptoms ranging from combinations of parkinsonism, dystonia and tremor. The average age at onset of symptoms was 37 years, appearing to decrease over three successive generations by an average of > 20 years, such that the third generation had symptom onset from ages 5–12 years. The discovery of such a prominent pattern of anticipation is somewhat surprising, given its lack of consistent documentation in the current literature; however, it points to the possibility of a triplet repeat mutation as a cause of some cases of BSPDC. Several candidate genes within the 14q locus have been mentioned, including a proteosome subunit, somatostatin receptor, kinesin receptor, paraplegin and the A kinase anchor protein (Geschwind et al., 1999). It will be important to determine whether other families with autosomal-dominant BSPDC have mutations in the same locus or whether there are several mutations leading to the variations in phenotype for this disorder. 56.3.4. Pathophysiology The pathogenesis of BG calcifications and BSPDC is unknown. Numerous histochemical studies and experimental models have been conducted to define the nature of these calcifications. Several different patterns of calcification have been shown histologically, associated with neuronal loss and gliosis in the BG and dentate (Matsumoto et al., 1998; Tsuchiya et al., 2002). On gross inspection, chalky yellow mineral deposits in the dentate and striatum are found, microscopically
corresponding to granular and stippling calcium deposits within the parenchyma and along capillaries (Manyam et al., 2001a). Matsumoto et al. (1998) found intense calcification surrounding veins in the BG and white matter, with loss of myelin sheaths and axons in a patient with cerebral lupus. Fujita et al. (2003) described three histologic patterns of cerebral calcification in a variety of neurodegenerative diseases, including Alzheimer’s disease, Pick disease and diffuse neurofibrillary tangles with calcification (DNTC), a disorder demonstrating Fahr’s-like calcification in the BG. Type 1 histology involved diffuse deposition within the tunica media of small and medium-sized vessels; type 2 consisted of spherical concretions in the parenchyma; and type 3 included rows of small calcifications lying along capillaries. This latter, pericapillary pattern of calcification may reflect the pattern most commonly seen in BPSDC, given its reproducibility in multiple histologic studies and its frequent presence in DNTC (Duckett et al., 1977; Matsumoto et al., 1998; Manyam et al., 2001a; Fujita et al., 2003). Other histologic patterns, however, such as intracellular deposits with minimal neuronal death, have also been reported (Takashima and Becker, 1985; Mahy et al., 1999). The molecular composition of cerebral calcifications consists of hydroxyapatite crystals assembled from various bone matrix proteins, a structure not unlike physiologic calcifications found elsewhere in the body (Smeyers-Verbeke et al., 1975; Fujita et al., 2003). Detailed chemical analyses of these deposits reveal that calcium and phosphorus are present in the greatest proportion, followed by trace quantities of magnesium, zinc, aluminum and iron (Smeyers-Verbeke et al., 1975; Duckett et al., 1977). Whether the deposits represent a primary deposition or dystrophic change from prior ischemic insult has yet to be determined. Several proposed mechanisms exist for the formation of BG calcifications, including altered vessel permeability to calcium (Lowenthal, 1986), changes in blood flow and resulting tissue ischemia (Lowenthal, 1986; Uygur et al., 1995), synaptic excitotoxicity (Mahy et al., 1999) or local shifts in calcium concentration, possibly due to parathyroid hormone-responsive enzymes (Lowenthal, 1986; Kurup and Kurup, 2002). Uygur et al. (1995) demonstrated decreased regional blood flow in the BG and frontal cortices through a brain SPECT study of a patient with BSPDC. However, it is not known whether this finding is a result or cause of the cerebral calcifications. Animal models of excitotoxicity have suggested a role for glutamate in calcium deposit formation, using the excitatory amino acid, ibotenic acid, to induce calcified inclusions in astrocytes in an in vivo rat brain (Mahy et al., 1999).
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485
Table 56.2 Treatment of idiopathic bilateral striopallidodentate calcinosis with dopaminergic medication Source
Number of cases
Response
Drug received
Klawans et al. (1976) Manyam et al. (2001a)
1 6
No improvement Improvement
Berendes and Dorstelmann (1978) Harati et al. (1984)
1
No improvement No improvement
Levodopa Levodopa No medication given Levodopa Levodopa
1 2 3 1 1
3
Mild improvement
Amantadine No medication given
1 2
56.3.5. Treatment of parkinsonism in BSPDC The parkinsonism of BSPDC has been variable with respect to response to dopaminergic treatment. Klawans et al. (1976) described a case of levodopa-resistant parkinsonism in association with BG calcifications, treated unsuccessfully for 30 months with levodopa doses up to 7 g/day, suggesting a dopaminergic ‘postsynaptic receptor site dysfunction’. Conversely, Manyam et al. (2001a) reported a levodopa-responsive case of BSPDC at doses of 1200 mg/day. Characteristic Lewy bodies, however, were found on autopsy, suggesting that the patient had levodopa-responsive Parkinson’s disease and BSPDC concurrently (Manyam et al., 2001a). Vermersch et al. (1992) also described levodopa-responsive BG calcinosis in patients who were already diagnosed with Parkinson’s disease prior to their CT scans. In addition, these calcifications were mostly unilateral, without mention of their extent or severity, opening the possibility that these cases were radiographically distinct from the BSPDC syndrome. In a review of the literature in which treatment of BSPDC was reported, 3/6 patients improved with dopaminergic treatment, 3/6 did not improve and 5 patients did not receive treatment (Table 56.2). This number of publications to date is insufficient to identify a consistent pattern regarding treatment of BSPDC.
56.4. Summary Calcification of the BG occurs in many contexts, ranging from incidental findings to disorders of mineral metabolism and familial forms of cerebral calcinosis. BSPDC, also known as Fahr’s disease, is an idiopathic, familial form of calcification of the BG presenting as a combination of parkinsonism, dementia and cerebellar signs. Although the terminology of BG calcifications remains controversial, the clinical findings of severe
forms remain predictable within a spectrum of frequently disabling symptoms. The underlying pathophysiology is not yet well understood. It is possible, however that clues from genetic evaluation, although the presentation is varied, may lead to a more detailed understanding of BSPDC. Additionally, data gleaned from an ongoing registry of BSPDC patients may be instrumental to improving our basic knowledge of this disorder over time.
References Alexander GE, DeLong MR, Strick PL (1986). Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci 9: 357–381. Bamberger H (1855). Beobachtungen und bemerkungen uber hirnkrankheiten. Verh Phy Med Ges 6: 325–328. Benke T, Karner E, Seppi K et al. (2004). Subacute dementia and imaging correlates in a case of Fahr’s disease. J Neurol Neurosurg Psychiatry 75: 1163–1165. Berendes K, Dorstelmann D (1978). Unsuccessful treatment with levodopa of a parkinsonian patient with calcification of the basal ganglia. J Neurol 218: 51–54. Brannan TS, Burger AA, Chaudhary MY (1980). Bilateral basal ganglia calcifications visualised on CT scan. J Neurol Neurosurg Psychiatry 43: 403–406. Cohen CR, Duchesneau PM, Weinstein MA (1980). Calcification of the basal ganglia as visualized by computed tomography. Neuroradiology 134: 97–99. Cummings JL, Gosenfeld LF, Houlihan JP et al. (1983). Neuropsychiatric disturbances associated with idiopathic calcification of the basal ganglia. Biol Psychiatry 18: 591–601. Delacour A (1850). Ossification des capillaries du cerveau. Annu Med Psychol 2: 458–461. Duckett S, Galle P, Escourolle R et al. (1977). Presence of zinc, aluminum, magnesium in striopallidodentate (SPD) calcifications (Fahr’s disease): Electron probe study. Acta Neuropathol (Berl) 38: 7–10. Ellie E, Julien J, Ferrer X (1989). Familial idiopathic striopallidodentate calcifications. Neurology 39: 381–385.
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Fahr I (1930). Idiopathipathische verkalking der hirume fasse. Zbl Allf Path 50: 129–133. Fenelon G, Gray F, Paillard F et al. (1993). A prospective study of patients with CT detected pallidal calcifications. J Neurol Neurosurg Psychiatry 56: 622–625. Fujita D, Terada S, Ishizu H et al. (2003). Immunohistological examination on intracranial calcification in neurodegenerative diseases. Acta Neuropathol (Berl) 259–264. Geschwind DH, Loginov M, Stern JM (1999). Identificatoin of a locus on chromosome 14q for idiopathic basal ganglia calcification (Fahr disease). Am J Hum Genet 65: 764–772. Harati Y, Jackson JA, Benjamin E (1984). Adult onset idiopathic familial brain calcifications. Arch Intern Med 144: 2425–2427. Harrington MG, Macpherson P, McIntosh WB et al. (1981). The significance of the incidental finding of basal ganglia calcification on computed tomography. J Neurol Neurosurg Psychiatry 44: 1168–1170. Illum F, Dupont E (1985). Prevalences of CT-detected calcification in the basal ganglia in idiopathic hypoparathyroidism and pseudoparathyroidism. Neuroradiology 27: 32–37. Klawans HL, Lupton M, Simon L (1976). Calcification of the basal ganglia as a cause of levodopa-resistant parkinsonism. Neurology 26: 221–225. Klein C, Vieregge P (1998). The confusing history of “Fahr’s disease”. Neurology 50 (Suppl 4): A59. Kobari M, Nogawa S, Sugimoto Y et al. (1997). Familial idiopathic brain calcification with autosomal dominant inheritance. Neurology 48: 645–649. Koller WC, Cochran JW, Klawans HL (1979). Calcification of the basal ganglia: Computerized tomography and clinical correlation. Neurology 29: 328–333. Kurup RK, Kurup PA (2002). Hypothalamic digoxin related membrane Naþ-Kþ ATPase inhibition and familial basal ganglia calcification. Neurosci Res 42: 35–44. Lauterbach EC, Spears TE, Prewett MJ et al. (1994). Neuropsychiatric disorders, myoclonus, and dystonia in calcification of basal ganglia pathways. Biol Psychiatry 35: 345–351. Lopez-Villegas D, Kulisevsky J, Deus J et al. (1996). Neuropsychological alterations in patients with computed tomography-detected basal ganglia calcification. Arch Neurol 53: 251–256. Lowenthal A (1986). Striopallidodentate calcifications (chapter 24). In: PJ Vinken, GW Bruyn, HL Klawans (Eds.), Handbook of Clinical Neurology, Vol. 5, Elsevier Science Publishers, New York, pp. 417–436. Mahy N, Prats A, Riveros A et al. (1999). Basal ganglia calcification induced by excitotoxicity: An experimental model characterised by electron microscopy and X-ray microanalysis. Acta Neuropathol (Berl) 98: 217–225. Manyam BV (1990). Bilateral strio-pallido-dentate calcinosis: A proposed classification of genetic and secondary causes. Mov Disord 5: 94. Manyam BV, Bhatt MH, Moore WD et al. (1992). Bilateral striopallidodentate calcinosis: Cerebropsinal fluid, imaging, and electrophysiological studies. Ann Neurol 31: 379–384.
Manyam BV, Walters AS, Keller IA et al. (2001a). Parkinsonism associated with autosomal dominant bilateral striopallidodentate calcinosis. Parkinsonism Relat Disord 7: 289–295. Manyam BV, Walters AS, Narla KR (2001b). Bilateral striopallidodentate calcinosis: Clinical characteristics of patients seen in a registry. Mov Disord 16: 258–264. Matsumoto R, Shintaku M, Suzuki S et al. (1998). Cerebral perivenous calcification in neuropsychiatric lupus erythematosus: A case report. Neuroradiology 40: 583–586. Moskowitz MA, Winickoff RN, Heinz ER (1971). Familial calcification of the basal ganglions: A metabolic and genetic study. N Engl J Med 285: 72–77. Murphy MJ (1979). Clinical correlations of CT scan-detected calcifications of the basal ganglia. Ann Neurol 6: 507–511. Naderi S, Colakoglu Z, Luleci G (1993). Calcification of basal ganglia associated with pontine calcification in four cases: A radiologic and genetic study. Clin Neurol Neurosurg 95: 155–157. Ostling S, Andreasson LA, Skoog I (2003). Basal ganglia calcification and psychotic symptoms in the very old. Int J Geriatr Psychiatry 18: 983–987. Rosenberg DR, Neylan TC, el-Alwar M et al. (1991). Neuropsychiatric symptoms associated with idiopathic calcification of the basal ganglia. J Nerv Ment Dis 179: 48–49. Sachs C, Ericson K, Erasmie U et al. (1979). Incidence of basal ganglia calcifications on computed tomography. J Comput Assist Tomogr 3: 339–344. Sachs C, Sjoberg H, Ericson K (1982). Basal ganglia calcifications on CT: Relation to hypoparathyroidism. Neurology 32: 779–782. Smeyers-Verbeke J, Michotte Y, Pelsmaeckers J et al. (1975). The chemical composition of idiopathic nonarteriosclerotic cerebral calcifications. Neurology 25: 48–57. Smits MG, Gabreels FJM, Thijssen HOM et al. (1983). Progressive idiopathic strio-pallido-dentate calcinosis (Fahr’s disease) with autosomal recessive inheritance. Report of three siblings. Eur Neurol 22: 58–64. Takashima S, Becker L (1985). Basal ganglia calcification in Down’s syndrome. J Neurol Neurosurg Psychiatry 48: 61–64. Tsuchiya K, Nakayama H, Iritani S et al. (2002). Distribution of basal ganglia lesions in diffuse neurofibrillary tangles with calcification: A clinicopathological study of five autopsy cases. Acta Neuropathol (Berl) 103: 555–564. Uygur GA, Liu Y, Hellman RS et al. (1995). Evaluation of regional cerebral blood flow in massive intracerebral calcifications. J Nucl Med 36: 610–612. Vermersch P, Leys D, Pruvo J et al. (1992). Parkinson’s disease and basal ganglia calcifications: Prevalence and clinico-radiological correlations. Clin Neurol Neurosurg 94: 213–217. Warren JD, Mummery CJ, Al-Din AS et al. (2002). Corticobasal degeneration syndrome with basal ganglia calcification: Fahr’s disease as a corticobasal look-alike? Mov Disord 17: 563–567. Yoshikawa H, Abe T (2003). Transient parkinsonism in bilateral striopallidodentate calcinosis. Pediatr Neurol 29: 75–77.
Handbook of Clinical Neurology, Vol. 84 (3rd series) Parkinson’s disease and related disorders, Part II W. C. Koller, E. Melamed, Editors # 2007 Elsevier B. V. All rights reserved
Chapter 57
Trauma and Parkinson’s disease OSCAR S. GERSHANIK* Laboratory of Experimental Parkinsonism, ININFA-CONICET, Buenos Aires, Argentina
57.1. Introduction The relationship between trauma and Parkinson’s disease (PD) and/or parkinsonism can be approached from different perspectives. We may focus, from an epidemiological perspective, on the existence of preceding trauma, to either the head or other body parts, as a risk factor for the subsequent development of PD; on the other hand, trauma may be the cause of secondary parkinsonism through different mechanisms; or we may look at the effects of trauma on pre-existing PD. All these approaches have been extensively dealt with in the literature and we will try to review them as comprehensively as possible to bring the reader an updated discussion on the subject (for reviews, see: Factor et al., 1988; Koller et al., 1989; Stern, 1991; Jankovic, 1994; Lees, 1997; Krauss and Jankovic, 2002). Trauma has long been held suspect as one of the contributing factors to the development of PD. Some of the earliest references in this regard date back to James Parkinson himself, who speculated, as he had no solid evidence to substantiate it, that the disease might be the consequence of a direct injury to the brainstem or the dural sheath surrounding it. He reasoned that, given the range of mobility that the upper segment of the spine had, this would make this region more susceptible to trauma (Parkinson, 1817). In their comprehensive historical review on the concept of trauma as an etiology of parkinsonism, Factor and collaborators (1988) thoroughly discuss not only the prevailing medical theories surrounding this issue in the 19th and early 20th century, but the socioeconomic factors that may have fueled them, among them the passing of the first workmen’s compensation legislation. Of interest is the fact that traumatic factors held
responsible for the development of PD were not only those sustained in the head, but different kinds of peripheral trauma (cuts, bruises, skin punctures, burns, usually in the subsequently affected limb or body part). Exposure to a damp environment and emotional trauma were also believed to be capable of inducing parkinsonism. Charcot (cited by Factor et al., 1988) advanced the ‘ascending neuritis’ hypothesis to explain the relationship between peripheral trauma and PD. According to this hypothesis, a peripheral injury would induce an ascending inflammatory reaction along the nerves that eventually reached the central nervous system. In the first part of the 20th century, several French authors reported the development of parkinsonism as a consequence of concussion associated with mesencephalic lesions in soldiers involved in World War I. Later on, in 1928, postmortem analysis of the brain of a patient who developed parkinsonism after sustaining a bullet injury to the head, showing hemorrhagic lesions at the basal ganglia level, gave credence for the first time to the existence of true cases of posttraumatic parkinsonism (Factor et al., 1988). Almost contemporary with this observation was the report by Patrick and Levy (1922) claiming that, in 15% of the cases of PD they had followed and studied, trauma was a contributing factor to its development. It was not until 1934, when Grimberg published his thorough analysis on ‘paralysis agitans and trauma’, that objective criticism of the hypothesis of trauma-induced parkinsonism was raised. Grimberg dismissed 84 out of 86 cases reported since 1873 onwards as not being related to trauma based on a number of factors (misdiagnosis, no definite history of trauma, pre-existing parkinsonian symptomatology antedating the ‘causative’ trauma, unclear temporal relationship between the occurrence of the trauma and the onset of parkinsonism, lack of a clear
*Professor Oscar S. Gershanik, Department of Neurology, Centro Neurolo´gico-Hospital Frances, Director, Laboratory of Experimental Parkinsonism, ININFA-CONICET, La Rioja 951 (1221) Buenos Aires, Argentina. E-mail:
[email protected]
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pathophysiological mechanism to explain such an association) (Grimberg, 1934). His review, together with the one published more recently in this same Handbook by Schwab and England in 1968, concluded that it was only in cases severe enough to cause traumatic injury to the midbrain, subsequently ascertained by the postmortem finding of hemorrhage in that same region, that one could establish a causal relationship between trauma and the development of parkinsonism (Schwab and England, 1968). These conclusions are only applicable to the diagnosis of posttraumatic parkinsonism. A different conceptual framework has to be applied to the still controversial issue of trauma as a risk factor for the development of PD.
57.2. Trauma as a risk factor for the development of Parkinson’s disease Current theories on the etiology and pathogenesis of PD consider this disorder to be multifactorial and the result of a combination of a genetic predisposition possibly interacting with environmental factors. That genes play a role in the etiology of PD is supported at present by the discovery of at least 11 forms of genetic parkinsonism that share clinical features and possibly pathogenetic mechanisms with the more common, as yet sporadic, form of the disease (Corti et al., 2005; OMIM Database, 2005). The quest for environmental exogenous triggering factors has remained elusive and only supported through indirect evidences gathered from numerous and extensive epidemiological studies. Age, sex, dietary habits, infections, environmental toxins and trauma are among the factors considered by these studies (Lai et al., 2002; Allam et al., 2003). Although a number of epidemiological studies addressing this question find a positive association between past history of trauma and later development of PD, a larger number dispute these findings. Table 57.1 lists the majority of published epidemiological studies that have looked at the issue of trauma as a risk factor for PD. Fourteen out of 19 case-control studies originating in different parts of the world, involving more than 1500 patients and over 2000 controls, failed to find a positive association between preexisting trauma and PD (for references, see Table 57.1). In addition, two very important cohort studies, the Rotterdam and the Olmsted county/Mayo Clinic studies, were also unable to establish a link between the development of PD and past history of head trauma (Williams et al., 1991; De Rijk et al., 1996). These studies included patients with reported head trauma of enough severity to cause loss of consciousness or amnesia, residual neurologic deficits
and skull fracture that were subsequently followed for a prolonged period of time. Morbidity ratios were not elevated for PD or other neurodegenerative disorders such as Alzheimer’s and motor neurone diseases (Williams et al., 1991; De Rijk et al., 1996). In only seven case-control studies, five of them carried out in North America (USA and Canada), one in the UK and one in Taiwan, was a positive association found. In the London study, Godwin-Austen and collaborators (1982) interviewed 350 patients and controls, trying to establish the relationship between smoking and PD and its association with several risk factors. They found that PD patients were more likely to have had head injury associated with loss of consciousness than controls. Unfortunately, as this was not the primary interest of this study, no numbers are given and the level of significance of this finding is not provided. Factor and Weiner (1991) interviewed 97 patients and 64 controls (spouses) seen consecutively in an outpatient clinic. In 32% of PD patients and 17% of controls there was a prior history of head trauma of any degree of severity (P < 0.05); when head trauma with alteration of consciousness was considered, the association was maintained at the same level of significance (20.6% of patients and 8% of controls). In the study by Stern et al. (1991), a detailed analysis of various environmental exposures and early life experiences was conducted in 80 patients with old-onset PD (age older than 60), 69 young-onset patients (age younger than 40: young-onset Parkinson’s disease (YOPD)) and 149 age- and sex-matched controls. They found that at least one episode of trauma ‘severe enough to cause vertigo, dizziness, blurred or double vision, seizures or convulsions, transient memory loss, personality changes or paralysis’ occurred more frequently in both old and youngonset patients prior to disease onset than in controls. This difference was found to be significant (odds ratio ¼ 2.7; P < 0.05). The study by Semchuk et al. (1993) was carried out in Calgary, Canada, and included 130 patients with neurologist-confirmed idiopathic parkinsonism and 2 matched controls adjusted by age and sex obtained randomly from the same community (random-digit dialing). They used a multivariate conditional logistic regression analysis method in which they controlled for any potential confounding or interaction between the different exposure variables considered. In four of the eight logistic regression models used, having a history of head trauma was significantly associated with the risk of developing PD (P < 0.001), second only to the existence of a positive family history.
TRAUMA AND PARKINSON’S DISEASE
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Table 57.1 Trauma and Parkinson’s disease: epidemiological studies
Author
Year
Number of patients/controls
Type of study
Association
Location
Nuti et al. Bower et al.
2004 2003
190/190 196/196
Case-control Case-control
Tuscany, Italy Minnesota, USA
Tsai et al.
2002
Case-control
Preux et al. Taylor et al.
2000 1999
30 YOPD/30 60 LOPD 140/280 140/147
Werneck and Alvarenga Kuopio et al. Smargiassi et al. McCann et al.
1999 1999 1998 1998
92/110 123/246 86/86 224/310
Case-control Case-control Case-control Case-control
No Yes P < 0.02 Yes P < 0.002 No Yes P < 0.0001 No No No No
De Michele et al. Seidler et al. De Rijk et al. Yang et al. Morano et al. Semchuk et al.
1996 1996 1996 1994 1994 1993
116/232 380/379 Rotterdam cohort 90/90 74/148 130/260
Case-control Case-control Cohort Case-control Case-control Case-control
Butterfield et al. Stern et al.
1993 1991
63/68 149/149
Case-control Case-control
Factor and Weiner
1991
97/64
Case-control
Williams et al.
1991
Cohort
Hofman et al. Tanner et al. Ward et al. Godwin-Austen et al.
1989 1987 1983 1982
Olmsted county cohort (821) 86/172 100/200 65/65 350/350
Case-control Case-control
Case-control Case-control Case-control Case-control
No No No No No Yes P < 0.001 No Yes P < 0.05 Yes P < 0.05 No No No No Yes More likely
Taiwan, China France Boston, USA Rio de Janeiro, Brazil Turku, Finland Emilia Romagna, Italy Queensland and NSW, Australia Campania/Molise, Italy Germany The Netherlands China Caceres, Spain Calgary, Canada Oregon, USA USA/Canada Miami/Albany, USA Minnesota, USA The Netherlands China USA/Canada/UK London, UK
YOPD, young-onset Parkinson’s disease; LOPD, late-onset Parkinson’s disease.
Taylor et al. (1999) recruited 140 PD (examined and followed by neurologists and movement disorders specialists) cases from the Boston University Medical Center, USA. Controls were in-laws or friends of the patients (n ¼ 147). For this study a positive history of head trauma was considered when it was severe enough ‘to cause loss of consciousness, blurred or double vision, dizziness, seizures or memory loss, rather than mere bruising, bleeding or stitches’. Twenty-five percent of the cases versus 7.5% of the controls had a history of head trauma according to this study. This difference was found to be highly significant (P < 0.0001). The most recent studies finding a positive association between head trauma and PD are those of Tsai
et al. (2002) and Bower et al. (2003), carried out in Taiwan and Minnesota respectively. In Tsai’s study YOPD cases were compared to late-onset cases and controls. They included 30 cases with age of onset before 40, 30 young controls and 60 late-onset cases. All participants in the study were administered a structured questionnaire in which all the potential risk factors under analysis were included. In the case of selfreported head injuries the information was verified against medical records to ascertain its validity. A multiple logistic regression analysis was used to examine the significance of all risk factors simultaneously. When compared with late-onset PD patients, YOPD had a substantially higher percentage of head injuries (37% versus
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10%; P < 0.002). Although the difference in the percentage having head injury was not statistically significant between YOPD and controls, the proportion of those having such an experience in the patient group was more than doubled (37% versus 17%). It is indeed interesting to note that this study found head trauma to be a risk factor only for YOPD and not for PD in general. The study by Bower et al. (2003) has several distinguishing features that differentiate it from other case-control studies. They conducted a population-based case-control study of incident PD cases and population controls nested within the Olmsted county cohort. The three key features of their study were the populationbased nature, the nesting within a records linkage system and the use of information about head trauma that was recorded historically before the onset of PD. They included 196 case-control pairs matched for age and sex. Because of the peculiar design of this study I believe it is interesting to analyze the results in more detail than in the previous studies. There were 13 head trauma events in the PD cases versus only 3 in the controls, this difference being statistically significant (P < 0.02). This association, however, was only restricted to the more severe cases. There was no difference in the frequency of mild head trauma with amnesia as the residual symptom between cases and controls. However, the frequency of mild head trauma with loss of consciousness combined with moderate or severe trauma was significantly higher in cases (5.6%) than in controls (0.5%). Using the frequency of head trauma among controls estimated in their study (1.5%), the authors computed a population-attributable risk for head trauma in PD of 5%. In men, head trauma was significantly more frequent in cases (9.9%) than in controls (1.7%). In women, the frequency of head trauma was the same in cases and controls (1.3%); however, the numbers were small (one event each). When they stratified cases by median age at onset of PD, the analysis showed no significant difference between cases and controls for patients with earlier age at onset. However, there was a significantly higher frequency of head trauma in cases (6.4%) than controls (0.0%) for patients with later onset (P < 0.02) (Bower et al., 2003). These findings are in absolute contrast to those of Tsai et al. (2002) and no reasonable explanation can be advanced to account for these differences. All of these studies were published after the introduction of levodopa, thus including levodopa-responsiveness as one of the diagnostic criteria, and the majority of them were conducted using very strict methodological approaches. It is therefore difficult to interpret these apparently conflicting findings. Several explanations can be offered to account for these differences. Methodological differences among the
different studies, both in regard to case ascertainment and data evaluation, including definition of head injury or trauma, may be the cause of this discrepancy. All case-control studies are retrospective and in those reporting an association between head injury and PD, the average interval between the reported trauma and the onset of the disease was 33.3 years. After so many years it is possible that recall bias may influence the outcome of these studies. Patients with chronic diseases are more likely than healthy individuals to recall any significant event in their lives that may offer an explanation for their present predicament. They are always looking for possible connections between life experiences and disease onset, as individuals carrying a chronic disease often feel unfairly dealt with by life. Unfortunately these arguments do not necessarily hold up to thorough scrutiny. In Factor’s study (Factor and Weiner, 1991) the association was still significant whether they considered any type of trauma or severe enough trauma to cause alteration of consciousness, suggesting that differences in definition of head injury may not be the cause of the discrepancy. If recall bias was the confounding factor, older patients would have reported more episodes of head trauma than patients 30 years their younger, which was not the case in the study by Stern et al. (1991), comparing young-onset with old-onset cases. In their study there was no difference in the prevalence of head trauma prior to disease onset between the two groups. We are therefore left with an unresolved dilemma, as no single retrospective study is free of methodological flaws or limitations in its ability to detect significant differences between the populations under study. It is worth noting that, even in those studies in which there were no statistically significant differences between cases and controls in regard to prevalence of head trauma, the PD group always had a higher frequency of reported head injuries than the controls. However, not even in those studies finding a positive association was head trauma the sole predictor, as it was usually associated with family history and exposure to other environmental factors (wellwater drinking, pesticide use, etc.) (Semchuk et al., 1993; Taylor et al., 1999). Head trauma might therefore be one of several risk factors acting in combination in a predisposed individual that precipitate the cascade of events leading to the development of PD. Head trauma may increase the risk of PD only in those individuals who carry a specific polymorphism of a susceptibility gene. This hypothesis refers to a model of gene–environment interaction that has also been proposed for Alzheimer’s disease (Bower et al., 2003).
TRAUMA AND PARKINSON’S DISEASE In a few of the publications reporting a positive association between head trauma and an increased risk of developing PD there have been attempts at finding the factors underlying this association. Three major hypotheses have been put forward (Factor and Weiner, 1991; Bower et al., 2003), as described below. First, an isolated episode of head trauma could lower the number of nigral cells, on top of which the normal decline of dopaminergic neurons occurring with age would be superimposed. This concept, also designated as the ‘single-hit hypothesis’ originally proposed by Calne and Langston (1983), has been abandoned for several reasons, the most important being the difference between the regional pattern of neuronal loss in PD compared to normal aging (Fearnley and Lees, 1991). Moreover, studies using fluorodopa positron emission tomography (PET) suggest that the rate of decline in striatal uptake is more rapid in PD than in normal aging (Morrish et al., 1998). Second, it has been proposed that head injury could somehow cause a disruption of the blood–brain barrier, thus allowing exogenous neurotoxins to enter the central nervous system and trigger the cascade of nigral degeneration (Graves et al., 1990). The finding of polymorphonuclear leukocyte infiltration of the brain tissue following a head trauma, on the other hand, may be an indication of immune-mediated changes leading to neurodegeneration (Bower et al., 2003). Both mechanisms may be secondary to trauma-induced disruption of the blood–brain barrier and could eventually cause a delayed neurodegenerative process. Finally, it has been proposed that head trauma may trigger an acute-phase response, causing the overexpression of one or several proteins that would eventually lead to cytoplasmic protein aggregation and cell death. This is in line with current theories suggesting that PD is the result of a complex disorder of the ubiquitin-proteasome system involved in protein degradation. By analogy, there is some evidence that the synthesis of apolipoprotein E, of ß-amyloid precursor protein or both increases markedly in the brain after head injury, leading to the trauma-related hypothesis of Alzheimer’s disease (Bower et al., 2003). At the cellular and molecular level, the mechanisms underlying secondary or delayed cell death following traumatic brain injury (TBI) are poorly understood. Experimental models of TBI suggest that diffuse and widespread neuronal damage and loss are progressive and prolonged for months to years after the initial insult in selectively vulnerable regions of the cortex, hippocampus, thalamus, striatum and subcortical nuclei (McIntosh et al., 1998). The cellular and molecular events triggered by TBI include possible alterations in intracellular calcium with resulting changes
491
in gene expression, activation of reactive oxygen species, activation of intracellular proteases (calpains), expression of neurotrophic factors and activation of cell death genes (apoptosis) (McIntosh et al., 1998; Bramlett and Dietrich, 2003). In addition, elevation of proinflammatory cytokines has also been demonstrated in animal models of brain trauma which could further exacerbate the neuronal damage initially induced by the head injury (Liu et al., 2003). All these factors may play a role in mediating delayed cell death after trauma. TBI, according to some, should be considered as both an inflammatory and/or a neurodegenerative disease. A research report by Uryu et al. (2003) has linked TBI to age-dependent synuclein (Syn) pathology in mice. Of interest is the fact that both genetically induced and sporadic PD have been linked to Syn deposition and pathology. Therefore any mechanism leading to modifications in the expression of Syn and/or its pathological deposition could be relevant to the understanding of the pathogenesis of PD. In Uryu’s paper, at 1 week post-TBI, the aged mouse brain showed a transient increase of a- and b-Syn immunoreactivity (IR) in the neuropil as well as an induction of g-Syn IR in subcortical axons. This was associated with strong labeling of striatal axon bundles by antibodies to altered or nitrated epitopes in a-Syn as well as by antibodies to inducible nitric oxide synthase. The latter findings are highly suggestive, as it is well known that nitration of a-Syn is a common feature of pathological forms of this protein in the Lewy bodies of diverse synucleinopathies (Uryu et al., 2003).
57.3. Posttraumatic parkinsonism In addition to considering trauma to the head as an epidemiological risk factor in the etiology of PD, both central lesions directly affecting the nigrostriatal tract and those indirectly caused by severe cranial trauma and peripheral trauma have been linked to the development of parkinsonism. 57.3.1. Central lesions and parkinsonism Single trauma to the head, as well as repetitive TBI such as that seen in boxers, can be the cause of secondary forms of parkinsonism. 57.3.1.1. Parkinsonism caused by a single trauma to the head Parkinsonism is an infrequent complication of a single trauma to the head, although rare instances of this syndrome caused by penetrating injuries to the brainstem by either a bullet or a knife have been reported (Koller
492
O. S. GERSHANIK
et al., 1989). The majority of authors conclude that the development of a parkinsonian syndrome after trauma to the head is more often seen in cases in which the injury is severe enough to result in a comatose or vegetative state; in these cases, the resulting parkinsonian syndrome is usually associated with mental status changes, cranial nerve dysfunction, pyramidal tract dysfunction and cerebellar disorders (Factor et al., 1988; Jellinger, 2003). In Grimberg’s seminal review of 86 cases of posttraumatic parkinsonism reported between 1873 and 1922, he concluded that only 2 of the cases could be accepted as posttraumatic in nature as the trauma was severe enough to produce permanent damage to specific areas of the brain; the trauma directly involved the head; and there was an unequivocal temporal relationship between the head injury and the development of parkinsonism (Grimberg, 1934; Jankovic, 1994). Nevertheless, even in survivors of severe head injury, the occurrence of parkinsonism is rare, as was the case in the large series reported by Krauss and Jankovic (2002). In a follow-up of 221 out of 264 survivors of severe head injury who had been admitted to hospital with a Glasgow Coma Score of 8 or less, only 2 cases of parkinsonism were observed (0.9%). Similarly, in Jellinger’s (1989) personal series of 520 autopsy cases of parkinsonism there were only 3 cases (0.6%) in which parkinsonism had developed after severe head injury with or without persistent vegetative state (PVS) and was associated with multiple brainstem damage resulting from transtentorial herniation; all of those brains had bilateral vascular necrotic lesions or anoxic scars in substantia nigra and other parts of the brainstem or basal ganglia. More recently, the same author (Jellinger, 2003) in a letter to the editor of the Journal of Neurology, Neurosurgery and Psychiatry, commented on his observations made in a series of 125 patients with PVS following head injury and survival times ranging from 1 to 10 years. There were 49 survivors and, in 19 of them, a mainly symmetrical, moderate to severe, parkinsonian syndrome was present. Treatment with levodopa induced partial or full improvement of symptomatology in 15, whereas 4 patients showed complete recovery from both PVS and parkinsonism. An additional 15 patients, upon recovery from the initial PVS, developed a progressive parkinsonian syndrome in which rigidity and bradykinesia were present in all cases, whereas in only 6 of them was it associated with unilateral or bilateral resting tremor. Thirty-four of the cases underwent magnetic resonance imaging (MRI) examination; in 32 of them, unilateral or bilateral lesions in the midbrain were present. Of the original series, 32 cases survived for at least 2 months without significant improvement of PVS until death;
neuropathological examination performed in 16 cases presenting with mild to severe parkinsonian features revealed multiple lesions in the rostral brainstem with unilateral or bilateral focal lesions in the substantia nigra. Of importance is the fact that it was not possible to establish a clear correlation between the severity of the pathology and the severity of the parkinsonian symptomatology. Moreover, there have been reports of significant pathological involvement of the substantia nigra following head injury without the development of a parkinsonian syndrome (Zijlmans et al., 2002; Jellinger, 2003). In the case reported by Zijlmans et al. (2002), confirmation of nigrostriatal damage was obtained through both MRI and dopamine transporter binding at the striatal level. Imaging studies showed in the T2-weighted sequence the presence of a hypointense lesion involving the right anteromedial substantia nigra and the right subthalamic nucleus indicative of a previous hemorrhage. N-omega-flouropropyl-2beta-carboxymethoxy-3beta{4-iodophenyl} tropane single-photon emission computed tomography ([123I]FP-CIT SPECT) binding was completely abolished in the right striatum and caudate nucleus, demonstrating an almost total loss of presynaptic dopamine terminals. The absence of parkinsonian symptomatology could be explained, according to the authors, by the concomitant involvement of the ipsilateral subthalamic nucleus (Zijlmans et al., 2002). Since Grimberg’s review and in addition to Krauss and Jellinger’s reports, there have been numerous publications documenting isolated cases or small series of patients presenting with parkinsonian features after sustaining head injuries causing varying degrees of brain dysfunction. Aside from a few cases due to direct trauma to the midbrain (knife or bullet injury) or a blunt head injury causing lesions at the basal ganglia level (Nayernouri, 1985; Giroud et al., 1988; Koller et al., 1989; Rondot et al., 1994; Doder et al., 1999; Bhatt et al., 2000; Matsuda et al., 2003; Kivi et al., 2005) (Table 57.2), the majority of the remaining cases are related to chronic subdural hematomas (CSH), indirectly causing involvement of subcortical structures. In a review of the literature, Wiest et al. (1999) were able to identify 16 published cases of parkinsonism secondary to CSH, in addition to their own case; 7 additional patients were indirectly cited by the author as reported in two of his referenced papers. The association between CHS and movement disorders is not frequent and has been estimated to occur in about 2% of patients. The majority of the patients reported were male, with an age range of 38–83 years, and presented within days to weeks after a trivial head injury with variable clinical symptomatology (focal deficit, general deterioration with headache, nausea, loss of sphincter control) associated to a parkinsonian
TRAUMA AND PARKINSON’S DISEASE
493
Table 57.2 Posttraumatic parkinsonism Author
Year
No. of cases
Mechanism of head injury
Associated features
Bruetsch et al.
