Handbook of Clinical Neurology pptx

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 Milwau-
kee 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 Dis-
orders clinical program at the Mount Sinai Medical Center in New York, and then to the University of North Car-
olina, 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 experiment al 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 Movem ent 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, befrien ding 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) ser-
ies, 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 pathogeni c
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 quar-
ter-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 parkin-
sonian disorders, which should appea l 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, sev-
eral 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 back-
ground of parkinsonism during the 1960s and early 1970s led to dramatic pharmacological advances in the man-
agement of Parkinson’s disease and profoundl y 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 man-
dated 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 dis-
orders 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 pub-
lisher, Elsevier B.V., and especially Ms Lynn Watt and Mr Michael Parkinson in Edinburgh for overs eeing 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 treme ndous progress in our understanding of this complex and fas-
cinating 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 impair-
ments. We now know how to distinguish better clinically between Parkinson’s disease and the various parkinso-
nian 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 bein g 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 dis-
ease 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 symp-
toms 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 stimula te 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 sudden ly, 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
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-Albrechts-
University, 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 Publi c 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
xii LIST OF CONTRIBUTORS
C. G. Goetz
Department of Neurological Sciences, Rush University
Medical Center, Chicago, IL, USA
J. G. Goldman
Department of Neurological Sciences, Rush University
Medical Center, Chicago, IL, USA
D. S. Goldstein

Clinical Neurocardiology Section, National Institute of
Neurological Disorders and Stroke, National Institutes
of Health, Bethesda, MD, USA
J M. Gracies
Department of Neurology, Mount Sinai Medical
Center, New York, NY, USA
J. T. Greenamyre
Department of Neurology, Emory University, Atlanta,
GA, 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
J. S. Hui
Department of Clinical Neurology, University of
Southern California, Los Angeles, CA, USA
J. Jankovic
Parkinson’s Disease Center and Movement Disorders
Clinic, Department of Neurology, Baylor College of
Medicine, Houston, TX, USA
P. Jenner
Neurodegenerative Disease Research Center, School
of Health and Biomedical Sciences, King’s College,
London, UK
M. Kasten
The Parkinson’s Institute, Sunnyvale, CA, USA
H. Kaufmann
Department of Neurology, Mount Sinai School of
Medicine, New York, NY, USA
W. C. Koller
y
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 Neurolo gical Studies,
University College London, London, UK
y
Deceased.
LIST OF CONTRIBUTORS xiii
F. A. Lenz
Department of Neurosurgery, Johns Hopkins Hospital,
Baltimore, MD, USA
N. Lev
Laboratory of Neuroscience and Department of
Neurology, Rabin Medical Center, Petah-Tikva,
Tel Aviv University, Tel Aviv, Israel
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
Y. Mizuno
Department of Neurology, Juntendo University School
of Medicine, Tokyo, Japan
H. Mochizuki
Department of Neurology, Juntendo University School
of Medicine, Tokyo, Japan
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
¨
tMarburg,
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
xiv 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
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
LIST OF CONTRIBUTORS xv
J. Volkmann
Department of Neurology, Christian-Albrechts-
University, 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
xvi LIST OF CONTRIBUTORS
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 3
Jean-Michel Gracies, Winona Tse, Mara Lugassy and Judith Frank (New York, NY, USA)
31. Neuroprotection in Parkinson’s disease: clinical trials 17
Fabrizio Stocchi (Rome, Italy)
32. Levodopa 31
Thomas D. H
€
albig and William C. Koller (New York, NY and Chapel Hill, NC, USA)
33. Dopamine agonists 73
Olivier Rascol, Tarik Slaoui, Wafa Regragui, Fabiene Ory-Magne,
Christine Brefel-Courbon and Jean-Louis Montastruc (Toulouse, France)
34. Monoamine oxidase A and B inhibitors in Parkinson’s disease 93
Moussa B. H. Youdim and Peter F. Riederer (Haifa, Israel and W
€
urzburg, Germany)
35. Anticholinergic medications 121
Yaroslau Compta and Eduardo Tolosa (Barc elona, Spain)
36. Antiglutamatergic drugs in the treatment of Parkinson’s disease 127
Marı
´
a Graciela Cers

osimo and Federico Eduardo Micheli (Buenos Aires, Argentina)
37. Investigational drugs 137
Carlo Colosimo and Giovanni Fabbrini (Rome, Italy)
38. The importance of patient groups and collaboration 151

