CONTRIBUTORS

Elan D. Louis, MD, MS, FAAN, Joseph H. Friedman, MD,

Guest Editor FAAN, FANA
Professor, Department Director, Movement Disorders
of Neurology, Department Program, Butler Hospital;
of Epidemiology (Chronic Professor, Chief, Division
Diseases); Chief, Division of Movement Disorders,
of Movements Disorders, Warren Alpert Medical School,
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Yale School of Medicine, Brown University, Providence,

Yale University, Rhode Island
New Haven, Connecticut
Relationship Disclosure: Dr Friedman has
Relationship Disclosure: Dr Louis serves received honoraria from Cambridge University
on the clinical advisory boards of CADENT Press, MedLink, and Springer Press. He has
Therapeutics and SAGE Therapeutics, Inc received research/grant support as site
and receives publishing royalties from investigator of clinical studies for the
Elsevier for Merritt’s Neurology. Michael J. Fox Foundation for Parkinson’s
Research and the National Institutes
Unlabeled Use of Products/Investigational of Health.
Use Disclosure: Dr Louis discusses the
unlabeled/investigational use of alprazolam, Unlabeled Use of Products/Investigational
benzodiazepines, carbidopa/levodopa, Use Disclosure: Dr Friedman discusses
clonazepam, gabapentin, primidone, and the unlabeled/investigational use of
topiramate for the treatment of essential α-methyl-para-tyrosine, botulinum toxin,
tremor; trihexyphenidyl for the treatment clozapine, deep brain stimulation, reserpine,
of dystonic tremor; acetazolamide, baclofen, and tetrabenazine for the treatment of
carbamazepine, clonazepam, ethosuximide, tardive syndromes.
and phenytoin for the treatment of orthostatic
tremor; pregabalin for the treatment of
neuropathic tremor; benzodiazepines
for the treatment of parkinsonian resting Paul Greene, MD
tremor; and phenobarbital to treat the side Associate Professor, Neurology,
effects of acute nausea and unsteadiness
that occur as a result of other treatments
Mount Sinai School of Medicine,
for tremor. New York, New York
Relationship Disclosure: Dr Greene reports
no disclosure.
John N. Caviness, MD, FAAN
Unlabeled Use of Products/Investigational
Professor, Department Use Disclosure: Dr Greene discusses the
of Neurology, Consultant unlabeled/investigational use of medications
in Neurology, Mayo Clinic, for the treatment of atypical parkinsonism,
none of which have been approved by the
Phoenix, Arizona US Food and Drug Administration.

Relationship Disclosure: Dr Caviness reports

no disclosure.

Unlabeled Use of Products/Investigational

Use Disclosure: Dr Caviness discusses
the unlabeled/investigational use of
anticholinergic medications, botulinum
toxin, carbamazepine, clonazepam, deep
brain stimulation, levetiracetam, sodium
oxybate, and tetrabenazine for the
treatment of myoclonus.

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 Joseph Jankovic, MD, FAAN TR001456 from the Office of Rare Diseases
Research at the National Center for Advancing
Professor, Department Translational Sciences and previously
of Neurology; Distinguished Chair received support through grant NS065701
in Movement Disorders; Director, from the National Institutes of Neurological
Disorders and Stroke. The Dystonia Coalition
Parkinson’s Disease Center and has received additional material or administrative
Movement Disorders Clinic, support from industry sponsors (Allergan,
Inc and Merz Pharmaceuticals) as well as
Baylor College of Medicine,
private foundations (the American Dystonia
Houston, Texas Society, Beat Dystonia, the Benign Essential
Blepharospasm Research Foundation, Cure
Relationship Disclosure: Dr Jankovic has Dystonia Now, Dystonia Europe, Dystonia Inc,
received personal compensation for serving Dystonia Ireland, the Dystonia Medical
on the advisory boards of and as a consultant Research Foundation, the Foundation for
for Parexel; Retrophin, Inc; and Teva Dystonia Research, the National Spasmodic
Pharmaceutical Industries Ltd. Dr Jankovic Dysphonia Association, and the National
has received personal compensation as an Spasmodic Torticollis Association).
editor for and has received royalties from
Cambridge University Press, Elsevier, Future Unlabeled Use of Products/Investigational
Science Group, and Hodder Arnold. Dr Jankovic Use Disclosure: Dr Jinnah discusses the
has received research/grant support from unlabeled/investigational use of alprazolam,
Allergan, CHDI Foundation, Dystonia Coalition, amphetamines, baclofen, benzodiazepines,
F. Hoffman-La Roche AG, Huntington Study benztropine, biperiden, botulinum neurotoxins,
Group, Michael J. Fox Foundation for Parkinson’s carbamazepine, carbidopa/levodopa,
Research, and the National Institutes carisoprodol, chlordiazepoxide, chlorzoxazone,
of Health. clonazepam, cyclobenzaprine, cyproheptadine,
diazepam, ethopropazine, gabapentin, lithium,
Unlabeled Use of Products/Investigational metaxalone, methocarbamol, nabilone
Use Disclosure: Dr Jankovic reports orphenadrine, procyclidine, riluzole, tizanidine,
no disclosure. trihexyphenidyl, and zolpidem for the
treatment of dystonia. Dr Jinnah discusses
the unlabeled/investigational use of thiamine
for the treatment of biotin-thiamine–responsive
H. A. Jinnah, MD, PhD basal ganglia disorder; folinic acid for the
Professor, Department treatment of cerebral folate deficiency;
chenodeoxycholic acid for the treatment
of Neurology, Department of cerebrotendinous xanthomatosis;
of Human Genetics, Emory 5-hydroxytryptophan and tetrahydrobiopterin
University School of Medicine, for the treatment of dopa-responsive dystonia;
cyclic pyranopterin monophosphate for the
Atlanta, Georgia treatment of molybdenum cofactor deficiency;
N-butyl-deoxynojirimycin for the treatment
Relationship Disclosure: Dr Jinnah has received of Niemann-Pick disease type C; tetrabenazine
personal compensation for serving on the for the treatment of oromandibular dystonia;
advisory boards of and as a consultant and deutetrabenazine, tetrabenazine,
for Abide Therapeutics, Inc; Allergan, Inc; and valbenazine and for the treatment
CoA Therapeutics; the International of tardive dystonia.
Neurotoxin Society; the International
Parkinson and Movement Disorders Society;
Medtronic; the Parkinson’s Foundation;
Psyadon Pharmaceuticals Inc; Retrophin, Inc;
and Saol Therapeutics. Dr Jinnah has
received grant support from the Benign
Essential Blepharospasm Research
Foundation, Cavion, Cure Dystonia Now,
the Dystonia Study Group, Ipsen Group,
National Institutes of Health (NIH), and
Retrophin, Inc. He also is principle investigator
for the Dystonia Coalition, which receives
the majority of its support through NIH grant

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CONTRIBUTORS (CONTINUED)

Joseph S. Kass, MD, JD, FAAN Toni S. Pearson, MBBS

Associate Dean, Office of Student Associate Professor,
Affairs; Professor of Neurology, Department of Neurology,
Psychiatry, and Medical Ethics; Washington University School
Director, Alzheimer’s Disease of Medicine, St. Louis, Missouri
and Memory Disorders Center,
Relationship Disclosure: Dr Pearson has
Baylor College of Medicine; received research/grant support from
Chief of Neurology, Ben Taub the National Institutes of Health/National
Institute of Neurological Disorders
General Hospital, Houston, Texas and Stroke.
Relationship Disclosure: Dr Kass serves
Unlabeled Use of Products/Investigational
as associate editor of medicolegal issues
Use Disclosure: Dr Pearson reports
for Continuum, as an associate editor for
no disclosure.
Continuum Audio, as a neurology section
editor of Ferri’s Clinical Advisor for Elsevier,
and as co-editor of Neurology Secrets,
Sixth Edition. Dr Kass has received personal
compensation for CME lectures Roser Pons, MD
from Pri-Med LLC. Associate Professor,
Department of Pediatric
Unlabeled Use of Products/Investigational
Use Disclosure: Dr Kass reports no disclosure. Neurology, National and
Kapodistrian University
of Athens, Athens, Greece
Sheng-Han Kuo, MD Relationship Disclosure: Dr Pons
Assistant Professor, Department has received personal compensation
of Neurology, Columbia University, for serving as a consultant for and on the
scientific advisory board of Biogen,
New York, New York for serving as a consultant for Guidepoint
on a rare metabolic disorder, and for
Relationship Disclosure: Dr Kuo has received serving as a speaker for Biogen and for
personal compensation for serving on the PTC Therapeutics.
medical advisory board of the International
Essential Tremor Foundation and on the Unlabeled Use of Products/Investigational
research advisory board of the National Use Disclosure: Dr Pons reports
Ataxia Foundation. Dr Kuo has received no disclosure.
research/grant support from the American
Brain Research Training Fellowship, American
Parkinson Disease Association, International
Essential Tremor Foundation, the Louis Rachel V. Rose, JD, MBA
V. Gerstner Jr Scholarship, National Ataxia
Foundation, for the National Institute Attorney, Rachel V. Rose
of Environmental Health Sciences pilot Attorney at Law PLLC; Affiliated
grant ES009089, as principal investigator
for studies from the National Institute
Faculty, Baylor College
of Neurological Disorders and Stroke of Medicine, Houston, Texas
(R01 NS104423, K08 NS083738), Parkinson’s
Foundation, and the Rare Disease Clinical Relationship Disclosure: Ms Rose serves
Research Network (RC1NS068897). on the editorial board of BC Advantage and
receives book royalties from the American
Unlabeled Use of Products/Investigational Use Bar Association.
Disclosure: Dr Kuo discusses the unlabeled/
investigational use of amantadine, baclofen, Unlabeled Use of Products/Investigational
chlorzoxazone, and riluzole for the treatment Use Disclosure: Ms Rose reports
of cerebellar ataxia; 4-aminopyridine for the no disclosure.
treatment of episodic ataxia type 2; deep brain
stimulation for the treatment of spinocerebellar
ataxia type 2; miglustat for the treatment of
Niemann-Pick disease type C; and varenicline
for spinocerebellar ataxia type 3.

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 Harvey S. Singer, MD, FAAN Mary Ann Thenganatt, MD
Professor of Neurology Neurologist, University
and Pediatrics, Department of Pennsylvania, Philadelphia,
of Neurology, Johns Hopkins Pennsylvania
University School of Medicine,
Relationship Disclosure: Dr Thenganatt
Johns Hopkins Hospital, has received an honorarium from
Baltimore, Maryland MedLink Neurology.

Relationship Disclosure: Dr Singer serves as Unlabeled Use of Products/Investigational

a consultant for Abide Therapeutics, Inc; Use Disclosure: Dr Thenganatt reports
Cello Health BioConsulting; ClearView no disclosure.
Healthcare Partners; Teva Pharmaceutical
Industries Ltd; and Trinity Partners, LLC.
Dr Singer receives publishing royalties
from Elsevier and research/grant support Theresa A. Zesiewicz,
from the Tourette Association of America. MD, FAAN
Unlabeled Use of Products/Investigational Professor, Department of
Use Disclosure: Dr Singer discusses the Neurology, Director, Frances
unlabeled/investigational use of baclofen,
J. Zesiewicz Foundation for
botulinum toxin, cannabidiol, clonazepam,
clonidine, deutetrabenazine, ecopipam, Parkinson’s Disease, Co-director,
fluphenazine, guanfacine, nabiximols, Movement Disorders
risperidone, sulpiride, tetrabenazine,
∆-9-tetrahydrocannibinol, tiapride,
Neuromodulation Center,
topiramate, and valbenazine. University of South Florida;
Director, Parkinson’s Disease
Research, Education, and Clinical
Pichet Termsarasab, MD Center, Parkinson’s Disease Center
Consultant Neurologist, Neurology at the James A. Haley Veteran’s
Division/Department of Medicine; Administration Hospital,
Faculty of Medicine, Ramathibodi Tampa, Florida
Hospital, Mahidol University, Relationship Disclosure: Dr Zesiewicz has
Bangkok, Thailand received personal compensation for serving
on the advisory boards of Boston Scientific;
Relationship Disclosure: Dr Termsarasab Reata Pharmaceuticals, Inc; and Steminent
serves as associate editor of the Journal Biotherapeutics. Dr Zesiewicz has received
of Clinical Movement Disorders and on the personal compensation as senior editor for
editorial board of Brain Science Journal. Neurodegenerative Disease Management
Dr Termsarasab has received personal and as a consultant for Steminent
compensation for speaking engagements Biotherapeutics. Dr Zesiewicz has received
for the American Academy of Neurology royalty payments as co-inventor of varenicline
and Novartis AG and receives publishing for treating imbalance (patent number
royalties from MedLink Neurology. 9,463,190) and nonataxic imbalance (patent
number 9,782,404). Dr Zesiewicz has received
Unlabeled Use of Products/Investigational research/grant support as principal
Use Disclosure: Dr Termsarasab discusses investigator/investigator for studies from
the unlabeled/investigational use of the AbbVie Inc; Biogen; Biohaven Pharmaceutics;
current recommended treatments of Boston Scientific; Bukwang Pharmaceuticals
chorea, none of which are approved by the Co, Ltd; Cala Health, Inc; Cavion; Friedreich’s
US Food and Drug Administration except the Ataxia Research Alliance; Houston Methodist
use of deutetrabenazine for the treatment Research Institute; National Institutes of Health
of chorea associated with Huntington (READISCA U01); Retrotope Inc; and Takeda
disease and tardive dyskinesia, tetrabenazine Development Center Americas, Inc.
for the treatment of chorea associated
with Huntington disease, and valbenazine Unlabeled Use of Products/Investigational
for the treatment of tardive dyskinesia. Use Disclosure: Dr Zesiewicz reports
no disclosure.

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CONTRIBUTORS (CONTINUED)

Self-Assessment and CME Test Writers

Adam G. Kelly, MD Allison L. Weathers, MD, FAAN

Associate Professor of Neurology; Associate Chief Medical
Chief, Neurovascular Division, Information Officer, Cleveland
University of Florida, Clinic; Assistant Professor,
Gainesville, Florida Cleveland Clinic Lerner College
of Medicine, Cleveland, Ohio
Relationship Disclosure: Dr Kelly has
received personal compensation as CME Relationship Disclosure: Dr Weathers serves
editor of Neurology. on the editorial board of Continuum and as
chair of the adult neurosciences specialty
Unlabeled Use of Products/Investigational steering board for Epic.
Use Disclosure: Dr Kelly reports
no disclosure. Unlabeled Use of Products/Investigational
Use Disclosure: Dr Weathers reports
no disclosure.

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
 EDITOR’S PREFACE

A Guide for the Nonplussed

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This issue of Continuum is devoted to the diagnosis and management

of our patients with movement disorders, whether hypokinetic (eg,
Parkinson disease and other parkinsonian disorders) or hyperkinetic
(eg, chorea, tremors, and myoclonus). My sincere thanks go to
Dr Elan D. Louis for so graciously accepting my invitation to be the
guest editor for this issue, and especially since he interrupted his academic-year
sabbatical to devote the immense amount of time and effort required to edit a
successful Continuum issue.

The issue begins with articles on the primarily Dr Pichet Termsarasab next reviews the disorders
hypokinetic movement disorders, starting with one that present with chorea, including Huntington
by Dr Theresa A. Zesiewicz, who informs us about disease and various other choreic disorders, including
the most current approach to the diagnosis those that may resemble Huntington disease.
and optimal management of our patients with Dr Sheng-Han Kuo then provides us with a practical
idiopathic Parkinson disease. Next, Dr Paul Greene approach to the diagnosis and management of the
discusses the pathologic underpinnings, clinical ataxias. In the article that follows, Dr John N.
features, and diagnosis of progressive supranuclear Caviness provides us with an approach to the
palsy, corticobasal degeneration, and multiple categorization, diagnosis, and management of the
system atrophy. Although these three various forms of myoclonus we can encounter in
neurodegenerative disorders have been our practices.
historically—and still occasionally—referred to as Dr Joseph H. Friedman then reviews the diagnosis
Parkinson plus syndromes (a term that seems to have and current approaches to management of the
devolved from the somewhat more apt term tardive syndromes, potentially debilitating
parkinsonism plus1), this arguably archaic moniker syndromes that unfortunately remain a significant
has been “subtracted” from Continuum since these public health problem due to exposure to any of the
(not uncommon) disorders are not related to currently available dopamine receptor–blocking
Parkinson disease and are distinct diseases that are agents. Drs Toni S. Pearson and Roser Pons next
diagnosable by their classic and unique clinical and provide a thorough review of the diagnosis and
pathologic features. management of the many movement disorders that
The issue then turns to the hyperkinetic may occur in childhood. In the final review article of
movement disorders, starting with the article by the issue, Drs Mary Ann Thenganatt and Joseph
Dr Harvey S. Singer, who reviews the diagnosis and Jankovic share their expertise in the diagnosis and
management of patients with tics and Tourette management of functional (ie, psychogenic)
syndrome. This is followed by the article by Dr Louis, movement disorders, including identification of
who discusses the diagnosis and management of those positive clinical features that should suggest
our patients with tremor, whether predominantly the diagnosis.
action or resting. Dr H. A. Jinnah then reviews the In this issue’s Medicolegal Issues article, Dr Joseph
diagnosis and management of the many disorders S. Kass and Ms Rachel V. Rose present a hypothetical
characterized by the presence of dystonia. case of a new patient requesting a refill for a

894 AUGUST 2019

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long-standing prescription for metoclopramide as a Continuum Audio interviews associated with this and
springboard for a discussion about ways to mitigate a other Continuum issues, available to all subscribers,
physician’s liability when prescribing medications and completing tests on the Continuum Audio web
with potentially serious long-lasting side effects such platform or mobile app. Continuum Audio is also
as tardive dyskinesia. accredited by the Royal College of Physicians and
After reading the issue and taking the Postreading Surgeons of Canada.
Self-Assessment and CME Test written by Drs Adam My deepest appreciation to Dr Louis for his expert
G. Kelly and Allison L. Weathers, you may earn guest editorship of this wonderful issue from its
up to 20 AMA PRA Category 1 CreditsTM toward inception. I would also like to thank him for his
self-assessment and CME or, for Canadian remarkable attentiveness to the details required in
participants, a maximum of 20 hours toward the such an issue and for enlisting such internationally
Self-Assessment Program (Section 3) of the expert authors in the field of movement disorders to
Maintenance of Certification Program of the Royal assist us in the diagnosis and management of the
College of Physicians and Surgeons of Canada. many patients with any of the wide and sometimes
Additional credit can be obtained by listening to perplexing variety of movement disorders who
present to us.
—STEVEN L. LEWIS, MD, FAAN
EDITOR-IN-CHIEF
My deepest appreciation to Dr Louis
. . . for enlisting such internationally © 2019 American Academy of Neurology.

expert authors . . . to assist us in the

diagnosis and management of the REFERENCE
many patients with any of the wide
and sometimes perplexing variety of 1 Stacy M, Jankovic J. Differential diagnosis of Parkinson’s disease and
the parkinsonism plus syndromes. Neurol Clinic 1992;10(2):341–359.
movement disorders . . . . doi:10.1016/S0733-8619(18)30214-7.

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 REVIEW ARTICLE


Parkinson Disease
C O N T I N U U M AUDIO By Theresa A. Zesiewicz, MD, FAAN
INTERVIEW AVAILABLE
ONLINE


VIDEO CONTENT ABSTRACT
A VA I L A B L E O N L I N E PURPOSE OF REVIEW:Parkinson disease is a common neurodegenerative
disorder that affects millions of people worldwide. Important advances in
CITE AS:
CONTINUUM (MINNEAP MINN) the treatment, etiology, and the pathogenesis of Parkinson disease have
2019;25(4, MOVEMENT DISORDERS): been made in the past 50 years. This article provides a review of the
896–918.
current understanding of Parkinson disease, including the epidemiology,
Address correspondence to
phenomenology, and treatment options of the disease.
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Dr Theresa A. Zesiewicz,
University of South Florida, 12901 RECENT FINDINGS: Parkinson disease is now recognized to be a heterogeneous
Bruce B. Downs Blvd, MDC Box
55, Tampa, FL 33612,
condition marked by both motor and nonmotor symptoms. It is composed
[email protected]. of preclinical, prodromal, and clinical phases. New medications with
improved ease of administration have been approved for its treatment.
RELATIONSHIP DISCLOSURE:
Dr Zesiewicz has received Innovative surgical therapies for Parkinson disease may be used when
personal compensation for motor symptoms persist despite optimal medical management.
serving on the advisory boards of
Boston Scientific; Reata
Pharmaceuticals, Inc; and SUMMARY: Parkinson disease is a complex, heterogeneous neurodegenerative
Steminent Biotherapeutics. Dr disorder. Considerable progress has been made in its treatment modalities,
Zesiewicz has received personal
compensation as senior editor for
both pharmacologic and surgical. While its cure remains elusive, exciting
Neurodegenerative Disease new research advances are on the horizon.
Management and as a consultant
for Steminent Biotherapeutics. Dr
Zesiewicz has received royalty
payments as co-inventor of
INTRODUCTION
varenicline for treating imbalance

P
(patent number 9,463,190) and arkinson disease is a chronic, progressive, and disabling disorder that
nonataxic imbalance (patent is characterized by both motor and nonmotor symptoms. The disease
number 9,782,404). Dr Zesiewicz
has received research/grant
affects millions of people worldwide and is the second most prevalent
support as principal investigator/ neurodegenerative condition next to Alzheimer disease.1 Patients
investigator for studies from experience progressive extrapyramidal motor symptoms, including
AbbVie Inc; Biogen; Biohaven
Pharmaceutics; Boston Scientific; tremor, bradykinesia, rigidity, imbalance, and a variety of nonmotor symptoms
Bukwang Pharmaceuticals Co, Ltd; such as sleep and mood disorders. Despite its progressive nature, it remains one
Cala Health, Inc; Cavion; of the few neurodegenerative diseases whose symptoms can be readily treated
Friedreich’s Ataxia Research
Alliance; Houston Methodist with dopamine replacement therapy.
Research Institute; National
Institutes of Health (READISCA
U01); Retrotope Inc; and Takeda BRIEF HISTORY OF PARKINSON DISEASE
Development Center
Americas, Inc.
The English physician, James Parkinson, first characterized Parkinson disease in
his 1817 monograph “An Essay on the Shaking Palsy.”2 Parkinson described
UNLABELED USE OF several people who presented with resting tremor, shuffling gait, stooped
PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
posture, sleep problems, and constipation. He noted the progressive nature of
Dr Zesiewicz reports no the disease and the great disability it incurred and called it paralysis agitans.
disclosure. Charcot3 later expounded on the disease, adding bradykinesia and rigidity to the
constellation of symptoms, and renamed the condition Parkinson disease.
© 2019 American Academy In the 1950s Carlsson4 found that levodopa reversed reserpine-induced
of Neurology. akinesia, paving the way for its use as a treatment for Parkinson disease. Cotzias

896 AUGUST 2019

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and colleagues5 discovered that levodopa improved symptoms of Parkinson KEY POINTS
disease in 1967 when he administered DL-dihydroxyphenylalanine (DOPA) to
● A renaissance of
patients with parkinsonism and achieved favorable results. Levodopa, when therapeutic options for
paired with carbidopa, became the mainstay of medical therapy and remains so Parkinson disease have
to this day. occurred in the last 50 years.
Significant advances were made in the latter part of the 20th century and in Levodopa remains the gold
standard for treatment of
the 21st century regarding the physiologic mechanisms and additional treatment
Parkinson disease, but
options for Parkinson disease. While levodopa continued to be the cornerstone of dopamine agonists,
medical management, an association was made between high-dose levodopa, monoamine oxidase type B
advanced disease progression, and the onset of motor fluctuations.6,7 Dopamine inhibitors, catechol-O-
methyltransferase
agonists, monoamine oxidase type B (MAO-B) inhibitors, and catechol-O-
inhibitors, and surgical
methyltransferase (COMT) inhibitors found a place in the therapeutic arsenal for procedures have greatly
the disease, along with novel forms of levodopa. expanded the therapeutic
Surgical treatments for disease symptoms that were resistant to optimal medical options.
management were also developed, including deep brain stimulation (DBS).
● Parkinson disease affects
The 21st century has also witnessed remarkable discoveries in the genetic millions of people
causes of Parkinson disease, while great strides have been made in the pathogenic worldwide, and its
mechanisms. Research continues to focus on potential neuroprotective and prevalence increases
neurorestorative therapies. greatly with advancing age.

EPIDEMIOLOGY OF PARKINSON DISEASE

Parkinson disease affects millions of people worldwide, and the number of
affected patients may double by 2030.8 It is estimated that Parkinson disease
affects about 1% of people older than 60 years of age in the United States.9,10 The
annual median age-standardized incidence rates of Parkinson disease in people
older than 65 years of age in high-income countries is 160 per 100,000.11 The
lifetime risk of Parkinson disease is 2% in men and 1.3% in woman aged 40 years
and older, when accounting for competing risks.11 The incidence of Parkinson
disease prior to age 50 is low but increases with advanced age. Men carry a greater
chance of having Parkinson disease than women. The overall age-standardized
incidence male-to-female ratio is estimated to be 1.46 (95% CI 1.24–1.72).12 No
area of the world is immune to Parkinson disease.

CLINICAL SYMPTOMS OF PARKINSON DISEASE

The motor and nonmotor symptoms of Parkinson disease are described below.

Motor Symptoms
The four cardinal motor symptoms of Parkinson disease are tremor, rigidity,
bradykinesia, and postural instability, as identified by the acronym TRAP
(tremor, rigidity, akinesia (or bradykinesia), and postural instability)
(TABLE 1-1).13 The secondary motor symptoms include diminished arm swing,
decreased blink rate, masked facies (hypomimia), decreased voice volume
(hypophonia), and difficulty turning over in bed.
Tremor refers to a rhythmic oscillation around a fixed point in the “rest” or
nonpostural position. Tremor is often the first motor symptom of Parkinson
disease and affects approximately 90% of patients at some point in their lives
(VIDEO 1-1, links.lww.com/CONT/A348).14 While the tremor of Parkinson disease
is typically a resting tremor, 50% of patients may also present with a tremor than
may reoccur with arms stretched outward.14 Tremors start asymmetrically and
are characterized by supination and pronation, or pill-rolling, eventually affecting

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PARKINSON DISEASE

the opposite side of the body. Tremors may be less responsive to pharmacologic
treatment, including levodopa.
Rigidity refers to stiffness or resistance of a limb when it is flexed passively,
activating both agonist and antagonist muscles, and may also be referred to as
cogwheeling.15 Bradykinesia refers to slowness of movement (akinesia refers to
lack of movement) and may occur during both initiation and continuation of
movement.16
Postural instability, or balance dysfunction, is experienced later in the
course of the disease, about a decade after initial diagnosis. Postural instability

TABLE 1-1 Premotor, Nonmotor, and Motor Symptoms of Parkinson disease

Premotor Symptoms
◆ Constipation
◆ Anosmia
◆ Rapid eye movement (REM) sleep behavior disorder
◆ Depression
Nonmotor Symptoms: Neuropsychiatric
◆ Depression
◆ Anxiety (mood disorders)
◆ Apathy
◆ Impulse control disorder
◆ Psychosis
◆ Anhedonia
◆ Hallucinations
◆ Abulia
◆ Attention deficit disorder
◆ Panic attacks
Nonmotor Symptoms: Cognitive
◆ Executive dysfunction
◆ Memory loss
◆ Dementia
Nonmotor Symptoms: Autonomic
◆ Orthostatic hypotension
◆ Constipation
◆ Fecal incontinence
◆ Nausea
◆ Vomiting
◆ Drooling

CONTINUED ON PAGE 899

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

correlates with disease severity and is elicited by the pull test. It is a
levodopa-resistant symptom, in contrast to bradykinesia, rigidity, and tremor.
Postural instability is a major cause of falls, contributing to hip fractures,
loss of independence, and nursing-home placement in those afflicted by
the disease.
Other terms related to Parkinson disease symptoms include dyskinesia, also
called levodopa-induced dyskinesia, which refers to abnormal, involuntary,
choreiform movements that may affect the limbs, head, and torso (VIDEO 1-2,
links.lww.com/CONT/A349). Levodopa-induced dyskinesia may also manifest

CONTINUED FROM PAGE 898

◆ Urinary incontinence and urgency

◆ Sexual dysfunction
◆ Altered cardiac reflexes
◆ Olfactory dysfunction
◆ Gastrointestinal dysfunction
◆ Increased sweating
◆ Dysphagia
Nonmotor Symptoms: Sleep Disorders
◆ Insomnia
◆ Somnolence
◆ Excessive daytime sleepiness
◆ Restless legs syndrome
◆ Sleep attacks
◆ Periodic limb movements of sleep
◆ REM sleep behavior disorder
◆ Vivid dreaming
Nonmotor Symptoms: Sensory Abnormalities
◆ Anosmia
◆ Pain
◆ Ageusia
◆ Numbness
◆ Paresthesia
Cardinal Motor Symptoms
◆ Tremor
◆ Rigidity
◆ Bradykinesia (or akinesia)
◆ Postural instability
◆ Gait disorder

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PARKINSON DISEASE

with ballism, myoclonus, dystonia, or a combination of these movements.17

Levodopa-induced dyskinesia may be further classified as peak-dose dyskinesia,
wearing-off or off-period dyskinesia, or diphasic dyskinesia. Diphasic dyskinesia
begins shortly after levodopa ingestion followed by improvement in parkinsonian
symptoms and dyskinesia and a subsequent return of dyskinesia as dopamine
levels decline.14
Dystonia refers to involuntary, prolonged muscle contractions with abnormal
postures, usually in the limbs. Dystonia usually occurs in concert with lower
dopamine levels, often in the early morning hours. Patients may experience toe
curling or foot inversion due to dorsiflexion or plantar flexion of the lower
extremity, possibly resulting in cramping or an aching of the affected leg.
Dystonia may also occur in the peak-dose, diphasic, or “off” states (VIDEO 1-3,
links.lww.com/CONT/A350).18
Motor fluctuations refer to “off” times, when poor response to levodopa
alternates with “on” time, or improved function. Motor fluctuations occur with
advancing disease, possibly due to fluctuating stimulation from levodopa on
postsynaptic receptors.19 Off periods may be either predictable, in which
symptoms emerge prior to the next dose, or nonpredictable. Dose failure refers
to levodopa that has a delayed clinical effect.20 Freezing is described by Giladi
and Nieuwboer21 as “an episodic inability (lasting seconds) to generate effective
stepping in the absence of any known cause other than parkinsonism or
high-level gait disorders. It is most commonly experienced during turning and
step initiation but also when faced with spatial constraint, stress, and distraction.”
Patients feel that their feet are glued to the ground, and this feeling is usually
episodic in nature.

Nonmotor Symptoms
In the last 20 years, there has been increasing recognition of the importance of
nonmotor symptoms (ie, symptoms other than those involved in movement,
such as tremor, rigidity, and bradykinesia) in diagnosing and treating Parkinson
disease. It is estimated that nearly all patients with Parkinson disease will
experience several concurrent nonmotor symptoms throughout the course of
the disease. The impact from nonmotor symptoms is often greater than that
of motor symptoms; unfortunately, nonmotor symptoms are often underrecognized.
The nonmotor symptoms of Parkinson disease are listed below and are included
in TABLE 1-1.

u Neuropsychiatric nonmotor symptoms including depression, apathy, impulse control

disorders, anxiety, psychosis, hallucinations, mood disorders, apathy, and abulia
u Cognitive nonmotor symptoms including executive dysfunction, memory loss, and dementia
u Dysautonomia including orthostatic hypotension, constipation, urinary incontinence,
sexual dysfunction, altered cardiac reflexes, olfactory dysfunction, gastrointestinal
dysfunction, and sweating
u Sleep disorders including insomnia, somnolence, excessive daytime sleepiness, restless
legs syndrome, sleep attacks, periodic limb movements of sleep, and rapid eye
movement (REM) sleep behavior disorder
u Sensory abnormalities including pain, numbness, fatigue, and olfactory impairment22

Nonmotor symptoms may also be subject to fluctuations. During off states,

patients may experience worsening in mood, anxiety, dysautonomia including

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sweating and temperature irregularities, pain/numbness, and other symptoms KEY POINTS
(CASE 1-1). Nonmotor on states may include mania, agitation, delusions,
● Clinical features of
paranoia, and impulsivity.23 Parkinson disease include
tremor, rigidity, akinesia (or
Premotor Symptoms bradykinesia), and postural
Premotor symptoms are defined as symptoms that predate motor symptoms of instability. Nonmotor
symptoms are commonly
Parkinson disease and include constipation, anosmia, REM sleep behavior
experienced by patients and
disorder, and depression (TABLE 1-1).25 often negatively impact
quality of life. Premotor
DIAGNOSIS OF PARKINSON DISEASE symptoms include
constipation, anosmia, rapid
Parkinson disease remains a clinical diagnosis. The asymmetric symptoms of
eye movement sleep
resting tremor, bradykinesia, and rigidity with favorable response to disorder, and depression.
dopaminergic therapy suggest its diagnosis. Exclusionary features may
include severe dysautonomia, early hallucinations, dementia preceding motor ● The diagnosis of
symptoms, and postural instability and freezing within the first 3 years after Parkinson disease is made
clinically. Red flags for
diagnosis (CASE 1-2).27 The UK Parkinson’s Disease Society Brain Bank atypical parkinsonism
Diagnostic Criteria28 are listed in TABLE 1-2.29 include severe
dysautonomia, early-onset
CLINICAL PROGRESSION OF PARKINSON DISEASE hallucinations and
dementia, freezing, postural
Parkinson disease is a neurodegenerative progressive disease. The Movement instability, and lack of
Disorder Task Force recently recognized three stages in early Parkinson response to levodopa.
disease14,30,31: (1) the preclinical phase, in which neurodegeneration begins but Red flags for atypical
patients lack clinical symptoms; (2) the prodromal phase, in which symptoms parkinsonism also include
early speech difficulties and
are present but are insufficient to make a diagnosis of Parkinson disease;
imbalance, poor response to
and (3) the clinical phase, in which parkinsonian symptoms are manifest levodopa, and symmetrical
and recognizable. symptoms.
While it is difficult to accurately predict the general disease progression,
motor fluctuations usually affect patients within 5 to 10 years after diagnosis, ● Parkinson disease may be
divided into preclinical,
while postural instability occurs after about 10 years. Patients usually have a prodromal, and clinical
“good” period early on after diagnosis, in which they benefit from dopaminergic phases. Patients generally
therapy. However, the disease is eventually marked by uneven response to experience good response
levodopa, motor complications and fluctuations, levodopa-induced dyskinesia, to levodopa for several
years following their
speech and swallowing deficits, freezing, falls, and imbalance. Patients with diagnosis.
younger-onset disease are more prone to levodopa-induced dyskinesia and motor
fluctuations, while patients with older-onset disease have more cognitive issues
and dysautonomia.32

DIFFERENTIAL DIAGNOSIS OF PARKINSON DISEASE

The diagnosis of Parkinson disease may be complex, and it is estimated that
approximately 25% of patients have been misdiagnosed with another disease. The
differential diagnosis of Parkinson disease includes tremor syndromes, such as
essential tremor, atypical parkinsonisms (previously known as Parkinson-plus
syndromes), as well as other tremor disorders, secondary parkinsonisms, and
other cognitive disorders.
Perhaps the most difficult differential diagnoses for Parkinson disease are the
atypical parkinsonisms. Red flags for atypical parkinsonisms include early speech
difficulties, imbalance, a lack of tremor (generally), symmetry of symptoms
(except for corticobasal degeneration), and a poor response to levodopa. The
atypical parkinsonisms include progressive supranuclear palsy, corticobasal
degeneration, diffuse Lewy body diseases, and multiple system atrophy

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PARKINSON DISEASE

CASE 1-1 A 72-year-old woman presented for evaluation of worsening Parkinson

disease symptoms, including tremor, bradykinesia, and rigidity that she
had experienced over the past year. She had been diagnosed with
Parkinson disease 6 years prior after developing an asymmetric resting
tremor and rigidity. She was placed on carbidopa/levodopa at that time,
and she had a definite and clear motor response to the medication. The
patient noticed worsening symptoms of bradykinesia and rigidity in the
past 2 years that required an increase in her carbidopa/levodopa
immediate-release dose.
The patient reported lightheadedness upon rising from a chair several
times a week along with fatigue and mild confusion. These symptoms
occurred more frequently in the summer months and when she became
overheated. She also reported heat and cold intolerance, urinary
frequency, and constipation. Blood pressure readings taken several times
a week with a home monitor recorded occasional drops in systolic
blood pressure of more than 20 mm Hg within a few minutes of standing,
with no compensatory increase in pulse.
Four years after her initial diagnosis of Parkinson disease, she was
referred to a cardiologist, who diagnosed her with autonomic dysfunction,
secondary to Parkinson disease. The patient made an effort to stay
hydrated, especially in hot weather. She wore elasticized stockings,
started to exercise more, and monitored her blood pressures daily.
Her health was otherwise good, and her physical examination,
urinalysis, laboratory tests, and brain MRI had been normal. Her
medications included carbidopa/levodopa 25 mg/100 mg 1.5 tablets
4 times a day and vitamins.
On current examination, the patient had mild bradykinesia, moderate
rigidity in the right arm and leg, mild rigidity in the left arm and leg, and a
mild resting tremor in her right hand. Mild hypophonia and hypomimia
were present. Her gait consisted of a mildly narrow base and shortened
strides, with mild en bloc turning. Supine and standing blood pressure and
pulse readings did not show current significant orthostasis (120/80 mm Hg
supine with a pulse of 70 beats/min, and 105/60 mm Hg standing with a
pulse of 72 beats/min.

COMMENT Autonomic dysfunction occurs in Parkinson disease and includes

cardiovascular, gastrointestinal, urologic, thermoregulatory, and sexual
dysfunction. One misconception is that the presence of autonomic
dysfunction occurs only in patients with multiple system atrophy, or
atypical parkinsonism. Autonomic dysfunction also affects many patients
with idiopathic Parkinson disease as well. While carbidopa/levodopa can
cause orthostatic hypotension, the disease process itself is often the root
cause.24 Symptoms of autonomic dysfunction are important to recognize in
Parkinson disease as they may be treatable.24

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 A 60-year-old man presented to a movement disorder center for initial CASE 1-2
evaluation of a right-sided resting tremor and stiffness that had begun
2 years earlier. The tremor started insidiously but worsened with time. He
was not bothered by his symptoms. The patient’s past medical history
was significant for hypertension. He reported olfactory loss and
constipation that began about 10 years ago.
Examination revealed a well-developed man who had mild
bradykinesia along with a right-sided (arm and leg) resting tremor and
rigidity. No rigidity or resting tremor was noted on his left side. Secondary
symptoms of hypophonia and hypomimia were present. Right-sided
finger taps, pronation-supination, hand movements, and toe tapping
were noticeably diminished. His gait revealed a mild right leg drag with
decreased right arm swing. No postural instability was noted. His vital
signs and his physical and general neurologic examination were otherwise
normal. A brain MRI performed by a previous neurologist was reviewed
and was unremarkable.
The patient was diagnosed with Parkinson disease. Potential
treatment options were discussed with the patient, including dopamine
agonists, anticholinergic medications, carbidopa/levodopa, monoamine
oxidase inhibitors, or a regimen of exercise without medication. While he
did not receive symptomatic treatment for the motor symptoms of the
disease, he agreed to be treated for constipation and to continue his
exercise regimen.

The patient received a diagnosis of clinically established Parkinson disease. COMMENT

The Movement Disorder Society Task Force describes parkinsonism as
“bradykinesia, in combination with either rest tremor, rigidity, or both.”26
After parkinsonism is established, the task at hand is to determine whether
parkinsonism is actually caused by Parkinson disease. The diagnosis of
clinically established Parkinson disease requires at least two supportive
criteria, which in this case are olfactory loss and resting tremor of a limb, as
well as the “absence of absolute exclusion criteria and no red flags.” The
exclusion criteria for Parkinson disease were also met, including the
absence of cerebellar abnormalities, downward vertical gaze palsy,
behavioral variant of frontotemporal dementia or primary progressive
aphasia, parkinsonian symptoms that are restricted to the lower limbs for
more than 3 years, drug-induced parkinsonism, and unequivocal cortical
sensory loss. No red flags for an alternative diagnosis were apparent, such
as rapid gait impairment, bulbar dysfunction, severe autonomic failure, or
recurrent falls. He also experienced prodromal symptoms of Parkinson
disease, including olfactory loss.
The patient decided against pharmacotherapy but was encouraged to
exercise. Evidence supports that patients with Parkinson disease obtain
short-term and long-term benefits from exercise, including improvements
in motor and nonmotor symptoms of the disease.

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PARKINSON DISEASE

TABLE 1-2 UK Parkinson’s Disease Society Brain Bank Clinical Diagnostic Criteriaa

Step 1: Diagnosis of Parkinsonian Syndrome

◆ Bradykinesia (slowness of initiation of voluntary movement with progressive reduction in
speed and amplitude of repetitive actions)
◆ And at least one of the following:
◇ Muscular rigidity
◇ 4–6Hz resting tremor
◇ Postural instability not caused by primary visual, vestibular, cerebellar, or proprioceptive
dysfunction
Step 2: Exclusion Criteria for Parkinson Disease
◆ History of repeated strokes with stepwise progression of parkinsonian features
◆ History of repeated head injury
◆ History of definite encephalitis
◆ Oculogyric crises
◆ Neuroleptic treatment at onset of symptoms
◆ More than one affected relative
◆ Sustained remission
◆ Strictly unilateral features after 3 years
◆ Supranuclear gaze palsy
◆ Cerebellar signs
◆ Early severe autonomic involvement
◆ Early severe dementia with disturbances of memory, language, and praxis
◆ Babinski sign
◆ Presence of a cerebral tumor or communicating hydrocephalus on CT scan
◆ Negative response to large doses of levodopa (if malabsorption excluded)
◆ MPTP exposure
Step 3: Supportive Prospective Positive Criteria for Parkinson Disease
◆ Three or more required for diagnosis of definite Parkinson disease
◇ Unilateral onset
◇ Resting tremor present
◇ Progressive disorder
◇ Persistent asymmetry affecting the side of onset most
◇ Excellent response (70–100%) to levodopa
◇ Severe levodopa-induced chorea
◇ Levodopa response for 5 years or more
◇ Clinical course of 10 years or more

CT = computed tomography; MPTP= 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

a
Reprinted with permission from Gibb WR and Lees AJ, J Neurol Neurosurg Psychiatry.29 © 1988 BMJ
Publishing Group Ltd.

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(cerebellar or parkinsonian type, MSA-C and MSA-P, respectively). The KEY POINT
atypical parkinsonisms usually include another prominent symptom aside
● Parkinson disease is
from motor dysfunction, such as dysautonomia (MSA-C and MSA-P), characterized by the loss of
supranuclear gaze palsy, and marked asymmetry/dystonia of one limb with dopaminergic neurons and
cortical findings (corticobasal degeneration).33 the presence of Lewy
bodies containing the
misfolded protein
ETIOLOGY OF PARKINSON DISEASE
α-synuclein.
Parkinson disease is characterized by the loss of dopaminergic neurons in the
nigrostriatal system and by the presence of Lewy bodies in the brainstem. Motor
symptoms become evident when 60% to 80% of dopaminergic neurons are lost
in the pars compacta of the substantia nigra.34
It appears that Parkinson disease is actually a heterogeneous disorder
characterized by various clinical presentations, age of onset, types of
nonmotor symptoms, and different rates of progression.35 While some
patients have a relatively benign disease course with favorable response
to dopaminergic therapy, others appear to progress more rapidly. Many
patients have a preponderance of nonmotor symptoms while others
do not.36

Genetic Causes of Parkinson Disease

Parkinson disease is likely caused by multiple factors that lead to the
deterioration of dopaminergic neurons. It is estimated that 5% to 10% of
patients have a genetic etiology for the disease. Monogenic forms of
Parkinson disease include PARK-SNCA, PARK-LRRK2, and PARK-VPS35,
among others.
Another genetic risk factor for Parkinson disease and for the Ashkenazi Jewish
population in particular is the glucocerebrosidase, or GBA1, the gene responsible
for Gaucher disease. GBA1 directs the production of the glucocerebrosidase
protein, which is involved in lysosomal activity. A genetic defect in GBA1 causes
a reduction in glucocerebrosidase activity, an increase in glucosylceramide,
and promotion of α-synuclein accumulation, leading to a a greater chance of
developing Parkinson disease.
The advancement of genetic research with whole exome genetic sequencing
should provide future directions in genetic causes of Parkinson disease, including
a greater understanding of pathogenetic etiologies.37,38

Environmental Causes of Parkinson Disease

Interest in whether environmental or toxic exposures can contribute to the
development of Parkinson disease was sparked by the association between
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a prodrug to the
neurotoxin MPP+, and parkinsonism during the 1980s.38 Some of the
environmental factors and toxic exposures that may be associated with
Parkinson disease include pesticides (rotenone and paraquat); heavy metals
(manganese, lead, and copper); well water; woodworking; head injury;
other substances including polychlorinated biphenyls, trichloroethylene,
perchloroethylene, and carbon tetrachloride; and rural living. Exposure to
toxins, including carbon monoxide, trace metals, organic solvents, and cyanide
have also been implicated as environmental risk factors. Alternatively, smoking
and caffeine intake are thought to reduce disease risk, although further studies
are ongoing.12,14

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PARKINSON DISEASE

NEUROIMAGING OF PARKINSON DISEASE

Neuroimaging technology such as the dopamine transporter single-
photon emission computed tomography (SPECT) scan may be helpful in
making a diagnosis of Parkinson disease. In 2011, the US Food and Drug
Administration approved dopamine transporter SPECT using ioflupane
I-123 injection.39 Dopamine transporter SPECT has a high sensitivity
(87% to 98%) and specificity (80% to 100%) when differentiating Parkinson
disease from essential tremor40–44 and is considered an adjunct to diagnostic
assessments. However, dopamine transporter SPECT is not a confirmatory
test for Parkinson disease, nor is it intended to differentiate between
Parkinson disease and other degenerative forms of parkinsonism, including
atypical parkinsonism. Clinicians may decide to order a dopamine transporter
SPECT when the diagnosis of a clinical tremor syndrome is uncertain
(eg, when differentiating between Parkinson disease and essential
tremor).