1935
1
None mentioned
Morsier GDz
1960
1
Nayernouri
1985
1
Giroud et al.
1988
1
Rondot et al.
1994
1
Doder et al.
1999
1
Bhatt et al.
2000
3
Matsuda et al.
2003
3
A 60-year-old man fell on a concrete surface, striking the occiput. Parkinsonian features developed 8 months later. On autopsy, there were fracture of the occipital and petrous bones; depigmentation of the nigra, petechial hemorrhages in the striatum (cited by Koller et al., 1989) Bullet injury to the substantia nigra (cited by Koller et al., 1989) A 37-year-old man received a blunt head injury causing coma. After 10 days the patient regained consciousness and developed an akinetic-rigid syndrome. A CT scan revealed bilateral low-density lesions of the substantia nigra A 61-year-old man sustained a facial concussion and became comatose. After recovery he developed bilateral tremor at rest, rigidity and bradykinesia. A CT scan performed 6 hours after the trauma revealed bilateral striatal hematomas A 38-year-old man attempted suicide with a firearm. The bullet lodged in the left midbrain. He recovered from coma over 15 days, developing resting and postural tremor associated with akinesia. A fluorodopa PET scan showed reduced uptake in the left striatum A 36-year-old man sustained a skull fracture in a road accident; he remained unconscious for 24 hours. Six weeks later he developed a coarse resting tremor and bradykinesia on the right side. MRI showed a lesion involving the left caudate and lenticular nucleus Three males aged 35, 39 and 46, all involved in traffic accidents. Loss of consciousness with recovery after a variable period (hours–30 days). Between 20 days and 5 months they developed an asymmetric akinetic-rigid syndrome with rest tremor. There was clinical improvement with levodopa. In all there was variable, asymmetrical, hemorrhagic involvement of the substantia nigra and/or putamen (MRI) Three males aged 14, 27 and 51, all involved in traffic accidents. All comatose on admission. Patients remained in a persistent vegetative state for 3–12 months. In all 3 cases there were asymmetrical rigidity, akinesia or tremor, with asymmetrical brainstem injury on MRI examination. Levodopa improved both the motor and cognitive status of the patients
None mentioned Coma
Coma
Coma and right hemiplegia, residual hemiparesis with spasticity, brisk tendon reflexes, Babinski sign, hemidystonia Abulia, forgetfulness
Coma Right hemiparesis in one; disorientation, rightsided weakness and slurred incoherent speech in another
Coma Spasticity and cognitive deterioration in one, left hemiparesis and oculomotor palsy in another, non-parkinsonian motor involvement and cognitive deterioration in another (Continued)
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O. S. GERSHANIK
Table 57.2 (Continued) Author
Year
No. of cases
Mechanism of head injury
Associated features
Kivi et al.
2005
1
In a pedestrian accident a 59-year-old woman sustained a severe head injury with a predominantly left brachiofacial hemiparesis. Several weeks after the trauma, clinical signs of a left-side hemiparkinsonism developed (resting tremor, hypophonia, hypomimia). Axial MRI (FLAIR) of the midbrain of the patient showed a hypointense lesion of the anterior part of the red nucleus and posterior part of the substantia nigra, indicating a hemosiderin deposit due to a previous hematoma
Hemiparesis, hyperreflexia and Babinski’s sign
CT, computed tomography; PET, positron emission tomography; MRI, magnetic resonance imaging; FLAIR, fluid-attenuated inversion recovery.
syndrome (in two-thirds of cases a complete parkinsonian syndrome was present). In a few cases, aside from mild headache, the only symptomatology present was pure parkinsonism. Surgical evacuation of the hematomas resulted in complete remission of the symptomatology in the majority of cases. In a few cases there was residual symptomatology (both parkinsonian and non-parkinsonian) after surgery. Incomplete remission was more frequently observed in bilateral hematomas. Several mechanisms have been proposed to explain the development of secondary parkinsonism to CSH: among them, direct mechanical compression of the basal ganglia, interference with its vascular supply or metabolic changes. Hemispheric displacement due to the hematoma may lead to distortion and compression of the midbrain, causing potentially reversible disturbances at different levels of the nigrostriatal pathway. However, most patients with a subdural hematoma of similar location do not develop parkinsonism, suggesting, in the view of some authors, that those patients who in fact develop a parkinsonian syndrome are especially vulnerable to injury to the dopaminergic system or are already in the preclinical stages of PD (Trosch and Ransom, 1990; Hageman and Horstink, 1994; Wiest et al., 1999). In the majority of cases of posttraumatic parkinsonism reported in the literature, the parkinsonian symptomatology did not develop immediately after the trauma. A delay of several days, weeks or even months is usually the case, sometimes making it difficult to establish a clear-cut cause-and-effect relationship between the traumatic event and the development of
parkinsonism, except in those cases in whom damage to the nigrostriatal tract can be demonstrated, either through imaging techniques or at autopsy. The reasons for this delay can be diverse; the initial brain injury caused by the trauma can set in motion a cascade of biochemical and metabolic changes that may lead to further neuronal damage; or in turn, the delay may be necessary for the development of sprouting, remyelinization, ephaptic transmission or central synaptic reorganization (Jankovic, 1994). 57.3.1.2. Parkinsonism caused by repetitive trauma to the head (boxer’s encephalopathy) A peculiar syndrome secondary to chronic TBI associated with boxing occurs in approximately 18–20% of professional boxers (Friedman, 1989). It was Martland who in 1928 first described this syndrome in the medical literature, followed by numerous reports that helped delineate the syndrome, including the presence of parkinsonian symptomatology ((Critchley, 1957; Roberts, 1969), cited by Factor et al., 1988; Stern, 1991). It is usually referred to in the literature as boxer’s encephalopathy, ‘punch-drunk’ syndrome or ‘dementia pugilistica’, and includes parkinsonian features and varying degrees of cognitive and behavioral impairments in its clinical presentation (Jordan, 2000). It has been reported to be more common in second-rate and slugging-type fighters (Guterman and Smith, 1987). Incidence and severity correlate with the length of the boxing career, number of bouts and increased sparring (Guterman and Smith, 1987; Jordan, 2000; Krauss and Jankovic, 2002). The parkinsonian features of this syndrome include gait
TRAUMA AND PARKINSON’S DISEASE disequilibrium, cogwheel rigidity, bradykinesia, hypophonia and even a resting tremor; other neurologic manifestations frequently present are: dementia, cerebellar dysfunction, marked dysarthria and pyramidal tract signs (Stern, 1991; Krauss and Jankovic, 2002). Neurological symptoms usually become manifest long after the end of the boxing career, on average 16 years after the last fight (Jankovic, 1994). The encephalopathy may run a progressive course or remain stable at any level. Three stages of clinical deterioration have been described, consisting initially of affective disturbances and additional psychiatric symptoms; later on there is worsening of the psychiatric manifestations and parkinsonism gradually develops. Finally in the last stage there is significant decrease of cognitive function together with signs of more extensive neurological involvement (cerebellar and pyramidal) (Guterman and Smith, 1987). The neuropathology of boxer’s encephalopathy was classically described by Corsellis et al. (1973) in a postmortem study of 15 boxers. In addition to petechial hemorrhages in the cortex and brainstem and gliosis of the cerebellum, he found marked loss of pigmented neurons in the substantia nigra, especially in the lateral and intermediate cell groups, without Lewy bodies. Numerous neurofibrillary tangles without senile plaques were present in the cerebral cortex. Corsellis’ cases were more recently re-examined using immunocytochemical methods and an antibody raised to the beta-protein present in Alzheimer’s disease plaques. In all cases with substantial tangle formation there was evidence of extensive beta-protein immunoreactive deposits (plaques). These diffuse ‘plaques’ were not visible with Congo red or standard silver stains, which may explain Corsellis’ failure to detect the presence of senile plaques. The degree of beta-protein (amyloid component) deposition was comparable to that seen in Alzheimer’s disease (Roberts et al., 1990). These data suggest that Alzheimer’s disease and boxer’s encephalopathy may share common pathogenetic mechanisms and perhaps its development is linked to the presence of a genetic predisposition (Stern, 1991; Jankovic, 1994; Jordan, 2000; Krauss and Jankovic, 2002). Recent studies in professional boxers, establishing a correlation between the presence of the e4 allele and significantly greater scores on a scale measuring chronic encephalopathy, lend support to this hypothesis (Jordan et al., 1997). The observed neuropathology of this syndrome is presumed to be the result of the cumulative effects of repeated subclinical concussions secondary to rotational and shearing acceleration forces induced by direct blows to the head (Krauss and Jankovic, 2002). The rapid rotation of the cranium in relation to a relatively stationary brain
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may cause stretching and rupturing of vessels, focal ischemia, petechial hemorrhages, axonal injury and edema. It is possible that the long axons of the nigrostriatal tract are particularly vulnerable to the effects of mechanical shearing produced by trauma to the head (Jankovic, 1994). Several in vivo studies have explored the functional consequences of these lesions; proton magnetic resonance spectroscopy studies have demonstrated a significant reduction in the concentration of N-acetylaspartate in the striatum of patients with boxer’s encephalopathy, suggesting the existence of terminal field involvement and striatal neuronal loss in addition to nigral damage (Davie et al., 1995). PET may help in differentiating these cases from idiopathic parkinsonism, as in patients with boxer’s encephalopathy mean caudate and putamen [18F]dopa uptake is similarly reduced by approximately 40% when compared to controls and mean caudate uptake is much lower than that observed in idiopathic parkinsonism, suggesting that in boxer’s encephalopathy there is a uniform loss of nigrostriatal terminal function (Turjanski et al., 1997). 57.3.2. Peripheral lesions and parkinsonism The role of peripheral trauma in the development of secondary parkinsonism is still an unresolved issue and evidence supporting this relationship is scarce and inconclusive (Factor et al., 1988; Koller et al., 1989). In Factor et al.’s (1988) review of the historical concept of trauma as etiology of parkinsonism, most of the cases of peripherally induced parkinsonism reported in the late 19th and early 20th centuries could be dismissed as not related for lack of conclusive evidence and probably stimulated by the passing of workmen’s compensation laws. Even Charcot’s ‘ascending neuritis’ hypothesis of the mechanism by which peripheral trauma could lead to the development of parkinsonism, although convenient, does not resist a thorough analysis (Factor et al., 1988). Nevertheless, more recently, Schott (1986), Jankovic (1994) and Cardoso and Jankovic (1995) contributed to the re-emergence of the hypothesis that peripheral trauma could somehow contribute to the etiology of parkinsonism. In Schott’s review (1986) of 10 patients in whom various involuntary movement disorders developed after trauma that was predominantly or entirely peripheral, 3 of the cases corresponded to parkinsonism. The interval between injury and onset of parkinsonian symptomatology ranged from 48 hours to 4 weeks; the injured and painful part was the area initially affected by involuntary movements, although more
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widespread involvement subsequently occurred. These clinical features, which resembled the phenomena experienced by some patients with causalgia, led the author to believe in the possibility of common mechanisms. Cardoso and Jankovic (1995), in reviewing the records of patients evaluated in the Movement Disorders Clinic at Baylor College of Medicine, Houston, TX, USA between 1977 and 1993, found 28 patients in whom the onset of tremor, parkinsonism or both was antatomically and temporally related to local injury. Eleven of these patients had parkinsonian features in addition to tremor (both postural and resting); in a few cases, dystonia, myoclonus and a complex regional pain syndrome were also present. In all cases the development of parkinsonian symptoms was temporally related to the occurrence of trauma (latency to onset 46.6 56.0 days) and the anatomical region where the symptoms began was that involved in the peripheral injury; nevertheless the movement disorder displayed a tendency to spread beyond the original site of injury. In 3 of the patients [18F]dopa PET uptake in the striatum was decreased, similar to what is found in classical idiopathic parkinsonism; however, only 6 of the patients responded to levodopa therapy; a family history of essential tremor was present in 2. It could be argued that the occurrence of parkinsonism after peripheral trauma was purely coincidental or that in fact peripheral trauma could unmask subclinical parkinsonism or worsen pre-existing subtle parkinsonian symptoms that had been previously undetected. The possibility that peripheral injury could somehow induce plastic changes and central motor reorganization through modifications in spinal excitability, retrograde axonal transport of neurotrophic factors or upregulation of immediate early-response genes was discussed by Cardoso and Jankovic (1995). Using the criteria of Jankovic (1994) and Cardoso and Jankovic (1995) for the diagnosis of parkinsonism induced by a peripheral injury, Morris et al. (1998) reported on a case of parkinsonism following electrical injury to the hand and reviewed 9 additional cases reported in the literature. Their case was a 39-yearold man who sustained an electrical injury to his right hand; 3–4 weeks later he developed progressive bradykinesia and rigidity initially confined to the right upper extremity. Upon examination 3 years later the parkinsonian symptomatology had spread, involving the ipsilateral lower extremity and the contralateral arm. Levodopa significantly improved the symptomatology; however, the patient could not obtain sustained benefit because of gastric intolerance. An MRI failed to demonstrate the presence of a central lesion and an
[18F]dopa PET scan showed asymmetrically reduced putamenal uptake. Speculations on the mechanism of action of electrical injury as a triggering factor for the development of parkinsonism are similar to those originally postulated by Jankovic (1994) and Cardoso and Jankovic (1995). Quinn and Maraganore (2000), in a letter to the editor discussing Morris et al.’s (1998) report, strongly question the validity of their assertions on the basis of epidemiological data and biological plausibility.
57.4. Worsening of parkinsonism by trauma Anecdotal reports referred in the literature and in the author’s own experience support the notion that trauma, as well as other medical conditions (such as infections and surgery) may occasionally worsen parkinsonian symptomatology in patients with an established diagnosis of PD (Goetz and Stebbins, 1991; Wiest et al., 1999; Chou and Gutmann, 2001). Goetz and Stebbins (1991) followed 10 parkinsonian patients who sustained trauma to the head in motor vehicle accidents; in all cases disability significantly increased immediately after trauma, to return to baseline levels in the ensuing weeks. This transient deterioration did not cause persistent increased disability or an alteration in the natural course of the disease. In Wiest et al.’s (1999) and Chou and Gutmann’s (2001) cases with a long-standing history of levodopa-responsive PD, the presence of rapid deterioration of pre-existing symptomatology in the context of frequent falls and occasional head trauma suggested the possibility of subdural hematoma. Imaging studies confirmed the presence of subdural hematoma in both cases. After surgical evacuation of the hematomas the patients returned to their baseline levels in a few days. There is, however, no clear explanation to account for this phenomenon; on the other hand, there is experimental evidence that in behaviorally normal rats with partial lesions of the nigrostriatal rats, a stressful stimulus (glucose deprivation, electrical tail shock or exposure to severe cold) may unmask a previously undetected motor deficit (akinesia) (Snyder et al., 1985). It may be argued that in these animals the stressful stimuli triggered a series of biochemical events that altered a precarious compensatory state. Similarly, the degree of clinical disability in PD patients may be the result of a balance between the degree of nigrostriatal damage, compensatory endogenous mechanisms and medication. Any stressful stimuli, be it trauma, infection or surgery, may break this delicate balance and cause transient increased disability.
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57.5. Conclusions After careful evaluation of all the evidence reviewed thus far we may conclude: 1. Although several case-control and two cohort studies failed to establish that trauma to the head can influence the subsequent development of PD, others have, in fact, found that severe head trauma increases the risk of PD. It is perhaps valid to assume that history of preceding head trauma, together with family history and other environmental factors, plays at least a partial role in the etiology of PD. 2. Albeit infrequent, posttraumatic parkinsonism resulting from direct injury to the basal ganglia and substantia nigra or indirect involvement of these structures secondary to a severe cranial trauma does indeed exist. 3. Repetitive cranial trauma such as that experienced by boxers may result in the development of a form of parkinsonism associated with other motor, behavioral and cognitive disorders encompassed in boxer’s encephalopathy. 4. The possible occurrence of parkinsonism induced by peripheral trauma is still controversial and there is not enough supportive evidence to accept its existence. 5. Trauma, as well as infectious disorders, surgical interventions and stress, may aggravate preexisting PD.
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Jordan BD, Relkin NR, Ravdin LD et al. (1997). Apolipoprotein E epsilon4 associated with chronic traumatic brain injury in boxing. JAMA 278 (2): 136–140. Kivi A, Trottenberg T, Kupsch A et al. (2005). Levodoparesponsive posttraumatic parkinsonism is not associated with changes of echogenicity of the substantia nigra. Mov Disord 20 (2): 258–260. Koller WC, Wong GF, Lang A (1989). Posttraumatic movement disorders: A review. Mov Disord 4 (1): 20–36. Krauss JK, Jankovic J (2002). Head injury and posttraumatic movement disorders. Neurosurgery 50 (5): 927–939. Kuopio AM, Marttila RJ, Helenius H et al. (1999). Environmental risk factors in Parkinson’s disease. Mov Disord 14 (6): 928–939. Lai BC, Marion SA, Teschke K et al. (2002). Occupational and environmental risk factors for Parkinson’s disease. Parkinsonism Relat Disord 8 (5): 297–309. Lees AJ (1997). Trauma and Parkinson disease. Rev Neurol 153 (10): 541–546. Liu B, Gao HM, Hong JS (2003). Parkinson’s disease and exposure to infectious agents and pesticides and the occurrence of brain injuries: Role of neuroinflammation. Environ Health Perspect 111 (8): 1065–1073. Martland HS (1928). Punch drunk. JAMA 91:1103–1107. Matsuda W, Matsumura A, Komatsu Y et al. (2003). Awakenings from persistent vegetative state: Report of three cases with parkinsonism and brain stem lesions on MRI. J Neurol Neurosurg Psychiatry 74 (11): 1571–1573. McCann SJ, LeCouteur DG, Green AC et al. (1998). The epidemiology of Parkinson’s disease in an Australian population. Neuroepidemiology 17 (6): 310–317. McIntosh TK, Saatman KE, Raghupathi R et al. (1998). The Dorothy Russell Memorial Lecture. The molecular and cellular sequelae of experimental traumatic brain injury: Pathogenetic mechanisms. Neuropathol Appl Neurobiol 24: 251–267. Morano A, Jimenez-Jimenez FJ, Molina JA et al. (1994). Riskfactors for Parkinson’s disease: Case-control study in the province of Caceres, Spain. Acta Neurol Scand 89 (3): 164–170. Morris HR, Moriabadi NF, Lees AJ et al. (1998). Parkinsonism following electrical injury to the hand. Mov Disord 13 (3): 600–602. Morrish PK, Rakshi JS, Bailey DL et al. (1998). 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. Nayernouri T (1985). Posttraumatic parkinsonism. Surg Neurol 24 (3): 263–264. Nuti A, Ceravolo R, Dell’Agnello G et al. (2004). Environmental factors and Parkinson’s disease: A case-control study in the Tuscany region of Italy. Parkinsonism Relat Disord 10: 481–485. OMIM “Online Mendelian Inheritance in Man” Database, 2005. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db¼ OMIM Parkinson J (1817). An Essay on the Shaking Palsy. Whittingham and Rowland, for Sherwood Neely and Jones, London.
Patrick HU, Levy PM (1922). Parkinson’s disease. A clinical study of one hundred and forty-six cases. Arch Neurol Psychiat 7:711–720. Preux PM, Condet A, Anglade C et al. (2000). Parkinson’s disease and environmental factors. Matched case-control study in the Limousin region, France. Neuroepidemiology 19 (6): 333–7. Quinn N, Maraganore D (2000). Parkinsonism following electrical injury to the hand. Mov Disord 15 (3): 587–588. Roberts GW, Allsop D, Bruton C (1990). The occult aftermath of boxing. J Neurol Neurosurg Psychiatry 53 (5): 373–378. Rondot P, Bathien N, de Recondo J et al. (1994). Dystoniaparkinsonism syndrome resulting from a bullet injury in the midbrain. J Neurol Neurosurg Psychiatry 57 (5): 658. Schwab RS, England AC (1968). Parkinsonism due to various specific causes. In: Vinken PJ, Bruyn GW, (Eds.), Handbook of Clinical Neurology, 1st. edn, Vol. 6. North Holland Publishing Co, Amsterdam, pp. 230–233. Schott GD (1986). Induction of involuntary movements by peripheral trauma: An analogy with causalgia. Lancet 2 (8509): 712–716. Seidler A, Hellenbrand W, Robra BP et al. (1996). Possible environmental, occupational, and other etiologic factors for Parkinson’s disease: A case-control study in Germany. Neurology 46 (5): 1275–1284. Semchuk KM, Love EJ, Lee RG (1993). Parkinson’s disease: A test of the multifactorial etiologic hypothesis. Neurology 43 (6): 1173–1180. Smargiassi A, Mutti A, De Rosa A et al. (1998). A case-control study of occupational and environmental risk factors for Parkinson’s disease in the Emilia-Romagna region of Italy. Neurotoxicology 19 (4–5): 709–712. Snyder AM, Stricker EM, Zigmond MJ (1985). Stressinduced neurological impairments in an animal model of parkinsonism. Ann Neurol 18: 544–551. Stern M, Dulaney E, Gruber SB et al. (1991). The epidemiology of Parkinson’s disease. A case-control study of young-onset and old-onset patients. Arch Neurol 48 (9): 903–907. Stern MB (1991). Head trauma as a risk factor for Parkinson’s disease. Mov Disord 6 (2): 95–97. Tanner CM, Chen B, Wang WZ et al. (1987). Environmental factors in the etiology of Parkinson’s disease. Can J Neurol Sci 14 (3 Suppl): 419–423. Taylor CA, Saint-Hilaire MH, Cupples LA et al. (1999). Environmental, medical, and family history risk factors for Parkinson’s disease: A New England-based case control study. Am J Med Genet 88 (6): 742–749. Trosch RM, Ransom BR (1990). Levodopa-responsive parkinsonism following central herniation due to bilateral subdural hematomas. Neurology 40 (2): 376–377. Tsai CH, Lo SK, See LC et al. (2002). Environmental risk factors of young onset Parkinson’s disease: A case-control study. Clin Neurol Neurosurg 104 (4): 328–333. Turjanski N, Lees AJ, Brooks DJ (1997). Dopaminergic function in patients with posttraumatic parkinsonism: An 18F-dopa PET study. Neurology 49 (1): 183–189.
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Handbook of Clinical Neurology, Vol. 84 (3rd series) Parkinson’s disease and related disorders, Part II W. C. Koller, E. Melamed, Editors # 2007 Elsevier B. V. All rights reserved
Chapter 58
Psychogenic parkinsonism VASILIKI KOUKOUNI AND KAILASH P. BHATIA* Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, London, UK
58.1. Definition The term ‘psychogenic’ is derived from a Greek word meaning ‘created by the soul’ and is applied to diseases that cannot be attributed to a certain lesion or dysfunction of a system. Parkinsonism is defined by a constellation of features, the hallmark being bradykinesia associated with tremor, rigidity and impairment of postural reflexes. The most common cause is Parkinson’s disease (PD). There are other forms of parkinsonism, including the so-called atypical parkinsonian conditions, like multiple systems atrophy (MSA) or progressive supranuclear palsy (PSP), and also acquired or secondary forms of parkinsonism. Some of them can be accompanied by cognitive decline and psychiatric manifestations. Although psychogenic forms of a variety of different movement disorders, such as psychogenic dystonia or psychogenic tremor, have been well described in the literature over the years, little is mentioned about psychogenic parkinsonism.
58.2. Epidemiology Psychogenic parkinsonism is perhaps the rarest of the different forms of the psychogenic movement disorders (PMD). In retrospective studies conducted in large movement disorder clinics it accounted for only 1.9–7% of all PMDs (Fahn and Williams, 1988; Factor et al., 1995; Miyasaki et al., 2003) and 0.5% or less of all patients presenting with parkinsonism (Factor et al., 1995; Lang et al., 1995). In 1995, Factor et al. described 28 patients with PMDs, 2 of whom were diagnosed as having psychogenic parkinsonism (7%). At the Movement Disorders Clinic of
the Toronto Western Hospital, over a period of 20 months, 64 patients were diagnosed with PMD and psychogenic parkinsonism accounted for 6.1% of these (Miyasaki et al., 2003). In another series from Columbia-Presbyterian Medical Center, New York, USA, including 131 patients, the respective figure was 1.9% (Fahn and Williams, 1988).
58.3. Natural history In 1988, Walters et al. described the case of a 64year-old man who presented with atypical symptoms of parkinsonism that resolved spontaneously 1 year after the discontinuation of levodopa. Since then, two large studies have been performed regarding psychogenic parkinsonism. Of the 14 cases of psychogenic parkinsonism described by Lang et al. (1995) in three academic movement disorders centers, the average age of the patients was 47 years (range 21– 63 years). Both sexes were equally involved, in contrast to the other PMD, where there is usually a female predisposition (Fahn and Williams, 1988; Koller et al., 1989; Monday and Jankovic, 1993; Kim et al., 1999). The mean duration of the symptoms prior to the diagnosis was 5 years, ranging from 4 months to 13 years. In one recent study, reported only in abstract form, from three large movement disorder centers in Augusta, GA, USA and London, UK, a retrospective chart review of 9 patients diagnosed with psychogenic parkinsonism was reported (Morgan et al., 2004). The mean age of onset of the symptoms was 50 years, with a range of 34–72 years, and the disease duration varied from several months to 28 years. Interestingly, there was a 2:1 male-to-female ratio.
*Correspondence to: Prof. Kailash Bhatia, Institute of Neurology, Sobell Department of Motor Neuroscience and Movement Disorders, 7 Queen Square, London WC1N 3BG, UK. E-mail:
[email protected], Tel: þ44-20-7837-3611, Ext: 4253, Fax: þ44-20-7676-2175.
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58.4. Clinical manifestations The onset of the disease is abrupt in the vast majority of patients, which is unlike typical PD. According to the studies performed by Lang et al. (1995) and Morgan et al. (2004), there was an abrupt onset in about two-thirds of patients (71.2% and 78% respectively). Precipitating factors such as work-related injuries and motor vehicle accidents with minor injuries that possibly may not have involved the head are a common feature (Lang et al., 1995). A total of 43% of the patients studied by Lang and 77% of those studied by Morgan presented with unilateral symptoms, typically involving the dominant-hand side. The most prominent feature is tremor, which bore all the characteristics of psychogenic tremor. Classical PD tremor is asymmetric, pill-rolling, resting tremor at a rate of 3–4 Hz, involving the thumb and index finger. A faster tremor of 6–7 Hz can appear on keeping the arms outstretched. On the other hand, psychogenic tremor can be present at rest and persist even during position and intentional movements, at the same frequency (Koller et al., 1989). Although wrists, elbows and shoulders are commonly affected, fingers are rarely involved, unlike typical PD (Deuschl et al., 1998). Another important characteristic is variability. The tremor may increase when the attention is drawn to the affected limb or when the patient is asked about it and can improve dramatically or even disappear when the patient’s attention is withdrawn from the area involved (Campbell, 1979) or if the patient is distracted by mental activity (e.g. mental arithmetic) or complex motor tasks (e.g. finger-to-nose and tandem walking) (Elble and Koller, 1990). Parkinsonian rest tremor, e.g. in PD, quite often appears when the patient is walking or being distracted. Entrainment, meaning change of the original tremor frequency to match the frequency of a repetitive task performed in another limb (e.g. tapping) or side-to-side tongue movements (Kim et al., 1999), is also common. Koller and Biary (1989) suggested that PD patients are capable of voluntarily suppressing their tremor for an average of 48 seconds, if they are allowed to concentrate on it, in contrast to the psychogenic patients where the opposite tends to happen. The psychogenic tremor can also vary in terms of direction (e.g. from supination–pronation orientation to flexion–extension) (Koller et al., 1989) and amplitude (e.g. when a limb is weighed) (Deuschl et al., 1998). As pointed out by Lang et al. (1995), limb rigidity is uncommon and, when it is present, the examiner has a sense of voluntary resistance. This also subsides when the patient is distracted. Deuschl et al. (1998)
suggested that there is a co-activation of agonist and antagonist muscles in psychogenic tremor that is supported by electromyographic (EMG) analysis and clinical evaluation, which can produce a cogwheel-like resistance to passive movement, which subsides when the patient is relaxed. True bradykinesia with typical arrests in movement is never observed, although all the patients in Lang’s series (Lang et al., 1995) demonstrated slowness of voluntary movements and in some of them this was their initial and main complaint. Slowness is present throughout the performance of rapid repetitive and alternating movements, but without the fatiguing and decreasing amplitude that is seen in true parkinsonian patients. The patients often seem to struggle and put more effort than needed into performing the tasks. They are grimacing, sighing and look exhausted and may use their whole body in order to do a minor movement. Despite the severe slowness, some patients may demonstrate exquisite ability in doing specific tasks, like writing with normal speed (Lang et al., 1995). Some of the patients seen by Lang et al. (1995) demonstrated facial masking, but in the majority of them it was attributed to an underlying depression. Walking can be slow and stiff, with reduced or even absent arm-swing on the affected side. The arm may be held tightly extended and adducted to the side and this can persist while running. The patients usually respond in a theatrical way on postural stability testing, flinging up both their arms (even the affected one) equally and symmetrically and retropulsing but never falling (Lang et al., 1995). An exaggerated startle, when the backwards pull test is performed to test postural stability, is often seen. Another important feature noted by both studies done by Lang et al. (1995) and Morgan et al. (2004) is that disability is usually maximal from the early stages of the disease and affects all aspects of everyday life. Most patients give up work and are sometimes unable to perform their normal daily activities. Most patients also complain of multiple other somatic symptoms, like generalized fatigue, non-specific pains, memory disturbance and impaired vision, and have signs like give-away weakness of a limb or non-anatomic sensory loss (Lang et al., 1995). Fahn and Williams (1988) published a classification of psychogenic dystonia, which can be applied to all PMDs. According to this, a movement disorder can be classified as: (1) documented, meaning symptoms are relieved by psychotherapy, suggestion or placebo or the patient is witnessed as being free of symptoms when left alone; (2) clinically established, meaning the movement disorder is inconsistent over time or is
PSYCHOGENIC PARKINSONISM incongruent with the classic condition and any of the following are present: other definitely psychogenic neurologic signs, multiple somatizations or an obvious psychiatric disturbance; (3) probably psychogenic, meaning that movements are inconsistent or incongruent with the classic movement disorder but no other features provide support for a diagnosis of psychogenicity or that the movement disorder is consistent and congruent with the classic disorder but other features of psychogenicity are present; and (4) possibly psychogenic, meaning it is suspected that the movements are psychogenic if an obvious emotional disturbance is present. Most psychogenic PD patients would fall into the ‘documented’ or ‘clinically established’ categories.
58.5. Diagnosis The first clues of psychogenicity in a patient presenting with parkinsonism can be obtained by history (Table 58.1). This may include a history of a psychiatric disease or a long medical history involving multiple operations, admissions to hospitals and a long catalog of diagnostic tests previously done. Events prior to the onset of the disease, such as accidents, stressful situations or work-related injuries with litigation or compensation pending, can be indicative of a possible non-organic cause of the symptoms. An impressive fact is that PMDs are more frequent in Table 58.1 Clues suggesting psychogenic parkinsonism (Lang et al., 1995) Onset
Often abrupt
Course Distribution Tremor
Static, maximum disability early Dominant side most affected Rest, postural, action: reduces with distraction/ concentration, increases with attention ‘Voluntary resistance’, cogwheeling absent, may decrease with distraction No true fatiguing, marked slowness, bizarre features Atypical, arm held stiffly at side, antalgic if pain is associated Extreme or bizarre responses to minimal displacement False weakness, non-anatomic sensory loss Varied, usually evident but accurate definition not always possible Litigation, compensation (receiving or pending)
Rigidity Bradykinesia Gait Postural stability Other neurologic features Psychiatric features Other
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people employed in health professions (Koller et al., 1989; Fahn, 1994; Kim et al., 1999) and in those who have witnessed the disorder in other family members (Koller et al., 1989). Elements in clinical examination are also revealing as well as responses to therapeutic procedures (Table 58.2). The use of placebo as diagnostic and therapeutic procedure remains controversial, as it gives rise to ethical considerations and can affect the physician–patient relationship. It is suggested by Sa et al. (2004) that the use of placebo should be reserved for cases in which the diagnosis of psychogenicity remains uncertain after a thorough investigation and follow-up. It can also prove useful in the differential diagnosis of complex movement disorders and in cases where organic and psychogenic etiologies coexist (Monday and Jankovic, 1993; Koller Table 58.2 Clues suggesting that a movement disorder may be psychogenic (Miyasaki et al., 2003; Sa et al., 2004) Historical 1. 2. 3. 4. 5. 6. 7. 8. 9.
