Vol 28.5 - Movement Disorders.2022

OCTOBER 2022
VOL. 28 NO. 5 Movement Disorders

Guest Editor: Kathleen L. Poston, MD, MS, FAAN
1266 Editor’s Preface

Editor-in-Chief: Steven L. Lewis, MD, FAAN
REVIEW ARTICLES
1268 Prodromal α-Synucleinopathies

Lana M. Chahine, MD, FAAN
1281 Diagnosis and Medical Management of Parkinson Disease

Avner Thaler, MD, PhD; Roy N. Alcalay, MD, MS
1301 Surgical Therapies for Parkinson Disease

Ashley E. Rawls, MD, MS
1314 Diagnosis and Treatment of Cognitive and Neuropsychiatric

Symptoms in Parkinson Disease and Dementia With Lewy
Bodies
Daniel Weintraub, MD; David Irwin, MD
1333 Diagnosis and Treatment of Essential Tremor

Aparna Wagle Shukla, MD
1350 Multiple System Atrophy

Daniel O. Claassen, MD, MS, FAAN
1364 Progressive Supranuclear Palsy and Corticobasal Syndrome

Alexander Pantelyat, MD, FAAN
DENOTES CONTINUUM
1379 Chorea
AUDIO INTERVIEW
Erin Furr Stimming, MD, FAAN; Danny Bega, MD
DENOTES VIDEO
CONTENT 1409 Neurodegenerative Cerebellar Ataxia
Liana S. Rosenthal, MD, PhD
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

1435 The Dystonias
Christopher D. Stephen, MB ChB, FRCP, SM
1476 Diagnosing Common Movement Disorders in Children

Jennifer A. O’Malley, MD, PhD
1520 Palliative Care and Movement Disorders

Maya Katz, MD
SELF-ASSESSMENT AND CME
1256 Learning Objectives and Core Competencies
1531 Instructions for Completing Postreading Self-Assessment and CME

Test and Tally Sheet
1533 Postreading Self-Assessment and CME Test
1546 Postreading Self-Assessment and CME Test—Preferred Responses
1557 Index
List of Abbreviations (Back Cover)

CONTRIBUTORS a
Kathleen L. Poston, MD, MS, Roy N. Alcalay, MD, MS

FAAN, Chief, Movement Disorders
Guest Editor Division, Tel Aviv Sourasky
Edward F. and Irene Thiele Medical Center, Tel Aviv, Israel;
Pimley Professor in Neurology Associate Professor of Clinical
and Neurological Sciences; Neurology, Department of
Chief, Movement Disorders, Neurology, Columbia University
Stanford University, Irving Medical Center, New York,
Stanford, California New York
Relationship Disclosure: Dr Poston has Relationship Disclosure: Dr Alcalay has
received personal compensation in the received personal compensation in the
range of $0 to $499 for serving on a clinical range of $500 to $4999 for serving as a
advisory board for Amprion Inc and a data consultant for AVROBIO, Inc; Caraway
safety monitoring board for the National Therapeutics, Inc; GlaxoSmithKline plc;
Institutes of Health, in the range of $500 to Janssen Global Services, LLC; Merck & Co,
$4999 for serving as an associate editor for Inc; Ono Pharmaceutical Co, Ltd; and Takeda
the Movement Disorders Journal and as an Pharmaceutical Company. Dr Alcalay has
assistant editor for Annals of Neurology, and received personal compensation in the
in the range of $10,000 to $49,999 for serving range of $10,000 to $49,999 for serving as a
on a scientific advisory board for CuraSen consultant for Sanofi. The institution of
Therapeutics, Inc. Dr Poston has stock in Dr Alcalay has received research support
Amprion Inc and CuraSen Therapeutics, from Biogen, the Department of Defense,
Inc, and has received intellectual property The Michael J. Fox Foundation, the National
interests from a discovery or technology Institutes of Health, and the Parkinson’s
relating to health care. The institution of Foundation.
Dr Poston has received research support
from the Alzheimer's Drug Discovery Unlabeled Use of Products/Investigational
Foundation, the Lewy Body Dementia Use Disclosure: Dr Alcalay reports no
Association, Inc, The Michael J. Fox disclosure.
Foundation, and the National Institutes of
Health.
Unlabeled Use of Products/Investigational

Use Disclosure: Dr Poston reports no
disclosure.
a
All relevant financial relationships have been mitigated.
1258 O C TO B ER 2 0 2 2

Danny Bega, MD Daniel O. Claassen, MD, MS,
Associate Professor of FAAN
Neurology and Director, Division Chief, Behavioral and
Neurology Residency, Director, Cognitive Neurology; Professor,
Huntington’s Disease Society of Neurology, Vanderbilt
America Center of Excellence, University Medical Center,
Northwestern University Nashville, Tennessee
Feinberg School of Medicine,
Relationship Disclosure: Dr Claassen has
Chicago, Illinois received personal compensation in the range
of $500 to $4999 for serving as a consultant
Relationship Disclosure: Dr Bega has for Spark Therapeutics, Inc and as an editor,
received personal compensation in the associate editor, or editorial advisory board
range of $500 to $4999 for serving on a member for HD Insights. Dr Claassen has
speakers bureau for Acorda Therapeutics; received personal compensation in the range
Adamas Pharmaceuticals, Inc; Kyowa Kirin of $5000 to $9999 for serving as a consultant
Co, Ltd; Neurocrine Biosciences, Inc; and and on a scientific advisory or data safety
Teva Pharmaceutical Industries Ltd and as an monitoring board for Teva Neuroscience,
editor, associate editor, or editorial advisory Inc. Dr Claassen has received personal
board member for the Annals of Clinical compensation in the range of $50,000 to
and Translational Neurology/American $99,999 for serving as a consultant for Alterity
Neurological Association. The institution Therapeutics. The institution of Dr Claassen
of Dr Bega has received research support has received research support from AbbVie
from the Huntington’s Disease Society of Inc; the CHDI Foundation; Genentech, Inc/
America. R. Hoffman-La Roche Ltd; the Griffin Family
Foundation; the Huntington’s Disease Society
Unlabeled Use of Products/Investigational of America; the National Institutes of Health,
Use Disclosure: Dr Bega discusses Neurocrine Biosciences, Inc/Huntington
the unlabeled/investigational use Study Group; Prilenia Therapeutics; the US
of amantadine, benzodiazepines, Department of Defense; and Vaccinex Inc.
botulinum toxin injections, cannabinoids,
carbamazepine, clozapine, deep brain Unlabeled Use of Products/Investigational
stimulation, olanzapine, quetiapine, Use Disclosure: Dr Claassen discusses the
risperidone, and valbenazine for the unlabeled/investigational use of acarbose
treatment of Huntington disease and other (α-glucosidase inhibitor) for postprandial
causes of chorea. hypotension, baclofen and gabapentin for
pain/dystonia, levetiracetam for cerebellar
outflow tremor, serotonin norepinephrine
reuptake inhibitors (eg, duloxetine) for pain,
Lana Chahine, MD, FAAN and short-acting antihypertensives
Associate Professor, (eg, nifedipine, transdermal topical
nitroglycerin) for supine hypertension.
Department of Neurology,
University of Pittsburgh,
Pittsburgh, Pennsylvania
Relationship Disclosure: Dr Chahine has
received personal compensation in the
range of $500 to $4999 for serving as a
consultant for Gray Matters Technology
Services. Dr Chahine has received publishing
royalties from a publication relating to
health care. The institution of Dr Chahine has
received research support from the Biogen/
Parkinson Study Group, The Michael J. Fox
Foundation, and University of Pittsburgh
Medical Center.

Use Disclosure: Dr Chahine reports no
disclosure.
C O N T I N U U M J O U R N A L .C O M 1259

CONTRIBUTORS a (CONTINUED)
Erin Furr Stimming, MD, FAAN David Irwin, MD

Professor of Neurology and Assistant Professor of
Director, Neurology Clerkship, Neurology, University of
Director, Huntington’s Disease Pennsylvania, Perelman
Society of America Center of School of Medicine
Excellence, The University of Philadelphia, Pennsylvania
Texas Health Science Center at
Relationship Disclosure: Dr Irwin has received
Houston, McGovern Medical personal compensation in the range of $500
School, Houston, Texas to $4999 for serving on a scientific advisory
or data safety monitoring board for Denali
Relationship Disclosure: Dr Furr-Stimming Therapeutics. The institution of Dr Irwin has
has received personal compensation in received research support from the National
the range of $500 to $4999 for serving as a Institutes of Health (U19-AG062418).
consultant for Teva Pharmaceutical Industries
Ltd and Wave Life Sciences, on a scientific Unlabeled Use of Products/Investigational
advisory board for Amneal Pharmaceuticals Use Disclosure: Dr Irwin discusses the use
LLC, and on a speakers bureau for Sunovion of several medications and treatments for
Pharmaceuticals Inc and Teva Pharmaceutical the neuropsychiatric symptoms of Parkinson
Industries Ltd. Dr Furr Stimming has served disease and dementia with Lewy bodies,
as an editor and author for McGraw Hill and none of which are approved by the US
Oxford University Press. The institution of Food and Drug Administration, except for
Dr Furr Stimming has received research rivastigmine for the treatment of Parkinson
support from the CHDI Foundation; Cures dementia and pimavanserin for the
Within Reach; Huntington Study Group/ treatment of psychosis in Parkinson disease.
Neurocrine Biosciences, Inc; the Huntington's
Disease Society of America; F. Hoffman-La
Roche/Genetech, Inc; the National Institutes
of Health/University of Iowa; uniQure NV; Maya Katz, MD
and Vaccinex Inc. Clinical Associate Professor of
Unlabeled Use of Products/Investigational Neurology, Stanford University,
Use Disclosure: Dr Furr Stimming Stanford, California
discusses the unlabeled/investigational
use of amantadine, benzodiazepines, Relationship Disclosure: Dr Katz has received
botulinum toxin injections, cannabinoids, research support from the National Institutes
carbamazepine, clozapine, deep brain of Health (1R01NR016037-01A1).
stimulation, olanzapine, quetiapine,
risperidone, and valbenazine for the Unlabeled Use of Products/Investigational
treatment of Huntington disease and other Use Disclosure: Dr Katz reports no
causes of chorea. disclosures.
a
1260 O C TO B ER 2 0 2 2

Jennifer A. O’Malley, MD, PhD Ashley E. Rawls, MD, MS
Clinical Assistant Professor, Assistant Professor of
Neurology and Pediatrics, Neurology, University of
Stanford University School of Florida, Norman Fixel Institute
Medicine, Palo Alto, California for Neurological Diseases,
Relationship Disclosure: Dr O’Malley has
Gainesville, Florida
Relationship Disclosure: Dr Rawls has received
range of $5000 to $9999 for serving on a
personal compensation in the range of $500 to
speakers bureau for PTC Therapeutics and
$4999 for serving as an editor, associate editor,
has stock in Doximity. The institution of Dr
or editorial advisory board member for JAMA
O’Malley has received research support
Neurology and as a physician expert panelist
from Grace Science, LLC.
with Mediflix, Inc.
Use Disclosure: Dr O’Malley discusses the
Use Disclosure: Dr Rawls discusses the
unlabeled/investigational use of deep
unlabeled/investigational use of closed-
brain stimulation for movement disorders
loop deep brain stimulation for the
in children and gene therapy for aromatic
treatment of Parkinson disease.
L-amino acid decarboxylase deficiency.

Alexander Pantelyat, MD,
Director, Johns Hopkins Ataxia
FAAN
Center; Co-Director, Johns
Director, Atypical Parkinsonism
Hopkins Lewy Body Disease
Center; Assistant Professor
Association Research Center
of Neurology, Johns Hopkins
of Excellence; Associate
University School of Medicine,
Professor of Neurology, Johns
Baltimore, Maryland
Hopkins University School of
Relationship Disclosure: Dr Pantelyat has Medicine, Baltimore, Maryland
range of $5000 to $9999 for serving as Relationship Disclosure: Dr Rosenthal
a scientific advisory board member for has received personal compensation
MedRhythms, Inc, and in the range of $10,000 in the range of $500 to $4999 for
to $49,999 for serving as an expert witness serving as a consultant for Biohaven
for Kelly & Ignoffo Law Group. The institution Pharmaceuticals and on a scientific
of Dr Pantelyat has received research advisory or data safety monitoring
support from the National Institutes of board for Reata Pharmaceuticals, Inc;
Health/National Institute on Aging. has received research support from
Biohaven Pharmaceuticals, The Daniel B.
Unlabeled Use of Products/Investigational and Florence E. Green Foundation, the
Use Disclosure: Dr Pantelyat discusses Gordon and Marilyn Macklin Foundation,
the unlabeled/investigational use of The Michael J. Fox Foundation, the
dextromethorphan/quinidine or selective National Ataxia Foundation, the National
serotonin reuptake inhibitors (SSRIs) for Institutes of Health, and Pfizer Inc; and
the treatment of pseudobulbar affect has a noncompensated relationship as a
in progressive supranuclear palsy (PSP) Medical Director, ex-officio Member of
and corticobasal syndrome (CBS); the Board with National Ataxia Foundation
methylphenidate or modafinil for the that is relevant to American Academy of
treatment of apathy in PSP and CBS; Neurology interests or activities.
miglustat for Niemann-Pick disease type
C; onabotulinumtoxinA for the treatment Unlabeled Use of Products/Investigational
of sialorrhea, cervical and limb dystonia/ Use Disclosure: Dr Rosenthal discusses
spasticity, muscle pain, and eyelid opening the unlabeled/investigational use
apraxia/blepharospasm in PSP and CBS; and of medications for the treatment of
SSRIs for the treatment of depression and neurodegenerative spinocerebellar ataxias,
anxiety in PSP and CBS. none of which are approved by the US Food
and Drug Administration.

Christopher D. Stephen, MB for the treatment of homocystinuria; biotin

and thiamine for the treatment of biotin-
ChB, FRCP, SM thiamine–responsive basal ganglia disease
Instructor in Neurology, Harvard and biotinidase deficiency; and coenzyme
Medical School; Attending Q10 for the treatment of coenzyme Q10
deficiency.
Neurologist, Movement
Disorders Unit, Ataxia Center,
Dystonia Clinic, Department
of Neurology, Massachusetts Avner Thaler, MD, PhD
General Hospital, Brigham Assistant Professor of
and Women's Hospital, Neurology, Sackler Faculty
Boston, Massachusetts of Medicine, Sagol School
of Neuroscience, Tel Aviv
Relationship Disclosure: Dr Stephen has University; Tel Aviv Sourasky
received personal compensation in the range
of $500 to $4999 for serving on a scientific
Medical Center, Tel Aviv, Israel
advisory or data safety monitoring board
for SwanBio Therapeutics, Inc, has received Relationship Disclosure: Dr Thaler has
research support from the National Institutes received personal compensation in the
of Health/National Institute of Neurological range of $500 to $4999 for serving as a
Disorders and Stroke (1K23NS118045-01A1), and consultant for AbbVie Inc. The institution
has received honoraria in the range of $500 of Dr Thaler has received research support
to $4999 from the International Parkinson and from Biogen and The Michael J. Fox
Movement Disorder Society. The institution Foundation.
of Dr Stephen has received research support
from Sanofi. Unlabeled Use of Products/Investigational
Use Disclosure: Dr Thaler reports no
Unlabeled Use of Products/Investigational disclosure.
Use Disclosure: Dr Stephen discusses
the unlabeled/investigational use of
medications and therapies, none of which
are approved by the US Food and Drug Aparna Wagle Shukla, MD
Administration (FDA) except for botulinum
Professor, Department of
toxin injections; medications and therapies
for the treatment of paroxysmal dystonia, Neurology, Norman Fixel
none of which are approved by the FDA for Institute for Neurological
this indication; medications and therapies
for the treatment of status dystonicus/
Diseases, University of Florida
dystonic storm, none of which are approved Health, Gainesville, Florida
by the FDA for this indication; dopamine
agonists for the treatment of dystonia Relationship Disclosure: Dr Wagle Shukla
parkinsonism; ethylenediaminetetraacetic has received personal compensation in
acid chelation therapy for the treatment the range of $500 to $4999 for serving as a
of dystonia/parkinsonism with manganese consultant for Jazz Pharmaceuticals, Inc,
accumulation; dopamine agonists, as a reviewer with the National Institutes
monoamine oxidase inhibitors, and of Health, and as the Vice President of the
pyridoxine for the treatment of aromatic board of directors for the Tremor Research
L-amino acid decarboxylase deficiency; Group and in the range of $5000 to $9999
levodopa and 5-hydroxytryptophan for the for serving on a scientific advisory board for
treatment of complex dopa-responsive Acadia Pharmaceuticals Inc. The institution
dystonia; L-carnitine for the treatment of Dr Wagle Shukla has received research
of glutaric aciduria type 1, methylmalonic support from the National Institutes of
aciduria, and propionic acidemia; vitamin B6 Health.

Use Disclosure: Dr Wagle Shukla reports no
disclosure.
a
1262 O C TO B ER 2 0 2 2

Daniel Weintraub, MD
Professor of Psychiatry,
University of Pennsylvania
School of Medicine,
Philadelphia, Pennsylvania
Relationship Disclosure: Dr Weintraub has

range of $10,000 to $49,999 for serving as a
consultant for Clintrex and on a scientific
advisory or data safety monitoring board for
Acadia Pharmaceuticals Inc. Dr Weintraub
has received personal compensation in
the range of $500 to $4999 for serving as a
consultant for Eisai Co, Ltd; Jansen Global
Services, LLC; Sage Therapeutics, Inc;
Scion Pharmaceuticals, Signant Health,
and Sunovian Pharmaceuticals Inc, and for
serving as an editor, associate editor, or
editorial advisory board member for the
Movement Disorder Society. Dr Weintraub
has received intellectual property interests
from a discovery or technology relating to
health care. The institution of Dr Weintraub
has received research support from The
Michael J. Fox Foundation, the International
Parkinson and Movement Disorder Society,
and the National Institutes of Health.

Use Disclosure: Dr Weintraub discusses the
use of several medications and treatments
for the neuropsychiatric symptoms of
Parkinson disease and dementia with
Lewy bodies, none of which are approved
by the US Food and Drug Administration,
except for rivastigmine for the treatment
of Parkinson dementia and pimavanserin
for the treatment of psychosis in Parkinson
disease.

Self-Assessment and CME Test Writers
Adam G. Kelly, MD, FAAN D. Joanne Lynn, MD, FAAN

Associate Professor of Neurology; Clinical Professor Emerita,
Director of Teleneurology and Department of Neurology, The
Regional Neurology, University of Ohio State University College of
Rochester, Rochester, New York Medicine, Columbus, Ohio
Relationship Disclosure: Dr Kelly has Relationship Disclosure: Dr Lynn has
received personal compensation in the received personal compensation in the
range of $500 to $4999 for serving as a range of $500 to $4999 for serving as a
consultant for Included Health, Inc, and Continuum Self-Assessment and CME
a CME question writer for the American question writer for the American Academy
Academy of Neurology and in the range of of Neurology; has received publishing
$5000 to $9999 for serving as a CME editor royalties from Wolters Kluwer Health, Inc;
for the American Academy of Neurology. and has stock in Abbott Laboratories,
AbbVie Inc, Amgen Inc, Biogen, Bristol-Myers
Unlabeled Use of Products/Investigational Squibb Company, Merck & Co Inc, Pfizer Inc,
Use Disclosure: Dr Kelly reports no Regeneron Pharmaceuticals Inc, and Zimmer
disclosure. Biomet.

Use Disclosure: Dr Lynn reports no
disclosure.
a
1264 O C TO B ER 2 0 2 2

EDITOR’S PREFACE
Moving On
This issue of Continuum, the penultimate issue under my editorship
of this journal, is devoted to the contemporary diagnosis and
evolving management options available for our patients with
disorders of movement. To accomplish this goal, I am indebted to
our guest editor, Dr Kathleen Poston, who assembled such a
well-organized and inclusive set of topics and outstanding content experts to cover
the wide variety of movement disorders, whether hypokinetic or hyperkinetic, that
present to us.
The issue aptly begins with the article by Dr Lana In the following article, Dr Liana S. Rosenthal
M. Chahine, who discusses the assessment, describes the differential diagnosis, classification,
management, and counseling of individuals who are evaluation, and management of neurodegenerative
prodromal or at risk for an α-synucleinopathy. Next, causes of cerebellar ataxia. Dr Christopher D.
Drs Avner Thaler and Roy N. Alcalay review the key Stephen then reviews the classification of genetic and
symptoms, genetic basis, diagnosis, and contemporary idiopathic dystonias, their medical and surgical
medical management of Parkinson disease. This is management options, and the recognition and
followed by the article from Dr Ashley E. Rawls, who emergency management of dystonic storm.
discusses the surgical therapies for Parkinson disease, Dr Jennifer A. O’Malley next provides an
including anticipated outcomes and appropriate extensive review of common movement disorders in
patient selection for these management options. children, providing us with the information needed
Drs Daniel Weintraub and David Irwin then review the to distinguish benign versus pathologic movements
diagnosis and management of the range of cognitive in infancy and childhood and to recognize those
and neuropsychiatric symptoms that may occur in movement disorders that are symptomatic of
patients with Parkinson disease and dementia with treatable and “not to be missed” conditions.
Lewy bodies. In the final review article of the issue, Dr Maya
Dr Aparna Wagle Shukla then discusses the Katz reviews the role of palliative care in the
diagnosis and treatment of essential tremor, treatment of neurodegenerative movement
including distinguishing essential tremor from other disorders, describing advance care planning and the
tremor disorders. Dr Daniel O. Claassen next specialized approach palliative care provides in
provides a review of the current diagnostic criteria clinical communication and symptom management.
and management approach to patients with multiple After reading the issue and taking the Postreading
system atrophy. This is followed by the article from Self-Assessment and CME Test written by Drs Adam
Dr Alexander Pantelyat, who reviews the diagnosis G. Kelly and D. Joanne Lynn, and edited by Dr Joseph
and management of progressive supranuclear palsy E. Safdieh, associate editor of Continuum and
and corticobasal syndrome. associate editor of self-assessment and CME, readers
Drs Erin Furr Stimming and Danny Bega then may earn up to 20 AMA PRA Category 1 CreditsTM
discuss the broad differential diagnosis, diagnostic toward self-assessment CME or, for Canadian
approach, and management strategies for patients participants, a maximum of 20 hours toward the
with hereditary and acquired causes of chorea. Self-Assessment Program (Section 3) of the
1266 OCTOBER 2022

Maintenance of Certification Program of the Royal This issue also features Continuum articles read
College of Physicians and Surgeons of Canada. aloud. Different from Continuum Audio, these are
Additional credit can be obtained by listening to recordings read verbatim from the print articles by
Continuum Audio interviews associated with this and Dr Michael Kentris and other narrators. The audio
other Continuum issues, available to all subscribers, files are available to all Continuum subscribers in the
and completing tests on the Continuum Audio web AAN’s Online Learning Center at continpub.com/
platform or mobile app. Continuum Audio is also CME. I encourage you to listen and submit the survey
accredited by the Royal College of Physicians and with your feedback.
Surgeons of Canada. I would like to offer my deepest thanks to
Dr Poston for her outstanding work assembling this
encyclopedic issue and for enlisting such an amazing
group of expert clinicians to provide us with such
…I am indebted to our guest editor, clear guidance on the current diagnosis of, and
Dr Kathleen Poston, who assembled available management options for, the spectrum of
such a well-organized and inclusive hypokinetic and hyperkinetic movement disorders
that we may encounter in practice.
set of topics and outstanding
—STEVEN L. LEWIS, MD, FAAN
content experts to cover the wide
EDITOR-IN-CHIEF
variety of movement disorders…that
present to us. © 2022 American Academy of Neurology.
CONTINUUMJOURNAL.COM 1267

REVIEW ARTICLE
Prodromal
α-Synucleinopathies

C O N T I N UU M A UD I O
I NT E R V I E W A V AI L A B L E
ONLINE
By Lana M. Chahine, MD, FAAN
ABSTRACT
PURPOSE OF REVIEW: This article describes prodromal α-synucleinopathies.
RECENT FINDINGS: The pathology underlying α-synucleinopathies, which

include Parkinson disease, multiple system atrophy, and dementia with
Lewy bodies, begins years before the presence of the full syndrome that is
the basis for the clinical diagnosis of each of these disorders. This
“prodromal” phase may manifest with various signs or symptoms. In
addition to individuals in the prodromal phase, some individuals are
asymptomatic but are at risk for α-synucleinopathies owing to genetic
predisposition or other risk factors.
SUMMARY: Clinicians are increasingly seeing patients in the clinical setting

who are prodromal or at risk for α-synucleinopathies, and this article
CITE AS:
reviews the approach to these patient populations, which includes
CONTINUUM (MINNEAP MINN)
2022;28(5, MOVEMENT DISORDERS): identifying clinical features, assessment, and counseling.
1268–1280.
Address correspondence to
Dr Lana M. Chahine, Department INTRODUCTION
of Neurology, University of
Pittsburgh, 3471 Fifth Ave, α-Synucleinopathies, including Parkinson disease (PD), multiple system atrophy
Pittsburgh, PA, 15213, (MSA), and dementia with Lewy bodies (DLB), are disorders marked clinically
lchahine2018@gmail.com. by parkinsonism and pathologically by deposition of α-synuclein in neurons and
RELATIONSHIP DISCLOSURE: supportive structures. The pathology underlying these disorders begins years
Dr Chahine has received personal before the clinical syndromes that constitute current diagnostic criteria are fully
compensation in the range of
$500 to $4999 for serving as a
present. This phase may manifest with various signs or symptoms. Individuals
consultant for Gray Matters with a presumed underlying α-synucleinopathy and signs or symptoms
Technology Services and has presumably attributable to this are termed prodromal. In addition to individuals
received publishing royalties
from a publication relating to
in the prodromal phase, some individuals are asymptomatic but are at risk for
health care. The institution of α-synucleinopathies owing to genetic predisposition or other risk factors.
Dr Chahine has received research Clinicians are increasingly seeing individuals in the clinical setting who are
support from the Biogen/
Parkinson Study Group, The prodromal or at risk for α-synucleinopathies, and this article reviews the
Michael J. Fox Foundation, and approach to this population of patients.
University of Pittsburgh Medical
Among the α-synucleinopathies, the features of individuals who will
Center.
eventually develop PD are best characterized, but many of these features are
UNLABELED USE OF shared by patients with DLB and MSA. These features can be considered in three
PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
broad categories: risk factors, signs and symptoms, and biomarkers. As of the
Dr Chahine reports no disclosure. writing of this article, none of these features are useful in isolation and are best
considered in combination in relation to their specificity for presumed
© 2022 American Academy underlying α-synucleinopathy and, most importantly, within the appropriate
of Neurology. clinical context.
1268 OCTOBER 2022

RISK FACTORS FOR α-SYNUCLEINOPATHIES KEY POINTS
The two categories of risk factors for α-synucleinopathies include (1) exogeneous
● In determining an
behavioral and environmental risk factors and (2) endogenous biological individual’s risk for
risk factors. Parkinson disease,
behavioral/environmental
Behavioral and Environmental Risk Factors risk factors, signs and
symptoms, and biomarker
Behavioral and environmental risk factors for PD include head trauma and
changes are best considered
regular exposure to pesticides and organic solvents.1-3 Rural living, the in combination.
occupation of farming, and well-water drinking are also correlated with
increased PD risk,2 which may be related to exposure to pesticides and organic ● Although several
solvents. Use of caffeine, nicotine, and calcium channel blockers has been environmental and
behavioral factors, including
associated with reduced risk of PD, and data on the effect of anti-inflammatories some medications, have
and statins are conflicting.2,3 While these chemicals may be risk factors for PD, been identified as increasing
the possibility of reverse causation must be kept in mind, whereby behavioral, the risk of Parkinson
personality, or even prodromal features predispose certain individuals to disease, none of these
medications should
exposure to these chemicals.3 This also applies, and is perhaps best exemplified, necessarily be prescribed or
in the increased risk of PD seen in individuals taking beta-blockers.2 Thus, in a withheld from patients until
prodromal individual, based on available data, none of these medications should further studies link these
necessarily be prescribed or withheld (outside of a clinical trial) specifically factors as being causal in
Parkinson disease.
because of the reported relationship with α-synucleinopathy risk. Metabolic/
vascular factors associated with increased risk for PD include diabetes, low
plasma urate levels, and physical inactivity.3 A relationship may also exist
between α-synucleinopathy and body fat composition and hypertension.2,4
Biological Risk Factors

Biological risk factors for α-synucleinopathies include male sex and genotype.5
Males have a 1.3 to 2.0 times higher risk for α-synucleinopathy compared with
females; while this suggests a hormonal contribution, the mechanism explaining
this remains to be elucidated.3 In terms of genetic risk factors, the genetic
contribution to PD is estimated to be about 30%6 (ie, genetic factors explain
about 30% of PD risk), although this is far from being fully understood.
Three broad genetic risk factors may be considered.4 The first category is
composed of highly penetrant mutations in genes that are established causes of
monogenic PD; these include, for example, duplication/triplications in SNCA or
VPS35 (autosomal dominant), or mutations in parkin or PINK1. The second
broad category of genetic PD risk factors is the presence of pathogenic mutations,
which have been associated with increased PD risk, although with varying
degrees of penetrance.4 The two most common genetic risk factors for PD are
mutations in the LRRK2 gene and the glucocerebrosidase (GBA) gene. Mutations
in the GBA gene are also risk factors for DLB7; genetic risk factors for MSA are
not well defined. Some mutations in the LRRK2 and GBA genes are more
pathogenic, and thus more penetrant, than others. The penetrance varies with
age and the specific mutation; for example, among GBA mutation carriers,
cumulative risk for PD is estimated at 7.6% at age 50 years but 30% at age
80 years8; more severe mutations carry a higher risk. Individuals of certain
backgrounds, including those with Ashkenazi Jewish ancestry and North African
Berbers, are more likely to harbor mutations in these genes. Not surprisingly,
considering the latter point, is that individuals with a family history of PD are at
higher risk for PD.2,3 While genetic factors may drive a large part of this
relationship, it is likely that environmental and behavioral risk factors contribute

PRODROMAL α-SYNUCLEINOPATHIES
as well. The third broad category of genetic PD risk factors is a composite of

single-nucleotide polymorphisms across several genes; over 80 risk loci for PD
have been identified, and the genotype at each of these loci has been synthesized,
in the research setting, into a “polygenic risk score.” Refer to the article
“Diagnosis and Management of Parkinson Disease” by Avner Thaler, MD, PhD,
and Roy N. Alcalay, MD, MS,9 in this issue of Continuum for more information
regarding genetic contributors to PD.
SIGNS AND SYMPTOMS OF PRODROMAL α-SYNUCLEINOPATHIES

The α-synucleinopathy prodrome may be conceptualized as a syndrome
with a broad range of predominantly nonmotor manifestations2 that are often
similar, but of lesser severity, to those seen in fully manifested disease. In the
prodrome, the prevalence and severity of signs and symptoms may vary
according to the presence of other risk factors. Interpretation of research studies
in which the sample has been “enriched” for risk of α-synucleinopathy, based on
genotype, symptoms, or biomarkers, warrants consideration, especially in
relation to the degree to which research samples translate to the profile of
individuals seen in the clinic. Nevertheless, in the clinic, eliciting information
about the spectrum of possible features during the clinical interview and
examination is an important part of the assessment of individuals who may be
prodromal or at risk.
Olfactory Dysfunction
Olfactory loss, marked by a reduction in olfactory identification, discrimination,
and increased thresholds, occurs in more than 90% of individuals with PD; it is
also common in DLB and in some subtypes of MSA. Olfactory changes may
precede the diagnosis of these disorders by years or even decades.10 Olfactory
loss is nonspecific; it is observed with advancing age and can be secondary to
peripheral disorders such as viral infections and nasal mucosa abnormalities.
In the research setting, however, it has been combined with other clinical
and biomarker features of prodromal α-synucleinopathies, and as such is a
key feature for identifying individuals at risk for α-synucleinopathies.11
While translation of these research findings to the clinical setting has yet to
be fully defined, screening for subjective olfactory changes is part of the
clinical assessment of the individuals presumed to be at risk for
α-synucleinopathies.
Autonomic Dysfunction
Symptoms of autonomic dysfunction may be among the earliest manifestations
of α-synucleinopathy,12 possibly due to early involvement of the vagus nerve and
even more peripheral structures (such as the intestines) with α-synuclein
pathology.13,14 Indeed, pure autonomic failure is a rare autonomic nervous
system disorder presumed to be due to a peripheral α-synucleinopathy and
may progress to involve central structures and manifest with parkinsonism
as well.15
Symptomatic orthostatic light-headedness may be one of the earliest features
recalled by individuals who are later diagnosed with an α-synucleinopathy.12
Neurogenic orthostatic hypotension can be diagnosed through findings of
orthostatic light-headedness and objective reductions in systolic and diastolic
blood pressure4,5 (reduction of ≥20 mm Hg systolic or ≥10 mm Hg diastolic)
1270 OCTOBER 2022

without the commensurate expected increase in heart rate on change from KEY POINTS
supine to sitting or sitting to standing.
● Both the clinical history
Genitourinary symptoms are part of the prodrome of all α- and neurologic examination
synucleinopathies.12,16,17 While specific urinary symptoms have not been well are an important part of the
studied, data from early PD populations indicate that urinary frequency, assessment of individuals
urgency, and incomplete bladder emptying may be present in the prodrome. who may be at risk or
prodromal.
Sexual dysfunction, including reduced libido, occurs in both sexes; in males,
erectile dysfunction can occur.5,17,18 ● While dysautonomia is
Constipation (defined by a spontaneous bowel movement frequency of less necessary for the diagnosis
than once every 2 days) or at least weekly need for a laxative5 is also a feature of of multiple system atrophy,
the prodrome of all α-synucleinopathies.2,16,17,19 the presence of mild
dysautonomia in someone
A key question remains as to whether specific features or severity of early with other prodromal
autonomic dysfunction is different in patients with PD, DLB, and MSA. features does not
While this would be hypothesized based on the prominent occurrence of necessarily imply a multiple
dysautonomia in some subtypes of MSA, and intermediate severity of autonomic system atrophy diagnosis
and can occur in people who
symptoms in DLB as compared with PD and MSA,20 data are limited. Autonomic develop Parkinson disease
dysfunction is seen even in early mild PD, and the presence of mild or dementia with Lewy
dysautonomia in a patient with other prodromal features does not necessarily bodies.
indicate a future diagnosis of MSA.
● Rapid eye movement
(REM) sleep behavior
DISORDERS OF SLEEP AND WAKEFULNESS disorder that occurs in the
Disorders of sleep and wakefulness are a core component of the absence of secondary
α-synucleinopathy prodrome and occur in PD, DLB, and MSA. Rapid eye causes (idiopathic or
isolated REM sleep behavior
movement (REM) sleep behavior disorder (RBD) is a parasomnia marked
disorder) is highly specific of
clinically by the occurrence of dream enactment behavior and vivid dreams. future risk of Parkinson
Physiologically, RBD is marked by REM sleep without atonia, or a loss of the disease, dementia with
normal atonia that characterizes REM sleep; normally most muscles are Lewy bodies, or multiple
paralyzed during REM sleep, except for the diaphragm and extraocular muscles. system atrophy.
In RBD, that atonia is lost. On polysomnography, this manifests with

increased muscle activity seen on surface EMG electrodes placed, for example,
on the chin or limbs. When RBD is isolated and idiopathic (ie, occurring in
the absence of secondary causes of RBD), it is highly specific of future risk of
α-synucleinopathy5,21; at least half, and perhaps as many as 80%, of individuals
with RBD will go on to be diagnosed with an α-synucleinopathy on long-term
follow-up.22 When encountering an individual with RBD, it is important to
evaluate for secondary causes, such as narcolepsy, structural brainstem lesions,
and immune-mediated disorders.23 Thus, RBD should not be considered isolated
without appropriate clinical evaluation, including a thorough history,
examination, and structural imaging, as appropriate. Some medications, such as
antidepressants, may lead to RBD or result in patients having a lower threshold
for RBD. In a subset of individuals with antidepressant-related RBD, the
indication for the antidepressant (ie, depression) may also be a prodromal
feature of an α-synucleinopathy.23
Other disorders of sleep and wakefulness are seen in the prodrome of
α-synucleinopathy, although these disorders are common in older adults and are
substantially less specific than RBD for risk of neurodegeneration.5 These
disorders include excessive daytime sleepiness, which is another feature of the
PD prodrome,5,24 and restless legs syndrome, which occurs in the earliest stages
of PD.25 Insomnia is common in PD, but there are conflicting data on its
prevalence in the PD prodrome.

COGNITIVE DYSFUNCTION AND OTHER NEUROPSYCHIATRIC

DISORDERS
Cognitive changes occur in the prodrome of DLB but also in PD. This has been
investigated in several different populations, including community-dwelling
older adults, as well as in individuals at risk for α-synucleinopathies based on
genotype, presence of olfactory deficit, dopamine transporter–binding abnormalities,
and RBD. Collectively, these studies have demonstrated mild
abnormalities in multiple domains. In individuals with RBD, cognitive
abnormalities are common, occurring in up to two-thirds of research cohorts,
and involve multiple cognitive domains, including memory, visuospatial
function, and executive function.26 The presence of mild cognitive impairment is
a strong predictor of dementia in individuals with RBD, but mild cognitive
changes may not necessarily portend DLB. Other neuropsychiatric disorders,
including depression and anxiety, are also part of the syndrome of prodromal α-
synucleinopathy.2,5,17 For more information on cognitive and neuropsychiatric
manifestations of PD and DLB, refer to the article “Diagnosis and Treatment of
Cognitive and Neuropsychiatric Symptoms in Parkinson Disease and Dementia
With Lewy Bodies” by Daniel Weintraub, MD, and David Irwin, MD,27 in this
issue of Continuum.
MOTOR ABNORMALITIES
Motor features of parkinsonism are a core diagnostic criterion for the clinical
diagnosis of PD, DLB, and MSA. Motor features that are “subthreshold” (ie,
those that are too mild or subtle to evoke the diagnosis of the disease) are part of
FIGURE 1-1
Risk factors for and signs, symptoms, and putative biomarkers of Parkinson disease and other
prodromal α-synucleinopathies.
a
All these biomarkers are investigational for prodromal α-synucleinopathies. None have yet been validated
for clinical purposes.
CSF = cerebrospinal fluid; EEG = electroencephalogram; MRI = magnetic resonance imaging; PET = positron
emission tomography; REM = rapid eye movement; SPECT = single-photon emission computed tomography.
1272 OCTOBER 2022

the prodrome of α-synucleinopathies.5,28 Prospective longitudinal studies in KEY POINTS
community-dwelling older adults or those with RBD, and without diagnostic
● Based on current
evidence of clear parkinsonism at baseline, have demonstrated a consistent evidence, use of biomarkers
pattern of progression of motor changes beginning as early as 7 years prior to to identify individuals with
diagnosis, starting with voice/facial expression changes, limb bradykinesia, then prodromal features would
rigidity and gait changes. Subtle changes in finger tapping may appear as early as be best confined to the
research context and is not
15 years before diagnosis. These motor changes may even translate into
yet appropriate in the
functional abnormalities in instrumental activities of daily living.29 The clinical setting.
determination of what constitutes subthreshold motor changes versus those that
are sufficient to make a diagnosis remains qualitative currently, requiring ● Criteria for identifying
integration of the clinical history and other findings. However, in the future, prodromal Parkinson
disease and prodromal
quantitative motor measures may aid a more objective determination. dementia with Lewy bodies
are useful for research but
BIOMARKERS OF α-SYNUCLEINOPATHIES are not ready to be applied
Biomarkers form a core component of research criteria for prodromal DLB and clinically for diagnostic or
prognostic purposes.
PD (the operative word being research); the utility of these biomarkers in the
clinical setting is not yet known. In a clinical encounter with individuals with
prodromal symptoms, the role of these biomarkers is not yet clear. However,
clinicians may encounter questions about these biomarkers from patients, thus
familiarity with these biomarkers is important. In addition, the scientific
literature is ever-expanding; ongoing observational studies will soon report on
key findings, and clinical trials in prodromal populations will soon be underway.
As is evident from FIGURE 1-1, several promising investigational biomarkers
have emerged that will likely be useful for identifying prodromal
synucleinopathies. However, their predictive value in the clinical setting is not
yet understood, and when and how to use them in the clinical setting is still under
investigation. Until then, use of biomarkers to identify individuals with
prodromal features would be best confined to the research context and are not
yet appropriate in the clinical setting. On the other hand, their utility to confirm a
diagnosis of α-synucleinopathy on clinical grounds, such as with the use of
dopamine transporter single-photon emission computed tomography (SPECT)
scan in clinically established disease,30 is appropriate where applicable.
RESEARCH CRITERIA FOR PRODROMAL α-SYNUCLEINOPATHIES

Research criteria have been put forth to define prodromal DLB31 and prodromal
PD.4,5 These criteria use a combination of the aforementioned risk factors,
clinical features, and biomarkers that weigh the features based on best available
evidence. In the research setting, these criteria so far demonstrate good specificity
but variable and generally low sensitivity. As they are refined, and as more
features are added to them, these criteria are expected to improve in accuracy.4
While these criteria provide a useful framework in which to understand the clinical
presentation of individuals who are prodromal or at risk for α-synucleinopathy, the
current applicability of these criteria in the clinical setting is not defined and cannot
yet be applied in the clinic for diagnostic or prognostic purposes.
EPIDEMIOLOGY
Because many prodromal features are nonspecific, data on the epidemiology of
α-synucleinopathies should be interpreted with caution. With this in mind, the
prevalence of prodromal PD in a population-based study (community-dwelling
older adults) as defined by research criteria was estimated as 2.3%, and the

prevalence of RBD in the older-adult population is at least 2.2%. This is similar to

the prevalence of PD in older adults in the United States.3 Also, like PD and DLB,
prodromal PD is more common in men.
Individuals who are prodromal or at risk for an α-synucleinopathy may exhibit
an evolution of parkinsonism, cognitive changes, and other clinical symptoms
over time (ie, with longitudinal follow-up). In many cases, a diagnosis of PD,
DLB, or MSA will become apparent (this has sometimes been referred to in the
research setting as “phenoconversion”). In individuals with features of
prodromal α-synucleinopathies who go on to develop a diagnosable disorder,
approximately 55% develop PD, 45% develop DLB, and rare individuals develop
MSA.15,21 Certain features may help predict which disorder will emerge, but
given the substantial overlap in clinical features among these disorders, caution is
required in making predictions and especially in providing prognosis.
Some at-risk groups, such as those with idiopathic RBD, have a higher
likelihood of receiving a diagnosis compared with other groups, such as
asymptomatic carriers of genetic mutations. The rate of onset of diagnosed PD is
best understood in RBD, where it occurs at a rate of about 6% per year.21
Considering that PD may be 2 to 4 times more common than DLB, but that DLB
is likely underdiagnosed,32 it is probable that more individuals who are
prodromal will go on to develop PD rather than DLB, but this certainly varies
according to the presenting features. More severe cognitive dysfunction does
predict dementia onset in an individual with idiopathic RBD.21
PATHOPHYSIOLOGY
The broad range of signs and symptoms seen in prodromal α-synucleinopathies
may reflect involvement of the autonomic nervous system and regions of the
central nervous system in a specific pattern. The spread of pathology is likely not
FIGURE 1-2
The hypothesis by Braak and colleagues34 posits caudorostral pattern spread of α-synuclein,
which in turn may account for the progression of clinical and biomarker features of the
prodromal syndrome in some individuals who develop an α-synucleinopathy.
GU = genitourinary; RBD = rapid eye movement sleep behavior disorder.
Figure designed by Michelle Chahine Sinno.
1274 OCTOBER 2022

the same in all individuals who go on to develop an α-synucleinopathy.13,14,33 It is KEY POINT
useful, however, to consider the model by Braak and colleagues34 of the
● Longitudinal follow-up of
neuropathologic staging system of PD to help conceptualize the neuroanatomic individuals who are
localization of the clinical and biomarker features of the prodromal syndrome prodromal or at risk for an α-
(FIGURE 1-2). The hypothesis posits a caudorostral pattern spread of α-synuclein synucleinopathy may show
possibly beginning in the periphery, then involving the medulla and olfactory an evolution of
parkinsonism, cognitive
bulb, and ascending to more rostral structures, including the substantia nigra
changes, and other signs and
and then the cortex. This hypothesis has some evidence to support it; although, symptoms, which may
at least in some patients, the progression of pathology follows a different culminate into the clinical
pattern.13,14,33 syndromes that constitute
diagnostic criteria for
Parkinson disease, dementia
CLINICAL EVALUATION AND MANAGEMENT with Lewy bodies, or
Individuals who are at risk or prodromal for an α-synucleinopathy are most likely multiple system atrophy.
to be seen by neurologists when they begin to manifest symptoms, such as the
individual with idiopathic RBD depicted in CASE 1-1. However, with increasing
access to genetic testing, including direct-to-consumer testing, individuals who
learn of their PD risk from genotyping may also seek evaluation by neurologists,
even if they are asymptomatic.
The evaluation of at-risk or prodromal individuals in the clinic centers on
thorough history taking and examination. An extensive review of systems that
covers the many possible symptoms, including olfactory changes, autonomic
dysfunction, sleep disorders, neuropsychiatric features, and motor features, is
necessary. Imaging is only appropriate when a clinical need is warranted (eg, a
patient with focal neurologic abnormalities) to rule out structural causes for
idiopathic RBD. Currently, for an individual who is asymptomatic or who does
not have clinical features suggestive of a diagnosis of PD, DLB, or MSA, a
dopamine transporter SPECT scan, or other biomarker testing, is not necessary
and may even be inappropriate (for all the reasons that testing that is neither
indicated nor validated for clinical purposes may be inappropriate in the
clinical setting).
PROVISION OF INFORMATION AND COUNSELING

Provision of accurate information and education is a key part of the care in
individuals who are prodromal or at risk for an α-synucleinopathy. Most
health care providers, as well as at-risk individuals, believe that there are benefits
to disclosing risks for an α-synucleinopathy, but the possibility of harm is
also acknowledged.35-38 The potential harms and benefits of sharing the risk
of neurodegenerative diseases in individuals prodromal or at risk have been
studied in other populations, including those prodromal for Alzheimer disease,
and small studies in individuals at risk for α-synucleinopathy.39 In general,
learning about the risk is associated with anxiety and short-term psychological
distress, but the risk for long-term severe psychological distress is low. Most
individuals prefer to have the knowledge than not to have it,39 but some
individuals categorically ask to not be given information about their risk, and
it is critical that these wishes be respected, although frequently reassessed on
follow-up. The extent of information provided should be guided by the wishes
and preferences of the individual patient. In scenarios where the individual
wants to know their risk, a balance must be achieved between relaying what is
known versus what is not known. The probabilistic nature of genetic risk factors
may be difficult for some individuals to understand, and special care is needed to

educate patients about these concepts. Avoiding therapeutic misconception and

false reassurance from “negative” (or absent) risk factors is important, too. In the
case of genetic testing for PD risk, provision of pretesting genetic counseling is an
important way to ensure that an individual understands what the results might
mean, so that they can make an informed decision about whether or not to be
tested, especially when asymptomatic. Genetic testing, including direct-to-
consumer testing without pretesting genetic counseling, is becoming
increasingly available, as depicted in CASE 1-2. Just as with symptomatic
prodromal individuals, dedicated time for counseling and support should be
provided to those who are asymptomatic but at risk.
CASE 1-1 A 65-year-old man presented to the neurology clinic accompanied by his
wife. They were referred by their primary care physician. They reported
that for the past 3 years he has had “scary” nighttime episodes a few times
a month, and these had been increasing in frequency. He reported that he
sometimes seems to “act out” his dreams. For example, when dreaming of
diving into a pool, he woke up after falling onto the floor. His wife
reported several instances where he seemed to be dreaming of being in a
fight, and he would wake her up yelling and, in one instance, was
inadvertently hitting out at her while asleep.
The patient and his wife were queried about various symptoms,
including other sleep symptoms and changes in mood, smell, cognition,
gastrointestinal symptoms, and motor function. The patient reported a
recent depressed mood and some anxiety. The patient had no significant
past medical history, including no vascular risk factors. Family history
revealed a maternal uncle with Parkinson disease.
Neurologic examination was normal. A previously acquired brain MRI
was reviewed and was normal. An overnight polysomnogram (sleep study)
was ordered, which showed increased muscle activity during rapid eye
movement (REM) sleep (REM sleep without atonia) but no other sleep
disorder; specifically no evidence of sleep apnea or other REM sleep
behavior disorder (RBD) mimics were observed.
A diagnosis of isolated RBD was made. On a follow-up visit 1 week later,
safety measures and symptomatic therapy for RBD were instituted, as
well as counseling to the patient and his wife about the risk of a
neurodegenerative parkinsonian syndrome. The patient was referred to a
counselor for management of his anxiety and depressed mood. The
patient was also encouraged to institute a regular exercise program, and
possible research participation was discussed. Periodic follow-up with
the neurologist was recommended.
COMMENT This case exemplifies the presentation of individuals with RBD in the clinical
setting. RBD is a highly specific feature of prodromal α-synucleinopathies.
Management includes institution of safety measures, symptomatic therapy
as appropriate, and discussion of opportunities for research participation.
1276 OCTOBER 2022

PREVENTIVE MEASURES
No proven treatments are currently available that prevent progression to a
diagnosed disorder in individuals at risk or prodromal for an α-synucleinopathy.
However, several modifiable risk factors have been identified, and basic risk
factor reduction and modification should be instituted where appropriate. This
includes avoidance of activities that increase risk for head trauma, and use of
protective equipment such as helmets, or use of face masks and gloves when
A 45-year-old woman presented to the neurology clinic for evaluation. CASE 1-2
She brought genetic testing results from an at-home test kit that she
acquired after seeing a commercial on television promising to provide
important genetic information about her health. The report she received
from the company stated that she has a G2019S LRRK2 mutation and that
she is therefore at increased risk of Parkinson disease (PD). She shared
her concern and anxiety about having this mutation and asked what it
meant for her and her children. The neurologist reviewed the report and
confirmed through the company’s website that the testing was
performed in a certified laboratory; confirmatory genetic testing was
therefore not deemed necessary in this case.
She had no significant past medical history. She denied motor changes,
olfactory loss, dream enactment, depression, or constipation, among
other nonmotor features that were reviewed in detail. Her family history
was notable for PD in her maternal uncle. Her neurologic examination was
entirely normal.
She was provided with reassurance that she did not currently have
evidence of PD, and the existing data on her risk were reviewed.40 She
was interested in additional information, and she was referred to a
genetic counselor for more thorough counseling and to help her learn
more about the risk for her children. She was also provided with
information about an observational research study that is recruiting
asymptomatic carriers of mutations associated with PD risk to investigate
biomarkers that can help accurately predict risk in such individuals. She
was advised to return for a follow-up neurologic visit in 1 year or earlier as
needed.
This case illustrates the context within which individuals who are at risk for COMMENT
α-synucleinopathies but are asymptomatic may be seen in the clinical
setting. As genetic testing becomes increasingly available both clinically
and commercially, including the widespread dissemination of direct-to-
consumer advertising for genetic testing in the United States, individuals
may increasingly learn about their risk of PD without appropriate pretest
counseling. Such individuals may seek care from neurologists to learn more
about their risk and the most appropriate management approach. As with
symptomatic prodromal individuals, so too should dedicated time for
counseling, support, and discussion of opportunities for research
participation be provided to those who are asymptomatic but at risk.

KEY POINT applying pesticides. The mechanism by which vascular risk factors such as
diabetes contribute to risk of an α-synucleinopathy is not understood, but
● In individuals at risk
or prodromal for an
given the contribution of vascular risk factors, in general, to various health
α-synucleinopathy, outcomes, vascular risk factor modification in an individual with prodromal
currently no treatments are α-synucleinopathy is advisable. Until further evidence is available, prescription
proven to prevent of calcium channel blockers, beta-blockers, statins, nonsteroidal
progression to a diagnosed
anti-inflammatory drugs, or any other medication, and recommendations for use
disorder. However, several
modifiable risk factors have of nicotine and caffeine, should not be influenced by the putative relationship of
been identified, and basic these medication classes to PD risk.
risk factor reduction and Higher physical activity has been associated with reduced PD risk,4,41
modification should be
although the mechanisms for this are not understood. At least in some part, this
instituted where
appropriate. relationship could be a manifestation of the prodrome of neurodegeneration
rather than a modifier of it.42 However, given the general health benefits of
exercise, it is appropriate to encourage individuals who are at risk or prodromal
to institute a regular exercise regimen.
Also, part of the management of an individual at risk or prodromal for α-
synucleinopathy is the discussion of available research opportunities, whether
those are observational studies or clinical trials.
CONCLUSION
Individuals who will later be diagnosed with an α-synucleinopathy may present
to the clinic with early symptoms or signs or because of a known or suspected
genetic risk. The prodrome of α-synucleinopathies is marked by nonmotor and
motor features that, at least in some individuals, follow a pattern of progression
consistent with hypothesized progression of underlying pathology through the
nervous stem. Nonmotor features range from common but nonspecific changes
such as constipation or olfactory dysfunction to less common and more specific
features such as RBD. Biomarker abnormalities have been described, which are
under intensive investigation, but are not yet suitable for clinical use. The
management of individuals who are prodromal or at risk for α-synucleinopathies
centers on counseling, supportive care, and periodic, consistent follow-up to
monitor for the emergence of signs and symptoms that form the basis of a clinical
diagnosis of an α-synucleinopathy.
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09642-0
16 Plouvier AO, Hameleers RJ, van den Heuvel EA,
et al. Prodromal symptoms and early detection 29 Darweesh SK, Verlinden VJ, Stricker BH, et al.
of Parkinson’s disease in general practice: a Trajectories of prediagnostic functioning in
nested case-control study. Fam Pract 2014;31(4): Parkinson’s disease. Brain 2017;140(2):429-441.
373-378. doi:10.1093/fampra/cmu025 doi:10.1093/brain/aww291
17 Schrag A, Horsfall L, Walters K, et al. 30 Postuma RB, Berg D, Stern M, et al. MDS clinical
Prediagnostic presentations of Parkinson’s diagnostic criteria for Parkinson’s disease.
disease in primary care: a case-control study. Mov Disord 2015;30(12):1591-1601. doi:10.1002/
Lancet Neurol 2015;14(1):57-64. doi:10.1016/S1474- mds.26424
4422(14)70287-X
31 McKeith IG, Ferman TJ, Thomas AJ, et al.
18 Durcan R, Wiblin L, Lawson RA, et al. Prevalence Research criteria for the diagnosis of prodromal
and duration of non-motor symptoms in dementia with Lewy bodies. Neurology 2020;
prodromal Parkinson’s disease. Eur J Neurol 2019; 94(17):743-755. doi:10.1212/
26(7):979-985. doi:10.1111/ene.13919 WNL.0000000000009323
19 Abbott RD, Petrovitch H, White LR, et al. 32 Vann Jones S, O’Brien JT. The prevalence and
Frequency of bowel movements and the future incidence of dementia with Lewy bodies: a
risk of Parkinson’s disease. Neurology 2001;57(3): systematic review of population and clinical
456-462. doi:10.1212/wnl.57.3.456 studies. Psychol Med 2014;44(4):673-683.
doi:10.1017/S0033291713000494

33 Adler CH, Beach TG, Zhang N, et al. Unified 38 Arnaldi D, Antelmi E, St Louis EK, et al. Idiopathic
staging system for Lewy body disorders: REM sleep behavior disorder and
clinicopathologic correlations and comparison to neurodegenerative risk: to tell or not to tell to the
Braak staging. J Neuropathol Exp Neurol 2019; patient? How to minimize the risk? Sleep Med
78(10):891-899. doi:10.1093/jnen/nlz080 Rev 2017;36:82-95. doi:10.1016/j.smrv.2016.11.002
34 Braak H, Del Tredici K, Rub U, et al. Staging of 39 Schaeffer E, Rogge A, Nieding K, et al. Patients’
brain pathology related to sporadic Parkinson’s views on the ethical challenges of early Parkinson
disease. Neurobiol Aging 2003;24(2):197-211. disease detection. Neurology 2020;94(19):
doi:10.1016/s0197-4580(02)00065-9 e2037-e2044. doi:10.1212/
WNL.0000000000009400
35 Dommershuijsen LJ, Darweesh SKL, Luik AI, et al.
Ethical considerations in screening for rapid eye 40 Marder K, Wang Y, Alcalay RN, et al. Age-specific
movement sleep behavior disorder in the general penetrance of LRRK2 G2019S in the Michael J.
population. Mov Disord 2020;35:1939-1944. Fox Ashkenazi Jewish LRRK2 consortium.
doi:10.1002/mds.28262 Neurology 2015;85(1):89-95. doi:10.1212/WNL.
0000000000001708
36 St Louis EK. Prognostic counseling for patients
with idiopathic/isolated REM sleep behavior 41 Fang X, Han D, Cheng Q, et al. Association of
disorder: should we tell them what’s coming? levels of physical activity with risk of Parkinson
Yes. Mov Disord Clin Pract 2019;6(8):667-668. disease: a systematic review and meta-analysis.
doi:10.1002/mdc3.12814 JAMA Netw Open 2018;1:e182421. doi:10.1001/
jamanetworkopen.2018.2421
37 Sixel-Döring F. Prognostic counseling for
patients with idiopathic/isolated rapid eye 42 Sommerlad A, Sabia S, Livingston G, et al. Leisure
movement sleep behavior disorder: should we activity participation and risk of dementia: an
tell them what’s coming? No. Mov Disord Clin 18-year follow-up of the Whitehall II Study.
Pract 2019;6(8):669-671. doi:10.1002/mdc3.12813 Neurology 2020;95(20):e2803-e2815. doi:10.1212/
WNL.0000000000010966
1280 OCTOBER 2022

Diagnosis and Medical REVIEW ARTICLE

Management of C O N T I N U UM A U D I O
I NT E R V I E W A V A I L AB L E
ONLINE
Parkinson Disease
By Avner Thaler, MD, PhD; Roy N. Alcalay, MD, MS
ABSTRACT
PURPOSE OF REVIEW: Parkinson disease (PD) is a common neurodegenerative CITE AS:
movement disorder, the prevalence of which is rising as the world CONTINUUM (MINNEAP MINN)
2022;28(5, MOVEMENT DISORDERS):
population ages. It may present with motor and nonmotor symptoms, 1281–1300.
and symptomatic treatment significantly improves quality of life. This
article provides an overview of the workup and differential diagnosis for Address correspondence to
PD and reviews genetic and environmental risk factors and current Dr Roy N. Alcalay MD, MS,
6 Weizman St, Tel Aviv 6423906,
treatments. Israel, RNA2104@columbia.edu
RELATIONSHIP DISCLOSURE:
RECENT FINDINGS:Novel treatments for the motor (eg, fluctuations and off
Dr Thaler has received personal
times) and nonmotor (eg, hallucinations and orthostatic hypotension) compensation in the range of
complications of PD have been approved in recent years. In addition, with $500 to $4999 for serving as a
consultant for AbbVie Inc. The
recent advances in our understanding of the genetics of PD, significant institution of Dr Thaler has
research is focusing on identifying at-risk populations and introducing received research support from
genetically targeted interventions (precision medicine). Biogen and The Michael J. Fox
Foundation. Dr Alcalay has
received personal
SUMMARY: PD is a heterogeneous neurodegenerative movement disorder. compensation in the range of
Affected individuals may receive substantial symptomatic relief from $500 to $4999 for serving as a
consultant for AVROBIO, Inc;
nonpharmacologic, pharmacologic, and surgical interventions. Although Caraway Therapeutics, Inc;
no intervention to modify the progression of PD is currently available, GlaxoSmithKline plc; Janssen
Global Services, LLC; Merck &
precision medicine and modulation of the immune system are a major focus
Co, Inc; Ono Pharmaceutical Co,
of ongoing research. Ltd; and Takeda Pharmaceutical
Company. Dr Alcalay has
received personal
$10,000 to $49,999 for serving as
a consultant for Sanofi. The
institution of Dr Alcalay has
INTRODUCTION received research support from
P
arkinson disease (PD) is the second most common neurodegenerative Biogen, the Department of
Defense, The Michael J. Fox
disorder,1 afflicting more than 6.1 million people across the world as of Foundation, the National
2016,2 with effective symptomatic treatment available for decades.3 Institutes of Health, and the
Parkinson’s Foundation.
The natural history of PD is heterogeneous and includes a wide range
of motor and nonmotor symptoms. The traditional definition of PD is UNLABELED USE OF
based on cardinal motor symptoms, including bradykinesia, resting tremor, PRODUCTS/INVESTIGATIONAL
rigidity, and gait impairment4; however, more recent diagnostic criteria have USE DISCLOSURE:
Drs Thaler and Alcalay report no
been developed that integrate nonmotor symptoms, including autonomic, disclosures.
affective, cognitive, and sleep impairments (refer to the section on clinical
diagnosis later in this article). Because of the heterogeneity in symptoms and rate © 2022 American Academy
of progression, clinical management should be tailored individually. of Neurology.

DIAGNOSIS AND MANAGEMENT OF PARKINSON DISEASE
RISK FACTORS
Age is the single most important risk factor for PD.5 Juvenile PD, defined as onset
younger than 21 years of age, is exceedingly rare, and only 5% to 10% of patients
are diagnosed before the age of 50.6 Mean age at onset is approximately 60 but
varies across studies, and women are less often affected than men.5 To date,
most studies have been performed on patients of European decent, thus less is
known about PD prevalence and clinical presentation in underrepresented
populations. Specifically, it remains unknown whether people of African descent
have a lower prevalence and incidence of PD or if prevalence/incidence
discrepancies are a result of disparities in health care access.7
TABLE 2-1 Major Genetic Causes and Risk Factors for Parkinson Disease
Gene(s) Mode of inheritance Population Phenotype

SNCA (additional Autosomal dominant point Mostly European; A53T mutation Early-onset Parkinson disease (PD)
gene symbols: mutations, duplications, and more common in Greece with more rapid progression than in
PARK1, PARK4) triplications with incomplete idiopathic PD; good levodopa
penetrance response but early fluctuations11;
psychiatric features in gene
duplication cases; dementia may be
present early
PRKN (Parkin) Autosomal recessive; role of Worldwide; mutations relatively Early-onset PD with slow rate of
(previous gene heterozygous mutations is common when PD onset is in progression; atypical features may
symbol: PARK2) controversial third or fourth decade of life be present (dystonia, prominent
freezing of gait)12; less cognitive
impairment than in idiopathic PD
PINK1 (previous Autosomal recessive; role of Rare; worldwide Early-onset PD with slow rate of
gene symbol: heterozygous mutations is progression; good levodopa
PARK6) controversial response13; some atypical features
such as dystonia
PARK7 (previous Autosomal recessive; role of Rare; Dutch, Italian Case reports only; early-onset PD
gene symbol: DJ1) heterozygous mutations is with good levodopa response but
unknown with motor fluctuations14
LRRK2 (previous Autosomal dominant with Present worldwide; varies by Similar motor phenotype with slower
gene symbol: incomplete penetrance mutation: G2019S (North African rate of progression than idiopathic
PARK8) Berber and Ashkenazi Jews), PD15; fewer nonmotor
R1441G/C/H (Spanish Basque), manifestations, including cognitive
G2385R (Chinese, Japanese, changes, than in idiopathic PD
Korean), I2020T (Japanese)
VPS35 (PARK17) Autosomal dominant European, Japanese Case reports only; similar to
idiopathic PD16
GBA Autosomal dominant, with Worldwide; highest risk in Similar motor phenotype as in
markedly reduced Ashkenazi Jewish populations idiopathic PD but with more rapid
penetrance (may be motor and cognitive progression17;
considered a risk factor) more severe nonmotor features than
in idiopathic PD, particularly
cognitive impairment; earlier onset
and more severe motor and
nonmotor features in homozygotes/
compound heterozygotes
1282 OCTOBER 2022

PD is a genetically complex disorder that can result from genetic KEY POINTS
alterations, environmental exposures, and the interaction among these factors.
● Older age and male sex
Of all environmental risks, exposure to pesticides has been most consistently are the most established risk
associated with PD risk; consumption of dairy products, rural living, and factors for Parkinson
traumatic brain injury have also been associated with increased risk.8 In contrast, disease (PD). The most
consumption of coffee, smoking, physical activity, and use of nonsteroidal established environmental
risk factor for PD is pesticide
anti-inflammatory drugs are associated with lower risk for PD.8 Several toxins
exposure.
can produce a clinical syndrome resembling PD, including 1-methyl-4-phenyl-1,
2,3,6-tetrahydropyridine (MPTP), which causes irreversible damage to ● The seven genes clearly
dopaminergic neurons in the substantia nigra.9 associated with PD risk are
SNCA, LRRK2, and VPS35
(dominant); PRKN, PINK1,
Genetic Risk Factors and DJ-1 (recessive); and
Significant headway has been made in the understanding of PD genetics within GBA (risk factor).
the past 2 decades. Genetic risk factors can be crudely organized by the level of
risk they convey. Rare pathogenic variants in SNCA, LRRK2, and VPS35 cause ● The definitive diagnosis of
PD is based on pathology.
dominantly inherited PD, with varying levels of penetrance. Homozygous and The two key required criteria
compound heterozygous mutations in PRKN, PINK1, and PARK7 (previously are atrophy of dopaminergic
known as DJ-1) can cause recessively inherited PD. Glucocerebrosidase (GBA) cells in the substantia nigra
pathogenic variants are relatively common but convey a lower risk for PD. and accumulation of
α-synuclein.
Combined, pathogenic variants in these seven genes are present in about 10% to
15% of all people with PD.10 TABLE 2-1 summarizes clinical and phenotypic data
on these seven genes.11-17 Currently, clinical genetic testing is rarely offered in
the workup of PD,18 but with the rapid evolution of genetic research, clinical
genetic testing is on the rise.10 Various commercial laboratories offer different
PD panels that look for mutations among the 5 to 62 genes associated with an
increased risk of PD.19 Most of these panels include the seven genes mentioned
above. In addition to mendelian inheritance, many single-nucleotide
polymorphisms (SNPs) are associated with a mildly increased risk of PD; combined,
these may have a significant role in the development of PD. Recent research studies
have analyzed the risk of these SNPs when combined to generate a polygenic risk
score, with a high polygenic risk score suggesting a high risk of PD diagnosis.20
Currently, polygenic risk scores are not commercially available for PD.
DIAGNOSIS OF PARKINSON DISEASE

The gold standard diagnosis of PD is by pathology, which is not, of course,
practiced in the clinical setting. This section describes the pathologic and clinical
diagnosis of PD.
Pathology: the Gold Standard Diagnosis

The definitive diagnosis of PD is based on pathology, which is obtained by
postmortem analysis. The two key criteria for the diagnosis are atrophy of
dopaminergic cells in the substantia nigra, not otherwise explained, and
accumulation of α-synuclein in Lewy bodies and neurites in the brain.21 Indeed,
many of the motor symptoms that define PD are a result of cell loss in the
substantia nigra dopaminergic neurons. This results in an imbalance between the
direct and indirect pathways of the basal ganglia, leading to bradykinesia.22
When PD symptoms appear, up to 60% of the dopaminergic neurons have
already been lost.23 This loss is greatest in the ventrolateral tier of the substantia
nigra and in the caudal putamen.24 The primary cause of this slowly progressive
cellular atrophy is unknown. Several mechanisms have been implicated in PD

pathophysiology, including mitochondrial, proteasomal, and lysosomal

dysfunction; protein aggregation; oxidative stress; and neuroinflammation.25 In
many autopsies of people with PD, and especially in those who died at advanced
age, mixed pathology (of Alzheimerlike and vascular changes) may be found.
Identifying mixed pathology highlights the role of additional pathologic
processes (in addition to α-synuclein deposition) in the development of PD
symptoms (eg, cognitive impairment) and may reduce enthusiasm in identifying
α-synuclein as a potential target for future PD therapies.26,27
Clinical Diagnosis
Historically, the clinical criteria for the diagnosis of PD were developed in
comparison to the gold standard pathologic diagnosis (ie, criteria that will
accurately predict the pathologic diagnosis based on motor symptoms).4 In 2015,
the International Parkinson and Movement Disorder Society (MDS) updated
its criteria for PD diagnosis (MDS-PD)28 to improve diagnostic accuracy relative
to the previously used Queen Square Brain Bank criteria.29 In the MDS-PD
criteria, the motor syndrome remains the core feature of the disease, but
nonmotor features are also included.
The diagnosis of PD is based on major motor manifestations: bradykinesia in
combination with either resting tremor or rigidity or both. The assessment of
these symptoms should be performed according to the revised MDS-Unified
Parkinson's Disease Rating Scale (UPDRS) to encourage interrater reliability
among examiners.30 Bradykinesia is defined as slowness in movement and
reduction in amplitude or speed of continuous movements. It should be assessed
in each limb separately. Rigidity is defined as increased resistance to passive
movement, with cogwheel phenomena usually present on examination. Resting
tremor is a 4-Hz to 6-Hz tremor in a fully resting limb. Postural instability, which
is a feature of parkinsonism, is not a part of the MDS-PD criteria as it usually
appears at later stages of PD.
Supportive criteria for the diagnosis of PD include beneficial response to
dopaminergic therapy (ie, to levodopa or dopamine agonists), levodopa-induced
dyskinesia, hyposmia, and cardiac sympathetic denervation as demonstrated on
metaiodobenzylguanidine (MIBG) scintigraphy. Observations that make the
diagnosis of PD less likely include supranuclear gaze palsy (suggesting a
TABLE 2-2 Hoehn and Yahr Scale for Severity of Parkinson Diseasea
Stage Clinical symptoms
1 Unilateral involvement only
2 Bilateral involvement without impairment of balance
3 Mild to moderate bilateral disease, some postural instability, physically independent
4 Severe disability, still able to walk or stand unassisted
5 Uses wheelchair or bedridden unless assisted
a
Data from Hoehn MM, Yahr MD, Neurology.34
1284 OCTOBER 2022

diagnosis of progressive supranuclear palsy [PSP]), cerebellar symptoms KEY POINTS
(indicating a diagnosis of multiple system atrophy [MSA] or PSP), parkinsonism
● The clinical diagnosis of
restricted to the lower limbs for more than 3 years (suggestive of vascular PD was historically based on
parkinsonism), a diagnosis of probable frontotemporal dementia, recent motor symptoms. More
treatment with a dopamine receptor blocker or dopamine depletor, absence of recently, nonmotor
response to high-dose levodopa (>600 mg/d), cortical sensory loss, and normal symptoms were added to
the criteria to improve
presynaptic dopaminergic imaging.28
accuracy.
In addition, several red flags were proposed to indicate the possibility of an
alternative diagnosis: ● Postural instability, which
is a feature of parkinsonism,
u Rapid progression requiring use of wheelchair within 5 years of diagnosis (often seen in is not a part of the
MSA and PSP) International Parkinson and
u No motor progression for 5 years (suggesting essential tremor) Movement Disorders
Society criteria for PD
u Early bulbar dysfunction (dysphonia, dysarthria, or dysphagia, suggesting MSA) diagnosis as it usually
u Inspiratory respiratory dysfunction (stridor, suggesting MSA) appears at later stages
of PD.
u Severe autonomic failure within 5 years of diagnosis (orthostatic hypotension or urinary
incontinence, suggesting MSA or dementia with Lewy bodies [DLB]) ● Clinical red flags raise
u Recurrent falls (>1 per year) within 3 years of diagnosis (suggesting PSP) suspicion to an alternative
diagnosis, most often
u Disproportionate anterocollis within 10 years of diagnosis (suggesting MSA) multiple system atrophy,
progressive supranuclear
u Absence of nonmotor symptoms (suggesting either dystonic or essential tremor)
palsy, or dementia with
u Unexplained pyramidal signs (seen in PSP and MSA) Lewy bodies.
u Bilateral symmetric disease from onset (seen in PSP and MSA)
● The Hoehn and Yahr scale
is often used to capture the
Diagnostic errors, which depend on the clinical presentation,31 are common severity and progression of
in early stages of PD and improve with longer follow-up as the development motor symptoms of PD. The
of additional symptoms and the time course of symptom progression are Movement Disorders
Society Unified Parkinson’s
considered. Up to 15% of patients with an initial clinical diagnosis of PD are found Disease Rating Scale is used
to be misdiagnosed based on postmortem pathology.32 When the primary to quantify disease severity.
presentation is tremor, essential tremor and other causes of tremor may lead to a
diagnostic error. When the primary symptoms are bradykinesia, rigidity, and
gait impairment, the differential diagnosis of PD includes vascular parkinsonism,
MSA, PSP, and corticobasal degeneration.
Progression of Motor Symptoms

The motor symptoms of PD tend to progress over time. After the initiation
of dopaminergic treatment, motor fluctuations may appear, in which the effect
of the dopaminergic therapy does not last until the next dose is administered,
and an on-off phenomenon develops, in which patients may feel that their
symptoms are well controlled in the on state and less controlled in the off state.
Further, dyskinesia may appear at the peak of the dopaminergic effect or before or
after doses. Freezing of gait is a common PD symptom that may appear later in the
disease course; it is defined as a brief episodic absence or reduction of forward
progression of the feet despite the intention to walk.33 Freezing episodes can be
triggered by motor, cognitive, or affective causes.
The severity of the motor symptoms of PD can be described using the
five-point Hoehn and Yahr scale (TABLE 2-2)34; however, the rate of motor
progression of PD is very heterogeneous and nonlinear. A 2020 study that
assessed patients with PD without access to treatment identified that 40% of
participants reached Hoehn and Yahr stage 3 after 7 years of disease.35

TABLE 2-3 Nonmotor Symptoms of Parkinson Diseasea
Treatment proven in Parkinson Treatment for condition in

Symptom Stage of occurrence disease generalb
Depression Prodromal or after diagnosis Selective serotonin reuptake Tetracyclic antidepressants,

inhibitors (SSRIs), serotonin trazodone, mirtazapine,
norepinephrine reuptake bupropion, monoamine oxidase
inhibitors (SNRIs), pramipexole, B (MAO-B) inhibitors
nortriptyline, desipramine
Anxiety Prodromal or after diagnosis SSRIs Benzodiazepines
Apathy Any stage Piribedil (still investigational),

rivastigmine
Hallucinations and Late stage Pimavanserin, clozapine, First- and second-generation

psychosis quetiapine antipsychotics
Impulse control Late stage or as a result of Cessation of dopamine agonist

disorders dopamine agonist use use
Moderate to severe Mild cognitive impairment Cholinesterase inhibitors N-methyl-D-aspartate (NMDA)

cognitive impairment can appear as early as at time antagonist
and dementia of diagnosis or the prodromal
stage; dementia appears in
late stage
Orthostatic Prodromal or after diagnosis Droxidopa, midodrine, Pyridostigmine, atomoxetine,

hypotension fludrocortisone pseudoephedrine
Urinary dysfunction Any stage; early urinary Solifenacin Antimuscarinics, β-adrenergic

and incontinence symptoms may be receptor agonists
concerning for multiple
system atrophy
Erectile dysfunction Prodromal or after diagnosis Sildenafil Tadalafil, vardenafil, avanafil
Constipation Prodromal or after diagnosis Hydration, probiotics, fiber, Lactulose, linaclotide

lubiprostone, macrogol
Excessive sweating Late stage Anticholinergics
Rapid eye movement Prodromal or after diagnosis Melatonin, clonazepam

disorder
Sleep fragmentation Prodromal, after diagnosis, or Rotigotine, eszopiclone,

and insomnia late stage melatonin
Excessive daytime Prodromal, after diagnosis, or Modafinil

sleepiness late stage
Pain Prodromal or after diagnosis MAO-B inhibitors, oxycodone/ Nonsteroidal anti-inflammatory

naloxone prolonged release drugs, acetaminophen, opioids,
cannabis
Fatigue Prodromal, after diagnosis, or Rasagiline

late stage
Olfactory dysfunction Prodromal or after diagnosis
a
Data from Seppi K, et al, Mov Disord.36
b
Blank entries indicate a lack of data.
1286 OCTOBER 2022

Nonmotor Symptoms KEY POINTS
The nonmotor features of the disease significantly affect patients’ well-being
● The diagnosis of PD is
(TABLE 2-3).36 Dementia often occurs as PD progresses, and up to half of primarily clinical. Ancillary
people with PD will report substantial cognitive impairment within 10 years diagnostic tests can be
of diagnosis,37 resulting from neuronal loss and both dopaminergic and useful when the clinical
cholinergic impairment.38 The cognitive domains involved include frontal/ diagnosis remains unclear.
executive, memory, visuospatial, and, less commonly, language. Patients should
● MRI or other structural
be screened yearly for cognitive decline.39 It should be noted that the MDS-PD imaging may detect causes
criteria do not consider dementia as an exclusion criterion for PD, regardless of secondary parkinsonism,
of when it develops in relation to motor symptoms.28 Further, the new MDS-PD such as hydrocephalus or
criteria recommend that for patients with a diagnosis of DLB made according stroke.
to consensus criteria, the diagnosis can optionally be qualified as PD (DLB ● Dopamine transporter
subtype). For more information, refer to the article “Diagnosis and Treatment of single-photon emission
Cognitive and Neuropsychiatric Symptoms in Parkinson Disease and Dementia computed tomography may
With Lewy Bodies” by Daniel Weintraub, MD, and David Irwin, MD,40 in this be helpful in detecting
dopamine deficiency but is
issue of Continuum. less useful in tracking the
Autonomic dysfunction is also common in PD, in both early and late stages of progression of intermediate
the disease.41 It is associated with both motor symptom severity and cognitive or advanced stages of PD or
deterioration42 and is caused by accumulation of α-synuclein within the central in distinguishing PD from
other neurodegenerative
and peripheral nervous systems.43 However, severe autonomic involvement is
parkinsonian syndromes.
suggestive of MSA. For more information on MSA, refer to the article “Multiple
System Atrophy” by Daniel O. Claassen, MD, MS, FAAN,44 in this issue of
Continuum.
ANCILLARY DIAGNOSTIC METHODS

PD is primarily a clinical diagnosis. However, ancillary diagnostic tests can
sometimes assist the diagnosis in cases in which the clinical diagnosis is not clear.
Structural Imaging
Structural MRI is usually normal in patients with PD; however, it can be useful in
detecting causes of secondary parkinsonism, such as infarcts, iron deposition,
normal pressure hydrocephalus, or space-occupying lesions such as neoplasms.45
New protocols, including neuromelanin imaging and high-resolution structural
scans of the substantia nigra, may hold promise for future structural assistance
in diagnosis.46
Radiotracer Imaging
Radionuclide tracers can assess presynaptic and postsynaptic striatal
dopaminergic functions using positron emission tomography (PET) or
single-photon emission computed tomography (SPECT) imaging. Dopamine
transporter SPECT detects loss of striatal dopaminergic terminals and can
assist in the identification of nigrostriatal degeneration and distinguish these
cases from non-neurodegenerative cases (eg, essential tremor, psychogenic
or vascular causes) (CASE 2-1). Dopamine transporter SPECT may also be
useful in evaluating patients with parkinsonism who are treated with dopamine
blockers.47 However, dopamine transporter SPECT cannot distinguish between
the different neurodegenerative parkinsonian syndromes.48 A rapid decline
in nigrostriatal terminals up to 4 years from diagnosis of PD has been reported,
with a floor effect for change in striatal binding afterward. Thus, dopamine
transporter SPECT is a good tool for the detection of neurodegeneration but

less so for the assessment of progression of disease in intermediate or advanced

stages.49
α-Synuclein Tissue Markers

α-Synuclein deposition is the pathologic hallmark of PD; however, no
α-synuclein radiotracer is commercially available. Conversion assays that
amplify α-synuclein using either real-time quaking-induced conversion (RT-QuIC)
assay or protein misfolding cyclic amplification, currently termed synuclein
CASE 2-1 A 65-year-old woman with a long history of tremor presented with
worsening symptoms. She had been diagnosed with essential tremor
27 years earlier because of bilateral hand tremor affecting her
handwriting and her ability to eat certain foods like soup. Propranolol
provided mild symptomatic effect, and she could not tolerate primidone.
More recently, her handwriting, which was always tremulous, became
small, and her gait became slower and more effortful. She was
concerned she may have developed Parkinson disease (PD) since her
father died of PD.
Neurologic examination was significant for bilateral action and
postural tremor in her hands. She also had a resting tremor in her right arm
and reduced arm swing while walking. Rapid alternating movements,
including finger taps and opening and closing her fists, were mildly
slower on the right than on the left.
The patient’s diagnosis of essential tremor was confirmed, based on
her long-standing action tremor, but given her new symptoms, PD was
suspected as well. MRI of the brain was within normal limits. Dopamine
transporter single-photon emission computed tomography (SPECT)
demonstrated reduced radiotracer uptake in the left and right striata,
with more extensive involvement in the putamen relative to caudate.
Deficits were more pronounced on the left caudate and putamen
compared with the right.
Given the mild PD symptoms, she chose to defer pharmacologic
treatment and was referred to physical therapy for gait training and an
exercise program. Twelve months later, rasagiline 1 mg was started with
mild improvement of motor symptoms.
COMMENT When the neurologic examination cannot conclusively distinguish between

essential tremor and PD, dopamine transporter SPECT imaging can be
helpful in establishing a diagnosis. Dopamine transporter SPECT, however,
would not help distinguish between PD and other syndromes of dopamine
deficiency, such as multiple system atrophy. Physical activity should be
encouraged for patients with PD. Nonpharmacologic treatment, such as
physical therapy and occupational therapy, can be extremely helpful in
alleviating symptoms of stiffness and may improve gait. No evidence
supports postponing symptomatic therapy when symptoms are disruptive.
1288 OCTOBER 2022

seeding assays, have emerged as promising α-synuclein biomarkers with KEY POINTS
excellent sensitivity and specificity for distinguishing PD from controls
● Exercise and physical
using either CSF or tissue as substrates.50 These tests are often performed activity should be
for research purposes, but they are now emerging for clinical use. It is recommended for all
anticipated that when they are more widely clinically available these assays patients with PD.
will be very useful in clinically complicated cases (eg, when normal
● No evidence exists that
pressure hydrocephalus is suspected or if PD is suspected in patients taking
early pharmacologic (eg,
dopamine blockers). levodopa) treatment of
Parkinson disease has
SUBTYPING PARKINSON DISEASE disease-modifying
The heterogeneity of disease progression makes counseling patients on PD properties. However,
neither does evidence exist
prognosis and designing clinical trials challenging. Genetic profiles may for the benefit of delaying
explain some of the heterogeneity (TABLE 2-1), but most patients are not carriers pharmacologic treatment.
of mutations in mendelian genes. Another useful classification of patients is
based on the predominant motor symptoms. Patients may be divided into
three groups: those with tremor-dominant features, those with postural
instability-gait difficulty, and an intermediate group. The differential diagnosis
for tremor-dominant PD includes essential tremor and dystonic tremor. In
tremor cases in which the diagnosis is not clear, dopamine transporter SPECT
may be useful. Patients with PD with the tremor-dominant subtype tend to
have slower progression and less cognitive involvement compared to those
with postural instability-gait difficulty.51 When the primary symptoms are
postural instability and gait difficulty, dopamine transporter SPECT may not
be as useful, because the differential diagnosis includes other causes of
parkinsonism, such as PSP or MSA, in which the scan would demonstrate
reduced uptake similar to that seen in patients with PD.52
MANAGEMENT OF PARKINSON DISEASE SYMPTOMS

Nonpharmacologic interventions for treating the motor symptoms of PD may
include physical therapy, occupational therapy, speech-language therapy, and
exercise, with mounting evidence of efficacy for each.53 Assessment and
treatment of motor and nonmotor symptoms by a multidisciplinary team is
advised.54 All newly diagnosed patients should be screened for depression and
treated as needed.36 An exercise program and in-person and online support
groups may be extremely helpful. Tai chi has been shown to be efficacious for
balance issues in PD.55
Many factors should be considered when choosing the timing and type of
treatment in PD, including age, comorbidities, symptom severity, potential
adverse effect profile, cost, and patient preferences. Given that no interventions
to slow the rate of progression are available and that all currently available
treatments are considered symptomatic,56 no evidence exists for the added value
of early pharmacologic treatment. However, neither does evidence exist for the
benefit of delaying pharmacologic treatment.3
Levodopa
Levodopa is a precursor of dopamine; when supplemented with a peripheral
decarboxylase inhibitor, sufficient levels of dopa enter the striatum and improve
motor function. It does not correct the underlying neurodegenerative disruption.
Levodopa remains the mainstay of pharmacologic treatment in PD, even 50 years
after its discovery.

Dopaminergic pharmacotherapy should be initiated at the lowest dose

that provides symptomatic relief when motor symptoms cause impairment in
daily function. After a period of good motor response (the “honeymoon”),
levodopa-related complications may occur, mainly dyskinesias and motor
fluctuations (on-off periods), which are a major source of disability for
many patients. Dyskinesias appear in up to 40% of patients treated with
levodopa after 4 years, with higher risks among young patients treated with
higher doses of levodopa,57 and can be separated into peak dose (when
plasma levels of the drug are at their maximum) and diphasic dyskinesia
(which occurs at lower drug levels). Chronic constipation and simultaneous
intake of proteinaceous meals might increase off symptoms because of
poor medication absorption.58 Additional strategies to overcome off
symptoms, including adjustment of dose timing and introduction of additional
drugs (eg, dopamine agonists, catechol-O-methyltransferase [COMT]
inhibitors) which might improve on time but potentially with more
dyskinesias.58
Previous notions that early initiation of levodopa treatment might be
deleterious have been disproven59 and delaying levodopa treatment was not
shown to reduce motor complications and dyskinesia.60 Thus, it is not the
duration of levodopa therapy that is associated with the drug-related motor
complications but rather the disease progression itself.60 In addition,
levodopa does not seem to have a negative impact on the progression of the
neurodegenerative process at the basis of PD35; however, it does not seem to have
a positive disease-modifying effect either.59 Certain motor features of PD (eg,
bradykinesia and rigidity) respond better than others (eg, postural instability,
freezing of gait, and dysarthria) to dopaminergic treatment; however, they all
may respond to some extent.35
Comparing levodopa to dopamine agonists and monoamine oxidase type B
(MAO-B) inhibitors has indicated that although all three therapies are efficacious,
levodopa treatment is best tolerated and maximizes improvement in
mobility scores.61
Dopamine Agonists
Dopamine agonists are synthetic compounds that act as agonists to the
dopaminergic D2 receptors within the central nervous system, thus mimicking
the function of dopamine. First-generation compounds, which were ergoline
derived (pergolide, bromocriptine, cabergoline, lisuride), may cause cardiac
valvulopathy and are rarely used. The FDA currently approves dopamine
agonists as tablets (pramipexole, ropinirole), patch (rotigotine), sublingual film
(apomorphine), and subcutaneous injections (apomorphine). The side effect
profile of dopamine agonists includes nausea, leg edema, orthostatic
hypotension, sleep attacks, and impulse control disorders58 such as gambling,
hoarding, excessive shopping, binge eating, and hypersexuality. Impulse control
disorders may have devastating psychological, social, legal, and economic
consequences. When impulse control orders occur, a reduction in the dosage of
dopamine agonist therapy is warranted; however, this might be complicated by
the development of a dopamine agonist withdrawal syndrome, which is
characterized by agitation, anxiety, depression, fatigue, and autonomic
symptoms including orthostatic hypotension and irritability, despite
compensatory increases in levodopa dosage.62
1290 OCTOBER 2022

Amantadine KEY POINTS
Amantadine, an N-methyl-D-aspartate (NMDA) receptor antagonist,63 was
● Comparing levodopa to
approved for the treatment of PD in 1973, and its extended-release form was dopamine agonists and
approved for the treatment of levodopa-induced dyskinesia. It has a mild monamine oxidase type B
antiparkinsonian effect and may be efficacious in treating resting tremor; it can inhibitors has indicated that
be administered orally or intravenously (in some countries). Side effects include although all three therapies
are efficacious, levodopa
confusion, hallucinations, ankle edema, constipation, and livedo reticularis.64
treatment is best tolerated
and maximizes improvement
Monoamine Oxidase Type B Inhibitors in mobility scores.
MAO-B inhibitors (rasagiline and selegiline) improve motor symptoms in early
PD to a lesser extent than dopamine agonists and levodopa.61 A potential ● When impulse control
disorder occurs, reduction
interaction may occur with selective serotonin reuptake inhibitors (SSRIs) and in the dosage of dopamine
other antidepressants that might cause serotonin syndrome; however, this is agonist therapy is
extremely rare.65 Although the ADAGIO (Attenuation of Disease progression warranted; however, this
with Azilect GIven Once-daily) study demonstrated a benefit of early-start might be complicated by the
development of a dopamine
treatment with rasagiline and a potential for disease modification, a follow-up agonist withdrawal
study failed to substantiate these findings.66 The MAO-B inhibitor safinamide syndrome.
has been FDA approved as an add-on treatment for patients who are currently
taking carbidopa/levodopa and experiencing off episodes. ● When motor symptoms
advance, a key
consideration is to reduce
Anticholinergics the motor off time and
Anticholinergics are effective in relieving some motor symptoms of PD, fluctuations. Continuous
especially tremor.67 However, cognitive changes while taking the medications levodopa administration or
deep brain stimulation
are common, and they should therefore only be considered in younger patients
should be considered.
and with extreme caution. In one study, exposure to anticholinergic drugs was
associated with increased risk of dementia.68 Additional side effects include dry
mouth, constipation, and urinary retention, making this class of drugs less
favorable for use among patients with PD.
TREATMENTS FOR ADVANCED STAGES OF PARKINSON DISEASE

Levodopa is also used to treat advanced PD. In these cases, a shorter time
interval between doses, treatment of constipation, and taking the medication
on an empty stomach are recommended to improve absorption. Extended-
release levodopa formulations are another method for the treatment
of fluctuations.
COMT inhibitors, such as entacapone and opicapone, are useful in the
treatment of motor complications.69 They enhance levodopa’s duration of action
and reduce motor fluctuations. MAO-B inhibitors (such as safinamide and other
medications) and zonisamide have been found useful in treating motor
fluctuations70; however, zonisamide is not FDA approved for this purpose.
Istradefylline, a selective adenosine A2A receptor antagonist, has been approved
as an add-on to carbidopa/levodopa for the treatment of off periods in patients
with PD.71
Another phenomenon that may happen in advanced PD is a sudden off state,
for which rescue drugs are indicated. Apomorphine delivered by subcutaneous
injection or inhaled levodopa is indicated for treatment of sudden off time.
A sublingual form of apomorphine was also recently FDA-approved to reduce
off time.72 Debilitating fluctuations are a reason to introduce device-aided
therapies, such as deep brain stimulation, subcutaneous apomorphine and
levodopa-carbidopa intestinal gel, discussed in the coming sections.