CLINICAL RATING SCALES FOR PARKINSON DISEASE

Clinical rating scales are useful to follow the progression of Parkinson
disease and are used in clinical trials. The Unified Parkinson's Disease Rating
Scale (UPDRS),45 recently revised to the Movement Disorder Society-
Sponsored Revision (MDS-UPDRS),46 is a commonly used and validated
research scale that contains four parts: cognition and mood, activities of
daily living, motor examination, and motor complications. The Unified
Dyskinesia Rating Scale (UDysRS) is used to evaluate abnormal involuntary
movements, or dyskinesia, that occur with advancing Parkinson disease.47
The Hoehn and Yahr Scale describes five stages of Parkinson disease:
unilateral symptoms, bilateral symptoms, postural instability with worsening
bilateral symptoms, worsening symptoms with the inability to live alone
or independently, and wheelchair or bed assistance.48 Other clinical rating
scales commonly used are the Schwab and England Activities of Daily
Living Scale,49 the Parkinson’s Disease Questionnaire (PDQ-39 and
PDQ-8),50 and the Parkinson’s Disease Non-motor Symptoms (PD NMS)
Questionnaire.51 Patient diaries may provide invaluable information on
motor fluctuations in relation to medication intake,52 and kinematic sensors
may use new technology to detect and measure motor fluctuations in
the future.53

PHARMACOLOGIC AGENTS FOR PARKINSON DISEASE

Levodopa is the gold standard for dopamine replacement therapy in Parkinson
disease. It is administered with a dopa decarboxylase inhibitor (carbidopa) to
reduce its peripheral breakdown and lessen nausea. Levodopa is particularly
effective in treating akinesia and rigidity, with more variable effects on tremor.14
Clinical research suggests that levodopa treatment does not worsen disease
progression.54
Carbidopa/levodopa is available as immediate-release, extended-release,
and orally disintegrating tablets. A newer formulation of extended-release
carbidopa/levodopa (IPX066) was designed for rapid absorption, ease of
administration, and longer duration of clinical benefit55,56 (TABLE 1-3).
IPX066 has clinically been shown to improve on time without troublesome
dyskinesia time while reducing off time in advanced Parkinson disease.55,56 A

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levodopa inhalation powder has also been FDA-approved for intermittent KEY POINTS
treatment of off episodes in patients with Parkinson disease who take
● Parkinson disease
carbidopa/levodopa. remains a clinical diagnosis.
Another formulation of levodopa is levodopa/carbidopa intestinal gel, Neuroimaging techniques
which provides continuous infusion using a percutaneous endoscopic such as dopamine
gastrostomy with jejunal extension (PEG-J) tube.57 Clinical trials have shown transporter single-photon
emission computed
that levodopa/carbidopa intestinal gel reduces plasma levodopa fluctuations
tomography are helpful in
and off time and increases on time without troublesome dyskinesia compared differentiating between
to oral medication in patients with advanced disease.58 Levodopa/carbidopa essential tremor and tremor
intestinal gel may be recommended for patients with Parkinson disease who from parkinsonian
syndromes.
experience motor fluctuations and dyskinesia who cannot be optimally treated
with oral medication. Patients with advanced Parkinson disease who are not ● Clinical rating scales
candidates for surgical management may also benefit from levodopa/carbidopa and patient diaries are
intestinal gel. Adverse events secondary to levodopa/carbidopa intestinal gel helpful in monitoring disease
usually pertain to issues with the PEG-J. There are reports of polyneuropathy progression and are
useful tools in clinical
(either a sensory polyneuropathy or a more severe neuropathy resembling research trials.
Guillain-Barré syndrome) in some patients who have received levodopa/
carbidopa intestinal gel.59
Dopamine agonists directly stimulate dopamine receptors, thereby
bypassing degenerating dopaminergic neurons in the brain. Non–ergot
dopamine agonists are used as both monotherapy and adjunctive therapy in
the treatment of Parkinson disease. They have longer half-lives (greater than
6 hours) than levodopa, but also have a higher incidence of psychiatric side
effects, including hallucinations and impulse control disorders as well as
potential “sleep attacks” (ie, episodes of sudden onset of sleep). Dopamine
agonists include pramipexole, ropinirole (available in immediate-release and
extended-release formulations), rotigotine (transdermal formulation), and
apomorphine for subcutaneous use as a rescue medication for acute
off periods.
COMT inhibitors reduce the breakdown of levodopa to 3-O-methyldopa
and increase the plasma half-life of levodopa and its area under the curve.60
COMT inhibitors are used in conjunction with levodopa to improve
end-of-dose wearing-off time, although they may increase dyskinesia.
Currently available COMT inhibitors include entacapone and tolcapone,
a COMT inhibitor that carries a black box warning for potential liver
toxicity.61–63
MAO-B inhibitors prevent levodopa degradation in the brain and limit its
reuptake. They were initially thought to provide antioxidative properties in
patients with Parkinson disease. Selegiline is a selective and irreversible MAO-B
inhibitor approved as adjunctive medication to levodopa in patients with motor
fluctuations. Rasagiline, a second-generation MAO-B inhibitor, lacks the
amphetamine metabolites of selegiline and may be used as monotherapy and
adjunct therapy. Safinamide is another potent, reversible MAO-B inhibitor that
has been recently approved as adjunct therapy in patients with Parkinson disease
with motor fluctuations.64
An N-methyl-D-aspartate (NMDA) receptor antagonist, amantadine, was
originally used as an antiviral medication in the 1960s and has antidyskinetic
properties. A newer preparation of amantadine, ADS-5102, is an extended-release
form of amantadine that may be used to treat levodopa-induced dyskinesia in
patients with Parkinson disease.65

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PARKINSON DISEASE

TABLE 1-3 Pharmacologic Treatment of Parkinson Disease

Name Class Dosage Strength Administration Indication

Carbidopa/ Levodopa 25 mg/100 mg;10 mg/ Oral Treatment of Parkinson

levodopa 100 mg; 25 mg/250 mg disease (PD) symptoms
immediate release

Carbidopa/ Levodopa 50 mg/200 mg; 25 mg/100 mg Oral Treatment of PD

levodopa symptoms
extended release

Carbidopa/ Levodopa 25 mg/100 mg; 10 mg/100 mg; Sublingual Treatment of PD

levodopa orally 25 mg/250 mg symptoms
disintegrating

Carbidopa/ Levodopa 23.75 mg/95 mg; 36.25 mg/ Oral Treatment of PD

levodopa 145 mg; 48.75 mg/195 mg; symptoms
extended-release 61.25 mg/245 mg
capsules

Carbidopa/ Levodopa 4.63 mg/mL carbidopa and Enteral Treatment of motor

levodopa enteral 20 mg/mL levodopa; 100 mL total fluctuations in advanced
suspension in one cassette for infusion PD

Levodopa Levodopa 84 mg, 168 mg, 252 mg, 336 mg, Oral inhalation Intermittent treatment
inhalation powder 420 mg of off episodes in
patients with PD using
carbidopa/levodopa

Carbidopa/ Levodopa plus 12.5 mg/50 mg/200 mg; 18.75 mg/ Oral Indicated for end-of-
levodopa/ catechol-O- 75 mg/200 mg; 25 mg/100 mg/ dose wearing off
entacapone methyltransferase 200 mg; 31.25 mg/125 mg/200 mg;
(COMT) inhibitor 37.5 mg/150 mg/200 mg; 50 mg/
200 mg/200 mg

Pramipexole Dopamine agonist 0.125 mg, 0.25 mg, 0.5 mg, Oral Treatment of PD
immediate release 0.75 mg, 1 mg, 1.5 mg symptoms

Pramipexole Dopamine agonist 0.375 mg, 0.75 mg, 1.5 mg, 2.25 mg, Oral Treatment of PD
extended release 3 mg, 3.75 mg, 4.5 mg symptoms

Ropinirole Dopamine agonist 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, Oral Treatment of PD
immediate release 4 mg, 5 mg symptoms

Ropinirole Dopamine agonist 2 mg, 4 mg, 6 mg, 8 mg, 12 mg Oral Treatment of PD

extended release symptoms

Rotigotine Dopamine agonist 2 mg/24 hours, 4 mg/24 hours, Transdermal Treatment of PD

6 mg/24 hours patch symptoms

Apomorphine Dopamine agonist 0.2 mL (2 mg)–0.6 mL (6 mg) Subcutaneous Acute, intermittent

hydrochloride treatment of
hypomobility, off
episodes (end-of-dose
wearing off and
unpredictable on/off
episodes) associated
with advanced
Parkinson disease

CONTINUED ON PAGE 909

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CONTINUED FROM PAGE 908

Name Class Dosage Strength Administration Indication

Entacapone COMT inhibitor 200–1600 mg (200 mg/d–200 mg Oral Adjunct to levodopa

up to 8 times per day) in therapy in patients with
conjunction with levodopa/ PD with end-of-dose
carbidopa wearing off

Tolcapone COMT inhibitor 100 mg 3 times a day–200 mg Oral Adjunct to levodopa

3 times a day in conjunction with therapy in patients with
levodopa/carbidopa PD with end-of-dose
wearing off

Selegiline Monoamine oxidase 10 mg/d (5 mg 2 times a day, Oral Adjunct to levodopa

type B (MAO-B) breakfast and lunch) therapy in patients with
inhibitor PD who experience a
deterioration in positive
response to the
levodopa therapy

Selegiline oral MAO-B inhibitor 1.25 mg, 2.5 mg Sublingual Adjunct to levodopa
disintegrating therapy in patients with
PD who experience a
deterioration in positive
response to the
levodopa therapy

Rasagiline MAO-B inhibitor 0.5 mg, 1 mg; monotherapy: 1 mg Oral Treatment of PD

symptoms:
monotherapy and
adjunctive therapy with
levodopa

Safinamide MAO-B inhibitor 50 mg/d, 100 mg/d Oral Indicated as an add-on

therapy for those taking
carbidopa/ levodopa
for off time

Amantadine N-methyl-D-aspartate 100 mg capsules or tablets Oral Medications for

immediate release (NMDA) antagonist treatment of Parkinson
disease

Amantadine NMDA antagonist 137 mg, 274 mg Oral Treatment of dyskinesia

extended-release in patients with PD
capsule receiving levodopa
therapy

Amantadine NMDA antagonist 129 mg, 193 mg, 258 mg Oral Treatment of dyskinesia
extended-release in patients with PD
tablet receiving levodopa
therapy

Trihexyphenidyl Anticholinergic 2 mg, 5 mg Oral Used to treat tremor in

Parkinson disease

Benztropine Anticholinergic 0.5 mg Oral Used to treat tremor in

Parkinson disease

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PARKINSON DISEASE

Anticholinergic medications such as trihexyphenidyl and benztropine were

the original drugs used to treat Parkinson disease. They are used to treat tremor
in younger patients with Parkinson disease as their side effects include confusion,
dry mouth, urinary retention, and constipation.

TREATMENT OF PARKINSON DISEASE

A number of therapeutic options exist for Parkinson disease. Treatment options
must be targeted to both motor and nonmotor symptoms. Management of
patients may differ depending on disease severity and duration.

CASE 1-3 A 75-year-old woman presented for evaluation of an arm tremor. The
patient’s primary care physician observed a right-sided resting tremor
during a routine well care visit earlier that year and referred her to a
movement disorders center for evaluation. She dragged her right leg
when walking and reported stiffness and pain in her right arm and leg. She
reported daytime somnolence due to a long history of insomnia, and
described mild forgetfulness.
On examination, the patient was mildly hypertensive, but her vital
signs and physical examination were otherwise normal. Her Mini-Mental
State Examination was 27 out of 30. The patient had moderate
bradykinesia, moderate resting tremor in her right hand, and mild resting
tremor in her left hand, with rigidity noted in all limbs. She had
moderately stooped axial posture, and she had a narrow-based gait with
shortened strides. The patient took several steps back on the pull test
but recovered unaided.
The patient was diagnosed with Parkinson disease. She was placed
on carbidopa/levodopa 25 mg/100 mg, 1 tablet 4 times daily, with tablets
taken before meals. She returned to clinic after 6 weeks with marked
improvement in motor symptoms.

COMMENT The patient had Parkinson disease and exhibited the cardinal symptoms of
bradykinesia, resting tremor, and rigidity. She demonstrated supportive
criteria for the disease as well as the absence of exclusionary criteria and
red flags. The symptoms were bothersome to the patient, so treatment
was appropriate.
Levodopa remains the gold standard of treating Parkinson disease
and is the single most effective agent to treat all stages of the disease.70
The patient was in her midseventies, had mild cognitive impairment and
excessive daytime sleepiness, and was clearly in need of dopaminergic
therapy.
Dopamine agonists were not used in this case as they can worsen
excessive daytime sleepiness and exacerbate neuropsychiatric
symptoms. Anticholinergic medications might improve her tremor, but
will do little for the bradykinesia and rigidity she experiences, and
patients who are 70 years of age and older may also be more prone to
experiencing side effects from their use.

910 AUGUST 2019

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Early Parkinson Disease KEY POINTS
Treatment of Parkinson disease consists of a dopamine replacement
● While levodopa is the
strategy to improve disease symptoms, as neuroprotective therapies gold standard in the
are not yet available. Patients should be offered dopaminergic treatment of Parkinson
treatment when their symptoms become bothersome. There is no known disease, it is now available in
benefit of withholding treatment from patients who have disease several formulations that
may provide ease of
symptoms.66
administration and improved
When a patient is newly diagnosed with Parkinson disease, it is important to efficacy. Other available
determine whether symptoms are bothersome enough to the patient to warrant medications are dopamine
treatment while also keeping nonmotor symptoms in mind. Factors to be agonists, catechol-O-
methyltransferase
taken into consideration are the patient’s age, comorbid conditions, employment
inhibitors, monoamine
status, and other quality-of-life issues. For example, has the patient presented to oxidase type B inhibitors, an
a neurology clinic to obtain a diagnosis, a second opinion, or for symptom N-methyl-D-aspartate
treatment? antagonist, and
A discussion about treatment of early Parkinson disease requires a short anticholinergic medications.

review regarding the controversy over initiating levodopa treatment in younger ● Patients with Parkinson
patients. Levodopa is a safe and efficacious medication for practically reversing disease should be offered
disease symptoms for a period of time. Motor fluctuations and dyskinesias may dopaminergic treatment
be more closely associated with longer disease duration and higher levodopa when their symptoms are
bothersome. Patients with
daily dose rather than the duration of levodopa therapy.67 Pulsatile delivery of Parkinson disease should be
levodopa also contributes to dyskinesia.68 As the disease progresses, higher and encouraged to exercise, as
more frequent doses of levodopa are required. While no definitive evidence long as it is performed
indicates that levodopa induces cell death, symptomatic therapy should be safely.
initiated while also considering both short-term and long-term potential
side effects.66
Dopamine agonists, MAO-B inhibitors, or anticholinergic medications may be
initiated in patients with Parkinson disease who are younger than 70 years of
age. However, non–levodopa medications eventually will be insufficient to
effectively ameliorate motor symptoms, and patients will need to be treated with
levodopa (levodopa rescue).
Treatment of younger patients with levodopa should be considered if
symptoms are bothersome enough to cause suffering or interfere with qualify
of life. Younger patients may need more effective control of their symptoms
with levodopa if they need to remain employed or have other responsibilities
including childcare or eldercare. Patients may also be unable to receive optimal
treatment with non–levodopa agents because of untoward side effects. Several
studies suggest that starting treatment with levodopa leads to better long-term
motor outcomes and better functioning long-term.20 In older patients with
evidence of cognitive decline, excessive daytime sleepiness, or other comorbid
conditions, it is more appropriate to initiate treatment for Parkinson disease
with levodopa. Dopamine agonists, MAO-B inhibitors, and anticholinergic
medications are more likely than levodopa to cause cognitive side effects in
the elderly.
Exercise should be encouraged for all patients with Parkinson disease as
long as it is performed safely. Some evidence suggests that long-term aerobic
exercise may slow Parkinson disease progression.69 Studies to confirm this
hypothesis are ongoing.19 Exercise modalities include core strength training
exercises, tai chi, yoga, boxing, and dance and music therapy. Cognitive
training with puzzles and computer games should also be encouraged
(CASE 1-3).

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PARKINSON DISEASE

Advanced Parkinson Disease

As Parkinson disease advances, the reduced storage and release capacity of
endogenous dopamine can lead to the shortened duration of levodopa benefit.
Patients will experience a decline in medication efficacy in which symptoms
return prior to the next dose, referred to as predictable wearing off. Motor
fluctuations and levodopa-induced dyskinesia set in, and in time may occur
with troublesome dyskinesia for much of the waking day. Motor fluctuations
may be caused by pulsatile stimulation of dopamine receptors. Gastric
emptying issues with advanced disease may further contribute to uneven
medication absorption. Nonmotor fluctuations may occur as well, including
depression, fatigue, and anxiety.
The aim of Parkinson disease treatment is to optimize on time and reduce
off time while minimizing troublesome levodopa-induced dyskinesia. Off
time may be treated by taking Parkinson disease medications more frequently,
using an extended-release form of levodopa, adding a COMT inhibitor or
MAO-B inhibitor, or by the addition of a dopamine agonist to provide a more
stable response.
Treatment of levodopa-induced dyskinesia requires identifying its occurrence
in relation to levodopa dosing. Redistribution of medication doses, as well as
changing forms of medication from immediate-release to extended-release
formulations, for example, may improve motor fluctuations and levodopa-
induced dyskinesia. Amantadine has been shown to treat levodopa-induced
dyskinesia and is now available as an extended-release formation, which has
been shown to reduce levodopa-induced dyskinesia and off time.65 In patients
with advanced Parkinson disease who are suboptimally treated despite best
medical practice using oral medications, levodopa/carbidopa intestinal gel or
surgical management may be considered.

Surgical Treatment of Parkinson Disease

Surgical treatment of Parkinson disease was developed for patients who,
despite medication optimization, experience motor symptoms that cannot be
satisfactorily ameliorated by medication. A common surgical treatment is
DBS, which targets the subthalamic nucleus, globus pallidus internus, or
ventral intermediate nucleus of the thalamus for tremor-predominant
Parkinson disease with otherwise minimal symptoms. DBS involves modulating
the brain circuitry using electrical stimulation from an implanted current
source.71 It has been demonstrated to improve tremor, dyskinesia, and motor
fluctuations and has been used to treat thousands of patients with Parkinson
disease worldwide.
DBS is a programmable procedure, and patient selection and accurate
implantation at the optimal target are keys for surgical success. Many centers
consider 75 years of age or even slightly older to be an approximate upper limit.72
Most DBS procedures are performed about 10 years after diagnosis, but the
EARLYSTIM (Controlled Trial of Deep Brain Stimulation in Early Patients
with Parkinson’s Disease) trial suggests that DBS may be used earlier in the
course of the disease.73 Exclusionary criteria for DBS include the presence of
an atypical parkinsonism, unstable psychiatric disease, advanced disease with
significant dementia, comorbidities that preclude surgical candidacy, and
advanced age. Patients typically receive neuropsychiatric evaluation prior to
surgery to assess their suitability for surgery and estimate their risk of cognitive

912 AUGUST 2019

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impairment. Patients also receive medical clearance and imaging with MRI to KEY POINTS
identify strokes, atrophy, or other abnormalities that could interfere with
● The aim of Parkinson
successful lead placement. disease treatment is to
Surgical planning for DBS typically involves preoperative imaging optimize on time and reduce
including an MRI of the brain. The target is identified via patient-specific off time while minimizing
anatomy (so-called direct targeting) with or without reference to the troublesome levodopa-
induced dyskinesia.
consensus stereotactic coordinates established for each target (so-called indirect
Treatment of levodopa-
targeting), and a trajectory is planned to avoid vascular and other critical induced dyskinesia
intracranial structures. Lead placement may be further refined using requires identifying its
microelectrode recording with or without stimulation mapping.71 DBS electrodes occurrence in relation to
levodopa dosing.
are implanted into the appropriate cerebral target causing a microlesion, and an
implanted pulse generator is placed under the skin near the clavicle. Several ● Surgical treatment of
weeks after surgery, when the microlesion effect has subsided, the implanted Parkinson disease was
pulse generator is programmed with stimulation parameters designed to deliver developed for patients who,
current to the appropriate areas to improve symptoms.74 The patient returns to despite medication
optimization, experience
the movement disorder or neurologic center, where frequency, voltage, and motor symptoms that
pulse width parameters are configured in accordance with the patient’s cannot be satisfactorily
symptoms. Possible complications of DBS include medical issues such as ameliorated by medication.
myocardial infarction, pneumonia, deep vein thrombosis, and pulmonary
embolism and surgical issues such as cerebral hematoma, stroke, seizures,
infections, and hardware dysfunction, all reported in a small percentage of
patients. Side effects may include paresthesia, dysarthria, ataxia, and mood
dysregulation, which are typically reversible and ameliorated by changing the
stimulation parameters.

OFFICE VISIT
Patients with Parkinson disease will most likely visit a neurology or movement
disorder specialist for treatment. Health care providers must pay attention to
both motor and nonmotor symptoms of the disease. Information about any
recent falls, swallowing issues, comorbid conditions, hospitalizations, or a
change in living arrangements should be obtained. Nonmotor symptoms
including constipation, pain, and mood disorders should not be neglected (refer
to the section on nonmotor symptoms). Patients should be encouraged to visit
their primary care physicians and other specialists for general health and
psychiatric care.

Medication Adjustment for Motor Function

When evaluating a patient with Parkinson disease for medication adjustment, it
is important to remember that this is a disease of timing. Failure to understand a
patient’s motor and nonmotor response to his or her medication schedule
throughout the entire day may preclude precise medication adjustments from
being made. Rarely will this information be obtained by simply calculating the
total daily dose of Parkinson disease medications or asking general questions,
such as “How are you doing?” or “Are you having any problems?” Patient diaries,
indicating the times medications are taken and the clinical response throughout
a 24-hour period are usually very helpful in obtaining a pattern of motor
responses to medications.
Medication adjustments may begin after taking an account of Parkinson
disease medications and the times they are dosed. The creation of a lined chart
may be helpful. The number of doses taken throughout the day should be filled in

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PARKINSON DISEASE

the table according to when the patient reports they are taken. Attention should
be paid to whether the medications have been given in immediate-release or
controlled-release forms.
Questions regarding motor response may include the following:

u How much time does it take for your Parkinson disease medications to take effect
after each dose?
u How long does the effect of each medication last? (Record this information for each
dose interval.)
u Do you develop dyskinesia during the mid-dose period? Does dyskinesia occur toward
the beginning or end of the dose interval?
u Do you experience wearing off toward the end of the dose interval? Can you estimate
how long this occurs before the next dose begins?
u Do you experience early morning dystonia or pain or curling in your limbs? Does dystonia
occur at other times during the day?
u Do you have periods of the day when your medications do not seem to work? Do
these periods occur around meal times?

Armed with this information, changes to medication dosing may be tailored to

provide maximum on time and minimum off time. For example, if predictable
wearing off occurs, the medication dose may need to be increased or given more
frequently or another formulation of carbidopa/levodopa may be used. If early
morning dystonia occurs, patients may benefit from a carbidopa/levodopa
controlled release at bedtime. If patients report lack of medication efficacy after a
protein meal, they might be counseled to eat smaller doses of protein throughout
the day. Bothersome dyskinesia may also be treated with an NMDA antagonist
or by redistributing carbidopa/levodopa.

CONCLUSION
Parkinson disease is a complex neurodegenerative disease that appears to be a
heterogeneous disorder. Exciting research continues to take place regarding the
etiology and pathogenesis of the disease. Novel neuroimaging techniques such
as SPECT scans may now assist with disease diagnosis. New formulations of
Parkinson disease medications are available for easier administration and
improved clinical efficacy.
Treatment of Parkinson disease continues to be symptomatic, however,
and the disease cannot yet be cured. The realization that Parkinson disease
has a preclinical phase has prompted the need for early biomarkers.
Research continues to focus on neuroprotective and disease-modifying
strategies, including therapies targeting α-synuclein. Future research in the
etiology, pathophysiology, and ultimately a cure for Parkinson disease
remains hopeful, considering the remarkable progress made in the last
half century.

ACKNOWLEDGMENTS
The author would like to thank Shaila Ghanekar and Yarema Bezchlibnyk, MD,
PhD, FRCSC, for their help and guidance.

914 AUGUST 2019

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VIDEO LEGENDS
VIDEO 1-1 VIDEO 1-3
Parkinson disease. Video shows a 67-year-old Dystonia. Video shows a 64-year-old man
man with Parkinson disease exhibiting resting with advanced Parkinson disease, off
tremor of his right arm and decreased arm swing carbidopa/levodopa, exhibiting involuntary
during gait testing. dorsiflexion of his feet, consistent with
links.lww.com/CONT/A348 “off” dystonia.
© 2019 American Academy of Neurology. links.lww.com/CONT/A350
© 2019 American Academy of Neurology.
VIDEO 1-2
Dyskinesia. Video shows a 67-year-old man with
advanced Parkinson disease exhibiting involuntary
choreiform movements in his limbs, neck, and torso,
consistent with levodopa-induced dyskinesia.
links.lww.com/CONT/A349
© 2019 American Academy of Neurology.

REFERENCES

1 Hirtz D, Thurman DJ, Gwinn-Hardy K, et al. 10 de Lau LM, Breteler MM. Epidemiology of
How common are the “common” neurologic Parkinson's disease. Lancet Neurol 2006;5(6):
disorders? Neurology 2007:68(5):326–327. 525–535. doi:10.1016/S1474-4422(06)70471-9.
doi:10.1212/01.wnl.0000252807.38124.a3.
11 Elbaz A, Bower JH, Maraganore DM, et al. Risk
2 Parkinson J. An essay on the shaking palsy. tables for parkinsonism and Parkinson’s disease.
London: Whittingham and Rowland Sherwood, J Clin Epidemiol 2002;55(1):25–31. doi:10.1016/
Neely and Jones, 1817. S0895-4356(01)00425-5.
3 Charcot JM. Lectures on the diseases of the 12 Taylor KS, Cook JA, Counsell CE. (2007)
nervous system, delivered at La Salpetriere. Heterogeneity in male to female risk for
London: The New Sydenham Society, 1877. Parkinson’s disease. J Neurol Neurosurg
Psychiatry 78(8):905–906. doi:10.1136/jnnp.
4 Carlsson A, Lindqvist M, Magnusson T.
2006.104695.
3,4-Dihydroxyphenylalanine and
5-hydroxytryptophan as reserpine 13 Jankovic J. Parkinson’s disease: clinical features
antagonists. Nature 1957;180(4596):1200. and diagnosis. J Neurol Neurosurg Psychiatry
doi:10.1038/1801200a0. 2008;79(4):368–376. doi:10.1136/jnnp.2007.
131045.
5 Cotzias GC, Van Woert MH, Schiffer LM.
Aromatic amino acids and modification of 14 Obeso J, Stamelou M, Geotz CG, et al. Past,
Parkinsonism. N Engl J Med 1967;282(7):31–33. present, and future of Parkinson’s disease: a
doi:10.1056/NEJM196702162760703. doi:10.1056/ special essay on the 200th anniversary of the
NEJM196702162760703. shaking palsy. Mov Disord 2017;32(9):1264–1310.
doi:10.1002/mds.27115.
6 Olanow CW, Watts RL, Koller WC. An algorithm
(decision tree) for the management of 15 Samii A, Nutt JG, Ransom BR. Parkinson's disease.
Parkinson’s disease (2001): treatment guidelines. Lancet 2004;363(9423):1783–1793. doi:10.1016/
Neurology 2001;56(11 suppl 5):S1–S88. doi:10.1212/ S0140-6736(04)16305-8.
WNL.56.suppl_5.S1.
16 Berardelli A, Rothwell JC, Thompson PD, Hallett M.
7 Ahlskog JE, Muenter MD. Frequency of Pathophysiology of bradykinesia in Parkinson's
levodopa-related dyskinesias and motor disease. Brain 2001;124(pt 11):2131–2146. doi:
fluctuations as estimated from the cumulative 10.1093/brain/124.11.2131.
literature. Mov Disord 2001;16(3):448–458.
17 Luquin MR, Scipioni O, Vaamonde J, et al.
doi:10.1002/mds.1090.
Levodopa-induced dyskinesias in Parkinson’s
8 Cell Signaling Technology. Cell Signaling disease: clinical and pharmacological
Technology web site. Dopamine signaling in classification. Mov Disord 1992:7(2):117–124.
Parkinson's disease interactive pathway. doi:10.1002/mds.870070204.
cellsignal.com/reference/pathway/parkinsons_
18 Tolosa E, Compta Y. Dystonia in Parkinson’s
disease.html. Accessed June 9, 2019.
disease. J Neurol 2006;253(suppl 7):vii7–vii13.
9 Nussbaum RL, Ellis CE. Alzheimer’s disease and doi:10.1007/s00415-006-7003-6.
Parkinson’s disease. N Engl J Med 2003;348:
19 Aquino CC, Fox SH. Clinical spectrum of
1356–1364.
levodopa-induced complications. Mov Disord
2015;30(1):80–89. doi:10.1002/mds.26125.

CONTINUUMJOURNAL.COM 915

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

PARKINSON DISEASE

20 Morgan JC, Fox SH. Treating the motor symptoms 34 Hirsch E, Graybiel AM, Agid YA. Melanized
of Parkinson disease. Continuum (Minneap Minn) dopaminergic neurons are differentially
2016;22(4):1064–1085. doi:10.1212/CON. susceptible to degeneration in Parkinson’s
0000000000000355. disease. Nature 1988;334(6180):345–348.
doi:10.1038/334345a0.
21 Giladi N, Nieuwboer A. Understanding and
treating freezing of gait in parkinsonism, 35 Lang AE, Obeso JA. Time to move beyond
proposed working definition, and setting the nigrostriatal dopamine deficiency on Parkinson’s
stage. Mov Disord 2008;23(suppl 2):S423–S425. disease. Ann Neurol 2004;55(6):761–765.
doi:10.1002/mds.21027. doi:10.1002/ana.20102.
22 Chaudhuri KR, Healy DG, Schapira AH; National 36 Nutt JG. Motor subtype in Parkinson's disease:
Institute for Clinical Excellence. Non-motor different disorders or different stages of
symptoms of Parkinson's disease: diagnosis and disease? Mov Disord 2016;31(7):957–961.
management. Lancet Neurol 2006;5(3):235–245. doi:10.1002/mds.26657.
doi:10.1016/S1474-4422(06)70373-8.
37 Gan-Or Z, Liong C, Alcalay RN. GBA-associated
23 Storch A, Schneider CB, Wolz M, et al. Nonmotor Parkinson's disease and other synucleinopathies.
fluctuations in Parkinson disease: severity and Curr Neurol Neurosci Rep 2018;18(8):44.
correlation with motor complications. Neurology doi:10.1007/s11910-018-0860-4.
2013;80(9):800–809. doi:10.1212/WNL.
38 Mazzulli JR, Xu YH, Sun Y, et al. Gaucher
0b013e318285c0ed.
disease glucocerebrosidase and α-synuclein
24 Pfeiffer RF. Management of autonomic form a bidirectional pathogenic loop in
dysfunction in Parkinson’s disease. Semin Neurol synucleinopathies. Cell 2011;146:37–52.
2017;37(2):176–185. doi:10.1055/s-0037-1601568. doi:10.1016/j.cell.2011.06.001.
25 Goldman JG, Postuma R. Premotor and nonmotor 39 Hauser RA, Grosset DG. [123I]FP-CIT (DaTscan)
features of Parkinson's disease. Curr Opin SPECT brain imaging in patients with suspected
Neurol 2014;27(4):434–441. doi:10.1097/WCO. parkinsonian syndromes. J Neuroimaging 2012;
0000000000000112. 22(3):225–230. doi:10.1111/j.1552-6569.2011.
00583.x.
26 Postuma RB, Berg D, Stern M, et al. MDS clinical
diagnostic criteria for Parkinson's disease. 40 Benamer TS, Patterson J, Grosset DG, et al.
Mov Disord 2015;30(12):1591–1601. doi:10.1002/ Accurate differentiation of parkinsonism and
mds.26424. essential tremor using visual assessment of
[123I]-FP-CIT SPECT imaging: the [123I]-FP-CIT
27 Gelb DJ, Oliver E, Gilman S. Diagnostic criteria for
study group. Mov Disord 2000;15(3):503–510.
Parkinson’s disease. Arch Neurol 1999;56(1):
doi:10.1002/1531-8257(200005)15:3<503::AID-
33–39. doi:10.1001/archneur.56.1.33.
MDS1013>3.0.CO;2-V.
28 Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy
41 Benamer HT, Oertel WH, Patterson J, et al.
of clinical diagnosis of idiopathic Parkinson’s
Prospective study of presynaptic dopaminergic
disease: a clinico-pathological study of 100
imaging in patients with mild parkinsonism and
cases. J Neurol Neurosurg Psychiatry 1992;55(3):
tremor disorders: part 1. Baseline and 3-month
181–184. doi:10.1136/jnnp.55.3.181.
observations. Mov Disord 2003;18(9):977–984.
29 Gibb WR, Lees AJ. The relevance of the Lewy doi:10.1002/mds.10482.
body to the pathogenesis of idiopathic Parkinson’s
42 Asenbaum S, Pirker W, Angelberger P, et al. [123I]
disease. J Neurol Neurosurg Psychiatry 1988;51(6):
beta-CIT and SPECT in essential tremor and
745–752. doi:10.1136/jnnp.51.6.745.
Parkinson’s disease. J Neural Transm (Vienna)
30 Berg D, Lang AE, Postuma RB, et al. Changing the 1998;105(10–12):1213–1228. doi:10.1007/
research criteria for the diagnosis of Parkinson’s s007020050124.
disease: obstacles and opportunities. Lancet
43 Jennings DL, Seibyl JP, Oakes D, et al. (123I) beta-
Neurol 2013;12(5):514–524. doi:10.1016/S1474-
CIT and single-photon emission computed
4422(13)70047-4.
tomographic imaging vs clinical evaluation in
31 Stern MB, Lang A, Poewe W. Toward a redefinition Parkinsonian syndrome: unmasking an early
of Parkinson’s disease. Mov Disord 2012;27(1): diagnosis. Arch Neurol 2004;61(8):1224–1229.
54–60. doi:10.1002/mds.24051. doi:10.1001/archneur.61.8.1224.

32 Kempster PA, Williams DR, Selikhova M, et al. 44 Pagano G. Niccolini F, Politis M. Imaging in
Patterns of levodopa response in Parkinson's Parkinson’s disease. Clin Med (Lond) 2016;16(4):
disease: a clinico-pathological study. Brain 371–375. doi:10.7861/clinmedicine.
2007;130(pt 8):2123–2128. doi:10.1093/brain/
45 Fahn S, Elton RL, UPDRS program members.
awm142.
Unified Parkinson’s disease rating scale. In: Fahn S,
33 McFarland NR, Hess CW. Recognizing atypical Marsden CD, Goldstein M, Calne DB, editors.
Parkinsonisms: “Red Flags” and therapeutic Recent developments in Parkinson’s disease,
approaches. Semin Neurol 2017;37(2):215–227. vol. 2. Florham Park, NJ: Macmillan Healthcare
doi:10.1055/s-0037-1602422. Information, 1987:153–163, 293–304.

916 AUGUST 2019

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

46 Goetz CG, Tilley BC, Shaftman SR, et al. 58 Wirdefeldt K, Odin P, Nyholm D. Levodopa-
Movement Disorder Society-sponsored revision carbidopa intestinal gel in patients with
of the Unified Parkinson’s Disease Rating Scale Parkinson's disease: a systematic review.
(MDS-UPDRS): scale presentation and clinimetric CNS Drugs 2016;30(5):381–404. doi:10.1007/
testing results. Mov Disord 2008;23(15):41–47. s40263-016-0336-5.
doi:10.1002/mds.22340.
59 Onofrj M, Bonanni L, Cossu G, et al. Emergencies
47 Goetz CG, Nutt JG, Stebbins GT. The Unified in parkinsonism: akinetic crisis, life-threatening
Dyskinesia Rating Scale: presentation and dyskinesias, and polyneuropathy during L-Dopa
clinimetric profile. Mov Disord 2008;23(16): gel treatment. Parkinsonism Relat Disord 2009;
2398–403. doi:10.1002/mds.22341. 15(suppl 3):S233–S236. doi:10.1016/S1353-
8020(09)70821-1.
48 Hoehn MM, Yahr MD. Parkinsonism: onset,
progression, and mortality. Neurology 1967;17(5): 60 Deleu D, Northway MG, Hanssens Y. Clinical
427–442. pharmacokinetic and pharmacodynamic
properties of drugs used in the treatment of
49 Schwab RS, England AC. Projection technique for
Parkinson’s Disease. Clinical Pharmacokinet
evaluating surgery in Parkinson’s disease. In:
2002;41(4):261–309. doi:10.2165/00003088-
Gillingham FJ, Donaldson MC, editors. Third
200241040-00003.
symposium on Parkinson’s disease. Edinburgh:
Livingston, 1969:152–157. 61 Olanow CW, Watkins PB. Tolcapone. Clin
Neuropharmacol 2007;30(5):287–294.
50 Zhang JL, Chan P. Reliability and validity of
doi:10.1097/wnf.0b013e318038d2b6.
PDQ-39: a quality-of-life measure for patients
with PD in China. Qual Life Res 2012;21(7): 62 Truong DD. Tolcapone: review of its
1217–1221. doi:10.1007/s11136-011-0026-1. pharmacology and use as adjunctive therapy in
patients with Parkinson’s disease. Clin Interv
51 Storch A, Schneider CB, Klingelhöfer L, et al.
Aging 2009;4:109–113. doi:10.2147/CIA.S3787.
Quantitative assessment of non-motor
PMC 2685232.
fluctuations in Parkinson's disease using the
Non-Motor Symptoms Scale (NMSS). J Neural 63 Valeant Pharmaceuticals International. Tasmar
Transm (Vienna) 2015;122(12):1673–1684. (tolcapone). www.accessdata.fda.gov/
doi:10.1007/s00702-015-1437-x. drugsatfda_docs/label/2006/020697s010lbl.pdf.
Accessed June 7, 2019.
52 Hauser RA, Friedlander J, Zesiewicz TA, et al. A
home diary to assess functional status in patients 64 Stocchi F, Arnold G, Onofrj M, et al. Improvement
with Parkinson's disease with motor fluctuations of motor function in early Parkinson disease
and dyskinesia. Clin Neuropharmacol 2000;23(2): by safinamide. Neurology 2004;63(4):
75–81. 746–748. doi:10.1212/01.WNL.0000134672.
44217.F7.
53 Rodríguez-Molinero A, Pérez-López C, Samà A,
et al. A kinematic sensor and algorithm to detect 65 Pahwa R, Tanner CM, Hauser RA, et al. Amantadine
motor fluctuations in Parkinson disease: extended release for levodopa-induced
validation study under real conditions of use. dyskinesia in Parkinson's disease (EASED Study).
JMIR Rehabil Assist Technol 2018;5(1):e8. Mov Disord 2015;30(6):788–795. doi:10.1002/
doi:10.2196/rehab.8335. mds.26159.
54 Fahn S, Oakes D, Shoulson I, et al. Levodopa and 66 Olanow CW. Levodopa: effect on cell death
the progression of Parkinson’s disease. N Engl J and the natural history of Parkinson's disease.
Med 2004;351(24):2498–2508. doi:10.1056/ Mov Disord 2015;30(1):37–44. doi:10.1002/
NEJMoa033447. mds.26119.
55 Hauser RA, Hsu A, Kell S, et al. Extended-release 67 Cilia R, Akpalu A, Sarfo FS, et al. The modern
carbidopa-levodopa (IPX066) compared with pre-levodopa era of Parkinson’s disease: insights
immediate-release carbidopa-levodopa in into motor complications from sub-Saharan
patients with Parkinson's disease and motor Africa. Brain 2014;137(pt 10):2731–2742.
fluctuations: a phase 3 randomised, double-blind doi:10.1093/brain/awu195.
trial. Lancet Neurol 2013;12(4):346–356.
68 Espay AJ, Lang AE. Common myths in the use
doi:10.1016/S1474-4422(13)70025-5.
of levodopa in Parkinson’s disease: when
56 Morgan JC, Dhall R, Rubens R, et al. Dosing clinical trials misinform clinical practice. JAMA
patterns during conversion to IPX066, Neurol 2017;74(6):633–634. doi:10.1001/
extended-release carbidopa-levodopa jamaneurol.2017.0348.
(ER CD-LD), in Parkinson's disease with motor
69 Ahlskog E. Aerobic exercise: evidence for a
fluctuations. Parkinsons Dis 2018;2018:9763057.
direct brain effect to slow Parkinson disease
doi:10.1155/2018/9763057.
progression. Mayo Clin Proc 2018;93(3):360–372.
57 Fernandez HH, Odin P. Levodopa-carbidopa doi:10.1016/j.mayocp.2017.12.015.
intestinal gel for treatment of advanced
70 Lewitt PA. Levodopa for the treatment of
Parkinson's disease. Curr Med Res Opin 2011;
Parkinson's disease. N Engl J Med 2008;359(23):
27(5):907–919. doi:10.1185/03007995.
2468–2476. doi:10.1056/NEJMct0800326.
2011.560146.

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PARKINSON DISEASE

71 Benabid AL, Pollak P, Seigneuret E, et al. 73 Bari AA, Thum J, Babayan D, Lozano AM. Current
Chronic VIM thalamic stimulation in Parkinson’s and expected advances in deep brain stimulation
disease, essential tremor and extra-pyramidal for movement disorders. Prog Neurol Surg 2018;
dyskinesias. Acta Neurochir Suppl (Wien) 1993;58: 33:222–229. doi:10.1159/000481106.
39–44. doi:10.1007/978-3-7091-9297-9_8.
74 Schuepbach WM, Rau J, Knudsen K, et al.
72 DeLong MR, Huang KT, Gallis J, et al. Effect of Neurostimulation for Parkinson’s disease
advancing age on outcomes of deep brain with early motor complications. N Engl J Med
stimulation for Parkinson disease. JAMA Neurol 2013;368(7):610–622. doi:10.1056/
2014;71(10):1290–1295. doi:10.1001/jamaneurol. NEJMoa1205158.
2014.1272.

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 Progressive Supranuclear REVIEW ARTICLE


Palsy, Corticobasal 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

Degeneration, and 
VIDEO CONTENT

Multiple System Atrophy A V AI L A B L E O N L I N E

By Paul Greene, MD

ABSTRACT
PURPOSE OF REVIEW: Patients who have parkinsonian features, especially
Downloaded from http://journals.lww.com/continuum by BhDMf5ePHKbH4TTImqenVJ8WlwlLSkxgQL8l5tAGR0ztQKfE9dfXzUa0Fmli1DHP on 08/03/2019

without tremor, that are not responsive to levodopa, usually have one of
these three major neurodegenerative disorders rather than Parkinson
disease: progressive supranuclear palsy (PSP), multiple system atrophy
(MSA), or corticobasal degeneration (CBD). Each of these disorders
eventually develops signs and symptoms that distinguish it from idiopathic
Parkinson disease, but these may not be present at disease onset.
Although these conditions are not generally treatable, it is still important to
correctly diagnose the condition as soon as possible.

RECENT FINDINGS: In recent years, it has been increasingly recognized that the
symptoms of these diseases do not accurately predict the pathology, and the
pathology does not accurately predict the clinical syndrome. Despite this,
interest has grown in treating these diseases by targeting misfolded tau (in the
case of PSP and CBD) and misfolded α-synuclein (in the case of MSA). CITE AS:
CONTINUUM (MINNEAP MINN)
2019;25(4, MOVEMENT DISORDERS):
SUMMARY: Knowledge of the characteristic signs and symptoms of PSP, 919–935.
MSA, and CBD are essential in diagnosing and managing patients who have
atypical parkinsonian syndromes. Address correspondence to
Dr Paul Greene, Mt. Sinai School
of Medicine, 5 E 98th St,
New York, NY 10029,
[email protected].
INTRODUCTION RELATIONSHIP DISCLOSURE:

A
fter the introduction of levodopa to treat Parkinson disease (PD) in Dr Greene reports no disclosure.
the late 1960s, the pathologies and clinical pictures of dopamine
UNLABELED USE OF
deficiency syndromes broadened dramatically. Clinicians identified PRODUCTS/INVESTIGATIONAL
patients who had signs of dopamine deficiency (masked facies, USE DISCLOSURE:
Dr Greene discusses the
hypophonia, rigidity, slowness of movement and gait, loss of
unlabeled/investigational use of
postural reflexes, and sometimes resting tremor and other features) but, unlike medications for the treatment
patients with PD, had minimal or no improvement with levodopa. As a group, of atypical parkinsonism, none
of which have been approved
these patients are said to have atypical parkinsonism. Today, the most common by the US Food and Drug
of these disorders are progressive supranuclear palsy (PSP), followed by multiple Administration.
system atrophy (MSA) and corticobasal degeneration (CBD). The major problem,
especially for PSP and CBD, is that patients with typical clinical signs and © 2019 American Academy
symptoms of the disease may have very different pathologies, and patients of Neurology.

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PSP, CBD, AND MSA

with the same pathology may have different clinical signs and symptoms.
Unfortunately, no definitive diagnostic tests are easily available to distinguish
these diseases from each other during life. The gold standard diagnostic test is
autopsy, but autopsies are highly selected and may lead to conclusions that do
not represent the entire population of a disease.
The history of MSA extends back at least to 1900.1 In 1900, Dejerine and
Thomas2 described cases of late-onset ataxia and parkinsonism, later termed
olivopontocerebellar atrophy. In 1960, Shy and Drager3 presented two cases of
men aged 39 and 49 who developed impotence and urinary disturbance followed
by multiple autonomic deficits, parkinsonism, ataxia, and, in one case, lower
motor neuron disease, which was referred to as Shy-Drager syndrome.3 In 1960
and 1961, Adams, van Bogaert, and van der Eecken4,5 reported four cases of
patients with gliosis of the striatum and degeneration of the substantia nigra who
had rapidly progressive parkinsonism but also autonomic failure and cerebellar
deficits, which they referred to as striatonigral degeneration. Similar cases had
been reported before these three reports, but these reports were the first to
identify each of these conditions as a syndrome. In 1969, Graham and
Oppenheimer6 reviewed the published literature on patients with autonomic
failure and either clinical symptoms or pathology indicating cerebellar and
striatonigral involvement. They felt these syndromes overlapped so much that
they should all be labeled MSA.6 In 1998, Lantos1 described α-synuclein deposits
in glia (glial cytoplasmic inclusions) in all three conditions, making it even more
likely they were all part of the same spectrum.
In 1964, Steele, Richardson, and Olszewski7 coined the term progressive
supranuclear palsy (PSP) after reporting on patients with parkinsonism, loss of
postural reflexes, supranuclear gaze palsy, axial rigidity, pseudobulbar state, and
dementia who had midbrain and pontine degeneration as well as neuronal loss
in the substantia nigra.
In 1968, Rebeiz and colleagues8 reported on three patients with asymmetric
parkinsonism, apraxia, involuntary elevation of upper and lower extremities,
and posturing, which would probably now be called dystonia, and a unique
pathology involving the cortex as well as the basal ganglia and cerebellum and
with neuronal achromasia. They referred to this as corticodentatonigral
degeneration with neuronal achromasia, which was later shortened to
corticobasal degeneration (CBD).
Although PSP, CBD, and MSA are difficult to accurately clinically diagnose at
this time, this article presents the signs and symptoms of these conditions based
primarily on clinical experience. Although relatively large series of patients with
these conditions have been published based on autopsy, this article bases descriptions
primarily on clinical experience. The reason for this choice is that autopsy series have
two major shortcomings: (1) autopsies are rarely based on random or consecutive
selection, leading to referral bias that is impossible to quantify and (2) the history and
physical examinations in most autopsy series are not performed systematically
by movement disorder specialists and sometimes not even by neurologists.
For more information on clinical features of autopsy-documented cases of
PSP, CBD, and MSA, refer to Respondek and colleagues,9 Armstrong and
colleagues,10 and Wenning and colleagues,11 respectively.

PROGRESSIVE SUPRANUCLEAR PALSY

Currently, the most commonly diagnosed of these three syndromes is PSP.