Abrupt onset Static course Spontaneous remissions Obvious psychiatric disturbance Multiple somatizations Employed in health profession Pending litigation or compensation Presence of secondary gain Young age
Clinical 1. Inconsistent character of movement (amplitude, frequency, distribution, selective ability) 2. Paroxysmal movement disorder 3. Movements increase with attention or decrease with distraction 4. Ability to trigger or relieve the abnormal movements with unusual or non-physiological interventions. (e.g. trigger points of the body) 5. False weakness 6. False sensory complaints 7. Self-inflected injuries 8. Deliberate slowness of movements 9. Functional disability out of proportion to exam findings 10. Movement abnormality that is bizarre, multiple or difficult to classify Therapeutic responses 1. Unresponsive to appropriate medications 2. Response to placebos 3. Remission with psychotherapy
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et al., 2002). When there is strong evidence for psychogenic parkinsonism, sodium amytal can be used alternatively, as it may ameliorate psychogenic tremor. Furthermore, spontaneous remissions and improvement of symptoms with psychiatric consultation and psychotherapy are strongly suggestive of their psychogenic origin (Fahn, 1994). Admission to hospital can prove beneficial, as it allows continuous observation of the patient, as well as psychiatric estimation and intervention. Investigations including imaging (computed tomography (CT) and magnetic resonance imaging (MRI)) may be useful in order to exclude a structural lesion. Relevant blood tests should always be performed in order to exclude possible organic conditions and also convince the patient that the physician pays the appropriate attention to the patient’s complaints (Fahn, 1994; Sa et al., 2004). As PD and other parkinsonian disorders have a presynaptic dopaminergic defect, dopamine transporter (DAT) single-photon emission computed tomography (SPECT) and fluorodopa (18F-dopa) positron emission tomography (PET) scans may be useful to differentiate psychogenic parkinsonism from organic parkinsonian conditions. It should be kept in mind that DAT SPECT and 18F-dopa PET scans can be normal in doparesponsive dystonia-parkinsonism, manganese and neuroleptic-induced parkinsonism, akinetic-rigid Huntington’s disease, X-linked parkinsonism and other conditions (Lang et al., 1995). There are also a small number of PD patients in whom scans were found to be apparently normal (Whone et al., 2003). In Lang’s series (Lang et al., 1995) 4 patients underwent 18F-dopa PET; the scan was abnormal in only 1 patient and this raised the suspicion of an underlying organic PD. In Morgan’s series (Morgan et al., 2004), DAT SPECT scans were performed in 2 patients and they both proved to be normal. In any case, an abnormal result on DAT or 18F-dopa PET would be in favor of organic parkinsonism (Tolosa et al., 2003). Electrophysiological studies, including EMG, accelerometry (Zeuner et al., 2003) and frequency analysis (Brown and Thompson, 2001), have been used in the literature for the establishment of the psychogenic origin of the tremor, but they do not have much use in the day-to-day clinical service. Psychogenic tremor has a frequency of less than 6 Hz, as hardly anyone can produce a voluntary tremor over 7 Hz (Elble and Koller, 1990). Large fluctuations in tremor amplitude (e.g. with weighing) and frequency and also improvement of tremor with distractibility are noted during the examination. It should, however, be kept in mind that patients with PD or essential tremor can demonstrate variations in tremor amplitude with stress or emotion, but these are only minimal (Koller et al.,
1989). Also drug treatment can reduce the tremor amplitude but it will not affect the frequency (Koller et al., 1989). Zeuner et al. (2003), used accelerometry to measure frequency changes during tapping in a group of psychogenic tremor patients and a group with parkinsonian and essential tremor patients. They concluded that a significant absolute change in tremor frequency and marked variability in tapping were noted in psychogenic tremor patients and suggested that the change in frequency is more characteristic than entrainment in those patients. It should be emphasized that patients with organic PMDs can demonstrate additional psychogenic symptoms, which usually affect the same part of the body as the underlying organic movement disorder (Ranawaya et al., 1990). This, along with the fact that psychogenic parkinsonism is mainly a diagnosis of exclusion, makes the diagnosis a challenging issue that should be established with extreme caution, preferably by a movement disorders specialist or an experienced neurologist, with the assistance of a psychiatrist.
58.6. Psychiatric diagnosis It would be useful to define some of the conditions seen in patients with psychogenic disorders, according to the American Psychiatric Association’s (1995) Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). In somatoform disorders, the symptoms suggest a general medical condition but they cannot be fully explained by the presence of a specific medical disorder, exposure to a substance or by any other mental disorder and cause significant distress or impairment in social, occupational or other areas of functioning. The symptoms are not intentionally produced or feigned. They include somatization and conversion disorders. Somatization disorders begin before the age of 30 and occur over a period of many years, resulting in medical treatment or significant impairment in social, occupational or other areas of functioning. Conversion disorder is characterized by symptoms or deficits affecting voluntary motor or sensory function that suggest a neurological or other medical condition and is usually preceded by conflicts or other stressors. On the other hand, factitious disorders, such as Munchausen’s syndrome, are intentionally produced and the motivation is for the patient to assume the sick role. In malingering the symptoms are again intentionally produced and motivated by external incentives (e.g. avoiding work or military duty or obtaining compensation). The establishment of the underlying psychiatric disorder in psychogenic parkinsonism and all other psychogenic disorders, although crucial for diagnosis
PSYCHOGENIC PARKINSONISM and treatment, is not always possible. In Lang’s series (Lang et al., 1995) there was evidence of somatoform disorders (35.7%), especially conversion disorders and depression (14.3%), in some patients and litigation or compensation issues in a few others (21.4%), whereas the psychiatric disorder was not clearly identified in 3 of them (21.4%). In other series, regarding other PMDs, the most common psychiatric diagnoses were depression, anxiety and conversion and somatization disorders (Koller et al., 1989; Factor et al., 1995; Kim et al., 2003).
58.7. Treatment When the diagnosis of psychogenic parkinsonism is established, it should be presented to the patient with extreme caution and a non-judgmental character, to gain trust and acceptance. It should be pointed out that the ‘parkinsonism’ is not due to a lesion or a severe dysfunction of the nervous system and that it can be fully resolved with the appropriate approach. A neuropsychiatric evaluation should be suggested, especially to those who had a long-standing disease with multiple investigations and ineffective treatments (Sa et al., 2004). It is important that the patient is approached in a way that does not make him/her feel that he/she is ‘crazy’. It was suggested by Ford et al. (1995) that a possible neurobiological explanation for the patient’s symptoms could be presented. It should perhaps be explained that the mind and the body are in strong association with each other and that dysfunction of the one can affect the other, as happens with numerous other diseases (Fahn, 1994). A psychiatrist should be involved, preferably early in the course of the investigation, providing psychotherapy and positive reinforcement. Cognitive-behavioral therapy should also be considered. As discussed earlier, the use of placebo is controversial and should only be used to establish the diagnosis (Fahn, 1994). Alternatively, mild antidepressants and anxiolytics can be used to manage the underlying depression and anxiety, along with a periodical neurological assessment (Koller et al., 2002).
58.8. Prognosis The prognosis for functional recovery is variable and relatively poor. In a follow-up study of patients with medically unexplained movement disorders, the presenting symptom remained unchanged in 14% of patients, although in 38% of them it had worsened (Crimlisk et al., 1998). A prospective study done by Feinstein et al. (2001) regarding the psychiatric outcome in patients with PMDs revealed that there was
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a persistence in abnormal movements in more than 90% of patients. In Lang’s series (Lang et al., 1995), 2 patients had spontaneous long remissions, 1 had complete but short remission and one had marked but incomplete response to psychotherapy and haloperidol. In Morgan’s series (Morgan et al., 2004), 5 patients attended follow-up; 2 of them had abrupt resolution of their symptoms, 1 was cured after intensive inpatient psychotherapy and 2 remained convinced that they had PD. Generally, in all PMDs, the prognosis depends on the underlying psychiatric disorder, the acute or insidious onset and the course of the disease, the premorbid functioning and the presence of an identifiable trigger. The prognosis is supposed to be better when the onset of the disease is acute, with a short duration of symptoms and when there is a specific emotional event that preceded the onset of the disease of a previously healthy individual (Koller et al., 2002). Conversion disorders with recent onset are considered to have better prognoses than factitious disorders and malingering, which usually respond poorly and unpredictably (Miyasaki et al., 2003).
References American Psychiatric Association (1995). Diagnostic and Statistical Manual of Mental Disorders, 4th edn. (DSMIV). International Version with ICD-10 Codes, Washington DC, pp. 457–487. Brown P, Thompson PD (2001). Electrophysiological aids to the diagnosis of psychogenic jerks, spasms, and tremor. Mov Disord 16 (4): 595–599. Campbell J (1979). The shortest paper. Neurology 29: 1633. Crimlisk HL, Bhatia KP, Cope H et al. (1998). Slater revisited: 6 year follow-up study of patients with medically unexplained motor symptoms. BMJ 316: 582–586. Deuschl G, Ko¨ster B, Lu¨cking CH et al. (1998). Diagnostic and pathophysiological aspects of psychogenic tremors. Mov Disord 13: 294–302. Elble RJ, Koller WC (1990). Unusual forms of tremor. In: RJ Elble, WC Koller (Eds.), Tremor. The Johns Hopkins University Press, Baltimore, pp. 154–157. Factor SA, Podskalny GD, Molho ES (1995). Psychogenic movement disorders: frequency, clinical profile and characteristics. J Neurol Neurosurg Psychiatry 59: 406–412. Fahn S (1994). Psychogenic movement disorders. In: CD Marsden, S Fahn (Eds.), Movement Disorders.3rd edn. Buttenw Heinem, Oxford, pp. 359–372. Fahn S, Williams PJ (1988). Psychogenic dystonia. Adv Neurol 50: 431–455. Feinstein A, Stergiopoulos V, Fine J et al. (2001). Psychiatric outcome in patients with a psychogenic movement disorder: A prospective study. Neuropsychiatry Neuropsychol Behav Neurol 14 (3): 169–176. Ford B, Williams DT, Fahn S (1995). Treatment of psychogenic movement disorders. In: R Kurlan, (Ed.). Treatment of Movement Disorders. JP Lippincott, Philadelphia, pp. 475–485.
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Kim YJ, Pakiam ASI, Lang AE (1999). Historical and clinical features of psychogenic tremor: review of 70 cases. Can J Neurol Sci 26: 190–195. Koller WC, Biary NM (1989). Volitional control of involuntary movements. Mov Disord 4 (2): 153–156. Koller WC, Lang AE, Vetre-Overfield B et al. (1989). Psychogenic tremors. Neurology 39: 1094–1099. Koller WC, Marjama-Lyons J, Troster AJ (2002). Psychogenic movement disorders. In: JJ Jankovic, E Tolosa (Eds.), Parkinson’s Disease and Movement Disorders. Lippincott, Philadelphia, pp. 546–552. Lang AE, Koller WC, Fahn S (1995). Psychogenic parkinsonism. Arch Neurol 52: 802–810. Miyasaki JI, Sa DS, Galvez-Jimenez N et al. (2003). Psychogenic movement disorders. Can J Neurol Sci 30 (Suppl 1): S94–S100. Monday K, Jankovic J (1993). Psychogenic myoclonus. Neurology 43: 349–352. Morgan JC, Mir P, Mahapatra RK et al. (2004). Psychogenic parkinsonism: clinical features of a large case series. Mov Disord 19 (Suppl 9): S345–S346.
Ranawaya R, Riley D, Lang A (1990). Psychogenic dyskinesias in patients with organic movement disorders. Mov Disord 5: 127–133. Sa DS, Galvez-Jimenez N, Lang AE (2004). Psychogenic movement disorders. In: R Watts, WC Koller (Eds.), Movement Disorders, Neurologic Principles and Practice, 2nd edn. McGraw Hill, New York, pp. 891–914. Tolosa E, Coehlo M, Gallardo M (2003). DAT Imaging in drug-induced and psychogenic parkinsonism. Mov Disord 18 (Suppl 7): S28–S33. Whone AL, Watts RL, Stoessl AJ et al. (2003), REAL-PET Study Group. Slower progression of Parkinson’s disease with ropinirole versus levodopa: The REAL-PET study. Ann Neurol 54: 93–101. Walters AS, Boudwin J, Wright D et al. (1988). Three hysterical movement disorders. Psychol Rep 62: 979–985. Zeuner KE, Shoge RO, Goldstein SR et al. (2003). Accelerometry to distinguish psychogenic from essential or parkinsonian tremor. Neurology 61: 584–550.
Handbook of Clinical Neurology, Vol. 84 (3rd series) Parkinson’s disease and related disorders, Part II W. C. Koller, E. Melamed, Editors # 2007 Elsevier B. V. All rights reserved
Chapter 59
Parkinsonism and dystonia RUTH H. WALKER* Movement Disorders Clinic, Department of Neurology, James J. Peters Veterans Affairs Medical Center, Bronx, NY and Department of Neurology, Mount Sinai School of Medicine, New York, NY, USA
59.1. Introduction 59.1.1. The dopamine connection The commonalities and distinctions between parkinsonism and dystonia have long intrigued clinicians and researchers in the field of movement disorders. The clinical features of both can be seen in conditions in which dopaminergic neurotransmission is impaired; however, dystonia can also be seen in a wide variety of other conditions, in which the pathophysiology is far from clear. Dysfunction of the dopaminergic system in parkinsonism has been known since the 1960s; in dystonia this has been inferred from empirical evidence for many years and is slowly becoming clarified from scientific studies. 59.1.2. Phenomenology of dystonia Phenomenologically, dystonia is classified as a hyperkinetic movement disorder, in which involuntary muscle contractions result in abnormal postures and movements (Fahn et al., 1998). An imbalance of flexor and extensor activity may cause hyperextension or flexion at a joint, which is often, although not invariably, dynamic. In some cases, alternation of flexion and extension results in tremor, rather than abnormal posture, which may confuse the diagnosis. In other cases, particularly those due to secondary causes (e.g. structural brain lesions), the abnormal posture is fixed and does not resolve during relaxation or even sleep. Dystonia can affect any part of the body and often has a characteristic distribution in different diseases. Axial involvement may be present in combination with axial parkinsonism. A strictly unilateral presentation may indicate a contralateral structural lesion; however,
in patients with generalized dystonia from a variety of causes, symptoms often develop asymmetrically and remain worse on one side throughout the course of the disease. A number of the pediatric metabolic genetic disorders cause specifically orofacial dyskinesias. Some authors have described the movements seen in dystonia as bradykinetic, but the slowness of actions in dystonia is of a different quality to that seen in PD, being due to an increase in muscle activation in a pattern which counteracts the intended movement, hypothesized to be a consequence of decreased inhibition of unwanted motor activity (Mink, 1996, 2003; Perlmutter et al., 1997; Kaji, 2001). This is in contrast to difficulty in initiating movement (akinesia), due to inadequate and discoordinated muscle activity and prolongation of movement time, superimposed upon muscle rigidity, as seen in Parkinson’s disease (PD) (Hallett, 2003). 59.1.3. Classification of dystonia The classification of dystonia is in a state of flux, as various genes become identified as causes of what used to be called ‘idiopathic’ dystonia. The term ‘primary’ is now used for cases in which dystonia is the major, and often the sole, symptom. These are typically due to genetic causes and other etiologies, such as a structural lesion, must be excluded by clinical, radiological and laboratory evaluations (Fahn et al., 1998). In addition, there must be no response to levodopa, excluding dopa-reponsive dystonia (DRD) (Fahn et al., 1998; Bressman, 2004). ‘Secondary’ dystonias are those in which dystonia is due to another disease process (Fahn et al., 1998; Bressman, 2004). This may be one of the inherited ‘dystonia-plus’ syndromes, in which dystonia is part of a symptom complex, such as myoclonus–dystonia or DRD; acquired, such as a
*Correspondence to: Ruth H. Walker, Department of Neurology, James J. Peters Veterans Affairs Medical Center (127), 130 W. Kingsbridge Road, Bronx NY 10468, USA. E-mail:
[email protected], Tel: þ1-718-584-9000-x5915, Fax: þ1-718-741-4708.
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structural lesion, for example stroke, tumor or head trauma or drug-induced; or heredodegenerative, in which dystonia may be a manifestation of an inherited disease such as Huntington’s disease (HD), spinocerebellar ataxia (SCA) type III, Lubag (Filipino X-linked dystonia–parkinsonism) or chromosome 17 frontotemporal dementia and parkinsonism. In addition, secondary dystonia may be present in the apparently sporadic (and rarely inherited) parkinsonian syndromes, including idiopathic PD, multiple system atrophy (MSA), corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP). In this review, the disorders have been classified as ‘parkinsonian disorders with dystonia’, ‘dystonic disorders with parkinsonism’ and ‘mixed movement disorders’, in which the phenomenology may vary and there may be variety of neurologic features, including dystonia and parkinsonism.
59.1.4. Pathophysiology According to the commonly accepted model of the basal ganglia (Albin et al., 1989; DeLong, 1990), the direct and indirect pathways from the striatum have opposing effects upon the activity of the subthalamic nucleus (STN) and its projection targets, the internal segment of the globus pallidus (GPi) and the substantia nigra pars reticulata (SNpr) (Fig. 59.1A). These nuclei are viewed as the main source of output of the basal ganglia and send inhibitory projections to a number of targets, including the thalamus centromedian pars fascicularis (CM-pf), the pedunculopontine nucleus (PPN) and the substantia nigra pars compacta (SNpc). The projection from the striatum to the GPi – the direct pathway – is GABAergic and inhibits the activity of GPi neurons. The projection from the striatum to the
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Fig. 59.1. For full color figure, see plate section. (A) During normal function of the basal ganglia, the direct pathway from the striatum inhibits neurons of the internal segment of the globus pallidus (GPi), disinhibiting the motor pattern generator, consisting of the motor thalamic nuclei and their projections to the cortex. The neurons which select the motor program are represented as being surrounded by a network, controlled by the indirect pathway, which reduces the generation of unwanted movements. (B) In Parkinson’s disease, with loss of the dopaminergic input to the striatum, the direct pathway is less active, with increased activity of the inhibitory neurons of the GPi, which further inhibit the motor pattern generators. The indirect pathway is disinhibited by the loss of dopamine, resulting in a decreased inhibition of the subthalamic nucleus (STN) and the GPi. The ‘surround-inhibitory’ neurons of the GPi also have increased activity and unselected movements are also decreased. Dashed lines, decreased activity; thicker lines, increased activity. (C) In dystonia, there is increased activity of the direct pathway, with decreased inhibition of the thalamocortical motor pattern generators. There is decreased surround inhibition via the indirect pathway, with loss of inhibition of unselected movements. GABA, gamma-aminobutyric acid; SNc¼SNpc, substantia nigra pars compacta; GPe, globus pallidus pars externa. Adapted from Mink (2003) with permission. Copyright # 2003, American Medical Association. All rights reserved.
globus pallidus pars externa (GPe), the indirect pathway, is also GABAergic and an increase in activity of this pathway inhibits the GABAergic GPe and disinhibits the STN. The STN sends an excitatory projection to the GPi and SNpr, thus the neuronal activity of these structures usually changes in parallel. In PD a decrease in the dopaminergic input to the striatum results in decreased activation of the direct pathway by dopamine D1-receptors and decreased inhibition of the GPi. The indirect pathway is inhibited by dopamine D2-receptors, thus dopamine depletion results in increased activity of the inhibitory striatoGPe pathway. These neurons inhibit the GPe, which reduces its inhibition of the glutamatergic STN neurons (Bergman et al., 1994) (Fig. 59.1B). The STN shows an increase in activity, resulting in increased stimulation by STN neurons of the internal segment of the GPi and the SNpr (Carpenter et al., 1981; Kitai and Kita, 1987) and increased activity in the projections from these structures. This model has been borne out by data from a variety of animal models of dopamine depletion and intraoperative recordings in PD (Wichmann et al., 1994; Eidelberg et al., 1997; Rodriguez et al., 1998; Vitek et al., 1998).
Alterations in regional blood flow in various brain areas reflect changes in neuronal activity in PD and correlate to some extent with the above model (Eidelberg et al., 1990; Jenkins et al., 1992; Playford et al., 1992). A correspondence is seen with disease severity (Eidelberg et al., 1995) and these alterations can be normalized by various therapeutic interventions (Jenkins et al., 1992; Playford et al., 1992; Jahanshahi et al., 1995; Eidelberg et al., 1996; Fukuda et al., 2001). However, these metabolic studies represent levels of synaptic activity and do not distinguish between excitatory or inhibitory neurons, or afferents or interneurons, so do not necessarily help us understand the precise mechanism of dysfunction in PD at a neuronal level. In another model which has been proposed, based upon a ‘center-surround’ pattern, the direct pathway serves to activate a motor program and the indirect pathway focuses and selects movements by inhibiting unwanted motor programs (Mink, 1996, 2003; Perlmutter et al., 1997; Kaji, 2001). Thus, in PD, there is less activation of motor programs via the direct pathway and excessive focusing via the indirect pathway, resulting in inadequate movement (Fig. 59.1B).
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In dystonia, the converse may be proposed: increased D1-mediated stimulation of the direct pathway and increased D2-mediated inhibition of the indirect pathway to the GPe, with disinhibition of the GPe, an increase in the inhibitory GPe-subthalamic pathway, with resultant decreased STN activity and thus decreased GPi neuronal activity (Mink, 1996, 2003; Berardelli et al., 1998; Kaji, 2001) (Fig. 59.1C). According to the model, this would cause increased activation and loss of selectivity of motor pattern generators and decreased inhibitory ‘surround’ (Mink, 1996, 2003), resulting in the excessive muscle contractions and the overflow of movements which we see clinically. Dysfunction of the direct pathway in dystonia is suggested by an increase in the striatal-GPi pathway activity seen on functional imaging (Eidelberg et al., 1995). This would result in a decrease in GPi activity and disinhibition of the thalamus. There are data supporting dysfunction of the indirect pathway; however these are harder to interpret and to translate to the model. Whatever the mechanism, the changes must ultimately be explicable in terms of loss of a component of the basal ganglia, as dystonia can be seen in a number of neurodegenerative disorders, in addition to those cases in which there is no evidence of neurodegeneration, for example in DYT1 dystonia or when is a medication side-effect. There is evidence of decreased dopamine D2-receptor binding (Perlmutter et al., 1998). However, decreased D2-receptor binding was also found in non-manifesting DYT1 mutation carriers (Asanuma et al., 2005). One explanation was that this was to a lesser extent than in symptomatic carriers. Alternatively, additional factors may be required for the motor symptoms to manifest clinically. Other functional imaging (Eidelberg, 1998; Meunier et al., 2001) and neuropsychological studies (Heiman et al., 2004) of non-manifesting DYT1 carriers also suggested subtle changes in brain networks which do not manifest as a movement disorder. In contrast to DYT1 dystonia, in DRD an increase in dopamine D2-receptors was found, with unchanged D1 and dopamine transporter labeling (Rinne et al., 2004). The model (Figure 59.1C) predicts decreased activity of the striato-GPe connection of the indirect pathway in dystonia, which could be as a consequence of inhibition from increased postsynaptic dopamine D2 stimulation. However, it is not known whether the tracer imaging results demonstrate a primary or compensatory change and whether the D2-receptors are pre- or postsynaptic. Additionally the DRD patients were being treated with levodopa, making it difficult to interpret the data and fit them to the model. Recent work upon the neuropathology of Lubag (DYT3) suggests a possible mechanism for dopaminergic
hyperactivity as the etiology of dystonia (Goto et al., 2005) (discussed in more detail on p. 514). Other studies suggest changes in the sensorimotor cortex in dystonia. For example, an increase in size in receptive fields of cortical sensory neurons and a loss of specificity of cortical motor topography has been observed in dystonia (Byl et al., 1996; Lenz et al., 1999; Bara-Jimenez et al., 2000; Quartarone et al., 2003). Decreased cortical inhibition in focal hand dystonia (Ridding et al., 1995; Ikoma et al., 1996; Sohn and Hallett, 2004), likely due to a reduction in cortical gammaaminobutyric acid (GABA) (Levy and Hallett, 2002) suggests that decreased focusing is present in the sensorimotor cortex, either as a primary or secondary phenomenon. There is evidence for aberrant neuronal plasticity in dystonia in experimental situations (Byl et al., 1996) and in clinical practice, when focal dystonia develops as the consequence of excessive performance of the same task, as is seen in musicians’ and other task-specific dystonia. The presence of a sensory trick or geste antagoniste, when the patient can correct the movement with a light touch, certainly suggests involvement of sensory circuits. When dystonia is due to a structural lesion of the putamen, the model would predict that neurons of the indirect pathway were preferentially damaged, as decreased function of the first connection of the indirect pathway is postulated (as opposed to increased activity in the striato-GPi direct pathway). There is as yet no neuropathological evidence to support this, thus we do not know whether the model fits these clinical situations. In addition, the model does not explain why pallidotomy should reduce the symptoms of dystonia. However, intraoperative recordings from small numbers of patients with dystonia undergoing surgery suggest that neuronal firing patterns show abnormal bursting patterns rather than an absolute reduction in rate (Vitek et al., 1999; Silberstein et al., 2003) and that it is the information thus encoded which causes the loss of movement selectivity. The model proposes different mechanisms for the different clinical manifestations of basal ganglia dysfunction. The presence of both simultaneously due to a single disease process suggests a topographical variation in signal processing, possibly within a single structure of the basal ganglia. 59.1.5. The function of dopamine in the striatum The precise function of dopamine within the striatum at the synaptic level still remains to be fully elucidated. The relationship between dopamine and glutamate release from corticostriatal afferents is complex and interdependent. Glutamatergic corticostriatal axons synapse
PARKINSONISM AND DYSTONIA on the heads of spines of striatal medium spiny neurons, with nigrostriatal dopaminergic terminals synapsing on the spine shafts, thus the release of dopamine is ideally positioned anatomically to modulate the effect of inputs from sensorimotor cortex (Smith et al., 1994). The effect of dopamine upon the postsynaptic medium spiny neurons which bear dopamine receptors depends upon a number of variables. These include dopamine receptor subtype (Calabresi et al., 1987, 1997), recent activation by corticostriatal glutamate release in a single spike or burst (long-term potentiation or longterm depression (Calabresi et al., 1996; Arbuthnott et al., 2000)), hyperpolarization by GABAergic inputs (from globus pallidus or local axon collaterals) and probably other factors as yet undetermined. Release of dopamine itself is also modified by a number of factors, including recent neuronal activity (Cragg, 2003), corticostriatal afferents (Avshalumov et al., 2003), inputs from cholinergic interneurons (Partridge et al., 2002; Rice and Cragg, 2004), nitric oxide synthase-containing interneurons (Saka et al., 2002) and GABAergic afferents (Juranyi et al., 2003). In addition, dopamine modulates glutamate release from corticostriatal terminals via dopamine D2-receptors (Bamford et al., 2004a, b). Evidence from these studies suggests that dopamine facilitates more active, but inhibits less active, corticostriatal inputs (Bamford et al., 2004b). Dopamine also facilitates the effects of glutamatergic inputs upon medium spiny neurons, via postsynaptic D1-receptors (Flores-Hernandez et al., 2002). In combination, these mechanisms serve to reinforce selection of more active signals and to filter out weaker ones. This may be represented in the circuit diagram (Fig. 59.1) by the ‘center-surround’ model being present in the striatum as well as further downstream in the globus pallidus. When dopamine is decreased, as in PD, there may be a loss of facilitation of corticostriatal signals from the motor cortex, with resultant difficulty in initiation and slowness of movement. In dystonia, there appears to be an excess of movement, often following the initiation of a specific action. This may be the consequence of a loss of signal selection, with unwanted corticostriatal signals being transmitted as discussed above. There is evidence from functional imaging studies of alterations in various indicators of striatal dopaminergic neurotransmission in DYT1 dystonia (Playford et al., 1993; Perlmutter et al., 1998) and DRD (Rinne et al., 2004); however, these results should be interpreted with caution. Preliminary evidence from transgenic mice carrying a mutation of torsinA, the cause of DYT1 dystonia (Shashidharan et al., 2002, 2005; Bao et al., 2006) and from a small number of humans with DYT1 dystonia (Augood et al., 2002; Rostasy et al., 2003), suggested that
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dopamine levels were decreased and turnover increased. Clearly further study is necessary to determine the precise nature of dopaminergic dysfunction in dystonia.
59.2. Parkinsonian disorders with dystonia (Table 59.1) 59.2.1. Parkinson’s disease (sporadic) Dystonia may be a feature of PD in a variety of circumstances. A frequent early manifestation of PD is with limb, typically leg, dystonia. This may persist as a feature during ‘off’ periods, particularly during the night and early morning, when patients are not medicated for an extended period. Such dystonia is distinct from the dystonia seen during ‘on’ periods, in that it is fixed and painful. Characteristically this is described as a painful cramp of the calf muscles and foot, with the foot and toes plantar-flexed. It is possible that the foot region of the putamen is particularly vulnerable to disruptions of dopaminergic function. In addition to the foot dystonia seen in early PD, both childhood-onset DYT1 dystonia (Bressman et al., 1998) and DRD (Segawa and Nomura, 1993) typically present with foot dystonia, before spreading more rostrally. The body is represented topographically in the putamen, with the foot region being located dorsally (Gerardin et al., 2003); therefore, there may be an anatomic reason for the location of this symptom. Truncal dystonia, resulting in forward and/or lateral flexion of the spine (camptocormia) is seen in advanced PD (Djaldetti et al., 1999) and may respond to dopaminergic agents or deep brain stimulation (DBS), but often becomes fixed. This can be a severely disabling feature of the disease. Dystonia of other regions has also been reported in PD, including cervical, cranial and upper limb (Katchen and Duvoisin, 1986; LeWitt et al., 1986; Poewe et al., 1988; Morrison and Patterson, 1992). Dystonia is often a component of levodopa-induced dyskinesias. Levodopa-induced dyskinesias can be seen as blood levels of medication are increasing or wearing off (on–off dyskinesias) or at the peak dose of medication. Peak-dose dyskinesias involve the arms, trunk and neck and are usually choreiform but may incorporate more sustained involuntary muscle contractions, either alone or in combination with rapid, flowing movements. On–off dyskinesias tend to involve the legs and often have a dystonic component. The dyskinesias which occur as levodopa or dopamine levels are changing are hypothesized to be the result of an imbalance of dopamine transmission between different pathways or possibly between adjacent striatal microcircuits. Therapies which smooth out serum/brain
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Table 59.1 Parkinsonian disorders in which dystonia may occur Other neurological features
Genetic tests
Other useful tests
Disease
Inheritance
Dystonia
Parkinsonism
Parkinson’s disease
Sporadic, AR, AD
þ, off, peakdose
þþþ
Subcortical dementia
Parkin, DJ-1, PINK1, a-synuclein, LRRK2
Postencephalitic parkinsonism Progressive supranuclear palsy Corticobasal degeneration
Sporadic
þþ
þþþ
Dementia
–
Response to levodopa, dopamine transporter imaging –
Sporadic
þþ
þþþ
–
–
Sporadic
þþ
þþþ
–
–
Sporadic
þ
þþþ
–
Sporadic
þþ
þþ
Dementia, vertical gaze palsy Focal cortical signs, alien limb Autonomic, cerebellar Chorea
–
Fe in putamen on MRI –
AD, sporadic
þ
þþþ
Dementia
tau
Sporadic
þ
þþ
Dementia, corticospinal
–
Multiple system atrophy Primary pallidal degeneration Frontotemporal dementia and parkinsonism Neuronal intermediate filament disease
–
AD, autosomal dominant; AR, autosomal recessive; – absent; þ mild; þþ moderate; þþþ marked; MRI, magnetic resonance imaging.
levodopa/dopaminergic levels are usually beneficial, such as catechol-O-methyltransferase inhibitors or the use of longer-acting dopaminergic agents. DBS of the STN is also helpful as it enables less dopaminergic medication to be used. 59.2.2. Inherited Parkinson’s disease There is debate as to whether disease due to some of the causative mutations identified to date, such as of parkin and PARK8, can truly be called PD, as the pathologic hallmark, the Lewy body, is often (but not invariably) absent in these cases (Singleton, 2004). However, the clinical criteria in terms of symptomatology, disease progression and response to levodopa are otherwise identical to ‘idiopathic’ PD, so for the purpose of classification they are included here. Mutation of the parkin gene typically results in disease onset in the 20s and 30s and may be the result of either heterozygosity or homozygosity for mutant alleles. Dystonia, sometimes exercise-induced (Khan et al., 2003), is often a presenting feature in these patients, but appears to be more related to young age
of onset rather than the presence of the causative mutation (Quinn et al., 1987; Khan et al., 2003; Lohmann et al., 2003; Tan et al., 2003b). The response to levodopa is usually striking and this feature, in combination with prominent dystonia, may even suggest a diagnosis of DRD (Tassin et al., 2000). Autosomal-dominant inheritance, for example of asynuclein (Polymeropoulos et al., 1997) or LRRK2 (Zimprich et al., 2004) mutations, tends to result in more typical disease. Autosomal-recessive inheritance of mutations of other genes causing early-onset PD, DJ-1 (Bonifati et al., 2003) and PINK1 (Valente et al., 2004), do not appear to be specifically characterized by dystonia, although the rarity of these mutations as a cause of either sporadic or familial early-onset PD (Clark et al., 2004), means that a typical phenotype is not yet fully characterized. 59.2.3. Postencephalitic parkinsonism Postencephalitic parkinsonism was the consequence of von Economo’s encephalitis, which affected many people in the earlier part of the 20th century. Although
PARKINSONISM AND DYSTONIA this pandemic was temporally coincident with the influenza pandemic, it has not been confirmed that encephalitis lethargica was due to the influenza virus. This condition is often understood to be a hypokinetic-rigid syndrome; however, dystonia and other hyperkinetic movements were quite prominent (Evidente et al., 1998; Albanese, 2003). Dystonia usually appeared to be cranial segmental in distribution, although the limbs were also involved (Morrison and Patterson, 1992; Evidente et al., 1998). Contemporary encephalitides may occasionally cause this syndrome. For example, parkinsonism and dystonia have been reported following Japanese encephalitis (Murgod et al., 2001). 59.2.4. Progressive supranuclear palsy The dystonias seen in this parkinsonian neurodegenerative condition are strikingly different from those seen in PD. Blepharospasm is a frequent feature and may be functionally very limiting, but responds well to botulinum toxin injection. Extension of the trunk and neck is characteristic, with retropulsion, unlike in PD, where there tends to be forward flexion. Although usually associated with a diagnosis of CBD, limb dystonia has been reported in neuropathologically confirmed PSP (Barclay and Lang, 1997; Oide et al., 2002). Diagnostic pathological changes are neurofibrillary tangles in the basal ganglia and midbrain. Dystonic dyskinesias are rare as a side-effect of levodopa therapy in this condition, but may occur (Barclay and Lang, 1997; Tan et al., 2003a). Functional benefits from dopaminergic medications in PSP and the following conditions are usually minimal. 59.2.5. Corticobasal degeneration CBD is characterized by an asymmetric presentation of parkinsonism, dystonia and cortical deficits, due to pathology of the basal ganglia and cortex. Limb dystonia may result in flexion contractures of the hand and arm. The leg tends to be extended at the knee and the foot plantar-flexed and inverted. The ‘alien-limb’ phenomenon may be seen, in which the patient’s hand performs involuntary semipurposeful movements and is presumed to be due to involvement of cortical motor areas. 59.2.6. Multiple system atrophy The parkinsonism of MSA is due to degeneration of the GABAergic medium spiny striatonigral neurons, which receive inputs from the nigrostriatal dopaminergic neurons. In addition, degeneration of either cerebellar outputs or neurons of the autonomic nervous system
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comprises the syndrome. Typically, the parkinsonism is midline with marked axial rigidity and falling and cervical antecollis is often seen (Boesch et al., 2002). Limb dystonia may also be present (Boesch et al., 2002). 59.2.7. Frontotemporal dementia and parkinsonism This disease can be seen in an autosomal-dominant familial form, associated with heterozygous mutation of the gene for tau protein on chromosome 17 (Hutton et al., 1998), or may be sporadic. Neuropathologically, mutations of tau result in typical deposits of this protein (Taniguchi et al., 2004). In cases due to tau mutations, parkinsonism, rather than frontotemporal dementia, may be associated with a particular genetic haplotype (Walker et al., 2002a) and dystonia, particularly cranial, may be present (Walker et al., 2002a). 59.2.8. Primary pallidal degeneration Rarely, cases of bradykinesia and dystonia have been reported in which neuropathological changes were limited to the globus pallidus (Aizawa et al., 1991). The onset was in adulthood and the disease was distinct from PD in that there was no increase in muscle tone. Onset at younger age has also been reported, associated with marked rigidity and more choreiform and dystonic movements. 59.2.9. Neuronal intermediate filament inclusion disease This rare sporadic disorder may present with a variety of neurologic features, including frontotemporal dementia, behavioral change, corticospinal signs and parkinsonism in young adulthood (Cairns et al., 2004). Limb dystonia may also be seen, along with supranuclear palsy and buccal apraxia. The diagnosis is made neuropathologically with the finding of characteristic neuronal inclusions which are immunoreactive for phosphorylated intermediate filament (Cairns et al., 2004).