CASE 2-2 A 68-year-old man presented for a follow-up visit for Parkinson disease
(PD). He was diagnosed 9 years earlier when he developed resting tremor
in his right hand and stiffness. Since his diagnosis, he had been treated
with monamine oxidase type B (MAO-B) inhibitors and levodopa in
escalating doses. Four years after diagnosis, he developed fluctuations,
with each levodopa dose lasting 4 hours. At the time, entacapone (a
catechol-O-methyltransferase [COMT] inhibitor) was added, and the
levodopa dose was increased to be taken every 4 hours while awake.
When the duration of the on time further decreased to 3 hours, the
levodopa formulation was changed to an extended-release capsule;
however, dyskinesia developed. Furthermore, he developed spells in
which he would abruptly reach an off state. These spells made him
hesitate to leave home on his own.
The patient presented for a follow-up visit to check his options for
further therapies. The dosage of levodopa was reduced and amantadine
extended-release capsule was added to address the dyskinesia, and
inhaled levodopa was prescribed for off spells. A discussion about deep
brain stimulation was initiated, and the patient was interested in pursuing
it. In preparation for the procedure, he had an MRI, which was within
normal limits, and neuropsychological testing, which identified deficits
that were diagnosed as mild cognitive impairment with executive
dysfunction. He chose to pursue genetic testing, which revealed a
heterozygous mutation in the glucocerebrosidase (GBA) gene. Because of
the cognitive changes, which can represent higher risk for worse
outcome for deep brain stimulation, he decided to pursue
levodopa-carbidopa intestinal gel treatment. He underwent
percutaneous endoscopic gastrojejunostomy for the administration of
levodopa-carbidopa intestinal gel successfully, and his fluctuations
significantly improved.
COMMENT In recent years, the treatment of fluctuations and sudden spells of the off
state, which are complications of moderate and advanced PD, has
improved significantly. Treatment options include pharmacologic and
surgical interventions. Combined, these interventions improve the quality
of life of patients struggling with the motor complications of PD and
levodopa treatment.
Cognitive changes are common as PD advances and can be subtle, mild,
or severe, causing PD dementia. Roughly 10% to 15% of people with PD carry
a pathogenic variant in one of seven genes linked to PD risk. Carriers of
pathogenic variants in glucocerebrosidase are at risk for faster motor and
cognitive progression. Clinical trials targeting the biological pathway of the
gene are ongoing. Deep brain stimulation surgery may aggravate cognitive
changes. Alternative interventions, such as levodopa-carbidopa intestinal
gel, may be indicated, as in this patient.
1292 OCTOBER 2022

Deep Brain Stimulation/Focused Ultrasound KEY POINT
Neurosurgical intervention targeting the basal ganglia with high-frequency
● Careful adjustment of the
stimulation (deep brain stimulation) or with lesioning (focused ultrasound) dopaminergic treatment is a
are currently approved for the treatment of motor complications in PD as they logical first step in the
have been proven to improve the motor signs and quality of life of patients treatment of nonmotor
with PD.73 Magnetic resonance-guided focused ultrasound targets basal symptoms in PD.
ganglia structures without craniotomy and electrode placement. For more
information on deep brain stimulation and focused ultrasound, refer to the
article “Surgical Therapies for Parkinson Disease” by Ashley E. Rawls, MD,
MS,74 in this issue of Continuum.
Apomorphine
As mentioned above, apomorphine is a short-acting dopamine agonist. It
can be delivered subcutaneously either intermittently via injection or
continuously via pump (in some countries but not the United States).75 It may
provide rapid relief from PD symptoms, but intermittent injections have
a short half-life.76
Levodopa-Carbidopa Intestinal Gel

The use of levodopa-carbidopa intestinal gel via pump aims to reach a steady
plasma concentration of levodopa by bypassing the stomach to continuously
improve motor performance.77 It is used for 16 hours daily, with evidence of
improved quality of life and improvement in both motor symptoms and
nonmotor symptoms such as sleep.78 Peripheral neuropathy due to vitamin B
complex deficiency may become an issue with chronic treatment.79
CHOOSING AMONG THE DIFFERENT ADVANCED-STAGE THERAPIES

Currently, no randomized controlled trials have compared the efficacy of the
different advanced treatments. However, deep brain stimulation seems to have
the most positive effect but with the highest potential for adverse effects.80
CASE 2-2 illustrates the complexity of decision making in advanced PD.
TREATMENT OF NONMOTOR SYMPTOMS

The medications for PD discussed above focus on the motor symptoms of the
disease; however, the nonmotor symptoms are often more debilitating and
require specific attention. Some of the nonmotor symptoms, such as depression,
anxiety, and pain, can fluctuate similarly to the motor symptoms between the on
and off states; hence, dopaminergic treatment might be considered as treatment.
However, the same treatment might worsen other nonmotor symptoms, such as
hallucinations, orthostatic hypotension, and psychosis. Careful adjustment of the
dopaminergic treatment is a logical first step in the treatment of nonmotor
symptoms in PD. Randomized controlled trials for nonmotor symptoms in PD
are lacking, although these symptoms significantly affect the quality of life of
patients with PD.
Depression
SSRIs and serotonin norepinephrine reuptake inhibitors (SNRIs), specifically
venlafaxine and paroxetine, have been found efficacious for the treatment
of depression in PD.81 However, another study did not replicate these findings for
SSRIs.82 The updated MDS task force report on nonmotor treatment in PD lists

other SSRIs and SNRIs as possibly useful for the treatment of depression in PD.36
Pramipexole, a dopamine agonist, has been found to be efficacious for the
treatment of depression in PD.83 Furthermore, the tricyclic antidepressants
nortriptyline and desipramine are labeled likely efficacious. A 2021 meta-analysis
found electroconvulsive therapy useful for the treatment of refractory
depression in PD; however, the number of participants was relatively small.84
Hallucinations and Psychosis

Given that most antipsychotic drugs block dopamine receptors, the treatment of
hallucinations in PD can be challenging. Both PD itself and its treatment increase
the risk for hallucinations. The only FDA-approved drug for the treatment of
hallucinations and psychosis in PD is pimavanserin, a selective serotonin
5-hydroxytryptamine, serotonin receptor 2A (5-HT2A) inverse agonist.85
Although concerns about the safety of pimavanserin have been raised, a recent
study of Medicare beneficiaries demonstrated lower mortality among
pimavanserin users than those treated with atypical antipsychotic medications.86
Of the antipsychotic drugs used for schizophrenia, the two that are not primarily
dopamine blockers are quetiapine and clozapine.87 Clinical trials have shown
clozapine to be effective in treating PD-related psychosis,88 but the need for
monitoring agranulocytosis hinders its use. Quetiapine, which is widely used in
the treatment of PD-related psychosis, has not been demonstrated to be superior
to placebo in clinical trials.89 Other antipsychotic agents block dopamine and
should be avoided, if possible, in people with PD.
Urinary Incontinence
Urinary incontinence in PD can have several causes, including motor, sensory,
and autonomic function impairments.90 Thus, the nature and cause of the
urinary symptoms should be ascertained before treatment initiation. Many
different compounds are used for the treatment of urinary incontinence, several
of which have prominent anticholinergic properties that have the potential of
affecting both motor and cognitive functions in PD.91 Solifenacin is used to treat
overactive bladder and neurogenic detrusor overactivity. It has been assessed for
PD with partial symptomatic improvement; however, it, too, carries peripheral
antimuscarinic side effects.92 Mirabegron, a selective β3 agonist, has also been
shown to effectively treat overactive bladder in patients with PD.
Orthostatic Hypotension
Orthostatic hypotension is diagnosed by a drop of 20 mm Hg in systolic or
10 mm Hg in diastolic blood pressure with standing. It is common in patients
with PD, may be asymptomatic, and can cause falls.93 Nonpharmacologic
interventions such as increased fluid intake, slow transitions from recumbency to
standing, and specific leg-strengthening exercises might be effective in treating
this condition.
Droxidopa (a norepinephrine prodrug) and midodrine (an α1 receptor
agonist) are considered efficacious for the short-term treatment of orthostatic
hypotension in PD94 and should be taken 20 minutes before upright activity.
They should be avoided before supine activity. Fludrocortisone, which is taken
daily, is approved for the treatment of orthostatic hypotension and is labeled
possibly useful in the updated MDS task force report on the treatment of
nonmotor symptoms.36
1294 OCTOBER 2022

Cognitive Decline KEY POINTS
A meta-analysis of cholinesterase inhibitors demonstrated improvement in
● Hallucinations in PD may
cognitive functions in patients with PD and dementia95; however, this has not been significantly impair quality of
demonstrated for cognitive impairment without dementia in PD.36 For more life and limit the use of
information, refer to the article “Diagnosis and Treatment of Cognitive and dopaminergic intervention.
Neuropsychiatric Symptoms in Parkinson Disease and Dementia With Lewy Careful management of
hallucinations is indicated.
Bodies” by Daniel Weintraub, MD, and David Irwin, MD,40 in this issue
of Continuum. ● Although the link
between rapid eye
Constipation movement (REM) sleep
Constipation is prevalent in PD both before and after diagnosis. Many treatments behavior disorder and PD is
well established, evidence
are available for constipation, including adequate hydration, physical activity, on effective management of
and associated medications.96 Lubiprostone, probiotics, and fibers are considered REM sleep behavior disorder
useful in the treatment of constipation in PD.97,98 is insufficient.
Rapid Eye Movement Sleep Behavior Disorder

When patients have rapid eye movement (REM) sleep behavior disorder
(RBD), it is important to maintain a safe sleep environment, including
the removal of sharp objects near the bed and the addition of bedrails, if
indicated. Potential aggravators of RBD should be addressed, including the
use of SSRIs, SNRIs, or tricyclic antidepressants.99 Treatment options for RBD
include clonazepam or melatonin, although no firm evidence supports
their use.
Impulse Control Disorders

Patients with a premorbid history of behavioral addictions or drug abuse and
younger patients are at increased risk for impulse control disorders. A slow
decrease of dopamine agonists until discontinuation of use is the mainstay
of treatment.100
Apathy
Although apathy has a significant negative effect on both patients and
caregivers, no official guidelines for the treatment of this condition are
currently available. Some studies detected improvement in apathy scores
when treating depression and cognitive impairment with rivastigmine and
rotigotine.101
Anxiety
Anxiety in PD is often treated with SSRIs and, to a much lesser extent,
benzodiazepines because of their adverse effect profile, which includes cognitive
impairment and falls.102 Anxiety and depression are often treated simultaneously
with a single agent in PD.102
Pain
Several mechanisms are involved in pain in PD, including musculoskeletal,
dystonic, radicular, and central mechanisms. The first step in treating pain is to
assess which mechanism is involved.103 One study identified safinamide, a novel
MAO-B inhibitor, as efficacious in treating pain in patients with motor
fluctuations.104 Cannabis has also been assessed for pain relief in PD with
positive effects.105

CONCLUSION
PD is a common neurodegenerative disease with numerous symptomatic
treatments for both the motor and nonmotor symptoms but no disease-
modifying treatments. Nonmotor symptoms have a large impact on quality of life
and require clinical attention similar to the motor symptoms of the disease.
The discovery of genetic causes of PD has opened the way for targeted trials;
the results of these trials, together with α-synuclein–reducing treatments, are
anticipated to change the way we treat the disease.
ACKNOWLEDGMENT
The authors would like to thank Adina Wise, MD, for her careful English editing.
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WNL.0000000000003127
1300 OCTOBER 2022

Surgical Therapies for REVIEW ARTICLE
Parkinson Disease

C O N T I N U UM A U D I O
ONLINE
By Ashley E. Rawls, MD, MS
ABSTRACT
PURPOSE OF REVIEW: Parkinson disease (PD) is a progressive
neurodegenerative disorder that is often difficult to manage with
medications alone. This article reviews the current therapeutic surgical
interventions for PD, patient selection criteria, timing of patient referral to
surgical services, procedure overview, and future directions.
Adaptive, or closed-loop, deep brain stimulation is a

RECENT FINDINGS:
promising therapy that can detect ongoing circuit changes and deliver
appropriate stimulation based on the patient’s dominant symptom and
level of dopaminergic medication.
SUMMARY: Patients with PD can benefit from surgical interventions that can
be added to their medication regimen. These patients should be referred
to comprehensive centers that offer complete multidisciplinary screening
CITE AS:
evaluation to ensure appropriate patient selection and intervention CONTINUUM (MINNEAP MINN)
selection. With the appropriate surgical intervention and continued 2022;28(5, MOVEMENT DISORDERS):
1301–1313.
management from their care team, patients with PD can maximize their
quality of life. Address correspondence to
Dr Ashley E. Rawls, University of
Florida Norman Fixel Institute
for Neurological Diseases,
INTRODUCTION 3009 SW Williston Rd,
Gainesville, FL 32608,
P
arkinson disease (PD), the second most common neurodegenerative ashley.rawls@neurology.ufl.edu.
disorder after Alzheimer disease, involves continued degeneration of
dopaminergic neurons in the substantia nigra, which leads to clinical Dr Rawls has received personal
signs of resting tremor, bradykinesia, and rigidity.1 Presynaptic compensation in the range of
storage of dopamine in neurons in the striatum acts as a buffer against $500 to $4999 for serving as an
editor, associate editor, or
fluctuation in plasma levodopa levels.2 Over time, these dopaminergic neurons editorial advisory board
are lost, and the clinical response to levodopa starts to follow plasma levels more member for JAMA Neurology
closely.2 As a result, patients develop more significant treatment-related motor and as a physician expert
panelist with Mediflix, Inc.
fluctuations, increased motor symptoms, worsening nonmotor symptoms, and
an overall worsening quality of life.3 Those with advanced PD are also at an UNLABELED USE OF
increased risk for cognitive and psychiatric issues.2 PRODUCTS/INVESTIGATIONAL

USE DISCLOSURE:
Surgical therapies for PD began in the early 1900s with lesioning techniques.4 Dr Rawls discusses the
Deep brain stimulation (DBS) was introduced in 1987, followed by levodopa/ unlabeled/investigational use of
closed-loop deep brain
carbidopa intestinal gel infusion systems in 2015, and then MRI-guided focused stimulation for the treatment of
ultrasound (MRIgFUS) in 2016. These treatment options are not cures but are Parkinson disease.
ways to provide relief for the levodopa-responsive symptoms of PD. Like other
medications and procedures used to treat PD, these surgical interventions do not © 2022 American Academy
reverse, slow down, or stop disease progression but are used to manage the of Neurology.

SURGICAL THERAPIES FOR PARKINSON DISEASE
symptoms associated with PD. Refer to TABLE 3-1 for a simplified overview of
surgical options in PD. This article explores the surgical and procedural
interventions for patients with PD, patient selection criteria, procedure
overview, and treatment outcomes.
DEEP BRAIN STIMULATION

DBS uses electrical impulses provided by a fully implantable system to modulate
the three main symptoms of tremor, bradykinesia, and rigidity that are normally
levodopa responsive in patients with PD.5 DBS provides an adjustable and
reversible means of targeted therapy to modulate the pathologic state
contributing to these symptoms.5 The primary goal of DBS surgery is to improve
disabling or troublesome motor symptoms that have persisted despite optimized
medical therapy.6 With this in mind, the three broad indications for DBS in
patients with PD are (1) a very disabling off state that occurs more than 20% of
the day while awake; (2) troublesome dyskinesias when receiving optimal
medical therapy; and (3) treatment of patients with tremor that is inadequately
controlled despite optimized medical therapy (CASE 3-1).
All surgical candidates must have the diagnosis of clinically probable PD,
which can be evaluated via the Parkinson’s UK Brain Bank or Movement
Disorders Society criteria.6-8 The diagnosis of PD must be fairly certain, as
atypical forms of parkinsonism (eg, multiple system atrophy, progressive
supranuclear palsy, corticobasal syndrome, vascular parkinsonism,
neuroleptic-induced parkinsonism) have generally unfavorable outcomes with
DBS and are therefore part of the exclusionary conditions.6 Red flags indicating
that a patient may have an atypical parkinsonism include early falls, poor
levodopa response (except for resting tremor), vertical gaze palsy, early severe
autonomic dysfunction, and significant early cognitive impairment.6 Some
centers may survey a patient for at least 5 years following PD diagnosis to verify
that the diagnosis is not an atypical parkinsonism.6
TABLE 3-1 Simplified Overview of Surgical Options for Parkinson Disease
MRI-guided
Deep brain focused Levodopa/carbidopa Stereotactic
stimulation ultrasound intestinal gel infusion radiosurgery
Unilateral therapy only X X
Permanent implanted foreign bodies X X
Helps levodopa-resistant tremor X X X
Contraindicated in patients with severe X X X

cognitive impairment or dementia
Requires patient to be able to tolerate X X X

MRI scan
Requires several months after X X

procedure to titrate to optimal control
MRI = magnetic resonance imaging.
1302 OCTOBER 2022

In 1999, selection criteria for DBS were created in the form of the Core
Assessment Program for Surgical Interventional Therapies in Parkinson’s Disease
(CAPSIT-PD).9 They were designed to facilitate clinical research but were then
also used for guidance in the clinical practice of DBS centers globally.9 Briefly,
CAPSIT-PD recommended that a patient should have a diagnosis of idiopathic
PD and a minimum disease duration of 5 years to exclude people with atypical
parkinsonism.9 The next recommendation from CAPSIT-PD was confirming
dopaminergic responsiveness via a levodopa or apomorphine challenge test,
demonstrating at least a 33% decrease in the Unified Parkinson Disease Rating
Scale (UPDRS) part III score during the best on medication state.9
Patients considering DBS should be referred to an experienced surgical center
where their candidacy can be assessed by a multidisciplinary team, including a
movement disorders–trained neurologist, stereotactic or functionally trained
neurosurgeon, psychiatrist, neuropsychologist, physical therapist, occupational
therapist, and speech therapist.6 These teams may be further augmented by a
social worker, nutritionist, and financial counselor.6 As part of the workup for
surgical candidacy, patients will need to have a brain MRI and
neuropsychological testing within 1 year prior to DBS surgery.6 Ideal DBS
candidates are younger, have little or no cognitive impairment, have motor
A 52-year-old woman presented with worsening symptoms of Parkinson CASE 3-1

disease (PD). The patient had presented 4 years earlier with symptoms of
bilateral asymmetric resting tremor, body stiffness, rigidity, and
decreased unilateral arm swing and shortly thereafter was diagnosed
with young-onset PD. She was prescribed antiparkinsonian medications,
which significantly improved her symptoms of rigidity and bradykinesia;
however, she continued to have bilateral hand tremor that was
uncontrolled despite best medical management.
The patient wished to have better control of her tremor bilaterally,
which was interfering with her job. Deep brain stimulation (DBS) was
considered the best surgical option for this patient, as she was young and
therefore would likely need therapy titration as PD progressed, and she
did not have significant medical comorbidities. Additionally, the patient
wanted control of her bilateral tremor, which could be addressed with
DBS, as focused ultrasound and lesional therapies are currently
performed unilaterally because of potential side effects.
This case exemplifies how to assess a patient appropriately for DBS for PD COMMENT
treatment, particularly for tremor that is inadequately treated despite
optimized medical therapy. The patient’s tremor did not appear to be
levodopa responsive, so levodopa/carbidopa intestinal gel infusion was
unlikely to treat this tremor effectively. Although this patient’s tremor did
not appear to be levodopa responsive, resting tremor responds well to DBS
regardless of medication responsiveness. It would have been reasonable,
therefore, for the physician to refer this patient to an experienced surgical
center with a multidisciplinary team to assess the patient’s candidacy.

symptoms that fluctuate throughout the day, and are high functioning when
their medications are optimized. While there is not a specific age limitation for
this procedure, there are inherent surgical risks and medical comorbidities that
increase with age, and many surgical centers are reasonably reluctant to operate
on any patients aged 80 years or older.6
PD symptoms that are responsive to levodopa can be improved with DBS;
however, an exception to this is resting tremor, which may not be levodopa
responsive but can still improve with DBS.
The ability of DBS to improve levodopa-responsive PD symptoms (ie, resting
tremor, bradykinesia, and rigidity) should be discussed with the patient and their
caregiver early in the treatment course.6 However, symptoms that do not
respond well to levodopa, including gait problems, postural instability, and
speech difficulty, do not respond well to DBS.6 The one consistent exception to
this rule is that resting tremor can be refractory to levodopa treatment yet
respond well to DBS.6 Patients with tremor-predominant PD are often ideal
candidates for DBS therapy, and tremor that is inadequately treated despite
optimized medical therapy is one of the three primary indications for considering
DBS in a patient with PD.
Medical clearance should be obtained prior to surgery, as medical
comorbidities such as obesity, cardiac conditions, and pulmonary conditions can
increase surgical risk. Care should be taken to thoroughly evaluate patients for
neuropsychological performance below the expected norms for their age and
education level, as patients with pronounced executive and memory impairment
have a higher postoperative risk for worsened cognitive dysfunction.6 Cognitive
impairment severe enough to be categorized as dementia is generally an
exclusion for DBS surgery.
Risks of the surgery include infection of the implanted system, brain
hemorrhage, cognitive decline, and exacerbation of preexisting gait issues or
mood problems.6 These serious risks are reported in 1% to 5% of patients,
although this may differ between institutions.6
DBS surgery may be performed bilaterally at the same time or with each
side staged at different times, depending on the preference of the neurosurgeon
and the surgical center. Regardless, patient recovery generally takes several
days to weeks.6 In addition, optimal programming of the DBS device requires
several neurology clinic visits that occur over the course of 6 months after the
surgery.6 This expectation that improvement happens progressively over
6 months, rather than all at once, is critical for patients and families to
understand. Once programming is optimally adjusted, follow-up visits usually
occur every 3 to 6 months, depending on the patient’s needs.4,6 FIGURE 3-1
illustrates a schematic of an implanted DBS device.10 Patients and their
caregivers need to understand the risks and benefits of DBS and that it is not a
cure but, rather, another treatment option for their PD symptoms.6 This
conversation should begin early in the process, so that the patient and caregiver
can make an informed decision with their provider about whether this
intervention is appropriate to pursue.
Expected outcomes should be considered in light of the three indications for
DBS surgery: troublesome dyskinesias, frequent dosing because of troublesome
off time, and medication-resistant tremor. Large multicenter studies report that,
on average, daily off time and dyskinesias were improved by subthalamic
nucleus (STN) stimulation (69.1% and 62.5% of patients showed improvement,
1304 OCTOBER 2022

respectively).11 The STN target is thought KEY POINTS
to be associated with increased medication
● Surgical interventions do
reduction compared with the globus not slow down, stop, or
pallidus internus (GPi) target, while the reverse disease progression
GPi target is thought to be better at but are used to manage the
addressing dyskinesias.6 Neuropsychiatric symptoms associated with
Parkinson disease.
effects of STN-DBS include potential
worsening of depression and anxiety and ● The three indications for
impulse control disorders.12 Despite stable deep brain stimulation
improvements in global outcomes of DBS, surgery for the treatment of
patients can have worsening of gait Parkinson disease include
troublesome dyskinesias,
impairment and speech disturbances, as frequent dosing because of
well as persistent levodopa-resistant troublesome off time, and
freezing of gait.13 Overall, many studies medication-resistant
FIGURE 3-1 tremor.
Illustration of the deep brain show that no significant differences are
stimulation system. found in long-term control of motor ● Parkinson disease
Reprinted with permission from Xiao Y, et al, symptoms between the two sites.7 symptoms that are
10
IEEE Trans Biomed Eng. © 2021 IEEE.
Currently, clinical DBS therapy only responsive to levodopa can
involves “open-loop” neurostimulation, be improved with deep brain
stimulation; however, an
meaning that stimulation continues
exception to this is resting
to be applied at the parameters it was set at without sensing brain signals for tremor, which may not be
feedback.14 Future directions for DBS involve adaptive “closed-loop” therapy, in levodopa responsive but
which local field potentials of the target structure are recorded through can still improve with deep
brain stimulation.
implanted electrodes, which in turn deliver stimulation.14 The adaptive DBS
system can vary its current based on an input “biomarker” (such as beta band ● Disadvantages of deep
oscillations), which can decrease stimulation-induced long-term side effects such brain stimulation include
as dyskinesias or speech problems.15 The optimal closed-loop system would be risks associated with brain
able to concurrently sense and stimulate, while automatically adapting to the surgery, hardware failure,
infection risks, and concerns
patient’s dominant symptom and level of dopaminergic medication.14 about patients with
significant cognitive
MRI-GUIDED FOCUSED ULTRASOUND impairment.
MRIgFUS was approved by the US Food and Drug Administration (FDA) in 2016
● Deep brain stimulation
for the treatment of unilateral essential tremor, PD tremor, and PD-related
can be performed on both
dyskinesia.16,17 Bradykinesia and rigidity often respond well to levodopa in sides of the brain and is
patients with PD; however, as mentioned previously, resting tremor can be adjustable over time.
refractory to levodopa.1,6 Following creation of phased-array transducers in the
1990s, transferring energy through the cranium is now possible without ● Commercial deep brain
stimulation systems provide
requiring an incision.4 The transducer elements emit ultrasound beams, which continuous stimulation
result in ablation by thermal coagulation when focused on a target.18 For these without sensing brain signals
patients with clinically probable PD, MRIgFUS can be used as another method to for feedback (ie, open loop).
address symptoms poorly controlled with levodopa without a craniotomy, There is ongoing research on
deep brain stimulation
electrode penetration, anesthesia, or ionizing radiation.1,19 Patients may consider systems that sense brain
MRIgFUS when restrictions to DBS are present, such as surgical risks, concerns signals for feedback (ie,
about multiple clinic visits for stimulator setting optimization, or a patient’s closed loop).
reluctance to undergo brain surgery or have an implanted device.4,5
Contraindications to the MRIgFUS procedure include claustrophobia, inability to
lay flat for an extended period of time, inability to communicate during
procedures, and implants that are not MRI compatible.18 Some facilities may
exclude patients who have a history of craniotomy, as the imaging that is used for
planning may be inaccurate.18 Briefly, patients with PD with asymmetric tremor

and mild bradykinesia or rigidity may consider MRIgFUS with the target of the
ventral intermediate nucleus (VIM) of the thalamus.18 For patients with more
asymmetric bradykinesia and rigidity, the GPi target may be chosen.18 Initial
MRI and CT scans are taken the day prior to the procedure for planning, and then
the day of the procedure a stereotactic frame is attached to the patient’s head
with local anesthetic.18 A helmet-type transducer containing 1024 ultrasound
elements is placed on the patient’s head, and then the patient enters the MRI
scanner.18 The helmet-type transducer circulates chilled water to keep the scalp
from absorbing too much heat during the procedure.18 At the beginning of the
procedure, a low amount of energy is applied to confirm whether the target site
has a temperature increase, and then the patient’s symptoms are tested.18 All
throughout this process, the MRI scanner is taking real-time images and
thermometry to assess when the target lesion reaches appropriate
temperatures and measures adjacent structures for excessive heating.17 If the
patient’s tremor is suppressed without observed complications, then the
temperature is increased to create the final lesion.18 No consensus exists on the
target size of the final lesion in the VIM of the thalamus; however, general
practice is to make a large lesion while avoiding the internal capsule and the
ventral caudal thalamus.18
Although MRIgFUS does not involve a craniotomy or incision, an irreversible
lesion is made, which could potentially result in permanent neurologic deficits.16
CASE 3-2 A 65-year-old man with a history of hypertension and hyperlipidemia

initially presented with a chief complaint of dominant hand resting tremor
that affected his daily activities, such as using utensils, writing, and
typing. On initial examination, he exhibited some mild rigidity and
bradykinesia with reduced unilateral arm swing, but these issues did not
inhibit his actions significantly.
The patient was diagnosed with tremor-predominant Parkinson
disease (PD), and he was administered various forms of levodopa,
dopamine agonists, and anticholinergics over a period of 5 years without
successful improvement in his tremor.
He wished to have better control of his dominant hand tremor, but he
did not wish to have a foreign device left in his body or trepanation of his
skull. MRI-guided focused ultrasound or gamma knife stereotactic
radiosurgery targeting the ventral intermediate nucleus (VIM) of the
thalamus was deemed appropriate for this patient, given that his main
symptom was unilateral tremor, and he did not wish to have an implanted
device.
COMMENT This case exemplifies options for a patient with tremor-predominant PD

who did not wish to have an implanted device or undergo brain surgery.
The patient should also be counseled that, as his PD progresses, he may
develop nondominant hand tremor; however, at this time, both MRI-guided
focused ultrasound and stereotactic radiosurgery targeting the VIM of the
thalamus are primarily performed unilaterally.
1306 OCTOBER 2022

Side effects can include motor weakness, ataxia, gait disturbance, sensory KEY POINTS
disturbance, and speech issues.16,18 A skilled operator is needed to balance the
● MRI-guided focused
potential side effects versus efficacy of the procedure as large lesions are ultrasound may be
expected to be more effective, although this increases the risk of side effects.16 considered when there are
CASE 3-2 presents a typical case, and FIGURE 3-2 illustrates a schematic of the restrictions to deep brain
MRIgFUS device.19 stimulation or other reasons
that prohibit brain surgery.
In the randomized controlled trial by Elias and colleagues,17 MRIgFUS reduced
total tremor scores in the contralateral hand by 47%, with only minimal ● MRI-guided focused
improvement in head and vocal tremors. Adverse events included gait ultrasound uses multiple
disturbances in 36% and sensory disturbances in 38% of participants, which ultrasound beams that
persisted at 1 year in 9% and 14% of participants, respectively.17 Maesawa and converge on a brain target to
create an irreversible lesion.
colleagues19 found that the therapeutic effect of MRIgFUS at 6 months could be
expected to persist for 2 years, although sometimes a recurrence of tremor ● An advantage of
occurred during the first year following treatment. MRI-guided focused
At this juncture, MRIgFUS is only FDA approved for unilateral tremor. If a ultrasound is that no foreign
bodies are present in the
patient has bilateral tremor or axial tremor involving head or neck, then DBS patient following surgery.
may be a more appropriate treatment choice.18 Current investigations use Disadvantages include that
MRIgFUS subthalamotomy at an early stage (EarlyFocus), which focuses on the US Food and Drug
short-term safety of MRIgFUS subthalamotomy in patients with PD for fewer Administration has only
approved this treatment for
than 5 years from diagnosis.20 Creating a lesion in the STN had been avoided in
one side of the brain, and it
the past, as this could lead to hyperkinetic complications of chorea and is not adjustable.
ballismus.18 A single-arm clinical trial is assessing early safety and efficacy of
bilateral treatment of medication-refractory essential tremor with MRIgFUS, ● During stereotactic
with estimated study completion date in March 2026.21 Additionally, the Bilateral radiosurgery, multiple
beams of radiation converge
Essential Tremor Treatment with FUS (BEST-FUS) study sponsored by on the brain target to create
University Health Network, Toronto, Canada, aims to perform contralateral an irreversible lesion.
MRIgFUS treatment on study participants who have previously undergone
successful unilateral MRIgFUS, with an estimated study date completion in ● An advantage of
stereotactic radiosurgery is
October 2024.19,22 that no foreign bodies are
present in the patient
OTHER LESIONAL THERAPIES following surgery.
Surgical therapies for PD began in the early 1900s with lesioning techniques, such Disadvantages include that
the US Food and Drug
as cryothalamotomy and chemothalamotomy.4 Following the introduction of
Administration has only
levodopa in 1968, which revolutionized the patient’s ability to treat clinical approved this treatment for
symptoms, ablative surgery for this indication decreased.4 The interest in one side of the brain, it is not
ablative techniques increased again, however, after the long-term side effects of adjustable, and there is
potential radiation risk.
levodopa became more prominent.4 Patients may select these therapies if they
have an aversion to having an implanted device. Similar to MRIgFUS, however, a
balance must be found between the lesion size and the risk of side effects, as
larger lesions are suspected to be more effective but have an increased frequency
of side effects.16 Depending on the target (eg, VIM of thalamus, GPi, STN), side
effects can include gait disturbance, paresthesia, dysarthria, ataxia, and weakness.18
Stereotactic radiosurgery uses externally generated ionized radiation to target
a specific site in the central nervous system.23 VIM of the thalamus is
preferentially targeted in patients with tremor-predominant symptoms, while
GPi or STN is targeted in those with advanced motor fluctuations.18 During this
procedure, multiple beams of radiation converge onto the target, delivering a
dose of radiation that can vary from 120 Gy to 200 Gy depending on the
institution.24 There is also a concern for latent radiation effects and potential risk
for secondary neoplasia.15,25 Niranjan and colleagues26 discussed using bilateral

FIGURE 3-2
Illustration of MRI-guided focused ultrasound. The beams of ultrasound emerge from the
transducer (A) with 1024 elements (E) and are focused on the target (F) under the guidance of
MRI (D). Degassed chilled water is circulated inside the space between the membrane (B) and
the scalp (G) of the patient. Phased-array transducer (A), membrane (B), stereotactic frame
(C), MRI scanner (D), elements (E), target (F), and scalp (G).
Reprinted from Maesawa S, et al, Neurol Med Chir (Tokyo).19 © 2021 The Japan Neurosurgical Society.
CASE 3-3 An 83-year-old woman presented for gait disturbance. She had been
diagnosed with akinetic-rigid Parkinson disease 15 years prior. The patient
had initially done well on levodopa replacement; however, over the past
year, she experienced increased motor fluctuations and appeared to
have issues with gastric emptying. Although the patient was able to
perform her activities of daily living independently, her son, who she
lived with, managed the patient’s medications and finances. Her past
medical history was also notable for a history of stroke, ventricular
tachycardia for which she had an automatic implantable cardioverter-
defibrillator, hypertension, hyperlipidemia, diabetes, and cognitive
impairment. The patient’s medications included levodopa every 2 hours
with at least 2 dose failures per day, and the patient and family wanted to
explore other treatment options for consistent dopaminergic delivery.
Levodopa/carbidopa intestinal gel infusion was considered the
optimal treatment option for this patient since it could be managed with
the help of a caregiver. The patient’s automatic implantable
cardioverter-defibrillator was not MRI compatible, which precluded
MRI-guided focused ultrasound. Given the patient’s cognitive impairment
and medical comorbidities, deep brain stimulation was not considered
the best option for this patient.
COMMENT This case exemplifies the impact that cognitive impairment and other
clinical factors have on selecting surgical treatments for patients with
Parkinson disease.
1308 OCTOBER 2022

gamma knife thalamotomy for bilateral tremor; however, this therapy is KEY POINTS
generally applied unilaterally in clinical practice.24
● The levodopa/carbidopa
Stereotactic radiofrequency ablation is initiated by inserting a lesioning probe intestinal gel infusion
through a burr hole in the skull to the target area.4 The tip of the lesioning probe system provides levodopa
is heated to create an irreversible lesion by coagulating brain tissue at the target infusion through a
site.4,19 With this intervention, contralateral motor UPDRS score was improved percutaneous endoscopic
gastrojejunostomy,
by 41% and dyskinesias by 57% at 1 year following unilateral pallidotomy.23
providing continuous levels
Alternatively, unilateral subthalamotomy showed a 31% motor improvement on throughout the day.
the Unified Parkinson’s Disease Rating Scale at 2 years.27
● The levodopa/carbidopa
LEVODOPA/CARBIDOPA INTESTINAL GEL INFUSION intestinal gel infusion
system may not be
Levodopa/carbidopa intestinal gel infusion treatment offers another option for appropriate for patients
continuous dopaminergic therapy for patients with PD.3 In 2015, the FDA with poor response to
approved levodopa/carbidopa intestinal gel infusion in the United States for use in levodopa or who have
patients with PD with motor fluctuations.3,26 CASE 3-3 presents a typical case of a difficulty handling the
infusion pump.
patient for whom levodopa/carbidopa intestinal gel infusion may be appropriate,
and FIGURE 3-3 shows the levodopa/carbidopa intestinal gel infusion schematic.28
Levodopa taken orally can cause pulsatile receptor stimulation in
dopaminergic neurons because of the short half-life, leading to motor
fluctuations such as dyskinesias and frequent or sudden off periods.28 Gastric
emptying is a rate-limiting step for orally administered levodopa, which is
absorbed in the proximal small intestine.29 Thus, gastric motility issues can lead
to fluctuating plasma concentrations of levodopa, producing motor
fluctuations.30 The levodopa/carbidopa intestinal gel infusion system provides
continuous carbidopa and levodopa infusion through a percutaneous endoscopic
gastrojejunostomy (PEG-J) tube via a portable infusion pump.30 An advantage of
levodopa/carbidopa intestinal gel infusion over orally provided levodopa is that it
can deliver continuous rather than pulsatile medication throughout the day, and
delivery of the levodopa bypasses the stomach to the jejunum, avoiding problems
that arise with gastric emptying issues.26 By doing so, this stabilizes the motor
fluctuations during the awake period, as plasma levodopa concentrations reach a
steady state.2 Continuous infusion of levodopa/carbidopa intestinal gel has
shown extended “on” time without disabling dyskinesias, decreased “off” time,
and decreased unpredictable “off” periods.31 Levodopa/carbidopa intestinal gel
infusion may not be an appropriate treatment for patients with poor response to
levodopa or significant difficulty handling the infusion pump.32
A patient with PD will be evaluated by the neurologist for appropriate
candidacy for levodopa/carbidopa intestinal gel infusion treatment; this involves
identifying the presence of troublesome motor fluctuations not controlled with
optimal oral medical management and determining that the patient is still
responsive to levodopa.26 It is important to determine if the patient has the
understanding and physical ability to operate the levodopa/carbidopa intestinal
gel infusion system, and if not, then it must be determined if the patient has
sufficient caregiver support to assist them.26 The next step is to refer the patient
to a proceduralist to place the PEG-J tube (eg, a gastroenterologist, general
surgeon, or interventional radiologist).26 Standard of practice in the United
States is to wait at least 1 week following PEG-J tube placement to start levodopa/
carbidopa intestinal gel infusion to allow for adequate healing time.26 However,
in other countries, some clinicians will use the tube within 24 to 48 hours of
placing it; this can also be considered for patients who have logistical concerns

FIGURE 3-3
The levodopa/carbidopa intestinal gel system.
PEG = percutaneous endoscopic gastrojejunostomy.
Modified from Amjad F, et al, Adv Ther.28 © 2019 The Authors.
with travel.26 Over the next few visits, the levodopa/carbidopa intestinal gel
infusion pump will be titrated to achieve maximal therapeutic benefit based on
the input from the patient, the caregiver, and the clinic staff. Clinic appointments
are initially scheduled for every 2 to 6 weeks, depending on the patient’s
need, and then once the target infusion dosage is reached, clinic visits can resume
every 3 to 6 months.26 Many clinicians will wait to discontinue nonlevodopa
antiparkinsonian medications to lessen undesirable side effects, such as increased
akinesia, restless legs, and dopamine agonist withdrawal syndrome.26 During a
typical day, the levodopa/carbidopa intestinal gel infusion pump is usually
titrated for hours when the patient is awake, and then is turned off and
disconnected during sleep; during this time, the patient can take oral levodopa if
needed.26 Issues related to the placement of the PEG-J tube include granuloma
formation, abdominal pain, and peritonitis or stoma infection.3 Device-related
problems include dislocation and occlusion of tubing, broken connectors, and
accidental removal.3,31 Side effects from levodopa infusion itself can include
hyperkinesia, hallucinations, hyperhomocysteinemia, vitamin B12 deficiency,
and polyneuropathy.32
Several research studies have shown that levodopa/carbidopa intestinal gel
infusion treatment reduces off time by about 1.9 hours per day, increases on time
without troublesome dyskinesias by about 1.86 hours per day, and increases on
time without any dyskinesias by 2.28 hours per day when compared with oral
levodopa treatment.33 Compared to patients not taking antiparkinsonian
treatment, patients using levodopa/carbidopa intestinal gel infusion had off time
reduced by 4.4 hours per day, and on time without troublesome dyskinesias was
increased by 4.8 hours per day.33
1310 OCTOBER 2022

Future directions of levodopa/carbidopa intestinal gel infusion include KEY POINTS
making smaller pump devices for easier transportation. Furthermore, adding
● Typically, the levodopa/
entacapone to the levodopa/carbidopa intestinal gel has been considered, which carbidopa intestinal gel
would aim to increase levodopa’s length of action; this could lead to a reduction infusion pump is on during
of solution volume needed while decreasing the treatment costs associated with the day and is shut off at
each cassette.32 night.
● Advantages of the
HEALTH DISPARITIES IN SURGICAL THERAPIES levodopa/carbidopa
The accelerated implementation of telehealth during the COVID-19 pandemic intestinal gel infusion
has increased outreach of physicians to patients who may be homebound, have system include that the
pump can be disconnected
transportation difficulties, or have other restrictions. Although there has been a
when not in use and can be
dramatic increase in households with Internet access, differences in access may used in patients with
continue, especially for those with financial constraints, those with lower significant cognitive
education levels, and patients who are not proficient in English.34 It is imperative impairment. Disadvantages
include risks associated with
that future outreach and research consider limited access or understanding of
percutaneous endoscopic
technology in relation to patient care.34 Regarding DBS, several studies have gastrojejunostomy tube
shown that this therapy is underused by certain populations, particularly African placement and
Americans.35 The proportion of African American patients diagnosed with PD maintenance.
ranges from 4.8% to 28%; however, only 0.6% of patients who undergo DBS are
African American.36 African American and Hispanic/Latino patients may seek
treatment later in the disease course, have less access to practitioner visits, and
have less secure social support networks.35,36 Future research is necessary to
identify barriers that underrepresented and underserved populations face when
considering surgical interventions for PD, and more education is necessary to
bring awareness to the medical community regarding bias and disparities in
offering these more invasive, yet highly effective, interventions to all eligible
patients with PD.
CONCLUSION
PD is a progressive neurodegenerative disorder, and as the disease advances,
patients may have increased motor complications and treatment-related
fluctuations, and surgical therapies may offer a highly effective therapeutic
route. Referrals for surgical interventions for PD should be made to either
multidisciplinary centers or groups that have significant experience with that
intervention. It is the responsibility of the referring provider to discuss with
patients that these surgical interventions do not slow, reverse, or stop PD
progression. Conversely, the appropriate intervention for the patient can
improve quality of life by potentially decreasing dyskinesia, decreasing off times,
increasing on times, and providing more stable therapy on a daily basis. Refer to
TABLE 3-1 for a simplified overview of surgical options in PD.
USEFUL WEBSITES
FOCUSED ULTRASOUND FOUNDATION AMERICAN ASSOCIATION OF NEUROLOGICAL SURGEONS
This website provides information regarding how This website provides an overview of deep brain
focused ultrasound is used for the treatment of stimulation and the workup needed for referral for
tremor and where to find institutions that are implantation.
providing this treatment.
aans.org/en/Patients/Neurosurgical-Conditions-and-
fusfoundation.org Treatments/Deep-Brain-Stimulation#:~:text=DBS%
20is%20a%20surgical%20intervention,obsessive%
2Dcompulsive%20disorder%20and%20epilepsy

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REVIEW ARTICLE

Diagnosis and Treatment
ONLINE
of Cognitive and
Neuropsychiatric
Symptoms in Parkinson
Disease and Dementia
With Lewy Bodies
By Daniel Weintraub, MD; David Irwin, MD
CITE AS:
CONTINUUM (MINNEAP MINN) ABSTRACT
PURPOSE OF REVIEW: This article summarizes the underlying biology and
1314–1332.
current diagnostic and treatment strategies for the cognitive and
Address correspondence to neuropsychiatric features of Parkinson disease (PD) and dementia with
Dr Daniel Weintraub 3615 Lewy bodies (DLB).
Chestnut St, #330,
Philadelphia, PA 19104,
daniel.weintraub@pennmedicine. RECENT FINDINGS:Cognitive impairment and neuropsychiatric symptoms
upenn.edu.
have been increasingly recognized in PD and DLB, leading to improved
RELATIONSHIP DISCLOSURE: diagnosis and treatment strategies. While PD is most associated with and
Dr Weintraub has received diagnosed by the presence of motor symptoms, nonmotor symptoms
personal compensation in the
range of $10,000 to $49,999 for can often be the most debilitating for patients. Neuropsychiatric
serving as a consultant for symptoms are highly prevalent nonmotor features and include cognitive
Clintrex and on a scientific
impairment, depression, anxiety, psychosis, impulse control disorders,
advisory or data safety
monitoring board for Acadia and apathy. Neuropsychiatric symptoms can be difficult to recognize
Pharmaceuticals Inc. and diagnose in patients with PD, in part because of comorbidity and
Dr Weintraub has received
Continued on page 1332
symptom overlap with core PD features. Treatment strategies are a
combination of pharmacologic and nonpharmacologic interventions used
UNLABELED USE OF in the general population and those specific to PD. DLB is a clinical
PRODUC TS/INVESTIGATIONAL
USE DISC LOSURE:
dementia syndrome, often with similar cognitive, behavioral, autonomic,
Drs Weintraub and Irwin discuss and motor features as PD. Moreover, DLB has shared underlying
the use of several medications pathophysiology with PD, as both are associated with postmortem findings
and treatments for the
neuropsychiatric symptoms of of α-synuclein neuropathology at autopsy and have shared genetic risk and
Parkinson disease and dementia prodromal symptoms. DLB is clinically differentiated from PD by the
with Lewy bodies, none of
presenting features of cognitive impairment in DLB, compared with the
which are approved by the US
Food and Drug Administration, variable onset of cognitive impairment occurring 1 year or more after
except for rivastigmine for the established motor onset in PD. Thus, diagnosis and treatment of cognitive
treatment of Parkinson
dementia and pimavanserin for
impairment and neuropsychiatric symptoms in DLB are similar to that of
the treatment of psychosis in PD and have important implications for maintaining patient independence and
Parkinson disease. providing support for caregivers because motor, cognitive, and
© 2022 American Academy neuropsychiatric symptoms have an additive effect on patient functional
of Neurology. disability.
1314 OCTOBER 2022

SUMMARY: A careful history and physical examination are often needed to KEY POINTS
accurately diagnose and treat the heterogeneous cognitive and behavioral
● Both Parkinson disease
symptoms of PD and DLB. Accurate diagnosis and treatment of and dementia with Lewy
neuropsychiatric symptoms and cognitive impairment in PD and DLB are bodies are classified as
important, as these are a considerable source of patient disability and Lewy body disorders
caregiver burden. because of the shared
underlying α-synuclein
neuropathology.
● Parkinson disease
INTRODUCTION dementia and dementia with
W
hile Parkinson disease (PD) is considered a movement disorder Lewy bodies are
differentiated from each
and is diagnosed on that basis, the high prevalence of other by the timing of the
associated neuropsychiatric symptoms suggests that PD is onset of cognitive
actually more accurately conceptualized as a neuropsychiatric impairment and dementia; in
disorder. Only in the past 50 years—with the introduction of dementia with Lewy bodies,
dementia is an early
levodopa and other PD medications and treatments, the increasing life span of presenting feature
patients, and increasing awareness and research—have neuropsychiatric and compared with Parkinson
cognitive disorders (here collectively referred to as neuropsychiatric symptoms) disease, where cognitive
gained recognition as being common, often disabling, symptoms associated with impairment is variable and
dementia occurs at least
worse outcomes and increased caregiver burden that require special clinical 1 year after the onset of
expertise for good management. The most commonly studied neuropsychiatric motor symptoms.
symptoms are cognitive impairment (both mild cognitive impairment [MCI] and
dementia), depression, and psychosis, and other common and significant ● The majority of patients
with Parkinson disease,
neuropsychiatric symptoms are impulse control disorders, anxiety symptoms,
especially those who are
and apathy. older and with long-standing
Dementia with Lewy bodies (DLB) is a clinical neurodegenerative dementia disease, develop significant
syndrome that includes core clinical neuropsychiatric features of well-defined cognitive impairment.
visual hallucinations and fluctuations in cognition, along with motor
● Patients with Parkinson
parkinsonism, similar to PD. These constellations of clinical symptoms and signs disease can experience
correspond to a high specificity for underlying α-synuclein Lewy bodies in the impairments in any of the
neocortex and help differentiate DLB from other neurodegenerative dementia major cognitive domains,
syndromes, such as Alzheimer disease (AD). DLB has shared underlying biology even at the stage of mild
cognitive impairment.
with PD, as both are classified as α-synucleinopathies owing to the postmortem
findings of α-synuclein Lewy bodies in the brainstem and/or neocortex in both ● Choice of Parkinson
syndromes. Moreover, cognitive impairment and dementia are common in PD disease medication at
(ie, Parkinson disease dementia [PDD]), and clinical neuropsychiatric symptoms disease onset does not
appear to impact long-term
are often similar in PD and DLB). Thus, PD, PD-MCI, PDD, and DLB represent a
cognitive course, but use of
clinicopathologic spectrum of Lewy body disorders corresponding to the variable medications with significant
topology of α-synuclein neuropathology in the neuraxis that currently cannot be anticholinergic properties
directly detected in vivo using imaging or other diagnostic testing. The clinical may be associated with
differentiation of DLB from PD is currently based on the onset of cognitive worse long-term cognitive
outcomes.
impairment in the disease course, where DLB has prominent presenting features
of cognitive impairment and neuropsychiatric symptoms with or without motor ● For Parkinson disease
parkinsonism. In contrast, PDD is characterized by cognitive impairment and dementia, cholinesterase
dementia with variable onset in the disease course, ranging from 1 year to inhibitors are of modest
benefit, and there is no clear
decades after the onset of established PD; however, 2015 Movement Disorder benefit for memantine. For
Society clinical criteria for PD do not make the distinction of the 1-year rule to Parkinson disease–mild
differentiate PDD from DLB,1 but this is still a matter of debate.2 cognitive impairment, no
Accurate diagnosis and treatment of neuropsychiatric symptoms and medication has been shown
to be efficacious.
cognitive impairment in PD and DLB are important, as these are a considerable

COGNITIVE AND NEUROPSYCHIATRIC SYMPTOMS IN PD AND DLB
source of patient disability and caregiver burden. DLB is less studied in

therapeutic trials compared with AD, thus established clinical data to guide
treatment decisions are limited. Moreover, pharmacologic treatment choices for
the various clinical, cognitive, and neuropsychiatric symptoms and the motor
and autonomic features of PD and DLB can often antagonize each other because
of competing mechanisms of action. Thus, a detailed and careful history and
physical examination are needed for accurate diagnosis of these features, and
treatment decisions should be individualized to specific patient needs and
medical comorbidities.
PARKINSON DISEASE
This section discusses the epidemiology, diagnosis, and management of
neuropsychiatric symptoms of PD.
Cognition
The original assumption, based on early cross-sectional studies, was that
approximately 30% of patients with PD have PDD (CASE 4-1). However, recent
longitudinal studies suggest that dementia may actually occur long term in the
overwhelming majority of patients with PD. In addition, up to one-third of
CASE 4-1 A 68-year-old woman presented with cognitive difficulty in the setting of
an established Parkinson disease (PD) diagnosis 3 years prior. Her initial
motor symptoms were characterized by asymmetric rest tremor with
associated bradykinesia, cogwheel rigidity, and mild postural instability.
She had maintained good response to dopaminergic therapies and had
been functioning independently at home until recently developing
progressive memory impairments. Her husband noted that she often
repeated elements of conversations and asked the same questions
repeatedly. She had also experienced some fluctuation in attention at
times. She missed dosages of her levodopa medication, prompting her
husband to start administering the medication to her. She also started to
have hallucinations of people in the room. She misplaced items often and
had delusions of intruders invading the home to steal from her.
On examination, she had hypophonic but fluent spontaneous speech
with some word-finding pauses and circumlocutions. On confrontation
naming, she had difficulty with relatively common items such as finding
the name for a mushroom or camel after being presented with line
drawings of these items.
On episodic memory evaluation, she reproduced up to five words on
three successive presentations of a six-word list. The patient was able to
recall 0 of these words following a brief delay, with poor recognition with
semantic cues. Her copy of a complex figure was poorly organized, with
spatial distortions and omissions. After a brief delay, she had poor recall
of the design elements. She also exhibited difficulties with digit span and
oral trials tests.
The patient was diagnosed with PD dementia (PDD) due to the
emergence of cognitive impairment in the setting of established PD for
1316 OCTOBER 2022

patients with PD have MCI (PD-MCI), which is associated with both more rapid
progression to dementia3 and increased mortality risk,4 even in early disease.
Even newly diagnosed patients with PD have a relatively high prevalence (10% to
20%) of cognitive deficits and decline. Changes in cognition have even been
reported in prodromal PD.
The profile of cognitive performance in PD was previously thought to be
distinct from AD, with greater initial impairment in executive abilities and
attention in early PD, compared with greater memory and language impairments
in early AD. However, recent research has demonstrated that initial cognitive
impairment in PD can occur across a range of cognitive domains (ie, executive,
memory, visuospatial, attentional, and even language abilities). Patients can also
experience cognitive fluctuations, either in the context of nonmotor fluctuations
or, for those with dementia, fluctuating alertness similar to that reported in DLB
(see below).5
A major step forward for the field was the publication of clinical criteria for the
diagnosis of PDD, followed by recommended diagnostic criteria and guidelines,
including recommended cognitive testing, for PD-MCI.6 The transition from
MCI to dementia is marked by broader and more severe cognitive deficits and
meaningful impact on daily function. Published research has demonstrated high
3 years with cognitive impairment in attention, executive, visuospatial,

language, and episodic memory domains. Brain MRI showed diffuse
frontoparietal atrophy and moderate reduction in hippocampal volumes.
Lowering the levodopa dosage was effective in reducing visual
hallucinations, and she showed improvement in attention and
cognition for approximately 18 months on treatment with a cholinesterase
inhibitor.
Over the next 3 years, she had added disability from cognitive and
motor impairment, eventually resulting in death from sequelae of
end-stage dementia. A primary diagnosis of transitional stage Lewy body
disease with α-synuclein–positive Lewy bodies/Lewy neurites
throughout the brainstem and limbic regions was found at autopsy, with a
secondary diagnosis of intermediate-level Alzheimer disease
neuropathologic change (Amyloid Thal stage 2, Braak tau stage 2, and
CERAD plaque stage 3 [A2B2C3]) with widespread cortical amyloid (Thal
phase 3), including moderate neuritic plaques (CERAD C2), and moderate
levels of tau-positive neurofibrillary tangles in the medial temporal and
temporal neocortex (Braak stage B2).
The mixed cognitive features of episodic memory and language difficulties COMMENT
along with relatively short time interval from onset of PD to dementia
(3 years) are likely to have been contributed to by the presence of
Alzheimer disease (AD) co-pathology in this case. This case illustrates the
influence of AD co-pathology on clinical features of dementia in PD and the
spectrum of cognitive impairment across PDD and dementia with Lewy
bodies.

rates of conversion to PDD using PD-MCI criteria7 and that commonly used
cognitive tests are sensitive to cognitive deficits in patients with PD without
dementia.8 In addition, several cognitive instruments have been validated for use in
PD, including the Parkinson Disease–Cognitive Rating Scale (PD-CRS), Parkinson
Neuropsychometric Dementia Assessment (PANDA), Scales for Outcomes of
Parkinson Disease–Cognition (SCOPA-COG), Mattis Dementia Rating Scale–2
(DRS-2), and Montreal Cognitive Assessment (MoCA). In addition, two PD- and
cognition-specific daily function questionnaires (Penn Parkinson’s Daily Activities
Questionnaire–15 [PDAQ-15] and Parkinson Disease–Cognitive Functional Rating
Scale [PD-CFRS]) have been developed and validated, and performance-based
functional cognition measures have recently been validated in PD (UCSD
Performance-based Skills Assessment [UPSA]) or been shown to be sensitive to
change in a PD-MCI clinical trial (Everyday Cognition Battery [ECB]).
Regarding PD medications, the initial choice of PD medication class (eg,
levodopa versus dopamine agonist versus a monoamine oxidase B [MAO-B]
inhibitor) does not seem to matter in terms of long-term dementia rates. In
contrast, the association between anticholinergic medication use and long-term
cognitive decline in PD is stronger and is a concern given how common the use of
medications with anticholinergic properties is in this population.
Only one large, positive cholinesterase inhibitor randomized controlled trial
(RCT) in PDD has been published, but this was close to 2 decades ago.9 In this
study, statistically significant, but clinically modest, effects were observed for
rivastigmine on a range of outcome measures, and cholinesterase inhibitor
treatment was associated with increased adverse events (eg, nausea, vomiting,
tremor, and dizziness). A similar RCT of donepezil for PDD produced similar
numerical results but, owing to an outlier site, was a negative study. In two RCTs
that enrolled a mix of patients with PDD and DLB, memantine, an N-methyl
D-aspartate (NMDA) antagonist, was partially beneficial for PDD in only one
study. The treatment landscape for PD-MCI based on RCT evidence is limited,
with failed RCTs for both rasagiline (an MAO-B inhibitor) and the rivastigmine
patch, although the latter study showed a secondary, positive effect on a
performance-based measure of cognitive functioning.
For nonpharmacologic approaches, multiple preliminary studies10,11 suggest
that cognitive and physical training or activity may lead to short-term
improvement in some cognitive abilities. Research shows an association between
cognitive impairment in PD and both vascular risk factors and pathology,12 and
there are similar associations for both orthostatic hypotension13 and obstructive
sleep apnea14; therefore, treating these other common comorbid medical or
nonmotor disorders is also important.
Preliminary studies of novel treatments such as blarcamesine (a sigma-1
receptor agonist) and neflamapimod (a p38α kinase inhibitor) have been shown
to improve cognition in patients with PDD and DLB. Other medications to
improve cognition, such as the cortical enhancer IRL752, are being investigated
for tolerability and safety. Early initiation of the cholinesterase inhibitor
donepezil has been shown to slow cognitive decline over 2 years in patients with
PD without dementia who are APOE ε4 carriers.15
Depression
While depression is common in the general population, it is significantly more
common in patients with PD. Depression occurs in approximately 20% of patients
1318 OCTOBER 2022

with PD at any given time, with a cumulative prevalence significantly higher KEY POINTS
(30% to 50%), and a 60% prevalence in patients with late-stage disease. Depression
● Management of comorbid
can occur even in prodromal disease,16 and depression and antidepressant treatment medical conditions
are common at disease onset and increase in early disease.17 associated with cognitive
Because of the common overlapping motor and nonmotor symptoms, impairment in Parkinson
such as slowness, fatigue, weight loss, and insomnia, diagnosing depression disease may lead to
improvement in cognitive
in patients with PD can be extremely challenging.18 Despite this, instruments
abilities.
such as the Beck Depression Inventory, Hamilton Depression Rating Scale,
Montgomery-Asberg Depression Rating Scale, Geriatric Depression Scale, and ● Accurately diagnosing
the Hospital Anxiety and Depression Scale have all been validated for use in depression in Parkinson
patients with PD, often with cutoff scores different than those recommended for disease can be complicated
because of symptom
the general population. overlap between depression
Historically, intervention research for neuropsychiatric symptoms in PD has symptoms, apathy, and core
focused on pharmacologic treatment, and only recently have nonpharmacologic Parkinson disease
treatments received greater attention.19 Although few large-scale antidepressant symptoms.
RCTs for depression have been conducted, updated guidance can be gleaned ● A range of
from meta-analyses.20 Findings support the efficacy and tolerability of several antidepressants and
classes of antidepressants, including selective serotonin reuptake inhibitors Parkinson disease
(SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), and tricyclic medications have been
shown to be efficacious for
antidepressants, with comparable effect sizes across different drug classes. No
the treatment of depression
class of antidepressants has been shown to significantly worsen motor function. in Parkinson disease.
Current evidence does not support the use of reversible, selective MAO-B
inhibitors as monotherapy for PD depression. Dopamine agonists may also ● There is increasing
confer mood benefit, even accounting for their effect on motor symptoms. Novel evidence for the efficacy of
psychotherapy for
medications, such as nabilone (a strong agonist for the cannabinoid receptors depression and anxiety in
CB1 and CB2), are still under investigation. Parkinson disease.
Psychological interventions for depression, such as cognitive-behavioral
therapy (CBT), are beneficial in treating PD. Recently, RCTs of a telemedicine ● Symptoms occurring as
part of nonmotor
intervention found that a 3-month course of PD-tailored CBT (administered fluctuations are a common
either by phone or web-based video conferencing) was associated with presentation of significant
significant improvements in depression when compared with usual care,21-23 anxiety, even panic attacks,
with results comparable to those observed in face-to-face trials. Various forms of in Parkinson disease.
aerobic training (eg, stretching-strengthening exercise, walking, and stepping
● There have been no
movement) have also been found to positively impact depression.24 Research on efficacy pharmacologic
repetitive transcranial magnetic stimulation for depression in PD has produced randomized clinical trials for
mixed results.19 For severe or refractory depression, it has been well established anxiety disorders in
that electroconvulsive therapy is effective, safe, and well tolerated in PD, with Parkinson disease, but in
clinical practice,
the added benefit of temporary improvement in parkinsonism. Evidence also antidepressants and
suggests that bright light therapy is effective for treating depression and sleep sometimes benzodiazepines
disturbances in PD.25 are used.
● It is now recognized that

Anxiety hallucinations in a range of
Clinically significant symptoms of anxiety are present in 30% to 35% of patients sensory domains, not just
with PD at any given time, with about one-third of those patients meeting visual hallucinations, can
criteria for more than one anxiety disorder. Anxiety most commonly presents occur in Parkinson disease.
as generalized anxiety disorder, but can also present as panic attacks, social
phobia, and agoraphobia, and is frequently comorbid with depression, with
65% to 90% of patients with one type of affective disorder meeting criteria for
the other. Similar to depression, anxiety can present many years before the
diagnosis of PD.

Depression and anxiety are commonly reported features of “off” periods

(ie, nonmotor fluctuations), occurring in approximately 35% of patients
with this complication.26 Nonmotor fluctuations are psychiatric, cognitive,
autonomic, or other nonmotor symptoms that vary during the course of the day,
typically related to chronic PD medication–induced “on” and “off” periods.
Distinguishing between persistent affective symptoms and those occurring
primarily in the context of “off” periods is not always straightforward, and a
given individual can have both.
To date, the only PD-specific assessment for anxiety is the Parkinson Anxiety
Scale, a 12-item self-report scale including persistent anxiety, episodic anxiety,
and avoidance behavior domains.27 The Beck Anxiety Inventory, Hamilton
Anxiety Rating Scale, and the anxiety section of the Hospital Anxiety and
Depression Scale were used to help develop the Parkinson Anxiety Scale and are
also used in assessing anxiety in patients with PD. More broad instruments used
to evaluate multiple neuropsychiatric symptoms, such as the Unified Parkinson’s
Disease Rating Scale (UPDRS) part I, Movement Disorder Society–Non-Motor
Rating Scale (MDS-NMS), and the Non-Motor Symptoms Questionnaire
(NMSQ), include basic anxiety questions but are not comprehensive.
To date, no pharmacologic RCTs for the treatment of anxiety in PD have been
published. In clinical practice, antidepressants (eg, SSRIs) are most commonly
used, although some patients require the use of benzodiazepines (eg, lorazepam
or alprazolam). The first nonpharmacologic RCT specifically targeting anxiety in
PD found CBT was superior to clinical monitoring in reducing situational anxiety
as well as helping with avoidance behavior and social anxiety.28 An 8-week study
of mindfulness-based yoga, using principles of self-transcendence, resulted in
significant decreases in both anxiety and depression, compared with the control
condition (resistance and strength training exercises).29 Another area of clinical
and research focus is the use of dance-based therapies (eg, ballet) for a range of
nonmotor symptoms in PD.
Psychosis
For psychosis, minor hallucinations (ie, passage and presence phenomena and
illusions) occur in up to 45%, visual hallucinations in 15%, nonvisual
hallucinations in 35%, and delusions in 4% of patients with PD. Hallucinations are
predominantly visual, but auditory, tactile, and olfactory hallucinations also
occur. Psychosis increases over time, with a cumulative prevalence as high as
60%, and is associated with institutionalization and increased mortality, but
minor hallucinations can also occur in patients with de novo untreated PD.30
Recently, an updated definition and criteria for psychosis in mild and major
neurocognitive disorders were published; criteria include hallucinations (either
visual or auditory) or delusions that have been present for at least 1 month, cause
disruption in daily functioning, and have followed the onset of symptoms of
cognitive impairment.31 The presence of psychosis can be identified through
global instruments, such as the UPDRS Part 1, MDS-NMS, Nonmotor Symptoms
Scale (NMSS), NMSQ, and SCOPA-PC. The Parkinson Psychosis Rating Scale
(PPRS) is one of two scales currently validated for evaluating psychosis severity
in PD. The other PD-specific psychosis instrument is the Parkinson Psychosis
Questionnaire (PPQ), which assesses the frequency and severity of sleep
disturbances, hallucinations/illusions, delusions, and orientation. Another
instrument, the Scale for Assessment of Positive Symptoms for Parkinson’s
1320 OCTOBER 2022

Disease Psychosis (SAPS-PD), showed responsivity to change with antipsychotic KEY POINTS
treatment in the pivotal study for pimavanserin.32
● Management of psychosis
Good general management principles for psychosis in PD include decreasing in Parkinson disease
dopamine replacement therapy to the extent possible, ruling out delirium, and includes a mix of trying to
minimizing anticholinergic medication use. Cholinesterase inhibitors are sometimes lessen dopamine
recommended, but a study of their use to prevent incident psychosis was negative.33 replacement therapy
exposure and judicious use
The most notable pharmacologic treatment advance for PD psychosis is the
of antipsychotic medication.
antipsychotic pimavanserin, a serotonin 2A receptor (5-HT2A) inverse agonist/
antagonist approved by the US Food and Drug Administration (FDA) for PD ● Antipsychotic use in
psychosis and recently shown to be beneficial for all dementia-related psychosis, patients with Parkinson
including DLB (see the following section on DLB).34 Quetiapine has little RCT disease may be associated
with an increased risk of
evidence to support its use but remains the most commonly used antipsychotic in mortality and morbidity, as
PD, while clozapine is efficacious but rarely used, primarily because of the has been reported for
frequent, long-term blood drawing required to monitor for development of Alzheimer disease.
agranulocytosis.19 Preliminary evidence that antipsychotic use in PD is associated
● Screening for
with increased mortality and morbidity risk,35 similar to that reported in AD, impulsive-compulsive
requires additional study. Electroconvulsive therapy has also shown to be disorders should include the
effective in improving psychosis symptoms, as well as depression and motor range of impulse control
symptoms, without adversely affecting cognitive functioning.36 disorders and related
behaviors reported to occur
in Parkinson disease, with
Impulse Control Disorders attention to any comorbid
Impulse control disorders (eg, pathologic gambling, buying, sexual behaviors, disorders.
and eating) have a cross-sectional prevalence of 14%, with cumulative 5-year
incidence rates reported up to 46% in patients with PD. An increased risk is ● Management of impulse
control disorders and
reported only in treated patients, with the highest risk associated with dopamine related behaviors involves
agonists and lesser risks for other medications. Dopamine dysregulation a mix of decreasing
syndrome (or compulsive PD medication use) and punding (ie, repetitive dopamine replacement
non–goal-directed activity) overlap with impulse control disorders but occur therapy, particularly
dopamine agonists,
primarily with very high levodopa doses. psychopharmacology, and
One instrument to measure the severity of impulse control disorder behaviors psychotherapy.
is the Questionnaire for Impulsive-Compulsive Disorders–Rating Scale
(QUIP-RS). This instrument asks patients to estimate how often they experience ● Although evidence from
randomized clinical trials is
impulsive-compulsive thoughts and behaviors related to gambling, sex, eating,
limited, dopamine agonists,
buying, hobbyism, punding, and PD medication abuse. Another recommended cholinesterase inhibitors,
instrument is the Ardouin Scale for Behavior, which assesses both hyper- and and stimulants can be used
hypodopaminergic behaviors. Impulse control disorders are also assessed in in the management of
apathy in Parkinson disease.
broader, commonly used PD questionnaires, including the MDS-NMS, NMSQ,
and SCOPA-PC, although these provide limited detail. ● Overall, deep brain
For clinically significant impulse control disorder symptoms, attempts should stimulation surgery is
be made to decrease overall dopamine replacement therapy and discontinue associated with an increase
dopamine agonists if possible, although stopping dopamine agonist treatment in apathy symptoms
postoperatively.
can be associated with dopamine agonist withdrawal syndrome, which is
characterized by psychological and physiologic symptoms similar to other
substance use disorder withdrawal syndromes. If successful, discontinuation
of the dopamine agonist and any other offending medications (eg, amantadine,
MAO-B inhibitors) can be offset by a concomitant increase in levodopa dose.
If unsuccessful, and the patient is otherwise a good candidate, consideration can
be given to deep brain stimulation (DBS) surgery, as it often allows for a
significant decrease in dopamine replacement therapy postoperatively.
Regarding psychiatric treatment, both naltrexone,37 an opioid antagonist that

is FDA-approved for the treatment of alcohol use disorder, and CBT38 have been
explored as management options for impulse control disorders, yielding positive
initial signals in need of further study.
Apathy
The reported prevalence of apathy in PD ranges widely, from 15% to 70%
(mean of 35%). It is comorbid and overlaps symptomatically with depression but
remains common even when excluding patients with dementia and depression.
Severity and frequency of apathy in patients with PD can be measured using
the Apathy Evaluation Scale, the Apathy Scale, the Apathy Inventory, and the
Lille Apathy Rating Scale. While these instruments are not PD-specific, they are
sensitive and specific enough to identify clinically significant apathy in this
population. An abbreviated version of the Apathy Evaluation Scale, the AES-
12PD, has been developed to better target patients with PD and their symptoms.
The presence of apathy is briefly identified in other global PD questionnaires,
such as the UPDRS Part I and the MDS-NMS.
Treatment options for apathy are currently very limited. There is mixed evidence
for dopamine agonist treatment, and there is preliminary support
for use of cholinesterase inhibitors.39 Clinically, stimulants (eg, methylphenidate
and amphetamines) are used, although no clinical trials support this. While
DBS may prove clinically useful for treating motor symptoms, it may adversely
affect disorders of motivation, including apathy. Overall, DBS in the subthalamic
nucleus has been shown to lead to an increase in apathy40; in one study this
was especially true in those displaying impulse control disorders preoperatively and
was independent of the change in dopamine replacement therapy, while patients
demonstrating apathy preoperatively were at higher risk of developing an incident
impulse control disorder postoperatively.41 An active area of research is the use of
mobile devices as a behavioral approach to enhance motivation.
DEMENTIA WITH LEWY BODIES

The current clinical nomenclature of the term “dementia with Lewy bodies” has
its origins from the initial descriptions of postmortem microscopic findings of
eosinophilic intracellular proteinaceous neuronal inclusions in PD by Fritz
Heinrich Lewy in the early 20th century. These postmortem findings of
characteristic neuronal inclusions composed of misfolded α-synuclein proteins
(ie, Lewy bodies and Lewy neurites) are now considered the hallmark and gold
standard for diagnosis of PD.
Advances in postmortem detection of α-synuclein pathology led to increasing
recognition of widespread cortical Lewy bodies and Lewy neurites as a common
neuropathologic substrate for aging-related dementia. In 1995, the first DLB
consortium meeting was held in Newcastle, UK, to define the clinical diagnostic
criteria and terminology for DLB and to standardize pathologic measures for
improved diagnosis. Since that time, the consortium has met four times to refine
the criteria and pathologic methods. The Fourth International DLB Consortium
was held in December 2015, and the modern clinical criteria were updated42 to
include indicative biomarkers for underlying α-synucleinopathy (FIGURE 4-1).42,43
DLB is characterized by the presence of two or more core clinical features of
an early progressive dementia, along with motor Parkinsonism, well-formed
recurrent visual hallucinations, periodic fluctuations in cognition, and rapid eye
movement (REM) sleep behavior disorder (RBD), the latter of which may
1322 OCTOBER 2022

KEY POINTS
● Neuropsychiatric
symptoms are core features
of dementia with Lewy
bodies. These include
well-formed spontaneous
and recurrent visual
hallucinations and cognitive
fluctuations. Depression,
anxiety, and apathy are also
common features.
● The presence of one or

more pathogenic mutations
in the glucocerebrosidase A
gene, known to cause
autosomal recessive
Gaucher disease, is an
important genetic risk factor
for Parkinson disease and
dementia with Lewy bodies.
● Rapid eye movement

disorder is highly predictive
of underlying α-synuclein
FIGURE 4-1 pathology and eventual
Clinical criteria for Parkinson disease dementia and dementia with Lewy bodies. Green text clinical conversion to
indicates clinical features included in diagnostic criteria of both dementia with Lewy bodies Parkinson disease or
and Parkinson disease dementia. Gold text indicates known shared clinical features not dementia with Lewy bodies.
explicitly mentioned in both criteria. Red text indicates differing clinical features of timing of
dementia onset in the course of disease. ● Patients fulfilling criteria
a
Data from McKeith IG, et al, Mov Disord42 and Emre M, et al, Lancet Neurol.43 for probable dementia with
Lewy bodies are highly likely
to have underlying
α-synuclein pathology, but
precede cognitive impairment by several years. Supportive features include many patients with clinical
neuroleptic (ie, antipsychotic) sensitivity, autonomic dysfunction (orthostatic Alzheimer disease are found
to also have varying amounts
hypotension, constipation, erectile dysfunction), hyposmia, postural instability,
of α-synuclein pathology in
depression, anxiety, and apathy. These clinical features are often shared with PDD the brain.
(FIGURE 4-1), with the distinction that the cognitive impairment in DLB is defined
by the somewhat arbitrary “1-year rule,” where dementia onset occurs within 1 year ● Up to 50% of all Lewy
of the onset of motor parkinsonism, as compared with PDD, where dementia occurs body disorders (ie,
Parkinson disease,
in the setting of 1 year or more of established PD diagnosis. This clinical distinction Parkinson disease mild
of PDD and DLB is currently a matter of debate, in part owing to the shared cognitive impairment,
pathophysiology of these syndromes. Indeed, no pathologic substrate has been Parkinson disease dementia,
found at autopsy that can reliably differentiate these clinically defined disorders.44 and dementia with Lewy
bodies) have sufficient
Moreover, both PDD and DLB share genetic risk, including plaques and tangles in the
glucocerebrosidase A mutation carrier status45,46 (CASE 4-2) and preclinical/ brain postmortem for a
prodromal features such as RBD.47 Because of these shared biological second neuropathologic
underpinnings, it is currently unclear if therapeutic trials for symptomatic or diagnosis of Alzheimer
disease. These patients with
disease-modifying therapies would benefit to include mixed populations of mixed pathology have a
patients with PDD and DLB.48 Indeed, many previous therapeutic trials cited worse prognosis and unique
above included both patients with PDD and DLB.43,49 clinical features.
There is also evidence of unique biology in DLB compared with PD/PDD,
including postmortem findings of relative sparing of the striatal nigral system in

some patients with DLB.50 Moreover, the DLB clinical syndrome is useful for
patient care to direct appropriate supportive care and symptomatic therapies
since the clinical needs in patients with DLB may often differ from that of some
patients with PD who experience a long time interval of motor symptoms
without prominent cognitive impairment.
The DLB clinical diagnostic criteria are highly specific to identify patients with
underlying synucleinopathy but with variable sensitivity,51 as roughly 50% of
patients with clinically diagnosed AD will have additional α-synuclein Lewy
body/Lewy neurite pathology postmortem, often with clinical features suggestive
of DLB but not fulfilling full criteria.52 The most recent DLB criteria await further
validation, and incorporation of biomarkers indicative of underlying α-synuclein
pathology (eg, polysomnogram for RBD, dopamine transporter imaging,
cardiac scintigraphy), and increased recognition of RBD as a strong clinical
indicator of underlying synucleinopathy may further improve diagnostic
CASE 4-2 A 63-year-old man presented for cognitive evaluation after developing
difficulty with multitasking over the course of the past 2 years. These
symptoms caused him significant anxiety and frustration and interfered
with his ability to maintain appointments and pay bills. His wife had
noticed these changes; she had found errors in his record keeping for
their finances and took over this responsibility. She also began
supervising his medication administration. The patient had also been less
motivated for social activities. Near the onset of these difficulties, he
reported seeing shadows moving at night in the room when there was
nothing there. He then reported seeing children playing in their living
room on occasion. He noted that this was not particularly disturbing to
him and that he did not believe they were truly present. The patient’s
wife reported that his cognitive symptoms waxed and waned throughout
the day, with periods of disorganized speech. His walking became slow,
and he was off balance.
On review of systems, it was noted that he had experienced active
sleep for the past 10 years that included sudden jerking movement of his
limbs, loud vocalizations, and punching behavior, which previously
injured his wife. He underwent a polysomnogram several years before the
onset of cognitive symptoms, which confirmed rapid eye movement
(REM) sleep behavior disorder (RBD). His family history was notable for
Gaucher disease, and genetic testing in the patient previously revealed
he was an asymptomatic carrier of one allele of a pathogenic mutation in
the glucocerebrosidase A gene.
On examination, he had slow hypophonic speech with word-finding
pauses and circumlocutions. He largely maintained attention throughout
the examination with good effort, but he had periodic fluctuations in
concentration during tasks that often required repetition of instructions
to maintain set. He had reduced verbal fluency (six “F” words in
60 seconds without a clear phonetic or semantic strategy), reduced digit
span, and poor performance on oral trail task. He had delayed recall of
five of six words, with recognition of the remaining word with a semantic
1324 OCTOBER 2022

accuracy. Importantly, emerging biomarkers for AD neuropathology, including
FDA-approved positron emission tomography (PET) tracers to detect AD
pathology,53 do not rule out a diagnosis of DLB in patients meeting clinical criteria,
as clinically significant levels of additional AD neuropathology are a common
postmortem finding in up to 70% of patients with DLB.44 Moreover, mixed AD
neuropathology is associated with more rapid clinical decline54 and specific
cognitive features (see Cognition and Cognitive Fluctuations section and CASE 4-1)
in DLB. Therefore, emerging biomarkers for AD neuropathology may have
prognostic value in DLB and could help stratify clinical trial design to identify
subgroups of patients with more homogenous clinical features and
underlying biology.48
Difficulties in diagnostic accuracy and the clinical and pathologic overlap with
AD and PD make traditional epidemiology studies of DLB challenging. Thus,
most estimates are likely lower than the true occurrence of DLB. The incidence of
cue. He had difficulty with visual construction of a complex figure and

perception of line orientation. Elemental neurologic examination
revealed bradykinesia with decrement on fine movements and rare
myoclonic jerks. Findings included increased tone in the arms and legs
with some cogwheeling. He had no resting tremor but had a fine
sustention tremor. He had a parkinsonian gait with anteroflexed posture
and short steps. Pull-back test found evidence of postural instability with
four to five steps.
The diagnosis of dementia with Lewy bodies (DLB) was considered as
the patient had all the core features (dementia, parkinsonism, visual
hallucinations, and cognitive fluctuations) in addition to long-standing
RBD, which was sufficient for a diagnosis of probable DLB (FIGURE 4-1). A
brain MRI, lumbar puncture, and blood tests for common etiologies that
could contribute to cognitive impairment or mimic DLB in a patient of this
age range were performed and were unrevealing.
The cognitive and motor difficulties declined over the course of
4 years, with increasing confusion, cognitive impairment, apathy, and
motor disability. There was some stabilization of cognitive testing for
approximately 1 year with use of a cholinesterase inhibitor and mild
response of motor symptoms to levodopa. He also developed orthostatic
hypotension and syncopal episodes. In the fourth year of disease, he had
reduced oral intake and complete disorientation and entered hospice
care for failure to thrive.
On autopsy, there was a high burden of α-synuclein–positive Lewy bodies COMMENT

and Lewy neurites throughout the brainstem, limbic regions, and
neocortex, consistent with a primary neuropathologic diagnosis of diffuse
stage Lewy body disease without any secondary pathologies. The patient
had genetic risk as a carrier of the glucocerebrosidase A mutation, and
prodromal features of RBD prior to onset of cognitive impairment and
development of other core features of DLB.

clinical DLB is estimated to be 3.5 per 100,000 person-years, which increases

rapidly with age to >30 per 100,000 person-years in those older than 6555; thus,
age is a strong risk factor for DLB. DLB and underlying synucleinopathy has been
associated with increased frequency in male patients for reasons currently
unclear but could be related to increased longevity in women or potential
protective effects of estrogen on development of synucleinopathy. Indeed, the
study of environmental risk factors of DLB is scant, but one report found
oophorectomy prior to the age of 45 is associated with increased risk of DLB.56
Because of the clinical heterogeneity of DLB, >30% of patients have a delay in
≥2 years from the initial patient visit to obtain a diagnosis, and a similar number
are seen by four or more different physicians before obtaining a formal diagnosis,
posing a significant diagnostic challenge.57 Thus, increased awareness and
education of physicians are needed to improve diagnosis and treatment for DLB.
Recently, diagnostic toolkits have been developed as part of the UK National
Institute for Health Research DIAMOND Lewy Programme (improving the
DIagnosis And Management Of Neurodegenerative Dementia of Lewy body type)
to provide clinicians with assessment tools to improve the diagnosis of DLB.58
Cognition and Cognitive Fluctuations

Progressive cognitive impairment and dementia is a core clinical feature and
often presenting symptom of DLB. The cognitive profile of DLB, similar to PD, is
often prominent attention and executive impairment along with visuospatial and
perceptual difficulties. These cognitive domains are captured in most general
cognitive screening assessments, such as the MoCA, and can be further
characterized by additional tests such as letter-number sequencing, digit span
(ie, reciting a list of random digits in forward and reverse order), verbal fluency
tasks (ie, asking for the number of words beginning with “F” in 60 seconds),
constructional tasks (eg, Rey-Osterrieth complex figure copy), and judgment of
line orientation.
Fluctuations in attention and cognition are a core clinical feature of DLB and
cause significant disability. The features of cognitive fluctuation range from
periodic episodes of disorientation or disorganized speech to more prolonged
episodes (ie, a day or more) of confusion, or even minimal responsiveness, which
may be confused with stroke or seizure. Excessive daytime sleepiness and
extreme fatigue despite adequate sleep have been recognized as additional
features of cognitive fluctuation. Fluctuations may be observed during
examination and often are diagnosed with careful history from a reliable
caregiver informant. Structured questionnaires such as the Mayo Fluctuations
Scale59 and the Dementia Cognitive Fluctuation Scale60 can be useful to detect
the presence of cognitive fluctuations and improve diagnosis of DLB. Cognitive
fluctuations pose a significant challenge to therapeutic trials in DLB, as they are
difficult to measure objectively and could influence study outcomes.48
There is considerable heterogeneity of cognitive impairment in DLB, and it is
not uncommon for patients to have additional episodic memory and language
difficulties, in particular confrontation naming. Episodic memory can be probed
using a variety of list-learning tasks where a sequence of words of variable length
are presented for immediate recall, and after delay of varying time intervals,
delayed recall is assessed. These tasks can be modified further by addition of a foil
list of semantically related words in the interim prior to delayed recall, and
recognition can be tested by use of semantic or phonologic cues for missed
1326 OCTOBER 2022

words. Alternative approaches using a recall of items of a brief verbal story or KEY POINTS
recall of a complex figure copy after a delay can also be used. Language
● Treatment choices in
assessments include observations of spontaneous speech for fluency and motor dementia with Lewy bodies
features of dysarthria as well as assessment of repetition, comprehension, and need to be individualized to
naming. Confrontation naming can be assessed using physical objects or line patient and medical
drawings of objects of varying frequency as visual stimuli, such as in the Boston comorbidities. The
heterogeneous cognitive,
Naming Test. Episodic memory loss and deficits in confrontation naming are
motor, and autonomic
linked to temporal lobe functioning, and in PDD/DLB is associated with symptoms of dementia with
underlying mixed AD tau pathology.61,62 Thus, the presence of significant levels Lewy bodies often require
of AD neuropathology in Lewy body disorders may influence the clinical careful selection and
titration of medications
expression of dementia.
since many symptomatic
choices have potentially
Management of Dementia With Lewy Bodies competing mechanisms of
There are currently no FDA-approved medications specifically for DLB, and action. Careful titration to
management is largely supportive. Implementation of increased supervision and the lowest effective dose is
often a beneficial strategy.
structured activities throughout the day are critical to help keep patients engaged
with cognitively stimulating activities and reduce agitation and risk of safety ● Data for pharmacologic
issues. Data to support symptomatic treatment in DLB are largely limited to and nonpharmacologic
meta-analyses and relatively small often open-label clinical trials with various management of dementia
with Lewy bodies are largely
compositions of patients with PDD/DLB. Recently, a Delphi study of expert restricted to small
clinicians produced an evidence-based management toolkit to guide clinical open-labeled trials and
treatment of DLB,63 including cognitive impairment. Importantly, treatment meta-analyses. There are
choices should be individualized to address the most disabling or problematic considerable data and
general consensus among
symptoms reported by patients and caregivers and also address medical
experts for the use of
comorbidities. cholinesterase inhibitors as
As aforementioned, cholinesterase inhibitors have shown benefit in DLB as first-line treatment for
well as PDD for cognitive symptoms and may improve cognitive fluctuations and cognitive impairment and
fluctuations in dementia
visual hallucinations. While response may be modest in some patients,
with Lewy bodies.
withdrawal of cholinesterase inhibitors may cause an exacerbation of symptoms.
As such, treatment is usually maintained through mild to moderate stages of ● Visual hallucinations in
disease, and slow taper can be considered in more advanced stages of disease.64 patients with dementia with
There are also some data to suggest efficacy of memantine, a glutaminergic agent Lewy bodies are often
well-formed objects such as
used in moderate to severe AD, for global functioning in patients with DLB43; the people, animals, or objects.
common co-occurrence of AD pathology in DLB also suggests there could be Patients initially have good
potential benefit of these AD symptomatic therapies that restore deficient insight but progressively
neurotransmitters in DLB, but further study is needed. these can cause anxiety or
agitation.
Visual Hallucinations and Psychosis ● There are associations of

Spontaneous and well-formed recurrent visual hallucinations are another core sex and risk for Lewy body
clinical feature of DLB. As aforementioned in PD, hallucinations may also take disorders, with greater
frequency of men with
form of other modalities as well. It is important to exclude medical or iatrogenic
α-synuclein pathology.
causes of hallucinations, and a careful history is often helpful to elicit the features
of well-formed objects such as people, animals, or other objects more typical of
DLB. Moreover, as aforementioned, dopamine replacement therapy can
exacerbate hallucinations, lowering dosage may improve symptoms if tolerated
from a motor standpoint. These characteristic symptoms may be accompanied
by or preceded by simple visual illusions or misidentification of visual stimuli,
such as seeing people or objects in shadows. A noise pareidolia test to detect and
quantify this phenomenon may have diagnostic utility in DLB.65 The
Neuropsychiatric Inventory (NPI) is a commonly used assessment scale of

KEY POINTS caregiver report of frequency and severity of neuropsychiatric symptoms used
for various neurodegenerative dementias, including DLB. Usually, insight is
● The clinical diagnosis of
dementia with Lewy bodies
preserved in early stages of the disease, but hallucinations can become
often takes several years to increasingly frightening or disturbing to patients.
establish in part because of Refractory visual hallucinations or agitation that create a safety hazard not
the lack of accurate manageable by nonpharmacologic means can potentially be cautiously treated
diagnostic tests specific to
with second-generation antipsychotics with minimal dopamine D2 receptor
cortical α-synuclein and the
need to detect progressive activity (eg, quetiapine or clozapine) to find the lowest effective dose, but this
cognitive impairment for has not been systematically studied in DLB. The current boxed warning for
diagnosis. Efforts to increased risk of mortality66 associated with antipsychotics in older-adult
increase accessibility of
patients with dementia is of further consideration for avoiding this class of
assessment tools for the
unique clinical medication in DLB. Typical neuroleptics such as haloperidol or injectable
neuropsychiatric symptoms neuroleptics are absolutely contraindicated because of risk of severe
can help improve diagnosis hypersensitivity reaction (ie, worsening of motor parkinsonism, cognitive
and treatment of dementia impairment, and/or neuroleptic malignant syndrome). As mentioned previously,
with Lewy bodies.
the antipsychotic pimavanserin has been proven effective for hallucinations and
● Core clinical features of delusions in PD32 and more recently in a study including various forms of
dementia in dementia with dementia, including DLB,34 but this medication is currently FDA approved only
Lewy bodies are attention, for PD psychosis.
executive, and visuospatial
dysfunction, but episodic
memory and language
difficulties are not CONCLUSION
uncommon and have been Understanding of neuropsychiatric symptoms in PD has improved significantly
linked to Alzheimer disease
over the past 2 decades. Neuropsychiatric symptoms have a cumulative
co-pathology.
prevalence far higher than cross-sectional studies have reported, with many
● Cognitive fluctuations are disorders, including dementia, having a cumulative frequency of more than 50%
core neuropsychiatric of all patients with PD. Evidence shows that neuropsychiatric symptoms are
symptoms of dementia with associated with excess disability, worse quality of life and outcomes, and greater
Lewy bodies and can range
from periodic confusion and caregiver burden. Significant advances have been made in their assessment
disorganized speech to (eg, questionnaires and rating scales) and diagnosis (ie, diagnostic criteria),
more prolonged episodes of which has improved clinical management and research. Additionally, evidence
confusion and depressed finds that their neurobiology is a complicated mix of PD and other
consciousness as well as
excessive daytime fatigue.
neurodegenerative disease pathology, neurotransmitter deficits, neural circuitry
Detection and treatment of derangement, and genetic influences. PD treatments have a complex and varied
cognitive fluctuations can effect on neuropsychiatric symptoms, and current treatment options, while
be aided by standardized growing, remain quite limited. Reducing the impact of PD on patients and their
caregiver questionnaires.
families will require improved recognition and development of better therapies
● There is an urgent need for the numerous clinically significant neuropsychiatric symptoms that occur.
for therapeutic trials to Similarly, in DLB, increased recognition of the clinical syndrome by health
guide treatment decisions in care professionals and increased awareness in the lay public are needed to
dementia with Lewy bodies.
improve diagnosis and treatment. DLB has shared clinical and biological features
● It is important to first rule with PD, but there is also considerable heterogeneity in these clinical features,
out delirium or other and the variable expression of mixed AD neuropathology appears to be one
medical etiologies for visual important biological influence on clinical presentation and prognosis in PD/PDD
hallucinations and remove and DLB. This is important, as FDA-approved diagnostics and treatments for AD
or lower potentially
exacerbating medications,
currently exist, but the data to guide their potential use in PD, other than
such as dopaminergic rivastigmine and pimavanserin, and DLB are limited. Cognitive and
therapies. neuropsychiatric symptoms of DLB require a personalized approach in treatment
to select appropriate symptomatic medical regimens that do not exacerbate
motor or autonomic symptoms. Randomized placebo-controlled therapeutic
1328 OCTOBER 2022

trials are needed in DLB to guide treatment decisions and develop future KEY POINT
symptomatic and potential disease-modifying agents. Further research is needed
● The data on effective
to define the optimal study populations for inclusion into therapeutic trials (ie, pharmacotherapy for visual
PDD and DLB and/or stratification by AD biomarker profile) and develop novel hallucinations in dementia
clinical assessment tools sensitive to the unique neuropsychiatric symptom with Lewy bodies are
features of DLB, such as cognitive fluctuations, which could influence clinical limited. When problematic,
careful use of low-dose
trial outcomes.
second-generation
neuroleptics may be helpful,
but it is important to
ACKNOWLEDGMENT consider patient age and
medical comorbidities
This work was supported by a grant from the National Institutes of Health
because of boxed warnings
(U19-AG062418; Dr Irwin). for the use of these in older
adults.
USEFUL WEBSITE
DIAMOND LEWY
This website provides clinicians with assessment
tools to improve the diagnosis of dementia with
Lewy bodies.
research.ncl.ac.uk/diamondlewy/about/
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trial. Lancet Neurol 2010;9(10):969-977. bodies. J Neurol Neurosurg Psychiatry 2017;88(2):
doi:10.1016/S1474-4422(10)70194-0 113-118. doi:10.1136/jnnp-2016-313775
44 Irwin DJ, Grossman M, Weintraub D, et al. 55 Savica R, Grossardt B, Bower J, Boeve BF, Ahlskog
Neuropathological and genetic correlates JE, Rocca WA. Incidence of dementia with Lewy
of survival and dementia onset in bodies and Parkinson disease dementia. JAMA
synucleinopathies: a retrospective analysis. Neurol 2013;70(11):1396-1402. doi:10.1001/
Lancet Neurol 2017;16(1):55-65. doi:10.1016/S1474- jamaneurol.2013.3579
4422(16)30291-5
56 Boot B, Orr C, Ahlskog JE, et al. Risk factors for
45 Sidransky E, Nalls MA, Aasly JO, et al. Multicenter dementia with Lewy bodies: a case-control
analysis of glucocerebrosidase mutations in study. Neurology 2013;81(9):833-840. doi:10.1212/
Parkinson’s disease. N Engl J Med 2009;361(17): WNL.0b013e3182a2cbd1
1651-1661. doi:10.1056/NEJMoa0901281
57 Galvin JE, Duda JE, Kaufer DI, Lippa CF, Taylor A,
46 Chia R, Sabir MS, Bandres-Ciga S, et al. Genome Zarit SH. Lewy body dementia: the caregiver
sequencing analysis identifies new loci experience of clinical care. Parkinsonism Relat
associated with Lewy body dementia and Disord 2010;16(6):388-392. doi:10.1016/j.
provides insights into its genetic architecture. parkreldis.2010.03.007
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58 Thomas AJ, Taylor JP, McKeith I, et al. Revision of
s41588-021-00785-3
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47 Postuma RB, Iranzo A, Hu M, et al. Risk and of Lewy body dementia: the DIAMOND Lewy
predictors of dementia and parkinsonism in study. Int J Geriatr Psychiatry 2018;33(10):
idiopathic REM sleep behaviour disorder: a 1293-1304. doi:10.1002/gps.4948
multicentre study. Brain 2019;142(3):744-759.
59 Ferman TJ, Smith GE, Boeve BF, et al. DLB
doi:10.1093/brain/awz030
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48 Goldman JG, Forsberg LK, Boeve BF. Challenges differentiate DLB from AD and normal aging.
and opportunities for improving the landscape Neurology 2004;62(2):181-187. doi:10.1212/
for Lewy body dementia clinical trials. wnl.62.2.181
Alzheimers Res Ther 2020;12(1):137. doi:10.1186/
60 Lee DR, McKeith I, Mosimann U, et al. The
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dementia cognitive fluctuation scale, a new
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cognitive fluctuations in people with dementia.
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doi:10.1016/j.jagp.2013.01.072

61 Ryman SG, Yutsis M, Tian L, et al. Cognition at 64 Pakrasi S, Thomas A, Mosimann UP, et al.
each stage of Lewy body disease with Cholinesterase inhibitors in advanced dementia
co-occurring Alzheimer’s disease pathology. with Lewy bodies: increase or stop? Int J Geriatr
J Alzheimers Dis 2021;80(3):1243-1256. Psychiatry 2006;21(8):719-721. doi:10.1002/
doi:10.3233/JAD-201187 gps.1547
62 Coughlin DG, Hurtig HI, Irwin DJ. Pathological 65 Mamiya Y, Nishio Y, Watanabe H, et al. The
influences on clinical heterogeneity in Lewy body pareidolia test: a simple neuropsychological test
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63 Taylor JP, McKeith IG, Burn DJ, et al. New
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DISCLOSURE
Continued from page 1314 health care. The institution of Dr Weintraub has
received research support from The Michael J. Fox
personal compensation in the range of $500 to Foundation, the International Parkinson and
$4,999 for serving as a consultant for Eisai Co, Ltd; Movement Disorder Society, and the National
Jansen Global Services, LLC; Sage Therapeutics, Institutes of Health. Dr Irwin has received personal
Inc; Scion Pharmaceuticals, Signant Health, and compensation in the range of $500 to $4,999 for
Sunovian Pharmaceuticals Inc, and for serving as an serving on a scientific advisory or data safety
editor, associate editor, or editorial advisory board monitoring board for Denali Therapeutics. The
member for the Movement Disorder Society. institution of Dr Irwin has received research
Dr Weintraub has received intellectual property support from the National Institutes of Health
interests from a discovery or technology relating to (U19-AG062418).
1332 OCTOBER 2022

Diagnosis and Treatment REVIEW ARTICLE

of Essential Tremor C O N T I N U UM A U D I O
ONLINE
By Aparna Wagle Shukla, MD

VIDEO CONTENT
A V AI L A B L E O N L I N E
ABSTRACT
PURPOSE OF REVIEW: Essential tremor is a chronic, progressive syndrome that
primarily presents with an action tremor involving the arms and hands. This
article reviews the history and physical examination features pertinent for
diagnosis, differential diagnoses, and treatments and approaches for
optimal control of symptoms.
RECENT FINDINGS: Essential tremor is a syndrome with symptoms extending

beyond tremor to involve disturbances in gait, speech, cognition, and
mood. Although the new guidelines on the definition and biaxial CITE AS:
classification scheme have provided clarity, some tremor experts have 2022;28(5, MOVEMENT DISORDERS):
critiqued the recently coined term essential tremor plus. For treatment, 1333–1349.
new orthotic devices and peripheral stimulation devices are now available
in addition to pharmacologic and surgical options. Address correspondence to
Dr Aparna Wagle Shukla, Norman
Fixel Institute for Neurological
Disorders, 3009 Williston Rd,
SUMMARY: Essential tremor has a rich clinical phenomenology with many Gainesville, FL 32608, aparna.
subtleties and nuances. A detailed history with open-ended questions and shukla@neurology.ufl.edu.
focused questions encompassing medical history, social history, and
family history is key for establishing the diagnosis. The presence of Dr Wagle Shukla has received
bilateral action tremor for 3 years and absence of isolated head and personal compensation in the
range of $500 to $4999 for
voice tremor and absence of task- and position-dependent tremor are serving as a consultant for Jazz
necessary for diagnosis. Dystonic tremor, Parkinson disease tremor, Pharmaceuticals, Inc, as a
physiologic tremor, and drug-induced tremor are common differential reviewer with the National
Institutes of Health, and as the
diagnoses. Differentiating these tremor disorders from essential tremor Vice President of the board of
based on phenomenology and physical examination alone could be directors for the Tremor
challenging; thus, clinicians should seek additional clues from a Research Group and in the
detailed history. Treatment could begin with noninvasive and serving on a scientific
nonpharmacologic therapies, especially in mild cases. As the severity advisory board for Acadia
Pharmaceuticals Inc. The
increases, they can advance stepwise to include pharmacotherapies institution of Dr Wagle Shukla
and surgical interventions. With the growing recognition that essential has received research support
tremor is not a monosymptomatic disorder, management should involve from the National Institutes
of Health.
a multidisciplinary team. Furthermore, treatment selection should be
based on shared decision making between patients and providers that UNLABELED USE OF
gives due consideration to severity of symptoms, level of functional PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
disability, impact on social interactions, patient preferences, and Dr Wagle Shukla reports no
patient expectations. disclosure.
© 2022 American Academy

of Neurology.