920 AUGUST 2019

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Clinical Symptoms and Signs KEY POINTS
The signs and symptoms of PSP vary, probably because different parts of the
● Patients with
brain may be affected first and to different degrees. Patients with the classic parkinsonian features who
presentation, also called Richardson syndrome, develop a symmetric akinetic do not improve with
rigid syndrome with axial greater than limb rigidity, lack of resting tremor levodopa usually do not
(although they may have an action tremor), early development of a supranuclear have idiopathic Parkinson
disease and often have
gaze palsy, and lack of response to levodopa.12 Supranuclear gaze palsy is the
either progressive
inability to look up or down on command, but upgaze is present when the neck is supranuclear palsy, multiple
passively flexed, and downgaze is present when the neck is passively extended system atrophy, or
(ie, the doll’s eyes maneuver). Patients may have continuous square-wave jerks corticobasal degeneration.
and other oculomotor disturbances, early loss of postural reflexes leading to falls,
● Progressive supranuclear
and progressive dementia. Square-wave jerks are involuntary horizontal saccades palsy is a likely diagnosis in
that go alternately to the right and then to the left with brief pauses before patients with parkinsonian
changing direction. features and early
Patients with PSP often have an unusual facial expression, labeled dystonia, development of a
supranuclear gaze palsy.
with deep nasolabial folds and furrowed brow, giving them an angry or puzzled
expression. Patients may have hypophonia, often have growling speech, and ● Some patients with
frequently become aphonic. Patients with PSP develop dysphagia early in the progressive supranuclear
course of the disease, and aspiration pneumonia is common. They often have a palsy do not develop a
supranuclear gaze palsy
broad-based, slightly ataxic gait and often walk with their arms abducted and
until later in the course of
elbows flexed (a “gunslinger” gait). Gait freezing is common, and freezing of the disease. Early features
speech and manual movements may also occur. that suggest progressive
Patients with Richardson syndrome (and other PSP subtypes) have a large supranuclear palsy are an
angry or puzzled look,
variety of visual symptoms and signs. Patients with PSP often have limited
growling speech, early
downgaze and report difficulty reading, seeing the food on their plates, and development of dysphagia,
looking at their feet while walking. They report diplopia, blurred vision, or more and a broad-based gait with
vague visual disturbances. They often have a severe reduction in blink rate and abducted arms.
lid retraction, giving them a staring appearance. They have loss of vertical
optokinetic nystagmus, and they may also develop blepharospasm. Occasionally,
patients with PSP are unable to open their eyes, even without activation of the
orbicularis oculi, which is referred to as apraxia of eyelid opening; even less
commonly, patients are unable to close their eyes on command, referred to as
apraxia of eyelid closing. It is now known that the apraxia of eyelid opening is not
a true apraxia but a result of prolonged levator palpebrae inhibition following
normal antagonist inhibition after a blink.13
The dementia of Richardson syndrome usually involves bradyphrenia
(ie, difficulty with attention and difficulty shifting tasks) and is considered a
subcortical dementia, but the dementia of other PSP subtypes may differ, and
mixed features of dementia are not uncommon. Bradyphrenia is when patients
can answer questions and reason appropriately but take longer to do these tasks
than would be reasonably expected. Patients usually have frontal release signs,
such as glabellar, snout, and grasp reflexes. Depression is common, but apathy
without depression is also common. Disinhibition leads to frequent falls in those
with poor balance. Emotional incontinence can lead to emotionless crying or
laughing (pseudobulbar palsy). A patient with Richardson syndrome is described
in CASE 2-1.
Some patients with the pathology of PSP present with what looks like levodopa-
responsive, asymmetric PD with resting tremor. These patients go on to lose
levodopa responsiveness and develop imbalance, eye movement abnormalities,
and the other signs and symptoms of classic PSP, which is referred to as PSP with

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PSP, CBD, AND MSA

predominant parkinsonism (PSP-P). Some patients’ symptoms begin with gait

freezing, micrographia, and imbalance, which is referred to as pure akinesia or
PSP with progressive gait freezing (PSP-PGF). Some patients present with
nonfluent primary progressive aphasia or progressive apraxia of speech, referred
to as PSP with predominant speech/language disorder (PSP-SL). Other patients
have PSP with predominant corticobasal syndrome (PSP-CBS).
As the number of autopsies on patients with PSP grows, less common initial
symptoms of PSP pathology have resulted in more categories, such as PSP with
predominant ocular motor dysfunction (PSP-OM), which begins with oculomotor
signs/symptoms; PSP with predominant postural instability (PSP-PI); PSP with
predominant frontal presentation (PSP-F), which begins with a frontal syndrome

CASE 2-1 A 68-year-old woman presented for a neurologic consultation because of

a 2-year history of progressive neurologic symptoms. She had begun
losing her balance and falling since age 66. Shortly after that, her speech
had become difficult to understand, and she coughed when swallowing
liquids. She did not have diplopia but described blurred vision, especially
when she looked down to read or to see the food on her plate. Her family
noticed that she was impulsive and sometimes would begin laughing at
odd times. She was forgetful and seemed confused at times. Her balance
continued to worsen, and she fell sideways if she used a walker, so she
began to use a wheelchair. She needed help to dress and feed herself,
but it was not clear if this was because of lack of dexterity or confusion.
She developed apraxia of eyelid opening, which did not improve with
botulinum toxin injections in a low dose. She had a history of diabetes
mellitus, hyperlipidemia, and hypertension.
On examination she had glabellar, snout, and bilateral grasp reflexes.
She had a furrowed brow but no other facial dystonia. She had apraxia of
eyelid opening and a markedly reduced blink rate when her eyes were
forced open. She had continuous square-wave jerks. She had no
downgaze and reduced upgaze but full range with doll’s eyes maneuver
and had no saccades in any direction. She had a mildly soft voice with a
growling quality. She had no resting tremor. She had mild rigidity of the
neck in the anterior-posterior direction but no limb rigidity. Her rapid
alternating movements were slow and clumsy in all limbs. She needed
assistance to rise from a chair. She fell spontaneously in all directions.
When supported, she had a slow, broad-based gait with marked reduction
in stride. She turned en bloc and had start-and-turn freezing of gait.

COMMENT This case shows a typical presentation and examination for the classic
presentation of progressive supranuclear palsy (PSP) (PSP–Richardson
syndrome). The supranuclear gaze palsy developed fairly early, making the
diagnosis easier, but some patients with PSP may not develop eye
movement abnormalities until late in the course. The early loss of postural
stability, growling voice, furrowed brow, and apraxia of eyelid opening
were important clues to the correct diagnosis.

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including behavioral changes such as irritability and other personality changes, KEY POINTS
lack of insight, inappropriate behavior, impulsivity, and stereotyped behaviors;
● A minority of patients
PSP with cerebellar ataxia (PSP-C), which begins with ataxia; and PSP with with the pathology of
primary lateral sclerosis (PSP-PLS), which starts with a generalized spasticity progressive supranuclear
syndrome similar to primary lateral sclerosis.12 In some patients with PSP palsy may have signs and
pathology, symptoms may start with just dementia, although no abbreviation for symptoms suggesting a
variety of conditions,
the terminology currently exists,
including corticobasal
To complicate matters even more, a variety of other pathologies may present degeneration and, rarely,
clinically as PSP (sometimes called PSP syndrome). These include the pathologies idiopathic Parkinson
of Whipple disease, Niemann-Pick disease type C, Gaucher disease, prion disease, disease, primary progressive
aphasia, cerebellar ataxia,
Alzheimer disease, and others.12
frontotemporal dementia,
The course of PSP depends on the initial symptoms but the course can vary and primary lateral
even with the same initial symptoms. Duration of disease ranges from 2 years to sclerosis.
28 years (mean of 8.7 years) depending on the subtype.14 The life-threatening
symptoms of all forms of PSP are loss of balance leading to falls, aspiration, and ● Other pathologies may
produce signs and
infection due to pressure ulcers. symptoms suggestive of
progressive supranuclear
Pathology palsy, including Alzheimer
The pathology of PSP consists of widespread atrophy and neuronal loss with disease, some
marked atrophy of the midbrain, subthalamic nucleus, dentate nucleus, and frontotemporal dementias,
Whipple disease,
superior cerebellar peduncle but also of the frontal cortex and other basal ganglia
Niemann-Pick disease type C,
structures.15 Accumulation occurs of mainly 4-repeat tau in neurofibrillary and Gaucher disease.
tangles in neurons in widespread areas including the subthalamic nucleus, globus
pallidus, substantia nigra, locus coeruleus, periaqueductal gray matter, superior ● The pathology of
colliculi, inferior olive, red nucleus, oculomotor nuclei, and the prefrontal and progressive supranuclear
palsy is characterized by
precentral cortex. Tau also accumulates in astrocytes (called tufted astrocytes), deposits of 4-repeat
distinct from the astrocytic plaques in CBD, and accumulations in tau in astrocytes and
oligodendroglia (called coiled bodies) and threadlike processes in the white oligodendroglia in multiple
matter. For a detailed description of the pathology of the subtypes of PSP, see the regions of the basal ganglia
and cortex of the brain.
study by Dickson and colleages.15
● Preliminary studies of
Treatment agents that interfere with
Treatment options for the symptoms of PSP are similar to the options in the other the formation or spread of
disorders discussed in the section below on the treatment of symptoms in PSP, misfolded tau are being
conducted with the hope of
MSA, and CBD. Attempts to treat the disease itself have not had success as of
stopping or slowing the
2019.14 The most recent attempts to arrest or at least modify the course of PD and progression of progressive
the syndromes discussed here depend on the hypothesis that diseases involving supranuclear palsy.
misfolded tau or α-synuclein depend on the prionlike properties of misfolded tau
or α-synuclein.14,16 Clinical trials are underway of agents that might potentially
reduce the spread of misfolded tau in PSP.14

CORTICOBASAL DEGENERATION
The classic presentation of CBD combines markedly asymmetric rigidity and
bradykinesia with focal or hemidystonia and cortical deficits. Most patients
develop symptoms in their fifties to seventies.

Clinical Symptoms and Signs

As with the other syndromes discussed in this article, the parkinsonism is usually
without tremor, does not respond to dopamine replacement therapy, and loss of
balance usually occurs early in the course. The dystonia, which may be painful,
develops gradually but often becomes severe and fixed, leading to contractures.

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PSP, CBD, AND MSA

The patient’s dystonia may make it difficult to assess apraxia. Speech is hesitant
and dysarthric, and aphasia and apraxia of speech occur. Other cortical signs
may include apraxia (difficulty performing motor activities despite normal
understanding and normal sensory/motor systems); cortical sensory loss
(eg, two-point discrimination, agraphesthesia [difficulty recognizing letters/numbers
written on the skin with eyes closed] and astereognosis [difficulty recognizing
objects by touch alone]); cortical myoclonus (spontaneous or reflex, or both),
which can be diagnosed accurately only with electrophysiology but usually
consists of multifocal, very rapid shocklike jerks; alien limb phenomenon

CASE 2-2 A 78-year-old woman presented for evaluation of a 2-year history of

neurologic symptoms. Her initial symptoms were slowness, difficulty
walking, and imbalance causing falls in all directions. One year after
onset, she began to rub the fingers of her right hand on her leg. She lost
dexterity in that hand, developed dystonic posturing, and switched to
using her left hand. She then developed jerks of her right arm that were
present at rest and increased when she tried to use her arm. When she
lifted the right arm while sitting, her right leg would rise off the ground.
She noticed that she had difficulty performing tasks with her left hand,
although that hand was not particularly slow or stiff. The hand would
sometimes move out of her control. Her voice became soft and hoarse, and
she had difficulty finding the words she wanted and spoke in short phrases.
She developed mild to moderate forgetfulness. She had been diagnosed
with parkinsonism and given carbidopa/levodopa without benefit.
On examination she had no frontal release signs. Extraocular
movements were intact without nystagmus or square-wave jerks. She had
mild hypomimia and hypophonia. She had no resting tremor but had a
coarse, jerky action greater than postural tremor of the left upper
extremity that suggested myoclonus as well as tremor. She had mild
slowing and rigidity of the left upper extremity. Her right upper extremity
could not be tested because of severe dystonic posturing that increased
when she tried to use the hand. She had slowing of the right more than the
left lower extremity. She could not imitate picking up a key with her left
hand and could not identify a penny or paper clip placed in either hand.
She could not recognize letters written on her left hand with her eyes
closed. She needed assistance to rise from a chair. Her dystonic posturing
of the right upper extremity worsened with walking, she had a slow gait
with decreased stride, and she had very poor postural reflexes.

COMMENT The asymmetric dystonia suggests corticobasal degeneration (CBD),

although it may occur in progressive supranuclear palsy as well. The
presence of myoclonus in one limb and apraxia, astereognosis, and
agraphesthesia make the diagnosis of CBD more likely. Most patients with
CBD have dystonia, myoclonus, and cortical deficits all on the same side,
but occasionally they may have dystonia on one side and the other findings
on the opposite side as in this patient.

924 AUGUST 2019

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(involuntary movements of a limb together with the patient’s feeling that the KEY POINTS
limb does not belong to him or her); aphasia; apraxia of speech; and even
● The clinical hallmarks
hemiparesis. Dementia is common in patients with CBD. of classic corticobasal
Although some patients with CBD do make movements with a limb that seems degeneration are
foreign to them, they often have an overflow phenomenon in which movement parkinsonism combined
in one limb triggers an involuntary movement in another, usually ipsilateral, with unilateral dystonia,
myoclonus, and cortical
limb. Resting tremor is very rare, but action tremor, often combined with
deficits such as apraxia,
myoclonus, is common. Supranuclear gaze palsies can occur late in the disease. cortical sensory loss, and
CASE 2-2 describes a patient with classic CBD. alien limb phenomenon.

Pathology ● As in progressive
supranuclear palsy, the
The pathology of CBD consists of asymmetric cortical atrophy usually in the
pathology of corticobasal
frontoparietal region with relative sparing of the occipital lobes. Swollen degeneration also involves
vacuolated neurons are found in the atrophic cortical areas and to a lesser widespread deposition of
degree in the affected subcortical regions. These ballooned neurons contain 4-repeat tau but also
includes asymmetric
phosphorylated neurofilaments and sometimes tau and ubiquitin. As with
cortical atrophy and
PSP, widespread neuronal loss and gliosis is seen, not just in the affected neuronal, oligodendroglial,
cortex but also in the globus pallidus, putamen, red nucleus, thalamus, and astrocytic deposits
subthalamic nucleus, substantia nigra, locus coeruleus, and, to a lesser degree, distinct from the deposits in
in the dentate nucleus. Remaining neurons in affected areas contain progressive supranuclear
palsy.
inclusions: globose tangles called corticobasal bodies and tau fibrils around
nuclei of oligodendroglia called coiled bodies. Unlike the tufted astrocytes in ● As with progressive
PSP, the typical glial findings are tau-containing processes surrounding supranuclear palsy, multiple
astrocytes called astrocytic plaques. As in PSP, 4-repeat tau predominates, but pathologies may mimic the
signs and symptoms of
the insoluble tau fragments in CBD have a different ultrastructure from the corticobasal degeneration,
insoluble fragments of tau in PSP.17 including progressive
As with PSP, the pathology of CBD may also present as multiple other supranuclear palsy,
syndromes: a classic PSP syndrome, primary nonfluent aphasia, a frontal Alzheimer disease, Pick
disease, and Creutzfeldt-
dementia with executive dysfunction and behavioral change, pure Alzheimerlike
Jakob disease. When this
dementia or, rarely, idiopathic PD.10,17 Also, as in PSP, a variety of other happens, it is known as
pathologies can mimic the clinical features of CBD, known as corticobasal corticobasal syndrome.
syndrome (CBS). These include the pathologies of PSP, Alzheimer disease, Pick Similarly, the pathology of
corticobasal degeneration
disease, frontotemporal lobar degeneration with ubiquitin– and TDP-43–positive
may present as progressive
inclusions, dementia with Lewy bodies, frontotemporal lobar degeneration supranuclear palsy, primary
with fused-in-sarcoma–positive inclusions, and Creutzfeldt-Jakob disease.18 nonfluent aphasia,
Consensus criteria have been proposed for the clinical diagnosis of CBD, but Alzheimer disease, and
the criteria have proven neither sensitive nor specific (sensitivity was 68.4%, other conditions.
specificity was described as low but percentage was not given).10,19 VIDEO 2-1
(links.lww.com/CONT/A56) and VIDEO 2-2 (links.lww.com/CONT/A204) contain
examples of patients with CBS and CBD, respectively.20,21

Treatment
As with PSP, the current attempts at treating CBD itself as opposed to treating
the symptoms are focused on detoxifying misfolded tau.22

MULTIPLE SYSTEM ATROPHY

PSP and CBD have overlapping symptoms with PD despite having a pathology
that includes misfolded tau and not–misfolded α-synuclein. MSA also shares
symptoms with PD, and its pathology includes misfolded α-synuclein, not–
misfolded tau, but MSA also can have a variety of complex presentations.

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PSP, CBD, AND MSA

Clinical Symptoms and Signs

When middle-aged patients have sporadic disease with parkinsonism
(usually including bradykinesia and rigidity), autonomic insufficiency
(usually including urinary incontinence or retention, orthostatic
hypotension sometimes alternating with hypertension, anhidrosis, and
impotence in men), and cerebellar abnormalities (including ataxia,
dysmetria, and nystagmus), MSA is the most likely diagnosis. However,

CASE 2-3 A 58-year-old right-handed man presented for a movement disorders

consultation for a 3-year history of progressive neurologic symptoms
that began with impotence, urinary incontinence followed by urinary
retention, and loss of balance leading to multiple falls. He then developed
curling of toes on his right foot, right greater than left rigidity, and
generalized slowing. He had no resting or action tremor. He had been
diagnosed with Parkinson disease but developed severe orthostasis
when given carbidopa/levodopa. Attempts to control his orthostasis with
fludrocortisone and then midodrine led to episodes of hypertension.
About 3 years after the onset, he developed laryngeal stridor that
persisted during sleep and was treated with a tracheostomy. He went on
to develop constipation and dysphagia.
On examination, his extraocular movements were intact with
occasional square-wave jerks and bilateral sustained end-gaze
nystagmus. He had moderate hypomimia and mild hypophonia with
tachyphemia (as he spoke, his voice got softer and his speech became
faster to the point where his words overlapped each other). He had
occasional inspiratory stridor. He had no resting tremor and mild left
greater than right intention tremor. He had occasional myoclonic jerks
of both lower extremities and mild rigidity of his neck and extremities,
left greater than right and upper extremities greater than lower
extremities. He used his arms to rise slowly from a chair, had a mild left
kyphoscoliosis, and had start-and-turn freezing of gait. When he was not
freezing, he had a broad-based gait and reduced stride and pace. His arm
swing was reduced on the left greater than right side, and he scuffed
both heels. His pull test was markedly positive, and he tended to fall not
only backward but to the right and left.
His dexterity and gait did not improve with levodopa, but his daytime
stridor did disappear.

COMMENT This patient has multiple system atrophy with predominant parkinsonism
(MSA-P), although his initial symptoms were autonomic dysfunction. His
orthostasis was severe, but this can be seen in dementia with Lewy bodies
as well. The stridor was a major clue that the diagnosis was MSA. In
addition, he also had some signs of cerebellar dysfunction: sustained
nystagmus, broad-based gait, and falling to the side as well as forward and
backward. Stridor in patients with MSA may respond to levodopa even
when other motor manifestations do not.

926 AUGUST 2019

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patients diagnosed with MSA (either clinically or pathologically) often KEY POINT
initially have symptoms in just one of these categories, although they
● Middle-aged patients
eventually develop additional symptoms. Patients starting with bradykinesia presenting with
and rigidity (called MSA with predominant parkinsonism [MSA-P]) usually parkinsonism, autonomic
do not have resting tremor and do not improve with levodopa. However, a insufficiency, and ataxia
significant minority of patients may have resting tremor and respond well to usually have multiple system
atrophy. However, many
levodopa, at least for some time. Most symptoms are bilateral and symmetric but
patients with multiple
some may resemble idiopathic asymmetric PD. Patients starting with ataxia system atrophy may initially
and other cerebellar features (eg, scanning speech, hypometric saccades, only have symptoms in one
square-wave jerks) would be consistent with MSA with predominant cerebellar or two of these categories,
making the correct diagnosis
ataxia (MSA-C). There is not currently a category of MSA with predominant
more difficult. The
autonomic symptoms (MSA-A) even for patients that begin with autonomic development of laryngeal
symptoms. Nonetheless, there are patients with pure autonomic failure that stridor is a strong clue that
eventually develop an MSA syndrome and have the pathology of MSA. the diagnosis is multiple
Any of these subtypes may also develop some other characteristic (although system atrophy.

not pathognomonic) features. Axial dystonia (including anterocollis) is

common.23 A variety of gastric motility problems may evolve. Laryngeal stridor,
which often occurs at night but sometimes during the day as well, can be
life-threatening. Stridor is the choking sound made when the vocal cords
involuntarily adduct during breathing. In patients with MSA, this happens
during inspiration.
Since MSA is a synucleinopathy, sleep disturbances such as rapid eye
movement (REM) sleep behavior disorder are common. Other sleep
symptoms such as dysrhythmic breathing and central apnea can also occur.
Cases of pathologic MSA that combined amyotrophy mimicking
amyotrophic lateral sclerosis (ALS) with parkinsonism have been reported.24
Dementia in MSA was usually reported to be mild, but recently, cases with the
pathology of MSA were reported to have a frontotemporal-type dementia
called frontotemporal lobar degeneration–synuclein. Patients with this
variant can have CBS, progressive nonfluent aphasia, or behavioral-variant
frontotemporal dementia.25
Most forms of the disease progress rapidly, and more than 40% of
people diagnosed with probable MSA were severely disabled or used a
wheelchair by 5 years after onset, although patients with cerebellar deficit
predominance seem to progress more slowly.11 As with the other disorders
discussed in this article, patients can die of pulmonary, urinary tract, and
pressure ulcer infections and complications of falls. Unlike PSP and CBD,
patients with MSA are also at risk for anoxic damage from stridor and
cardiopulmonary arrest due to autonomic dysfunction. Consensus criteria
for the clinical diagnosis of MSA were proposed in 2008.26 VIDEO 2-3 (links.lww.
com/CONT/A283) includes an example of a patient with MSA, and CASE 2-3
describes a typical patient with MSA-P.

Pathology
Classically, the pathology of MSA consists of widespread neuronal loss and atrophy
including striatonigral, cerebellar, autonomic, and corticospinal pathways. These
can involve the substantia nigra, globus pallidus, parts of the cerebellum, middle
cerebellar peduncle, inferior olives, intermediolateral cell columns, corticospinal
tracts, anterior horn cells, and other structures. Unlike in PSP, the subthalamic
nucleus, dentate nucleus, and superior cerebellar peduncle are relatively uninvolved.

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PSP, CBD, AND MSA

TABLE 2-1 Distinguishing Diagnostic Features of Progressive Supranuclear Palsy,

Corticobasal Degeneration, and Multiple System Atrophy

Feature Progressive Supranuclear Palsy Corticobasal Degeneration Multiple System Atrophy

Improvement with Very small subgroup, usually Rare Small subgroup (multiple system
levodopa modest and short lived atrophy with predominant
parkinsonism), usually modest

Early imbalance Common Common Common

leading to falls

Resting tremor Very uncommon (may occur in Probably very uncommon Very uncommon but possible
progressive supranuclear palsy (hard to separate from
with predominant parkinsonism myoclonus)
or progressive supranuclear
palsy–Richardson syndrome)

Early dysphagia/ Common Common, somewhat later Common, somewhat later

aspiration than progressive than progressive supranuclear
supranuclear palsy palsy

Supranuclear gaze Common; early in many but not all Occurs in small subgroup Very uncommon but possible
palsy patients

Axial rigidity Marked axial rigidity, especially Common, often not Common, often not dramatic
in progressive supranuclear dramatic
palsy–Richardson syndrome

Facial dystonia Very common Uncommon In a subgroup as a side effect of

levodopa

Growling voice Common Uncommon Unlike typical progressive

supranuclear palsy growl, MSA
with predominant cerebellar
ataxia may have loud,
unmodulated speech

Cortical deficits Very small subgroup (progressive Very common Very uncommon
(eg, apraxia, agnosia, supranuclear palsy–corticobasal
astereognosis) syndrome)

Focal cortical Small subgroup (progressive Common Small subgroup

myoclonus supranuclear palsy–corticobasal
degeneration)

Ataxia/cerebellar Gait ataxia is common, limb ataxia Rare Cerebellar signs sometime
deficits rarely reported during the course are common

Autonomic failure Some features common Same as progressive Multiple failures common
orthostasis (eg, impotence, constipation, supranuclear palsy (eg, urinary retention, sweating)
urinary urgency), but orthostasis
uncommon

Inspiratory stridor Very rare Very rare Small but significant minority

928 AUGUST 2019

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 The characteristic microscopic finding is the glial cytoplasmic inclusion KEY POINTS
consisting mainly of α-synuclein. These inclusions occur throughout the
● Unlike progressive
brain, but mostly in the basal ganglia. There are also neuronal nuclear and supranuclear palsy and
cytoplasmic inclusions and dystrophic neurites in striatonigral and cerebellar corticobasal degeneration,
structures but also in some cortical structures. The neuronal cytoplasmic multiple system atrophy is a
inclusions take various forms including Picklike bodies, ring-shaped, and synucleinopathy, not a
tauopathy. This may have
neurofibrillary tangle–like inclusions. The predominant symptoms in MSA
implications for future
roughly correlate with the regions most affected pathologically. In a small treatments.
minority of patients with MSA, synuclein pathology results in the presence of
Lewy bodies.25 ● Like progressive
As with PSP and CBD, other pathologies can produce signs and symptoms that supranuclear palsy and
corticobasal degeneration,
can be confused with MSA; spinocerebellar ataxias (especially types 1, 2, 3, 6, and 7), there are widespread
fragile X tremor-ataxia syndrome, and inflammatory diseases such as paraneoplastic pathologic abnormalities in
conditions can rarely be misdiagnosed as MSA.26 multiple system atrophy, but
the characteristic inclusions
contain α-synuclein, not tau.
Treatment The first identified
Attempts to treat MSA rather than just the symptoms of MSA have so far been abnormality was a glial
unsuccessful.25 As with PD, new attempts at treating MSA have focused on cytoplasmic inclusion
detoxifying misfolded α-synuclein, which remains a promising approach.25 containing α-synuclein, but
neuronal inclusions have
TABLE 2-1 summarizes the distinguishing clinical features of PSP, MSA, and
also been identified. Rarely,
CBD. TABLE 2-2 summarizes the pathologic features of these diseases. Lewy bodies are found in
multiple system atrophy.
EPIDEMIOLOGY AND GENETICS OF PSP, CBD, and MSA
● There has been an
The reported prevalence of each syndrome is probably underestimated in clinical
intensive search for genetic
studies and overestimated in pathologic studies since unusual cases are more risk factors for these
likely to come to autopsy. Among the three disorders discussed here, PSP is most conditions. Some candidate
commonly reported in clinical studies. A recent study reported estimates of the genes have been identified,
prevalence of clinically defined PSP as about 1.4/100,000 to 6.4/100,000 and the but this has not currently
led to any therapeutic
prevalence of clinically defined MSA as about 1.9/100,000 to 4.4/100,000 in innovations. Some genes
people older than 50 years of age.27 The prevalence of CBS based on clinical have been identified that
criteria was about 2/100,000 in a population initially defined by all physicians, occasionally produce one
including primary care doctors, and then refined.28 of these syndromes, but
those, so far, have been
Citing a large community-based autopsy study of 233 cases, a recent report responsible for only a small
estimated the prevalence of PSP as 15.8% of the prevalence of PD, the prevalence percentage of known cases.
of MSA as 4.7% of the prevalence of PD, and the prevalence of CBD as 2.1% of
the prevalence of PD.29 That study followed all 1920 people living in two districts
of Vienna for up to 13 years, of which 233 had autopsies after dying in one target
hospital. The study does not report how many people died in other hospitals,
perhaps producing bias. Also, it is extremely likely that people with non-PD
diagnoses died more often during that period than people with PD, which would
increase their relative prevalence. However, the relative prevalence of PSP
versus MSA versus CBD should be more accurate.
In the past, PSP, CBD, MSA, and their syndromes were thought to be
sporadic, but recently a small number of rare genetic conditions have been
identified that may be clinically diagnosed as PSP, MSA or CBD, including
mutations in the genes MAPT and PGRN (for tau and progranulin) as well as
mutations in C9orf72 (commonly causing familial ALS and frontotemporal
dementia), TARDBP, CHMP2B, and other rare genetic disorders.30 Multiple
genetic susceptibility variants have been proposed for PSP and CBD (in the
microtubule-associated protein tau or MAPT gene and other genes that can

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PSP, CBD, AND MSA

affect the tau protein) and for MSA (in the gene COQ2) but the significance of
these findings is not clear.31

DISTIGUISHING THESE DISORDERS FROM PARKINSON DISEASE AND

FROM EACH OTHER
The clinical diagnosis of PSP is primarily based on the history, signs, and
symptoms, as mentioned above. There are auxiliary tests that may occasionally
be helpful, but none are definitive except for autopsy. Midbrain atrophy in
PSP may give a characteristic sign on brain MRI (sometimes called the
hummingbird sign on sagittal MRI or morning glory sign on axial MRI)
(FIGURE 2-132), and these may be specific but are not sensitive.33 Supranuclear
vertical ophthalmoparesis early in the course of disease suggests PSP–Richardson
syndrome, but this can also develop in CBD, usually later in the course.
The ophthalmoparesis is usually horizontal in MSA. Demonstration of a
dopamine deficiency state by fludeoxyglucose positron emission tomography
(FDG-PET) or dopamine transporter imaging is sensitive for many forms of

TABLE 2-2 Pathology of Progressive Supranuclear Palsy, Corticobasal Degeneration,

and Multiple System Atrophy

Disease Involved Structures Characteristic Pathology

Progressive Widespread neuronal loss and atrophy of the Neurofibrillary tangles in neurons in the involved
supranuclear midbrain, substantia nigra, subthalamic nucleus, areas consisting of mainly abnormally
palsy globus pallidus, dentate nucleus, superior phosphorylated 4-repeat tau; tau inclusions in
cerebellar peduncle, and multiple areas of the astrocytes consisting of fibrils in a tuft
frontal cortex; the particular frontal areas involved configuration (tufted astrocytes); tau inclusions in
depend on the subtype of progressive oligodendroglia that form perinuclear fibers
supranuclear palsy (coiled bodies); tau-containing threadlike
structures in the white matter (neuropil threads)

Corticobasal Widespread neuronal loss and atrophy Swollen, vacuolated neurons containing
degeneration asymmetrically in the cortex, usually maximal in the phosphorylated neurofilaments and sometimes
frontoparietal areas and much less involvement of 4-repeat tau are found in affected areas, more
the occipital lobes; widespread neuronal loss and commonly in cortical areas, which are common in
gliosis in the globus pallidus, putamen, red nucleus, corticobasal degeneration but are not specific for
thalamus, subthalamic nucleus, substantia nigra, that disease; the 4-repeat tau has a different
locus coeruleus, and dentate nucleus structure from the 4-repeat tau typical of
progressive supranuclear palsy; tau inclusions in
astrocytes (astrocytic plaques) are more diffuse
than the tufted astrocytes of progressive
supranuclear palsy; tau-containing threads
(neuropil threads) in gray and white matter of the
cortex in corticobasal degeneration

Multiple system Widespread neuronal loss and atrophy in the Abnormal inclusions in multiple system atrophy
atrophy substantia nigra, globus pallidus, putamen, contain abnormal α-synuclein, not tau; the
thalamus, parts of the cerebellum, middle characteristic inclusion is the glial cytoplasmic
cerebellar peduncle, inferior olives, red nucleus, inclusion; there are less frequent glial nuclear
intermediolateral cell columns, corticospinal tracts, inclusions containing α-synuclein and α-synuclein-
anterior horn cells, and other structures; containing neuronal cytoplasmic inclusions (similar
subthalamic nucleus, dentate nucleus, and superior in structure to the glial cytoplasmic inclusions) and
cerebellar peduncle are relatively uninvolved neuronal nuclear inclusions (consisting of
networks of fibrils) as well as dystrophic neurites
in involved structures

930 AUGUST 2019

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FIGURE 2-1
Hummingbird sign and morning glory sign. T1-weighted images of the brain in a patient with
clinically diagnosed progressive supranuclear palsy. A, Hummingbird sign is shown (box). B,
Arrows indicate morning glory sign.
Reprinted from Saeed U, et al, Transl Neurodegener.32 © 2017 The Authors.

PSP but does not distinguish PSP from PD, CBD, or MSA and may not be
sensitive for all subtypes.14
The most important clinical clues to the diagnosis of CBD/CBS are focal
cortical deficits such as myoclonus, apraxia, and aphasia. However, these can
occur in a minority of patients with PSP and other conditions.
It is currently very difficult to identify MSA in patients whose MSA begins
with isolated cerebellar signs or autonomic failure. Fluorodopa PET can
accurately identify patients with unsuspected dopaminergic deficiency,
but the test is currently not easily
available. Brain MRI in patients with
MSA may show hyperintensity in the
dorsolateral margin of the putamen
(putaminal slit sign) (FIGURE 2-234)
and cruciform increased signal in the
pons (hot cross bun sign) (FIGURE 2-3),
but the sensitivity of these tests, while
unknown, is probably low.26,35 If
orthostasis is an early feature in a patient
with parkinsonism, the diagnosis may be
either MSA or diffuse Lewy body disease.
In MSA, the central preganglionic
sympathetic neurons are mostly affected
(plasma epinephrine is normal when the
patient is supine but fails to rise when
FIGURE 2-2
the patient stands), and this may
Putaminal slit sign. Axial T2-weighted
differentiate it from diffuse Lewy MRI of a patient with autopsy-
body disease, where the autonomic confirmed multiple system atrophy
impairment affects mostly peripheral with predominant parkinsonism
postganglionic neurons. showing slitlike hyperintensity in the
dorsolateral putamen (arrows).
Moderate to marked cognitive impairment Reprinted with permission from Horimoto Y,
is common is PSP and CBD but uncommon et al, J Neurol.34 © 2002 Steinkopff Verlag.

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PSP, CBD, AND MSA

in MSA. Visual hallucinations and

levodopa-induced dyskinesias are
more likely to be present in PD
than in PSP-P or the other
syndromes. Frontotemporal lobar
degeneration–parkinsonism can
mimic any of these conditions,
especially if the dementia lags
FIGURE 2-3 behind the motor symptoms.
Hot cross bun sign. Proton density MRI sequence The use of biomarkers for
of a patient with clinically defined multiple system PSP, CBD, and MSA is being
atrophy showing the hot cross bun sign in the pons
(arrows).
studied. The hope is that
Reprinted from Saeed U, et al, Transl Neurodegener.32 treatment strategies for these
© 2017 The Authors. diseases are more likely to be
successful if used early in the
course and that specific biomarkers would allow identification of the disease
before symptoms develop or when symptoms are very mild. However, currently
tested biomarkers lack sufficient specificity and sensitivity for clinical use.14,22

TREATMENT OF SYMPTOMS IN PSP, MSA, and CBD

Since none of these diseases are curable, treatment is directed to specific
symptoms, many of which can occur in any of the conditions. Medications are
usually ineffective for parkinsonian symptoms in these conditions, but
occasionally provide benefit, at least temporarily, especially in PSP-P and MSA.
Treating patients with MSA with dopaminergic agents often worsens
orthostasis, which may be difficult to manage since blood pressure support
agents such as supplemental salt, fludrocortisone, midodrine, desmopressin, and
other agents may produce hypertension. Botulinum toxin injections can treat
apraxia of eyelid opening, blepharospasm, painful dystonia or rigidity, and
sialorrhea. Botulinum toxin type B is more potent at reducing sialorrhea but
is more painful to inject than botulinum toxin type A. However, patients with
these syndromes are at higher risk for developing dysphagia, and it is prudent to
start with lower doses than are used for PD. A pseudobulbar state can be treated
with tricyclic antidepressants or dextromethorphan/quinidine.
Depression can be treated as it is for PD (it is not known if some antidepressants
are better than others for these syndromes). Patients with all forms of parkinsonism
do not tolerate dopamine receptor–blocking agents that are sometimes used as
adjunctive antidepressive medications. Desmopressin at bedtime may help avoid
nocturnal incontinence (and also help orthostasis). Constipation is managed
similarly to idiopathic PD but may be less responsive to treatment. Mild constipation
may be successfully managed with high-fiber diets or laxatives such as bisacodyl
or senna. Liquifying stool with agents such as polyethylene glycol or lactulose may
help more severe cases. Newer laxatives such as lubiprostone or linaclotide have
also been used in PD. Feeding tubes can be used for patients with dysphagia who
are at risk of aspiration, but not all patients and families choose this option.

CONCLUSION
PSP, CBD, and MSA were first identified by pathology that involved the
substantia nigra but, unlike PD, also involve other cortical and subcortical

932 AUGUST 2019

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 KEY POINTS
structures. Once levodopa was introduced for the treatment of PD, these diseases
could be suspected when people with dopamine deficiency symptoms (soft ● The typical features of
voice, facial masking, rigidity, bradykinesia, postural change, generalized progressive supranuclear
slowing, including gait) did not improve with levodopa, had relatively early palsy (supranuclear gaze
development of dysphagia and imbalance compared to patients with PD, and palsy), corticobasal
degeneration (cortical
had other neurologic signs not seen in patients with PD. Initially, it appeared myoclonus and other focal
that the three conditions were easily separated. In addition to parkinsonian cortical deficits), and
features, people with PSP develop multiple visual abnormalities including a multiple system atrophy
supranuclear gaze palsy, have early dysphagia leading to aspiration (autonomic failure and
ataxia) suggest the correct
pneumonia, have a growling voice, tend to have marked axial rigidity, and diagnosis but do not achieve
start falling in the first few years of disease. People with CBD have marked both sensitivity and
limb dystonia (often unilateral and painful), cortical signs such as multifocal specificity.
myoclonus, apraxia, agnosia, agraphesthesia, and falls in the first years of
● Some symptoms of
disease. People with MSA have some combination of autonomic failure (eg,
progressive supranuclear
orthostasis, urinary frequency/urgency or urinary retention, constipation, palsy, corticobasal
impotence in men) and cerebellar deficits (eg, gait and limb ataxia, scanning degeneration, and
speech). Inspiratory stridor, although uncommon in MSA, is not seen in the multiple system atrophy
can be treated, such
other conditions.
as constipation;
As more autopsies were conducted, it became clear that the signs and blepharospasm and other
symptoms of PSP and CBD could be identical in some patients. In addition, dystonias (with botulinum
some other disease pathologies could look like PSP or CBD, and PSP or CBD toxin injections);
pathology could look like other diseases as well. Although some signs and orthostasis; depression;
pain; pseudobulbar affect;
symptoms are characteristic of each of these diseases, it has been difficult to and other symptoms.
devise clinical guidelines for these conditions that are both highly sensitive
and highly specific.
Most recently, there has been a hypothesis that misfolded tau (in PSP and
CBD) and misfolded α-synuclein (in MSA) may act like prions and drive the
progression of these conditions. Studies are now underway to slow or stop the
spread of these proteins inside the brain.

VIDEO LEGENDS
VIDEO 2-1 VIDEO 2-3
Corticobasal syndrome. Video shows a 75-year- Multiple system atrophy. Video shows a man with
old woman clinically diagnosed with corticobasal signs of a mild cerebellar syndrome. On initial
syndrome. Among other features, she illustrates an presentation (not shown), he had a hint of facial
asymmetric parkinsonism with a markedly dystonic masking, decreased arm swing, and some dystonic
right arm, myoclonus, ideomotor apraxia, and posturing with his right arm when walking. He
cortical sensory loss. developed bowel and bladder dysfunction, erectile
links.lww.com/CONT/A56 dysfunction, temperature dysregulation, and a
cerebellar syndrome (primarily scanning speech and
Reproduced with permission from Williams DR, ataxia). Video shows mild flattening of the left
Litvan I, Continuum (Minneap Minn).20 © 2013 nasolabial fold, depression of the left corner of the
American Academy of Neurology. mouth and, at times, a widened left palpebral fissure.
VIDEO 2-2 Video also shows his mildly broad-based stance and
Corticobasal degeneration. Video shows an gait and his difficulty standing with feet together and
80-year-old man demonstrating progressive eyes closed. When walking, occasionally either foot
asymmetric limb dysfunction, rigidity, will be placed either laterally or medially, especially
bradykinesia, dystonia, apraxia, and cortical when walking quickly. His right arm tends to be flexed,
sensory deficits consistent with probable and his stride and arm swing are reduced on the right
corticobasal degeneration. (most obviously when walking quickly). When pulled
links.lww.com/CONT/A204 backward, he moves his feet quickly to recover, which
may throw him off balance. The patient later
Reproduced with permission from McFarland NR, developed clear signs of parkinsonism (not shown) that
Continuum (Minneap Minn).21 © 2016 American were not responsive to levodopa, and he did not
Academy of Neurology. develop orthostasis until late in the disease course.
links.lww.com/CONT/A283
© 2019 American Academy of Neurology.

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PSP, CBD, AND MSA

REFERENCES

1 Lantos PL. The definition of multiple system 14 Armstrong MJ. Progressive supranuclear palsy:
atrophy: a review of recent developments. an update. Curr Neurol Neurosci Rep 2018;18(3):
J Neuropathol Exp Neurol 1998;57(12):1099–1111. 12. doi:10.1007/s11910-018-0819-5.
2 Dejerine J, Thomas AA. L’atrophie olivo-ponto- 15 Dickson DW, Ahmed Z, Algom AA, et al.
cerebelleuse. Nouv Iconog Salpetriere 1900;13: Neuropathology of variants of progressive
330–370. supranuclear palsy. Curr Opinion Neurol 2010;
23(4):394–400. doi:10.1097/WCO.0b013e32833be924.
3 Shy GM, Drager GA. A neurologic syndrome
associated with orthostatic hypotension. Arch 16 Ayers JI, Giasson BI, Borchelt DR. Prion-like
Neurol 1960;2:511–527. doi: 10.1001/archneur. spreading in tauopathies. Biol Psychiatry 2018;
1960.03840110025004. 83(4):337–346. doi:10.1016/j.biopsych.2017.04.003.
4 Van der Eecken H, Adams RD, van Bogaert L. 17 Kouri N, Whitwell JL, Josephs KA, et al.
Striopallidal-nigral degeneration. An hitherto Corticobasal degeneration: a pathologically
undescribed lesion in paralysis agitans. distinct 4R tauopathy. Nat Rev Neurol 2011;7(5):
J Neuropathol Exp Neurol 1960;19:159–161. 263–272. doi:10.1038/nrneurol.2011.43.
5 Adams RD, van Bogaert L, van der Eecken H. 18 Boeve BF. The multiple phenotypes of corticobasal
Nigro-striate and cerebello-nigro-striate syndrome and corticobasal degeneration:
degeneration. (Clinical uniqueness and pathological implications for further study. J Mol Neurosci
variability of presenile degeneration of the 2011;45(3):350–353. doi:10.1007/s12031-011-9624-1.
extrapyramidal rigidity type) [in French]. Psychiat
19 Alexander SK, Rittman T, Xuereb JH, et al. Validation
Neurol (Basel) 1961;142:219–259.
of the new consensus criteria for the diagnosis of
6 Graham JG, Oppenheimer DR. Orthostatic corticobasal degeneration. J Neurol Neurosurg
hypotension and nicotine sensitivity in a case Psychiatry 2014;85(8):923–927. doi:10.1136/
of multiple system atrophy. J Neurol Neurosurg jnnp-2013-307035.
Psychiatry 1969;32(1):28–34.
20 Williams DR, Litvan I. Parkinsonian syndromes.
7 Steele JC, Richardson JC, Olszewski J. Progressive Continuum (Minneap Minn) 2013;19(5, Movement
supranuclear palsy. A heterogeneous degeneration Disorders):1189–1212. doi:10.1212/01.CON.
involving the brain stem, basal ganglia and 0000436152.24038.e0.
cerebellum with vertical gaze and pseudobulbar
21 McFarland NR. Diagnostic approach to atypical
palsy, nuchal dystonia and dementia. Arch
parkinsonian syndromes. (Minneap Minn) 2016;
Neurol 1964;10:333–359. doi:10.1001/archneur.
22(4, Movement Disorders):1117–1142. doi: 10.1212/
1964.00460160003001.
CON.0000000000000348.
8 Rebeiz JJ, Kolodny EH, Richardson EP Jr.
22 Ali F, Josephs KA. Corticobasal degeneration: key
Corticodentatonigral degeneration with neuronal
emerging issues. J Neurol 2018;265(2):439–445.
achromasia. Arch Neurol 1968;18(1):20–33.
doi:10.1007/s00415-017-8644-3.
doi:10.1001/archneur.1968.00470310034003.
23 Palma JA, Norcliffe-Kaufmann L, Kaufmann H.
9 Respondek G, Stamelou M, Kurz C, et al.
Diagnosis of multiple system atrophy. Auton
The phenotypic spectrum of progressive
Neurosci 2018;211:15–25. doi:10.1016/j.autneu.
supranuclear palsy: a retrospective multicenter
2017.10.007.
study of 100 definite cases. Mov Disord 2014;
29(14):758–766. doi:10.1002/mds.26054. 24 Sima AA, Caplan M, D’Amato CJ, et al. Fulminant
multiple system atrophy in a young adult presenting
10 Armstrong MJ, Litvan I, Lang AE, et al. Criteria for
as motor neuron disease. Neurology 1993;43(10):
the diagnosis of corticobasal degeneration.
2031–2035. doi:10.1212/WNL.43.10.2031.
Neurology 2013;80(5):496–503. doi:10.1212/WNL.
0b013e31827f0fd1. 25 Koga A, Dickson DW. Recent advances in
neuropathology, biomarkers and therapeutic
11 Wenning GK, Ben Shlomo Y, Magalhães M. Clinical
approach of multiple system atrophy. J Neurol
features and natural history of multiple system
Neurosurg Psychiatry 2018;89(2):175–184. doi:10.1136/
atrophy. An analysis of 100 cases. Brain 1994;
jnnp-2017-315813.
117(pt 4):835–845. doi: 10.1093/brain/117.4.835.
26 Gilman S, Wenning GK, Low PA, et al. Second
12 Höglinger GU, Respondek G, Stamelou M, et al.
consensus statement on the diagnosis of
Clinical diagnosis of progressive supranuclear
multiple system atrophy. Neurology 2008;71(9):
palsy: the Movement Disorder Society criteria.
670–676. doi:10.1212/01.
Mov Disord 2017;32(6):853–864. doi:10.1002/
wnl.0000324625.00404.15.
mds.26987.
27 Erkkinen MG, Kim MO, Geschwind MD. Clinical
13 Esteban A, Giménez-Roldán S. Involuntary closure
neurology and epidemiology of the major
of eyelids in parkinsonism. Electrophysiological
neurodegenerative diseases. Cold Spring Harb
evidence for prolonged inhibition of the levator
Perspect Biol 2018;10(4):a033118. doi:10.1101/
palpebrae muscles. J Neurol Sci 1988;85(3):
cshperspect.a033118.
333–345. doi:10.1016/0022-510X(88)90191-8.

934 AUGUST 2019

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

28 Coyle-Gilchrist ITS, Dick KM, Patterson K, et al. 33 Mueller C, Hussle A, Krismer F, et al. The diagnostic
Prevalence, characteristics, and survival of accuracy of the hummingbird and morning glory
frontotemporal lobar degeneration syndromes. sign in patients with neurodegenerative
Neurology 2016;86(18):1736–1743. doi:10.1212/ parkinsonism. Parkinsonism Relat Disord 2018;54:
WNL.0000000000002638. 90–94. doi:10.1016/j.parkreldis.2018.04.005.
29 Respondek G, Kurz C, Arzberger T, et al. Which 34 Horimoto Y, Aiba I, Yasuda T, et al. Longitudinal
ante mortem clinical features predict progressive MRI study of multiple system atrophy–when do
supranuclear palsy pathology? Mov Disord 2017; the findings appear, and what is the course?
32(7):995–1005. doi:10.1002/mds.27034. J Neurol 2002;249(7):847–854. doi:10.1007/
s00415-002-0734-0.
30 Baizabal-Carvallo JF, Jankovic J. Parkinsonism,
movement disorders and genetics in frontotemporal 35 Way C, Pettersson D, Hiller A. The ‘hot cross bun’
dementia. Nature Rev Neurol 2016;12(3):175–185. sign is not always multiple system atrophy:
doi:10.1038/nrneurol.2016.14. etiologies of 11 cases. J Mov Disord 2019;12(1):
27–30. doi:10.14802/jmd.18031.
31 Stamelou M, Bhatia KP. Atypical parkinsonism—
new advances. Curr Opin Neurol 2016;29(4):
480–485. doi:10.1097/WCO.0000000000000355.
32 Saeed U, Compagnone J, Aviv RI, et al. Imaging
biomarkers in Parkinson’s disease and parkinsonian
syndromes: current and emerging concepts.
Transl Neurodegener 2017;6:8. doi:10.1186/
s40035-017-0076-6.

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 REVIEW ARTICLE


Tics and Tourette
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
Syndrome
By Harvey S. Singer, MD, FAAN

VIDEO CONTENT
A VA I L A B L E O N L I N E

ABSTRACT
PURPOSE OF REVIEW: The purpose of this article is to present current
information on the phenomenology, epidemiology, comorbidities, and
pathophysiology of tic disorders and discuss therapy options. It is hoped
that a greater understanding of each of these components will provide
Downloaded from http://journals.lww.com/continuum by BhDMf5ePHKbH4TTImqenVLIlg0cBmue4T5mm7WKE1WkwapLJtCp3kAo1PIu4JaP0YSZXFg1EEvs= on 08/03/2019

clinicians with the necessary information to deliver thoughtful and optimal

care to affected individuals.