59.3. Dystonic disorders with parkinsonism Only dystonic conditions with parkinsonian features are described in detail here. These and the other genetically defined dystonias are summarized in Table 59.2 59.3.1. Lubag (DYT3) X-linked dystonia-parkinsonism is found solely amongst Filipinos from the province of Capiz on the island of Panay (Lee et al., 1976). Although mostly males are
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Table 59.2 The genetically defined dystonias with genes and gene products (where known) Name
Inheritance
Gene
Location
Protein
Parkinsonism
DYT1 DYT2 DYT3
Primary torsion dystonia Generalized early onset Lubag
AD AR X-linked
DYT1 ? DYT3
9q34 ? Xq31.1
– – þþþ
DYT4
Whispering dysphonia
AD
? ATP7B
? 13q14.3
DYT5
Dopa-responsive dystonia Adolescent-onset mixed Adult cervical and upper-limb dystonia Paroxysmal nonkinesogenic dyskinesia Episodic choreoathetosis/ataxia spasticity Paroxysmal kinesogenic choreoathetosis/ dystonia Myoclonus-dystonia Rapid-onset dystoniaparkinsonism Cranal, cervical and upper-limb dystonia Dopa-responsive dystonia Myoclonus dystonia
AD AR AD AD
GCH-1 TH – –
14q22.1 11p15.5 8p 18p
torsinA ? Multiple transcript system ? Copper-transporting ATPase 2 GTP cyclohydrolase-1 Tyrosine hydroxylase ? ?
AD
–
2q23
?
–
AD
–
1p21
?
–
AD
–
16p
Sodium channels?
–
AD AD
SGCE ATP1A3
7q21 19q13
– þþ
AD
–
AD
–
1p36.13– 32 14q13
E-sarcoglycan Naþ/Kþ-ATPase a3 subunit ? ?
þþþ
AD
–
18p.11
?
DYT6 DYT7 DYT8
DYT9
DYT10
DYT11 DYT12 DYT13 DYT14 DYT15
– þþþ – –
–
AD, autosomal dominant; AR, autosomal recessive; – absent; þ mild; þþ moderate; þþþ marked; ATPase, adenosine triphosphatase; GTP, guanosine triphosphate.
affected, symptomatic carrier females have occasionally been reported, but tend to have a milder phenotype (Waters et al., 1993b; Evidente et al., 2004). Onset is from the teens to the mid-40s, with progression over 5–7 years and then stabilization. Presentation is often with focal dystonia (lubag describes the twisting movements and wa-eg, the abnormal sustained postures, in the local Illongo dialect) and may vary widely (Evidente et al., 2002). Parkinsonism (sud-sud, named for the shuffling gait) may be an early or presenting feature and most patients have mixed features. There is minimal response to levodopa and antidystonic agents (Evidente et al., 2002). A benefit has been reported with the GABA-A receptor agonist zolpidem (Evidente, 2002). The causative gene has been identified as coding for a multiple transcript system whose function is not yet known (Nolte et al., 2003).
An elegant study comparing the neuropathology of parkinsonian cases with dystonic cases found, in dystonic cases, predominant loss of striatal projection neurons in striosomes and patchy loss in the surrounding matrix (Goto et al., 2005). This work supports the ‘three-pathway model’ of basal ganglia function, which emphasizes the relative roles of striosomes and matrix (Graybiel et al., 2000). According to this model, loss of the inhibitory striosomal projection to the SNpc results in increased dopaminergic activity, thus causing increased activity of the neurons of the direct pathway and hence the decreased activity of the GPi, in accordance with the traditional model (Fig. 59.1C). As the disease progresses, striatal neuronal loss becomes more widespread and loss of the striato-GPi neurons, which were previously hyperactive, results in parkinsonism. Other previous reports have also shown mosaic degeneration of the striatum in Lubag (Waters et al., 1993a; Singleton et al., 2004).
PARKINSONISM AND DYSTONIA This diagnosis should be considered in any Filipino, even women, presenting with any movement disorder and a detailed family history should be taken so that appropriate counseling can be given (Evidente et al., 2002). An Italian family has been reported with parkinsonism and dystonia affecting males in an apparently Xlinked manner (Fabbrini et al., 2005). Linkage to the DYT3 locus was demonstrated, but no disease-causing mutations were detected in the gene. 59.3.2. Dopa-responsive dystonia (Segawa disease) (DYT5, DYT14) DRD is due to a variety of mutations of the gene for guanosine triphosphate cyclohydrolase-1 (GTP-CH1) (Ichinose et al., 1999) or for tyrosine hydoxylase (TH). GTP-CH1 is a key enzyme involved in the synthesis of tetrahydrobiopterin, which is a necessary cofactor for the synthesis of TH. DRD is typically autosomal-dominant with incomplete penetrance, affecting females more than males (Furukawa et al., 1998). Autosomal-recessive inheritance of mutations of the gene for TH may also be responsible for a very similar disease (Hoffmann et al., 2003). Another locus responsible for autosomal-dominant DRD has been identified on chromosome 14, although the gene product is not yet known (Nygaard et al., 1993). Onset is in childhood, with mixed features of parkinsonism and lower-limb dystonia. Very young onset with severe spasticity may be mistaken for cerebral palsy (Nygaard et al., 1994). This disorder is characteristically exquisitely responsive to low or moderate doses of levodopa and even young children who are misdiagnosed for a number of years may recover significant function. Neuropathologically, there is decreased immunoreactivity for TH in the SNpc, but no signs of neuronal loss or Lewy bodies (Ichinose et al., 1999; Grotzsch et al., 2002). 59.3.3. Rapid-onset dystonia-parkinsonism (DYT12) This disorder is inherited in an autosomal-dominant manner (Brashear et al., 1998) and is due to mutation of ATP1A3 which encodes for the a3 subunit of Naþ/Kþ-ATPase (de Carvalho et al., 2004). The onset may be in the teens or 20s and is often seen following a period of physiologic stress, such as prolonged physical exertion, fever or childbirth, when symptoms evolve over a period of hours or days and then plateau. Dystonia typically affects the cranial musculature or the limbs and patients have additionally bradykinesia, dysphagia, dysarthria and gait
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instability. From a single case report there are no neuropathological abnormalities (Pittock et al., 2000).
59.4. Mixed movement disorders 59.4.1. Autosomal-dominant (Table 59.3) 59.4.1.1. Huntington’s disease The juvenile form of this genetic disorder, with age of onset younger than 20 years, known as the Westphal variant, is characterized by a parkinsonian presentation, often with marked dystonia. These tend to result from paternal inheritance, when there is greater instability of the trinucleotide repeat expansion. In adult-onset HD, as the disease advances, chorea often gives way to more parkinsonian and dystonic features, with severe bradykinesia or akinesia, rigidity and postural impairment (Penney et al., 1990; Kremer et al., 1992). Rarely, HD may even present as levodopa-responsive parkinsonism with very mild chorea (Reuter et al., 2000). The juvenile form may also respond to both levodopa (Low and Allsop, 1973) and dopamine agonists (Bonelli et al., 2002), suggesting that the deficit is of presynaptic nigral dopaminergic neurons. Although degeneration of striatal medium spiny neurons is well documented as the primary neuropathologic abnormality, loss of neurons from the SN, both pars compacta and pars reticulata, has also been described (Bugiani et al., 1984; Oyanagi et al., 1989). One clue to the diagnosis of HD is, of course, a positive family history, although in consideration of late-onset disease or non-paternity, a negative pedigree should not pre-empt genetic testing. 59.4.1.2. Huntington’s disease-like 2 Huntington’s disease-like 2 (HDL2) (Margolis et al., 2001) is a trinucleotide repeat expansion disease (Holmes et al., 2001), which bears a striking resemblance to HD in many clinical, genetic and neuropathological aspects. The genetic mutation associated with HDL2 has been characterized as a CTG/CAG trinucleotide repeat expansion within the junctophilin-3 (JPH3) gene on chromosome 16q24.3 (Holmes et al., 2001). In the normal population the repeat length ranges from 6 to 27 CTG/CAG triplets, whereas affected individuals have 41–58 triplets. The repeat lies within an alternatively spliced exon of JPH3 and because of variable splice acceptor sites may encode either polyalanine or polyleucine or may be untranslated. Whether the expanded repeat is translated or even transcribed remains unknown. There can be marked variations in phenotype and parkinsonism, chorea or dystonia may be present (Walker et al., 2003a). The initial symptoms are often
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Table 59.3 Mixed movement disorders in which parkinsonism and dystonia may both occur; autosomal-dominant (AD), X-linked inheritance and sporadic Other neuroloDystonia Parkinsonism gical features
Affected protein Other useful tests
Huntington’s disease AD Huntington’s disease-like 2 AD
þ þþ
þ þþ
Chorea Chorea
Huntingtin Junctophilin-3
Spinocerebellar ataxia III Spinocerebellar ataxia 17
þ þ
þþ þþ
Chorea Chorea
þþ
þ
þþ
þþ
Chorea, ataxia Chorea
Ataxin 3 TATA-binding protein Atrophin
Disease
Inheritance
AD AD
Dentatorubropallidoluysian AD atrophy Neuroferritinopathy AD Fahr’s disease (idiopathic basal ganglia calcification)
AD, other
þþ
þþ
Ataxia, chorea, cognitive, behavioral changes
McLeod syndrome
X-linked
þþ
þ
Neuroleptic-induced
Sporadic
Tardive dyskinesia Alzheimer’s disease
Sporadic Sporadic, AD
þþþ þþþ (acute) þþþ ?þ þ –
Chorea, seizures, peripheral neuropathy – Chorea Dementia, rigidity
Ferritin light chain ?
XK
– Acanthocytosis (10%) – – – Ferritin, Fe in basal ganglia on MRI Calcification on neuroimaging; rule out parathyroid disease Kell and Kx ag, acanthocytosis, CK, LFTs
–
–
– Presenilin, amyloid precursor protein
– –
– absent; þ mild; þþ moderate; þþþ marked; CK, creatine kinase; LFTs, liver function tests; MRI, magnetic resonance imaging.
a change in personality and cognitive functioning, evolving over 10 years or more to frank dementia. The neurologic presentation varies within families and in some cases changes with evolution of the disease. The relationship between clinical features and size of the trinucleotide repeat expansion at this point remains uncertain, although, as in HD, the size of the repeat correlates inversely with the age of onset (Margolis et al., 2004). The range of phenotypes is similar to that observed in HD, although parkinsonism can be prominent in adultonset cases, as compared with HD when this presentation is usually associated with juvenile onset with very long repeat expansions. The mechanism of the phenotypic variation in HDL2 remains to be determined. All patients reported to date have been of African ancestry (Holmes et al., 2001; Margolis et al., 2001, 2004) and no patients of Caucasian ancestry have yet been found (Andrew et al., 1994; Bauer et al., 2002; Stevanin et al., 2002). Occasionally, acanthocytosis
can be found on peripheral blood smear, resulting in confusion of the diagnosis with neuroacanthocytosis (Walker et al., 2002b, 2003b). 59.4.1.3. Spinocerebellar ataxias and dentatorubropallidoluysian atrophy The phenotypes of the SCAs can involve movement disorders, in addition to signs and symptoms of cerebellar neurodegeneration. These neurodegenerative disorders are inherited in an autosomal-dominant manner and are usually due to expanded trinucleotide repeats within various proteins. The size of the expansions does not in general appear to correlate with the phenotype. The most common SCA in most populations, SCA III (Machado–Joseph disease) can present with parkinsonism, dystonia and chorea, usually in association with the typical cerebellar signs and eye findings.
PARKINSONISM AND DYSTONIA A variety of movement disorders may be seen in SCA 17, including parkinsonism, dystonia and chorea (Stevanin et al., 2003; Zuhlke et al., 2003), in addition to the typical phenotype of ataxia, dementia and hyperreflexia. SCA II has been reported to present with levodoparesponsive parkinsonism (Shan et al., 2001; Furtado et al., 2004) but not dystonia. Dentatorubropallidoluysian atrophy (DRPLA) is found more often in Japanese populations, but rarely in Caucasian (Le Ber et al., 2003; Martins et al., 2003) or African-American (Burke et al., 1994) families and may present with movement disorders, including dystonia, myoclonus and chorea. Usual features are ataxia and dementia. Seizures are common in patients with onset below the age of 20, but tend to decrease with time and are rare in older-onset patients. 59.4.1.4. Neuroferritinopathy This is one of the disorders that falls under the classification of neurodegeneration with brain iron accumulation (NBIA), as the mutation of ferritin light chain results in iron deposition in the basal ganglia (Curtis et al., 2001). However, unlike the other disorders (panthothenate kinase-associated neurodegeneration, aceruloplasminemia; see below), most of which are inherited in an autosomal-recessive fashion, this is an autosomal-dominant disorder. This may result in a variety of movement disorders, including chorea, dystonia and parkinsonism (Crompton et al., 2004; Mir et al., 2004), with onset at age 40–55 years. Cognitive impairment is not normally seen, although it can occasionally be a feature (Wills et al., 2002). Serum ferritin values tend to be below, or at the lower end of, the normal range. 59.4.1.5. Fahr’s Disease Fahr’s disease (idiopathic basal ganglia calcification; IBGC) refers to a heterogeneous group of disorders in which there is deposition of calcium in the basal ganglia and other cerebral regions, particularly the deep cerebellar nuclei. The clinical picture may include dystonia, parkinsonism, chorea, ataxia, cognitive impairment and behavioral changes. In one family, linkage to 14q was demonstrated (IBC1) (Geschwind et al., 1999) although the gene has not yet been identified. In several other families with autosomal-dominant inheritance, linkage to this locus was excluded (Brodaty et al., 2002; Oliveira et al., 2004). In other families (Reske-Nielsen et al., 1988; Younes-Mhenni et al., 2002), the pattern of inheritance and additional clinical features suggest mitochondrial inheritance.
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59.4.2. X-linked recessive (Table 59.3) 59.4.2.1. McLeod syndrome The X-linked McLeod neuroacanthocytosis syndrome (Symmans et al., 1979; Takashima et al., 1994; Danek et al., 2001) is similar to autosomal-recessive choreaacanthocytosis (ChAc) (see below) in its neurological presentation, but other organ systems are also involved. Onset of clinical symptoms is typically in mid to late adulthood (Danek et al., 2001; Jung et al., 2001a). Patients may present with subtle neurobehavioral changes, particularly subcortical dementia, which are sometimes only fully recognized when the movement disorder develops. In addition to chorea, dystonia and parkinsonism may also be seen. Facial hyperkinesias with dysarthria and involuntary vocalizations are frequent, although the self-mutilating lip-biting seen in autosomal-recessive ChAc is not characteristic. Peripheral sensorimotor neuropathy and areflexia are typical. Seizures are seen in 50% and can usually be controlled with standard anticonvulsant medications. Cardiomyopathy is present in approximately twothirds of patients and cardiac arrhythmias may be a significant source of morbidity and mortality (Danek et al., 2001). Elevated serum creatine kinase (often into the 1000s) is an invariable finding and frank myopathy is common (Kawakami et al., 1999; Danek et al., 2001). Liver enzymes are elevated and hepatosplenomegaly is present in 40% of patients and may lead to evaluation for liver disease prior to neurologic presentation (Walker et al., 2005). Often patients are identified, as was the eponymous subject McLeod, at blood banks by blood antigen typing. Rare patients with the McLeod red blood cell antigen phenotype, but without any neurological or systemic abnormalities, have been reported (Jung et al., 2003; Walker et al., in press). Occasionally carrier females have been symptomatic, presumably due to X-chromosome inactivation (Hardie et al., 1991; Ueyama et al., 2000; Jung et al., 2001a). Neuroimaging typically shows a decrease in basal ganglia volume (Danek et al., 2001), although whitematter changes have also been reported (Nicholl et al., 2004). Neuropathologic findings appear nonspecific, with neuronal loss and reactive gliosis (Brin et al., 1993; Geser et al., 2006). The phenotype is defined by the characteristics of the red blood cell (RBC) Kell antigen system (Allen et al., 1961), the third most important erythrocyte antigen system after ABO and rhesus. Mutation of the XK gene causes reduced or absent XK protein. As the XK protein is closely associated with the Kell proteins and determines Kell antigen expression, this results in a reduction in the Kell protein on the RBC membrane
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(Russo et al., 1998). Patients thus have absent Kx antigen expression and reduced Kell antigen expression. The diagnosis can only be confirmed at specialized laboratories which have the requisite panel of anti-Kell and anti-Kx antibodies. XK may function as a membrane transport protein (Ho et al., 1994) and has been found in muscle and brain in addition to RBCs (Ho et al., 1994; Jung et al., 2001a, b; Russo et al., 2000). This abnormality of RBC membrane proteins is presumably the cause of the characteristic acanthocytosis. 59.4.3. Autosomal-recessive (Table 59.4) 59.4.3.1. Chorea-acanthocytosis ChAc, previously known as neuroacanthocytosis or Levine–Critchley syndrome (Levine et al., 1960; Critchley et al., 1968), is an autosomal-recessive disorder due to a mutation of the VPS13A gene (formerly CHAC) (Velayos-Baeza et al., 2004) located on chromosome 9q21 (Rubio et al., 1999; Ueno et al., 2001). Similar to XK (see above), this protein appears to be involved in membrane processing and sorting, which may account for the RBC membrane abnormalities. The movement disorder in this neurodegenerative disease is typically chorea, presenting in young to mid-adulthood with marked lingual-buccal-facial dyskinesia and self-mutilation (Rampoldi et al., 2002). As with several other basal ganglia disorders described here, these patients may present with psychiatric (Rovito and Pirone, 1963; Bruneau et al., 2003), behavioral or cognitive problems. Dystonia is found in 50% of patients (Rampoldi et al., 2002). Other abnormal movements are often seen, including vocal and motor tics (Saiki et al., 2004). Parkinsonism is reported in 32% of patients (Rampoldi et al., 2002) and may be a presenting feature (Bostantjopoulou et al., 2000). Widespread involvement of the nervous system is suggested by the presence of seizures, cognitive impairment and peripheral neuropathy. Outside the nervous system, the liver and spleen may be enlarged, with abnormal liver function tests, although this is less common than in McLeod syndrome (Rampoldi et al., 2002). Unlike McLeod syndrome, cardiomyopathy is very rare. A Japanese family with apparent autosomal-dominant inheritance of this disorder, documented mutations of VPS13A and an apparently identical phenotype to the autosomal-recessive form has been reported (Saiki et al., 2003). Diagnosis of this disorder can be confirmed by a quantitative test for chorein (Dobson-Stone et al., 2004). Neuropathologically, there is degeneration of the caudate nucleus and putamen and there may be marked loss of substantia nigra neurons, corresponding
to the clinical appearance of parkinsonism (Rinne et al., 1994). 59.4.3.2. Wilson’s disease This autosomal-recessive disorder of copper metabolism may present with a variety of abnormal movements. The causative mutation is of the ATP7B gene, resulting in an inability to transport copper on to ceruloplasmin, with resultant copper accumulation in brain, liver, cornea and elsewhere. The typical neurological presentation is with an asymmetric, flapping arm tremor, which may vary in amplitude, distribution and the position in which it is elicited. The gait is often affected and may be parkinsonian or cerebellar. Dystonia of the face, tongue and pharynx can be seen, which, in combination with cerebellar dysfunction, may result in dysarthria. The classic risus sardonicus of Wilson’s disease is due to dystonia affecting the lower facial muscles. A hereditary whispering dysphonia (DYT4) is associated with Wilson’s disease (Elwes and Saunders, 1986). Limb and trunk dystonia can also be a feature, although these are extremely uncommon as a presentation of Wilson’s disease in the absence of hepatic features. In a series of patients with cervical dystonia as the sole symptom, no cases of Wilson’s disease were detected (Risvoll and Kerty, 2001). On neuroimaging and neuropathological evaluation, the basal ganglia and brainstem are consistently affected by abnormal copper deposition (Magalhaes et al., 1994; Sener, 2003; Page et al., 2004), thus the presence of movement disorders is not surprising. The importance of awareness of Wilson’s disease as part of the differential diagnosis of movement disorders is that it is one of the few etiologies that can be effectively treated, thus a high level of suspicion is always warranted. Testing for serum ceruloplasmin levels, 24-hour copper excretion and slit-lamp examination for Kayser–Fleischer rings are all necessary to exclude the diagnosis. 59.4.3.3. Aceruloplasminemia Deficiency of ceruloplasmin, due to autosomal-recessive inheritance of mutations of the gene for ceruloplasmin, results in iron deposition in the retina, pancreas, cerebellum and basal ganglia (Miyajima, 2003; Xu et al., 2004). Typical presentation is of retinal degeneration and diabetes mellitus in the 20s. In the 40s and 50s neurological signs appear, usually ataxia. Subsequently dystonia, especially orofacial, parkinsonism and chorea, may develop. Dementia may manifest in later years. Symptomatic heteroplasmic carriers have also been reported.
Table 59.4 Mixed movement disorders in which parkinsonism and dystonia may both occur; autosomal-recessive (AR) inheritance Dystonia
Parkinsonism
Other neurological features
Affected protein
Other tests
Chorea-acanthocytosis
AR
þþ
þ
Chorein
Wilson’s disease
AR
þþ
þþ
Chorea, peripheral neuropathy, seizures Tremor, ataxia
Aceruloplasminemia Pantothenate kinaseassociated neurodegeneration GM1 gangliosidosis type 3
AR AR
þþ þþ
þþ þ
Ataxia, chorea Chorea, spasticity, dementia, retinal degeneration
Ceruloplasmin Pantothenate kinase 2
Acanthocytosis, CK, LFTs, chorein assay Ceruloplasmin, Cu excretion, Kayser– Fleischer rings Fe on MRI in basal ganglia Acanthocytes (8%)
AR
þþ
þ
Cerebellar, dysarthria, dementia
b-galactosidase
GM2 gangliosidosis lateonset
AR
þþ
þ/–
Hexosaminidase A
Niemann–Pick type C
AR
þþ
þ
Gaucher disease type III
AR
þ (facial)
þþ
Glutaric aciduria
AR
þþ
þ
Cerebellar, spasticity, seizures, peripheral neuropathy, supranuclear vertical gaze palsy Supranuclar vertical gaze palsy, cerebellar, intention tremor Seizures, myoclonus, horizontal gaze palsy Encephalopathy
2-Hydroxyglutaric aciduria
AR
þ
þþ
Encephalopathy, seizures
Homocystinuria
AR
þþ
þ/–
Biotin-responsive basal ganglia disease Juvenile neuronal ceroid lipofuscinosis Adult neuronal ceroid lipofuscinosis Neuronal intranuclear (hyaline) inclusion disease
AR
þþ
þþ
AR
þ
þþ
Vascular thrombosis, mental retardation Encephalopathy, quadriparesis, spasicity, seizures Dementia, seizures, visual loss
AR
þ (facial)
þþ
AR (also sprodic, AD?)
þþ
þþ
Epilepsy, myoclonus dementia; extrapyramidal signs, dementia Cerebellar, corticospinal
ATP7B
Sphingomyelinase Glucocerebroside
Bone marrow – foam or Gaucher-like cells High T2 in basal ganglia on MRI Bone marrow – sea-blue histiocytes Bone marrow – Gaucher cells Urinary amino acids
Glutaryl-coenzyme A dehydrogenase 2-hydroxyglutaric acid dehydrogenase (l or d isoform) Cystathione beta-synthase
Urinary amino acids
?Biotin transporter
Biotin-responsiveness
CLN3
Skin biopsy
–
Skin biopsy
–
Neuropathology
Urinary amino acids
519
AD, autosomal dominant; AR, autosomal recessive; – absent; þ mild; þþ moderate; þþþ marked; CK, creatine kinase; LFTs, liver function tests; MRI, magnetic resonance imaging.
PARKINSONISM AND DYSTONIA
Inheritance
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Copper metabolism is not disturbed by the lack of ceruloplasmin. However, as ceruloplasmin functions as a ferroxidase, iron oxidation from Fe2þ to Fe3þ is impaired and neurons are also more vulnerable to oxidative stress. Neuropathologically, astrocytes and neurons laden with iron are found in the cerebellum, basal ganglia and cortex (Miyajima, 2003; Xu et al., 2004). 59.4.3.4. Pantothenate kinase-associated neurodegeneration The disorder now known as pantothenate kinase-associated neurodegeneration (PKAN) is due to mutations of pantothenate kinase 2 (PANK2) located on chromosome 20p13 (Zhou et al., 2001). The course in typical cases is of disease onset by the age of 10 years with dystonia and a rapid progression over the next 10 years (Hayflick et al., 2003). Orofacial and limb dystonia, choreoathetosis and spasticity are characteristic early features. Approximately one-third of typical cases develop cognitive impairment and two-thirds have retinopathy. The typical magnetic resonance imaging (MRI) ‘eye of the tiger’ pattern of iron deposition in the globus pallidus was seen in the majority of these patients (Hayflick et al., 2003; Hartig et al., 2006). 8% of typical PANK patients have acanthocytosis. The occasional reported association of decreased prebetalipoprotein levels (hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa and pallidal degeneration: HARP syndrome) (Orrell et al., 1995; Malandrini et al., 1996) in patients with PANK2 mutations (Ching et al., 2002) does not appear to be of clinical significance and may be observed in normal subjects (Houlden et al., 2003; Danek and Hegele, 2004). In atypical cases disease onset is after the age of 20, with dystonia, rigidity and gait freezing, but slower progression. Early speech difficulty, with pallilalia or dysarthria, is common, as are cognitive decline and personality change. These patients do not tend to have retinopathy. In one-third of these there is a mutation of PANK2 and the diagnostic MRI finding, whereas in two-thirds PANK2 mutations were not found, nor was there the typical MRI image (Hayflick et al., 2003). These are classified as NBIA without PANK2 mutation. The majority of clinically typical cases are due to mutations of PANK2 causing protein truncation. Pantothenate kinase catalyzes the rate-limiting step in the synthesis of coenzyme A from vitamin B5 (pantothenate). The amount of active enzyme correlates with the disease phenotype, as typical patients have no active enzyme but atypical patients, in whom there is a missense mutation of PANK2, may have some
enzyme function (Hayflick et al., 2003). The distribution of the neurological lesions is thought to relate to the accumulation of iron and other neurotoxic substances and to local tissue demand for coenzyme A (Zhou et al., 2001). 59.4.3.5. GM1 gangliosidosis The late-onset, chronic form (adult; type 3) of GM1 gangliosidosis is slowly progressive and may present during childhood or as late as the fourth decade. This form affects only the central nervous system and does not affect the skeletal system. Dystonia is often marked, especially orofacial, and dysarthria and dysphagia may be severe. Features of parkinsonism are also reported (Goldman et al., 1981; Uyama et al., 1992; Yoshida et al., 1994; Muthane et al., 2004). MRI frequently shows bilateral putaminal hyperintensities on T2 sequences (Uyama et al., 1992; Muthane et al., 2004). 59.4.3.6. GM2 gangliosidosis The late-onset forms of GM2 gangliosidosis may occur in childhood, adolescence or adulthood as either subacute or chronic forms. Dystonia and choreoathetosis have been reported in the subacute forms, along with dysarthria, speech loss, ataxia, spasticity, seizures and behavioral changes (Meek et al., 1984; Hardie et al., 1988; Nardocci et al., 1992). In general, cerebellar and corticospinal abnormalities tend to predominate over basal ganglia-related symptomatology. Parkinsonism has rarely been reported (Inzelberg and Korczyn, 1994). Supranuclear ophthalmoplegia and oculomotor apraxia may occur (Specola et al., 1990) and thus this disorder should be considered in atypical presentations of PSP. 59.4.3.7. Niemann–Pick type C This disorder may present in childhood or even late into adulthood with cerebellar signs, intention tremor and dysarthria. Dystonia and chorea-athetosis may be present and, as with GM2 gangliosidosis, the presence of supranuclear gaze palsy, specifically loss of vertical gaze, may lead this disorder to resemble PSP (Coleman et al., 1988; Cardoso and Camargos, 2000). 59.4.3.8. Gaucher disease type III The neuropathic form of this disease presents from childhood until early adulthood, with action myoclonus and seizures and a supranuclear palsy of horizontal gaze. Occasionally facial grimacing may be observed. An association between heterozygous carriers of the mutation and variably treatment-responsive parkinsonism has been reported (Tayebi et al., 2003;
PARKINSONISM AND DYSTONIA Aharon-Peretz et al., 2004; Goker-Alpan et al., 2004). It is hypothesized that mutations of the glucocerebrosidase gene confer susceptibility to parkinsonism, possibly by interfering with protein degradation in the SNpc. 59.4.3.9. Glutaric aciduria Glutaric acidura typically presents with generalized dystonia and parkinsonism may also be a feature (Gascon et al., 1994), in addition to the other features of encephalopathy. Often the presentation is catastrophic in early infancy, but occasionally it may present more gradually in later childhood or even adulthood. On MRI, dilation of the sylvian fissures and lesions of the putamen can be seen. 2-Hydroxyglutaric aciduria is considerably rarer and has been reported as a cause of parkinsonism with dystonia (Owens and Okun, 2004). 59.4.3.10. Homocystinuria Movement disorders are uncommon in this disorder, which is characterized by marfanoid features, cataracts, vascular thrombosis and variable mental retardation. Occasionally severe dystonia may be seen (Hagberg et al., 1970; Davous and Rondot, 1983; Kempster et al., 1988; Berardelli et al., 1991). Parkinsonism has occasionally been reported (Keskin and Yurdakul, 1996), in one case in the brother of a patient with severe dystonia (Ekinci et al., 2004). 59.4.3.11. Biotin-responsive basal ganglia disease This disorder, probably of autosomal-recessive inheritance, was reported in a series of 10 patients, who had onset in infancy of a subacute encephalopathy, progressing to dystonia, quadriparesis, cogwheel rigidity, cranial neuropathies and seizures (Ozand et al., 1998). Symptoms improved remarkably with the administration of biotin, but recurred when it was discontinued. 59.4.3.12. Neuronal ceroid lipofuscinoses The combination of dystonia and parkinsonism has not been reported in the various forms of neuronal ceroid liposcinosis; however, they are individually rare features at different stages of the disease, indicating the potential for basal ganglia involvement. Mutations of a number of genes (CLN1, CLN2, CLN3, CLN5, CLN6, CLN8) for endosomal-lysosomal proteins have been reported to be associated with different disease phenotypes (Mole, 2004). Dystonia has occasionally been reported in the infantile form, along with an unusual phenotype
521
of microcephaly and hypotonia, with atrophy of the caudate nuclei, due to a mutation of CLN2 (Simonati et al., 2000). This encodes for a lysosomal enzyme tripetidyl peptidase. In the juvenile form (late-onset Batten disease; Spielmeyer–Vogt disease), usually due to mutations of CLN3, a gene for a membrane protein of unknown function, involvement of the extrapyramidal system is typically a late feature, following intellectual decline, visual loss and seizures (Aberg et al., 2001). Rigidity and impaired postural reflexes usually occur late, although occasionally may be presenting features. Dystonia may sometimes be seen (Boustany et al., 1988). The adult form (Kufs disease) may present in one of two forms, with epilepsy, myoclonus dementia and extrapyramidal signs (Yoshioka et al., 1999; Nijssen et al., 2002) or with behavioral disturbances, dementia and facial dyskinesias. Parkinsonism has been reported (Nijssen et al., 2002), but not dystonia. The gene has been assigned the name CLN4, but it has not as yet been identified. 59.4.3.13. Neuronal intranuclear hyaline inclusion disease This is a heterogeneous disorder diagnosed neuropathologically with widespread intranuclear inclusions throughout the central, peripheral and autonomic nervous system (Takahashi-Fujigasaki, 2003). The onset may be at any age and those with young onset tend to have parkinsonism and dystonia, in addition to behavioral changes, corticospinal, cerebellar signs and seizures. Autosomal-recessive inheritance is suggested by several affected sib-pairs, although in one family autosomal-dominant inheritance was apparent (Takahashi-Fujigasaki, 2003). 59.4.4. Sporadic (Table 59.3) 59.4.4.1. Drug-induced syndromes Treatment with the classic dopamine receptor-blocking antipsychotic agents, such as thorazine, chlorpromazine, haloperidol, perphenazine and many others, may result in an acute dystonic crisis characterized by extension of the neck and rolling up of the eyes in the head, known as an oculogyric crisis. This happens particularly in young males following initiation of therapy with an intramuscular depot injection. These episodes respond well to intravenous anticholinergic agents and these medications are often given orally prophylactically. The dopamine receptor-blocking effects of the neuroleptics are well-recognized as a cause of iatrogenic
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parkinsonism, but are becoming less widespread as the atypical antipsychotics, such as clozapine, olanzepine, quetiapine, aripiprazole and ziprasidone, are used more extensively. Although risperidone was initially classified as an atypical antipsychotic, clinical experience demonstrates that it may often cause parkinsonism, especially in patients with an underlying neurodegenerative process, and thus should be avoided in these patients. Once the offending medication is removed, the symptoms of parkinsonism should resolve. There is less awareness of the potential side-effects of other dopamine receptor-blocking agents not used as neuroleptics, such as metoclopramide, compazine, flunarizine and cinnarizine, but these medications can also be responsible for the generation of the same range of movement disorders. The more serious and long-lasting consequence of classic neuroleptic use is tardive dyskinesia. Choreiform orofacial dyskinesias are the most typical form, but tardive dystonias are not uncommon, including blepharospasm, spasmodic dysphonia, cervical and truncal dystonia. The movements may emerge as the medication is discontinued or whilst it is still being used. In the latter situation, patients may manifest both dystonia and parkinsonism.
59.4.4.2. Alzheimer’s disease A variety of movement disorders can be seen in Alzheimer’s disease. Myoclonus may be seen in sporadic cases and in patients with presenilin mutations. Occasional families with mutations of amyloid precursor protein may have prominent parkinsonism and myoclonus (Edwards-Lee et al., 2005), but this is not typical. Generalized rigidity is often a feature of latestage disease and facial masking may give a parkinsonian appearance. Retrocollis can also occur and responds well to injection of botulinum toxin. Patients with Alzheimer’s disease are particularly vulnerable to side-effects of medications, in particular to parkinsonism or dystonia induced by neuroleptics, including risperidone (Magnuson et al., 2000). Truncal dystonia (Pisa syndrome) has been reported following the use of acetylcholinesterase inhibitors (Kwak et al., 2000; Miyaoka et al., 2001).