DIAGNOSIS AND TREATMENT OF ESSENTIAL TREMOR
INTRODUCTION
T
remor is an involuntary, rhythmic, oscillatory movement of a body
part.1 Essential tremor is a chronic, progressive syndrome that
primarily presents with an action tremor involving the arms and
hands. Essential tremor is among the most prevalent movement
disorders with a pooled prevalence estimate of about 1% across all
ages in population studies.2 The prevalence increases to 5% in people who
are older than 60 years and to 20% in people who are older than 95 years.3 Diagnosis
of essential tremor is clinical; however, the process is not straightforward because
the syndrome is highly nuanced. Many debates and discussions surround the
terminology, nosology, and phenomenology. The term essential implies a disorder
lacking a known proximate cause (ie, idiopathic) or, similar to essential
hypertension and essential thrombocythemia, a disorder that is unitary and
intrinsic to an individual.4 However, the pitfall of the continued use of the
term became increasingly apparent as the etiology and pathophysiologic
understanding of the disorder advanced. Despite serious concerns, a task force
CASE 5-1 A 72-year-old man presented for a neurologic consultation with a

bilateral hand tremor first noticed in high school. However, the tremor
was intially mild, intermittent, and did not affect day-to-day functioning.
He had several family members with similar tremors, including his
mother, grandmother, maternal uncle, and a cousin. He worked as an
accountant, and the tremor did not become bothersome until he reached
his fifties when it began to interfere with writing, typing, and using the
computer mouse and keyboard. At home, he had trouble using garage and
gardening tools and pouring himself coffee. He avoided going to
restaurants with friends because he had difficulty eating spaghetti with a
fork and soup with a spoon. He observed that a glass of wine helped his
tremor. He had been treated with propranolol 160 mg/d, which helped
him some. He later started receiving primidone as an additional
medication for further control of tremors. He tolerated both drugs
without dizziness, nausea, and gait imbalance. However, as the
symptoms continued despite adequate doses of medications, he decided
to seek early retirement.
The arm tremor was moderately severe on examination, involving the
metacarpophalangeal and wrist joints when he was asked to stretch his
arms forward. The tremor was also noted when asked to write, draw
spirals, and perform the finger-nose-finger maneuver. The tremor was
absent when his arm was resting. He decided to consider deep brain
stimulation surgery for control of his symptoms.
COMMENT This case illustrates the age of onset and familial nature of essential tremor,
gradual worsening of symptoms over decades, kinetic tremor interfering
with day-to-day fine motor activities, long-term social and professional
consequences, and consideration of surgical treatments when
pharmacologic agents do not alleviate symptoms.
1334 OCTOBER 2022

commissioned by the International Parkinson and Movement Disorder Society KEY POINTS
decided to retain the term because clinicians and researchers widely used it
● The involuntary
and patients and their families requested its continued use. The task force movements of essential
proposed a new biaxial scheme for classifying the tremor syndrome. The first tremor are both rhythmic
axis emphasizes detailed consensual clinical phenotyping based on the age of and oscillatory.
onset, sex, body distribution, and temporal evolution of symptoms, and the
● Tremor syndrome
second axis focuses on etiologic considerations.1 Alongside the recent
classification is biaxial, first
developments in clinical definitions and classifications, many treatments have based on clinical
emerged that can effectively control the symptoms. The purpose of this article is to phenotyping and second
discuss and recognize the clinical subtleties when approaching a patient with based on underlying
essential tremor for an accurate diagnosis and selection of appropriate treatments. etiologies.
● Essential tremor is among

MEDICAL HISTORY the most prevalent
A thorough history is an invaluable tool for the establishment of the diagnosis. The movement disorders.
first part of the interview should include open-ended questions to obtain pertinent
● Isolated tremor syndrome
clinical information. The characteristic history of essential tremor is the presence of of bilateral upper limb
a hand tremor that frequently interferes with activities of daily living such as eating, action tremor present for at
drinking, pouring, handling utensils, dressing, and using keys or other household least 3 years is a
tools. Some patients report using a smartphone, computer keyboard, and mouse as requirement for the
diagnosis of essential
quite problematic. The second part of the interview should include focused tremor.
questions with the following items for further improvement of diagnostic certainty.
SEX, AGE AT ONSET, AND TEMPORAL EVOLUTION

The prevalence estimates for men and women are about the same,5,6 and
symptoms present insidiously for most individuals. The age of onset in
multiple clinical studies has revealed a bimodal distribution pattern with peaks
occurring around the third and seventh decades of life. However,
community-based studies have found a steady age-associated increase in the
prevalence.7-9 Overall, an estimated 2% worsening of symptoms has been
reported to occur on a year-to-year basis.10 Some investigators have found
phenotypic differences between early-onset and late-onset essential tremor.11
Early-onset essential tremor is frequently associated with a positive family
history and a presence of a mild, stable tremor that progresses over many years
whereas late-onset essential tremor is observed to progress at a faster pace.12
DURATION OF SYMPTOMS, BODY DISTRIBUTION, AND ACTIVATION

CONDITIONS
The new definition for essential tremor requires the presence of an isolated
tremor of the arms and hands for at least 3 years that may or may not be
accompanied by a tremor in the head, voice, or lower limbs. Tremor less than
3 years is an indeterminate syndrome. A 3-year guardrail is meant to reduce the
odds of diagnosing concurrent neurologic signs (eg, dystonia, parkinsonism, or
ataxia).1 If other neurologic signs begin to codominate, regardless of whether
they occur early in the course or later after 3 years, symptoms should be labeled
as a combined tremor syndrome. Essential tremor is primarily an action tremor
syndrome affecting the arms that interferes with day-to-day motor tasks
(postural and kinetic components) (CASE 5-1). Sometimes essential tremor
worsens with precision goal-directed tasks (intention component), thus lending
difficulties in performing fine motor tasks such as working with a screwdriver,
inserting keys in a lock, applying makeup, or wearing jewelry. Essential tremor

in 20% of patients manifests during the resting state (resting component),

especially in long-standing cases; however, the tremor usually affects only the arms.
Essential tremor is not a task- and position-specific tremor. Head and voice tremors
usually evolve in 30% to 40% of patients after the onset of arm tremor.1 Isolated
focal tremor affecting the head or voice is inconsistent with the diagnosis. Head
tremor occurs when sitting, standing, and walking but tends to disappear when
lying down. Voice tremor is seen to manifest and affect daily conversations.13
Indeed, arm tremor is functionally disabling, but pronounced head and voice
tremors can lead to social embarrassment in day-to-day functioning.
DIET AND SOCIAL HISTORY

Dietary history including consumption of alcohol14 or environmental history that
contributes to essential tremor pathogenesis could provide clues for etiologic
origins. Some interest has been shown in assessing the relationship between high
amounts of meat in the diet and linkage with essential tremor because harmane,
which has tremorgenic properties, is abundantly present in meat.15 Eating meat
cooked at high temperatures for a long time is a particular risk,16 but a high
adherence to the Mediterranean composite diet, known for its high antioxidant
content, has been suggested to lower the odds of essential tremor.17 Besides
toxicity effects related to chronic consumption of alcohol,18 essential tremor has
been found to exacerbate with caffeine and improve with alcoholic drinks in the
acute clinical setting.19,20
FAMILY HISTORY
Ascertainment of family history is critical because essential tremor has shown
high rates (30% to 70%) of heritability.14,21 The family history is often consistent
with a Mendelian pattern of inheritance.14 The vast majority (more than 80%) of
patients with early-onset essential tremor report at least one affected first-degree
family member.9 Although several studies including genome-wide association
studies, linkage analysis, and whole-exome sequencing have attempted to advance
the genetic understanding, only a few reliable and replicable findings are available
so far. One such example is the single nucleotide polymorphism identified in the
region of LINGO1.22 Whether a single rare high-penetrant variant or many common
low-penetrant variants contribute to familial aggregation remains unclear.23
NEUROLOGIC EXAMINATION
The patient should be relaxed and seated comfortably. Bilateral arm tremor
elicited during postural and kinetic motor tasks is a hallmark finding. The
postural component is examined by having the patient outstretch both arms
extended directly forward, parallel to the ground, with the wrists straight and the
fingers extended and slightly abducted. The rhythmic oscillatory movements
comparable to a pendulum swinging from a fixed point (the shoulder joint in this
case) are usually distal, involving the metacarpophalangeal and wrist joints. The
oscillatory movements are flexion-extension rather than pronation-supination.
Another task for examining the postural component is an assumption of a
wing-beating position. The patient extends the arm outward and flexes the elbow
parallel to the ground to position the wrist under the chin. In this position, the
oscillatory movement increases in amplitude and tends to involve the proximal
wrist or elbow joints (these joints become the distal pendulum). In the
wing-beating posture, tremors in both arms sometimes oscillate out of phase,
1336 OCTOBER 2022

which could be leveraged for functional benefits. For example, a patient holding KEY POINT
a cup with both hands can counterbalance the dropping movement of one hand
● Patients with early-onset
with the other (VIDEO 5-1). The kinetic component is examined by asking patients to essential tremor commonly
perform standard tasks such as pouring water from a cup, writing a sentence, or report at least one affected
drawing spirals on a paper following standardized instructions. In the spiral- first-degree family member.
drawing task, tremor waveforms are drawn perpendicular to the pen movement,
and they characteristically align along an axis. A spiral drawn using the right hand
reveals an axis pointing toward the upper right quadrant, whereas a spiral drawn
with the left-hand points toward the upper left quadrant. This alignment is not
usually seen in other tremor disorders such as dystonic tremor and Parkinson
disease tremor. The intentional component can be elicited by patients touching their
nose precisely with their fingers and touching the examiners’ fingers, going back
and forth. This elicits a worsening of tremor amplitude because the task requires
a high level of visuomotor coordination. Another task is the dot approximation
task which requires the patient to point a pen close to a marking made on the paper.
The intentional component of head tremor can be evident when the patient
attempts to reach a spoon or cup during meals. For the resting component, it is
imperative that the patient is examined in a proper resting position. Patients should
be sitting on a chair with the arms fully relaxed and resting on the armrest or the
arms supported on their lap. If possible, patients could also be examined in a
lying-down position to achieve a proper resting condition.
GAIT AND COGNITION

It is increasingly recognized that essential tremor is not a monosymptomatic
disorder but is frequently associated with gait and cognitive changes.24,25 These
nonmotor abnormalities arguably justify the label “essential tremor is a tremor
syndrome,” as proposed by the Movement Disorders Society.1 Some have
advocated that essential tremor should be regarded as a disease or a family of
diseases. The disease entity encompasses a good amount of knowledge on
etiology, clinical presentation, course, and prognosis. As the knowledge of genes,
environmental factors, pathophysiology, and the natural disease course have
considerably advanced, it is reasonable to consider essential tremor as a disease.
Gait changes, which can be revealed during a simple bedside tandem walking
task, are frequently seen in essential tremor.26-28 Most studies have found that
about 30% to 50% of patients with essential tremor have two or more missteps
during walking.27-29 Gait impairment, albeit mild in most patients, can become
moderately severe and bothersome in some patients. These abnormalities, which
increase the susceptibility to falls, are more commonly associated with the head
tremor than the arm tremor.27 Neurologic examination should encompass
cognitive assessment to capture deficits in attention, concentration, working
memory, executive function, language, and global cognitive function; these have
been reported to be present in essential tremor.30
ESTABLISHMENT OF DIAGNOSIS
According to a recent consensus statement released by the Movement Disorder
Society, essential tremor is defined as an isolated tremor syndrome of bilateral
upper limb action tremor of at least a 3-year duration, with or without a tremor in
other locations (eg, head, voice, or lower limbs), and absence of other neurologic
signs, such as dystonia, ataxia, or parkinsonism.1 The consensus panel also
introduced a new term, essential tremor plus, defined as a tremor with the

characteristics of essential tremor with additional soft neurologic signs of

uncertain clinical significance, such as impaired tandem gait, questionable
dystonic posturing, memory impairment, or other mild neurologic signs of
unknown clinical significance. Essential tremor with a resting component is also
included within the spectrum of essential tremor plus.1 Many groups of
investigators have raised concerns over the term because the descriptors are
relatively subjective and it is not known whether essential tremor plus is
biologically distinct from essential tremor.31 Until further research sheds insights
into this newly coined entity, it is prudent that the clinician continues to document
the co-occurring neurologic features noted during the neurologic examination.
DIFFERENTIAL DIAGNOSIS
The overdiagnosis of essential tremor is common because many tremor disorders
can have overlapping phenomenology (FIGURE 5-1). Indeed, studies show that
30% to 50% of “essential tremor” cases have diagnoses other than essential
tremor, with many of these patients having dystonia or Parkinson disease.32
TREMOR IN DYSTONIA
The 2013 criteria laid out by the Movement Disorders Society propose that
dystonic tremor is a tremor in a body part affected by dystonia, and tremor
associated with dystonia is a label to be considered when dystonia and tremor are
found to affect different body parts.33 Although this criterion is debatable, in
clinical experience, patients with focal and/or segmental dystonia frequently
exhibit tremors affecting the head, arm, or voice.34 The prototypical history
FIGURE 5-1
Differential diagnoses of essential tremor with key characteristics for individual tremor disorders.
1338 OCTOBER 2022

consists of a 45- to 50-year-old woman presenting to the clinic with a long history
of isolated head tremor. Unlike essential tremor, the head tremor noticeable when
patients are seated comfortably upright in the chair may not resolve when they
assume a supine position. The patient may additionally report accompanying
symptoms of pulling, tightness, and spasms (described as “knots”) in the neck and
shoulder muscle groups. Restriction in head movements will result in pain, fatigue,
and difficulties with reading a book, watching television, driving a car, or working
for long strenuous hours on a computer. Patients sometimes have bioccipital
headaches. The head and neck symptoms could improve partially in response
to alcohol consumption, further complicating the distinction from essential
tremor. Symptoms could also be mitigated when the head is held in certain
positions (CASE 5-2). Sometimes the patient may endorse a “sensory trick,”
resulting in a “magical” disappearance of abnormal movements or posture.
A careful neurologic examination will provide further clues for diagnosis.
Besides the twisting movement and posture and apparent neck muscle
hypertrophy related to dystonia, the coarse and jerky or fine and rhythmic
character of the head tremor that is generally slow is elicitable during the
A 48-year-old woman presented with a chief complaint of head tremor, CASE 5-2
occipital headaches, head pulling, and neck muscle tightness for 3 years.
She had spasms and knots in her shoulder muscles. It was easier for her to
look to the right than the left. Her head tremor worsened when she
looked to the left. She worked as a schoolteacher, and her symptoms
worsened toward the end of the day. She found herself holding her chin
when talking to coworkers and children in the school. She could watch
television or read a book only if she had a pillow to support her head. She
denied symptoms in her eyes, jaws, and arms.
On examination, her head appeared to be preferentially turned to the
right and tilted toward her right shoulder. She had a mild to moderate
head tremor that worsened when asked to close her eyes and turn her
head to the extreme left. The head tremor was jerky and irregular and
persisted even when she laid down on her back on the examining bed. An
arm tremor was not observable. Her left sternocleidomastoid muscle was
slightly hypertrophic.
She was treated with IM onabotulinumtoxinA injections administered
every 12 weeks. OnabotulinumtoxinA was targeted mainly to the left
sternocleidomastoid, right splenius capitis, and right longissimus capitis
muscles, which helped control her headaches, neck pain, spasms, and
tremor. However, she reported the benefits lasted for only 9 of 12 weeks.
This case illustrates the characteristic history and examination features of a COMMENT
patient with cervical dystonia presenting with dystonic head tremor. The
age of onset; female sex; abnormal posturing; irregular, jerky tremor;
presence of sensory trick; hypertrophy of muscles; presence of null point;
and persistence of tremor during recumbent positioning all support a
diagnosis of dystonic tremor.

maintenance of posture or kinetic tasks (VIDEO 5-2). The examiner may observe
the head tremor as directional with a “null point,” which is a point during
performance of voluntary head movements that leads to the complete
disappearance of tremor. For example, in a patient with right torticollis (head
turned to the right) with head tremor, if the patient is instructed to turn to the
extreme left (against the will of dystonia), the tremor may worsen, but a
nullification may occur when the head turns in the same direction as dystonia
(following the will of dystonia). Sometimes, patients may not exhibit rhythmic
or oscillatory qualities during a clinical examination.1 Thus, whether the
“tremor” in the strictest sense of the word is a tremor is debatable. FIGURE 5-2
represents a simple illustration of rhythmicity, oscillations, sinusoidal waves, or
sawtooth waves that can be assessed with kinematic analysis.35
Arm tremors may occur with or without dystonic posture and movements.
Dystonic arm tremor is jerky, is usually a little proximal, and frequently manifests
in a resting position. However, if the arm tremor is fine and rhythmic, it may be
difficult to distinguish from essential tremor. In these circumstances, features
evident in the history could provide clues. Arm tremor in dystonia usually
manifests several years after the onset of head tremor. Head tremor reveals clear
underlying cervical dystonia, unlike a head tremor of essential tremor. Besides fine
motor difficulties involving distal hand fingers, patients may report trouble
holding a glass or cup or throwing a softball (proximal muscles). Tremor is mild in
many cases and is remarkably asymmetric or unilateral. The posturing of the arm
is appreciable during the physical examination as splaying and spooning of fingers,
thumb hyperextension, and/or shoulder elevation.36 The spiral drawing typically
does not reveal an axis.37 If dystonia involves other body parts, that can provide
FIGURE 5-2
Conceptual understanding of tremor. The horizontal arrows indicate the time interval
between two successive peaks of periodic waves. Rhythmic tremor that is regularly recurrent
has a constant interval. Irregular tremors with changing time intervals will clinically appear as
jerky. Oscillation indicates rotation around a central plane. Vertical arrows of different
lengths mean that the tremor is nonoscillatory. Such tremors clinically appear as directional.
If the periodic waves lose their sinusoidal characteristics and assume sawtooth waves, such
tremors will also clinically appear jerky.
1340 OCTOBER 2022

further clues. When the dystonic tremor affects the voice, patients report voice KEY POINTS
breaks or strangulated speech, which is not the case for essential tremor.
● Essential tremor is a
Distinguishing dystonic tremor from essential tremor is not always that syndrome with symptoms in
straightforward because these clues are not necessarily seen in all patients. many patients extending
Sometimes, the history can be confusing; for example, one family member reports beyond tremor to involve
classic essential tremor, but another member has clear history and examination disturbances in gait, speech,
mood, and cognition.
features consistent with a diagnosis of dystonia. Sometimes, patients with essential
tremor begin to exhibit dystonic characteristics with the progression of time. These ● Essential tremor with a
quandaries have resulted in considerable debates that will likely be resolved as resting component or
high-resolution imaging and physiology-based markers for reliable differentiation accompanied by soft signs
of the two tremor disorders become available in clinical practice.38,39 of dystonic posturing or
parkinsonism is labeled as
essential tremor plus;
PARKINSON DISEASE TREMOR currently, no evidence has
Although postural and kinetic components are the main elements of essential been found that essential
tremor, the presence of a resting tremor seen in a small proportion of patients tremor plus is biologically
distinct from essential
with advanced essential tremor can potentially lead to an erroneous diagnosis of tremor.
Parkinson disease. The arms and hands should be fully supported by the patient’s
lap or the armrests of the examination chair to elicit a true resting component ● Dystonic head tremor
(VIDEO 5-3).40 The resting component of essential tremor could be differentiated commonly affects women in
their fifth decade and
from tremor in Parkinson disease by noting observations during coactivation
includes headaches, neck
motor tasks such as walking or counting backward. These tasks do not increase pain, posturing, and isolated
amplitude in essential tremor, but a worsening of tremor in Parkinson disease head tremor.
will be seen.41 The resting tremor component in essential tremor is seen to mainly
involve the arms, but the resting tremor of Parkinson disease can affect both ● Isolated head tremor,
voice tremor, and task- or
arms and legs. Although a certain degree of asymmetry is commonly seen, position-specific tremor
essential tremor is a symmetric disease. However, tremor in Parkinson disease is should not be diagnosed as
remarkably unilateral or asymmetric.41 With the patient’s arms stretched in a essential tremor.
postural position, the arm tremor in Parkinson disease reveals a reemergent
● Unlike essential tremor,
quality (a tremor that occurs after a finite latency period from the time the dystonic head tremor often
patient assumes a horizontal posture of the arm to the onset of the wrist and/or persists when the patient is
finger tremor), which is not seen in essential tremor. Other clues supporting a examined while lying down.
diagnosis of Parkinson disease tremor include a history of rapid eye movement
● The tremor in dystonia
(REM) sleep behavior disorder or anosmia, pronounced bradykinesia, rigidity,
may be neither rhythmic nor
and gait and speech disturbances. Jaw tremor in Parkinson disease is seen when oscillatory.
the patient’s mouth is closed, whereas essential tremor appears during speaking.
These clinical features may not always be evident; thus, additional testing such as ● Arm tremor in dystonia is
dopamine transporter imaging for demonstration of presynaptic nigrostriatal frequently unilateral and
asymmetric.
dopaminergic innervation in Parkinson disease is used.42 In recent times,
measuring phosphorylated α-synuclein in CSF or peripheral tissue, such as a skin ● Unlike essential tremor,
biopsy, has been described in patients with Parkinson disease and might be dystonic arm tremor may not
useful in distinguishing patients with Parkinson disease tremor from those with reveal a clear axis during the
spiral-drawing task.
essential tremor.43 However, the accuracy, sensitivity, specificity, and the
optimal tissue analysis technique will require more studies before a broader ● Based on physical
implementation in clinical practice. examination alone, dystonic
tremor may not be
PHYSIOLOGIC AND DRUG-INDUCED TREMOR distinguishable from
essential tremor; history
In theory, when exposed to certain physiologic conditions, all healthy people are must be given consideration.
vulnerable to developing a tremor. Enhanced physiologic tremor occurs when
physiologic conditions such as hypoglycemia, hypothermia, hyperthyroidism, or
anxiety are heightened.44 Tremor is usually bilateral, affects the arm

symmetrically, and may affect the voice but tends to skip the head. Usually, no
intentional component is present during the finger-nose-finger maneuver.
Sometimes exposure to drugs leads to tremors as a side effect. Drug-induced
tremor is fast (high frequency), fine (low amplitude), and rhythmic in
most patients. Although psychotropic drugs, such as selective serotonin
reuptake inhibitors (SSRIs), tricyclic antidepressants, neuroleptics, and lithium
(CASE 5-3), are commonly implicated as a cause of drug-induced tremor; many
nonpsychotropic drugs such as β-agonists, immunosuppressants, and hormonal
therapies can also cause or exacerbate tremor.44 Most tremor-inducing drugs
cause postural tremor, but tremors induced by psychotropics and neuroleptics
can have resting and intentional components.45,46 Physiologic tremor is usually
fast (high frequency), fine (low amplitude), and rhythmic in most patients, but
sometimes, in patients receiving medications such as valproic acid, the tremor
can exhibit a coarse character (VIDEO 5-4). A simple bedside assessment may not
reliably distinguish enhanced physiologic tremor from essential tremor.47
Clinical electrophysiology testing may provide additional helpful information.
During EMG recordings, enhanced physiologic tremor generally exhibits a higher
frequency and lower amplitude. Given a predominant peripheral (mechanical)
origin, the response pattern to inertial loading, which applies weights to the wrist,
may reveal distinct findings. With inertial loading, the mechanical component
may sometimes separate from the central component, leading to a display of two
frequency peaks, which is not the case for essential tremor.48
CASE 5-3 A 55-year-old man presented for evaluation of a 1-year history of bilateral
symmetric hand tremor alongside progressive slowness of movements,
decreased facial expression, and a slight shuffling gait. Further
questioning revealed that the tremor appeared when he would sit on a
sofa with his arms resting as well as when his arms were engaged in
eating, drinking, dressing, and writing. His medical history revealed
treatments for long-standing bipolar disorder. He had been prescribed
lithium for the past year with doses titrated to 1800 mg/d.
On examination, he had a hypomimic facial expression, bradykinesia,
rigidity, a parkinsonian gait, and a bilateral fine distal hand tremor. He
underwent a trial with carbidopa/levodopa; doses were escalated to a
total daily dose of 1000 mg/d of levodopa with no improvement of
symptoms. He underwent dopamine transporter imaging, which was
unremarkable.
COMMENT This case exemplifies the importance of obtaining medication history,

which can provide important clues for a diagnosis of drug-induced tremor.
The patient had been receiving lithium for treatment of bipolar disorder; his
lithium levels were found to be 1.5 mEq/L instead of the recommended
therapeutic range of 0.6 mEq/L to 1.2 mEq/L. The history of symmetric
bilateral hand tremors was temporally related to the initiation of lithium
therapy. The case illustrates that lithium-induced tremors can be
potentially confused with essential tremor in clinical practice.
1342 OCTOBER 2022

TREMORS SECONDARY TO A STRUCTURAL AND GENETIC ETIOLOGIES KEY POINTS
Holmes tremor occurs in the setting of stroke, head trauma, and demyelination
● Unlike essential tremor,
involving brain regions in tremorgenic circuitry connecting the cerebellum, red resting tremor in Parkinson
nucleus, and thalamus. The Holmes tremor is usually slow and unilateral, disease increases in
affects the proximal arm, and reveals a kinetic > postural > resting component amplitude with walking and
(VIDEO 5-5).49 Another example of secondary tremor is fragile X-associated mental calculation and is
generally asymmetric.
tremor/ataxia syndrome. This syndrome is an X-linked recessive disorder
presenting with bilateral arm tremor in older men. The postural and kinetic ● Unlike essential tremor,
components are pronounced, but sometimes, notable resting and intentional arm tremor in Parkinson
components are present.50 As the name of the syndrome implies, these may have disease reveals a
features of progressive ataxia and sometimes parkinsonism and cognitive reemergent quality (a tremor
that occurs after a finite
impairment. Wilson Disease is an autosomal recessive disease that leads to latency period from the time
abnormal copper metabolism resulting in excessive deposition of copper in the patient assumes a
various tissues, including the brain. A tremor well appreciated during the horizontal posture of the
wing-beating position is a prototypical tremor, but a wide-ranging arm to the onset of the wrist
and/or finger tremor).
phenomenology can be seen. These tremors can be distinguished from essential
tremor based on other elements in the history and examination features such as ● In contrast to essential
cognitive changes, ataxia, and parkinsonism.51 tremor, the jaw tremor of
Parkinson disease is more
often noted when the
NEUROPATHIC AND FUNCTIONAL TREMOR
patient’s mouth is closed
Patients with acquired and familial neuropathies may also exhibit mild to and relaxed rather than
moderate action tremor of the arms. In these patients, important clues can be while the patient is
obtained from the history because the tremor often begins after the onset of speaking.
neuropathy. Although the severity of neuropathy correlates with the occurrence
● Head tremor is not a
of tremor, it does not necessarily correlate with the severity of the tremor.52 feature of enhanced
Functional tremor, a tremor without known organic etiology, should be on the physiologic tremor or
list of differential diagnoses. Functional tremor often has an abrupt-onset tremor drug-induced action tremor.
that fluctuates remarkably in amplitude and frequency and is distractible,
● Holmes tremor has
suggestible, and entrainable. Sometimes, a patient has a history of spontaneous resting, postural, and kinetic
remission. Examination features that are highly supportive of an underlying components.
functional basis include entrainment, distractibility, and suggestibility.
● Fragile X-associated
tremor/ataxia syndrome has
MANAGEMENT
a prominent intentional
Essential tremor is a syndrome with symptoms extending beyond tremor in component.
many patients to involve disturbances in gait, speech, mood, and cognition. A
multidisciplinary team involving neurology, neurosurgery, occupational ● Wilson disease has
therapy, physical therapy, neuropsychology, and psychiatry is warranted for a prominent wing-beating
postural tremor.
comprehensive assessment and high-quality holistic care (FIGURE 5-3).
Many options are available for treating the motor symptoms, and treatment ● Functional tremor is
selections mainly depend on the severity of symptoms, level of functional abrupt in onset and
disability, impact on social interactions, patient preferences, and patient distractible, suggestible,
and entrainable.
expectations.53-57 It is critical to treat the individual patient and not the disease.
A stepladder approach for treating essential tremor symptoms is proposed ● Management of
(FIGURE 5-4), and shared decision making between the patients and their essential tremor requires a
clinical providers at each step is encouraged. When the symptoms are mild, multidisciplinary team, and
nonpharmacologic therapies could be the first consideration. Occupational treatment selection requires
shared decision making
therapists can help develop a practical, individualized approach. An occupational between patients and
therapy evaluation will focus on modification of the functional task and encourages providers.
the use of compensatory strategies such as proper body mechanics and core
stability for hand control. Several adaptive devices, such as weighted spoons, forks,

FIGURE 5-3
Multidisciplinary team for management of essential tremor, which should be centered on the
patient and not the disease.
FIGURE 5-4
Stepwise approach for management of arm symptoms in essential tremor. Treatments assigned to
step 2 or 3 can be combined with treatments in step 1. Surgical treatments, even though powerful,
are considered only when the tremor is refractory to pharmacologic therapies.
DBS = deep brain stimulation; MRI = magnetic resonance imaging.
1344 OCTOBER 2022

utensils, or rocker knives; weighted pencils and pens; and modified computer KEY POINTS
mouses and keyboards, are available for a more efficient task performance. In
● Adaptive tools, orthotic
recent times, many wearable orthotic devices have become available. Although devices, limb cooling,
some devices follow the principles of increasing weights around the wrist to and peripheral stimulation
stabilize the arm mechanically, some use tuned mass damper technology to devices are useful
dampen vibrations and a gyroscope to reduce the angular momentum. Peripheral nonpharmacologic therapies
for essential tremor.
limb cooling with icepacks around the forearm is another technique that
modulates the feedback from the peripheral muscles to the brain that can ● If the tremor severity
temporarily control the tremor.58 In 2022, a peripheral wearable device that does not reduce despite
stimulates the median and radial nerve at the wrist to modulate the peripheral multiple medication trials,
feedback59 was cleared by the US Food and Drug Administration (FDA) to treat surgical intervention may
be warranted.
essential tremor symptoms.60 Thus, it is increasingly recognized that
nonpharmacologic therapies can potentially improve patients’ quality of life
without presenting many risks.
When the symptoms interfere significantly with activities of daily living,
pharmacologic therapies are initiated.61 Beta-blockers are FDA-approved
first-line agents for the treatment of essential tremor. Short- and long-acting
propranolol reduces tremor by 50% to 70% in 50% of patients at daily doses
varying from 60 mg/d to 200 mg/d.55 Dizziness, fatigue, erectile dysfunction,
and sedation are common side effects. Propranolol, a nonselective beta-blocker,
is contraindicated for patients with bronchial asthma. However, cardioselective
atenolol and metoprolol, which do not affect the bronchial muscles, could be
used in these circumstances.62,63 Primidone is an alternative first-line therapy
and is effective at a total daily dose of 250 mg/d. Besides direct benefits related
to actions against sodium channels in the neuronal membrane, the efficacy
of primidone is related to the metabolites such as phenobarbital and
phenylethylmalonamide.53 Confusion, ataxia, and nausea are side effects more
commonly seen in older patients using high doses. These side effects could be
minimized with the initiation of therapy at low doses and slow titration.64 In one
study, pretreatment with phenobarbital initiated 3 days before primidone was
found to mitigate the psychotropic side effects.65 Combined therapy with
propranolol and primidone has been observed to yield better clinical outcomes.
Although the medications improve arm tremor, efficacy in controlling the
head tremor is limited. When the arm and/or head tremor persists or the
medications cannot be tolerated, the next step in the treatment ladder is to use
topiramate,66 gabapentin,67 benzodiazepines,68 and botulinum toxin type A
injections.69,70 The medications investigated in clinical trials have shown these
agents to be relatively less efficacious compared with the first-line agents or have
revealed insufficient evidence for controlling symptoms.71 Thus, prescribing
these drugs is more justified in the presence of comorbidities. For example,
benzodiazepines could be chosen if psychiatric comorbidities are present.
Surgical intervention is recommended for symptoms that are refractory to all
available medications yet are functionally disabling and socially embarrassing.
Multiple surgical modalities are available, each with risks and benefits that need
due consideration. Deep brain stimulation is the most frequently used surgical
procedure; it electrically modulates the behavior of the tremor circuitry. Deep
brain stimulation has gained widespread acceptance and popularity because of its
efficacy in controlling arm and head tremors, and, more importantly, unlike
thalamotomy, which involves creating a lesion, the surgery is nondestructive and
reversible in nature. It can be used to treat bilateral tremor symptoms without the

high risk of severe complications, such as dysarthria, dysphagia, and ataxia reported
in studies with bilateral thalamotomy procedures.72 The main disadvantages are
high expenses and potential risks related to infection, seizure, stroke, and hardware
complications. The implantation of a battery in the chest with replacement at
appropriate time intervals requires general anesthesia, although rechargeable
batteries are becoming commonly available. In 2016, the FDA approved transcranial
MRI-guided focused ultrasound (MRgFUS) treatment, which is noninvasive or
minimally invasive and involves creating permanent lesions with ultrasound
energy.73 Although direct comparison has not been performed, MRgFUS has
efficacy similar to deep brain stimulation. The MRgFUS procedure does not require
drilling of a burr hole and implantation of hardware. It is essential to discuss that
complete hair removal is needed, and the patients will need to lie in an MRI scanner
for 3 to 4 hours during the MRgFUS procedure.74 No data are available on long-term
follow-up or whether unilateral MRgFUS can effectively control axial symptoms
such as head tremor. Nevertheless, because the procedure is noninvasive and has
immediate benefits, more and more centers are offering this procedure. Another
noninvasive procedure is stereotactic radiosurgery, which does not require a burr
hole or hair removal; however, the procedure is used less often because the clinical
benefits are delayed and unpredictable.72
CONCLUSION
Essential tremor is among the most prevalent movement disorders. A thorough
history and detailed neurologic examination are required to identify the patterns
and nuances for an accurate diagnosis. Treatments for tremor control involve the
use of adaptive and orthotic devices, pharmacotherapies, and surgical
interventions in medication-refractory cases. Because essential tremor is not a
monosymptomatic disorder, ideal management involves a multidisciplinary
team of a neurologist; neuropsychologist; occupational, speech, and physical
therapists; and in some cases a neurosurgeon.
VIDEO LEGENDS
VIDEO 5-1 VIDEO 5-2
Clinical characteristics of essential tremor. The Head tremor in patients with cervical dystonia. The
first segment shows a 65-year-old woman with mild video shows a 68-year-old woman with cervical
bilateral slightly asymmetric postural tremor dystonia and slow head-bobbing, a 78-year-old
affecting the arms, most significantly in amplitude at woman with right arm dystonic tremor, and a
the wrist joint, rather than more proximal or distal 71-year-old man with cervical dystonia and a jerky
joints. Generally, the tremor involves wrist head tremor that remains persistent when he is lying
flexion-extension rather than rotation-supination. supine with his head at rest.
The kinetic component is observed during a dot
approximation task. The next segment shows a © 2022 American Academy of Neurology.
60-year-old man with a similar asymmetric postural
arm tremor. The final segment reveals the out-of- VIDEO 5-3
phase character seen in some patients (seesaw Resting tremor assessment in Parkinson disease.
effect seen when arms are held in the wing-beating The video shows a 78-year-old man diagnosed with
position). When a bimanual task is performed (not Parkinson disease exhibiting a resting tremor in his
shown in the video), the movement direction of one left hand when his arm is resting on the armrest. A
side could potentially cancel the out-of-phase resting tremor is seen in both legs, more in his left
direction of the other side; this can be leveraged by than in his right. Resting tremor in his hand is also
the patients during a functional task. elicited with his arm resting in his lap (both positions
are commonly used during the neurologic
© 2022 American Academy of Neurology. examination). Tremor in Parkinson disease involves
the distal joints (fingers and wrist), is characterized
by wrist pronation-supination, and has a slight
pill-rolling quality.
© 2022 American Academy of Neurology.
1346 OCTOBER 2022

VIDEO 5-4 VIDEO 5-5
Bilateral physiologic arm tremor. The video reveals Head and arm tremor in a patient with cerebellar
a spectrum of physiologic tremors. The first patient lesions. The video shows a 48-year-old woman
is a 75-year-old woman presenting with a tremor diagnosed with multiple sclerosis with lesions
that manifested within a few months of using involving the cerebellum and the brainstem; she
valproic acid for a mood disorder. The tremor was presented with tremors of bilateral arms and head.
coarse with resting, postural, and kinetic The tremor in her left arm is seen during resting,
components. The second patient is a 50-year-old postural elevation, and kinetic tasks. The tremor is
woman with generalized anxiety disorder; she had more pronounced proximally and has a significant
fine rhythmic distal tremors involving her hands. intentional component.
© 2022 American Academy of Neurology. © 2022 American Academy of Neurology.
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doi:10.1136/jnnp-2020-324061

REVIEW ARTICLE

Multiple System Atrophy
C O N T I N UU M A UD I O By Daniel O. Claassen, MD, MS, FAAN
ONLINE
ABSTRACT
CITE AS: PURPOSE OF REVIEW: Patientswith multiple system atrophy (MSA) can present
with diverse clinical manifestations, and the clinical care required is
1350–1363. complex and requires a thoughtful approach to emerging symptoms and
treatment decisions.
Dr Daniel O. Claassen, Vanderbilt
Medical Center, 301 Medical RECENT FINDINGS: Even though it is a rare disease, MSA is often encountered
Center Dr, Ste 3930, Nashville, in clinical practice. New developments in biofluid biomarkers and
TN 37232, daniel.claassen@
vumc.org.
diagnostic assessments offer potential for earlier and more accurate
diagnosis. This article describes recent findings, such as the use of skin
RELATIONSHIP DISCLOSURE: biopsies, neuroimaging, and novel treatment concepts (eg, central
Dr Claassen has received
noradrenergic augmentation).
serving as a consultant for Spark SUMMARY: MSA is a complex disease. This article provides a summary of
Therapeutics, Inc and as an
editor, associate editor, or treatment options for diverse symptoms that include autonomic, sleep,
editorial advisory board mood, and motor manifestations of the disease to help clinicians care for
member for HD Insights.
patients with MSA. Providing comprehensive care for patients with MSA
Dr Claassen has received
personal compensation in the requires an understanding of the diverse symptomatology that patients
range of $5000 to $9999 for develop over time and should include an interdisciplinary team.
serving as a consultant and on a
scientific advisory or data safety
monitoring board for Teva
Neuroscience, Inc. Dr Claassen
has received personal INTRODUCTION
M
$50,000 to $99,999 for serving ultiple system atrophy (MSA) is a neurodegenerative disorder
as a consultant for Alterity that presents with diverse motor, autonomic, and sleep-related
Therapeutics. The institution of
symptoms and has a rather severe clinical course. Over the
years, different diagnostic terms, such as Shy-Drager
UNLABELED USE OF
syndrome,1 olivopontocerebellar atrophy, and striatonigral
2
PRODUCTS/INVESTIGATIONAL degeneration, have been used to describe atypical parkinsonian presentations,
USE DISCLOSURE: where these terms reflect the predominant autonomic, ataxic, and poorly
Dr Claassen discusses the
unlabeled/investigational use of
responsive parkinsonian symptoms encountered in MSA. MSA is considered an
acarbose (α-glucosidase α-synucleinopathy because of the predominant α-synuclein–positive cytoplasmic
inhibitor) for postprandial inclusions that classically localize to oligodendrocytes, termed glial cytoplasmic
hypotension, baclofen and
gabapentin for pain/dystonia, inclusions.3 Although Lewy body inclusions are typically identified in the
levetiracetam for cerebellar cytoplasm of neurons, other pathologic hallmarks include gliosis and axonal
outflow tremor, serotonin
degeneration, distinguishing MSA from Parkinson disease (PD).4
norepinephrine reuptake
inhibitors (eg, duloxetine) for MSA can be challenging to diagnose early in the disease course, and clinicians
pain, and short-acting are generally cautious when diagnosing a patient with MSA, given the rather
antihypertensives (eg,
nifedipine, transdermal
ominous life expectancy of 6 to 10 years after diagnosis.5 The presence of certain
nitropaste) for supine clinical signs tend to lead to consideration of MSA, and new diagnostic tools can
hypertension. help sort through diagnostic dilemmas. Clinically, the most telling signs that
© 2022 American Academy suggest MSA are examination findings of parkinsonian motor symptoms,
of Neurology. cerebellar/ataxic symptoms, pyramidal findings, and autonomic dysfunction.6
1350 OCTOBER 2022

Given that all these symptoms do not occur in all patients, MSA may be KEY POINTS
diagnosed by several different specialists: urologists for patients presenting with
● Although multiple system
neurogenic bladder symptoms, autonomic specialists for those presenting with atrophy (MSA) has been
orthostasis, and neurologists and movement disorder specialists for those with designated as MSA with
early gait ataxia, falls, and poorly responsive symptoms to dopaminergic predominant parkinsonism
treatments. Although MSA has been designated as MSA with predominant or MSA with predominant
cerebellar ataxia, it is more
parkinsonism (MSA-P) or MSA with predominant cerebellar ataxia (MSA-C), it
common to see an overlap
is common to see an overlap of symptoms, especially over time, that makes this of symptoms that make this
distinction difficult.7 Furthermore, past efforts to designate patients as having distinction difficult.
possible or probable MSA reflect the severity of symptoms, but current tools can
allow for improved diagnosis early in the disease. On many occasions, a clinician ● The most common
prodromal symptoms for
will find at autopsy that a patient who was clinically diagnosed as having PD has MSA include rapid eye
pathologic findings of MSA or that a patient clinically diagnosed with MSA has movement (REM) sleep
pathologic findings of dementia with Lewy bodies (DLB); thus, this disorder behavior disorder and
presents unique diagnostic challenges.8 MSA-C symptoms can be difficult to autonomic failure.
distinguish from other progressive ataxias. For more information on progressive ● Patients with pure
ataxias, refer to the article “Neurodegenerative Cerebellar Ataxia” by Liana S. autonomic failure have a
Rosenthal, MD, PhD,9 in this issue of Continuum. high likelihood of
Certain clinical symptoms make the diagnosis of MSA more likely. These progressing to a central
α-synuclein disease; those
symptoms include the presence of pyramidal findings (eg, Babinski signs and
who progress to MSA tend
brisk lower extremity reflexes), striatal toe,10 early gait instability and falls with to be younger and have
rapid progression to immobility,11 facial dystonia and early prominent facial intact smell and an increase
dyskinesia in response to levodopa,12 ataxic dysarthria,13 dysphagia, in heart rate after 3 minutes
of standing up from a supine
anterocollis,14 cold hands/feet and purple glove sign,15 early and severe urinary
position.
symptoms,16 rubral tremor,17 myoclonus, stridor, and neck pain.18 A systematic
approach can help ensure that these symptoms and signs are thoroughly
evaluated.
PRODROMAL AND EARLY SYMPTOMS

The most common prodromal symptoms for MSA include rapid eye movement
(REM) sleep behavior disorder (RBD) and autonomic failure.19 RBD, although
experienced by most patients with MSA, is a common symptom in other α-
synucleinopathies (such as PD and DLB) and not specific for MSA.20 Patients
with idiopathic RBD who have intact smell and more severe urinary symptoms
tend to develop MSA.21 Pure autonomic failure is a syndrome that presents with
orthostatic hypotension and reduction in sweating and pathologically with
degeneration of peripheral autonomic neurons.22 Lewy body aggregation has
been described within sympathetic ganglia and autonomic axons, but typically
no motor or cognitive symptoms are seen that would alert the clinician to a
diagnosis of PD or DLB.23 Patients with pure autonomic failure have a high
likelihood of progressing to a central α-synuclein disease, and those who progress
to MSA tend to be younger and have intact smell and an increase in heart rate
after 3 minutes of standing up from a supine position.19,24 The latter symptom is
suggestive of central noradrenergic failure (as postganglionic sympathetic
neurons are preserved in MSA), which may be the basis of autonomic failure in
MSA; resting supine plasma norepinephrine is generally higher in patients with
MSA than pure autonomic failure.25 Early bladder autonomic dysfunction can
also be a prodromal symptom of MSA. Up to 20% of patients note symptoms of
urinary retention, which likely localize to cell loss in the Onuf nucleus, a group of
anterior horn cells in the sacral spinal cord.16

MULTIPLE SYSTEM ATROPHY
AUTONOMIC SYMPTOMS
The clinical presentation of autonomic symptoms is often described as a waxing
and waning process that can predate or coincide with the manifestation of other
motor and sleep symptoms. Clinical symptoms of autonomic dysfunction are
ubiquitously encountered in MSA, such that a methodical review of systems can
help clinicians make diagnostic and treatment decisions.
CASE 6-1 A 62-year-old woman presented to the neurology clinic with unexplained
neurogenic bladder symptoms. A thorough urologic workup had revealed
concerns for a central process. She also noted orthostatic hypotension
symptoms along with cervical neck pain, fatigue, and changes to her
speech; her friends thought she sounded intoxicated. She also described
pseudobulbar symptoms.
On examination, she had an orthostatic blood pressure drop of greater
than 30 mm Hg systolic after 3 minutes of standing. She had evidence of
parkinsonism and mixed dysarthria (ataxic and hypokinetic).
A brain MRI was obtained, which showed evidence of putaminal
atrophy, a putaminal hyperintense rim, and increased iron in the lentiform
nucleus (FIGURES 6-1A through 6-1C). A skin biopsy showed phosphorylated
α-synuclein deposition (FIGURE 6-1D).
FIGURE 6-1
Imaging and skin biopsy of the patient in CASE 6-1. A, Axial T1-weighted MRI shows
putaminal atrophy. B, Axial fluid-attenuated inversion recovery (FLAIR) MRI shows a
putaminal hyperintense rim (arrow). C, Axial quantitative susceptibility imaging shows
increased iron in the lentiform nucleus. D, Skin biopsy shows PGP 9.5 immunostained
nerve fibers, where the red regions indicate phosphorylated α-synuclein deposition.
COMMENT This case represents a confluence of clinical, radiologic, and histologic

features supportive of a diagnosis of multiple system atrophy. The
presence of the putaminal hyperintense rim is a telltale sign of multiple
system atrophy, given the clinical presentation described. New options for
skin biopsies represent an emerging diagnostic aid.
1352 OCTOBER 2022

Assessment of Autonomic Symptoms KEY POINT
Autonomic symptoms in MSA can range from sexual dysfunction to orthostasis,
● A reduction of systolic
pain, and bowel and bladder symptoms.18 Erectile dysfunction in men and blood pressure of at least
anorgasmia in women are often noted by patients, and these symptoms 20 mm Hg or diastolic blood
necessitate that a detailed history be obtained.26 Urinary hesitancy, incontinence, pressure of at least
and neurogenic bladder are commonly noted. Orthostatic symptoms, including 10 mm Hg within 3 minutes
of standing without
postexercise fatigue, lightheadedness, syncope, and progressive inability to stand
compensatory heart rate
or sit, result in substantial morbidity.27 Many patients describe neck pain, which increase is diagnostic of
is termed the coat-hanger sign; this symptom may be indicative of orthostatic orthostatic hypotension.
hypotension or neck dystonia.28 Other autonomic symptoms include
constipation, changes to gastric emptying, and anhidrosis (CASE 6-1). Anhidrosis
can be assessed with a thermoregulatory sweat test, but this tool is infrequently
employed given the medical infrastructure necessary for its use.29 The cold hand
sign is likely related to impaired vasomotor response, and clinical symptoms can
include a violaceous coloration to the extremities with delayed capillary refill
after blanching.30
Clinical assessments of autonomic function are important not only for
diagnosis but also for characterizing the severity of symptoms. Orthostatic vital
signs, which measure blood pressure and heart rate changes to position, are the
most effective and efficient method in the evaluation of autonomic function.
Heart rate and brachial blood pressure should be tested after 10 minutes in the
supine position and then after 1, 3, 5, and 10 minutes of standing (assuming the
patient can stand for that duration), with the blood pressure cuff kept at
heart level. A reduction of systolic blood pressure of at least 20 mm Hg or
diastolic blood pressure of at least 10 mm Hg within 3 minutes of standing,
without compensatory heart rate increase, is diagnostic for orthostatic
hypotension.
Tilt-table testing can be performed in most tertiary care centers. Heart rate
variability with controlled respiration and determination of systolic blood
pressure and heart rate responses to posture and the Valsalva maneuver can be
useful in determining the intactness of autonomic reflexes. These assessments
can be performed in a controlled setting with tilt-table testing. This procedure
can provide the clinician with a documented diagnosis of sympathetic
dysfunction, which can aid in the workup and treatment decisions for patients.31
Plasma catecholamines may help distinguish pure autonomic failure from
MSA; patients with MSA have normal levels of norepinephrine, whereas patients
with pure autonomic failure have low norepinephrine levels. These findings
support the premise that patients with MSA have intact residual sympathetic
tone and postganglionic noradrenergic fibers and, as such, can have a significant
pressor effect from administration of the norepinephrine reuptake inhibitor
atomoxetine or the α-2 antagonist yohimbine.32
The quantitative sudomotor axon reflex test (QSART) and thermoregulatory
sweat test can be used in tandem to assess postganglionic sympathetic sudomotor
axon integrity. QSART is a procedure where acetylcholine is administered via
iontophoresis to assess sweat response. In the thermoregulatory sweat test, a
yellow powder is placed on the skin, the participant is put in a heated room, and
as the participant sweats the powder changes from yellow to purple. This
procedure investigates the integrity of the thermoregulatory pathway that
localizes from the hypothalamus to the sweat gland.29 MSA is diagnosed in
patients who have impaired sweating but have a normal QSART response,

TABLE 6-1 Medications Used for the Management of Symptoms in Multiple System
Atrophy
Clinical symptom Medication Typical dose Clinical notes
Orthostatic Midodrine 2.5-15 mg per dose, usually Strong pressor effect; need to
hypotension up to 4 times a day if observe for supine hypertension
necessary
Fludrocortisone 0.1 mg 2 times a day Beware of potassium loss and

increased cardiac risk
Droxidopa 100-600 mg 3 times a day Ensure monitoring for supine

hypertension
Pyridostigmine 60 mg daily Can be also useful for severe

constipation
Atomoxetine 18 mg daily Note low dose for orthostatic

hypotension symptoms
Postprandial Acarbose (α-glucosidase 25-50 mg with each meal Can cause gastrointestinal upset
hypotension inhibitor)
Supine hypertension Short-acting antihypertensives For example, nifedipine Recommend collaboration with
10 mg at bedtime cardiology
Transdermal nitroglycerin paste 5 mg at bedtime
Urinary retention Antimuscarinic Trospium 20 mg 2 times Recommend collaborative

a day treatment with urologist
Beta 3 adrenergic Mirabegron 25 mg a day

receptor agonists titrating to 50 mg a day;
vibegron 75 mg a day
Parkinsonism Carbidopa/levodopa 25/100-mg tablets, typically Check for durability of response;

up to 6 tablets a day can reduce blood pressure
Dopamine agonists For example, pramipexole Caution as this can cause lower
0.5 mg 3 times a day blood pressure
Monoamine B oxidase For example, rasagiline Caution because of a detrimental

inhibitors 1 mg daily effect on blood pressure and a lack
of efficacy
Cerebellar Levetiracetam 250-500 mg 2 times a day This, or other antiseizure

outflow tremor medications, can sometimes
improve tremor severity
Pain/dystonia Baclofen 5-20 mg 3 times a day Can help dystonic pain symptoms
Gabapentin 100-900 mg 3 times a day Can help dystonic pain symptoms,

along with restlessness of legs
at night
Pain Serotonin norepinephrine For example, duloxetine Central noradrenergic effect may
reuptake inhibitors (SNRIs) 60 mg daily help blood pressure as well
1354 OCTOBER 2022

indicating a preganglionic lesion. If a reduced or absent QSART response is KEY POINT
noted, a postganglionic lesion is suggested.
● Elevating the head of the
bed during the night should
Treatment of Autonomic Symptoms be encouraged in the
As with orthostatic symptoms encountered in PD or DLB, nonpharmacologic management of supine
options should be incorporated early into the clinical management of MSA. hypertension in patients
with MSA.
Encouraging patients to drink a bolus (eg, 10 ounces) of water, especially first
thing in the morning, can help achieve the overarching goal of increasing fluid
intake and thus increasing blood volume.31 Many patients note postprandial
hypotension, so patients should have more frequent and smaller meals, with
fewer carbohydrates.33 Acarbose can be helpful for patients who experience
postprandial hypotension. A high-salt diet, abdominal binders, and lifestyle
accommodations for low blood pressure can also be helpful.34
Medications for orthostatic hypotension include mineralocorticoids such as
fludrocortisone, but this class of medication is associated with increased cardiac
morbidity, thus it is recommended at lower doses (eg, 0.1 mg 2 times a day)
(TABLE 6-1).35 The adrenergic receptor agonist midodrine can quickly and
robustly increase blood pressure and does not cross the blood-brain barrier.
Droxidopa, a norepinephrine precursor, can provide benefit to patients through
increasing norepinephrine levels. As mentioned earlier, a low dose of
atomoxetine has a robust pressor effect in patients with MSA. Pyridostigmine, a
peripheral acetylcholinesterase inhibitor, provides a pressor effect enhancing
nicotinic neurotransmission at the level of the sympathetic ganglia34 and can also
help patients with constipation. The key challenge with all these therapies is that
the durability of the medications wanes with time, so working with the patient
and caregiver to adjust lifestyle and medications and manage acute events
(especially urinary tract infections, which are prone to causing dramatic
worsening in orthostatic hypotension symptoms) is important.
One of the more complicated issues in MSA is supine hypertension.36
During the night while patients are supine, increased sodium excretion and
pressure natriuresis can result in worse symptoms in the morning. Elevating
the head of the bed at night can help with this symptom and should
be discussed with the patient. Other methods to reduce supine hypertension
include carbohydrates (eg, alcoholic drinks) right before bedtime,
short-acting antihypertensives such as nifedipine, or even transdermal
nitroglycerin ointment.37
BLADDER COMPLICATIONS
Bladder sonography is an effective assessment used to assess urinary retention in
MSA. Patients are asked to voluntarily void, and sonography estimates the
volume of residual urine. Reducing postvoid residual can be beneficial to
patients, and beta-3 receptor agonists should be considered as first-line
treatments. These medications relax the smooth muscle of the bladder and
reduce the risk of urinary retention compared to antimuscarinic agents because
they do not impact voiding contractions. If antimuscarinic medications are
used, the author prefers trospium as it does not cross the blood-brain barrier
or worsen cognitive symptoms. For refractory bladder symptoms,
self-catheterization 3 to 4 times per day is necessary over time, and newer
methods can help patients manage this difficult procedure.38 A permanent
transcutaneous suprapubic catheter may be required as the severity of bladder

dysfunction progresses, and this decision should be discussed with a urologist

given the complexities regarding infection and maintenance.
MOTOR SYMPTOMS
Although patients may be characterized based on the predominant ataxic or
parkinsonian presentations, in most cases, both symptoms will be present. It
remains to be seen whether classifying patients as having MSA-C or MSA-P will
inform clinical progression or therapeutic response to putative disease-modifying
therapies, but several important themes arise in patient assessment and treatment.
First, characterization of the dysarthria pattern can be useful not only in diagnosis
(ie, identifying an early ataxic dysarthria may alert the clinician to the diagnosis of
MSA with ataxic components) but also in effective speech therapy options. Given
CASE 6-2 A 52-year-old man presented as a referral from his primary care physician
for unexplained gait instability and falls. He lived alone and had noted a
recent episode of falling out of bed at night, suggestive of rapid eye
movement (REM) sleep behavior disorder. He was noted to have ataxic
dysarthria, ataxic gait, and large-amplitude tremor on finger-nose testing
but normal blood pressure and no orthostatic symptoms. MRI showed
cerebellar atrophy, middle cerebellar peduncle atrophy, and the “hot
cross bun” sign (FIGURE 6-2).
FIGURE 6-2
Imaging of the patient in CASE 6-2. A, Sagittal T1-weighted image shows evidence of
cerebellar atrophy. B, Axial T1-weighted image shows middle cerebellar peduncle atrophy.
C, D, Axial fluid-attenuated inversion recovery (FLAIR) MRI shows the hot cross bun sign in
the upper (C, arrow) and lower (D, arrow) pons.
COMMENT This case illustrates the presentation of multiple system atrophy with
predominant cerebellar ataxia, with imaging signs indicative of cerebellar
and related network degeneration. Interpreting the brain MRI results in
light of the clinical findings is necessary, as these imaging findings can be
found in other ataxic disorders. It is difficult to ascertain sleep history in
patients who live alone, and formal sleep evaluation is necessary.
1356 OCTOBER 2022

the ubiquitous nature of speech training treatments for PD, many patients with KEY POINT
MSA are prescribed PD-specific therapies but will need different management.
● Early integration of
For example, the author has found that patients benefit from therapy strategies physical therapy and gait
that improve communication efficacy rather than therapies that focus on speech safety is key in managing
production improvements. Furthermore, early symptoms of dysphagia can be MSA gait symptoms.
managed with swallowing strategies, and it is helpful to establish care with a
speech therapist early on to recognize and manage these symptoms. Patients note
that progressive speech symptoms are a source of disability, thus managing these
symptoms is critically important.
Other motor symptoms include gait instability and falls (CASE 6-2). Aside
from being an early symptom that alerts the clinician to a diagnosis of MSA,
progressive inability to walk and propensity for falls invariably result in the need
for a wheelchair or assistive walking device. Several reasons for gait instability
exist, including autonomic symptoms, gait ataxia, postural instability, and
parkinsonism. Levodopa is an effective treatment for patients with MSA with
parkinsonian symptoms, and the effect can be durable for an average of 3 years.39
It is clinically important to identify modifiable causes for gait instability, and
early integration of physical therapy and gait safety is key in managing MSA gait
symptoms. It is worth noting that certain dopaminergic medications, especially
monoamine oxidase B inhibitors, dopamine agonists, and levodopa, can lower
blood pressure and exacerbate orthostatic hypotension.
Tremor symptoms in MSA differ from those commonly encountered in PD.
Patients tend to have a postural tremor with cerebellar outflow features, and
myoclonus is often seen early in the course of disease. Treatment of tremor can
be challenging; however, antiseizure medications such as levetiracetam have
proven useful in similar tremor syndromes and may be tried.40
The assessment of ataxia should not be limited to finger-nose and knee-shin
assessments but should include an assessment of the finger-chase test.41 The
finger-chase test is performed by instructing the participant to follow the
movements of the examiner’s index finger and grading the degree of dysmetria.
The patient is asked to place their index finger in front of the examiner’s index
finger, as close as possible but not touching. When the examiner moves their
finger randomly in a horizontal, diagonal, or vertical direction, the patient is
instructed to follow the examiner’s finger with their finger as quickly as possible.
Dysmetria is evaluated based on the presence and degree of overshoot by the
patient in relation to the examiner’s finger. Tandem gait is also useful to assess,
as this can help the clinician identify ataxic features that may underlie gait
instability. Early referral to occupational therapy and physical therapy can help
patients manage these symptoms, prevent falls, and maintain activities of
daily living as long as possible, as medication options for ataxic symptoms
are limited.
Dystonic symptoms in MSA can range from risus sardonicus (lower facial
dystonia) to anterocollis to limb dystonia. Dystonic symptoms can be associated
with pain, and, although marginally responsive to levodopa, these symptoms can
be quite debilitating to patients. Previous trials of deep brain stimulation
targeting the globus pallidum internus, or even pallidotomy, have yielded mixed
results but can be considered as treatment options42 in patients whose symptoms
are medication refractory. Of note, patients diagnosed with idiopathic PD who
receive subthalamic nucleus targeted deep brain stimulation for medication
refractory motor symptoms and who decline rapidly can be retrospectively

identified as having MSA,42 where the diagnosis of MSA is often made at autopsy.
Clinical findings that should alert clinicians to MSA include severe urinary
symptoms, rapid progression of motor symptoms, and motor fluctuations.43-46
PAIN
Pain is one of the more common symptoms of MSA and that is often overlooked.
Although only a handful of studies have assessed pain in MSA,47,48 about 50%
of patients with MSA note some aspect of pain.46 As mentioned earlier, the
coat-hanger sign of pain is probably the most common pain symptom considered
during the clinical workup, but in addition to this, many patients will note
symptoms of generalized pain, migraines, and burning dysesthesia; these
symptoms can sometimes relate to dystonic findings. No systematic studies have
assessed therapies for pain symptoms, but retrospective studies suggest
treatment with γ-aminobutyric acid–mediated (GABAergic) medications
(eg, baclofen, gabapentin), dopamine treatments, serotonin norepinephrine
reuptake inhibitors (SNRIs; eg, duloxetine) and regular analgesics are
used in practice. Identifying these symptoms in practice and working
with pain management specialists can help to improve the quality of life
of patients.
MOOD SYMPTOMS
Anxiety, depression, and mood lability (pseudobulbar symptoms) can be
noted in the course of MSA.49 Typical therapies for this include selective
serotonin reuptake inhibitors (SSRIs), which can provide relief.50 More so, the
diagnosis of MSA can itself be challenging for patients. Many patients note
symptoms of depression and demoralization and struggle with end-of-life
concerns when receiving this diagnosis. Given these challenges, it is extremely
helpful to involve palliative care strategies with patients and families. Some
clinics have palliative care referral options in place, but often clinicians can
educate local counselors or social workers about the nature of MSA to help
establish the framework and goals for these interactions. Online support groups
are now emerging, allowing patients who live in diverse regions to interact and
offer peer support.51
SLEEP SYMPTOMS
Aside from RBD, one of the greatest sleep concerns for patients with
MSA is nocturnal stridor. This, along with obstructive sleep apnea,
necessitates consultation with a sleep specialist for interventions that can
improve hypoventilation (eg, continuous positive airway pressure [CPAP]
or bilevel positive airway pressure [BiPAP]). Sleep dysfunction is a
major cause of death in MSA,52,53 thus this referral should be prioritized in
all patients.
Treatment of RBD is typically with melatonin and/or clonazepam, but
clinicians should be aware that relying on a medical history for RBD can be
tenuous, as sleep-disordered breathing can sometimes be interpreted by
caregivers as dream enactment. When any concern is present, obtaining a
polysomnogram is necessary. Caregivers can sometimes record the sound of
breathing at night, which can inform the clinician of the presence of stridor.54 In
some cases, laryngoscopy is necessary to evaluate potential vocal cord
abnormalities (such as dystonia55), which can be another cause of stridor.
1358 OCTOBER 2022

NEUROIMAGING KEY POINTS
The use of brain MRI assessments in the routine workup of patients is ubiquitous,
● Identifying pain
and many patients may already have had a brain MRI. Noncontrast imaging is symptoms is important in
sufficient for most assessments, but to ensure a good-quality structural scan, maintaining the quality of
T1-weighted, T2-weighted/fluid-attenuated inversion recovery (FLAIR), T2*- life of patients with MSA.
weighted gradient recalled echo (GRE), T2-weighted fast spin echo images, and
● Clinicians can educate
diffusion-weighted imaging studies should be performed.56 The most common
local counselors or social
MRI findings in MSA include the hot cross-bun sign, the putaminal hyperintense workers about the nature of
rim, and brainstem/cerebellar atrophy. On T2-weighted imaging, the MSA to help establish the
hyperintense cross can be visualized in the pons and is a result of pontocerebellar framework and goals for
fiber degeneration with a preserved corticospinal tract. Structurally, atrophy of interactions.
the pons, middle cerebellar peduncle, and cerebellum may also be seen on
T1-weighted imaging. Many patients with these features also have ataxic
symptoms; thus, interpreting clinical findings in the context of MRI results is
imperative. This is especially important when evaluating the hyperintense rim
bordering the putamen. As visualized on T2*-weighted imaging, the
hyperintense rim is largely a result of accumulating iron in the putamen; this
accumulation can also be visualized using new methods such as quantitative
susceptibility imaging.57 Atrophy of the putamen is also evident on T1-weighted
imaging, and some contemporary segmentation tools may help quantify this
volume. In the putamen, diffusion-weighted imaging studies show greater
diffusivity in patients with MSA.58
Fludeoxyglucose positron emission tomography (FDG-PET) imaging can be
useful in early evaluation of patients who present with atypical clinical findings.
In these studies, cerebellar hypometabolism or reductions in lentiform nucleus
metabolism can identify patterns of metabolic derangement that distinguish
MSA from progressive supranuclear palsy or other atypical parkinsonian
disorders. Three-dimensional stereotactic surface projection maps allow for
improved visualization of these findings.59
123
Iodine-metaiodobenzylguanidine (123I-MIBG) scintigraphy is an imaging
application to assess cardiac sympathetic innervation. Although this method
may not be covered by many insurers, on some occasions, justifying the use of
this scan for the workup of dramatic changes in blood pressure can ensure
coverage. In MSA, cardiac 123I-MIBG uptake is preserved, but in PD it is
reduced. Therefore, this test is most useful to differentiate MSA from PD in a
patient with autonomic symptoms and parkinsonism. The outcome measure
for this image is the heart to mediastinum ratio, which is calculated by
dividing the count density of the left ventricle by the count density of the
mediastinum. A ratio of 1.7 is an accepted cutoff, but care must be taken to
account for exogenous factors that can impact this ratio (eg, myocardial
infarction or use of medications that alter norepinephrine may result in an
inaccurate ratio calculation).60
EMERGING DIAGNOSTIC OPTIONS FOR MULTIPLE SYSTEM ATROPHY

One emerging biomarker that may have future clinical implications is
neurofilament light chain (NfL), a marker of axonal degeneration. Elevated
CSF NfL may distinguish MSA from other α-synucleinopathies (such as PD)
but, more important, may also provide insights into the severity of disease.61
Given that the full clinical implications of this assay have not yet been
determined and that it is not yet clinically available, it remains an assay for

KEY POINT research purposes (target validation, assessing disease progression, and
stratifying patients).
● The use of activity of daily
living screening tools for
Another recent development is the use of skin biopsies, which are emerging as
patients, such as the Unified a tool to identify α-synucleinopathies by identifying phosphorylated α-synuclein
Multiple System Atrophy in cutaneous nerves. These studies, although relatively new in their application
Rating Scale Part 1, can help to MSA, suggest that a diagnostic benefit may exist. For example, in a patient
direct care of patients
who presents early with gait impairment and RBD, a skin biopsy may help
with MSA.
identify the presence of phosphorylated α-synuclein. Second, abnormal α-
synuclein deposits are located mainly in the somatic terminals in MSA but are
located in autonomic fibers in PD and other synucleinopathies.62 Thus, skin
biopsies can offer important diagnostic clues for the clinician and have the
potential to distinguish between MSA and PD in a patient with parkinsonism.
Further research is necessary to determine the proper techniques; ideal analysis
approach; and the accuracy, sensitivity, and specificity for diagnosis.
CONCLUSION
The management of MSA highlights an imperative need in clinical practice: to
develop interdisciplinary teams that focus on patient-centered care. This can
be challenging given the complexities of clinical systems that are often confined
to rigid template utilization and disjointed clinical space; much effort and
imagination are necessary on the part of the MSA clinician. However, the effort
of developing this system can reap large rewards that benefit patients with MSA.
Several practical recommendations should be considered in this effort. First,
simple screening tools for patients should be incorporated, such as the Unified
Multiple System Atrophy Rating Scale (UMSARS) Part 1. This can help identify
current challenges with swallowing, gait, urinary issues, and communication
and prioritize visits for clinical care. Second, a social worker or case manager
should be incorporated into clinical practice. The psychosocial impact of this
disease is profound. Providing counseling on disclosing the disease to the
patient and patient’s children, managing clinical decline, addressing
demoralization from dealing with a chronic disease, finding and accessing
critical resources for care, managing and setting palliative care goals, and
receiving integrated support from a medical system are tasks that require time
and dedicated effort from staff.
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DISCLOSURE
Continued from page 1350 Foundation; the Huntington’s Disease Society of
America; the National Institutes of Health,
Dr Claassen has received research support from Neurocrine Biosciences, Inc/Huntington Study
AbbVie Inc; the CHDI Foundation; Genentech, Inc/ Group; Prilenia Therapeutics; the US Department of
R. Hoffman-La Roche Ltd; the Griffin Family Defense; and Vaccinex Inc.

REVIEW ARTICLE

Progressive Supranuclear
ONLINE
Palsy and Corticobasal

VIDEO CONTENT
Syndrome
A VA I L A B L E O N L I N E By Alexander Pantelyat, MD, FAAN
CITE AS:
CONTINUUM (MINNEAP MINN) ABSTRACT
2022;28(5, MOVEMENT DISORDERS): PURPOSE OF REVIEW: The differential diagnosis of parkinsonism (tremor, rigidity,
1364–1378.
bradykinesia, and gait difficulty/postural instability) is broad and includes
Address correspondence to two neurodegenerative conditions that exist on a clinicopathologic
Dr Alexander Pantelyat, 600 N
Wolfe St, Meyer 6-181C, Baltimore,
spectrum: progressive supranuclear palsy (PSP) and corticobasal
MD 21287, apantel1@jhmi.edu. syndrome (CBS). Early in their clinical course, PSP and CBS may be difficult
to distinguish from Parkinson disease and several other illnesses, but it is
Dr Pantelyat has received crucial to do so because of implications for management and prognosis.
RECENT FINDINGS:Early accurate diagnosis of PSP and CBS remains a
serving as a scientific advisory
board member for MedRhythms, challenge because of heterogeneity in presenting symptoms and high
Inc, and in the range of $10,000 frequency of coexisting pathologies (especially Alzheimer disease and
to $49,999 for serving as an
expert witness for Kelly &
vascular disease). It is increasingly recognized that patients with PSP, CBS,
Ignoffo Law Group. The and other parkinsonian disorders require multidisciplinary care for optimal
institution of Dr Pantelyat has outcomes. With the recent proliferation of biomarker studies and
received research support from
the National Institutes of Health/ therapeutic trials for tauopathies, there is growing hope that better
National Institute on Aging. treatments for PSP and CBS are on the horizon.
UNLABELED USE OF
PRODUCTS/INVESTIGATIONAL SUMMARY: Although PSP and CBS currently lack disease-modifying
USE DISCLOSURE: therapies, it is important to diagnose them as early as possible so that the
Dr Pantelyat discusses the
patient can benefit from the many available symptomatic therapies,
dextromethorphan/quinidine or support groups, and a growing number of clinical trials.
selective serotonin reuptake
inhibitors (SSRIs) for the
treatment of pseudobulbar
affect in progressive INTRODUCTION
P
supranuclear palsy (PSP) and
corticobasal syndrome (CBS);
rogressive supranuclear palsy (PSP) and corticobasal syndrome/
methylphenidate or modafinil corticobasal degeneration (CBS/CBD) are atypical parkinsonian
for the treatment of apathy in disorders that are often grouped together on the basis of shared
PSP and CBS; miglustat for
Niemann-Pick disease type C; clinical and pathologic (4-repeat tau in both PSP and CBD) features.
onabotulinumtoxinA for the They have considerable clinical overlap with each other and can also
treatment of sialorrhea, cervical
be difficult to distinguish from Parkinson disease, other degenerative
and limb dystonia/spasticity,
muscle pain, and eyelid opening parkinsonian disorders (such as dementia with Lewy bodies and multiple system
apraxia/blepharospasm in PSP atrophy [MSA]), normal pressure hydrocephalus, and vascular parkinsonism.
and CBS; and SSRIs for the
treatment of depression and
However, it is important to identify PSP and CBS clinically to select appropriate
anxiety in PSP and CBS. management options (importantly, avoiding medications that may worsen
symptoms), counsel patients and their families regarding prognosis, and refer for
© 2022 American Academy biomarker studies and clinical trials whenever appropriate. Although PSP and
of Neurology. CBS significantly impair patients’ daily functioning and often shorten the life
1364 OCTOBER 2022

span, care for these patients is far from futile because effective symptomatic KEY POINTS
therapies and management strategies already exist and can meaningfully
● The pathologic hallmark
improve quality of life. of progressive supranuclear
PSP–Richardson syndrome (PSP-RS, or classic PSP) was first described in a palsy is the presence of tau
case series in 19641 and referred to a clinical description of postural instability, protein isoforms with four
vertical gaze palsy and pseudobulbar palsy, parkinsonism with axial rigidity, and microtubule-binding
repeats (4-repeat tau), in
frontal-executive cognitive impairment; the condition was associated with
astrocytic tufts (most
regional neuronal loss in the midbrain, basal ganglia, cerebellum, and cortex. The specific for progressive
first description of CBS was in 1925, when Lhermitte and colleagues2 described a supranuclear palsy),
72-year-old patient with loss of arm function along with rigidity, ideomotor oligodendrocytic coils, and
neurofibrillary tangles (least
apraxia, cortical sensory loss, muscle jerks, and alien limb phenomenon. Four
specific).
decades later in 1968, Rebeiz and colleagues3 described the condition currently
known as CBD in three patients with the above-mentioned clinical features and ● It is important to perform
neurodegeneration in the frontoparietal cortices, substantia nigra, and cerebellar genetic testing in patients
dentate, along with swollen cortical cells (now referred to as balloon neurons) on with early age at symptom
onset or a clear family
brain autopsy. Since then, there have been major strides in clarifying the history of atypical
pathology and pathophysiology, describing clinical biomarkers and symptomatic parkinsonism. Among
treatments, and forming support groups for those affected by PSP and CBS, but genetic mimics of
disease-modifying treatments remain elusive. Despite several disappointments progressive supranuclear
palsy, Niemann-Pick disease
over the past decade, clinical trials remain a beacon of hope for patients affected type C stands out, as it is a
by these diseases. treatable condition.
PROGRESSIVE SUPRANUCLEAR PALSY ● Progressive supranuclear

palsy–Richardson syndrome
This section describes the epidemiology, pathology, genetics, clinical
(classic progressive
presentations, and prognosis of PSP. supranuclear palsy) refers to
akinetic-rigid parkinsonism
Epidemiology with early falls and vertical
PSP has a prevalence of 5 to 7 per 100,000.4 The annual incidence increases with eye movement impairment.
age (the key risk factor identified to date) from about 2 per 100,000 in the sixth ● Current clinical diagnostic
decade of life to about 15 per 100,000 in the ninth decade. These incidence and criteria for progressive
prevalence rates may significantly underestimate the true rates because the supranuclear palsy include
phenotypic range of PSP was formally expanded only 4 years ago, and PSP-RS levels of diagnostic
certainty that offer
(classic PSP) may account for only about 50% of PSP cases. Average age at trade-offs between
symptom onset is 65 years, and cases with age at onset before 40 years are highly specificity and sensitivity.
unusual. Early-onset PSP is defined as that with symptoms beginning at age
55 years or earlier.5 To date, no clear sex predominance or notable sex differences ● Optokinetic nystagmus
testing can be helpful in
in disease onset and duration or clinical progression have been identified. Data on
assessing saccades if gross
racial and ethnic differences in PSP epidemiology are lacking. saccade testing is equivocal.
Aside from age, the key risk factor for all neurodegenerative forms of
parkinsonism, specific risk factors for PSP have remained elusive. Lower ● Progressive supranuclear
education levels (high school completion or lower versus college completion or palsy–parkinsonism is the
second most common
higher) are associated with incident PSP, and studies have indicated associations progressive supranuclear
with duration of exposure to well water and industrial waste. In a study of 150 palsy variant and can be
women with clinically diagnosed PSP and 150 age-matched control women, any difficult to distinguish from
exposure to estrogen replacement therapy was associated with a halved risk of Parkinson disease for
several years from symptom
PSP (odds ratio, 0.52; 95% CI, 0.30-0.92; P=.03).6 onset.
Pathology and Genetics

As for other neurodegenerative parkinsonian disorders, definite diagnosis of PSP
requires neuropathologic examination on autopsy. The pathologic hallmark of

PROGRESSIVE SUPRANUCLEAR PALSY AND CORTICOBASAL SYNDROME
PSP is presence of microtubule-associated protein tau aggregates, mostly

containing isoforms with four microtubule-binding repeats (4-repeat tau), in
astrocytic tufts (most specific for PSP), oligodendrocytic coils, and
neurofibrillary tangles (least specific).7 Additional pathologic features include
straight filaments and globose tangles. The most common brain areas affected by
4-repeat tau pathology in PSP are the midbrain (substantia nigra, oculomotor
complex, and the rostral interstitial nucleus of the medial longitudinal fasciculus,
which specifically controls vertical gaze), subthalamic nucleus, internal globus
pallidus, cerebellum (dentate nucleus), periaqueductal gray matter, superior
colliculi, base of the pons, and prefrontal cortex. Pathologically, PSP is a
proteinopathy (specifically, 4-repeat tauopathy) on the spectrum of FTLD; other
proteinopathies on this spectrum include FTLD-TDP-43 and FTLD-FUS8
(FIGURE 7-19).
PSP is defined as a sporadic disorder, and the complete mechanism of tau
accumulation remains to be determined. Tau is a key structural protein involved
in stabilizing microtubules and axonal transport. Normal tau contains six
isoforms that are formed by alternative splicing of the microtubule-associated
protein tau (MAPT) gene on chromosome 17. Tau aggregates in PSP involve
FIGURE 7-1
Clinical, genetic, and pathologic spectrum of misfolded proteins in neurodegenerative
disease. PSP and CBD are highlighted with a red square on the phenotype row. Several
neurodegenerative diseases are associated with a misfolded and aggregated protein, such
that the same misfolded protein is found in different clinical phenotypes and the same
phenotype might be the result of different misfolded proteins.
AD = Alzheimer disease; ALS = amyotrophic lateral sclerosis; bvFTD = behavioral frontotemporal dementia;
CBD = corticobasal degeneration; CJD = Creutzfeldt-Jakob disease; DLB = dementia with Lewy bodies;
FTD MND = frontotemporal dementia with motor neuron disease; GSS = Gerstmann-Sträussler-Scheinker
disease; LPA = logopenic aphasia; NFT = neurofibrillary tangle; PD = Parkinson disease; PDD = Parkinson
disease dementia; PNFA = progressive nonfluent aphasia; PSP = progressive supranuclear palsy; SD =
semantic dementia.
Reprinted with permission from Villemagne VL, et al, Lancet Neurol.9 © 2015 Elsevier Inc.
1366 OCTOBER 2022

abnormal tau phosphorylation; in addition, mitochondrial dysfunction, KEY POINTS
microglial activation, abnormal epigenetic modulation, and posttranslational
● The parkinsonism in
modification and transcellular tau spread are believed to contribute to the progressive supranuclear
development of PSP pathology.10 palsy–parkinsonism can be
The strongest genetic link to PSP across studies involves mutations in MAPT; tremor-predominant or
H1 haplotype homozygosity confers increased risk of developing both PSP and akinetic-rigid and may have
a levodopa response,
CBD, while H2 haplotype homozygosity makes PSP diagnosis less likely. In
although typically without
addition to MAPT mutations, C9orf72, GRN, FUS, TARDBP, VCP, and CHMP2B motor fluctuations or
mutations have been associated with clinical PSP syndromes.11-14 Genetic mimics dyskinesias.
of PSP are described in detail elsewhere,13 but several worth mentioning include
Kufor-Rakeb syndrome (ATP13A2 mutations), spinocerebellar ataxias (types 1-3, ● Frontal-executive
cognitive impairment is an
7, and 17), and Niemann-Pick disease type C, which is specifically associated with important feature of both
vertical gaze palsy. It is reasonable to consider genetic testing and to test for progressive supranuclear
NPC1 and NPC2 mutations in all early-onset or familial PSP cases because of palsy and corticobasal
disease-specific therapeutic options (miglustat is approved by the US Food and syndrome.
Drug Administration [FDA] for the treatment of Gaucher disease and by the ● Key differential diagnosis
European Medicines Agency for Niemann-Pick disease type C specifically). considerations for
Clinical Presentations palsy include Parkinson
disease, other degenerative
National Institute of Neurological Disorders and Stroke and Society for PSP
parkinsonian disorders (such
(NINDS-SPSP) criteria were published in 1996 and until recently remained the as dementia with Lewy
most widely used criteria for clinical PSP diagnosis.15 Probable PSP (ie, PSP-RS) bodies and multiple system
as defined by these criteria required the presence of vertical supranuclear gaze atrophy), normal pressure
hydrocephalus, and vascular
palsy with postural instability and repeated falls within the first year of symptom
parkinsonism.
onset. Although these criteria were autopsy-validated and had specificity of 95%
to 100% for probable PSP, they lacked sensitivity (only 24%), particularly at the ● The easily measured ratio
initial visit.16 Recognizing these limitations and the broader range of PSP of midsagittal midbrain to
presentations (particularly in the first 3 to 4 years of symptom onset), the pontine base distances on
T1-weighted MRI of less than
International Parkinson and Movement Disorder Society (MDS)–endorsed PSP 0.5 is highly sensitive and
Study Group developed new diagnostic PSP criteria, published in 2017.16 These specific for progressive
criteria define eight PSP variants and group clinical PSP features into four supranuclear palsy–
functional domains (ocular, postural instability, akinesia, and cognitive Richardson syndrome but
not other progressive
dysfunction). Each domain has three features arranged by levels of diagnostic supranuclear palsy variants.
certainty; when domains are considered together and key clinical features are
determined for a given patient based on history and examination, this allows the ● Corticobasal syndrome
clinician to define the PSP predominance (or variant) as well as the degree of refers to the patient’s
clinical presentation and
diagnostic certainty (probable PSP, most specific/likely to be confirmed by
typically includes
autopsy and advisable for clinical trial and diagnostic biomarker study asymmetric presentation of
enrollment; possible PSP, useful for clinical care and epidemiologic studies; and limb rigidity, akinesia,
suggestive of PSP, most sensitive/suitable for earliest possible clinical dystonia, myoclonus, and
identification but lacking in specificity).16,17 In a multisite autopsy cohort, the apraxia. Corticobasal
degeneration is the term
clinical MDS PSP criteria had overall sensitivity of 88% (far superior to referring to specific
NINDS-SPSP criteria) and specificity of 86% (similar to NINDS-SPSP criteria).18 4-repeat tau pathology on
Supranuclear gaze palsy and selective vertical saccade slowing and amplitude brain autopsy.
reduction are the most specific clinical PSP features overall, with downward
saccade dysfunction being more specific than upward dysfunction.16,19
The predominance types as defined by the MDS PSP criteria include PSP-RS,
PSP with predominant parkinsonism (PSP-P), PSP with predominant frontal
presentation (PSP-F), PSP with progressive gait freezing (PSP-PGF) (all
diagnosable with the highest level of clinical certainty—probable PSP); PSP with

predominant corticobasal syndrome (PSP-CBS) and PSP with predominant

speech-language disorder (PSP-SL) (diagnosable at the intermediate level of
certainty—possible PSP); and PSP with predominant ocular motor dysfunction
(PSP-OM) and PSP with predominant postural instability (PSP-PI) (diagnosable
at the lowest level of certainty—suggestive of PSP).16 These suggestive variants
contain clinical features that may represent early evidence of PSP and often
develop into PSP-RS over time. The clinical PSP variant for a patient may change
over time as additional clinical features emerge, typically converging on
PSP-RS.17 Additional phenotypes include the PSP cerebellar variant, but the
CASE 7-1 A 65-year-old man presented for a neurologic consultation because of a

2.5-year history of unprovoked falls occurring both backward and
forward. He would quickly stand up on his heels from a seated position
and often fell back into the seat. While eating, he began to leave food on
the part of the plate closest to him and developed messy eating habits
(overstuffing his mouth and spilling food onto his clothes) over the past
6 months. He described a chronic sense of “dizziness” that was not
positional. He also became more withdrawn, participated in
conversations less frequently, and developed a tendency to laugh at
inappropriate times. He denied loss of smell or dream enactment. The
patient had a past medical history of hyperlipidemia but no family history
of parkinsonian disorders or dementia.
On neurologic examination, the patient was fully oriented and scored
23 of 30 on the Montreal Cognitive Assessment, with points lost for
visuospatial/executive, attention, and verbal fluency items. There was
bilateral ideomotor limb dyspraxia. Ocular pursuits were partially limited
in the vertical plane (with intact oculocephalic reflex), and gross saccade
testing revealed selective slowing and amplitude reduction of downward
saccades compared with horizontal saccades. There was mild hypomimia
with reduced blink rate and moderate hypokinetic dysarthria. He had
moderate neck rigidity and mild leg rigidity, while arm tone was within
normal limits. There was moderate hypokinesia (amplitude reduction) out
of proportion to slowing on finger and toe tapping. Tremor and dysmetria
were absent. Dystonic posturing was present in the hands. He was unable
to rise from a chair without use of his hands, his posture was upright, and
his gait was slowed with reduced stride length and pulsion on turns. Pull
test was positive and descent into the chair was uncontrolled.
COMMENT This case demonstrates the typical history and examination of progressive
supranuclear palsy (PSP)–Richardson syndrome, the most common clinical
variant of PSP. The patient had repeated unprovoked falls within 3 years of
symptom onset and limited vertical pursuits; he thus meets clinical
diagnostic criteria for probable PSP–Richardson syndrome. He lacks
clinical synucleinopathy markers, and another parkinsonian disorder is
unlikely. His age at symptom onset is typical for PSP.
1368 OCTOBER 2022

paucity of autopsy-confirmed cases and unclear clinical differentiation from KEY POINTS
MSA cerebellar type led to its omission from the MDS criteria.16
● Corticobasal
PSP-RS likely accounts for about 50% of overall PSP presentations and is degeneration is most
defined as the combination of vertical supranuclear gaze palsy or vertical greater specifically characterized
than horizontal saccade slowing and amplitude reduction, plus either by astrocytic plaques,
unprovoked falls or a positive pull test within 3 years of symptom onset whereas progressive
supranuclear palsy has
(CASE 7-1).16-19 Optokinetic nystagmus testing can be helpful in assessing
tufted astrocytes.
saccades if gross saccade testing is equivocal.16 As PSP-RS progresses, horizontal
saccades and pursuits can become severely impaired as well (reflecting pontine ● Corticobasal
degeneration), at times leading to complete ophthalmoplegia. PSP-P is the degeneration pathology
second most common PSP variant in large cohort studies and accounts for about accounts for only about 50%
of corticobasal syndrome
20% of autopsy-confirmed cases. This is the variant most difficult to distinguish cases. The remainder of
from Parkinson disease in the first several years of symptoms; probable PSP-P is corticobasal syndrome
defined by the combination of either vertical supranuclear gaze palsy or selective cases are due to progressive
vertical saccade impairment, plus clinically notable parkinsonism (CASE 7-2). supranuclear palsy,
Alzheimer disease, and
The parkinsonism in PSP-P can be tremor-predominant (with resting tremor) or rarely other pathologies.
akinetic-rigid and may have a levodopa response (although typically without
motor fluctuations or dyskinesias), particularly in the first 5 years of symptom ● Although it is a classic
onset.16 Possible PSP-CBS is alternatively defined as a probable 4-repeat sign, alien limb phenomenon
occurs in only about 20% of
tauopathy in recognition of this syndrome’s strong association with both PSP and
patients with
CBD pathologies; notably, a PSP-RS–like syndrome is described in the CBS autopsy-confirmed
criteria (see CBS/CBD section below), further underscoring the clinical overlap corticobasal degeneration.
between PSP and CBS and justifying the umbrella designation of probable
4-repeat tauopathy. Frontal-executive cognitive impairment is common in both ● When completing a
levodopa trial in progressive
PSP and CBS and is often present early in the disease course. Additional PSP supranuclear palsy or
variants are described in TABLE 7-1.16 corticobasal syndrome,
Additional PSP features include cervical dystonia (typically retrocollis, as maintain maximum tolerated
distinguished from the anterocollis common in MSA), hypokinetic dysarthria (at levodopa dose for at least
1 month before gradual
times described as growling speech), oropharyngeal dysphagia, neurogenic tapering.
bladder dysfunction, pseudobulbar affect, and insomnia (typically without rapid
eye movement [REM] sleep behavior disorder, although this has been reported in ● Dopaminergic
autopsy-defined PSP). Signs of PSP on examination also include the procerus medications other than
levodopa are best avoided
sign (vertical forehead furrowing associated with corrugator supercilii muscle
in progressive supranuclear
contraction), which is often associated with a surprised look on the face; eyelid palsy and corticobasal
opening apraxia/lid levator inhibition and blepharospasm; rocket sign (patient syndrome because of side
impulsively arises from a seated position and falls backward), applause sign effects and lack of efficacy.
(excessive clapping when asked to repeat the same number of claps as the
● Anticholinergic
examiner—a nonspecific sign of frontal disinhibition seen in other disorders), medications should be
and a grasp reflex. avoided in progressive
Key differential diagnosis considerations for PSP include Parkinson disease, supranuclear palsy and
other degenerative parkinsonian disorders (such as dementia with Lewy bodies corticobasal syndrome
whenever possible because
and MSA), normal pressure hydrocephalus, and vascular parkinsonism. MRI in of the risk of worsening
PSP-RS demonstrates midbrain atrophy (described as “hummingbird” or cognitive impairment.
“penguin” signs on midsagittal images and as “Mickey Mouse” or “morning
glory” signs on axial images) (FIGURE 7-220). Two independent pathologically
confirmed cohort studies found that the easily measured ratio of midsagittal
midbrain to pontine base distances on T1-weighted MRI of less than 0.5 is highly
sensitive and specific for PSP.21,22 Changes in midbrain, third ventricle, and
frontal lobe volumes also track well with PSP-RS progression.23 However,
these imaging findings are less reliable for PSP variants. Free-water diffusion

on MRI may be helpful for distinguishing between Parkinson disease,

MSA-parkinsonism, and PSP and is currently under further investigation.24 Tau
positron emission tomographic (PET) imaging has been studied in PSP and other
tauopathies in recent years; although there have been promising group-level
findings, current ligands do not appear as sensitive to pure 4-repeat tauopathies
compared with mixed 3-repeat/4-repeat tauopathies (eg, Alzheimer disease). In
addition, off-target ligand binding and group-level binding ratio overlaps have
thus far limited clinical applications for patient-level diagnosis using tau PET.
Dopamine transporter imaging is typically abnormal in PSP but does not
differentiate between degenerative parkinsonian syndromes.
CASE 7-2 A 72-year-old woman presented to the movement disorders clinic for a
second opinion regarding suspected Parkinson disease. Her main
complaints included about 4 years of right-hand tremor, right-sided arm
and leg stiffness, loss of fine motor coordination, and some balance loss
without falls. In the past 9 months she had also begun to experience
horizontal double vision that resolved on closing either eye. She had no
significant past medical history or pertinent family history and no
reported loss of smell, dream enactment, or prior dopamine blocker
exposure. She had been taking carbidopa/levodopa, 25/100 mg, 3 tablets
3 times per day, for 2 years and felt that it was providing some benefit for
her tremor, without clear kicking in or wearing off between doses and
without reported dyskinesias.
On neurologic examination, her mental status was intact, and she did
not have ideomotor apraxia. Ocular pursuits were within normal limits.
Gross saccade testing revealed mild amplitude and velocity reduction of
vertical saccades relative to horizontal saccade performance, and this
was supported by optokinetic nystagmus testing. She had slight
hypokinetic dysarthria, mild hypophonia, and slight hypomimia. She had
mild neck and moderate right arm and leg rigidity (with cogwheeling at
the wrist), right greater than left bradykinesia on finger and toe tapping,
right arm dystonia most prominent on walking (elbow flexion, wrist
flexion, and finger flexion), and a mild resting tremor in the right hand.
There was no dysmetria or dysdiadochokinesia. She was able to rise
quickly without using her arms, and her gait was moderately slowed with
multistep turns. Pull test was negative.
COMMENT This patient presented with all four cardinal parkinsonian signs and some
tremor response to levodopa, without motor fluctuations. Her selective
vertical saccade slowing is an absolute exclusion criterion for the diagnosis
of Parkinson disease, and she meets clinical diagnostic criteria for probable
progressive supranuclear palsy (PSP)–parkinsonism based on saccade
abnormalities and presence of asymmetric partially levodopa-responsive
parkinsonism with tremor. PSP-parkinsonism is the second most common
PSP variant and can be particularly difficult to distinguish from Parkinson
disease for several years from symptom onset.
1370 OCTOBER 2022

Prognosis
PSP is a progressive disease that severely affects quality of life and leads to
dependence on others for daily activities. PSP-RS carries the worst prognosis
among PSP variants, with dependence for care occurring within about 4 years
from symptom onset and death within about 7.5 (interquartile range, 6-9) years
from symptom onset.25 PSP-P is associated with the most benign prognosis
among PSP variants, and patients can remain independent for several years;
survival of more than 10 years is not uncommon.25 A recent UK study26 involving
Diagnosis of Progressive Supranuclear Palsy Variants (Predominance Types)a,b TABLE 7-1
Diagnostic Variant (predominance

certainty level type) Description
Definite PSP Any clinical presentation Neuropathologic diagnosis
Probable PSP PSP–Richardson syndrome Vertical supranuclear gaze palsy or selective vertical saccade
impairment + unprovoked falls or a positive pull test within 3 years
of symptom onset
PSP-parkinsonism Vertical supranuclear gaze palsy or selective vertical saccade
impairment + clinically notable parkinsonism (tremor-predominant
or akinetic-rigid, levodopa-resistant or levodopa-responsive)
PSP–frontal presentation Vertical supranuclear gaze palsy or selective vertical saccade
impairment + at least 3 of the following features that persist over
time: (1) apathy, (2) bradyphrenia (slowed thinking), (3) dysexecutive
syndrome, (4) reduced phonemic verbal fluency, (5) impulsivity,
disinhibition, or perseveration
PSP–progressive gait freezing Vertical supranuclear gaze palsy or selective vertical saccade
impairment + progressive gait freezing starting within 3 years of
symptom onset that is levodopa-resistant and associated with
absent or mild limb rigidity, tremor, and dementia
PSP–speech language disorder Vertical supranuclear gaze palsy or selective vertical saccade
impairment + progressive speech/language disorder including
nonfluent/agrammatic primary progressive aphasia and/or
apraxia of speech
Possible PSP PSP–corticobasal syndrome; Vertical supranuclear gaze palsy or selective vertical saccade
probable 4-repeat tauopathy impairment + at least one sign from the following two groups: (1) limb
or orobuccal apraxia; cortical sensory deficit; alien limb phenomenon
(semipurposeful movements beyond limb levitation), and (2) limb
rigidity; limb akinesia/bradykinesia; limb myoclonus
PSP–speech language disorder Vertical supranuclear gaze palsy or selective vertical saccade
impairment + progressive speech/language disorder including
nonfluent/agrammatic primary progressive aphasia and/or
apraxia of speech
Suggestive of PSP PSP–Ocular motor dysfunction Selective vertical saccade impairment or frequent macro
square-wave jerks or eyelid-opening apraxia
PSP–postural instability Unprovoked falls or a positive pull test within 3 years
of symptom onset
PSP = progressive supranuclear palsy.

a
Data from Höglinger GU, et al, Mov Disord.16
b
Levels of diagnostic certainty reflect strength of clinicopathologic correlation for a given variant/predominance type. Note that several
additional combinations of diagnostic certainty levels and clinical presentations from Höglinger and colleagues16 are omitted for clarity.

FIGURE 7-2
Imaging features of progressive supranuclear palsy. T1-weighted images of the brain in a
patient with clinically diagnosed progressive supranuclear palsy. A, Sagittal image shows
hummingbird sign (box). B, Axial image shows morning glory sign (arrows).
Reprinted from Saeed U, et al, Transl Neurodegener.20 © 2017 The Authors.
227 patients (20% with pathologic confirmation) followed for a mean (SD) time of
21.6 (15.6) months found that PSP variants other than RS had significantly longer
survival and slower progression on the PSP Rating Scale.27 Patients with non-RS
variants also took longer to present to subspecialty clinics. These effects were driven
mainly by “subcortical” PSP variants (PSP-P, PSP-PGF, PSP-PI, and PSP-OM) that
were characterized by slower motor and cognitive progression. Notably, 77% of this
cohort had PSP-RS, and thus other variants were grouped into subcortical and
cortical clusters because of small sample sizes of individual variants.
Early falls and dementia and early onset of dysphagia are important predictors
of survival in PSP, whereas supranuclear gaze palsy is not clearly associated with
prognosis, nor is levodopa response.25
CORTICOBASAL SYNDROME/DEGENERATION
The term corticobasal syndrome (CBS) refers to the clinical presentation, whereas
the term corticobasal degeneration (CBD) refers to specific 4-repeat tau pathology
identified at autopsy (see below). CBS is frequently associated with pathology
other than CBD, necessitating this distinction in terminology.
Epidemiology
CBS is less common than PSP, with an estimated annual incidence of less than 1
per 100,000. It accounts for about 5% of parkinsonism evaluated in movement
disorder clinics. Prevalence is estimated at 5 to 7 per 100,000, but estimates are
limited by the clinicopathologic heterogeneity of the disorder. Several early
studies suggested that CBS is more common in women, but recent data indicate
that prevalence among sexes is similar.28 There are no known racial or ethnic risk
factors for CBS, and clear evidence for environmental risk factors is absent.
Average age at onset is 64 years, and onset before age 45 is vanishingly rare.
Pathology and Genetics

As with PSP, CBD pathology is characterized by the presence of
hyperphosphorylated 4-repeat tau inclusions.29 These are present in astrocytes,
1372 OCTOBER 2022

glia, and neurons, with the latter two affected in more advanced stages of disease. KEY POINTS
Astrocytic tau pathology is important for discriminating PSP and CBD (although
● Pseudobulbar affect is a
overlap exists—CBD pathology is distinguishable from PSP with only 90% symptom of both
specificity according to established criteria): CBD is characterized by astrocytic progressive supranuclear
plaques, whereas PSP has tufted astrocytes.29 Oligodendroglial tau inclusions palsy and corticobasal
called coiled bodies can also help distinguish CBD from PSP pathology. The syndrome and may improve
with selective serotonin
originally described ballooned or achromatic neurons are less specific. CBD
reuptake inhibitors or
generally has more cortical pathology than PSP, although recognition of cortical dextromethorphan/
PSP variants such as PSP-CBS and PSP-SL has rendered this distinction less quinidine.
relevant. Perirolandic cortex and basal ganglia are usually affected earlier in the
disease course, with subsequent posterior spread into the parietal lobes. Cortical ● Depression and anxiety
are common in progressive
involvement can predominate over basal ganglia involvement early on. There is supranuclear palsy and
often asymmetric hemispheric distribution for reasons that remain to be clarified. corticobasal syndrome;
Like PSP, CBS is considered a sporadic disorder. Genetic mimics of PSP are selective serotonin reuptake
described in detail elsewhere.30 To summarize, genetics of CBS/CBD have strong inhibitors can be effective at
standard doses.
overlap with those of PSP; MAPT H1/H1 haplotype homozygosity has been
linked to CBD, and multiple MAPT mutations have been reported in families and ● Modafinil or
single cases. GRN mutations, LRRK2 mutations (usually associated with familial methylphenidate may be
Parkinson disease), and C9orf72 repeat expansions have rarely been reported.30 A helpful for apathy in
genome-wide association study found a shared genetic risk factor for CBD and
palsy and corticobasal
PSP at 3p22 of the myelin-associated oligodendrocyte basic protein (MOBP) gene syndrome.
in addition to MAPT.31
CBS is associated with CBD pathology in only about 50% of cases, with PSP and ● Botulinum toxin injections
Alzheimer disease pathology each accounting for 20% to 25% of cases and rarer can help a range of
symptoms in progressive
associations with TDP-43, Pick disease, and Lewy body pathology.29 supranuclear palsy and
corticobasal syndrome,
Clinical Presentations including sialorrhea, cervical
Consensus criteria from 201332 defined several clinical presentations and limb dystonia/
spasticity, muscle pain, and
associated with CBD pathology. Probable CBS is characterized by an eyelid opening apraxia/
asymmetric presentation and at least two of (a) limb rigidity or akinesia, limb blepharospasm.
dystonia, and limb myoclonus, plus two of (b) orobuccal or limb apraxia,
cortical sensory deficit, and alien limb phenomenon (semipurposeful ● Rehabilitation plays a key
role in improving and
movements beyond limb levitation) (CASE 7-3).32 Additional variants are
maintaining function in
described in TABLE 7-232 and have overlap with PSP variants described above. progressive supranuclear
Although these criteria usefully broaden the clinical heterogeneity associated palsy and corticobasal
with CBD pathology, they lack specificity, necessitating further refinements syndrome and should be
maintained throughout the
in the future.33
entire disease course.
Alien limb phenomenon is a classic sign of CBS that reflects parietal lobe
pathology but is present in only about 20% of patients with autopsy-confirmed ● Physical therapy targets
CBD.32 It can affect the arms or legs and is associated with lack of awareness of gait and balance
movement on the patient’s part; when attention is brought to the limb, patients rehabilitation and fall
prevention in progressive
often report strong feelings of disgust and rejection of the limb as their own. supranuclear palsy and
Apraxia in CBS can affect the limbs (most common; can be ideomotor, corticobasal syndrome.
nonrepresentational, or both) as well as speech, gait, eyelid, and ocular
movements (although whether ocular apraxia constitutes true apraxia is ● Occupational therapy
targets upper extremity
controversial) (VIDEO 7-134). Prominent apraxia can also be present in PSP.
function, range of motion,
Myoclonus in CBS is thought to be cortical in origin. Clinically notable dystonia is and adaptive device use in
present in many patients but is difficult to differentiate from rigidity and progressive supranuclear
spasticity. The parkinsonism in CBS is usually highly asymmetric. Additional palsy and corticobasal
syndrome.
features may include optic ataxia, oculomotor apraxia and simultanagnosia

(Balint syndrome, as associated with posterior cortical atrophy on MRI),

memory loss (thought to be observed more often in CBS with underlying
Alzheimer disease pathology), calculation difficulties, writing difficulties,
right-left confusion, finger agnosia, gait apraxia, and pseudobulbar affect. The
frontal behavioral-spatial syndrome is difficult to distinguish from behavioral
variant frontotemporal dementia but typically has prominent visuospatial
deficits that are absent in the latter.33
MRI in CBS lacks specific findings, although frontoparietal atrophy out of
proportion to atrophy elsewhere is common (FIGURE 7-335). Although clinical
presentation in CBS is typically asymmetric, the degree of asymmetry on MRI
does not correlate well with clinical findings. Recent studies using in vivo tau
PET to differentiate between CBD and Alzheimer disease on a group level
are promising and reviewed elsewhere36; patient-level differentiation between
PSP and CBD in vivo remains elusive. Dopamine transporter imaging may be
CASE 7-3 A 68-year-old left-handed man presented for a neurologic consultation

because of gradually progressive left-sided incoordination and loss of
function over the past 3 years, stating that his left hand “stopped
listening” to what he wanted it to do. He also reported recent memory
loss. In the past year, he had been forced to switch to using his
nondominant right hand for tasks including shaving, brushing his teeth,
and buttoning. He had had several recent driving accidents, misjudging
his vehicle’s distance from other cars and stationary objects. His balance
had been impaired over the past year, and he had sustained several falls
to the left side. There was no relevant past medical or family history.
On examination, his Montreal Cognitive Assessment score was 21 of 30,
with points lost for cube copy, clock numbers/hands, letter fluency, 2 of
5 correct serial 7s, and 1 of 5 word recall (with 2 of 4 cued recall). There
was no alien limb phenomenon. Pursuit and gross saccade testing were
within normal limits. He had cortical sensory loss (1 of 4 single-digit
numbers identified in the left palm; 3 of 4 in the right palm) and ideomotor
dyspraxia. There was infrequent myoclonic jerking in the left arm, which
was flexed at the elbow, wrist, and all metacarpophalangeal joints of the
hand. There was severe lead-pipe rigidity in the left arm, moderate
rigidity in the left leg, and slight rigidity on the right side. Finger tapping
could not be performed on the left and was slightly slowed on the right.
Deep tendon reflexes were 3+ on the left and 2+ on the right, and he had a
left-sided grasp reflex and left extensor plantar response. Gait was severely
slowed, there was freezing with turns, and the pull test was positive.
COMMENT This patient’s presentation is typical of corticobasal syndrome (CBS). He

meets probable CBS criteria based on asymmetric limb rigidity and akinesia,
limb dystonia, myoclonus, and apraxia as well as cortical sensory loss.
Parietal atrophy is expected on brain MRI review but may not reflect the
asymmetry of clinical findings. His memory loss and impaired verbal recall
may indicate that his CBS is due to underlying Alzheimer disease pathology.
1374 OCTOBER 2022

normal early in the course of CBS (prior to significant basal ganglia involvement)37
and does not differentiate among degenerative parkinsonian syndromes.
Prognosis
Survival in CBS is similar to that in PSP-RS, estimated at about 7 years from
symptom onset. There is significant variability in survival, with a reported range
in autopsy-supported CBD of between 2.5 and 12.5 years from symptom onset.
The most common cause of death in CBS is complications of immobility or
dysphagia, such as aspiration pneumonia and urosepsis.
MANAGEMENT OF PROGRESSIVE SUPRANUCLEAR PALSY AND

CORTICOBASAL SYNDROME
Although no disease-modifying treatment for PSP or CBS exists, many
management options can substantially improve patients’ quality of life and
daily functioning. A detailed review of PSP and CBS management can be
found in the recently published best practices consensus statement of the
CurePSP Centers of Care.38
A trial of levodopa (eg, as carbidopa/levodopa, 25/100 mg or 25/250 mg)
should be given to every patient with PSP and CBS to address parkinsonism.
This medication should be gradually increased to 900 to 1200 mg levodopa per
day in divided doses and maintained for at least 1 month before tapering if no
improvement is noted. Only about 10% of patients with PSP-RS report a subjective
levodopa response, but patients with PSP-P frequently have a significant response,
albeit typically without motor fluctuations as observed in Parkinson disease.
Parkinsonism in CBS is almost universally levodopa-unresponsive, although
tremor may respond to levodopa in some cases. Dopaminergic medications other
than levodopa are best avoided in PSP and CBS because of side effects and lack of
Clinical Syndromes Associated With Corticobasal Degeneration Pathologya TABLE 7-2
Syndrome Description
Probable corticobasal syndrome Asymmetric presentation of at least two of (a) limb rigidity or akinesia,
(b) limb dystonia, (c) limb myoclonus, plus two of (d) orobuccal or limb apraxia,
(e) cortical sensory deficit, (f ) alien limb phenomenon (semipurposeful
movements beyond limb levitation)
Possible corticobasal syndrome May be symmetric; one of (a) limb rigidity or akinesia, (b) limb dystonia,
(c) limb myoclonus, plus one of (d) orobuccal or limb apraxia, (e) cortical sensory
deficit, (f ) alien limb phenomenon
Frontal behavioral-spatial syndrome Two of (a) executive dysfunction, (b) behavioral or personality changes, (c)
visuospatial deficits
Nonfluent/agrammatic variant of primary Effortful, agrammatic speech plus one of (a) impaired grammar/sentence
progressive aphasia comprehension with relatively preserved single word comprehension or
(b) groping, distorted speech production (apraxia of speech)
Progressive supranuclear palsy syndrome Three of (a) axial or symmetric limb rigidity or bradykinesia, (b) postural
instability or falls, (c) urinary incontinence, (d) behavioral changes,
(e) supranuclear vertical gaze palsy or decreased vertical saccade velocity
a
Modified with permission from Armstrong MJ, et al, Neurology.32 © 2013 American Academy of Neurology.