CITE AS: RECENT FINDINGS: Recent advances include the finding that Tourette
CONTINUUM (MINNEAP MINN)
2019;25(4, MOVEMENT DISORDERS):
syndrome is likely due to a combination of several different genes, both
936–958. low-effect and larger-effect variants, plus environmental factors.
Pathophysiologically, increasing evidence supports involvement of the
Address correspondence to cortical–basal ganglia–thalamocortical circuit; however, the primary
Dr Harvey S. Singer, Professor of
Neurology and Pediatrics, Johns location and neurotransmitter remain controversial. Behavioral therapy
Hopkins Hospital, Rubenstein is first-line treatment, and pharmacotherapy is based on tic severity.
Child Health Building, 200 N
Several newer therapeutic agents are under investigation (eg, valbenazine,
Wolfe St, Ste 2141 Baltimore,
MD 21287, [email protected]. deutetrabenazine, cannabinoids), and deep brain stimulation is a
promising therapy.
RELATIONSHIP DISCLOSURE:
Dr Singer serves as a consultant
for Abide Therapeutics, Inc; Cello SUMMARY: Tics, defined as sudden, rapid, recurrent, nonrhythmic motor
Health BioConsulting; ClearView movements or vocalizations, are essential components of Tourette
Healthcare Partners; Teva
Pharmaceutical Industries Ltd; syndrome. Although some tics may be mild, others can cause significant
and Trinity Partners, LLC. psychosocial, physical, and functional difficulties that affect daily
Dr Singer receives publishing activities. In addition to tics, most affected individuals have coexisting
royalties from Elsevier and
research/grant support from the neuropsychological difficulties (attention deficit hyperactivity disorder,
Tourette Association of America. obsessive-compulsive disorder, anxiety, mood disorder, disruptive
UNLABELED USE OF
behaviors, schizotypal traits, suicidal behavior, personality disorder,
PRODUCTS/INVESTIGATIONAL antisocial activities, and sleep disorders) that can further impact social and
USE DISCLOSURE: academic activities or employment.
Dr Singer discusses the
unlabeled/investigational use of
baclofen, botulinum toxin,
cannabidiol, clonazepam,
clonidine, deutetrabenazine, INTRODUCTION

T
ecopipam, fluphenazine,
ourette syndrome, also known as Gilles de la Tourette syndrome or
guanfacine, nabiximols,
risperidone, sulpiride, Tourette disorder, is a complex, childhood-onset neuropsychiatric
tetrabenazine, Δ-9- condition that includes multiple phenotypic motor and vocal tics. The
tetrahydrocannibinol, tiapride,
topiramate, and valbenazine.
condition is named after the French physician Georges Gilles de la
Tourette, who in 1885 reported nine patients with the “maladie of
tics.”1 Before Tourette’s report, motor and vocal tics had been reported in the
© 2019 American Academy context of witchcraft, in well-known historical individuals, and in the medical
of Neurology. literature by Jean Itard in 1825.2

936 AUGUST 2019

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 Tourette syndrome affects children, adolescents, and adults worldwide and
represents only one entity in a spectrum of tic disorders ranging from a
provisional form to those associated with general medical conditions. Although
some tics may be mild, others can result in psychosocial, physical, and functional
difficulties that affect social activities, academic achievements, and employment
performance. Comorbid or co-occurring conditions are common in patients with
Tourette syndrome, the most common being obsessive-compulsive disorder,
attention deficit hyperactivity disorder (ADHD), anxiety, mood disorders,
disruptive behaviors, learning difficulties, and alterations of sleep. The
underlying pathophysiology, in terms of both anatomic localization and the
primary neurochemical abnormality, remains unclear. Therapeutically,
behavioral therapy is the first-line option, followed by various standard and
emerging pharmacologic treatments and, finally, deep brain stimulation.

TIC PHENOMENOLOGY
Tics are sudden, rapid, recurrent, nonrhythmic motor movements or
vocalizations (phonic productions).

Categories and Types

Tics are classified into two larger categories (motor and phonic), with each being
subdivided into a simple and complex grouping. Brief, rapid, abrupt jerklike,
nonrhythmic movements that involve only a single muscle or localized group
are considered simple (eye blink, head jerk, shoulder shrug) (VIDEO 3-1,3 links.
lww.com/CONT/A284). In contrast, complex tics involve either a cluster of
simple actions or a more coordinated pattern of movements. Complex motor tics
can be nonpurposeful (facial or body contortions) (VIDEO 3-2, links.lww.com/
CONT/A285 and VIDEO 3-3, links.lww.com/CONT/A286) or appear purposeful
but actually serve no purpose (touching, hitting, smelling, jumping, bending,
imitating observed movements [echopraxia], and making obscene gestures
[copropraxia]). They may have a dystonic quality (oculogyric movements,
sustained mouth opening, body posturing, torticollis) or have a tonic character
(prolonged tensing of abdominal muscles, immobility, staring), labeled by some
as blocking tics.4 In approximately 4% to 5% of patients, self-injurious
(“malignant”) tics can cause myelopathies, ocular damage, or body injuries.5,6
Simple vocal tics include various sounds and noises (grunts, barks, hoots,
hollers, moans, groans, sniffs, and throat clearing) (VIDEO 3-4, links.lww.com/
CONT/A287 and VIDEO 3-5, links.lww.com/CONT/A288). Complex vocalizations
(VIDEO 3-6, links.lww.com/CONT/A289) involve linguistically meaningful
vocalizations and utterances; the repetition of words, syllables, or phrases;
echolalia (repeating other people’s words); palilalia (repeating one’s own
words); or coprolalia (obscene words or profanity). Although coprolalia is
commonly associated with Tourette syndrome, only a small minority (about 10%
to 19%) of individuals with Tourette syndrome have this symptom.7,8 Vocal
alterations can also include pauses and hesitations in speech, word interjections,
changes in tone/pitch, and prolongations of words.
While the distinction between motor and vocal tics is often emphasized, some
vocalizations can be secondary to a nasal, pharyngeal, chest, or abdominal motor
tic. For example, a rapid contraction of the chest or abdomen can lead to the
expulsion of air and production of a simple vocalization. Although it has been
suggested that tics can mimic almost any movement or sound, uncommon tics

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TICS AND TOURETTE SYNDROME

have included anterior-posterior movements of the external ear, sign language

tics, palatal movements, air swallowing, vomiting, and retching.

Characteristics
Tics have several characteristics that are useful in identifying their presence,
including precipitating factors, a waxing and waning pattern, admixture of new
and old tics, a premonitory urge that resolves when the tic is done, reduction
when engrossed, and variable severity. They can range from infrequent and
unnoticed to very frequent, intense, intrusive, and even self-injurious. Tics are
exacerbated by stress, anxiety, excitement, anger, fatigue, elevated temperatures,
or infections.9,10 These conditions, however, do not account for more prolonged
changes in tic severity.11 Tics are reduced when the individual is concentrating on
a physical or mental task or sleeping. Although most parents and patients report
that tics do not occur while sleeping, polysomnograms have identified their
presence in all phases of sleep.12 About 90% of adults13 and 37% of children14
report a premonitory urge/sensation just before a motor or phonic tic. Vaguely
defined as an urge, mounting tension, pressure, itch, or feeling, it is generally
localized to the region of the tic and resolves when the tic is permitted to occur.15
Many individuals can briefly suppress their tics, although this effort may
trigger an exacerbation of premonitory sensations or a sense of increased
internal tension.
Tic disorders are more common in males than in females (ratio of 3:1 to 4:1)
and usually begin between the ages of 4 and 8. Motor tics usually precede vocal
tics, with initial simple motor tics involving the face, head, or neck. Tics can be
highly variable and fluctuate, and an individual’s tic repertoire evolves over time.
Statistically, the maximum severity of tics tends to occur between 8 and 12 years
of age,16 with tics declining in severity throughout the teenaged to early
adulthood years.16,17 An approximate rule of thirds suggests that one-third of tics
disappear, one-third improve, and one-third continue to fluctuate.18 Although
many adults have reported the resolution of tics, formal assessments have
indicated otherwise.19 Assumptions that adult tic severity can be predicted by
childhood tic severity, childhood fine motor skills, and reduced childhood
MRI caudate volumes require additional confirmation. Tics can persist into
adulthood and, for some, can be severe and debilitating.20 In addition,
symptom worsening has occurred in adults after prolonged periods of clinical
remission.21 Adult-onset tic disorders (formally, other specified tic disorder
with onset after age 18 years) have been reported and often include severe
symptoms, greater social morbidity, and poorer response to medications
compared to childhood-onset tic disorders.22
Neurologic examination and neuroimaging studies are typically normal.
“Soft” neurologic findings may include coordination issues, synkinesis
(involuntary muscular movements accompanying voluntary movements), and
motor restlessness, especially in individuals with ADHD.

DIAGNOSIS
The diagnosis of a tic disorder is based on historical features and observation of the
tics; there is no definitive diagnostic laboratory test. Tics must be differentiated
from drug-induced movements (akathisia, dystonia, parkinsonism), obsessive-
compulsive behaviors, hyperactivity, antisocial behaviors, and stereotypies.23
In contrast to tics, which are commonly associated with a premonitory urge,

938 AUGUST 2019

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compulsions are complex activities that are performed to prevent or relieve KEY POINTS
anxiety, are executed in a rigid pattern, and may be done in response to an
● Tics have several
obsession. Motor stereotypies typically have an earlier onset, fixed pattern, characteristics that are
rhythmic quality, prolonged duration, and lack of a premonitory urge and stop useful in identifying their
abruptly with distraction.24 Individuals with stuttering may also have an array of presence, including
nonspeech motor ticlike behaviors, including eye blinking, ocular deviation, precipitating factors, a
waxing and waning pattern,
head jerks, and limb and trunk movements.25 In practice, repetitive sniffing,
admixture of new and old
throat clearing, and coughing tics are often mistakenly attributed to allergies, tics, a premonitory urge that
sinusitis, or pulmonary issues; eye blinking tics are mistakenly thought to stem resolves when the tic is done,
from ophthalmic problems; and ocular tics are confused with opsoclonus. reduction when engrossed,
and variable severity.
Psychogenic disorders that present with ticlike movements can arise in
childhood but are more common in adults; they are also more common in ● Tics can be highly variable
females than in males.26 Nevertheless, it may be difficult, at times, to distinguish and fluctuate, and an
a functional movement in an individual with preexisting typical tics. Clues individual’s tic repertoire
helpful in identifying a psychogenic movement include predisposing factors, the evolves over time.
lack of a premonitory sense, inability to briefly suppress the tics, other functional ● The diagnosis of a tic
movements, and the lack of response to otherwise effective therapies. disorder is based on historical
features and observation of
Specific Tic Diagnoses the tics; no definitive
diagnostic laboratory test
The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5),
has yet been established.
includes five tic categories27:

u Provisional tic disorder designates an individual whose tics (motor or vocal) have been
present for less than 1 year since first tic onset, and onset is before age 18 years. The
disturbance cannot be attributable to the psychological effects of a substance or other
medical conditions. For example, tics can result as a direct consequence of a variety
of neurodegenerative disorders (eg, neuroacanthocytosis, Huntington disease,
neurodegeneration with brain iron accumulation), neurocutaneous syndromes,
and Creutzfeldt-Jakob disease.3,28 Tics have also been reported in association with
infections, Sydenham chorea, toxins (carbon monoxide), stroke, head and peripheral
trauma, and surgery. Drugs reported to induce tics include cocaine, lamotrigine, and
neuroleptics.29 Significant data exist refuting the concept that stimulant medications
are precipitating agents for tics.30
u Chronic motor or vocal tic disorder indicates the presence of either motor or vocal tics, but
not both, for longer than 1 year, without regard for tic frequency. Onset is before 18 years
of age, and tics cannot be attributed to the use of drugs or other medical condition. Note
that multiple characteristics overlap in individuals with chronic motor tic disorder and
individuals with Tourette syndrome.31
u Tourette disorder is also called Tourette syndrome, and both have very similar formal
criteria,27,32 except that when originally proposed, the age of onset for Tourette syndrome
was before 21 years of age as compared to before 18 years of age for Tourette disorder.
Other criteria include the presence of multiple motor tics and at least one vocal tic, a
waxing and waning course, a duration of longer than 1 year, and tics that are neither
substance-induced nor due to a general medical condition.

The last two categories apply to tic disorders that cause clinical
distress/impairment but do not meet criteria for either of the aforementioned
three tic disorders or any neurodevelopmental disorder.

u Other specified tic disorder is a diagnosis used when the clinician chooses to
communicate the reason why the individual failed to meet the criteria for a tic disorder,
(eg, other specified tic disorder with an age of onset of older than 18 years).
u Unspecified tic disorder is a diagnosis used when the criteria for a tic disorder are not met,
and there is insufficient information to make a more specific diagnosis.

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TICS AND TOURETTE SYNDROME

TIC RATING SCALES

The Yale Global Tic Severity Scale, a semistructured clinical interview, is the
most widely used tic severity assessment instrument.33 It consists of the Total Tic
Score, composed of five separate ratings (number, frequency, intensity,
complexity, and interference) on a scale of 0 to 5 for both motor (maximum
of 25 points) and vocal (maximum of 25 points) tics, and the Tic Impairment
Score, a ranking of impairment based on the impact of the tic disorder on
self-esteem, family life, and social acceptance (maximum of 50 points). Although
tic severity might be expected to correlate with impairment, studies have
shown that this is not necessarily the case.17 The Gilles de la Tourette Syndrome
Health-Related Quality of Life Scale is a 27-item patient-reported Tourette
syndrome–specific scale with psychological, physical, obsessional, and cognitive
subscales.34 The Premonitory Urge for Tics Scale characterizes and quantifies
premonitory urges.35

EPIDEMIOLOGY
Simple tics are relatively common in childhood, with reports of prevalence
(the number of cases in the population at a given time) being 6% to 12% (range of
4% to 24%).36,37 For Tourette syndrome, which occurs worldwide with common
features in all cultures and races, prevalence estimates have been variable,
with estimates ranging from 0.3% to 1%. In two meta-analyses, prevalence in
children was 0.52%38 and 0.77%39 but increased to 1.06% when only boys were
considered.39 Another estimate is that an additional 1% to 3% of children and
adolescents have a mild unidentified form. The variations in reported prevalence
are believed to be associated with differences in assessment methods and
measures. Several studies have documented that Tourette syndrome is common
in children with autistic spectrum disorders40; however, no correlation with
the severity of autistic symptoms has been seen. Mortality rates are reportedly
higher in Tourette syndrome and chronic motor or vocal tic disorder, irrespective
of the presence of comorbidities.41 Parents of children with chronic tic disorders
have higher rates of psychiatric illnesses, greater in mothers than fathers,
although whether this is associated with parental stress or environmental,
genetic, or other factors is unclear.42

COMORBIDITIES
Most individuals with Tourette syndrome (an estimated 86% to 90%) have at
least one comorbid/coexisting neuropsychological problem.43 These additional
issues add an extra clinical burden, and, for some, the clinical impact may be
greater than that caused by tics. Health-related quality of life assessments
have shown that outcome is predicted by the presence of comorbidities,
such as ADHD and obsessive-compulsive disorder (OCD), rather than tic
severity.44,45 Coexisting neuropsychological issues add a significant additional
burden to patients with Tourette syndrome or chronic motor or vocal tic
disorder.44,46 It has also been suggested that less severe tic phenotypes have
lower rates of comorbidity.47 In a study examining parent attribution of
impairment in home activities, non–tic-related concerns were a greater
problem.48
Longitudinal studies in patients with Tourette syndrome have suggested a
decline in both ADHD and OCD during adolescence although other
psychopathologies persist.17 Recognizing the common presence and detrimental

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effect of coexisting problems, physicians caring for patients with tic disorders KEY POINTS
must be knowledgeable about and continually assess for them.
● Simple tics are relatively
common in childhood, with
Attention Deficit Hyperactivity Disorder reports of prevalence (the
number of cases in the
ADHD symptoms (inattentiveness, hyperactivity-impulsivity, or both) usually
population at a given time)
precede the onset of tics by 2 to 3 years. ADHD is reported to affect about 50% being 6% to 12% (range of 4%
(range of 21% to 90%) of referred patients with Tourette syndrome.49 In patients to 24%).
with tics, the addition of ADHD symptoms correlates with increased deficits in
the ability to plan, working memory, and inhibitory control and increased ● Most individuals with
Tourette syndrome have at
psychosocial and school difficulties, aggressiveness, disruptive behaviors, least one comorbid/coexisting
emotional problems, functional impairment, and learning disabilities.50,51 neuropsychological problem.
Tourette syndrome and ADHD are not believed to be alternative phenotypes of a
single underlying genetic cause but rather to have a shared genetic susceptibility ● Coexisting
neuropsychological issues
and overlap in their underlying neurobiology.43,52
add a significant additional
burden to patients with
Obsessive-Compulsive Disorder Tourette syndrome or
chronic motor or vocal
Obsessive-compulsive behaviors usually emerge during early adolescence, tic disorder.
several years after the onset of tics, although an earlier age of onset has been
suggested.43,53 The DSM-5 criteria for OCD require that obsessions, compulsions,
or both occupy at least 1 hour per day or cause significant clinical distress or
functional impairment. A lifetime comorbid diagnosis of OCD is present in about
50% of patients with Tourette syndrome; symptoms typically becoming more
severe at a later age.54,55 In Tourette syndrome, obsessive-compulsive behaviors
usually include a need for order or routine and a requirement for things to be
symmetric or “just right.” Hence, the execution of tics must occur in a particular
fashion and sequence (eg, number of times, order, both sides of the body) and
often requires a certain “just right” sense/feeling before stopping. Other common
obsessive-compulsive behaviors include counting; arranging; ordering;
hoarding; touching; tapping; rubbing; checking for errors; and a higher
frequency of aggressive, sexual, religious, and symmetry-related obsessions. In
contrast, in OCD without tics, individuals typically have contamination and
cleaning compulsions. Genetic associations between OCD and Tourette
syndrome are complex, with a higher degree of heritability in both conditions
(refer to the Genetics section later in this article).

Anxiety and Mood Disorders

The prevalence of anxiety and depression in Tourette syndrome is variable
depending on the ages evaluated and methodologies used. For example, the
presence of generalized anxiety disorder in subjects with Tourette syndrome has
ranged from 19% to 80%, with increased rates in children and youth with
Tourette syndrome.53 A high-risk period for anxiety issues begins at age 4, and a
high-risk period for mood disorders begins at age 7.43 The presence of depression
in patients with Tourette syndrome has correlated positively with earlier onset
and a longer duration of tics.56 Suicidality, both thoughts and attempts, also has a
higher prevalence in Tourette syndrome.57 Hence suicidal behavior should be
monitored closely, especially in individuals with a history of persistent tics
beyond young adulthood, suicide attempts, and psychiatric issues. The presence
of ADHD is claimed to mediate anxiety and disruptive behaviors, whereas
individuals with comorbid OCD are more likely to have a mood disorder.43

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TICS AND TOURETTE SYNDROME

CASE 3-1 A 9-year-old boy presented for a neurologic consultation for tics. He had
developed eye-blinking tics at age 7 and subsequently gradually
developed a variety of other motor tics, including head turning, neck
stretching, and facial grimacing, and vocal tics that included throat
clearing and grunting sounds. Over the years, his tics had a waxing and
waning course. They were worse when he was stressed or fatigued.
Nothing clearly made them better, and they were not present during
sleep. He denied having a premonitory urge. At the time of evaluation,
motor tics were occurring approximately once per hour but at times more
frequently. The movements were not interfering with his daily activities.
Vocal tics occurred about once every 3 hours, were quieter than his
normal voice, and did not interfere with his communication. He had
received only a few comments in the academic setting, his tics were not
causing any physical issues nor disrupting his classroom, and he had been
on no prior tic-suppressing therapy.
The patient had a history of attention deficit hyperactivity disorder
since age 4 and was started on a stimulant medication (amphetamine) at
age 6 years and 9 months. He had no history of obsessive-compulsive
behaviors, anxiety, or mood issues. He did, however, have disruptive
behaviors, with yelling, crying out, and banging on objects, and was easily
angered when he did not get his way.
The patient was the product of an uncomplicated pregnancy and
delivery, his early development was normal, and his general health was
good. His family history was positive for childhood tics in his father. His
neurologic examination was normal other than the occasional tics that
were observed.

COMMENT This case illustrates a typical presentation of a child with Tourette

syndrome, with gradual onset and evolving course of both motor and
vocal tics and with tics causing only a limited psychosocial or physical
effect. This patient also had attention deficit hyperactivity disorder and
disruptive behaviors; most patients with Tourette syndrome have at
least one comorbidity, which may have a significant effect on quality of
life. He also had a positive family history, with his father having had
childhood tics. Although this patient’s tics began after the initiation of a
stimulant medication, these medications have not been scientifically
proven to cause tics, and no changes were recommended in this patient.
Tic-suppressing therapy should be reserve for individuals whose tics are
causing psychosocial, physical, functional, or other difficulties. If
needed, Comprehensive Behavioral Intervention for Tics (CBIT) should
be tried before tic-suppressing pharmacotherapy is considered. Tics
generally improve in the teenage and early adulthood years.

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Disruptive Behaviors KEY POINT
Disruptive behaviors, including episodic outbursts, rage, and difficulty with
● Tourette syndrome is
aggression, are common in patients with Tourette syndrome.43,58 Episodic currently classified as a
behavioral outbursts and anger control problems are reported in 25% to 70% of polygenic inherited
Tourette syndrome populations.59 The role of other comorbidities as a causative disorder, suggesting that a
factor for disruptive behaviors is unclear. Self-injurious behavior in Tourette combination of a variety of
genes (some common, some
syndrome has been shown to correlate with impulsivity and impulse control.60
with a low effect or rare, and
others having a larger effect)
Other Neuropsychological Symptoms and environmental factors
Poor self-concept, reduced self-esteem, antisocial activities, oppositional are all involved in its
transmission.
behaviors, schizotypal traits, and personality disorders are more frequent in
individuals with Tourette syndrome. Their cause, however, appears to be
more strongly related to psychiatric comorbidities, family, or economic issues
than to tic severity.61,62 Approximately two-thirds of patients with Tourette
syndrome had abnormal scores on the Child Behavior Checklist; identified
clinical problems included obsessive-compulsive behaviors, aggressiveness,
hyperactivity, immaturity, withdrawal, and somatic symptoms.63 No
evidence has shown that patients with Tourette syndrome are more likely to
engage in criminal behavior than those without Tourette syndrome.64

Academic Difficulties
Intellectual function is typically normal in Tourette syndrome; however, some
children have executive function issues, differences between performance and
verbal IQ testing, impairment of visual-perceptual achievement, and a reduction
of visual-motor skills.46 A variety of factors account for poor school performance
in children with Tourette syndrome, including disruptive tics, psychosocial
difficulties, ADHD, OCD, learning disabilities, and use of medications.51,65
Individuals with Tourette syndrome or chronic motor or vocal tic disorder are
more likely to academically underachieve, even after accounting for various
comorbidities.66

Sleep Disorders
Sleep disorders, including difficulties falling and staying asleep, restlessness,
arousals, and parasomnias, are common in Tourette syndrome.67,68 Sleep issues
have been associated with the presence of comorbidities such as ADHD, anxiety,
mood disorders, or OCD69; however, others have suggested that sleep problems
in Tourette syndrome are not fully explainable by these associated conditions.67
The effective management of sleep problems has been reported to improve tic
control in both severity and impact on life (CASE 3-1).70

ETIOLOGY
The precise etiology for Tourette syndrome remains undetermined; however,
there is strong agreement that it is associated with polygenic and environmental
vulnerability factors.

Genetics
Tourette syndrome is currently classified as a polygenic inherited disorder,
suggesting that a combination of a variety of genes (some common, some with
a low effect or rare, and others having a larger effect) and environmental
factors are all involved in its transmission.71–73 An inherited nature for Tourette

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TICS AND TOURETTE SYNDROME

syndrome is supported by findings, including a population-based heritability

estimate of 0.77 (a value of 1 indicating 100% heritability), a 15-fold increased
risk of developing Tourette syndrome/chronic motor or vocal tic disorder in
siblings of individuals with Tourette syndrome, a positive family history for tics
in about one-half of patients, and monozygotic twins having an 86%
concordance rate with chronic motor or vocal tic disorder compared to 20% in
dizygotic twins.74 A genetic predisposition is also believed to increase tic severity
and the rate of comorbidities and psychosocial and educational difficulties.75
A variety of explanations have been put forth to explain why no definitive
causative gene mutation or risk allele has been identified, with possibilities
including phenotypic and genotypic heterogeneity, variations in polygenic
burden, rare mutations (inherited or de novo), epigenetic factors, and gene-
environment interactions.76 The list of suggested prenatal and perinatal
epigenetic risk factors is extensive: limited perinatal care, maternal nausea and
vomiting, low birth weight, reduced 5-minute Apgar scores, thimerosal use
during the pregnancy, maternal emotional stress, and smoking. Limitations to
these studies include the use of retrospective data and clinic-derived rather
than epidemiologically derived samples.
Recognizing the absence of definitive risk genes for Tourette syndrome,
several potential susceptibility genes have been suggested but not confirmed
including the SLITRK1 gene, located at 13q31.1, and a mutation located in the
gene encoding L-histidine decarboxylase (HDC). Genome-wide investigations of
copy number variations have identified two significant loci: deletions in NRXN1
(encodes neurexin 1) and duplications of CNTN6 (encodes contactin). In a large
genome-wide association study, no single marker attained significance; however,
the single-nucleotide polymorphism with the strongest signal was located within
an intron of COL27A1 (encodes collagen-α1 chains).77 In another study, the top
single-nucleotide polymorphism associated with Tourette syndrome was an
intergenic region distal to NTN4, which encodes an axon guidance protein that is
expressed in the developing striatum.78 In an expanded whole-exome sequencing
study, de novo variants carried more risk in individuals with unaffected parents,
CELSR3 was identified as a risk gene, and genes mutated in Tourette syndrome
were enriched for those relating to cell polarity.71 Additional studies are required
to confirm a link between potential susceptibility genes and the underlying
neurobiology of Tourette syndrome.
Tourette syndrome and OCD are clinically associated, and each is highly
heritable, suggesting a potential shared genetic liability.79,80 Nevertheless, specific
shared gene variants have been difficult to identify. For example, evidence of
16p13.11 deletions is stronger in OCD than in Tourette syndrome. In contrast, a
significant overlap of de novo sequence variants was identified between Tourette
syndrome and OCD and of de novo copy number variants between Tourette
syndrome and autistic spectrum disorder.71 An analysis of shared heritability in
23 different neurologic and psychiatric disorders suggested that a significant
proportion of Tourette syndrome polygenic heritability is shared with OCD,
ADHD, and migraine.73

Possible Autoimmune Disorder

Although supporting data are very limited, several immune-mediated mechanisms,
including microglial dysfunction, reduced numbers of regulatory T cells, altered
gamma globulin, and an increased response to pathogens, have been proposed as

944 AUGUST 2019

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potential contributing etiologic factors for tics.81 Tic symptoms have also been KEY POINT
claimed to be associated with a preceding group A β-hemolytic streptococcal
● The existence of pediatric
infection, known as pediatric autoimmune neuropsychiatric disorders associated autoimmune neuropsychiatric
with streptococcal infections (PANDAS). In PANDAS, it is hypothesized that disorders associated with
streptococcal-induced polyreactive antibodies, through the process of molecular streptococcal infections
mimicry, recognize and disrupt either neuronal extracellular surface or (PANDAS) and its proposed
therapy are extremely
intracellular antigens. The existence of PANDAS and its proposed therapy are
controversial.
extremely controversial.82,83

PATHOPHYSIOLOGY
Pathophysiological models of Tourette syndrome typically include the disruption of
specific circuits involved in motor activity and their associated neurotransmitters.

Circuits
A series of parallel cortical–basal ganglia–thalamocortical circuits provide a
framework for understanding the pathophysiology of tics and associated
behaviors (FIGURE 3-1).

CORTICOSTRIATAL CONNECTIONS. The three major corticostriatal circuits

thought to be involved with Tourette syndrome symptomatology are the
association, motor, and limbic circuits. The broad association circuit comprises
two major components. The first is a circuit linking dorsolateral Brodmann
areas 9 and 10 with the dorsolateral head of the caudate. This pathway is
involved with executive functions (flexibility, organization, constructional
strategy, verbal and design fluency), motor planning (sequential and
alternating reciprocal motor tasks), and goal-directed behaviors. The second
component is a lateral orbitofrontal circuit linking the inferior lateral prefrontal
cortex (Brodmann areas 11 and 12) with the ventral medial caudate. This circuit is
associated with obsessive-compulsive behaviors, personality changes, mania,
disinhibition, and irritability. The motor circuit originates from the
supplementary motor area and premotor cortex and projects to the putamen in a
somatotopic distribution. This pathway is involved with habitual behaviors and
is therefore favored by some to be the anatomical site associated with the
production of tics. The limbic circuit arises from the anterior cingulate gyrus and
projects to the ventral striatum, which also receives input from the amygdala,
hippocampus, medial orbitofrontal cortex, entorhinal area, and perirhinal
cortex. The ventral striatum (nucleus accumbens and olfactory tubercle) serves
as the integrating site for information pertaining to emotion, motivation, vigor,
reward, attention, and autonomic factors.

STRIATAL–GLOBUS PALLIDUS–THALAMIC CONNECTIONS. The striatal–globus

pallidus–thalamic connections model is a simplistic model that fails to fully
recognize the complex interactions between components and focuses on “direct”
and “indirect” pathways. The direct pathway transmits striatal information
monosynaptically from medium-sized spiny neurons containing dopamine D1
receptors to the globus pallidus internus/substantia nigra pars reticulata region,
where it has an inhibitory effect. In contrast, the indirect pathway conveys
information from medium-sized spiny neurons containing dopamine D2
receptors to the globus pallidus externus, from the globus pallidus externus to the
subthalamic nucleus, and then to the globus pallidus interna/substantia nigra pars
reticulata, where it has an activating effect. Neurons in the globus pallidus

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TICS AND TOURETTE SYNDROME

FIGURE 3-1
Cortical–basal ganglia–thalamocortical circuit.
D1 = dopamine D1 receptor; D2 = dopamine D2 receptor; GPe = globus pallidus externus; GPi = globus
pallidus internus; Mthal = motor thalamus; MSN = medium-sized spiny neuron; NAC = nucleus accumbens;
SMA = supplementary motor area; SNpr = substantia nigra pars reticulata; STN = subthalamic nucleus.

internus/substantia nigra pars reticulata region, in turn, affect the firing of cells in
the thalamus that project to the cortex. In sum, the direct pathway facilitates motor
activity via disinhibition of thalamocortical neurons and the indirect pathway
reduces motor activity by increasing the inhibition of thalamocortical neurons.

THALAMUS. The motor thalamus is part of a closed loop, receiving input

from cortical association, premotor, and motor areas; basal ganglia; and the
cerebellum (dentate nucleus). In addition, short subcortical loops exist between
the thalamus and striatum.

Possible Location of the Abnormality

Direct and indirect evidence is available to support hypotheses that implicate
various individual components of the cortical–basal ganglia–thalamocortical

946 AUGUST 2019

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circuit as the primary anatomic abnormality in Tourette syndrome.3,84 Nevertheless, KEY POINTS
identification of the true primary site remains an area of active discussion.
● A series of parallel
cortical–basal ganglia–
CORTEX. Evidence supporting a primary cortical involvement in tics includes thalamocortical circuits
the following: provide a framework for
understanding the
u A frequent association of tics with neuropsychiatric comorbidities pathophysiology of tics and
associated behaviors.
u A preceding sensory premonitory urge that is associated with activation of several
cortical regions
● Identification of the true
u Postmortem studies demonstrating changes in dopamine transporter and D2 receptor primary site of anatomic
densities in the frontal cortex not identified in the striatum abnormality in Tourette
syndrome remains an area of
u Volumetric MRI studies showing larger dorsal prefrontal and parietooccipital areas; active discussion.
changes in prefrontal, frontal, sensorimotor, cingulate and temporal areas; and
alterations of the corpus callosum
u Functional connectivity studies showing increased connections between cortical–basal
ganglia networks and widespread immature functional connectivity
u Areas of cortical hypermetabolism in positron emission tomography (PET) studies
u Reduced inhibition within the motor cortex
u Animal models showing that disruption of cortical activity leads to ticlike behaviors

BASAL GANGLIA. Evidence supporting basal ganglia involvement in Tourette

syndrome includes its association with other movement disorders; postmortem
studies showing reduced density of parvalbumin-positive interneurons, choline
acetyltransferase–positive cholinergic interneurons, and medium-sized spiny
neurons in the striatum; and animal models demonstrating that the disruption of
the glutamate/GABA balance within the striatum causes ticlike behaviors. In
contrast, imaging studies of the caudate and putamen have been variable. For
example, individual reports have suggested putamen volumes were smaller in
children and adults, larger in children, asymmetric, or contained only white
matter changes.

OTHER. Preliminary imaging and animal model studies also provide support for
involvement of the amygdala, hippocampus, ventral striatum, thalamus, midbrain,
and cerebellum. A favored proposal suggests the presence of a complex circuit in
which a failure anywhere within the cortical–basal ganglia–thalamocortical circuit,
or even one involving inputs to the circuit, can lead to an aberrant message arriving
at the primary motor cortex and enabling the tic.84

Neurotransmitter Abnormality
Strong evidence supports involvement of cortical–basal ganglia–thalamocortical
circuits in the pathophysiology of tic disorders. Several neurotransmitters,
including dopamine, glutamate, GABA, serotonin, acetylcholine, norepinephrine,
endogenous cannabinoids, opioids, histamine, and adenosine, are active
participants within these circuits and may be dynamic factors in the
pathophysiology of tics. Hence, an additional area of controversy is whether a
specific neurotransmitter or combination of neurotransmitters is relevant in the
pathogenesis of tics. Several published reviews discuss the evidence supporting
individual neurotransmitter abnormalities in Tourette syndrome.84,85 In general,
data used to support a particular neurotransmitter hypothesis are derived from
clinical responses to specific classes of medications; genetic protocols; CSF, blood,

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TICS AND TOURETTE SYNDROME

or urine measurements; imaging protocols (magnetic resonance spectroscopy,

PET, single-photon emission computed tomography [SPECT]); and a limited
number of neurochemical assays on postmortem brain tissues.
Strong neurochemical evidence in Tourette syndrome supports a dopaminergic
abnormality, either presynaptic and postsynaptic dysfunctions, or a favored
intrasynaptic abnormality involving the phasic (stimulus-induced) release of
dopamine.86 Despite this claim, investigations in humans and animal models have
identified imbalances in other neurotransmitter systems. Thus, when trying to
determine a primary neurotransmitter abnormality in Tourette syndrome, it is
important to recognize that within complex integrated circuits, a change in one
neurotransmitter has a significant effect on the function of other interconnected
transmitters. Additionally, within a multitransmitter interconnected system, a
successful pharmacotherapy does not necessarily indicate that the primary
neurotransmitter abnormality is being targeted.

TREATMENT
The establishment of an effective therapeutic plan requires the careful initial
assessment of tics, determining the presence of co-occurring issues, and clarifying
the resulting impairment of each issue. Further, it is essential to clarify whether
tics or associated problems, such as ADHD, OCD, anxiety, school problems, or
behavioral disorders, represent the greatest impairment.
The first step in treatment (FIGURE 3-2) is education of the patient, his/her
family, and the school or workplace about the diagnosis, its potential coexisting
issues, and indications for therapy. Tics have no cure and fluctuate, and supportive

FIGURE 3-2
Approaches to the treatment of tics.
VMAT-2 = vesicular monoamine transporter-2.
a
Approved by the US Food and Drug Administration for the treatment of tics.
b
Medications are under investigation.
c
Medications are not available in the United states.

948 AUGUST 2019

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care is often sufficient for many individuals with milder tics. Specific criteria for KEY POINTS
initiating behavioral or pharmacologic tic-suppressing therapy include the
● It is important to
presence of psychosocial problems (eg, loss of self-esteem; peer problems; recognize that within a
difficulty participating in academic, work, family, social, and after-school multitransmitter
activities), tic-induced musculoskeletal/physical difficulties, and disruption of interconnected system,
classroom/work settings. The goal of treatment is to reduce tics to a degree at a successful
pharmacotherapy does not
which they are no longer causing significant problems.
necessarily indicate that the
primary neurotransmitter
Nonpharmacologic Treatments abnormality is being
Randomized blinded controlled trials have established the safety and efficacy of targeted.
habit reversal training for tics. Various practice guidelines have also suggested
● The establishment of an
that habit reversal training should be the first-line intervention for tics. effective therapeutic plan
The treatment program now known as CBIT includes three major for Tourette syndrome and
components: (1) awareness training to make the patient more aware of his/her tics requires careful initial
tics and the premonitory urge, (2) competing response training to provide a assessment of tics,
determining the presence of
substitutive behavior to perform as soon as the tic or urge appears, and (3) co-occurring issues, and
functional intervention (self-monitoring, relaxation training, and contingency clarifying the resulting
management) to help identify changes in daily activities that could be beneficial impairment of each issue.
in reducing tics.87,88 CBIT has been shown to be beneficial in several large studies
● The first step in treatment
and is particularly appealing given its safety and lack of side effects. Recognizing
of Tourette syndrome is
a deficiency of trained therapists, the use of telemedicine and home-based education of the patient,
parent-directed therapy are being assessed. Exposure and response prevention, his/her family, and the
another behavioral technique, asks the patient to experience the urge to tic while school or workplace about
the diagnosis, its potential
actively suppressing tics.
coexisting issues, and
Many families and patients with tics have been attracted to the use of various indications for therapy.
complementary or alternative medicines,89–92 including numerous natural
supplements (eg, vitamins B, C, and E; magnesium; calcium; flaxseed and fish oil; ● Specific criteria for
omega-3 fatty acids; and herbal medicines). To date, however, evidence regarding initiating behavioral or
pharmacologic tic-
the efficacy or safety of complementary or alternative medicine treatments for tics suppressing therapy include
is limited. Acupuncture, self-hypnosis, and plum blossom needle therapy also have the presence of psychosocial
very limited support. A randomized controlled trial with biofeedback failed to problems, tic-induced
produce a clinical effect greater than placebo. Since many complementary or musculoskeletal/physical
difficulties, and disruption of
alternative medicines are pursued independent of a physician’s suggestion, an classroom/work settings.
active and open discussion of these therapies is recommended.
● Various practice
Pharmacotherapy guidelines have suggested
that habit reversal training,
Recommendations regarding the sequence of pharmacologic therapy vary. In
more specifically
general, a two-tiered approach to the use of pharmacotherapy is recommended Comprehensive Behavioral
for treating tics with use of tier 1 medications for milder tics and use of tier 2 Intervention for Tics (CBIT)
medications reserved for more difficult to control symptoms (FIGURE 3-2). should be the first-line
Therapeutic agents should initially be prescribed at their lowest effective dosage intervention for tics.

and gradually increased as needed. Patients should be carefully followed and ● In general, a two-tiered
have periodic evaluations assessing medication efficacy, side effects, and the approach to the use of
requirement for continued therapy. Recognizing that treatment is symptomatic, pharmacotherapy is
if tics remain under good control for a significant period, a gradual taper of the recommended for treating
tics, with use of tier 1
medication during a nonstressful time should be considered. Currently, only medications for milder tics
pimozide, haloperidol, and aripiprazole have US Food and Drug Administration and use of tier 2 medications
(FDA) approval for use as tic-suppressing agents. The extent of supporting reserved for more difficult
evidence for medications has been reviewed, and individual drug selection is to control symptoms.
often based on physician experience.91

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TICS AND TOURETTE SYNDROME

TIER 1 MEDICATIONS. As a category, tier 1 medications are less effective in

suppressing tics but have fewer and generally less significant side effects.
Medications in this category typically include clonidine, guanfacine, topiramate,
clonazepam, and baclofen. Therapeutically, the two α-adrenergic agonists
(clonidine and guanfacine) have beneficial effects for both tic suppression and
treatment of ADHD.93 A study comparing extended-release guanfacine to placebo
did not, however, confirm a clinically meaningful effect size within the
guanfacine group.94 The efficacy of anticonvulsants is varied; topiramate, a
broad-spectrum anticonvulsant medication, was superior to placebo in reducing
tics,95 whereas levetiracetam was not beneficial.96 Clonazepam is often
prescribed for tics, despite limited studies confirming its tic-suppressing effect.
Baclofen, a GABA-B receptor agonist, has been variably effective as a treatment
for Tourette syndrome.97

TIER 2 MEDICATIONS. As a category, tier 2 medications are more effective in

suppressing tics than tier 1 medications but are associated with more significant
side effects that frequently limit their usefulness. Medications in this category
include the dopamine receptor antagonists (typical and atypical antipsychotics)
and the vesicular monoamine transporter-2 inhibitors. Several recent reviews
provide updates on the efficacy and safety of these therapies.98,99 Long-term side
effects seen in patients receiving either typical or atypical antipsychotics include
weight gain, sedation, drowsiness, hyperprolactinemia, extrapyramidal symptoms,
including tardive dyskinesia, and QTc prolongation. It has been suggested that
tardive dyskinesia is less common in patients with Tourette syndrome treated
with atypical antipsychotics as compared to typical antipsychotics.
Typical antipsychotics are primary dopamine antagonists that are further
subdivided based on their effect on either the D1 or D2 receptor. The two
FDA-approved antipsychotics in this category, pimozide and haloperidol, are
both D2 antagonists. Pimozide is generally preferred because of fewer side
effects. Sulpiride and tiapride have been beneficial in European trials but are
not available in the United States. A new D1 receptor antagonist, ecopipam, has been
effective in small Tourette syndrome trials in both adults and children.100
Fluphenazine, a combined D1 and D2 receptor inhibitor, has also been shown to be
effective in several small studies and a retrospective chart review.101
Atypical antipsychotics are characterized by a relatively greater affinity for
5-hydroxytryptamine 2 (5-HT2) receptors than for D2 receptors, a reduced
potential for extrapyramidal side effects, and a possible benefit for behavioral
comorbidities (anxiety, mood, disruptive behaviors). In this category, aripiprazole
and risperidone are the two most widely studied medications for tics.98
Aripiprazole, FDA approved for tics, has a different mechanism from the
others, being a partial agonist at dopamine receptors.
Vesicular monoamine transporter-2 inhibitors exert their effect by blocking
the transport of dopamine into presynaptic vesicles, thereby depleting levels at
the synaptic terminal. Tetrabenazine has been shown to be beneficial in
open-label trials,98 although concerns exist about its use in individuals with
depression and suicidality. Two new vesicular monoamine transporter-2
inhibitors approved for use in tardive dyskinesia are currently being evaluated
for the treatment of tics. Deutetrabenazine, a deuterated form of tetrabenazine,
has a longer half-life and improved absorption. Valbenazine, a purified parent
drug of the (+)-α-isomer of tetrabenazine, has a half-life of about 24 hours.

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Preliminary studies suggest that both valbenazine and deutetrabenazine have KEY POINT
fewer side effects than tetrabenazine, but which will be more effective for tic
● Deep brain stimulation is a
suppression remains undetermined. stereotactic treatment that
has significant potential for
Other Medications the treatment of tics.
Several small studies and case reports have suggested that cannabinoids may
have a beneficial effect on tics in patients with Tourette syndrome.102,103
Pharmacologic approaches have included smoking marijuana or using extracts
from the cannabis plant, including Δ-9-tetrahydrocannibinol (THC),
cannabidiol, and nabiximols (combinations of THC and cannabidiol). The most
common side effects are sedation, dizziness, headaches, a “high” (euphoria
feeling), red eyes, increased appetite, psychosis, depression, and cognitive
impairment.84 Several reviews, however, have emphasized the lack of evidence
with regard to the use of cannabinoids and the requirement for additional
testing. A second investigative approach to cannabinoid therapy involves
attempts to modulate the brain’s existing endocannabinoid system.
Botulinum toxin has a beneficial chemodenervation effect on severe localized
tics (eg, violent head thrusts), dystonic motor tics, and vocal tics and reduces the
premonitory sensory component (CASE 3-2).104,105

Brain Stimulation
Repetitive transcranial magnetic stimulation is a noninvasive technique that
uses brief repetitive intense magnetic fields generated by a coil placed over the
scalp to produce an electromagnetic field in the underlying brain region. Several
small trials in Tourette syndrome using low-frequency inhibiting repetitive
transcranial magnetic stimulation (1 Hz) suggest that it can have a beneficial
effect, especially if the supplementary motor area is targeted.106 A single
double-blind randomized placebo trial, however, showed no significant
difference between active and sham treatment.107 A small study using cathodal
transcranial direct current stimulation was unsuccessful in two-thirds of patients
with severe tics.108
Deep brain stimulation is a stereotactic treatment that has significant potential
for the treatment of tics.109,110 The centromedian parafascicular complex of the
thalamus and anteromedial globus pallidus internus have been the most
commonly stimulated sites, but the optimal target has yet to be determined.
Although most reports describe a beneficial effect, interpretation is confounded
by variations in methodologies, differences in complications, variable use of
standard outcome measures, and the lack of a control population. Suggested
criteria for the use of deep brain stimulation in patients with tics include
the following:

u Disabling tics with a Yale Global Tic Severity Scale score of more than 35/50
u Failed behavioral therapy (CBIT)
u Failed medication trials from pharmacologic groups including α-adrenergic agonists
(guanfacine, clonidine) and dopamine antagonists (including one typical and one
atypical antipsychotic), plus one additional category (vesicular monoamine
transporter-2 inhibitors)
u Evaluation by a multidisciplinary team (eg, neurologist, neurosurgeon, psychiatrist,
neuropsychologist, deep brain stimulation programmer)
u Treated and stable comorbid conditions110

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TICS AND TOURETTE SYNDROME

Deep brain stimulation for patients younger than 18 years of age should have
additional institutional approval (CASE 3-2).

CONCLUSION
Tourette syndrome is a heterogeneous disorder with variable and fluctuating
motor and vocal tics as well as frequent co-occurring neuropsychiatric

CASE 3-2 A 19-year-old man was referred for a second opinion regarding the
treatment of Tourette syndrome. He was diagnosed with Tourette
syndrome at 8 years of age. His history included numerous intermittent
and fluctuating motor tics (ocular deviations, forceful head jerks,
shoulder shrugs, facial and body contortions, abdominal jerks, hitting,
jumping, and copropraxia) and vocal tics (coprolalia, echolalia, palilalia,
shouts, and screams).
Over the past several weeks, his tics had dramatically increased without
a clear precipitating event. Both motor and vocal tics were occurring every
few minutes. The motor tics were extremely forceful and complex and
included violent head flexion and extension movements that were causing
persistent neck discomfort. Recent x-rays of his neck were normal. His
vocal tics were very loud and interfered with his social activities. He had
recently left college and returned home because of his discomfort.
He was on 20 mg/d aripiprazole after clonidine, guanfacine, pimozide,
haloperidol, and risperidone had failed to control his tics. He was also on
sertraline and clonazepam for anxiety and obsessive-compulsive disorder.
On examination, he was extremely anxious and had frequent motor tics,
including very painful exaggerated head thrusts, and coprolalia.
Neurologic examination showed marked discomfort with neck flexion and
extension and cervical spine tenderness. Tone, strength, sensation, and
reflexes were normal.

COMMENT Although many tics have a benign course, a sudden worsening of

symptoms, such as in this patient, is not unusual. Exacerbations are often
associated with increased stress, fatigue, anxiety, illness, or the use of
certain medications. At times, however, no clear precipitating event may
be identified. As in this patient, tics can be extremely violent, and
movements of the head and neck can cause cervical dislocations,
myelopathies, and subdural hematomas. Tics that are potentially self-
injurious require immediate attention.
Both typical and atypical antidepressants had failed for this patient, but
he had never been prescribed a trial of a vesicular monoamine
transporter-2 inhibitor, which he was then treated with. Because of the
potential for further self-injury and the need for gradual adjustment of his
medications, he also received cervical muscle botulinum toxin therapy. If
further treatment is required, deep brain stimulation is a promising
therapeutic option.

952 AUGUST 2019

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conditions. While tics are the defining symptom, for some, the presence of
comorbid conditions may be a greater impairment. Providing education
to the affected individual and others in his or her life is essential. If tics
are causing psychosocial or physical problems or frequent disruptions within
the school, home, or work environment, behavioral and pharmacologic
therapies may be beneficial. Tics have no cure; behavioral therapy (CBIT) is
considered first-line therapy, and pharmacotherapy should be based on tic
severity. If required, appropriate therapies should be initiated for co-occurring
conditions. Ongoing follow-up is essential to monitor the patient’s progress,
adjust therapy, and assess for side effects. Tourette syndrome is currently
believed to be a polygenic inherited disorder, and the discovery of additional
susceptibility genes is expected. Although controversy regarding the precise
anatomic localization and neurotransmitter abnormality is ongoing, progress is
being made. It is expected that a better understanding of the genetics and
pathophysiologic mechanism in Tourette syndrome will lead to improved care
and newer therapies.