59.5. Therapy Therapy for these disorders ideally would be directed towards the etiologic causes; however, in the majority of cases this is not possible. The challenge in symptomatic treatment when both parkinsonism and dystonia
are present is to improve both aspects of the movement disorder, without the treatment for one exacerbating the other. In a small number of disorders, therapy is definitive and essential to minimize disease progression. It is important to consider the diagnosis of dopa-responsive dystonia, especially in pediatric cases with an atypical presentation which may resemble cerebral palsy (Nygaard et al., 1994). A diagnostic trial of levodopa is obligatory in most cases of dystonia and definitely in cases with concomitant parkinsonism. The diagnosis of Wilson’s disease is also important to consider in almost every unusual presentation of a movement disorder, in order to institute the appropriate therapy if indicated. Parkinsonism may respond to dopaminergic agents, especially if there is impairment of the nigrostriatal pathway, rather than of the striatal medium spiny projection neurons which bear the postsynaptic dopamine receptors. Levodopa/carbidopa is usually the first-line medication and should be increased very cautiously, with careful monitoring for worsening of psychiatric symptoms and hyperkinetic movements. The usual strategy is gradually to increase the levodopa over a number of weeks to approximately 2000 mg, if tolerated, and then slowly to decrease the dose. If there is no benefit from this, then dopamine receptor agonists should be tried. Benefits have been reported in patients with secondary parkinsonism of a variety of etiologies (Low and Allsop, 1973; Bonelli et al., 2002; Tayebi et al., 2003; Goker-Alpan et al., 2004). Treatment of dystonia may be frustrating and the use of systemic medications may result in exacerbation of neuropsychiatric symptoms. Local injections of botulinum toxin may be helpful. The armamentarium of potentially effective medications includes agents with a wide variety of mechanisms of action. Anticholinergics, benzodiazepines, anticonvulsants and baclofen (oral or intrathecal (Ford et al., 1996; Walker et al., 2000)) may all be useful, but results can be quite variable. The newer atypical antipsychotics, such as quetiapine, clozapine, aripiprazole and ziprasidone, may also have benefits, with less potential for exacerbating parkinsonism or causing tardive dyskinesias as can be seen with the typical antipsychotics. DBS of either the GPi or the STN has become accepted as treatment for advanced PD and can also have good results in primary (Toda et al., 2004; Vidailhet et al., 2005) or tardive (Trottenberg et al., 2005) dystonia. In general, secondary parkinsonian or dystonic (Eltahawy et al., 2004) disorders do not tend to benefit from surgical interventions, probably due to more extensive disruption of neuronal pathways than in primary dystonia or PD. Occasional cases
PARKINSONISM AND DYSTONIA may respond (Wohrle et al., 2003; Umemura et al., 2004). A case report of DBS of the GPi in HD (Moro et al., 2004) was promising, although in a case of ChAc it was not beneficial (Wihl et al., 2001). The motor thalamus has also been proposed as a potentially promising site for DBS and has been reported as having positive results in a patient with ChAc (Burbaud et al., 2002). It is suspected that the mechanisms of action of DBS in PD and dystonia are different as the stimulation parameters at which benefits are seen may differ significantly in the two conditions. It is postulated that blocking disordered neuronal signaling from the output nuclei of the basal ganglia, the GPi and SNpr, is the critical aspect of DBS; however, this therapy is still poorly understood. A number of the disorders described here may present initially with subtle psychiatric or neurobehavioral features. The use of neuroleptics may mask the correct diagnosis, being presumed to be the cause of any movement disorders that develop. A high degree of suspicion is necessary as well as alertness for the presence of additional neurologic or medical features, a family history or an unusual disease course that may provide important clues to the correct diagnosis.
59.6. Conclusion The phenomenology and pathophysiology of diseases in which parkinsonism and dystonia coexist may lead us to important insights into the function of the basal ganglia and of dopamine specifically. An anatomically related vulnerability to dopamine dysfunction, presumably within the putamen, is suggested by the pattern of onset, for example, the prominence of foot dystonia in early PD, childhood-onset DYT1 dystonia and DRD. Disturbances in dopaminergic neurotransmission are clearly implicated in parkinsonism and dystonia. However, the benefits of mere replacement are limited, particularly in dystonia, and it is evident that dopamine is more than an ‘on–off switch’ for movement. The partial positive effects seen with the wide variety of medications used therapeutically in dystonia suggest complex interactions of a number of different neurotransmitters. Sound scientific methodology requires that we do not infer the function of a specific component in a system by the consequences of its dysfunction. However, it is impossible to resist speculating about the role of dopamine in motor programs and how its deficiency may result in both impaired and excessive movement. Models of basal ganglia function are invaluable in designing experiments and potential therapeutic strategies. The limitation of the models in explaining the coexistence of hypo- and hyperkinetic disorders suggests that yet another layer of complexity is required.
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Handbook of Clinical Neurology, Vol. 84 (3rd series) Parkinson’s disease and related disorders, Part II W. C. Koller, E. Melamed, Editors # 2007 Elsevier B. V. All rights reserved
Chapter 60
Dementia with Lewy bodies IAN MCKEITH* Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, UK
60.1. Introduction Dementia with Lewy bodies (DLB) is the preferred term (McKeith et al., 1996) for a clinicopathological syndrome that has been variously labeled over the last 40 years as diffuse Lewy body disease (DLBD) (Kosaka et al., 1984; Dickson et al., 1987; Lennox et al., 1989a), dementia associated with cortical Lewy bodies (DCLB) (Byrne et al., 1991), the Lewy body variant of Alzheimer’s disease (LBVAD) (Hansen et al., 1990; Fo¨rstl et al., 1993), senile dementia of Lewy body type (SDLT) (Perry et al., 1989a, b, 1990) and Lewy body dementia (LBD) (Gibb et al., 1987). Initially regarded as uncommon, DLB is now thought to account for up to 20% of all elderly cases of dementia reaching autopsy (Jellinger, 1996), with a clinical presentation primarily characterized by cognitive decline leading to dementia, accompanied in the majority of cases (75%) by extrapyramidal motor features and additional neuropsychiatric features. 60.1.1. Prevalence and incidence There is very little systematically collected information about the prevalence, incidence and associated risk factors for DLB (McKeith et al., 2004a). A community study of 85þ-year-olds in Finland found that 5.0% met clinical diagnostic criteria for DLB, representing 22% of all demented cases (Rahkonen et al., 2003). This is similar to other clinical estimates (Shergill et al., 1994; Stevens et al., 2002) and consistent with estimates of Lewy body (LB) prevalence (15%) in a dementia case register followed to autopsy (Holmes et al., 1999). Little is known about risk factors for LB disease except for male sex and age of onset, which is on average 10 years greater for DLB (mean
75 years in most studies) than for Parkinson’s disease (PD). 60.1.2. Dementia with Lewy bodies and dementia in Parkinson’s disease At autopsy DLB is neuropathologically indistinguishable from dementia occurring late in the course of PD (PDD). This has led to a continuing debate about the relationship between these two clinically defined syndromes. Most clinicians find it helpful to make a distinction between DLB and PDD based on the temporal sequence in which symptoms appear. This approach is (understandably) not generally favored by some contemporary neuroscience researchers, who regard the different clinical presentations as simply representing different points on a common spectrum of LB disease with shared abnormalities in a-synuclein metabolism. This unified approach to classification is probably preferable for molecular and genetic studies and for developing therapeutic agents. The extent to which PD, PDD and DLB are similar remains to be investigated in further depth. For example, a proposal to stage LB pathology in the brain has relatively recently been proposed for PD (Braak et al., 2003). This postulates a progressive spread from the medulla oblongata and olfactory bulb (presymptomatic stages 1 and 2) through the substantia nigra and other midbrain nuclei and basal forebrain (symptomatic stages 3 and 4), eventually encroaching upon the telencephalic cortex in end-stages 5 and 6. It has been suggested that in DLB the burden of pathology is differently distributed, with greater emphasis on the cortex (Kosaka et al., 1996). The validity of the Braak staging scheme and its relevance to DLB remain to be determined. The remainder of the chapter will focus on
*Correspondence to: Professor Ian McKeith, Institute for Ageing and Health, Newcastle General Hospital, Westgate Road, Newcastle upon Tyne NE4 6BE, UK. E-mail:
[email protected], Tel: þ44-(0)191-256-3018, Fax: þ44-(0)191-219-5071.
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clinical, pathological and management aspects of DLB. PDD is covered in detail in Chapter 18. 60.1.3. Clinical significance of dementia with Lewy bodies Until the last decade DLB was not widely recognized as a common form of dementia in older people and the majority of cases were probably incorrectly diagnosed in the clinic as Alzheimer’s disease (AD) or vascular dementia (McKeith et al., 1994). Although case reports describing dementia in association with LB pathology had been published intermittently during the previous 30 years (Okazaki et al., 1961; Kosaka et al., 1984), it was the advent of antiubiquitin immunocytochemical staining (Lennox et al., 1989a, b) that prompted widespread recognition that LB pathology was common in patients with dementia. It was only after this that operationalized criteria for DLB started to be developed. The history of these developments has been reviewed elsewhere (McKeith, 2005a) and a Consortium on DLB was established in 1985 to set internationally agreed standards for clinical and pathological diagnosis (McKeith et al., 2005). The importance of recognizing DLB relates particularly to its pharmacological management, with reports of good responsiveness to cholinesterase inhibitors (ChEIs) (McKeith et al., 2000; Aarsland et al., 2004), extreme sensitivity to the sideeffects of neuroleptics (McKeith et al., 1992a; Ballard et al., 1998a) and limited responsiveness to levodopa (Bonelli et al., 2004; Molloy et al., 2005).
60.2. Clinical features The central characteristic of DLB is a progressive dementia with marked impairments in visuoperceptual, attentional and executive functions reflecting a combination of cortical and subcortical damage. The clinical picture does not always conform to the classic description of a dementia syndrome, e.g. as described in Diagnostic and Statistical Manual of Mental Disorders (DSM-IVR), which requires a combination of decline in memory and at least one other cognitive function, in the context of unimpaired consciousness. In DLB disturbances in the patient’s level of alertness and attention are usually apparent and often severe, and the cognitive deficits do not always include severe memory loss. Fluctuating cognition, recurrent visual hallucinations (VHs) and extrapyramidal motor symptoms are the core features by which DLB is recognized clinically (McKeith et al., 1996), although these features are now known to be absent in a significant minority of cases, particularly those with significant additional Alzheimer pathology (Merdes et al., 2003). The onset tends to be insidious,
although reports of a period of increased confusion or prominent hallucinations may give the impression of a sudden onset. In the first instance the patient may be considered to have a delirium rather than a dementia syndrome. The course is almost invariably progressive, with cognitive function scores declining about 10% per annum. In one study over 1 year, subjects with DLB, AD and vascular dementia had similar rates of overall cognitive decline, approximately 4–5 points on MiniMental State Examination (MMSE) and 12–14 points on Cambridge Cognitive Examination (CAMCOG) (Ballard et al., 2001). Survival times from onset until death are also similar to AD (Walker et al., 2000a), although a minority of DLB patients have a very rapid disease course (Armstrong et al., 1991; Lopez et al., 2000; Collerton et al., 2003). 60.2.1. Cognition The profile of neuropsychological impairments in patients with DLB differs from that of AD and other dementia syndromes (Collerton et al., 2003), reflecting the combined involvement of cortical and subcortical pathways and relative sparing of the hippocampus. Episodic recall and recognition (Calderon et al., 2001; Collerton et al., 2003) can be relatively preserved in the early stages, in contrast to AD, in which memory failure is often the presenting complaint. Patients with DLB perform better than those with AD on tests of verbal memory (McKeith et al., 1992b) but worse on visuospatial performance tasks (Walker et al., 1997) and tests of attention (Sahgal et al., 1992). This profile may be harder to recognize later in the disease when global cognitive difficulties obscure the picture. It has been suggested that this ‘double discrimination’ can help differentiate DLB from AD, with relative preservation of confrontation naming, short- and medium-term recall as well as recognition, and greater impairment on verbal fluency, visual perception and performance tasks (Walker et al., 1997; Connor et al., 1998; Ferman et al., 1999; Collerton et al., 2003; Mormont et al., 2003). Despite these selective patterns of impairment, composite global cognitive assessment tools such as MMSE cannot be relied upon to distinguish DLB from other common dementia syndromes (Ala et al., 2004) and detailed neuropsychological assessment is often required. Computer-based test systems may be particularly useful to capture elements of attentional (Wesnes et al., 2002) and visuoperceptual performance (Mosimann et al., 2004) in DLB. 60.2.2. Cognitive fluctuation Fluctuations in cognitive function, which may vary over minutes, hours or days, occur in 50–75% of
DEMENTIA WITH LEWY BODIES patients and are associated with shifting levels of attention and alertness. Cognitive fluctuations may contribute to large variability in repeated test scores, e.g. 5 MMSE points difference over the course of a few days or weeks (Mega et al., 1996), making it difficult to be sure of the severity of cognitive impairment by a single examination. The assessment of fluctuating cognitive impairment poses considerable difficulty to many clinicians and has been repeatedly cited as a reason for low clinical ascertainment of DLB (Mega et al., 1996; Litvan et al., 1998). Newly proposed care-giver and observer-rated scales may be particularly helpful in this regard (Walker et al., 2000b). Questions such as ‘are there episodes when his/her thinking seems quite clear and then becomes muddled?’ were originally thought to be useful probes (Ballard et al., 1993), although two recent studies found most carers responded positively to such questions regardless of diagnostic subtype (Bradshaw et al., 2004; Ferman et al., 2004). These investigators also established that more reliable predictors of DLB diagnosis are objective questions about daytime sleepiness, episodes of staring blankly or incoherent speech and qualitative assessment of the range of fluctuation, e.g. best versus worst. Recording variation in attentional performance using a computer-based test system offers an independent method of measuring fluctuation which is also sensitive to drug treatment effects (Wesnes et al., 2002). 60.2.3. Recurrent visual hallucinations Recurrent VHs are the most characteristic neuropsychiatric feature of DLB, occurring in up to 80% of cases, and they are often the symptom which first alerts the clinician to a DLB diagnosis. Their presence early in the course of illness (Ballard et al., 1999) and their persistence throughout (McShane et al., 1998) help to distinguish them from the transient perceptual disturbances that may occasionally occur in dementias of other etiology or during delirium. Well-formed, detailed and animate figures are experienced, provoking emotional responses varying through fear, amusement or indifference, usually with some insight into the unreality of the episode once it is over. Why VH and other visual symptoms such as illusions and misidentifications are so common in DLB (Ballard et al., 1999; Mosimann et al., 2006) is not known but it seems probable that they are closely related to the pronounced visuoperceptual and attentional deficits. Meta-analysis of neuropschological studies in different neurogenerative disorders reveals a significant and positive association between the severity of visuoperceptual impairments and the frequency of VH, DLB
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having the highest of all (Collerton et al., 2003). A novel perception and attention deficit model for recurrent complex VH suggests that a combination of impaired attentional binding and poor sensory activation of a correct proto-object, in conjunction with a relatively intact scene representation, bias perception to allow the intrusion of a hallucinatory proto-object into a scene perception. Incorporation of this image into a context-specific hallucinatory scene representation accounts for repetitive hallucinations (Collerton et al., 2005). These impairments, which are underpinned by disturbances in a lateral frontal cortexventral visual stream system, are consistent with the known distribution of neurochemical and pathological deficits of DLB, as discussed later in this chapter. 60.2.4. Other neuropsychiatric features Neuropsychiatric features other than VH are common in DLB (Del-Ser et al., 2000), but none is quite so characteristic and most are also equally prevalent in other dementing disorders. Auditory hallucinations occur in about 20% of DLB cases and, together with olfactory and tactile hallucinations, may lead to initial diagnoses of late-onset psychosis (Birkett et al., 1992) or temporal lobe epilepsy (McKeith et al., 1992b), the latter particularly when they are associated with apparent disturbances of consciousness. Delusions are common in DLB, occurring in over half and usually being based on recollections of hallucinations and perceptual disturbances. They consequently have a fixed, complex and bizarre content that contrasts with the mundane and often poorly formed persecutory ideas encountered in AD patients that are usually based upon forgetfulness and confabulation. The assessment of depression, which is also frequently encountered in DLB (McKeith et al., 1992b), is complicated not only by apathy and attentional deficits, but by extrapyramidal motor dysfunction, including facial and body bradykinesia (Klatka et al., 1996). Apathy is another common feature of DLB and may mimic depression or excessive daytime somnolence. Anxiety, agitation and behavioral disturbances are frequently secondary to fluctuating confusion and hallucinations and may improve when these are treated. 60.2.5. Sleep disorders Sleep disorders have recently been recognized as common in DLB, with daytime somnolence and nocturnal restlessness (Boeve et al., 1998; Grace et al., 1998) sometimes as a prodromal feature. Rapid-eye movement (REM) sleep–wakefulness dissociations may explain several features of DLB that are characteristic
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of narcolepsy (REM sleep behavior disorder (RBD), daytime hypersomnolence, VHs and cataplexy) (Boeve et al., 2001). RBD is manifested by vivid and often frightening dreams during REM sleep, but without the normal muscle atonia typical of REM sleep. Patients therefore appear to ‘act out their dreams’, vocalizing, flailing limbs and moving around the bed, sometimes violently. Vivid visual images are often reported, although the patient may have little recall of these episodes. The history is obtained from the bed-partner who may report many years of this sleep disorder prior to the onset of dementia and parkinsonism (Boeve et al., 2004). RBD is frequently associated with LB disease and only rarely with other neurodegenerative disorders (Boeve et al., 2003). Sleep disorders may contribute to the fluctuations typical of DLB and their treatment may improve fluctuations and quality of life (Boeve et al., 2003).
repeated falls and syncope and the transient losses of consciousness that are seen in some DLB patients (Ballard et al., 1998b).
60.2.6. Motor parkinsonism
Based upon these observations, attempts were made to describe the typical course of illness (Burkhardt et al., 1988; Crystal et al., 1990; McKeith et al., 1992b) and the first formal clinical diagnostic criteria were proposed. The Nottingham (UK) group based their proposed system upon the clinical characteristics of 15 personal cases, the largest individual series published at that time (Byrne et al., 1989). Seven were men, the mean age at onset was 72 years and the mean duration of illness was 5.5 years. A total of 40% presented with symptoms and signs of idiopathic PD, with cognitive impairment occurring 1–4 years later. A further 20% had parkinsonism and mild cognitive impairment at presentation and the remaining 40% showed motor features later in their illnesses, gait disturbance and postural abnormalities being most common. These latter cases presented with neuropsychiatric features only, in various combinations of cognitive impairment, paranoid delusions and visual or auditory hallucinations. Fourteen of the 15 were demented before death, the exception presenting with classic PD and later becoming depressed, irritable and mildly forgetful with frequent falls. Fluctuating cognition with episodic confusion, for which no adequate underlying cause could be found, was observed in 80% of the Nottingham cases. Byrne et al. (1991) also drew attention to the frequent occurrence of depression (20%) and psychosis (33%). This led to the first formal proposal of operational criteria for DCLB. The presence of extrapyramidal features was mandatory, although these could be mild and occur late in the course of the illness. Since at least 25% of DLB cases reported in the whole literature (Kosaka and Iseki, 1998; Papka et al., 1998) never have motor parkinsonism, the sensitivity of the Nottingham criteria was inevitably restricted by this requirement,
Extrapyramidal signs (EPS) are reported in 25–50% of DLB cases at diagnosis and 75–80% develop some EPS during the natural course. This means that up to 25% of patients with pathologically confirmed LB disease will have no clinical history of parkinsonism and clinicians must be prepared to consider and diagnose DLB in its absence. Originally said to ‘be mild and to appear late in the clinical course’, the profile of EPS in DLB is now generally thought to be similar to that in age-matched non-demented PD patients with regard to overall severity (Aarsland et al., 2001b). There is however greater symmetry and axial tendency, postural instability and facial impassivity but less tremor (Burn et al., 2003). The rate of motor deterioration on the Unified Parkinson’s Disease Rating Scale (UPDRS) (Fahn and Elton, 1987) is about 10% per annum, similar to PD (Ballard et al., 2000a). Levodopa-responsiveness is reduced in DLB compared with PD (Bonelli et al., 2004; Molloy et al., 2005), possibly due to additional intrinsic striatal pathology and dysfunction (Duda et al., 2002) and the fact that some of the parkinsonian features are non-dopaminergic in origin (Burn and McKeith, 2004). 60.2.7. Autonomic dysfunction Severe autonomic dysfunction may occur early in the clinical course, producing orthostatic hypotension, neurocardiovascular instability, urinary incontinence, constipation and impotence as well as eating and swallowing difficulties (Kuzuhara and Yoshimura, 1993; Del-Ser et al., 1996; Horimoto et al., 2003; McKeith, 2003). Autonomic dysfunction may also contribute to
60.3. Clinical diagnostic criteria for dementia with Lewy bodies Following the recognition of LB pathology in neuropathological autopsy series of elderly patients with dementia, several preliminary attempts were made to describe the clinical course and characteristics by which these patients could be identified antemortem (Okazaki et al., 1961; Kosaka, 1978; Kosaka et al., 1984; Byrne et al., 1989; Gibb et al., 1989; Crystal et al., 1990; Hansen et al., 1990; Perry et al., 1990; Fo¨rstl and Levy, 1991; Kuzuhara and Yoshimura, 1993). 60.3.1. Early diagnostic criteria
DEMENTIA WITH LEWY BODIES which may have been influenced by the inclusion in their sample of 5 cases who had motor-only PD diagnosed for at least 12 months before neuropsychiatric features developed. According to current criteria these cases would be regarded as having PDD and not a primary diagnosis of DLB. The Newcastle upon Tyne (UK) criteria which were formulated at about the same time, based upon a series of 21 autopsy cases sampled from a geriatric psychiatry service, stipulated the presence of fluctuating cognitive impairment plus two of the following three items: (1) visual and/or auditory hallucinations, which are usually accompanied by secondary paranoid delusions; (2) mild spontaneous extrapyramidal features or neuroleptic sensitivity syndrome, i.e. exaggerated adverse responses to standard doses of neuroleptic medication; and (3) repeated unexplained falls and/or transient clouding or loss of consciousness. Applied retrospectively to a sample of autopsyconfirmed cases, these criteria identified 71% of LB pathology cases on initial presentation and 86% between presentation and death. Although some of the cases also met clinical criteria for AD, no AD cases met the proposed LB criteria, indicating that the core features selected have good specificity. Applied to another independent sample of DLB, AD and vascular dementia patients, the Newcastle criteria yielded a 74% sensitivity rate, averaged across four raters, and a specificity of 95%. Inter-rater agreement was highest and diagnosis most accurate (90% versus 55% sensitivity) among more experienced clinicians. The most common errors among less experienced clinicians were failure to recognize cognitive fluctuations unique to DLB patients, and a tendency to overvalue comorbid disease as responsible for the clinical presentation (McKeith et al., 1994). The clinical narrative that accompanied these criteria described the evolution of the disease in three stages (McKeith et al., 1992b): The first stage is often recognised only in retrospect and may extend back one to three years pre-presentation with occasional minor episodes of forgetfulness, sometimes described as lapses of concentration or ‘switching off’. A brief period of delirium is sometimes noted for the first time, often associated with genuine physical illness and/or surgical procedures. Disturbed sleep, nightmares and daytime drowsiness often persist after recovery. Progression to the second stage frequently prompts psychiatric or medical referral. A more sustained cognitive impairment is established, albeit with marked fluctuations in severity.
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Recurrent confusional episodes are accompanied by vivid hallucinatory experiences, visual misidentification syndromes and topographical disorientation. Extensive medical screening is usually negative. Attentional deficits are apparent as apathy, and daytime somnolence and sleep behaviour disorder may be severe. Gait disorder and bradykinesia are often overlooked, particularly in elderly subjects. Frequent falls occur due either to postural instability or syncope. The third and final stage often begins with a sudden increase in behavioural disturbance leading to requests for sedation or hospital admission by perplexed and exhausted carers. The natural course from this point is variable and obscured by the high incidence of adverse reactions to neuroleptic medication. For patients not receiving, or tolerating neuroleptics, a progressive decline into severe dementia with dysphasia and dyspraxia occurs over months or years, with death usually due to cardiac or pulmonary disease. During this terminal phase patients show continuing behavioural disturbance including vocal and motor responses to hallucinatory phenomena. Lucid intervals with some retention of recent memory function and insight may still be apparent. Neurological disability is often profound with fixed flexion deformities of the neck and trunk and severe gait impairment.
60.3.2. The dementia with Lewy bodies Consortium Consensus Criteria By the early 1990s it was becoming apparent that DLB was a relatively common dementia subtype and that the several research groups investigating it were adopting different terminologies for what were essentially the same patients. The Consortium on DLB therefore met in October 1995 in Newcastle upon Tyne to agree common clinical and pathological methods and nomenclature. The Consensus Criteria (McKeith et al., 1996) which resulted were largely based on the symptom content of the earlier Newcastle and Nottingham schemes and followed the general structure of operationalized criteria already in use for AD (McKhann et al., 1984), assigning levels of ‘possible’ and ‘probable’ clinical diagnosis. The particular characteristics of the cognitive impairments of DLB were described in some detail as differing from the dementia syndrome of AD. Probable DLB is diagnosed when two of the three key symptoms in Table 60.1 are present, namely fluctuation, VHs or
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Table 60.1 Consensus guidelines for the clinical diagnosis of probable and possible dementia with Lewy bodies (DLB) 1. Central feature Progressive cognitive decline of sufficient magnitude to interfere with normal social and occupational function. Prominent or persistent memory impairment may not necessarily occur in the early stages but is usually evident with progression. Deficits on tests of attention and of frontal subcortical skills and visuospatial ability may be especially prominent 2. Core features (two core features essential for a diagnosis of probable, one for possible DLB) Fluctuating cognition with pronounced variations in attention and alertness Recurrent visual hallucinations that are typically well formed and detailed Spontaneous features of parkinsonism 3. Supportive features Repeated falls Syncope Transient loss of consciousness Neuroleptic sensitivity Systematized delusions Hallucinations in other modalities Rapid-eye movement sleep behavior disorder Depression 4. Features less likely to be present History of stroke Any other physical illness or brain disorder sufficient enough to interfere with cognitive performance Reproduced from McKeith et al. (1996) with permission from Lippincott/Williams & Wilkins.
spontaneous motor features of parkinsonism and possible DLB if only one is present. Several retrospective and two prospective studies subsequently examined the predictive accuracy of Consensus clinical criteria for probable DLB (Litvan et al., 2003). These suggested that sensitivity of case detection was variable and, although high in one prospective study (McKeith et al., 2000b), was unacceptably low in several others. In contrast, specificity was generally found to be high. The main criticism of the Consensus criteria was lack of operationalization of the core feature items, fluctuation in particular (Mega et al., 1996). Modified versions of the criteria were proposed which essentially traded increased sensitivity against reduced diagnostic specificity (Luis et al., 1999; Litvan et al., 2003). However, a later series of neuropathological autopsy studies revealed a further reason for the failure of the clinical criteria to detect demented cases with LB. These studies suggested that DLB patients with additional neocortical tangle (Alzheimer) pathology often lacked the typical
DLB cognitive profile, showing pronounced memory deficits and a clinical presentation more characteristic of AD. Fluctuation, VHs and parkinsonism were generally absent in such cases or if present were masked by the Alzheimer-like clinical picture. The Consensus criteria are then able to detect DLB cases with a high positive predictive value, but even when used in conjunction with optimal clinical assessment tools for core features, will inevitably fail to detect a significant proportion of DLB cases in whom those features are absent. 60.3.3. Revised consensus criteria for the clinical diagnosis of dementia with Lewy bodies In order to address the perceived shortcomings of the original diagnostic criteria, the DLB Consortium met again in 2003 to resolve improved methods of identifying cases antemortem (McKeith et al., 2005). No major amendments to the three core features of DLB were proposed, but better methods for their clinical assessment (Table 60.2) were recommended for use in diagnosis and for measurement of symptom severity. A new category of features ‘suggestive’ of DLB was described, comprising RBD, severe neuroleptic sensitivity or abnormal dopamine transporter (DAT) neuroimaging. If one or more of these suggestive features is present, in addition to one or more core features, a diagnosis of probable DLB is made. Possible DLB can be diagnosed if one or more is present in a patient with dementia even in the absence of any core features. Suggestive features therefore have a similar diagnostic weighting as core clinical features but are not considered sufficient, even in combination, to warrant a diagnosis of probable DLB if all three core features are absent. The revised criteria are also more explicit about the importance to be attached to clinical and radiological evidence of cerebrovascular disease (McKeith et al., 2005) since pathological and imaging studies suggest that white-matter lesions (periventricular and deep white matter), microvascular changes and lacunes may be present in up to 30% of DLB cases (McKeith, et al., 2000b; Jellinger, 2003).
60.4. Differential diagnosis The main differential diagnoses of DLB are AD, vascular dementia, PDD, atypical parkinsonian syndromes such as progressive supranuclear palsy (PSP), MSA, corticobasal degeneration (CBD) and also Creutzfeldt–Jakob disease (CJD) (McKeith et al., 1996). The mainstay of differential diagnosis remains careful evaluation by a specialist clinician familiar with these disorders and
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Table 60.2 Revised criteria for the clinical diagnosis of dementia with Lewy bodies (DLB) 1. Central feature (essential for a diagnosis of possible or probable DLB) Dementia defined as progressive cognitive decline of sufficient magnitude to interfere with normal social or occupational function. Prominent or persistent memory impairment may not necessarily occur in the early stages but is usually evident with progression. Deficits on tests of attention, executive function and visuospatial ability may be especially prominent 2. Core features (two core features are sufficient for a diagnosis of probable DLB, one for possible DLB) Fluctuating cognition with pronounced variations in attention and alertness Recurrent visual hallucinations that are typically well formed and detailed Spontaneous features of parkinsonism 3. Suggestive features (if one or more of these is present in the presence of one or more core features, a diagnosis of probable DLB can be made. In the absence of any core features, one or more suggestive features is sufficient for possible DLB. Probable DLB should not be diagnosed on the basis of suggestive features alone) Rapid-eye movement sleep behavior disorder Severe neuroleptic sensitivity Low dopamine transporter uptake in basal ganglia demonstrated by SPECT or PET imaging 4. Supportive features (commonly present but not proven to have diagnostic specificity) Repeated falls and syncope Transient, unexplained loss of consciousness Severe autonomic dysfunction, e.g. orthostatic hypotension, urinary incontinence Hallucinations in other modalities Systematized delusions Depression Relative preservation of medial temporal lobe structures on CT/MRI scan Generalized low uptake on SPECT/PET perfusion scan with reduced occipital activity Abnormal (low-uptake) MIBG myocardial scintigraphy Prominent slow-wave activity on EEG with temporal lobe transient sharp waves 5. A diagnosis of DLB is less likely In the presence of cerebrovascular disease evident as focal neurological signs or on brain imaging In the presence of any other physical illness or brain disorder sufficient to account in part or in total for the clinical picture If parkinsonism only appears for the first time at a stage of severe dementia 6. Temporal sequence of symptoms DLB should be diagnosed when dementia occurs before or concurrently with parkinsonism (if it is present). The term Parkinson’s disease dementia (PDD) should be used to describe dementia that occurs in the context of well-established Parkinson’s disease. In a practice setting the term that is most appropriate to the clinical situation should be used and generic terms such as Lewy body disease are often helpful. In research studies in which distinction needs to be made between DLB and PDD, the existing 1-year rule between the onset of dementia and parkinsonism DLB continues to be recommended. Adoption of other time periods will simply confound data pooling or comparison between studies. In other research settings that may include clinicopathologic studies and clinical trials, both clinical phenotypes may be considered collectively under categories such as Lewy body disease or a-synucleinopathy. Reproduced from McKeith et al. (2005) with permission from Lippincott/Williams & Wilkins. SPECT, single-photon emission computed tomography; PET, positron emission tomography; CT, computed tomography; MRI, magnetic resonance imaging; MIBG, 123I-metaiodobenzylguanadine; EEG, electroencephalogram.
incorporating a history from an independent informant. Enquiry should be made not only about cognitive, psychiatric and motor features, but also about other symptom domains such as sleep or autonomic dysfunction. 60.4.1. Role of investigations There are as yet no clinically applicable electrophysiological, genotypic or cerebrospinal fluid markers to support a DLB diagnosis (McKeith et al., 2004a) but
neuroimaging investigations may be helpful. Changes associated with DLB include preservation of hippocampal and medial temporal lobe volume on magnetic resonance imaging (Barber et al., 1999, 2000a) (Fig. 60.1) and occipital hypoperfusion on single-photon emission computed tomography (SPECT) (Lobotesis et al., 2001; Colloby et al., 2002). Other features, such as generalized atrophy (Barber et al., 2000a), white-matter changes (Barber et al., 2000b) and rates of progression of whole-brain atrophy (O’Brien et al., 2001), appear to
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Fig. 60.1. Coronal magnetic resonance imaging (MRI) scan of patients with Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) matched for clinical severity of dementia. Medial temporal lobe (particularly hippocampal) atrophy is less pronounced in DLB, consistent with autopsy findings. Courtesy of Dr. Emma Burton. Reproduced from McKeith et al. (2004a), The Lancet Neurology, with permission from Elsevier.
be unhelpful in differential diagnosis. Functional imaging of the DAT defines integrity of the nigrostriatal dopaminergic system and currently has its main clinical application in assisting diagnosis of patients with tremor of uncertain etiology (Marshall and Grosset, 2003). Imaging with specific SPECT ligands for DAT provides a marker for presynaptic neuronal degeneration. DAT imaging is abnormal in idiopathic PD, multiple system atrophy (MSA) and PSP and does not distinguish between these disorders. Low striatal uptake has also been reported in DLB but is normal in AD (Piggott et al., 1999), making DAT scanning particularly useful in distinguishing between the two disorders (O’Brien et al., 2004; Walker et al., 2004) (Fig. 60.2). Scintigraphy with MIBG (Yoshita et al., 2001) enables the quantification of postganglionic sympathetic cardiac innervation and has also been suggested to have high sensitivity and specificity in the differential diagnosis of DLB from AD (Taki et al., 2004).
An issue, already alluded to in section 60.1.1 , which repeatedly causes difficulty in diagnosing DLB, is uncertainty about its relationship with PDD. PDD is similar to DLB (Aarsland et al., 2003; Emre, 2003) with respect to fluctuating neuropsychological function (Ballard et al., 2002), neuropsychiatric features (Aarsland et al., 2001a) and extrapyramidal motor features (Aarsland et al., 2001b). The findings at autopsy are also similar in DLB and PDD and the clinical history cannot be extrapolated from the neuropathological findings. The 1996 Consensus statement recommended an arbitrary ‘1-year rule’ that proposes that the onset of dementia within 12 months of parkinsonism qualifies as DLB and more than 12 months of parkinsonism before dementia qualifies as PDD. As previously stated, this distinction between DLB and PDD as two distinct clinical phenotypes, based solely on the temporal sequence of appearance of symptoms, has been criticized by those who regard the different clinical presentations as simply representing different points on a common spectrum of LB disease (Hardy, 2003). This approach to classification may be preferable for molecular and genetic studies and for developing therapeutics. Clinicians on the other hand prefer diagnostic labels that describe the symptoms as patients present to them and this will often include consideration of the temporal course. The revised Consensus statement recommends that, for clinical, operational definitions, DLB should be diagnosed when dementia occurs before or concurrently with parkinsonism and PDD should be used to describe dementia that occurs in the context of well-established PD. In a practice setting the term that is most appropriate to the clinical situation should be used and generic terms such as LB disease are often more helpful. In research studies in which distinction is made between DLB and PDD, the 1-year rule between the onset of dementia and parkinsonism for DLB continues to be recommended. Further research efforts which lead to better understanding of the molecular basis for these disorders may lead to modifications in these temporal considerations. 60.4.3. Pathology and etiology
Fig. 60.2. For full color figure, see plate section. Singlephoton emission computed tomography (SPECT) images of the dopamine transporter at the level of the striatum using fluoropropyl (FP)-CIT show marked reduction of activity in dementia with Lewy bodies (DLB) compared with normal activity in Alzheimer’s disease (AD) and normal aging. Courtesy of Professor JT O’Brien. Reproduced from McKeith et al. (2004a), The Lancet Neurology, with permission from Elsevier.