FIGURE 7-3
Imaging features of corticobasal syndrome/degeneration. T1-weighted magnetization-
prepared rapid gradient-echo MRI sequence showing bilateral parietal-occipital atrophy in
coronal (A), sagittal (B, left hemisphere), and axial (C) views.
Modified with permission from Pantelyat A, et al, Neurology.35 © 2011 American Academy of Neurology.
efficacy. Anticholinergic medications should also be avoided in PSP and CBS

whenever possible because of risk of worsening cognitive impairment.
Pseudobulbar affect is a symptom of both PSP and CBS and may improve with
selective serotonin reuptake inhibitors (SSRIs) or dextromethorphan/quinidine.
Depression and anxiety are common in PSP and CBS; SSRIs can be effective at
standard doses. Modafinil or methylphenidate may be helpful for apathy in PSP
and CBS. Botulinum toxin injections can help a range of symptoms in PSP and
CBS, including sialorrhea, cervical and limb dystonia/spasticity, muscle pain, and
eyelid-opening apraxia/blepharospasm.
Rehabilitation plays a key role in improving and maintaining function in PSP
and CBS and should be maintained throughout the entire disease course. Physical
therapy targets gait and balance rehabilitation and fall prevention in PSP and
CBS. Occupational therapy targets upper extremity function, range of motion,
and adaptive device use in PSP and CBS. Speech/swallow therapy targets
dysarthria, aphasia, and dysphagia in PSP and CBS. Periodic swallow evaluations
help assess aspiration risk and guide dietary modifications for liquids and solids.
Online support groups for patients, care partners, and adult children of those
with PSP and CBS are available through the CurePSP website (psp.org). Although
there have been 2 recently failed clinical trials of anti-tau monoclonal antibodies in
PSP (tilavonemab and gosuranemab), there is reason for hope: the microtubule-
binding domain anti-tau bepranemab is under investigation in Europe; the
Rho-kinase inhibitor fasudil is being investigated for PSP and CBS; an antisense
oligonucleotide phase 1 trial in PSP is recruiting; and a number of other intervention
trials and longitudinal cohort studies are active on clinicaltrials.gov.
CONCLUSION
PSP and CBS are complex atypical parkinsonian disorders that share many clinical
features and have pathologic overlap. They are most often caused by abnormal
buildup of 4-repeat tau protein in specific brain regions. Multiple clinical variants
of both PSP and CBS have been formally recognized in diagnostic criteria that have
greatly expanded the original symptom descriptions of these disorders. Although
there are no disease-modifying treatments for PSP and CBS, multiple helpful
symptomatic management options are available and the number of clinical trials is
increasing, making early accurate diagnosis crucial.
1376 OCTOBER 2022

KEY POINTS
USEFUL RESOURCE
ATYPICAL PARKINSONIAN DISORDERS ● Speech/swallow therapy
This is a tutorial for medical professionals about
atypical parkinsonian disorders including PSP, CBS/ targets dysarthria, aphasia,
CBD, and MSA. It includes information about and dysphagia in progressive
diagnosis and management. Videos start at 42:58 supranuclear palsy and
and demonstrate key examination findings that help
diagnose PSP, CBS/CBD, and MSA clinically.
corticobasal syndrome.
youtube.com/watch?v=BtEiNlivgeI ● Periodic swallow

evaluations help assess
aspiration risk and guide
dietary modifications for
VIDEO LEGEND liquids and solids.
VIDEO 7-1
Corticobasal syndrome. Video shows a 75-year-
old woman clinically diagnosed with corticobasal
● The number of clinical
syndrome. Among other features, she illustrates trials for progressive
an asymmetric parkinsonism with a markedly supranuclear palsy and
dystonic right arm, myoclonus, ideomotor corticobasal syndrome is
apraxia, and cortical sensory loss.
growing, and it is important
Reproduced with permission from Williams DR, to refer patients for trial
Litvan I, Continuum (Minneap Minn).34 screening as early as
© 2013 American Academy of Neurology. possible.
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Brain Commun 2021;3(3):fcab206. doi:10.1093/ 694872. doi:10.3389/fneur.2021.694872
braincomms/fcab206
1378 OCTOBER 2022

Chorea REVIEW ARTICLE

By Erin Furr Stimming, MD, FAAN; Danny Bega, MD C O N T I N U UM A U D I O
ONLINE
ABSTRACT 
VIDEO CONTENT
PURPOSE OF REVIEW: Thisarticle provides an overview of the diagnostic and A V AI L A B L E O N L I N E
therapeutic approach to a patient with chorea. The phenomenology of
chorea is described in addition to other common hyperkinetic movements CITE AS:
that may be mistaken for or coexist with chorea. Chorea can be acquired or CONTINUUM (MINNEAP MINN)
hereditary. Key historical and clinical features that can aid in determining 2022;28(5, MOVEMENT DISORDERS):
1379–1408.
the etiology are reviewed, and pharmacologic and nonpharmacologic
treatment strategies are discussed. Address correspondence to
Dr Erin Furr Stimming, 6431
Fannin St, MSB 7.004, Houston,
RECENT FINDINGS: Clinical investigations are under way to target transcription
TX 77030, erin.e.furr@uth.tmc.
and translation of the mutant huntingtin protein as a potential disease- edu.
modifying strategy in Huntington disease (HD). Additional heritable factors
RELATIONSHIP DISCLOSURE :
have been revealed through genome-wide association studies. Symptom- Dr Furr Stimming has received
focused treatments for HD are are being studied, including a third vesicular personal compensation in the
monoamine transporter-2 (VMAT2) inhibitor for chorea attenuation and range of $500 to $4999 for
serving as a consultant for Teva
drugs to target irritability and cognitive impairment. Increased availability Pharmaceutical Industries Ltd
of genetic testing has led to increased awareness of HD mimics (eg, and Wave Life Sciences, on a
C9orf72 and IgLON5). scientific advisory board for
Amneal Pharmaceuticals LLC,
and on speakers bureaus for
SUMMARY: Chorea is a relatively common hyperkinetic disorder with a broad Sunovion Pharmaceuticals Inc
and Teva Pharmaceutical
differential. The first step in the approach to a patient with chorea is accurately Industries Ltd. Dr Furr Stimming
defining the phenomenology. Once it has been determined that the patient has served as an editor and
has chorea, the investigation into determining an etiology can begin. Factors author for McGraw Hill and
Oxford University Press. The
such as age of onset, time course, family history, unique clinical features, and institution of Dr Furr Stimming
imaging and laboratory findings can guide the diagnosis. Treatments for most has received research support
causes of chorea are purely symptomatic, although it is important to recognize from the CHDI Foundation;
Cures Within Reach; Huntington
causes that are reversible or have disease-modifying interventions. Study Group/Neurocrine
Biosciences, Inc; the
INTRODUCTION
C
UNLABELED USE OF
horea is a hyperkinetic movement disorder that derives its name PRODUCTS/INVESTIGATIONAL
from choreia, a Greek term for dance. Using the term chorea in USE DISCLOSURE :
medicine dates back to the Middle Ages when Chorea Sancti Viti, or Drs Furr Stimming and Bega
discuss the unlabeled/
dancing mania, occurred during the black plague epidemics. investigational use of
Although it is not clear whether this was mass functional neurologic amantadine, benzodiazepines,
botulinum toxin injections,
disorder or a temporal coincidence, the terminology was coined in this era and
cannabinoids, carbamazepine,
later used by Thomas Sydenham to describe a specific type of chorea.1 clozapine, deep brain
In modern-day neurology, chorea refers to involuntary random, irregular, stimulation, olanzapine,
quietipine, risperidone, and
purposeless movements that flow from one body part to the next. The valbenazine for the treatment of
unpredictable fragmented movements may involve the limbs, trunk, neck, face, Huntington disease and other
and tongue. The velocity of chorea can vary from fast (which may make it causes of chorea.
difficult to differentiate from myoclonus) to slow (which may make it difficult © 2022 American Academy
to differentiate from dystonia). The intensity, frequency, and amplitude of of Neurology.

CHOREA
chorea may vary from subtle low-amplitude movements of varying frequency

in the upper face to severe large-amplitude movements in the limbs and trunk.2-4
Chorea may initially manifest as fidgeting and go unnoticed or denied by
patients, despite usually being detectable by others. Some patients disguise
chorea by incorporating it into a voluntary movement. Motor impersistence is
another common associated feature of chorea (independent of the etiology) and
is demonstrated by the inability to maintain a grasp on the examiner’s hand
(ie, milkmaid’s grip) or sustain tongue protrusion.2,5
CHOREA VERSUS OTHER HYPERKINETIC MOVEMENTS

Differentiating chorea from other hyperkinetic movements can be challenging,
especially when various movements coexist. Recognizing the phenomenology of
the movements observed can direct the diagnostic approach and treatment strategy.
Dystonia
Dystonia is defined by sustained muscle contractions and abnormal postures that
are repetitive, patterned, twisting, and sometimes tremulous. Compared to
chorea, dystonic movements are generally slower. Dystonia may occur at rest;
however, it is typically triggered by voluntary actions. Unique features of
dystonia include an alleviating maneuver (previously described as a sensory
trick), a null point, and mirror movements.6,7 Of note, dystonic movements can
coexist with chorea.
Dyskinesia
Dyskinesia is a general term for abnormal movements, one of which is chorea.
The term is most frequently used for specific medication-induced hyperkinetic
conditions, such as levodopa-induced dyskinesia in Parkinson disease (PD) or
tardive dyskinesia induced by neuroleptic medications.8 Chorea and
choreoathetoid movements are the most common forms of levodopa-induced
dyskinesia9; however, dyskinesia is not synonymous with chorea.
Myoclonus
Myoclonus is a brief lightninglike jerk that is usually described as the quickest
movement a body part can produce, ranging from approximately 50 to 200
milliseconds.10 This movement disorder can be caused by muscle contraction
(positive myoclonus) or sudden interruption of muscle activity (negative
myoclonus). Asterixis, which often appears in metabolic encephalopathies, is a
form of negative myoclonus. Chorea also has fast movement fragments, but,
unlike in myoclonus, the movements occur together with slower movements to
produce a flowing quality.10,11
Tremor
Rhythmicity, oscillation, and predictability are important factors that distinguish
tremor from chorea. Tremors are generally classified by their location, the
posture in which they occur, amplitude, and frequency. Tremors may
accompany other movement disorders, such as dystonia.12
Tics
Tics are nonrhythmic, recurrent, patterned movements or vocalizations usually
associated with a premonitory urge and some degree of suppressibility. Tics may
1380 OCTOBER 2022

be simple or complex and can vary in type, severity, and anatomic location. The KEY POINTS
repetitiveness, accompanying urge, and suppressibility of tics differentiate them
● Chorea refers to random,
from chorea.13-15 irregular, purposeless
movements that flow from
Ballism one body part to the next.
Ballism, or ballismus, is a high-amplitude movement that usually involves
● Chorea is generalized in
proximal parts of the limbs (ie, shoulder or hip), often described as a flinging or
many patients; however, its
kicking movement.16 localized distribution may
act as an important
Athetosis diagnostic factor to
Athetosis is of lower amplitude than chorea and often distal, although it may determine the underlying
etiology. For example,
involve the trunk. It is a writhing movement with slow continuous flow rather forehead involvement is
than the fragmented sequence seen in chorea.17,18 Chorea may coexist more common in Huntington
with athetosis. disease. Orobuccolingual
chorea is more common in
tardive syndromes.
EVALUATING CHOREA
In addition to associated neurologic signs, the location or distribution of chorea
can be an important clue when narrowing the differential diagnosis.
Body Distribution
Chorea is generalized in many cases; however, its localized distribution may
act as an important diagnostic factor to determine the underlying etiology
(FIGURE 8-1).19,20
HEMICHOREA. Hemichorea has been classically associated with focal vascular

lesions of the contralateral subthalamic nucleus or basal ganglia. However,
vascular lesions in other territories, such as the thalamus or temporoparietal
cortex, have also been implicated in causing chorea.21 Other etiologies that
may cause hemichorea with focal lesions are nonketotic hyperglycemia and
opportunistic infections in the setting of human immunodeficiency virus
FIGURE 8-1
Distribution of chorea and potential causes.

CHOREA
(HIV) and acquired immunodeficiency syndrome (AIDS).16,22,23 Some

conditions may cause hemichorea in the absence of an apparent brain lesion.
Examples include autoimmune chorea (eg, Sydenham chorea), paraneoplastic
syndromes, and variant Creutzfeldt-Jakob disease.24,25 However, these
conditions may also present as generalized chorea.
OROBUCCOLINGUAL CHOREA. Orobuccolingual chorea may present in several

conditions, with the most common being tardive syndromes.8 Involvement of
the orobuccolingual muscles may occur in paraneoplastic syndromes (eg,
N-methyl-D-aspartate [NMDA] receptor encephalitis), polycythemia vera,
and chorea-acanthocytosis.25-27 In chorea-acanthocytosis, chorea is frequently
accompanied by oromandibular and lingual dystonia, leading to tongue
protrusion and feeding dystonia.19,28 Other etiologies of chorea may present
with oromandibular dystonia. Some examples are Lesch-Nyhan syndrome,
Lubag disease (X-linked dystonia-parkinsonism), Wilson disease, and
pantothenate kinase–associated neurodegeneration (PKAN).29-32
FACIAL OR FOREHEAD CHOREA. Chorea involving the forehead/upper face,

manifested by frontalis contraction, intermittently widened palpebral
fissures, and irregular blinking, is common in Huntington disease (HD). This
is not a pathognomonic feature of HD but is far less common in tardive
syndromes and can therefore help when seen in addition to delayed ocular
saccade initiation and velocity or other features common in HD.
Evaluation
Observation throughout the encounter is of utmost importance when evaluating
an individual with chorea. Multiple scales are available to rate chorea severity;
however, if a rating scale is not used, describing the location and severity of the
chorea is sufficient. One of the most widely recognized validated scales is the
Unified Huntington’s Disease Rating Scale (UHDRS), in which the total maximal
chorea score within the motor section of the scale is used to measure the severity
of chorea ranging from absent to severe. The chorea is rated in seven body
regions: the face, orobuccolingual, trunk, and each limb independently.33 The
Abnormal Involuntary Movement Scale (AIMS) is another commonly used scale
to evaluate chorea in the setting of tardive dyskinesia and assess chorea severity
in various locations.34
When evaluating chorea, the entire body should be visible, including the feet
(without socks), with the patient sitting on an examination table. It is imperative
to evaluate the chorea throughout the encounter, as the severity can fluctuate
with distraction.33 Like most hyperkinetic movements, the severity may increase
with heightened emotion. Observing gait (more specifically, tandem gait) can
illuminate the severity of the chorea.
Although mild chorea may go unnoticed by patients and their caregivers,
moderate chorea is typically more apparent. In HD, anosognosia is common;
therefore, individuals may be unaware of even severe chorea. Chorea usually
affects the limbs, trunk, and face. Less frequently, it can interfere with
respiration and phonation, presenting with slurred speech or involuntary
vocalizations (eg, grunting, humming). Chorea usually presents at rest,
disappears during sleep, and may increase with distracting maneuvers such as
counting backward. Chorea may be partially suppressible or camouflaged by
1382 OCTOBER 2022

the patient. Motor impersistence, as mentioned above, is a common KEY POINTS
phenomenon in individuals with chorea. This can be demonstrated by asking the
● Because the differential
patient to squeeze the examiner’s finger or sustain tongue protrusion for diagnosis for chorea is
10 seconds.35,36 broad, it is generally helpful
to begin by categorizing
PATHOPHYSIOLOGY chorea as (1) inherited versus
acquired and (2) childhood
The pathophysiology of chorea is linked to the neural network connecting the
onset versus adult onset.
thalamus to the basal ganglia, including the striatum, globus pallidus externus,
and globus pallidus internus as well as related nuclei (eg, the subthalamic nucleus ● Clues to differentiate
and substantia nigra). The classic model of basal ganglia function describes the inherited choreas from
direct and indirect pathways that originate from striatal medium spiny neurons. acquired choreas include
the timeline (acute,
According to this model, a cortical impulse activates medium spiny neurons subacute, or chronic
with the release of glutamate. Medium spiny neurons control downstream [>1 year]) and course (static,
pathways with γ-aminobutyric acid (GABA), a naturally inhibitory signal. In the paroxysmal, or progressive).
direct pathway, the inhibition of the globus pallidus internus, which is also
γ-aminobutyric acid–mediated (GABAergic), results in disinhibition of the
thalamus and locomotor activation. Conversely, the indirect pathway activates
the globus pallidus internus with inhibition of the excitatory subthalamic nucleus
and ultimately reduces locomotion. In addition to the cortical impulses, the
substantia nigra pars compacta controls medium spiny neurons and downstream
pathways by releasing dopamine. Although chorea has different etiologies, many
of its various forms can be explained by decreased inhibitory input of the globus
pallidus internus to the thalamus, resulting in facilitation of thalamocortical
motor drive.23,37
However, some discrepancies exist. For example, internal pallidal ablation
(globus pallidus internus pallidotomy) has been successfully used in treating
some forms of chorea, whereas according to the classic model, it should actually
increase thalamocortical motor drive and worsen chorea. In another example,
findings on positron emission tomography (PET) have shown evidence of striatal
hypometabolism in HD and some other causes of chorea, which correlates with
neuronal loss. Conversely, in patients with hyperthyroidism, polycythemia vera,
and Sydenham chorea, hypermetabolism of the striatum was found. These
inconsistencies suggest a more complex mechanism and even different
pathophysiology among variants of chorea.23,38
APPROACH TO THE DIAGNOSIS OF CHOREA

The differential diagnosis for chorea is broad, but it is generally helpful to begin
by categorizing chorea as (1) inherited versus acquired and (2) childhood onset
versus adult onset. Many algorithms have been published to help work through
the differential diagnosis of chorea, and these general categories serve as
guidelines.16,23,39,40 When assessing chorea, a careful family history should
always be elicited, although the absence of a family history should not be relied
on as an exclusion for a hereditary etiology.
Among acquired choreas, causes include postinfectious, autoimmune,
drug-induced, vascular, and metabolic abnormalities; however, the emphasis is
typically on identifying potentially treatable or reversible conditions.41
Additional features that aid in the differential diagnosis discussed in this article
include time course (acute, subacute, or chronic [>1 year] and static, paroxysmal,
or progressive), comorbid history and examination features, and comorbid
imaging or laboratory features.

CHOREA
Hereditary Choreas
HD is the most common cause of adult-onset hereditary chorea, but even in
HD, 5% of cases represent a de novo HTT pathogenic variant or expansions in
the nonpathogenic but mutable range (ie, CAG repeats may expand in
successive generations into the pathogenic range), and family history may be
incomplete, incorrect, or unknown.42 Among other hereditary causes, some
share phenotypic characteristics with HD and are considered HD mimics or
phenocopies and others have different inheritance patterns and unique
features that may lead to their consideration, but all are considered rarer than
HD and therefore considered only after a negative test for the HTT
pathogenic variant.
HUNTINGTON DISEASE. HD is the most common cause of adult-onset hereditary

chorea (VIDEO 8-1 and VIDEO 8-2), affecting approximately 5 per 100,000 to 12
per 100,000 people.43 It is caused by an autosomal dominant trinucleotide
repeat expansion (CAG) in the huntingtin gene (HTT) on chromosome 4p16.3.
Repeat lengths of 40 and above have full penetrance, with a phenotype
consisting of progressive motor, cognitive, and behavioral changes. The precise
mechanism for the degenerative changes in HD is unclear, but mutant
huntingtin protein forms nuclear aggregates in the striatum, particularly leading
to loss of medium spiny neurons. A CAG repeat length of 26 or lower is
considered normal (TABLE 8-144). Individuals who have 36 to 39 CAG repeats are
considered to have reduced penetrance but can still develop the disease. In those
with 27 to 35 CAG repeats, the phenomenon of “anticipation” via paternal
inheritance can pose risk for expansion into the HD range in the next generation.
Although HD symptom onset can occur at any age, the average age of onset
is in the third or fourth decade of life, and the average lifespan is approximately
15 to 20 years after symptom onset. The age of motor onset is inversely correlated
with the number of CAG repeats; however, this only accounts for approximately
50% to 70% of the variance.45 Through genome-wide association studies
evaluating large cohorts, the Genetic Modifiers of Huntington’s Disease
(GeM-HD) Consortium has identified genes involved in DNA maintenance and
repair that have been implicated in modifying motor symptom onset by likely
influencing somatic expansion of the HTT CAG repeat.46,47 The GeM-HD
Consortium and others determined that the uninterrupted CAG repeat length
TABLE 8-1 CAG Repeats in Huntington Diseasea
Risk to
CAG repeat count Classification Disease status offspring
<26 Normal Will not be affected None
27-35 Intermediate Will not be affected? (case reports of symptomatic individuals) Increased
36-39 Reduced penetrance May or may not be affected 50%
40+ Full penetrance Will be affected 50%
a
Data from Nance MA, et al.44
1384 OCTOBER 2022

is more influential in contributing to the age of motor onset than the KEY POINTS
polyglutamine length.47
● Huntington disease is the
Prodromal HD can occur approximately 10 years before a clinical most common cause of
diagnosis.46 During this period, subtle motor and nonmotor symptoms maybe adult-onset hereditary
be present but are not significant enough to warrant a clinical diagnosis. chorea. It is imperative that
A clinical diagnosis of HD has historically been based on motor symptoms. genetic counseling occur
before testing.
However, cognitive and behavioral symptoms can be deleterious and may
precede significant motor symptoms. Reilmann and colleagues48 proposed a ● Huntington disease
revision of the diagnostic criteria to include nonmotor features, more mimics or phenocopies
specifically cognitive symptoms, when making a diagnosis. Subsequently, a include several inherited
Movement Disorder Society task force proposed a refinement of the clinical rare degenerative
conditions and may be
diagnostic criteria.49,50 Efforts are under way to expand upon this for both associated with the triad of
clinical and research purposes. chorea, dementia, and
Juvenile HD (also known as the Westphal variant) occurs before the age of 20 behavioral disturbances.
and is associated with CAG repeat lengths higher than 55; it phenotypically can
present with akinesia, parkinsonism, and seizures rather than chorea. Although
chorea is the most common and prototypical movement disorder associated with
HD, especially among those with onset in middle age or older adult life, other
movements often seen include ataxia, dystonia, parkinsonism, tics, dysarthria,
dysphagia, and impaired ocular saccade initiation and velocity.43 In fact, delayed
ocular saccade initiation can be a helpful clue when trying to differentiate HD
from other causes of chorea.43
Cognitive decline eventually occurs in all individuals with HD. Executive
dysfunction is common, including impairments in planning, working memory,
and attention. The cognitive symptoms are progressive and lead to functional
decline and dependence. Behavioral features are variable among individuals with
HD. Depression, irritability, anxiety, and impulsivity are among the most
common psychiatric symptoms and can contribute to the high suicide rate in this
population. Obsessive-compulsive symptoms and apathy are not uncommon,
and, unlike other neuropsychiatric features, apathy longitudinally worsens over
time. Psychosis can also be seen, albeit rarely.49,51
HUNTINGTON DISEASE MIMICS/PHENOCOPIES. Hereditary conditions that mimic

HD should be considered whenever testing for the pathogenic variant does
not reveal an expansion in the HTT gene. These conditions make up 1% to
7% of HD-negative genetic choreas.16,23,52 The shared phenotype is a
hereditary progressive neuropsychiatric condition involving chorea, cognitive
impairment, and psychiatric or behavioral abnormalities. Unfortunately,
the cause of HD phenocopies remains undetermined in the majority of those
with a negative gene test.53
HUNTINGTON DISEASE–LIKE DISORDERS. Four genes associated with Huntington

disease–like (HDL) syndromes have been described. HDL2 is a rare autosomal
dominant pathogenic variant in the gene encoding junctophilin-3 (JPH3). Like
HD, it is associated with a CAG trinucleotide repeat expansion. It resembles HD
and has primarily been reported in individuals of African descent. HDL1 is
caused by a pathogenic variant in the prion protein gene ( PRNP) and can mimic
HD; however, acquired prion diseases such as Creutzfeldt-Jakob disease can also
be associated with chorea. HDL3 is exceedingly rare and is associated with
ferritin-associated basal ganglia disease.54 HDL4 is also known as spinocerebellar

CHOREA
ataxia type 17 (SCA17) and is discussed in the section on spinocerebellar ataxia

type 17 and other hereditary ataxias.
DENTATORUBRAL PALLIDOLUYSIAN ATROPHY. Similar to HD, dentatorubral

pallidoluysian atrophy (DRPLA) is inherited via an autosomal dominant pattern
with a trinucleotide CAG expansion. The pathogenic variant in DRPLA is in the
atrophin-1 gene (ATN1) on chromosome 12p13. Although very rare, DRPLA has
a higher prevalence in individuals of Japanese ancestry, in which the prevalence
is 0.2 per 100,000 to 0.4 per 100,000 people.55 Cases have also been described in
the Haw River Valley region of North Carolina.56 The clinical phenotype is
similar to HD, although epilepsy may also be seen. MRIs of individuals with
DRPLA show characteristic white matter changes and atrophy in regions
indicated in the name of the disorder: the dentate, red nucleus, and pallidum.
C9ORF72. Expanded hexanucleotide repeat pathogenic variants in the C9orf72

gene have increasingly been associated with various neurologic conditions, in
particular motor neuron disease and frontotemporal dementia. In fact, the
pathogenic variant is one of the most common genetic causes of amyotrophic
lateral sclerosis and frontotemporal lobar degeneration in some populations. The
gene is thought to have a role in membrane trafficking, which may be relevant to
various neurologic conditions. The expression can vary even among individuals
in the same family. Although chorea is a rare manifestation of this pathogenic
variant, it is now recognized among the most common phenocopies of HD,
particularly among a UK-based cohort.52
SPINOCEREBELLAR ATAXIA TYPE 17 AND OTHER HEREDITARY ATAXIAS. Many primary

chorea syndromes such as HD can have ataxia as a comorbid feature, and,
likewise, many primary ataxia disorders can have chorea as a feature. Hereditary
ataxias have heterogeneous inheritance patterns, although many, such as SCA17,
are autosomal dominant. In most cases, cerebellar atrophy is apparent on MRI.
Among the autosomal dominant forms of hereditary ataxia, SCA17 can affect
White and Asian populations and can have a phenotype that mimics HD, with
neuropsychiatric features and hyperkinetic movements; it has therefore also
been termed HDL4. Like HD, SCA17 is a trinucleotide CAG repeat expansion
disorder. In this case, the pathogenic variant is in TBP on chromosome 6q27.57
Other SCAs can also have phenotypes that overlap with HD. SCA3 is among the
most common autosomal dominant spinocerebellar ataxias and can also cause
chorea. Autosomal recessive ataxias that cause chorea include Friedreich ataxia,
ataxia telangiectasia, and ataxia with oculomotor apraxia types 1 and 2.
OTHER HEREDITARY CHOREAS. Inheritance patterns for hereditary causes of

chorea can also include autosomal recessive and X-linked disorders.
NEUROACANTHOCYTOSIS. Neuroacanthocytosis refers to a group of extremely rare

disorders with the characteristic feature of acanthocytes (spiculated, abnormally
shaped red blood cells) found on peripheral blood smear. Chorea-acanthocytosis
is a rare autosomal recessive cause of chorea seen in 1 per 1 million to 3 per
1 million individuals.58 Although generalized chorea is seen, movement in the
orofacial and orobuccolingual regions is characteristically predominant. This can
lead to self-injurious mutilation of the orobuccolingual region as well as
1386 OCTOBER 2022

prominent hypersalivation and dysphagia with lingual dystonia. Acanthocytes KEY POINTS
are characteristically seen on peripheral blood smear, although both false
● Pathogenic variants in
positives and false negatives can occur. Chorea-acanthocytosis is caused by a ATN1 dentatorubral
pathogenic variant in the VPS13A gene, which encodes for the protein chorein. pallidoluysian atrophy are
An X-linked form of the disease is known as McLeod syndrome and is associated associated with
with comorbid neuropathy and cardiomyopathy. HDL2 and the syndrome of characteristic MRI changes
in the dentate, red nucleus,
brain iron accumulation may also be causes of neuroacanthocytosis. and pallidum.
HEREDITARY DISORDERS ASSOCIATED WITH BASAL GANGLIA MINERALIZATION. ● Pathogenic variants in

Hereditary forms of chorea can result from abnormal mineral accumulation in C9orf72 can mimic
Huntington disease, but
the basal ganglia. This includes iron (neurodegeneration with brain iron
variable expression may also
accumulation [NBIA] disorders), calcium (Fahr disease), and copper (Wilson include amyotrophic lateral
disease), each of which may have corresponding MRI abnormalities. sclerosis and
frontotemporal dementia.
NEURODEGENERATION WITH BRAIN IRON ACCUMULATION. NBIA disorders are a
● Pathogenic variants in
heterogeneous group of disorders in which iron accumulates in the basal ganglia, VPS13A cause chorea-
leading to various movement disorders. Some of these disorders are related to acanthocytosis, with
genes directly involved in iron metabolism, whereas others are related to genes characteristic
involved in lysosomal or autophagy pathways.59 MRI of the brain is invariably orobuccolingual chorea and
acanthocytes on blood
abnormal in these conditions and can have characteristic patterns of iron
smear. McLeod syndrome is
accumulation in each condition. As a group, NBIA disorders vary in age of onset an X-linked form.
and inheritance patterns. NBIA disorders occur in 1 per 500,000 people, with
about half of these cases being PKAN. PKAN is an autosomal recessive disorder ● Chorea can result from
caused by a pathogenic variant in the pantothenate kinase 2 gene ( PANK2) and abnormal mineral
accumulation in the basal
can present from early childhood to midadulthood. It has a characteristic pattern ganglia. This includes iron
of signal change in the basal ganglia on MRI known as the eye of the tiger sign.60 (neurodegeneration with
PKAN is also described as a neuroacanthocytosis syndrome. Adult-onset NBIA brain iron accumulation),
disorders include the rare conditions of aceruloplasminemia and calcium (Fahr disease), and
copper (Wilson disease),
neuroferritinopathy. Aceruloplasminemia is caused by a recessive pathogenic each of which may have
variant in the CP gene encoding ceruloplasmin, whereas neuroferritinopathy is corresponding MRI
caused by a dominant pathogenic variant in the gene for ferritin light abnormalities.
chain (FTL).
BASAL GANGLIA CALCIFICATIONS/FAHR DISEASE. Minor calcifications in the basal

ganglia are not uncommon on imaging, but more significant accumulations can
lead to movement disorders. Parkinsonism and tremor are the most common
movement disorders that arise from basal ganglia calcifications, but chorea can
also be seen. The calcification will often show up prominently on head CT,
involving cerebellar and brainstem structures in addition to the basal ganglia.
The inheritance pattern is often autosomal dominant, although different genes
have been implicated, including SLC20A2 and XPR1. Secondary causes of basal
ganglia calcifications may include endocrine abnormalities such as
hypoparathyroidism, TORCH infections (toxoplasmosis, other infections,
rubella, cytomegalovirus infection, and herpes simplex), and certain toxic
exposures (eg, carbon monoxide).61
WILSON DISEASE. Wilson disease is an autosomal recessive genetic disorder that

results from pathogenic variants in the gene encoding the ATP7B protein.
ATP7B is a P-type ATPase that mediates ATP-dependent transport of copper.
ATP7B is highly expressed in hepatocytes, where it has dual roles in copper

CHOREA
CASE 8-1 A 34-year-old right-handed woman presented to the clinic for

involuntary movements. The patient had been “fidgety” since childhood
but never thought much about it until her primary care physician
recommended she see a neurologist. Her father had similar movements,
as did her 12-year-old daughter, who was delayed in meeting her motor
milestones. The patient denied any significant past medical history
except for hypothyroidism (for which she was taking levothyroxine) and
asthma, although she did not have additional details about her diagnosis.
She endorsed mild anxiety but denied any other significant psychiatric
symptoms.
Neurologic examination revealed involuntary, arrhythmic, low- to
moderate-amplitude movements in the extremities and trunk consistent
with choreoathetoid movements in addition to intermittent bilateral
upper extremity myoclonus (VIDEO 8-3). Her tone was normal throughout,
she had normal saccade initiation and velocity, and tongue protrusion
was sustained for 9 seconds. Gait revealed a slightly wide base, normal
stride, impaired tandem gait with bilateral upper extremity dystonic
posturing, and distal upper extremity chorea.
Brain MRI and laboratory studies were normal. Genetic testing (HTT
test) previously performed by her primary care physician had not
revealed a pathogenic CAG expansion on either allele. Additional genetic
testing revealed a pathogenic variant in the NKX2-1 gene. A diagnosis of
benign hereditary chorea was made. Treatment was initiated with a
vesicular monoamine transporter-2 (VMAT2) inhibitor, and the patient
was counseled about the importance of preventive cancer screening.
COMMENT In this patient, clues to the diagnosis of benign hereditary chorea included
a family history suggesting an autosomal dominant inheritance pattern,
normal brain MRI, hypothyroidism, and respiratory symptoms. In addition,
childhood onset of chorea would be atypical for juvenile-onset Huntington
disease as the phenotype is typically hypokinetic. The clinical features of
NKX2-1 benign hereditary chorea have become more clearly delineated
with increased reporting of cases caused by various pathogenic variants
within this gene, highlighting hypotonia, motor developmental delay,
chorea, hypothyroidism, and recurrent respiratory tract infections as the
core features of brain-lung-thyroid syndrome. Treatment is symptomatic,
and multiple medications have been reported as being effective, including
carbidopa/levodopa. Additional neurologic findings may include
myoclonus, tremor, dystonia, and cognitive deficits, which brings into
question the terminology currently used to describe this syndrome. A
renaming to NKX2-1–related disorder has recently been proposed.64
1388 OCTOBER 2022

metabolism. First, ATP7B facilitates incorporation of copper into ceruloplasmin, KEY POINT
which is then secreted into the bloodstream. Second, ATP7B promotes the biliary
● Mutations in ADCY5 are
excretion of copper by sequestering copper into vesicles that are excreted into bile associated with childhood
via exocytosis. Pathogenic variants in ATP7B lead to impaired copper excretion, hypotonia. The chorea that
resulting in copper accumulation in hepatocytes with resultant hepatotoxicity and may develop worsens with
accumulation of excess copper in other organs, including the brain. Neurologic sleep deprivation.
symptoms can be the presenting manifestation in about 18% to 68% of patients.
Anyone younger than 50 years of age with unexplained neurologic or hepatic
findings should be considered for screening for Wilson disease using serum
ceruloplasmin, 24-hour urine copper, and slit-lamp eye examination for
Kayser-Fleisher rings. Neurologic symptoms are broad, but common
manifestations include dysarthria, dystonia, tremor, ataxia, chorea, and
parkinsonism. MRI of the brain in patients with Wilson disease commonly reveals
changes within the bilateral basal ganglia as well as the thalami and brainstem on
T1- or T2-weighted sequences. Hyperintense T2 signal in the midbrain surrounding
the red nuclei in this condition has been dubbed the face of the giant panda sign.62
Nonwilsonian causes of liver failure with portosystemic shunting can cause an
acquired hepatolenticular degeneration due to deposition of other minerals and
toxins, such as manganese, in the basal ganglia. Similar to copper deposition,
these minerals can have a hyperintense T1 signal in the basal ganglia on MRI.
BENIGN HEREDITARY CHOREA. Familial forms of chorea that have an onset in

childhood and remain fairly stable or only mildly progressive are suggestive of
benign hereditary chorea. Although many cases are truly benign, some are
associated with increased risk of malignancy and with pulmonary or thyroid
disorders—a triad known as the brain-lung-thyroid disease—depending on the
severity of the pathogenic variant in the thyroid transcription factor 1 gene
(TITF1/NKX2-1). The pattern of inheritance is typically autosomal dominant.
In the first few years of life, some individuals with benign hereditary chorea
will experience hypotonia and some delay in motor milestones, but it is
generally stable after the first decade of life. Unlike other forms of hereditary
chorea, cognitive decline is less common (CASE 8-1).63
ADCY5-RELATED CHOREA. Adenylyl cyclase 5 (ADCY5) mutation-related

disorders are typically associated with childhood hypotonia and
developmental delay. However, chorea (particularly of the orobuccolingual
area) that fluctuates in severity (particularly worsening with drowsiness and
sleep deprivation) has been described. The gene is involved in the synthesis of
a cyclic adenosine monophosphate (cAMP) second messenger involved in
intracellular processes of medium spiny neurons. The inheritance can occur in
an autosomal dominant pattern or occur as a de novo pathogenic variant.65
PAROXYSMAL KINESIGENIC AND NONKINESIGENIC DYSKINESIA. Paroxysmal

kinesigenic dyskinesia and paroxysmal nonkinesigenic dyskinesia are
hereditary paroxysmal or episodic movement disorders that occur in
childhood and are most commonly associated with chorea or dystonia. Unlike
other conditions described here, individuals typically have a normal
neurologic examination between episodes, and the disorders can often be
confused with functional movement disorders. In paroxysmal kinesigenic
dyskinesia (also known as DYT10), episodes typically last seconds to minutes

CHOREA
and can occur countless times per day. Episodes are triggered by movement, but
individuals will often describe a prodromal sensation before an episode. The
choreiform movements can affect any body region but are often asymmetric,
and they typically respond well to carbamazepine. In paroxysmal nonkinesigenic
dyskinesia (also known as DYT8), episodes are typically longer, lasting minutes
to hours. Episodes are also less frequent than in paroxysmal kinesigenic
dyskinesia and are not triggered by movement but rather by stress, extremes of
temperature, alcohol, or excitement. Paroxysmal nonkinesigenic dyskinesia is
less responsive to pharmacotherapy than paroxysmal kinesigenic dyskinesia.
Paroxysmal kinesigenic dyskinesia is associated with autosomal dominant
pathogenic variants in the proline-rich transmembrane protein 2 gene ( PRRT2);
the same gene has been associated with other conditions such as hemiplegic
migraine and episodic ataxia. Paroxysmal nonkinesigenic dyskinesia is also an
autosomal dominant disorder, due to a pathogenic variant in the
myofibrillogenesis regulator 1 gene (MR-1). Another related condition,
paroxysmal exercise-induced chorea, is associated with a deficiency in the
glucose-transporter 1 (GLUT-1).66
Acquired/Secondary Choreas
Etiologies of acquired choreas include postinfectious, autoimmune,
drug-induced, vascular, and metabolic abnormalities. The workup emphasizes
ruling out potentially treatable or reversible conditions first. Additional features
to pay attention to include time course, comorbid history, examination features,
and imaging or laboratory features.
SYDENHAM CHOREA. Sydenham (or poststreptococcal) chorea is the most

common cause of chorea in childhood (VIDEO 8-4). Onset is typically acute or
subacute in children after an infection with group A streptococci and is
thought to result from antibodies produced against the bacteria that bind to
basal ganglia neurons. Confirmation of group A streptococci infection on
throat culture, positive antistreptolysin O or antideoxyribonuclease (DNAse)
antibodies, or carditis may support the diagnosis. However, because of the
variable lag from infection to onset of symptoms, antistreptolysin O titers and
antibodies can have false negatives, and a diagnosis is typically made clinically.66
Chorea and athetosis in the body and hands are common, but additional findings
may include ticlike behaviors, irritability, and impairments in attention.
Symptoms often naturally self-resolve over months, although in rare cases may
persist or recur. Recurrence occurring in pregnancy, typically in the first
trimester, is known as chorea gravidarum.
SYSTEMIC LUPUS ERYTHEMATOSUS AND OTHER AUTOIMMUNE-RELATED CHOREAS.

Chorea is a rare manifestation of systemic lupus erythematosus (SLE) but
rarely (1% to 4% of cases of systemic lupus erythematosus) may be seen as a
presenting manifestation of the disease.40 This may be related to circulating
antiphospholipid and anticardiolipin antibodies, although vascular
phenomena have also been proposed. Behçet disease, Sjögren syndrome, and
celiac disease are all systemic autoimmune conditions with antibodies that can
be rarely associated with chorea. Anti-NMDA receptor encephalitis is a known
cause of autoimmune encephalitis. Like other forms of limbic encephalitis, it
can be associated with epilepsy and behavioral changes. Other
1390 OCTOBER 2022

neurobehavioral features, including chorea and catatonia, are seen commonly KEY POINTS
with NMDA receptor encephalitis. In some patients, particularly in young
● Paroxysmal disorders of
women, NMDA receptor antibodies can be paraneoplastic related to ovarian chorea have characteristic
teratomas. Immunoglobulinlike cell adhesion molecule 5 (IgLON5) is an triggers. Paroxysmal
antibody that has been discovered recently in association with parasomnias nonkinesigenic dyskinesia is
but can be associated with cognitive impairment, gaze palsies, and chorea.40 triggered by stress,
extremes of temperature,
alcohol, or excitement.
PARANEOPLASTIC CHOREA. Paraneoplastic causes of chorea should be Paroxysmal kinesigenic
considered in adults, particularly when the onset is subacute and associated dyskinesia episodes are
with other systemic findings such as weight loss. Chorea often develops before shorter and more frequent
and triggered by movement.
tumor diagnosis, and early recognition may lead to detection of occult
malignancies. Antibodies to nuclear and cytoplasmic antigens, such as anti-Hu ● Sydenham chorea is the
and anti–collapsin response mediator protein 5 (CRMP-5) antibodies, most common cause of
associated with small cell lung cancer are among the most common to cause chorea in childhood.
chorea (CASE 8-2). Additional antibodies targeting intracellular antigens
● Antiphospholipid
include anti-Ma and antibodies directed at P/Q calcium channels. These antibodies are associated
antibodies indicate a T-cell–mediated immune response and may be less with systemic lupus
responsive to immunotherapy. Antibodies to cell surface proteins, including erythematosus,
leucine-rich glioma inactivated protein 1 (LGI1), contactin-associated hypercoagulability, and
chorea.
proteinlike 2 (CASPR2), and NMDA antibodies, may be more likely to
improve with immunotherapy. As noted above, anti-NMDA antibodies have ● IgLON5 is an antibody that
been associated with ovarian teratomas but may also be seen as described has been discovered
above without a neoplasm.40,67 recently in association with
parasomnias but can be
associated with cognitive
STRUCTURAL/LESIONAL CHOREA. Any structural lesion involving the basal impairment, gaze palsies,
ganglia has the potential to cause chorea. In the perinatal period, vascular and chorea.
phenomena leading to cerebral palsy can frequently cause choreiform and
dystonic movements. Dyskinetic cerebral palsy represents 14% of all cases of ● Structural or vascular
lesions should be
cerebral palsy. Although imaging may show periventricular leukomalacia or considered in cases of focal
thalamic and basal ganglia lesions, normal structural imaging is also common or hemibody chorea.
in these cases.66 Focal lesions occurring at any age, including ischemic strokes,
hemorrhages, demyelinating lesions, and space-occupying lesions (ie,
neoplasms), can cause chorea in the contralateral limbs when involving basal
ganglia structures. Of hemorrhagic or ischemic strokes, 1% to 4% have been
associated with movement disorders contralateral to the side of the injury,
with movements including chorea, hemiballismus, and dystonia. The onset
can be acute at the time of the stroke or delayed. Lesions in the caudate,
putamen, globus pallidus, subthalamic nucleus, or thalamus can all be
associated with chorea.68 Polycythemia vera, a myeloproliferative disorder,
has also been associated with chorea. It has been suggested to occur as a result
of hyperviscosity impacting blood flow to the basal ganglia, although an
underlying molecular explanation has also been proposed. Imaging the brain
to look for a structural lesion is the first step in diagnosis whenever a patient
presents with hemibody or focal-onset chorea.
PARAINFECTIOUS CHOREA. Chorea can be caused by viral infections, either

as a result of a cytotoxic effect of the virus or by a cytokine-mediated or
parainfectious mechanism. When chorea occurs in the setting of a viral
infection, it typically has an acute or subacute onset and develops over the
course of the infection itself. It is often associated with encephalopathy and

CHOREA
other signs of systemic illness. It can be unilateral or generalized and typically

improves over days to weeks as the infection is treated. Viruses associated
with chorea include measles, mumps, rubella, varicella-zoster, influenza,
herpesvirus, Epstein-Barr virus, tick-borne encephalitis, West Nile
encephalitis, cytomegalovirus, Japanese B encephalitis, and HIV.40 In HIV,
chorea can be the direct result of the virus or due to other opportunistic
infections (eg, toxoplasmosis, syphilis). Most TORCH infections (as described
in the section on basal ganglia calcifications) can also cause chorea.
TOXIC/METABOLIC CAUSES OF CHOREA. Medication-induced chorea is common

and frequently encountered in neurologic practice. Levodopa-induced
CASE 8-2 A 78-year-old man was referred to the movement disorder clinic by his
primary neurologist for further evaluation of new-onset involuntary
movements. The patient reported involuntary movements in his upper
and lower extremities, impaired gait, and worsening balance for the past
few months. He did not have any psychiatric symptoms. He reported a
recent unintentional weight loss of approximately 9 kg (20 lb) over a
2-month period. He denied any significant past medical history. He had
no history of alcohol or illicit drug use; however, he did endorse previous
tobacco use (an approximately 30-pack-year history). The patient denied
any family history of chorea or any neurologic diseases.
Neurologic examination revealed normal ocular pursuit, slightly
delayed saccade initiation and velocity, and involuntary nonrhythmic
moderate-amplitude purposeless movements throughout but more
prominent in the lower extremities (VIDEO 8-5). Gait revealed a slightly
widened base, shortened stride, inability to attempt tandem, and
positive pull test. The remainder of the neurologic examination was
normal, including strength, sensation, tone, and reflexes.
The initial laboratory workup was normal. CSF studies revealed
elevated protein and elevated white blood cell count with lymphocytic
predominance and normal glucose. No malignant cells were detected on
flow cytometry. Brain MRI demonstrated subtle T2 hyperintensities in the
striatum. Chest CT revealed a circumscribed lesion in the right lower lobe
and hilar lymphadenopathy. A paraneoplastic panel was positive for
collapsin response mediator protein-5 (CRMP-5) IgG antibodies in the
serum and CSF. Biopsy of the right lower lobe lesion revealed small cell
carcinoma of the lung. The patient received a brief course of IV
methylprednisolone. Tumor resection and chemotherapy led to
resolution of the chorea.
COMMENT In this patient, the duration of symptoms (subacute), unintentional weight

loss, and history of smoking suggested a paraneoplastic etiology. Although
chorea of paraneoplastic etiology is rare, a high level of vigilance should be
maintained in the appropriate clinical context. Chorea generally resolves
after the identification and removal of the underlying malignancy.
1392 OCTOBER 2022

dyskinesia in patients with PD and tardive dyskinesia from chronic KEY POINTS
neuroleptic exposure are among the most common causes of chorea.69
● Dopaminergic
Levodopa-induced dyskinesia occurs in approximately 50% of people with PD medications and
at 5 years and correlates with disease duration, higher doses of levodopa, lower antidopaminergic
weight, female sex, and younger age at onset. Multiple pathogenic medications can cause
mechanisms have been described, including pulsatile, nonphysiologic choreiform movements.
Careful medication history
stimulation of dopamine receptors.70 Prolonged exposure to
and timeline of exposure are
dopamine-receptor blocking agents, such as many antipsychotic and important.
antiemetic medications, leads to dopamine receptor hypersensitivity. The
result is often a characteristic buccolingual masticatory chorea, although any ● Hyperglycemia is a
region of the body can be involved. Other pharmacologic agents that have common metabolic cause of
acute-onset chorea
been reported to cause chorea include central nervous system stimulants (eg, associated with T1 signal
amphetamines), anticholinergics, antihistamines, antidepressants, antiseizure change in the contralateral
medications, and oral contraceptives (TABLE 8-2).16,19,23,71 In most cases, the chorea putamen on MRI.
remits with removal of the offending agent, but with tardive dyskinesia,
movements may sometimes persist or worsen even once the offending agent
is discontinued.
Various metabolic derangements have been associated with chorea, the most
common of which is acute-onset chorea secondary to nonketotic hyperglycemia
(CASE 8-3 and VIDEO 8-6), in which a characteristic hyperintense T1 signal is
often seen in the contralateral putamen. Additional endocrinologic changes
associated with chorea include hypocalcemia, hypoparathyroidism,
hyponatremia or hypernatremia, hypomagnesemia, and uremia. Toxins,
including carbon monoxide, manganese, organophosphates, and mercury, have
also been associated with basal ganglia injury and subsequent chorea.16,24,40
APPLYING FOUR FEATURES IN THE DIAGNOSIS OF CHOREA

Various algorithms can guide the assessment of a patient with chorea.16,24,39,40
Considering the time course, age of onset, comorbid history/examination
findings, and comorbid data findings may aid the clinician in distinguishing
between causes of chorea and developing a more targeted diagnostic plan
(TABLE 8-3 and TABLE 8-4). Hereditary causes are more often insidious and
chronic, whereas acquired causes may have a more subacute presentation. Static
and paroxysmal causes have also been discussed. Episodic chorea can be seen in
paroxysmal kinesigenic and nonkinesigenic dyskinesia, while static chorea is
more likely due to an acquired cause such as a vascular lesion. Childhood onset
often raises suspicion for Sydenham chorea, whereas adult onset should raise
suspicion for HD and HD mimics. Further inquiry into ethnicity; inheritance
pattern; drug exposures; location of the chorea (eg, focal, diffuse,
orobuccolingual); and comorbid neurologic, psychiatric, systemic, and cognitive
features may guide diagnosis. Finally, bloodwork and imaging may aid in the
diagnosis of select hereditary, structural, autoimmune, or metabolic causes.
In adults, genetic counseling followed by an HD gene test remains the most
appropriate first step when hereditary chorea is suspected given the prevalence
of HD compared to other hereditary conditions. If the HD test is negative,
additional workup can be guided by the clinical phenotype, presumed
inheritance pattern, and additional test results. Among HD phenocopies, Wild
and colleagues16 reported that SCA17 accounts for 1.1% of HD phenocopies,
HDL2 for 0.7%, Friedreich ataxia (JPH3) for 0.35%, and inherited prion disease
( PRNP) for 0.24%. Testing for these pathogenic variants can now be performed

CHOREA
via a single panel, or targeted assessments can be done based on features

described of each above. In a 2014 review of 514 HD phenocopies, 1.95% were
found to have the C9orf72 expansion, leading the authors to propose this
pathogenic variant as the most common phenocopy to test for after an HD gene
test is negative.52 Regardless, the majority of patients with HD phenocopies still
do not attain a formal genetic diagnosis.
MANAGEMENT OF CHOREA
Chorea may cause physical disability, functional impairment, and social isolation.
It is important to understand the impact of the chorea on the patient’s well-being
and function to determine whether treatment is warranted. In some conditions
such as HD, it is often outsiders or family members who notice the chorea more
than the patient. The first step in managing chorea is to determine whether the
impact of the movements requires treatment at all. Chorea that is mild and does
TABLE 8-2 Drugs That May Induce Choreaa
Antidepressants
◆ Fluoxetine
◆ Fluvoxamine
◆ Paroxetine
◆ Tricyclic antidepressants
Antiseizure medications
◆ Carbamazepine
◆ Ethosuximide
◆ Lamotrigine
◆ Phenytoin
◆ Phenobarbital
◆ Valproic acid
◆ Zonisamide
Antihistamines (H1 or H2 blockers)
◆ Cimetidine
◆ Cyclizine
◆ Cyproheptadine
◆ Diphenhydramine
Antiparkinsonian drugs
◆ Levodopa
◆ Dopamine agonists
◆ Anticholinergic drugs (eg, trihexyphenidyl)
CONTINUED ON PAGE 1395
1394 OCTOBER 2022

not interfere with daily function, dexterity, or mobility does not necessarily need
to be treated. It is important to be aware, however, that lack of awareness of
deficits (anosognosia) is a common feature of some neurodegenerative diseases,
including HD. As a result, the clinician and family should attempt to judge the
impact of the chorea in collaboration with the patient.
Management of Secondary Chorea

When chorea results from an underlying disease, disease-specific therapy is often
the most effective approach to treatment.41 It is important not to miss the
opportunity to treat conditions that are reversible. Chorea that results from
structural, metabolic, or infectious causes can often be self-limited and may not
require symptomatic treatment outside of the acute setting. Therapies for
specific causes of chorea include penicillin for Sydenham chorea; antimicrobials
for central nervous system infections; immunotherapy for autoimmune
CONTINUED FROM PAGE 1394
Calcium-channel blockers
◆ Flunarizineb
◆ Verapamil
Dopamine antagonists
◆ Butyrophenones
◆ Benzamides
◆ Dopamine antagonist antiemetics
◆ Phenothiazines
Psychostimulants
◆ Amphetamines
◆ Cocaine
Other medications
◆ Baclofen
◆ Cyclosporine
◆ Digoxin
◆ Fluoroquinolones
◆ Lithium
◆ Methadone
◆ Methotrexate
◆ Oral contraceptives, estrogen replacement therapy
◆ Steroids
◆ Theophylline
a
Data from Mestre TA,19 Cardoso F, et al,24 and Zesiewicz TA and Sullivan KL.71
b
Flunarizine is not currently approved by the US Food and Drug Administration (FDA) to be marketed in the
United States.

CHOREA
conditions; blood sugar control for hyperglycemia; management of abnormalities

in sodium, calcium, or thyroid levels; chelation for Wilson disease; and
phlebotomy for polycythemia. For chorea due to paraneoplastic causes,
immunotherapies may be used, but treating the underlying cancer is critical.
Chorea that is caused by levodopa often improves with reducing the dose of
levodopa and/or supplementing with other medications such as amantadine. Of
note, an extended-release form of amantadine has been approved to manage
levodopa-induced chorea.74 For tardive dyskinesia, vesicular monoamine
transporter-2 (VMAT2) inhibitors (often called dopamine depleters) are
recommended, and evidence is insufficient to support or refute withdrawing or
switching the offending/causative agent. Instead, the appropriateness of the
offending agent should be reviewed and assessed, and if necessary,
dopamine-depleting agents are recommended.75
Most genetic causes of chorea are treated symptomatically; however, Wilson
disease is an exception. Screening for Wilson disease early whenever suspicion
CASE 8-3 A 91-year-old right-handed man presented to the emergency department

with insidious-onset right arm pain. During the emergency department
evaluation, he was noted to have abnormal movements described as
involuntary dancing movements involving the right arm and leg. The
patient was unaware of these symptoms and could not state the onset
time but suggested that perhaps it was present for a few weeks or
months at most. No urge was associated with the movements. The patient
lived alone and reported being independent with activities of daily living.
He denied that the movements interfered with any activities of daily
living. His past medical history was notable for hypertension and newly
diagnosed type 2 diabetes mellitus. No medication changes had been
made recently, and he was not taking any medication for diabetes. He
denied any significant neurologic family history.
On examination, the patient had involuntary nonrhythmic, asynchronized,
midfrequency, mid- to high-amplitude writhing/dancelike movements in
the right upper and lower extremities. The movements were more proximal
than distal and not distractible. The intensity/amplitude reduced with
concentration. Intermittent irregular mouth movements were noted, which
disappeared when the patient was asked to relax. Initially, some overflow
movements on the left side were noted; however, they disappeared when
the patient relaxed. The arm movements were present at rest and with
action. The intensity of movement was moderate.
Brain MRI showed signal change in the left putamen on T1-weighted
images (FIGURE 8-272). His serum glucose was 380 mg/dL, and his hemoglobin
A1c was greater than assay (>13.9%). Eight months previously, his hemoglobin
A1c had been 7.2%.
A diagnosis of hyperglycemia-associated chorea was made. He was
hospitalized for a week, and glycemic control was achieved with insulin and
oral hypoglycemic medication. By the time of discharge, his choreiform
movements were significantly reduced and symptomatic therapy was not
initiated.73
1396 OCTOBER 2022

exists is critical because disease-modifying therapy with chelation and zinc can
reduce copper deposition, modify the disease course, and improve symptoms.62
For NBIA disorders, no clear treatment guidelines have been established,
although case reports of chelation therapies have been described in some of these
conditions.41 Paroxysmal kinesigenic dyskinesia and paroxysmal nonkinesigenic
dyskinesia may respond to antiseizure medications and dietary changes, as
discussed above. For other genetic causes of chorea, including HD, management
is primarily symptomatic and supportive.
Pharmacologic Management of Chorea

VMAT2 inhibitors deplete the release of dopamine presynaptically by preventing
packaging of monoamines into presynaptic storage vesicles. This results in fewer
movements as less dopamine is released from presynaptic terminals in the
nigrostriatal pathway. Two VMAT2 inhibitors are approved by the US Food and
Drug Administration (FDA) for the management of chorea related to HD:
FIGURE 8-2
Imaging of the patient in CASE 8-3. Axial
T1-weighted MRI shows signal change in
the left putamen.
Reprinted from Prakash N, Interactin.72
© 2022 John Wiley & Sons, Inc.
The acute to subacute onset of chorea in this patient, in addition to its COMMENT
location, pointed toward an acquired cause of chorea. The location
(hemichorea) suggests a structural or vascular etiology requiring
neuroimaging and laboratory studies, and in this case led to the diagnosis
of nonketotic hyperglycemia-associated chorea. Late-onset chorea can be
seen in Huntington disease; however, the location, timeline, family history,
and subsequent neuroimaging and laboratory findings eliminate this from
the differential.

CHOREA
TABLE 8-3 Differential Diagnosis of Hereditary Chorea
Pathogenic Select history Select laboratory

variant/ and examination and imaging
Disorder inheritance Onset Time course features findings
Huntington disease Autosomal Third to fourth Progressive Most common CAG repeat
dominant decades over hereditary chorea expansion (>35) in
15-20 years HTT
HTT on Juvenile Chorea and dystonia
chromosome Huntington are common Caudate/striatal
4p16.3 disease before atrophy on MRI
Parkinsonism and
age 20 (>55
seizures (juvenile)
repeats)
Other features:
36-39 repeats is
neuropsychiatric
reduced
disorder and dementia,
penetrance
motor impersistence,
range
impaired saccades
Paternal
anticipation
Huntington Autosomal Second to fifth Rapidly Huntington disease Octapeptide

disease–like 1 dominant decades progressive phenocopy repeat in PRNP
PRNP on Myoclonus, rapid MRI similar to
chromosome progression Huntington
20p13 disease
Huntington Autosomal Second to fifth Similar to Huntington disease CAG repeat

disease–like 2 dominant decades Huntington phenocopy expansion in JPH3
disease
JPH3 on African ancestry MRI similar to
chromosome Huntington
16q24.2 disease
Acanthocytes
may be present
Dentatorubral- Autosomal Adult- or Variable, Huntington disease CAG repeat

pallidoluysian dominant childhood-onset progressive phenocopy expansion in ATN1
atrophy forms
ATN1 on Japanese ancestry MRI fluid-
chromosome attenuated
May have seizures and
12p13 inversion recovery
myoclonus
(FLAIR) signal
Haw River syndrome in change in
North Carolina dentate, red
nucleus, pallidum
C9orf72 Autosomal Third to fifth Variable, Variable phenotypes GGGGCC repeat

dominant decades progressive seen, including expansion in
frontotemporal C9orf72
Chromosome 9
dementia and motor
hexanucleotide Generalized
neuron disease
expansion cerebral atrophy
(amyotrophic lateral
sclerosis)
Possibly the most
common phenocopy of
Huntington disease
1398 OCTOBER 2022


Spinocerebellar Autosomal First through Variable, Huntington disease CAG repeat

ataxia type 17/ dominant fourth decades, progressive phenocopy expansion in
Huntington variable TBP; cerebellar
TBP on White or Asian
disease–like 4 atrophy
chromosome populations
6q27
Ataxia
Friedreich ataxia Autosomal Typically Variable, Ataxia, areflexia, GAA repeat

recessive childhood onset progressive neuropathy, expansion in FTX
without chorea, cardiomyopathy,
FXN mutation Abnormal nerve
but adult/late diabetes, foot
on chromosome conduction
onset with deformities
9q21.11 studies
chorea is
possible
Chorea- Autosomal Second to fourth Variable, Orobuccolingual Acanthocytes on

acanthocytosis recessive decades, variable progressive chorea peripheral blood
smear
Chorein protein Self-injurious oral
VPS13A gene mutilation, Elevated creatine
hypersalivation, kinase
dysphagia, lingual
dystonia, rubber
man gait
McLeod syndrome X-linked Second to fifth Variable, Cardiomyopathy, Acanthocytes on

decades, variable progressive seizures, axonopathy peripheral blood
XK for Kx
smear
antigen on red
blood cell Elevated creatine
surface kinase
Neuroferritinopathy Autosomal Fourth to fifth Variable, Orobuccal chorea MRI with basal
dominant decades, variable progressive ganglia iron
Northern England
accumulation on
FTL on
T2-weighted and
chromosome
gradient recalled
19q13.33
echo (GRE) images
Low serum ferritin
Aceruloplasminemia Autosomal Fourth to fifth Variable, Dystonia, ataxia, MRI with basal
recessive decades, variable progressive diabetes, retinal ganglia iron
degeneration accumulation on
CP on
T2-weighted and
chromosome 3q
GRE images
Absent serum
ceruloplasmin

CHOREA
CONTINUED FROM PAGE 1399FROM PAGE 1399

CONTINUED

Fahr disease Autosomal Third to fourth Variable Tremor, parkinsonism CT/MRI with basal
dominant decades, variable ganglia,
brainstem,
SLC20A2 on
cerebellar
chromosome
calcifications
8p11.21
Other genes
include XPR1
Wilson disease Autosomal Childhood or Varies by Gastrointestinal Low serum

recessive early adult onset response to symptoms, ceruloplasmin,
(usually before treatment Kayser-Fleischer rings, elevated 24-hour
ATP7b on
age 50) wing-beat tremor, urine copper,
chromosome Can remain
dystonia, parkinsonism, elevated liver
13q14.3 stable with
ataxia enzymes,
chelation or be
elevated liver
cured with liver
copper, liver
transplantation
fibrosis/cirrhosis
Face of the giant
panda sign on
T2-weighted MRI
Benign hereditary Autosomal Childhood onset Static or slight Stable course None
chorea dominant progression
Pulmonary or thyroid
NKX2-1 (thyroid problems (brain-lung-
transcription thyroid syndrome)
factor) on
No dementia
chromosome
14q13.3
Adenylyl cyclase Autosomal Childhood onset Variable, Childhood hypotonia None

type 5 dominant paroxysmal
Facial myoclonus,
ADCY5 on worsening with sleep
chromosome deprivation
3q21.1
Paroxysmal Autosomal Childhood onset Paroxysmal Episodes lasting None

kinesogenic dominant seconds to minutes
dyskinesia
PRRT2 on Numerous per day,
chromosome triggered by movement
16p11.2 (DYT10)
Responsive to
carbamazepine
Paroxysmal Autosomal Childhood onset Paroxysmal Episodes triggered by None

nonkinesigenic dominant stress, extremes of
dyskinesia temperature, alcohol,
MR-1 gene on
or excitement
chromosome
2q35 (DYT8) Lasts minutes to hours
CT = computed tomography; EMG = electromyography; MRI = magnetic resonance imaging.
1400 OCTOBER 2022

tetrabenazine and deutetrabenazine. The TETRA-HD (Efficacy and Safety of KEY POINTS
Tetrabenazine in Chorea) study provided Class I evidence of the efficacy of
● It is important to
tetrabenazine based on improvement in motor chorea scores on the UHDRS.76 determine whether chorea is
Potential side effects that may limit the use of tetrabenazine include depression troublesome or bothersome
and suicidal ideation, sedation, and parkinsonism. Deutetrabenazine is also FDA before initiating a
approved for the management of HD chorea. It is chemically identical to medication. Anosognosia is
not uncommon, especially in
tetrabenazine, except that the metabolic profile is altered by replacing key
Huntington disease;
hydrogen atoms with deuterium. The incorporation of deuterium results in a therefore, collecting input
longer half-life, less frequent dosing, and more stable serum drug levels. The from the patient and their
FIRST-HD (First Time Use of SD-809 in Huntington Disease) study care partner is essential.
demonstrated significant improvement in UHDRS scores in patients with HD
● Vesicular monoamine
compared to placebo.77 Deutetrabenazine was also studied for the management transporter-2 (VMAT2)
of tardive dyskinesia, and the ARM-TD (Aim to Reduce Movements in Tardive inhibitors are the only class
Dyskinesia) study demonstrated Class I evidence of improvement in AIMS of medications currently
scores in this population compared to placebo.78 Deutetrabenazine is now approved by the US Food
and Drug Administration for
approved for the management of HD chorea and tardive dyskinesia, and has the treatment of tardive
been used off label for the management of other forms of chorea. It is thought to dyskinesia and/or chorea
have less potential for side effects, such as mood disorders and sedation, than associated with Huntington
tetrabenazine, but patients should still be monitored for changes in mood, disease.
suicidal ideation, and parkinsonism. Another VMAT2 inhibitor, valbenazine, is
also FDA approved for the management of tardive dyskinesia. Valbenazine has a
once-daily dosing profile and was shown in the KINECT-3 (A Phase 3 Study of
NBI-98854 for the Treatment of Tardive Dyskinesia) trial to effectively improve
AIMS scores compared to placebo in patients with tardive dyskinesia.79 It is
currently being studied for other conditions, including HD chorea.
Neuroleptics are frequently used off-label for the management of chorea in
various disorders, including HD. D2-receptor blockade occurs with both typical
and atypical neuroleptics and results in inhibition of the indirect pathway,
thereby reducing movements. Despite having less disease-specific evidence for
their use in chorea, neuroleptics are often used as adjunctive treatments for
behavioral and psychiatric issues in HD and other degenerative choreas. They are
sometimes also considered off-label for effects on weight gain and sleep.
Neuroleptics with greater D2 blockade, such as typical neuroleptics, risperidone,
and olanzapine, may be more effective in treating chorea than neuroleptics such
as quetiapine and clozapine, which have lower D2 blockade. Neuroleptics should
be used with caution because of the risk of metabolic syndrome, somnolence,
parkinsonism, and tardive dyskinesia.
Another medication that is sometimes used off-label in the management of
chorea is the NMDA receptor antagonist amantadine. Evidence for the benefit of
amantadine has already been discussed in the context of levodopa-induced
dyskinesia, but evidence for use in other forms of chorea, including HD and
tardive dyskinesia, is limited.
Antiseizure medications have multiple sites of action, including in the basal
ganglia, although they are rarely used in the neurodegenerative choreas. These
medications are used more often in pediatric patients and can be useful in
patients who also have seizures, such as those with neuroacanthocytosis, juvenile
HD, or DRPLA.80
When chorea is comorbid with dystonia, particularly when the onset is focal,
botulinum toxin injections may be considered. However, botulinum toxin is not
approved specifically for the management of chorea.

CHOREA
TABLE 8-4 Differential Diagnosis of Acquired Chorea
Select history and Select laboratory and

Category/disorder Onset Time course examination features imaging findings
Sydenham chorea Childhood or early Self-limited Ticlike behaviors, Throat culture (group A
adolescence irritability, inattention streptococci), anti-
streptolysin-O antibody,
Acute onset History of
anti-DNAse antibody
streptococcal
After strep
infection
infection
Can be associated
with chorea
gravidarum later in life
Other autoimmune
disorders
Systemic lupus Often middle-age NMDA is rapidly Systemic features for Erythrocyte sedimentation
erythematosus/ adulthood; insidious progressive; relevant condition (ie, rate, antinuclear antibody
antiphospholipid in the context of a others are variable rash, arthralgia, panel, celiac antibodies,
antibody syndrome systemic disease oral ulcers); anti–double-stranded DNA
or subacute primary thrombotic events/ antibody, anticardiolipin,
Behçet disease,
manifestation miscarriages lupus anticoagulant
Sjögren syndrome,
for antiphospholipid antibodies, pregnancy test
celiac disease
antibody syndrome (chorea gravidarum),
anti-NMDA antibody,
anti-IgLON5 antibodies
in serum or CSF
Anti-N-methyl-D- NMDA is subacute NMDA is associated

aspartate (NMDA) with limbic encephalitis
receptor encephalitis and ovarian teratomas
IgLON5 IgLON5 is usually IgLON5 is associated

insidious in middle with parasomnias,
age cognitive impairment,
and gaze palsies
Paraneoplastic
Small cell lung cancer, Adulthood Progressive, may Systemic findings, Anti-Hu, collapsin
ovarian teratomas Subacute be associated with although the response mediator protein
encephalitis and neurologic features (CRMP-5), anti-Ma, and
development of may appear before antibodies directed at the
systemic systemic findings are P/Q calcium channel,
symptoms in some present leucine-rich glioma
cases inactivated 1 (LGI1),
contactin-associated
proteinlike 2 (CASPR2),
NMDA
CT or positron emission
tomography (PET) scan of
full body, testicular
ultrasound/testicular
ultrasound
1402 OCTOBER 2022

Select history and Select laboratory and

Category/disorder Onset Time course examination features imaging findings
Structural/lesional
Cerebral palsy/ Perinatal period Cerebral palsy has Hemibody or focal MRI of the brain
periventricular for cerebral palsy/ stable, chronic chorea with stroke, hemorrhage,
leukomalacia periventricular course or other focal basal
May be associated
leukomalacia ganglia pathology
Ischemic stroke, Strokes and with signs of elevated
hemorrhage Any age for other demyelinating intracranial pressure if
causes listed lesions may be space-occupying
Demyelinating lesion
most severe at lesion
Acute/subacute
Other space-occupying onset and may
lesion: neoplasm, abscess gradually improve
Space-occupying
lesions may be
slowly progressive
Parainfectious
Measles, mumps, rubella, Acute or subacute Often follows the Often associated Brain imaging, viral panels
varicella-zoster virus, course of the with systemic illness in serum and CSF
influenza, herpesvirus, infection or encephalopathy;
Epstein-Barr virus, unilateral or
tick-borne encephalitis, generalized; viral
West Nile encephalitis, causes tend to
cytomegalovirus, improve with
Japanese encephalitis, resolution of
human immunodeficiency the infection
virus (HIV)
Toxic/metabolic
Medications (refer to Improvement with
TABLE 8-2) correction or removal
of offending agent
Hyperglycemia, Variable; typically Static or Complete blood cell count,

hypocalcemia, insidious with progressive with chemistry (including
hypoparathyroidism, medications, but medications, then glucose, sodium, calcium,
hyponatremia, more acute with static or improved thyroid function tests,
hypernatremia, metabolic or toxic with removal of and parathyroid tests)
hypomagnesemia, causes; any age offending agent
uremia Brain MRI
Polycythemia Static with toxic Hematocrit raised in

injury to basal polycythemia
ganglia
Carbon monoxide, Gradual History of exposures

manganese, mercury, improvement with
organophosphates resolution of
metabolic
derangement
CSF = cerebrospinal fluid; CT = computed tomography; DNA = deoxyribonucleic acid; MRI = magnetic resonance imaging.

CHOREA
Research on the use of cannabinoids for chorea is inconclusive. Cannabinoid

receptors are present throughout the basal ganglia; cannabinoid receptor
type 1 (CB1) receptors, in particular, are reduced as part of the degenerative
process in HD. Although this suggests a rationale for manipulation of the
endocannabinoid system in the symptomatic management of hyperkinetic
movements, randomized controlled studies have thus far shown
inconsistent results.80,81
Nonpharmacologic Management of Chorea

Deep brain stimulation may be a treatment option for medication-refractory
hyperkinetic movement disorders. Deep brain stimulation has been studied in
HD chorea and tardive dyskinesia, but usage remains investigational
(VIDEO 8-7). Targeting the globus pallidus internus has been shown to have
antichoreic effects, but the cognitive and neuropsychiatric features of
degenerative conditions such as HD make this a limited treatment option in
most cases.82
A multidisciplinary approach to the management of chorea is critical to
address the movements themselves as well as the comorbid complications
associated with many conditions that cause chorea, such as HD. Addressing
the psychiatric and cognitive aspects of neurodegenerative diseases is as
important as managing the motor aspects. Individuals with neurodegenerative
diseases can benefit from working with speech, occupational, and physical
therapists; social workers; psychiatrists; neuropsychologists; and genetic
counselors to address the myriad of functional and social issues associated
with their disease. Caloric demands are higher among individuals
with chorea, particularly in HD, and nutrition consultations may be
helpful in developing a healthy high-caloric diet. Trunk and limb chorea may
lead to balance disorders and falls; therefore, working with physical
therapists on balance training and core strengthening and implementing
assistive devices may be useful. Multidisciplinary rehabilitation programs
have been shown to improve motor and balance deterioration in people
with HD.83
CONCLUSION
Neurologists should recognize the pattern of involuntary, random,
nonrhythmic, purposeless, movements as consistent with chorea. Collecting a
detailed history and identifying the location of the chorea in addition to
supportive neurologic signs will help narrow the differential and focus the
diagnostic and therapeutic approach. If the chorea negatively impacts quality
of life and functional independence, symptomatic medications are available. A
multidisciplinary approach is preferred when treating individuals with
chorea, especially those with a multifaceted neurodegenerative disease such
as HD.
ACKNOWLEDGMENT
The authors would like to thank Shayan A. Zadegan, MD, for assistance with the
literature review.
1404 OCTOBER 2022

VIDEO LEGENDS
VIDEO 8-1 VIDEO 8-5
Huntington disease. Video shows a 33-year-old Generalized chorea secondary to CRMP5
man with genetically confirmed early-onset antibodies. Video shows the 78-year-old man in
Huntington disease. Examination reveals slowed CASE 8-2 who presented with a subacute onset of
ocular pursuit, saccade initiation and velocity, motor generalized chorea. The nonrhythmic
impersistence (impaired sustained tongue moderate-amplitude purposeless appendicular
protrusion), impaired finger tapping and pronation/ movements are generalized, slightly more
supination and Luria hand sequences, generalized prominent in the lower extremities. Gait reveals a
bradykinesia, and chorea. Gait is wide based with slightly widened base, shortened stride, and distal
bilateral upper extremity dystonic posturing. upper extremity chorea.
© 2022 American Academy of Neurology. Video courtesy of Bill Ondo, MD.
VIDEO 8-2 VIDEO 8-6

Huntington disease. Video shows a 42-year-old Hemichorea secondary to nonketotic
man with motor manifest Huntington disease hyperglycemia. Video shows a 51-year-old woman
demonstrating generalized chorea, impaired rapid with left hemichorea, which involves her face, arm,
finger tapping, and pronation/supination. and leg. Her serum glucose level was 527 mg/dL
Appendicular chorea and dystonia are seen during with a hemoglobin A1C of 12.6%. The brain MRI of the
attempted tandem gait. patient demonstrated T1 hyperintensity in the right
© 2022 American Academy of Neurology. posterior putamen. The history, imaging, and clinical
presentation led to a diagnosis of hemichorea
secondary to nonketotic hyperglycemia.
VIDEO 8-3
Generalized chorea secondary to benign Video courtesy of Amy Durand, MD, and Jorge
hereditary chorea. Video shows the 34-year-old Patino Murillas, MD.
woman in CASE 8-1 with chronic generalized
nonrhythmic moderate-amplitude purposeless VIDEO 8-7
truncal and appendicular movements. The patient Hemiballismus secondary to deep brain
has a strong family history of chorea (father and two stimulation of the subthalamic nucleus. Video
young daughters) and has a history of asthma and shows a 64-year-old woman with Parkinson disease
hypothyroidism suggestive of a clinical diagnosis of who presented with an acute onset of left
benign hereditary chorea due to mutation in the hemiballismus that occurred after programming
NKX2-1 gene. deep brain stimulation (DBS) of the right
subthalamic nucleus. The patient experienced
involuntary, high-amplitude proximal movements in
the left upper and left lower extremity. The
VIDEO 8-4 movements resolved with deep brain stimulation
Sydenham chorea. Video shows a 10-year-old boy reprogramming.
who presented with a subacute onset of
generalized chorea that began after an infection Video courtesy of Gage Van Horn, MD.
with group A streptococcus.
Video courtesy of Bill Ondo, MD.
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1471-2377-9-62
DISCLOSURE
Continued from page 1379 Kyowa Kirin Co, Ltd; Neurocrine Biosciences, Inc;
and Teva Pharmaceutical Industries Ltd and as an
Huntington's Disease Society of America; F. editor, associate editor, or editorial advisory board
Hoffman-La Roche/Genetech, Inc; the National member for the Annals of Clinical and Translational
Institutes of Health/University of Iowa; uniQure NV; Neurology/American Neurological Association.
and Vaccinex Inc. Dr Bega has received personal The institution of Dr Bega has received research
compensation in the range of $500 to $4999 for support from the Huntington’s Disease Society of
serving on speakers bureaus for Acorda America.
Therapeutics; Adamas Pharmaceuticals, Inc;
1408 OCTOBER 2022

Neurodegenerative REVIEW ARTICLE

Cerebellar Ataxia C O N T I N U UM A U D I O
ONLINE
By Liana S. Rosenthal, MD, PhD

VIDEO CONTENT
A V AI L A B L E O N L I N E
ABSTRACT
PURPOSE OF REVIEW: Neurodegenerative cerebellar ataxia is a diverse
CITE AS:
collection of diseases that are unified by gait and balance abnormalities, CONTINUUM (MINNEAP MINN)
appendicular incoordination, and abnormalities of eye movement and 2022;28(5, MOVEMENT DISORDERS):
1409–1434.
speech. The differential diagnosis is broad, ranging from paraneoplastic
syndromes that progress quite rapidly to unidentified genetic disorders Address correspondence to
that progress slowly over the course of decades. This article highlights the Dr Liana S. Rosenthal, Johns
Hopkins Neurology, 10751 Falls
diagnostic process, including the differential diagnosis, as well as Rd, Ste 250, Lutherville, MD,
treatment approaches and symptomatic management. The pillars of 21093, Liana.Rosenthal@jhmi.
treatment are physical, occupational, and speech therapy as well as edu.
counseling and discussions of disease prognosis, genetics, and RELATIONSHIP DISCLOSURE :

reproductive choices. There are many ways to help patients with Dr Rosenthal has received
neurodegenerative cerebellar ataxia and improve their quality of life. personal compensation in the
serving as a consultant for
RECENT FINDINGS: Recent years have seen significant improvements in genetic Biohaven Pharmaceuticals and
on a scientific advisory or data
testing, with reductions in cost of both Sanger sequencing and whole
safety monitoring board for
exome sequencing and increasing availability of the latter. These Reata Pharmaceuticals, Inc; has
improvements increase clinicians’ ability to identify the etiology of received research support from
Biohaven Pharmaceuticals, The
neurodegenerative cerebellar ataxia and suggest future treatments. Daniel B. and Florence E. Green
Although no medication has been approved by the US Food and Drug Foundation, the Gordon and
Administration (FDA) for treatment of cerebellar ataxia, research and Marilyn Macklin Foundation, The
Michael J. Fox Foundation, the
clinical trials for these diseases are increasing. National Ataxia Foundation, the
National Institutes of Health,
SUMMARY: Neurodegenerative cerebellar ataxia is characterized by and Pfizer Inc; and has a
noncompensated relationship
dysarthria, dysmetria, oculomotor abnormalities, and ataxic gait. It has a as a Medical Director, ex-officio
broad differential diagnosis, and numerous options exist for managing Member of the Board with
National Ataxia Foundation that
symptoms. Although no medications have been approved specifically for is relevant to American
cerebellar ataxia, treatment options are available to improve patients’ Academy of Neurology interests
quality of life. or activities.
UNLABELED USE OF
USE DISCLOSURE :
INTRODUCTION Dr Rosenthal discusses the
A
taxia is defined as an incoordination of muscle movement, and
medications for the treatment
diagnosis is often based on the characteristic gait and balance of neurodegenerative
difficulties that patients experience. Individuals with ataxia also spinocerebellar ataxias, none of
which are approved by the US
often experience incoordination of the limbs, speech, and eye Food and Drug Administration.
movements, as well as other neurologic, cognitive, and psychiatric
changes. This collection of symptoms results in far-reaching effects on patients’
function; therefore, the disease presents numerous treatment challenges and © 2022 American Academy
opportunities for improved care. Because many types of ataxia have genetic of Neurology.

NEURODEGENERATIVE CEREBELLAR ATAXIA
underpinnings, affected individuals have great potential to benefit from new

methods of gene sequencing and interpretation and gene therapy.
Ataxia can be classified based on localization of the predominant etiology into
three broad types: (1) sensory ataxia due to small or large fiber neuropathy in the
feet; (2) vestibular ataxia due to changes in or dysfunction of the semicircular
canals, otolith organs, or both; and (3) cerebellar ataxia due to changes in or
dysfunction of the cerebellum. As is usual in neurologic systems, individuals may
present with signs and symptoms of more than one type of ataxia, but the
classification is based on the primary driver of the symptoms.
Although ataxia can develop acutely such as in posterior circulation strokes
causing damage to the cerebellum, this article focuses on neurodegenerative
ataxia due to changes in or dysfunction of the cerebellum. It includes discussion
of the pathophysiology of the cerebellum and cerebellar localization at the
bedside, as well as diagnostic testing, differential diagnosis, management, and
treatment. Although multiple system atrophy (MSA) is a neurodegenerative
cerebellar ataxia, that disease warrants greater discussion. For more information
on MSA, refer to the article “Multiple System Atrophy” by Daniel O. Claassen,
MD, MS, FAAN,1 in this issue of Continuum. Pediatric cerebellar ataxias are also
discussed primarily in the pediatric movement disorder article, so for more
information, refer to “Diagnosing Common Movement Disorders in Children”
by Jennifer A. O’Malley, MD, PhD,2 in this issue of Continuum.
ANATOMY OF THE CEREBELLUM

The cerebellum is tucked underneath the cerebral cortex and next to the
brainstem and has extensive connections to both of those structures. It has a
cortex that branches and folds, central white matter, and deep nuclei. The gray
matter constituting the cortex is divided into three layers: (1) the external
molecular layer, which contains the outer stellate cells and inner basket cells; (2)
the middle layer, which contains the Purkinje cells; and (3) the internal granular
layer, which contains granular cells. The deep cerebellar nuclei (the dentate
nucleus, interposed nuclei, and fastigial nucleus) are the only output cells of the
cerebellar cortex and send their excitatory signal to numerous brain regions.
The cerebellar circuitry is designed to modify signals from the brain, process
those signals, and then send the processed signals back to different brain areas. The
signal begins in the cerebral cortex and then synapses on neurons in the pontine
nuclei. The axons from the contralateral pontine nuclei, called mossy fibers
because of the appearance of their synaptic terminals, then synapse on the
granular cells in the inner layer of the cerebellar cortex gray matter. The axons of
the granular cells are parallel fibers that ascend to the molecular layer of the
cerebellum, bifurcate, and form T-shaped branches that then synapse on many
Purkinje cells. Each Purkinje cell receives input from many parallel fibers, and
each parallel fiber modulates tens of thousands of Purkinje cells. The Purkinje cells
also receive direct modulatory input on their dendritic shaft from the inferior
olive’s climbing fibers, thus allowing the climbing fibers to modulate the parallel
fiber–to–Purkinje connection.3 The Purkinje cells then receive further inhibitory
input from the basket and stellate interneurons in the molecular layer that shape
the spike activity of the Purkinje cell output.4 The GABA-ergic Purkinje cells then
inhibit the deep cerebellar nuclei, which in turn also receive excitatory inputs from
the mossy and climbing fibers, thus creating a loop in which the Purkinje cells
modulate the excitatory outputs from the deep cerebellar nuclei.
1410 OCTOBER 2022

This circuitry is repeated in all parts of the cerebellum, which can be KEY POINTS
divided into different lobes based on function. The vermis and paravermis
● Ataxia can be classified
make up the central portion of the cerebellum and are also referred to as the into three broad types: (1)
spinocerebellum. The vermis is responsible for axial function, while the paravermis sensory ataxia due to
is responsible primarily for limb function. The spinocerebellum receives sensory neuropathy in the feet; (2)
input from the trigeminal nucleus and the dorsal column of the spinal cord vestibular ataxia due to
dysfunction of the
and then connects to (1) the fastigial nuclei to modulate eye movements and
semicircular canals, otolith
(2) the rubrospinal and vestibulospinal tract to modulate muscle tone. The organs, or both; and (3)
cerebrocerebellar hemispheres are located on each side of the vermis and cerebellar ataxia due to
paravermis and are responsible for motor planning and timing (primarily dysfunction of the
cerebellum.
anterior lobe) as well as cognition (primarily posterior lobe).5,6 The
cerebrocerebellum receives input from the ipsilateral primary and supplementary ● The vermis is responsible
motor cortex and the contralateral inferior olivary nucleus and connects to for axial function, while the
the cerebral premotor and motor cortex and the red nucleus. Finally, tucked paravermis is responsible
into the underside of the cerebellum is the flocculonodular lobe, which is also primarily for limb function.
called the vestibulocerebellum and is responsible for the vestibular system. It ● Patients with cerebellar
receives input from the ipsilateral vestibular nuclei and pretectal area of the ataxia describe falls and
midbrain and visual cortex and then connects directly back to the clumsiness but often
vestibular nucleus.7 describe the initial
symptoms as being difficulty
The vasculature of the cerebellum originates from the vertebrobasilar
maintaining balance on
anterior system and is divided such that the three primary vessels cover uneven ground, when going
different portions of the cerebellar lobes. The superior cerebellar artery up or (primarily) down stairs,
supplies the superior area of the vermis and the superomedial cortex, the or when running.
anterior inferior cerebellar artery (AICA) supplies the anterior inferior
● Examination of individuals
cerebellum, flocculus, and middle cerebellar peduncle, and the posterior with cerebellar ataxia
inferior cerebellar artery (PICA) supplies the cerebellar nuclei, the inferior usually reveals a
surface of the vermis, and the undersurface area of the cerebellar hemisphere. wide-based gait with some
The superior cerebellar artery, AICA, and PICA all also provide blood supply titubation observed,
specifically on turns.
to different areas of the brainstem and have additional branches within the
cerebellum, which explains the variation in examination and MRI findings
following strokes of these vessels. Although the focus of this article is on
cerebellar neurodegenerative syndromes, the clinical findings and
examination are often similar between individuals with cerebellar stroke
and these neurodegenerative diseases.
DIAGNOSIS OF CEREBELLAR ATAXIA AND CLINICAL FINDINGS

The diagnosis of cerebellar ataxia relies on the bedside examination and may be
supported by evidence on imaging and other investigations.
Cerebellar Signs and Symptoms on Bedside Examination

The localization of a patient’s symptoms to the cerebellum relies on identification
of characteristic changes in balance, gait, speech, swallowing, eye, and
appendicular movements.
BALANCE AND GAIT. Most individuals with cerebellar ataxia present with balance
and gait difficulties. Patients describe falls and clumsiness but often describe the
initial symptoms as being difficulty maintaining balance on uneven ground,
when going up or (primarily) down stairs, or when running. Examination
usually reveals a wide-based gait with some titubation observed, specifically
on turns (VIDEO 9-1). Because this same gait can be observed in sensory or

vestibular-based ataxia, the remainder of the examination allows for

cerebellar localization.
SPEECH AND SWALLOWING. Speech, swallowing, and eye movement abnormalities

are especially important for cerebellar localization, as these findings indicate that the
lesion is above the spinal cord. Although speech abnormalities vary slightly among
the different ataxias, most individuals have a scanning-type speech, with difficulties
with prosody, vocal modulation, articulation, and phonation.8 This pattern is
different from that heard in individuals with Parkinson disease in that hypophonia is
not prominent in the cerebellar ataxias. Dysphagia is also very common in
individuals with cerebellar ataxia, although its prevalence varies widely across the
different etiologies of cerebellar ataxia. Individuals often report coughing while
ingesting food and liquid and getting food or pills stuck in their throats.
EYE MOVEMENTS AND VISION. Eye movement changes are often the best way to
localize the patient’s ataxia to the cerebellum. Patients describe the world moving
around (oscillopsia); delayed focusing when they move their eyes; difficulty looking
up, especially when lying down (eg, individuals who bench press weights will
have difficulty looking at the bar); difficulty with reading signs when in a moving
car; or challenges looking down long grocery store aisles. On examination, these
symptoms manifest as downbeat nystagmus, saccadic intrusions on smooth pursuit,
square-wave jerks, and hypermetric and hypometric saccades. Downbeat
nystagmus is the most classic examination finding and localizes to changes in
the bilateral flocculus lobe of the cerebellum as well as the craniocervical junction
and bilateral medial longitudinal fasciculi (VIDEO 9-2), although, when combined
with other cerebellar findings, the flocculus localization seems the most likely for
these patients. However, individuals without downbeat nystagmus can have
cerebellar localization, with hypermetric and hypometric saccades also observed
in most individuals with cerebellar ataxia. These saccadic eye movement changes
are essentially the eye manifestations of the undershoot and overshoot observed
in the appendicular examination, as described subsequently. Individuals with
a pure cerebellar ataxia have a normal vestibular system and therefore a normal
head impulse test, but many neurodegenerative ataxias also feature vestibular
involvement, so assessing the vestibular system facilitates the differential
diagnosis.
APPENDICULAR ATAXIA. Individuals with appendicular ataxia describe

significant clumsiness, manifesting as knocking over drinks at the dinner
table, hitting the wrong letter on a computer or phone keyboard, and having
difficulty with activities of daily living such as cutting food, fastening buttons,
and pulling up zippers. It is important to determine whether this clumsiness is
due to cerebellar lesions or an alternative localization, most often
extrapyramidal lesions. Sometimes it is possible to distinguish between the
two in the history by determining whether patients experience difficulty
meeting their target (eg, grabbing the fork and knife, finding the button)
versus a feeling that their fingers will not do what their brain is asking. On
examination, patients demonstrate past pointing on the finger chase test,
dysdiadochokinesia, and dysmetria on the finger-to-nose test, although often
a finger-to-chin test is better to ensure that patients do not hit themselves in
the eye. Tremors are also commonly noted in individuals with ataxia, although
1412 OCTOBER 2022

sometimes what is described as tremor is nonrhythmic and really a KEY POINTS
combination of truncal ataxia and dysmetria.
● Speech, swallowing, and
eye movement
Extracerebellar Signs and Symptoms on Bedside Examination abnormalities are especially
Numerous extracerebellar signs and symptoms may be present that are part of important for cerebellar
the larger cerebellar syndrome and may significantly worsen the individual’s localization, as these
findings indicate that the
quality of life.
lesion is above the spinal
cord.
SENSORY ATAXIA. Individuals with degenerative cerebellar ataxia often have a
mild sensory ataxia, and patients sometimes describe numbness or tingling in ● Eye movement changes,
their feet. However, the gait and balance abnormalities are out of proportion to specifically downbeat
nystagmus, square-wave
what would be expected from the sensory ataxia findings alone. Reductions in jerks, and hypermetric or
pain and temperature and vibration and proprioception usually have a stocking- hypometric saccades, are
glove distribution. often the best way to
localize the patient’s ataxia
to the cerebellum.
EXTRAPYRAMIDAL FINDINGS AND MIMICS. Muscle cramps and stiffness as well as
slowness and clumsiness are also common concerns in individuals with cerebellar ● Individuals with
ataxia. Examination of muscle tone reveals both a pyramidal and extrapyramidal cerebellar lesions often
localization depending on the etiology of the cerebellar degeneration, with report difficulty meeting
their target with their hands,
spasticity in some patients and rigidity in others; in some patients, the bedside
while individuals with
examination reveals a clear muscle tightness, but whether it is rigidity or extrapyramidal lesions often
spasticity is difficult to determine. Individuals with cerebellar ataxia without report that their fingers will
extrapyramidal involvement often demonstrate pauses and clumsiness on finger not do what their brain is
asking.
tapping, hand opening and closing, and pronation and supination but do not have
a decrementing bradykinesia (VIDEO 9-3). As discussed further below, many of ● Individuals with
the genetic ataxias do have extrapyramidal involvement and therefore feature cerebellar ataxia without
true decrementing bradykinesia, although such findings also point toward MSA extrapyramidal involvement
as a possible diagnosis. often demonstrate pauses
and clumsiness on finger
tapping, hand opening and
AUTONOMIC NERVOUS SYSTEM. Although changes in the autonomic nervous closing, and pronation and
system are often discussed in the context of individuals with MSA, autonomic supination but do not have a
nervous system involvement is also very common in the other decrementing bradykinesia.
neurodegenerative ataxias discussed in this article. Patients commonly report
● Individuals with what is
urinary urgency, frequency, and incontinence; lightheadedness when standing; known as cerebellar
and sometimes sexual dysfunction. In one survey, lower urinary tract symptoms cognitive affective
were reported in 8% to 50% of men with a variety of genetic spinocerebellar syndrome present with
challenges in executive
ataxias; also reported were clear changes in urodynamic studies performed on a
function, linguistic
smaller subset of the same cohort.9 Another analysis of nine individuals with processing, and spatial
spinocerebellar ataxia (SCA) type 2 identified autonomic nervous system cognition.
symptoms and neurophysiologic study changes in all the individuals, ranging
from urinary tract to cardiovascular system to gastrointestinal dysfunction.10
Although such detailed analysis is not available for all the SCAs and
neurodegenerative ataxias, these findings show that autonomic nervous system
dysfunction is part of the overall clinical picture and should be addressed as part
of patient care.
COGNITION. The cerebellum plays a critical role in cognition, and individuals with
cerebellar neurodegeneration often report cognitive difficulties. Individuals with
what is known as cerebellar cognitive affective syndrome11 present with
challenges in executive function, linguistic processing, and spatial cognition.