Mary Baker and Jill Rasmussen (Sevenoaks and Redhill, UK)
SECTION 6 Complications of therapy
39. Motor and non-motor fluctuations 159
Susan H. Fox and Anthony E. Lang (Toronto, ON, Canada)
40. Levodopa-induced dyskinesias in Parkinson’s disease 185
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)
41. Treatment-induced mental changes in Parkinson’s disease 219
Kelvin L. Chou and Joseph H. Friedman (Warwick, RI, USA)
SECTION 7 Surgical treatment
42. Ablative surgery for the treatment of Parkinson’s disease 243
Frederick A. Lenz (Baltimore, MD, USA)
43. Deep brain stimulation 261
J. Volkmann and G. Deuschl (Kiel, Germany)
44. Transplantation 279
Curt R. Freed, W. Michael Zawada, Maureen Leehey,
Wenbo Zhou and Robert E. Breeze (Denver, CO, USA)
45. Gene therapy approaches for the treatment of Parkinson’s disease 291
Biplob Dass and Jeffrey H. Kordower (Chicago, IL, USA)
SECTION 8 Other parkinsonian syndromes
46. Multiple system atrophy 307
Ronald F. Pfeiffer (Memphis, TN, USA)
47. Progressive supranuclear palsy 327
David J. Burn and Andrew J. Lees (Newcastle upon Tyne and London, UK)
48. Corticobasal degeneration 351
Natividad P. Stover, Harrison C. Walker and Ray L. Watts (Birmingham, AL, USA)

49. Infectious basis to the pathogenesis of Parkinson’s disease 373
V. Dhawan and K. Ray Chaudhuri (London, UK)
50. Toxic causes of parkinsonism 385
Nirit Lev, Eldad Melamed and Daniel Offen (Petah-Tikva and Tel-Aviv, Israel)
51. Drug-induced parkinsonism 399
Federico Eduardo Micheli and Marı
´
a Graciela Cers

osimo (Buenos Aires, Argentina)
52. Vascular parkinsonism 417
Yacov Balash and Amos D. Korczyn (Tel-Aviv and Ramat-Aviv, Israel)
53. Old age and Parkinson’s disease 427
Alex Rajput and Ali H. Rajput (Saskatoon, SK, Canada)
54. Other degenerative processes 445
J. Carsten Mo
¨
ller and Wolfgang H. Oertel (Marburg, Germany)
55. Hydrocephalus and structural lesions 459
John G. L. Morris, Brian Owler, Mariese A. Hely and
Victor S. C. Fung (Sydney, NSW, Australia)
xviii CONTENTS
56. Calcification of the basal ganglia 479
Jennifer S. Hui and Mark F. Lew (Los Angeles, CA, USA)
57. Trauma and Parkinson’s disease 487
Oscar S. Gershanik (Buenos Aires, Argentina)
58. Psychogenic parkinsonism 501
Vasiliki Koukouni and Kailash P. Bhatia (London, UK)
59. Parkinsonism and dystonia 507
Ruth H. Walker (Bornx and New York, NY, USA)