VIDEO LEGENDS
VIDEO 3-1 VIDEO 3-4
Tourette syndrome. Video shows a boy with Dystonic, vocal, and holding (blocking) tics. Video
Tourette syndrome demonstrating frequent shows a boy with Tourette syndrome exhibiting a
blinking, alternating facial contractions, tongue dystonic extension of his neck associated with
protrusions, and mouth openings. repetitive expiratory grunting sounds. In addition, he
links.lww.com/CONT/A284 demonstrates a holding (blocking) tic, during which
time he stops breathing and is completely motionless.
Reproduced with permission from Singer HS.3 links.lww.com/CONT/A287
© 2016 Elsevier.
Reproduced with permission from Singer HS.3
VIDEO 3-2 © 2016 Elsevier.
Dystonic tics. Video shows a girl exhibiting facial
tics manifested by repetitive sustained contractions VIDEO 3-5
of facial muscles, resulting in grimacing and neck Complex motor and phonic tics. Video shows a
muscle contractions typical of dystonic tics. 17-year-old girl with severe Tourette syndrome
links.lww.com/CONT/A285 exhibiting complex motor tics and loud screaming
phonic tics.
Reproduced with permission from Singer HS.3 links.lww.com/CONT/A288
© 2016 Elsevier.
Reproduced with permission from Singer HS.3
VIDEO 3-3 © 2016 Elsevier.
Repetitive complex movements. Video shows a
boy with Tourette syndrome displaying repetitive, VIDEO 3-6
complex movements produced by contractions of Complex motor and phonic tics. Video shows a boy
his shoulder and trunk muscles, preceded by an with severe Tourette syndrome exhibiting complex
intense premonitory sensation of a chill. motor and loud phonic tics, including coprolalia.
links.lww.com/CONT/A286 links.lww.com/CONT/A289
Reproduced with permission from Singer HS.3 Reproduced with permission from Singer HS.3
© 2016 Elsevier. © 2016 Elsevier.

USEFUL WEBSITE
TOURETTE ASSOCIATION OF AMERICA
The Tourette Association of America provides
educational materials and information about
research efforts, support groups, and other
services to assist patients and their families
in coping with the problems associated with
Tourette syndrome.
tourette.org

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TICS AND TOURETTE SYNDROME

REFERENCES

1 Gilles dela Tourette G. Étude sur une affection 14 Banaschewski T, Woerner W, Rothenberger A.
nerveuse caractèrisée par de l’incoordination Premonitory sensory phenomena and suppressibility
motrice accompagnée d’écholalie et de coprolalie of tics in Tourette syndrome: developmental
(jumping, latah, myriachit). Paris: Aux bureaux du aspects in children and adolescents. Dev Med
Progrès médical : V.-A. Delahaye et Lecrosnier; Child Neurol 2003;45(10):700–703. doi:10.1017/
1885. 68 p. (Publications du Progrès médical). S0012162203001294.
2 Kushner HI. Medical fictions: the case of the 15 Prado HS, Rosário MC, Lee J, et al. Sensory
cursing marquise and the (re)construction of phenomena in obsessive-compulsive disorder and
Gilles de la Tourette’s syndrome. Bull Hist Med tic disorders: a review of the literature. CNS Spectr
1995;69(2):224–254. 2008;13(5):425–432. doi:10.1017/S1092852900016606.
3 Singer HS. Tics and Tourette syndrome. In: Singer 16 Shprecher DR, Gannon K, Agarwal N, et al. Elucidating
HS, Mink J, Gilbert DL, Jankovic J. Movement the nature and mechanism of tic improvement in
disorders in childhood. 2nd ed. London, UK: tourette syndrome: a pilot study. Tremor Other
Elsevier, 2016:81–109. Hyperkinet Mov (N Y) 2014;4:217. doi:10.7916/
D8TH8JQQ.
4 Cavanna AE, Robertson MM, Critchley HD. Catatonic
signs in Gilles de la Tourette syndrome. Cogn 17 Groth C, Mol Debes N, Rask CU, et al. Course of
Behav Neurol 2008;21(1):34–37. doi:10.1097/ Tourette syndrome and comorbidities in a
WNN.0b013e318165a9cf. large prospective clinical study. J Am Acad
5 Robertson MM, Trimble MR, Lees AJ. Self-injurious Child Adolesc Psychiatry 2017;56(4):304–312.
behaviour and the Gilles de la Tourette syndrome: doi:10.1016/j.jaac.2017.01.010.
a clinical study and review of the literature. 18 Erenberg G, Cruse RP, Rothner AD. The natural
Psychol Med 1989;19(3):611–625. doi:10.1017/ history of Tourette syndrome: a follow-up study.
S0033291700024211. Ann Neurol 1987;22(3):383–385. doi:10.1002/
6 Cheung MY, Shahed J, Jankovic J. Malignant ana.410220317.
Tourette syndrome. Mov Disord 2007;22(12): 19 Pappert EJ, Goetz CG, Louis ED, et al. Objective
1743–1750. doi:10.1002/mds.21599. assessments of longitudinal outcome in Gilles de la
7 Freeman RD, Zinner SH, Müller-Vahl KR, et al. Tourette’s syndrome. Neurology 2003;61(7):
Coprophenomena in Tourette syndrome. 936–940. doi:10.1212/01.WNL.0000086370.10186.7C.
Dev Med Child Neurol 2009;51(3):218–227.
20 Jankovic J, Gelineau-Kattner R, Davidson A.
doi:10.1111/j.1469-8749.2008.03135.x.
Tourette’s syndrome in adults. Mov Disord 2010;
8 Robertson MM, Eapen V, Singer HS, et al. Gilles 25(13):2171–2175. doi:10.1002/mds.23199.
de la Tourette syndrome. Nat Rev Dis Primers
21 Schaefer SM, Chow CA, Louis ED, Robakis D. Tic
2017;3:16097. doi:10.1038/nrdp.2016.97.
exacerbation in adults with Tourette syndrome: a
9 Lin H, Katsovich L, Ghebremichael M, et al. case series. Tremor Other Hyperkinet Mov (N Y)
Psychosocial stress predicts future symptom 2017;7:450. doi:10.7916/D8FF3Z1Q.
severities in children and adolescents with
22 Eapen V, Lees AJ, Lakke JP et al. Adult-onset tic
Tourette syndrome and/or obsessive-compulsive
disorders. Mov Disord 2002;17(4):735–740.
disorder. J Child Psychol Psychiatry 2007;48(2):
doi:10.1002/mds.10180.
157–166. doi:10.1111/j.1469-7610.2006.01687.x.
23 Kompoliti K, Goetz CG. Hyperkinetic movement
10 Hoekstra PJ, Steenhuis MP, Kallenberg CG,
disorders misdiagnosed as tics in Gilles de la
Minderaa RB. Association of small life events with
Tourette syndrome. Mov Disord 1998;13(3):
self reports of tic severity in pediatric and adult tic
477–480. doi:10.1002/mds.870130317.
disorder patients: a prospective longitudinal study.
J Clin Psychiatry 2004;65(3):426–431. 24 Mahone EM, Bridges D, Prahme C, Singer HS.
Repetitive arm and hand movements (complex
11 Horesh N, Zimmerman S, Steinberg T, et al. Is
motor stereotypies) in children. J Pediatr 2004;
onset of Tourette syndrome influenced by life
145(3):391–395. doi:10.1016/j.jpeds.2004.06.014.
events? J Neural Transm (Vienna) 2008;115(5):
787–793. doi:10.1007/s00702-007-0014-3. 25 Van Borsel J, Tetnowski JA. Fluency disorders in
genetic syndromes. J Fluency Disord 2007;32(4):
12 Cohrs S, Rasch T, Altmeyer S, et al. Decreased
279–296. doi:10.1016/j.jfludis.2007.07.002.
sleep quality and increased sleep related
movements in patients with Tourette’s syndrome. 26 Baizabal-Carvallo JF, Jankovic J. The clinical features
J Neurol Neurosurg Psychiatry 2001;70(2):192–197. of psychogenic movement disorders resembling
doi:10.1136/jnnp.70.2.192. tics. J Neurol Neurosurg Psychiatry 2014;85(5):
573–575. doi:10.1136/jnnp-2013-305594.
13 Kwak C, Dat Vuong K, Jankovic J. Premonitory
sensory phenomenon in Tourette’s syndrome. 27 American Psychiatric Association. Diagnostic and
Mov Disord 2003;18(12):1530–1533. doi:10.1002/ statistical manual of mental disorders, 5th ed
mds.10618. (DSM-5). Washington, DC: American Psychiatric
Association, 2013.

954 AUGUST 2019

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

28 Jankovic J, Mejia NI. Tics associated with other 42 Leivonen S, Scharf JM, Mathews CA, et al.
disorders. Adv Neurol 2006;99:61–68. Parental psychopathology and Tourette
syndrome/chronic tic disorder in offspring: a
29 Kim DD, Barr AM, Chung Y, et al. Antipsychotic-
nationwide case–control study. J Am Acad Child
associated symptoms of Tourette syndrome: a
Adolesc Psychiatry 2017;56(4):297–303.e4.
systematic review. CNS Drugs 2018;32(10):
doi:10.1016/j.jaac.2017.01.009.
917–938. doi:10.1007/s40263-018-0559-8.
43 Hirschtritt ME, Lee PC, Pauls DL, et al. Lifetime
30 Friedland S, Walkup JT. Meta-assurance: no tic
prevalence, age of risk, and genetic relationships
exacerbation caused by stimulants. J Am Acad
of comorbid psychiatric disorders in Tourette
Child Adolesc Psychiatry 2015;54(9):706–708.
syndrome. JAMA Psychiatry 2015;72(4):325–333.
doi:10.1016/j.jaac.2015.06.018.
doi:10.1001/jamapsychiatry.2014.2650.
31 Saccomani L, Fabiana V, Manuela B, Giambattista
44 Cavanna AE, Rickards H. The psychopathological
R. Tourette syndrome and chronic tics in a
spectrum of Gilles de la Tourette syndrome.
sample of children and adolescents. Brain Dev
Neurosci Biobehav Rev 2013;37(6):1008–1015.
2005;27(5):349–352. doi:10.1016/j.
doi:10.1016/j.neubiorev.2012.10.011.
braindev.2004.09.007.
45 Storch EA, Merlo LJ, Lack C, et al. Quality of life in
32 Definitions and classification of tic disorders.
youth with Tourette’s syndrome and chronic tic
The Tourette Syndrome Classification Study
disorder. J Clin Child Adolesc Psychol 2007;36(2):
Group. Arch Neurol 1993;50(10):1013–1016.
217–227. doi:10.1080/15374410701279545.
33 Leckman JF, Riddle MA, Hardin MT, et al. The Yale
46 Channon S, Pratt P, Robertson MM. Executive
Global Tic Severity Scale: initial testing of a
function, memory, and learning in Tourette’s
clinician-rated scale of tic severity. J Am Acad
syndrome. Neuropsychology 2003;17(2):247–254.
Child Adolesc Psychiatry 1989;28(4):566–573.
doi:10.1037/0894-4105.17.2.247.
doi:10.1097/00004583-198907000-00015.
47 Khalifa N, Knorring AL. Psychopathology in a
34 Cavanna AE, Schrag A, Morley D, et al. The Gilles
Swedish population of school children with tic
de la Tourette syndrome—quality of life scale
disorders. J Am Acad Child Adolesc Psychiatry
(GTS-QOL): development and validation.
2006;45(11):1346–1353. doi:10.1097/01.
Neurology 2008;71(18):1410–1416. doi:10.1212/01.
chi.0000251210.98749.83.
wnl.0000327890.02893.61.
35 Woods DW, Piacentini J, Himle MB, Chang S. 48 Stiede JT, Alexander JR, Wellen B, et al.
Premonitory Urge for Tics Scale (PUTS): initial Differentiating tic-related from non-tic-related
psychometric results and examination of the impairment in children with persistent tic
premonitory urge phenomenon in youths with tic disorders. Compr Psychiatry 2018;87:38–45.
disorders. J Dev Behav Pediatr 2005;26(6): doi:10.1016/j.comppsych.2018.07.017.
397–403. doi:10.1097/00004703-200512000-00001. 49 Comings DE, Comings BG. A controlled study of
36 Kurlan R, McDermott MP, Deeley C, et al. Prevalence Tourette syndrome. I. Attention-deficit disorder,
of tics in schoolchildren and association with learning disorders, and school problems. Am J
placement in special education. Neurology 2001; Hum Genet 1987;41(5):701–741.
57(8):1383–1388. doi:10.1212/WNL.57.8.1383. 50 Termine C, Luoni C, Fontolan S, et al. Impact of
37 Robertson MM. The prevalence and epidemiology co-morbid attention-deficit and hyperactivity
of Gilles de la Tourette syndrome. Part 2: tentative disorder on cognitive function in male children
explanations for differing prevalence figures in with Tourette syndrome: a controlled study.
GTS, including the possible effects of Psychiatry Res 2016;243:263–267. doi:10.1016/j.
psychopathology, aetiology, cultural psychres.2016.06.048.
differences, and differing phenotypes.
51 Huckeba W, Chapieski L, Hiscock M, Glaze D.
J Psychosom Res 2008;65(5):473–486.
Arithmetic performance in children with Tourette
doi:10.1016/j.jpsychores.2008.03.007.
syndrome: relative contribution of cognitive and
38 Scharf JM, Miller LL, Gauvin CA, et al. Population attentional factors. J Clin Exp Neuropsychol 2008;
prevalence of Tourette syndrome: a systematic 30(4):410–420. doi:10.1080/13803390701494970.
review and meta-analysis. Mov Disord 2015;30(2):
52 Stewart SE, Illmann C, Geller DA, et al. A
221–228. doi:10.1002/mds.26089.
controlled family study of attention-deficit/
39 Knight T, Steeves T, Day L, et al. Prevalence of tic hyperactivity disorder and Tourette’s disorder.
disorders: a systematic review and J Am Acad Child Adolesc Psychiatry 2006;45(11):
meta-analysis. Pediatr Neurol 2012;47(2):77–90. 1354–1362. doi:10.1097/01.chi.0000251211.36868.fe.
doi:10.1016/j.pediatrneurol.2012.05.002.
53 Martino D, Ganos C, Pringsheim TM. Tourette
40 Canitano R, Vivanti G. Tics and Tourette syndrome and chronic tic disorders: the clinical
syndrome in autism spectrum disorders. Autism spectrum beyond tics. Int Rev Neurobiol 2017;
2007;11(1):19–28. doi:10.1177/1362361307070992. 134:1461–1490. doi:10.1016/bs.irn.2017.05.006.
41 Meier SM, Dalsgaard S, Mortensen PB, et al. 54 Gaze C, Kepley HO, Walkup JT. Co-occurring
Mortality risk in a nationwide cohort of psychiatric disorders in children and adolescents
individuals with tic disorders and with tourette with Tourette syndrome. J Child Neurol 2006;
syndrome. Mov Disord 2017;32(4):605–609. 21(8):657–664. doi:10.1177/08830738060210081301.
doi:10.1002/mds.26939.

CONTINUUMJOURNAL.COM 955

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

TICS AND TOURETTE SYNDROME

55 Lombroso PJ, Scahill L. Tourette syndrome and 69 Kirov R, Kinkelbur J, Banaschewski T, Rothenberger
obsessive–compulsive disorder. Brain Dev 2008; A. Sleep patterns in children with attention-
30(4):231–237. doi:10.1016/j.braindev.2007.09.001. deficit/hyperactivity disorder, tic disorder,
and comorbidity. J Child Psychol Psychiatry
56 Rickards H, Robertson M. A controlled study of
2007;48(6):561–570. doi:10.1111/j.1469-7610.
psychopathology and associated symptoms in
2007.01729.x.
Tourette syndrome. World J Biol Psychiatry 2003;
4(2):64–68. doi:10.3109/15622970309167953. 70 Ghosh D, Rizkala A, Khuhro A. Management of
sleep problems helps improve tic control in children
57 Storch EA, Hanks CE, Mink JW, et al. Suicidal
with Tourette Syndrome/chronic tic disorder.
thoughts and behaviors in children and
Poster presented at: 47th Child Neurology
adolescents with chronic tic disorders. Depress
Society Meeting; Chicago IL, Annals of Neurology,
Anxiety 2015;32(10):744–753. doi:10.1002/da.22357.
84: issue 522, Oct 2018, S370.
58 Budman CL, Rockmore L, Stokes J, Sossin M.
71 Wang S, Mandell JD, Kumar Y, et al. De novo
Clinical phenomenology of episodic rage in
sequence and copy number variants are strongly
children with Tourette syndrome. J Psychosom
associated with Tourette disorder and implicate
Res 2003;55(1):59–65. doi:10.1016/S0022-
cell polarity in pathogenesis. Cell Rep 2018;24(13):
3999(02)00584-6.
3544. doi:10.1016/j.celrep.2018.12.024.
59 Mol Debes NM. Co-morbid disorders in Tourette
72 Fernandez TV, State MW, Pittenger C. Tourette
syndrome. Behav Neurol 2013;27(1):7–14.
disorder and other tic disorders. In: Geschwind
doi:10.3233/BEN-120275.
DH, Paulson HL, Klein C, editors. Handbook of
60 Mathews C, Waller J, Glidden D, et al. Self injurious Clinical Neurology. Amsterdam, the Netherlands:
behaviour in Tourette syndrome: correlates Elsevier, 2018:343–354.
with impulsivity and impulse control. J Neurol
73 Brainstorm Consortium; Anttila V, Bulik-Sullivan B,
Neurosurg Psychiatry 2004;75(8):1149–1155.
et al. Analysis of shared heritability in common
doi:10.1136/jnnp.2003.020693.
disorders of the brain. Science 2018;360(6395):
61 Silvestri PR, Baglioni V, Cardona F, Cavanna AE. 048991. doi:10.1126/science.aap8757.
Self-concept and self-esteem in patients with 74 Mataix-Cols D, Isomura K, Pérez-Vigil A, et al.
chronic tic disorders: a systematic literature review. Familial risks of Tourette syndrome and chronic
Eur J Paediatr Neurol 2018;22(5):749–756. tic disorders. A population-based cohort study.
doi:10.1016/j.ejpn.2018.05.008. JAMA Psychiatry 2015;72(8):787–793. doi:10.1001/
62 Cavanna AE, Robertson MM, Critchley HD. jamapsychiatry.2015.0627.
Schizotypal personality traits in Gilles de la 75 Pauls DL, Abramovitch A, Rauch SL, Geller DA.
Tourette syndrome. Acta Neurol Scand 2007;116(6): Obsessive-compulsive disorder: an integrative
385–391. doi:10.1111/j.1600-0404.2007.00879.x. genetic and neurobiological perspective. Nat Rev
63 Ghanizadeh A, Mosallaei S. Psychiatric disorders and Neurosci 2014;15(6):410–424. doi:10.1038/nrn3746.
behavioral problems in children and adolescents 76 Georgitsi M, Willsey AJ, Mathews CA, et al.
with Tourette syndrome. Brain Dev 2009;31(1): The genetic etiology of Tourette syndrome:
15–19. doi:10.1016/j.braindev.2008.03.010. large-scale collaborative efforts on the precipice
64 Jankovic J, Kwak C, Frankoff R. Tourette’s syndrome of discovery. Front Neurosci 2016;10:351.
and the law. J Neuropsychiatry Clin Neurosci 2006; doi:10.3389/fnins.2016.00351.
18(1):86–95. doi:10.1176/jnp.18.1.86. 77 Scharf JM, Moorjani P, Fagerness J, et al. Lack of
65 Singer HS, Schuerholz LJ, Denckla MB. Learning association between SLITRK1var321 and Tourette
difficulties in children with Tourette syndrome. syndrome in a large family-based sample.
J Child Neurol 1995;10(suppl 1):S58–S61. doi:10.1177/ Neurology 2008;70(16 pt 2):1495–1496. doi:10.1212/
08830738950100S112. 01.wnl.0000296833.25484.bb.

66 Pérez-Vigil A, Fernández de la Cruz L, Brander G, 78 Lai Wing Sun K, Correia JP, Kennedy TE. Netrins:
et al. Association of Tourette syndrome and versatile extracellular cues with diverse
chronic tic disorders with objective indicators functions. Development 2011;138(11):2153–2169.
of educational attainment: a population-based doi:10.1242/dev.044529.
sibling comparison study. JAMA Neurol 2018; 79 Browne HA, Hansen SN, Buxbaum JD, et al.
75(9):1098–1105. doi:10.1001/jamaneurol.2018.1194. Familial clustering of tic disorders and
67 Lee WT, Huang HL, Wong LC, et al. Tourette obsessive-compulsive disorder. JAMA
syndrome as an independent risk factor for Psychiatry 2015;72(4):359–366. doi:10.1001/
subsequent sleep disorders in children: a jamapsychiatry.2014.2656.
nationwide population-based case–control Study. 80 Yu D, Mathews CA, Scharf JM, et al. Cross-
Sleep 2017;40(3). doi:10.1093/sleep/zsw072. disorder genome-wide analyses suggest a
complex genetic relationship between
68 Ghosh D, Rajan PV, Das D, et al. Sleep disorders in
Tourette’s syndrome and OCD. Am J Psychiatry
children with Tourette syndrome. Pediatr Neurol
2015;172(1):82–93. doi:10.1176/appi.ajp.2014.
2014;51(1):31–35. doi:10.1016/j.pediatrneurol.
13101306.
2014.03.017.

956 AUGUST 2019

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

81 Martino D, Zis P, Buttiglione M. The role of 94 Murphy TK, Fernandez TV, Coffey BJ, et al.
immune mechanisms in Tourette syndrome. Extended-release guanfacine does not show a
Brain Res 2015;1617:126–143. doi:10.1016/j. large effect on tic severity in children with
brainres.2014.04.027. chronic tic disorders. J Child Adolesc
Psychopharmacol 2017;27(9):762–770.
82 Gilbert DL, Mink JW, Singer HS. A pediatric
doi:10.1089/cap.2017.0024.
neurology perspective on pediatric autoimmune
neuropsychiatric disorder associated with 95 Yang CS, Zhang LL, Zeng LN, et al. Topiramate for
streptococcal infection and pediatric acute-onset Tourette’s syndrome in children: a meta-analysis.
neuropsychiatric syndrome. J Pediatr 2018;199: Pediatr Neurol 2013;49(5):344–350. doi:10.1016/j.
243–251. doi:10.1016/j.jpeds.2018.04.035. pediatrneurol.2013.05.002.
83 Singer HS. Autoantibody-associated movement 96 Smith-Hicks CL, Bridges DD, Paynter NP, Singer
disorders in children: proven and proposed. HS. A double blind randomized placebo control
Semin Pediatr Neurol 2017;24(3):168–179. trial of levetiracetam in Tourette syndrome.
doi:10.1016/j.spen.2017.08.003. Mov Disord 2007;22(12):1764–1770. doi:10.1002/
mds.21615.
84 Augustine F, Singer HS. Merging the pathophysiology
and pharmacotherapy of tics. Tremor Other 97 Singer HS, Wendlandt J, Krieger M, Giuliano J.
Hyperkinet Mov 2018;8:595. doi:10.7916/D8H14JTX. Baclofen treatment in Tourette syndrome: a
85 Singer HS. The neurochemistry of Tourette double-blind, placebo-controlled, crossover
syndrome. In: Martino D, Leckman JF, editors. trial. Neurology 2001;56(5):599–604. doi:10.1212/
Tourette syndrome. London, UK: Oxford University WNL.56.5.599.
Press, 2013. oxfordmedicine.com/view/10. 98 Mogwitz S, Buse J, Wolff N, Roessner V. Update
1093/med/9780199796267.001.0001/med- on the pharmacological treatment of tics with
9780199796267-chapter-13. Accessed June 5, dopamine-modulating agents. ACS Chem
2019. Neurosci 2018;9(4):651–672. doi:10.1021/
86 Singer HS, Szymanski S, Giuliano J, et al. Elevated acschemneuro.7b00460.
intrasynaptic dopamine release in Tourette’s 99 Quezada J, Coffman KA. Current approaches
syndrome measured by PET. Am J Psychiatry and new developments in the pharmacological
2002;159(8):1329–1336. doi:10.1176/appi. management of Tourette syndrome. CNS
ajp.159.8.1329. Drugs 2018;32(1):33–45. doi:10.1007/s40263-017-
87 Piacentini J, Woods DW, Scahill L, et al. Behavior 0486-0.
therapy for children with Tourette disorder: a 100 Gilbert DL, Murphy TK, Jankovic J, et al.
randomized controlled trial. JAMA 2010;303(19): Ecopipam, a D1 receptor antagonist, for treatment
1929–1937. doi:10.1001/jama.2010.607. of tourette syndrome in children: a randomized,
88 Wile DJ, Pringsheim TM. Behavior therapy for placebo-controlled crossover study. Mov Disord
Tourette syndrome: a systematic review and Aug;33(8):1272–1280. doi:10.1002/mds.27457.
meta-analysis. Curr Treat Options Neurol 2013; 101 Wijemanne S, Wu LJ, Jankovic J. Long-term
15(4):385–395. doi:10.1007/s11940-013-0238-5. efficacy and safety of fluphenazine in patients
89 Kompoliti K, Fan W, Leurgans S. Complementary with Tourette syndrome. Mov Disord 2014;29(1):
and alternative medicine use in Gilles de la 126–130. doi:10.1002/mds.25692.
Tourette syndrome. Mov Disord 2009;24(13): 102 Whiting PF, Wolff RF, Deshpande S, et al.
2015–2019. doi:10.1002/mds.22724. Cannabinoids for medical use: a systematic
90 Sharp AN, Singer HS. Standard, complementary, review and meta-analysis. JAMA 2015;313(24):
and future treatment options for tics. Curr Dev 2456–2473. doi:10.1001/jama.2015.6358.
Disord Rep 2018;5(2):101–107. doi:10.1007/s40474- 103 Kanaan AS, Jakubovski E, Müller-Vahl K. Significant
018-0138-1. tic reduction in an otherwise treatment-resistant
91 Pringsheim T, Holler-Managan Y, Okun MS, et al. patient with Gilles de la Tourette syndrome
Comprehensive systematic review summary: following treatment with nabiximols. Brain Sci
treatment of tics in people with Tourette 2017 26;7(5): pii: E47. doi:10.3390/brainsci7050047.
syndrome and chronic tic disorders. Neurology 104 Kwak CH, Hanna PA, Jankovic J. Botulinum toxin
2019;92(19):907–915. doi:10.1212/WNL. in the treatment of tics. Arch Neurol 2000;57(8):
0000000000007467. 1190–1193. doi:10.1001/archneur.57.8.1190.
92 Kumar A, Duda L, Mainali G, et al. A comprehensive 105 Vincent DA Jr. Botulinum toxin in the management
review of Tourette syndrome and complementary of laryngeal tics. J Voice 2008;22(2):251–256.
alternative medicine. Curr Dev Disord Rep 2018; doi:10.1016/j.jvoice.2006.08.014.
5(2):95–100. doi:10.1007/s40474-018-0137-2.
106 Grados M, Huselid R, Duque-Serrano L. Transcranial
93 Singer HS. Treatment of tics and tourette syndrome. magnetic stimulation in Tourette syndrome: a
Curr Treat Options Neurol 2010;12(6):539–561. historical perspective, its current use and the
doi:10.1007/s11940-010-0095-4. influence of comorbidities in treatment
response. Brain Sci 2018;8(7). pii: E129.
doi:10.3390/brainsci8070129.

CONTINUUMJOURNAL.COM 957

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TICS AND TOURETTE SYNDROME

107 Landeros-Weisenberger A, Mantovani A, 109 Martinez-Ramirez D, Jimenez-Shahed J,

Motlagh MG, et al. Randomized sham controlled Leckman JF, et al. Efficacy and safety of deep
double-blind trial of repetitive transcranial brain stimulation in Tourette syndrome: the
magnetic stimulation for adults with severe International Tourette Syndrome Deep Brain
Tourette syndrome. Brain Stimul 2015;8(3): Stimulation Public Database and Registry. JAMA
574–581. doi:10.1016/j.brs.2014.11.015. Neurol 2018;75(3):353–359. doi:10.1001/jamaneurol.
2017.4317.
108 Behler N, Leitner B, Mezger E, et al. Cathodal
tDCS over motor cortex does not improve 110 Schrock LE, Mink JW, Woods DW, et al. Tourette
Tourette syndrome: lessons learned from a case syndrome deep brain stimulation: a review and
series. Front Behav Neurosci 2018;12:194. updated recommendations. Mov Disord 2015;
doi:10.3389/fnbeh.2018.00194. 30(4):448–471. doi:10.1002/mds.26094.

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 Tremor REVIEW ARTICLE


By Elan D. Louis, MD, MS, FAAN 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


ABSTRACT VIDEO CONTENT
PURPOSE OF REVIEW: Tremor may be defined as an involuntary movement that A V AI L A B L E O N L I N E

is rhythmic (ie, regularly recurrent) and oscillatory (ie, rotating around a

central plane) and may manifest in a variety of ways; accordingly, tremor
has a rich clinical phenomenology. Consequently, the diagnosis of tremor CITE AS:
disorders can be challenging, and misdiagnoses are common. The goal of CONTINUUM (MINNEAP MINN)
this article is to provide the reader with straightforward approaches to the 2019;25(4, MOVEMENT DISORDERS):
959–975.
Downloaded from http://journals.lww.com/continuum by BhDMf5ePHKbH4TTImqenVM+rzkOt3HMm8hfkljXjBDe9RBsO9WLQvnBAJkpIOU2NjRI9B8gYNeE= on 08/03/2019

diagnosis and treatment of tremors.

Address correspondence to
Focused ultrasound thalamotomy of the ventral
RECENT FINDINGS: Dr Elan D. Louis, Yale School of
Medicine, Department of
intermediate nucleus of the thalamus is an emerging and promising therapy
Neurology, LCI 710, 15 York St,
for the treatment of essential tremor. PO Box 20818, New Haven,
CT 06520-8018,
[email protected].
SUMMARY: The evaluation should start with a detailed tremor history
followed by a focused neurologic examination, which should attend to the RELATIONSHIP DISCLOSURE:
many subtleties of tremor phenomenology. Among other things, the history Dr Louis serves on the clinical
advisory boards of CADENT
and examination are used to establish whether the primary tremor is an Therapeutics and SAGE
action tremor (ie, postural, kinetic, or intention tremor) or a resting tremor. Therapeutics, Inc and receives
The clinician should then formulate two sets of diagnoses: disorders in publishing royalties from
Elsevier for Merritt’s Neurology.
which action tremor is the predominant tremor versus those in which
resting tremor is the predominant tremor. Among the most common of UNLABELED USE OF
PRODUCTS/INVESTIGATIONAL
the former type are essential tremor, enhanced physiologic tremor, USE DISCLOSURE:
drug-induced tremor, dystonic tremor, primary writing tremor, orthostatic Dr Louis discusses the
tremor, and cerebellar tremor. Parkinson disease is the most common unlabeled/investigational use of
alprazolam, benzodiazepines,
disorder of resting tremor. This article details the clinical features of each carbidopa/levodopa,
of these disorders, as well as those of additional tremor disorders. clonazepam, gabapentin,
primidone, and topiramate for
the treatment of essential
tremor; trihexyphenidyl for the
treatment of dystonic tremor;
INTRODUCTION acetazolamide, baclofen,

H
carbamazepine, clonazepam,
umans have been documenting their tremors for thousands of ethosuximide, and phenytoin
years.1 Tremor is defined as an involuntary movement that is both for the treatment of orthostatic
rhythmic (ie, regularly recurrent) and oscillatory (ie, rotating tremor; pregabalin for the
treatment of neuropathic
around a central plane).2 Tremor may manifest in a vast array of tremor; benzodiazepines for the
ways. As such, the clinical phenomenology is very rich, and it treatment of parkinsonian
resting tremor; and
should be no surprise that numerous methods for classifying tremors exit. Thus,
phenobarbital to treat the side
tremors may be classified based on speed (ie, frequency measured in hertz), effects of acute nausea and
regions of the body affected (eg, arm, voice, head), activation state in which unsteadiness that occur as
a result of other treatments
tremor manifests (eg, when the body part is at rest), occurrence of associated for tremor.
medical conditions (eg, hyperthyroidism), and the brain region from which the
tremor arises (eg, basal ganglia, cerebellum). Because there are many ways to
classify and divide tremor, a large nomenclature applies to tremor. The richness © 2019 American Academy
of the clinical phenomenology and its associated nomenclature can be daunting of Neurology.

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TREMOR

to the clinician. The goal of this article is to provide the reader with a basic
approach to the diagnosis and management of the patient with tremor. This
approach includes a medical history, a focused neurologic examination,
diagnosis, and, finally, treatment.

APPROACH TO EVALUATING THE PATIENT WITH TREMOR

The approach to the patient involves a medical history followed by a
neurologic examination.

Medical History
The first set of questions should be directed at determining whether the tremor is
one that occurs with action or at rest. It is best to begin with an initial question
that is open-ended (eg, “Can you tell me about your tremor?” or “What type
of tremor do you have?” or “When do you notice tremor?”). After this initial
question, more specific questions, such as “Does your hand shake when you are
writing?” or “Does your hand shake when you are trying to eat something?” may
be asked to further ascertain whether the tremor is an action tremor or a resting
tremor. This is then followed by additional questions that elicit information on
the following items:

u The body areas that seem to be shaking (eg, arms, head, voice)
u The limb positions that bring on the tremor and, conversely, those that seem to lessen it
u The age at which tremor began
u How the tremor has changed over the years
u The presence of other involuntary movements
u The presence of other neurologic symptoms aside from tremor
u The presence of pulling sensations or discomfort in the body part that is shaking
u The use of medications that seem to produce or exacerbate tremor
u Dietary factors that exacerbate tremor (eg, coffee and other forms of caffeine)
u Symptoms of thyroid diseases (eg, weight loss, heat intolerance)
u Family history of “shaking” or tremor (eg, the presence of affected first-degree relatives
is often reported by patients with essential tremor, among whom the pattern of
inheritance may resemble that of an autosomal dominant disease)

Neurologic Examination
After the medical history, a detailed and focused neurologic examination should
be performed. First, the examiner should ask the patient to raise his or her arms
against gravity, with the palms down in front and then in the wing-beat position
with the hands facing one another in the midline. If a postural tremor is present
during sustained arm extension, the examiner should assess the following:

u Whether the tremor is regularly recurrent and oscillatory

u Which joints are involved (eg, elbow, wrist, metacarpophalangeal joints) and in what
directions (eg, for the wrist, flexion-extension, pronation-supination)
u Whether the tremor in each arm is synchronous with that of the other arm (ie, in phase or
out of phase)
u Whether the tremor has a reemergent quality (ie, initially absent and the time it takes
to emerge)

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u Whether the tremor is accompanied by abnormal postures KEY POINTS
u Whether any features of psychogenic tremor are present, including distractibility (ie, a
decrease or cessation of tremor when volitionally performing a task [eg, finger tapping ● Tremors are involuntary
with opposite hand]), entrainment (ie, the tremor may be brought into a specific rhythm), or movements that are both
suggestibility (ie, the examiner may induce tremor with certain stimuli) rhythmic and oscillatory.

● An initial step in
Next, the examiner should attempt to elicit kinetic tremor—a tremor that
evaluating patients with
occurs during voluntary movements. Thus, the examiner may ask the patient to tremor is to determine
perform the finger-nose-finger maneuver, pour water between cups, draw whether the tremor is
spirals, or write a sentence. The examiner should assess the following items: primarily present at rest or
with activity.
u Does the tremor have an intentional component (ie, does the tremor worsen as the limb
● The key feature of
approaches a target [eg, during the finger-nose-finger maneuver])?
essential tremor is kinetic
u Are dystonic movements or postures present (eg, do some of the fingers flex, extend, or tremor.
twist during the finger-nose-finger maneuver)?
● The kinetic tremor of
u What is the relative severity of the kinetic tremor that is being observed to that which was
essential tremor is typically
observed during sustained posture (above)?
slightly asymmetric.

Next, the examiner should assess whether there is any tremor at rest in the ● Approximately one-half
patient’s arms or legs. Tremor at rest in the arms can be assessed while the patient of patients with essential
is seated, standing, walking, and lying down. Resting tremor in the legs can be tremor exhibit intention
tremor during the finger-
assessed while the patient is seated or lying down. In addition, tremor while nose-finger maneuver.
standing (ie, orthostatic tremor) may be assessed while the patient is standing in
a stationary position.
Finally, the examiner may assess for tremor in the head (ie, neck) (while the
patient is seated and lying down), jaw (with the patient’s mouth closed and then
with the mouth held open), facial muscles (eg, forehead, cheek), chin, tongue,
and voice (during sustained phonation and during speech).

DIAGNOSIS
The history and physical examination are first used to establish whether the main
type of tremor is an action tremor (ie, postural, kinetic, or intention tremor) or a
tremor at rest. Indeed, this is a primary point of divergence: those diseases in
which action tremor is the predominant tremor versus those diseases in which
resting tremor is the predominant tremor, each of which will be discussed in
turn, beginning with the former because these are both of a larger variety and
more prevalent.

DISEASES IN WHICH ACTION TREMOR IS PREDOMINANT

This section discusses the most commonly encountered diseases and those
diseases that have a particularly distinctive set of clinical features.

Essential Tremor
The central clinical feature of essential tremor is kinetic tremor. This is generally
observed during numerous activities of daily living, ranging from eating to
writing, and may be elicited on neurologic examination during a variety of
maneuvers (eg, finger-nose-finger maneuver, spiral drawing, pouring water
between two cups) (VIDEO 4-1, links.lww.com/CONT/A278). Rather than being
totally symmetric, the tremor is usually slightly asymmetric, affecting one arm
more than the other. In approximately 5% of patients, this tremor is markedly
asymmetric or unilateral.3 In approximately 50% of patients with essential

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TREMOR

tremor, the tremor has an intentional component, with observed worsening as

the patient approaches the target during the finger-nose-finger maneuver.
Interestingly, intention tremor in essential tremor is not limited to the arms; in
fact, 10% of patients exhibit such tremor in their neck when their head
approaches a target. This may be observed when the patient lowers his or
her head, for example, to meet an approaching cup or a spoon. In addition to
kinetic tremor, patients with essential tremor often have a postural tremor (ie,
tremor that occurs when the body part is held motionless against the force of
gravity), although the amplitude of this tremor is generally lower than that of
the kinetic tremor.4 The tremor in the two arms is generally out of phase,
creating a seesaw effect when the arms are being held in a wing-beat position.
This lack of phasic synchrony accounts for the observation that functionality may
improve when two hands rather than one hand are used to hold a glass or cup
because the tremors in each arm cancel one another out to some degree.
The postural tremor of essential tremor is generally of greatest amplitude
at the wrist joint and generally involves wrist flexion-extension rather than
rotation-supination, although this is not always the case.5 Tremor at rest, without
other cardinal features of parkinsonism such as bradykinesia or rigidity, occurs in
approximately 1% to 35% of patients with essential tremor, depending on the
method of ascertaining the cases (eg, population, brain repository), but in
contrast to that of Parkinson disease (PD), it is a late feature and has only been
observed in the arm (ie, does not involve the leg).

CASE 4-1 A 68-year-old woman presented with tremor, which she noticed when
holding an eating utensil and when writing. The tremor had begun about
5 years previously, and it seemed to be getting worse, little by little, with
each passing year. Her father and one of her two sisters had had a similar
tremor. Although she was unaware of it herself, one of her children told
her he sometimes noticed a mild, side-to-side head tremor.
She had previously been treated with propranolol but was unable to
tolerate more than 80 mg/d because her heart rate dropped below
60 beats/min. Furthermore, this dose had resulted in only a modest (ie, 10%)
reduction in her tremor. She had also taken primidone, 50 mg in the morning,
but the initial dose made her nauseated, and she did not take it again.
On examination, the tremor was noticeable when she drew spirals and
performed the finger-nose-finger maneuver, and it worsened slightly as she
approached her nose during this maneuver. She also had a postural tremor,
but it was considerably less than the tremor observed while she used her
hands to write. She was started on topiramate 25 mg/d and was gradually
increased to 200 mg/d, resulting in a moderate reduction in the amplitude
of her tremor.

COMMENT This case illustrates the slowly progressive and often familial nature of
essential tremor, the fact that the central defining clinical feature of
essential tremor is kinetic tremor, and the presence of head tremor in some
patients with essential tremor, particularly women.

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 The motor features of essential tremor are not limited to tremor. Another KEY POINTS
motor feature of essential tremor is gait ataxia, which may be brought out by
● The postural tremor in
asking patients to walk tandem. The number of missteps in essential tremor is essential tremor is generally
in excess of that seen in control subjects of similar age. In most patients with out of phase; this can create
essential tremor, this ataxia is mild, although in some patients it may reach moderate a seesaw effect when the
severity. In general, the ataxia results in a reduction in patients’ confidence in patients’ arms are held in
the wing-beat position.
balance and a mild but significant increase in the number of near falls and falls in
patients with essential tremor compared with age-matched controls.6 ● Resting tremor may occur
In most individuals with essential tremor, the tremor worsens over time, in patients with severe or
and several patterns of progression have been described; the two most common long-standing essential
are late-life onset (after the age of 60) with steady progression and early-life tremor, but it is restricted
to the arms.
onset (ie, before the age of 40) with mild, stable tremor for many years that then,
in the sixties and onward, progresses steadily (CASE 4-1). The least common ● Neck tremor is several
pattern is that of early-life onset with marked worsening over the ensuing times more common in
decade. Surprisingly few prospective, longitudinal natural history studies of women with essential
tremor than in men with
essential tremor exist; however, the best estimates are that the average annual essential tremor.
increase in tremor severity from baseline is between 3.1% and 5.3%, and the
median annual increase from baseline is between 1.8% and 2.0%.7
Over time, the tremor has a tendency to spread beyond the upper limbs as
patients develop cranial tremors involving the neck (most common), voice, or
jaw. These cranial tremors are particularly prevalent in women with essential
tremor, among whom the prevalence of neck tremor is several times higher than
that of men with essential tremor.8 Neck tremor in essential tremor often begins
as a unidirectional tremor, either “no-no” (ie, horizontal) or “yes-yes” (ie, vertical);
with time this can evolve into a more complex, multidirectional tremor.9
Unless it is particularly severe, the neck tremor, which is a postural tremor,
should resolve while the patient is lying on his or her back with the head fully
at rest. An interesting feature of the neck tremor is that patients with essential
tremor are often unaware of its presence (ie, they have an agnosia for it),
particularly when it is mild. The jaw tremor is more often seen when the patient’s
mouth is open rather than closed; the latter is more a feature of the jaw tremor
found in patients with PD.
The presence of dystonic posturing in essential tremor cases is controversial,
although it is likely that a mild dystonic posture in the tremulous arm in some
cases does not preclude a diagnosis of essential tremor, especially when the
dystonic posture is a late finding in a patient with essential tremor with
long-standing and severe tremor.2
The overdiagnosis of essential tremor is common. Indeed, studies show that
30% to 50% of “essential tremor” cases have diagnoses other than essential
tremor, with many of these patients having PD or dystonia.10 Differentiation
from PD may be achieved, however, by the absence in essential tremor of
rigidity, hypomimia, and bradykinesia accompanied by decrement (ie, patients
with essential tremor have absence of a sequential decrement in amplitude
during finger taps). The characteristics of the tremor are also important in
distinguishing a patient with essential tremor from one with PD. The presence of
isolated resting tremor, isolated postural tremor (ie, postural tremor with
minimal kinetic tremor), postural tremor predominantly involving the
metacarpophalangeal joints rather than the wrist, or postural tremor characterized
by greater wrist rotation than wrist flexion and extension are indicators that
the likely diagnosis is PD rather than essential tremor. Reemergent tremor is a

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TREMOR

type of postural tremor that commences after a brief latency of several seconds
and is another feature of PD. The use of dopamine transporter (DAT) imaging
can be useful in distinguishing patients with essential tremor from those with
parkinsonism, although its use is supplemental to clinical information derived
from the history and examination.11,12
Aside from a mild dystonic posture, noted above, dystonic postures, movements,
or tremor are not features of essential tremor. In addition, dystonic tremor
is often neither rhythmic nor oscillatory. The patient should be assessed for
the presence of neck dystonia, which is characterized by head tilt or rotation,
hypertrophy of the sternocleidomastoid or other neck muscles, the presence of a
tremor null-point, or a sensory trick by history (ie, a maneuver such as touching
the chin or back of the head that lessens the tremor).
Scanning or dysarthric speech or nystagmus may be present in patients with
spinocerebellar ataxias; however, these are not features of essential tremor.
Hyperthyroidism can be assessed by clinical history (eg, symptoms of weight loss
or heat intolerance) as can the use of medications (eg, lithium, prednisone,
valproate) or other substances (eg, tobacco, caffeine) that may produce or
exacerbate action tremor.
A difficult differential is between that of mild essential tremor and enhanced
physiologic tremor, although the presence of neck tremor should exclude
the latter. Computerized tremor analysis with inertial loading can assist with this
differential, although this is often not available outside of research-oriented
tertiary referral centers. In patients with a tremor of central origin (eg, essential
tremor), the primary tremor frequency should not change with inertial
loading; in patients with enhanced physiologic tremor, the frequency will
reduce. Other features that support an essential tremor diagnosis are the
presence of essential tremor in one or more first-degree relatives. A reported
reduction in tremor with ethanol use is often used as a diagnostic tool; however,
this is not very specific and of limited utility. Indeed, patients with most
tremor disorders often experience a reduction in tremor following ethanol
consumption.
The main motivators for treatment in essential tremor are embarrassment
and functional disability. Beta-blockers (especially propranolol) and primidone,
alone or in combination, are the most effective pharmacologic agents, although
many patients choose to discontinue these medications because of their limited
efficacy and side effects.
Propranolol has been used in doses up to 360 mg/d, although doses in excess
of 80 mg/d to 100 mg/d are rarely tolerated in patients who are elderly, with
the main issue being bradycardia. A conservative starting dose is 20 mg/d,
and this is gradually increased as noted above. Asthma is only a relative
contraindication to the use of propranolol, and propranolol use should be
considered on a case-by-case basis. Primidone can be given in doses up to
1500 mg/d, although lower doses (eg, starting with 25 mg and gradually
increasing to 500 mg/d) are often effective. Acute nausea or unsteadiness is
observed in approximately 25% of patients, irrespective of the starting dose, and
in the author’s experience, preloading with phenobarbital (ie, 30 mg 2 times a
day for 3 days) is one method to avoid this unwanted side effect. Propranolol
and primidone may result in mild to moderate reduction in the amplitude of
tremor in 30% to 70% of patients with essential tremor. If the tremor is mild, it
may be abolished.

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 Other agents that have been used include topiramate, gabapentin, and KEY POINTS
benzodiazepines (alprazolam or clonazepam). IM botulinum toxin injections
● Neck tremor is always
for wrist tremor are also beneficial for some patients.13 pathologic. It is not a feature
Deep brain stimulation (DBS) surgery (ventral intermediate nucleus of the of enhanced physiologic
thalamus) and gamma knife surgery (thalamus) markedly reduce the severity of the tremor.
tremor in patients with severe pharmacologically refractory tremor, with reductions
● Although limb tremor may
in upper limb tremor often of greater magnitude than can be achieved with the
be present, head tremor
use of medication. More recently, focused ultrasound thalamotomy (ventral should not be a feature of
intermediate nucleus) has demonstrated similar effects, although long-term drug-induced action tremor.
benefits are not fully known.14 These surgeries are generally reserved for patients
who have failed to adequately respond to appropriate pharmacologic trials.

Enhanced Physiologic Tremor

This type of action tremor occurs in the hands in virtually all people. The
postural and kinetic components of this tremor are generally several hertz faster
than those seen in essential tremor, and the amplitude is generally lower than that
seen in essential tremor, with the major caveat that at disease onset patients with
essential tremor have a low-amplitude tremor that may be difficult to distinguish
from enhanced physiologic tremor.15 In contrast to essential tremor, there is no
intentional component on the finger-nose-finger maneuver. Enhanced physiologic
tremor may be evident in the voice and hands; however, it is not present in the
neck; neck tremor is always pathologic. A mild ratchetlike quality to arm
movements or mild cogwheeling during passive arm movement may be present,
but this is not accompanied by rigidity. On quantitative computerized tremor
analysis, inertial loading reveals a pattern that is consistent with peripherally
generated rather than centrally generated tremor (ie, an observed reduction in the
primary tremor frequency with inertial loading).
Many of these individuals present to the doctor because they are also anxious;
hence, treatment should begin by reassuring them that they do not appear to
have either PD or essential tremor. Beta-blockers at a low dose (eg, propranolol
up to 60 mg/d or used in a 10-mg to 60-mg dose on an as-needed basis) and
judicious use of benzodiazepines may be effective.