These cognitive changes were once thought to be related to the cerebellar

connections to the cortex, but more recent research has demonstrated that the
relevant processes occur in the cerebellum itself, particularly the more posterior
part of the cerebellum, with the anterior cerebellum being more related to motor
processes).6 Cerebellar cognitive affective syndrome has been identified in
individuals with acute (eg, stroke) and more subacute (eg, neurodegeneration,
tumors) disorders of cerebellar processes and can be measured using a validated
scale12 that is specific to the cerebellar deficits. The recognition that these
cognitive changes are part of the disease process is a critical part of counseling for
patients and their families and is an area of intensive research, both to better
understand the disorder and to identify more effective treatments.
PSYCHIATRIC CHANGES. Psychiatric changes associated with cerebellar disease may

cause significant challenges for patients and their families and are found in almost
all patients. Although depression can certainly be part of the disease course,
anxiety and irritability coupled with disinhibition are more common.13 Patients
often report feeling particularly anxious in crowds of people or whenever they
need to walk and maneuver to get somewhere without falling. The irritability and
disinhibition are most often noticed by the spouse or care partner of the individual
with ataxia and are often described as “going from an emotional 0 to 60” in the
snap of a finger. The individual with ataxia is sometimes not aware of this change,
but it may cause significant difficulties in their personal relationships.
IMAGING AND TESTING TO AID IN DIAGNOSIS AND LOCALIZATION

Although localization is always based on clinical examination, additional testing
including MRI, nerve conduction studies/EMG, and other studies is supportive
and helps narrow the differential diagnosis regarding etiology.
MRI
MRI of the brain can facilitate localization and may be helpful in the differential
diagnosis for patients with ataxia symptoms. In addition to ruling out congenital
abnormalities, strokes, and masses, the midline sagittal T1-weighted image is
ideal to evaluate cerebellar atrophy, although axial sections showing a widened
fourth ventricle are also helpful. Absence of cerebellar atrophy does not change
the localization, as an overall normal-sized cerebellum may be observed,
especially in individuals with recent-onset ataxia, but the presence of cerebellar
atrophy helps confirm the localization. Evaluation of the pattern of atrophy
within the cerebellum is also helpful; vermal atrophy is observed in individuals
for whom alcohol use disorder is the primary cause of ataxia. Brainstem
evaluation for a hot cross bun sign (as observed in MSA because of pontine fiber
atrophy) or a hummingbird sign (as observed in progressive supranuclear palsy
because of midbrain atrophy) is also useful for guiding the differential diagnosis,
but again, absence of these imaging findings does not exclude these diagnoses.
Adult-onset leukodystrophies, some of which also have prominent cerebellar
findings, have specific patterns of white matter hyperintensities,14 and middle
cerebellar peduncle and corpus collosum fluid-attenuated inversion recovery
(FLAIR) hyperintensities are major radiologic diagnostic signs of fragile X
tremor-ataxia syndrome (FXTAS).15 Neurodegeneration with brain iron
accumulation is also identified on the basis of a brain MRI. A cervical spine MRI may
also be useful in the differential diagnosis, both for evaluating whether the patient
1414 OCTOBER 2022

has additional cervical stenosis or cord impingement contributing to the disease and KEY POINT
for evaluating any brainstem and cervical spine abnormalities that are secondary to
● Absence of cerebellar
the ataxic syndrome. For example, a narrowing of the brainstem and cervical cord atrophy does not change the
called the tadpole sign may be observed in adult-onset Alexander disease.16 localization, as an overall
normal-sized cerebellum
Vestibular Testing and Nerve Conduction Studies/EMG may be observed even
among individuals with
Vestibular testing and nerve conduction studies/EMG may also play a role in
significant cerebellar
localization and assisting with the differential diagnosis. Vestibular testing and dysfunction. The presence
subsequent pathologic evaluations have identified vestibular abnormalities in of cerebellar atrophy,
many of the different SCAs17-19 as well as other forms of ataxia,20 with changes in though, helps to confirm the
localization.
vestibular testing sometimes even predicting subsequent motor decline in
SCA6.21 In addition, vestibular areflexia is part of cerebellar ataxia with
neuropathy and vestibular areflexia syndrome (CANVAS), a somewhat recently
identified cause of cerebellar ataxia due to RFC1 gene expansion. Although
autopsy studies have identified a vestibular neuronopathy as the cause of these
changes in CANVAS,22 bedside examination of these patients reveals head
movement–induced oscillopsia or abnormal head impulse test.
Nerve conduction studies/EMG may also play a role in diagnostic evaluation
and narrowing the differential diagnosis, as many of the cerebellar ataxias also
have peripheral nerve involvement. In individuals with SCA types 1, 2, 3, and 6, a
mixed axonal and demyelinating sensorimotor neuropathy is the most common,
with prevalence estimates of these findings ranging from 22% for SCA3 to 82%
for SCA1.23 In addition, nerve conduction velocities are slower in patients with
SCA1, a finding that separates SCA1 from the other SCAs and therefore is
especially useful with regard to the differential diagnosis and genetic testing.23
SCA2 and SCA3 are more likely sensorimotor neuronopathies, while the other
SCAs are axonal sensorimotor polyneuropathies. Demyelinating nerve damage is
relatively rare among the ataxias and points to a few specific diagnoses, including
toxic insults and rare subsets of Charcot-Marie-Tooth disease.24 Finally, as its
name implies, CANVAS includes abnormal nerve conduction testing consistent
with a sensory deficit as part of its diagnostic criteria.22
ADDITIONAL EVALUATION. Significant blood work, CSF analysis, and additional

imaging (eg, positron emission tomography [PET] scans) may also be critical in
narrowing the differential diagnosis among the neurodegenerative cerebellar
ataxias. The detailed tests that may be ordered are reviewed in the differential
diagnosis section as they pertain to the different possible etiologies.
RATING SCALES. The Scale for the Assessment and Rating of Ataxia (SARA)25 is
one of the more widely used rating scales both in research and to follow patient
changes over time. It allows for the evaluation of gait, stance, and speech as well
as truncal and appendicular ataxia and takes about 15 minutes to administer. The
International Cooperative Ataxia Rating Scale (ICARS)26 includes many of the
same assessments as the SARA in addition to eye movement evaluation and
handwriting and fine motor changes, resulting in an administration time of about
20 to 30 minutes. The ICARS is used primarily in research. The Brief Ataxia
Rating Scale (BARS)27 includes assessments of gait, speech, and appendicular
ataxia. It has good clinometric properties and takes only about 5 minutes to
administer but has not been as widely adopted as the SARA. The modified
Friedreich Ataxia Rating Scale (mFARS) is used in most research on Friedreich

ataxia and includes assessment of bulbar function, appendicular ataxia, and

stability. It takes about 20 to 30 minutes to administer.
APPROACH TO DIFFERENTIAL DIAGNOSIS

Localization to the cerebellum and the subsequent diagnosis of
neurodegenerative cerebellar ataxia lead to the next phase of determining the
etiology of the patient’s disorder. The patient history will indicate whether it is
important to consider toxic exposure (eg, to alcohol or medication) as a possible
cause. Cerebellar ataxia from alcohol exposure is one of the better-known causes
of cerebellar degeneration and is associated with greater midline than
appendicular findings on examination and vermal cerebellar atrophy. Long
duration of drinking, large amount of alcohol consumed overall, and the
presence of binge drinking are all associated with sufficient cerebellar changes to
cause a clinically significant ataxia, although it was found that even in individuals
who drank continuously for more than 10 years, the prevalence of cerebellar
ataxia was only 14.6%.28 Therefore, alcohol should be considered as only one
TABLE 9-1 Recommended Laboratory Tests for Cerebellar Ataxia
Laboratory tests Related diagnoses
Routine laboratory tests
Serum electrolytes Metabolic abnormalities
Complete blood cell count Lymphoproliferative disorders
Renal function and liver function Renal and hepatic disease, respectively
Glycated hemoglobin (hemoglobin A1c) Diabetes mellitus
Creatine kinase Myopathy
Thyroid-stimulating hormone (TSH) Hyperthyroidism/hypothyroidism
Inflammatory markers and infectious disease
Erythrocyte sedimentation rate Inflammation/vasculitis
Antinuclear antibody Systemic lupus erythematosus (SLE)/

rheumatologic disease
Human T-cell lymphotropic virus type 1 (HTLV-1) HTLV-associated ataxia

or type 2 (HTLV-2) antibody
Human immunodeficiency virus (HIV) HIV-associated ataxia
Borrelia burgdorferi antibody Lyme disease
Rapid plasma reagin (RPR)/fluorescein treponemal antibody Neurosyphilis
Autoimmune and neoplastic
Sjögren syndrome A (SSA)/Ro and Sjögren syndrome (SSB)/La Sjögren disease
1416 OCTOBER 2022

possible contributor to the patient’s cerebellar ataxia, along with genetic29 or
autoimmune etiologies.30 In addition, many different medications can contribute
to or cause acute or chronic cerebellar ataxia, which should be screened for as
part of the medical history.31
Assuming that the history is unrevealing, testing for nongenetic and then
genetic etiologies is an iterative process, circling back on each possibility to
ensure that all reasonable and appropriate testing to identify the etiology has
occurred. In the absence of a clear family history of cerebellar disease, which
would of course prompt genetic testing first, the first step is testing for reversible
or targeted treatment etiologies (TABLE 9-1). This testing consists primarily of
blood work to evaluate for vitamin deficiencies, paraneoplastic syndromes, and
autoimmune etiologies; in addition, the workup thus far should be evaluated to
determine the need for additional testing (eg, a history and MRI consistent with
Creutzfeldt-Jakob disease would lead to CSF testing of 14-3-3 and real-time
quaking-induced conversion [RT-QuIC]–based Creutzfeldt-Jakob disease
testing). If no reversible or targeted treatment cause is identified, genetic testing
Laboratory tests Related diagnoses
Thyroid peroxidase antibody Steroid-responsive encephalopathy secondary

to autoimmune thyroiditis
Celiac antibody panel Celiac disease
Glutamic acid decarboxylase 65 (GAD-65) antibody Stiff person syndrome/GAD-related ataxia
Paraneoplastic panel, including anti-Hu, N-methyl-D-aspartate Paraneoplastic cerebellar ataxia

(NMDA) receptor antibody, anti-Yo, and anti-Ri
Serum and urine protein electrophoresis Lymphoproliferative disorders
Vitamin deficiencies and metal toxicities
Vitamin B12/methylmalonic acid/homocysteine Subacute combined degeneration of the spinal cord
Folate Folate deficiency
Vitamin E Ataxia with vitamin E deficiency
Ferritin Neuroferritinopathy
Ceruloplasmin, urine, and serum copper Copper deficiency, Wilson disease
Heavy metals, urine Heavy metal toxicity
Other
Coenzyme Q10 Coenzyme Q10 deficiency ataxia
α-Fetoprotein tumor marker Ataxia-telangiectasia
Lactic acid and pyruvic acid Mitochondrial disorders
Data from Fogel BL and Perlman S, Nat Clin Pract Neurol,32 Ramirez-Zamora A, et al, Mov Disord.33

is then performed, which includes testing for trinucleotide repeat syndromes and
whole exome sequencing. If those results are all unremarkable, additional
assessment is performed for even more rare etiologies. Throughout this process,
MSA should always be considered in the differential diagnosis.
Targeted Treatment Differential Diagnosis and Workup

Experts differ with regard to which laboratory tests should be performed as
part of the initial workup.32,33 This author’s practice is to focus testing on any
diagnosis that would immediately change management (CASE 9-1) (TABLE 9-1).
When evaluating the results of this blood work, it is important to distinguish
between those that are outside of normative values and those that are actually
diagnostic for the cause of cerebellar ataxia. A good example is anti–glutamic
acid decarboxylase (GAD) levels. Anti-GAD levels are elevated slightly in
individuals with diabetes and even in healthy controls but are elevated
significantly in anti-GAD–related ataxia and stiff person syndrome (significant
elevation defined as diagnostic for anti-GAD-related ataxia is 20 nmol/L or
more than 1000-fold higher than the upper limit of normal at the Mayo
Clinic Laboratory34). For still other laboratory tests, there are no known
CASE 9-1 A 42-year-old woman presented because of unsteady walking. Beginning

about 3 years previously, she had noted difficulties when running on a
trail near her house and when walking on the sand at the beach on
vacation. Although she was not concerned about these problems, her
wife noted her unsteady walking and asked her if she had been drinking
alcohol in the middle of the day. Her primary care doctor ordered a brain
MRI, which was interpreted as unremarkable. The patient’s walking
problems then worsened, and she noted difficulties descending stairs.
About 2 years before presentation, she noted that her speech was
intermittently slurred, especially when she was tired or after drinking
even half of a glass of wine, and she had begun to fall as often as twice a
month. The patient was referred for a neurologic evaluation.
Her past medical history was notable only for hypothyroidism. Family
history did not reveal the presence of a neurodegenerative disorder in
any family member. The patient’s two children, ages 15 and 18, were
healthy, and she did not have any grandchildren. She was a social drinker,
having about one glass of wine per week. She did not smoke or use illicit
drugs. Her only medications were levothyroxine and acetaminophen as
needed for menstrual headaches.
Neurologic examination was notable for slightly hypermetric saccades,
dysmetria, and a wide-based gait. Review of the initial MRI from 1 year
previously showed possible cerebellar atrophy. Repeat brain MRI
confirmed a wide fourth ventricle and vermal as well as cerebellar
hemisphere atrophy. Routine laboratory tests ordered by her primary care
doctor including a complete blood cell count, complete metabolic panel,
thyroid-stimulating hormone (TSH), and thyroxine were all unremarkable.
Laboratory workup for treatable causes of cerebellar ataxia was ordered
including a paraneoplastic panel. Although most of the results were
1418 OCTOBER 2022

published data indicating the sensitivity and specificity for different cutoff
values to diagnose that abnormality as contributing to or causing ataxia.
Clinicians are therefore left without guidance regarding whether to attribute
midlevel results to their patient’s cerebellar ataxia, and such decisions come
down to clinical gestalt. More research is clearly needed to identify criterion
standards for diagnosis and cutoff values for each of the most common
laboratory abnormalities.
Genetic Counseling, Testing, and Assessment

Genetic testing begins with a comprehensive family history as well as
counseling. The family history will help to ascertain whether there is any clear
inheritance pattern (eg, autosomal dominant, autosomal recessive, X-linked)
or any other clues that can help guide decision-making (ie, a grandchild with
developmental delay may point toward testing for FXTAS, or a history of
hearing loss may point to mitochondrial etiologies in the right context). In
addition, there is growing recognition of CANVAS, caused by an RFC1
mutation, as an important etiology of neurodegenerative cerebellar ataxia.
Specifically, an RFC1 gene expansion was identified in 3.2% of individuals
unrevealing, the antinuclear antibody was 1:160, and the glutamic acid
decarboxylase 65 (GAD65) antibody titer was 1:1280.
The patient was diagnosed with anti-GAD–related ataxia. Given the
prevalence of anti-GAD antibodies in a number of paraneoplastic
syndromes, she underwent whole-body positron emission tomography
(PET) CT, which was negative for any concerning areas of high uptake. She
was not able to obtain insurance approval for rituximab, so she underwent
plasma exchange while also starting intensive physical therapy, speech
therapy, and daily exercise. She reported some improvement, including
reduction of her low back pain, which she had attributed to poor posture
but was actually stiffness related to her GAD antibodies. With this progress,
her insurance company approved rituximab, and she noted a slow and
steady improvement on this treatment, with significantly fewer falls and
greater ease in walking up and down stairs.
This patient’s history, examination, and more recent MRI all confirm the COMMENT
cerebellar localization of her many symptoms. As she only had symptoms
for 3 years, testing for paraneoplastic conditions was critical, although in
her case such testing was unremarkable. It is also always important to test
for causes of ataxia that would change immediate management, and
testing for GAD65 antibodies is part of that analysis. A GAD65 antibody titer
of 1:1280 is significantly elevated and diagnostic of anti-GAD related ataxia.
By testing for the treatable causes of ataxia, the clinician could be
comfortable that the etiology of this patient’s ataxia was identified and
could move forward with treatment.

with ataxia of previously unknown etiology35 and 34% of individuals with

sensory neuropathy from a cohort of individuals with chronic idiopathic
axonal polyneuropathy of unknown etiology.36
Counseling of the patient and family is also a critical step in the process. Patients
and their family members must understand the meaning of both a positive and a
negative genetic test and have the opportunity to put in place any infrastructure
they may need prior to testing (eg, in the United States, patients should consider
getting long-term care insurance and disability insurance before genetic testing,
as a positive result will likely preclude obtaining those types of insurance later).
Equally important for the patient to understand is that a negative test does not rule
out genetic causes, as not all genes are tested for.
Genetic counseling should also include a discussion of reproductive choices.
For many of the genetically identified SCAs, as well as other genetic diseases,
in vitro fertilization with preimplantation genetic diagnosis allows for
eradication of the genetic disease in the next generation. Embryos are tested
for the SCA gene, and only those without the mutation are transplanted
back into the uterus of the woman. Couples can then have children who do not
have the SCA gene. Undergoing in vitro fertilization with preimplantation
genetic diagnosis requires a known mutation in the family, hence the need for
extensive genetic testing.
Genetic testing options that are widely available currently consist of Sanger
sequencing methods, which are used to test for trinucleotide repeat disorders,
and whole exome sequencing, which is used to test for the other genetic
mutations. In the absence of clinical or family history guidance regarding
which genetic etiology to look for, this author typically starts with assessing
for the trinucleotide repeat ataxias, as these are more common. If that testing
is negative, whole exome sequencing is performed. See TABLE 9-2 for details
on the different genetic ataxias, including their inheritance patterns and
clinical findings.
One of the biggest challenges in genetic testing for individuals with ataxia is
the cost of testing and the relative difficulty of obtaining insurance coverage for
that testing, along with the corresponding time spent by the neurologist and
other office staff members in obtaining prior authorization. Nevertheless, a
growing number of companies are offering testing, and costs have decreased
considerably over the past 5 years. Keeping track of the different companies, the
tests they offer, and the costs of testing is a major project. The National Ataxia
Foundation website (ataxia.org/ataxia-genetic-test-options/) contains a list of
companies and which tests they offer that at the time of this writing was last
updated in 2019 but is a reasonable place to start the process of identifying
sources of genetic testing.
Additional Neurodegenerative Etiologies

If genetic testing is not successful in identifying the etiology of cerebellar ataxia,
the next step is to evaluate for other diagnostic possibilities. Chief among these
are the adult-onset versions of many of the newborn and pediatric metabolic
disorders, including Gaucher disease, Niemann-Pick disease, carbohydrate-
deficient glycoprotein syndromes, and leukodystrophies. Many of these are
screened for in the whole exome sequencing discussed above, but it is always
worthwhile to circle back through these disorders in cases of rare mutations
causing these abnormalities.
1420 OCTOBER 2022

TREATMENT KEY POINTS
The most important principle in the treatment of neurodegenerative cerebellar
● Testing for nongenetic
ataxia is that although no disease-modifying therapy or even medications and then genetic etiologies
specifically approved to treat cerebellar ataxia currently exist, there is always is an iterative process,
something that can be done to improve the individual’s quality of life (CASE 9-2). circling back on each
If a treatable etiology was identified during the workup, the next step in possibility to ensure that all
reasonable and appropriate
management would obviously be implementing that treatment, along with
testing to identify the
following some of the more general treatment recommendations described etiology has occurred.
below. For example, an ataxia caused by vitamin E deficiency would warrant
vitamin E supplementation, and an autoimmune-based ataxia might warrant ● When evaluating the
steroids, intravenous immunoglobulin (IVIg), or rituximab, as appropriate. results of blood work, it is
important to distinguish
Episodic ataxia often responds to acetazolamide and 4-aminopyridine, with between those results that
some patients reporting an almost complete elimination of episodes with these are outside of normative
medications. values and those results that
For the ataxias with genetic or unknown causes, the treatment focus is on are actually diagnostic for
the cause of the cerebellar
symptomatic therapy for disease management. Symptomatic therapy includes ataxia.
nonpharmacologic and pharmacologic approaches, with many ataxia specialists
emphasizing the former given their fewer side effects. ● For many of the
genetically identified
spinocerebellar ataxias, as
Nonpharmacologic Approaches
well as other genetic
Nonpharmacologic treatment options may improve quality of life and function diseases, in vitro fertilization
and are critical to the long-term management of cerebellar ataxia. with preimplantation
genetic diagnosis allows for
eradication of the genetic
BALANCE AND GAIT. Difficulty with balance and gait is often the presenting
disease in the next
symptom for individuals with cerebellar ataxia, and these impairments can generation.
be expected to worsen over time. Nevertheless, exercise has been shown to
improve ataxia motor symptoms and is critical to maintain function for as long as ● If genetic testing is not
possible. Exercise improves individuals’ scores on the SARA,37,38 as well as successful in identifying the
etiology of cerebellar ataxia,
walking speed and other walking parameters. Many of these benefits have been the next step is to evaluate
sustained for at least a month after the end of an intensive exercise treatment for other diagnostic
program,39 although they eventually decline. Thus, exercise does not modify the possibilities.
disease38 but clearly improves symptoms and, by extension, function. Most of
● The most important
the evidence regarding exercise is in favor of high-intensity exercise programs,40
principle in the treatment
and exercise programs that are subjectively more challenging to the individual of neurodegenerative
result in greater objective improvement.39 Tai chi was shown to improve balance cerebellar ataxia is that
in individuals with ataxia in a small study,41 and yoga has been shown to improve although no disease-
modifying therapy or even
balance in individuals with other neurodegenerative diseases but has not yet
medications specifically
been formally evaluated in neurodegenerative cerebellar ataxia. approved to treat cerebellar
ataxia are currently known,
SPEECH AND SWALLOWING. Speech and swallowing therapy is the mainstay of there is always something
treatment for individuals with cerebellar ataxia who experience changes in that can be done to improve
the individual’s quality of life.
these functions. In speech therapy, the speech-language pathologist determines
the main areas of speech that are challenging to the patient, with most patients ● Exercise has been shown
exhibiting changes in the pitch of their voice.42 Treatment is then targeted to improve ataxia motor
to the area of the most need, with additional work on vocal endurance (ie, symptoms and is critical to
maintain function for as long
reading out loud daily to build up the relevant muscles and coordination so as possible.
that speech is still clear when the patient is tired). Swallowing evaluation is
also critical to avoid aspiration pneumonia or choking. Bedside swallow testing
and a videofluoroscopic swallow study are the primary swallowing assessments
performed by speech-language pathologists and are followed by treatment that

TABLE 9-2 Overview of the Most Common Genetic Ataxias and the Clinical Clues that
Indicate That Testing for That Ataxia Should Be Prioritized
Disease Gene Clinical clues
Autosomal dominant
Spinocerebellar ataxia ATXN1 Pyramidal signs, ophthalmoplegia, bulbar

type 1 (SCA1) dysfunction
SCA2 ATXN2 Parkinsonism, very slow saccades, peripheral

neuropathy
SCA3 ATXN3 Dystonia, parkinsonism, peripheral neuropathy,

most common SCA in many populations
SCA5 SPTBN2 Descendants of paternal grandparents of Abraham

Lincoln
SCA6 CACNA1A Downbeat nystagmus, mostly purely cerebellar
SCA7 ATXN7 Retinal degeneration
SCA8 ATXN8/ Slowly progressive

ATXN8OS
SCA10 ATXN10 Seizures common but not always present
SCA11 TTBK2 Progression over decades, hyperreflexia, no

extrapyramidal or sensory signs
SCA12 PPP2R2B More common in India than in the United States,

action tremors (upper limb and head)
SCA13 KCNC3 Infantile-onset form is nonprogressive; childhood-

and adult-onset forms are slowly progressive and
include spasticity
SCA14 PRKCG Slowly progressive, axial myoclonus, parkinsonism,

dysarthria, nystagmus
SCA15 ITPR1 Slowly progressive gait and limb ataxia, dysarthria,

impaired vestibuloocular reflex
SCA17 TBP Cognitive impairment, parkinsonism, dystonia,

chorea, spasticity, epilepsy, psychiatric
abnormalities
SCA19/22 KCND3 Myoclonus, cerebellar, cognitive impairment,

peripheral neuropathy
SCA23 PDYN Hyperreflexia, gait ataxia, ocular dysmetria, slowed

saccades
SCA26 EEF2 Slowly progressive, mostly purely cerebellar
SCA27 FGF14 Early-onset tremor, can have episodes of

worsening, neuropsychiatric symptoms
SCA28 AFG3L2 Very slowly progressive, ophthalmoparesis,

hyperreflexia, spasticity
SCA29 ITPR1 Early onset, developmental delay/cognitive

impairment
1422 OCTOBER 2022

SCA35 TGM6 Spasmodic torticollis, hyperreflexia
SCA44 GRM1 Dysdiadochokinesis, dysmetria, slowly progressive,

hyperreflexia, spasticity
Episodic ataxia type 1 (EA1) KCNA1 Generally pediatric onset, constant myokymia,
neuromyotonia, episodes are seconds to minutes
EA2 CACNA1A Generally pediatric onset, many patients have

generalized weakness, episodes are 30 minutes to
6 hours
EA5 CACNB4 Adult onset, juvenile myoclonic epilepsy, episodes

are hours to sometimes weeks
EA6 SLC1A3 Pediatric onset, episodic hypotonia, episodes are

hours to days
Spastic ataxia type 1 (SPAX1) VAMP1 Lower-limb spasticity, head jerks, ocular movement
abnormalities, dysphagia, dysarthria
Dentatorubral-pallidoluysian atrophy (DRPLA) ATN1 Progressive ataxia, dementia, chorea, myoclonus,

psychosis, epilepsy
Alexander disease GFAP Atrophy of the medulla and cervical spine leading to
“tadpole sign” on MRI, progressive, seizures,
cognitive deficits/delays
X-linked dominant
Fragile X tremor-ataxia syndrome (FXTAS) FMR1 Middle cerebellar peduncle sign on brain MRI,
grandson developmental delay, progressive
intention tremor, executive dysfunction
Autosomal recessive
Friedreich ataxia (ATX-FXN) FXN Often preadolescent onset, cardiomyopathy,

scoliois, square-wave jerks, spinal cord atrophy
Cerebellar ataxia with neuropathy and vestibular RFC1 Late onset, slowly progressive, bilateral
areflexia syndrome (CANVAS) vestibulopathy, sensory neuropathy
Spastic paraplegia type 7 HSP/ATX-SPG7 (SPG7) SPG7 T2 hyperintensity of the dentate nucleus on MRI,
progressive weakness and spasticity of lower limbs,
significant urinary sphincter dysfunction, pes cavus,
spasticity, pyramidal signs, ophthalmoparesis
Autosomal recessive spastic ataxia of SACS Early onset, peripheral neuropathy with distal
Charlevoix-Saguenay ATX/HSP-SACS (ARSACS) wasting and weakness, pyramidal tract signs,
thickened retinal hypermyelinated nerve fibers,
vermis atrophy
Autosomal recessive cerebellar ataxia ADCK3 Epilepsy, myoclonus, ischemic episodes, impaired
type 2 ATX-ADCK3 (ARCA2) cognition, exercise intolerance, developmental
delay

Autosomal recessive
ATX-ANO10 (ARCA3) ANO10 Pure cerebellar ataxia, sometimes cognitive

impairment, upper motor neuron signs, cognitive
impairment, epilepsy
Autosomal recessive spinocerebellar ataxia SYNE1 Pure cerebellar ataxia, gait ataxia, slowly
type 1 ATX-SYNE1 (ARCA1/SCAR8) progressive, occasional upper and/or lower motor
neuron involvement
Autosomal recessive spinocerebellar SYT14 Childhood psychomotor delay, slowly progressive,

ataxia type 11 (SCAR11) disturbed smooth pursuit
Spinocerebellar ataxia with axonal neuropathy TDP1 Axonal sensorimotor neuropathy, distal sensory
(SCAN1) impairment, pes cavus, reduced reflexes, steppage gait
Ataxia with oculomotor apraxia type 1 APTX Childhood onset, oculomotor apraxia, peripheral
ATX-APTX (AOA1) axonal motor neuropathy, elevated α-fetoprotein
ATX-SETX (AOA2) SETX Juvenile onset, oculomotor apraxia, progressive,

elevated α-fetoprotein, axonal sensorimotor
polyneuropathy, head tremor, chorea
Ataxia-telangiectasia ATX-ATM ATM Infantile onset, progressive ataxia, telangiectasias,

immunodeficiency, increased cancer frequency,
oculomotor apraxia, choreoathetosis
Ataxia-telangiectasia–like disorder ATX-MRE11A MRE11A Slowly progressive, oculomotor apraxia, no

telangiectasia, extrapyramidal myoclonus,
childhood onset
Posterior column ataxia with retinitis FLVCR1 Early-onset retinitis pigmentosa, slowly
pigmentosa (PCARP) progressive, late-onset gait ataxia
Autosomal recessive spastic ataxia type 4 MTPAP MTPAP Infantile onset, slowly progressive, spastic
(SPAX4) paraparesis, optic atrophy, pyramidal signs,
developmental delay
POLG and POLG-related ataxias (SANDO, MIRAS, POLG Progressive external ophthalmoplegia, sensory and
SCAE) cerebellar ataxic neuropathy, myoclonus, epilepsy,
sensorineural hearing loss
Marinesco-Sjögren syndrome ATX-SIL1 SIL1 Childhood onset, rapid development of cataracts,

cerebellar signs and atrophy, myopathy
Ataxia with vitamin E deficiency ATX-TTPA (AVED) TTPA Retinitis pigmentosa, cervical dystonia, positive
Romberg or Babinski sign, low serum vitamin E,
dysdiadochokinesia, dorsal column involvement,
loss of distal joint position proprioception, teenage
onset, possible cervical dystonia
Autosomal dominant and autosomal recessive
Gillespie syndrome ATX-ITPR1 ITPR1 Early onset, iris hypoplasia, congenital hypotonia,
intellectual disability, facial dysmorphism, allelic
with SCA15 and SCA29
1424 OCTOBER 2022

may include behavioral modifications or dietary changes, both of which have KEY POINT
been shown to be effective.43 ● Swallowing difficulties
may be treated by
ADDITIONAL THERAPEUTIC MODALITIES. Occupational therapy is also routinely behavioral modifications or
recommended for individuals with cerebellar ataxia. As with speech therapy, there dietary changes, both of
has not been sufficient research to demonstrate occupational therapy efficacy for which have been shown to
be effective.
appendicular ataxia or other specific symptoms. Nevertheless, when combined
with physical therapy, there is Class III evidence that occupational therapy
improves global functional status and may diminish symptoms of depression.44
Vestibular therapy has strong support for improving vestibular dysfunction45 and
is therefore an option for individuals with cerebellar ataxia who also have
vestibular dysfunction, although, again, no specific research has been conducted
to evaluate the efficacy of vestibular physical therapy in cerebellar ataxia.
AUTONOMIC NERVOUS SYSTEM. In addition to the below-mentioned medication

recommendations, several behavioral modifications may be effective in the
management of autonomic nervous system symptoms in individuals with
ataxia. For all of these recommendations, the research indicates efficacy for
the symptom in other populations, not specifically for those with ataxia. Bolus
water drinking is effective for orthostatic hypotension,46 as are compression
stockings, but only those that include coverage of the abdomen were deemed to
be effective for symptomatic treatment.47 For urinary incontinence, bladder
training, pelvic floor muscle training, and a combination of both have been
shown to improve stress or urgency incontinence.48
COGNITIVE AND PSYCHIATRIC. Nonpharmacologic management of cognitive

change and dementia includes exercise, cognitive rehabilitation and
stimulation-based occupational therapy, assistive technology, and behavioral
techniques as well as assistive devices. Again, these treatment recommendations
have not been evaluated specifically in individuals with cerebellar ataxia but rather
in those with cognitive and psychiatric symptoms from other etiologies.
Nevertheless, exercise reduced progression of dependence on others for
completing activities of daily living but did not improve other end points,
including cognition.49 Cognitive stimulation and a more specific cognitive
stimulation therapy may also benefit patients with cognitive changes. Many
individuals with cognitive change and dementia also experience significant
depression, apathy, or both, which may also improve with nonpharmacologic
management.49 For individuals with cognitive change and those with psychiatric
symptoms separate from cognitive change, mental health therapy and counseling
have been shown to improve mood and possibly even cognition.
Nonpharmacologic therapy for depression and anxiety typically includes different
forms of counseling ranging from psychodynamic therapy to cognitive-behavioral
therapy. Although these modalities have not been studied directly in ataxia,
numerous investigations involving people with Parkinson disease have found
significant benefits of these approaches.50 Further, individuals experiencing
anxiety and stress report benefit from mindfulness or meditation, although
randomized trials testing these modalities in ataxia are needed.
INVASIVE AND NONINVASIVE NEUROSTIMULATION. Growing evidence indicates

that deep brain stimulation (DBS) may help the tremor and dystonia that are

prominent features of many of the cerebellar ataxias, although distinguishing

between dysmetria from the ataxia and true tremor may be challenging,
therefore limiting the efficacy of DBS overall. Common DBS targets for
the tremor in ataxia include the ventral intermediate nucleus (VIM) of the
thalamus as well as the posterior subthalamic area and the bilateral subthalamic
nucleus (STN). Many individuals with ataxia who underwent DBS experience
gait dysfunction in the postoperative period, and three different case series
reported no improvement in ataxia symptoms with DBS.51-53 Noninvasive
stimulation, either transcranial magnetic stimulation (TMS) or transcranial
direct current stimulation (tDCS), has also been evaluated extensively as
treatment for individuals with ataxia. In one of the larger TMS studies, 24
individuals were randomly assigned to receive either sham or 5 sessions of
active cerebellar 1-Hz deep repetitive TMS. Those who received the TMS
demonstrated significant improvement on two separate ataxia rating scales,
although more and larger studies are needed to evaluate the sustainability and
generalizability of these results.54 Similarly positive results were observed in a
small study evaluating cerebellospinal tDCS as a treatment for patients with
CASE 9-2 A 55-year-old man presented for a neurologic consultation for evaluation
of balance problems. He reported that he started to notice balance
changes about 5 years previously, although his wife noted that he was
sometimes unsteady when tired or after drinking a single beer beginning
about 7 to 10 years previously. In the past 3 years he had experienced
increased unsteadiness with some falls, as well as occasional diplopia,
difficulty reading, and clumsiness when typing, all leading to a decrease
in his work productivity. His wife also reported that he exhibited mild
forgetfulness and significantly increased irritability and explosiveness.
Neither had noted acting out of his dreams, constipation, hyposmia,
symptomatic orthostasis, or erectile dysfunction. His past medical
history was notable only for hypertension and hyperlipidemia. Family
history was notable for a grandson with some developmental delay, but
no family members had ataxia. For many years, he drank 4 to 5 beers per
day on a few days per week, but in the last 10 to 20 years, he had
consumed no more than 1 to 2 beers once a week.
Neurologic examination showed hypermetric saccades, downbeat
nystagmus, a possible catch-up saccade on the head impulse test, and
slight difficulties with vocal modulation. He also had dysmetria and
dysdiadochokinesia, clumsiness with finger tapping but no decrementing
bradykinesia, normal tone, and a slightly wide-based gait with inability to
complete tandem gait. Sensory examination showed a slight decrease in
temperature sensation in a stocking-glove distribution.
Brain MRI showed mild cerebellar atrophy affecting both vermal and
cerebellar hemispheres. Laboratory testing for treatable causes
identified a slightly positive antinuclear antibody at 1:80 and a glutamic
acid decarboxylase 65 (GAD65) level of 7 nmol/L. These were determined
not to have caused his ataxia. He underwent genetic testing, first for the
most common autosomal dominant and autosomal recessive diseases,
1426 OCTOBER 2022

neurodegenerative cerebellar ataxia. Individuals underwent sham treatment or
tDCS 5 days per week for 2 weeks and subsequently demonstrated improvement
in numerous motor measurements of ataxia.55 Wider adaptation of tDCS and
TMS is limited by issues of availability and cost. Neither modality is covered by
US health insurance for the treatment of ataxia.
ALCOHOL AVOIDANCE. Although cerebellar deficits persist in individuals with

alcohol-induced ataxia even after they stop consuming alcohol, avoiding
alcohol will prevent further toxic damage. Likewise, individuals with cerebellar
ataxia due to non–alcohol-related etiologies can prevent additional toxic damage
by stopping alcohol consumption. No research has been conducted regarding
the extent of damage caused by a single drink or an occasional drink of alcohol in
individuals with neurodegenerative cerebellar ataxia. However, given the
mechanism through which alcohol affects the cerebellum, abstaining from
alcohol is recommended for individuals with ataxia. Individuals with ataxia
who are driving should be advised not to drive after consuming even one drink,
as alcohol impairs function faster in those with underlying cerebellar disease.
which was unremarkable, and then whole exome sequencing. The

diseases tested for included Friedreich ataxia, fragile X tremor-ataxia
syndrome (FXTAS), and cerebellar ataxia with neuropathy and vestibular
areflexia syndrome (CANVAS). His whole exome sequencing revealed a
variant of unknown significance in the POLG gene, which is known to be
associated with ataxia. Testing of his unaffected sister and mother,
however, identified the same variant, making it highly unlikely that the
variant was the cause of his ataxia.
Despite extensive testing, the etiology of the patient’s ataxia was not
determined. Throughout the diagnostic process, symptomatic therapy
was begun, including physical, occupational, and speech therapy, which
included exercises to do at home. He said that as a result of doing these
exercises his gait felt more stable and he was falling less.
4-Aminopyridine was prescribed for his downbeat nystagmus, which
improved his ability to work on his computer.
He was going to be evaluated to see if he was a good candidate for a
torso-stabilizing vest, and he was considering paying out of pocket for
transcranial direct current stimulation treatment.
This patient’s symptoms and signs were localized to the cerebellum; the COMMENT
likelihood of multiple system atrophy was determined to be low given the
lack of α-synuclein signs on history and lack of parkinsonism on
examination. Although the cause of the patient’s ataxia was not identified,
symptomatic treatments improved his symptoms slightly. Moreover, the
inability to identify a genetic cause reassured his children and their
partners that there was nothing else they could or should do as part of their
reproductive decision making.

Pharmacologic Approaches
Many small randomized controlled trials have been performed to identify
pharmacologic options for the treatment of cerebellar ataxia. In real-world
situations, these medications have variable efficacy but can sometimes
significantly improve symptomatic management and quality of life.
BALANCE, GAIT, APPENDICULAR ATAXIA. The end points in the clinical trials of
potential pharmaceutical treatments are usually total SARA or total ICARS
scores, showing whether the treatment is resulting in overall improvement,
not necessarily improvement in a specific symptom. Class I evidence exists
for riluzole improving ataxia at 8 weeks and 12 months in individuals with
SCA and Friedreich ataxia, respectively, with Class I evidence for 4-aminopyridine
reducing episodes in individuals with episodic ataxia type 2.56 Class II evidence
exists for improvement at 12 weeks for valproic acid treatment in individuals with
SCA3 and improvement at 10 to 14 days for thyroid-stimulating hormone
(TSH)–releasing hormone (TRH) injections in individuals with spinocerebellar
degeneration.56 However, the long-term negative side effects of valproic acid and
short duration of the TRH study limit their clinical utility. Branched chain amino
acids and IV trehalose meet level B recommendations for management of ataxia
symptoms but clearly require further investigation.57
EYE MOVEMENTS. Numerous pharmacologic treatments are used routinely for

nystagmus in individuals with ataxia, and these medications may be helpful to
improve, but not eliminate, the oscillopsia experienced by many people with
cerebellar ataxia. 4-Aminopyridine improves downbeat nystagmus and can
therefore be very beneficial for some patients.58 Baclofen is also effective in the
treatment of periodic alternating nystagmus58 and may be effective for treatment
of downbeat and upbeat nystagmus, although the primary trial for baclofen in
downbeat and upbeat nystagmus offers only Class IV evidence.59 Finally,
memantine and gabapentin, used independently or together, have resulted in
improvement in median eye speed and visual acuity, although gabapentin was also
associated with some subsequent unsteadiness.60
ADDITIONAL PHARMACOLOGIC RECOMMENDATIONS. For the other additional

symptoms noted in individuals with cerebellar ataxia, including tremors,
parkinsonism, dystonia, autonomic nervous system changes, cognitive
changes, and psychiatric symptoms, the pharmacologic treatment
recommendations do not go beyond what is typically used for other neurologic
diseases. For example, tremor treatment is usually based on essential
tremor management, although the tremor in cerebellar ataxia is often more
dysmetric than essential tremor in character. In accordance with essential
tremor management, the author typically starts with propranolol or
primidone and then considers topiramate, benzodiazepines, or even
botulinum toxin.61 Carbidopa/levodopa remains the mainstay of treatment
for parkinsonism, although amantadine is often also used because of small
studies involving Friedreich ataxia and other ataxias showing improvement in
gait and appendicular ataxia.62-64 The autonomic nervous system changes
observed, including symptomatic orthostasis and neurogenic bladder, may
respond to midodrine or fludrocortisone65 and behavioral measures for the
former and mirabegron and solifenacin or sometimes even self-catheterization
1428 OCTOBER 2022

for the latter.66 For cognitive changes, the author typically starts with KEY POINT
acetylcholinesterase inhibitor medications and then adds the N-methyl-D-
● Several therapies for
aspartate (NMDA) receptor antagonist memantine.67 The depression, neurodegenerative
anxiety, and irritability associated with ataxia often respond well to selective cerebellar ataxias are in
serotonin reuptake inhibitors (SSRIs), including fluoxetine and citalopram. earlier stages of
Like all treatment considerations, the choice of which medication to use for development, increasing the
possibilities for new
different symptoms is based on the severity and impact of the symptom, the symptomatic or even
side effect profile, and the potential for medication interactions. disease-modifying therapies
in the future.
PHARMACOLOGIC THERAPIES BASED ON CURRENT BASIC SCIENCE RESEARCH. The
choice of which medication to use for a particular symptom may also be based on
preliminary basic science research. Strong preclinical evidence indicates that
citalopram administered to SCA3 mouse models results in reduction in ataxin-3
aggregation and improvement in motor function.68 The dose is a bit problematic
in that the mouse model gave citalopram at 8 mg/kg, which would translate to a
very high human dose. Randomized trials of citalopram in humans for ataxia
have not been undertaken, to the best of the author’s knowledge. Nevertheless, it
is reasonable to consider as a medication at safe, currently approved dose levels.
In addition, strong preclinical evidence indicates that a combination of baclofen
and chlorzoxazone results in stabilization of the cerebellar membranes.69 Thus, it
is possible that this combination in humans, if tolerated, could slow disease
progression. Again, clinical evidence has not been published regarding the
efficacy and safety of this combination in humans.
EMERGING PHARMACOLOGIC THERAPIES. Two new medications are worth

discussing in greater detail. Omaveloxolone is an Nrf2 activator that improves
mitochondrial function. In addition to strong preclinical evidence, a large phase 2
study showed that individuals treated with omaveloxolone for 48 weeks had
improvement in the mFARS compared with those receiving placebo, whose
score on the rating scale actually worsened.70 The authors of the study concluded
that omaveloxolone is a potential therapeutic agent for treatment of Friedreich
ataxia, and the US Food and Drug Administration (FDA) has granted the
medication a fast-track designation status, which will expedite development of
the drug. Troriluzole is a prodrug of riluzole and has a similar mechanism of
reducing synaptic glutamate levels. A phase 3 study of troriluzole in the more
common SCAs was recently completed, although results have not yet been
published in a peer-reviewed journal. Other therapies are in earlier stages of
development,71 increasing the possibilities for new symptomatic or even
disease-modifying therapies in the future.
PROGNOSIS
Prognosis in individuals with cerebellar ataxia varies significantly. Those with
the more common SCAs typically progress a bit faster, with individuals with
SCA types 1, 2, and 3 progressing from symptom onset to using a wheelchair
within about 10 years and to death within about 20 years. Individuals with
other SCAs may progress more slowly, but the rate depends on the etiology.
People with Friedreich ataxia have seen a significant improvement in life
expectancy, with death now typically occurring at age 40 to 60, but this life
expectancy is still significantly lower than that of the general population,
and morbidity remains high, with most individuals using a wheelchair 11 to

15 years after symptom onset.72 In the absence of treatment, individuals with

paraneoplastic cerebellar ataxia typically progress quite rapidly from symptom
onset to severe morbidity, underscoring the need for urgent evaluation for
this etiology.
Within these wide ranges, there are a few predictors of prognosis in
those with a known genetic etiology. Specifically, within each of the SCAs,
individuals with a greater trinucleotide repeat length progress faster than
those with a lower repeat length. Individuals with a greater repeat length
also usually have an earlier age at disease onset than those with a greater
repeat length. Racial and ethnic factors can also affect age at onset and
rate of progression, with Asian people with SCA3 having an older age at
onset, Black people having a greater severity of SCA3 ataxia, and White
people with SCA3 more likely to experience depression.73 Research is still
needed to discover the reasons behind these differences, including whether
the various populations have specific genetic modifiers versus (or in
addition to) different social determinants of health. Although no large
studies have been conducted evaluating health disparities in individuals
with ataxia, a recent small study indicated that a higher education level was
associated with slower disease progression in individuals with SCA3 after
controlling for repeat length, but it was also associated with younger age at
onset.74 More research is clearly needed to evaluate these relationships
further.
CONCLUSION
Research is being conducted in numerous areas related to neurodegenerative
cerebellar ataxia, which may lead to improved diagnosis as well as
disease-modifying therapies. Whole exome sequencing is widely available
and currently clinically interpretable when ordered through a number of
laboratories, while whole genome testing is still not routinely performed.
Whole genome sequencing will allow for evaluation of noncoding pathogenic
variants, but currently it is still difficult to interpret for most movement
disorder neurologists, and it is generally cost prohibitive for patients. Further
advances in diagnosis using functional imaging will also enable evaluation
of changes in cerebellar circuitry and its relationships, which will expand
our understanding of the pathophysiology of these diseases as well as
allow identification of different phenotypic presentations of the same
disease.
With regard to treatments, there are many exciting possibilities. Antisense
oligonucleotides have successfully reduced ataxin-3 load in the CSF and
cerebellum of SCA3 mouse models75 and are now being moved into human
studies, with antisense oligonucleotides for SCA types 1 and 2 surely not
far behind. Gene therapy methods are also in development, including the
use of an adeno-associated virus vector as well as CRISPR/Cas9-mediated
approaches to gene therapy.76 These advances, coupled with the
pharmaceutical developments discussed above, have the potential to usher
in a new age of treatment for neurodegenerative cerebellar ataxias. While
basic and clinical researchers work to develop these advances, clinicians and
patients can work now to optimize current function. There is always
something we can do to help our patients.
1430 OCTOBER 2022

VIDEO LEGENDS
VIDEO 9-1 VIDEO 9-3

Wide-based, ataxic gait. Video shows a 55-year-old Nondecrementing finger tapping. Video shows a
woman with ataxia demonstrating a characteristic woman with a right middle cerebellar peduncle
wide-based gait. She occasionally requires support stroke undergoing bradykinesia testing. The left
of a wall, occasionally crosses her feet, and appears finger tap examination is largely normal. On the right,
off-balance on turns. She also weaves when initially pauses and decrements are seen, but then
walking. she corrects herself and makes the taps larger again.
© 2022 American Academy of Neurology. © 2022 American Academy of Neurology.
VIDEO 9-2
Downbeat nystagmus. Video shows a 77-year-old
man with ataxia of unknown etiology with downbeat
nystagmus. Although occasional downbeats are
observed at primary gaze, they are much better
observed at both right and left end gaze.
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1434 OCTOBER 2022

The Dystonias REVIEW ARTICLE

By Christopher D. Stephen, MB ChB, FRCP, SM C O N T I N U UM A U D I O
ONLINE
ABSTRACT CITE AS:

PURPOSE OF REVIEW: This article discusses the most recent findings regarding CONTINUUM (MINNEAP MINN)
the diagnosis, classification, and management of genetic and idiopathic
1435–1475.
dystonia.
RECENT FINDINGS:A new approach to classifying dystonia has been created Dr Christopher D. Stephen,
Dystonia Center, Department of
with the aim to increase the recognition and diagnosis of dystonia. Neurology Massachusetts
Molecular biology and genetic studies have identified several genes and General Hospital, 55 Fruit St,
biological pathways involved in dystonia. Boston, MA 02114,
cstephen@mgh.harvard.edu.
SUMMARY: Dystonia is a common movement disorder involving abnormal, RELATIONSHIP DISCLOSURE:

Dr Stephen has received
often twisting, postures and is a challenging condition to diagnose. The
pathophysiology of dystonia involves abnormalities in brain motor networks range of $500 to $4999 for
in the context of genetic factors. Dystonia has genetic, idiopathic, and serving on a scientific advisory
or data safety monitoring board
acquired forms, with a wide phenotypic spectrum, and for SwanBio Therapeutics, Inc,
is a common feature in complex neurologic disorders. Dystonia can be has received research support
isolated or combined with another movement disorder and may be focal, from the National Institutes of
Health/National Institute of
segmental, multifocal, or generalized in distribution, with some forms Neurological Disorders and
only occurring during the performance of specific tasks (task-specific Stroke (1K23NS118045-01A1), and
dystonia). Dystonia is classified by clinical characteristics and presumed has received honoraria in the
range of $500 to $4999 from the
etiology. The management of dystonia involves accurate diagnosis, followed International Parkinson and
by treatment with botulinum toxin injections, oral medications, and surgical Movement Disorder Society.
The institution of Dr Stephen
therapies (mainly deep brain stimulation), as well as pathogenesis-directed has received research support
treatments, including the prospect of disease-modifying or gene therapies. from Sanofi.
UNLABELED USE OF
USE DISCLOSURE:
INTRODUCTION Dr Stephen discusses the
D
ystonia is the third most common movement disorder after essential unlabeled/investigational use of
medications and therapies,
tremor and Parkinson disease (PD).1 Dystonia involves sustained or none of which are approved by
intermittent muscle contractions, often resulting in twisting and the US Food and Drug
Administration (FDA) except for
repetitive patterned movements and abnormal postures related to botulinum toxin injections;
co-contraction of agonist and antagonist muscles.1 Dystonia may medications and therapies for
occur in isolation or in combination with other movement disorders or in the the treatment of paroxysmal
dystonia, none of which are
setting of other primary neurologic disorders or may be acquired; misdiagnosis approved by the FDA for this
frequently occurs.1,2 Most forms of dystonia are idiopathic; however, several indication; medications and
genetic dystonias have been identified, and acquired forms are typically related therapies for the treatment of
status dystonicus/dystonic
to lesions in the basal ganglia or more global brain injury. The pathophysiology of storm, none of which are
dystonia is currently thought to represent a brain network disorder involving approved by the FDA for this
indication; dopamine agonists
several brain regions, including the basal ganglia, cerebellum, thalamus, and
for the treatment of dystonia
sensorimotor cortex, resulting in abnormal neural motor programs.3 Treatment Continued on page 1475
involves regular botulinum toxin injections, and oral medications are unreliable. © 2022 American Academy
Deep brain stimulation (DBS) can be highly effective in select cases. of Neurology.

THE DYSTONIAS
CLINICAL FEATURES AND CLASSIFICATION OF DYSTONIA

The term dystonia can be used as both a clinical descriptor of an abnormal posture,
frequently with a twisting quality, and a group of diseases in which dystonia is the
main clinical feature. The dystonias result from idiopathic, genetic, acquired, and
other causes. No reliable diagnostic test exists for idiopathic dystonia, as imaging
and laboratory testing are typically normal in patients with dystonia; however,
genetic testing may lead to a definitive diagnosis in forms of genetic dystonia.
Dystonia Phenomenology
Core clinical features of dystonia include influence by voluntary action, overflow
dystonia (unintentional muscle contraction distinct anatomically from the
primary movement), mirror dystonia (unilateral abnormal posturing elicited
by contralateral movements), and, in some cases, dystonic tremor (movements
are oscillatory but not strictly rhythmic, jerky, and patterned).4 Dystonia and
dystonic tremor may also have a directional nature, with movements worse in
certain positions and improved in others (a “null point”). Another core feature
is the presence of alleviating maneuvers (sensory tricks, or geste antagoniste),
typically involving simple movements but not forceful opposition to the
dystonic movement.1 Dystonia is typically exacerbated by anxiety, stress, or
heightened emotions or occurs when the patient is tired or fatigued; dystonia
decreases with relaxation, generally resolving during sleep.5 A useful approach to
the clinical diagnosis of dystonia was provided by Albanese and Lalli6
(TABLE 10-17).
Classification of Dystonia
The 2013 consensus classification of dystonia involves two distinct axes1:
u Axis I (clinical characteristics) involves (1) age of onset, (2) body distribution, (3) temporal
pattern, and (4) associated clinical features.1
u Axis II (etiology) addresses two complementary characteristics: (1) underlying nervous
system pathology (imaging/diagnostic testing), and (2) whether the disorder is inherited,
acquired, or idiopathic.1
CLINICAL CHARACTERISTIC CLASSIFICATION OF DYSTONIA. Age of onset and body

distribution can clinically differentiate dystonia (TABLE 10-28). Focal dystonia
involves a single body region. Segmental dystonia involves two or more adjacent
body segments, including the involvement of both arms or both legs. Multifocal
dystonia involves at least two noncontiguous or more (contiguous/noncontiguous)
body regions. Generalized dystonia has truncal involvement and at least two
other distant sites. Hemidystonia involves multiple body regions restricted to a
single side. Examples of dystonia phenomenology are shown in FIGURE 10-1.9
The temporal pattern of dystonia is subdivided into four distinct types. In a
persistent pattern, dystonia presence and severity are roughly similar throughout
the day.8 Action-specific/task-specific dystonia only occurs during a particular
activity, such as writing, typing, playing an instrument, or singing.10 Paroxysmal
dystonia involves sudden, discrete episodes of dystonia, with return to neurologic
baseline.11 Diurnal variation (mild symptoms on awakening and worsening as the
day progresses) is classically seen in dopa-responsive dystonia.12
Dystonia can either be isolated or combined with another movement disorder.
In isolated dystonia, dystonia is the only clinical motor feature other than tremor
1436 OCTOBER 2022

(generally phenomenologically dystonic in nature). In contrast, combined KEY POINTS
dystonia is associated with other movement disorders, including myoclonus,
● The term dystonia can be
parkinsonism, ataxia, or chorea/dyskinesias. Dystonia is frequently associated used as both a clinical
with neuropsychiatric symptoms, whereas cognitive decline generally only descriptor of an abnormal
occurs in degenerative/progressive dystonias.5,13 TABLE 10-314 lists the common posture, frequently with a
isolated/combined genetic dystonias, and TABLE 10-413,15 lists more complex twisting, patterned quality
and a group of diseases,
phenotypes. Dystonia can be differentiated by rate of symptomatic progression.
where dystonia is the main
Focal dystonias generally follow a subacute or slow worsening of symptoms, clinical feature.
followed by a plateau, at least initially. Subsequent spread to segmental/
multifocal distributions may occur but generally plateaus.13 ● The dystonias include
idiopathic, genetic,
acquired, and other causes.
ETIOLOGIC CLASSIFICATION OF DYSTONIA. The etiology of dystonia can be No reliable diagnostic test
differentiated by identifiable anatomic changes and pattern of inheritance. In (outside of genetic testing)
most causes of dystonia, brain degeneration or structural brain lesions are absent. currently exists, as imaging
Important changes have occurred in the nomenclature of the genetic dystonias and laboratory testing are
typically normal in patients
and other movement disorders16 and were updated in 2022.17 The previous system with dystonia.
of assigning locus symbols (eg, DYT1 and DYT6) was used to provide names for
conditions, frequently before identification of the disease-causing gene. Over ● Clinical features of
time, this resulted in several issues, including erroneous, duplicated, missing, or dystonia include influence
by voluntary action,
unconfirmed loci; more than one designation applied to the same disorder; a
overflow/mirror dystonia,
discrepancy between risk factor versus disease-causing genes; and discordance and a “null point.” Sensory
between the predominant phenotypes of diseases.16 According to the new tricks should be specifically
nomenclature, only isolated genetic dystonias (dystonia as the primary feature) inquired about and assessed
on examination.
were designated “DYT” followed by the gene name (eg, DYT-TOR1A, formerly
DYT1), whereas combined dystonias have a double prefix, including both ● Dystonia is classified
movement phenotypes (eg, DYT/PARK-TAF1, formerly DYT3). Paroxysmal based on clinical
dyskinesias/dystonias have the prefix PxMD,12 while those without a consistent characteristics (age of
core phenotype are designated mixed movement disorders (MxMD).17 onset, body distribution,
temporal pattern, and
associated clinical features)
DIAGNOSTIC CHALLENGES IN DYSTONIA and etiology (underlying
Diagnosing dystonia continues to be challenging, including differentiating dystonia nervous system pathology or
from other mimics and because of the wide clinical spectrum.6 Lalli and Albanese4 whether the condition is
inherited, acquired, or
have suggested clinical clues to guide the diagnosis of isolated dystonia, with idiopathic).
common misdiagnoses occurring in patients thought to have PD, essential tremor,
myoclonus, tics, functional (“psychogenic”) dystonia, headaches, and scoliosis. ● Nomenclature of genetic
PD can not only present with concurrent dystonia but parkinsonian features dystonias involves referring
to the movement disorder
may be confused with dystonia in certain situations. Complicating diagnosis,
type (including if combined)
dystonia is common in patients with PD: 30% develop off-state dystonia, and and gene name, not DYT
10% to 15% may develop (generally lower) limb dystonia (which may be a locus, using recently
presenting feature, particularly in early-onset parkinsonism), while updated criteria.
blepharospasm, apraxia of eyelid opening (mainly in atypical parkinsonism), and
● The diagnosis of dystonia
truncal/axial dystonia (including camptocormia and Pisa syndrome) can occur.4 is challenging. Common
Additionally, dystonia may also resemble PD, as slowness of movement in a misdiagnoses occur in
dystonic limb may be confused with parkinsonian bradykinesia, increased tone patients thought to have
from dystonia may mimic rigidity, and a dystonic tremor, if observed at rest, Parkinson disease, essential
tremor, myoclonus, tics,
may be misconstrued as a parkinsonian tremor. Even patients with genetic functional (“psychogenic”)
dystonia syndromes, such as DYT-TOR1A and dopa-responsive dystonia, can be dystonia, headaches, and
misdiagnosed as having PD.4 However, in isolated dystonia, other than tremor, scoliosis.
there is no development of diagnostic features of parkinsonism, without the
essential presence of bradykinesia (a required criterion of parkinsonism,

THE DYSTONIAS
comprising slowness with specific characteristics of decrement/fatiguing

with multiple iterations, or hesitations/interruptions), or true rigidity (the
presence of “lead pipe” rigidity, with or without cogwheeling at the wrist),
per the Movement Disorders Society criteria.18 Differentiating dystonia from
PD is more challenging in combined forms of dystonia, particularly in dystonia
parkinsonism, where true parkinsonism does occur. In general, causes of
genetic dystonia parkinsonism have a much earlier age of onset than typical PD,
although some cases may be clinically indistinguishable, in which case the
TABLE 10-1 Clinical Criteria for Examination Signs Observed in Dystoniaa
Clinical
examination sign Description Notes
Dystonic postures Affected body part (neck, trunk, limb) is flexed or If concern exists for task-specific dystonia, the
twisted along its longitudinal axis (not possible in clinician must observe directly or examine a video
cranial or laryngeal dystonia) of the patient performing the particular task (eg,
writing, typing, playing a musical instrument
A sensation of tightness and traction (pulling) is [should be asked to bring instrument if possible]
present in the affected part in the upper limbs, or walking, running, using a
bicycle in the lower limbs). Similarly, in paroxysmal
Incomplete phenomenology: at least one feature
forms, replication of the movement (kinesigenic)
Complete phenomenology: both features is essential, so clinician should ask the patient to
perform triggering movements or try to exercise,
if possible (exercise/exertion induced). If not able
to provoke an episode in the clinic, a video of the
episode is essential to make a diagnosis
(particularly in nonkinesigenic forms).
Dystonic Movements have a twisting nature or a pull in a In the case of vocal/laryngeal dystonia, the
movements preferred direction (including dystonic tremor) clinician must assess for the individual vocal
features described in the section on adult-onset
Movements are repetitive and patterned (ie, idiopathic focal/segmental isolated dystonia.
consistent and predictable) Identifying dystonic movements may be more
complex in combined dystonia, in which the
Movements are often sustained at peak severity
presence of multiple superimposed abnormal
and lessen at a given posture (a “null point”), which
movements may hamper assessment.
may also be seen in dystonic tremor
Incomplete phenomenology: at least one feature
Complete phenomenology: at least two features
Geste antagoniste Alleviation of dystonia occurs during the geste Although not considered a geste, other alleviating
(sensory tricks) movement, usually soon after the patient performs maneuvers include walking backward, which can
the maneuver alleviate lower extremity dystonia, or lying flat,
which can alleviate truncal and cervical dystonia.
Alleviation may last for the duration of the geste or The presence of highly atypical or bizarre
slowly wanes in effectiveness spontaneously apparent “sensory tricks” in a suggestive clinical
before its end context, or specific examiner maneuvers leading
to dramatic reduction or cessation of abnormal
posture or spasms (such as a centrally placed
tuning fork on the head) may suggest a diagnosis
of functional dystonia.7
1438 OCTOBER 2022

clinician must instead rely on the presence of a family history, imaging, and
other relevant features.19 Furthermore, the presence of task- or position-specific
tremor, head or vocal tremor, normal dopamine transporter single-photon
emission computed tomography (SPECT), and lack of symptomatic benefit
with dopaminergic therapy (an exception being dopa-responsive dystonia) are all
hallmarks of dystonia.
As a common diagnostic quandary, dystonia may be confused with essential
tremor, particularly when essential tremor presents with head and vocal tremor,
Clinical
examination sign Description Notes
Geste antagoniste The geste is simple, natural, and “elegant,” but

(sensory tricks) never forceful
The geste does not push or pull the affected body

part, but simply touches it (sensory trick) or
accompanies it during alleviation of dystonia (not
physically resisting the movement)
Present: requires all features
Mirror dystonia At least three different types of repetitive tasks are Dystonia in one body part can be brought on
performed at slow and fast speeds in the when performing tasks in any other body part; for
nonaffected limb example, lower extremity tasks and walking,
particularly with stress gait (walking on heels and
Examples of tasks used to assess for upper tiptoes) can exacerbate or unveil not only lower
extremity dystonia: sequential finger movements, extremity dystonia but also upper extremity
piano-playing movements, hand opening/closing, dystonia.
hand pronation/supination, normal writing (ideally
in cursive), specific writing tasks (writing with the
nondominant hand, cursive ‘l’ loops across the
page, Archimedean spirals)
Examples of tasks used to assess for lower

extremity dystonia: leg agility (heel stomping), toe
tapping, and alternating heel and toe tapping
Present: Dystonic posturing in the contralateral

limb occurs during at least one task
Overflow dystonia Dystonic movement or dystonic postures extend

beyond the commonly involved body region (an
unintentional muscle contraction that accompanies
but is anatomically distinct from the primary
dystonic movement)
The movement is observed at least once,

ipsilaterally or contralaterally, either by inspection
or, if available, by EMG mapping, coinciding with
the peak of the dystonic movements
Present: requires both features
EMG = electromyography.
a
Modified with permission from Albanese A, Lalli S, Mov Disord.6 © 2009 Movement Disorder Society.

THE DYSTONIAS
TABLE 10-2 Classification of Dystonia by Body Distributiona
Type of Number of body parts

dystonia affected Examples and Details
Focal 1 Examples:
Eyelids (blepharospasm with eye closure spasms; may cause vision problems or,
at worst, functional blindness)
Mouth/tongue/palate (oromandibular dystonia, which can impair speech and
swallowing); task-specific forms include embouchure dystonia (occurring when
engaging the embouchure when performing a wind instrument), and several
other tasks generally involving repetitive heavy speech users have been
identified, including telemarketers, bingo callers, people who are chanting/
reciting prayers
Larynx (spasmodic dysphonia from dystonic involvement of the vocal cords);

generally occurs as the patient begins to speak, but certain words and phrases
may be more difficult than others; adductor-type spasmodic dysphonia
(strained, strangled, and course voice, with variations in pitch and vocal breaks
with or without vocal tremor); abductor-type spasmodic dysphonia (less
common, with whispering and breathy speech); task-specific forms include
singer’s dystonia (occurs only while singing, often in professional singers) and in
other professional voice users
Neck (cervical dystonia, leading to abnormal neck posture and frequent cause of
neck pain); subtypes include torticollis (neck rotation), laterocollis (tilting owing
to lateral flexion), retrocollis (neck extension), and anterocollis (neck flexion)
Hand/arm (abnormal posturing and/or tremor of the hand or arm generally

during daily activities or when performing specific hand tasks); task-specific
forms (eg, writer’s cramp, musician’s focal hand dystonia) or other non–task-
specific dynamic dystonia
Foot/leg (abnormal posturing of the lower extremity, typically when walking but
can also be present when doing other seated tasks or at rest); task-specific
runner’s or bicycling dystonia, or other non–task-specific dynamic lower
extremity dystonia
Trunk (abnormal posturing of the trunk when walking and typically resolves when
lying flat or when leaning against a wall or other surface); subtypes include
bending forward (camptocormia), backward (opisthotonus), and sideways (Pisa
syndrome, particularly in Parkinson disease)
Segmental ≥2 contiguous body Examples:

parts
Meige syndrome (eyes and lower face with or without neck involvement)
Axial (neck and trunk)
Brachial (arm and trunk; both arms with or without neck or trunk involvement)
Crural (leg and trunk; both legs with or without trunk involvement)
Multifocal ≥2 noncontiguous body Example:

parts
Faciobrachial (blepharospasm and writer's cramp)
Hemidystonia ≥2 Ipsilateral arm and leg (dystonia only affects one side of the body)
Generalized ≥3 Trunk and ≥ 2 other sites; with or without leg involvement
a
Modified with permission from Klein C, et al, Gene Rev.8 © 1993-2022 University of Washington, Seattle.
1440 OCTOBER 2022

FIGURE 10-1
Clinical phenomenology of dystonia. A, Oromandibular dystonia with tongue protrusion posturing is shown in a patient with
tardive dystonia; B, in the same patient, the abnormal tongue posture, with curling in the mouth, is highlighted. C, In a patient
with X-linked dystonia parkinsonism (DYT/PARK-TAF1, DYT3), severe jaw opening dystonia is shown as a part of multifocal
dystonia, predominantly involving head and neck segmental dystonia. D, Image shows focal idiopathic cervical dystonia with
laterocollis (lateral flexion) to the right, (E) with normalization of neck posturing in the same patient by using a sensory trick of
wearing a scarf and applying tension to the posterior neck. F, Focal truncal dystonia with Pisa syndrome is shown in a patient
with Parkinson disease. G, Image shows severe segmental dystonia involving truncal extension and neck extension
(retrocollis). H, Segmental dystonia with idiopathic Meige syndrome is shown, highlighting bilateral eyelid spasm and lower
facial spasm. I, Idiopathic left hemifacial spasm is shown, highlighting the left eyebrow elevation in keeping with the “other
Babinski sign” (co-contraction of the orbicularis and frontalis muscles, causing ipsilateral eyebrow elevation during unilateral
eye closure, which cannot be reproduced voluntarily) and (J) abnormal left lower facial posturing related to lower facial
spasms in the same patient with a tortuous vertebrobasilar system, which may be an etiologic factor. K, Multifocal bilateral
hand dystonia is shown in a patient with rapid-onset dystonia parkinsonism (DYT/PARK-ATP1A3). L, Multifocal bilateral arm
dystonia is shown with notable abnormal wrist extensor posturing and right shoulder adduction in a patient with DYT-THAP1
(DYT6) dystonia. M, Task-specific focal hand dystonia is shown in a violinist who exhibits flexion dystonia of the left little
greater than ring fingers. N, Focal left foot dystonia involves excessive plantarflexion in a patient with task-specific walking/
running dystonia. O, Left foot dystonia with toe curling is shown in a patient with generalized dystonia in the setting of X-linked
dystonia parkinsonism (DYT/PARK-TAF1, DYT3).
Reprinted with permission from Stephen CD, et al, Elsevier.9 © 2022 Elsevier.

THE DYSTONIAS
TABLE 10-3 Common Genetic Dystonia Subtypesa
Designation Pattern of Dystonia

Classification (gene locus) Onset inheritance distribution Other relevant features
Isolated dystonia DYT-TOR1A Childhood Autosomal Generalized Most common genetic dystoniab
(DYT1) dominant
More common in Ashkenazi Jewish
ancestry
Focal onset, frequently in the lower

limbs and subsequently generalizes
Cranial involvement rare
Reduced penetrance
Deep brain stimulation highly effectiveb
DYT-THAP1 Adult/ Autosomal Neck, limbs, Often prominent cranial involvement

(DYT6) childhood dominant orofacial,
(rarely and larynx Also frequent onset in an arm
autosomal
Deep brain stimulation
recessive)
beneficialb
DYT-ANO3 Adult/ Autosomal Neck, larynx, Onset typically cervical, followed by

(DYT24) childhood dominant orofacial, and laryngeal
upper limbs
Frequent tremor, may resemble
essential tremor
DYT-GNAL Adult Autosomal Neck, limbs, Onset typically cervical

(DYT25) dominant orofacial,
(rarely and larynx
autosomal
recessive)
DYT-HPCA Childhood Autosomal Distal limbs, Generalized in childhood, segmental in

(DYT2) recessive craniocervical, adolescence onset
generalized
Onset distally and later craniocervical
involvement
Combined dystonia DYT/PARK- Adult X-linked Orofacial, neck, Filipino ancestry,b often to
TAF1 (DYT3) recessive limbs, and trunk Panay Island
Parkinsonism
Wide phenotypic spectrum ranging from
severe generalized dystonia to pure
parkinsonism or combination
Unique dystonic parkinsonian gait14
MRI with striatal atrophy
Deep brain stimulation beneficial
DYT/PARK - Childhood Autosomal Limbs and trunk Dopa responsiveb

GCH1 dominant
(DYT5a) (rarely Diurnal variation (worse in evenings)
autosomal
Spasticity
recessive)
Familial cerebral palsy
1442 OCTOBER 2022


DYT/ Childhood Autosomal Limbs, trunk, and Dopa responsiveb
PARK-TH recessive orofacial
(DYT5b) Diurnal variation
Gait disorder
Myoclonus
Spasticity
May be associated with oculogyric crises
Deep brain stimulation beneficialb
DYT/PARK- Childhood Autosomal Variable Dopa responsiveb

SPR recessive
(rarely Diurnal variation
autosomal
Intellectual/developmental delay (motor/
dominant)
speech)
High CSF biopterin/dihydrobiopterin
May be associated with oculogyric crises
DYT/PARK- Adult/ Autosomal Orofacial, cervical, Considerable clinical heterogeneity:

ATP1A3 childhood dominant larynx, and limbs alternating hemiplegia of childhood;
(DYT12) rapid-onset dystonia parkinsonism; common
bulbar involvement; CAPOS syndrome
Sudden onset after infection/febrile illness
Fluctuating course
Exacerbations with fever, physical stress,

alcohol
Chorea
May have seizures
DYT-PRKRA Childhood Autosomal Orofacial, larynx, Limb/cervical onset

(DYT16) dominant neck, trunk, and
limbs No response to levodopa
Deep brain stimulation possibly beneficial
DYT-VAC14 Childhood Autosomal Generalized Clinical heterogeneity: dystonia parkinsonism,

recessive developmental delay, and retinitis
pigmentosa, Yunis-Varón–like syndrome
Can have limb onset and rapid

generalization
No documented response to levodopa
Imaging may have brain iron accumulation
Deep brain stimulation potentially

beneficialb

THE DYSTONIAS
CONTINUED
CONTINUED FROM FROM PAGE 1443
PAGE 1443

Combined dystonia DYT-SGCE Childhood Autosomal Neck, upper limbs, Myoclonus is alcohol responsive (may lead
(DYT11) dominant and orofacial to alcohol dependence)
Myoclonus
Neuropsychiatric symptoms
DYT-KCTD17 Adult/ Autosomal Cranial and Scarce response to alcohol

(DYT26) childhood dominant cervical
Initial mild upper extremity myoclonus/
jerky tremor
Later upper limb/craniocervical dystonia
DYT-KMT2B Childhood Autosomal Frequently Increasingly recognized as a common

(DYT28) dominant generalized, cause of early-onset generalized dystonia
orofacial, larynx, (may have isolated dystonia)b
neck, limbs,
Chorea and myoclonus
and trunk
Microcephaly
Short stature
Neuropsychiatric symptoms
Intellectual/developmental delay
Oculomotor apraxia
Misdiagnosis as “cerebral palsy”
Paroxysmal PxMD- Childhood Autosomal Variable Paroxysmal kinesigenic dyskinesia
PRRT2 dominant
(DYT10/ Attacks triggered by sudden voluntary
DYT19) movements, stress, startle, sleep deprivation
Migraine (may be hemiplegic)
May have epilepsy
Possible role for deep brain stimulation
TMEM151A Childhood Autosomal Variable Paroxysmal kinesigenic dyskinesia

dominant
Majority without a family history
Attacks very brief, with a predominant,

dystonic phenomenology
May have epilepsy
PxMD- Childhood Autosomal Variable Paroxysmal nonkinesigenic dyskinesia with

PNKD dominant choreoathetosis, ballismus
(DYT8/
DYT20) Attacks triggered by alcohol, caffeine,
stress, hunger, fatigue, tobacco
Possible role for deep brain stimulation
1444 OCTOBER 2022


PxMD- Childhood Autosomal Legs most Paroxysmal exertional dyskinesia with
SLC2A1 dominant commonly choreoathetosis
(DYT9/
DYT18)
PxMD- Childhood Autosomal Variable Paroxysmal exertional dyskinesia

ECHS1 recessive
Severe developmental delay
Infantile encephalopathy with choreoathetosis
Optic atrophy
Cardiomyopathy
Sensorineural hearing loss
Autosomal Childhood Autosomal Variable Paroxysmal hypnogenic dyskinesia
dominant dominant
frontal lobe
epilepsy
(CHRNA4)
Other/complex DYT- Adult/ Autosomal Orofacial, larynx, Whispering dysphonia

TUBB4A childhood dominant neck, limbs
(DYT4) Hobby horse gait
Ptosis, edentulous, facial atrophy
May have hypomyelinating
leukodystrophy
DYT-MECR Childhood Autosomal Generalized Optic atrophy

(DYT29) recessive
Basal ganglia abnormalities
MxMD- Childhood Autosomal Generalized Axial hypotonia
ADCY5 dominant,
de novo, Developmental delay
rare
Facial twitching
autosomal
recessive Chorea
Myoclonus
Oculomotor apraxia
Triggered by sleep transitions, emotional

stress, illness, sneezing, caffeine
DYT-ACTB Childhood Autosomal Generalized Sensorineural deafness
dominant
Intellectual/developmental delay
Dysmorphic facies
CAPOS = cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (syndrome); CSF = cerebrospinal fluid;
a
Modified with permission from Klein C, et al, Gene Rev.8 © 1993-2022 University of Washington, Seattle.
b
These are key features either pertaining to the diagnosis or high-yield treatment features, such as levodopa responsiveness or demonstrable
efficacy of DBS.

THE DYSTONIAS
TABLE 10-4 Complex Genetic and Sporadic Dystoniasa
Pattern of
Disorder inheritance Gene(s) Relevant clinical features
Disorders with predominant chorea or parkinsonism
Dopamine transporter Autosomal recessive SLC6A3 Dystonia and parkinsonism, occasional chorea
deficiency syndrome in infancy, mild developmental delay, truncal
(DYT/PARK-SLC6A3) hypotonia, ocular flutter/oculogyric crises,
saccade initiation failure
Disorders of heavy metal metabolism
Wilson disease Autosomal recessive ATP7B Dystonia, occasional parkinsonism/chorea,

(DYT-ATP7B) characteristic “flapping” tremor, orofacial
dyskinesia,a liver diseasea
Kayser-Fleischer ringsa (slit-lamp examination;

may be possible to be seen with naked eye)
Laboratory testing: low ceruloplasmin,b low

serum copper,b high 24-hour urine copperb
MRI: face of the giant panda sign (in midbrain)

and face of the miniature panda (in pons)b
Hypermanganesemia Autosomal recessive SLC30A10 Parkinsonism, hypermanganesemia,b

with dystonia, polycythemia, chronic liver disease
polycythemia, and
cirrhosis (DYT/PARK- MRI: T1 hyperintensities in the basal ganglia
SLC30A10) and cerebellumb
Hypermanganesemia Autosomal recessive SLC39A14 Hypermanganesemiab

with dystonia 2
(DYT-SLC39A14) MRI: T1 hyperintensities in the basal ganglia
and cerebellumb
Neurodegeneration with brain iron accumulation (NBIA)
Aceruloplasminemia Autosomal recessive CP Dystonia, ataxia, chorea, parkinsonism,

(NBIA/DYT/PARK-CP) tremors; cognitive impairment, psychiatric
symptoms; diabetes mellitus; retinal
degeneration
MRI with iron accumulation: hypointensity of

basal ganglia, thalamus, red nucleus, occipital
cortex, and cerebellar dentate nucleib
Woodhouse-Sakati Autosomal recessive DCAF17 Dystonia deafness syndrome,b

syndrome (NBIA/ hypogonadism,b alopecia; seizures, cognitive
DYT-DCAF17) impairment; diabetes mellitus, thyroid
dysfunction; acanthosis nigricans, keratoconus,
camptodactyly
MRI with iron accumulation: involving the

globus pallidus, substantia nigra, and other
areas of the basal gangliab
1446 OCTOBER 2022

Pattern of
Pantothenate kinase– Autosomal recessive PANK2 Parkinsonism, chorea, spasticity, cognitive
associated decline, gaze palsy, psychiatric symptoms,
neurodegeneration pigmentary retinopathy
(NBIA/DYT-PANK2)
MRI: eye of the tiger sign, with brain iron
accumulationb
PLA2G6-associated Autosomal recessive PLA2G6 Parkinsonism, cognitive decline, pyramidal

neurodegeneration signs, psychiatric symptoms (adults), ataxia
(NBIA/DYT/PARK- (childhood)
PLA2G6)
MRI: may have brain iron accumulationb;
cerebellar hypoplasia and T2 hyperintensities
in the cerebellum
Lysosomal storage diseases
GM1-gangliosidosis Autosomal recessive GLB1 Type III, chronic/adult form; dystonia,

(DYT/PARK-GLB1) parkinsonism; pyramidal signs; cognitive
deficits; skeletal abnormalities and short
stature; corneal cloudingb; cardiomyopathyb
MRI: hyperintensity of caudate nucleus and

putamen with signs of diffuse
hypomyelination on T2-weighted sequencesb
Disorders of purine metabolism
Lesch-Nyhan syndrome X-linked recessive HPRT1 Chorea, occasionally ballism; chronic liver
(DYT/CHOR-HPRT7) disease; developmental delay/intellectual
disability; abnormal eye movements;
self-injurious behavior; hyperuricemia; renal
failure
Mitochondrial disorders
Mitochondrial Autosomal recessive ACAT1 Metabolic decompensation and basal ganglia

acetoacetyl-CoA injury during acute stress resulting in dystonia
thiolase deficiency (DYT/ and chorea
CHOR-ACAT1)
Mitochondrial complex Autosomal recessive COX20 Hypotonia, ataxia, dysarthria, sensory

IV deficiency nuclear neuropathy
type 11 (DYT-COX20)
Leber hereditary optic Mitochondrial Pathogenic Optic neuropathy/dystonia (G14459A

neuropathy (DYT-mt- inheritance variants in the mutation); juvenile-onset subacute vision loss;
ND6) mitochondrial encephalopathy, spasticity, bulbar
DNA dysfunction; cognitive impairment
Deafness-dystonia-optic X-linked recessive TIMM8A Dystonia (particularly oromandibular) and

neuronopathy syndrome sensorineural deafnessb (not necessarily
(Mohr-Tranebjaerg present); visual impairment; cognitive
syndrome) (DYT- impairment, behavioral problems; pyramidal
TIMM8A) signs

THE DYSTONIAS
CONTINUED
PAGE 1447
Pattern of
Mitochondrial disorders
SUCLA2-related Autosomal recessive SUCLA2 Encephalomyopathic form, with mild

mitochondrial DNA methylmalonic aciduria; severe hypotonia,
depletion syndrome developmental delay, seizures; progressive
(DYT-SUCLA2) spasticity, cerebral atrophy; sensorineural
hearing lossb; ophthalmoplegia; feeding
problems and postnatal growth retardation
Other dystonia- Autosomal SERAC1, BCAP31, Dystonia and deafnessb

deafness syndromes dominant, autosomal FITM2, DDP
recessive, X-linked
recessive
Organic acidurias
Glutaric aciduria type 1 Autosomal recessive GCDH Newborn screening; chorea, parkinsonism,
(DYT/CHOR-GCDH) acute metabolic crises with basal ganglia
injury, severe truncal hypotonia,
macrocephaly, orofacial dyskinesia, spasticity;
cognitive impairment (variable)
Imaging: enlarged subdural spaces,b subdural

hygroma/hemorrhages
Methylmalonic acidemia Autosomal recessive MCEE, MMAA, Newborn screening; chorea, occasional ataxia;
including DYT/CHOR- MMAB, seizures, lethargy, and hypotonia;
MUT MMADHC, ketoacidosis, hyperammonemia;
MMUT developmental delay, spasticity
Acute metabolic crises,b with confusion/

encephalopathy, basal ganglia injury
(predominantly globus pallidus)
Propionic acidemia (DYT/ Autosomal recessive PCCA, PCCB Dystonia, occasionally chorea; neonatal-onset
CHOR-PCCA/PCCB) vomiting, seizures, lethargy, and hypotonia;
ketoacidosis, hyperammonemia;
developmental delay; spasticity;
cardiomyopathy
Acute metabolic crisesb with confusion/

encephalopathy with basal ganglia injury
(putamen/caudate)
Aminoacidurias
Aromatic L-amino acid Autosomal recessive DDC Dystonia, occasionally

decarboxylase
deficiency (DYT-DDC) Chorea; developmental delay, truncal
hypotonia; oculogyric crises, ptosis;
autonomic symptoms; sleep disorder with
diurnal fluctuations and sleep benefit
Dihydropteridine Autosomal recessive QDPR Dystonia; parkinsonism; developmental delay,

reductase deficiency truncal hypotonia, seizures, autonomic
(DYT/PARK-QDPR) dysfunction; hyperphenylalaninemia
1448 OCTOBER 2022

Pattern of
Non-BH4-deficiency Autosomal recessive DNAJC12 Dystonia, parkinsonism; developmental delay;
hyperphenylalaninemia hyperphenylalaninemia
(DYT-DNAJC12)
6-Pyruvoyl- Autosomal recessive PTS Dystonia, parkinsonism

tetrahydropterin
synthase deficiency
(DYT/PARK-PTS)
Disorders of biotin metabolism
Biotin-thiamine– Autosomal recessive SLC19A3 Dystonia, parkinsonism (mainly rigidity),

responsive basal ganglia occasionally ataxia, chorea; subacute
disease (DYT-SLC19A3) encephalopathy/coma (often triggered by
febrile illness); cranial nerve palsy, pyramidal
signs; intellectual disability; epilepsy;
responsive to thiamine and/or biotin therapyb
MRI: symmetric and bilateral edematous

lesions in caudate nucleus, putamen, and
cortexb
Other metabolic
Primary coenzyme Q10 Autosomal recessive COQ8A May present with early-onset focal hand
deficiency dystonia15; early-onset exercise intolerance,
ataxia, tremor, epilepsy
Unpredictable responses to coenzyme Q10

supplementationb
Disorders with predominant ataxia
Spinocerebellar ataxias Autosomal dominant ATXN3, ATXN2, Various presentations and can be associated
(SCAs) TBP, ATXN1, with multiple movement disorders, including
CACNA1A, parkinsonism or action tremor; frequent
PPP2R2B, prominent, sometimes generalized, dystonia
PRKCG, ATXN7, particularly in early-onset SCA3; dystonia most
11q12, and others common in SCA3, followed by SCA2, SCA17,
and less frequent in SCA1, SCA6, SCA12 (often
with cervical dystonia), and SCA14; rare in
SCA7 and SCA20, but can be seen in others
Sporadic neurodegenerative disorders
Idiopathic Parkinson N/A Dystonia frequently in young-onset Parkinson

disease disease; often involving a foot, or cervical
dystonia; tends to remain focal

THE DYSTONIAS
CONTINUED
CONTINUED FROM 15FROM PAGE 1449
PAGE 1449
Pattern of
Sporadic neurodegenerative disorders
Atypical parkinsonism N/A Focal/segmental dystonia most common

distribution but can also involve the trunk
Progressive supranuclear palsy: often

blepharospasm or cervical dystonia
(frequently retrocollis)
Multiple system atrophy: cervical dystonia,

often anterocollis
Corticobasal syndrome: unilateral focal hand

dystonia often spreading on affected side to
become hemidystonia, associated with
cortical sensory loss
CT = computed tomography; MRI = magnetic resonance imaging; N/A = not applicable.

a
Data from Marras C, et al, Mov Disord16 and Klein C, et al, Gene Rev.8
b
Indicates key clinical, radiologic, or treatment features.
as cervical dystonic tremor with vocal tremor may present similarly.4

Essential tremor typically presents as a bilateral, largely symmetric, postural
and kinetic tremor, frequently involving the head and voice (and less so,
the face and jaw), which is commonly alcohol responsive (a nonspecific
feature, as dystonia may also be alcohol responsive), and patients frequently have
a positive family history. In comparison, dystonic tremor is not strictly rhythmic or
oscillatory and is irregular, tends to involve the neck and less so a limb, and can
improve with sensory tricks, particularly in cervical dystonia. Red flags indicating
dystonia include an isolated head tremor, head tremor that is associated with neck
pain or asymmetric neck muscle hypertrophy, vocal tremor with inability to
change vocal pitch, and lack of tremor improvement with typical essential
tremor treatments.6,20
Patients with myoclonus and dystonia may both have fast, jerky movements
that can mimic tremor. The two forms of abnormal movement can be
differentiated by EMG; spasm duration of less than 200 ms is found in myoclonus,
and spasm duration of more than 200 ms is found in other forms.6 Myoclonus and
dystonia co-occur in myoclonus-dystonia, while essential myoclonus has no
associated dystonia.
Tics can have dystonic features and may coexist with dystonia. Features not
present in dystonia include some more specifically associated neuropsychiatric
symptoms (attention deficit hyperactivity disorder/obsessive-compulsive
disorder are common in patients with tics but not dystonia) and a premonitory
urge prior to the movements (not present in dystonia).4
Functional dystonia can be particularly challenging to differentiate from
“organic” dystonia.7 Features suggestive of a diagnosis of functional dystonia, as
described in detail by Frucht and colleagues,7 include an abrupt onset of
symptoms, the hallmarks of inconsistency/incongruity, a resting dystonia at
1450 OCTOBER 2022

onset, no evidence of co-contraction/overflow dystonia, the presence of highly KEY POINT
atypical or bizarre “sensory tricks,” or examiner maneuvers such as the placement
● Despite increasing
of a vibrating tuning fork which result in dramatic improvement of posturing recognition, limited data
(which may also leverage suggestibility).21,22 The use of a risk score based on exist on dystonia
historical features has also been proposed to help facilitate a diagnosis.23 Clinical epidemiology. Given the
features of functional dystonia phenomenology are shown in FIGURE 10-2. In common misdiagnoses, the
prevalence of dystonia may
comparison, in dystonia, a gradual onset occurs (other than in rare exceptions,
be up to 1 in 1000 individuals.
such as rapid-onset dystonia parkinsonism), movements and postures are There are age, sex, racial,
consistent and congruous over time, typical sensory tricks occur, and no associated ethnic, and geographic
functional neurologic features exist (although clinicians should be aware that both variations.
“organic” and functional movement disorders can coexist).
Headache and neck pain are nonspecific symptoms but both are commonly found
in craniocervical dystonia. While headaches can be associated with some head
posturing (to reduce activation of muscles in spasm), the relief of pain by sensory
tricks, the presence of asymmetric neck muscle hypertrophy, and an excellent
response to botulinum toxin injections may suggest a dystonic cause.4
Finally, scoliosis may be either idiopathic or degenerative, with a family
history in roughly 30%, suggesting genetic cause in some cases.4 Scoliosis may be
an initial manifestation of dystonia, particularly in childhood-onset cases.
Dystonic appearance of the movements/postures (eg, a tendency to
spasmodically pull to one side versus a static fixed posture) and a family history
of dystonia may instead suggest an underlying diagnosis of dystonia.4
Acquired dystonia includes many conditions, often involving lesions of the basal
ganglia or more global injury (TABLE 10-5).12,24,25 Numerous pseudodystonias, which
mimic dystonia, also exist and result from musculoskeletal disease or dysfunction in
sensory, motor, or other neurologic pathways (TABLE 10-6).26 Therefore, all patients
with dystonic symptoms should have a careful history and physical examination to
look for “rule in” signs suggestive of dystonia,6 excluding conditions that mimic
dystonia, as well as looking for the presence of additional movement disorders, which
may suggest a combined phenotype. Challenges in combined dystonias are even more
fraught than in isolated dystonias, given the rapidly expanding phenotypic spectrum
of complex movement disorders (TABLES 10-3 and 10-4). In genetic dystonias, even if
there are presumed pathognomonic findings on history, examination, or
investigations suggesting a specific diagnosis, surprises can occur, as one phenotype
can be related to many genes, and one gene can yield multiple phenotypes.27
EPIDEMIOLOGY OF DYSTONIA
Despite increasing recognition, limited data on dystonia epidemiology exist. A
recent meta-analysis reported an overall prevalence of primary focal dystonia of
16.4 per 100,000 individuals.28 However, given diagnostic difficulties, current
estimates likely represent an underestimate, with some studies suggesting a
prevalence of up to 1 per 1000 individuals.29 Focal dystonia is more common than
widespread involvement, and combined dystonias are very rare. Idiopathic
isolated dystonias are the most common, with cervical dystonia generally the
most common form (3 to 13 per 100,000)28 however, blepharospasm is the more
prevalent form in Japan and Italy.28 Dystonia prevalence increases with age and is
different between the sexes. While dystonia is more common in women overall, this
is generally related to the high relative prevalence of focal craniocervical dystonias,
which have a clear female predilection. There are also racial, ethnic, and geographic
differences, including from founder mutations (eg, DYT-TOR1A is more common

THE DYSTONIAS
FIGURE 10-2
Examples of functional dystonia phenomenology, which is distinct from that seen in “organic” dystonia. A, Functional cranial
dystonia is shown in a patient with bilateral lip pulling (pulling of this kind is typically unilateral in “organic” dystonia other than
in the setting of risus sardonicus, which is phenomenologically distinct). B, Patient exhibits functional blepharospasm with
eyes tightly shut (left) and forcefully open when concentrating (right) (distinct from “organic” dystonia, as the eye closure was
sporadic and very severe; in this case, provocative maneuvers, such as tight eye closure, did not trigger spasms, which is
highly atypical and highlights the inconsistency). C, Three examples of functional foot dystonia illustrating the typical
posturing involving fixed dystonia with plantarflexion and inversion (left); in this same patient, extension of the great toe with
flexion of the others toes is shown (middle); in a different patient, paroxysmal dystonia involving plantarflexion and toe
curling is shown (right); this is distinct from organic dystonia, as fixed dystonia at onset is highly unusual and tends to occur in
more advanced disease, and the symptomatology is inconsistent. D, Three examples are shown of varying dystonic upper
extremity posturing in a patient with paroxysmal functional dystonia: the right arm extended with wrist flexion and fisting
(left); elbow flexion with wrist flexion akin to carpopedal spasm (middle); and shoulder abduction, elbow flexion, and wrist
flexion with a limp hand (right) (distinct from “organic” dystonia where the phenomenology of episodes in paroxysmal
dystonia/dyskinesia is typically stereotyped).
Reprinted with permission from Frucht L, et al, Front Neurol.7 © 2020 Frontiers Media S. A.
1452 OCTOBER 2022

in people of Ashkenazi Jewish ancestry,30 and X-linked dystonia-parkinsonism KEY POINT
[DYT-TAF1] is almost exclusively found in people of Filipino ancestry).31
● Adult-onset idiopathic
focal/segmental dystonias
ADULT-ONSET IDIOPATHIC FOCAL/SEGMENTAL ISOLATED DYSTONIA are the most common
Adult-onset idiopathic focal and segmental dystonias are the most common dystonic conditions and
dystonic conditions (segmental less common than focal) and infrequently infrequently generalize,
although there may be
generalize, although they may progress to involve other tasks (if task specific) or
progression over time.
spread to a more widespread distribution over time.13 Dystonia is generally These include cervical,
persistent, with rare spontaneous remission, and 68% of remissions subsequently cranial, oromandibular,
relapse.32 These are differentiated from early-onset dystonias, where symptoms laryngeal, limb, and truncal
dystonia.
begin before 26 years of age, frequently have a genetic cause, and often
generalize.1
Of the adult-onset focal dystonias, cervical dystonia (“torticollis”) is generally
the most common (FIGURES 10-1D through 1E) and is illustrated in CASE 10-1.
Cervical dystonia generally presents in middle age (often in the forties),
frequently with gradually worsening neck pain and eventually developing into
abnormal neck posturing. This can involve torticollis (neck rotation), laterocollis
(tilting from lateral flexion), retrocollis (extension), and anterocollis (flexion), as
well as shoulder elevation, or a combination. Sensory tricks are frequently beneficial
(eg, touching the chin, head, or face, or applying pressure/tension to the posterior
neck) but may wane in effectiveness. Associated head tremor occurs in 30% to 60%
of patients, and hand tremor, which can mimic essential tremor, occurs in 25% of
patients5; 20% may develop segmental/multifocal dystonia, often cranial
(blepharospasm/oromandibular), writer’s cramp, or truncal dystonia.33
Cranial dystonia can involve the eyelids, lower face, jaw, and tongue and c
an occur in isolation or in combination (FIGURES 10-1A through 1C and 1H
through 1J). Blepharospasm (involuntary spasms of orbicularis oculi/
surrounding muscles) is the most common type of cranial dystonia.
Blepharospasm may be preceded by a feeling of eye irritation and photophobia,
generally with initially mild eye blinking in both eyes, which gradually worsens.
Patients with severe cases can have episodes of prolonged eye closure, which
may be sight limiting.5 Triggers include bright sunlight, stress and anxiety,
computer work, watching television, and other eye strain.34 Lower facial spasms
indicate the presence of Meige syndrome, a segmental craniocervical dystonia.
Oromandibular dystonia involves the jaw muscles, causing jaw opening
(lateral pterygoids/digastrics), (FIGURE 10-1C) or closing (medial pterygoids,
masseters, and temporalis), with asymmetric contraction causing lateral
deviation, protrusion, or retraction, sometimes with jaw tremor.5 Talking and
chewing typically worsen symptoms. Sensory tricks are present in one-third and
include pressure on the lips/teeth, touching the tongue to the hard palate, or
placing an item between the teeth or in the cheek.5 Tongue dystonia is a rare
oromandibular dystonia involving tongue protrusion/curling (FIGURES 10-1A
and 1B). Task-specific forms include embouchure dystonia (a subset of
musician’s dystonia) and other forms in repetitive/heavy speech users.
Laryngeal dystonia (spasmodic dysphonia) involves vocal fold muscles
affecting voice production during speaking. In some cases, singing and shouting
are also affected.35 Laryngeal dystonia is more common in women (80%), and
the adductor form is more common than abductor, singer’s dystonia, or adductor
respiratory forms, with dystonic tremor occurring in up to 30% of patients.35
Adductor spasmodic dysphonia results in a strained, strangled, and coarse voice

THE DYSTONIAS
TABLE 10-5 Acquired Nongenetic Causes of Dystoniaa
Cause Etiology Examples and clinical features
Acquired Prenatal and postnatal Post–cardiac arrest

brain lesions hypoxia/ischemia,
hypoglycemia “Cerebral palsy”: dystonia may be unilateral but can be generalized depending on
the severity and degree of hypoxia (caution: cases of genetic dystonias may mimic
acquired cerebral palsy,25 most notably dopa-responsive dystonia12)
Bronchopulmonary dysplasia: dystonia may be unilateral but can be generalized

depending on the severity and degree of hypoxia
Hypoglycemia
Infections (causing Creutzfeldt-Jakob disease (and other prion diseases, often associated with ataxia
basal ganglia lesions)/ and dementia), rapidly progressive: mainly focal dystonia in earlier stages followed
encephalitis later by generalized dystonia
Mycoplasma pneumoniae: dystonia contralateral to lesion
Tuberculosis: dystonia contralateral to lesion
Japanese B encephalitis: dystonia or other movement disorders as part of viral

encephalitis, with prominent basal ganglia involvement
Parainfectious Reye syndrome: varying degrees of dystonia

disorders
Subacute sclerosing panencephalitis: dystonia (may be generalized) and

parkinsonism
Autoimmune disorders Multiple sclerosis: related to demyelinating lesion location and burden; most
common movement disorders are tremor, ataxia, and restless legs syndrome, but
tonic spasms involving paroxysmal dystonia associated with a spinal cord lesion are
common, and other cases may have focal (and exceedingly rare generalized)
dystonia
Antiphospholipid-antibody syndrome: may have dystonia or chorea and may be

unilateral
Paraneoplastic encephalitis (including faciobrachial dystonic seizures caused by

anti-LGI1 encephalitis)
Metabolic disorders Kernicterus: varying degrees of dystonia and may be generalized
Hepatic encephalopathy: liver disease, often associated with ataxia, with MRI
revealing T1 hyperintensity in the basal ganglia
Hypoparathyroidism
Osmotic demyelination syndrome: arises from inappropriate treatment of

hyponatremia/hypernatremia and may have late dystonia, which may be focal
(cases involving cervical, cranial, and laryngeal dystonia), as well as parkinsonism
1454 OCTOBER 2022

Cause Etiology Examples and clinical features
Vascular disorders Stroke sequelae of basal ganglia lesions, particularly involving the putamen
(differentiation from the fixed posture related to spasticity), contralateral
hemidystonia
Arteriovenous malformation of the basal ganglia, contralateral hemidystonia
Traumatic brain injury Often contralateral if unilateral injury but may have bilateral involvement
Intraparenchymal Brain abscess or tumor, with or without involvement of the basal ganglia
space-occupying
lesions (direct effects)
Increased intracranial Brain abscess, tumor, or other space-occupying lesion, including from radiation
pressure
Subdural/epidural hematoma
Physical interactions Electrocution
Ionizing radiation/radiation therapy
Toxic causes Carbon monoxide, methanol, disulfiram, or cyanide poisoning; MRI with high T2
signal in basal ganglia; delayed dystonia parkinsonism
Manganese (ephedrone abuse, chronic liver disease, or total parenteral nutrition)

causing combined dystonia parkinsonism with T1 hyperintensity in the basal ganglia
on MRI
Wasp sting encephalopathy: acute dystonic reaction with evidence of

pallidostriatal necrosis on MRI
Drug-induced Neuroleptic drugs Acute dystonic reactions

dystonia (antipsychotics and
other medications with Tardive dystonia, which may be accompanied by other tardive movement disorders
action at the dopamine (dyskinesia, drug-induced parkinsonism) and may frequently present focally as
receptor) isolated retrocollis or blepharospasm and less commonly oromandibular dystonia
and can cause truncal dystonia with extension; may respond to deep brain
stimulation
Anti-seizure Tardive dystonia or other tardive movement disorders

medications
LGI1 = leucine-rich glioma inactivated protein 1; MRI = magnetic resonance imaging.

a
Data from Dressler D, Handb Clin Neurol,24 and Klein C, et al, GeneReviews.8

THE DYSTONIAS
TABLE 10-6 Distribution and Etiology of Pseudodystoniaa
Dystonia-mimicking
phenotype Corresponding pseudodystonia
Blepharospasm Dermatochalasis (eyebrow elevation to prevent ptosis, no spasms)
Ptosis (eyebrow elevation to prevent ptosis, no spasms)
Myotonia (presence of myokymia)
Functional dystoniab
Oromandibular dystonia Tetanus (severe pain and spasms; can become generalized)
Hypoglossal nerve damage (persistent tongue deviation, without dynamic element, ipsilateral
tongue weakness on examination)
Cervical dystonia Klippel-Feil syndrome (abnormal posturing related to cervical vertebral fusion; can be seen on
x-ray)
Congenital muscular torticollis (present from birth and fixed)
Cervical soft tissue mass (need to examine neck, tilts away from mass)
Sandifer syndrome (associated with esophageal reflex, in which head tilting relieves
gastrointestinal distress)
Vestibulopathy (causing secondary head tilt to avoid sensation, with associated vertigo/
disequilibrium)
Trochlear/abducens cranial nerve palsy (causing secondary head tilt given visual misalignment;
brain imaging if not chronic)
Head drop related to neuromuscular weakness (true neck weakness on examination, fatigability
in myasthenic syndromes, associated weakness in other locations)
Dystonic tics (presence of premonitory urge, history of tics in childhood [generally ≤10 years of
age], other motor/vocal tics)
Focal hand dystonia Dupuytren contracture (fixed posturing, notable palmar nodule)
Trigger finger (intermittent, evidence of triggering when opening hand from a fist, palpable snap
on palpating A1 pulley)
Peripheral entrapment neuropathy (weakness of predominantly ulnar [flexion of ring/little

fingers, claw hand], median [thumb dysfunction, causing “ape hand”], or radial [wrist and finger
drop] muscles leading to abnormal postures); severe sensorimotor peripheral neuropathy or
ganglionopathy can cause secondary abnormal hand posturing (eg, Friedreich ataxia causing
fixed distal finger flexion deformities)
Other causes of hand/finger weakness (such as amyotrophic lateral sclerosis, causing various
abnormal postures)
Carpopedal spasms (generally bilateral tonic spasms involving wrist, thumb, and finger flexion,
seen in hypocalcemia [positive Trousseau and Chvostek signs] or other electrolyte imbalance)
1456 OCTOBER 2022

Dystonia-mimicking
phenotype Corresponding pseudodystonia
Focal foot dystonia Carpopedal spasms (generally bilateral tonic spasms involving mainly hand and, less commonly,
foot plantarflexion and toe flexion; seen in hypocalcemia [positive Trousseau and Chvostek
signs] or other electrolyte imbalance)
Any cause of focal spasticity or foot weakness (including footdrop from fibular [peroneal] nerve
palsy or radiculopathy)
Hemidystonia Intraparenchymal brain lesion (neoplasm, abscess, vascular, inflammatory, congenital; imaging
important to assess for ipsilateral or intramedullary lesion)c
Stroke (sudden onset; brain imaging important to look for corresponding lesion in contralateral
cortex or brainstem, with appearance related to a combination of weakness, spasticity, and
other upper motor neuron pathology)c
Spinal cord lesionc (may have associated tonic spasms; spinal imaging)
Stiff person syndrome (focal limb onset and hyperlordosis, painful spasms; antibody testing;
immunomodulatory therapy)
Generalized dystonia Progressive encephalomyelitis with rigidity and myoclonus (antibody testing; immunomodulatory
therapy)
Tetanus (painful generalized muscle spasms and boardlike abdominal rigidity; tetanus vaccine
status)
Myelopathy (bilateral more than unilateral abnormal postures related to weakness, spasticity, or
deafferentation; bowel/bladder dysfunction; back/spinal pain; spinal imaging)c
Peripheral neuropathy (bilateral abnormal postures related to weakness with or without

deafferentation; nerve conduction studies and EMG)c
Subacute combined degeneration of the spinal cord (bilateral abnormal postures related to
weakness, spasticity or deafferentation; spinal imaging; vitamin B12, folate, homocysteine,
methylmalonic acid testing, with additional testing for mimics including copper and zinc [copper
deficiency myeloneuropathy] and vitamin E)c
EMG = electromyography.
a
Modified with permission from Berlot R, et al, Parkinsonism Relat Disord.26 © 2019 Elsevier.
b
Functional dystonia can mimic all forms of dystonia and may have a pathophysiologic overlap.
c
Related to deafferentation or corticospinal tract involvement.