60. Dementia with Lewy bodies 531
Ian McKeith (Newcastle upon Tyne, UK)
61. Myoclonus and parkinsonism 549
Daniel D. Truong and Roongroj Bhidayasiri (Fountain Valley and Los Angeles, CA,
USA and Bangkok, Thailand)
Subject index 561
Color plate section 571
CONTENTS xix
Section 5
Treatment of Parkinson’s disease
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 func-
tion 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, pharmaco-
logictherapyhasbeentheprimarystrategytomanage
these symptoms and has been considered the ‘gold-stan-
dard’ therapy. Ho wever, 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 phy-

sical exercise and investigations have been carried out to
evaluate techniques that may alleviate functional disabil-
ities in patients with PD. Despite this rising interest, sur-
veys 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 ther apy 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 indivi-
duals with mild to moderate disease, who are ambula-
tory 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 indi-
vidual with com promised 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 preser-
vation of as much functional independence as possible.
These strategies include adaptation of the home envir-
onment, 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 emis-
sion tomography (PET) scans, which has been considered
highly suggestive of increased endogenous dopamine
release (Ouchietal.,2001). In addition, exogenous levo-
dopa seems to be better absorbed during moderate-inten-
sity 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-tetrahy-
dropyridine (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: , Tel: 1-(212)-241-8569,
Fax: 1-(212)-987-7363.
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
to PD lesions that are then exercised show significant

sparing of striatal dopamine compared to lesioned ani-
mals that remain sedentary (Fisher et al., 2004; Poulton
and Muir, 2005). Further, one study showed that exercise
after MPTP exposure increases dopamine D
2
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 i psilateral forelimb. After casting of the unaf-
fected forelimb in unilaterally 6-OHDA-lesioned rats,
the forced use of the a ffected forelimb spares its func-
tion 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 sug-
gest 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 exer-
cise and activity prior to MPTP lesion, or to unilateral
forced limb use prior to contralateral lesioning with
6-OHDA, may prevent t he emergence of the beha-
vioral and neuroc hem ical deficits that normally fol-
low the administration of 6-OHD A (Cohen et al.,
2003; Faherty et al., 2005). In on e o f the s e st ud ie s,

animals receiving a unilateral cast had an increase in
glial cell-line derived neurotrophic factor (GDNF) pro-
tein 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 evalu-
ated with regard to their impact on motor deficits in
mild to moderate PD. Few studies have been con-
trolled 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 stiff-
ness 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-ma tched 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 extre-
mities may limit the ability to mount appropriate pos-
tural 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 under-
went 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 plan-
tar 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 wee k, 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 a fter the training period,
showing gai ns in strength in the PD patients that were
similar to those of the control subjects and improve-
ment on quantitative measures of gait such as s tride
length, gait velocity and postural angles (Scandalis
et al., 2001).
4 J. M. GRACIES ET AL.
30.1.2.2. Attentional strategies and sensory cueing
It is a common clinical observation that increased
attention or effort may allow improvements of remark-
able magnitude in motor tasks performed by PD
patients (Muller et al., 1997). This observation has
contributed to the development of cueing, an increas-
ingly 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 deac-
tivating the cortical subunits corresponding to a given

motor sequence (Morris and Iansek, 1996). In PD
however, the internal cues provided by the basal gang-
lia are no longer appropriately supplied. Thus, restora-
tion 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 dra-
matically reduces initiation and execution time and
improves motor sequencing (Georgiou et al., 1993;
Kritikos et al., 1995). Another study showed that a sin-
gle 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
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 metro-
nome set at the baseline walking cadence slowed ambu-
lation 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 audi-
tory 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 dur-
ing trials of natural walking interspersed with rando-
mized conditions in which subjects were verbally
instructed to increase arm swing, or step size or walk-
ing 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 addi-
tional 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 atten-
tion) 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).