Drug-Induced Action Tremor

A variety of medications may produce or exacerbate action tremors, and the
severity of these tremors may range from mild to severe (VIDEO 4-2, links.lww.
com/CONT/A279).16 These medications are inclusive of but not limited
to immunosuppressants (eg, cyclosporine), hormones (eg, levothyroxine),
antiepileptics (eg, valproic acid), and methylxanthines (eg, theophylline).
Several features can differentiate drug-induced action tremor from other forms
of action tremor. First, historically, the onset of tremor follows the initiation of
the medication. Second, there may be a dose-response relationship such that
higher doses of the medication are associated with greater tremor amplitude.
Third, discontinuing the medication should ultimately result in complete
resolution of tremor. Fourth, head tremor should not be a feature of drug-
induced action tremor. Finally, in the setting of a stable medication dose, the
tremor should not progressively worsen; this stands in contrast to the tremors of
essential tremor or PD, which progressively worsen with time.
The mechanisms that underlie drug-induced action tremors are not fully
understood, although these tremors are thought to represent a form of enhanced

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TREMOR

physiologic tremor. Additional evidence also exists that drug-induced action

tremor could be mediated through central mechanisms.17
The treatment of this type of tremor is to lower the dose of or discontinue the
causative medication. When this is not possible, beta-blockers (eg, propranolol,
10 mg/d to 360 mg/d) may be of some benefit.

Dystonic Tremor
A range of tremors may occur among patients who have been diagnosed with
dystonia, and a challenging differential is between the diagnosis of essential tremor
and the diagnosis of dystonic tremor.18–20 In patients who have been diagnosed with
dystonia, tremor may occur both in limbs that exhibit dystonic postures or
movements and in limbs that do not exhibit these. Furthermore, the tremor may
occur in limbs at rest as well as in limbs that are active (ie, during sustained posture
or during voluntary movements). What complicates matters is that, as noted above,
patients with long-standing and clinically advanced essential tremor may develop
mild dystonic posturing of the hand during arm extension. As a result, considerable
debate exists as to where essential tremor as a disease ends and where dystonia as a
disease begins and vice versa. One further point is that the tremor in patients
with dystonia is not always regularly recurrent. This raises the issue in these
patients as to whether the “tremor” is indeed, in the strictest sense of the word, a
tremor. This author sometimes uses the term tremulous rather than tremor to
describe such movements.
With this uncertainly in mind, when a clinician is confronted with an
individual patient, several issues should be taken into consideration. First, what

CASE 4-2 A 56-year-old woman presented with a chief complaint of head tremor
with some mild associated right-sided neck pain. The pain had begun
10 years previously. For 4 years, she had also felt an intermittent pulling
sensation in the neck region. She further noted that her head had been
turning to one side and sometimes it even felt a little shaky. She did not
report any tremor in her hands.
On examination, she had a mild to moderate postural tremor of the
right arm, with a little bit of flexed posturing of her index and middle
fingers. On the finger-nose-finger maneuver, no tremor was observable.
Her right sternocleidomastoid muscle was slightly hypertrophic, and her
head tended to preferentially turn to the left and shake intermittently;
the shakiness was irregular. This head tremor persisted even when she lay
down on her back on the examining table.
She was treated with IM botulinum toxin injections to several neck
muscles, which helped diminish her symptoms, although they did not
resolve completely.

COMMENT This case illustrates several important features of dystonic head (neck)
tremor: the tremor is often nonrhythmic, and it often persists in the
recumbent position. Furthermore, it may be accompanied by pain or pulling
sensations of the neck.

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are the features of the tremor itself? Second, does the patient exhibit dystonic KEY POINTS
movements or dystonic postures? In terms of the first question, the tremor itself
● The tremor in dystonia
in patients with dystonia may not be rhythmic or oscillatory (VIDEO 4-3, links. may be neither rhythmic nor
lww.com/CONT/A280); these features distinguish the tremor from that of oscillatory.
essential tremor. In terms of the second question, patients with dystonia may
exhibit a variety of sustained postures and/or twisting movements involving the ● Dystonic head tremor
often persists after the
neck, which do not occur in essential tremor. Patients may also exhibit one or
patient lies on his or her
more of a variety of dystonic postures during arm extension (eg, difficulty back; this is generally not
maintaining both hands strictly parallel while outstretched in a karate chop true of essential tremor.
position, thumb flexion during arm extension). These should not occur in
essential tremor unless the disease is advanced; furthermore, in essential tremor ● Primary writing tremor is a
tremor that occurs mainly
they should be of mild severity relative to the tremor itself. while writing but not during
Tremor in the neck or voice is another issue worth discussing. Patients with other tasks that involve the
neck dystonia (ie, torticollis) may also have neck tremor. This tremor is generally hands.
neither strictly rhythmic nor oscillatory (VIDEO 4-3, links.lww.com/CONT/
A280), and it may be accompanied by twisting or tilting of the neck, jerklike or
sustained neck deviation, hypertrophy of neck muscles, or pulling sensations or
pain in the neck (CASE 4-2). These clinical features do not occur in patients with
essential tremor. In addition, in contrast to the head tremor of essential tremor,
which generally resolves when the patient is lying on his or her back, dystonic
head tremor often persists while the patient is recumbent.21 Voice tremor may
also be present in patients with vocal cord dystonia (ie, spasmodic dysphonia)
but, in contrast to the voice tremor of essential tremor, is often associated with
voice breaks or strangulated speech.
The treatment of dystonic tremor includes the use of medications used to treat
dystonia (ie, trihexyphenidyl in a dose up to 10 mg/d in adults, baclofen up to
60 mg/d), benzodiazepines, or beta-blockers. For dystonic neck tremor, other
options include IM botulinum toxin injections or DBS surgery.

Primary Writing Tremor

Primary writing tremor is a task-specific tremor that occurs primarily or only
during writing and not at all or less so during other tasks that involve the use
of the hands.22 The current definition of primary writing tremor excludes
patients who have dystonic postures with hand tremor while writing (ie,
dystonic writing tremor). The disorder may be sporadic or inherited as an
autosomal dominant trait. Primary writing tremor has a frequency similar to that
seen in patients with essential tremor (ie, 4 Hz to 8 Hz), and it is relieved by
ethanol consumption in 30% to 50% of patients. The mechanisms that underlie
primary writing tremor are unclear; it is debated whether it represents a variant
of essential tremor or a variant of focal dystonia, and there are families in which
all three conditions are indeed present.23
Treatment of primary writing tremor includes the use of propranolol, primidone,
and anticholinergic medications (trihexyphenidyl 2 mg/d to 10 mg/d) as well as
the use of writing and hand orthotic devices. IM injections of botulinum toxin have
exhibited some benefit as well, as has stereotactic surgery in a limited number of
patients.22–24 Finally, some patients switch to writing with the other hand.23

Orthostatic Tremor
This is a rare syndrome characterized by unsteadiness on standing and high-
frequency tremor in the legs.25,26 The typical onset is in the sixth decade of life.

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TREMOR

Although most cases are sporadic, rare familial cases have been reported. Patients
more often note unsteadiness while standing rather than tremor per se. Because of
these symptoms, patients typically avoid situations in which they have to stand
still (eg, standing in lines). Indeed, they are eventually forced to sit down or walk
after a short time (ie, seconds to minutes), depending on the severity of the
disease. As the disease progresses, the tremor may begin to encroach upon the
stance phase of walking. On examination, the patient may see or feel a rapid
(14 Hz to 16 Hz) fine tremor in the calves. Due to its high frequency and low
amplitude, orthostatic tremor may be difficult to appreciate on visual inspection.
In some cases, the tremor may be heard when a stethoscope is placed over the
affected calf, sounding like a distant helicopter. The EMG indicates the presence
of a 14 Hz to 16 Hz synchronous tremor in the leg (especially in calf ) muscles.
A slower, larger-amplitude tremor may also be superimposed on top of this
tremor, perhaps representing a subharmonic of the high-frequency tremor, and
this can be more disabling for patients than the faster tremor. Numerous cases
occur in the setting of comorbid PD.
The treatment of orthostatic tremor is challenging.25 Many agents have
been used and often to little avail. The most commonly used agents are
clonazepam (0.5 mg/d to 4 mg/d), gabapentin (300 mg/d to 1800 mg/d), and
carbidopa/levodopa (25 mg/100 mg per day to 250 mg/1000 mg per day). Many
other agents have also been tried, including propranolol, primidone, phenytoin,
carbamazepine, ethosuximide, baclofen, and acetazolamide, although given the
rarity of the disorder no large-scale clinical trials have been conducted. DBS
surgery can also provide benefit to some patients.

Cerebellar Tremor
The term cerebellar tremor has classically been used to describe tremor that can
occur in patients with spinocerebellar ataxias and other classical disorders
originating in the cerebellum.27 In modern times, cerebellar tremor has
become equated exclusively with intention tremor.28 This is a tremor that
occurs with goal-directed movement (eg, finger-to-nose maneuver) and
worsens when approaching a target. However, cerebellar tremors (ie, tremors
of cerebellar origin) do not always present exclusively as intention tremor.
Indeed, the clinical phenomenology of tremor of cerebellar origin is
heterogeneous, and it extends beyond that of intention tremor to include
postural tremor, kinetic tremor, resting tremor, and orthostatic tremor.28 This
heterogeneity is consistent with the seminal work of Holmes,29 who described
a variety of tremors aside from intention tremor in the setting of cerebellar
lesions.30
On examination, patients with classically defined cerebellar tremor often
have other cerebellar signs, including saccadic eye movement abnormalities,
dysarthric or scanning speech, gait ataxia, and hypotonia. When these patients are
examined, it is important, although often difficult, to separate the tremor
(ie, rhythmic oscillatory movements) from problems with force and timing of
motion (ie, dysmetria); both may occur during the finger-nose-finger maneuver,
but the former generally improves with DBS surgery whereas the latter
might worsen.
A number of medications have been used to treat cerebellar tremor, although
their efficacy is limited. The most effective treatment for severe cerebellar
tremor is thalamic DBS surgery, with the caveat noted above.31

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Holmes Tremor KEY POINTS
Holmes tremor is also referred to as rubral tremor or midbrain tremor.32 In most
● In some cases, orthostatic
cases, the tremor is a unilateral and has three components: tremor at rest, tremor may be heard when a
postural tremor, and kinetic/intentional tremor, with the relative severity generally stethoscope is placed over
being such that kinetic tremor is greater than postural tremor which is greater the affected leg; the tremor
than resting tremor (VIDEO 4-4, links.lww.com/CONT/A281). The tremor is slow makes a sound like a distant
helicopter.
(<5 Hz).
In some cases, the tremor is severe and disabling and can render the affected ● The clinical
limb functionally useless. Patients generally have other neurologic signs as phenomenology of tremor
well, including hemiparesis, cranial nerve abnormalities, ataxia, hypoesthesia, of cerebellar origin is
and dystonia involving the same body region as the tremor. The tremor may occur heterogeneous, and it
extends beyond that of
in a variety of clinical settings (eg, in the setting of stroke, head trauma, or a variety intention tremor to include
of other processes, which can include multiple sclerosis), and when occurring after postural tremor, kinetic
an infarct, the tremor may arise after a latency of 1 month to 2 years. tremor, resting tremor, and
On brain imaging, a lesion is often but not always present in the pontine- orthostatic tremor.
midbrain region, affecting cerebellar outflow tracts and dopaminergic nigrostriatal ● Rubral tremor is strikingly
fibers,33 although lesions often occur elsewhere (eg, the thalamus),32,34 which asymmetric, and it has
is one of the motivations for referring to the tremor as Holmes tremor rather resting, postural, and kinetic
than rubral tremor or midbrain tremor. components.
As the dopaminergic system is involved in most cases, treatment with
● Psychogenic tremors
carbidopa/levodopa (25 mg/100 mg per day to 250 mg/1000 mg per day) has often have an abrupt onset.
been reported to be beneficial, improving all three components of tremor (ie,
resting, postural, and kinetic).32 In addition, medications that are used for the
treatment of essential tremor may be effective in alleviating the postural or
kinetic components of the tremor.32 DBS surgery has proven beneficial in some
cases as well, treating all three components of tremor.32

Psychogenic (Functional) Tremor

By history, the tremor in patients with psychogenic or functional tremor
often has an abrupt beginning with maximal tremor at onset rather than an
insidious onset followed by a slowly progressive course, as is typical of many
organic tremor disorders.35 Also, the tremor may fluctuate and have periods
of remission.
On examination, the tremor has nonphysiologic or unusual features (eg, the
tremor may exhibit variable frequency; the tremor may change direction; or
there may be an unusual combination of resting, postural, and kinetic tremors).
Positive signs may be seen that are suggestive of psychogenic tremor including
entrainment, distractibility, and suggestibility.35,36 Furthermore, many patients
show excessive exhaustion during the examination.35 Of note, during
quantitative computerized tremor analysis, inertial loading may produce a
paradoxical increase in tremor amplitude rather than the expected decrease in
amplitude that is observed with organic tremors.37
The treatment of psychogenic tremor begins with a discussion of the
diagnosis, recognition of the patient’s symptoms, and a referral to a psychiatrist
to explore underlying psychiatric issues. Some evidence exists that cognitive-
behavioral therapy is effective.38

Wilson Disease With Associated Tremor

Patients with Wilson disease may present with a wide variety of involuntary
movements, and common among these is tremor.39 Tremor is usually

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TREMOR

accompanied by other neurologic signs, although rare reports exist of isolated

tremor and even rarer reports exist of action tremor occurring in isolation.40
Although the prototypical tremor of Wilson disease is the wing-beat tremor
(ie, a proximal tremor, present while the shoulders are abducted and the arms
flexed at the elbows), it is not the most commonly observed tremor in Wilson
disease. In actuality, the tremor phenomenology is quite varied. A wide range of
tremors may occur, including kinetic, resting, postural, and intention tremors;
tremors that are symmetric or asymmetric; those that are low amplitude; others
that are of high amplitude; and those that are intermittent whereas others are
constant and progressive.41 Most of the large, published case series dealt with the
broad panoply of neurologic signs, and detailed video-based modern
characterization of the tremor phenomenology is lacking. According to one
series, 32% of patients exhibited tremor at the time of their initial presentation to
a tertiary care center41; in another report, 60% of patients exhibited tremor at
some point.42 Tremor most commonly occurs in the arms or hands, with one
study reporting 72% of patients having such a tremor39 and another study
reporting 82% of patients with this tremor type.43
Most patients present well before the age of 40 years, and the laboratory
workup may reveal a low serum ceruloplasmin level, an abnormal brain MRI
(hyperintensity on T2-weighted and fluid-attenuated inversion recovery
[FLAIR] images is characteristically present in the putamen, the most
commonly involved structure in the basal ganglia, followed by the striatum
and globus pallidus), a high 24-hour urine copper concentration, an abnormal
slit-lamp examination (ie, presence of Kayser-Fleischer rings), or elevated
liver function tests.44
Treatment with D-penicillamine, zinc, or trientine is recommended; little has
been written about the specific treatment of tremor as a neurologic sign.

Fragile X Tremor-Ataxia Syndrome

Fragile X tremor-ataxia syndrome (FXTAS) is an inherited degenerative disorder
that is associated with a broad range of neurologic symptoms and signs. The
syndrome, which primarily affects older men, is caused by a CGG repeat
expansion in the premutation range in the 50 noncoding region of the fragile X
mental retardation 1 (FMR1) gene.
As evident from the name of the disease, the core signs of FXTAS are
tremor, ataxia, and cognitive symptoms. Aside from intention tremor (noted in
70% of patients in a series of 20),45 kinetic and postural tremors are reported
to be common findings in patients with FXTAS,46 and these have variable
severity; unfortunately, their relative prevalence has not been well documented.
It deserves mention that, aside from these action tremors, resting tremor
occurs in these patients as well. In one of the initial articles on FXTAS,
Jacquemont and colleagues45 described the clinical spectrum of 20 patients,
and they documented the presence of resting tremor (in 10% of patients) in
addition to the commonly observed intention tremor (in 70% of patients).
Controlled trials evaluating symptomatic therapies for tremor have not
been reported in FXTAS. However, therapies used to treat similar tremors in
patients with essential tremor and PD have been tried with variable success;
furthermore, surgical therapy is effective for tremors associated with essential
tremor and PD and is an option for patients with FXTAS who have
medication-resistant and disabling tremors.47

970 AUGUST 2019

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Peripheral Neuropathy-Related Tremor KEY POINTS
Patients with several of the acquired and familial neuropathies may exhibit
● Wing-beat tremor is
mild-to-moderate postural and kinetic tremors of the arms.48,49 For some of considered a classic tremor
these neuropathies, such as IgM demyelinating paraproteinemic neuropathy, up in Wilson disease, but it is
to 90% of patients have been noted to exhibit such a tremor.50 These patients not the most common type
have a coexisting peripheral neuropathy in the same limb that is tremulous. of tremor in that disease.
The neuropathy and the tremor should be temporally linked, with tremor
● Although intention tremor
accompanying or following the onset of neuropathy. is common in patients with
On examination, a peripheral neuropathy characterized by weakness, wasting, fragile X tremor-ataxia
or diminished/absent deep tendon reflexes is readily apparent in the tremulous syndrome, kinetic, postural,
arm or arms. Although the severity of neuropathy correlates with the presence of and resting tremors may also
occur.
tremor,49 the severity of neuropathy does not necessarily correlate with the
severity of the tremor.51 The tremor disappears if neuropathic weakness progresses ● The resting tremor in
to the point of paralysis. Parkinson disease is
The underlying mechanisms are likely to be diverse and may involve both generally asymmetric.
central and peripheral components.52 If the tremor occurs in the setting
● In contrast to essential
of an immunoglobulin-mediated disease, then immunosuppressive or tremor, the jaw tremor of
immunomodulatory therapies, such as corticosteroids, IV immunoglobulin Parkinson disease is more
(IVIg), or plasma exchange may be used. Several studies report the use of often noted when the
patient’s mouth is closed
pregabalin (up to 450 mg/d) for the treatment of neuropathic tremor.48 The
and relaxed rather than
tremor may respond to IM botulinum toxin injections53 and to DBS surgery.54 while the patient is
speaking.
RESTING TREMOR
Entities that cause resting tremor are fewer than those that can cause kinetic
tremor. The main entities are PD and drug-induced tremor.

Parkinson Disease
Tremor in patients with PD is classically a tremor at rest. The resting tremor
is generally asymmetric, affecting one side of the body (ie, arm, leg, or both)
preferentially; it typically begins in one limb. In patients with upper limb tremor,
the tremor typically involves distal joints (eg, fingers and wrist) rather than
proximal joints (eg, elbow or shoulder). Aside from the arms, tremor may affect
the jaw, although in contrast to essential tremor, it is more often noted when
the patient’s mouth is closed and relaxed rather than while the patient is
speaking. In patients with PD, tremor rarely affects the head.
The treatment of parkinsonian resting tremor includes the use of anticholinergic
agents (trihexyphenidyl 2 mg/d to 10 mg/d), amantadine (up to 300 mg/d), as
well as carbidopa/levodopa (up to 500/2000 mg/d of carbidopa/levodopa),
dopamine agonists, and rasagiline.55,56 DBS surgery for tremor is reserved for
patients with PD who have severe tremor and who are refractory to medications.
Although resting tremor is one of the hallmark features of PD, a large proportion
of patients also have postural or kinetic tremor (or both) of the arms. Sometimes
the postural and kinetic tremors have a reemergent quality; this so-called
“reemergent tremor” surfaces after a latency of 1 or several seconds, has a
frequency that is similar to that of the resting tremor in PD, and often attains
amplitudes greater than that seen in patients with essential tremor (VIDEO 4-5,
links.lww.com/CONT/A282).57 This tremor tends to increase in severity (ie, it
crescendos) with sustained posture or during the course of repetitive movements
during which much of the limb is immobile (eg, while pouring water between
two cups, during which much of the movement is proximal rather than distal).

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TREMOR

The treatment of this type of tremor is similar to the treatment of the resting
tremor of PD, although it is less responsive to medications than resting tremor.

Drug-Induced Resting Tremor

Several medications (eg, dopamine-blocking agents [eg, haloperidol] or dopamine-
depleting agents [eg, tetrabenazine]) may cause resting tremor, which is generally
accompanied by other features of parkinsonism, such as bradykinesia and rigidity.
The tremor generally resembles a typical parkinsonian resting tremor and may even
be asymmetric, affecting one arm more than the other.58 As with other parkinsonian
tremors, the tremor may have a reemergent component as well. By the patient’s
history, the medication use should precede the onset of the tremor, and there may
be a dose-effect relationship. Unless there is an underlying disease of the basal
ganglia, stopping use of the medication should result in complete resolution of
tremor, although this may take weeks to months; rarely, it may take up to 1 year.59
The treatment of such tremor first involves the discontinuation of the causative
drug or a reduction in dosage if this is possible; although often in the setting of a
brittle underlying psychiatric problem, this is not possible.60 Carbidopa/levodopa,
amantadine, and anticholinergic agents (see dosages above) may lessen the
severity of this type of tremor and may even be used with the tremor-producing
medication if the latter cannot be discontinued.

CONCLUSION
Tremors are among the most common movement disorders. The diagnosis of
these disorders is challenging. The approach to a patient with tremor involves a
history and careful neurologic examination focused on the nuances of clinical
phenomenology. When generating the differential diagnosis, it is important to
first consider whether the primary type of tremor is an action tremor or a resting
tremor. As is true for the diagnosis of most disorders of involuntary movement,
arriving at the correct diagnosis is often based on pattern recognition.

VIDEO LEGENDS
VIDEO 4-1 VIDEO 4-4
Essential tremor. Video shows a man with essential Holmes tremor. Video show a woman with Holmes
tremor exhibiting a severe kinetic tremor while tremor exhibiting a unilateral, slow tremor at rest,
pouring water between two cups. The tremor is which worsens during sustained posture.
slightly asymmetric and is worse on the right. links.lww.com/CONT/A281
links.lww.com/CONT/A278
Courtesy of Sule Tinaz, MD, PhD.
© 2019 American Academy of Neurology. © 2019 American Academy of Neurology.

VIDEO 4-2 VIDEO 4-5

Drug-induced action tremor. Video shows a man Parkinson disease tremor. Video shows a woman
with drug-induced action tremor due to lithium with Parkinson disease exhibiting a resting tremor,
exhibiting both a postural and a kinetic tremor of primarily on the left, while seated. A reemergent
mild to moderate amplitude. tremor is apparent, emerging after several seconds
links.lww.com/CONT/A279 and then worsening, as she holds her arms in front
of her body.
Courtesy of Amar Patel, MD. links.lww.com/CONT/A282
© 2019 American Academy of Neurology.
© 2019 American Academy of Neurology.
VIDEO 4-3
Dystonic tremor. Video show a man with dystonic
tremor exhibiting a tremor in the neck that is neither
rhythmic nor oscillatory.
links.lww.com/CONT/A280
Courtesy of Sule Tinaz, MD, PhD, and Sara
Schaefer, MD.
© 2019 American Academy of Neurology.

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REFERENCES

1 Louis ED. Essential tremor. Arch Neurol 2000;57: 13 Mittal SO, Machado D, Richardson D, et al.
1522–1524. Botulinum toxin in essential hand tremor—a
randomized double-blind placebo-controlled
2 Bhatia KP, Bain P, Bajaj N, et al. Consensus
study with customized injection approach.
Statement on the classification of tremors. from
Parkinsonism Relat Disord 2018;pii:S1353-
the task force on tremor of the International
8020(18)30278–5. doi:10.1016/j.parkreldis.2018.06.019.
Parkinson and Movement Disorder Society.
Mov Disord 2018;33(1):75–87. doi:10.1002/ 14 Dallapiazza RF, Lee DJ, De Vloo P, et al. Outcomes
mds.27121. from stereotactic surgery for essential tremor.
J Neurol Neurosurg Psychiatry 2018;pii:jnnp-2018-
3 Phibbs F, Fang JY, Cooper MK, et al. Prevalence
318240. doi:10.1136/jnnp-2018-318240.
of unilateral tremor in autosomal dominant
essential tremor. Mov Disord 2009;24(1):108–111. 15 Elble RJ, Higgins C, Elble S. Electrophysiologic
doi:10.1002/mds.22113. transition from physiologic tremor to essential
tremor. Mov Disord 2005;20(8):1038–1042.
4 Louis ED. The primary type of tremor in essential
doi:10.1002/mds.20487.
tremor is kinetic rather than postural: cross-
sectional observation of tremor phenomenology 16 Morgan JC, Kurek JA, Davis JL, Sethi KD. Insights
in 369 cases. Eur J Neurol 2013;20(4):725–727. into pathophysiology from medication-induced
doi:10.1111/j.1468-1331.2012.03855.x. tremor. Tremor Other Hyperkinet Mov (N Y) 2017;
7:442. doi:10.7916/D8FJ2V9Q.
5 Sternberg EJ, Alcalay RN, Levy OA, Louis ED.
Postural and intention tremors: a detailed clinical 17 Raethjen J, Lemke MR, Lindemann M, et al.
study of essential tremor vs. Parkinson’s disease. Amitriptyline enhances the central component
Front Neurol 2013;4:51. doi:10.3389/fneur. of physiological tremor. J Neurol Neurosurg
2013.00051. Psychiatry 2001;70(1):78–82.
6 Rao AK, Gilman A, Louis ED. Balance confidence 18 Defazio G, Conte A, Gigante AF, et al. Is tremor in
and falls in nondemented essential tremor dystonia a phenotypic feature of dystonia?
patients: the role of cognition. Arch Phys Med Neurology 2015;84:1053–1059. doi:10.1212/WNL.
Rehabil 2014;95(10):1832–1837. doi:10.1016/ 0000000000001341.
j.apmr.2014.04.001.
19 Defazio G, Gigante AF, Abbruzzese G, et al. Tremor
7 Louis ED, Agnew A, Gillman A, et al. Estimating in primary adult-onset dystonia: prevalence and
annual rate of decline: prospective, longitudinal associated clinical features. J Neurol Neurosurg
data on arm tremor severity in two groups of Psychiatry 2013;84(10):404–408. doi:10.1212/
essential tremor cases. J Neurol Neurosurg WNL.0000000000001341.
Psychiatry 2011;82(7):761–765. doi:10.1136/jnnp.
20 Pandey S, Sarma N. Tremor in dystonia. Parkinsonism
2010.229740.
Relat Disord 2016;29:3–9. doi:10.1016/j.parkreldis.
8 Hardesty DE, Maraganore DM, Matsumoto JY, 2016.03.024.
Louis ED. Increased risk of head tremor in women
21 Agnew A, Frucht SJ, Louis ED. Supine head tremor:
with essential tremor: longitudinal data from the
a clinical comparison of essential tremor and
Rochester Epidemiology Project. Mov Disord
spasmodic torticollis patients. J Neurol Neurosurg
2004;19(5):529–533. doi:10.1002/mds.20096.
Psychiatry 2012;83(2):179–181. doi:10.1136/jnnp-
9 Robakis D, Louis ED. Head tremor in essential 2011-300823.
tremor: “yes-yes”, “no-no”, or “round and
22 Rana AQ, Vaid HM. A review of primary writing
round”? Parkinsonism Relat Disord 2016;22:
tremor. Int J Neurosci 2012;122(3):114–118.
98–101. doi:10.1016/j.parkreldis.2015.11.002.
doi:10.3109/00207454.2011.635827.
10 Jain S, Lo SE, Louis ED. Common misdiagnosis
23 Hai C, Yu-ping W, Hua W, Ying S. Advances in
of a common neurological disorder: how are we
primary writing tremor. Parkinsonism Relat Disord
misdiagnosing essential tremor? Arch Neurol
2010;16(9):561–565. doi:10.1016/j.parkreldis.
2006;63(8):1100–1104. doi:10.1001/archneur.
2010.06.013.
63.8.1100.
24 Papapetropoulos S, Singer C. Treatment of
11 Oravivattanakul S, Benchaya L, Wu G, et al.
primary writing tremor with botulinum toxin type
Dopamine transporter (DaT) scan utilization in a
A injections: report of a case series. Clin
movement disorder center. Mov Disord Clin
Neuropharmacol 2006;29(6):364–367.
Pract 2015;3(1):31–35. doi:10.1002/mdc3.12261.
doi:10.1097/01.WNF.0000236765.00785.9C.
12 Waln O, Wu Y, Perlman R, et al. Dopamine transporter
25 Yaltho TC, Ondo WG. Orthostatic tremor: a review
imaging in essential tremor with and without
of 45 cases. Parkinsonism Relat Disord 2014;20(7):
parkinsonian features. J Neural Transm (Vienna)
723–725. doi:10.1016/j.parkreldis.2014.03.013.
2015;122(11):1515–1521. doi:10.1007/s00702-015-
1419-z. 26 Benito-León J, Domingo-Santos Á. Orthostatic
tremor: an update on a rare entity. Tremor Other
Hyperkinet Mov (N Y) 2016;6:411. doi:10.7916/D81N81BT.

CONTINUUMJOURNAL.COM 973

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

TREMOR

27 Bodranghien F, Bastian A, Casali C, et al. 41 Starosta-Rubinstein S, Young AB, Kluin K, et al.

Consensus paper: revisiting the symptoms and Clinical assessment of 31 patients with Wilson's
signs of cerebellar syndrome. Cerebellum 2016; disease. Correlations with structural changes on
15(3):369–391. doi:10.1007/s12311-015-0687-3. magnetic resonance imaging. Arch Neurol 1987;
44(4):365–370. doi:10.1001/archneur.1987.
28 Lenka A, Louis ED. Revisiting the clinical
00520160007005.
phenomenology of “cerebellar tremor”: beyond
the intention tremor [published online ahead of 42 Machado A, Chien HF, Deguti MM, et al.
print December 18, 2018]. Cerebellum. doi:10.1007/ Neurological manifestations in Wilson’s disease:
s12311-018-0994-6. report of 119 cases. Mov Disord 2006;21(12):
2192–2196. doi:10.1002/mds.21170.
29 Holmes G. The cerebellum of man. Brain 1939;
62(1):1–30. 43 Saito T. Presenting symptoms and natural history of
Wilson disease. Eur J Pediatr 1987;146(3):261–265.
30 Holmes G. The Croonian lectures on the clinical
symptoms of cerebellar disease and their 44 Hedera P. Update on the clinical management of
interpretation. Lecture I. 1922. Cerebellum 2007; Wilson's disease. Appl Clin Genet 2017;10:9–19.
6(2):142–147. doi:10.2147/TACG.S79121.
31 Ramirez-Zamora A, Okun MS. Deep brain 45 Jacquemont S, Hagerman RJ, Leehey M, et al.
stimulation for the treatment of uncommon Fragile X premutation tremor/ataxia syndrome:
tremor syndromes. Expert Rev Neurother 2016; molecular, clinical, and neuroimaging correlates.
16(8):983–997. doi:10.1080/14737175.2016.1194756. Am J Hum Genet 2003;72(4):869–878.
doi:10.1086/374321.
32 Raina GB, Cersosimo MG, Folgar SS, et al. Holmes
tremor: clinical description, lesion localization, 46 Hall DA, O'Keefe JA. Fragile x-associated tremor
and treatment in a series of 29 cases. Neurology ataxia syndrome: the expanding clinical picture,
2016;86(10):931–938. doi:10.1212/WNL. pathophysiology, epidemiology, and update on
0000000000002440. treatment. Tremor Other Hyperkinet Mov (N Y)
2012;2:pii:tre-02-56-352-1. doi:10.7916/D8HD7TDS.
33 Goto S, Yamada K. Combination of thalamic Vim
stimulation and GPi pallidotomy synergistically 47 Leehey MA, Hagerman PJ. Fragile X-associated
abolishes Holmes' tremor. J Neurol Neurosurg tremor/ataxia syndrome. Handb Clin Neurol
Psychiatry 2004;75(8):1203–1204. doi:10.1136/ 2012;103:373–386. doi:10.1016/B978-0-444-51892-
jnnp.2003.023077. 7.00023-1.
34 Tan H, Turanli G, Ay H, Saatçi I. Rubral tremor 48 Alonso-Navarro H, Fernández-Díaz A, Martín-
after thalamic infarction in childhood. Pediatr Prieto M, et al. Tremor associated with chronic
Neurol 2001;25(5):409–412. doi:10.1016/S0887- inflammatory demyelinating peripheral neuropathy:
8994(01)00331-9. treatment with pregabalin. Clin Neuropharmacol
2008;31(4):241–244. doi:10.1097/WNF.
35 Schwingenschuh P, Deuschl G. Functional tremor.
0b013e3181585b71.
Handb Clin Neurol 2016;139:229–233. doi:10.1016/
B978-0-12-801772-2.00019-9. 49 Ahlskog MC, Kumar N, Mauermann ML, Klein CJ.
IgM-monoclonal gammopathy neuropathy and
36 Thenganatt MA, Jankovic J. Psychogenic tremor:
tremor: a first epidemiologic case control study.
a video guide to its distinguishing features.
Parkinsonism Relat Disord 2012;18(6):748–752.
Tremor Other Hyperkinet Mov (N Y) 2014;4:253.
doi:10.1016/j.parkreldis.2012.03.007.
doi:10.7916/D8FJ2F0Q.
50 Bain PG, Britton TC, Jenkins IH, et al. Tremor
37 Schwingenschuh P, Katschnig P, Seiler S, et al.
associated with benign IgM paraproteinaemic
Moving toward “laboratory-supported” criteria
neuropathy. Brain 1996;119(pt 3):789–799.
for psychogenic tremor. Mov Disord 2011;26(14):
doi:10.1093/brain/119.3.789.
2509–2515. doi:10.1002/mds.23922.
51 Dalakas MC, Teräväinen H, Engel WK. Tremor
38 Dallocchio C, Tinazzi M, Bombieri F, et al. Cognitive
as a feature of chronic relapsing and
behavioural therapy and adjunctive physical activity
dysgammaglobulinemic polyneuropathies.
for functional movement disorders (conversion
Incidence and management. Arch Neurol 1984;
disorder): a pilot, single-blinded, randomized study.
41(7):711–714. doi:10.1001/archneur.1984.
Psychother Psychosom 2016;85:381–383.
04050180033012.
doi:10.1159/000446660.
52 Pedersen SF, Pullman SL, Latov N, Brannagan TH
39 Czlonkowska A, Litwin T, Dzieżyc K, et al.
3rd. Physiological tremor analysis of patients
Characteristics of a newly diagnosed Polish cohort
with anti-myelin-associated glycoprotein
of patients with neurological manifestations of
associated neuropathy and tremor. Muscle
Wilson disease evaluated with the Unified Wilson’s
Nerve 1997;20(1):38–44. doi:10.1002/(SICI)1097-
Disease Rating Scale. BMC Neurol 2018;18(1):34.
4598(199701)20:1<38::AID-MUS5>3.0.CO;2-I.
doi:10.1186/s12883-018-1039-y.
53 Latino P, Pellicano C, Pontieri FE, Giovannelli M.
40 Frucht S, Sun D, Schiff N, et al. Arm tremor secondary
Treatment with botulinum toxin for anti-MAG
to Wilson's disease. Mov Disord 1998;13(2):
neuropathy-related arm tremor. Neurol Sci 2015;
351–353. doi:10.1002/mds.870130227.
36(2):333–334. doi:10.1007/s10072-014-1890-6.

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

54 McMaster J, Gibson G, Castro-Prado F, et al. 58 Sethi KD, Zamrini EY. Asymmetry in clinical
Neurosurgical treatment of tremor in anti- features of drug-induced parkinsonism.
myelin-associated glycoprotein neuropathy. J Neuropsychiatry Clin Neurosci 1990;2(1):64–66.
Neurology 2009;73(20):1707–1708. doi:10.1212/ doi:10.1176/jnp.2.1.64.
WNL.0b013e3181c1de66.
59 Burkhard PR. Acute and subacute drug-induced
55 Lew MF. Rasagiline treatment effects on movement disorders. Parkinsonism Relat Disord
parkinsonian tremor. Int J Neurosci 2013;123(12): 2014;20(suppl 1):S108–S112. doi:10.1016/S1353-
859–865. doi:10.3109/00207454.2013.812085. 8020(13)70027-0.
56 Elble RJ. Tremor and dopamine agonists. 60 Shuaib UA, Rajput AH, Robinson CA, Rajput A.
Neurology 2002;58(4 suppl 1):S57–S62. Neuroleptic-induced Parkinsonism: clinicopathological
doi:10.1212/WNL.58.suppl_1.S57. study. Mov Disord 2016;31(3):360–365. doi:10.1002/
mds.26467.
57 Jankovic J, Schwartz KS, Ondo W. Re-emergent
tremor of Parkinson's disease. J Neurol
Neurosurg Psychiatry 1999;67(5):646–650.

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 REVIEW ARTICLE


The Dystonias
C O N T I N UU M A UD I O By H. A. Jinnah, MD, PhD
I NT E R V I E W A V AI L A B L E
ONLINE

ABSTRACT
CITE AS:
PURPOSE OF REVIEW: This article provides a summary of the state of the art in
CONTINUUM (MINNEAP MINN)
2019;25(4, MOVEMENT DISORDERS): the diagnosis, classification, etiologies, and treatment of dystonia.
976–1000.

RECENT FINDINGS: Although many different clinical manifestations of dystonia

Address correspondence to
Dr H. A. Jinnah, Emory University,
have been recognized for decades, it is only in the past 5 years that a
Ste 6300 Woodruff Memorial broadly accepted approach has emerged for classifying them into specific
Building, 101 Woodruff Cir, subgroups. The new classification system aids clinical recognition and
Atlanta, GA 30322,
Downloaded from http://journals.lww.com/continuum by BhDMf5ePHKbH4TTImqenVLIlg0cBmue4kL2uokAnXVDW1FBurRKUopDoRCxYEDGm on 08/03/2019

[email protected]. diagnosis by focusing on key clinical features that help distinguish the
many subtypes. In the past few years, major advances have been made in
RELATIONSHIP DISCLOSURE:
the discovery of new genes as well as advances in our understanding of the
Dr Jinnah has received personal
compensation for serving on biological processes involved. These advances have led to major changes
the advisory boards of and in strategies for diagnosis of the inherited dystonias. An emerging trend is
as a consultant for Abide
Therapeutics, Inc; Allergan, Inc;
to move away from heavy reliance on the phenotype to target diagnostic
CoA Therapeutics; the testing toward a broader approach that involves large gene panels or
International Neurotoxin Society; whole exome sequencing.
the International Parkinson and
Movement Disorders Society;
Medtronic; the Parkinson's SUMMARY: The dystonias are a large family of phenotypically and
Foundation; Psyadon etiologically diverse disorders. The diagnosis of these disorders depends
Pharmaceuticals Inc; Retrophin,
Inc; and Saol Therapeutics. on clinical recognition of characteristic clinical features. Symptomatic
Dr Jinnah has received grant treatments are useful for all forms of dystonia and include oral
support from the Benign
Essential Blepharospasm
medications, botulinum toxins, and surgical procedures. Determination of
Research Foundation, Cavion, etiology is becoming increasingly important because the number of
Cure Dystonia Now, the Dystonia disorders is growing and more specific and sometimes disease-modifying
Study Group, Ipsen Group,
National Institutes of Health
therapies now exist.
(NIH), and Retrophin, Inc. He also
is principle investigator for the
Dystonia Coalition, which
receives the majority of its
support through NIH grant INTRODUCTION

T
TR001456 from the Office of Rare he dystonias are a diverse family of disorders that share an underlying
Diseases Research at the
National Center for Advancing
phenomenon of excessive contractions of specific muscle groups
Translational Sciences and leading to abnormal movements.1 Any region of the body can be
previously received support affected, and the overt manifestations depend on the severity and
through grant NS065701 from the
National Institutes of
distribution of muscles involved. In its mildest forms, abnormalities
Neurological Disorders and appear as slight distortions of otherwise normal movements. In patients who
Stroke. The Dystonia Coalition are more affected, abnormal movements have a more obvious appearance of
has received additional material
or administrative support from cramping, stiffening, jerking, or twisting. The most severe cases of dystonia
industry sponsors (Allergan, Inc are associated with fixed abnormal postures or joint deformities with
and Merz Pharmaceuticals) as
severe disability.
well as private foundations (the
American Dystonia Society, The causes of dystonia are similarly diverse.2 Some types of dystonia are
Continued on page 1000 associated with overt neuropathologic abnormalities of the brain that can be
© 2019 American Academy detected by neuroimaging or postmortem histopathologic studies, such as focal
of Neurology. lesions or degenerative changes. Some types of dystonia are acquired whereas

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others are inherited. Most cases are idiopathic with no apparent cause. This
article describes how to recognize the varying manifestations of dystonia, how
the many different subtypes are grouped, the causes and diagnostic evaluation
for the more common subtypes, and current treatment strategies.

DIAGNOSIS OF DYSTONIA
Dystonia is easy to recognize in its most classic expressions, in which patients
exhibit twisting movements and abnormal postures affecting many regions of
the body. Less severe expressions are often misdiagnosed. Several studies have
revealed that the average time from onset of symptoms to diagnosis can take
many years, even for the most common subtypes (TABLE 5-1).3–7 Part of the
reason for delayed diagnosis is that the definition of dystonia and the many
syndromes included under this umbrella term have evolved over the years.

Definition of Dystonia
The definition of dystonia has evolved considerably since it was first described
more than 100 years ago. In 2013, an international panel of experts agreed to the
following working definition:
Dystonia is defined as a movement disorder characterized by sustained
or intermittent muscle contractions causing abnormal, often repetitive,
movements, postures, or both. Dystonic movements are typically patterned
and twisting, and may be tremulous. Dystonia is often initiated or worsened
by voluntary action and associated with overflow muscle activation.1

One of the main reasons for delayed diagnosis is lack of appreciation that
abnormal movements in dystonia can fall into two broad categories that often
overlap. They can be slow and twisting and sometimes with abnormal postures
that appear to be fixed, such as the abnormal postures and slow but repetitive
deviations of the head in cervical dystonia or the overt twisting of a foot.
Alternatively, dystonic movements can be rapid and jerky, including the
periocular spasms of blepharospasm, voice breaks of laryngeal dystonia, dystonic
tremor, and myoclonic dystonia. In some patients, movements may be rapid and

Diagnostic Delays in Dystoniaa TABLE 5-1

Type of Dystonia Location of Study Years to Diagnosis

3
Adult-onset focal dystonias Australia 3.8
4
Adult-onset focal dystonias Canada 6.4

Blepharospasm Italy5 4.8

5
Cervical dystonia Italy 7.1

Cervical dystonia United States6 3.7

5
Hand dystonia Italy 10.1

Laryngeal dystonia United States7 4.4

a
This table describes the average length of time from symptom onset to diagnosis of dystonia.

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THE DYSTONIAS

repetitive, resembling tremor. In these cases, the term dystonic tremor is

sometimes used. Although the slow and twisting movements are readily
recognized, the rapid and repetitive movements are often missed.
Whether dystonic movements are slow or fast, several clues aid the
recognition. The first clue is that abnormal movements tend to be patterned,
which refers to a recurrent quality of sameness. This quality helps differentiate
dystonia from chorea, in which movements are more random. Motor tics can also
be patterned, but associated premonitory sensations occur, and abnormal
movements can be voluntarily suppressed. Dystonic movements usually lack
premonition and cannot be suppressed by will alone.
Another helpful clue is that dystonic movements tend to be triggered or
worsened by voluntary action. In some cases, dystonia emerges only with
specific tasks. For example, patients with writer’s cramp may have cramping
of hand muscles and abnormal postures or jerking with writing, yet there is
no difficulty with other fine motor skills such as brushing teeth, eating with a
fork and knife, or buttoning a shirt. Patients with musician’s dystonia may
have trouble playing one instrument but not another. Even when dystonias are
not task specific, most tend to be exaggerated by voluntary action.
Although not always present, identification of a geste antagoniste (sensory
trick) also can be a very helpful clue because it is unique to dystonia.8 Typical
examples include touching the lower face in cervical dystonia, touching the
upper face in blepharospasm, or putting a toothpick in the mouth in
oromandibular dystonia. Patients should always be asked if they can do anything
to suppress their abnormal movements because these tricks can be very odd and
patients are sometimes reluctant to mention them.
Finally, like many other
neurologic disorders, it is useful
to remember that stress and
fatigue tend to worsen dystonia.
Increased frequency of
depression and anxiety occurs
with many types of dystonia.9
These issues frequently lead to
misdiagnosis of dystonia as
stress-induced or a nervous habit.

Clinical Evaluation
The many types of dystonia are
grouped according to two main
axes: a clinical axis and an
etiologic axis (FIGURE 5-1). The
clinical history and examination
(axis I) should address four
dimensions that include age at
onset, body region affected,
specific temporal features, and
whether associated clinical FIGURE 5-1
Classification of the dystonias. The many types of
problems are present.1 Age at dystonia are classified according to two
onset is important because independent axes. One axis relates to clinical
subtypes that emerge in infancy features, and the other relates to etiology.

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are most commonly due to inherited metabolic disorders, those that arise in later KEY POINTS
childhood or adolescence are more often inherited isolated or degenerative
● Dystonic movements are
dystonias, and those that arise in later adulthood are most often idiopathic. not always slow; they can be
Early-onset cases often start in one body region and progress to broader rapid or jerky, or resemble
distributions over months or years, whereas late-onset cases tend to have a tremor.
slower and more limited progression.
● Dystonic movements tend
Almost any region of the body can be affected, either alone or in different
to be patterned, not
combinations. The focal dystonias affect a single body region, segmental random.
dystonia affects two or more contiguous body regions, and multifocal
dystonia affects two or more noncontiguous regions. Hemidystonia can be ● Dystonic movements are
viewed as a special subtype of generalized dystonia where half of the body is often triggered or worsened
by voluntary muscle activity.
involved, usually at least the arm and leg on one side. Generalized dystonia
occurs when the trunk is affected along with at least two other body ● Identification of a geste
regions. antagoniste (sensory trick)
Temporal aspects refer to variations over time. Dystonia can emerge over a can be a very helpful clue
because it is unique to
short period of time and remain relatively static thereafter. Dystonia can also
dystonia and is important to
progress rapidly over a few hours or days, it can progress more slowly over many ask patients about.
years, or it can progress in a stepwise fashion. Shorter-term variations also exist,
such as diurnal worsening in the evening in dopa-responsive dystonia, or ● The history and
episodic attacks on a relatively normal baseline in paroxysmal dyskinesias. examination of patients with
dystonia should focus on
Finally, it is important to determine if dystonia occurs in isolation or if it is four areas: body region
combined with other clinical problems. The term isolated dystonia is used when affected, age at onset,
no other relevant clinical problems apart from tremor occur, which is observed in temporal features, and
approximately half of patients with dystonia. The term combined dystonia refers ancillary neurologic
problems.
to syndromes in which dystonia is combined with other clinical problems. It may
be combined with other movement disorders, such as parkinsonism or ataxia,
with other neurologic problems, such as neuropathy or retinopathy, or with
systemic issues, such as liver or kidney disease.