The original delineation of DLB from other dementing disorders was made on the basis of neuropathological findings, i.e. the presence of cortical LB at autopsy. It is generally accepted that most DLB cases show asynuclein-positive LB and Lewy neurites (LN) together (Fig. 60.3) with abundant Alzheimer-type pathology, predominantly in the form of amyloid
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Fig. 60.3. For full color figure, see plate section. Neuropathology of dementia with Lewy bodies (DLB). Pathological a-synuclein aggregates assume many forms in DLB, including typical classical Lewy bodies (LBs) in the pigmented nuclei of the brainstem (A, B), cortical LBs in the neocortex (C) and amygdala, dystrophic or Lewy neurites (LNs) in the CA 2/3 subfield of Ammon’s horn (D) and neuroaxonal spheroids (E). The burden of a-synuclein aggregates in the neocortex (F) can be extreme with cortical LBs in the deeper layers (top left) and LNs throughout the cortical mantle to the pial surface (bottom right). The striatum is also affected (G) with primarily LNs (H) and dot-like aggregates (I). LNs tend to cluster around ß-amyloid plaques (J), which are also common in DLB, and are primarily axonal in location (K). (Antibodies: a-synuclein in A, C–I, and J, K (green); tyrosine hydroxylase in B; ß-amyloid in J (red); neurofilaments light chain in K (red).) Courtesy of Dr. John E Duda. Reproduced from McKeith et al. (2004a), The Lancet Neurology, with permission from Elsevier.
plaques. Tau-positive inclusions and neocortical neurofibrillary tangles sufficient to meet Braak stages V or VI (sufficient to qualify for a diagnosis of concomitant AD) occur in only a minority (10–25%) of cases. Alzheimer pathology of any type is not a prerequisite for the existence of dementia, however, since older patients with ‘pure’ LB disease (no plaques or tangles) may present clinically with cognitive impairment and other neuropsychiatric features. 60.4.4. Lewy bodies and Lewy-related pathologies Immunohistochemical and protein chemical studies indicate that LBs and LNs are pathological aggregations of a-synuclein, DLB being a member of the family of a-synucleinopathies (Jellinger, 2003) which also includes PD and MSA. LBs and LNs are associated with intermediate filaments, chaperone proteins
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and elements of the ubiquitin-proteasome system, indicating a role of the aggresomal response, but these features are not specific for LBs and are found in other neuronal inclusions (McNaught et al., 2002; Tanaka et al., 2004). Cortical LB density is not robustly correlated with either the severity or duration of dementia (Go´mez-Tortosa et al., 1999; Harding and Halliday, 2001), although associations have been reported with LB and plaque density in mid frontal cortex (Samuel et al., 1996). LNs and neurotransmitter deficits are better correlates of clinical symptoms (Go´mez-Tortosa et al., 1999; Perry et al., 2003c). Formal criteria for the pathological diagnosis of DLB have not yet been established in the way that they have for other neurodegenerative disorders. The original 1996 Consensus paper provided guidelines for sampling procedures and recommendations about staining and counting methods (McKeith et al., 1996), but these have had two subsequent revisions (McKeith et al., 1999, 2005). For the purposes of assessing Lewy-related pathology, the latest recommendation is to use a-synuclein immunohistochemistry and a semiquantitative grading of lesion density rather than the counting methods previously proposed. LB-type pathology is assigned according to the guidelines in the original Consensus report. Semiquantitative grading of LB severity is adopted rather than counting LB in various brain regions. The pattern of regional involvement is more important than total LB count. 60.4.5. Alzheimer-type pathology The guidelines have also been modified to address the issue of concomitant Alzheimer-type pathology, taking account of the pathoplastic effect that this has upon the clinical presentation. Cases are assigned a likelihood that the dementia can be attributed to AD pathology using the NIA–Reagan criteria (NIA, National Institute on Aging), which employs the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) method for assessing neuritic plaques (Mirra et al., 1991) and a topographic staging method for neurofibrillary degeneration (Harding et al., 2000). This approach allows the reporting pathologist not only to give a detailed semiquantitative description of the pathological findings in an individual case, but also to estimate the probability (low, intermediate or high) of the patient having had the characteristic DLB clinical syndrome. 60.4.6. Synuclein pathology in Alzheimer’s disease a-Synuclein immunoreactive deposits with many of the characteristics of LB have also been reported in
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60% of AD cases, particularly in the amygdalae (Hamilton, 2000) but seldom involving other brain regions to any significant extent. This distribution probably represents an end-stage phenomenon, with a secondary accumulation of aggregated synuclein in severely dysfunctional neurons that are already heavily burdened by plaque and tangle pathology (Lippa and McKeith, 2003). Such cases with amydalae-only LB are highly unlikely to be associated with the DLB clinical syndrome and their inclusion in a clinicopathological series serves to underestimate the diagnostic sensitivity of clinical criteria. 60.4.7. Genetics of dementia with Lewy bodies There are few reports to date of autosomal-dominant DLB families. This may partly be due to the relatively late onset of DLB but also to a failure to recognize the relationship of DLB with other phenotypes, including PD and autonomic dysfunction. The identification of mutations in the a-synuclein gene in familial PD (Polymeropoulos et al., 1997) has not been followed by similar findings in sporadic PD and DLB. Nor have associations been found with DLB with polymorphisms in the genes for presenilin 1, presenilin 2, and a1 antichymotrypsin. These genes are therefore unlikely to have a major influence on the pathogenesis of DLB. Because of the association of the 4 allele of the apolipoprotein E (APO E) gene on chromosome 19 and AD, and the presence of b-amyloid in DLB, several groups have reported genotyping studies. In DLB, the e4 allele frequency is elevated in a manner analogous to that found in AD (Benjamin et al., 1994). In PD no association is observed with APO E e4. There are, however, subtle differences in the APO E allele frequencies between AD and DLB, with a higher e2 allele frequency and a reduced frequency of the e4/4 genotype in DLB (Morris et al., 1996). Differences in the APO E frequencies may account for some of the differences between the two diseases in terms of clinical presentation and pathology, but it is unlikely that one single genetic determinant accounts for the differences between DLB and AD. Polymorphisms in other putative risk genes for DLB, which have not been reliably replicated, include the butyrylcholinesterase gene K variant (BCHE K), the cytochrome P-450 gene CYP2D6 (debrisoquine 4-hydroxylase) and N-acetyltransferase 2 gene locus. Butyrylcholinesterase gene K/K and atypical variants do however appear to have a role in modifying the level of cognitive impairment and responsiveness to ChEI responsiveness in DLB (O’Brien et al., 2003) and may also influence rate of progression of untreated disease (Perry et al., 2003a).
There are recent reports that triplication of the a-synuclein gene (SNCA) can cause DLB, PD and PDD whereas gene duplication is only associated with motor PD, suggesting a gene dose effect (Singleton and Gwinn-Hardy, 2004). However, SCNA multiplication is not found in most LB disease patients (Johnson et al., 2004). 60.4.8. Neurochemical pathology of dementia with Lewy bodies DLB is a disorder in which functional deficits might reasonably be postulated to be related to perturbations in neurotransmitter function, given the fluctuating nature of the clinical syndrome and the relative lack of major structural disruption of the cortex compared with AD. Neurochemical studies of transmitter and receptor function in frozen autopsy tissue lend some support to such a model. Neurotransmitter replacement treatments in DLB which are based on these observations have produced mixed results, with good response experienced by some patients receiving cholinergic, but a generally poor response to dopaminergic, treatments. 60.4.8.1. Dopaminergic system Although neuronal loss within the substantia nigra may be less in DLB than in PD, striatal dopamine concentrations are reduced to an equivalent level (Piggott et al., 1999). Within the striatum, dopamine D2-receptor levels are elevated in PD and this compensatory upregulation is maintained for several years. In contrast, D2-receptors are modestly reduced in DLB, particularly in the putamen (Piggott et al., 1999), contributing to severe neuroleptic sensitivity. Extrastriatal dopaminergic systems are also affected in PD and DLB. Mesocortical projections to the frontal cortex are implicated in working memory performance, and dopamine receptors are also expressed in temporal cortex (Farde et al., 1997). Investigations in PD have shown no change in early disease in cortical D1-receptors (Gnanalingham et al., 1993), whereas in advanced PD, functional imaging studies have indicated D2-receptors to be reduced by 40% in frontal cortex (Kaasinen et al., 2000). 60.4.8.2. Cholinergic system Cholinergic deficits are more marked in PD patients with dementia compared to those without, as evidenced by greater neuronal loss in the nucleus basalis of Meynert (Jellinger and Bancher, 1995). Furthermore, using [123I] iodobenzovasamicol (a marker of vesicular acetylcholine transporter) and SPECT brain
DEMENTIA WITH LEWY BODIES imaging, PDD cases demonstrate extensive cortical binding decreases similar to early-onset (age at onset < 64 years) AD (Kuhl et al., 1996). Not only are neocortical presynaptic cholinergic inputs reduced in DLB to a greater extent than in AD (Tiraboschi et al., 2000; Shinotoh et al., 2001), but there are also losses in the striatum and pedunculopontine pathway projecting to areas including the thalamus. Cortical choline acetyltransferase reductions in DLB correlate with cognitive impairment and VH. The cortical cholinergic deficit in DLB is, however, independent of the extent of Alzheimer-type pathology, although this pathology is associated with more severe cognitive impairment (Samuel et al., 1997). Nicotinic receptor density, measured using a-bungarotoxin binding (a7 subunit) is reported to be lower in hallucinating compared with non-hallucinating DLB patients (Court et al., 2001). In PDD and DLB, muscarinic M1-receptor binding is elevated. In DLB patients at least, this elevation is greater in individuals with delusions than those without (Ballard et al., 2000b), suggesting that this psychotic feature may be associated with a greater loss of presynaptic cholinergic activity and a consequent upregulation in the M1-receptor subtype. It is not yet established whether loss of cholinergic activity in the thalamic reticular formation, reflecting loss of pedunculopontine neurons, correlates with fluctuating attention and cognition. In summary, in both DLB and PDD, extrastriatal dopaminergic and particularly cholinergic deficits play a central role in mediating dementia.
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60.5.1. A problem-oriented approach to management It is helpful first to draw up a problem list of cognitive, psychiatric and motor disabilities and ask the patient and carer to identify the symptoms that they find most disabling or distressing and which carry highest priority for treatment (McKeith, 2005b). The clinician should explain, before any drugs are prescribed, that treatment gains in a target symptom may be associated with worsening of symptoms in other domains. The specific risks of neuroleptic sensitivity reactions should be mentioned in all cases and it is prudent to mark patient case notes and records with an alert to reduce the possibility of inadvertent neuroleptic prescribing, particularly in primary care or emergency room settings. Non-pharmacologic strategies for cognitive symptoms, including explanation, education, reassurance, orientation and memory prompts, attentional cues and targeted behavioral interventions are an integral part of the management of DLB and pharmacological treatment is most successful when prescribed as part of a comprehensive management approach (Cohen-Mansfield, 2006). Similarly, if a patient with DLB has become acutely confused and psychotic, intercurrent infection and subdural hematoma, in particular, should be actively excluded (McKeith et al., 1996). It cannot always be assumed that worsening of symptoms is simply part of the natural fluctuating history of DLB. Non-essential medications capable of causing confusion should be discontinued.
60.5. Clinical management 60.5.2. Antiparkinsonian agents The pharmacological management of DLB can be one of the most challenging issues facing neurologists, psychiatrists, geriatricians, primary care physicians or others caring for older people. Polypharmacy is the norm, with multiple pharmacological treatment targets including motor parkinsonism, cognitive failure, psychiatric symptoms and autonomic dysfunction. The positive effects of ChEIs seen in many DLB patients contrast with the severe, sometimes fatal, neuroleptic sensitivity reactions that are seen in up to 50% of patients exposed to such agents (McKeith et al., 1992a; Aarsland et al., 2005). There is an intermediate responsiveness to antiparkinsonian agents (Bonelli et al., 2004; Molloy et al., 2005). Since there are no treatments currently licenced for DLB, all prescribing to this group of patients is essentially ‘off-license’. In addition to the medicolegal and liability issues that this can pose for prescribers, health care providers may be reluctant to reimburse drug costs for DLB patients.
Levodopa monotherapy is generally accepted as the preferred option in DLB. Medication should generally be introduced at low doses and slowly increased to the least dose required to minimize disability. Levodoparesponsiveness is of the order of 50% in DLB (Bonelli et al., 2004; Molloy et al., 2005), considerably less than in uncomplicated PD but reminiscent of the loss in treatment sensitivity which comes later in the course of PD, especially as cognitive decline and dementia intervene. Although the reasons for this reduced response to treatment are unclear, it may be partially related to the development of synuclein-positive striatal pathology and associated neuronal dysfunction (Duda et al., 2002) which is no longer amenable to neurotransmitter replacement. Patients and carers will usually indicate when they feel that the lower acceptable limit of antiparkinsonian treatment has been reached. It is not uncommon to find that confusional and psychotic symptoms are not significantly ameliorated by dose
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reductions in antiparkinsonians, nor is motor disability substantially aggravated. This suggests that non-dopaminergic mechanisms may be playing a major role in symptom formation. Other antiparkinsonian medications, including selegeline, amantadine, catechol-O-methyltransferase inhibitors and dopamine agonists are contraindicated in DLB in view of concerns about inducing confusion and psychosis (visual illusions, hallucinations and delusions). Anticholinergics should also be avoided in both DLB and PDD, because they may cause mental clouding, impaired cognition and induce or aggravate hallucinations. There is evidence that their long-term use in PD may be associated with dementia (Pondal et al., 1996) and the accumulation of a higher density of plaque and tangle pathology (Perry et al., 2003b). 60.5.3. Cholinesterase inhibitors ChEIs appear to be effective and relatively safe in the treatment of neuropsychiatric and cognitive symptoms in DLB (Aarsland et al., 2004), but the number of patients studied is relatively small and larger trials are still needed. Apathy, anxiety, impaired attention, hallucinations, delusions, sleep disturbance and cognitive changes are the most frequently cited treatmentresponsive symptoms. Improvements are generally reported as greater than those achieved in AD (Samuel et al., 2000). The first report of benefit with ChEIs was with tacrine, which was administered in an open-label trial to 7 PDD patients. Mean age at the time of treatment was 74 years and the duration of PD before the onset of dementia was 7.6 years. In all cases there was a ‘greatly reduced’ frequency of VH (Hutchinson and Fazzini, 1996). Both MMSE scores and UPDRS motor scores improved significantly after treatment, suggesting that not only did cognitive and neuropsychiatric features improve with tacrine, but so did extrapyramidal motor function. This latter finding was unexpected since theoretical predictions would anticipate motor worsening. Subsequent studies in PDD and DLB have found no evidence for significant motor deterioration, although a minority of patients do experience dosedependent worsening of their tremor. If troublesome, this can be managed in most cases by ChEI dose reduction or increase in levodopa. The ChEI generally available at present are rivastigmine, donepezil and galantamine; all three prevent the inactivation of acetylcholine after its release from the neurone. Rivastigmine is a dual inhibitor of acetylcholinesterase and butyrylcholinesterase, whereas donepezil and galantamine are acetylcholinesteraseselective. Galantamine, the most recently licenced
ChEI, is additionally an allosteric modulator of nicotinic receptors. The outcomes of ChEI treatment of DLB and PDD have been comprehensively reviewed (Aarsland et al., 2004). Placebo-controlled randomized controlled trials of rivastigmine have shown benefits in DLB (McKeith et al., 2000a) and PDD (Emre et al., 2004), in addition to which there is some short-term (Maclean et al., 2001; Reading et al., 2001) and longterm open-label data (Grace et al., 2001). In the latter study MMSE and Neuropsychiatric Inventory (NPI) scores remained stable over the first 12 months of treatment, then gradually worsened, although not statistically significantly so even 2 years after baseline. Motor UPDRS scores tended to improve, probably because antiparkinsonian treatment was initiated over that time. With donepezil there is a double-blind cross-over study in PDD (Aarsland et al., 2002) and a series of open-label studies in DLB (Kaufer et al., 1998; Shea et al., 1998), including one reporting a rebound worsening of neuropsychiatric symptoms, when treatment was stopped abruptly (Minett et al., 2003). Although reinstatement of treatment may reverse such deterioration, it is recommended that DLB patients who are assessed as responding to ChEIs are maintained on treatment long-term. Attempts at switching from one ChEI to another were similarly associated with clinically significant withdrawal effects and the authors did not recommended this treatment strategy (Bhanji and Gauthier, 2003). With galantamine there are as yet only preliminary open-label data (Aarsland and Hutchinson, 2003; Edwards et al., 2004). Taken overall, the effects of the three available ChEIs appear similar, with doses in the same range as used in AD. Parkinsonian signs do not generally worsen on treatment. Predominant adverse effects are cholinergic in nature (nausea, vomiting, anorexia and somnolence) and are generally rated as mild or moderate. Hypersalivation, rhinorrhea and lacrimation were recorded in approximately 15% of DLB and PDD patients treated with donepezil (Thomas et al., 2005) and postural hypotension, falls and syncope are possibly also increased. This latter side-effect profile is consistent with the known pre-existing autonomic dysfunction in DLB and such symptoms are likely to occur with all procholinergic agents. The presence of VH in DLB predicted a good response to rivastigmine in DLB assessed using a computer-based system measuring attentional speed and accuracy (McKeith et al., 2004b). Cognitive reaction time, calculated by subtracting simple from choice reaction times, was however not improved by rivastigmine. This suggests that this cognitive component may be dopaminergically mediated, and the marked reductions that are seen in cognitive reaction time in DLB and
DEMENTIA WITH LEWY BODIES PDD but not in AD (Ballard et al., 2002; Wesnes et al., 2002) are related to a loss of mesocortical dopaminergic projections. 60.5.4. Antipsychotic agents Since hallucinations, delusions and associated behavioral disturbances are so frequent in DLB, a very common clinical scenario is for the clinician to consider using antipsychotic medication. Traditional agents with potent D2-receptor antagonism are associated with severe neuroleptic sensitivity reactions in up to 50% of DLB patients, leading to substantial morbidity and a two- to threefold increased mortality risk (McKeith et al., 1992a; Aarsland et al., 2005). These reactions are generally evident within the first few doses or after increase from a previously tolerated dose. Sensitivity reactions have also been reported for second-generation antipsychotic agents such as risperidone and olanzapine (McKeith et al., 1995; Walker et al., 1999). Newer atypicals with potentially more favorable pharmacological properties, such as quetiapine, clozapine and aripiprazole, have theoretical advantages in LB disease (Fernandez et al., 2003; Terao et al., 2003) but controlled clinical trial data are lacking and clinicians should remain vigilant to the possibility of adverse side-effects. If acute deterioration occurs in a confused elderly patient following neuroleptic administration, DLB should always be considered as part of the differential diagnosis. However, since up to 50% of DLB patients receiving typical or atypical antipsychotic agents do not react adversely, a history of neuroleptic tolerance does not therefore rule out a diagnosis of DLB and deliberate neuroleptic challenge is neither a safe nor a reliable diagnostic procedure. 60.5.5. Other pharmacological agents for symptomatic treatment Depression is common in DLB but there have been no systematic studies of its management. At the present time selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors (SNRIs) are probably the preferred pharmacological treatments. Tricylic antidepressants and those with anticholinergic properties should be avoided. Apathy is a common feature which may mimic depression or excessive daytime somnolence and which may improve with ChEIs. Anxiety is frequently secondary to fluctuating confusion and hallucinations and improves when these are treated. Small doses of benzodiazepines may offer short-term symptomatic relief but at the expense of worsening amnesia, alertness and motor function, with increased risk of falls. Sleep disorders are also
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frequently seen in LB disease and may be an early feature. RBD can be treated with clonazepam 0.25 mg at bedtime, melatonin 3 mg at bedtime or quetiapine 12.5 mg at bedtime and titrated slowly, monitoring for both efficacy and side-effects (McKeith et al., 2005). ChEIs may also be helpful for disturbed sleep (Reading et al., 2001). The frequent occurrence of electroencephalographic (EEG) abnormalities in DLB, incuding transient temporal slow waves, has prompted the use of carbamazepine and sodium valproate, usually for agitation or insomnia. No systematic reports of efficacy or sideeffects are available. The 5-HT3 antagonist ondansetron was reported as having antipsychotic effects in hallucinated PD patients but this has not been independently replicated and the high doses required make the cost prohibitive for routine practice (Harrison and McKeith, 1995). 60.5.6. Disease-modifying agents There are no disease-modifying pharmacological therapies for DLB. Better understanding of the neurobiology of synuclein may lead to the development of novel therapeutic interventions applicable to a diverse group of neurodegenerative disorders, including DLB, PD and MSA, but until then the clinician has only symptomatic treatments available. Clinical trial data suggest that ChEIs may potentially slow disease progression in AD, and similar effects could be anticipated in DLB.
60.6. Summary DLB is now established as a relatively common form of dementia in older people and is part of a larger spectrum of LB disease which has diverse clinical presentations, including PD, primary autonomic failure and RBD. Recent modifications to clinical and pathological guidelines for the assessment and diagnosis of DLB have been made (McKeith et al., 2005) and these will require independent validation in a variety of settings. Suspicion of a DLB diagnosis should be raised in the presence of any one of the proposed core or suggestive features and may be supported by the use of specifically designed assessment scales and appropriate neuroimaging techniques. ChEIs offer the greatest hope for symptomatic improvement in both psychotic and cognitive features of DLB and seem to offer these benefits without significant compromise of motor function. Ongoing multicenter, double-blind, placebocontrolled studies will hopefully clarify these issues, whereas long-term studies are required to assess the duration of benefit. Antipsychotic drugs need to be
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used sparingly and only when other pharmacological and non-pharmacological approaches fail to prevent severe distress or injurious behavior to self or others. Clinicians should be vigilant for severe neuroleptic sensitivity reactions. Clonazepam may have a particular role in the management of sleep disorders but the role of other sedatives and anticonvulsants is unproven. New-generation antidepressants may be helpful for persistent depressive symptoms. Disease-modifying treatments are urgently required. Better understanding of the pathobiological processing of synuclein proteins could ultimately lead to the development of novel therapeutic interventions for DLB.
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disease dementia and dementia with Lewy bodies. Am J Geriatr Psychiatry 14: 153–160. O’Brien JT, Paling S, Barber R et al. (2001). Progressive brain atrophy on serial MRI in dementia with Lewy bodies, AD, and vascular dementia. Neurology 56 (10): 1386–1388. O’Brien JT, Colloby SJ, Fenwick J et al. (2004). Dopamine transporter loss visualised with FP-CIT SPECT in dementia with Lewy bodies. Arch Neurol 61 (6): 919–925. O’Brien KK, Saxby BK, Ballard CG et al. (2003). Regulation of attention and response to therapy in dementia by butyrylcholinesterase. Pharmacogenetics 13: 231–239. Okazaki H, Lipkin LE, Aronson SM (1961). Diffuse intracytoplasmic ganglionic inclusions (Lewy type) associated with progressive dementia and quadriparesis in flexion. J Neuropathol Exp Neurol 20: 237–244. Papka M, Rubio A, Schiffer RB (1998). A review of Lewy body disease, an emerging concept of cortical dementia. J Neuropsychiatry Clin Neurosci 10: 267–279. Perry E, McKeith I, Ballard C (2003a). Butyrylcholinesterase and progression of cognitive deficits in dementia with Lewy bodies. Neurology 60 (11): 1852–1853. Perry EK, Kilford L, Lees AJ et al. (2003b). Increased Alzheimer pathology in Parkinson’s disease related to antimuscarinic drugs. Ann Neurol 54 (2): 235–238. Perry EK, Piggott MA, Johnson M et al. (2003c). Neurotransmitter correlates of neuropsychiatric symptoms in dementia with Lewy bodies. In: MA Bedard, Y Agid, S Chouinard et al. (Eds.), Mental and Behavioral Dysfunction in Movement Disorders. Humana Press Inc, Totowa, NJ, pp. 285–294. Perry RH, Irving D, Blessed G et al. (1989a). Clinically and neuropathologically distinct form of dementia in the elderly. Lancet 1 (8630): 166. Perry RH, Irving D, Blessed G et al. (1989b). Senile dementia of Lewy body type and spectrum of Lewy body disease. Lancet 1 (8646): 1088. Perry RH, Irving D, Blessed G et al. (1990). Senile dementia of Lewy body type. A clinically and neuropathologically distinct form of Lewy body dementia in the elderly. J Neurol Sci 95: 119–139. Piggott MA, Marshall EF, Thomas N et al. (1999). Striatal dopaminergic markers in dementia with Lewy bodies, Alzheimer’s and Parkinson’s diseases: rostrocaudal distribution. Brain 122: 1449–1468. Polymeropoulos MH, Lavedan C, Leroy E et al. (1997). Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276 (5321): 2045–2047. Pondal M, DelSer T, Bermejo F (1996). Anticholinergic therapy and dementia in patients with Parkinson’s disease. J Neurol 243 (7): 543–546. Rahkonen T, Eloniemi-Sulkava U, Rissanen S et al. (2003). Dementia with Lewy bodies according to the consensus criteria in a general population aged 75 years or older. J Neurol Neurosurg Psychiatry 74 (6): 720–724. Reading PJ, Luce AK, McKeith IG (2001). Rivastigmine in the treatment of parkinsonian psychosis and cognitive impairment. Mov Disord 16 (6): 1171–1174.
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Sahgal A, Galloway PH, McKeith IG et al. (1992). A comparative study of attentional deficits in senile dementias of Alzheimer and Lewy body types. Dementia 3: 350–354. Samuel W, Galasko D, Masliah E et al. (1996). Neocortical Lewy body counts correlate with dementia in the Lewy body variant of Alzheimer’s disease. J Neuropathol Exp Neurol 55 (1): 44–52. Samuel W, Alford M, Hofstetter CR et al. (1997). Dementia with Lewy bodies versus pure Alzheimer disease: differences in cognition, neuropathology, cholinergic dysfunction, and synapse density. J Neuropathol Exp Neurol 56: 499–508. Samuel W, Caligiuri M, Galasko D et al. (2000). Better cognitive and psychopathologic response to donepezil in patients prospectively diagnosed as dementia with Lewy bodies: a preliminary study. Int J Geriatr Psychiatry 15 (9): 794–802. Shea C, MacKnight C, Rockwood K (1998). Donepezil for treatment of dementia with Lewy bodies: a case series of nine patients. Int Psychogeriatr 10 (3): 229–238. Shergill S, Mullan E, D’ath P et al. (1994). What is the clinical prevalence of Lewy body dementia? Int J Geriatr Psychiatry 9: 907–912. Shinotoh H, Aotsuka A, Ota T et al. (2001). Brain cholinergic function in dementia with Lewy bodies and Alzheimer’s disease measured by PET. In: Abstracts. Proceedings of 5th International Conference on Progress in PD and AD: 74. Singleton A, Gwinn-Hardy K (2004). Parkinson’s disease and dementia with Lewy bodies: a difference in dose? Lancet 364 (9440): 1105–1107. Stevens T, Livingston G, Kitchen G et al. (2002). Islington study of dementia subtypes in the community. Br J Psychiatry 180: 270–276. Taki J, Yoshita M, Yamada M et al. (2004). Significance of I-123-MIBG scintigraphy as a pathophysiological indicator in the assessment of Parkinson’s disease and related disorders: it can be a specific marker for Lewy body disease. Ann Nucl Med 18 (6): 453–461. Tanaka M, Kim YM, Lee G et al. (2004). Aggresomes formed by alpha-synuclein and synphilin-1 are cytoprotective. J Biol Chem 279 (6): 4625–4631.
Terao T, Shimomura T, Izumi Y et al. (2003). Two cases of quetiapine augmentation for donepezil-refractory visual hallucinations in dementia with Lewy bodies. J Clin Psychiatry 64 (12): 1520–1521. Thomas AJ, Burn DJ, Rowan EN et al. (2005). A comparison of the efficacy of donepezil in Parkinson’s disease with dementia and dementia with Lewy bodies. Int J Geriatr Psychiatry 20: 938–944. Tiraboschi P, Hansen LA, Alford M et al. (2000). Cholinergic dysfunction in diseases with Lewy bodies. Neurology 54: 407–411. Walker MP, Ayre GA, Cummings JL et al. (2000a). The Clinician Assessment of Fluctuation and the One Day Fluctuation Assessment Scale. Two methods to assess fluctuating confusion in dementia. Br J Psychiatry 177: 252–256. Walker Z, Allan RL, Shergill S et al. (1997). Neuropsychological performance in Lewy body dementia and Alzheimer’s disease. Br J Psychiatry 170: 156–158. Walker Z, Grace J, Overshot R et al. (1999). Olanzapine in dementia with Lewy bodies: a clinical study. Int J Geriatr Psychiatry 14 (6): 459–466. Walker Z, Allen RL, Shergill S et al. (2000b). Three years survival in patients with a clinical diagnosis of dementia with Lewy bodies. Int J Geriatr Psychiatry 15: 267–273. Walker Z, Costa DC, Walker RWH et al. (2004). Striatal dopamine transporter in dementia with Lewy bodies and Parkinson disease: a comparison. Neurology 62 (9): 1568–1572. Wesnes KA, McKeith IG, Ferrara R et al. (2002). Effects of rivastigmine on cognitive function in dementia with Lewy bodies: a randomised placebo-controlled international study using the Cognitive Drug Research computerised assessment system. Dement Geriatr Cogn Disord 13 (3): 183–192. Yoshita M, Taki J, Yamada M (2001). A clinical role for I-123 MIBG myocardial scintigraphy in the distinction between dementia of the Alzheimer’s-type and dementia with Lewy bodies. J Neurol Neurosurg Psychiatry 71 (5): 583–588.
Handbook of Clinical Neurology, Vol. 84 (3rd series) Parkinson’s disease and related disorders, Part II W. C. Koller, E. Melamed, Editors # 2007 Elsevier B. V. All rights reserved
Chapter 61
Myoclonus and parkinsonism DANIEL D. TRUONG1* AND ROONGROJ BHIDAYASIRI1,2,3 1
The Parkinson’s and Movement Disorder Institute, Fountain Valley, CA, USA
2
Movement Disorders Group, Division of Neurology, Chulalongkorn University Hospital, Bangkok, Thailand
3
Department of Neurology, UCLA Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
61.1. Introduction Myoclonus is defined as sudden, brief, shock-like, involuntary movements caused by muscular contractions (positive myoclonus) or inhibitions (negative myoclonus) (Fahn et al., 1986). Myoclonus is not a diagnosis but rather a descriptive term denoting symptoms or signs that are non-specific in relation to their neuroanatomical source and pathogenesis. Despite its non-specific nature, myoclonus has been described in various conditions and has strong implications for the diagnosis, prognosis and treatment of the underlying disorder. Myoclonus has been classified according to clinical presentation, etiology, pathophysiology, pharmacological and biochemical pathology, with an attempt to establish the relationship between semiology, physiology and etiology (Marsden et al., 1981). Of these, the etiological classification is considered the most helpful and appropriate in clinical practice and includes physiological myoclonus, a normal manifestation in healthy people; essential myoclonus, where no other neurological deficit is present and can be sporadic or inherited; epileptic myoclonus, where epilepsy dominates the clinical picture and myoclonus is considered as an epileptic phenomenon; and symptomatic myoclonus, in the setting of an identifiable underlying disorder (Fahn et al., 1986). In a study conducted by Caviness (2002), symptomatic myoclonus was found to be the most common (72%), followed by epileptic myoclonus (17%) and essential myoclonus (11%). In symptomatic myoclonus, the features of myoclonus may not be distinctive. Instead, the history and associated clinical signs (such as seizures, ataxia and
mental status abnormalities) guide the physicians to the appropriate diagnosis and relevant investigations. Often, there is clinical and pathological evidence of diffuse nervous system involvement. Within the symptomatic group, posthypoxic syndrome and neurodegenerative disorders (particularly Alzheimer’s disease (AD) and Creutzfeldt–Jakob disease (CJD)), account for most of the cases (Caviness, 2002). Most myoclonus in neurodegenerative disease is classified as cortical, consistent with the well-known cortical pathology in AD and CJD. In AD, myoclonus is more likely to occur at a late stage when dementia is severe and tends to be multifocal, affecting distal muscles, both spontaneously and in response to various stimuli (Hauser et al., 1986). On the other hand, myoclonus is much more frequent and more likely to be generalized in CJD, although focal jerking in the face and limb can be seen initially (Van Everbroeck et al., 2004). The rapidly progressive dementia, associated neurological signs, including cortical blindness, cerebellar, parkinsonism and typical electroencephalographic (EEG) discharges, help distinguish CJD from the more common AD (Wojcieszek et al., 1994; Tschampa et al., 2001). When the disease is of longer duration, associated with myoclonus and rigidity, AD should be considered (Tschampa et al., 2001). Myoclonus is a recognized feature of many basal ganglia disorders where parkinsonian signs predominate. Although tremor is frequently observed in patients with idiopathic Parkinson’s disease (PD), myoclonus is much less common than tremor in parkinsonian syndromes and the presence of myoclonus usually suggests a less common cause of parkinsonism (Caviness et al., 2002a). Klawans et al. (1986) were
*Correspondence to: Daniel D. Truong, The Parkinson’s and Movement Disorder Institute, 9940 Talbert Ave, Fountain Valley, CA 92708, USA. E-mail:
[email protected], Tel: 714-378-5062, Fax: 714-378-5061.
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Table 61.1 Common causes of myoclonus and parkinsonism Idiopathic Parkinson’s disease Related to medications, including levodopa, dopamine agonists, amantadine Unrelated to medications Diffuse Lewy body disease Corticobasal degeneration Multiple system atrophy Encephalitis lethargica Juvenile-onset Huntington’s disease Dentatorubral-pallidoluysian atrophy Frontotemporal dementia with parkinsonism Chronic manganese poisoning
the first to report that myoclonus and parkinsonism occurred simultaneously in three conditions: (1) PD where patients are treated chronically with levodopa; (2) von Economo’s encephalitis; and (3) acutely in 1methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication. Since then, the association between myoclonus and parkinsonism has been described in other parkinsonian disorders, including multiple system atrophy (MSA), corticobasal degeneration (CBD), diffuse Lewy body disease (DLB), postencephalitic parkinsonism and frontotemporal dementia with parkinsonism (FTD) (Table 61.1) (Howard and Lees, 1987; Chen et al., 1992; Thompson et al., 1994b; Wenning et al., 1994; Louis et al., 1997; Caviness and Wszolek, 2002). In addition, myoclonus has been recognized in other neurological conditions in which parkinsonism may occur but is less prominent, such as cerebellar degenerations, Huntington’s disease (HD), dentatorubral-pallidoluysian atrophy (DRPLA) or even chronic manganese poisoning (Rodriguez et al., 1994; Thompson et al., 1994a; Thompson and Shibasaki, 2000; Ono et al., 2002). Although myoclonus has been reported in various parkinsonian syndromes, particularly cortical myoclonus in all Lewy body disorders, the mechanism of myoclonus is not identical across these different parkinsonian syndromes and different types of myoclonus may coexist in the same syndrome (Caviness et al., 2002a, b). Hence, electrophysiological studies play a crucial role in the evaluation of myoclonus in these parkinsonian disorders, not only for differential diagnosis, but also for better understanding of the physiological mechanism underlying each type of myoclonus. Indeed, certain patterns have some etiological specificity. The specific methods used in the neurophysiological study of myoclonus usually include,
but are not limited to, multichannel surface electromyography (EMG) recording with testing for longlatency EMG responses to nerve stimulation, EEG, EEG-EMG polygraphy with back-averaging and somatosensory evoked potentials (SEPs). Since the majority of myoclonic jerks are caused by hyperexcitability of groups of neurons in certain brain structures, the relationship of myoclonic jerks to EEG activities is of primary importance in the study of myoclonus (Shibasaki, 2000). Jerk-locked back-averaging is an extension of the EEG-EMG polygraph and its principle is to back-average the simultaneously recorded EEGs with respect to myoclonus. SEPs record EEG potentials time-locked to EMG events such as a myoclonus EMG discharge. A good example of the utility of electrophysiological studies is the differentiation between myoclonus in MSA and CBD (Table 61.2). Myoclonus in MSA has been reported to be typical of ‘cortical reflex myoclonus’, with enlarged SEPs, exaggerated long-latency EMG responses to median nerve stimulation and back-averaged EEG transients (Obeso et al., 1985). In contrast to MSA, there is no preceding cortical discharge time-locked to action myoclonus in CBD, SEPs are not enlarged and latency on stimulation of median nerve at the wrist is shorter (40 versus 50 ms) (Thompson et al., 1994b).