THE DYSTONIAS
with variations in pitch and vocal breaks. In contrast, abductor spasmodic

dysphonia involves voice breaks on voiceless consonants and a breathy voice
quality. In both forms, innate vocalizations during laughing, crying, and whispering
are unaffected. Singer’s dystonia occurs during singing, while adductor respiratory
dystonia involves inspiration, causing dyspnea, stridor, or obstruction.
Upper and particularly lower limb dystonia (FIGURES 10-1K through 1O) are
rare in adults and are frequently task-specific (FIGURES 10-1M and 1N).10 The
most common cause of upper extremity dystonia is writer’s cramp, a
task-specific dystonia affecting the hand, forearm, or upper arm that manifests
as abnormal posturing with writing.10 Writer’s cramp is more common in men
and may occur in the setting of excessive, repetitive hand use or overuse.10
Musician’s focal hand dystonia is a task-specific dystonia occurring when playing
a musical instrument (FIGURE 10-1M), is more common in men, typically occurs
at the peak of performance careers, is more common in professional musicians,
and can be associated with excessive practicing, overuse, or hand injury.36
Task-specific lower extremity dystonia includes runner’s dystonia, in which
abnormal posturing occurs in runners or joggers (can occur in high-level athletes
or amateurs), frequently in those preparing for a race, or where there has been a
precipitous escalation in the amount of running time. The posturing
predominantly involves plantarflexion, or inversion, but can have more proximal
involvement (FIGURE 10-1N).37 Although this can begin with running or jogging,
the posturing can involve other tasks, including cycling or walking on certain
terrain types, and frequently progresses to affect general walking.37
CASE 10-1 A 54-year-old man presented with a 1-year history of subacute development
of right neck and shoulder pain and right head tilting, which intensified in the
setting of significant work-related/interpersonal stress. His symptoms were
worse with anxiety, physical activities, and complex hand tasks.
On examination, he had a considerable right head tilt, with some left
rotation; full active range of neck motion and tension in his right levator
scapulae, splenius capitis, and upper trapezius; and hypertrophy of the
right sternocleidomastoid. His neck posture worsened with walking, with
certain hand tasks, and when looking down. The neck posturing
significantly improved when he wore a scarf (ie, tension) around his neck
(FIGURES 10-1D through 1E), and he experienced resolution when resting his
head against a surface.
He improved with targeted botulinum toxin injections, stress reduction,
and physical therapy. He experimented and harnessed further sensory
tricks, which over time required less stimulus to produce benefit and had a
wider area of effect.
COMMENT This case provides a classic example of adult-onset idiopathic cervical

dystonia, with typical sensory tricks. Although his symptoms occurred in
the setting of stress and anxiety, his examination and disease course were
inconsistent with a functional etiology.
1458 OCTOBER 2022

GENETIC FORMS OF DYSTONIA KEY POINTS
The presence of a family history of dystonia (which may need to be specifically
● Many genetic forms of
sought, as dystonic symptoms may frequently be misinterpreted as other dystonia exist. Genetic
conditions) should be carefully queried in any patient with dystonia, as this can isolated dystonias are
indicate a potentially genetic cause or susceptibility. This is of particular mainly autosomal dominant.
relevance in younger-onset cases and especially in generalized or combined
● Autosomal recessive
dystonia, where the index of suspicion for an underlying hereditary cause should
dystonia is much less
always be high. Many genetic forms of dystonia exist, with the most common common than autosomal
being isolated autosomal dominant dystonia and rare autosomal recessive forms. dominant cases and should
However, with the increased use and availability of next-generation exome and be suspected if there are
genome sequencing, new dystonic genes continue to be discovered. multiple affected individuals
within the same generation,
but not in their parents, or
Autosomal Dominant Isolated Dystonia parental consanguinity.
Autosomal dominant isolated dystonia is the most common form of genetic
dystonia. The presence of an autosomal dominant etiology should be suspected ● Combined dystonias
involve dystonia and other
when dystonia is present in multiple family members across generations and movement disorders,
particularly if this involves cases of early-onset generalized dystonia. However, frequently parkinsonism or
this may not always be the case, owing to de novo mutations or reduced myoclonus. Considerable
penetrance. clinical and genetic
heterogeneity exists.
DYT-TOR1A (DYT1), the most common early-onset generalized dystonia,
involves a GAG in-frame deletion in TOR1A and is particularly prevalent in
individuals of Ashkenazi Jewish ancestry, with reduced penetrance (30%).30 Onset
frequently involves focal leg or later arm involvement, then rapidly generalizes, while
20% may remain focal, often involving writer’s cramp.30 DBS is very beneficial.38,39
DYT-THAP1 (DYT6) is another common early-onset isolated dystonia with
reduced penetrance (48%).27 Onset is mainly craniocervical or in an arm, with
infrequent oromandibular involvement, and may generalize,40 as illustrated in
38,39
CASE 10-2. DBS is beneficial.
DYT-GNAL dystonia mainly occurs in adults, presents with cervical dystonia,
and may spread, leading to segmental dystonia.42 DYT-ANO3 dystonia also has a
cervical onset, often involving head and limb tremor, which may resemble
essential tremor.43
Autosomal Recessive Isolated Dystonia

Autosomal recessive dystonia is much less common than autosomal dominant
cases and should be suspected if multiple affected individuals are present within
the same generation, but not in their parents, or in the presence of parental
consanguinity. Previously referred to as “DYT2 dystonia,” several genes have been
identified in single families with autosomal recessive dystonia, although not all are
confirmed. Compound heterozygous mutations in HPCA are associated with
childhood-onset slowly generalizing dystonia, mainly in the craniocervical and
upper extremity regions.44 Other genes include VPS16 (late childhood–onset
cervical dystonia, later generalizing)29 and an uncertain role for COL6A3.45 There
have been homozygous variants reported in THAP139,40 and GNAL,46 suggesting
that these may also present in a recessive manner.
Genetic Combined Dystonia

Combined dystonias involve dystonia and other movement disorders, frequently
parkinsonism or myoclonus. DYT-GCH1 (DYT5a) is an autosomal dominant
(rarely autosomal recessive), typically childhood-onset dopa-responsive

THE DYSTONIAS
dystonia.47 It often begins as a focal foot dystonia and slowly spreads upward,
sometimes generalizing.47 Characteristic diurnal variation is seen, with
worsening in the evening, related to varying dopamine levels over the day.47
GCH1 carriers may develop later-life parkinsonism, mimicking PD.48 Patients
have an excellent response to levodopa although this may be complicated by
levodopa-induced dyskinesias.47,49
DYT/PARK-PRKRA (DYT16) involves early-onset limb or cervical dystonia
that progresses to severe generalized dystonia (including opisthotonus, sardonic
dystonic facies, and laryngeal involvement) and frequently mild levodopa-
nonresponsive parkinsonism.50 DBS has potential benefit.51
X-linked dystonia-parkinsonism (DYT/PARK-TAF1) is caused by the
insertion of a retrotransposon in intron 32 of TAF1 on the X chromosome in males
of Filipino ancestry.52 This causes an adult-onset movement disorder (onset in
the third to the fifth decades) with a considerable phenotypic spectrum, often
initially presenting with dystonia (predominantly axial or segmental neck/jaw
dystonia), which generalizes, and may have later-onset parkinsonism.31 Some
cases of X-linked dystonia-parkinsonism may present with pure parkinsonism
indistinguishable from PD,31 and others may have a characteristic knee bending
dystonic and parkinsonian gait.14 DBS is beneficial.38,39
CASE 10-2 A 10-year-old girl presented with slowly progressive difficulties with
writing. In retrospect, she had an awkward pencil grip at preschool,
causing her to change her writing hand. By age 8, she had developed
tremulousness of her right hand, with abnormal posturing and a tendency
to tuck her right arm into her side. By age 10, she developed similar
symptoms on the left side. She tried different pencil grips and a wrist
splint, but constraining the movements tended to aggravate them. She had
a history of normal birth and development and no significant family history.
On examination, she had abnormal bilateral arm spasmodic posturing
involving in-drawing of the arms with shoulder adduction and pronation;
bilateral wrist and finger flexion; and mild leg posturing with foot
inversion. Her gait was minimally affected. Handwriting triggered
posturing (FIGURE 10-1L), but she could compensate well. Brain MRI was
normal. Genetic testing revealed a heterozygous pathogenic variant in the
THAP1 gene, consistent with DYT-THAP1.
COMMENT This case illustrates the presentation of DYT-THAP1 disease with upper
extremity onset, without involvement of the craniocervical region, and with
slow generalization. Despite the absence of a family history,
childhood-onset isolated dystonia should be evaluated with genetic
testing. Certain THAP1 variants can also present in a recessive manner.40,41
Oral medications such as trihexyphenidyl can be useful and are generally
well tolerated in early-onset generalized dystonia, but these were deferred
in this case given parental concern for the side effects. She had
occupational therapy with good effect. Over the ensuing 3 years, her
symptoms plateaued, and she continued to compensate well at school.
1460 OCTOBER 2022

Rapid-onset dystonia parkinsonism (DYT/PARK-ATP1A3 [DYT12]), a rare KEY POINT
autosomal dominant combined dystonia, presents in adolescence or early adulthood
● The paroxysmal
with acute/subacute dystonia and prominent bulbar features and follows a dystonias/dyskinesias are
triggering event such as fever or physical or psychological stress.53 The dystonia has rare disorders involving
a rostrocaudal gradient and can be associated with parkinsonism, particularly episodic hyperkinetic
involving bradykinesia and postural instability. The two other classic phenotypes movements, including
dyskinesia or dystonic
include (1) infantile-onset alternating hemiplegia of childhood or (2) cerebellar
movements. These are
ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) typically early-onset
syndrome. Myriad rarer phenotypes also exist.54 Alternating hemiplegia of disorders arising in
childhood is an early childhood–onset disorder involving paroxysmal episodes of childhood or adolescence,
occurring very rarely after
alternating hemiparesis or hemidystonia and seizures, with progressive motor and
age 18.
cognitive impairment.53 Trigger avoidance is important, and dystonic attacks may
respond to benzodiazepines, anticholinergics (eg, trihexyphenidyl,
diphenhydramine), or flunarizine (not currently approved in the United States).
Recently discovered VAC14 mutations cause pediatric-onset (ages 1.5–
13 years) dystonia parkinsonism (DYT-VAC14), with striatonigral degeneration.55
Some cases show brain iron accumulation on neuroimaging,56 suggesting that this
should be included as a form of neurodegeneration with brain iron accumulation.57
Prominent dystonia with rapid generalization generally occurs with or without
parkinsonism, and younger-onset cases progress rapidly, with slower progression in
older patients.55 Severe neuropsychiatric symptoms were also observed in an
unpublished case from the author’s center. Beneficial medical treatments have not
been reported, including levodopa55; however, a single case treated with DBS had
substantial improvement in dystonia.56
KMT2B mutations have emerged as a common cause of autosomal dominant
childhood-onset generalized dystonia, although this is generally a combined
dystonia owing to complex features, including developmental delay,
microcephaly, short stature, and choreoathetosis or myoclonus.58 Patients have
good responses to DBS.38,39
Myoclonus-dystonia (DYT-SGCE) results in autosomal dominant, typically
childhood-onset generalized myoclonus predominantly involving the head/arms,
associated with mild dystonia, mainly involving cervical dystonia and writer’s
cramp.59 The myoclonus is frequently alcohol responsive, which may lead to
alcohol dependency, and patients should be counseled regarding this. Patients
frequently exhibit psychiatric features (anxiety, depression, and obsessive-
compulsive behavior).59,60
Paroxysmal Dystonias/Dyskinesias
The paroxysmal dystonias/dyskinesias are rare disorders involving episodic
hyperkinetic movements, including dyskinesia or dystonic movements. These
are typically early-onset disorders that arise in childhood or adolescence and very
rarely occur after age 18.11 The three main forms of paroxysmal dystonia/
dyskinesias include (1) paroxysmal kinesigenic dystonia/dyskinesia, (2)
paroxysmal nonkinesigenic dystonia/dyskinesia, and (3) paroxysmal exercise/
exertion-induced dystonia/dyskinesia. Clinical and genetic overlap are present.61
In paroxysmal dystonia/dyskinesias (commonly PRRT2 mutations), episodes
are triggered by sudden movement, involving brief (<1 minute), self-limiting
episodes of dystonic/choreiform posturing.62 Episodes occur frequently (up to
hundreds of times per day) and may be associated with seizures.62 TMEM151A
mutations have recently been described as an additional cause for paroxysmal

THE DYSTONIAS
kinesigenic dystonia/dyskinesias63 and, based on limited evidence, may have a

greater predilection for a dystonic presentation of episodes, although episodes
appear to respond to the same medications as other forms of paroxysmal
kinesigenic dystonia/dyskinesias.64
In paroxysmal exercise/exertion-induced dystonia/dyskinesia (commonly a
result of glucose transporter type 1 [GLUT1] deficiency caused by SLC2A1
mutations), episodes involve dystonic posturing/dyskinesia after prolonged
exercise, with a wide frequency range (often several per week) and generally
lasting for 5 to 40 minutes.11 The most common phenomenology is
exercise-induced foot dystonia (foot inversion after prolonged walking).2,11
Triggers include fasting, stress, and anxiety.11 Patients have normal blood glucose
levels, but lumbar puncture (which should be performed in all suspected cases)
reveals decreased CSF glucose (<60 mg/dL).65
In contrast, in paroxysmal nonkinesigenic dystonia/dyskinesia (commonly
PNKD [formerly MR-1] mutations), no movement/exertion-related trigger is
seen, and episodes are provoked by specific physical conditions (exertion,
fatigue, ill health/fever, menstruation, and psychological stress) or ingestion of
methylglyoxal-containing foods (eg, alcohol, coffee, tea, chocolate).11 Episodes
generally last from 1 minute to 2 hours and evolution occurs, with earlier dystonic
appearance becoming choreiform and abnormal speech from facial involvement.11
MANAGEMENT OF DYSTONIA
The management of dystonia involves first accurately diagnosing dystonia,
identifying the form of dystonia (idiopathic, genetic, or acquired), and
determining whether dystonia is isolated or combined with another movement
disorder or neurologic features, which may require separate treatment. The
therapeutic approach then involves the use of pathogenesis-directed treatments,
where available,9 and appropriate symptomatic medical treatment, including
botulinum toxin injections, rehabilitation, and consideration of surgical
therapies, including DBS. Tardive and paroxysmal dystonia have separate
treatment pathways. Status dystonicus/dystonic storm, which involves severe
and prolonged dystonic posturing, is a neurologic emergency associated with
systemic instability and frequently requires intensive care unit–level treatment.
Defining the Dystonia Diagnosis and Relevant Investigations

The first step of management requires accurate diagnosis. As most dystonia
syndromes have normal imaging/laboratory findings, diagnosis relies on
identifying the unique clinical signs of dystonia. If an idiopathic (generally late-
onset) dystonia is suspected, further diagnostic workup is not typically
necessary. Initial laboratory workup should include copper/ceruloplasmin/
24-hour urinary copper to rule out Wilson disease. Neuroimaging with brain MRI
is used to evaluate for a structural cause in adult-onset hemidystonia/generalized
dystonia, in rapidly progressive or combined dystonia, or in young-onset cases
and can guide further investigation.2 Younger-onset patients should have
laboratory evaluation, particularly if complex features are present. EEG should
be considered in patients with paroxysmal symptoms and if concern exists for
seizures. EMG is rarely necessary, unless there is concern for a neuromuscular
dystonia mimic, although this can be used to help identify dystonic features
(TABLE 10-1). Other targeted investigations include CSF analysis (typically
metabolic/neurotransmitter disorders) and disease-specific testing, including
1462 OCTOBER 2022

genetic testing, for young-onset, combined, or complex phenotypes with or KEY POINTS
without a family history, and all should have genetic counseling. Single-gene
● The first step of
testing can be reasonable if the phenotype is highly suggestive of a specific management requires
genetic entity; however, the clinical heterogeneity frequently necessitates the use accurate diagnosis. If an
of dystonia gene panels, with broader testing in combined phenotypes and idiopathic (generally late-
chromosomal microarray considered, particularly in early-onset dystonia with onset) dystonia is
suspected, further
developmental delay.66 If compelling evidence is present of a genetic etiology
diagnostic workup is not
despite negative testing, then next-generation exome or (if available) genome typically necessary.
sequencing (with or without sequencing of the mitochondrial DNA) should be
the next step, although these are more difficult to analyze (such as related to ● Directed workup includes
variants of unknown significance), and may result in unexpected laboratory testing to rule out
Wilson disease and
incidental findings.66,67 neuroimaging followed by
specific targeted testing,
Pathogenesis-directed Treatment for Dystonia including genetic testing
Disorders for which pathogenesis-directed treatments are available include with concomitant genetic
counseling.
dopa-responsive dystonia, Wilson disease, the paroxysmal dyskinesias, and rare,
complex metabolic dystonias (TABLE 10-7).8,68 Substrate reduction in Wilson disease ● Treatment of dystonia
involves oral penicillamine, trientine, and zinc therapy, coupled with avoiding depends on the diagnosis
hepatotoxic agents. Additional specific oral therapeutics include levodopa (GCH1, (idiopathic versus genetic)
and whether potential
TH, FTPS, and SPR mutations), or 5-hydroxytryptophan (FTPS/SPR mutations) in
pathogenesis-directed
dopa-responsive dystonias, and carbamazepine/other antiseizure medications in the treatments are available.
paroxysmal dystonias.68 Therefore, in addition to testing for Wilson disease, all Symptomatic medical
younger-onset patients, as well as adult-onset patients with atypical presentations, therapy often involves
botulinum toxin injections,
should also have a levodopa trial, as low-dose treatment in dopa-responsive dystonia
oral medications, and
typically provides significant symptom relief.47,49 Dietary interventions are rehabilitation, with deep
important in metabolic disorders and help avoid or mitigate potentially irreversible brain stimulation considered
neurologic damage (TABLE 10-4).68 Trigger avoidance is also important in for treatment-refractory
paroxysmal dyskinesias/dystonias, as is reducing fevers or excessive physical and cases or conditions where
good evidence of efficacy
emotional stresses in rapid-onset dystonia parkinsonism or metabolic causes of exists.
dystonia.68 The prospect of gene therapy for hereditary dystonia is highly
anticipated by patients and clinicians.69 ● Disorders for which
pathogenesis-directed
treatments are available
Symptomatic Treatment for Dystonia include dopa-responsive
The goal of symptomatic therapy is to provide relief from abnormal movements/ dystonia, Wilson disease,
postures, associated pain and discomfort, contractures or other orthopedic the paroxysmal dyskinesias,
complications of sustained abnormal postures, and medical comorbidities, and rare, complex
metabolic dystonias. All
including neuropsychiatric symptoms (FIGURE 10-3). Treatment should be
young-onset cases should
individualized (TABLE 10-8).70 have a trial of levodopa to
Encouraging the patient to identify and experiment with sensory tricks/gestes is assess for dopa-responsive
important, as this can lead to sometimes substantial improvement of dystonic dystonia.
movements and complement other treatments. Rehabilitation with physical therapy,
occupational therapy, or speech therapy is also important, depending on the dystonia
subtype.70,71 Rehabilitation can improve functional ability, prevent contractures in
persistent/fixed postures through targeted splinting and specific exercises/stretching,
facilitate sensorimotor retraining, and more effectively harness sensory tricks.
Symptomatic treatment of focal dystonia begins with botulinum toxin
injections and targeted rehabilitation therapy (depending on the distribution and
focal symptoms), with DBS in severe, refractory cases.72 Oral medications,
including benzodiazepines or anticholinergics, can also play an adjuvant role to
botulinum toxin injections.49 In generalized dystonia, the first-line treatment

THE DYSTONIAS
should be oral medications; botulinum toxin injections are indicated if there is

associated bothersome focal dystonia, and DBS is indicated in refractory cases.
However, early DBS treatment should be implemented in cases known to have
evidence of benefit, such as DYT-TOR1A and other genetic forms
(TABLE 10-3).38,39,51
Drug-induced/tardive dystonia has separate treatment, involving early
diagnosis and discontinuation of the offending drug, discontinuation of
anticholinergics, and consideration of specific antidyskinetic medications. These
include the dopamine-depleting vesicular monoamine transporter 2 inhibitors
valbenazine, deutetrabenazine, and tetrabenazine.73 Botulinum toxin injections
can be used in tardive focal dystonia, zolpidem can be used for tardive akathisia,
and amantadine can potentially be used to treat mild symptoms. DBS may be
beneficial in select treatment-refractory cases.73
TABLE 10-7 Pathogenesis-directed Therapies in Dystoniaa
Rationale for
treatment Movement disorder (gene[s]) Treatment
Reduction of toxic Wilson disease (ATP7B) Penicillamine, trientine, zinc
substrates
Dystonia/parkinsonism with manganese Ethylenediaminetetraacetic acid chelation therapy
accumulation (SLC39A14, SLC30A10)
Specific drugs Aromatic L-amino acid decarboxylase Dopamine agonists, monoamine oxidase B inhibitors,
deficiency (AADC) pyridoxine
Dopa-responsive dystonia (GCH1, TH) Levodopa
Dopa-responsive dystonia, complex Levodopa, 5-hydroxytryptophan

( PTPS, SPR)
GLUT1 deficiency and paroxysmal Ketogenic diet, triheptanoin

exercise/exertion-induced dyskinesia
(SLC2A1)
Paroxysmal kinesigenic dyskinesia (most Carbamazepine, other antiseizure medications

commonly PRRT2)
Dietary GLUT1 deficiency (SLC2A1) Ketogenic diet, triheptanoin

interventions
Glutaric aciduria type 1 (GCDH) Avoid or treat triggers, dietary lysine restriction, L-carnitine
Homocystinuria (CBS) Vitamin B6, dietary restriction of methionine, betaine
Methylmalonic aciduria (MMUT) Avoid or treat triggers, dietary protein restriction, L-carnitine
Propionic acidemia (PCCA, PCCB) Avoid or treat triggers, dietary protein restriction, L-carnitine
Vitamin Biotin-thiamine–responsive basal ganglia Biotin plus thiamine, avoid or treat triggers
supplements disease (SLC19A3)
Biotinidase deficiency (BTD) Biotin
Coenzyme Q10 deficiency (COQ8A and Coenzyme Q10 (variable benefit)

others)
Homocystinuria (CBS) Vitamin B6, dietary restriction of methionine, betaine
1464 OCTOBER 2022

Chemodenervation for Dystonia
The introduction of botulinum toxin, a highly potent biological toxin with seven
major serotypes (A-G) and produced by Clostridium botulinum, revolutionized
the treatment of focal dystonia.74 This results in local paresis of the injected
muscles but likely also contributes to altering sensory feedback. All forms of focal
dystonia are routinely injected, including the muscles of mastication, the tongue,
and vocal folds. The main serotypes are serotype A (onabotulinumtoxinA,
abobotulinumtoxinA, and incobotulinumtoxinA) and serotype B
(rimabotulinumtoxinB).74 Units and doses between different formulations are
generally not interchangeable, and transitioning to another form must be done
carefully, using appropriate dose calculations. The effects of botulinum toxin
generally last 12 to 24 weeks (mean duration, 15.5 weeks) in cervical dystonia.75
Patients therefore typically receive injections every 12 weeks, although many
Rationale for
treatment Movement disorder (gene[s]) Treatment
Trigger avoidance Alternating hemiplegia of childhood Avoid stress, fatigue, and sleep deprivation (flunarizineb can
(DYT/PARK-ATP1A3) help)
Biotin-thiamine–responsive basal ganglia Avoid fasting and aggressively treat infection or fever, as
disease (SLC19A3) this can lead to metabolic decompensation
Glutaric aciduria type 1 (GCDH) Avoid fasting and aggressively treat infection or fever, as
this can lead to metabolic decompensation
Methylmalonic aciduria (MMUT) Avoid dietary noncompliance or fasting and aggressively

treat infection or fever, as this can lead to metabolic
decompensation
Paroxysmal kinesigenic dyskinesia (most Avoid sudden voluntary movement, stress, startle, fatigue/
commonly PRRT2) sleep deprivation
Paroxysmal nonkinesigenic dyskinesia Avoid alcohol, caffeine, stress, excitement, chocolate,

(most commonly PNKD) significant temperature changes; aggressively treat fever;
menstruation may also be a trigger
Paroxysmal exercise/exertion-induced Avoid, when possible, excessive exercise (vast majority of

dyskinesia (most commonly SLC2A1) attacks), fasting, stress, anxiety
Propionic acidemia (PCCA, PCCB) Avoid dietary noncompliance or fasting and aggressively
treat infection or fever, as this can lead to metabolic
decompensation
Rapid-onset dystonia-parkinsonism (DYT/ Avoid, when possible, excess emotional or physical stress,
PARK-ATP1A3) fatigue, alcohol, excessive exercise, environmental stresses
(eg, bright lights, excessive heat or cold, loud noises in
alternating hemiplegia of childhood); aggressively treat
infection/fever; childbirth may be a trigger
a
Modified with permission from Stephen CD, et al, Elsevier.9 © 2022 Elsevier.
b
Flunarizine is not approved by the US Food and Drug Administration.

THE DYSTONIAS
FIGURE 10-3
Treatment modalities in dystonia. Treatment approaches to focal, generalized, and
combined dystonia, as well as for special cases involving paroxysmal dystonia/dyskinesia,
dopa-responsive disorders, and specific pathogenesis-directed treatments.
DBS = deep brain stimulation; GPi = globus pallidus internus; OT = occupational therapy; PED = paroxysmal
exercise-induced dyskinesia/dystonia; PKD = paroxysmal kinesigenic dyskinesia/dystonia; PNKD =
paroxysmal nonkinesigenic dyskinesia/dystonia; PT = physical therapy; rTMS = repetitive transcranial
magnetic stimulation; SLP = speech and language pathology; SPR: sepiapterin reductase; STN = subthalamic
nucleus; tDCS = transcranial direct current stimulation; TMS = transcranial magnetic stimulation.
Modified with permission from Balint B, et al, Nat Rev Dis Primers.2 © 2018 Springer Nature Limited.
patients experience a shorter duration of efficacy.74 Appropriate muscle selection

is important, as injection into extraneous muscles may result in inadequate
therapeutic response or exacerbation of symptoms. Dosing is also important,
with low doses having insufficient benefit and high doses causing excess
weakness and spread into adjacent, unintended muscles, causing functional
impairment. EMG and ultrasound guidance improve accuracy of muscle
targeting and are commonly used. Despite frequent sustained efficacy, patients
may discontinue treatment given inadequate efficacy, adverse effects,
inconvenience, and financial considerations.76 Longer-acting formulations of
botulinum toxin show potential promise, such as daxibotulinumtoxinA,
1466 OCTOBER 2022

which is currently in clinical trials for dystonia and has published data for
cosmetic dermatology indications, with data suggesting a median duration of
24 weeks.77 Patients rarely develop neutralizing antibodies, resulting in
greatly decreased efficacy, and can be assessed with a “frontalis test,” where
one side of the forehead frontalis muscles are injected and unilateral reduction
of eyebrow elevation suggests preserved efficacy.74
Oral Pharmacotherapy for Dystonia

Oral medications are generally considered in cases of generalized dystonia or
more severe disease. Certain medications, particularly the anticholinergics, are
more frequently trialed in younger patients, given better tolerability compared to
when used in older patients. FIGURE 10-4 represents the major neurotransmitters
serving as targets for oral medications.72
Dopaminergic therapy commonly involves levodopa therapy at low doses
(200 mg/d to 400 mg/d). Although mainly used for the treatment of
dopa-responsive dystonia, these may be beneficial in other forms of combined
dystonia (X-linked dystonia-parkinsonism and rapid-onset dystonia
parkinsonism), although with a less robust response.71
Antidopaminergic therapy (antipsychotics/neuroleptics), despite previous
extensive use, should be avoided given the high risks of sedation and
extrapyramidal side effects.70 Dopamine depleters, such as vesicular monoamine
transporter 2 inhibitors, have potential evidence for efficacy, such as in the
treatment of dystonia in Huntington disease, although the mainstay is for use in
tardive dystonia.70 Side effects may include transient acute dystonic reactions,
drug-induced parkinsonism, or akathisia, and given potential exacerbation of
depressive symptoms, dopamine depleters are contraindicated in patients who
have inadequately treated depression or suicidal ideation.70 Anticholinergic
therapy is beneficial in most types of dystonia, although is mainly used in
Factors Affecting Choice of Treatment in Dystonia TABLE 10-8
Symptom severity
◆ If symptoms are insufficiently bothersome, no treatment may be required; with more severe
symptoms, higher-risk treatments, including surgical management, may be required
Patient age
◆ Younger patients respond well and tolerate anticholinergics (such as trihexyphenidyl) much
better than older adults
Type of dystonia (isolated versus combined)
◆ In combined dystonia, other movement disorders may need to be treated (such as levodopa
for the treatment of parkinsonism or separate treatment of myoclonus with antiseizure
medications, benzodiazepines, or other medications)
Distribution of dystonia (focal versus more widespread)
◆ Focal dystonia treatment of choice is botulinum toxin injections (less efficacy with oral
medications)
◆ Generalized dystonia is generally best treated with oral medications, followed by deep
brain stimulation in medication-refractory cases; targeted botulinum toxin injections can be
used in particularly problematic body parts

THE DYSTONIAS
FIGURE 10-4
Neurochemical pathways and targets for oral pharmacologic treatment in dystonia. The
figure illustrates the three striatal neurotransmitters (cholinergic [pink], γ-aminobutyric acid–
mediated (GABA-ergic) [yellow, brown], and dopaminergic [blue]), and targets relevant to oral
dystonia medications. 1) Cholinergic system: Acetylcholine (ACh) is synthesized in presynaptic
terminals, catalyzed by choline acetyltransferase (ChAT), and transported into vesicles. ACh
then binds to muscarinic and/or nicotinic receptors for cellular effects. The remaining ACh is
metabolized by acetylcholinesterase (AChE), with uptake into the presynaptic terminal by
choline transporter [CHT]. 2) GABA-ergic system: GABA is synthesized from glutamate
presynaptically and transported to vesicles by vesicular GABA transporter (VGAT), released
into synaptic clefts, and binds to postsynaptic receptors. The remaining GABA at the synaptic
clefts is transported to presynaptic terminals by direct reuptake and indirect transport. 3)
Dopaminergic system: The medium spiny neurons receive input from substantia nigra pars
compacta (SNc) neurons. Dopamine is presynaptically synthesized from tyrosine by tyrosine
hydroxylase (TH), transported into vesicles by vesicular monoamine transporter 2 (VMAT2),
and released into the synaptic cleft, binding to postsynaptic dopamine receptors. Dopamine is
degraded by monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT), with
remaining dopamine transported to presynaptic terminals by dopamine transporters (DAT).
Anticholinergics are postsynaptic muscarinic antagonists. Baclofen is a GABAB agonist acting
presynaptically and postsynaptically. Benzodiazepines (BZDs) bind to GABAA receptors,
causing increased chloride channel opening and inhibitory signals. Levodopa is
postsynaptically converted to dopamine for direct effects. Dopamine-depleting agents (eg,
tetrabenazine [TBZ]), are VMAT2 inhibitors, impairing dopamine transport into vesicles, while
dopamine receptor blocking agents block postsynaptic dopamine receptors.
BH4 = tetrahydrobiopterin; ChI = cholinergic interneurons; DA = dopamine; DDC = dopa decarboxylase;
DOPAC = 3, 4-dihydroxyphenylacetic acid; GAT = GABA transporter; L-DOPA = levodopa; MSN = medium
spiny neuron; 3-MT = 3-methoxytyramine;TAN = tonically active neuron; VAChT = vesicular ACh transporter.
Reprinted with permission from Termsarasab P, et al, J Clin Mov Disord.72 © 2016 The Authors.
1468 OCTOBER 2022

generalized and less frequently segmental forms.70 Examples include KEY POINTS
trihexyphenidyl (starting at 1 mg/d and gradually increasing to 2 mg 3 times a
● The goal of symptomatic
day; higher doses may be required) or benztropine and are the most effective oral therapy for dystonia is to
medications overall, with a response rate of 71%, which wanes over time.78 provide relief from
Anticholinergic medications can have a bothersome side effect profile, including abnormal movements/
dry mouth, constipation, blurred vision, and most problematically, cognitive postures, associated pain
and discomfort,
changes, hallucinations, and drowsiness, limiting their use in older patients, and
contractures or other
can cause a crisis of anticholinergic delirium, which may require hospitalization.79 orthopedic complications of
Baclofen (starting at 5 mg/d and typically increasing to 30 mg/d to 120 mg/d in sustained abnormal
three to four divided doses) is frequently used in segmental/generalized dystonia postures, and medical
comorbidities, including
but also with certain focal dystonias.69 This may be particularly beneficial in
neuropsychiatric symptoms.
secondary dystonia in PD and complex dystonias, including dystonic cerebral This should be individualized
palsy.69,70 Use of intrathecal baclofen has decreased considerably since the for each patient.
advent of DBS but can be useful in spastic dystonia, particularly if there is trunk/
leg involvement; however, side effects are common.71 ● Treatment of drug-
induced/tardive dystonia
Benzodiazepines (second- and third-line agents) are commonly used as involves early diagnosis and
adjunctive medications. The drug of choice is clonazepam, given its longer half-life discontinuation of the
and twice-daily dosing, and is particularly beneficial in myoclonus-dystonia.70 offending drug,
Benzodiazepines may provide synergistic benefit in patients with unsatisfactory discontinuation of
anticholinergics, and
responses to anticholinergics. However, sedation, particularly in older patients, and specific antidyskinetic
risks of abuse (11% in a cervical dystonia cohort)80 limit their use. Other muscle medications, with DBS
relaxants with evidence of possible efficacy in dystonia include cyclobenzaprine, considered in severe,
metaxalone, carisoprodol, methocarbamol, orphenadrine, or chlorzoxazone for refractory cases.
muscular pain/spasms.69 Other medications include sodium oxybate (in
● Botulinum toxin injections
alcohol-responsive dystonia) and zolpidem (for blepharospasm, up to 5 mg/d to form the cornerstone of
20 mg/d) and zonisamide (for myoclonus dystonia).2 focal dystonia treatment.
In comparison, the paroxysmal dystonias/dyskinesias have specific Serotypes A and B are
treatments.81 In paroxysmal kinesigenic dystonia/dyskinesias, low-dose approved for treatment.
Patients generally receive
carbamazepine (50 mg/d to 200 mg/d) is frequently highly effective, and other injections every 12 weeks,
antiseizure medications include oxcarbazepine (75 mg/d to 300 mg/d), phenytoin although many patients
(100 mg/d to 200 mg/d, limited by side effects and need for long-term use), and experience a shorter
lacosamide (50 mg/d to 100 mg/d), with some benefit with valproic acid, duration of effect. Patients
rarely develop neutralizing
lamotrigine, levetiracetam, and topiramate.81 In paroxysmal nonkinesigenic antibodies, and this can be
dystonia/dyskinesia, treatment is less effective but includes low-dose assessed with a “frontalis
benzodiazepines (eg, clonazepam, diazepam), with reports of partial success with test.”
gabapentin and levetiracetam, and rare benefit from oxcarbazepine.81 In
● Oral medications for
paroxysmal exercise/exertion-induced dystonia/dyskinesia, treatment involves
dystonia treatment are
dietary modification with the ketogenic diet, L-carnitine supplementation, and generally considered in
triheptanoin, and partial benefit noted with levodopa, trihexyphenidyl, and cases of generalized
benzodiazepines.81 Minimal evidence exists for surgical management, involving dystonia or more severe
disease and are much better
right ventro-oral thalamotomy in paroxysmal nonkinesigenic dystonia/dyskinesia,
tolerated in younger
globus pallidus internus (GPi) DBS in clinical paroxysmal nonkinesigenic patients. These mainly
dystonia/dyskinesia, and right posteroventral pallidotomy in paroxysmal exercise/ involve dopaminergic
exertion-induced dystonia/dyskinesia.81 therapy, anticholinergics,
baclofen, and
benzodiazepines.
Noninvasive Brain Stimulation in Dystonia
Noninvasive brain stimulation is a developing area of potential therapy for
dystonia but is currently investigational and mainly used for research purposes.
These include repetitive transcranial magnetic stimulation and transcranial direct
current stimulation, which may be used as an adjunct to neurorehabilitation.82

THE DYSTONIAS
Surgical Treatment of Dystonia

Surgical treatments of dystonia include intrathecal baclofen pumps, ablative
lesioning (thalamotomy/pallidotomy), focused ultrasound, and DBS, targeting
the GPi, subthalamic nucleus (STN), or thalamus. Previously, peripheral
denervation was extensively used in cervical dystonia; however, this was poorly
tolerated and resulted in a high rate of recurrence and considerable side effects,
including weakness and dysphagia and hence is not recommended.
LESIONING THERAPY. Pallidal and thalamic lesioning were the first effective treatments
for dystonia and are still used in a small number of well-selected patients. MRI-guided
focused ultrasound has evidence of efficacy, although there may be symptom
recurrence, requiring repeat lesioning. Similar to other ablation techniques, it is
unclear whether this will prove safe for bilateral use, and hence all current
cases have been performed unilaterally. There have been reports of benefit in
musician’s focal hand dystonia83 and task-specific writing tremor.84
DEEP BRAIN STIMULATION FOR DYSTONIA. DBS has potential advantages over focused
ultrasound, including a more favorable side effect profile, the potential for
reversibility, and ability to adjust the stimulation direction and field. Indications
include severe medication-refractory generalized/segmental dystonia (class 1
evidence)85 and some focal dystonias, including medication-refractory cervical
dystonia.86 Although the bulk of data in DBS has involved targeting the GPi,
TABLE 10-9 Predictors of Deep Brain Stimulation Outcome in Dystonia
Disease factor Positive outcome Negative outcome
Patient selection Isolated generalized dystonia Acquired/complex dystonia
Younger age of onset Older age of onset
Judicious and appropriately selected Erroneous placement in functional dystonia/other

treatment of idiopathic or tardive dystonia pseudodystonia (TABLE 10-6)
No prior brain surgery Prior brain surgery
No other significant medical comorbidities Any significant medical, cognitive/neuropsychiatric

comorbidities
Dystonia Mobile dystonia Fixed posturing or contractures

phenomenology
No other movement disorders or Concomitant spasticity or ataxia
concomitant spasticity
Disease duration Short symptom duration Long symptom duration
Type of genetic DYT-TOR1A and other genetic dystonias with Genetic dystonias without data for efficacy (eg, DYT/
dystonia robust efficacy data (TABLE 10-3) PARK-ATP1A3 and others as outlined in TABLE 10-3)
Imaging pathology Normal brain MRI Abnormal brain MRI
Lead placement Appropriate lead placement Lead not in ideal location
Stimulation settings Optimal stimulation settings Inappropriate stimulation settings
1470 OCTOBER 2022

KEY POINTS
evidence is growing for efficacy of STN DBS in dystonia, which appears similarly
effective as the GPi, in isolated, segmental, and generalized dystonia, ● The paroxysmal
including in genetic forms.71 In comparison, thalamic DBS (eg, targeting the dystonias/dyskinesia have
thalamic ventralis intermedius nucleus) may be more effective than GPi DBS specific treatments:
Paroxysmal kinesigenic
for the treatment of dystonic tremor, and thalamic DBS also has potential dystonia/dyskinesia is
efficacy in acquired dystonia and spasmodic dysphonia.71 treated with anti-seizure
There are differential effects of DBS, with the best evidence of efficacy for medications, (typically
isolated generalized dystonia (particularly DYT-TOR1A), younger age at carbamazepine or
oxcarbazepine); paroxysmal
surgery, shorter disease duration, and higher baseline severity.71 In contrast, nonkinesigenic dystonia/
older age, longer duration, genetic forms that are less amenable to DBS, the dyskinesia is typically
presence of functional dystonia, and fixed posture/contractures portend a poor treated with low-dose
response (TABLE 10-9).81,87 Combined dystonia has a robust response to DBS in benzodiazepines; and
paroxysmal exercise/
specific genetic forms (KMT2B, SGCE, TAF1 mutations); a variable response in
exertion-induced dystonia/
ADCY5, GNAL, and THAP1 mutations; and reports of efficacy in PRKRA and dyskinesia is treated with
VAC14 mutations, while ATP1A3 does not tend to respond.38,39,51,56 There is ketogenic diet, L-carnitine
preliminary evidence of efficacy in acquired dystonia.88 supplementation, and
triheptanoin.
Electrode location is an important predictor of response, with signs that the
optimal GPi electrode location is the posterior ventral region.89 Limitations to ● Noninvasive brain
GPi placement include a 20% nonresponder rate, modest response in acquired/ stimulation is a developing
complex dystonia, slow response to stimulation, requiring high energy settings area of potential therapy for
for sufficient benefit, and risks of stimulation-induced bradykinesia.71 Other dystonia but has mainly
been used for research
potential DBS targets have included the STN, thalamus, and cerebellum.71,90 purposes and includes
transcranial magnetic
stimulation and transcranial
Treatment of Status Dystonicus/Dystonic Storm direct current stimulation.
Status dystonicus/dystonic storm involves acute decompensation of generalized
dystonia, with severe hyperkinetic movements, generally dystonia with or without ● Surgical treatments of
dyskinesias.91 This rare but serious situation represents the most dangerous dystonia include intrathecal
baclofen pumps, ablative
manifestation of dystonia and is a movement disorder emergency, which is fatal lesioning, and deep brain
in 10%.92 The uncontrolled movements cause muscle breakdown/rhabdomyolysis, stimulation.
which can lead to renal failure, and the syndrome is frequently associated with
systemic symptoms, including fever, hypertension, tachycardia/tachypnea, ● Focused ultrasound has
evidence for efficacy for
autonomic instability, which, paired with bulbar dysfunction, may lead to dystonia, although symptom
respiratory failure, all of which contribute to its high mortality.93 Potential recurrence is possible,
differential diagnoses can include neuroleptic malignant syndrome, serotonin requiring repeat lesioning.
syndrome, malignant hyperthermia, and drug intoxication or withdrawal.93 Status This is only approved for
unilateral use.
dystonicus is more common in men and children and is subacute, often occurring
in the setting of an intercurrent infection or recent change in medication.92 Other
precipitating events include trauma, anesthesia, surgery, metabolic abnormalities,
stress, and hormonal changes.92 DBS hardware failure is a common iatrogenic
cause.92 Dystonic storm generally occurs in acquired dystonia (dystonic cerebral
palsy); however, it can also occur in isolated (DYT-TOR1A, DYT-THAP1) and
combined (DYT/PARK-TH, X-linked dystonia-parkinsonism) genetic dystonias
and complex dystonia, and severe dystonic paroxysms may rarely occur in
paroxysmal nonkinesigenic dystonia/dyskinesia.91
Management involves a stepwise approach. The first 24 hours involve
supportive therapy, treating potential triggers, followed by oral dystonia
therapies (mainly tetrabenazine and trihexyphenidyl).92,93 During this stage,
patients should be assessed regarding candidacy for surgical treatment (DBS
ideally, or if unavailable, intrathecal baclofen), particularly in DYT-TOR1A or

THE DYSTONIAS
KEY POINTS other isolated dystonia.93 This should be promptly followed by intensive care
unit–level care, with treatment involving IV midazolam, followed as needed by
● DBS has potential
advantages over focused
propofol anesthesia, and as a third line, the use of barbiturates, nondepolarizing
ultrasound, including a more neuromuscular blockers, or botulinum toxin.92,93 If this is ineffective, bilateral
favorable side effect GPi rescue DBS should be considered (successful in 33.7%),92 and where
profile, the potential for unavailable, ablative pallidotomy has been used.92 The goal over subsequent
reversibility, and the ability
weeks is adequate symptomatic treatment.93
to adjust the stimulation
direction and field. The main
stimulation site is the globus
pallidus internus; however, CONCLUSION
efficacy has also been
Substantial challenges are associated with the clinical diagnosis of dystonia,
demonstrated in targeting
the subthalamic nucleus and although great advances have occurred regarding its etiologic underpinnings.
thalamus. Cerebellar Symptomatic treatment for focal dystonia currently involves chemodenervation,
stimulation is currently oral therapies, and rehabilitation. In DBS, therapeutic indications and potential
under investigation. stimulation targets continue to expand. Future pathogenesis-based therapies,
● Status dystonicus/
including gene therapy, are on the horizon.
dystonic storm is a medical
emergency, fatal in 10%.
Precipitants include ACKNOWLEDGMENT
infection, medication
changes, or deep brain
This work was supported by the National Institutes of Health/National Institute
stimulation hardware of Neurological Disorders and Stroke (1K23NS118045-01A1).
failure. Management
involves treating triggers
and oral dystonia therapies
followed by intensive care
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deep brain stimulation. Phenomenology and classification of dystonia: a XO, Sharma N. Dystonia. In: Zigmond M, Wiley C,
consensus update. Mov Disord 2013;28(7): Chesselet MF, editors. Neurobiology of brain
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DISCLOSURE
Continued from page 1435 complex dopa-responsive dystonia; L-carnitine for
the treatment of glutaric aciduria type 1,
parkinsonism; ethylenediaminetetraacetic acid methylmalonic aciduria, and propionic acidemia;
chelation therapy for the treatment of dystonia/ vitamin B6 for the treatment of homocystinuria;
parkinsonism with manganese accumulation; biotin and thiamine for the treatment of biotin-
dopamine agonists, monoamine oxidase inhibitors, thiamine–responsive basal ganglia disease and
and pyridoxine for the treatment of aromatic biotinidase deficiency; and coenzyme Q10 for the
L-amino acid decarboxylase deficiency; levodopa treatment of coenzyme Q10 deficiency.
and 5-hydroxytryptophan for the treatment of

REVIEW ARTICLE

Diagnosing Common
ONLINE
Movement Disorders in

VIDEO CONTENT
Children
A VA I L A B L E O N L I N E By Jennifer A. O’Malley, MD, PhD
ABSTRACT
PURPOSE OF REVIEW: This article is designed to help the clinician identify the
most common pediatric movement disorders and recognize benign versus
pathologic movements in infancy and childhood, with a particular focus on
treatable conditions and those that should not be missed.
As telehealth has become more prevalent as a means of

RECENT FINDINGS:
providing health care services, the challenges of obtaining relevant
examination findings during telehealth encounters for assessment of
CITE AS: children with movement disorders have become evident.
SUMMARY: Although many children who present with a chief complaint of
1476–1519.
“abnormal movements” are found to have a benign, self-resolving
Address correspondence to etiology, it is critical that neurologists accurately recognize benign versus
Dr Jennifer A. O’Malley, pathologic movements in children to ensure appropriate diagnosis and
Stanford University School of
Medicine, Department of
intervention.
Neurology, Division of Child
Neurology, 750 Welch Rd,
3rd Floor, Palo Alto, CA 94304,
omalleyj@stanford.edu.
INTRODUCTION
R
Dr O’Malley has received eferrals to neurologists because of abnormal movements are common
personal compensation in the in children. Although many children who present with a chief
serving on a speakers bureau
complaint of “abnormal movements” are found to have a benign,
for PTC Therapeutics and has self-resolving etiology, it is critical that neurologists accurately
stock in Doximity. The institution recognize benign versus pathologic movements in children to ensure
of Dr O’Malley has received
research support from Grace
appropriate intervention.
Science, LLC. Children may present with an isolated hyperkinetic or hypokinetic movement
disorder; however, mixed movement disorders are more common in young
UNLABELED USE OF
PRODUCTS/INVESTIGATIONAL patients than in adults. Pediatric movement disorders may present at any point
USE DISCLOSURE: during infancy or childhood. They can affect tone, posture, strength, and all
Dr O’Malley discusses the
phases of movement (planning, initiation, and execution) and can consist of
deep brain stimulation for aberrant voluntary or involuntary movements. As in adults, abnormal
movement disorders in children movements in children may be categorized as ataxia, spasticity, dystonia, chorea,
and gene therapy for aromatic
L-amino acid decarboxylase
myoclonus, tremor, or parkinsonism. However, given the overlap of symptoms
deficiency. as well as variability of presentation in most pediatric movement disorders,
classification into four main categories serves as a helpful framework: (1)
© 2022 American Academy transient developmental disorders, (2) paroxysmal movement disorders, (3)
of Neurology. secondary noninherited disorders, and (4) hereditary or metabolic disorders.1
1476 OCTOBER 2022

The emergence of a movement disorder in the setting of the developing KEY POINTS
nervous system presents a unique set of challenges to the managing physician. As
● Developmental control of
many childhood movement disorders are self-resolving, benign, or both, voluntary movement begins
recognition of benign versus pathologic movements in children is essential to at the head and neck and
accurate diagnosis and management. Understanding the fundamental principles progresses to the trunk and
of motor development is key to recognition of benign versus pathologic then the extremities
(rostrocaudal gradient).
movements in infants and children. Diagnostic competency relies heavily on a
thorough history, a detailed neurologic examination, and astute recognition of ● Coordinated movement
phenomenology (practiced pattern recognition) of both normal and abnormal involves the whole brain, not
movements. just the basal ganglia and
This article is designed to help the clinician identify and manage the most motor cortices but also the
brainstem, limbic system,
common pediatric movement disorders and to recognize benign versus cerebellum, frontal lobes,
pathologic movements in infancy and childhood. and nonmotor pathways.
NORMAL DEVELOPMENT OF MOTOR CONTROL ● Voluntary movement

involves an intricate balance
Effective diagnosis of movement disorders in children first requires recognition of “stop and go” signaling,
of normal versus abnormal movements across ages. Understanding several basic with dopamine playing the
principles of motor development is essential to making this distinction.2 role of fine motor
modulator.
Top-Down Approach
Control of voluntary movement begins at the head and neck and progresses to
the trunk and then the extremities. This “top-down” development of motor
control occurs in concert with progressively diminishing primitive reflexes
(eg, startle, palmar and plantar grasp) and emergence of postural reflexes
(eg, lateral propping and parachuting). This rostrocaudal developmental pattern
strategically protects the brain from injury: infants must attain head control and
the ability to catch themselves when falling (lateral propping, parachuting)
before they are able to achieve more gravity-defying skills such as sitting,
standing, and walking. Thus, retained primitive reflexes and/or failure to
develop postural reflexes are important hallmarks of motor delay.
Movement Employs the “Whole Brain”

The basal ganglia are essential for integration of inhibitory and excitatory
signaling from throughout the nervous system. The roles of the deep gray matter,
spinal cord, and motor cortex are certainly well established, but it is important to
remember that motor function also involves coordinated signaling from the
brainstem, limbic system, cerebellum, and frontal cortices as well as nonmotor
pathways. Appreciation of the complex integration of signaling from both motor
and nonmotor circuitry supports a much deeper understanding that voluntary
movement is truly a “whole brain” process.
Movement Requires a Fine Balance of Inhibitory and Excitatory Signaling

A balance of inhibitory γ-aminobutyric acid–mediated (GABA-ergic) or “brake”
signaling and excitatory glutamatergic or “gas” signaling is essential to
coordinated movement.3 Dopamine plays the important role of moderator
between these “stop and go” signals and is key to fine motor coordination, a
balance of selection of desired movements and inhibition of unwanted
movements. In children, this fine balance develops slowly over time. Control of
inhibitory signaling is a feature of advanced motor development and can be slow
to emerge even in typically developing children. As an example, consider the

DIAGNOSING COMMON MOVEMENT DISORDERS IN CHILDREN
typical, very active 7-year-old child whose behavior may be described as “all gas
and no brake,” which is evidence of normal, still-maturing motor inhibition.4
Voluntary Movement Is Multiphasic

Voluntary movement is the result of at least three key overlapping phases:
planning, initiation, and execution. The anatomic areas associated with each
phase certainly overlap, but motor planning (which includes learning, selection,
and timing of movements) is typically associated with the cortical association
areas, cerebellum, thalamus, and basal ganglia. The thalamus and motor cortex
are central to motor initiation, and complex signaling from the cortex,
cerebellum, brainstem, spinal cord, and musculoskeletal system is integrated
during motor execution. Impairment of any or several of these phases may result
in disordered movement. Recognizing which phase or phases of movement are
impaired may be helpful in guiding some treatment decisions.
OBTAINING AN EFFECTIVE PEDIATRIC MOVEMENT DISORDER

HISTORY
Effective diagnosis and treatment of pediatric movement disorders begins with a
comprehensive history. Ideally, this history can be obtained directly from the
child, with supporting information from the caregiver(s). It is important to
ask for details from even young children, as their level of insight may be
surprisingly informative. Although efficiency is important, often a little extra
time and patience during the history portion can go far toward gaining an
accurate understanding of the phenomenology of the child’s movement
of concern.
Phenomenology and History of Present Illness

A movement disorder history begins with a focus on primary phenomenology, or
pattern recognition, to aid in identifying and categorizing the movement of
concern. It is important to determine the onset, duration, location or distribution,
severity, and provoking and relieving factors. Are the movements episodic or
continuous? Do they wax and wane throughout the day? Are there times when
the movements worsen or resolve? Do they continue during sleep? Is the child
aware of the movements and, if so, is the child bothered by them? Do the
movements occur in multiple environments (home, school)? Can the child
control the movement? Can the child stop or start the movement on command?
Is the movement associated with any premonitory urge? Has the child developed
any techniques to stop, suppress, or interrupt the movements? Are the
movements painful, embarrassing, or annoying to the child?
Ask if the child has tried any medications or supplements to relieve the
movements. Has the child seen other providers to address the movements? What
have others (providers, family members, teachers, friends) said about the
movements? This question can be an opportunity to understand the child’s
thoughts and feelings about the movements and to provide needed education or
dispel any misleading information that may have been encountered. For
example, a child with unrecognized chorea who has been reprimanded for an
inability to sit still may feel very embarrassed by the chorea and work very hard
to minimize the movements. Or the child whose concerns have previously been
dismissed may be unintentionally embellishing the movements in effort to be
taken seriously.
1478 OCTOBER 2022

Birth History KEY POINTS
A birth history should be obtained for any pediatric complaint but can be
● Understanding phases of
especially important when evaluating for a movement disorder. This includes movement (motor planning,
maternal pregnancy history and history of any other pregnancy loss or infant initiation, and execution)
death. Maternal medication use during pregnancy is important when considering can help to better identify
abnormal movements in the neonate such as jitteriness or abnormal tone. History abnormal movements.
of prematurity, birth trauma, or hyperbilirubinemia (treated or untreated) may
● The clinician should ask
pose risk for abnormal movements related to underlying brain injury. The the child about their
clinician should ask specifically about any maternal risk factors or illnesses movements: what, where,
during pregnancy, birth weight, gestation age, head circumference at birth, when, with whom, wax/
method of delivery, use of forceps or vacuum extraction, and resuscitation wane, worsening, why (Why
do you think you have these
needed at the time of delivery. Perinatal infections, history of neonatal intensive movements?) (What do you
care unit hospitalization, or other infection or illness in the neonatal period may want help with?).
also be informative.
● The clinician should pay
careful attention to
Developmental History developmental milestones
A detailed developmental history is important even for those children who seem and watch for signs of subtle
to be developing typically. Outlining a specific timeline of achievement of delay when evaluating a
milestones (or failure to do so) in all domains including gross motor, fine motor, child for movement
disorders.
speech and language, and cognition can point to subtle signs of delay that could
be otherwise overlooked. For children with previously identified delay, ● The clinician should dig
understanding the presence or absence of, timing of, and response to deep on family history;
interventions such as physical, occupational, or speech therapy will help narrow encourage parents to ask
the differential diagnosis. their families about their
own childhood movements
when evaluating a child
Medical and Surgical History presenting with a movement
Caregivers may not think chronic illnesses such as asthma are relevant to a disorder.
movement complaint, so it is important to ask directly if the child has any other
diagnoses or uses medication for any condition. This is a good time to ask if the
child had any abnormal or extra movements in the past. Ask about early episodes
of atypical eye movements, torticollis, colic, or abnormal posturing in infancy
and early childhood. Was the child particularly clumsy or slow to toilet train, or
did they struggle to learn to use utensils to feed themselves?
Family History
A thorough family history is essential, and constructing a complete
multigeneration genogram can be revealing, especially if a genetic condition is
suspected. Often, especially with benign movement disorders such as tics and
stereotypies, there is a positive history of similar movements in one or both
parents in childhood. Encourage the parent to ask their own family members (the
grandparents, aunts, and uncles of the patient) if the parent had any similar
movements or “habits” as a child; the parent may not remember or may not be
aware of their own movements that resolved in early childhood. Examination of
family members can be very helpful when considering diagnoses with high
generational penetrance such as essential tremor and primary dystonias.
Psychosocial History
The psychosocial history is essential in the evaluation of a child with a movement
disorder. Ask about family living arrangements, who lives at home, and where
the child spends their time. Has anything recently changed about the child’s

living arrangements? If care is split between multiple households, are

expectations and routines similar or very different between locations? Have
caregivers recently changed jobs, moved, or undergone other major upheavals?
As previously mentioned, nonmotor and limbic circuitry also influences
voluntary movement. Emotions directly affect normal voluntary and involuntary
movements, and the same is true for disordered movements. Stress and anxiety
are increasingly common even in young children and may have a dramatic
impact on a child’s clinical presentation for both benign and pathologic
movement disorders. Thoughtful screening for anxiety, depression, obsessive-
compulsive disorder, eating disorders, self-harm, and suicidality is critical in
building a full understanding of the complexity of a child’s motor function.
Making an effort to normalize the concept of anxiety for children and their
families is important and can be powerful. Often children and their caregivers
deny a history of anxiety but can more easily identify with the concept of “worries.”
Reinforce that worry is normal and is part of how human beings have evolved—
without worry, we would not look both ways before crossing the street or behave
safely in the world. We all have worries; does this child worry more than others
or have specific worries that take up more time than they feel is appropriate?
Work to understand the impact of a child’s movement disorder on their
learning and education. Ask about inattention, hyperactivity, and attention
deficit hyperactivity disorder as well as school performance. Have the
movements directly or indirectly affected the child’s learning or academic
performance in any way? Are the movements contributing to any behavioral
challenges at school or in other environments? These details may aid in deciding
whether to offer symptomatic treatment.
PEDIATRIC MOVEMENT EXAMINATION

The essential components of the neurologic examination are similar in children
and adults. Children are more likely to present with mixed movement disorders,
which, when coupled with the moving target of ongoing development, can make
the pediatric neurologic examination challenging to interpret. The successful
completion of a neurologic examination focused on pediatric movement
disorders relies on several key skills.
Know the Developmental Milestones of Infancy and Childhood

The timing and pattern of emergence of developmental milestones are key to
understanding motor development. The clinician must also appreciate the
developmental relationship between resolution of primitive reflexes and
emergence of postural reflexes and how that relates to the acquisition of
motor milestones.
Utilize Observation
The majority of the neurologic examination can be completed by observation.
Recognizing and developing observational examination skills helps ensure that
nearly any patient encounter, in person or virtual, provides high-yield
examination data. Watching a child play provides detailed information about
mental status, intellectual function, cranial nerve function, fine and gross motor
function, tone, strength, endurance, coordination, and gait. Observational
examination skills are particularly relevant today as we incorporate more virtual
visits into regular clinical practice. Before the COVID-19 pandemic, it was
1480 OCTOBER 2022

difficult to imagine completing a relevant movement disorder examination KEY POINTS
remotely, yet now many of us find ourselves well practiced in eliciting valuable
● Understand both the
examination findings by video examination. Perhaps neurologists were manifestation and functional
particularly well prepared for this expansion of our skill set given our common impact of movements in
practice of using video examinations regularly for teaching and consulting on multiple environments when
challenging cases. It has long been common practice to ask a caregiver to capture evaluating a child presenting
with a movement disorder.
a movement of concern not observed in the office on home video for review by
the examiner. Real-time telehealth video examination can provide valuable ● Ask about and normalize
observation of the patient in their home, school, or other primary environment. worry to further explore the
It may be advantageous to ask the family to schedule the telehealth visit at the role of anxiety when
same time as ongoing in-home services such as physical or occupational therapy, evaluating a child presenting
with a movement disorder.
or to conduct the visit at the therapy office to coordinate with valuable input
from ancillary service providers who know the child well. Caregivers can be ● Understanding of
quickly taught to demonstrate many parts of the infant examination on video developmental milestones is
such as eliciting primitive and postural reflexes, demonstrating tone and key to recognizing normal
versus abnormal
reactivity through positioning the infant in vertical and horizontal suspension, movements.
and repeating any provoking stimuli for movements of concern on video
(feeding, diaper changing, etc). Even examination maneuvers such as ● Observation is an
handwriting samples or Archimedes spiral testing for tremor can be completed essential skill for the
pediatric movement
via telehealth by using technology such as screen sharing of virtual whiteboards
examination.
and electronic pencils used on tablet devices.
Build Engagement Deliberately

Some children are very quick to engage with the examiner, but others may be shy
or frightened by the appointment. For all children, starting the visit with a calm,
friendly introduction directly to the child will help the examiner gauge the child’s
willingness to engage. For those children who seem fearful or shy, give them time
and space. It can be helpful to turn attention to the caregiver, allowing the child to
explore the room on their own terms before redirecting your attention to the child.
Consider body language; sit down and allow space between yourself and the child,
with free access for the child to move easily to their caregiver. Allow the child to
become comfortable as you speak with the caregiver. It may help to allow the child
to think you are ignoring them. Try leaving some enticing toys close by to see if they
engage. Watch how the child sits, clings to their parents, or plays with an electronic
device of their own. Ask the child or caregiver about the child’s interests. During
telehealth visits, the examiner may encourage the child to engage by asking about
their toys, books, or pets visible on the screen. Siblings can be a distraction or a great
ally: younger children will often copy their older siblings quickly; older siblings will
often engage if they are asked to “help” demonstrate something for a younger
sibling or even to their pet. It is also fine to ask the family to take a moment to
remove a child from the room or to allow the patient to run off and play in the
background. Use of child-friendly virtual backgrounds by the examiner can be
particularly engaging; children can be asked to identify characters seen on screen or
count objects, identify colors, and so forth. Older children and adolescents may
engage with a background of their favorite or rival sports team, school, or activity.
If virtual backgrounds are not available to the examiner, consider keeping a supply
of engaging toys nearby to help maintain the child’s focus and attention.
Cooperative pets belonging to the examiner can be particularly engaging to young
children on screen, but be sure to ask the parent before engaging an animal to
ensure that the child is not fearful of that type of animal.

Be Flexible
Cognitive flexibility on the part of the examiner is essential. As neurologists,
we are often trained to perform the neurologic examination in a specific order
in an effort to stay organized and be thorough and efficient. This ritual can be
very reassuring to the examiner. However, when examining children, it pays
to “meet the child where they are” in terms of cooperativity and use whatever
activity they are actively engaged in at the moment as part of the examination.
It may be helpful to think of the pediatric neurologic examination in several
phases with key components intermixed between phases: (1) initial impression
(opportunity to assess mental status, intellectual function, social interaction,
ability to engage, basic cranial nerve function, basic assessment of motor
function and milestone attainment); (2) the child’s behavior and level of
function when the examiner’s attention is directed to the caregiver (opportunity
to assess the child’s ability to independently maintain attention to conversation
not directly involving them, and perform self-soothing, engagement, or self-
entertainment and to observe the child’s basic level of motor function); (3)
the child’s active behavior when examiner’s attention is directed to the child
(child’s ability to attend, cooperate, and perform specific tasks requested by
the examiner).
Use Creative Play

Children are not always cooperative or able to perform desired examination
maneuvers, so developing creative ways to observe specific movements is highly
valuable. For example, for a toddler with tremor, providing an engaging activity
such as coloring, using a puzzle, or reaching to help the examiner turn the
pages of a book can aid assessment of tremor qualities in different positions and
during different tasks. Anxious children may be calmed by “taking a walk”
and moving the encounter to the hallway, stairwell, or even outside, where it
may be easier to observe important gross motor activities such as walking,
running, and climbing.
Tone Is Dynamic
The intricacies of muscle tone are evidence of the elegance of finely tuned and
balanced central nervous system motor circuitry as the basis of human
movement. Too often, tone is thought of as a passive, single-state quality.
Effective assessment of tone requires demonstration not only at rest but also with
activation, with attention to reactivity, recruitment, and coordinated relaxation.
Normal infants can appear quite hypotonic when sleeping and may seem nearly
rigid when crying and distraught, a striking example of the high variability and
dynamic nature of appropriate muscle tone.
A Word About Motor Assessment Tools

Several rating scales are available to quantify normal and abnormal movement in
adults and children. These are described in more detail in subsequent sections
where relevant. Although some scales may be useful in monitoring improvement
or deterioration over time, many fall short of fully depicting the impact of
movement disorders on the lives of affected children. These assessment tools can
be used as helpful adjunct measures, but they should not replace or supersede
clinical assessment based on the provider’s obtained history and physical
examination.
1482 OCTOBER 2022

TRANSIENT DEVELOPMENTAL DISORDERS KEY POINTS
Transient developmental disorders include benign and common pediatric
● Making the examination
movement disorders. Infants and children commonly demonstrate movements fun and using play to elicit
that are confusing or alarming to their caregivers, resulting in a steady influx of movement patterns is key to
referrals of typically developing children to neurologists for “abnormal an efficient and thorough
movements.” Caregivers often seek medical care with an underlying fear that the movement examination in
children.
movements exhibited by their child could signal a serious neurologic problem
such as a seizure or brain tumor and may present with a high level of anxiety and ● Tone is dynamic.
sense of urgency regarding their child’s movements. Evaluating these children in Accurate and thorough
a timely manner can help ensure that the child is healthy and safe and provide understanding of tone
appropriate reassurance to caregivers. demands examination in
multiple states (at rest, with
Most benign movements in children are transient and typically hyperkinetic, activity, while asleep).
with phenomenology similar to myoclonus, dystonia, or dyskinesias.5,6 It is
helpful to group these conditions by typical age of presentation. Although some ● Many abnormal
of these conditions are common in children with concurrent developmental movements in children are
benign and will resolve with
disorders, all of these movements can and often do present in typically development.
developing children. Nevertheless, these movements can be very stressful for
families and, although not associated with neurodegeneration, can have a ● Tics and stereotypies are
significant impact on the quality of life of the affected child or their caregivers; the most common benign
movement disorders in
they may necessitate continued management and monitoring by the clinician.
childhood.
Benign movements presenting in infancy include diagnoses such as stereotypies,
benign neonatal sleep myoclonus, jitteriness, shuddering, paroxysmal tonic
upgaze, torticollis (including benign paroxysmal torticollis), head nodding,
spasmus nutans, benign dystonia of infancy, reflux (Sandifer syndrome), colic,
and self-stimulation. Older children and adolescents may present with
stereotypies, tics, and Tourette syndrome. Stereotypies and tics are the most
common of these benign disorders and are discussed below, with other disorders
briefly summarized in TABLE 11-1.5,6
Stereotypies
Stereotypies are benign, repetitive stereotyped movements typically involving
the hands, face, or both. Movements can range from appearing relatively simple
and subtle to quite complex. Frequency and duration are variable, and
stereotypies may be intermittent or persistent. Unlike tics, stereotypies are not
typically associated with a sense of urge. For a detailed review, see the article by
Katherine.7 Although the child may appear very engaged in the movements, as a
rule, stereotypies are interruptible and the child remains responsive (although
they may be inattentive to someone attempting to interrupt or distract them
from the movements). Families often worry that the presence of motor
stereotypies in their typically developing child is a harbinger of autism or another
pervasive developmental disorder. Reassurance is key, and repeated evaluation
at regular intervals can help ensure that the family is confident moving forward
with conservative management. Although many typically developing children
outgrow their stereotypies by early school age, others may continue to perform
stereotypies into adulthood. Many older children with retained motor
stereotypies report that they enjoy performing these movements, and some
describe accompanying intense visual imagery.8 The clinician should ask older
children what they are thinking or visualizing when they are performing their
stereotypies. Some may report very vivid descriptions of an imaginative world,
as if they were playing an exciting video game in their head. Realizing that their

TABLE 11-1 Common Benign Pediatric Movement Disordersa
Common
chief
complaints Age at onset
on → typical Typical Examination Follow-up or
presentation Diagnosis resolution presentation findings Workup treatment
Shaking Benign Neonatal Myoclonic jerks Normal None None

spell, rule neonatal period → of arms, legs, or
out seizures sleep midinfancy both during
myoclonus sleep; jerks
resolve upon
awakening
Jitteriness Neonatal Jittery, Mild Review maternal Monitor for

period → tremulous infant tremulous prenatal history improvement
midinfancy with otherwise movements (maternal through first year of
normal that resolve diabetes, use life
development with sleep in of SSRI/SNRI
an otherwise or other
normal infant medication,
maternal thyroid
abnormalities)
Check infant’s
TSH and glucose
Shuddering Infancy → Infant with Normal None None

midchildhood episodes of brisk
shivering/
shuddering; may
be provoked by
stimuli, infant is
typically not
bothered by
episodes
Benign Infancy → 2 y Myoclonic jerks Normal EEG is typically Follow to ensure

myoclonus not associated indicated to rule resolution with
of infancy with irritability or out seizure time
altered mental
status
Self- Infancy → Episodes are Normal; home Can be difficult None

stimulation early often described videos to distinguish
childhood and by family as capturing from seizure if no
beyond whole-body episodes are video available or
convulsions, but very helpful if event does not
when witnessed, for diagnosis occur in office, so
there is typically EEG is often
rocking, pelvic indicated to rule
thrusting, or out seizure
self-induced
stimulation of
groin region
1484 OCTOBER 2022

Common
chief
Shaking Sandifer Infancy → first Episodes of back Normal Can be difficult Gastrointestinal
spell, rule syndrome year of life arching/ to distinguish referral for
out seizures, stiffening often from infantile treatment of
possible associated with spasms, so EEG is underlying cause
infantile irritability due to often indicated
spasms gastrointestinal
reflux or hiatal
hernia
Abnormal Paroxysmal Infancy → Episodes of Normal Consider EEG if Consider risk of

movements, tonic upgaze midchildhood upward eye episodes are migraine in future
rule out deviation lasting concerning for
seizures minutes seizure
Benign Infancy → first Segmental Normal None if history Follow to ensure

dystonia of year of life dystonia, and examination resolution with
If an episode
infancy typically of are reassuring for time
is witnessed
upper limb, benign dystonia
on
which resolves diagnosis
examination
with voluntary
(typically
movement
shoulder
abduction
with forearm
pronation and
wrist flexion),
dystonic
posture
should
resolve with
voluntary
movement
and typically
does not
interfere with
function

CONTINUED
PAGE 1485
Common
chief
Abnormal Tics Early Highly variable Normal; may None Continued

movements, childhood, but often observe tics follow-up with
rule out often peaking involves in office or on neurology as
seizures in school- repeated video needed
aged children episodes of
Education of
and/or suppressible/
patient and family
adolescence, distractable
is critical
may continue movements or
into sounds such as Evaluate for typical
adulthood throat clearing, comorbidities such
eye rolling, or as anxiety,
facial grimacing; obsessive-
tics can also be compulsive
quite complex disorder, attention
involving any deficit
body regions hyperactivity
disorder
Conservative
management is
often appropriate;
medications can be
considered for
persistent,
disruptive, painful,
or embarrassing
tics
Abnormal Stereotypies Infancy or early Typically Normal None None

movements, childhood → bilateral
May elicit by
rule out midchildhood stereotyped
exciting the
seizures, rule or adolescence hand
child in the
out autism movements
examination
often associated
room
with facial
grimacing or Video
dramatic facial examination
expression from home
can be very
helpful
Neck Benign Infancy → Episodes of Look for Consider genetic Consider risk of
twisting paroxysmal midchildhood neck/head hypertrophy testing for migraine in future
torticollis twisting/tilting of unilateral primary dystonia
lasting hours to neck muscles if progressive or
days; may be other body
isolated or occur regions are
with pallor, involved
vomiting,
irritability, or
ataxia
1486 OCTOBER 2022

Common
chief
Head Spasmus Infancy → Episodes of Nystagmus, Brain MRI Regular neurology

nodding nutans resolves in a head bobbing head indicated to rule follow-up; typically
few months with neck bobbing, out intracranial resolves by age
twisting and torticollis lesion 3-4 y
abnormal eye
Ophthalmologic
movements
examination is
indicated
Consider EEG if
concern for
seizures
Head Early Episodic head Episodes of None Rule out visual

nodding childhood → nodding without lateral, impairment,
resolves after nystagmus or vertical, or oculomotor
a few months torticollis oblique head dysfunction, or
but can nodding brain malformation
persist in when sitting
childhood or vertical,
absent when
lying down
EEG = electroencephalogram; SNRI = serotonin norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor;
TSH = thyroid-stimulating hormone.
a
Data from Bonnet C, et al, Mov Disord,5 and Kurian MA and Dale R, Continuum (Minneap Minn).6

child is not distressed by their stereotypies but is actually enjoying performing

the movements can be reassuring for worried parents.
Stereotypies typically do not require intervention. Often, stereotypies wane
with development, especially as children gain more advanced language skills and
are better able to express themselves verbally. For those children who have
particularly intense stereotypies that are interfering with their ability to pay
attention and learn in school, or if the child is bothered by their own stereotypies,
some behavioral interventions (modification of environment, scheduled breaks,
quiet space for destimulation) or therapy methods (habit reversal, competing
response) may be helpful. Stereotypies typically do not respond to medications,
and daily treatment with medication for stereotypy suppression is not indicated.
Tics and Tourette Syndrome

Chronic motor and vocal tics or Tourette syndrome is a common diagnosis in
school-aged children and adolescents. Correct diagnosis of tics and Tourette
syndrome is essential to appropriate management.9 Tics are stereotyped movements
or sounds, typically associated with an urge to perform, and have some element
of suppressibility. A diagnosis of Tourette syndrome requires tic onset before the age
of 18, with a combination of at least one vocal and one motor tic occurring over a
duration of 1 year or more (motor and vocal tics do not need to co-occur), with tics
occurring nearly daily, with tic-free periods of less than 3 months in duration.
Children with tics who do not meet diagnostic criteria for Tourette syndrome may
be classified as having transient tic disorder. It is important to ask about prior tics or
“habits” that may have gone unrecognized at a younger age. Additionally, the sense
of urge and suppressibility are often difficult for the young patient to recognize or
report. It can be helpful to ask the child if they “feel like the tics have to come out,”
or “What happens if you try to stop the tics?” Children may give very creative
descriptions or drawings of their tic-associated urge if asked to do so.
Tics may be simple (blinking, grimacing, throat clearing) or complex and can
involve any part of the body. Unlike pathologic movement disorders, tics commonly
pause during voluntary movement and speech and may quickly resume when the
child is no longer engaged in speaking or another activity. Tics fluctuate in severity
and frequency over time and may wax and wane within the hour, day, or week. This
timing may correlate with more exciting or stressful times of day (in the morning on
the way to school, at the end of the school day), week (improved on weekends,
worse during the weekdays), or year (classically increased at the start of the school
year, improved over the summer). Tics typically do not occur during sleep but may
worsen at times of transition to sleep such as bedtime or when waking in the middle
of the night. Consider provoking factors, including other medications (especially
stimulants), caffeine intake, and emotional or physical stressors. Typical tic
comorbidities include anxiety, depression, obsessive-compulsive disorder, and
attention deficit hyperactivity disorder.
Although many children with tics or Tourette syndrome will never require
medication, appropriate use of tic-suppressing medications in those who develop
tics that are painful, embarrassing, or interfering with learning, in addition to
appropriate management of tic comorbidities, is essential to management.10-14
Nonpharmacologic intervention such as Comprehensive Behavioral Intervention
for Tics (CBIT) should be considered for patients who acknowledge their tics and
are motivated to learn to suppress them.15-18 CBIT can be completed in person or
using online resources.17 Understanding the association with urge can be helpful
1488 OCTOBER 2022

in guiding tic suppression therapies such as CBIT. Several algorithms for tic KEY POINTS
treatment have been published.9,19-22
● Benign motor
Recognition of tic comorbidities is essential to optimizing medication choices stereotypies typically do not
for patients. In general, first-line tic treatment includes CBIT with or without α2- require intervention.
adrenergic agonists (ie, guanfacine, clonidine); second-line agents are typically
non–dopamine blockers (eg, topiramate, selective serotonin reuptake inhibitors ● Urge and suppressibility
are key features of tics.
[SSRIs] and serotonin norepinephrine reuptake inhibitors [SNRIs], and muscle
relaxants such as baclofen); and third-line agents include dopamine blockers (such ● Nonpharmacologic
as typical and atypical antipsychotics). The most common side effects of first- and interventions for tics include
second-line agents include fatigue (guanfacine, clonidine, baclofen), mood comprehensive behavioral
changes (SSRI/SNRI), and appetite suppression (topiramate) but are typically well intervention for tics.
tolerated and dose dependent. Dopamine-blocking agents have a more complex ● Movement disorders in
side effect profile and require closer monitoring and are thus typically reserved for children can present with
more severe and/or medication-refractory tics. Surgical intervention using deep phenomenology similar to
brain stimulation (DBS) is typically reserved for adult patients with severe, that in adults and may be
categorized as chorea,
medication-refractory, and highly disabling Tourette syndrome.23,24 Medication
dystonia, myoclonus,
selection can be optimized by paying particular attention to identifying key drivers tremor, ataxia, spasticity,
for an individual with tics. For example, in a child who is particularly anxious, and parkinsonism.
treating the anxiety can contribute to dramatic tic reduction.
● Unlike adults, children
often present with a mixed
PATHOLOGIC MOVEMENT IN CHILDREN movement disorder; thus,
Movement disorders in children can present with phenomenology similar to that discerning the primary
in adults and may be categorized as chorea, dystonia, myoclonus, tremor, ataxia, phenomenology can be
spasticity, and parkinsonism. Unlike adults, children often present with a mixed challenging but remains the
foundation of accurate and
movement disorder; thus, discerning the primary phenomenology can be timely diagnosis and
challenging but remains the foundation of accurate and timely diagnosis and treatment.
treatment. Using the categories of paroxysmal movement disorders, disorders
with secondary noninherited causes, and hereditary or metabolic disorders can ● Sydenham chorea is a
common cause of treatable
help to build an informed differential diagnosis (TABLE 11-2). As the field of
acute-onset chorea in
neurogenomics moves forward, the list of identifiable etiologies of pediatric children. Early recognition
movement disorders is rapidly growing. A detailed review of each of these and diagnosis allow for
disorders is outside the scope of this article. The focus here is on accurate appropriate intervention
with steroids for symptom
identification of clinical movement disorder phenomenology in children and the
management.
most common diagnoses for each phenomenology.
Chorea
Chorea consists of brief, variable, unpredictable, nonstereotyped, nonsuppressible
irregular movements (CASE 11-1). Movements can be fast and chaotic or may have
an athetotic quality with slow, writhing action. Chorea can affect the entire body
and is most commonly seen in the head and neck and upper extremities. Chorea is
not sustained like dystonia and is slower and more fluid than myoclonus.
Amplitude is variable. Chorea often worsens with voluntary movement, and
specific examination maneuvers can be used to elicit chorea. Children with mild
low-amplitude chorea may seem fidgety, restless, or hyperactive. Higher-
amplitude chorea may present as ballismus, with the arms or legs appearing to
fling away from the body in an uncontrolled manner. Children often attempt to
minimize the chorea, sometimes sitting on their hands or adopting other positions
to reduce intrusions and excessive movement. Young children, especially those
who are prone to inattention and hyperactivity, may have very mild choreiform
movements that can be considered normal, classified as physiologic chorea.

TABLE 11-2 Categorical Framework for Disorders Associated With Pathologic

Movements in Childrena
Paroxysmal movement disorders

◆ Ataxia
◇ Episodic ataxias
→ Without myokymia
→ With myokymia
→ With paroxysmal choreoathetosis
◇ Paroxysmal tonic upgaze with ataxia
◇ Familial metabolic periodic ataxias
◇ Others
◆ Chorea/dystonia
◇ Paroxysmal dystonic choreoathetosis
◇ Paroxysmal kinesigenic choreoathetosis
→ Intermediate or exertion induced
→ Paroxysmal hypnogenic dyskinesia
→ Secondary paroxysmal dyskinesias
◇ Postpump chorea
◆ Startle
◇ Hyperekplexia
◇ Startle epilepsy
◇ Brainstem reticular reflex myoclonus
◇ Others
◆ Stereotypies
◇ Simple
◇ Complex motor
◇ With intense imagery
◆ Dyskinetic
◇ Restless legs syndrome
◇ Paroxysmal kinesigenic dyskinesia
◇ Paroxysmal nonkinesigenic dyskinesia
◆ Tics
◇ Transient
◇ Chronic motor
◇ Chronic vocal
◇ Tourette syndrome
1490 OCTOBER 2022

Secondary noninherited causes of movement disorders

◆ Structural
◇ Perinatal cerebral injury
→ Hypoxic-ischemic encephalopathy
→ Kernicterus
◇ Tumors
◇ Trauma
◇ Burns
◇ Hydrocephalus
→ Shunt malfunction
◆ Vascular
◇Stroke
◇Vascular malformation
◇Intracranial hemorrhage
◇Vasculitis
◆ Infection/postinfectious/autoimmune encephalitis
◇ Influenza
◇ Polio
◇ Mumps
◇ Measles
◇ Varicella
◇ St Louis
◇ Coxsackie
◇ Zika
◇ TORCH (toxoplasmosis, other infections, rubella, cytomegalovirus infection, and herpes
simplex)
◇ Human immunodeficiency virus (HIV)
◇ Subacute sclerosing panencephalitis
◇ N-methyl-D-aspartate receptor (NMDA-R)
◇ Postinfectious
→ Sydenham chorea
→ Acute disseminated encephalomyelitis (ADEM)
◇ Paraneoplastic
◆ Drug/toxin
◇ Dopamine related (eg, neuroleptics, metoclopramide, reserpine, α-methyldopa, L-dopa),
antiepileptic drugs (eg, lacosamide, valproate, phenytoin, vigabatrin)
◇ Chemotherapy (eg, vincristine, cytarabine, doxorubicin)

CONTINUED FROM PAGE 1491 CONTINUED FROM PAGE 1491

◇ Other (eg, calcium channel blockers, captopril, lithium, selective serotonin reuptake
inhibitors [SSRIs], buspirone)
◇ Toxins (eg, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine [MPTP], manganese, carbon
monoxide, cyanide, methanol, disulfiram)
◇ Ingestion
◇ Postanesthesia
◆ Hormonal disorders
◇ Thyroid
◇ Addison disease
◇ Hypoparathyroidism
◇ Diabetes
◆ Associated with general medical conditions
◇ Systemic lupus erythematosus
◇ Polycythemia
◇ Antiphospholipid syndrome
◆ Psychogenic
Hereditary/metabolic disorders associated with extrapyramidal symptoms
◆ Pediatric neurotransmitter diseases
◇ Tetrahydrobiopterin (BH4) metabolism
→ BH4 defects with hyperphenylalaninemia:
– Autosomal recessive form of guanosine triphosphate-1 cyclohydrolase deficiency
– 6-Pyruvotetrahydropterin synthase deficiency
– Dihydropteridine reductase deficiency
→ BH4 defects without hyperphenylalaninemia:
– Dopa-responsive dystonia
– Dihydropteridine reductase deficiency without hyperphenylalaninemia
– Sepiapterin reductase deficiency
◇ Primary defects of monoamine biosynthesis
→ Tyrosine hydroxylase deficiency
→ Aromatic L-amino acid cocarboxylase deficiency
◇ Transporter defect
→ Glucose transport defect (GLUT1) deficiency
◇ Juvenile Parkinson disease
◆ Trinucleotide repeat diseases
◇ Juvenile Huntington disease
◇ Dentatorubro-pallidoluysian atrophy (DRPLA)
◇ Spinocerebellar atrophy type 3 (Machado-Joseph disease) and type 7
1492 OCTOBER 2022

◇ Olivopontocerebellar atrophy type 1
◆ Metabolic disorders
◇ Mineral accumulation
→ Wilson disease
→ Neurodegeneration with brain iron accumulation
– Pantothenate kinase–associated neurodegeneration
– Neuroferritinopathy
– Hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal
degeneration (HARP) syndrome
→ Fahr syndrome
◇ Lysosomal disorders
→ Neuronal storage diseases
– GM1 gangliosidosis
– GM2 gangliosidosis
– Gaucher disease
– Niemann-Pick disease type C
– Fabry disease
– Mucolipidosis
– Sialidosis
→ Neuronal ceroid lipofuscinosis
→ White-matter (dysmyelinating) disorders
– Krabbe disease
– Metachromatic leukodystrophy
– Pelizaeus-Merzbacher disease
◇ Amino acid and organic acid disorders
→ Glutaric aciduria type 1
→ Methylmalonic acidurias
→ Homocystinuria
→ Hartnup disease
→ 2-Hydroxyglutaric acidurias
→ 3-Methylglutaconic acidurias
→ Nonketotic hyperglycinemia
→ Propionic acidurias
◇ Mitochondrial disorders
→ Leigh disease
→ Leber hereditary optic neuropathy
→ Fumerase deficiency

CONTINUED FROM PAGE 1493 CONTINUED FROM PAGE 1493

◇ Other metabolic disorders
→ Succinic semialdehyde dehydrogenase deficiency
→ Guanidinoacetate methyltransferase deficiency
→ Molybdenum cofactor deficiency
→ α-Ketoglutaric acidurias
→ Biotinidase and biotin deficiency
→ Carbohydrate-deficient glycoprotein deficiency
→ Congenital folate/B12 problems
→ Familial glucocorticoid deficiency
→ Glucose transport defects
→ Triose phosphate isomerase deficiency
→ Vitamin E deficiency
Other genetic causes
◆ Lesch-Nyhan syndrome
◆ Ataxia-telangiectasia
◆ Neuroacanthocytosis
◆ Genetic (DYT) primary dystonia
◆ Pallidal degenerations (ie, familial striatal necrosis, infantile bilateral striatal necrosis,
progressive pallidal degeneration)
◆ Pelizaeus-Merzbacher disease
◆ Canavan disease
◆ NGLY1 deficiency
◆ GNAO1 encephalopathy
◆ ADCY5-related dyskinesia
◆ NKX2-1-related disorders
◆ FOXG1 syndrome
a
Data from Singer HS, Semin Pediatr Neurol.1
Thus, careful history taking to explore timing, symptom onset, comorbidities,

and other factors is essential to determine the appropriate workup.
ACUTE CHOREA. The timing of chorea onset can be very informative with regard to
etiology. Acute chorea in children is most commonly due to toxic ingestion or
infectious or postinfectious causes.
SYDENHAM CHOREA. The most common type of acute-onset chorea in school-aged,

previously healthy children is Sydenham chorea, a postinfectious autoimmune
chorea. Sydenham chorea classically occurs as a sequela of group A β-hemolytic
streptococci infection but has been noted to occur in association with other
1494 OCTOBER 2022

infectious causes. Sydenham chorea develops quickly, over hours to days.
History should reveal prior infection (fever, cough, sore throat) in the past
6 months. Prior infection may have been mild or subtle. If there is no history of a
clear infection but suspicion for Sydenham chorea is high, then antistreptolysin
O (ASO) and anti-deoxyribonuclease B (anti-DNase B) titers should be obtained.
If history and examination suggest Sydenham chorea, then elevated ASO or
anti-DNase B titers can serve as relatively sensitive predictors of the disorder. If
suspicion for Sydenham chorea is low, then ASO and anti-DNase B titers are less
useful, and interpretation of these results can be complicated. In a child with
A 5-year-old boy with hypoplastic left heart with remote surgical repair CASE 11-1
presented to the emergency department with new uncontrolled
movements 10 days after discharge from a recent hospitalization for
multiple infections. His mother reported that he could no longer sit, walk,
or feed himself independently. Typically a very talkative child, he was
now refusing to speak.
On examination, he was afebrile with normal vital signs. He was in no
distress, with normal breathing, good perfusion, soft abdomen, and no
rashes. He had a well-healed sternotomy scar, consistent with his history
of cardiac surgery. He appeared very wiggly and restless and seemed
irritable but was oriented, alert, and able to at least attempt to follow
commands, although he was limited by his inability to control his arms,
legs, and head. He was lying in bed, refusing to sit up or speak. His gaze
was conjugate and his extraocular movements were intact, but his
excessive head wiggling caused him to blink frequently and struggle to
follow the examiner around the room. When supported in a seated
position, he was unable to hold his head still, and he had nearly
continuous writhing movements of his trunk. When reaching for objects
he demonstrated a variety of extra movements, which worsened with
intentional voluntary movement. In particular, his fingers appeared to
hyperextend when he was asked to open his hands, and, upon squeezing
the examiner’s fingers on command, he exhibited repetitive squeezing
movements of both hands. When asked to stick out his tongue, although
he seemed compliant, he could not keep his tongue still enough for the
examiner to adequately examine his mouth.
It was discovered that during his recent hospitalization he was
diagnosed with COVID-19 complicated by a group B streptococci
superinfection. He had been treated for both infections appropriately
and was discharged home, where he was well until onset of these new
movements.
Brain MRI and EEG were normal. Tests for erythrocyte sedimentation rate
and anti-deoxyribonuclease B (anti-DNase B) were equivocal (VIDEO 11-1).
The patient was diagnosed with Sydenham chorea and treated with a COMMENT
course of steroids. He experienced dramatic improvement within days of
treatment.