Laboratory Investigations
Each of the four clinical dimensions described above is important for describing a
syndromic pattern, which helps guide laboratory investigations to delineate
etiology, which falls in axis II (FIGURE 5-2). Universal algorithms for laboratory
investigations in the dystonias are challenging because of the remarkable
heterogeneity of clinical manifestations and causes. A comprehensive review
described more than 100 dystonic disorders organized into 18 tables based on
specific clinical features.2 Although several different algorithms have been
proposed,10–14 none is complete. Following are some general guidelines for
laboratory investigations.
For dystonias that first emerge in later adulthood (patients older than
40 years of age), laboratory investigations depend on body distribution,
whether additional neurologic features are present, and temporal aspects. For
the most common adult-onset focal or segmental dystonias, such as cervical
dystonia or blepharospasm, diagnostic testing is usually unrevealing. For
laryngeal dystonia, laryngoscopy is recommended to rule out structural
defects of the vocal apparatus.15 For the less common adult-onset cases with
hemidystonia or generalized dystonia, neuroimaging can be useful to reveal a
structural cause. Neuroimaging is also useful in patients with adult-onset
dystonia with rapid or severe progression of symptoms or if dystonia is
combined with other neurologic features, such as parkinsonism or ataxia. For

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THE DYSTONIAS

FIGURE 5-2
Workup of dystonia. The evaluation begins with clinical evaluation according to four main
clinical domains. The resulting syndromic pattern can be used to guide the approach to the
diagnostic workup.

most cases that emerge in later adulthood, genetic testing is not usually
conducted unless multiple family members are affected or a specific
syndromic pattern leads to suspicion for an inherited disorder. EEG is not
usually conducted unless dystonia appears in paroxysmal attacks. EMG is not
needed unless a neuromuscular disorder that may resemble dystonia is
suspected, such as myotonia or stiff person syndrome.
For dystonias that first emerge at an earlier age (in patients younger than
40 years), some laboratory investigations are almost always valuable.2 The

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diagnostic strategy for this group has evolved in the past few years, with multiple KEY POINTS
conflicting recommendations from different experts. Most experts recommend
● For the most common
neuroimaging because it can provide clues to guide diagnostic testing. Beyond focal dystonias that emerge
this step, strategies vary. Some experts advocate a “red flag” approach, in which after 40 years of age,
diagnostic testing is guided by the identification of telltale features from the laboratory investigations are
medical history, clinical examination, or neuroimaging. Examples of red flags usually not needed.
include the corneal Kayser-Fleischer ring of Wilson disease or the “eye of the
● For any dystonia that
tiger” sign on MRI for neurodegeneration with brain iron accumulation. emerges in a child or
Although this strategy can be useful when such telltale features are found, it does young adult, laboratory
not provide an adequate approach in all cases. Red flags are sometimes missing investigations are guided by
where they are expected, many disorders lack red flags, and it is difficult even for the history and examination.

experts to remember all the red flags. ● For almost all classic
A related strategy is to delineate a group of clinical abnormalities that form inherited dystonic disorders
a recognizable syndromic pattern to guide diagnostic testing. An example in children, late-onset cases
of this is Lesch-Nyhan disease, where patients present with early-onset or less severe cases are
known to occur in adults.
generalized dystonia, intellectual disability, tendencies toward self-harm, and
elevations of serum uric acid.16,17 This syndrome is unique; it is associated only ● Elucidating etiology is
with the HPRT1 gene, so single gene or enzyme testing is efficient.18 However, important because specific
many other disorders present with overlapping syndromes with many causes. treatments are available for
several types of dystonia.
It can be challenging even for experts to remember all syndromes, and partial
syndromes are hard to recognize. For almost all of the classic phenotypes
described for inherited disorders of children, adult-onset variant forms with
partial syndromes may occur. Furthermore, syndromic patterns are sometimes
misleading. An example involves the ATM gene, which is classically associated
with ataxia-telangiectasia in children. However, mutations in this gene can
sometimes cause isolated focal or generalized dystonia, sometimes in adults and
sometimes without telangiectasias.19 In the era of shotgun genetic testing that
may involve whole exome sequencing or large multigene panels, unexpected
results are common.20,21
A third strategy sometimes recommended is focusing laboratory
investigations specifically on disorders for which specific treatments exist.
The rationale for this strategy is that obtaining a definitive etiologic diagnosis
for dystonia often does not change clinical management because most are
managed symptomatically. According to this strategy, laboratory testing
should focus only on a smaller number of treatable disorders, such as Wilson
disease, for which specific treatments are available. This strategy is unwise.
Even when the cause does not have a specific treatment, many patients and
families find that obtaining a definitive etiologic diagnosis is useful for ending
an often long diagnostic odyssey.20,22–24 The information also provides valuable
information for counseling regarding the prognosis for the individual affected and
the potential risk for family members. A more important weakness of this
strategy is that the number of disorders with specific treatments has been
growing rapidly in recent years.
A recent review summarized more than 30 inherited disorders with specific
therapeutic interventions, and dystonia occurred in more than half of those
disorders.25 In these disorders, dystonia often is part of a more complex picture
with multiple neurologic and systemic problems. However, sometimes dystonia
is the sole initial presentation, and the diagnosis is delayed because the whole
syndrome has not yet evolved. At the same time, early treatment often is critical
to prevent permanent neurologic sequelae. The list of treatable disorders has

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THE DYSTONIAS

TABLE 5-2 Selected Dystonia Syndromes and Their Genesa

Isolated (Relatively Pure Dystonia)

◆ TOR1A
◇ Typical onset in arm or leg in childhood with generalized spread; other onset sites or
onset in adults may occur
◆ THAP1
◇ Typical onset in adolescents or young adults with segmental pattern involving face, neck,
larynx, and upper limbs
◆ ANO3
◇ Typical onset in adults with segmental pattern involving neck, larynx, and upper limbs;
coarse tremor is common
◆ GNAL
◇ Typical onset in adults with segmental pattern involving neck, larynx, and upper limbs
Combined (Other Relevant Features)
◆ Dopa-responsive dystonia phenotypes
◇ Metabolic phenotypes start in childhood; often combined with mild parkinsonism; most
commonly caused by GCH1, less commonly TH, SPR, and PTS; may resemble early-onset
degenerative Parkinson disease due to mutations in PRKN and PINK1
◆ Paroxysmal dyskinesia phenotypes
◇ Typical onset in childhood; often combined with chorea, tremor, and other movements;
different subtypes are triggered by sudden action, lengthy exercise, or stress; genes
include PRRT2, MR1, SLC2A1, and others
◆ Rapid-onset phenotypes with dystonia
◇ Typical onset in childhood or adolescents following physical or psychological stress;
causes include ATP1A3, GCDH, MUT, PCCA, PCCB, and SLC19A3
◆ MRI phenotypes with metal deposition
◇ Typical onset in childhood or early adults with parkinsonism and characteristic MRI;
copper accumulation occurs with ATP7B, manganese accumulation with SLC30A10 or
SLC39A14, iron accumulation with PANK2, PLA2G6, WDR45, and others
◆ Dystonia phenotypes with myoclonus
◇ Typical onset in childhood with dystonia in neck or upper limbs; myoclonus may
predominate; caused by SGCE, KCTD17, and RELN
◆ Dystonia phenotypes with ataxia
◇ Onset ranges from early childhood to later adulthood depending on subtype; many
potential causes including ATM, CTX, NPC, POLG, and several spinocerebellar ataxias

MRI = magnetic resonance imaging.

a
This table does not contain a complete listing of all dystonia syndromes and their genes. It includes the
more common subtypes, those with red flags or characteristic syndromes, those that are treatable, or those
with substantial recent progress.

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been growing each year, making it challenging to know what disorders should KEY POINT
be tested.
● Isolated dystonia may be
In view of these limitations of traditional strategies for laboratory the initial manifestation for
investigations, there is a growing trend toward the greater use of broad dystonia neurologic disorders
gene panels or whole exome sequencing. The red flags and syndromic strategies typically associated with
are useful only when the clinical clues point specifically to a single or small more complex syndromes.
number of potential diagnoses to target. Serial genetic testing, starting with
the most likely genes, should be avoided because it is frustrating and more
expensive than ordering a larger panel. If a dystonia gene panel is used, it is
important to know what it covers. Gene panels are not standardized across
testing laboratories. Some include as few as 12 genes, whereas others include
more than 100, often at the same cost. Even for large panels, current costs are
in the same range as brain MRI. A potentially useful approach for using the
various diagnostic strategies is shown in FIGURE 5-2, and some example
phenotypes are shown in TABLE 5-2.
Even when an etiologic diagnosis cannot be reached, it is important to
follow patients because new problems may arise that point to the cause. For
example, some patients may present with what appears to be an isolated focal
dystonia of the hand or foot, but signs of parkinsonism may develop months
or years after onset. In an older adult, this evolution may point to Parkinson
disease, where 10% to 15% of patients present with isolated dystonia of the
arm or leg.26 Alternatively, this evolution could point to one of the atypical
parkinsonian disorders for which the frequency of dystonia is even higher.27
In a child or young adult, this evolution may point to one of many inherited
metabolic or degenerative disorders in which dystonia and parkinsonism
are combined.28

CAUSES OF DYSTONIA
There have been enormous advances in elucidating the varied causes of dystonia
and in understanding the different biological mechanisms involved. This section
summarizes the major conceptual advances in three areas: genetic, physiologic,
and neuroanatomic.

Genetic Basis
Historically, most genes have been identified by a laborious process that
involved collecting large families, correlating the disease phenotype with known
genetic markers spread across the genome, and then sequencing DNA in the
chromosomal region with the best links between the phenotype and the known
markers. To aid this process of gene discovery, nomenclature was developed
that was based on linkage to chromosomal locations, or loci. Disorders with
dystonia were given the prefix DYT followed by a number, such as DYT1, DYT2,
DYT3, and so on.
This nomenclature has numerous flaws.29 In some cases, different DYT
loci ultimately were linked with the same gene. In other cases, multiple genes
were linked with the same DYT locus. Several DYT entries were found to be
erroneous or were never verified. The nomenclature also was clinically
misleading because it incorrectly implied that dystonia was a significant
feature of any disorder with a DYT label. The most serious drawback of this
nomenclature was that it was incomplete. It did not include dystonia genes
that were found before the DYT convention was established. Wilson disease

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THE DYSTONIAS

is one of many examples that was never included in the DYT lists despite the
fact that dystonia occurs in nearly all cases with neurologic involvement.
In fact, more than 100 inherited conditions exist in which dystonia may be a
major feature, a presenting feature, a dominant feature, or part of a more
complex syndrome.2 Only a small fraction of these disorders was assigned a
DYT label.
The next generation of genetic methods has led to major changes in our
approach to identifying genes for dystonia. A linkage-based nomenclature is
no longer central to gene discovery, and new genes are no longer consistently
being assigned DYT labels. Instead, a new nomenclature has been proposed.29
In the new nomenclature, the number is replaced by the gene name. For
example, TOR1A-associated dystonia (DYT1 according to the old nomenclature)
would be called DYT-TOR1A. Additionally, when the phenotype is mixed,
multiple prefixes may be combined, such as DYT for dystonia, PARK
for parkinsonism, or SCA for spinocerebellar ataxia. For example, dopa-
responsive dystonia (DYT5 in the old nomenclature) would be called
DYT/PARK-GCH1, DYT/PARK-TH, or DYT/PARK-SPR. The new convention
more accurately acknowledges the frequent occurrence of parkinsonism with
dystonia in dopa-responsive dystonia as well as at least three different
causative genes.
This new nomenclature is still evolving. It requires expertise in neurogenetics
and can be challenging to apply in routine clinical practice. For the practicing
neurologist, it is most useful to group genes by pattern of inheritance
(TABLE 5-3). The pattern of inheritance is important for genetic counseling,
and knowing the gene has implications for mechanism-specific treatments,
such as for Wilson disease. However, it is important to recognize that some of
the most common dystonia genes are dominant but inherited with reduced
penetrance (eg, GCH1, TOR1A, THAP1). This phenomenon may make
inheritance patterns difficult to recognize. In addition, considerable phenotypic
variation can occur in individual members of the same family with the same
genetic defect. For example, individual members of the same family can have
severe childhood-onset generalized dystonia, adolescent-onset segmental
dystonia, or adult-onset focal dystonia. This phenomenon can make it

TABLE 5-3 Classification of Genes by Pattern of Inheritancea

Pattern of
Inheritance Genes

Autosomal ANO3, ATP1A3, CIZ1, GCH1, GLUT1, GNAL, PNKD, PRRT2, SCA3, SGCE,
dominant SLC2A1, THAP1, TOR1A, TUBB4

Autosomal AADC, ATP7B, COL6A3, CYP27A1, GCDH, HPCA, KMT2B, NPC1 or NPC2,
recessive PCCA or PCCB, PLA2G6, PRKRA, SLC19A3, SLC39A14, SPR, TH

X-linked ARX, HPRT, MECP2, PLP1, TAF1, TIMM8A, WDR45

Mitochondrial MT-ATP6, MT-CO3, MT-ND1, MT-ND4, MT-TL1, MT-TK

a
These patterns can be challenging to recognize when families are smaller and because several dominantly
inherited dystonia genes have partial penetrance.

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challenging to identify individual family members who may have the same
disorder. Some of the most common or recently discovered genes and
their typical phenotypes are summarized in TABLE 5-2 and in multiple
recent reviews.20,30,31
Physiologic Basis
Historically, physiologists emphasized a cardinal defect that involved
co-contraction of antagonistic muscle groups in dystonia. However,
co-contraction of opposing muscles is not universal. Furthermore, co-contraction
of opposing muscles is not specific for dystonia because it can be seen in other
situations, such as stiff person syndrome, psychogenic dystonia, and voluntary
isometric contraction. Instead, the cardinal physiologic defect in dystonia is
excessive contraction of muscles. This overcontraction may take the form of
excessive force, unwanted repetitive contractions, or spread of contractions
to nearby muscles. When this spread involves opposing muscles, then
co-contraction of agonist and antagonist muscles can occur.
The physiologic basis for overcontraction of muscles is not yet understood,
and three main mechanisms have been proposed.32 One mechanism involves a
loss of inhibitory influences in the central nervous system. This loss of inhibition
has been described for many types of dystonia. Another mechanism involves
abnormalities of sensorimotor integration. Although overt sensory deficits are
not common, many studies have revealed subclinical defects in spatial and
temporal somatosensory discrimination thresholds for several types of dystonia.
A third mechanism is maladaptive plasticity, which again has been described for
many types of dystonia.
The molecular and cellular abnormalities responsible for these physiologic
defects have been the targets of intense scrutiny. The large number of genetic
and nongenetic causes for dystonia span very diverse biological processes
(TABLE 5-4).20,30,31 Inherited disorders with dystonia include defects in
metabolism (amino acids, carbohydrates, energy, lipids), heavy metal storage
(copper, iron, manganese), neurotransmitter defects, dysregulation of ion
channels (sodium, potassium, calcium), abnormal gene processing and

Grouping of Dystonia Genes by Related Biological Pathwaysa TABLE 5-4

Biological Process Genes

Dopamine signaling GCH1, TH, SPR, PTPS, AADC, VMAT2, PARKIN, PINK1, HPRT, GNAL

Cation transporters ATP1A3, ANO3, CACNA1A, CACNA1B, HPCA, KCTD17

Heavy metal ATP7B, PANK2, PLA2G6, SLC30A10, SLC39A14

accumulation

Metabolic abnormalities GLB1, HEXA, HEXB, HPRT1, NPC1, NPC2, SLC19A3

Mitochondrial MT-ATP6, MT-CO3, MT-ND1/MT-ND4, MT-TL1, MT-TK, PLA2G6,

dysfunction POLG, TIMM8A

Gene regulation APTX, ATM, PNKP, SETX, TAF1, THAP1

a
Dystonia genes relate to numerous biological processes, and only a few of the main genes are shown.

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THE DYSTONIAS

transcription, degenerative disorders, and others. It seems unlikely that all types
of dystonia are caused by a single molecular or cellular process. Instead, it is more
likely that these processes converge to affect specific neuroanatomic pathways
responsible for dystonia.
Acquired processes that may cause dystonia include vascular, infectious,
immunologic, or structural; drugs or toxins may also cause dystonia. Two
acquired forms of dystonia are especially important to recognize. The first is
tardive dystonia caused by dopamine-receptor–blocking drugs such as
neuroleptics or metoclopramide. These drugs more commonly provoke
repetitive oral and lingual movements of tardive dyskinesia. However, some
patients develop predominantly dystonic manifestations. The most common
patterns involve the craniocervical regions or backward arching of the trunk or
neck. The second acquired form of dystonia is functional (psychogenic)
dystonia, which can closely mimic organic dystonia. Features suggestive of
functional dystonia include nonpatterned movements (tendency to change body
regions or primary muscles involved over time), abrupt onset, attenuation with
distraction, or other unusual accompanying features (CASE 5-1).

Neuroanatomic Basis
Historically, abnormalities in the basal ganglia have been considered the cause of
all forms of dystonia.33 In fact, very good evidence suggests that the defects in the
basal ganglia can cause dystonia. One example is dopa-responsive dystonia,
which can be caused by inherited defects that affect the production of dopamine

CASE 5-1 A 56-year-old woman was referred for possible neuromodulation of

generalized dystonia because of uncontrolled twisting movements and
jerking of many parts of her body. Before this referral, previous trials of
several medications including carbidopa/levodopa and anticholinergics
had not been successful in alleviating her symptoms.
These movements started suddenly one morning and initially affected
one side of her face. Days later, the movements switched to the other
side of her face. Weeks later, both her arms began to twist, jerk, and flail.
The arm symptoms were intermittent, and occasionally her trunk and legs
were involved. Examination revealed obvious twisting and jerking
movements in many body regions. However, the movements were not
patterned and tended to change in quality and move from one region to
another. The movements stopped transiently when she was asked
to write.

COMMENT This patient may have functional (psychogenic) dystonia because of the
abrupt onset, nonpatterned nature of her movements over weeks and
even over the course of the examination, and distractibility.
Neuromodulation surgery should not be recommended for functional
dystonia. Although oral medications can sometimes help at least
transiently, best results are obtained with multidisciplinary care that
involves counseling and physical therapy.

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in the basal ganglia. Numerous other studies of dystonia have revealed focal KEY POINTS
lesions of the basal ganglia due to stroke, inherited metabolic defects, or other
● More than 100 known
pathologies. Even when lesions are not overtly visible on structural imaging causes for dystonia exist.
studies such as MRI or CT, abnormalities in the basal ganglia often can be found
using functional imaging studies such as positron emission tomography (PET) or ● Genetic forms of dystonia
functional MRI (fMRI). should be referred to by the
name of the gene, not the
More recently, many studies have indicated that all forms of dystonia may
DYT locus name.
not share the same anatomic pathology. Several studies have indicated that
dysfunction of other regions may also cause dystonia, most notably the ● Dystonia results from
cerebellum.33 Similar to the basal ganglia, both structural and functional dysfunction of a motor
imaging studies have pointed to the cerebellum for certain types of dystonia. network that includes the
basal ganglia, cerebellum,
Additionally, subclinical cerebellar signs occur in several types of dystonia,34 and sensorimotor cortex.
and recognition of a large group of disorders has been growing in which
dystonia and ataxia are combined.10,35
The modern conceptual framework is that dystonia results from dysfunction
of a motor network that involves the basal ganglia, cerebellum, and cerebral
cortex.33,36 Other regions may also play a role. For example, it has been suggested
that cervical dystonia results from defects in centers for head control in the
midbrain.37,38 How these networks might be affected to cause different types of
dystonia remains to be determined. Dystonia could be caused by defects in one
node of the network, a combination of nodes, or even abnormal communication
between nodes.34

TREATMENT
It is not feasible to use a universal treatment algorithm for all types of dystonia
because so many different subtypes exist. However, some general principles
are useful. As described above, a careful diagnostic evaluation is an essential
starting point because treatments are available to target the causal mechanisms
for some subtypes (TABLE 5-5).25 Other management options include counseling,
physical therapy, oral medications, botulinum neurotoxin (BoNT) injections,
and neurosurgical procedures.

Counseling
Counseling is an important starting place in management. Psychiatric
comorbidities are common, including depression, anxiety, and social
withdrawal.9 Many patients are misdiagnosed for years, leading to frustration
and mistrust of medical providers. Counseling is important for identifying any
comorbidities and regaining trust.
In addition, it is important to recognize that few therapies are curative for
dystonia. Most therapies are symptomatic, and the best outcomes are often
achieved with an empirical trial-and-error approach, which takes time and can
be frustrating. An early and frank discussion that sets realistic expectations for
treatment is essential. In addition, the Useful Websites section at the end of
this article lists several online resources that patients can turn to for more
information.

Physical Therapy and Related Procedures

Physical therapy and related procedures seem intuitively useful when patients
have excessive muscle contractions leading to soreness and abnormal postures.
As a result, many patients ask about physical therapy, stretching or

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THE DYSTONIAS

TABLE 5-5 Inherited Dystonias With Specific Treatments Available

Typical Age at
Disorder Gene Onseta Typical Clinical Featuresb Treatment
Abetalipoproteinemia MTTP Childhood to Progressive ataxia, chorea, Early treatment with vitamin E
(Bassen-Kornzweig early dystonia (often and reduced-fat diet can
syndrome) adulthood oromandibular), seizures, prevent or reduce symptoms
acanthocytosis, retinitis
pigmentosa, fat
malabsorption syndrome

Aromatic L-amino acid AADC Infancy Motor delay with hypotonia Dopamine agonists and
decarboxylase deficiency and dystonia, oculogyric monoamine oxidase inhibitors
crises, autonomic can partly reverse symptoms in
dysfunction some patients

Ataxia with vitamin E TTPA Childhood to Ataxia, visual loss, Early treatment with vitamin E
deficiency early neuropathy; occasionally can prevent or reduce symptoms
adulthood patients present instead
with dystonia

Biotin-thiamine– SLC19A3 Childhood Encephalopathic crisis Biotin and thiamine can reverse
responsive basal ganglia leading to generalized or prevent symptoms
disorder dystonia

Biotinidase deficiency BTD Infancy Encephalopathy with motor Early treatment with biotin can
delay, dystonia, seizures, prevent or reduce symptoms
visual and auditory
impairment, skin rash

Cerebral folate FLR1, Early childhood Developmental delay, Folinic acid can prevent or
deficiency SLC46A1 to ataxia, dystonia, seizures, reduce symptoms
adolescence and neuropsychiatric
disturbances

Cerebrotendinous CYP27A1 Late childhood Ataxia, spasticity, dementia, Chenodeoxycholic acid may
xanthomatosis to adulthood dystonia, myoclonus, and prevent progression or reverse
tendon xanthomas some symptoms

Cobalamin deficiencies Multiple Infancy Encephalopathy with motor Cobalamin derivatives or protein
(inherited subtypes A delay, ataxia, spasticity, restriction or both can mitigate
through G) dystonia, seizures, and bone symptoms
marrow abnormalities

Coenzyme Q10 deficiency Multiple Any age Varied phenotypes of Coenzyme Q10 can prevent or
progressive ataxia or reduce symptoms
encephalopathy,
sometimes with dystonia

Cerebral creatine GAMT, Infancy Global delay, myopathy, Creatine with or without arginine
deficiency type 3 AGAT generalized dystonia restriction can mitigate
symptoms

Dopa-responsive GCH1 Early childhood Dystonia often combined Levodopa can reverse
dystonia, classic to late with parkinsonism symptoms
adulthood

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CONTINUED FROM PAGE 988

Typical Age at
Disorder Gene Onseta Typical Clinical Featuresb Treatment
Dopa-responsive TH, PTPS, Infancy to Dystonia often combined Levodopa, 5-hydroxytryptophan,
dystonia, complicated SPR adolescence with parkinsonism, or tetrahydrobiopterin or a
oculogyric crises, and combination of them can
autonomic disturbances completely or partly reverse
symptoms

Dystonia with brain SLC30A10, Childhood Progressive dystonia with Chelation therapy can prevent or
manganese accumulation SLC39A14 parkinsonism, liver disease, at least partly reverse symptoms
and polycythemia

Galactosemia GALT, Childhood to Ataxia and tremor, lactose Lactose restriction can prevent
GALK1, early intolerance, sometimes with or mitigate symptoms
GALE adulthood mild dystonia

Glucose transporter type SLC2A1 Childhood to Developmental delay, Ketogenic diet or triheptanoin
1 deficiency adolescence seizures; sometimes can prevent or reduce symptoms
paroxysmal exertional
dystonia

Glutaric aciduria type 1 GCDH Early childhood Developmental delay with Avoiding or treating intercurrent
to early encephalopathic crisis illness with lysine restriction can
adulthood leading to generalized prevent encephalopathic crises
dystonia

Homocystinuria CBS Childhood Neurocognitive dysfunction, Methionine restriction prevents

myopia, ectopic lens; most symptoms
sometimes generalized or
paroxysmal dystonia

Maple syrup urine disease BCKDHA, Childhood Intermittent Leucine restriction with or
BCKDHB, encephalopathy and ataxia; without thiamine can prevent or
DBT sometimes with focal or mitigate symptoms
paroxysmal dystonia

Methylmalonic aciduria MUT Childhood Developmental delay, renal Avoiding or treating intercurrent
insufficiency, pancytopenia, illness with protein restriction
generalized dystonia after can prevent encephalopathic
encephalopathic crisis crises

Molybdenum cofactor MOCS1 Adolescence Developmental delay with Cyclic pyranopterin

deficiency (sulfite encephalopathy and monophosphate can prevent
oxidase) seizures; rarely patients symptoms
present with dystonia and
parkinsonism

Niemann-Pick disease NPC1, NPC2 Early childhood Dementia, ataxia, spasticity, N-butyl-deoxynojirimycin can
type C to early seizures, supranuclear gaze prevent or mitigate some
adulthood palsy; sometimes with symptoms
progressive generalized
dystonia

Propionic aciduria PCCA, Early childhood Developmental delay with Avoiding or treating intercurrent
PCCB to generalized dystonia after illness with protein restriction
adolescence encephalopathic crisis can prevent encephalopathic
crises

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THE DYSTONIAS

CONTINUED FROM PAGE 989

Typical Age at
Disorder Gene Onseta Typical Clinical Featuresb Treatment

Pyruvate dehydrogenase Multiple Infancy Progressive generalized or Thiamine, ketogenic diet, and
deficiency paroxysmal dystonia dichloroacetate can mitigate
symptoms

Rapid-onset dystonia- ATP1A3 Early childhood Psychomotor delay with Avoiding or treating intercurrent
parkinsonism to late bulbar or generalized illness can prevent
adulthood dystonia after encephalopathic crises
encephalopathic crisis

Wilson disease ATP7B Early childhood Liver disease, Kayser- Zinc or tetrathiomolybdate can
to late Fleischer rings, progressive prevent or reduce symptoms
adulthood dystonia, cognitive and
neuropsychiatric
abnormalities

a
For most childhood-onset disorders, rarely patients may present instead in adulthood.
b
Partial phenotypes are common.

TABLE 5-6 Oral Medications for Dystonia

Medication Class
and Example Indications Typical Dosing Common Side Effects
Anticholinergic

Trihexyphenidyl Any dystonia Start with 1 mg to 2 mg each night at Impaired mentation, dry mouth,
bedtime and increase by 1 mg to 2 mg dry eyes, constipation, urinary
every 2–7 days to maximum of 100 mg/d retention, blurry vision
in 3–4 divided doses

Dopaminergic

Carbidopa/ All childhood or early- Start with a half to 1 tablet of 25 mg/ Nausea, orthostasis, sleep
levodopa adult onset dystonia 100 mg and increase every 2–7 days to a disturbance
maximum levodopa dose of 20 mg/kg/d
in 3–4 divided doses

Tetrabenazine Tardive dystonia, Start with half of a 25 mg tablet Parkinsonism, impaired

oromandibular and increase by half to 1 tablet every mentation, depression,
dystonia 2–7 days to maximum of 100 mg/d drowsiness, restlessness
in 3–4 divided doses

γ-Aminobutyric acid–mediated

Clonazepam Any dystonia Start with 0.5 mg to 1.0 mg each night at Impaired mentation or
bedtime and increase by 0.5 mg to 1 mg coordination, drowsiness,
every 2–7 days to maximum of 6 mg/d fatigue, withdrawal reactions
in 3–4 divided doses

Baclofen Any dystonia Start with 5 mg to 10 mg 3 times a day Impaired mentation or

and increase by 5 mg to 10 mg every coordination, fatigue, nausea,
2–7 days to maximum of 40 mg 3 times a day dizziness, weakness, withdrawal
reactions

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strengthening exercises, yoga, chiropractic therapy, and others. Although some KEY POINT
patients seem to benefit from these procedures, the benefits are variable and
● All children and young
often short lived. Despite the many positive outcomes described for small open adults with unexplained
trials using various strategies, the largest and most rigorous studies fail to show dystonia must have a trial of
any consistent benefits.39 levodopa to rule out
In the absence of evidence-based recommendations, it is reasonable dopa-responsive dystonia.
to offer physical therapy or related procedures according to patient interests.
Options may include stretching to limit contractures, strengthening of
antagonistic muscles, and muscle relaxation techniques to reduce pain and
pulling.39 Care must be taken to find an experienced physical therapist
because some exercises or manipulations may cause unnecessary pain or
worsen dystonia.

Oral Medications
Many different oral medications are offered to patients with dystonia40,41; no
medications are approved for the treatment of dystonia by the US Food and Drug
Administration (FDA), so all uses are off-label. No medication has been subject
to large-scale, double-blinded, placebo-controlled trials. Although evidence-
based reviews have been published, the use of oral medications is based largely
on anecdotal experience and a few small nonblinded trials, retrospective reviews,
and expert consensus (TABLE 5-6).

DOPAMINE-RELATED DRUGS. Medications that stimulate or inhibit dopamine

transmission may be helpful for some patients with dystonia. Levodopa is very
effective in dopa-responsive dystonia, and all children and young adults with
unexplained dystonia should undergo a levodopa trial (CASE 5-2).42–44 Doses
as low as half of a 25-mg/100-mg tablet of carbidopa/levodopa 2 times a day may
be sufficient, although larger doses are sometimes required. For an adequate
trial, the dose must be titrated to 20 mg/kg/d of levodopa for children
(approximately 1000 mg/d of levodopa for an adult) divided in 3 doses a day for
a month.
In addition to dopa-responsive dystonia, levodopa can be at least partially
effective for several other disorders, such as dystonia that occurs in ataxia
telangiectasia,45 spinocerebellar ataxia type 3,46 or Parkinson disease. Levodopa is
not broadly useful for other types of dystonia, including the more common
adult-onset isolated focal or segmental dystonias.
Depletion of dopamine stores with inhibitors of the vesicular monoamine
transporter may be useful for some types of dystonia, such as tardive dystonia.
Most experience comes from tetrabenazine, although newer drugs such as
valbenazine and deutetrabenazine are probably equally effective with fewer side
effects. Typical side effects may include parkinsonism, drowsiness, depression,
anxiety, and akathisia. Dopamine receptor antagonists also are sometimes
recommended for certain types of dystonia. However, this class of medications is
generally discouraged because of the risk of acute dystonic reactions and
tardive dystonia.

ANTICHOLINERGICS. Drugs that block muscarinic acetylcholine receptors are

frequently prescribed because they seem to be at least partly effective for many
different types of dystonia, regardless of cause.47 Trihexyphenidyl is the most
commonly used although others may be equally effective, including

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THE DYSTONIAS

benztropine, biperiden, ethopropazine, orphenadrine, and procyclidine. High

doses are often required (TABLE 5-6).
Although children tolerate high doses better than adults do, they may
experience problems with school performance, and abnormal movements may
get worse.48,49 Dose-limiting side effects in adults include dry mouth or dry eyes,
constipation, urinary retention, memory loss, confusion, depression, blurry
vision, or worsening of narrow-angle glaucoma.

γ-AMINOBUTYRIC ACID–RELATED DRUGS. Baclofen is a γ-aminobutyric acid

(GABA) receptor ligand that is sometimes used to manage dystonia, especially
childhood-onset dystonias with coexisting spasticity. Children without spasticity
and adults with focal dystonia may also benefit, but responses vary. It also can be
given intrathecally via a chronically implanted minipump. Typical side effects
include sedation, confusion, dizziness, and loss of muscle tone. Sudden
discontinuation is associated with severe withdrawal reactions that may include
delirium and seizures.
Benzodiazepines amplify GABA transmission and also are prescribed for
dystonia. Examples include alprazolam, chlordiazepoxide, clonazepam, and
diazepam. Typical side effects include sedation, confusion, dizziness, or
depression. These drugs can be habit forming, so dose monitoring is important
and sudden discontinuation should be avoided.

MUSCLE RELAXANTS AND OTHER MEDICATIONS. Many patients request “muscle

relaxants” to address overactive and sore muscles. Baclofen and benzodiazepines
are sometimes included in this group. Others include carisoprodol,
chlorzoxazone, cyclobenzaprine, metaxalone, methocarbamol, and

CASE 5-2 A 34-year-old woman with a history of cerebral palsy presented to a

neurology clinic to establish care. She had severe generalized dystonia
affecting her trunk, neck, and all limbs. She was seriously disabled and
spent much of her time in a wheelchair. Brain MRI was normal. A careful
repeat history revealed worsening of her condition from the ages of 4 to
10 years, and she could not recall a trial of levodopa.
A trial of levodopa was initiated, resulting in dramatic improvement,
and she was eventually able to walk independently. Genetic testing
revealed a pathologic variant in the GCH1 gene, confirming a diagnosis of
dopa-responsive dystonia.

COMMENT This case emphasizes the importance of a levodopa trial in all patients with
early-onset dystonia, even those with a long-standing diagnosis of
“cerebral palsy.” Cerebral palsy does not typically worsen over time, and
the brain MRI often shows characteristic changes due to hypoxia-ischemia.
Despite many years of disability, levodopa can still produce dramatic
benefits in dopa-responsive dystonia. The most common error is to conduct
a levodopa trial with a very small dose. Current recommendations are to
push the levodopa dose to 20 mg/kg/d before concluding the trial failed.

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orphenadrine. Many patients seem to enjoy at least partial benefits from these KEY POINTS
medications, especially those with pain from muscle spasms.
● Carbamazepine and
Many other drugs also have been advocated for specific forms of dystonia. related anticonvulsant
Carbamazepine and related anticonvulsant medications can be remarkably medications may be
effective at very low doses for dystonic spasms in paroxysmal kinesigenic remarkably effective at very
dyskinesia.50,51 Alcohol can be beneficial in the myoclonus-dystonia syndrome, low doses in patients with
paroxysmal kinesigenic
but it may be habit forming and is therefore not recommended as a routine
dyskinesia.
therapy. Other options sometimes recommended include amphetamines,
cannabis-related products, cyproheptadine, gabapentin, lithium, nabilone, ● When treating dystonia, it
riluzole, tizanidine, and zolpidem. Responses vary considerably, and these is important to customize
medications are not widely used. both the dose and the
interval between doses for
optimal benefits with
Botulinum Neurotoxins botulinum toxin.
BoNTs are derived from the bacterium Clostridium botulinum. There are
seven serotypes, but only two are available as therapeutics. Type A is marketed ● Botulinum toxins are the
treatment of first choice for
as onabotulinumtoxinA, incobotulinumtoxinA, and abobotulinumtoxinA. Type focal and segmental
B is available as rimabotulinumtoxinB. Many articles compare the BoNTs in dystonias and sometimes
terms of efficacy, side effects, and formulations. Their similarities seem more the most discomforting
apparent than differences, so the formulation is chosen largely based on the aspects in generalized
dystonias.
preferences of individual clinicians. The overall utility of the BoNTs has
been summarized many times, including in several systematic evidence-based
reviews.52–54
Many resources describe their application including doses, muscle selection,
and the value of localization via EMG or ultrasound.55,56 Procedural details are
not reviewed here. Instead, this section focuses on some new trends.
BoNTs can be very effective for many types of dystonia. They are the
treatment of choice for focal and segmental dystonias. They can significantly
reduce abnormal movements, pain, and disability. The doses and specific
muscles injected must be customized according to individual needs. Benefits
usually emerge after 2 to 7 days and last for an average of 3 months.57 However,
the actual duration of benefit varies widely, from 8 to 16 weeks. As a result, it is
necessary to customize not only the dose and muscle pattern but also the interval
between doses.58,59 Offering a fixed interval of 12 weeks for all patients is
common but not ideal.
There also has been increasing recognition of subtypes of dystonia that are
more challenging to treat with BoNT than others. Of course, patients with
generalized dystonia cannot have all affected muscle groups treated, but it is
feasible to target the most uncomfortable areas in these patients. Patients with
cervical dystonia generally respond very well, but subtypes for which good
outcomes are more challenging include those with predominant anterocollis,
prominent head tremor, and long-standing fixed postures.60 Patients with
blepharospasm also generally respond well, but it can be difficult to get good
responses in patients who develop apraxia of eyelid opening.61 For laryngeal
dystonia, the adductor type is easier to treat than the abductor type.62 The most
challenging subtypes include hand63 or oromandibular dystonia.64 For these
disorders, achieving the ideal balance between alleviation of dystonia and
triggering of side effects can be difficult.
Side effects are generally temporary and related to spread of the BoNT to
nearby sites. For cervical or oromandibular dystonia, the most common side
effect is dysphagia. For blepharospasm, the most common side effects are ptosis,

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THE DYSTONIAS

diplopia, and dry eyes. For laryngeal dystonia, the most common side effect is a
hoarse voice.
Systemic side effects are uncommon. Some patients describe a flulike
syndrome for 3 to 5 days after their treatments.65 A recent study has raised
concern for a high prevalence of antibodies to BoNT in treated patients.66
However, the patients in this study were all actively being treated with BoNT,
with typical good therapeutic responses, so the clinical significance of these
antibodies remains unclear. The development of true immune-mediated
functional resistance to BoNT is rare, so alternative explanations should be
sought when patients do not respond, before ascribing poor outcomes
to antibodies.67,68

Surgical Procedures
Multiple surgical options are available for the treatment of dystonia when more
conservative therapies fail. Currently, the most commonly offered procedure
involves neuromodulation of brain activity via deep brain stimulation. Ablative
procedures involving select brain regions or peripheral targets are applied in
some circumstances.

CENTRAL NERVOUS SYSTEM NEUROMODULATION. Numerous extensive reviews

of neuromodulation have been published for both children and adults with
different forms of dystonia.69–71 This procedure is best applied by
multidisciplinary groups with expertise in patient selection and management of
complications. This section addresses practical issues of relevance to providers
who may counsel or refer patients for this treatment option.
Patient selection plays an important role in surgical outcomes. From the
clinical perspective, several characteristics help predict outcomes. As a general
rule, patients with shorter disease duration generally do better than those with
longer durations. Patients with mobile dystonia do better than those with tonic
postures or fixed contractures. Patients with isolated dystonia syndromes do
better than those with more complex clinical pictures that include spasticity,
ataxia, or other problems. Patients of all ages may respond well, although very
young patients (younger than 12 years of age) experience higher rates of surgical
complications, such as hardware infection or lead migration.
The etiology of dystonia also plays an important role in predicting outcomes.
Surgical outcomes are reliably good for certain subtypes and reliably poor for
others. As a result, elucidating the cause for dystonia is important when
considering neuromodulation. Historically, it was often asserted that isolated
dystonia syndromes responded better than dystonia syndromes combined with
other neurologic features. Such assertions are now considered oversimplified.
For example, good outcomes are typically associated with certain inherited
dystonias whether or not they are combined with other neurologic features, such
as DYT1 dystonia (TOR1A), myoclonus-dystonia (SGCE), and Lubag disease
(TAF1).72 Other inherited dystonias respond poorly, such as rapid-onset dystonia
parkinsonism (ATP1A3). Patients with isolated dystonia caused by THAP1
respond more variably.
Reliably good outcomes for neuromodulation are also expected for certain
acquired forms of dystonia, such as tardive dystonia due to neuroleptics.
Outcomes for dystonic cerebral palsy are more variable, with some patients
responding well and others not at all.48 Populations with unpredictable responses

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should be offered surgery only by experienced centers after careful counseling, KEY POINTS
ideally as part of longer-term efforts at elucidating the reasons for variable
● Deep brain stimulation is
responses. the most commonly offered
Long-term studies of neuromodulation surgery show sustained benefits lasting surgical treatment for
many years.73–76 Regular access to a center experienced with managing stimulator dystonia although ablative
settings and complications is essential. Shortly after surgery, regular visits are procedures may be
appropriate in some cases.
needed to adjust stimulator settings because benefits are sometimes delayed for
weeks or even months. After optimal settings are achieved, return visits must be ● Selection of patients
expected yearly to interrogate the device and ensure proper function. Long-term with dystonia for surgical
complications are not uncommon. In one study, 47 patients with DYT1 dystonia intervention should be
were monitored by an experienced multidisciplinary team for more than 10 years. done by experienced
multidisciplinary teams.
Overall, 8.5% had delayed equipment infections requiring antibiotics and
sometimes removal of equipment, 8.5% had equipment malfunction requiring ● Focused ultrasound is
reoperation, and 4.3% required reoperation for electrode repositioning.73 Close becoming more popular for
follow-up by the neuromodulation team is therefore important for identifying and ablative surgery in patients
with dystonia although
managing long-term complications. experience is still limited.
In the past few years, numerous advances have occurred in neuromodulation
therapy,70,71 including novel insights into rare forms of dystonia for which
there is little prior experience with surgery and exploration of neuroanatomic
targets beyond the traditional ones. There have been advances in the equipment
as well, including the development of smaller impulse generators, batteries
that are rechargeable or have longer lifespans, electrical contacts that can be
more precisely tuned, and stimulation that can adapt to specific physiologic
triggers. Some of these advances are already in use by specific neuromodulation
centers.

CENTRAL NERVOUS SYSTEM ABLATION. Lesioning specific parts of the brain

was commonly performed for dystonia before the widespread adoption of
neuromodulation. Neuromodulation has become the favored surgical
intervention because it is reversible and adjustable. However, interest in ablative
procedures has increased following the emergence of nonincisional methods,
such as focused ultrasound.70,71 Although experience is still relatively limited,
ablative approaches may be appropriate in some circumstances.
Permanent ablation may be offered as a palliative procedure to patients with
rapidly progressive neurodegenerative disorders with severe disability, patients
who are small or frail with a high risk of hardware-related complications,
those who cannot manage frequent return visits because of travel issues, or those
who merely do not wish to have chronically implanted hardware. Although the
newer ablative procedures are sometimes promoted as superior to deep brain
stimulation because they are “noninvasive,” it is important to recognize that they
still produce permanent brain lesions with all of the potential short-term risks
and long-term side effects.

PERIPHERAL SURGERIES. Peripheral surgeries for dystonia were common

in the past and are still available but are less commonly used now that
neuromodulation has become more popular. Patients with cervical dystonia may
undergo selective peripheral denervation when BoNT fails and other surgical
options are not feasible. Success rates are similar to those for neuromodulation.77,78
Permanent effects include sensory loss or dysesthesia in the neck, local scarring,
local muscle weakness and atrophy, and dysphagia.

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THE DYSTONIAS

Patients with blepharospasm may be offered several different procedures,

including removal of redundant eyelid skin, surgical shortening of the levator
palpebrae, frontalis suspension, and orbicularis oculi myectomy.79–81 Patients
with laryngeal dystonia also may be offered different procedures, including
modification of the nerves, muscles, or cartilaginous structure of the larynx.82 No
large-scale studies exist that document the long-term efficacy and safety of
these procedures.

CONCLUSION
In the past decade, there have been enormous strides in the appreciation of the
many clinical manifestations of the dystonias, how these manifestations should
be classified for optimal diagnostic and therapeutic value, their underlying
biological mechanisms, and how they should be treated. All types of dystonia are
treatable at least symptomatically, and several have treatments that target
underlying mechanisms. As our understanding of mechanisms continues to
evolve, it is likely that the number of dystonic disorders with more specific
treatments will continue to grow.

ACKNOWLEDGMENTS
Special appreciation goes to Laura Scorr, MD, for providing feedback on this
review. Dr Jinnah has received grant support from the National Institutes of
Health (NIH) and is principal investigator for the Dystonia Coalition, which
receives support through NIH grant TR001456 from the Office of Rare Diseases
Research at the National Center for Advancing Translational Sciences, and
previously received support through grant NS065701 from the National
Institutes of Neurological Disorders and Stroke.

USEFUL WEBSITES

BENIGN ESSENTIAL BLEPHAROSPASM RESEARCH NATIONAL SPASMODIC DYSPHONIA ASSOCIATION

FOUNDATION The National Spasmodic Dysphonia Association
The Benign Essential Blepharospasm Research provides information related to research,
Foundation provides information on blepharospasm awareness, and support of people living with
and Meige syndrome. spasmodic dystonia and other laryngeal dystonias.
blepharospasm.org dysphonia.org

DYSTONIA COALITION
NATIONAL SPASMODIC TORTICOLLIS ASSOCIATION
The Dystonia Coalition has researchers and
The National Spasmodic Torticollis Association
advocacy groups in the field working together to
provides information on the signs and symptoms
further research about dystonias.
and treatment options of cervical dystonia.
rarediseasesnetwork.org/cms/dystonia
torticollis.org
DYSTONIA MEDICAL RESEARCH FOUNDATION
The Dystonia Medical Research Foundation provides
support to people living with all types of dystonia.
dystonia-foundation.org

NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS

AND STROKE
The dystonias information page on the National
Institute of Neurological Disorders and Stroke
website provides information on what research is
underway for this group of disorders.
ninds.nih.gov/Disorders/All-Disorders/Dystonias-
Information-Page

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REFERENCES

1 Albanese A, Bhatia K, Bressman SB, et al. 15 Ludlow CL, Domangue R, Sharma D, et al.
Phenomenology and classification of dystonia: Consensus-based attributes for identifying
a consensus update. Mov Disord 2013;28(7): patients with spasmodic dysphonia and other
863–873. doi:10.1002/mds.25475. voice disorders. JAMA Otolaryngol Head Neck
Surg 2018;144(8):657–665. doi: 10.1001/
2 Fung VS, Jinnah HA, Bhatia K, Vidailhet M.
jamaoto.2018.0644.
Assessment of patients with isolated or
combined dystonia: an update on dystonia 16 Jinnah HA, Ceballos-Picot I, Torres RJ, et al.
syndromes. Mov Disord 2013;28(7):889–898. Attenuated variants of Lesch-Nyhan disease. Brain
doi:10.1002/mds.25549. 2010;133(pt 3):671–689. doi:10.1093/brain/awq013.
3 Powell AT, Bidewell JW, Walker AC. Diagnosing 17 Jinnah HA, Visser JE, Harris JC, et al. Delineation of
idiopathic dystonia: must it take so long? Aust the motor disorder of Lesch-Nyhan disease. Brain
Health Rev 1995;18(3):120–131. 2006;129(pt 5):1201–1217. doi:10.1093/brain/awl056.
4 Jog M, Chouinard S, Hobson D, et al. Causes for 18 Fu R, Ceballos-Picot I, Torres RJ, et al.
treatment delays in dystonia and hemifacial Genotype-phenotype correlations in
spasm: a Canadian survey. Can J Neurol Sci 2011; neurogenetics: Lesch-Nyhan disease as a model
38(5):704–711. doi:10.1017/S0317167100012270. disorder. Brain 2013;137(pt 5):1282–1303. doi:
10.1093/brain/awt202.
5 Macerollo A, Superbo M, Gigante AF, et al.
Diagnostic delay in adult-onset dystonia: data 19 Levy A, Lange AE. Ataxia-telangiectasia: a review
from an Italian movement disorder center. J Clin of movement disorders, clinical features, and
Neurosci 2015;22(3):608–610. doi:10.1016/j. genotype correlations. Mov Disord 2018;33(8):
jocn.2014.09.014. 1238–1247. doi:10.1002/mds.27319.
6 Tiderington E, Goodman EM, Rosen AR, et al. 20 Zech M, Jech R, Wagner M, et al. Molecular
How long does it take to diagnose cervical diversity of combined and complex dystonia:
dystonia? J Neurol Sci 2013;335(1–2):72–74. insights from diagnostic exome sequencing.
doi:10.1016/j.jns.2013.08.028. Neurogenetics 2017;18(4):195–205. doi:10.1007/
s10048-017-0521-9.
7 Creighton FX, Hapner E, Klein A, et al. Diagnostic
delays in spasmodic dysphonia: a call for 21 van Egmond ME, Lugtenberg CHA, Brouwer OF,
clinician education. J Voice 2015;29(5):592–594. et al. A post hoc study on gene panel analysis for
doi:10.1016/j.jvoice.2013.10.0228. the diagnosis of dystonia. Mov Disord 2017;32(4):
569–575. doi:10.1002/mds.26937.
8 Patel N, Hanfelt J, Marsh L, et al. Alleviating
manoeuvres (sensory tricks) in cervical dystonia. 22 Lazaridis KN, Schahl KA, Cousin MA, et al.
J Neurol Neurosurg Psychiatry 2014;85(8): Outcome of whole exome sequencing for
882–884. doi:10.1136/jnnp-2013-307316. diagnostic odyssey cases of an individualized
medicine clinic: the Mayo Clinic experience.
9 Zurowski M, McDonald W, Fox S, Marsh L.
Mayo Clin Proc 2016;91(3):297–307. doi:10.1016/j.
Psychiatric comorbidities in dystonia: emerging
mayocp.2015.12.018.
concepts. Mov Disord 2013;28(7):914–920.
doi:10.1002/mds.25501. 23 Sawyer SL, Hartley T, Dyment DA, et al. Utility of
whole-exome sequencing for those near the
10 Rossi M, Balint B, Millar Vernetti P, et al.Genetic
end of the diagnostic odyssey: time to address
dystonia-ataxia syndromes: clinical spectrum,
gaps in care. Clin Genet 2016;89(3):275–284.
diagnostic approach, and treatment options.
doi:10.1111/cge.12654.
Mov Disord Clin Pract 2018;5(4):373–382. doi:
10.1002/mdc3.12635. 24 Johnson NE. Whole-exome sequencing in
neurologic practice: reducing the diagnostic
11 van Egmond ME, Kuiper A, Eggink H, et al.
odyssey. Neurol Genet 2015;1(4):e37. doi:10.1212/
Dystonia in children and adolescents: a
NXG.0000000000000037.
systematic review and a new diagnostic
algorithm. J Neurol Neurosurg Psychiatry 2014; 25 Jinnah HA, Albanese A, Bhatia KP, et al. Treatable
86(7):774–781. doi:10.1136/jnnp-2014-309106. inherited rare movement disorders. Mov Disord
2018;33(1):21–35. doi:10.1002/mds.27140.
12 Charlesworth G, Bhatia KP, Wood NW. The genetics
of dystonia: new twists in an old tale. Brain 2013; 26 Wickremaratchi MM, Knipe MD, Sastry BS, et al.
136(pt 7):2017–2037. doi:10.1093/brain/awt138. The motor phenotype of Parkinson's disease in
relation to age at onset. Mov Disord 2011;26(3):
13 Camargos S, Cardoso F. New algorithm for
457–463. doi:10.1002/mds.23469.
the diagnosis of hereditary dystonia.
Arq Neuropsiquiatr 2012;70(9):715–717. 27 Yoon WT. Comparison of dystonia between
doi:10.1590/S0004-282X2012000900013. Parkinson's disease and atypical parkinsonism:
the clinical usefulness of dystonia distribution
14 Bertram KL, Williams DR. Diagnosis of dystonic
and characteristics in the differential diagnosis
syndromes—a new eight-question approach.
of parkinsonism. Neurol Neurochir Pol 2018;52(1):
Nat Rev Neurol 2012;8(5):275–283. doi:10.1038/
48–53. doi:10.1016/j.pjnns.2017.11.004.
nrneurol.2012.39.