PHYSICAL THERAPY IN PARKINSON’S DISEASE 5
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 mark ed on the floo r, over which
the patient is encouraged to step. In a series of experi-
ments, 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 hour s 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, zig-
zag 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 visuali-
zation 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 trans-
fers (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 i mpairment in PD, particu-
larly 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 tec hni-
que has not been systematically evaluated as a method
to improv e motor function in PD. In one controlled
study an improvement in rigidity was observed as
compared to baseline after a therapy program invol-
ving 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 contin-
ued 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, hemi-
paresis and other gait disorders (Hesse et al., 2 003).
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
(Miy ai et al., 2000, 2002; Pohl et al., 2003). However,
although these studies compared treadmill with non-
treadmill training, they were not controlled for the walk-
ing speed used in the training. In particular the non-tread-
mill training did not inv olve specific requirements of gait
velocity, step cadence or stride length. Under these cir-
cumstances, 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
6 J. M. GRACIES ET AL.
(Miyai et al., 2000, 2002; Pohl et al., 2003). In a study
which did control for walking speed by having subjects
walkfirstonthegroundandthenonatreadmillsetat
the same speed, both PD patients and age-matched con-
trols showed shorter stride lengths and higher stride fre-
quency in the treadmill condition (Zi jlstra 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 particu-
larly relevant to the PD patient population, in which
decreased stride length and impaired stride length regu-
lation 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 physi-
cal exercise in PD remains unknown. Most studies on
physical therapy in PD have been open and had fol-
low-up periods of less than 8 weeks, making the long-
term persistence of beneficial effects difficult to deter-
mine (Deane et al., 2001). However, in one recent
open-label trial 20 PD patients followed a comprehen-
sive rehabilitation program three times a week for
20 weeks. Following the program, there was a signifi-
cant improvement in Unified Parkinson’s Disease
Rating Scale (UPDRS) activities of daily living and
motor sections scores, self-assessment Parkinson’s Dis-
ease Disability scale, 10-meter walk test and Zung scale
for depression, which was still seen at the 3-month fol-
low-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 lim-
ited 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 in creased
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 n ot exercise regu larly com-
pared with patients who did. However, the odds ratios
were not adjusted for major health factors, such as cardi-
ovascular disease, lung disease, smoking or obesity.
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 ther-
apy groups (Marchese et al., 2000). The first group
underwent a 6-week program of posture control exer-
cises, passive and active stretch and walking exercises,
whereas the second group combined the same regimen
with a v ariety 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, wherea s 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 sug-
gested improved precision of arm movements as a con-
sequence 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 sys tematically compared
with individual therapy and group therapy studies have
not been controlled. In their study, Pacchetti and
PHYSICAL THERAPY IN PARKINSON’S DISEASE 7
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 exer-
cise schedule be intensified and expanded from orga-
nized 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 per-
formance 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 strat-
egy may also be suggested, i.e. the performance of phy-
sical 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 prob-
ably 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 exer-
cises 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
Lift the weight (bag) to the side, up & down
Repeat with each arm until fati
g
ued
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
Fig. 30.1. Stretches and exercises for the upper body.
8 J. M. GRACIES ET AL.
exercises should consist of vigorous series of light-
resistance 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 cardi-
orespiratory 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 contri-
bute 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 choos-
ing weights so as to avoid using maximal or near max-
imal intensity training (Khouw and Herbert, 1998)in
order to limit the risk of muscle and tendon strain in
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 mus-
cle 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 pur-
sued 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).
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
Stretch by bending forward
5 mins. on each side
Stand from sitting position without using hands.
Repeat as many times as possible until fati
g
ued.
Walk the same distance in as few steps as possible.
Stand with support and stretch legs for 5 mins.
STRETCHES & EXERCISES LOWER BODY
Fig. 30.2. Stretches and exercises for the lower body.
PHYSICAL THERAPY IN PARKINSON’S DISEASE 9
a sense of fatigue in the primary muscles involved (hip,
knee and s pinal e xtensors). T his sh ou ld lead to strengthen-
ing 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 dis-