CASE 11-2 An 11-year-old boy presented with a 6- to 8-year history of progressive

generalized dystonia that reportedly began in one ankle (it was thought to
be related to a minor sprain) and progressed over the next several years
to involve his entire body. He initially had some symptomatic relief with
benzodiazepines, but over time his dystonia spread and worsened in
severity, and it had become refractory to multiple medications including
clonazepam, baclofen, trihexyphenidyl, levodopa, and botulinum toxin
injections.
He was referred to the movement disorders clinic for further
evaluation. On initial examination, he had severe generalized dystonia
with notable cervical dystonia featuring retrocollis and laterocollis, jaw
opening dystonia for which his mother had tied a scarf under his chin to
aid with jaw closure, risus sardonicus, dystonic tremor, and dystonic
posturing of his arms and legs. His dystonia worsened with muscle
activation for voluntary movement. His truncal dystonia had contributed
to notable scoliosis. He was exceptionally thin with well-defined
musculature and minimal body fat. He was cognitively intact, and
receptive language was intact. Expressive language was severely limited
by orolingual dystonia and dystonic dysarthria; however, he could
attempt to follow verbal commands to participate in examination
maneuvers such as the finger-nose-finger test and manual muscle testing
(VIDEO 11-2). He was dependent on nasogastric feeding, as he was unable to
swallow safely, and he used a wheelchair. His current medications were
levodopa/carbidopa, trihexyphenidyl, baclofen, clonazepam,
gabapentin, dantrolene, and regular-interval botulinum toxin injections;
all interventions were optimized to maximum tolerated doses.
Prior brain MRI demonstrated nonprogressive mild cerebellar atrophy
with no other abnormality. He underwent extensive genetic testing
including whole exome and whole genome sequencing, which were
unrevealing.
After multidisciplinary evaluation by specialists in orthopedic surgery,
child neurology, pediatric neurosurgery, physical and occupational
therapy, speech therapy, neuropsychology, and social work and review
by the institutional deep brain stimulation (DBS) review board, the patient
underwent successful implantation of bilateral globus pallidus internus
DBS stimulators. He had marked improvement in his dystonia and was
able to wean off nearly all of his medications with the exception of
low-dose clonazepam.
COMMENT Although the history supported a high suspicion for DYT1 as a cause of this
child’s progressive generalized dystonia, genetic testing did not identify a
cause. It is important to consider pallidal DBS even in cases where genetic
testing is unrevealing.
1496 OCTOBER 2022

subacute chorea and absence of elevated ASO or anti-DNase B titers, an KEY POINTS
alternative diagnosis of systemic lupus erythematosus (SLE) or antiphospholipid
● Symptom severity in
antibody syndrome should be considered. Of course, other etiologies such as toxic Sydenham chorea is highly
(ingestion) or structural (stroke) must be considered at the time of diagnosis, variable, but children
depending on history and other examination findings. Although brain MRI is not commonly present with
necessary for children with clear cases of Sydenham chorea, it is often obtained in complaints of new
clumsiness (dropping items,
an effort to rule out other causes of acute-onset chorea. falling), gait instability,
Symptom severity in Sydenham chorea is highly variable, but children irritability, poor
commonly present with complaints of new clumsiness (dropping items, falling), coordination, and possible
gait instability, irritability, poor coordination, and possible changes in speech and changes in speech and
behavior.
behavior. On examination, classic findings of spooning sign (child is asked to
hold hands outstretched in front of them at shoulder height resulting in ● Sydenham chorea is a
hyperextension of fingers interrupted by choreic intrusions), touchdown sign form of rheumatic disease;
(child is asked to sit still with arms at shoulder height with elbows flexed at 90 thus, screening and
degrees and hands facing forward resulting in choreic intrusions disrupting arm monitoring for associated
cardiac involvement are
position), milkmaid’s grip (child is asked to use all fingers of one hand to squeeze imperative.
the examiner’s hand, but the child’s grip is interrupted with choreic intrusions
denoting motor impersistence), and tongue darting can help solidify the diagnosis. ● Genetic causes for chorea
These findings are not specific to Sydenham chorea but can be observed in other should be considered in any
child with new-onset
forms of chorea and are not necessary to provide the diagnosis of Sydenham chorea. subacute progressive
Sydenham chorea is a form of rheumatic disease; thus, screening and chorea, especially if
monitoring for associated cardiac involvement are imperative. Chronic penicillin accompanied by other
prophylaxis is indicated to reduce the risk of recurrent chorea but also for neurologic or psychiatric
features.
protection against carditis and development of secondary cardiac valve disease.
ECG, echocardiography, and evaluation by a cardiologist are appropriate. Steroid
treatment can shorten the duration of chorea and reduce symptom severity.
OTHER ACUTE CHOREA. In children with congenital heart disease who have
undergone surgical repair or bypass, postpump chorea should be considered in
the case of acute onset of choreiform movements in the postoperative period.
CHRONIC CHOREA. Chronic chorea may be acquired, as in children with structural

brain injury such as hypoxic-ischemic encephalopathy, cerebral palsy, and
stroke; toxin induced; autoimmune; or iatrogenic. Genetic causes of chorea
should be considered in any child with new-onset subacute progressive chorea,
especially if accompanied by other neurologic or psychiatric features. Genetic
causes of chorea in children include benign hereditary chorea, several
neurodegenerative diseases (Huntington disease, glutaric aciduria, Wilson
disease, GNAO1 encephalopathy, mitochondrial disease, Lesch-Nyhan
syndrome, phenylketonuria, neuroacanthocytoses), ataxia syndromes
(Friedreich ataxia, ataxia-telangiectasia, ataxia with oculomotor apraxia types 1
and 2, dentatorubral-pallidoluysian atrophy, spinocerebellar ataxia), and many
other disorders (ie, ADCY5, PDE10A, NKX2-1, GLUT-1, FOXG-1).
For an in-depth review of other causes of chorea, refer to the article “Chorea” by
Erin Furr Stimming, MD, FAAN, and Danny Bega, MD,25 in this issue of Continuum.
Dystonia
Dystonia is characterized by involuntary simultaneous contraction of opposing
muscles, leading to abnormal posture and impaired function of the affected area
(CASE 11-2). Dystonia can involve a particular part or region (focal, segmental)

or all (generalized) of the body. Dystonia is commonly mistaken for spasticity

in children who present with abnormal increased tone. Dystonia will often
“melt” away during sleep or with relaxation, whereas spastic muscles will remain
tight regardless of state. Dystonia often worsens with activity and may be
task-dependent, occurring only with specific motor sequences (as can be seen
in disorders such as writer’s cramp or musician’s dystonia). Also, unlike with
spasticity, patients with dystonia may be able to perform a “dystonic trick” or
geste antagoniste, a maneuver specific to the affected individual that allows them
to relieve the dystonia. Dystonic tremor may have a “null point,” a position in
which the tremor is minimized. In children, the clinical distinction between
dystonia and spasticity (and other movement disorders) is essential in
determining accurate disease etiology and appropriate treatments. Children with
increased tone are too often given the diagnosis of cerebral palsy, potentially
leading to a missed opportunity for appropriate diagnosis and intervention.
Children with basal ganglia injury related to cerebral palsy, stroke, or another
insult may present with a combination of movement disorders and can have
concurrent spasticity, dystonia, and chorea. Understanding which movement
disorder is most prominent can guide treatment decisions and avoid unintended
worsening of a concurrent movement problem. For example, in a child with
spasticity and dystonia, surgical intervention must be considered carefully, as
certain interventions for spasticity (selective dorsal rhizotomy) may improve the
spasticity but “unmask” concurrent dystonia, resulting in worsened motor
function.
Dystonia should be considered in any child with sustained abnormal postures.
Unlike tics, dystonia is not associated with urge, suppressibility, or a sense of
relief. Although some tics may appear to have dystonic features, careful history
and observation will help the examiner distinguish between the two.
TABLE 11-3 Common or Treatable Primary Dystonias of Childhood
Inheritance/gene
Diagnosis (protein) Name Presentation Intervention
DYT1 Autosomal dominant/ Early-onset Initial onset in arm or leg with Deep brain stimulation (DBS)
TOR1A (Torsin A) generalized torsion generalization
dystonia
DYT5 Autosomal dominant/ Dopa-responsive Childhood-onset progressive Levodopa

GCH1 (GTP dystonia (Segawa dystonia with dramatic
cyclohydrolase 1) disease) response to levodopa
DYT6 Autosomal Adolescent-onset Focal/segmental dystonia that Symptomatic, consider DBS

dominant/THAP1 dystonia of mixed progresses to generalized
type dystonia
DYT11 Autosomal Myoclonus dystonia Prominent myoclonus with Symptomatic, consider DBS
dominant/SGCE dystonia
(ε-sarcoglycan protein)
DYT12 Autosomal dominant/ Rapid-onset dystonia Abrupt onset of dystonia with Typically resistant to
ATP1a3 (Na/K ATPase parkinsonism rapid progression over hours to dystonia medications; may
α3 subunit) weeks consider DBS
1498 OCTOBER 2022

Dystonia can be primary (related to a genetic cause) or secondary (acquired, KEY POINTS
often with a structural etiology such as cerebral palsy, infection, kernicterus,
● For the child with
stroke, toxins, trauma, or autoimmune etiologies) (TABLE 11-3). Dystonia is a spasticity and dystonia,
prominent feature in several syndromes (TABLE 11-426). surgical intervention must
Treatment options are similar to those in adults and include both medications be considered carefully, as
and surgical interventions such as DBS. It is always prudent to trial levodopa for certain interventions for
spasticity (in particular,
any child with dystonia to rule out a treatable dopa-responsive dystonia. For a
selective dorsal rhizotomy)
detailed discussion of medical and surgical treatment of dystonia, including may improve the spasticity
dystonic storm, refer to the article “The Dystonias” by Christopher Stephen, but “unmask” concurrent
MB ChB, FRCP, SM,27 in this issue of Continuum. dystonia, resulting in
worsened motor function.
Myoclonus ● Surgical candidates

Myoclonus is characterized by rapid and short muscle jerks that are simple should be evaluated by a
movements. Myoclonus is unpredictable and appears much faster than voluntary multidisciplinary review
twitching or jerking. It is helpful to identify and describe the distribution (focal, board including specialists
in neurology, neurosurgery,
segmental, multifocal, generalized), origin (cortex, brainstem, spinal cord), state and physical, occupational,
(spontaneous at rest or with activity versus stimulus induced), and timing and speech therapy, as well
(irregular versus rhythmic). Both positive (occurring as sudden muscle as undergo a thorough
contraction) and negative (occurring as sudden muscle relaxation) myoclonus psychosocial evaluation.
may be observed.
● Surgical intervention with
It is important to recognize benign forms of myoclonus in children. Examples pallidal deep brain
of benign physiologic myoclonus include hiccups, exercise- or anxiety-induced stimulation should not be
myoclonus, benign neonatal sleep myoclonus, or hypnic jerks in older children. delayed for children with
medication-refractory
One of the most common myoclonus-related neurology consultations is for
progressive dystonia.
the infant with benign neonatal sleep myoclonus. Parents may present with
their otherwise healthy infant with reports of “jerking” while falling asleep or ● It is always prudent to
during sleep (typically during states of arousal). Key findings include an trial levodopa for any child
otherwise normal healthy infant with reported absence of jerks while awake with dystonia to rule out a
treatable dopa-responsive
and a history consistent with cessation of jerks when the infant is awakened. dystonia.
These babies are often admitted to the hospital by a concerned provider for
continuous EEG to rule out infantile spasms, but careful history taking and ● Examples of benign
examination can avoid unnecessary testing and medical escalation. Education physiologic myoclonus
include hiccups, exercise-
and reassurance of caregivers are appropriate, and no medication or other
or anxiety-induced
treatment is indicated. myoclonus, benign neonatal
In contrast to benign physiologic myoclonus, children may present with sleep myoclonus, or hypnic
hyperekplexia (a stimulus-induced exaggerated startle response), which jerks in older children.
warrants additional evaluation with genetic testing. Symptomatic treatment with
● The most common causes
clonazepam or other benzodiazepines may be effective. Some hereditary of tremor in children are the
hyperekplexias spontaneously improve or resolve, whereas others may be primary tremors:
associated with other neurologic impairments such as cognitive delay or epilepsy. developmental tremor,
Additional conditions associated with prominent myoclonus in childhood are enhanced physiologic
tremor, and essential
listed in TABLE 11-5. tremor.
Tremor
Tremor is a rhythmic, relatively symmetric oscillatory involuntary movement of
a body part.28 Tremor can occur as an isolated phenomenon or in conjunction
with other movement disorders in children. The most common causes of tremor
in children are the primary tremors: developmental tremor, enhanced
physiologic tremor, and essential tremor. Secondary tremor results from injury
affecting circuitry in the basal ganglia, brainstem, or cerebellum and may be

TABLE 11-4 Childhood Disorders With Prominent Dystoniaa
Autosomal recessive
◆ Aromatic L-amino acid decarboxylase deficiency
◆ Ataxia-telangiectasia
◆ Dopamine transporter deficiency
◆ Gangliosidoses
◆ Glutaric aciduria
◆ Hartnup disease
◆ Homocystinuria
◆ Juvenile Parkinson disease
◆ Metachromatic leukodystrophy
◆ Methylmalonic aciduria
◆ Niemann-Pick disease type C
◆ Neuroferritinopathy
◆ Pantothenate kinase–associated neurodegeneration
◆ Sepiapterin reductase deficiency
◆ Tyrosine hydroxylase deficiency
◆ Thiamine transporter 2 deficiency
◆ Triose phosphate
Autosomal dominant
◆ Dentatorubro-pallidoluysian atrophy (DRPLA)
◆ Hereditary spastic paraparesis with dystonia
◆ Huntington disease
◆ Spinocerebellar ataxias
Mitochondrial
◆ Leber disease
◆ Leigh syndrome
◆ Myoclonic epilepsy with ragged red fibers (MERRF)
◆ Mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS)
X-linked
◆ Dystonia-deafness
◆ Lesch-Nyhan syndrome
◆ Pelizaeus-Merzbacher disease
◆ Rett syndrome
Reprinted with permission from Singer H, et al, Saunders.26 © 2015 Academic Press.
1500 OCTOBER 2022

caused by a variety of mechanisms including toxins, medications, structural
lesions, and genetic or metabolic disorders.
On examination, fine and gross motor movements should be observed.
Tremor can be enhanced by asking the child to perform specific tasks such as
pouring water between cups, bringing a cup or bottle to their mouth, reaching
for small objects, coloring, or drawing. Even very young children can often
cooperate with handwriting or drawing samples and freehand spiral testing.
The child can be observed buttoning their coat, collecting toys into a bag, or
Disorders With Prominent Myoclonus Presenting in Infancy and Childhood TABLE 11-5
Startle syndromes
◆ Hereditary hyperekplexias
◆ Symptomatic startle disorders
◆ Startle epilepsy
◆ Neuropsychiatric startle syndromes
Primary myoclonic disorders
◆ Essential myoclonus
◆ Myoclonus-dystonia (DYT11)
◆ Benign myoclonus of early infancy
Epileptic myoclonus without encephalopathy
◆ Juvenile myoclonic epilepsy
◆ Benign familial myoclonic epilepsy
◆ Myoclonia with childhood absence epilepsies
Secondary myoclonus
◆ Opsoclonus-myoclonus ataxia syndrome
◆ Subacute sclerosing panencephalitis
◆ Postanoxic myoclonus
◆ Epilepsia partialis continua, Rasmussen encephalitis, myoclonia continua
Progressive myoclonic epilepsies
◆ Mitochondrial myopathies
◇ Myoclonic epilepsy with ragged red fibers (MERRF)
◆ Unverricht-Lundborg disease
◆ Lafora disease
◆ Neuronal ceroid lipofuscinosis
◆ North Sea progressive myoclonus epilepsy with ataxia
◆ Sialidosis
◆ Angelman syndrome
Others
◆ Autosomal dominant cortical myoclonus without epilepsy
◆ Hemifacial spasm

manipulating their parent’s smartphone. In infants and toddlers, feeding can be

observed. Children will naturally find ways to minimize their tremor. Encourage
the child to sit without leaning against a wall or the back of a chair to brace
themselves. The examiner should pay careful attention to when the tremor is
present and when it is absent. Is the tremor present at rest or only with action? Is
it unilateral or bilateral? Are there other accompanying neurologic signs such as
abnormal eye movements, ataxia, complaints of headache or dizziness, or
changes in speech or behavior?
Developmental tremor and enhanced physiologic tremors tend to fluctuate
and may be intermittent or observed only during specific tasks. The frequency is
often faster and the amplitude lower than with essential tremor. Developmental
tremor typically improves with age, whereas essential tremor persists or worsens.
Careful family history and examination of accompanying family members at the
time of neurologic examination is especially important in ruling in or out
essential tremor, although a family history of tremor does not ensure that a
child’s diagnosis is essential tremor, and other etiologies should be considered.
Education about the importance of lifestyle management is central to
empowering young patients to attain good tremor control. Typical tremor-provoking
stimuli include fatigue, poor sleep, anxiety, caffeine intake (coffee, tea, energy
drinks), skipping meals, many medications commonly used in children and
adolescents (SSRIs or SNRIs, stimulants, albuterol, antiseizure medications such
as valproate and phenytoin), and physiologic as well as emotional stressors.
Benign tremor can often be managed with only lifestyle modifications, avoiding
use of daily medications. Occupational therapy can be particularly helpful in
TABLE 11-6 Suggested Approach to the Child With Ataxiaa
1 Identify time-course group: acute, subacute, chronic nonprogressive, chronic progressive, or

episodic
2 Identify extracerebellar signs/symptoms and other accompanying neurologic or medical
conditions to help refine the differential diagnosis
3 Obtain an accurate three-generation family history
4 Initial laboratory tests:
A Acute onset: drug screen, specific testing for known ingestion, infectious workup if
indicated
B Chronic onset: α-fetoprotein, vitamin E, coenzyme Q10, IgG subclasses, albumin, creatine
kinase, and cholesterol panel
5 Neuroimaging: brain MRI with particular attention to presence or absence of cerebellar
atrophy, cerebral volume loss, white matter lesions, or basal ganglia lesions
6 Genetic testing: single gene, panel, whole exome sequencing; special consideration of
triplet repeat expansions (some spinocerebellar ataxias, dentatorubro-pallidoluysian
atrophy [DRPLA], and Friedreich ataxia)
7 Referrals: physical, occupational, and speech therapy; other subspecialists as indicated
(such as cardiology and endocrinology for Friedreich ataxia)
IgG = immunoglobulin G.
a
Data from Singer HS, et al29 and Pearson TS and Pons R, Continuum (Minneap Minn).30
1502 OCTOBER 2022

teaching children strategies to manage tremor as well as provision of individualized KEY POINTS
tremor tools such as specialized pen or pencil grips or weighted utensils.
● The clinician should
For patients with essential tremor, propranolol and primidone are first-line obtain a thorough family
medications. DBS should also be considered for adolescents with intractable history and examination of
essential tremor that interferes with learning or self-esteem. accompanying family
In the event of acute onset of new tremor, ingestion and withdrawal must members at the time of
neurologic examination for
be considered.
tremor.
Metabolic causes of tremor such as thyroid or other endocrine dysfunction
should be ruled out. Vitamin and mineral deficiencies should also be considered ● Toxic ingestion is at the
as potential etiologies for tremor. top of the differential
Tremor due to an underlying structural abnormality or associated neurologic diagnosis for acute ataxia.
syndrome is rarer, but it is important to recognize key findings on history

and examination that will help the clinician discriminate between enhanced
benign and pathologic tremor. Any child who presents with a new-onset tremor
in the setting of other neurologic signs or symptoms warrants immediate
neuroimaging.
For all young patients with tremor, repeat examination in 6 to 12 months, even
for those patients with benign etiologies, can ensure appropriate monitoring and
treatment and provide any additional support to optimize function.
Ataxia
Ataxia is defined as “inability to generate a normal or expected voluntary
movement trajectory that cannot be attributed to weakness or involuntary
muscle activity about the affected joints.”29 Children with ataxia may present as
clumsy or with extra movements and may have abnormal eye movements
(nystagmus, oculomotor apraxia), slow or slurred speech, tremor, head or trunk
bobbing or instability (titubation), and a wide-based lurching or staggering gait.
Subtle ataxia can be easily missed or mistaken for dyskinesia or even
hyperactivity. Understanding onset (acute, subacute, or chronic) and presence
or absence of progression is key, as it is helpful to think of childhood ataxias
grouped by onset and then by mode of genetic inheritance or other
accompanying features. TABLE 11-629,30 provides guidelines for the initial
diagnostic approach to the child with ataxia.
ACUTE ONSET. A common cause of acute ataxia in children is toxic ingestion. Toxic
ingestion is always at the top of the differential diagnosis for acute ataxia and may
be accidental in toddlers or related to substance abuse in adolescents. Common
substances ingested include alcohol, antiseizure medications, antihistamines, and
benzodiazepines. In the absence of clear toxin exposure, traumatic or vascular
causes such as stroke or vertebrobasilar dissection should also be considered.
Infectious and postinfectious causes must also be considered.
Recurrent acute ataxia may be metabolic in origin (look for a history
suggestive of neurometabolic disease); due to migraine (basilar migraine, which
may present without head pain), benign paroxysmal vertigo, or episodic ataxia
type 1 or 2; or functional in nature.
SUBACUTE ONSET. The differential diagnosis for subacute presentation of ataxia

includes acute cerebellar ataxia (usually postinfectious), opsoclonus-myoclonus
syndrome, acute disseminated encephalomyelitis (ADEM), Guillain-Barré
syndrome including Miller Fisher variant, and posterior fossa tumor.

CHRONIC ONSET. Chronic-onset ataxias may be progressive or nonprogressive, as

outlined in the following sections.
PROGRESSIVE. Chronic progressive ataxia can be associated with several genetic

mutations and is typically subdivided into three groups: autosomal dominant,
autosomal recessive, and spastic-ataxia, with the autosomal recessive ataxias
being the most common subgroup to present in children. Examples of
autosomal recessive chronic progressive ataxias in children include Friedreich
ataxia, ataxia-telangiectasia, ataxia with oculomotor apraxia types 1 and 2, and
ataxia with vitamin E deficiency. Friedreich ataxia and ataxia-telangiectasia are
the most common autosomal recessive ataxias presenting in children.
Examples of less common autosomal dominant ataxias include many of the
spinocerebellar ataxias and dentatorubral-pallidoluysian atrophy (DRPLA).
Ataxia-telangiectasia. Ataxia-telangiectasia is an autosomal recessive progressive

movement disorder with typical onset of neurologic symptoms between 1 and
4 years of age, characterized by ataxia, chorea, dystonia, athetosis, oculomotor
signs, and later development of telangiectasias. It may or may not be
accompanied by recurrent sinopulmonary infections. Ataxia may initially be
static or slow to progress, potentially delaying accurate diagnosis.
Ataxia-telangiectasia is accompanied by immunodeficiency, which, if present,
may warrant treatment with intravenous immunoglobulin (IVIg).
Ataxia-telangiectasia is detected by elevated serum α-fetoprotein, which is
typically sufficient to confirm the diagnosis. Additional testing may include ATM
gene sequencing and DNA radiosensitivity testing. Treatment of the movement
disorder is symptomatic, with no specific treatment for ataxia.
Friedreich ataxia. Friedreich ataxia is the most common autosomal recessive

ataxia in White populations and is due to GAA triplet repeat expansion in the
TABLE 11-7 Red Flag Findings That May Indicate a Genetic Etiology or Cerebral Palsy
Mimic in the Child With a Diagnosis of “Cerebral Palsy”a
◆ Normal brain MRI

◆ Severe symptoms without history of acquired injury
◆ Family history of the disorder or consanguinity
◆ Neurodevelopmental regression or progressively worsening phenotype
◆ Rigidity
◆ Isolated dystonia, chorea, ataxia, or hypotonia
◆ Spasticity involving lower extremities only
◆ Oculogyric crisis
◆ Paroxysmal motor symptoms
◆ Hyporeflexia/areflexia

a
Data from Lee RW, et al, Neuromolecular Med,31 and Pearson TS, et al, Mov Disord.32
1504 OCTOBER 2022

FRDA gene. Average age at onset is 15 years, with patients typically presenting KEY POINTS
with neurologic symptoms after the age of 2 years. Friedreich ataxia is
● Clinical distinction
characterized by progressive gait ataxia, dysarthria, limb weakness, axonal between spasticity,
neuropathy with impairment of proprioception and vibration, areflexia, and dystonia, and rigidity is
extensor plantar response. Patients with Friedreich ataxia are at high risk for essential for accurate
diabetes and dilated cardiomyopathy, the latter of which is a common diagnosis and appropriate
treatment of the hypertonic
contributor to early mortality.
child.
Ataxia with oculomotor apraxia types 1 and 2. Ataxia with oculomotor apraxia type ● Although spastic cerebral
1 (AOA1) and type 2 (AOA2) are progressive autosomal recessive ataxias palsy is the most common
presenting in childhood. Onset of symptoms in children with AOA1 is anywhere type, many children with
cerebral palsy present with
between age 2 and 18 years and includes ataxia, choreoathetosis, oculomotor a mixed movement disorder.
apraxia, sensory neuropathy, hyporeflexia, and cognitive impairment. AOA1 is
associated with a mutation in the PTX gene, with low serum albumin and high
cholesterol on laboratory evaluation and cerebellar atrophy on MRI. AOA2
typically presents in the teen years with onset between age 13 and 18 years and
features progressive ataxia and areflexia, but oculomotor apraxia is less
prevalent. AOA2 is associated with mutation in SETX, with elevated serum
α-fetoprotein and diffuse cerebellar atrophy on MRI. No disease-modifying
medical treatment is available for either AOA1 or AOA2.
Ataxia with vitamin E deficiency. Ataxia with vitamin E deficiency has onset in
early childhood and is characterized by progressive ataxia, retinitis pigmentosa,
and dystonia. Diagnostic testing reveals low vitamin E levels. Treatment includes
lifelong high daily doses of vitamin E.
NONPROGRESSIVE. In patients with chronic nonprogressive ataxia, neuroimaging

can aid in ruling out an associated congenital cerebellar malformation.
Spasticity
Spasticity is a common finding in children with disordered movement and can be
secondary to a structural cause or related to a primary genetic cause. The most
common cause of spasticity in children is cerebral palsy. It is critical to consider
other causes of spasticity in children who present with any of the “red flags”
discussed below (TABLE 11-731,32).
Spasticity is defined as increased tone with increased resistance to passive
stretch at a joint and is typically velocity dependent. Children with long-standing
spasticity may also have contractures limiting range of motion at a joint, which
can make testing for velocity dependence challenging. Dystonia and rigidity are
easily mistaken for spasticity. Clinical distinction between spasticity, dystonia,
and rigidity is essential for accurate diagnosis and appropriate treatment of the
hypertonic child (TABLE 11-8).
CEREBRAL PALSY. The most common cause of spasticity in children is cerebral

palsy, resulting from a wide variety of prenatal, perinatal, and postnatal insults
(eg, prematurity, hypoxic-ischemic encephalopathy, stroke, infections,
developmental brain malformation, vascular malformation, congenital heart
disease, trauma, kernicterus, or intracranial hemorrhage).33 Cerebral palsy is
typically classified into four types by primary motor disability: spastic,
dyskinetic, ataxic, or mixed type. Although spastic cerebral palsy is the most

common type,34 many children with cerebral palsy present with a mixed
movement disorder, with dystonia present in up to 75% of children classified as
having the predominant spastic type.35 Children with spasticity may also have
signs of chorea, ataxia, and other abnormal movements. Key principles regarding
the diagnosis of cerebral palsy are as follows: (1) Cerebral palsy is a clinical
description and not an etiology. (2) Cerebral palsy is a permanent disability. (3)
Cerebral palsy is a nonprogressive brain process, but the physical manifestations
of the disorder are not necessarily static.
PRIMARY/GENETIC SPASTICITY. A multitude of neurogenetic disorders masquerade

as various types of cerebral palsy, including leukodystrophies, neurotransmitter
disorders, neurometabolic disorders, and mitochondrial and genetic disorders.
As a rule, cerebral palsy is nonprogressive, and any child with progressive or
degenerative central nervous system symptoms requires further diagnostic
evaluation. Children with cerebral palsy should also have expected motor
symptoms and clear risk factors for the disorder, with neuroimaging supporting
the diagnosis. In any child with clinical signs and symptoms suggestive of
cerebral palsy but with absence of prenatal or perinatal risk factors or a normal
MRI, other possible diagnoses must be considered (TABLE 11-936). Metabolic or
genetic testing or both should be considered if neuroimaging reveals a
TABLE 11-8 Clinical Features of Spasticity, Dystonia, and Rigidity
Other
accompanying
Movement Muscle State examination
disorder Characteristics involvement Posture/positioning dependence findings
Spasticity Amplitude and Asymmetric Minimal fluctuation with Tone is similar Hyperreflexia
(pyramidal tract velocity involvement of change in position regardless of
Clonus
involvement) dependent; antagonist awake versus
examiner can muscles and asleep state
elicit “catch” on mainly affects
stretch antigravity
muscles
Dystonia Not dependent Opposing muscles Sustained and repetitive Improves or Normal reflexes
(extrapyramidal, on velocity (flexors and muscle contractions resolves in
Often
basal ganglia extensors) resulting in abnormal sleep
accompanied by
involvement) simultaneously posturing; may be
underlying
involved triggered by specific
hypotonia
positions, emotions,
pain, or stress
Rigidity Not dependent Opposing muscles Sustained increase of Can improve Common in
(extrapyramidal, on velocity (flexors and tone affecting both with sleep Parkinson
basal ganglia extensors) extensors and flexors disease and
involvement) simultaneously equally brain injury
involved
Typically very difficult to May have
stretch or test range of accompanying
motion of muscles; may tremor
feel like “lead pipe” or
“cogwheel”
1506 OCTOBER 2022

developmental malformation or imaging abnormality is isolated to the globus
pallidus or in the presence of any of the following: regression or new or
worsening symptoms, episodes of metabolic decompensation, no clear etiology, a
positive family history of “cerebral palsy,” a family history of consanguinity,
isolated hypotonia, evidence of rigidity, or paraplegia.31,37
SPASTICITY TREATMENT. Treatment of spasticity is multimodal, relying on

interdisciplinary care coordination between primary care, orthopedic surgery,
physical and occupational therapy, neurology, physical medicine and
rehabilitation, neurosurgery, and often other subspecialties such as
gastroenterology and pulmonology.
Oral medications such as baclofen, benzodiazepines, and trihexyphenidyl
can be used to treat spasticity that causes discomfort. Additional medications to
consider include tizanidine, dantrolene, and gabapentin. Although no
data support the efficacy of medical cannabis in cerebral palsy,38 many families
are using cannabidiol or cannabidiol with tetrahydrocannabinol supplements in
the hope of relieving spasticity; therefore, it is important to ask families about
use of any such supplements. Children with mild spasticity may not need any
medications for tone management during early childhood but may need
intervention as they grow and pursue more complex motor tasks.
Botulinum toxin injections for focal spasticity are approved by the US Food
and Drug Administration (FDA) for children 2 years old and older and may be
used in isolation or in conjunction with oral medications.39 Surgical interventions
for spasticity include intrathecal baclofen pump and selective dorsal
rhizotomy.40-42 Recognition of spasticity and distinction from dystonia and
rigidity is particularly important when considering possible etiologies as well as
appropriate therapeutic interventions for cerebral palsy. Some surgical
procedures targeting spasticity, such as selective dorsal rhizotomy, may actually
worsen a patient’s function if their dystonia is mistaken for spasticity. For
children with concurrent medication-refractory dystonia, DBS targeting the
globus pallidus internus can be considered.43 A care pathway for children with
cerebral palsy with dystonia has been published by the American Academy for
Cerebral Palsy and Developmental Medicine.44
Differential Diagnoses for Spastic Paraplegia in Childrena TABLE 11-9
◆ Diplegic cerebral palsy

◆ Structural (Chiari malformation, atlantoaxial subluxation)
◆ Hereditary spastic paraplegias
◆ Leukodystrophy
◆ Metabolic (eg, arginase deficiency, abetalipoproteinemia)
◆ Levodopa-responsive dystonia
◆ Infection (myelitis)
◆ Multiple sclerosis
a
Data from Salinas S, et al, Lancet Neurol.36

Parkinsonism
Parkinsonism in children is rare compared with other phenomenology but can be
a manifestation of many different disorders, including toxic exposure or genetic
or structural causes.45 As in adults, parkinsonism in children is characterized by
tremor, bradykinesia, akinesia, rigidity, and postural instability. Parkinsonism
typically reflects an underlying deficit in dopamine; thus, concurrent dystonia
may be present.46
Most commonly, acquired parkinsonism in children is secondary to use of
dopamine-blocking medications or other medications. The most common
autosomal recessive juvenile Parkinson disease is PARK2 disease, due to a
mutation in the parkin gene.47 Other childhood-onset degenerative disorders
associated with parkinsonism include Huntington disease, Rett syndrome,
neuronal intranuclear inclusion disease, pallido-pyramidal syndrome,
Kufor-Rakeb syndrome, PLA2G6-associated neurodegeneration with brain
iron accumulation, Fahr syndrome, pantothenate kinase–associated
neurodegeneration, Niemann-Pick disease type C, and juvenile neuronal ceroid
lipofuscinosis.48 Injury to the basal ganglia from stroke, tumor, hydrocephalus,
encephalitis, or postinfectious autoimmune or inflammatory processes may
manifest as parkinsonism or other movement disorders.
Parkinsonism in infants may be difficult to identify as such and should be
considered for any infant with hypotonia and reduced movement of
undetermined etiology. Parkinsonism can contribute to poor feeding and failure
to thrive. Monoamine neurotransmitter disorders are a heterogeneous group of
mostly autosomal recessively inherited neurologic disorders that typically
present as infantile-onset dystonia-parkinsonism.
Neurotransmitter disorders may result from (1) inability to synthesize
adequate or functional neurotransmitter molecules, (2) impaired
neurotransmitter transport, (3) mutations leading to difficulties with synthesis
of cofactors necessary for appropriate production of neurotransmitters, or (4)
inability to appropriately break down neurotransmitters. Examples of
primary neurotransmitter synthesis defects include deficiency in the enzyme
tyrosine hydroxylase or aromatic L-amino acid decarboxylase ultimately
resulting in insufficient production of dopamine, with profound consequences
for motor function and development. An example of defective monoamine
transport is dopamine transporter deficiency syndrome, in which dopamine
cannot be properly cleared from the synapse; this condition typically presents in
infancy as a hyperkinetic movement disorder with progression to severe
parkinsonism during early childhood. Tetrahydrobiopterin is a cofactor
necessary for monoamine synthesis; disorders such as sepiapterin reductase
deficiency or GTP cyclohydrolase 1 deficiency, an example of a dopamine-
responsive dystonia, impair production of this critical cofactor, resulting in
clinical movement disorders characterized by hypotonia, parkinsonism, and
dystonia. Neurotransmitter catabolism defects such as monoamine oxidase
deficiencies or dopamine β-hydroxylase deficiency may result in insufficient
breakdown of dopamine and impaired synthesis of norepinephrine and
epinephrine; as an example, monoamine oxidase deficiency typically
presents in boys with impaired attention, poor learning, and behavioral
problems and can be accompanied by autonomic symptoms such as flushing,
sweating, headaches, and diarrhea (reflective of deficiency of epinephrine
and norepinephrine).
1508 OCTOBER 2022

FUNCTIONAL MOVEMENT DISORDERS KEY POINTS
Functional movement disorders (previously referred to as conversion disorders,
● Key principles regarding
psychogenic movement disorders, or hysteria)49,50 are complex neurobehavioral the diagnosis of cerebral
disorders with poorly understood pathophysiology.51 These disorders may palsy are as follows: (1)
present in children of any age, although incidence is higher in the teen years.52,53 Cerebral palsy is a clinical
Children may present with features similar in appearance to any of the description and not an
etiology. (2) Cerebral palsy
phenomenologies previously discussed, but the disorders most commonly
is a permanent disability. (3)
involve tremor, dystonia, tics, or gait abnormalities.53,54 Although incidence is Cerebral palsy is a
similar between boys and girls at younger ages, there is a female preponderance nonprogressive brain
in adolescents.53,55 Historically, functional disorders were considered a “diagnosis process, but the physical
manifestations of the
of exclusion,” but a modern approach incorporates a balance between exercising
disorder are not necessarily
due diligence to rule out nonfunctional causes and recognizing key features that static.
support early diagnosis of a functional etiology. Early and accurate diagnosis
avoids excessive medical testing and treatment and delayed diagnosis and ● Botulinum toxin injections
enables implementation of appropriate interventions. The importance of for focal spasticity are
approved by the US Food
appropriate management of these diagnoses is further supported by data and Drug Administration for
demonstrating that positive prognostic indicators for a patient with a functional children 2 years old and
disorder include acceptance of the diagnosis by the patient and their caregivers older and may be used in
and identification and management of concurrent psychological stressors or isolation or in conjunction
with oral medications.
psychiatric disorders.51
Clues to a functional etiology include sudden onset with rapid progression of ● Recognition of spasticity
often severely abnormal movements that dramatically affect quality of life in a and distinction from
previously healthy child.55 Risk factors include unrecognized anxiety, unresolved dystonia and rigidity is
particularly important when
physical or psychological trauma, and other concurrent neurologic or psychiatric
considering possible
disorders. The neurologist plays an important role as the diagnostician and etiologies as well as
coordinator of a multidisciplinary intervention integrating psychology, appropriate therapeutic
psychiatry, and physical and occupational therapies as well as any additional interventions for cerebral
support services tailored to an individual’s recovery. palsy.
Periodically there have been events of mass sociogenic illness presenting as ● Some surgical procedures
functional movement disorders in children, such as psychogenic gait disorders targeting spasticity, such as
after H1N1 flu vaccination56 or sudden onset of ticlike movements in a group of selective dorsal rhizotomy,
students attending the same high school.57 Similarly, the incidence of functional may actually worsen a
patient’s function if their
tic disorders has noticeably increased in the setting of the current COVID-19 dystonia is mistaken for
pandemic, with many cases associated with social media use.58-60 The patients spasticity.
tend to be girls and young women in their teens and twenties with no prior history
of tic disorder who present with sudden, explosive onset of severely disabling ● Parkinsonism in infants
may be difficult to identify
ticlike behaviors, often including coprolalia and self-injurious behaviors (features
as such and should be
that are rare in children with tic disorders or Tourette syndrome).59 Patients may considered for any infant
share videos of their symptoms on social media sites, leading to increased with hypotonia and reduced
attention and feedback contributing to the persistence of their symptoms. movement of undetermined
etiology.
RARE BUT TREATABLE NEUROMETABOLIC MOVEMENT DISORDERS ● Early and accurate

NOT TO MISS diagnosis of functional
Although many pathologic pediatric movement disorders are not curable, movement disorders avoids
several treatable childhood neurometabolic disorders exist, which should not excessive medical testing
and treatment and delayed
be missed. Efficient and accurate diagnosis of these disorders is essential to diagnosis and enables
timely initiation of appropriate treatment. A detailed review of all neurometabolic implementation of
diseases manifesting as movement disorders is outside the scope of this article, appropriate interventions.
but key examples that are treatable and appear during childhood are summarized
in TABLE 11-10.

TABLE 11-10 Treatable Neurometabolic Disorders With Prominent Movement Disorder

Presenting in Infancy or Childhood
Movement examination
Diagnosis Presentation findings Diagnosis Treatment
Dopamine- Often presents with Typically starts with Rapid and remarkable Low-dose levodopa/
responsive dystonia gait abnormality due bilateral lower extremity response to low doses carbidopa
(also DYT5 or Segawa to lower extremity dystonia with of levodopa
disease) dystonia; may be progression to
Brain MRI: typically
mistaken for cerebral generalized dystonia
unrevealing
palsy or spastic
Diurnal fluctuation:
diplegia CSF: low neopterin,
symptoms worsen in
tetrabiopterin, and
afternoon and improve
homovanillic acid (HVA)
in morning and after
sleep Autosomal dominant
mutation in GTP
cyclohydrolase (GCH1)
6-Pyruvoyl- Progressive Hypotonia with Hyperphenylalanine on Replace

tetrahydropterin neurologic appendicular blood spot tetrahydrobiopterin
synthase deficiency deterioration hypertonia, hypokinesia,
Reduced biopterin and Provide
rigidity, chorea,
May deteriorate after elevated neopterin in neurotransmitter
dystonia, oculogyric
administration of urine precursors (levodopa
crises; diurnal
folate antagonists and serotonin)
fluctuation
Monoamine oxidase
inhibitors (MAOIs)
Sepiapterin Cerebral palsy–like Hypotonia, dystonia, CSF: low HVA and Provide
reductase deficiency picture with diurnal oculogyric crisis, 5-hydroxyindoleacetic neurotransmitter
fluctuation: parkinsonism acid (5-HIAA) with precursors (levodopa
oculogyric crisis elevated total biopterin, and serotonin)
(episodic dystonic dihydrobiopterin, and
Often dramatic
upgaze), paroxysmal sepiapterin
response to levodopa
stiffening and
hypotonia in infancy
Dihydropteridine Defect of Bulbar dysfunction, CSF: low HVA, 5-HIAA, Provide

reductase deficiency tetrahydrobiopterin dyskinesia, tremor, folate, elevated neurotransmitter
regeneration dystonia, chorea dihydrobioptin, raised or precursors (levodopa
normal biopterin levels and serotonin)
Feeding difficulty in
infancy with Folinic acid
hypersalivation,
microcephaly, delay,
but may be
asymptomatic
Tyrosine hydroxylase Type A: progressive Hypotonia, CSF: low HVA, normal Levodopa
deficiency extrapyramidal parkinsonism, dystonia, 5-HIAA, reduced ratio
movement disorder rigidity, diurnal HVA: 5-HIAA
with hypokinetic rigid variability
syndrome and
dystonia
Type B: complex
neonatal/infantile
encephalopathy
1510 OCTOBER 2022

Aromatic L-amino Hypotonia with Hypotonia, oculogyric CSF: low HVA, 5-HIAA, Gene therapy trials
acid decarboxylase oculogyric crises and crises, hypokinesia, 3-methoxy-4- ongoing
deficiency developmental failure chorea, dystonia hydroxyphenlyglycol
with raised
5-hydroxytryptophan,
L-dopa, and 3-O-
methyldopa
Low to absent plasma
aromatic L-amino acid
decarboxylase activity
Elevated urine
catecholamines
Brain dopamine- Developmental delay, Hypotonia, oculogyric Brain MRI: normal Pramipexole (chorea
serotonin vesicular hypotonia, sleep crises, parkinsonism, and dystonia worsen
CSF neurotransmitters
transport disease disturbance, tremor, focal on levodopa)
normal
autonomic dyskinesias
dysfunction Low urine dopamine and
norepinephrine
Elevated HVA and 5-HIAA
Dopamine Infant with hypotonia, Hypotonia, dyskinesia, Elevated CSF HVA Limited response to
transporter irritability, feeding progressive dystonia dopamine agonists
deficiency syndrome difficulty and dyskinesia with eye
involvement
GLUT1 deficiency Classically infantile Hypotonia, spasticity, Low CSF glucose Ketogenic diet
seizures, ataxia, dystonia
Low CSF-to–blood
encephalopathy,
glucose ratio
acquired
microcephaly
Cerebral folate Variable Identify cerebral folate High-dose folinic acid

deficiency presentation: receptor alpha (FRα)
antibodies
(1) Infantile onset: (1) Hypotonia, ataxia,
4-6 mo irritability/ pyramidal signs, Brain MRI: may be
insomnia, deceleration dyskinesias normal or may show
of head growth, frontotemporal atrophy,
developmental delay/ delayed myelination,
regression, epilepsy periventricular and
subcortical
(2) Spastic-ataxic (2) Spasticity, ataxia
demyelination
syndrome beginning
after age 1 y
(3) Autism (3) With or without
deficits seen in
infantile-onset group
(4) Dystonia/ (4) Dystonia
pyramidal syndrome

CONTINUED
PAGE 1511
Pyruvate Neurodevelopmental Brain MRI: bilaterally Treat acidosis

dehydrogenase delay, hypotonia, symmetric lesions in
Ketogenic diet
complex deficiency dystonia, episodic basal ganglia, thalamus,
peripheral weakness, brainstem Thiamine
ataxia, spasticity,
Elevated plasma and Dichloroacetate
cerebellar
urine lactate and (inhibitor of pyruvate
degeneration, seizures,
pyruvate dehydrogenase
intellectual disability
kinases and activator
of pyruvate
dehydrogenase)
Biotin-responsive Variable onset, Ataxia, dystonia, Brain MRI: abnormal Thiamine and biotin
basal ganglia disease typically between 3 dysarthria, pyramidal signal intensity in treatment
and 4 y signs caudate and putamen
Fever-triggered Diffuse involvement of
subacute cortical and subcortical
encephalopathy with white matter
seizures and ataxia
Ataxia with vitamin E Progressive sensory Generalized ataxia, Low plasma vitamin E Lifelong oral vitamin E
deficiency (AVED) ataxia hyporeflexia, weakness, supplementation
strabismus, dementia,
cardiac arrhythmias
May have dystonia,
myoclonus
Hypermanganesemia Generalized dystonia Dystonia Increased serum Early treatment with

in childhood/ manganese, repeat IV chelator
adolescence, polycythemia, low (edetate calcium
parkinsonism in ferritin disodium) infusion to
adulthood increase urinary
Hepatic cirrhosis
excretion of
Brain MRI: manganese
hyperintensities in basal
ganglia
Wilson disease Aged 8-12 y with Generalized rigidity, Low serum Copper chelation
isolated hepatic faciolinguopharyngeal ceruloplasmin and with D-penicillamine,
disorder rigidity, gross postural serum copper trientine, zinc
or intention tremor,
Neurologic symptoms Excess urinary copper
behavioral/cognitive
typically absent
changes ATP7B mutation
before age 7-10 y
Kayser-Fleischer rings
CSF = cerebrospinal fluid; IV = intravenous; MRI = magnetic resonance imaging.
1512 OCTOBER 2022

Clues to a possible underlying undiagnosed neurometabolic disorder KEY POINTS
contributing to the clinical presentation of a pediatric movement disorder
● Diurnal fluctuation of
include (1) diurnal fluctuation of disordered movement such as dystonia (such as symptoms may point to an
dopamine-responsive dystonia [also known as DYT5 and Segawa syndrome], or underlying neurometabolic
unrecognized sepiapterin reductase deficiency in a child presumed to have disorder.
cerebral palsy); (2) progression of symptom severity or accumulation of new
● Potentially
symptoms over time (such as is seen with cerebral folate deficiency); (3) clinical
life-threatening drug-
signs or symptoms suggestive of a specific neurotransmitter deficiency (such as induced movement
oculogyric crises with hypotonia and dystonia as seen in aromatic L-amino acid disorders include acute
decarboxylase deficiency); and (4) absence of history or other risk factors to dystonic reaction,
support a diagnosis such as cerebral palsy or autism. The neurologist should neuroleptic malignant
syndrome, and serotonin
pursue additional diagnostic evaluation for any child in whom a neurometabolic syndrome.
disorder is suspected.
● It is prudent to consider
PEDIATRIC MOVEMENT DISORDER EMERGENCIES referral for pediatric deep
brain stimulation for any
There are several pediatric movement disorder emergencies that a neurologist child with medication-
should be able to recognize and treat. A full review of movement disorder refractory dystonia, chorea,
emergencies was published by Kipps and colleagues.61 or tremor.
Drug-Induced Movement Disorders

The increased use of psychotropic and stimulant medications in children has
contributed to an increased incidence of drug-induced movement disorders in
this population.62 Additionally, young children are at high risk of accidental
ingestion of medications and other substances that may trigger abnormal
movements manifesting as chorea, dystonia (status dystonicus), parkinsonism
(hypokinetic/rigid syndrome), tremor, ataxia, myoclonus, akathisia,
stereotypies, tics, or dyskinesias. Such drug-induced movement disorders may
be acute or more insidious and can be caused by a wide array of substances. Key
clues to a drug-induced movement disorder are rapid onset of new severe
symptoms, temporal association with medication administration or recent
introduction of new medication, and known use or presence in the household of
a dopamine-blocking agent or stimulant medication (including many asthma
medications). Potentially life-threatening drug-induced movement disorders
include acute dystonic reaction, neuroleptic malignant syndrome, and serotonin
syndrome. A common presentation of drug-induced movement disorders is
ataxia in a young child due to accidental ingestion. Rapid recognition of the
adverse reaction with identification and immediate cessation of the offending
agent is essential. In the case of any acute drug-induced movement disorder,
careful monitoring of vital signs and respiratory drive is indicated. Acute
dystonic reactions are treated with anticholinergic medications
(diphenhydramine or benztropine) with or without benzodiazepines.63
Baclofen Withdrawal
Baclofen withdrawal is a potentially life-threatening movement disorder
emergency. Patients can present with a broad continuum of symptoms with
worsened spasticity, irritability or agitation, rigidity, dystonia (status
dystonicus), seizures, hypertension or hypotension with shock, tachycardia,
hyperthermia, altered mental status, hallucinations, and psychosis. In severe
cases, symptoms can proceed to rhabdomyolysis with subsequent cardiac and
renal injury, disseminated intravascular coagulation, multisystem organ

injury and failure, and death. Withdrawal can occur with sudden cessation of
oral or intrathecal baclofen or after recent decrease in dosing, unrecognized
empty baclofen pump, baclofen pump failure, or unintentionally turning a
baclofen pump off. Treatment includes immediate administration of baclofen
and/or oral or IV benzodiazepines in addition to supportive care (TABLE 11-11).
FUNCTIONAL NEUROSURGERY FOR PEDIATRIC MOVEMENT

DISORDERS
DBS is an increasingly available treatment for pediatric movement disorders
including chorea, dystonia, and tremor, and is an emerging treatment for
TABLE 11-11 Key Features of Pediatric Movement Disorder Emergenciesa
Presentation Examination findings Treatment
Acute Hyperacute onset of new Often involves dystonic contractions Mechanism: thought due to
dystonic dystonia typically shortly after of the face/neck but can be imbalance of dopamine and
reaction administration of offending segmental or generalized acetylcholine (ie, acetylcholine
agent overload)
Patient is often very anxious and
Typically in response to distressed Treatment: cessation of
offending dopamine receptor triggering agent
blocking agent (most commonly
First line: anticholinergics (ie,
antipsychotics and antiemetics,
diphenhydramine, benztropine)
but can be provoked by a long
Second line: benzodiazepine
list of various medications, eg,
antimalarial, antidepressants, Treat acute anxiety
antihistamines, anticonvulsants)
Status Persistent generalized dystonia Hypertension, tachycardia, Eliminate triggers including

dystonicus that is not responding to tachypnea, hyperthermia possible infection, pain (eg, from
medications, requiring constipation, irritation from
Generalized dystonia; often very rigid,
emergency treatment or feeding tube, skin breakdown,
irritable
hospitalization eye irritation, positioning, poorly
fitting orthotics or wheelchair)
Sometimes triggered by
concurrent illness, medication May require high-dose
changes benzodiazepines
May present with concurrent Provide pain control
respiratory distress
Aggressive hydration
Monitor closely for
rhabdomyolysis
Consider emergent pallidal
deep brain stimulation (DBS),
baclofen pump, pallidotomy for
medication-refractory cases
1514 OCTOBER 2022

medication-refractory severe tics. Just as referral for epilepsy surgery is
considered best practice for a child with medication-refractory epilepsy after a
trial of two antiseizure medications, it is prudent to consider referral for pediatric
DBS for a child with medication-refractory dystonia, chorea, or tremor.
Historically, DBS was reserved for children with primary dystonia; however,
therapeutic applications have broadened, and DBS can be effective for
secondary dystonia. Several anatomic targets for DBS for dystonia have been
described in the literature, the most common being the globus pallidus internus.
Targeted pallidotomy may also be considered in a child with severe dystonia who
cannot tolerate DBS.
Presentation Examination findings Treatment
Neuroleptic Acute to subacute onset of Hypertension, tachycardia, Eliminate cause

malignant diffuse rigidity with vital sign tachypnea, hyperthermia,
Dopaminergic agents
syndrome changes and examination hypersalivation, diaphoresis, pallor
findings as noted Dantrolene
Altered mental status (range from
Precipitated by dopamine alert with agitation to coma)
antagonists
Classic diffuse generalized
“lead-pipe” rigidity
Hyporeflexia
Serotonin Acute onset of agitation with Hypertension, tachycardia, Eliminate trigger

syndrome clonus and hyperreflexia as well tachypnea, hyperthermia, diaphoresis
Administration of serotonin
as examination findings as noted
Altered mental status (range from antagonists
Precipitated by serotonergic alert with or without agitation to coma)
agents
Dilated pupils
Hyperactive bowel sounds
Generalized hypertonia
Hyperreflexia, clonus
Baclofen Worsening hypertonia over hours Worsened spasticity with or without Emergent administration of
withdrawal to days in setting of sudden rigidity with or without dystonia baclofen
decrease in baclofen dosing or (status dystonicus)
Benzodiazepines, propofol,
abrupt cessation of baclofen use
Hypertension or hypotension with tizanidine, and other muscle
shock relaxants can also be
Tachycardia considered
Hyperthermia
Altered mental status: irritability/
agitation, seizures, hallucinations,
psychosis
Severe cases:
Rhabdomyolysis, disseminated
intravascular coagulation, multisystem
organ failure, death
a
For any of the emergency situations in this table, the first priority in treatment is ensuring a secure airway and managing vital signs.

CONCLUSION
This article focused on identifying key phenomenology of benign and pathologic
movement disorders in children. Following are key principles to remember in
assessing children for abnormal movement:
1 Children can present with a broad spectrum of abnormal movements, most of which are
benign. Recognizing benign movements in children is just as important as recognizing
pathologic movement.
2 Although children are not just “little adults,” they share many features in common with
adults when it comes to movement disorder phenomenology.
3 Children are more likely than adults to present with a mixed movement disorder.
Recognizing similarities and key differences in movement disorder phenomenology
between children and adults and understanding how those phenomenologies present at
various stages of development can help the clinician better categorize and treat abnormal
movements in children.
4 If a child has a neurologic condition, they are highly likely to also have some abnormal
movement on examination. Knowing when to treat versus when to reassure is an important
balance to strike.
5 Appropriate diagnosis and treatment of movement disorders in children can have a major
impact on development, learning, and quality of life, even for children with incurable
neurologic disorders.
VIDEO LEGENDS
VIDEO 11-1 VIDEO 11-2
Sydenham chorea. Video shows the 5-year-old boy Dystonia. Video demonstrates the clinical course of
from CASE 11-1 with a complicated medical history the 11-year-old boy from CASE 11-2 with progressive
who presented with acute generalized chorea generalized dystonia before and after pallidal deep
consistent with Sydenham chorea. Examination brain stimulation.
findings are shown on the video at the time of initial
presentation and after steroid treatment.
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REVIEW ARTICLE

Palliative Care and
ONLINE
Movement Disorders
By Maya Katz, MD
ABSTRACT
PURPOSE OF REVIEW: This article reviews the role of palliative care in the treatment
of patients with life-limiting neurodegenerative movement disorders.
RECENT FINDINGS: Growing evidence indicates that palliative care significantly

improves quality of life and symptom burden for people with Parkinson
disease and other serious movement disorders, while reducing caregiver
burnout. An emphasis on advance care planning guides goal-directed
treatment recommendations. Serious illness communication skills are
evidence-based methods of relaying bad medical news to patients and
mapping out values and goals in a way that provides comfort, emphasizes
patient autonomy, and builds coping and resiliency strategies.
SUMMARY: Palliative care, when offered alongside primary medical and

neurologic teams, provides an extra layer of support for people with
serious illnesses. The goal of palliative care is to intensively treat
total pain, which includes all of the physical, emotional, social, and
spiritual distress caused by serious illness. Serious illness communication
skills are key to providing empathic and goal-concordant care.
CITE AS:
CONTINUUM (MINNEAP MINN) INTRODUCTION
P
2022;28(5, MOVEMENT DISORDERS): alliative care is a medical specialty focused on caring for patients and
1520–1529.
caregivers affected by serious, life-limiting illness. Palliative care
offers a comprehensive approach to health and well-being by focusing
Dr Maya Katz, Stanford on aggressive treatment of the total pain caused by serious illness.
Neuroscience Health Center, Total pain is a key concept in palliative care and is defined as all of the
213 Quarry Rd, First Floor, Palo
Alto, CA 94304, mak2036@
physical, emotional, social, and spiritual distress caused by serious illness.1
stanford.edu. Parkinson disease (PD), dementia with Lewy bodies (DLB), Huntington disease,
and other serious movement disorders carry a tremendous total pain symptom
Dr Katz has received research burden. Evidence increasingly shows benefits of palliative care in the treatment
support from the National of these neurodegenerative disorders.2
Institutes of Health
This article reviews the role of palliative care in improving quality of life for
(1R01NR016037-01A1).
people with life-limiting neurodegenerative movement disorders. Serious illness
UNLABELED USE OF communication approaches related to palliative care are evidence-based methods
USE DISCLOSURE:
of giving bad medical news and carrying out advance care planning discussions
Dr Katz reports no disclosures. in a way that provides comfort and space for difficult emotions, increases
patient/caregiver coping and resiliency skills, and guides goal-concordant
© 2022 American Academy treatment recommendations. This article also discusses reducing burnout in
of Neurology. clinicians who provide palliative care.
1520 OCTOBER 2022

PALLIATIVE CARE NEEDS IN MOVEMENT DISORDERS KEY POINTS
The total symptom burden measured in patients with PD has been found to be
● Palliative care is
similar to the total symptom burden reported in patients with metastatic cancer specialized medical care for
and amyotrophic lateral sclerosis.3 Neurodegenerative movement disorders not people with serious,
only cause suffering by limiting functional independence because of mobility life-limiting illness.
impairment, but they also often cause significant nonmotor symptoms, including
● Total pain is a key
positional syncope, bowel and bladder dysfunction, mood disorders, insomnia,
concept in palliative care
and fatigue.4 The nonmotor symptoms often impair quality of life more than the that is defined as all of the
motor symptoms.5 physical, emotional, social,
Psychosis, dementia, and changes in personality and behavior are common in and spiritual distress caused
patients with neurodegenerative movement disorders and can challenge an by serious illness.
individual’s sense of self, further contributing to isolation. Changes in family ● The total symptom
roles, progressive loss of independence, and financial strain are a few examples of burden measured in
the kinds of severe emotional and psychosocial distress often caused by these Parkinson disease has been
disorders. Spiritual distress typically includes demoralization, grief, guilt, found to be similar to the
total symptom burden
isolation, existential distress, and death anxiety. Spiritual well-being was shown reported in metastatic
to be associated with a better quality of life, less anxiety and depression, and less cancer and amyotrophic
prolonged grief.6 Caregivers experience high rates of burnout as well as chronic lateral sclerosis.
grief and anticipatory grief.7,8 Evidence shows that nonmotor symptoms in PD
● Caregivers often
and atypical parkinsonian syndromes are undertreated.9,10 Palliative care
experience serious
emphasizes aggressive and intensive symptom management. The typical adjustment reactions,
palliative care team includes a palliative care physician, nurse, social worker, and burnout, chronic grief, and
chaplain who work together to identify and treat total pain. anticipatory grief.
A 2020 randomized clinical trial found that palliative care significantly
● Growing evidence shows
improves quality of life and symptom burden for people with PD and other that palliative care
serious movement disorders, while reducing caregiver burnout and improving significantly improves
advance care planning.2 The most significant benefit of palliative care was found quality of life and symptom
to be in symptom control. This study found that parkinsonian motor symptoms burden for people with
Parkinson disease and other
also improved in the palliative care arm without any significant change in serious movement
dopaminergic medications.2 Symptom burden significantly increases in the most disorders, while reducing
advanced stages of neurodegenerative movement disorders, and the benefits of caregiver burnout and
palliative care have been found to be greater in individuals with more advanced improving advance care
planning.
disease, although those with mild to moderate disease have also received
significant benefits with palliative care. ● Palliative care is
Palliative care is often equated to end-of-life care because it grew out of the applicable at all stages of
hospice movement, but according to the World Health Organization, palliative serious illness and in
care is “applicable early in the course of illness, in conjunction with other conjunction with other
treatments that are focused
therapies.”11 Earlier palliative care has even been shown to extend survival.12 on prolonging life.
Palliative care interventions can be used at the time of diagnosis to reduce the
intensity of an adjustment reaction by providing comfort for the difficult emotions
that will arise and by supporting coping and resiliency strategies. Palliative care
acts as an extra layer of support alongside the primary medical and neurologic team.
SERIOUS ILLNESS COMMUNICATION SKILLS

Communication between clinicians and those affected by serious illness is a part
of palliative care treatment. Serious illness communication approaches related to
palliative care are evidence-based, teachable techniques that enable clinicians to
break bad medical news and discuss advance care planning in a way that provides
comfort, improves patient and caregiver coping, and guides the delivery of
goal-concordant care.13

PALLIATIVE CARE AND MOVEMENT DISORDERS
The SPIKES (setting, perception, invitation, knowledge, emotions, strategy)

protocol is a common palliative care communication method for delivering a
serious illness diagnosis.14 Skillful disclosure of PD, Huntington disease, or
another serious movement disorder diagnosis allows patients and caregivers to
brace for serious medical news, while validating and supporting difficult
emotions that arise. Patients and caregivers are not able to fully absorb or engage
in discussions about treatment strategies if these conversations are started
when they are still flooded with emotions after receiving bad medical news
(TABLE 12-1).
Qualitative research indicates that advance care planning is important to
patients and caregivers affected by neurodegenerative movement disorders.15
For example, many caregivers of patients with DLB report that clinicians did not
give them the information they needed to be prepared for caring for their loved
one in the advanced stages of illness.14 Furthermore, anticipatory guidance
reduces the risk of complicated grief in caregivers during bereavement.16
TABLE 12-1 SPIKES Protocol
Term Definition Communication examples
Setting Establish an appropriate setting Minimize disruptions, have easy access to tissues
Perception Establish the patient’s and caregiver’s Ask questions such as:
perception of their symptoms and health status
“Can you give me a sense of what you think might be
causing your symptoms?”
“Have other doctors suggested a diagnosis, or have

you read anything online that pointed you in one
direction or another? It helps me to know where you’re
coming from.”
Invitation Obtain permission from the patient and Ask questions such as:
caregiver to provide the difficult medical news
“Would it be okay if I gave you my thoughts on where
things are with your illness?”
Assess how much information about the illness is

desired. Ask questions such as:
“Would it be okay for me to share my thoughts on

what’s causing your symptoms?
Knowledge Give a warning shot to allow the “I have difficult news”

patient/caregiver to brace for bad news
Deliver the serious illness diagnosis in a bite-size chunk
Example: “Your symptoms and examination are most

consistent with Parkinson disease,” then pause to
allow time for the patient and caregiver to process the
distressing information
Emotions Expect and validate the difficult emotions “That’s so difficult to hear. How are you doing with
that will arise after hearing bad medical that information?”
news with empathic communication
Strategy Develop a strategy for the future “Let’s focus on helping you live as well as you can for
as long as you can.”
1522 OCTOBER 2022

A myth in the medical field is that clinicians need to shield patients and KEY POINTS
caregivers from how serious a situation is or they will lose hope. Research
● Palliative care serious
indicates the opposite. Even one 20-minute advance care planning conversation illness communication skills
has been shown to reduce patient anxiety and depression.17 False hope from a are evidence-based
lack of clear communication about prognosis wastes valuable time. By using teachable techniques that
palliative care serious illness communication techniques for advance care enable clinicians to break
bad medical news and
planning discussions, such as the VitalTalk REMAP (reframe, expect emotion,
discuss advance care
map out, align, and plan) protocol, clinicians learn to help patients map out planning in a way that
values and priorities in the setting of receiving bad medical news.18 These provides comfort, improves
identified goals of care guide treatment recommendations, which creates space patient and caregiver
coping, and guides
for real hope (CASE 12-1).
treatment
The VitalTalk REMAP protocol is primarily used when there has been a recommendations.
significant worsening of the serious illness (TABLE 12-2). Role-playing these
discussions has been shown to be a highly effective method for learning these ● The SPIKES protocol is a
techniques, since it allows clinicians to practice these skills in small groups with palliative care
communication technique
simulated patients as they are guided by a specialist in serious illness used when giving a serious
communication.13 illness diagnosis. SPIKES
stands for setting,
PALLIATIVE CARE AND ETHICS perception, invitation,
knowledge, emotions, and
Palliative care emphasizes patient autonomy by exploring preferences for serious strategy.
illness communication. Anticipatory guidance is provided based on those
preferences. Goals of care are then identified so that treatments can be ● The REMAP protocol is a
recommended that are in line with patient values and priorities. This avoids the palliative care
communication technique
default medical care pathway that often leads to futile, unwanted, and expensive
developed by VitalTalk that
care.22About 25% of all of Medicare’s annual budget is spent covering the cost of is used when there is
care in the last 12 months of life,23 and much of this care is likely medically futile. significant worsening of the
A survey of critical care physicians working in five medical intensive care units serious illness. REMAP
reported giving 8.6% of patients probable futile care, and 11% of patients stands for reframe, expect
emotion, map out, align, and
received futile care over a 3-month period.24 plan.
Studies have shown that most people with PD and other serious neurologic
disorders want advance care planning early in the course of their illness to ● The high rates of
help plan and prepare for the future.15 The high rates of dementia and dementia and
communication difficulties
communication difficulties due to neurodegenerative movement disorders that occur owing to
make discussing advance care planning early in the course of the illness neurodegenerative
critical. movement disorders makes
Most people with PD and other serious illnesses have reported a preference to discussing advance care
planning early in the course
receive end-of-life care in familiar surroundings at home.25 Despite this, the
of the illness critical.
majority of people with PD in the United States die either in the hospital or
nursing home.26 A person with PD is more likely to die in a hospital than is a ● A documented advance
person from the general population.19 Only a minority of people dying with PD care plan increases the
receive hospice care. One multinational study of place of death of people with PD likelihood of dying at home
with hospice in a population
using death certificate data from 2008 showed that in New Zealand, no people of people with Parkinson
with PD died with hospice services, and in the United States, only 4% of people disease, and movement
with PD died with hospice services.26 In patients with PD, having a documented disorders palliative care
advance care plan increases the likelihood of dying at home with hospice, and clinics have been shown to
increase advance care
movement disorders palliative care clinics have been shown to increase advance planning.
care planning.25 The majority of people with PD who die in the hospital have been
found to have no documented discussion of advance care planning. For example,
one study found that 97% of people with PD who died in the hospital had no
documented discussion of advance care planning.27

Unfortunately, many older adults get caught in a cycle of being “rehabbed to

death,”28 where they move continuously between the hospital and the skilled
nursing facility/nursing home without interventions to understand individual
goals of care. The Medicare payment structure supports this cycle.
Since palliative care is a relatively new medical specialty, its integration into
neurology has been limited. Given the limited number of neuropalliative care
clinics worldwide and the impaired mobility seen in patients with movement
disorders, telemedicine is an emerging delivery method that increases access to
neuropalliative care29 and will hopefully continue to be covered by Medicare
CASE 12-1 A 55-year-old woman with a 9-year history of advanced multiple system
atrophy with predominant parkinsonism (MSA-P) presented to the
neuropalliative care clinic for an initial visit. She used a wheelchair,
reported severe fatigue, and was dependent for all activities of daily
living. Over the past year, she had experienced significant unintended
weight loss (30% over the past 6 months, with a body mass index of 17,
medically malnourished). In addition, she had been hospitalized twice in
the past year for aspiration pneumonia and sepsis. Her spouse, son, and
daughter were also at the visit. Cachexia, frailty, and temporal wasting
were identified on examination.
During the advance care planning discussion, the neuropalliative care
team asked her what she hoped for most when she looked to the future.
Her reply was that she was most looking forward to her son’s wedding,
which was planned for the following summer, about 15 months away. The
neuropalliative care doctor used the VitalTalk REMAP protocol to inform
the patient and her family that her life expectancy was unfortunately
likely 6 months or less.19-21 The patient’s and her family’s preferences for
receiving serious illness information were assessed by the clinician
before providing the difficult medical news in a way that was in line with
each person’s identified preferences. The patient was started on hospice
(she met criteria for the Medicare hospice benefit based on failure to
thrive).
After hearing about his mother’s predicted short life expectancy, her
son moved up his wedding to the next month, and she was able to attend.
She died in hospice care about 3 months later. Her family had pictures of
her at the wedding displayed at her memorial service.
COMMENT Mapping out values, hopes, and priorities is a critical step in advance care
planning and includes an exploration of a patient’s fears and worries as
they look ahead in addition to eliciting values, hopes, goals, and priorities
for the future. This conversation needs to be done after the patient’s
understanding of their illness is reviewed and accurate prognostic
information is provided (in a way that is in line with each person’s
preferences for receiving serious illness information). This allows patients
and families to plan ahead and to be more likely to reach their hopes and
goals.
1524 OCTOBER 2022

even after the end of the COVID-19 pandemic. Ultimately, neurologists who treat
people with serious neurologic disease will need to acquire primary
neuropalliative care skills to optimize access to palliative care for these patients
and caregivers.
Finally, neurologists who treat people with neurodegenerative movement
disorders and other serious and life-limiting neurologic conditions may receive
requests from some of their patients for medical-aid-in-dying medications. To be
eligible in the 10 US states where medical aid in dying is allowed, individuals
must have a diagnosis that is incurable and irreversible that will, within
reasonable medical judgment, result in death within 6 months. Eligible
individuals must be able to make medical decisions for themselves, which
excludes those with dementia and significant mental health issues. These
requests are not usually disclosures of suicidal ideation. In fact, suicidal ideation
REMAP Protocol TABLE 12-2
Term Communication examples

Reframe ASK:
Confirm a shared understanding of the current prognosis by exploring the patient’s and caregiver’s
perception of the current illness trajectory. Example: “How do you think your health is now compared with
1 year ago?”
ASK:
Obtain an invitation to share your clinical opinion. Example: “Would it be okay if I shared my sense of
where you are in the course of your disease?”
TELL:
Give the bad medical news in a small bite-size chunk with a warning shot and a short headline with the
main message, then pause.
Example: “I’m worried that we’re in a different place now with your disease, and time is much shorter than
we hoped.”
ASK:
Check in with the patient/caregiver about their response to the difficult news.
Example: “How are you doing with this information?”
Expect emotion Expect difficult emotions to arise and take time to provide validation and comfort.
Example: “I can’t imagine how difficult this is to hear for you.”
Map out Identify two to three big picture values and goals.
Example: “When you look ahead, what are you hoping for?”
Align Align with the patient’s goals of care.
Example: “From what I understand, maintaining your independence and being pain free are top priorities.”
Plan Recommend treatment plans that are based in the patient’s goals and values. Remind the patient and
caregiver that this is an ongoing conversation.
Example: “Let’s make a treatment plan that focuses on these goals. Remember this is an ongoing
conversation so that I can help you live as well as you can.”

would make the individual ineligible to receive the medical-aid-in-dying

medications. In response to this changing legal landscape around
physician-hastened death, in 2018,30 the American Academy of Neurology
revised its previous position statement, published in 1998,31 which had strongly
opposed physician participation in both physician-assisted suicide (prescription
of medication without physician administration) and euthanasia (prescription of
medication with physician administration). The revised position statement still
prohibits euthanasia but permits physician-hastened death in jurisdictions where
the practice is legal. The revised position statement does not obligate physicians
to participate in physician-hastened death if they oppose the practice and does
not obligate physicians to refer patients requesting aid in dying to practitioners
who participate in the practice.
Requests for the medical-aid-in-dying medications are most commonly
because of loss of autonomy or intractable suffering.32 After a patient makes a
request for the medical-aid-in-dying medication, the clinician’s first step is to
acknowledge and validate the difficult emotions expected with such a request.
Providing comfort and allowing space for difficult conversations related to goals
of care has been shown to reduce the severity of adjustment reactions in patients
with PD and related disorders.2 In addition, advance care planning discussions
have been shown to reduce the risk of complicated grief in caregivers of recently
placed nursing home residents.16 Second, clinicians should assess what is leading
the patient to make this request at that specific visit. The clinician needs to make
sure that a treatable cause of the patient’s suffering is not driving their request;
examples include depression or treatable pain.
REDUCING BURNOUT FOR THE CLINICIAN CAREGIVER

Palliative care stems from the hospice movement, which has made preventing
clinician burnout a top priority for more than 60 years. In palliative care,
clinicians are a type of caregiver, and they have a high risk of caregiver burnout.
Clinician burnout is a response to chronic interpersonal stressors in the
workplace and includes emotional exhaustion, feelings of cynicism and
desensitization or depersonalization toward work, and a sense of lack of personal
achievement or effectiveness.
Neurology has one of the highest rates of burnout compared with other
medical specialties,33 with the majority of neurology attendings in both clinical
and academic practices (about 60%),34 neurology residents (73%),35 and
neurology fellows (55%) reporting at least one symptom of burnout.
To reduce the risk of clinician burnout, palliative care creates a culture that
encourages clinicians to develop a balanced lifestyle and a regular self-care
practice. Professional time is dedicated to building resiliency skills. The main
concept in palliative care is that a clinician cannot provide high-quality medical
care if they are experiencing burnout. Preventing clinician burnout is therefore
essential to the core mission of providing high-quality care.36 System-level
interventions need to enable and support this goal.
TRENDS
Palliative care carries a negative cultural stigma given its strong association with
hospice and end-of-life care. Studies have shown a better adoption of “supportive
care” compared with “palliative care” among nonpalliative clinicians, with
clinicians more likely to refer a patient with serious illness to a “supportive care
1526 OCTOBER 2022

clinic” compared with a “palliative care clinic,” even when the services offered KEY POINTS
by the clinics are the same. Patients and caregivers are also much more likely to
● Requests for medical-
accept a referral to a “supportive care clinic” and reject a referral to a “palliative aid-in-dying medications are
care clinic,” even when the services described in each clinic are the same.37 typically a cry for help due
The stigma surrounding the word “palliative” deters clinicians from to unbearable symptoms
recommending the treatment and deters patients and caregivers from accepting from a serious illness and are
not usually disclosures of
the care. Awareness of this stigma has led the neuropalliative care clinics at the
suicidal ideation.
University of Rochester; University of California, San Francisco; and Stanford
University to call themselves neuro-supportive care clinics. ● Palliative care considers
clinicians to also be
caregivers, with a high risk of
caregiver burnout. Palliative
CONCLUSION care makes preventing
Palliative care emphasizes a holistic approach, patient autonomy, aggressive clinician burnout a top
symptom management of total pain, concern for the family, and clinical priority by placing
teamwork to provide goal-concordant care that focuses on optimizing quality of importance on developing a
balanced lifestyle, building
life for people dealing with serious, life-limiting illness. Growing evidence shows coping and resiliency skills,
that palliative care significantly improves quality of life and symptom burden for and developing systems-
people with neurologic movement disorders and their caregivers, while level improvements.
improving advance care planning to deliver goal-concordant care. Palliative care
● The stigma surrounding
has also been shown to reduce health care costs. Unfortunately, access to
the word “palliative” deters
palliative care for people with serious neurologic illness is scarce. Increasing clinicians from
access to feasible and effective palliative care through primary neuropalliative recommending the
care training and telemedicine programs, as well as comparative-effectiveness treatment and deters
patients/caregivers from
studies, should be a priority for health care research, delivery, and payment
accepting the care.
programs for patients and families affected by PD, DLB, and other serious Supportive care has been
neurologic movement disorders. shown to be much better
received by both clinicians
and patients and caregivers.
USEFUL WEBSITES ● Palliative care

EDUCATION IN PALLIATIVE AND END-OF-LIFE CARE (EPEC) VITALTALK emphasizes a holistic
FOR NEUROLOGY VitalTalk is an evidence-based program that
EPEC is a comprehensive instructional course on teaches serious illness communication skills using
approach, patient
primary palliative care skills for neurologists. role-plays with actors. autonomy, aggressive
bioethics.northwestern.edu/programs/epec/ vitaltalk.org
symptom management of
curricula/neurology-modules.html total pain, concern for the
family, and clinical
INTERNATIONAL NEUROPALLIATIVE CARE SOCIETY teamwork to provide
The International Neuropalliative Care Society
website is the central hub for research, education,
goal-concordant care that
meetings, and career mentorship in neuropalliative focuses on optimizing
care. quality of life for people
inpcs.org/i4a/pages/index.cfm?pageid=1 dealing with serious,
life-limiting illness.
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cmaj.160206

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POSTREADING TEST
ARTICLE 1: PRODROMAL α-SYNUCLEINOPATHIES
1 Abnormalities in which of the following sensory functions are most

common in the prodromal stages of Parkinson disease and other
α-synucleinopathies?
A hearing
B olfaction
C taste
D touch
E vision
2 A 55-year-old woman is seen in clinic for ongoing management

of her rapid eye movement (REM) sleep behavior disorder. Her
risk for subsequent development of Parkinson disease or other
α-synucleinopathy has been reviewed at prior clinic visits, and she
asks about pharmacologic or nonpharmacologic options that might
lower this risk. Which of the following interventions should she be
counseled to implement?
A aspirin
B calcium channel blocker
C ketogenic diet
D regular physical activity
E statin therapy
3 Which of the following is considered a risk factor for the development

of Parkinson disease or other forms of α-synucleinopathy?
A excess caffeine intake

B female sex
C obstructive sleep apnea
D pesticide exposure
E use of selective serotonin reuptake inhibitor therapy
1534 OCTOBER 2022

ARTICLE 2: DIAGNOSIS AND MEDICAL MANAGEMENT OF PARKINSON
DISEASE
4 The clinical diagnosis of Parkinson disease is based on the presence of

the major motor manifestations, including bradykinesia, rigidity, and
resting tremor. Which of the following clinical manifestations makes
the diagnosis of Parkinson disease less likely?
A cortical sensory loss

B depression
C erectile dysfunction
D hyposmia
E levodopa-induced dyskinesia
5 Which of the following clinical features is one of the red flags that
indicates the possibility of progressive supranuclear palsy as an
alternative diagnosis to Parkinson disease?
A disproportionate anterocollis within first decade after diagnosis

B early bulbar dysfunction
C frequent recurrent falls within 3 years of diagnosis
D respiratory stridor
E severe orthostatic hypotension
6 Radionuclide tracer studies such as the dopamine transporter

single-photon emission computed tomography (SPECT) can be helpful
to answer which of these clinical questions?
A assess progression of Parkinson disease in intermediate stages

B differentiate essential tremor from functional tremor
C differentiate Parkinson disease from essential tremor
D differentiate Parkinson disease from multiple system atrophy
E differentiate Parkinson disease from progressive supranuclear
palsy
7 Which of the following medications has been found to be efficacious for

the treatment of depression in Parkinson disease?
A amantadine
B apomorphine
C extended-release levodopa
D pramipexole
E zonisamide

POSTREADING TEST
ARTICLE 3: SURGICAL THERAPIES FOR PARKINSON DISEASE
8 A 62-year-old man with Parkinson disease (PD) is seen in clinic for

follow-up. Over the past several years, his tremor has become less
responsive to considerable increases in his levodopa dosing. He is also
beginning to notice significant motor fluctuations, and he and his wife
have noted some subtle worsening of his gait and posture. Referral for
deep brain stimulation (DBS) treatment is discussed. Which of the
following is an appropriate aspect of counseling for this patient
regarding DBS implantation?
A although his tremor may improve with DBS, other motor

manifestations of PD, such as bradykinesia and rigidity, are
expected to worsen
B he should not expect dramatic improvement in any gait, balance,
or posture symptoms following DBS treatment
C if he elects to proceed with DBS, he must have this implanted prior
to age 65
D marked improvement in his tremor should be seen immediately
following surgery; if not, then future improvement is highly unlikely
E since his tremor has become less responsive to levodopa over
time, he is not a candidate for DBS
9 Which of the following patient-related factors could be considered as a

reason to use MRI-guided focused ultrasound in place of deep brain
stimulator placement as a surgical treatment for Parkinson disease?
A age younger than 50 years

B inability to lie flat for prolonged periods of time
C lack of tremor responsiveness to levodopa therapy
D medical comorbidities suggesting high surgical risk
E presence of cognitive impairment
10 A 71-year-old woman with a 10-year history of Parkinson disease is seen

in clinic for follow-up. She and her family have reported progression of
her symptoms despite increasing doses of levodopa and other
medication adjustments. The possibility of deep brain stimulation
(DBS) is discussed. Which of the following, if present in this patient,
would be a relative contraindication to DBS surgery?
A bilateral, symmetric tremor and rigidity

B comorbid diagnosis of anxiety requiring pharmacotherapy
C disease duration of 10 or more years
D presence of treatment-related dyskinesias
E significant cognitive impairment
1536 OCTOBER 2022

ARTICLE 4: DIAGNOSIS AND TREATMENT OF COGNITIVE AND
NEUROPSYCHIATRIC SYMPTOMS IN PARKINSON DISEASE AND
11 The clinical differentiation of dementia with Lewy bodies from

Parkinson disease is primarily based on the presence of which of the
following features occurring before or within 1 year of the onset of
motor parkinsonism features?
A autonomic dysfunction
B delusions
C dementia
D depression
E hallucinations
12 Which medication demonstrated modest clinical benefits for Parkinson

disease dementia in the only large randomized controlled trial of
cholinesterase inhibitors for this condition?
A donepezil
B galantamine
C memantine
D rasagiline
E rivastigmine
13 Pathogenic mutations in which of the following genes have been shown

to be an important genetic risk factor for Parkinson disease dementia
and dementia with Lewy bodies?
A calcium homeostasis modulator 1

B glucocerebrosidase A
C presenilin 1
D sortilin-related receptor
E tyrosine kinase nonreceptor 1

POSTREADING TEST
ARTICLE 5: DIAGNOSIS AND TREATMENT OF ESSENTIAL TREMOR
14 Which of the following factors can be used to help in the potential

distinction between dystonic tremor and essential tremor affecting
the arms?
A dystonic tremor is usually highly sinusoidal or oscillatory

B dystonic tremor is usually more severe
C dystonic tremor is usually unilateral or asymmetric
D dystonic tremor usually resolves completely during resting
positions
E dystonic tremor usually shows a very strong axis during spiral
drawing
15 A 24-year-old graduate student is seen in clinic for evaluation of

tremor. He describes intermittent trembling of his right hand that he
notices when attempting to use a laser pointer while teaching classes,
although he admits that his left (nondominant) hand is likely affected
as well. He also feels that his voice gets shaky in these situations, which
are anxiety-provoking for him. Examination shows a fine, relatively
fast, rhythmic, postural tremor without significant tremor during
intentional movements. He has no family history of tremor, and he does
not have tremor in settings outside teaching. Which of the following is
the most likely diagnosis?
A dystonic tremor
B enhanced physiologic tremor
C essential tremor
D functional tremor
E Holmes tremor
16 Which of the following best explains differences in the epidemiology

and clinical features seen between early-onset and late-onset
essential tremor?
A early-onset essential tremor has a higher female-to-male

prevalence, approaching 3:1
B early-onset essential tremor has a more rapidly progressive
course
C early-onset essential tremor is more frequently associated with a
family history of essential tremor
D late-onset essential tremor is more likely to involve isolated head
and voice tremor
E late-onset essential tremor is more likely to respond to
propranolol treatment
1538 OCTOBER 2022

ARTICLE 6: MULTIPLE SYSTEM ATROPHY
17 In patients with idiopathic rapid eye movement (REM) sleep behavior

disorder, which of the following clinical features is associated with
future development of multiple system atrophy?
A anisocoria
B dysgeusia
C esophageal reflux
D impaired sense of smell
E severe urinary symptoms
18 Plasma catecholamine levels may be helpful to distinguish multiple

system atrophy from which of the following neurodegenerative
disorders?
A dementia with Lewy bodies

B Parkinson disease
C progressive supranuclear palsy
D pure autonomic failure
E spinocerebellar atrophy
19 The finding of a putaminal hyperintense rim on a fluid-attenuated

inversion recovery (FLAIR) image is a sign suggestive of which of the
following disorders?
A Alzheimer disease
B dementia with Lewy bodies
C multiple system atrophy
D Parkinson disease
E pure autonomic failure
20 Which of the following medications is a norepinephrine precursor that

is used to treat orthostatic hypotension in multiple system atrophy by
increasing norepinephrine levels?
A atomoxetine
B droxidopa
C fludrocortisone
D midodrine
E pyridostigmine

POSTREADING TEST
ARTICLE 7: PROGRESSIVE SUPRANUCLEAR PALSY AND CORTICOBASAL

SYNDROME
21 Patients with suspected progressive supranuclear palsy who report a

family history of similar symptoms, suggesting an inherited pattern,
should undergo genetic testing for which of the following conditions?
A adrenoleukodystrophy
B fragile X-associated tremor/ataxia syndrome
C Friedreich ataxia
D Kearns-Sayre syndrome
E Niemann-Pick disease type C
22 A 67-year-old man with hypertension and diabetes is seen in clinic for a

several-year history of progressive gait impairment. He initially
described some subjective imbalance that has now evolved to the point
of needing a walker for assistance. Despite using an assistive device, he
experiences frequent falls, usually backward. Examination is notable
for mild executive dysfunction, impaired vertical saccades, rigidity in
all four limbs, and an upright/unsteady posture. Which of the
following is the most likely diagnosis?
A corticobasal syndrome
B idiopathic Parkinson disease
C normal pressure hydrocephalus
D progressive supranuclear palsy
E vascular parkinsonism
23 Which of the following best describes the role for dopaminergic and
other symptomatic therapies in patients with suspected progressive
supranuclear palsy (PSP)?
A all patients with suspected PSP should undergo a trial of levodopa

therapy for at least 1 month to gauge responsiveness
B anticholinergic medications are well tolerated and highly effective
in treating parkinsonism in patients with PSP
C classic PSP has a more robust and sustained response to
dopaminergic therapy than other PSP variants
D dopamine agonists have stronger evidence than levodopa for
treatment of parkinsonism in patients with PSP
E selective serotonin reuptake inhibitors are relatively
contraindicated in patients with PSP
1540 OCTOBER 2022

ARTICLE 8: CHOREA
24 What is the most common cause of chorea in childhood?
A ADCY5-related chorea
B Fahr disease
C neuroacanthocytosis
D Sydenham chorea
E Wilson disease
25 Which disorder that can cause chorea is associated with the eye of the
tiger sign on cranial MRI?
A aceruloplasminemia
B dentatorubral pallidoluysian atrophy
C pantothenate kinase–associated neurodegeneration (PKAN)
D spinocerebellar ataxia type 17
E Wilson disease
26 Which of the following medications is reported to commonly cause

orobuccolingual chorea?
A atorvastatin
B clindamycin
C lisinopril
D metformin
E risperidone
27 Which one of the following is a pathogenic variant that can present

as a Huntington disease phenocopy and has also been linked to
amyotrophic lateral sclerosis/motor neuron disease and
frontotemporal dementia?
A C9orf72
B Friedreich ataxia
C HDL2
D inherited prion disease (PRNP)
E spinocerebellar ataxia type 17

POSTREADING TEST
ARTICLE 9: NEURODEGENERATIVE CEREBELLAR ATAXIA
28 Which of the following features of speech dysfunction is seen more

commonly in parkinsonism and less commonly in cerebellar ataxia
syndromes and may be helpful in distinguishing between the two
during patient evaluation?
A associated dysphagia
B dysprosody
C flaccid palatal weakness
D hypophonia
E scanning-style speech
29 Which of the following findings on nerve conduction studies/EMG

would be most helpful in distinguishing spinocerebellar ataxia type 1
from other types of spinocerebellar ataxia?
A conduction block
B decreased motor recruitment
C decreased sensory nerve action potential amplitudes
D increased insertional activity
E slower conduction velocities
30 Which of the following pharmacologic options may assist with

symptomatic oscillopsia experienced by patients with cerebellar ataxia
syndromes?
A 4-aminopyridine
B carbidopa/levodopa
C propranolol
D riluzole
E valproic acid
ARTICLE 10: THE DYSTONIAS
31 Meige syndrome is an example of which of the following types of body

distribution of dystonia?
A focal
B generalized
C hemidystonia
D multifocal
E segmental
1542 OCTOBER 2022

32 Which of the following is the most common genetic dystonia?
A DYT-ANO3 (formerly DYT24)

B DYT/PARK-TAF1 (formerly DYT3)
C DYT-THAP1 (formerly DYT6)
D DYT-TOR1A (formerly DYT1)
E PxMD-PNKD (formerly DYT8/20)
33 Which of the following dystonia disorders is responsive to

maintenance of a ketogenic diet?
A aromatic amino acid decarboxylase deficiency (AADC)

B biotinidase deficiency (BTD)
C GLUT1 deficiency (SLC2A1)
D methylmalonic aciduria (MMUT)
E Wilson disease (ATP7B)
34 Trihexyphenidyl exerts beneficial effects on dystonia by modulation

of activity of which neurotransmitter system?
A cannabinoid
B cholinergic
C dopamine
D γ-aminobutyric acid (GABA)
E serotonin
ARTICLE 11: DIAGNOSING COMMON MOVEMENT DISORDERS IN CHILDREN
35 A 10-year-old boy is seen in neurology clinic for abnormal movements.

His parents report that he has typical spells of flapping and wiggling of
both hands, lasting a few seconds in duration, for the last 6 to
12 months. Less frequently, these movements are accompanied by
facial grimacing for a few seconds. These events vary in terms of their
frequency and severity. He has developed normally to this point, and
his examination is unremarkable. Which of the following features
would suggest his movements are more likely related to stereotypies as
opposed to tics?
A complex nature of his hand-flapping movements

B lack of any abnormal movements affecting voice or phonation
C no urge to perform these movements
D onset of symptoms at age 10
E variable frequency

POSTREADING TEST
36 A 13-year-old boy is seen in clinic for follow-up of his diagnosis of

Tourette syndrome. Since his last visit 4 months ago, he and his parents
have noted a significant increase in his motor and verbal tics, which
seem to correspond with the beginning of the school year. He has been
undergoing comprehensive behavioral intervention for tics (CBIT)
without significant benefit to this point, and his parents are concerned
that his school performance is declining as a consequence of his tics.
Which of the following is the best next step in management?
A guanfacine
B paroxetine
C recommend changing to a home-schooling program
D referral for deep brain stimulation evaluation
E risperidone
37 A 4-year-old girl is seen in the emergency department for the acute

onset of clumsiness, noted by her parents earlier today. She is afebrile
and without other signs of infection. Neurologic examination is notable
for incoordination of her extremities and gait unsteadiness with a
wide-based stumbling gait. Which of the following is the best next step
in management?
A administer diphenhydramine and benztropine

B check antistreptolysin O and anti-deoxyribonuclease B titers
C lumbar puncture
D thorough history for possible medication or substance exposures
E urgent brain MRI
38 A 15-year-old girl with spastic quadriparetic cerebral palsy (treated

with baclofen) and epilepsy (treated with valproate) is seen in the
emergency department for worsening muscle tightness and altered
behavior. Three days ago, she developed flulike symptoms with
vomiting and diarrhea and has been unable to eat or tolerate her oral
medications since symptom onset. Beginning yesterday, her caregivers
noted increased agitation, decreased interaction, and significant
increase in her extremity tone. Examination is notable for these
findings along with hypertension and tachycardia. Which of the
following is the most likely diagnosis?
A acute dystonic reaction

B baclofen withdrawal
C neuroleptic malignant syndrome
D serotonin syndrome
E status epilepticus
1544 OCTOBER 2022

ARTICLE 12: PALLIATIVE CARE AND MOVEMENT DISORDERS
39 Studies suggest that a referral to a palliative care clinic may have a

greater likelihood of acceptance if it is instead termed as which of the
following?
A comfort care
B end-of-life care
C hospice care
D neuropalliative care
E supportive care
40 Which of the following is a true statement about people with

Parkinson disease with regard to end-of-life care?
A most have had documented advance care discussions

B most receive hospice care
C most would prefer to die at home
D they are less likely to die in a hospital than the general population
E they have low rates of nursing home deaths

Postreading
SELF-ASSESSMENT
AND CME
Self-Assessment and
CME Test—Preferred
Responses
By Adam G. Kelly, MD, FAAN; D. Joanne Lynn, MD, FAAN
MOVEMENT DISORDERS
Following are the preferred responses to the questions in the Postreading
Self-Assessment and CME Test in this Continuum issue. The preferred
response is followed by an explanation and a reference with which you
may seek more specific information. You are encouraged to review the
responses and explanations carefully to evaluate your general
understanding of the article topic. The comments and references included
with each question are intended to encourage independent study.
US PARTICIPANTS: Upon
completion of the Postreading Self-Assessment and
CME Test and issue evaluation online at continpub.com/CME, participants
may earn up to 20 AMA PRA Category 1 Credits™ toward SA-CME. US
participants have up to 3 years from the date of publication online to earn
SA-CME credits.
CANADIAN PARTICIPANTS: This program is an Accredited Self-Assessment

Program (Section 3) as defined by the Maintenance of Certification
Program of the Royal College of Physicians and Surgeons of Canada and
approved by the University of Calgary Office of Continuing Medical
Education and Professional Development. Refer to the CME tab on
ContinuumJournal.com for dates of accreditation. Canadian participants
should visit MAINPORT (mainport.org) to record learning and outcomes.
Canadian participants can claim a maximum of 20 hours per issue (credits
are automatically calculated).
1546 OCTOBER 2022

ARTICLE 1: PRODROMAL α -SYNUCLEINOPATHIES
1 The preferred response is B (olfaction). Altered olfactory function,

although relatively nonspecific and potentially related to other etiologies,
is frequently seen as a prodromal manifestation in patients with
synucleinopathies, whether they be hereditary or sporadic. Screening
for olfactory loss is part of the evaluation of patients at risk for
α-synucleinopathy. For more information, refer to page 1270 of the
Continuum article “Prodromal α-Synucleinopathies.”
2 The preferred response is D (regular physical activity). Although the

presence of vascular risk factors and risk of α-synucleinopathy
development may be linked, no strong evidence supports the routine
implementation of aspirin, blood pressure control, or statin medications
to lower this risk. Some data show an association between regular
physical activity and a lower risk of the development of Parkinson
disease, so this healthy lifestyle habit should be recommended to
patients felt to be at risk for α-synucleinopathy. For more information,
refer to page 1278 of the Continuum article “Prodromal α-Synucleinopathies.”
3 The preferred response is D (pesticide exposure). Risk factors for

synucleinopathies, including Parkinson disease (PD), are generally
categorized as behavioral/environmental or biological factors. Of the
options listed here, pesticide exposure is associated with a higher risk of
α-synucleinopathy development. The relationship between rural living
and increased risk of PD may in part be accounted for by the risk of PD
related to pesticide exposure. For more information, refer to page 1269
of the Continuum article “Prodromal α-Synucleinopathies.”
ARTICLE 2: DIAGNOSIS AND MEDICAL MANAGEMENT OF PARKINSON

DISEASE
4 The preferred response is A (cortical sensory loss). Observations that

make the diagnosis of Parkinson disease (PD) less likely include
supranuclear gaze palsy, cerebellar symptoms, restriction of
parkinsonism to the lower limbs for more than 3 years, absence of
response to high-dose levodopa, features consistent with
frontotemporal dementia, and cortical sensory loss. These clinical
features are suggestive of alternative diagnoses. Depression, erectile
dysfunction, and hyposmia are all features of PD that may be present in
early stages. Levodopa-induced dyskinesia is considered to be one of
the supportive criteria for the diagnosis of PD. For more information,
refer to pages 1284 to 1285 of the Continuum article “Diagnosis and
Medical Management of Parkinson Disease.”

POSTREADING TEST—PREFERRED RESPONSES
5 The preferred response is C (frequent recurrent falls within 3 years of

diagnosis). One of the clinical features that serves as a red flag to
indicate the possibility of progressive supranuclear palsy as an
alternative diagnosis to Parkinson disease is the occurrence of frequent
recurrent falls (>1 per year) within the first 3 years after diagnosis. The
other choices are more suggestive of multiple system atrophy as an
alternative diagnosis. For more information, refer to page 1285 of the
Continuum article “Diagnosis and Medical Management of Parkinson
Disease.”
6 The preferred response is C (differentiate Parkinson disease from

essential tremor). The dopamine transporter single-photon emission
computed tomography (SPECT) scan detects loss of striatal
dopaminergic terminals and so can be of use to differentiate
nigrostriatal degeneration in Parkinson disease from essential tremor. It
is not useful to differentiate between different types of
neurodegenerative parkinsonian syndromes or to assess progression in
intermediate or advanced stages of Parkinson disease. For more
information, refer to page 1287 of the Continuum article “Diagnosis and
Medical Management of Parkinson Disease.”
7 The preferred response is D (pramipexole). Pramipexole is a dopamine

agonist that has demonstrated efficacy in the treatment of depression
in Parkinson disease. For more information, refer to pages 1293 to 1294 of
the Continuum article “Diagnosis and Medical Management of
Parkinson Disease.”
ARTICLE 3: SURGICAL THERAPIES FOR PARKINSON DISEASE
8 The preferred response is B (he should not expect dramatic

improvement in any gait, balance, or posture symptoms following deep
brain stimulation [DBS] treatment). In general, patients with Parkinson
disease who are considering DBS treatment should anticipate
improvement in symptoms that are responsive to dopaminergic therapy.
These include tremor, bradykinesia, and rigidity, although this
improvement can take months while device programming is being
optimized. On the contrary, patients who may be candidates for DBS
should be counseled that symptoms of PD that are less dopamine-
responsive, such as gait changes, postural instability, and cognitive
impairment, are generally less responsive to DBS as well. For more
information, refer to page 1304 of the Continuum article “Surgical
Therapies for Parkinson Disease.”
1548 OCTOBER 2022

9 The preferred response is D (medical comorbidities suggesting high
surgical risk). MRI-guided focused ultrasound (MRIgFUS) is a surgical
option for patients with Parkinson disease, particularly those with
asymmetric tremor and other motor manifestations. The decision of
when to consider MRIgFUS versus deep brain stimulation (DBS) should
be tailored to the individual patient, although some general principles
may suggest one approach being favored over another. Unlike DBS,
MRIgFUS does not involve anesthesia or brain surgery; as a result, it may
be preferred in patients with significant medical comorbidities that
increase perioperative risk. For more information, refer to page 1305 of
the Continuum article “Surgical Therapies for Parkinson Disease.”
10 The preferred response is E (significant cognitive impairment). Deep

brain stimulation (DBS) should be considered as a treatment option for
patients with Parkinson disease who continue to experience significant
tremor and other motor manifestations despite optimization of their
dopaminergic therapy or whose treatment is limited by the
development of dyskinesias. Candidates for DBS should undergo a
thorough evaluation, including an evaluation for dementia, as this is a
contraindication to surgery. For more information, refer to page 1304 of
the Continuum article “Surgical Therapies for Parkinson Disease.”
ARTICLE 4: DIAGNOSIS AND TREATMENT OF COGNITIVE AND

NEUROPSYCHIATRIC SYMPTOMS IN PARKINSON DISEASE AND
11 The preferred response is C (dementia). Both Parkinson disease (PD)

and dementia with Lewy bodies (DLB) share similar neuropsychiatric,
motor, and autonomic symptoms as well as overlapping
pathophysiology. DLB is currently clinically differentiated from PD by
the dominance of cognitive impairment as a presenting characteristic as
opposed to variable onset of cognitive impairment at least 1 year after
established motor symptoms in PD. For more information, refer to
page 1315 of the Continuum article “Diagnosis and Treatment of
Cognitive and Neuropsychiatric Symptoms in Parkinson Disease and
Dementia with Lewy Bodies.”
12 The preferred response is E (rivastigmine). A large randomized

controlled trial of treatment with rivastigmine in Parkinson disease
dementia showed modest, significant benefits for a range of outcome
measures, and these were accompanied by an increase in adverse side
effects. Other studies have failed to show robust benefits. For more
Treatment of Cognitive and Neuropsychiatric Symptoms in Parkinson
Disease and Dementia with Lewy Bodies.”