61.2. Myoclonus in idiopathic Parkinson’s disease Unilateral resting tremor in the distal limb is usually the first motor manifestation in the majority of patients with PD. While tremor, either at rest or during muscle activation, is common in PD, myoclonus is much less prevalent and was originally described as a consequence of levodopa therapy. In a study of 12 PD patients who developed myoclonus after taking levodopa for 12 months, abnormal movements consisted of single, abrupt jerks of the extremities, which were bilateral and symmetrical or occasionally in an arm or leg on the same side (Klawans et al., 1975). In general, the trunk and limbs are most commonly affected, whereas facial muscle involvement is unusual. Myoclonus can occur during sleep, fatigue, dozing or even wakefulness, but abates with levodopa cessation. Luquin et al. (1992) reported spontaneous and action myoclonus with multifocal distribution in only 6 out of 168 patients with levodopa-induced dyskinesias, whereas Marconi et al. (1994) observed sporadic myoclonic jerks in most patients (10 out of 15 patients) during the 10–20 minutes following absorption of levodopa. Methylsergide, a serotonin-specific antagonist, has been reported to improve levodopa-induced
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Table 61.2 Electrophysiological findings in various subtypes of myoclonus Back-averaged EEG transients
SEPs
Reflex responses
Bursts typically less than 75 ms
Variable but focal sharp-wave 10–40 ms before jerks
Enlarged cortical component
C reflex at rest
Bursts < 100 ms
Time-locked association
C reflex at rest
No consistent abnormalities
Variable burst properties
No correlate
Enlarged cortical component possible Normal
Spinal
Normal
Bursts > 100 ms and rhythmic
No correlate
Normal
Peripheral
Normal
Variable burst, may be denervation
No correlate
Normal
Types
EEG findings
EMG
Cortical
Cortical– subcortical
Variable, may show epileptiform discharges and slow waves Generalized spike and wave
Subcortical– supraspinal
Sometimes reflex response to sound Variable but can be very short in latency Normal
EEG, electroencephalogram; EMG, electromyogram; SEPs, somatosensory evoked potentials. Reproduced from Caviness and Brown (2004), The Lancet Neurology, with permission from Elsevier.
myoclonus, without worsening levodopa-induced dyskinesias (Klawans et al., 1975). In addition to levodopa, other medications have been shown to induce myoclonus in PD. The dopamine agonist bromocriptine was reported to induce nocturnal myoclonus in 6 PD patients after the levodopa was discontinued (Vardi et al., 1978). Another patient with generalized dystonia from anoxic brain injury also developed myoclonus affecting the proximal arms and axial muscles following the increasing doses of bromocriptine (Buchman et al., 1987). When bromocriptine was discontinued, the myoclonus improved but the dystonia worsened. Amantadine, a dopamine-reuptake inhibitor, a dopamine agonist and an N-methyl-D-aspartate (NMDA) receptor agonist, can also cause myoclonus and delirium. It was implicated as a cause of ‘vocal’ myoclonus affecting the larynx, pharynx and face in a PD patient who was on concomitant levodopa (Pfeiffer, 1996). The myoclonus resolved after discontinuation of amantadine. In addition, amantadine has also been reported to induce delirium and multifocal myoclonic jerks in all extremities, neck, tongue and face in another 2 PD patients (Matsunaga et al., 2001). One patient also had renal impairment with toxic levels of amantadine. Recently, the occurrence of myoclonus unrelated to medication has been recognized, with the incidence of approximately 5% in non-demented PD patients in a
tertiary care center (Caviness et al., 1998, 2002b). The myoclonus in PD in this category is typically of small amplitude, occurring during muscle activation, and may seem repetitive and rhythmic enough to resemble action tremor. However, the movement is irregular in both timing and amplitude and thus deserves the term ‘myoclonus’. In a few cases, frequent (> 6 Hz) repetitive rhythmic trains of EMG discharges coincided with a movement that could overlap with a tremor phenotype. The myoclonus is rarely present at rest and reflex myoclonus cannot be demonstrated to touch, stretch or tendon reflexes. The amplitude is often greater on one side, but not always the same side as the more prominent parkinsonian signs. This myoclonus is very different from the levodopainduced myoclonus reported by Klawans et al. (1975) because the latter usually occurs at rest, often during sleep or drowsiness, and is sensitive to levodopa dosage. In addition, this small-amplitude myoclonus was present even before levodopa therapy in 1 of the 2 patients with levodopa-responsive parkinsonism (Caviness et al., 1998). Because this type of myoclonus can be observed in early and moderate stages of non-demented PD patients, advanced parkinsonism or dementia is generally not considered as a requirement. This is in contrast to asterixis observed in PD, which is associated with signs of chronic drug toxicity, dementia and its reversal following drug withdrawal (Glantz et al., 1982).
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Electrophysiological studies of myoclonus in PD reported by Caviness et al. (2002b) are quite different from the cortical reflex myoclonus physiology. EMG recording during muscle activation showed irregular, multifocal, brief (< 50 ms) myoclonic EMG discharges. Back-averaging consistently showed a focal, short-latency, EEG transient prior to the myoclonic EMG discharges. Furthermore, cortical SEPs were not enlarged and long-latency EMG responses at rest were not present. Corticomuscular coherence is also increased in PD patients with small-amplitude myoclonus (Caviness et al., 2003b). Indeed, these electrophysiological findings distinguish myoclonus in PD from the myoclonus seen in MSA, CBD, AD, minipolymyoclonus and cortical tremor. The mechanisms for the cortical myoclonus in PD are probably secondary to the lack of inhibitory influences or excessive excitation of the sensorimotor cortex produced by the neurodegeneration locally around the sensorimotor cortical region (Caviness et al., 2002b).
61.3. Myoclonus in diffuse Lewy body disease Myoclonus in DLB is similar to myoclonus in PD, although the former is more clinically impressive, with larger amplitude, and is much more likely to occur at rest (Fig. 61.1) (Caviness, 2002, 2003). Myoclonus in DLB is also more common, occurring in about 15–20% of cases (Burkhardt et al., 1988; Louis et al.,
1997). The source of myoclonus in DLB is cortical and previously published series of myoclonus in PD showed electrophysiological characteristics that are indistinguishable from the DLB series, even though myoclonus in DLB is clinically more severe (Caviness et al., 2002b, 2003a). In addition, myoclonus seen in PD and DLB also showed many properties in common with the myoclonus that was previously reported in individuals with hereditary DLB (Caviness et al., 2000). However, the electrophysiological properties of myoclonus in Lewy body disorders differ from those of myoclonus in AD. The fact that cortical myoclonus shares similar physiological properties across a spectrum of Lewy body disorders suggests that a unifying mechanism may be responsible for its occurrence. It is at present unclear if the abnormal basal ganglia output to the cortex, cortical pathology itself (either within the sensorimotor region or more diffusely in the motor circuits in the frontal and parietal lobes) or both in some way facilitate cortical myoclonus. Compared to the pathology in PD, there is more widespread cortical pathology in DLB, which may explain why myoclonus in DLB is more severe. However, the neuropathological examination of previously reported cases only showed occasional Lewy bodies in the pre- and postcentral gyri as well as parietal, cingulate and entorhinal cortex (Caviness et al., 1998). Furthermore, there is no correlation between cortical myoclonus and the severity of
+
LEFT DELT
20.00 mV
LEFT BICEP
− 0.00
0.25
0.50
0.75
1.00 S
1.25
1.50
1.75
2.00
Fig. 61.1. Rectified surface electromyogram (EMG) of left deltoid and left biceps during the finger-to-nose maneuver in a patient with dementia with Lewy bodies. The EMG burst in the center of the figure produced a myoclonic jerk. Courtesy of Dr. John Caviness, Mayo Clinic, Scottsdale, AZ.
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RFCU
850 mV 100 ms
RFDI
Fig. 61.2. Polygram in a patient with corticobasal degeneration demonstrating spontaneous myoclonus. Two bipolar surface electromyogram channels are shown. RFCU, right flexor carpi ulnaris; RFDI, right first dorsal interosseous. Courtesy of Dr. Zoltan Mari, Human Motor Control Section, NINDS.
parkinsonism in DLB. It is unclear if cortical myoclonus is a marker for cortical dysfunction in DLB and is related to the presence of cognitive dysfunction. It is possible that cortical pathology in DLB exerts some influence on the abnormal basal ganglia output to the cortex.
61.4. Myoclonus in corticobasal degeneration The most frequent clinical presentation in CBD is a progressive levodopa-unresponsive akinetic-rigid syndrome associated with both cortical and basal ganglia dysfunction (Kompoliti et al., 1998). A clinical diagnostic criterion has been proposed to include manifestations reflecting dysfunction of the cortex (corticosensory loss, apraxia, frontal lobe reflexes, hyperreflexia, Babinski’s sign) and basal ganglia (akinesia, rigidity, limb dystonia, postural instability) (Riley and Lang, 2000). When specific signs are absent, the evolution of asymmetric rigid dystonia and reflex myoclonus is highly suggestive of CBD. At the time of presentation, myoclonus of one limb has been reported in one-third of cases and usually evolves in a further 20% over the following 2 years as the disease progresses (Rinne et al., 1994). Overall, approximately 50% of patients with CBD develop myoclonus during the course of illness (Rinne et al., 1994). The tremor in CBD is usually of 6–8 Hz action postural and action tremor, more irregular and also jerky (Stover et al., 2004). A jerky tremor may precede the appearance of myoclonus in the limb early in the condition (Brunt et al., 1995). Myoclonus is best demonstrated during action or maintenance of a posture in distal muscles; it is also stimulus-sensitive in most cases, easily elicited by
cutaneous stimuli (Fig. 61.2). However, it may be masked by increased muscle tone. Action and reflex myoclonus are characteristic (Thompson and Shibasaki, 2000). The presence of spontaneous myoclonus is difficult to judge because of the action myoclonus in the setting of rigidity and alien-limb movements, which interfere with the ability to complete relaxation. Attempts to move the limb voluntarily are interrupted by trains of repetitive-action myoclonus. The myoclonus in CBD is focal in distribution and predominantly distal. They are stimulus-sensitive and closely resemble those of cortical reflex myoclonus (Fig. 61.3) (Riley et al., 1990; Chen et al., 1992; Thompson et al., 1994b; Carella et al., 1997). Thompson et al. (1994b) studied the clinical and physiological characteristics of myoclonus in 14 patients with CBD, compared to 13 patients with epilepsia partialis continua and progressive myoclonic ataxia. Although hypersynchronous short-duration bursts of muscle activity are common to both (often comprising runs of 2–4 discharges with an interburst interval of 60–80 ms), major differences between myoclonus in CBD and ‘typical’ cortical reflex myoclonus exist (Thompson and Shibasaki, 2000). First of all, myoclonus in CBD is not generally associated with enlarged or ‘giant’ SEPs, in contrast to ‘typical’ cortical reflex myoclonus. Secondly, cortical potentials of myoclonus in CBD do not precede each myoclonic jerk on back-averaged EEG. In addition, the latency of reflex myoclonic jerks is shorter, about 40 ms in CBD, in contrast to 50–60 ms in ‘typical’ cortical reflex myoclonus. Lastly, the estimates of the cortical delay for generation of myoclonic activity in ‘typical’
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Lt biceps br.
triceps br.
rhomboid
Rt biceps br.
triceps br.
rhomboid 500 mV 1 sec Fig. 61.3. Electromyogram polygraph obtained from a patient with clinical diagnosis of corticobasal ganglionic degeneration. Repetitive spontaneous discharges are seen in the right biceps and triceps muscles almost synchronously at an approximate rate of 7–8 Hz. Courtesy of Dr. Hiroshi Shibasaki, Kyoto University, Kyoto, Japan, reprinted with permission from Elsevier.
cortical reflex myoclonus associated with ‘giant’ SEPs (6.9 3.7 ms) are significantly longer than those of myoclonus in CBD (1.4 0.8 ms) (Thompson et al., 1994b). Different patterns of abnormality in cortical reflex myoclonus may be explained by the differences in the processing and relay of sensory information in thalamocortical pathways. In addition, other factors, such as fatigue, if present, may influence the occurrence of periodic discharges in the cortex and muscles in patients with CBD (Manto et al., 2000). The combination of focal, predominantly distal, hypersynchronous jerks, evidence of enhanced cortical excitability, together with the known pathology in CBD suggests that the myoclonus in these patients may be cortical in origin, despite the fact that backaveraging fails to detect a cortical correlate to spontaneous or action-induced jerks and ‘giant’ SEPs are seldom found (Thompson et al., 1994b; Monza et al., 2003). Furthermore, the study involving magnetoencephalogram also supported the role of precentral cortex in generating spontaneous myoclonus (Mima et al., 1998). Grosse et al. (2003) evaluated EEG-EMG and EMG-EMG coherence and phase in 5 patients with clinically probable CBD and unilateral, action-induced stimulus-sensitive myoclonus. All patients exhibited
dramatic inflated EMG-EMG coherence in the absence of any evidence of a pathological corticospinal drive as determined by EEG-EMG coherence, raising the possibility of involvement of subcortical motor systems in the myoclonus of CBD. Since the latency of reflex myoclonus in CBD is only 1–2 ms longer than the sum of afferent and efferent times to and from the cortex, it is therefore possible that myoclonus in CBD is due to the direct sensory input to motor cortical areas that activate corticospinal tract output (Thompson et al., 1994b). Alternatively, prominent parietal involvement in CBD could result in a loss of inhibitory input from the somatosensory area to the motor cortex or thalamic pathology, possibly resulting in a loss of thalamocortical recurrent inhibition (Shafiq and Lang, 2002). Shafiq and Lang (2002) provided their personal experience of evaluating 1 patient with CBD whose reflex latencies were consistent with ‘typical’ cortical reflex myoclonus and other patients with a CBD phenotype whose reflex myoclonus also did not have ‘classical’ electrophysiological features of CBD, described by Thompson et al. (1994b). Whether there are electrophysiological features that are specific and sensitive for the pathology of CBD in order to confirm
MYOCLONUS AND PARKINSONISM or exclude the diagnosis remains uncertain and more studies are needed to address this issue.
61.5. Myoclonus in multiple system atrophy MSA encompasses a wide spectrum of clinical presentations with various combinations of extrapyramidal, pyramidal, cerebellar and autonomic signs and symptoms (Quinn, 1989). Since a statement on the diagnosis of MSA was published in 1998 (Gilman et al., 1998a, b), definite MSA is restricted to patients with postmortem pathological confirmation. A possible diagnosis may be conferred in patients with either parkinsonism with poor levodopa-responsiveness or cerebellar parkinsonism. A probable diagnosis applies to patients presenting with autonomic failure, urinary dysfunction and poor levodopa-responsive parkinsonism or cerebellar dysfunction. Although myoclonus is not recognized as a feature in the diagnostic criteria, it is increasingly recognized as a common manifestation in MSA. Indeed, involuntary movements of the hands and fingers during posture and action were described in 1 of the 3 original cases by Adams et al. (1964). Such movements are usually referred to as ‘jerky tremor’ by some authors and at least two series have reported an upper-extremity small-amplitude ‘jerky postural tremor’ in 20% and 55% of cases (Wenning et al., 1994; Colosimo et al., 1995; Gouider-Khouja et al., 1995). Myoclonus predominantly occurs in the parkinsoniantype MSA (MSA-P), although stimulus-sensitive myoclonus can also occur in cerebellar-type MSA (MSA-C) and the literature is split as to whether this stimulus-sensitive myoclonus is more prevalent in MSA-P or MSA-C (Obeso et al., 1985; Rodriguez et al., 1994; Wenning et al., 1994; Salazar et al., 2000). Wenning et al. (1994) reported that myoclonus was present in 37% of those with MSA-P and 6% of those in MSA-C, whereas Obeso et al. (1985) found that stimulus-sensitive myoclonus occurred more frequently in patients with MSA-C. However, 92% of their patients exhibited bradykinesia and 50% had rigidity. Salazar et al. (2000) proposed the term ‘minipolymyoclonus’ to describe ‘jerky tremor’ in 82% of patients with MSA-P. Clinical observation showed that patients with MSA-P had abnormal involuntary movements predominantly in the hands and fingers with maintenance of a posture or at the beginning of an action. Clinically, these movements were jerky, irregular and not entirely rhythmic. Neurophysiological evidence also favored these movements as a form of postural and reflex myoclonus (Salazar et al., 2000). The EMG activity recorded in the forearm and hand muscles was not usually regular but made of synchronous burst
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and silent periods of variable duration and amplitude and electrical stimuli elicited synchronized reflex response of the type observed in reflex myoclonus. Despite the direct neurophysiological evidence of reflex myoclonus in these patients, authors cannot firmly conclude the cortical origin of the myoclonus, since no EEG spikes and no cortical activity timelocked to the EMG bursts were obtained (Salazar et al., 2000). In a separate study, typical cortical reflex myoclonus in the olivopontocerebellar form of MSA is well recognized and characterized by stimulussensitive myoclonus with enlargement of the P25-N33 component of the cortical SEPs (Rodriguez et al., 1994). Photic cortical reflex myoclonus with generalized muscle jerks may also occur in both olivopontocerebellar and striatonigral forms of MSA (MSA-C and MSA-P, respectively) (Artieda and Obeso, 1993). Electrophysiological studies recorded a large (36.9 mV) positive/negative wave maximum in the mid frontal region following visual stimuli (3.8 ms later) preceding the myoclonus in a time-locked fashion. The myoclonus markedly improved following levodopa and piracetam. In addition to a cortical origin on various forms of myoclonus in patients with MSA, Clouston et al. (1996) evaluated 1 patient with non-dopa-responsive parkinsonism who exhibited early autonomic symptoms, a marked sleep disturbance and myoclonus with a brainstem origin that was both spontaneous and induced by somatosensory stimuli. No giant SEPs and no preceding EEG activity were recorded. In addition, reflex latencies were compatible with a brainstem myoclonus and there was no evidence of photically induced myoclonus following discontinuation of levodopa. The mechanism of brainstem myoclonus is thought to be disruption of the lower brainstem reticular formation, which may also explain abnormal sleep architecture in this patient (Hallett et al., 1977). Furthermore, hyperexcitability of the cortex and brainstem has been reported in a patient with MSA-P, who exhibited postural and action myoclonus (Kofler et al., 1998). Interestingly, facial and whole-body jerks in response to tapping the nose, consistent with exaggerated startle response, indicating an underlying brainstem dysfunction, were also observed. Although isolated cortical reflex myoclonus is frequently encountered in patients with MSA, the authors emphasize that exaggerated startle response secondary to brainstem hyperexcitability can also occur in a case of definite MSA (Kofler et al., 2000). The authors further hypothesized that brainstem atrophy with loss of pontine nuclei and glial cytoplasmic inclusion deposition in the reticular formation may be responsible for startle responses in their case (Kofler et al., 2000).
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61.6. Myoclonus in encephalitis lethargica Encephalitis lethargica (von Economo’s encephalitis) appeared suddenly in 1917–1918 and was pandemic for the next 10 years (von Economo, 1931). Since then, no further epidemics have occurred and the exact etiology has never been identified. However, rare cases resembling von Economo’s encephalitis continued to be reported (Howard and Lees, 1987; Blunt et al., 1997). Although the manifestations were protean, three main clinical presentations have been described (Howard and Lees, 1987). The commonest variety, the somnolent-ophthalmoplegic form, started with an influenza-like illness, which was followed by increasing drowsiness and confusion, progression to continuous sleep, stupor and finally coma. In addition to external ophthalmoplegia, oculogyric crisis and nystagmus, a smaller number of patients presented with bradykinesia and mutism, whereas a third hyperkinetic group developed extreme motor restlessness, dyskinesia and myoclonus. In fact, Klawans et al. (1986) included von Economo’s encephalitis as one of the three conditions in which myolonus and parkinsonism occurred. They reported that adrenocorticotropic hormone relieved all symptoms the first time it was given and twice more brought about significant amelioration of all symptoms, especially the myoclonus. In general, myoclonic movements tended to occur at onset and often subsided as the patient recovered (McAlpine, 1920). However, myoclonus persisted indefinitely in some patients (Rail et al., 1981). Although characterized at the time as a separate entity, epidemic hiccup may have been another form of myoclonus in encephalitis lethargica. Hiccups occurred sporadically in small epidemics during the 1920s and were sometimes one of the first symptoms hailing the onset of encephalitis lethargica (Loewe and Strauss, 1919).
following peripheral nerve stimulation had a latency of approximately 40 ms, similar to CBD, and were unlike ‘typical’ cortical reflex myoclonus. Caviness and Kurth (1997) reported the electrophysiological findings of myoclonus in a patient with HD who was studied postoperatively following a bilateral fetal cell transplant in the striatum. Incomplete transient improvement was seen in the myoclonus, followed by gradual deterioration. The myoclonus itself was consistent with ‘typical’ cortical reflex myoclonus with enlarged SEPs, unlike those reported by Thompson et al. (1994a). The reason for the transient improvement of the myoclonus is unclear, but this study raised the possible role of basal ganglia in the modulation of cortical myoclonic activity.
61.8. Myoclonus in dentatorubralpallidoluysian atrophy DRPLA is a rare autosomal-dominant neurodegenerative disorder, characterized by various combinations of cerebellar ataxia, chorea, myoclonus, epilepsy, parkinsonism, dementia and psychiatric symptoms (Naito and Oyanagi, 1982). After the gene was identified in 1994, DRPLA became known as one of the CAG repeat expansion diseases, in which the responsible gene is located on chromosome 12p, and its product is called atrophin-1 with prominent ‘anticipation’ (Koide et al., 1994; Nagafuchi et al., 1994). The condition has mainly been described in Japan (Kanazawa, 1998). Myoclonus is a distinctive feature of some families with myoclonus epilepsy phenotype of this condition, although uncommon (Thompson, 2002). Although a cortical source is likely for the myoclonus because of the epileptiform activity on the EEG, a detailed electrophysiological examination of the myoclonus has not been reported.
61.7. Myoclonus in Huntington’s disease
61.9. Myoclonus in frontotemporal dementia with parkinsonism
Myoclonus is uncommon in HD, but recognized in a young-onset akinetic-rigid form when it is often accompanied by seizures (Gambardella et al., 2001; Thompson, 2002). Myoclonus and seizures may occur in the early stages of juvenile HD and dominate its clinical picture. The myoclonus is usually stimulus-sensitive and induced by action (Thompson et al., 1994a). Thompson et al. (1994a) studied 3 patients with young-onset HD who were the offspring of an affected father. Neurophysiological studies documented generalized and multifocal action myoclonus of cortical origin that was strikingly stimulus-sensitive, without enlargement of the cortical SEPs. Furthermore, reflex myoclonus in hand muscles
FTD, linked to chromosome 17 (FTD-17), is associated with tau protein mutations (Foster et al., 1997). Pallidopontonigral degeneration (PPND) is one example of a FTD-17 syndrome (Wszolek et al., 1992; Caviness and Wszolek, 2002). The clinical manifestations include frontal lobe behavior, psychiatric problems and memory loss. Motor symptoms associated with FTD-17 consist of akinetic-rigid parkinsonian features without resting tremor, dystonia, spasticity and occasional amyotrophy. Most patients harboring exon-10 missense and intronic mutations in the tau gene develop a parkinsonian phenotype. Myoclonus is rarely seen in FTD-17 kindreds but
MYOCLONUS AND PARKINSONISM has been reported with the N279K, P301S and V337M tau mutations (Caviness and Wszolek, 2002; Tsuboi et al., 2002). Not all affected individuals with PPND develop myoclonus. Myoclonus is invariably present in the upper extremities of rather small, subtle and actioninduced, without detectable activation with rest or stimuli (Caviness and Wszolek, 2002). Caviness and Wszolek (2002) observed that clinical progression is more advanced for the myoclonus cases than for those without myoclonus, although the explanation is unclear. Previous EMG studies reported muscle activation tremor-like discharges in 3 subjects and definite myoclonic discharges in 1 (Wszolek et al., 1998). Further study demonstrated at least two different myoclonus physiological patterns in PPND, associated with the N279K tau mutation (Caviness et al., 2003c). The absence of a back-averaged EEG transient characterized the myoclonus physiology associated with disease progression, whereas pre-myoclonus EEG transient was present in the myoclonus that occurred in one of the individuals with stage 0 (presymptomatic but gene-positive) (Caviness et al., 2003c). However, the physiology of myoclonus may change over the course of the disorder, reflecting progressive cortical pathology and other brain regions. So far, the exact physiology of myoclonus in this disorder is still unclear, although cortical origin has been proposed, based on the findings of the cortical transient back-averaged to the myoclonus in one of the at-risk individuals.
61.10. Myoclonus in chronic manganese poisoning Manganese is a paramagnetic heavy metal that is widely distributed in the environment, in air, water and food. It has long been appreciated that manganese exposure can cause neurotoxicity and certain brain areas, including globus pallidus and substantia nigra pars reticulata, are preferentially affected (Yamada et al., 1986). Substantia nigra pars compacta and striatal dopamine are relatively spared. The most common neurological manifestations of chronic manganese poisoning are extrapyramidal syndromes, especially parkinsonism, comprising bradykinesia, rigidity and postural instability (Olanow, 2004). Magnetic resonance imaging (MRI) studies in manganese-intoxicated patients demonstrated a characteristic signal abnormality on T1-weighted images that are not seen in normal individuals or PD patients or other forms of parkinsonism (Olanow, 2004). In addition to parkinsonism, chorea, tremor and myclonus have been described in patients with chronic
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manganese poisoning (Pal et al., 1999; Ono et al., 2002). Ono et al. (2002) reported a 17-year-old welder with myoclonic involuntary movements involving the right upper and lower extremities who showed elevated levels of manganese in the blood and hair and characteristic MRI abnormalities. Electrophysiological studies indicated absence of ‘giant’ SEPs or paroxysmal discharge in jerk-locked EEG averaging. Chelation therapy with Ca-EDTA (EDTA, ethylene diamine tetra acetic acid) improved the myoclonus and MRI abnormalities. Although the exact mechanism of myoclonus in chronic manganese poisoning is uncertain, authors proposed that subcortical neural circuits via globus pallidus might have been involved (Ono et al., 2002). Since Klawans et al. (1986) first reported 3 patients in whom the onset of parkinsonian signs was clinically associated with myoclonic movements, more conditions have been recognized to encompass a variety of atypical parkinsonian syndromes as well as recently identified neurodegenerative disorders. In addition to clinical descriptions of myoclonus, more advances have been made in electrophysiological and molecular studies to understand better the pathophysiology, etiology, neuroanatomy and possible therapeutic options of various subtypes of myoclonus. In the setting of patients with predominant parkinsonian features, the occurrence of myoclonus should alert physicians to the possibility of many different neurodegenerative disorders, not limited to PD. Although the use of clinical neurophysiology helps in defining the nature of the EMG discharges in such disorders, the current ability of these techniques to provide absolute specificity and sensitivity is still lacking. Therefore, further studies in various parkinsonian disorders are needed to clarify neurochemical, electrophysiology, molecular pathophysiology and neural networks of myoclonus, which will hopefully lead to the development of therapeutic targets in these progressive disorders.
Acknowledgments Roongroj Bhidayasiri (UK) is supported by the Lilian Schorr Postdoctoral Fellowship of the Parkinson’s Disease Foundation (PDF). Daniel D. Truong is supported by the Parkinson’s and Movement Disorder Foundation and the Long Beach Memorial Foundation.