tance using as few steps as possible (Fig. 30.2). When
stride length improvement over that distance is maxi-
mized (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 train-
ing 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 gradu-
ally 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 strate-
gies 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 active ly conc entrat e on them,
possibly even to r ehears e them mentall y a s a new task
each time, as opposed to just doing them. This corre-
sponds 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 fundame nt al difference between
automatic and consciously controlled movements;
and (2) the need to s witch to conscious movement
control for virtually all daily motor activities, particu-
larly 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 strate-
gies below.
However, teaching and maintaining such discipline
can become a highly c hallenging proposition in advanced
PD, depending on the presence of depression and par-
ticularly 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 hope-
lessness and pessimism, as well as decreased motiva-
tion and drive (Brown et al., 1988). This may
undermine the moti vation to practice or to change
daily living strategies. Apathy and abulia (lack o f
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 demen-
tia, in particular frontal dysexecutive features (perse-
verations, impulsivity), may hamper the ability to
pursue a strict but slower routine of conscious rehear-
sal when performing daily activities that used to be
automatic. In these cases, the care -giver of ten
becomes the primary focus of the teaching a nd the
person effectively responsible for implementing the
discipli ne 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 con-
stitute a significant problem, occurring in up to one-
third 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 defici ent internal
motor cues normally provided by the basal ganglia

(Morris et al., 1995). Specific attentional strategies
may also be usef ul (see below).
10 J. M. GRACIES ET AL.
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 epi-
sodes are common such as doorways and narrow hall-
ways. 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 accompa-
nied, 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. Acous-
tic 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, transfer-
ring 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 strate-
gies that have the additional advantage of generat-
ing 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 distrac-
tion 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
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 situa-
tions 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 elemen-
tary 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 w hen a
strong first step is achieved the second and third
steps naturally follow.
 Movement planning and attention – switching back
from automatic movements to consciously con-
trolled 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 tur n
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 main-
taining 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
PHYSICAL THERAPY IN PARKINSON’S DISEASE 11
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 d o 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 move-
ment 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 allevi-
ate 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 o r 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, swing-
ing 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 plac ed back under-
neath 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 signif-
icant 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 mini-
mize 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 balan-
cing deficits may be accentuated. The set-shifting dif-
ficulties 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 ben-
eficial in PD to avoid performing two tasks simul ta-
neously. In a study comparing PD patients to age-
matched 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 vari-
able 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 perfor-
mance 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 pre-
vious 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 pos-
tural stability between groups when subjects simply
stood on a platform, but PD patients showed signifi-
cantly 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 encour-
aged 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
12 J. M. GRACIES ET AL.
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 indepen-
dence 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 inde-
pendent. 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 indi-
viduals at risk for trippi ng 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 sta-
bility and prevent falls in general a nd parti cularly in
orthopedic conditions, the impact of chronic walker
use in PD needs to be critically examined. The argu-
ments for or against a walker should be weighed on a

case-by-case ba sis, as the use of wa lkers ma y w ors en
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 walk-
inginPD(Cubo et al., 2003). Both wheeled a nd stan-
dard walkers significantly slowed gait compared to
unassisted wa lking, a nd t he standard walker also
increased freezing. In addition to potentially exacer-
bating 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
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 pro-
spective study, but anecdotal evidence has been suffi-
ciently 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 provid-
ing specific training to the patient is also questionable.
Patients with PD often handle canes improperly, carry-
ing 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 perfor-
mance, involving the simultaneous activities of walking
and carrying an object. As described above, performing
additional tasks while walking can result in gait dete-
rioration. 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 sup-
posed 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 ca ne or a walke r is conside red, the
indication should be determined objectively and
accurately: psychological reassurance, social signa l,
objective improvement in stability, reduction in
energy consumption during gait. Whichever indica-
tions 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 fre ezing 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 neces-
sarily 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 dys-
kinesias, 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 co mplicated by heterogeneous treat-
ment methods, different outcome measures and varying
PHYSICAL THERAPY IN PARKINSON’S DISEASE 13