13 The preferred response is B (glucocerebrosidase A). Mutations of the

glucocerebrosidase A gene is a risk factor for the development of both
Parkinson disease dementia and dementia with Lewy bodies. For more
Treatment of Cognitive and Neuropsychiatric Symptoms in Parkinson
Disease and Dementia with Lewy Bodies.”
ARTICLE 5: DIAGNOSIS AND TREATMENT OF ESSENTIAL TREMOR
14 The preferred response is C (dystonic tremor is usually unilateral or

asymmetric). Abnormal movements related to dystonic tremor and
those related to essential tremor can be challenging to distinguish from
one another. That being said, some factors can be useful during history
or physical assessment, including the fact that, unlike essential tremor,
dystonic tremor is almost always unilateral or markedly asymmetric. For
more information, refer to pages 1340 to 1341 of the Continuum article
“Diagnosis and Treatment of Essential Tremor.”
15 The preferred response is B (enhanced physiologic tremor). This

patient is presenting with symptoms of bilateral upper extremity and
voice tremor that are worsened under situations of stress/anxiety. His
examination shows a fine, relatively fast, low-amplitude postural tremor
without an intentional component. This history and examination are
highly suggestive of enhanced physiologic tremor. Although he notes
more involvement in his right hand, arguing toward some asymmetry,
this is more likely a manifestation of his being right-hand dominant. For
16 The preferred response is C (early-onset essential tremor is more

frequently associated with a family history of essential tremor).
Although not replicated in all studies, in general, the age of onset of
essential tremor is felt to follow a bimodal distribution with early-onset
and late-onset groups. Several epidemiologic and phenotypic
differences have been identified between these groups, with
early-onset essential tremor having a more slowly progressive course
and more likely to be associated with a positive family history of tremor.
For more information, refer to page 1335 of the Continuum article
1550 OCTOBER 2022

17 The preferred response is E (severe urinary symptoms). Rapid eye

movement (REM) sleep behavior disorder is one of the most common
prodromal symptoms for multiple system atrophy. For patients with
idiopathic REM sleep behavior disorder, the presence of intact sense of
smell and more severe urinary symptoms is associated with a tendency
to eventually develop multiple system atrophy. For more information,
refer to page 1351 of the Continuum article “Multiple System Atrophy.”
18 The preferred response is D (pure autonomic failure). Patients with

pure autonomic failure may have low norepinephrine levels. These
levels will be normal in multiple system atrophy and the other disorders
listed. For more information, refer to page 1353 of the Continuum article
“Multiple System Atrophy.”
19 The preferred response is C (multiple system atrophy). A rim of

hyperintensity of the lateral putaminal border (the putaminal rim or slit
sign) is a relatively specific sign of multiple system atrophy. Other MRI
findings seen in multiple system atrophy include putaminal atrophy,
brainstem atrophy, abnormal signal in the middle cerebellar peduncles,
and the hot cross bun sign, which refers to a cross-shaped
hyperintensity of the pons on T2-weighted images. This is caused by
degeneration of pontine neurons and myelinated transverse
pontocerebellar fibers. For more information, refer to page 1359 of the
Continuum article “Multiple System Atrophy.”
20 The preferred response is B (droxidopa). Droxidopa is a norepinephrine

precursor that can ameliorate orthostatic hypotension by increasing
norepinephrine levels. The other medications listed are also used to
treat this condition via other mechanisms. For more information, refer
to page 1355 of the Continuum article “Multiple System Atrophy.”
ARTICLE 7: PROGRESSIVE SUPRANUCLEAR PALSY AND CORTICOBASAL

SYNDROME
21 The preferred response is E (Niemann-Pick disease type C). In general,

progressive supranuclear palsy (PSP) is considered a sporadic condition
although some associated genetic mutations have been identified.
More importantly, several PSP mimics have a clear inherited pattern; as
a result, eliciting a family history of relatives with similar phenotypes
should prompt consideration of alternative diagnoses. Among the PSP
mimics, it is reasonable to test for Niemann-Pick disease type C since
there is a disease-specific treatment option for this disorder. For more

information, refer to page 1366 of the Continuum article “Progressive

Supranuclear Palsy and Corticobasal Syndrome.”
22 The preferred response is D (progressive supranuclear palsy). This

patient’s clinical presentation is highly suggestive of progressive
supranuclear palsy, Richardson syndrome variant, based on the
progressive nature of his primary symptom of gait/balance function, as
well as the examination findings of impaired vertical eye movements,
mild cognitive dysfunction, and axial/appendicular rigidity. For more
information, refer to page 1368 of the Continuum article “Progressive
Supranuclear Palsy and Corticobasal Syndrome.”
23 The preferred response is A (all patients with suspected progressive

supranuclear palsy [PSP] should undergo a trial of levodopa therapy
for at least 1 month to gauge responsiveness). PSP, corticobasal
syndrome (CBS), and other disorders of parkinsonism do not have the
same avid response to levodopa and other forms of dopaminergic
therapy as is seen in idiopathic Parkinson disease. However, a proportion of
patients will benefit from dopaminergic therapy and, as a result, patients
with suspected PSP or CBS should undergo an empiric trial of levodopa
therapy for a minimum of 1 month to monitor for any clinical improvement.
For more information, refer to pages 1375 to 1376 of the Continuum
article “Progressive Supranuclear Palsy and Corticobasal Syndrome.”
ARTICLE 8: CHOREA
24 The preferred response is D (Sydenham chorea). Sydenham chorea is

the most common cause of chorea in childhood and follows infection
with group A streptococci. Other causes of chorea in childhood include
cerebral palsy, head trauma, toxins, infections, and autoimmune
diseases as well as several rare inherited diseases. For more
information, refer to page 1390 of the Continuum article “Chorea.”
25 The preferred response is C (pantothenate kinase–associated

neurodegeneration [PKAN]). PKAN is an autosomal recessive disorder
associated with a characteristic MRI pattern of signal change in the
basal ganglia known as the eye of the tiger sign. This sign refers to a
symmetric low signal intensity around a central area of high signal
intensity in the globus pallidus bilaterally on T2-weighted MRI.
Aceruloplasminemia is associated with iron accumulation in the basal
ganglia. Dentatorubral pallidoluysian atrophy has characteristic white
matter changes and atrophy in the dentate, red nucleus, and pallidum.
Spinocerebellar ataxias are usually associated with cerebellar atrophy
apparent on MRI. Wilson disease is associated with the face of the giant
panda sign on MRI. For more information, refer to page 1387 of the
Continuum article “Chorea.”
1552 OCTOBER 2022

26 The preferred response is E (risperidone). Orobuccolingual movements
consistent with tardive dyskinesia are commonly caused by
dopmamine-receptor blocking medications such as risperidone. Other
pharmacologic agents that can cause chorea include dopaminergics and
antidepressants, central nervous system stimulants, anticholinergics,
antihistamines, anticonvulsants, and oral contraceptives. For more
information, refer to pages 1392 to 1393 of the Continuum article
“Chorea.”
27 The preferred response is A (C9orf72). In the evaluation of an adult

presenting with suspected hereditary chorea, genetic counseling
followed by a gene test for Huntington disease is the first step in
evaluation. After that, testing for pathogenic variants can be
performed in a targeted fashion based on clinical features or as a
panel. An expanded hexanucleotide repeat variant of C9orf72
accounts for almost 2% of Huntington disease phenocopies according
to a single review of 514 patients presenting with Huntington disease
phenocopies. This gene is thought to have a role in membrane
trafficking and is associated with motor neuron disease and
frontotemporal lobar degeneration as well as chorea. For more
information, refer to pages 1393 to 1394 of the Continuum article
“Chorea.”
ARTICLE 9: NEURODEGENERATIVE CEREBELLAR ATAXIA
28 The preferred response is D (hypophonia). While parkinsonism and

cerebellar ataxia syndromes can both involve alterations in speech, and
some of these alterations can overlap, the finding of hypophonia is a
potential clue to a diagnosis of Parkinson disease or other form of
parkinsonism, as this feature is less commonly seen in primary
cerebellar disorders. For more information, refer to page 1412 of the
Continuum article “Neurodegenerative Cerebellar Ataxia.”
29 The preferred response is E (slower conduction velocities). Nerve

conduction studies/EMG can assist in the diagnosis of patients with
suspected cerebellar ataxia syndromes, since many disorders,
particularly hereditary syndromes like spinocerebellar ataxias (SCAs),
have peripheral nerve involvement. While mixed axonal and
demyelinating sensorimotor neuropathies are seen most commonly in
SCAs, the degree of nerve conduction slowing is more significant in
spinocerebellar ataxia type 1 and is a potential clue to this disorder. For
more information, refer to page 1415 of the Continuum article
“Neurodegenerative Cerebellar Ataxia.”

30 The preferred response is A (4-aminopyridine). Oscillopsia is a

common and bothersome symptom experienced by patients with
cerebellar disorders of various etiologies. While multiple
pharmacotherapies have shown to have some benefit in suppressing
oscillopsia and nystagmus (eg, baclofen, memantine, gabapentin), the
strongest evidence exists for the use of 4-aminopyridine in this setting.
For more information, refer to page 1428 of the Continuum article
“Neurodegenerative Cerebellar Ataxia.”
31 The preferred response is E (segmental). Meige syndrome involves the

eyes and lower face and may extend to the neck. Since these are two or
more contiguous body parts, it is classified as a segmental dystonia. For more
information, refer to page 1436 of the Continuum article “The Dystonias.”
32 The preferred response is D (DYT-TOR1A [formerly DYT1]). The

DYT-TOR1A is the most common genetic dystonia. It has a focal onset,
often in the lower limbs, and then gradually generalizes. The
inheritance pattern is autosomal dominant, and it is more common in
people of Ashkenazi Jewish ancestry. Deep brain stimulation is a highly
effective treatment modality for this dystonia. For more information,
refer to page 1459 of the Continuum article “The Dystonias.”
33 The preferred response is C (GLUT1 deficiency [SLC2A1]). Dietary

interventions are important treatment approaches for several of the
metabolic disorders that cause dystonia. Paroxysmal exercise/
exertion-induced dystonia/dyskinesia, frequently due to GLUT1
deficiency, may respond to maintenance of a ketogenic diet as well as
treatment with triheptanoin. Biotinidase deficiency is treated with
biotin supplementation. Aromatic amino acid decarboxylase deficiency
may respond to pyridoxine supplementation as well as treatment with
dopamine agonists or monoamine oxidase inhibitors. Methylmalonic
aciduria is managed by compliance with a special low-protein diet.
Wilson disease is treated with limitation of dietary copper as well as use
of decoppering agents. For more information, refer to page 1463 of the
Continuum article “The Dystonias.”
34 The preferred response is B (cholinergic). Anticholinergic agents such

as trihexyphenidyl and benztropine are effective for treatment of generalized
and segmental forms of dystonia, although the benefit may wane over time.
The effect is mediated by decreased activation of the M1 cholinergic
receptors of medium spiny neurons in the striatum. For more information,
refer to pages 1467 to 1468 of the Continuum article “The Dystonias.”
1554 OCTOBER 2022

ARTICLE 11: DIAGNOSING COMMON MOVEMENT DISORDERS IN CHILDREN
35 The preferred response is C (no urge to perform these movements).

This patient is being evaluated for brief, repetitive abnormal
movements that developed around age 10, and the major differential
diagnosis would be stereotypies versus tics. While age of symptom
onset and some features of the movements can be seen in both of
these possibilities (eg, brief nature, variable frequency), some factors
are more likely with one or the other. Of the possibilities listed here, no
urge to perform the movements would be more supportive of a
diagnosis of stereotypies instead of tics. For more information, refer to
page 1483 of the Continuum article “Diagnosing Common Movement
Disorders in Children.”
36 The preferred response is A (guanfacine). This patient with a

preexisting diagnosis of Tourette syndrome is experiencing an increase
in tic frequency with corresponding decline in school achievement,
despite the use of a nonpharmacologic approach (cognitive-behavioral
therapy). Given the impairment in school performance, initiating a
pharmacologic approach seems appropriate in his case; first-line agents
in this situation would include guanfacine or clonidine. For more
information, refer to page 1488 of the Continuum article “Diagnosing
Common Movement Disorders in Children.”
37 The preferred response is D (thorough history for possible medication

or substance exposures). This child is presenting with an acute ataxia
syndrome. Especially in the absence of any focal features or signs/
symptoms of infection, an accidental exposure resulting in a toxic
syndrome is the most likely explanation for her symptoms. Eliciting a
thorough history from family members or other caregivers regarding
what medications or substances the child might have been exposed to is
an appropriate next step. For more information, refer to page 1503
of the Continuum article “Diagnosing Common Movement Disorders
in Children.”
38 The preferred response is B (baclofen withdrawal). This patient, who

has been unable to take her medications for 3 days, is progressing
with a marked increase in motor tone as well as acute encephalopathy.
While this could potentially place her at risk for status epilepticus, the
clinical presentation described here would be more consistent with
baclofen withdrawal syndrome. This is a life-threatening neurologic
emergency that clinicians should be prepared to recognize and
manage urgently. For more information, refer to pages 1513 to 1514 of
the Continuum article “Diagnosing Common Movement Disorders
in Children.”

ARTICLE 12: PALLIATIVE CARE AND MOVEMENT DISORDERS
39 The preferred response is E (supportive care). Although palliative care

has been demonstrated to lead to better outcomes for patients,
significant stigma is related to the term palliative care since it is
associated with hospice and end-of-life care. Studies have shown that
patients are more likely to accept a referral to a supportive care clinic
than to a palliative care clinic. This has resulted in the adoption of
several terms with more positive connotations for palliative care. For
“Palliative Care and Movement Disorders.”
40 The preferred response is C (most would prefer to die at home).

According to studies, the majority of people with Parkinson disease and
other serious illnesses have reported that they would prefer to die at
home. Unfortunately, people with Parkinson disease are more likely to
die in a hospital than the general population and only a minority receive
hospice care. Advance care planning increases the likelihood of dying
at home with hospice care. For more information, refer to pages 1523 to
1524 of the Continuum article “Palliative Care and Movement Disorders.”
1556 OCTOBER 2022

LEARNING OBJECTIVES AND CORE COMPETENCIES
Learning Objectives Core Competencies

Upon completion of this Continuum: Lifelong
Learning in Neurology Movement Disorders issue, This Continuum: Lifelong Learning in Neurology
participants will be able to: Movement Disorders issue covers the following
core competencies:
◆ Assess and manage individuals who are prodromal
or at risk for α-synucleinopathies ◆ Patient Care and Procedural Skills
◆ Describe the key symptoms, prodromal stage, genetic ◆ Medical Knowledge

basis, and current treatments of Parkinson disease
◆ Practice-Based Learning and Improvement
◆ Discuss advanced surgical therapies for Parkinson
disease, appropriate patient selection, and outcomes ◆ Interpersonal and Communication Skills
of each therapy
◆ Professionalism
◆ Assess and manage the wide range of psychiatric
and cognitive complications occurring in Parkinson ◆ Systems-Based Practice
disease and dementia with Lewy bodies
◆ Diagnose and manage patients with essential

tremor and distinguish essential tremor from
other tremor disorders
◆ Develop a comprehensive approach to the diagnosis

and treatment of multiple system atrophy
◆ Diagnose and treat patients with progressive

supranuclear palsy and corticobasal syndrome
◆ Discuss the phenomenology of chorea and the

differential diagnosis and management strategies
for hereditary and acquired causes of chorea
◆ Describe the differential diagnosis, evaluation, and

management of neurodegenerative cerebellar ataxia
◆ Diagnose and classify genetic and idiopathic dystonia

and discuss the multidisciplinary treatment of
dystonia, including pharmacologic, surgical, and
rehabilitation therapies, and the emergency
treatment of status dystonicus/dystonic storm
◆ Identify the most common pediatric movement

disorders and recognize benign versus pathologic
movements in infancy and childhood with a particular
focus on treatable conditions and those that should
not be missed
◆ Discuss the role of palliative care in the treatment of

life-limiting neurodegenerative movement disorders,
including the specialized approach of palliative care
to symptom management, clinical communication,
and advance care planning
1256 O C TO B ER 2 0 2 2

LIST OF ABBREVIATIONS
MS Multiple sclerosis
Movement Disorders MSA Multiple system atrophy
MSA-C Multiple system atrophy with predominant
cerebellar ataxia
MSA-P Multiple system atrophy with predominant
5-HT2A 5-Hydroxytryptamine, serotonin receptor 2A parkinsonism
AD Alzheimer disease NBIA Neurodegeneration with brain iron accumulation
AES Apathy Evaluation Scale NfL Neurofilament light chain
AICA Anterior inferior cerebellar artery NINDS-SPSP National Institute of Neurological Disorders and Stroke
and Society for PSP
AIDS Acquired immunodeficiency syndrome
NMDA N-methyl-
-methyl-D-aspartate
AIMS Abnormal Involuntary Movement Scale
NMSQ Nonmotor Symptom Questionnaire
Anti-DNase B Anti-deoxyribonuclease B
NMSS Non-Motor Symptoms Scale
AOA Ataxia with oculomotor apraxia
NPI Neuropsychiatric Inventory
ASO Antistreptolysin O
PANDA Parkinson Neuropsychometric Dementia Assessment
ATP Adenosine triphosphate
PD Parkinson disease
ATPase Adenosine triphosphatase
PDAQ-15 Parkinson’s Daily Activities Questionnaire–15
BiPAP Bilevel positive airway pressure
PD-CFRS Parkinson Disease–Cognitive Functional Rating Scale
CANVAS Cerebellar ataxia with neuropathy and vestibular
areflexia syndrome PD-CRS Parkinson Disease–Cognitive Rating Scale
CAPOS Cerebellar ataxia, areflexia, pes cavus, optic atrophy, PDD Parkinson disease dementia
and sensorineural hearing loss [syndrome] PEG-J Percutaneous endoscopic gastrojejunostomy
CASPR2 Contactin-associated proteinlike 2 PET Positron emission tomography
CBD Corticobasal degeneration PICA Posterior inferior cerebellar artery
CBIT Comprehensive Behavioral Intervention for Tics PKAN Pantothenate kinase–associated neurodegeneration
CBS Corticobasal syndrome PPQ Parkinson Psychosis Questionnaire
CBT Cognitive-behavioral therapy PPRS Parkinson Psychosis Rating Scale
COMT Catechol-O-methyltransferase
Catechol- -methyltransferase PSP Progressive supranuclear palsy
CPAP Continuous positive airway pressure PSP-CBS Progressive supranuclear palsy with predominant
CSF Cerebrospinal fluid corticobasal syndrome
CT Computed tomography PSP-F Progressive supranuclear palsy with predominant
frontal presentation
DBS Deep brain stimulation
PSP-OM Progressive supranuclear palsy with predominant
DLB Dementia with Lewy bodies ocular motor dysfunction
DNA Deoxyribonucleic acid PSP-PGF Progressive supranuclear palsy with progressive
DNAse Deoxyribonuclease gait freezing
DRPLA Dentatorubral-pallidoluysian atrophy PSP-P Progressive supranuclear palsy with predominant
DRS-2 Dementia Rating Scale–2 parkinsonism
ECB Everyday Cognition Battery PSP-PI Progressive supranuclear palsy with predominant
postural instability
EEG Electroencephalogram
PSP-RS Progressive supranuclear palsy–Richardson syndrome
EMG Electromyography
PSP-SL Progressive supranuclear palsy with predominant
ET Essential tremor speech-language disorder
FDA US Food and Drug Administration QSART Quantitative sudomotor axon reflex test
FDG-PET Fludeoxyglucose positron emission tomography QSM Quantitative susceptibility imaging
FLAIR Fluid-attenuated inversion recovery QUIP-RS Questionnaire for Impulsive-Compulsive
FTLD Frontotemporal lobar degeneration Disorders-Rating Scale
FUS Focused ultrasound RBD Rapid eye movement sleep behavior disorder
FXTAS Fragile X tremor-ataxia syndrome REM Rapid eye movement
GABA γ-Aminobutyric
-Aminobutyric acid RT-QuIC Real-time quaking-induced conversion
GABA-ergic γ-Aminobutyric
-Aminobutyric acid–mediated SAPS-PD Scale for the Assessment of Positive Symptoms for
GAD Glutamic acid decarboxylase Parkinson Disease
GeM-HD Genetic Modifiers of Huntington’s Disease SCA Spinocerebellar ataxias
[Consortium] SCOPA-COG Scales for Outcomes of Parkinson Disease–Cognition
GPi Globus pallidus internus SLE Systemic lupus erythematosus
GRE Gradient recalled echo SNP Single-nucleotide polymorphism
HD Huntington disease SNRI Serotonin norepinephrine reuptake inhibitor
HDL Huntington disease–like SPECT Single-photon emission computed tomography
HIV Human immunodeficiency syndrome SSRI Selective serotonin reuptake inhibitor
IgG Immunoglobulin G STN Subthalamic nucleus
IM Intramuscular tDCS Transcranial direct current stimulation
IV Intravenous TMS Transcranial magnetic stimulation
IVIg Intravenous immunoglobulin TRH Thyroid-stimulating hormone (TSH)–releasing hormone
LARS Lille Apathy Rating Scale TSH Thyroid-stimulating hormone
LGI1 Leucine-rich glioma inactivated protein 1 UHDRS Unified Huntington’s Disease Rating Scale
MAO-B Monamine oxidase type B UPDRS Unified Parkinson’s Disease Rating Scale
MCI Mild cognitive impairment UPSA UCSD Performance-based Skills Assessment
MDS International Parkinson and Movement Disorder VIM Ventralis intermedius
Society
VMAT2 Vesicular monoamine transporter-2
MDS-NMS Movement Disorder Society–Nonmotor Symptoms
MIBG Metaiodobenzylguanidine
MoCA Montreal Cognitive Assessment
MRI Magnetic resonance imaging © 2022 American Academy of Neurology.
MRIgFUS Magnetic resonance imaging–guided focused
ultrasound

MOVEMENT DISORDERS
ARTICLE 1: PRODROMAL
α -SYNUCLEINOPATHIES
Lana M. Chahine, MD, FAAN. Continuum (Minneap Minn). October 2022;
28 (5 Movement Disorders):1268–1280.
ABSTRACT
PURPOSE OF REVIEW:
This article describes prodromal α-synucleinopathies.
RECENT FINDINGS:
The pathology underlying α-synucleinopathies, which include Parkinson disease, multiple
system atrophy, and dementia with Lewy bodies, begins years before the presence of the full
syndrome that is the basis for the clinical diagnosis of each of these disorders. This “prodromal”
phase may manifest with various signs or symptoms. In addition to individuals in the prodromal
phase, some individuals are asymptomatic but are at risk for α-synucleinopathies owing to
genetic predisposition or other risk factors.
SUMMARY:
Clinicians are increasingly seeing patients in the clinical setting who are prodromal or at risk for
α-synucleinopathies, and this article reviews the approach to these patient populations, which
includes identifying clinical features, assessment, and counseling.
KEY POINTS
• In determining an individual’s risk for Parkinson disease, behavioral/environmental risk factors, signs and
symptoms, and biomarker changes are best considered in combination.
• Although several environmental and behavioral factors, including some medications, have been identified as
increasing the risk of Parkinson disease, none of these medications should necessarily be prescribed or
withheld from patients until further studies link these factors as being causal in Parkinson disease.
• Both the clinical history and neurologic examination are an important part of the assessment of individuals
who may be at risk or prodromal.
• While dysautonomia is necessary for the diagnosis of multiple system atrophy, the presence of mild
dysautonomia in someone with other prodromal features does not necessarily imply a multiple system
atrophy diagnosis and can occur in people who develop Parkinson disease or dementia with Lewy bodies.
• Rapid eye movement (REM) sleep behavior disorder that occurs in the absence of secondary causes
(idiopathic or isolated REM sleep behavior disorder) is highly specific of future risk of Parkinson disease,
dementia with Lewy bodies, or multiple system atrophy.

• Based on current evidence, use of biomarkers to identify individuals with prodromal features would be best
confined to the research context and is not yet appropriate in the clinical setting.
• Criteria for identifying prodromal Parkinson disease and prodromal dementia with Lewy bodies are useful for
research but are not ready to be applied clinically for diagnostic or prognostic purposes.
• Longitudinal follow-up of individuals who are prodromal or at risk for an α-synucleinopathy may show an
evolution of parkinsonism, cognitive changes, and other signs and symptoms, which may culminate into the
clinical syndromes that constitute diagnostic criteria for Parkinson disease, dementia with Lewy bodies, or
multiple system atrophy.
• In individuals at risk or prodromal for an α-synucleinopathy, currently no treatments are proven to prevent
progression to a diagnosed disorder. However, several modifiable risk factors have been identified, and
basic risk factor reduction and modification should be instituted where appropriate.
ARTICLE 2: DIAGNOSIS AND MEDICAL

MANAGEMENT OF PARKINSON DISEASE
Avner Thaler, MD, PhD; Roy N. Alcalay, MD, MS. Continuum (Minneap Minn). October 2022;
ABSTRACT
PURPOSE OF REVIEW:
Parkinson disease (PD) is a common neurodegenerative movement disorder, the prevalence of
which is rising as the world population ages. It may present with motor and nonmotor symptoms,
and symptomatic treatment significantly improves quality of life. This article provides an
overview of the workup and differential diagnosis for PD and reviews genetic and environmental
risk factors and current treatments.
RECENT FINDINGS:
Novel treatments for the motor (eg, fluctuations and off times) and nonmotor (eg, hallucinations
and orthostatic hypotension) complications of PD have been approved in recent years. In
addition, with recent advances in our understanding of the genetics of PD, significant research is
focusing on identifying at-risk populations and introducing genetically targeted interventions
(precision medicine).
SUMMARY:
PD is a heterogeneous neurodegenerative movement disorder. Affected individuals may receive
substantial symptomatic relief from nonpharmacologic, pharmacologic, and surgical
interventions. Although no intervention to modify the progression of PD is currently available,
precision medicine and modulation of the immune system are a major focus of ongoing research.
KEY POINTS
• Older age and male sex are the most established risk factors for Parkinson disease (PD). The most established
environmental risk factor for PD is pesticide exposure.
• The seven genes clearly associated with PD risk are SNCA, LRRK2, and VPS35 (dominant); PRKN, PINK1, and
DJ-1 (recessive); and GBA (risk factor).
• The definitive diagnosis of PD is based on pathology. The two key required criteria are atrophy of
dopaminergic cells in the substantia nigra and accumulation of α-synuclein.
• The clinical diagnosis of PD was historically based on motor symptoms. More recently, nonmotor symptoms
were added to the criteria to improve accuracy.

• Postural instability, which is a feature of parkinsonism, is not a part of the International Parkinson and
Movement Disorders Society criteria for PD diagnosis as it usually appears at later stages of PD.
• Clinical red flags raise suspicion to an alternative diagnosis, most often multiple system atrophy, progressive
supranuclear palsy, or dementia with Lewy bodies.
• The Hoehn and Yahr scale is often used to capture the severity and progression of motor symptoms of PD.
The Movement Disorders Society Unified Parkinson’s Disease Rating Scale is used to quantify disease severity.
• The diagnosis of PD is primarily clinical. Ancillary diagnostic tests can be useful when the clinical diagnosis
remains unclear.
• MRI or other structural imaging may detect causes of secondary parkinsonism, such as hydrocephalus or
stroke.
• Dopamine transporter single-photon emission computed tomography may be helpful in detecting dopamine
deficiency but is less useful in tracking the progression of intermediate or advanced stages of PD or in
distinguishing PD from other neurodegenerative parkinsonian syndromes.
• Exercise and physical activity should be recommended for all patients with PD.
• No evidence exists that early pharmacologic (eg, levodopa) treatment of Parkinson disease has
disease-modifying properties. However, neither does evidence exist for the benefit of delaying
pharmacologic treatment.
• Comparing levodopa to dopamine agonists and monamine oxidase type B inhibitors has indicated that
although all three therapies are efficacious, levodopa treatment is best tolerated and maximizes
improvement in mobility scores.
• When impulse control disorder occurs, reduction in the dosage of dopamine agonist therapy is warranted;
however, this might be complicated by the development of a dopamine agonist withdrawal syndrome.
• When motor symptoms advance, a key consideration is to reduce the motor off time and fluctuations.
Continuous levodopa administration or deep brain stimulation should be considered.
• Careful adjustment of the dopaminergic treatment is a logical first step in the treatment of nonmotor
symptoms in PD.
• Hallucinations in PD may significantly impair quality of life and limit the use of dopaminergic intervention.
Careful management of hallucinations is indicated.
• Although the link between rapid eye movement (REM) sleep behavior disorder and PD is well established,
evidence on effective management of REM sleep behavior disorder is insufficient.
ARTICLE 3: SURGICAL THERAPIES FOR

PARKINSON DISEASE
Ashley E. Rawls, MD, MS. Continuum (Minneap Minn). October 2022;
ABSTRACT
PURPOSE OF REVIEW::
Parkinson disease (PD) is a progressive neurodegenerative disorder that is often difficult to
manage with medications alone. This article reviews the current therapeutic surgical
interventions for PD, patient selection criteria, timing of patient referral to surgical services,
procedure overview, and future directions.
RECENT FINDINGS:
Adaptive, or closed-loop, deep brain stimulation is a promising therapy that can detect ongoing
circuit changes and deliver appropriate stimulation based on the patient’s dominant symptom
and level of dopaminergic medication.

SUMMARY:
Patients with PD can benefit from surgical interventions that can be added to their medication
regimen. These patients should be referred to comprehensive centers that offer complete
multidisciplinary screening evaluation to ensure appropriate patient selection and intervention
selection. With the appropriate surgical intervention and continued management from their care
team, patients with PD can maximize their quality of life.
KEY POINTS
• Surgical interventions do not slow down, stop, or reverse disease progression but are used to manage the
symptoms associated with Parkinson disease.
• The three indications for deep brain stimulation surgery for the treatment of Parkinson disease include
troublesome dyskinesias, frequent dosing because of troublesome off time, and medication-resistant tremor.
• Parkinson disease symptoms that are responsive to levodopa can be improved with deep brain stimulation;
however, an exception to this is resting tremor, which may not be levodopa responsive but can still improve
with deep brain stimulation.
• Disadvantages of deep brain stimulation include risks associated with brain surgery, hardware failure,
infection risks, and concerns about patients with significant cognitive impairment.
• Deep brain stimulation can be performed on both sides of the brain and is adjustable over time.
• Commercial deep brain stimulation systems provide continuous stimulation without sensing brain signals for
feedback (ie, open loop). There is ongoing research on deep brain stimulation systems that sense brain
signals for feedback (ie, closed loop).
• MRI-guided focused ultrasound may be considered when there are restrictions to deep brain stimulation or
other reasons that prohibit brain surgery.
• MRI-guided focused ultrasound uses multiple ultrasound beams that converge on a brain target to create an
irreversible lesion.
• An advantage of MRI-guided focused ultrasound is that no foreign bodies are present in the patient following
surgery. Disadvantages include that the US Food and Drug Administration has only approved this treatment
for one side of the brain, and it is not adjustable.
• During stereotactic radiosurgery, multiple beams of radiation converge on the brain target to create an
irreversible lesion.
• An advantage of stereotactic radiosurgery is that no foreign bodies are present in the patient following
surgery. Disadvantages include that the US Food and Drug Administration has only approved this treatment
for one side of the brain, it is not adjustable, and there is potential radiation risk.
• The levodopa/carbidopa intestinal gel infusion system provides levodopa infusion through a percutaneous
endoscopic gastrojejunostomy, providing continuous levels throughout the day.
• The levodopa/carbidopa intestinal gel infusion system may not be appropriate for patients with poor
response to levodopa or who have difficulty handling the infusion pump.
• Typically, the levodopa/carbidopa intestinal gel infusion pump is on during the day and is shut off at night.
• Advantages of the levodopa/carbidopa intestinal gel infusion system include that the pump can be
disconnected when not in use and can be used in patients with significant cognitive impairment.
Disadvantages include risks associated with percutaneous endoscopic gastrojejunostomy tube placement
and maintenance.

ARTICLE 4: DIAGNOSIS AND TREATMENT
OF COGNITIVE AND NEUROPSYCHIATRIC
SYMPTOMS IN PARKINSON DISEASE AND
Daniel Weintraub, MD; David Irwin, MD. Continuum (Minneap Minn). October 2022;
ABSTRACT
PURPOSE OF REVIEW:
This article summarizes the underlying biology and current diagnostic and treatment strategies
for the cognitive and neuropsychiatric features of Parkinson disease (PD) and dementia with
Lewy bodies (DLB).
RECENT FINDINGS:
Cognitive impairment and neuropsychiatric symptoms have been increasingly recognized in PD
and DLB, leading to improved diagnosis and treatment strategies. While PD is most associated
with and diagnosed by the presence of motor symptoms, nonmotor symptoms can often be the
most debilitating for patients. Neuropsychiatric symptoms are highly prevalent nonmotor
features and include cognitive impairment, depression, anxiety, psychosis, impulse control
disorders, and apathy. Neuropsychiatric symptoms can be difficult to recognize and diagnose in
patients with PD, in part because of comorbidity and symptom overlap with core PD features.
Treatment strategies are a combination of pharmacologic and nonpharmacologic interventions
used in the general population and those specific to PD. DLB is a clinical dementia syndrome,
often with similar cognitive, behavioral, autonomic, and motor features as PD. Moreover, DLB
has shared underlying pathophysiology with PD, as both are associated with postmortem
findings of α-synuclein neuropathology at autopsy and have shared genetic risk and prodromal
symptoms. DLB is clinically differentiated from PD by the presenting features of cognitive
impairment in DLB, compared with the variable onset of cognitive impairment occurring 1year
or more after established motor onset in PD. Thus, diagnosis and treatment of cognitive
impairment and neuropsychiatric symptoms in DLB are similar to that of PD and have important
implications for maintaining patient independence and providing support for caregivers
because motor, cognitive, and neuropsychiatric symptoms have an additive effect on patient
functional disability.
SUMMARY:
A careful history and physical examination are often needed to accurately diagnose and treat the
heterogeneous cognitive and behavioral symptoms of PD and DLB. Accurate diagnosis and
treatment of neuropsychiatric symptoms and cognitive impairment in PD and DLB are important,
as these are a considerable source of patient disability and caregiver burden.
KEY POINTS
• Both Parkinson disease and dementia with Lewy bodies are classified as Lewy body disorders because of the
shared underlying α-synuclein neuropathology.
• Parkinson disease dementia and dementia with Lewy bodies are differentiated from each other by the timing
of the onset of cognitive impairment and dementia; in dementia with Lewy bodies, dementia is an early

presenting feature compared with Parkinson disease, where cognitive impairment is variable and dementia
occurs at least 1 year after the onset of motor symptoms.
• The majority of patients with Parkinson disease, especially those who are older and with long-standing
disease, develop significant cognitive impairment.
• Patients with Parkinson disease can experience impairments in any of the major cognitive domains, even at
the stage of mild cognitive impairment.
• Choice of Parkinson disease medication at disease onset does not appear to impact long-term cognitive
course, but use of medications with significant anticholinergic properties may be associated with worse
long-term cognitive outcomes.
• For Parkinson disease dementia, cholinesterase inhibitors are of modest benefit, and there is no clear
benefit for memantine. For Parkinson disease–mild cognitive impairment, no medication has been shown to
be efficacious.
• Management of comorbid medical conditions associated with cognitive impairment in Parkinson disease may
lead to improvement in cognitive abilities.
• Accurately diagnosing depression in Parkinson disease can be complicated because of symptom overlap
between depression symptoms, apathy, and core Parkinson disease symptoms.
• A range of antidepressants and Parkinson disease medications have been shown to be efficacious for the
treatment of depression in Parkinson disease.
• There is increasing evidence for the efficacy of psychotherapy for depression and anxiety in Parkinson
disease.
• Symptoms occurring as part of nonmotor fluctuations are a common presentation of significant anxiety, even
panic attacks, in Parkinson disease.
• There have been no efficacy pharmacologic randomized clinical trials for anxiety disorders in Parkinson
disease, but in clinical practice, antidepressants and sometimes benzodiazepines are used.
• It is now recognized that hallucinations in a range of sensory domains, not just visual hallucinations, can occur
in Parkinson disease.
• Management of psychosis in Parkinson disease includes a mix of trying to lessen dopamine replacement
therapy exposure and judicious use of antipsychotic medication.
• Antipsychotic use in patients with Parkinson disease may be associated with an increased risk of mortality
and morbidity, as has been reported for Alzheimer disease.
• Screening for impulsive-compulsive disorders should include the range of impulse control disorders and
related behaviors reported to occur in Parkinson disease, with attention to any comorbid disorders.
• Management of impulse control disorders and related behaviors involves a mix of decreasing dopamine
replacement therapy, particularly dopamine agonists, psychopharmacology, and psychotherapy.
• Although evidence from randomized clinical trials is limited, dopamine agonists, cholinesterase inhibitors,
and stimulants can be used in the management of apathy in Parkinson disease.
• Overall, deep brain stimulation surgery is associated with an increase in apathy symptoms postoperatively.
• Neuropsychiatric symptoms are core features of dementia with Lewy bodies. These include well-formed
spontaneous and recurrent visual hallucinations and cognitive fluctuations. Depression, anxiety, and apathy
are also common features.
• The presence of one or more pathogenic mutations in the glucocerebrosidase A gene, known to cause
autosomal recessive Gaucher disease, is an important genetic risk factor for Parkinson disease and dementia
with Lewy bodies.
• Rapid eye movement (REM) sleep behavior disorder is highly predictive of underlying α-synuclein pathology
and eventual clinical conversion to Parkinson disease or dementia with Lewy bodies.
• Patients fulfilling criteria for probable dementia with Lewy bodies are highly likely to have underlying
α-synuclein pathology, but many patients with clinical Alzheimer disease are found to also have varying
amounts of α-synuclein pathology in the brain.
• Up to 50% of all Lewy body disorders (ie, Parkinson disease, Parkinson disease mild cognitive impairment,
Parkinson disease dementia, and dementia with Lewy bodies) have sufficient plaques and tangles in the brain

postmortem for a second neuropathologic diagnosis of Alzheimer disease. These patients with mixed
pathology have a worse prognosis and unique clinical features.
• There are associations of sex and risk for Lewy body disorders, with greater frequency of men with
α-synuclein pathology.
• The clinical diagnosis of dementia with Lewy bodies often takes several years to establish in part because of
the lack of accurate diagnostic tests specific to cortical α-synuclein and the need to detect progressive
cognitive impairment for diagnosis. Efforts to increase accessibility of assessment tools for the unique
clinical neuropsychiatric symptoms can help improve diagnosis and treatment of dementia with Lewy bodies.
• Core clinical features of dementia in dementia with Lewy bodies are attention, executive, and visuospatial
dysfunction, but episodic memory and language difficulties are not uncommon and have been linked to
Alzheimer disease co-pathology.
• Cognitive fluctuations are core neuropsychiatric symptoms of dementia with Lewy bodies and can range
from periodic confusion and disorganized speech to more prolonged episodes of confusion and depressed
consciousness as well as excessive daytime fatigue. Detection and treatment of cognitive fluctuations can be
aided by standardized caregiver questionnaires.
• There is an urgent need for therapeutic trials to guide treatment decisions in dementia with Lewy bodies.
• Treatment choices in dementia with Lewy bodies need to be individualized to patient and medical
comorbidities. The heterogeneous cognitive, motor, and autonomic symptoms of dementia with Lewy bodies
often require careful selection and titration of medications since many symptomatic choices have potentially
competing mechanisms of action. Careful titration to the lowest effective dose is often a beneficial strategy.
• Data for pharmacologic and nonpharmacologic management of dementia with Lewy bodies are largely
restricted to small open-labeled trials and meta-analyses. There are considerable data and general
consensus among experts for the use of cholinesterase inhibitors as first-line treatment for cognitive
impairment and fluctuations in dementia with Lewy bodies.
• Visual hallucinations in patients with dementia with Lewy bodies are often well-formed objects such as
people, animals, or objects. Patients initially have good insight but progressively these can cause anxiety
or agitation.
• It is important to first rule out delirium or other medical etiologies for visual hallucinations and remove or
lower potentially exacerbating medications, such as dopaminergic therapies.
• The data on effective pharmacotherapy for visual hallucinations in dementia with Lewy bodies are limited.
When problematic, careful use of low-dose second-generation neuroleptics may be helpful, but it is
important to consider patient age and medical comorbidities. It is also important to first rule out delirium or
other medical etiologies and remove or lower potentially exacerbating medications such as dopaminergic
therapies.
ARTICLE 5: DIAGNOSIS AND TREATMENT

OF ESSENTIAL TREMOR
Aparna Wagle Shukla, MD. Continuum (Minneap Minn). October 2022;
ABSTRACT
PURPOSE OF REVIEW:
Essential tremor is a chronic, progressive syndrome that primarily presents with an action tremor
involving the arms and hands. This article reviews the history and physical examination features
pertinent for diagnosis, differential diagnoses, and treatments and approaches for optimal
control of symptoms.

RECENT FINDINGS:
Essential tremor is a syndrome with symptoms extending beyond tremor to involve disturbances
in gait, speech, cognition, and mood. Although the new guidelines on the definition and biaxial
classification scheme have provided clarity, some tremor experts have critiqued the recently
coined term essential tremor plus. For treatment, new orthotic devices and peripheral
stimulation devices are now available in addition to pharmacologic and surgical options.
SUMMARY:
Essential tremor has a rich clinical phenomenology with many subtleties and nuances. A detailed
history with open-ended questions and focused questions encompassing medical history, social
history, and family history is key for establishing the diagnosis. The presence of bilateral action
tremor for 3years and absence of isolated head and voice tremor and absence of task- and
position-dependent tremor are necessary for diagnosis. Dystonic tremor, Parkinson disease
tremor, physiologic tremor, and drug-induced tremor are common differential diagnoses.
Differentiating these tremor disorders from essential tremor based on phenomenology and
physical examination alone could be challenging; thus, clinicians should seek additional clues
from a detailed history. Treatment could begin with noninvasive and nonpharmacologic
therapies, especially in mild cases. As the severity increases, they can advance stepwise to
include pharmacotherapies and surgical interventions. With the growing recognition that
essential tremor is not a monosymptomatic disorder, management should involve a
multidisciplinary team. Furthermore, treatment selection should be based on shared decision
making between patients and providers that gives due consideration to severity of symptoms,
level of functional disability, impact on social interactions, patient preferences, and
patient expectations.
KEY POINTS
• The involuntary movements of essential tremor are both rhythmic and oscillatory.
• Tremor syndrome classification is biaxial, first based on clinical phenotyping and second based on
underlying etiologies.
• Essential tremor is among the most prevalent movement disorders.
• Isolated tremor syndrome of bilateral upper limb action tremor present for at least 3years is a requirement
for the diagnosis of essential tremor.
• Patients with early-onset essential tremor commonly report at least one affected first-degree family member.
• Essential tremor is a syndrome with symptoms in many patients extending beyond tremor to involve
disturbances in gait, speech, mood, and cognition.
• Essential tremor with a resting component or accompanied by soft signs of dystonic posturing or
parkinsonism is labeled as essential tremor plus; currently, no evidence has been found that essential tremor
plus is biologically distinct from essential tremor.
• Dystonic head tremor commonly affects women in their fifth decade and includes headaches, neck pain,
posturing, and isolated head tremor.
• Isolated head tremor, voice tremor, and task- or position-specific tremor should not be diagnosed as
essential tremor.
• Unlike essential tremor, dystonic head tremor often persists when the patient is examined while lying down.
• The tremor in dystonia may be neither rhythmic nor oscillatory.
• Arm tremor in dystonia is frequently unilateral and asymmetric.
• Unlike essential tremor, dystonic arm tremor may not reveal a clear axis during the spiral-drawing task.
• Based on physical examination alone, dystonic tremor may not be distinguishable from essential tremor;
history must be given consideration.
• Unlike essential tremor, resting tremor in Parkinson disease increases in amplitude with walking and mental
calculation and is generally asymmetric.

• Unlike essential tremor, arm tremor in Parkinson disease reveals a reemergent quality (a tremor that occurs
after a finite latency period from the time the patient assumes a horizontal posture of the arm to the onset of
the wrist and/or finger tremor).
• In contrast to essential tremor, the jaw tremor of Parkinson disease is more often noted when the patient’s
mouth is closed and relaxed rather than while the patient is speaking.
• Head tremor is not a feature of enhanced physiologic tremor or drug-induced action tremor.
• Holmes tremor has resting, postural, and kinetic components.
• Fragile X-associated tremor/ataxia syndrome has a prominent intentional component.
• Wilson disease has prominent wing-beating postural tremor.
• Functional tremor is abrupt in onset and distractible, suggestible, and entrainable.
• Management of essential tremor requires a multidisciplinary team, and treatment selection requires shared
decision making between patients and providers.
• Adaptive tools, orthotic devices, limb cooling, and peripheral stimulation devices are useful
nonpharmacologic therapies for essential tremor.
• If the tremor is severity does not reduce despite multiple medication trials, surgical intervention may be warranted.

Daniel O. Claassen, MD, MS, FAAN. Continuum (Minneap Minn). October 2022;
ABSTRACT
PURPOSE OF REVIEW:
Patients with multiple system atrophy (MSA) can present with diverse clinical manifestations,
and the clinical care required is complex and requires a thoughtful approach to emerging
symptoms and treatment decisions.
RECENT FINDINGS:
Even though it is a rare disease, MSA is often encountered in clinical practice. New
developments in biofluid biomarkers and diagnostic assessments offer potential for earlier and
more accurate diagnosis. This article describes recent findings, such as the use of skin biopsies,
neuroimaging, and novel treatment concepts (eg, central noradrenergic augmentation).
SUMMARY:
MSA is a complex disease. This article provides a summary of treatment options for diverse
symptoms that include autonomic, sleep, mood, and motor manifestations of the disease to help
clinicians care for patients with MSA. Providing comprehensive care for patients with MSA
requires an understanding of the diverse symptomatology that patients develop over time and
should include an interdisciplinary team.
KEY POINTS
• Although multiple system atrophy (MSA) has been designated as MSA with predominant parkinsonism or
MSA with predominant cerebellar ataxia, it is more common to see an overlap of symptoms that make this
distinction difficult.
• The most common prodromal symptoms for MSA include rapid eye movement (REM) sleep behavior disorder
and autonomic failure.
• Patients with pure autonomic failure have a high likelihood of progressing to a central α-synuclein disease;
those who progress to MSA tend to be younger and have intact smell and an increase in heart rate after 3
minutes of standing up from a supine position.

• A reduction of systolic blood pressure of at least 20mm Hg or diastolic blood pressure of at least 10 mm Hg
within 3 minutes of standing without compensatory heart rate increase is diagnostic of orthostatic
hypotension.
• Elevating the head of the bed during the night should be encouraged in the management of supine
hypertension in patients with MSA.
• Early integration of physical therapy and gait safety is key in managing MSA gait symptoms.
• Identifying pain symptoms is important in maintaining the quality of life of patients with MSA.
• Clinicians can educate local counselors or social workers about the nature of MSA to help establish the
framework and goals for interactions.
• The use of activity of daily living screening tools for patients, such as the Unified Multiple System Atrophy
Rating Scale Part 1, can help direct care of patients with MSA.
ARTICLE 7: PROGRESSIVE
SUPRANUCLEAR PALSY AND
CORTICOBASAL SYNDROME
Alexander Pantelyat, MD, FAAN. Continuum (Minneap Minn). October 2022;
ABSTRACT
PURPOSE OF REVIEW:
The differential diagnosis of parkinsonism (tremor, rigidity, bradykinesia, and gait difficulty/
postural instability) is broad and includes two neurodegenerative conditions that exist on a
clinicopathologic spectrum: progressive supranuclear palsy (PSP) and corticobasal syndrome
(CBS). Early in their clinical course, PSP and CBS may be difficult to distinguish from Parkinson
disease and several other illnesses, but it is crucial to do so because of implications for
management and prognosis.
RECENT FINDINGS:
Early accurate diagnosis of PSP and CBS remains a challenge because of heterogeneity in
presenting symptoms and high frequency of coexisting pathologies (especially Alzheimer
disease and vascular disease). It is increasingly recognized that patients with PSP, CBS, and other
parkinsonian disorders require multidisciplinary care for optimal outcomes. With the recent
proliferation of biomarker studies and therapeutic trials for tauopathies, there is growing hope
that better treatments for PSP and CBS are on the horizon.
SUMMARY:
Although PSP and CBS currently lack disease-modifying therapies, it is important to diagnose
them as early as possible so that the patient can benefit from the many available symptomatic
therapies, support groups, and a growing number of clinical trials.
KEY POINTS
• The pathologic hallmark of progressive supranuclear palsy is the presence of tau protein isoforms with four
microtubule-binding repeats (4-repeat tau), in astrocytic tufts (most specific for progressive supranuclear
palsy), oligodendrocytic coils, and neurofibrillary tangles (least specific).

• It is important to perform genetic testing in patients with early age at symptom onset or a clear family history
of atypical parkinsonism. Among genetic mimics of progressive supranuclear palsy, Niemann-Pick disease
type C stands out, as it is a treatable condition.
• Progressive supranuclear palsy–Richardson syndrome (classic progressive supranuclear palsy) refers to
akinetic-rigid parkinsonism with early falls and vertical eye movement impairment.
• Current clinical diagnostic criteria for progressive supranuclear palsy include levels of diagnostic certainty
that offer trade-offs between specificity and sensitivity.
• Optokinetic nystagmus testing can be helpful in assessing saccades if gross saccade testing is equivocal.
• Progressive supranuclear palsy–parkinsonism is the second most common progressive supranuclear palsy
variant and can be difficult to distinguish from Parkinson disease for several years from symptom onset.
• The parkinsonism in progressive supranuclear palsy–parkinsonism can be tremor-predominant or
akinetic-rigid and may have a levodopa response, although typically without motor fluctuations
or dyskinesias.
• Frontal-executive cognitive impairment is an important feature of both progressive supranuclear palsy and
• Key differential diagnosis considerations for progressive supranuclear palsy include Parkinson disease, other
degenerative parkinsonian disorders (such as dementia with Lewy bodies and multiple system atrophy),
normal pressure hydrocephalus, and vascular parkinsonism.
• The easily measured ratio of midsagittal midbrain to pontine base distances on T1-weighted MRI of less than
0.5 is highly sensitive and specific for progressive supranuclear palsy–Richardson syndrome but not other
progressive supranuclear palsy variants.
• Corticobasal syndrome refers to the patient’s clinical presentation and typically includes asymmetric
presentation of limb rigidity, akinesia, dystonia, myoclonus, and apraxia. Corticobasal degeneration is the
term referring to specific 4-repeat tau pathology on brain autopsy.
• Corticobasal degeneration is most specifically characterized by astrocytic plaques, whereas progressive
supranuclear palsy has tufted astrocytes.
• Corticobasal degeneration pathology accounts for only about 50% of corticobasal syndrome cases. The
remainder of corticobasal syndrome cases are due to progressive supranuclear palsy, Alzheimer disease, and
rarely other pathologies.
• Although it is a classic sign, alien limb phenomenon occurs in only about 20% of patients with
autopsy-confirmed corticobasal degeneration.
• When completing a levodopa trial in progressive supranuclear palsy or corticobasal syndrome, maintain
maximum tolerated levodopa dose for at least 1 month before gradual tapering.
• Dopaminergic medications other than levodopa are best avoided in progressive supranuclear palsy and
corticobasal syndrome because of side effects and lack of efficacy.
• Anticholinergic medications should be avoided in progressive supranuclear palsy and corticobasal syndrome
whenever possible because of the risk of worsening cognitive impairment.
• Pseudobulbar affect is a symptom of both progressive supranuclear palsy and corticobasal syndrome and
may improve with selective serotonin reuptake inhibitors or dextromethorphan/quinidine.
• Depression and anxiety are common in progressive supranuclear palsy and corticobasal syndrome; selective
serotonin reuptake inhibitors can be effective at standard doses.
• Modafinil or methylphenidate may be helpful for apathy in progressive supranuclear palsy and corticobasal
syndrome.
• Botulinum toxin injections can help a range of symptoms in progressive supranuclear palsy and corticobasal
syndrome, including sialorrhea, cervical and limb dystonia/spasticity, muscle pain, and eyelid opening
apraxia/blepharospasm.
• Rehabilitation plays a key role in improving and maintaining function in progressive supranuclear palsy and
corticobasal syndrome and should be maintained throughout the entire disease course.
• Physical therapy targets gait and balance rehabilitation and fall prevention in progressive supranuclear palsy
and corticobasal syndrome.

• Occupational therapy targets upper extremity function, range of motion, and adaptive device use in
progressive supranuclear palsy and corticobasal syndrome.
• Speech/swallow therapy targets dysarthria, aphasia, and dysphagia in progressive supranuclear palsy and
• Periodic swallow evaluations help assess aspiration risk and guide dietary modifications for liquids and
solids.
• The number of clinical trials for progressive supranuclear palsy and corticobasal syndrome is growing, and it
is important to refer patients for trial screening as early as possible.
ARTICLE 8: CHOREA
Erin Furr Stimming, MD, FAAN; Danny Bega, MD. Continuum (Minneap Minn).
October 2022; 28 (5 Movement Disorders):1379–1408.
ABSTRACT
PURPOSE OF REVIEW:
This article provides an overview of the diagnostic and therapeutic approach to a patient with
chorea. The phenomenology of chorea is described in addition to other common hyperkinetic
movements that may be mistaken for or coexist with chorea. Chorea can be acquired or
hereditary. Key historical and clinical features that can aid in determining the etiology are
reviewed, and pharmacologic and nonpharmacologic treatment strategies are discussed.
RECENT FINDINGS:
Clinical investigations are under way to target transcription and translation of the mutant
huntingtin protein as a potential disease-modifying strategy in Huntington disease (HD).
Additional heritable factors have been revealed through genome-wide association studies.
Symptom-focused treatments for HD are are being studied, including a third vesicular
monoamine transporter-2 (VMAT2) inhibitor for chorea attenuation and drugs to target irritability
and cognitive impairment. Increased availability of genetic testing has led to increased
awareness of HD mimics (eg, C9orf72 and IgLON5).
SUMMARY:
Chorea is a relatively common hyperkinetic disorder with a broad differential. The first step in
the approach to a patient with chorea is accurately defining the phenomenology. Once it has
been determined that the patient has chorea, the investigation into determining an etiology can
begin. Factors such as age of onset, time course, family history, unique clinical features, and
imaging and laboratory findings can guide the diagnosis. Treatments for most causes of chorea
are purely symptomatic, although it is important to recognize causes that are reversible or have
disease-modifying interventions.
KEY POINTS
• Chorea refers to random, irregular, purposeless movements that flow from one body part to the next.
• Chorea is generalized in many patients; however, its localized distribution may act as an important diagnostic
factor to determine the underlying etiology. For example, forehead involvement is more common in
Huntington disease. Orobuccolingual chorea is more common in tardive syndromes.
• Because the differential diagnosis for chorea is broad, it is generally helpful to begin by categorizing chorea
as (1) inherited versus acquired and (2) childhood onset versus adult onset.
• Clues to differentiate inherited choreas from acquired choreas include the timeline (acute, subacute, or
chronic [>1 year]) and course (static, paroxysmal, or progressive).

• Huntington disease is the most common cause of adult-onset hereditary chorea. It is imperative that genetic
counseling occur before testing.
• Huntington disease mimics or phenocopies include several inherited rare degenerative conditions and may
be associated with the triad of chorea, dementia, and behavioral disturbances.
• Pathogenic variants in ATN1 dentatorubral pallidoluysian atrophy are associated with characteristic MRI
changes in the dentate, red nucleus, and pallidum.
• Pathogenic variants in C9orf72 can mimic Huntington disease, but variable expression may also include
amyotrophic lateral sclerosis and frontotemporal dementia.
• Pathogenic variants in VPS13A cause chorea-acanthocytosis, with characteristic orobuccolingual chorea and
acanthocytes on blood smear. McLeod syndrome is an X-linked form.
• Chorea can result from abnormal mineral accumulation in the basal ganglia. This includes iron
(neurodegeneration with brain iron accumulation), calcium (Fahr disease), and copper (Wilson disease), each
of which may have corresponding MRI abnormalities.
• Mutations in ADCY5 are associated with childhood hypotonia. The chorea that may develop worsens with
sleep deprivation.
• Paroxysmal disorders of chorea have characteristic triggers. Paroxysmal nonkinesigenic dyskinesia is
triggered by stress, extremes of temperature, alcohol, or excitement. Paroxysmal kinesigenic dyskinesia
episodes are shorter and more frequent and triggered by movement.
• Sydenham chorea is the most common cause of chorea in childhood.
• Antiphospholipid antibodies are associated with systemic lupus erythematosus, hypercoagulability,
and chorea.
• IgLON5 is an antibody that has been discovered recently in association with parasomnias but can be
associated with cognitive impairment, gaze palsies, and chorea.
• Structural or vascular lesions should be considered in cases of focal or hemibody chorea.
• Dopaminergic medications and antidopaminergic medications can cause choreiform movements. Careful
medication history and timeline of exposure are important.
• Hyperglycemia is a common metabolic cause of acute-onset chorea associated with T1 signal change in the
contralateral putamen on MRI.
• It is important to determine whether chorea is troublesome or bothersome before initiating a medication.
Anosognosia is not uncommon, especially in Huntington disease; therefore, collecting input from the patient
and their care partner is essential.
• Vesicular monoamine transporter-2 (VMAT2) inhibitors are the only class of medications currently approved
by the US Food and Drug Administration for the treatment of tardive dyskinesia and/or chorea associated
with Huntington disease.
ARTICLE 9: NEURODEGENERATIVE
CEREBELLAR ATAXIA
Liana S. Rosenthal, MD, PhD. Continuum (Minneap Minn). October 2022;
ABSTRACT
PURPOSE OF REVIEW:
Neurodegenerative cerebellar ataxia is a diverse collection of diseases that are unified by gait
and balance abnormalities, appendicular incoordination, and abnormalities of eye movement
and speech. The differential diagnosis is broad, ranging from paraneoplastic syndromes that
progress quite rapidly to unidentified genetic disorders that progress slowly over the course of

decades. This article highlights the diagnostic process, including the differential diagnosis, as
well as treatment approaches and symptomatic management. The pillars of treatment are
physical, occupational, and speech therapy as well as counseling and discussions of disease
prognosis, genetics, and reproductive choices. There are many ways to help patients with
neurodegenerative cerebellar ataxia and improve their quality of life.
RECENT FINDINGS:
Recent years have seen significant improvements in genetic testing, with reductions in cost of
both Sanger sequencing and whole exome sequencing and increasing availability of the latter.
These improvements increase clinicians’ ability to identify the etiology of neurodegenerative
cerebellar ataxia and suggest future treatments. Although no medication has been approved by
the US Food and Drug Administration (FDA) for treatment of cerebellar ataxia, research and
clinical trials for these diseases are increasing.
SUMMARY:
Neurodegenerative cerebellar ataxia is characterized by dysarthria, dysmetria, oculomotor
abnormalities, and ataxic gait. It has a broad differential diagnosis, and numerous options exist
for managing symptoms. Although no medications have been approved specifically for
cerebellar ataxia, treatment options are available to improve patients’ quality of life.
KEY POINTS
• Ataxia can be classified into three broad types: (1) sensory ataxia due to neuropathy in the feet; (2) vestibular
ataxia due to dysfunction of the semicircular canals, otolith organs, or both; and (3) cerebellar ataxia due to
dysfunction of the cerebellum.
• The vermis is responsible for axial function, while the paravermis is responsible primarily for limb function.
• Patients with cerebellar ataxia describe falls and clumsiness but often describe the initial symptoms as being
difficulty maintaining balance on uneven ground, when going up or (primarily) down stairs, or when running.
• Examination of individuals with cerebellar ataxia usually reveals a wide-based gait with some titubation
observed, specifically on turns.
• Speech, swallowing, and eye movement abnormalities are especially important for cerebellar localization, as
these findings indicate that the lesion is above the spinal cord.
• Eye movement changes, specifically downbeat nystagmus, square-wave jerks, and hypermetric or
hypometric saccades, are often the best way to localize the patient’s ataxia to the cerebellum.
• Individuals with cerebellar lesions often report difficulty meeting their target with their hands, while
individuals with extrapyramidal lesions often report that their fingers will not do what their brain is asking.
• Individuals with cerebellar ataxia without extrapyramidal involvement often demonstrate pauses and
clumsiness on finger tapping, hand opening and closing, and pronation and supination but do not have a
decrementing bradykinesia.
• Individuals with what is known as cerebellar cognitive affective syndrome present with challenges in
executive function, linguistic processing, and spatial cognition.
• Absence of cerebellar atrophy does not change the localization, as an overall normal-sized cerebellum may
be observed even among individuals with significant cerebellar dysfunction. The presence of cerebellar
atrophy, though, helps to confirm the localization.
• Testing for nongenetic and then genetic etiologies is an iterative process, circling back on each possibility to
ensure that all reasonable and appropriate testing to identify the etiology has occurred.
• When evaluating the results of blood work, it is important to distinguish between those results that
are outside of normative values and those results that are actually diagnostic for the cause of the
cerebellar ataxia.
• For many of the genetically identified spinocerebellar ataxias, as well as other genetic diseases, in vitro
fertilization with preimplantation genetic diagnosis allows for eradication of the genetic disease in the
next generation.

• If genetic testing is not successful in identifying the etiology of cerebellar ataxia, the next step is to evaluate
for other diagnostic possibilities.
• The most important principle in the treatment of neurodegenerative cerebellar ataxia is that although no
disease-modifying therapy or even medications specifically approved to treat cerebellar ataxia are currently
known, there is always something that can be done to improve the individual’s quality of life.
• Exercise has been shown to improve ataxia motor symptoms and is critical to maintain function for as long
as possible.
• Swallowing difficulties may be treated by behavioral modifications or dietary changes, both of which have
been shown to be effective.
• Several therapies for neurodegenerative cerebellar ataxias are in earlier stages of development, increasing
the possibilities for new symptomatic or even disease-modifying therapies in the future.

Christopher D. Stephen, MB ChB, FRCP, SM. Continuum (Minneap Minn).
October 2022; 28 (5 Movement Disorders):1435–1475.
ABSTRACT
PURPOSE OF REVIEW:
This article discusses the most recent findings regarding the diagnosis, classification, and
management of genetic and idiopathic dystonia.
RECENT FINDINGS:
A new approach to classifying dystonia has been created with the aim to increase the recognition
and diagnosis of dystonia. Molecular biology and genetic studies have identified several genes
and biological pathways involved in dystonia.
SUMMARY:
Dystonia is a common movement disorder involving abnormal, often twisting, postures and is a
challenging condition to diagnose. The pathophysiology of dystonia involves abnormalities in
brain motor networks in the context of genetic factors. Dystonia has genetic, idiopathic, and
acquired forms, with a wide phenotypic spectrum, and is a common feature in complex
neurologic disorders. Dystonia can be isolated or combined with another movement disorder
and may be focal, segmental, multifocal, or generalized in distribution, with some forms only
occurring during the performance of specific tasks (task-specific dystonia). Dystonia is classified
by clinical characteristics and presumed etiology. The management of dystonia involves
accurate diagnosis, followed by treatment with botulinum toxin injections, oral medications, and
surgical therapies (mainly deep brain stimulation), as well as pathogenesis-directed treatments,
including the prospect of disease-modifying or gene therapies.
KEY POINTS
• The term dystonia can be used as both a clinical descriptor of an abnormal posture, frequently with a
twisting, patterned quality and a group of diseases, where dystonia is the main clinical feature.
• The dystonias include idiopathic, genetic, acquired, and other causes. No reliable diagnostic test (outside
of genetic testing) currently exists, as imaging and laboratory testing are typically normal in patients
with dystonia.
• Clinical features of dystonia include influence by voluntary action, overflow/mirror dystonia, and a “null
point.” Sensory tricks should be specifically inquired about and assessed on examination.

• Dystonia is classified based on clinical characteristics (age of onset, body distribution, temporal pattern, and
associated clinical features) and etiology (underlying nervous system pathology or whether the condition is
inherited, acquired, or idiopathic).
• Nomenclature of genetic dystonias involves referring to the movement disorder type (including if combined)
and gene name, not DYT locus, using recently updated criteria.
• The diagnosis of dystonia is challenging. Common misdiagnoses occur in patients thought to have Parkinson
disease, essential tremor, myoclonus, tics, functional (“psychogenic”) dystonia, headaches, and scoliosis.
• Despite increasing recognition, limited data exist on dystonia epidemiology. Given the common
misdiagnoses, the prevalence of dystonia may be up to 1 in 1000 individuals. There are age, sex, racial, ethnic,
and geographic variations.
• Adult-onset idiopathic focal/segmental dystonias are the most common dystonic conditions and
infrequently generalize, although there may be progression over time. These include cervical, cranial,
oromandibular, laryngeal, limb, and truncal dystonia.
• Many genetic forms of dystonia exist. Genetic isolated dystonias are mainly autosomal dominant.
• Autosomal recessive dystonia is much less common than autosomal dominant cases and should be
suspected if there are multiple affected individuals within the same generation, but not in their parents, or
parental consanguinity.
• Combined dystonias involve dystonia and other movement disorders, frequently parkinsonism or myoclonus.
Considerable clinical and genetic heterogeneity exists.
• The paroxysmal dystonias/dyskinesias are rare disorders involving episodic hyperkinetic movements,
including dyskinesia or dystonic movements. These are typically early-onset disorders arising in childhood or
adolescence, occurring very rarely after age 18.
• The first step of management requires accurate diagnosis. If an idiopathic (generally late-onset) dystonia is
suspected, further diagnostic workup is not typically necessary.
• Directed workup includes laboratory testing to rule out Wilson disease and neuroimaging followed by
specific targeted testing, including genetic testing with concomitant genetic counseling.
• Treatment of dystonia depends on the diagnosis (idiopathic versus genetic) and whether potential
pathogenesis-directed treatments are available. Symptomatic medical therapy often involves botulinum
toxin injections, oral medications, and rehabilitation, with deep brain stimulation considered for
treatment-refractory cases or conditions where good evidence of efficacy exists.
• Disorders for which pathogenesis-directed treatments are available include dopa-responsive dystonia,
Wilson disease, the paroxysmal dyskinesias, and rare, complex metabolic dystonias. All young-onset cases
should have a trial of levodopa to assess for dopa-responsive dystonia.
• The goal of symptomatic therapy for dystonia is to provide relief from abnormal movements/postures,
associated pain and discomfort, contractures or other orthopedic complications of sustained abnormal
postures, and medical comorbidities, including neuropsychiatric symptoms. This should be individualized for
each patient.
• Treatment of drug-induced/tardive dystonia involves early diagnosis and discontinuation of the offending
drug, discontinuation of anticholinergics, and specific antidyskinetic medications, with DBS considered in
severe, refractory cases.
• Botulinum toxin injections form the cornerstone of focal dystonia treatment. Serotypes A and B are approved
for treatment. Patients generally receive injections every 12 weeks, although many patients experience a
shorter duration of effect. Patients rarely develop neutralizing antibodies, and this can be assessed with a
“frontalis test.”
• Oral medications for dystonia treatment are generally considered in cases of generalized dystonia or more
severe disease and are much better tolerated in younger patients. These mainly involve dopaminergic
therapy, anticholinergics, baclofen, and benzodiazepines.
• The paroxysmal dystonias/dyskinesia have specific treatments: Paroxysmal kinesigenic dystonia/dyskinesia
is treated with anti-seizure medications, (typically carbamazepine or oxcarbazepine); paroxysmal
nonkinesigenic dystonia/dyskinesia is typically treated with low-dose benzodiazepines; and paroxysmal

exercise/exertion-induced dystonia/dyskinesia is treated with ketogenic diet, L-carnitine supplementation,
and triheptanoin.
• Noninvasive brain stimulation is a developing area of potential therapy for dystonia but has mainly been used
for research purposes and includes transcranial magnetic stimulation and transcranial direct current
stimulation.
• Surgical treatments of dystonia include intrathecal baclofen pumps, ablative lesioning, and deep brain
stimulation.
• Focused ultrasound has evidence for efficacy for dystonia, although symptom recurrence is possible,
requiring repeat lesioning. This is only approved for unilateral use.
• DBS has potential advantages over focused ultrasound, including a more favorable side effect profile, the
potential for reversibility, and the ability to adjust the stimulation direction and field. The main stimulation
site is the globus pallidus internus; however, efficacy has also been demonstrated in targeting the
subthalamic nucleus and thalamus. Cerebellar stimulation is currently under investigation.
• Status dystonicus/dystonic storm is a medical emergency, fatal in 10%. Precipitants include infection,
medication changes, or deep brain stimulation hardware failure. Management involves treating triggers
and oral dystonia therapies followed by intensive care unit–level care and consideration of rescue deep
brain stimulation.
ARTICLE 11: DIAGNOSING COMMON

MOVEMENT DISORDERS IN CHILDREN
Jennifer A. O’Malley, MD, PhD. Continuum (Minneap Minn). October 2022;
ABSTRACT
PURPOSE OF REVIEW:
This article is designed to help the clinician identify the most common pediatric movement
disorders and recognize benign versus pathologic movements in infancy and childhood, with a
particular focus on treatable conditions and those that should not be missed.
RECENT FINDINGS:
As telehealth has become more prevalent as a means of providing health care services, the
challenges of obtaining relevant examination findings during telehealth encounters for
assessment of children with movement disorders have become evident.
SUMMARY:
Although many children who present with a chief complaint of “abnormal movements” are found
to have a benign, self-resolving etiology, it is critical that neurologists accurately recognize
benign versus pathologic movements in children to ensure appropriate diagnosis and
intervention.
KEY POINTS
• Developmental control of voluntary movement begins at the head and neck and progresses to the trunk and
then the extremities (rostrocaudal gradient).
• Coordinated movement involves the whole brain, not just the basal ganglia and motor cortices but also the
brainstem, limbic system, cerebellum, frontal lobes, and nonmotor pathways.
• Voluntary movement involves an intricate balance of “stop and go” signaling, with dopamine playing the role
of fine motor modulator.

• Understanding phases of movement (motor planning, initiation, and execution) can help to better identify
abnormal movements.
• The clinician should ask the child about their movements: what, where, when, with whom, wax/wane,
worsening, why (Why do you think you have these movements?) (What do you want help with?).
• The clinician should pay careful attention to developmental milestones and watch for signs of subtle delay
when evaluating a child for movement disorders.
• The clinician should dig deep on family history; encourage parents to ask their families about their own
childhood movements when evaluating a child presenting with a movement disorder.
• Understand both the manifestation and functional impact of movements in multiple environments when
evaluating a child presenting with a movement disorder.
• Ask about and normalize worry to further explore the role of anxiety when evaluating a child presenting with
a movement disorder.
• Understanding of developmental milestones is key to recognizing normal versus abnormal movements.
• Observation is an essential skill for the pediatric movement examination.
• Making the examination fun and using play to elicit movement patterns is key to an efficient and thorough
movement examination in children.
• Tone is dynamic. Accurate and thorough understanding of tone demands examination in multiple states
(at rest, with activity, while asleep).
• Many abnormal movements in children are benign and will resolve with development.
• Tics and stereotypies are the most common benign movement disorders in childhood.
• Benign motor stereotypies typically do not require intervention.
• Urge and suppressibility are key features of tics.
• Nonpharmacologic interventions for tics include comprehensive behavioral intervention for tics.
• Movement disorders in children can present with phenomenology similar to that in adults and may be
categorized as chorea, dystonia, myoclonus, tremor, ataxia, spasticity, and parkinsonism.
• Unlike adults, children often present with a mixed movement disorder; thus, discerning the primary
phenomenology can be challenging but remains the foundation of accurate and timely diagnosis
and treatment.
• Sydenham chorea is a common cause of treatable acute-onset chorea in children. Early recognition and
diagnosis allow for appropriate intervention with steroids for symptom management.
• Symptom severity in Sydenham chorea is highly variable, but children commonly present with complaints of
new clumsiness (dropping items, falling), gait instability, irritability, poor coordination, and possible changes
in speech and behavior.
• Sydenham chorea is a form of rheumatic disease; thus, screening and monitoring for associated cardiac
involvement are imperative.
• Genetic causes for chorea should be considered in any child with new-onset subacute progressive chorea,
especially if accompanied by other neurologic or psychiatric features.
• For the child with spasticity and dystonia, surgical intervention must be considered carefully, as certain
interventions for spasticity (in particular, selective dorsal rhizotomy) may improve the spasticity but
“unmask” concurrent dystonia, resulting in worsened motor function.
• Surgical candidates should be evaluated by a multidisciplinary review board including specialists in
neurology, neurosurgery, and physical, occupational, and speech therapy, as well as undergo a thorough
psychosocial evaluation.
• Surgical intervention with pallidal deep brain stimulation should not be delayed for children with
medication-refractory progressive dystonia.
• It is always prudent to trial levodopa for any child with dystonia to rule out a treatable dopa-responsive dystonia.
• Examples of benign physiologic myoclonus include hiccups, exercise- or anxiety-induced myoclonus, benign
neonatal sleep myoclonus, or hypnic jerks in older children.
• The most common causes of tremor in children are the primary tremors: developmental tremor, enhanced
physiologic tremor, and essential tremor.

• The clinician should obtain a thorough family history and examination of accompanying family members at
the time of neurologic examination for tremor.
• Toxic ingestion is at the top of the differential diagnosis for acute ataxia.
• Clinical distinction between spasticity, dystonia, and rigidity is essential for accurate diagnosis and
appropriate treatment of the hypertonic child.
• Although spastic cerebral palsy is the most common type, many children with cerebral palsy present with a
mixed movement disorder.
• Key principles regarding the diagnosis of cerebral palsy are as follows: (1) Cerebral palsy is a clinical
description and not an etiology. (2) Cerebral palsy is a permanent disability. (3) Cerebral palsy is a
nonprogressive brain process, but the physical manifestations of the disorder are not necessarily static.
• Botulinum toxin injections for focal spasticity are approved by the US Food and Drug Administration for
children 2 years old and older and may be used in isolation or in conjunction with oral medications.
• Recognition of spasticity and distinction from dystonia and rigidity is particularly important when considering
possible etiologies as well as appropriate therapeutic interventions for cerebral palsy.
• Some surgical procedures targeting spasticity, such as selective dorsal rhizotomy, may actually worsen a
patient’s function if their dystonia is mistaken for spasticity.
• Parkinsonism in infants may be difficult to identify as such and should be considered for any infant with
hypotonia and reduced movement of undetermined etiology.
• Early and accurate diagnosis of functional movement disorders avoids excessive medical testing and
treatment and delayed diagnosis and enables implementation of appropriate interventions.
• Diurnal fluctuation of symptoms may point to an underlying neurometabolic disorder.
• Potentially life-threatening drug-induced movement disorders include acute dystonic reaction, neuroleptic
malignant syndrome, and serotonin syndrome.
• It is prudent to consider referral for pediatric deep brain stimulation for any child with medication-refractory
dystonia, chorea, or tremor.
ARTICLE 12: PALLIATIVE CARE AND

MOVEMENT DISORDERS
Maya Katz, MD. Continuum (Minneap Minn). October 2022;
ABSTRACT
PURPOSE OF REVIEW:
This article reviews the role of palliative care in the treatment of patients with life-limiting
neurodegenerative movement disorders.
RECENT FINDINGS:
Growing evidence indicates that palliative care significantly improves quality of life and
symptom burden for people with Parkinson disease and other serious movement disorders,
while reducing caregiver burnout. An emphasis on advance care planning guides goal-directed
treatment recommendations. Serious illness communication skills are evidence-based methods
of relaying bad medical news to patients and mapping out values and goals in a way that provides
comfort, emphasizes patient autonomy, and builds coping and resiliency strategies.
SUMMARY:
Palliative care, when offered alongside primary medical and neurologic teams, provides an extra
layer of support for people with serious illnesses. The goal of palliative care is to intensively treat

total pain, which includes all of the physical, emotional, social, and spiritual distress caused by
serious illness. Serious illness communication skills are key to providing empathic and
goal-concordant care.
KEY POINTS
• Palliative care is specialized medical care for people with serious, life-limiting illness.
• Total pain is a key concept in palliative care that is defined as all of the physical, emotional, social, and
spiritual distress caused by serious illness.
• The total symptom burden measured in Parkinson disease has been found to be similar to the total symptom
burden reported in metastatic cancer and amyotrophic lateral sclerosis.
• Caregivers often experience serious adjustment reactions, burnout, chronic grief, and anticipatory grief.
• Growing evidence shows that palliative care significantly improves quality of life and symptom burden for
people with Parkinson disease and other serious movement disorders, while reducing caregiver burnout and
improving advance care planning.
• Palliative care is applicable at all stages of serious illness and in conjunction with other treatments that are
focused on prolonging life.
• Palliative care serious illness communication skills are evidence-based teachable techniques that enable
clinicians to break bad medical news and discuss advance care planning in a way that provides comfort,
improves patient and caregiver coping, and guides treatment recommendations.
• The SPIKES protocol is a palliative care communication technique used when giving a serious illness
diagnosis. SPIKES stands for: setting, perception, invitation, knowledge, emotions, and strategy.
• The REMAP protocol is a palliative care communication technique developed by VitalTalk that is used when
there is significant worsening of the serious illness. REMAP stands for: reframe, expect emotion, map out,
align, and plan.
• The high rates of dementia and communication difficulties that occur owing to neurodegenerative movement
disorders makes discussing advance care planning early in the course of the illness critical.
• A documented advance care plan increases the likelihood of dying at home with hospice in a population of
people with Parkinson disease, and movement disorders palliative care clinics have been shown to increase
advance care planning.
• Requests for medical-aid-in-dying medications are typically a cry for help due to unbearable symptoms from
a serious illness and are not usually disclosures of suicidal ideation.
• Palliative care considers clinicians to also be caregivers, with a high risk of caregiver burnout. Palliative care
makes preventing clinician burnout a top priority by placing importance on developing a balanced lifestyle,
building coping and resiliency skills, and developing systems-level improvements.
• The stigma surrounding the word “palliative” deters clinicians from recommending the treatment and deters
patients/caregivers from accepting the care. Supportive care has been shown to be much better received by
both clinicians and patients and caregivers.
• Palliative care emphasizes a holistic approach, patient autonomy, aggressive symptom management of total
pain, concern for the family, and clinical teamwork to provide goal-concordant care that focuses on
optimizing quality of life for people dealing with serious, life-limiting illness.

Issue Overview
Movement Disorders, Volume 28, Number 5, October 2022
Continuum: Lifelong Learning in Neurology® is designed to help practicing neurologists stay
abreast of advances in the field while simultaneously developing lifelong self-directed learning
skills.
Learning Objectives
Upon completion of this Continuum: Lifelong Learning in Neurology Movement Disorders issue,
participants will be able to:
 Assess and manage individuals who are prodromal or at risk for α-synucleinopathies
 Describe the key symptoms, prodromal stage, genetic basis, and current treatments of
Parkinson disease
 Discuss advanced surgical therapies for Parkinson disease, appropriate patient selection,
and outcomes of each therapy
 Assess and manage the wide range of psychiatric and cognitive complications occurring
in Parkinson disease and dementia with Lewy bodies
 Diagnose and manage patients with essential tremor and distinguish essential tremor from
other tremor disorders
 Develop a comprehensive approach to the diagnosis and treatment of multiple system

atrophy
 Diagnose and treat patients with progressive supranuclear palsy and corticobasal
syndrome
 Discuss the phenomenology of chorea and the differential diagnosis and management
strategies for hereditary and acquired causes of chorea
 Describe the differential diagnosis, evaluation, and management of neurodegenerative

cerebellar ataxia
 Diagnose and classify genetic and idiopathic dystonia and discuss the multidisciplinary
treatment of dystonia, including pharmacologic, surgical, and rehabilitation therapies, and
the emergency treatment of status dystonicus/dystonic storm
 Identify the most common pediatric movement disorders and recognize benign versus
pathologic movements in infancy and childhood with a particular focus on treatable
conditions and those that should not be missed
 Discuss the role of palliative care in the treatment of life-limiting neurodegenerative

movement disorders, including the specialized approach of palliative care to symptom
management, clinical communication, and advance care planning
Core Competencies

This Continuum: Lifelong Learning in Neurology Movement Disorders issue covers the
following core competencies:
 Patient Care and Procedural Skills
 Medical Knowledge
 Practice-Based Learning and Improvement
 Interpersonal and Communication Skills
 Professionalism
 Systems-Based Practice

Contributors
Kathleen L. Poston, MD, MS, FAAN, Guest Editor

Edward F. and Irene Thiele Pimley Professor in Neurology and Neurological Sciences; Chief,
Movement Disorders, Stanford University, Stanford, California
Relationship Disclosure: Dr Poston has received personal compensation in the range of $0 to $499 for serving on a
clinical advisory board for Amprion Inc and a data safety monitoring board for the National Institutes of Health, in
the range of $500 to $4999 for serving as an associate editor for the Movement Disorders Journal and as an assistant
editor for Annals of Neurology, and in the range of $10,000 to $49,999 for serving on a scientific advisory board for
CuraSen Therapeutics, Inc. Dr Poston has stock in Amprion Inc and CuraSen Therapeutics, Inc, and has received
intellectual property interests from a discovery or technology relating to health care. The institution of Dr Poston has
received research support from the Alzheimer's Drug Discovery Foundation, the Lewy Body Dementia Association,
Inc, The Michael J. Fox Foundation, and the National Institutes of Health.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Poston reports no disclosure.
Roy N. Alcalay, MD, MS

Chief, Movement Disorders Division, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel;
Associate Professor of Clinical Neurology, Department of Neurology, Columbia University
Irving Medical Center, New York, New York
Relationship Disclosure: Dr Alcalay has received personal compensation in the range of $500 to $4999 for serving
as a consultant for AVROBIO, Inc; Caraway Therapeutics, Inc; GlaxoSmithKline plc; Janssen Global Services,
LLC; Merck & Co, Inc; Ono Pharmaceutical Co, Ltd; and Takeda Pharmaceutical Company. Dr Alcalay has
received personal compensation in the range of $10,000 to $49,999 for serving as a consultant for Sanofi. The
institution of Dr Alcalay has received research support from Biogen, the Department of Defense, The Michael J. Fox
Foundation, the National Institutes of Health, and the Parkinson’s Foundation.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Alcalay reports no disclosure.
Danny Bega, MD
Associate Professor of Neurology and Director, Neurology Residency, Director, Huntington’s
Disease Society of America Center of Excellence, Northwestern University Feinberg School of
Medicine, Chicago, Illinois
Relationship Disclosure: Dr Bega has received personal compensation in the range of $500 to $4999 for serving on a
speakers bureau for Acorda Therapeutics; Adamas Pharmaceuticals, Inc; Kyowa Kirin Co, Ltd; Neurocrine
Biosciences, Inc; and Teva Pharmaceutical Industries Ltd and as an editor, associate editor, or editorial advisory
board member for the Annals of Clinical and Translational Neurology/American Neurological Association. The
institution of Dr Bega has received research support from the Huntington’s Disease Society of America.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Bega discusses the unlabeled/investigational use of
amantadine, benzodiazepines, botulinum toxin injections, cannabinoids, carbamazepine, clozapine, deep brain
stimulation, olanzapine, quetiapine, risperidone, and valbenazine for the treatment of Huntington disease and other
causes of chorea.
Lana Chahine, MD, FAAN

Associate Professor, Department of Neurology, University of Pittsburgh, Pittsburgh,
Pennsylvania
Relationship Disclosure: Dr Chahine has received personal compensation in the range of $500 to $4999 for serving
as a consultant for Gray Matters Technology Services. Dr Chahine has received publishing royalties from a
publication relating to health care. The institution of Dr Chahine has received research support from the
Biogen/Parkinson Study Group, The Michael J. Fox Foundation, and University of Pittsburgh Medical Center.

Unlabeled Use of Products/Investigational Use Disclosure: Dr Chahine reports no disclosure.
Daniel O. Claassen, MD, MS, FAAN

Division Chief, Behavioral and Cognitive Neurology; Professor, Neurology, Vanderbilt
University Medical Center, Nashville, Tennessee
Relationship Disclosure: Dr Claassen has received personal compensation in the range of $500 to $4999 for serving
as a consultant for Spark Therapeutics, Inc and as an editor, associate editor, or editorial advisory board member for
HD Insights. Dr Claassen has received personal compensation in the range of $5000 to $9999 for serving as a
consultant and on a scientific advisory or data safety monitoring board for Teva Neuroscience, Inc. Dr Claassen has
received personal compensation in the range of $50,000 to $99,999 for serving as a consultant for Alterity
Therapeutics. The institution of Dr Claassen has received research support from AbbVie Inc; the CHDI Foundation;
Genentech, Inc/R. Hoffman-La Roche Ltd; the Griffin Family Foundation; the Huntington’s Disease Society of
America; the National Institutes of Health, Neurocrine Biosciences, Inc/Huntington Study Group; Prilenia
Therapeutics; the US Department of Defense; and Vaccinex Inc.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Claassen discusses the unlabeled/investigational use
of acarbose (α-glucosidase inhibitor) for postprandial hypotension, baclofen and gabapentin for pain/dystonia,
levetiracetam for cerebellar outflow tremor, serotonin norepinephrine reuptake inhibitors (eg, duloxetine) for pain,
and short-acting antihypertensives (eg, nifedipine, transdermal topical nitroglycerin) for supine hypertension.
Erin Furr Stimming, MD, FAAN

Professor of Neurology and Director, Neurology Clerkship, Director, Huntington’s Disease
Society of America Center of Excellence, The University of Texas Health Science Center at
Houston, McGovern Medical School, Houston, Texas
Relationship Disclosure: Relationship Disclosure: Dr Furr-Stimming has received personal compensation in the
range of $500 to $4999 for serving as a consultant for Teva Pharmaceutical Industries Ltd and Wave Life Sciences,
on a scientific advisory board for Amneal Pharmaceuticals LLC, and on a speakers bureau for Sunovion
Pharmaceuticals Inc and Teva Pharmaceutical Industries Ltd. Dr Furr Stimming has served as an editor and author
for McGraw Hill and Oxford University Press. The institution of Dr Furr Stimming has received research support
from the CHDI Foundation; Cures Within Reach; Huntington Study Group/Neurocrine Biosciences, Inc; the
Huntington's Disease Society of America; F. Hoffman-La Roche/Genetech, Inc; the National Institutes of
Health/University of Iowa; uniQure NV; and Vaccinex Inc.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Furr Stimming discusses the unlabeled/investigational
use of amantadine, benzodiazepines, botulinum toxin injections, cannabinoids, carbamazepine, clozapine, deep brain
stimulation, olanzapine, quetiapine, risperidone, and valbenazine for the treatment of Huntington disease and other
causes of chorea.
David Irwin, MD
Assistant Professor of Neurology, University of Pennsylvania, Perelman School of Medicine
Philadelphia, Pennsylvania
Relationship Disclosure: Dr Irwin has received personal compensation in the range of $500 to $4999 for serving on
a scientific advisory or data safety monitoring board for Denali Therapeutics. The institution of Dr Irwin has
received research support from the National Institutes of Health (U19-AG062418).
Unlabeled Use of Products/Investigational Use Disclosure: Dr Irwin discusses the use of several medications and
treatments for the neuropsychiatric symptoms of Parkinson disease and dementia with Lewy bodies, none of which
are approved by the US Food and Drug Administration, except for rivastigmine for the treatment of Parkinson
dementia and pimavanserin for the treatment of psychosis in Parkinson disease.

Maya Katz, MD
Clinical Associate Professor of Neurology, Stanford University, Stanford, California
Relationship Disclosure: Dr Katz has received research support from the National Institutes of Health
(1R01NR016037-01A1).
Unlabeled Use of Products/Investigational Use Disclosure: Dr Katz reports no disclosures.
Jennifer A. O’Malley, MD, PhD

Clinical Assistant Professor, Neurology and Pediatrics, Stanford University School of Medicine,
Palo Alto, California
Relationship Disclosure: Dr O’Malley has received personal compensation in the range of $5000 to $9999 for
serving on a speakers bureau for PTC Therapeutics and has stock in Doximity. The institution of Dr O’Malley has
received research support from Grace Science, LLC.
Unlabeled Use of Products/Investigational Use Disclosure: Dr O’Malley discusses the unlabeled/investigational use
of deep brain stimulation for movement disorders in children and gene therapy for aromatic L-amino acid
decarboxylase deficiency.
Alexander Pantelyat, MD, FAAN

Director, Atypical Parkinsonism Center; Assistant Professor of Neurology, Johns Hopkins
University School of Medicine, Baltimore, Maryland
Relationship Disclosure: Dr Pantelyat has received personal compensation in the range of $5000 to $9999 for
serving as a scientific advisory board member for MedRhythms, Inc, and in the range of $10,000 to $49,999 for
serving as an expert witness for Kelly & Ignoffo Law Group. The institution of Dr Pantelyat has received research
support from the National Institutes of Health/National Institute on Aging.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Pantelyat discusses the unlabeled/investigational use
of dextromethorphan/quinidine or selective serotonin reuptake inhibitors (SSRIs) for the treatment of pseudobulbar
affect in progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS); methylphenidate or modafinil for
the treatment of apathy in PSP and CBS; miglustat for Niemann-Pick disease type C; onabotulinumtoxinA for the
treatment of sialorrhea, cervical and limb dystonia/spasticity, muscle pain, and eyelid opening
apraxia/blepharospasm in PSP and CBS; and SSRIs for the treatment of depression and anxiety in PSP and CBS.
Ashley E. Rawls, MD, MS

Assistant Professor of Neurology, University of Florida, Norman Fixel Institute for Neurological
Diseases, Gainesville, Florida
Relationship Disclosure: Dr Rawls has received personal compensation in the range of $500 to $4999 for serving as
an editor, associate editor, or editorial advisory board member for JAMA Neurology and as a physician expert
panelist with Mediflix, Inc.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Rawls discusses the unlabeled/investigational use of
closed-loop deep brain stimulation for the treatment of Parkinson disease.

Director, Johns Hopkins Ataxia Center; Co-Director, Johns Hopkins Lewy Body Disease
Association Research Center of Excellence; Associate Professor of Neurology, Johns Hopkins
University School of Medicine, Baltimore, Maryland
Relationship Disclosure: Dr Rosenthal has received personal compensation in the range of $500 to $4999 for serving
as a consultant for Biohaven Pharmaceuticals and on a scientific advisory or data safety monitoring board for Reata

Pharmaceuticals, Inc; has received research support from Biohaven Pharmaceuticals, The Daniel B. and Florence E.
Green Foundation, the Gordon and Marilyn Macklin Foundation, The Michael J. Fox Foundation, the National
Ataxia Foundation, the National Institutes of Health, and Pfizer Inc; and has a noncompensated relationship as a
Medical Director, ex-officio Member of the Board with National Ataxia Foundation that is relevant to American
Academy of Neurology interests or activities.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Rosenthal discusses the unlabeled/investigational use
of medications for the treatment of neurodegenerative spinocerebellar ataxias, none of which are approved by the
US Food and Drug Administration.
Christopher D. Stephen, MB ChB, FRCP, SM

Instructor in Neurology, Harvard Medical School; Attending Neurologist, Movement Disorders
Unit, Ataxia Center, Dystonia Clinic, Department of Neurology, Massachusetts General
Hospital, Brigham and Women's Hospital, Boston, Massachusetts
Relationship Disclosure: Dr Stephen has received personal compensation in the range of $500 to $4999 for serving
on a scientific advisory or data safety monitoring board for SwanBio Therapeutics, Inc, has received research
support from the National Institutes of Health/National Institute of Neurological Disorders and Stroke
(1K23NS118045-01A1), and has received honoraria in the range of $500 to $4999 from the International Parkinson
and Movement Disorder Society. The institution of Dr Stephen has received research support from Sanofi.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Stephen discusses the unlabeled/investigational use of
medications and therapies, none of which are approved by the US Food and Drug Administration (FDA) except for
botulinum toxin injections; medications and therapies for the treatment of paroxysmal dystonia, none of which are
approved by the FDA for this indication; medications and therapies for the treatment of status dystonicus/dystonic
storm, none of which are approved by the FDA for this indication; dopamine agonists for the treatment of dystonia
parkinsonism; ethylenediaminetetraacetic acid chelation therapy for the treatment of dystonia/parkinsonism with
manganese accumulation; dopamine agonists, monoamine oxidase inhibitors, and pyridoxine for the treatment of
aromatic L-amino acid decarboxylase deficiency; levodopa and 5-hydroxytryptophan for the treatment of complex
dopa-responsive dystonia; L-carnitine for the treatment of glutaric aciduria type 1, methylmalonic aciduria, and
propionic acidemia; vitamin B6 for the treatment of homocystinuria; biotin and thiamine for the treatment of biotin-
thiamine–responsive basal ganglia disease and biotinidase deficiency; and coenzyme Q10 for the treatment of
coenzyme Q10 deficiency.
Avner Thaler, MD, PhD

Assistant Professor of Neurology, Sackler Faculty of Medicine, Sagol School of Neuroscience,
Tel Aviv University; Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
Relationship Disclosure: Dr Thaler has received personal compensation in the range of $500 to $4999 for serving as
a consultant for AbbVie Inc. The institution of Dr Thaler has received research support from Biogen and The
Michael J. Fox Foundation.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Thaler reports no disclosure.
Aparna Wagle Shukla, MD

Professor, Department of Neurology, Norman Fixel Institute for Neurological Diseases,
University of Florida Health, Gainesville, Florida
Relationship Disclosure: Dr Wagle Shukla has received personal compensation in the range of $500 to $4999 for
serving as a consultant for Jazz Pharmaceuticals, Inc, as a reviewer with the National Institutes of Health, and as the
Vice President of the board of directors for the Tremor Research Group and in the range of $5000 to $9999 for
serving on a scientific advisory board for Acadia Pharmaceuticals Inc. The institution of Dr Wagle Shukla has
received research support from the National Institutes of Health.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Wagle Shukla reports no disclosure.

Daniel Weintraub, MD
Professor of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia,
Pennsylvania
Relationship Disclosure: Dr Weintraub has received personal compensation in the range of $10,000 to $49,999 for
serving as a consultant for Clintrex and on a scientific advisory or data safety monitoring board for Acadia
Pharmaceuticals Inc. Dr Weintraub has received personal compensation in the range of $500 to $4999 for serving as
a consultant for Eisai Co, Ltd; Jansen Global Services, LLC; Sage Therapeutics, Inc; Scion Pharmaceuticals, Signant
Health, and Sunovian Pharmaceuticals Inc, and for serving as an editor, associate editor, or editorial advisory board
member for the Movement Disorder Society. Dr Weintraub has received intellectual property interests from a
discovery or technology relating to health care. The institution of Dr Weintraub has received research support from
The Michael J. Fox Foundation, the International Parkinson and Movement Disorder Society, and the National
Institutes of Health.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Weintraub discusses the use of several medications
and treatments for the neuropsychiatric symptoms of Parkinson disease and dementia with Lewy bodies, none of
which are approved by the US Food and Drug Administration, except for rivastigmine for the treatment of Parkinson
dementia and pimavanserin for the treatment of psychosis in Parkinson disease.
Self-Assessment and CME Test Writers
Adam G. Kelly, MD, FAAN

Associate Professor of Neurology; Director of Teleneurology and Regional Neurology,
University of Rochester, Rochester, New York
Relationship Disclosure: Dr Kelly has received personal compensation in the range of $500 to $4999 for serving as a
consultant for Included Health, Inc, and a CME question writer for the American Academy of Neurology and in the
range of $5000 to $9999 for serving as a CME editor for the American Academy of Neurology.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Kelly reports no disclosure.
D. Joanne Lynn, MD, FAAN

Clinical Professor Emerita, Department of Neurology, The Ohio State University College of
Medicine, Columbus, Ohio
Relationship Disclosure: Dr Lynn has received personal compensation in the range of $500 to $4999 for serving as a
Continuum Self-Assessment and CME question writer for the American Academy of Neurology; has received
publishing royalties from Wolters Kluwer Health, Inc; and has stock in Abbott Laboratories, AbbVie Inc, Amgen
Inc, Biogen, Bristol-Myers Squibb Company, Merck & Co Inc, Pfizer Inc, Regeneron Pharmaceuticals Inc, and
Zimmer Biomet.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Lynn reports no disclosure.

Methods of Participation and Instructions for Use
Continuum: Lifelong Learning in Neurology® is designed to help practicing neurologists stay
abreast of advances in the field while simultaneously developing lifelong self-directed learning
skills. In Continuum, the process of absorbing, integrating, and applying the material presented is
as important as, if not more important than, the material itself.
The goals of Continuum include disseminating up-to-date information to the practicing

neurologist in a lively, interactive format; fostering self-assessment and lifelong study skills;
encouraging critical thinking; and, in the final analysis, strengthening and improving patient
care.
Each Continuum issue is prepared by distinguished authors who are acknowledged leaders in
their respective fields. Six issues are published annually and are composed of review articles,
case-based discussions on ethical and practice issues related to the issue topic, coding
information, and comprehensive continuing medical education (CME) and self-assessment
offerings. For detailed instructions regarding Continuum CME and self-assessment activities,
visit continpub.com/CME.
The review articles emphasize clinical issues emerging in the field in recent years. Case reports
and vignettes are used liberally, as are tables and illustrations. Audio interviews with the authors
of Continuum articles are published alongside each article, and video material relating to the
issue topic accompanies issues when applicable.
The text can be reviewed and digested most effectively by establishing a regular schedule of
study in the office or at home, either alone or in an interactive group. If subscribers use such
regular and perhaps new study habits, Continuum’s goal of establishing lifelong learning patterns
can be met.

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OCTOBER 2022

VOL. 28 NO. 5 Movement Disorders

1266 Editor’s Preface

1268 Prodromal α-Synucleinopathies

1281 Diagnosis and Medical Management of Parkinson Disease

1301 Surgical Therapies for Parkinson Disease

1314 Diagnosis and Treatment of Cognitive and Neuropsychiatric

1333 Diagnosis and Treatment of Essential Tremor

1350 Multiple System Atrophy

1364 Progressive Supranuclear Palsy and Corticobasal Syndrome

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

1476 Diagnosing Common Movement Disorders in Children

1520 Palliative Care and Movement Disorders

SELF-ASSESSMENT AND CME

1256 Learning Objectives and Core Competencies

1531 Instructions for Completing Postreading Self-Assessment and CME

1533 Postreading Self-Assessment and CME Test

1546 Postreading Self-Assessment and CME Test—Preferred Responses

List of Abbreviations (Back Cover)

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Kathleen L. Poston, MD, MS, Roy N. Alcalay, MD, MS

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RECENT FINDINGS: The pathology underlying α-synucleinopathies, which

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Biological Risk Factors

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as well. The third broad category of genetic PD risk factors is a composite of

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In RBD, that atonia is lost. On polysomnography, this manifests with

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COGNITIVE DYSFUNCTION AND OTHER NEUROPSYCHIATRIC

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RESEARCH CRITERIA FOR PRODROMAL α-SYNUCLEINOPATHIES

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prevalence of RBD in the older-adult population is at least 2.2%. This is similar to

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