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Index Page numbers in italic, e.g. 96, refer to figures. Page numbers in bold, e.g. 435, denote tables. acetylcholine, 102–3, 121, 128, 142, 335, 540, 542 acetylcholine esterase, 102, 141, 335, 522, 542 adenosine, 21, 142, 146, 190–1 aging eye movement, 434 gait abnormality, 432 motor abnormalities, 435 slowing, 429 Parkinson’s disease and, 437–9 posture, 431–2 tone change, 430–1 tremor disorders, 435–7 akathisia, 45, 169, 173–4, 224, 226, 399–400, 401, 402, 406, 409–11 Alzheimer’s disease, 358 and Parkinson’s disease, 439 dystonia and, 516, 522 Lewy bodies and, 404, 446 mixed movement disorders in, 522 a-synuclein and, 539–40 with parkinsonism, 364, 439, 516 aminoindane, 96, 107 amphetamine 19–20, 96, 105, 107, 110, 139, 165, 228, 280–1, 295–9, 388–9, 410, see also methamphetamine amyloid precursor protein, 106 amyotrophic lateral sclerosisparkinsonism dementia complex of Guam, 336, 392–3 antiapoptotic proteins, 105 anticholinergic drugs in clinical practice, 121–3, 142, 320, 401, 411, 419 effectiveness, 318–19 side effects, 406 tremor and, 123 mechanism, 121–2 antiglutamatergic drugs, 127–8 amatadine, 128–31 for motor complications, 130–1 pharmacology, 128–9
antiglutamatergic drugs (Continued ) amatadine (Continued ) for prevention of disease progression, 130–1 side-effects, 131 for symptoms of parkinsonism, 129 budipine, 128, 131–3 dextromethorphan, 128, 132, 143 memantine, 127–8, 131–2, 202 remacemide, 21, 128, 133 riluzole, 21, 128, 133–4, 202 antioxidants for neuroprotection in Parkinson’s disease, 19–22 apomorphine, see dopamine agonist(s): apomorphine apoptosis, 18, 22, 44, 103, 104, 105, 107, 127, 138–9, 297, 382, 390–1, 393, 409, 491 apraxia, 357 equilibrium, 462 gait, 433–4, 434, 438, 461–2 ideomotor, 355–6, 461 kinetic, 356, 461, 474, 476 armantadine, 143
ballooned neuron (BN), 336, 352, 358, 358, 360, 361, 380, 445, 460, 465 basal ganglia calcification epidemiology, 479–81 etiology, 480 history, 479 hypoparathyroidism and, 480, 480 pathophysiology, 484–5 treatment, 485, 485 circuitry, 192–3, 508–9 neurophysiology, 196–7 Bcl-2 family proteins antiapoptotic (Bcl-2), 105 proapoptotic (Bad, Bax), 105 befloxatone, 94 beta-methylaminoalanine (BMAA), 392–3, 392 BIA-3-202, 141
bilateral striopallidodentate calcinosis, 479, 480, 481, 482–5, 483, 485 boxer’s encephalopathy, see parkinsonism: posttraumatic: repetitive head trauma bradykinesia in Alzheimer’s disease, 364, 406, 439 in corticobasal disease, 353, 356, 357 essential tremor and, 436 in Japanese B encephalitis, 379 MPTP-induced, 390 in mixed movement disorders, 515 myoclonus and, 555–7 in old age with parkinsonism, 428–9, 429, 432 in pallidonigroluysian degeneration, 450 in Parkinson’s disease and parkinsonism, 17, 77, 159, 243, 292, 310, 315, 330, 364, 385, 390, 393, 399, 401, 417, 427–8, 430, 434, 462, 501–3, 503 in progressive supranuclear palsy, 332, 343 measurement, 162, 404 mechanisms, 243–4, 263, 422, 438 in posttraumatic parkinsonism, 493, 495 in Rett syndrome, 453 therapy, 7 treatment deep brain stimulation, 267, 269 drug, 51, 101, 111, 112, 129, 144–5 surgical, 249, 250–2, 254 transplantation, 282, 287 in tuberculosis, 376 bradyphenia, 327 brofaromine, 94 burden of diseases, 151–2 buspirone, 143 BW 137OU87, 94
cabergoline, 37–8, 48, 73–5, 74, 78, 78–84, 80, 86, 137, 164, 191, 200
562 carbon monoxide, 393–4, 419, 480 caroxazone, 94 catecholamines, 31, 34, 103, 315, 422, 437 catechol-O-methyltransferase inhibitors (COMT) clinical effects, 55, 56 inhibition, 54 entacapone, 54–8, 56–7, 75, 83, 98, 102, 112, 113, 164–6, 437 tolcapone, 54–8, 56–7, 80–1, 102, 164–5, 437 and MAO inhibitors, 102–3 side-effects, 56, 56–8 Charcot, Jean-Martin, 31, 121, 327, 351, 487, 495 chlorpromazine, 399, 408, 521 choline acetyltransferase, 541 chorea acanthocytosis, 447, 449–50, 517–18 clorgyline, 94, 96 clozapine, 143 Cockayne’s syndrome, 480 coenzyme A, 446, 520 corticobasal degeneration history, 351–3 diagnosis, 353–4 cognitive and neuropsychiatric, 356–7, 357 cortical symptoms, 355–6, 357 differential, 364 motor symptoms, 354–5, 357 electrophysiological studies, 362–3 epidemiology, 353 imaging studies, 361–2 laboratory studies, 363 myoclonus and, 550 parkinsonism and, 512 pathology ballooned neurons in, 358, 360 macroscopic, 358, 361 microscopic, 358, 358–9, 361 tau, 359–60 tau mutations and ultrastructure, 360–1, 361 therapy for cognitive and neuropsychiatric symptoms, 364 for gastrointestinal symptoms, 365 for motor symptoms, 363 for orthostatic hypotension, 365 for urinary symptoms, 365 Creutzfeldt-Jakob disease, 286, 332, 355, 380, 364, 535, 549 cystercercosis, 480 cytokines, 140, 374, 387, 491
INDEX deep brain stimulation (DBS), 205 adverse effects, 269–70 clinical efficacy, 266 comparison, 268–9 pallidal, 266, 266–7 subthalamic, 267, 267 thalamic, 266 magnetic resonance imaging, 263 methodology safety issues, 265 surgical preparation, 263–4 target location, 264, 264–5 patient selection, 270–2 advanced Parkinson’s disease, 271–2 tremor, 271 physiological mechanisms, 261–3 systemic, 262–3 thalamic, 262 dementia aging and, 434 in corticobasal degeneration, 357 frontotemporal, 153, 364, 508, 512, 556–7 chromosome 17 and, 332, 338–9, 351, 353, 356–7, 360–1, 363, 381, 445–6, 512, 513, 550, 556 parkinsonism and, 513, 550, 556 with Lewy bodies (DLB), 364 antiparkinsonian agents for, 541 antipsychotic agents for, 543 cholinergic system and, 540 cholinesterase inhibitors for, 542 clinical features, 532–4 clinical significance of, 532 cognition and, 532–3 diagnostic features, 534–6, 536–7 differential diagnosis, 536–41 dopaminergic system and, 540 etiology, 538–9 genetics of, 540 hallucinations in, 533 magnetic resonance imaging of, 538 management, 541 motor parkinsonism and, 534 myoclonus and, 550 pathology, 538–40, 539–40 prevalence and incidence, 531 relationship to dementia in Parkinson’s disease, 531, 538 sleep disorders, 533–4 deprenyl, 94 depression in corticobasal degeneration, 357, 357 in dementia with Lewy bodies 536, 540
depression (Continued ) measurement scales for, 7, 111 in multiple system atrophy, 314 in Parkinson’s disease, 10, 40, 45, 81, 86, 99–103, 108, 114, 129, 169, 169–70, 226, 269–70, 331, 403–4, 429, 502, 505, 511, 534 in progressive supranuclear palsy, 330, 340, 341–2 non-parkinsonian, 81 therapy resistant, 100 as treatment side-effect, 229, 231–2, 270–1 treatment, 94, 94–5, 170 dextromethorphan, 143 diffuse Lewy body disease (DLBD), see dementia: with Lewy bodies; Lewy body disease DJ-1, 336, 512, 512 DL-dopa, 31, 35 donepezil, 141, 341, 542 dopamine agonists, see dopamine agonist(s) antagonists, 200–1, 400 biosynthesis, 32, 32–3 degradation, 32, 32–3 -enhancing agents, see catechol-Omethyltransferase inhibitors loss, 422, 430, 435, 439 monoamine oxidase-B inhibitors, 53–4 pharmacology, 31–3 metabolization, 32–3 synthesis and storage, 31–2 receptors, 24, 34, 42, 73–5, 82, 98, 128, 161–3, 167, 188, 191, 203, 280, 400, 409, 422, 511, 522, 540 release, 3, 76, 146, 280, 294, 394 reuptake, 32, 121, 140, 341, 551 signaling, 382 structure, 34 transporters, 3–4, 24, 32, 50, 77, 98, 140, 298, 309, 340, 362, 390, 404, 420, 473, 492, 504, 510, 536, 537, 538 working memory and, 540 dopamine agonist(s), 37 apomorphine, 39, 47, 73, 74, 78, 80, 81, 83, 85–6, 134, 137, 144–5, 162, 167–8, 172, 174, 191, 198, 201, 202–3, 280, 292–3, 298, 320, 341–2, 392, 474 bromocriptine, 74, 78, 80 cabergoline, see cabergoline clinical trials with, 76–82
INDEX dopamine agonist(s) (Continued ) clinical trials with (Continued ) levodopa-naı¨ve Parkinson’s patients, 76–9 motor complication prevention, 79–80 non-motor complication prevention, 81 dihydroergocryptine, 74, 78, 80 efficacy, 73–80, 80, 85–6 as levodopa adjunct, 79 lisuride, 74, 78, 80 for neuroprotection in Parkinson’s disease, 25–6, 76 Parkinson’s disease management with, 84–6 pergolide, see pergolide piribedil, 76, 78, 80 pharmacology, 73 pharmacodynamics, 75–6 pharmacokinetic properties, 73, 74 receptor sensitivity, 75–6 pramipexole, 74, 78, 80 receptor D2 agonists, 98 ropinirole, see ropinirole safety issues, 82 synthesis, 98 type A adverse reactions central, 82–3 peripheral, 82 type B adverse reactions, 83–4 dopaminergic drugs, 40, 42, 59, 140, 145, 168, 170–1, 187, 191, 196, 197, 198, 203–4, 205–6, 222, 228, 269, 399, 406, 420, 433, see also dopamine agonist(s); dopamine: antagonists neurons, 21, 23, 26, 32, 40, 48–9, 96, 103, 140, 146, 159, 285, 291, 295–6, 338, 374, 379, 385, 387–92, 394, 417, 421, 491, 513, 515 systems, 3, 19, 36, 42, 74, 96, 127, 161, 174, 200–1, 335, 386, 388, 394, 403–4, 422, 448, 494, 507, 538, 540 Down’s syndrome, 480 drug-induced movement disorders (DIMD), 399–400, 403, 405–6, 409–11 DU-127090, 141 dysarthria, 35, 249–52, 269, 307, 313, 315, 319, 333, 340, 352–6, 357, 364, 447, 451, 482, 495, 515, 517–18, 519, 520 dyskinesia antidyskinetic drugs, 142–5
dyskinesia (Continued ) antidyskinetic drugs (Continued ) glutamatergic, 142–4, see also glutamatergic: antagonists biochemistry and molecular biology, 188–94 dopaminergic receptors, 188 early genes, 191 GABA receptors, 191, 193 glutamatergic receptors, 188–200 neuropeptides and adenosine receptors, 190–3 serotonergic receptors, 193–4 choreic and dystonic movements, 186 deep brain stimulation (DBS), 205 diphasia, 45 diphasic, 186, 186–7 dopamine agonists and, 81 entacapone, 57 incidence in Parkinson’s disease, 48 levodopa-induced (LID), 44–5, 143, 160, 186, 205 clinical presentation, 185–8 symptomatic drugs for, 143 surgery for, 207–8 morphological basis, 197–9 neurophysiology, 196, 196–7 nocturnal myoclonus, 187 non-dopaminergic drugs for, 145–7 noradrenergic drugs, 144–5 adenosine receptors and, 146 serotonergic, 146 synaptic vesicular proteins and, 146–7 off-period, 186, 186–7 pathophysiology classic model, 194 synaptic plasticity, 195–6 surgery, 204–8, 244 treatment pharmacological, 199–204 surgery, 204–8, 244 without benefit, 187 dysphagia, 340, 357, 365 dystonia ablative surgery for, 244 in cerebral toxoplasmosis, 378 chlorpromazine and, 399 classification, 507–8 in corticobasal degeneration, 357 dopamine and, 507, 508, 511 dopa-responsive (Segawa disease), 515 genetically defined, 514 in HIV/AIDS, 378 lubag (DYT3), 513–15 mixed movement disorder and 516, see also mixed movement disorders
563 dystonia (Continued ) neuronal intermediate filament inclusion disease and, 513 Parkinson’s disease and, 512, 513–15 inherited, 512 postencephalitic, 512–13 sporadic, 511–12 pathophysiology, 508–10 primary pallidal degeneration and, 513 progressive supranuclear palsy and, 513 rapid-onset (DYT12), 515
encephalitis lethargica, 327, 373, 376, 379–80, 399, 513, 550, 556 Epstein-Barr virus (EBV), 373, 381 excitotoxicity, 17, 20, 24, 43, 76, 127, 138–9, 385, 484
Fahr’s disease, see basal ganglia: calcification fibroblast growth factors 107, 287, 294, see also growth factors fludrocortisones, 39, 320, 365 fluoxetine, 143 FTDP-17, see dementia: frontotemporal: chromosome 17 and frontotemporal dementia, see dementia: frontotemporal
GABA, see gamma-aminobutyric acid gait apraxia, 433–4, 434, 438, 461–2 gama-aminobutyric acid (GABA) cells, 107, 130, 132, 189–91, 194, 205, 243, 453, 509, 510–11, 513 receptors, 48, 163, 191, 193, 514 genes immediate early (IEG), 409, 496 gene therapy for Parkinson’s disease drug development strategy, 292 glial-derived neurotrophic factor (GDNF) delivery in, 295–8, 299–300 neurorestoration in 6-hydroxydopamine lesioning and, 297–8 MPTP and, 298 neuroturin, 299 therapeutic enzyme delivery in, 292–4 trophic molecule delivery in, 294–5 viral vectors adeno-associated virus, 293 adenovirus, 293
564 gene therapy for Parkinson’s disease (Continued ) viral vectors (Continued ) herpes simplex virus, 293 lentivirus, 293, 299–300 glial cell line-derived neurotrophic factor (GDNF), 4, 23–4, 106, 107, 292, 293, 294–9, 300, 301 glial cells, 4, 33, 49, 96, 287, 300, 337, 374, 382, 446 globus pallidus, 21, 48, 99, 127, 142, 163, 196, 229, 229, 243, 247, 262–3, 296, 298, 315, 334–6, 353, 360, 394, 418, 446–7, 449–51, 474, 476, 479–80, 508, 509, 511, 513, 520, 557 glutamate antagonists, see antiglutamatergic drugs neurotransmitter function, 21, 127 neuroprotection by, 21 receptors, 128, 163, 188–91 release, 99, 133, 142, 294, 511, see also antiglutamatergic drugs toxicity, 21, 103, 127, 484 glutamatergic antagonists, 142, 143, 202, see also antiglutamatergic drugs neurons, 21, 127, 196, 509 pathways, 127, 188, 194, 208, 509, 511 receptors, 127–8, 188–90, 196 see also glutamate growth factors fibroblast, 107, 287, 294 insulin-like, 287, 309 nerve, 26, 105, 107, 138, 134, 280, 391 Guam, amyotrophic lateral sclerosisparkinsonism dementia complex of, 336, 392–3
INDEX hydrocephalus (Continued ) normal-pressure (NPH) (Continued ) clinical features, 460–1, 461 cognitive changes in, 462–3 drugs, 470–1 history, 459 imaging, 463–4, 463–5, 467, 476 incontinence and, 462 mechanisms, 465–7 shunting, 469–70 treatment, 467, 468–9 hydroxyaminoindane, 96 hyperhomocysteinemia, 43–4, 422 hyperreflexia, 312–13, 315, 330, 353, 356, 357, 376, 452–3, 460–1, 466, 494, 517, 533 hypoparathyroidism, 479, 480, 480 hypotension, see orthostatic hypotension hypothyroidism, 480
idazoxan, 143 influenza A virus, 374, 375, 379 insulin-like growth factor, 287, 309, see also growth factors iproniazid, 94 iron in Parkinson’s disease, 18, 389 deposition, 315–16, 409, 421, 446–7, 484, 517–18, 520 metabolism, 447, 520 neurodegeneration and, 44, 446–8 oxidative stress and, 103 transport, 409 isocarboxazid, 94 istradefylline, 141, 146
Japanese B encephalitis virus, 374, 379
KF-17837, 141 Hallervorden-Spatz syndrome, 446, 480 Helicobacter pylori, 374, 376, 380–1 hemiparkinson-hemiatrophy (HPHA) syndrome, 448–9 HIV-AIDS, 292–3, 373–4, 375–6, 377–8, 407, 480 hippocampus, 102–3, 163, 195, 352, 357–8, 419, 463, 491, 532 Huntington’s disease, 21, 23, 355, 362, 405, 447, 450, 482, 504, 508, 515, 516, 550, 556 hydrocephalus neurological features, 466, 466–7 normal-pressure (NPH), 459
lazabemide, 94 L-dopa, see levodopa lead intoxication, 480 learning, 7, 265, 379 long-term potentiation and, 163, 195 memory and, 234 motor, 195 spatial, 102 testing, 232, 233, 252 leprosy, 381 lesions basal ganglia, 419, 420 brainstem, 418–19 globus, 474
lesions (Continued ) hemorrhagic, 418, 487 nigrostriatal, 61, 294, 379–81, 406 striatum, 474 structural, in parkinsonism, 459, 471, 474–6, 475, 504, 507–8, 510 thalamic, 229, 251, 262, 265, 474, 476 white-matter, 394, 419–20, 422, 464, 536 levodopa cheese reaction and, 95 dopamine synthesis and, 98 aging and, 434 dopa-cecarboxylase inhibition and, 34–5 dyskinesias and, 44–8, 48, 186, 197 early versus late L-dopa (ELLDOPA) studies, 35, 35 history of use, 31 motor complications, 45 clinical presentation, 46–8 effects, 37 fluctuations, 44–8 mechanisms, 46–8 prevalence, 47 onset, 46 in neuroprotection for Parkinson’s disease, 25 side-effects, 36, 38, 39–44 hallucinations, 38, 39–41 hyperhomocysteinemia, 43 impulse control deficits, 41–2 melanoma, 42–3 nausea, 36, 38 orthostatic hypotension, 38–9 sleep disturbances, 38 somnolence, 38 withdrawal rate for adverse events, 38 therapy strategies infusion, 51–2 oral formulations, 50–1 slow-release preparations, 52–3 tolerance, 36–44 treatment of Parkinson’s disease, 35–6, 44–5, 141 Lewy bodies in Alzheimer’s disease, 404, 446 degeneration, 39–40 dementia with, see dementia: with Lewy bodies in Parkinson’s disease, 427 Lewy body disease, 81, 102, 114, 363, 427, 436, 438–9, 531, 537, 550, 550, 552 locus ceruleus, 39, 96, 99, 101, 103, 307, 315, 352, 358–60 lymphocytes, 373, 391, 447
INDEX manganese parkinsonism induction by, 389–90, 504, 550 poisoning, 550, 550, 557 melanoma, 42–3, 105, 112 melevodopa, 140, 141 mental changes from Parkinson’s disease treatment drug-induced psychosis, 219, 220 with clear sensorium, 220 hallucinations, 220–2, 221 with impaired sensorium/ dementia, 220 long-term outcome, 225 treatment, 222–5 mood and anxiety fluctuations, 225–6 repetitive/compulsive disorders, 226–7 dopamine dysregulation syndrome, 227 gambling, pathological, 228 punding, 228 surgery-induced, 229 adverse cognitive effects, 232–4 anxiety, 232 apathy, 232 depression, 231–2 executive function changes, 234 learning and memory disorders, 234 mania, 230–1 neuropsychological tests for, 233 psychosis, 229 visuospatial function changes, 234–5 methamphetamine, 96, 98, 106–7, 110, 280, 410 methanol, parkinsonism induction by, 393 methemoglobinopathies, 480 methotrexate, 480 midodrine, 39, 320, 365 milacemide, 94 mitochondria(l) abnormalities, 17, 104 bioenergetics, 21 cell survival/death and, 105 complex I, 48, 139, 338, 387, 391–2, 394, 410 II, 392, 410 dysfunction, 21, 44, 127, 327, 337, 385 function, 21–2, 104–5, 107, 139, 385–7 genes and inheritance, 337, 517 membrane, 21–2, 104–5, 107, 480 myopathies, 480
mitochondria(l) (Continued ) see also oxidative stress mixed movement disorders in Alzheimer’s disease, 522, see also Alzheimer’s disease autosomal-dominant Huntington’s disease, 515, 516 Huntington’s disease-like 2, 515–16, 516 autosomal-recessive, 519 aceruloplasminemia, 518–19 chorea acanthocytosis, 518 Gaucher disease type III, 520–1 glutaric aciduria, 521 GM1 gangliosidosis, 520 Niemann-Pick type C, 520 pantothenate kinase-associated neurodegeneration, 520 Wilson’s disease, 518, 519 biotin-responsive basal ganglia disease, 521 dentatorubropallidoluysian atrophy, 516, 517, 550, 556 drug-induced, 521 dystonia and, 516 Fahr’s disease, 516, 517 homocystinuria, 521 neuroferritinopathy, 517 neuronal intranuclear hyaline inclusion disease, 521 parkinsonism and, 516 spinocerebellar ataxia, 516, 516–17 therapy, 522 X-linked recessive, 517 McLeod syndrome, 517–18 moclobemide, 94, 95, 97 monoamine oxidase, 94 monoamine oxidase inhibitors, see monoamine oxidase-A inhibitors; monoamine oxidase-AþB inhibitors; monoamine oxidase-B inhibitors monoamine oxidase-A inhibitors for depression, 94 discovery of, 93–5 distribution, 95, 97 irreversible, 94, 96 in Parkinson’s disease, 99–101 reversible, 94, 97 structure, 96 substrates, 97 tyramine metabolism inhibition by, 95 tyrosine metabolism and, 98 see also specific drugs monoamine oxidase-AþB inhibitors for depression, 94 irreversible, 94, 96, 102
565 monoamine oxidase-AþB inhibitors (Continued ) reversible, 94, 96, 142 structure, 96 substrates, 97 see also specific drugs monoamine oxidase-B inhibitors for depression, 94 discovery of, 93–5 distribution, 95, 97 irreversible, 94 for Parkinson’s disease, 19–22, 98–9, 108–12 reversible, 94 structure, 94, 96 substrates, 97 tyramine metabolism inhibition by, 95 tyrosine metabolism and, 98 see also specific drugs motor fluctuations in Parkinson’s disease epidemiology, 161 levodopa-induced, 159–60, 160 dose-related, 160 dyskinesia, 160 motor blocks, 160 on-off fluctuations, 160 tachykinetic problems, 160 treatment, 164–8 unpredictable sudden offs, 159–60 pathophysiology, 161–3 pharmacodynamics, 162–3 pharmacokinetics, 161–2 spontaneous, 161 see also non-motor fluctuations in parkinsonism MPTP (1-methyl-4-phenyl-1,2,3,6tetrahydropyrodine) -induced parkinsonism, 18, 391 lesions, 4, 23, 142, 144, 163, 173, 190, 294, 298, 300, 390–1 toxicity, 18 -treated animals, 21, 48, 56, 102, 144, 188, 293, 391 multiple system atrophy categories, 314 clinical features, 310–14, 315 behavioral disorders, 314 cardiovascular dysfunction, 312 cerebellar dysfunction, 313 disordered sleep, 313–14 dystonia, 310, 402, 433–4, 508, 512, 513 gastrointestinal dysfunction, 312 genital dysfunction, 311 parkinsonism, 310 pyramidal dysfunction, 313
566 multiple system atrophy (Continued ) clinical features (Continued ) thermoregulatory dysfunction, 313 urinary dysfunction, 311–12 consensus criteria, 314, 315 diagnosis autonomic function tests, 317 differential, 364, 380, 438, 451 functional neuroimaging, 316–17 neurophysiological testing, 317–18 structural neuroimaging, 316 epidemiology analytical, 308–9 descriptive, 308 history, 307–8 glial cytoplasmic inclusions, 316 myoclonus and, 550, 555 neuropathology macroscopic, 314–15, 421 microscopic, 315 parkinsonism and, 512 sonographic brain images, 421 treatment of cardiovascular dysfunction, 319–20 of gastrointestinal dysfunction, 320 of genital dysfunction, 319 of motor disorders, 318–19 of urinary dysfunction, 319 myoclonus, 357 causes, 550 chronic manganese poisoning and, 557 classification, 549 corticobasal degeneration and, 553, 553–5 dentatorubropallidoluysian atrophy and, 556 in diffuse Lewy body disease, 552–3, 552 electrophysiological findings, 551 encephalitis lethargica and, 556 frontotemporal dementia with parkinsonism and, 556–7 idiopathic Parkinson’s disease and, 550 in multiple system atrophy, 555
nabilone, 143 naloxone, 143 nerve growth factor 26, 105, 107, 138, 139, 280, 391, see also growth factors neurodegeneration with brain iron accumulation (NBIA), 446–8, 517, 520
INDEX neurofibromatosis, 480 neuronal death, 105, 139, 373, 484 mechanism, 104 models, 76–7 prevention, 104 propargylamines and, 104 see also neuroprotection in Parkinson’s disease neuroprotection in Parkinson’s disease amyloid precursor protein and, 106 drugs antiapoptotic agents, 21–2 antiexcitotoxic agents, 20–1 antioxidants, 18–22 CEP-1347, 138 development status of, 138 dopamine agonists, 25–6, 140–2 E-2007, 138 GPI-1485, 138 leteprinim, 138 levodopa 25, 140, see also levodopa liatermine, 138 MITO-4509, 138 monoamine oxidase-B inhibitors, 18–22 ONO-2506, 138 PAN-408, 138 PYM-50028, 138 propargylamine, 106 rasagiline (Azilect, Agilect), 103, 106, 110–12 selegiline, 103, 106, 109 sonic hedgehog protein agonist, 138 TCH-346, 138 V-10367, 138 zydis selegine, 110, 139, 165 mitochondrial modulation, 139–40 antiapoptotic kinase inhibitors, 139–40 minocycline, 140 neuroimmunophilin, 139 neurorescuing agents, 103–8 physical activity and, 3 primate model, 297 restorative therapies and, 22–4 therapies, 138–40 monoamine oxidase inhibitors, 138–9, see also monoamine oxidase-AþB inhibitors: irreversible; rasagiline; zydis selegiline therapeutic design, 17 neurotransplantation for Parkinson’s disease adrenal medulla, 281–2 age and, 285
neurotransplantation for Parkinson’s disease (Continued ) alternative tissue sources for, 286 donor neurons for, 285–6 dopamine neurons and, 286 effects of, 283 experimental basis for, 279–81 fluorodopa positron emission tomography evaluation of, 283 human fetal dopamine cell, 282–5 nialamide, 94 nitric oxide, 338, 374, 491, 511 Nocardia asteroides, 374, 380, 382 non-motor fluctuations in parkinsonism autonomic symptoms, 171–3 dysphagia, 172 dyspnea, 172 management, 173 orthostatic hypotension, 171 sphincter function, 172 thermoregulation, 171 classification, 168, 169 epidemiology, 169 neuropsychiatric, 169–71 mood, 169–70 psychotic symptoms, 170–1 sensory, 173 akathisia, 173 dysthesia, 173 management, 174 pain, 173 noradrenaline, 95 NS-2330, 141
olanzapine, 143 1-methyl-4phenyl-1,2,3,6tetrahydropyridine, see MPTP orthostatic hypotension, 34, 36, 38, 39, 81–2, 98, 169, 171–2, 220, 225, 308, 311–13, 315, 317–20, 336, 365, 534, 537, 542 oxidative stress, 18, 44, 48–9, 76, 103, 107, 327, 337–8, 342, 385, 387, 390, 392, 409
pallidonigroluysian degeneration, 450–1 pallidopyramidal disease, 451–2 palsy progressive supranuclear, see progressive supranuclear palsy pseudobulbar, 341, 371, 393, 417, 419, 423 pargyline, 94 paralysis agitans, see Parkinson’s disease
INDEX parkin gene, 161, 250, 340, 448, 512, 512 Parkinson, James, 31, 351, 436, 487 Parkinson’s disease aging and bradykinesia and, 428–30 cogwheeling phenomenon, 430–1, 431, 436, 503 eye movement, 434 gait abnormality, 432–4, 434 motor slowing, 429 normal, 428 paratonia, 429, 430, 431 primitive reflexes, 434–5 tone change, 430, 431 agricultural chemicals and atrazine, 387, 388 maneb, 387, 388 organochlorine compounds, 388, 388 paraquat, 387, 388 rotenone, 386–7, 387 Alzheimer’s disease and, 439 animal models, 13, 21, 133, 139–40, 146, 162–3, 185, 188–9, 194, 198–9, 262, 279, 293, 294–5, 297, 386, 391, 394, 509 annonacin and, 393, 393 anticholinergic drugs, see anticholinergic drugs antiglutamatergics, see antiglutamatergic drugs atypical, 270, 309–10, 318, 328, 334–6, 351, 353, 355, 363, 421, 501, 536, 557 carbon monoxide poisoning and, 393–4, 419, 480 cycad toxin and, 392, 392–3 dementia and, 364, see also dementia drug-induced 6-hydroxydopamine, 3, 49, 75, 103, 185, 280, 292, 297, 386, 390, 392 methanol, 393 MPTP, see MPTP 6-OHDA, 3–4, 49, 103, 185, 188–93, 195–6, 198–9, 201, 208, 280–1, 285, 292–9, 392 reserpine, 31, 75, 201, 399, 408, 411 see also parkinsonism: druginduced environmental risk factors, 385–6 excitoxicity and, see excitoxicity freezing, 5, 17, 19, 45, 109, 160, 168, 401, 401, 417–19, 420, 433, 437, 462, 520 strategies, 10–13
Parkinson’s disease (Continued ) GDNF proteins receptors and actions, 4, 23, 105, 139, 281, 287, 292, 293, 294–5, 299 gene therapy, see gene therapy for Parkinson’s disease hereditary factors, 385 history, see Charcot, Jean-Martin; Parkinson, James hypersexuality and, 42, 82, 167, 170, 227, 270 idiopathic, 251, 380–1, 406, 488, 495–6, 549, 550 imaging, 421 incidence, 385 infectious basis animal studies, 381–2 Epstein-Barr virus (EBV), 373, 381 Helicobacter pylori, 374, 376, 380–1 HIV, 374–6, 375–6, 377, 407, 480 immunology, 373–4 influenza A virus, 374, 375, 379 Japanese B encephalitis virus, 374, 379 leprosy, 381 Nocardia asteroides, 374, 380–2 prion protein, 153, 337, 363, 374, 381 Toxoplasma gondii, 374, 376, 377–8, 378, 407, 480 transmissible spongiform encephalopathy, 381–2 tuberculosis, 376, 377, 379, 480 isoquinoline derivatives and, 103, 338, 391–2 iron and, see iron metals and, 389 copper, 363, 389–90, 518 iron, see iron manganese, 389–90, 504, 550 methanol and, 393 mood disorders, 170, 227, 230, 270 anxiety, 45, 108, 131, 153, 160, 169, 169–70, 225–7, 229, 232, 270, 357, 450, 505, 533, 542–3 apathy, 10, 169, 229, 231–2, 270, 314, 330, 333, 334, 357, 399, 450, 462, 533, 542–3 depression, see depression: in Parkinson’s disease mania, 45, 227–8, 229, 230–1, 270 motor fluctuations, see motor fluctuations in Parkinson’s disease MPTP -induced parkinsonism, 18, 391
567 Parkinson’s disease (Continued ) MPTP (Continued ) lesions, 4, 23, 142, 144, 163, 173, 190, 294, 298, 300, 390–1 toxicity, 18 -treated animals, 21, 48, 56, 102, 144, 188, 293, 391 multiple system atrophy and, see multiple system atrophy myoclonus and, 550 neuroprotection in, see neuroprotection in Parkinson’s disease oxidative stress and, see oxidative stress patient advocacy groups (PAGs) advocacy by, 154 collaboration and partnerships, 152 future, 155 policy and, 153–4 research issues, 152–5 responsible advocacy, 152 pesticide models maneb, 386, 387, 388 paraquat, 386, 387, 388 rotenone, 21, 44, 386–7, 387, 393 physical exercise and, 3–8 physical therapy for, see physical therapy postural reflexes, 431 progressive supranuclear palsy and, see progressive supranuclear palsy risk factors, 408 alcohol, 227–8, 309, 319, 408, 436–7 coffee and caffeine, 17 gender, 83, 131, 401, 406–7 head trauma, 461, 488–91, 496–7, 508 metals, see Parkinson’s disease: metals and obesity, 1 pesticide exposure, see Parkinson’s disease: pesticide models smoking, 7, 17, 43, 108, 309, 386, 406, 488 sensory symptom(s), 169, 173–4 selegiline monotherapy, 108 sleep disorders, 40, 222, 357, 533–4, 543–4 speech disorders, 138, 354 surgery, see also surgery: ablative pallidotomy, 248–50, 254 radio-, 253 subthalamotomy, 252–4 thalamotomy, 250–2, 254
568 Parkinson’s disease (Continued ) symptoms, 17, 417, 427 transplantation for, see neurotransplantation for Parkinson’s disease trauma and as risk factor, 488–91 epidemiology, 489 posttraumatic parkinsonism, see parkinsonism: posttraumatic treatment gene therapy, see gene therapy for Parkinson’s disease with levodopa, 35–6, see also levodopa mental changes from, 219–28, see also mental changes from Parkinson’s disease treatment parkinsonism amytrophic lateral sclerosisparkinsonism dementia complex of Guam, 336, 392–3 Alzheimer’s and, 439 arteriovenous malformation and, 471 intracerebral hemorrhage, 471 midbrain cavernoma, 471, 472 brain imaging, 420–1 dystonia and, see also dystonia dopa-responsive (Segawa disease), 515 lubag (DYT3), 513–15 rapid-onset (DYT12), 515 drug-induced (DIP) age/dementia and, 405–6 cigarette smoking and, 406 cinnarizine, 406–8, 408, 409–10, 522 diagnosis, 403–5 drugs causing/aggravating, 408 flunarizine, 409–10 gender and, 406 genetics and, 406 history, 399–400 HIV and, 407 magnetic resonance spectroscopy, 405 neuroleptics and, 409 pathology, 403–4 pre-existing movement disorders and, 406 prevalence, 400–1 progression of, 402–3 schizophrenia subtype and, 407 serotonin reuptake inhibitors and, 410 symptoms, 401, 401–2 ventricular/brain ratio, 407
INDEX parkinsonism (Continued ) drug-induced (DIP) (Continued ) treatment, 410–11 frontotemporal dementia and, see dementia: frontotemporal history, 417, 459 lesions, see lesions mechanism for motor symptoms bradykinesia, 243–4 dyskinesia, 244 dystonia, 244 tremor, 244 myoclonus and, see myoclonus postencephalitic, 512 posttraumatic, 491, 493–4 central lesions, 491 peripheral lesions, 495–6 repetitive head trauma, 494–5, 497 single head trauma, 491–2, 494 worsening of parkinsonism, 496 psychogenic clinical manifestations, 502–3 description, 501 diagnosis, 503, 503–5 epidemiology, 501–2 natural history, 501 prognosis, 505 treatment, 505 stroke and, 439 substantia nigra and, 459 symptomatic agents, 141 symptoms, 399, 417 tumors and, 473–4 vascular and Parkinson’s disease, 421–2 imaging methods, 421 history, 417 pergolide, 73, 74, 75, 77–81, 78, 80, 83–4, 86, 164, 222, 228, 341, 363 phenelzine, 94 physical exercise metabolic effects, 3–7 neuroprotective effects, 3–7 and Parkinson’s disease, 8–10, 8–9 see also physical therapy physical therapy for advanced Parkinson’s disease discipline and, 10 freezing episodes, 10–13 appendicular and axial stretch, 6, 8–9 attentional strategies, 5–6 compensation strategies, 10–13 ambulation assistive devices, 13 freezing episodes, 10–13 home environment modification, 13 sensory cues, 11
physical therapy (Continued ) long-term effects, 7–8 resistance training, 4 sensory cueing and, 5–6 training techniques, 4 treadmill training, 6–7 see also physical exercise postencephalitic parkinsonism (PEP), 327–8, 336, 382 clinical features, 380 epidemiology, 376, 379 pramipexole (Mirapex), 24, 37–8, 48, 49, 73, 74, 75, 77–86, 78, 80, 164, 200, 222, 228, 341, 363 prion protein/disease, 153, 337, 363, 374, 381 progressive supranuclear palsy (PSP) brain parenchyma sonography (BPS), 335 cerebral fluid analysis, 334 clinical features, 330–1, 340 heterogeneity, 332–3 diagnosis criteria, 331–2, 332–3 differential, 364 epidemiology age of onset, 329, 329 incidence, 328, 328 prevalence, 328–9, 329 sex ratio, 329, 329 familial, 338 functional imaging, 335–6 history, 327–8 magnetic resonance imaging (MRI), 334–5 management adrenergic agents, 341 cholinergic agents, 341 dopaminergic agents, 341 neurotransmitter replacement and, 340 non-pharmacological, 342 palliative treatments, 340 natural history, 331 neuropsychological assessment, 333–4, 336 nortriptyline and, 341 pathology molecular, 338–40 neuro-, 336, 337 tau aggregation and cell death, 337–8 parkinsonism and, 512 propargylamine, 105–6 propranolol, 143 proteosome inhibition, 104
INDEX protein kinase, 107, 390 synthesis, 104–5 translation, 22, 342 pseudohypoparathyroidism, 480 psychogenic movement disorders (PMD), 501, 503
quinpirole, 201
rasagiline, 20, 53, 94, 98, 104–6 adverse effects, 111 developmental status, 141 effects long–term, 112 short–term, 94, 98–104, 104–6, 107–8, 111, 113, 138–9 efficacy, 113, 98, 165 structure, 96 see also monamine oxidase-B inhibitors reactive oxygen species (ROS), 385 Rett syndrome, 452–4 reversible monoamine oxidase (MOA)A inhibitors RIMA, 97, 99, 101, 114 moclobemide, 94, 94–5, 97–8, 99–102, 108, 112, 114 ritanserin, 143 ropinirole (Requip) dyskinesias, 48 metabolism, 74 pharmacological properties, 74 treatment, 24–5, 73–4, 77–83, 78, 80, 85–6, 222, 228 effectiveness, 37–38, 49, 75 rotenone, 21, 44, 386–7, 387, 393 rotigotine, 73, 86, 141, 164
safanamide, 94, 96, 141, 142 sarizotan, 143 selegiline as levodopa adjunct, 109 effects, 94, 103–4, 104–6, 109, 223, 433 neuroprotection, 109 in Parkinson’s disease treatment, 18–19, 94, 98–103, 105, 107–8, 108–9, 165, 341, 438 structure, 96 serotonin (5-HT), 32, 93, 97, 100, 142, 143, 146, 170, 227, 232, 364, 382, 391, 400, 410, 453, 543, 550 SKF-82958, 191, 201
SKF-39392, 201 sleep disorders, 40, 222, 357, 533–4, 543–4 SLV-308, 141, 142 somatostatin (SOM), 320, 363, 484 speech in bilateral striopallidodentate calcinosis, 482–3 in chorea acanthocytosis, 449 in corticobasal degeneration, 352, 354–6, 365 in dementia with Lewy body disease, 533 in GM2 gangliosidosis, 520 in pantothenate kinase-associated neurodegeneration, 520 in Parkinson’s disease, 3, 138, 229, 401, 429, 447 in progressive supranuclear palsy, 331, 340, 340 surgery and, 204, 224, 246, 250–3, 269 SPD-473, 141 SR-57667, 141 Steele-Richardson-Olszewski syndrome, see progressive supranuclear palsy substantia nigra pars compacta (SNc or SNpc) in corticobasal degeneration, 361 deep brain stimulation and, 263–4, 270 degeneration, 17, 103, 107, 159, 280, 287, 307, 315, 352, 361, 390, 417, 427, 435, 445, 450, 452–3, 492, 493, 495, 508, 531, 540 dopamine synthesis and, 98 neurons, 96, 190, 192, 197, 243, 285, 291, 373, 385, 388–9, 391 oxidative stress and, 48, 76 in Parkinson’s disease, 18, 21, 99, 389, 421, 509, 531, see also substantia nigra pars compacta: degeneration in progressive supranuclear palsy, 336, 337 subthalamic nucleus (STN) deep brain stimulation and, 168, 205–6, 229, 261, 263–4, 267, 267–8, 285, 449 Parkinson disease and, 20, 229, 243, 294 progressive supranuclear palsy and, 336, 337 surgery, 205 sumanirole, 141
569 surgery ablative microelectrode localization, 246 physiological localization, 245 radiological localization, 245 stereotactic lesioning techniques, 246 stereotactic surgical techniques, 245 for dyskinesia, 204–8, 244 deep brain stimulation (DBS), 205 of globus pallidum, 204 subthalamic nucleus, 204–7 for dystonia, 244 mental changes following, 229, 232–5 for Parkinson’s disease, see Parkinson’s disease: surgery radio-, 253 speech impairment from, 204, 224, 246, 250–3, 269 a-synuclein abnormalities and mutations, 297, 340, 351, 512, 531, 540 Alzheimer’s disease and, 539–40 degradation, 316 expression, 315 in glial cytoplasmic inclusions and Lewy bodies, 307, 315, 316, 359, 374, 381, 385, 388, 538–9, 539 metals and, 389–90 neuroprotection and, 138 and synucleinopathies, 307, 313, 330, 340, 351, 357, 359, 363, 374, 491, 539 systemic lupus erythematosus, 418, 480
talipexole, 141 tau protein, 333–4, 338–9, 343, 360, 445, 513, 556 tolcapone, 57 toloxatone, 94 toxoplasmosis and Toxoplasma gondii, 374, 376, 377–8, 378, 407, 480 transcranial ultrasonography, 318, 336, 342, 405, 420–1, 448 transmissible spongiform encephalopathy, 381–2 transplantation for Parkinson’s disease, see neurotransplantation for Parkinson’s disease tranylcypromine, 94 tremor ablative surgery, 244 aging and, 434 in corticobasal degeneration, 357
570 tremor (Continued ) essential, 250, 253, 404–6, 435–6, 496, 504 tone testing, 430–1 tuberculosis, 376, 377, 379, 480 tuberous sclerosis, 480 tyrosine, 98 cheese reaction and, 95
INDEX tyrosine (Continued ) hydroxylase, 31, 32, 98, 101, 103, 107, 286, 292, 293, 382, 388, 514, 539 potentiation of cardiovascular effects, 95
VR-2006, 141
UCHL-1, 309
zydis selegiline, 110, 139, 165
working memory, 540 World Health Organization (WHO), 151, 155, 271