CONTINUUMJOURNAL.COM 997

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

THE DYSTONIAS

28 Schneider SA, Bhatia KP, Hardy J. Complicated 43 Lee WW, Jeon BS. Clinical spectrum of
recessive dystonia parkinsonism syndromes. dopa-responsive dystonia and related disorders.
Mov Disord 2009;24(4):490–499. doi:10.1002/ Curr Neurol Neurosci Rep 2014;14(7):461.
mds.22314. doi:10.1007/s11910-014-0461-9.
29 Marras C, Lang A, van de Warrenburg BP, et al. 44 Kurian MA, Gissen P, Smith M, et al. The
Nomenclature of genetic movement disorders: monoamine neurotransmitter disorders: an
recommendations of the International Parkinson expanding range of neurological syndromes.
and Movement Disorder Society Task Force. Mov Lancet Neurol 2011;10(8):721–733. doi:10.1016/
Disord 2016;31(4):436–457. doi:10.1002/mds.26527. S1474-4422(11)70141-7.
30 Weisheit CE, Pappas SS, Dauer WT. Inherited 45 Charlesworth G, Mohire MD, Schneider SA, et al.
dystonias: clinical features and molecular Ataxia telangiectasia presenting as dopa-
pathways. Handb Clin Neurol 2018;147:241–254. responsive cervical dystonia. Neurology 2013;
doi:10.1016/B978-0-444-63233-3.00016-6. 81(13):1148–1151. doi:10.1212/WNL.0b013e3182a55fa2.
31 Balint B, Mencacci NE, Valente EM, et al. 46 Wilder-Smith E, Tan EK, Law HY, et al.
Dystonia. Nat Rev Dis Primers 2018;4(1):25. Spinocerebellar ataxia type 3 presenting as an
doi:10.1038/s41572-018-0023-6. L-DOPA responsive dystonia phenotype in a
Chinese family. J Neurol Sci 2003;213(1–2):25–28.
32 Quartarone A, Hallett M. Emerging concepts in
doi:10.1016/S0022-510X(03)00129-1.
the physiological basis of dystonia. Mov Disord
2013;28(7):958–967. doi:10.1002/mds.25532. 47 Greene P, Shale H, Fahn S. Experience with high
dosages of anticholinergic and other drugs in the
33 Neychev VK, Gross RE, Lehéricy S, et al.The
treatment of torsion dystonia. Adv Neurol 1988;
functional neuroanatomy of dystonia.
50:547–556.
Neurobiol Dis 2011;42(2):185–201. doi:10.1016/
j.nbd.2011.01.026. 48 Fehlings D, Brown L, Harvey A, et al.
Pharmacological and neurosurgical interventions
34 Prudente CN, Hess EJ, Jinnah HA. Dystonia as a
for managing dystonia in cerebral palsy: a
network disorder: what is the role of the
systematic review. Dev Med Child Neurol 2018;
cerebellum? Neuroscience 2014;260:23–35.
60(4):356–366. doi:10.1111/dmcn.13652.
doi:10.1016/j.neuroscience.2013.11.062.
49 Harvey AR, Baker LB, Reddihough DS, et al.
35 Nibbeling EA, Delnooz CC, de Koning TJ, et al.
Trihexyphenidyl for dystonia in cerebral palsy.
Using the shared genetics of dystonia and ataxia
Cochrane Database Syst Rev 2018;5: CD012430.
to unravel their pathogenesis. Neurosci Biobehav
doi:10.1002/14651858.CD012430.pub2.
Rev 2017;75:22–39. doi:10.1016/j.neubiorev.
2017.01.033. 50 Houser MK, Soland VL, Bhatia KP, et al. Paroxysmal
kinesigenic choreoathetosis: a report of 26
36 Jinnah HA, Neychev V, Hess EJ. The anatomical
patients. J Neurol 1999;246(2):120–126. doi:10.1007/
basis for dystonia: the motor network model.
s004150050318.
Tremor Other Hyperkinet Mov (N Y) 2017;7:506.
doi:10.7916/D8V69X3S. 51 Demirkiran M, Jankovic J. Paroxysmal dyskinesias:
clinical features and classification. Ann Neurol 1995;
37 Shaikh AG, Zee DS, Crawford JD, Jinnah HA.
38(4):571–579. doi:10.1002/ana.410380405.
Cervical dystonia: a neural integrator disorder.
Brain 2017;139(pt 10):2590–2599. doi:10.1093/ 52 Simpson DM, Hallett M, Ashman EJ, et al.
brain/aww141. Practice guideline update summary: botulinum
neurotoxin for the treatment of blepharospasm,
38 Hutchinson M, Isa T, Molloy A, et al. Cervical
cervical dystonia, adult spasticity, and headache:
dystonia: a disorder of the midbrain network for
report of the Guideline Development
covert attentional orienting. Front Neurol 2014;
Subcommittee of the American Academy of
5:54. doi:10.3389/fneur.2014.00054.
Neurology. Neurology 2016;86(19):1818–1826.
39 Prudente CN, Zetterberg L, Bring A, et al. doi:10.1212/WNL.0000000000002560.
Systematic review of rehabilitation in focal
53 Castelão M, Marques RE, Duarte GS, et al.
dystonias: classification and recommendations.
Botulinum toxin type A therapy for cervical
Mov Disord Clin Pract 2018;5(3):237–245.
dystonia. Cochrane Database Syst Rev 2017;12:
doi:10.1002/mdc3.12574.
CD003633. doi:10.1002/14651858.CD003633.pub3.
40 Pirio Richardson S, Wegele AR, Skipper B, et al.
54 Hallett M, Albanese A, Dressler D, et al.
Dystonia treatment: patterns of medication use
Evidence-based review and assessment of
in an international cohort. Neurology 2017;88(6):
botulinum neurotoxin for the treatment of
1–8. doi:10.1212/WNL.0000000000003596.
movement disorders. Toxicon 2013;67:94–114.
41 Jinnah HA, Factor S. Diagnosis and treatment of doi:10.1016/j.toxicon.2012.12.004.
dystonia. In: Jankovic J, editor. Neurologic clinics.
55 Truong D, Dressler D, Hallet M, Zachary C. Manual
Elsevier, 2015:77–100. doi:10.1016/j.ncl.
of botulinum toxin. Cambridge: Cambridge
2014.09.002.
University Press, 2009.
42 Wijemanne S, Jankovic J. Dopa-responsive
56 Jost W, Valerius KP. Pictorial atlas of botulinum
dystonia—clinical and genetic heterogeneity.
toxin injection: dosage, localization, application.
Nat Rev Neurol 2015;11(7):414–424. doi:10.1038/
Berlin: Quintessence Publishing Company, 2008.
nrneurol.2015.86.

998 AUGUST 2019

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

57 Marsh WA, Monroe DM, Brin MF, Gallagher CJ. 70 Cury RG, Kalia SK, Shah BB, et al. Surgical
Systematic review and meta-analysis of the treatment of dystonia. Expert Rev
duration of clinical effect of onabotulinumtoxinA Neurother 2018;18(6):477–492.
in cervical dystonia. BMC Neurol 2014;14:91. doi:10.1080/14737175.2018.1478288.
doi:10.1186/1471-2377-14-91.
71 Krack P, Martinez-Fernandez R, Del Alamo M,
58 Ojo OO, Fernandez HH. Is it time for flexibility in Obeso JA. Current applications and limitations of
botulinum inter-injection intervals? Toxicon 2015; surgical treatments for movement disorders.
107(pt A):72–76. doi:10.1016/j.toxicon.2015.09.037. Mov Disord 2017;32(1):36–52. doi:10.1002/mds.26890.
59 Evidente VG, Pappert EJ. Botulinum toxin therapy 72 Jinnah HA, Alterman R, Klein C, et al. Deep brain
for cervical dystonia: the science of dosing. stimulation for dystonia: a novel perspective on
Tremor Other Hyperkinet Mov (N Y) 2014;4:273. the value of genetic testing. J Neural Transm
doi:10.7916/D84X56BF. (Vienna) 2017;124(4):417–430. doi:10.1007/
s00702-016-1656-9.
60 Jinnah HA, Goodmann E, Rosen AR, et al.
Botulinum toxin treatment failures in cervical 73 Panov F, Gologorsky Y, Connors G, et al. Deep
dystonia: causes, management, and outcomes. brain stimulation in DYT1 dystonia: a 10-year
J Neurol 2016;263(6):1188–1194. doi:10.1007/ experience. Neurosurgery 2013;73(1):86–93;
s00415-016-8136-x. discussion 93. doi:10.1227/01.
neu.0000429841.84083.c8.
61 Esposito M, Fasano A, Crisci C, et al. The
combined treatment with orbital and pretarsal 74 Tagliati M, Krack P, Volkmann J, et al. Long-term
botulinum toxin injections in the management of management of DBS in dystonia: response to
poorly responsive blepharospasm. Neurol Sci stimulation, adverse events, battery changes,
2013;35(3):397–400. doi:10.1007/s10072-013-1526-2. and special considerations. Mov Disord 2011;
26(suppl 1):S54–S62. doi:10.1002/mds.23535.
62 Patel AB, Bansberg SF, Adler CH, et al. The Mayo
Clinic Arizona spasmodic dysphonia experience: 75 Volkmann J, Wolters A, Kupsch A, et al. Pallidal
a demographic analysis of 718 patients. Ann deep brain stimulation in patients with primary
Otol Rhinol Laryngol 2015;124(11):859–863. generalised or segmental dystonia: 5-year
doi:10.1177/0003489415588557. follow-up of a randomised trial. Lancet Neurol
2012;11(12):1029–1038. doi:10.1016/S1474-4422(12)
63 Lungu C, Karp BI, Alter K, et al.Long-term follow-up
70257-0.
of botulinum toxin therapy for focal hand dystonia:
outcome at 10 years or more. Mov Disord 2011;26 76 Reese R, Gruber D, Schoenecker T, et al.Long-term
(4):750–753. doi:10.1002/mds.23504. clinical outcome in Meige syndrome treated with
internal pallidum deep brain stimulation. Mov Disord
64 Termsarasab P, Tanenbaum DR, Frucht SJ. The
2011;26(4):691–698. doi:10.1002/mds.23549.
phenomenology and natural history of idiopathic
lower cranial dystonia. J Clin Mov Disord 2014;1:3. 77 Contarino MF, Van Den Munckhof P, Tijssen MA,
doi:10.1186/2054-7072-1-3. et al. Selective peripheral denervation:
comparison with pallidal stimulation and
65 George EB, Cotton AC, Shneyder N, Jinnah HA.
literature review. J Neurol 2014;261:300–308.
A strategy for managing flu-like symptoms after
doi:10.1007/s00415-013-7188-4.
botulinum toxin injections. J Neurol 2018;265(8):
1932–1933. doi:10.1007/s00415-018-8934-4. 78 Ravindran K, Ganesh Kumar N, Englot DJ, et al.
Deep brain stimulation versus peripheral
66 Albrecht P, Jansen A, Lee JI, et al.High prevalence
denervation for cervical dystonia: a systematic
of neutralizing antibodies after long-term botulium
review and meta-analysis. World Neurosurg 2018;
neurotoxin therapy. Neurology 2019;92(1)
pii: S1878-8750(18)32485-9. doi:10.1016/j.
e48–e54. doi:10.1212/WNL.0000000000006688.
wneu.2018.10.178.
67 Jinnah HA, Comella CL, Perlmutter J, et al.
79 Georgescu D, Vagefi MR, McMullan TF, et al.
Longitudinal studies of botulinum toxin in
Upper eyelid myectomy in blepharospasm with
cervical dystonia: why do patients discontinue
associated apraxia of lid opening. Am J
therapy? Toxicon 2018;147:89–95. doi:10.1016/j.
Ophthalmol 2008;145(3):541–547. doi:10.1016/j.
toxicon.2017.09.004.
ajo.2007.10.017.
68 Ferreira JJ, Colosimo C, Bhidayasiri R, et al.
80 Grivet D, Robert PY, Thuret G, et al. Assessment
Factors influencing secondary non-response to
of blepharospasm surgery using an improved
botulinum toxin type A injections in cervical
disability scale: study of 138 patients. Ophthalmic
dystonia. Parkinsonism Relat Disord 2015;21(2):
Plast Reconstr Surg 2005;21(3):230–234. doi:
111–115. doi:10.1016/j.parkreldis.2014.09.034.
10.1097/01.IOP.0000162429.97307.4D.
69 Hale AT, Monsour MA, Rolston JD, et al.Deep
81 Pariseau B, Worley MW, Anderson RL. Myectomy
brain stimulation in pediatric dystonia: a
for blepharospasm 2013. Curr Opin Ophthalmol
systematic review [published online ahead of
2013;24(5):488–493. doi:10.1097/
print November 5, 2018]. Neurosurg Rev
ICU.0b013e3283645aee.
doi:10.1007/s10143-018-1047-9.
82 Ludlow CL. Treatment for spasmodic dysphonia:
limitations of current approaches. Curr Opin
Otolaryngol Head Neck Surg 2009;17(3):160–165.
doi:10.1097/MOO.0b013e32832aef6f.

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THE DYSTONIAS

DISCLOSURE
Continued from page 976 ethopropazine, gabapentin, lithium, metaxalone,
methocarbamol, nabilone orphenadrine,
Beat Dystonia, the Benign Essential Blepharospasm procyclidine, riluzole, tizanidine, trihexyphenidyl,
Research Foundation, Cure Dystonia Now, Dystonia and zolpidem for the treatment of dystonia.
Europe, Dystonia Inc, Dystonia Ireland, the Dystonia Dr Jinnah discusses the unlabeled/investigational
Medical Research Foundation, the Foundation for use of thiamine for the treatment of biotin-
Dystonia Research, the National Spasmodic thiamine–responsive basal ganglia disorder;
Dysphonia Association, and the National Spasmodic folinic acid for the treatment of cerebral folate
Torticollis Association). deficiency; chenodeoxycholic acid for the
treatment of cerebrotendinous xanthomatosis;
UNLABELED USE OF 5-hydroxytryptophan and tetrahydrobiopterin for
PRODUCTS/INVESTIGATIONAL the treatment of dopa-responsive dystonia;
USE DISCLOSURE: cyclic pyranopterin monophosphate for the
Dr Jinnah discusses the unlabeled/investigational treatment of molybdenum cofactor deficiency;
use of alprazolam, amphetamines, baclofen, N-butyl-deoxynojirimycin for the treatment of
benzodiazepines, benztropine, biperiden, Niemann-Pick disease type C; tetrabenazine for
botulinum neurotoxins, carbamazepine, the treatment of oromandibular dystonia; and
carbidopa/levodopa, carisoprodol, deutetrabenazine, tetrabenazine, and
chlordiazepoxide, chlorzoxazone, clonazepam, valbenazine and for the treatment of tardive
cyclobenzaprine, cyproheptadine, diazepam, dystonia.

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 Chorea REVIEW ARTICLE


By Pichet Termsarasab, MD 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


ABSTRACT VIDEO CONTENT
PURPOSE OF REVIEW: Thisarticle provides an overview of the approach A V AI L A B L E O N L I N E

to chorea in clinical practice, beginning with a discussion of the

phenomenologic features of chorea and how to differentiate it from
other movement disorders. The diagnostic approach, clinical features of
important acquired and genetic choreas, and therapeutic principles are
also discussed. Practical clinical points and caveats are included.
CITE AS:
Downloaded from http://journals.lww.com/continuum by BhDMf5ePHKbH4TTImqenVJRkcJu5k+K7I5ndWRW42YRjtejChE4A8GpDCazI8QREzHyuJ6fR60k= on 08/03/2019

CONTINUUM (MINNEAP MINN)

RECENT FINDINGS: C9orf72 disease is the most common Huntington disease 2019;25(4, MOVEMENT DISORDERS):
1001–1035.
phenocopy, according to studies in the European population. Anti-IgLON5
disease can present with chorea. The role of immunotherapies in
Address correspondence to
Sydenham chorea has increased, and further clinical studies may be useful. Dr Pichet Termsarasab,
Benign hereditary chorea is a syndrome or phenotype due to mutations in Ramathibodi Hospital, Mahidol
University, Bangkok, Thailand,
several genes, including NKX2-1, ADCY5, GNAO1, and PDE10A. New-generation [email protected].
presynaptic dopamine-depleting agents provide more options for
symptomatic treatment of chorea with fewer adverse effects. Deep brain RELATIONSHIP DISCLOSURE:
Dr Termsarasab serves as
stimulation has been performed in several choreic disorders, but features associate editor of the Journal
other than chorea and the neurodegenerative nature should be taken into of Clinical Movement Disorders
consideration. Studies on genetic interventions for Huntington disease and on the editorial board
of Brain Science Journal.
are ongoing. Dr Termsarasab has received
personal compensation for
SUMMARY: Clinical features remain crucial in guiding the differential speaking engagements for the
American Academy of
diagnosis and appropriate investigations in chorea. Given the complexity Neurology and Novartis AG and
of most choreic disorders, treating only the chorea is not sufficient. A receives publishing royalties
comprehensive and multidisciplinary approach is required. from MedLink Neurology.

UNLABELED USE OF
PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
INTRODUCTION
Dr Termsarasab discusses the

C
horea is derived from the Greek word χορεία, meaning dance. unlabeled/investigational
It is characterized by the random and flowing quality of the use of the current
recommended treatments of
movements, giving it a dancelike appearance. Randomness is the chorea, none of which are
key phenomenologic feature in the identification of chorea. The approved by the US Food and
movements typically flit from one body region to another in an Drug Administration except the
use of deutetrabenazine for the
unpredictable fashion. treatment of chorea associated
The differential diagnosis of chorea is broad. However, with clinical features with Huntington disease and
including demographic data, time course, associated medical and neurologic tardive dyskinesia,
tetrabenazine for the treatment
features, and known prevalence, the search for the etiology of chorea can be of chorea associated with
performed efficiently. A “shotgun approach” can be reserved for when no diagnostic Huntington disease, and
valbenazine for the treatment of
clues are present. This article discusses the general diagnostic approach to chorea,
tardive dyskinesia.
clinical clues to common and important choreic disorders, and therapeutic principles.
The first section of the article discusses general phenomenologic features of
chorea and how to differentiate chorea from other movement disorders. The next © 2019 American Academy
section covers the general approach to chorea, beginning with the three body of Neurology.

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CHOREA

distributions that can be an important clue. A proposed practical approach to

chorea is presented, and how other clinical information can serve as diagnostic
clues is discussed. Selected important acquired and genetic etiologies of chorea
are discussed in subsequent sections, and paroxysmal movement disorders that
can present with chorea are also briefly discussed. Therapeutic principles of
chorea are delineated in the final section.

PHENOMENOLOGIC FEATURES OF CHOREA

In addition to the two main phenomenologic features of randomness and a
flowing quality, patients with chorea often blend or incorporate the chorea into
their normal movements, as if they are attempting to hide it. This phenomenon
is called parakinesia. For example, when chorea is present in the arm, a patient
may try to blend chorea by lifting or moving the arm to a target in the same
direction as the choreic movements.
Another feature of chorea is motor impersistence. This is not only seen in
Huntington disease (HD) or Sydenham chorea but also in other causes of chorea.
It is defined by an inability to perform sustained motor activities. Two tasks that
should be examined clinically include tongue protrusion and handgrip. Tongue
protrusion cannot be maintained, and the tongue retracts back into the mouth after
several seconds. For handgrip, when a patient attempts to squeeze an examiner’s
fingers, waxing-and-waning grip strength (called milkmaid’s grip) can be felt.
Ballism is a variant of chorea characterized by large-amplitude flinging
movements involving proximal extremities (VIDEO 6-1, links.lww.com/CONT/A351).
The diagnostic and treatment approaches for ballism are the same as for chorea.
Athetosis (“without fixed position”), originally described in 1871 by William
Hammond, remains controversial. While some experts categorize athetosis as a
variant of chorea, it has been argued to be a form of dystonia by others.1 Athetosis is
characterized by slow writhing movements typically involving distal extremities,
although other body parts, such as the face, can be involved. When dystonia, such
as dystonic hand posturing, coexists with flowing movements, it is sometimes
difficult to separate athetosis from dystonia, resulting in the so-called
dystonic-choreoathetoid movements seen in cerebral palsy.
The velocity of chorea can vary. The flowing component of chorea is usually faster
than that of dystonia but not as fast as the jerking component of myoclonus. However,
when chorea has a quick velocity along with low amplitude, it may appear quite
jerky and can be mistaken as myoclonic jerks. Chorea has a wide variation of severity;
patients with a mild degree can appear fidgety, and thus chorea may be overlooked.
Therefore, it is important to observe patients with their socks off and legs hanging from
the examination table to examine small choreic movements in the feet and toes.

DIFFERENTIATING CHOREA FROM OTHER ABNORMAL MOVEMENTS

Dystonia can have motor overflow mimicking the flowing movements of chorea,
but an abnormal posturing typically coexists. In addition, dystonia produces
patterned movements that are predictable, in contrast to the randomness of
chorea. Sensory tricks, a null point, and mirror movements are supportive
features of dystonia. Dystonic tremor that is usually irregular and jerky, when
present, is clinically distinct from the flowing quality of chorea.
As mentioned earlier, chorea with a quick velocity may resemble myoclonic
jerks, but the randomness of chorea distinguishes the two. In addition, the
jerks in chorea are not as brief as those in myoclonus, which are “lightninglike”

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because of typical burst durations of less than 200 milliseconds. Stimulus KEY POINTS
sensitivity, if present, also supports the identification of myoclonus. However,
● Randomness is the key
when the jerks are frequent, stimulus sensitivity may be difficult to assess, and phenomenologic feature of
spontaneous jerks should not be mistaken as stimulus sensitive. chorea.
Common movement patterns and body distribution, such as eye blinking or
shoulder shrugging, help identify tics. However, with uncommon patterns of ● Chorea with quick
velocities may look jerky,
tics, the presence of a premonitory urge and suppressibility will help distinguish
resembling myoclonic jerks.
them from chorea.
Stereotypies, as seen in anti–N-methyl-D-aspartate (NMDA) receptor
encephalitis or tardive syndrome with orobuccolingual involvement, can have a
flowing quality similar to chorea. However, its stereotypic pattern, as if the same
video is running in a repetitive loop, distinguishes it from chorea.
Large-amplitude cerebellar outflow tremor with proximal extremity
involvement may look similar to chorea. However, regular oscillation around the
axis and activation of the tremor with movements (postural and kinetic
components) distinguish it from chorea.

APPROACH TO CHOREA
Given an extensive differential diagnosis, chorea can be challenging to many
clinicians. Nevertheless, there are some important clinical features that can
serve as diagnostic clues to the specific diagnosis. These include three body
distributions and other crucial features.

FIGURE 6-1
Body distribution as a phenomenologic clue in chorea. The differential diagnoses are
demonstrated in each distribution.
PKAN = pantothenate kinase–associated neurodegeneration.
a
Locations outside the subthalamic nucleus can also be involved.

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CHOREA

Body Distribution as a Clue

While the list of disorders presenting with generalized chorea is extensive, three
body distributions carry a more limited number of possible diagnoses and serve
as useful diagnostic clues (FIGURE 6-1). These include hemichorea,
orobuccolingual, and forehead distributions.

HEMICHOREA. Lesions leading to hemichorea are classically localized to the

contralateral subthalamic nucleus. However, the lesions are not restricted to the
subthalamic nucleus and can be located in other anatomic locations, such as the
contralateral basal ganglia or corona radiata.2 Systemic disorders, such as
nonketotic hyperglycemia and polycythemia vera, can also present with
hemichorea or very asymmetric involvement.3,4 Sydenham chorea can also have
a very asymmetric presentation or even hemichorea. Therefore, systemic

CASE 6-1 A 77-year-old woman presented with abnormal movements of her left
arm, left leg, and left face. She had a history of type 2 diabetes mellitus
and poor compliance. She had run out of her medications and not taken
them for 2 weeks before developing abnormal flinging movements of her
left arm upon waking up in the morning, followed a few days later by
movements in her left leg and left face. The movements had gradually
become worse over the week, prompting her to seek medical attention.
On presentation to the hospital, examination revealed left
hemichorea/hemiballism involving her left arm, left leg, and left face
(VIDEO 6-2, links.lww.com/CONT/A352). The chorea abated during sleep.
Blood testing on presentation showed a glucose level of 445 mg/dL and
hemoglobin A1c of 12%. She had no ketosis.
The diagnosis of left hemichorea/hemiballism secondary to nonketotic
hyperglycemia was made, which was initially managed by IV and
subcutaneous insulin. Her oral diabetic medications were resumed, with
improvement in her blood glucose level. MRI of the brain revealed a
hyperintense signal on T1-weighted images in the right (contralateral)
putamen (FIGURE 6-2A). A faint hyperdense signal could also be seen on a
CT scan without contrast in the same region (FIGURE 6-2B).
Her chorea was not adequately improved with blood glucose control
alone, and haloperidol was started at 0.5 mg/d with about 50%
improvement in her hemichorea. The dose was then increased to 0.5 mg
2 times a day with further improvement. She required low-dose
haloperidol for several weeks before the chorea subsided.

COMMENT The acute temporal profile in this patient is suggestive of an acquired cause
of chorea. Hemichorea/hemiballism can be a manifestation of systemic
disorders such as nonketotic hyperglycemia or polycythemia vera.
Nonketotic hyperglycemia is common among Asian populations, especially
women (this patient was from Thailand). Blood glucose control serves as a
specific treatment, but most patients will also need symptomatic
therapies, as chorea may take several weeks or months to resolve.

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etiologies should always be kept in the differential diagnosis, especially when
neuroimaging does not reveal any structural lesions.
Nonketotic hyperglycemia–induced hemichorea is common in Asians,
especially women. With a high index of suspicion, diagnosis can easily be made
by blood glucose testing, even in patients with no previous history of diabetes
mellitus.5 MRI of the brain typically demonstrates a hyperintense signal in the
putamen and caudate nuclei on T1-weighted images, usually more prominent on
the side contralateral to hemichorea. While blood sugar control is the therapeutic
mainstay, symptomatic treatment of chorea for at least several weeks or a few
months is also often needed (CASE 6-1).
OROBUCCOLINGUAL INVOLVEMENT. Choreic movements in the orobuccolingual
or lower cranial region are classically seen in tardive syndrome and acquired

FIGURE 6-2
Imaging of the patient in CASE 6-1 with nonketotic hyperglycemia. A, Axial T1-weighted MRI
shows hyperintense signal in the right putamen (red arrow), contralateral to the side of
hemichorea. B, CT scan of the same patient demonstrates mild hyperdensity in the same
region (white arrow).

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CHOREA

hepatocerebral degeneration. Of note, in tardive syndrome with orobuccolingual

involvement, stereotypy may be a more precise phenomenologic term, since
the movements are often repetitive. Lateral lingual movements, as if the patient
has candy in his or her cheek (called the bonbon sign), can be seen in patients with
orobuccolingual involvement in tardive syndrome. Levodopa-induced dyskinesia
in multiple system atrophy tends to involve the orobuccolingual region, as
opposed to limb dyskinesia in classic Parkinson disease.
In some choreic disorders, dystonia (not chorea) in the orobuccolingual
region can coexist. These include neuroacanthocytosis syndromes,
neurodegeneration with brain iron accumulation disorders such as pantothenate
kinase–associated neurodegeneration and neuroferritinopathy, X-linked
dystonia-parkinsonism (also known as Lubag disease), Wilson disease, and
Lesch-Nyhan syndrome.
Neuroacanthocytosis syndromes are a group of disorders in which progressive
neurodegeneration is associated with acanthocytes.6 The two main disorders
are chorea-acanthocytosis (autosomal recessive inheritance) and McLeod
syndrome (X-linked inheritance). Chorea-acanthocytosis can present with
severe tongue protrusion dystonia, especially when eating, or feeding dystonia,
which can interfere with appropriate oral intake and cause lip and tongue biting.
In contrast, orobuccolingual involvement, including feeding dystonia, is much
less commonly seen in McLeod syndrome. Of note, when considering disorders
that can present with oromandibular dystonia and self-mutilating behavior,
Lesch-Nyhan syndrome is also in the differential diagnosis, in addition to
chorea-acanthocytosis. Lesch-Nyhan syndrome is an X-linked recessive disorder
that typically has an onset within the first few years of life, whereas onset of
chorea-acanthocytosis is usually in early adulthood.

FOREHEAD CHOREA. Forehead muscles are often involved in HD, in which

wiggling of the eyebrows or activation of the frontalis muscle can be seen.7
Forehead involvement can be a useful supportive clinical feature to distinguish
HD from tardive dyskinesia, in which the forehead is usually spared. However,
cases of HD without forehead chorea and cases of tardive dyskinesia with
forehead involvement can sometimes be seen.

DIAGNOSTIC APPROACH
Useful diagnostic clues include demographic data (eg, age, gender, and
ethnicity); family history; coexisting movement phenomenology such as
dystonia, myoclonus, or tics; and associated clinical features, such as seizures,
neuropathy, and myopathy. Given the broad differential diagnosis of chorea, the
clinical approach can be challenging to clinicians. A proposed practical clinical
approach is illustrated in FIGURE 6-3. The three most crucial features are time
course, age group, and known prevalence.
As a general rule, acquired or sporadic causes of chorea usually present with
an acute or subacute temporal profile, whereas genetic causes are chronic
(longer than 1 year in duration). It is crucial to identify acquired causes, as many
of them are treatable. Autoimmune etiologies should always be included in the
differential diagnosis, especially in subacute presentations; these disorders
typically respond to immunotherapies, including IV immunoglobulin (IVIg),
steroids, other immunosuppressive agents, and plasma exchange. In recent
years, the number of autoimmune neurologic disorders has been expanding
with advances in neuroimmunology and identification of novel autoantibodies.

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 KEY POINTS

● Chorea in one of three

body distributions
(hemichorea,
orobuccolingual
involvement, and forehead
chorea) can serve as a clue
to narrow down the
differential diagnoses.

● Structural lesions and

systemic disorders (such as
nonketotic hyperglycemia
and polycythemia vera) can
cause hemichorea.

● Sydenham chorea can

present with hemichorea or
very asymmetric
involvement.

FIGURE 6-3 ● The time course can help

Diagnostic approach to chorea. classify chorea into acquired
BHC = benign hereditary chorea; SCA17 = spinocerebellar ataxia type 17. and genetic etiologies.
a
The association between the temporal profile and sporadic versus genetic causes of chorea is only a
general rule. In clinical practice, overlaps (ie, genetic chorea with temporal profile of less than 1 year) can ● Age group and known
occur, but these are not common. prevalence are very
important diagnostic clues
in chorea.
Age group and known prevalence are also crucial diagnostic clues in chorea. In
the pediatric population, Sydenham chorea is the most common cause of ● The most common
acquired chorea and the most common among all choreic disorders, excluding acquired chorea in children
choreoathetoid cerebral palsy. In adults, HD is by far the most common genetic is Sydenham chorea.
cause, whereas C9orf72 disease is the second most common according to studies
● The most common
in the European population8 and spinocerebellar ataxia type 17 (SCA17) is the genetic chorea in adults is
third. Before the discovery of the C9orf72 gene, SCA17 was thought to be the Huntington disease,
second most common genetic cause of chorea. In 2011, C9orf72 gene mutations followed by C9orf72 disease
with the GGGGCC hexanucleotide repeat expansion were discovered in familial and spinocerebellar ataxia
type 17.
frontotemporal dementia with amyotrophic lateral sclerosis. Subsequently, the
clinical spectrum has broadened, and studies in HD phenocopies (patients with ● The most common
negative HD gene testing) revealed that C9orf72 disease is even more common than genetic chorea in children is
SCA17. The most common genetic cause of chorea in children is benign hereditary benign hereditary chorea.
chorea. It is important to note that when a child presents with chorea, the diagnosis
● A negative family history
is very unlikely to be HD, since juvenile HD typically presents with parkinsonism does not exclude genetic
(also known as the Westphal variant), dystonia, and seizures, rather than chorea. causes of chorea.
While family history can be a helpful diagnostic clue, a negative family history
does not exclude the possibility of having a genetic chorea. This can be due to
nonpaternity, incomplete penetrance, de novo mutations, or undiagnosed
affected parents with symptoms, such as depression or suicidality, incorrectly
attributed to other causes. Common genetic causes of chorea, including HD,
C9orf72 disease, SCA17, and benign hereditary chorea, are autosomal dominant.
In most repeat expansion disorders such as HD, larger numbers of repeats occur
in successive generations and are associated with earlier age at onset. This
phenomenon is called anticipation and has been reported in C9orf72 disease9 but
much less frequently in SCA17. Absence of male-to-male transmission is a

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CHOREA

TABLE 6-1 Acquired Causes of Choreaa

Category Examples

Structural lesion Vascular causes: ischemic and hemorrhagic strokes,

vascular malformation (eg, Moyamoya syndrome)

Tumors

Demyelinating lesions

Metabolic/endocrine Nonketotic hyperglycemia

Hypoglycemia

Hypocalcemia

Hyponatremia/hypernatremia

Uremia

Acquired hepatocerebral degeneration

Hyperthyroidism

Hypoparathyroidism/hyperparathyroidism

Infectious Toxoplasmosis

HIV encephalopathy

Prion diseases

Drug-induced Levodopa

Cocaine (“crack-dancing”)

Amphetamine

Anticonvulsants

Lithium

Anticholinergics

Neuroleptic withdrawal

Autoimmune/paraneoplastic Sydenham chorea

Rheumatologic diseases: systemic lupus erythematosus,

antiphospholipid antibody syndrome, systemic sclerosis

Autoimmune neurologic syndromes: anti–CRMP-5,

anti-NMDA, anti-Hu (ANNA-1), anti-Yo, anti-LGI1, anti-
CASPR2, anti-GAD65, anti-IgLON5

Other Polycythemia vera

Postpump chorea

ANNA-1 = antineuronal nuclear antibody type 1; CASPR2 = contactin-associated proteinlike 2;

CRMP-5 = collapsin response mediator protein-5; GAD65 = glutamic acid decarboxylase 65; HIV = human
immunodeficiency virus; LGI1 = leucine-rich glioma inactivated 1; NMDA = N-methyl-D-aspartate.
a
Modified with permission from Termsarasab P.11 © 2017 American Academy of Neurology.

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hallmark of X-linked disorders, examples of which include McLeod syndrome KEY POINTS
and Lesch-Nyhan syndrome. Notably, while much more common in males,
● Huntington disease–like 2
females can also be affected because of skewed inactivation of X chromosomes. is almost exclusively seen in
Ethnicity can be an important diagnostic clue. For example, Huntington patients with African
disease–like 2 (HDL2) is almost exclusively seen in patients with African ancestry ancestry.
and has been reported to be a common cause of HD phenocopies in South African
● Autoimmune chorea
patients with African ancestry.10
should be included in the
differential diagnoses of
ACQUIRED CAUSES OF CHOREA chorea with a subacute
The list of acquired causes of chorea is extensive but can be grouped into at least temporal profile.
six categories, including structural, metabolic/endocrine, infectious, drug-
induced, autoimmune/paraneoplastic, and others (TABLE 6-111). Among these,
levodopa-induced chorea (or dyskinesia) is the most common acquired cause
encountered in movement disorders clinics.
Chorea can be an initial presentation in several disorders, such as
polycythemia vera, systemic lupus erythematosus (VIDEO 6-3, links.lww.com/
CONT/A353), antiphospholipid antibody syndrome, and diabetes mellitus (with
nonketotic hyperglycemia). Therefore, an absence of a known underlying medical
problem should not dissuade clinicians from considering that particular etiology.
Autoimmune and paraneoplastic etiologies are considered “don’t miss,”
diagnoses, especially when a patient presents with a subacute time course, since
they can be treated with immunotherapies. In adults, autoimmune etiologies
include anti-Hu, anti–collapsin response mediator protein-5 (CRMP-5),
anti-NMDA receptor encephalitis, anti–leucine-rich glioma inactivated 1 (LGI1),
anti–contactin-associated proteinlike 2 (CASPR2), and antistriational antibody
diseases.12 With more clinical recognition of anti-NMDA receptor encephalitis in
the past decade, a variety of associated movement disorders, including chorea,
dystonia, and myoclonus, have been reported. Stereotypic movements in
orobuccolingual muscles, arms, and legs are characteristic. A 2018 study found that
dystonia, chorea, and stereotypies are the most common abnormal movements in
this disorder.13 Some patients may have been misdiagnosed with tardive
dyskinesia, but important clues are an encephalopathic clinical picture and no
previous history of neuroleptic use. It is crucial to search for an underlying tumor
or malignancy in some of these autoimmune/paraneoplastic disorders (eg, ovarian
teratoma in women with anti-NMDA receptor encephalitis).
Anti-IgLON5 disease has recently been described.14,15 Clinical features
include obstructive sleep apnea, rapid eye movement (REM) and non-REM
parasomnias, dementia, chorea, and vertical supranuclear gaze palsy. Parasomnia can
manifest as finalistic behaviors during sleep in which a patient acts as if he or she is
performing work activities, such as installing an antenna or threading electrical wires.
Despite being an autoimmune disorder, most patients with anti-IgLON5 disease have
a chronic temporal profile longer than 1 year. Earlier detection may be possible when
the disorder is better recognized. Interestingly, neuropathologic studies of anti-IgLON5
disease also demonstrated neurodegeneration with mixed 3-repeat and 4-repeat
tauopathy.16 Further studies may provide insight on the link between autoimmunity
and neurodegeneration and determine which is primary in the pathogenesis.
In children, Sydenham chorea (VIDEO 6-4, links.lww.com/CONT/A35417)
is the most common autoimmune chorea. When considering rheumatic heart
disease in the era of antibiotics, it remains a health care burden worldwide with
higher prevalence in some geographic distributions. In the United States,

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CHOREA

Sydenham chorea is still the most common cause of chorea in the pediatric
population, after choreoathetoid cerebral palsy. Patients typically develop
chorea 2 to 3 months after group A β-hemolytic streptococcal throat infection.
Therefore, when chorea is already present, throat culture is usually negative
and not helpful. Furthermore, antibody testing usually performed in clinical
practice (including antistreptolysin O [ASO] and antideoxyribonuclease B [anti-
DNase B]), although having higher diagnostic yields than throat culture, does not
have high sensitivity. In addition to chorea, patients may have tics and
neurobehavioral features, such as anxiety, irritability, attention deficit
hyperactivity disorder, and obsessive-compulsive behaviors, that can sometimes
be disruptive. Thus, the term Sydenham disease has been proposed to cover the
entire spectrum of its clinical features. Some patients have severe hypotonia
along with florid chorea, called chorea paralytica.
Recognition of Sydenham chorea is important, since patients will require a cardiac
workup, particularly echocardiography, and secondary antibiotic prophylaxis
with long-term penicillin, the duration of which depends on the severity of
carditis. Treatment of Sydenham chorea is discussed further in the treatment
section of this article. Sydenham chorea can recur in 20% to 50% of patients, and
persistent symptoms after 2-year follow-up have been reported in up to 50%.18
Chorea gravidarum refers to chorea that initially emerges, reemerges, or
exacerbates during pregnancy. It is a descriptive terminology rather than specific
diagnostic entity, as underlying etiologies such as HD, systemic lupus
erythematosus, antiphospholipid antibody syndrome, and hyperthyroidism should
always be sought. Patients with a history of Sydenham chorea in childhood can have
reemergence of chorea during pregnancy. However, thorough investigations for
other potential underlying causes of chorea in these patients should not be
neglected. Another hormonal-related chorea is chorea that may emerge or reemerge
during the use of oral contraceptive pills, and the same principles should be applied.
Chorea gravidarum can improve spontaneously in the third trimester or shortly
after the patient gives birth,19 and treatment may not be required. Nevertheless, the
most crucial “don’t-miss” step is searching for an underlying etiology.
The workup for acquired causes of chorea can be extensive. If diagnostic clues
are present, a targeted approach can be pursued. In clinical practice, if no
diagnostic clues are present, the first-tier testing includes complete blood cell
count, thyroid function tests, liver function tests, serum electrolytes, serum
calcium, antinuclear antibody, anti–double-stranded DNA antibody, lupus
anticoagulant, and antiphospholipid antibody syndrome workup. When patients
present with a subacute temporal profile, antibody testing in both serum and CSF
should be considered in addition to routine CSF studies.

GENETIC CAUSES OF CHOREA

The most common genetic cause of chorea in adults is HD. Other genetic disorders
that can mimic HD (ie, HD phenocopies) will subsequently be discussed.
Benign hereditary chorea is the most common genetic chorea in children.

Huntington Disease
HD is by far the most common genetic chorea in adults (TABLE 6-2). Geographic
variability is seen, with higher prevalence in some regions because of founder
effects, such as in Venezuela around Lake Maracaibo. Clinical features can be
grouped into three major categories: movement disorders, cognitive impairment,

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and neuropsychiatric features. It is important not to overlook the latter two KEY POINTS
domains, which can be more debilitating than chorea itself. Regarding motor
● Neuropsychiatric features
symptoms, chorea is the main phenomenology in adults but not in children. The such as irritability, attention
forehead is usually involved, and forehead chorea can be useful to distinguish HD deficit hyperactivity
from tardive dyskinesia. In addition to chorea, other abnormal movements, disorder, and obsessive-
including dystonia, myoclonus, and ataxia, can coexist. While dystonic compulsive behavior
can be seen in Sydenham
components such as pelvic tilting can be apparent during walking, the gait
chorea.
pattern is quite complex and probably attributed to more than just a combination
of chorea and dystonia.20 During the natural course of the disease, the severity of ● It is important to search
chorea increases and then plateaus. Subsequently, in later stages, chorea for an underlying etiology in
gradually subsides and parkinsonian features become more prominent.21 hormonal-related chorea,
including chorea gravidarum
Hyperkinetic movements transition into an akinetic-rigid syndrome in the later and estrogen-induced
stages. One implication of this evolution is that symptomatic treatment of chorea chorea.
in HD requires periodic revision over the course of the disease (CASE 6-2).
Cognitive dysfunction in HD includes subcortical dementia, impaired frontal ● Nonmotor features in
Huntington disease are
executive function, disinhibition, difficulty with multitasking, and short-term often more debilitating than
memory impairment. Neuropsychiatric features include depression, suicidal chorea itself.
ideation, anxiety, irritability, apathy, aggression, psychosis, obsessive-
compulsive behaviors, and reduced awareness of deficit.22 ● Chorea is gradually
replaced by parkinsonian
Another important diagnostic clue is eye movement abnormalities. Delayed
features in later stages of
initiation of saccades is a hallmark oculomotor abnormality in HD.23 Other Huntington disease; thus,
choreic disorders with delayed initiation of saccades include ataxia-telangiectasia the treatment regimen
and oculomotor apraxia types 1 and 2. However, these disorders typically present requires revision
at a younger age, and coexisting neuropsychiatric features are uncommon. periodically.

Another eye movement abnormality in HD is an impaired antisaccade task. This ● Delayed initiation of
can be seen by asking the patient to look to the side contralateral to the side on saccades is a hallmark eye
which the examiner is holding up a finger. Patients with HD tend to look to the movement abnormality in
ipsilateral side, reflecting frontal disinhibition. Huntington disease.
HD is an autosomal dominant disorder due to CAG repeat expansion in the
● Senile chorea should not
HTT (also known as IT15) gene on chromosome 4p encoding the huntingtin be used as a diagnosis, and
protein. Individuals with 40 or more CAG repeats have complete penetrance an underlying etiology
(FIGURE 6-4), with an inverse correlation between the number of repeats and the should be sought.
age at onset. Individuals with between 36 and 39 CAG repeats are manifesting
● Children with Huntington
carriers with incomplete penetrance; not all individuals with CAG repeats in this disease typically do not
range will develop HD manifestations during their lifetime. Patients with lower present with chorea but
numbers of repeats tend to have presentation of chorea in late life, which has rather parkinsonism,
been called senile chorea. However, this term is considered obsolete and should dystonia, and seizures.
not be used as a diagnosis. A careful search for underlying etiologies, including ● Age at onset in
HD, should be conducted. Generally, individuals with fewer than 36 CAG repeats Huntington disease is
(35 or fewer) will not manifest the symptoms or signs of HD. Nevertheless, rare determined by the number
case reports exist of manifest HD with an intermediate number (27 to 35) of CAG of CAG repeats, genetic
modifiers, and
repeats. Anticipation tends to occur when unstable CAG repeats are inherited
environmental factors.
from the father, because of CAG-repeat instability during spermatogenesis.
Children with manifest HD typically have 50 to 60 CAG repeats or more. In
contrast to the adult-onset form, juvenile HD (onset at younger than 20 years of
age) typically presents with parkinsonism (also known as the Westphal variant)
and dystonia rather than chorea, as well as seizures. Nevertheless, not only the
number of CAG repeats but also genetic modifiers and environmental factors
contribute to the age at onset24; therefore, the age at onset in an individual cannot
be accurately predicted exclusively from the number of CAG repeats.

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CHOREA

TABLE 6-2 Genetic Causes of Chorea That Primarily Present in Adulthooda

Pattern of Gene (Protein Selected Clinical Clues

Disorder Inheritance Encoded) (Other Than Chorea) Remarks/Caveats
Huntington disease Autosomal CAG repeat expansion Chorea (forehead involvement Founder effect in
dominant in HTT (also known as common), psychiatric (anxiety, some regions (eg,
IT15) gene (huntingtin) depression, obsessive-compulsive Venezuela around
disorder) and cognitive features Lake Maracaibo)
36–39 repeats:
but found
reduced penetrance Delayed initiation of saccades,
worldwide
abnormal antisaccade task
≥40: full penetrance
Consider genetic
Motor impersistence (tongue
>60: juvenile counseling before
and milkmaid’s grip)
Huntington disease genetic testing,
(Westphal variant) Hung-up and pendular knee jerks especially
predictive testing
Patients can have dystonia
and parkinsonism
Parkinsonism becomes more
prominent upon progression
(when chorea “dies out”)
Gait can be complex
Children: parkinsonism
(Westphal variant) and
seizures; typically no chorea

C9orf72 disease Autosomal GGGGCC repeat Phenotypic variability: some Recently found
dominant expansion in C9orf72 patients have frontotemporal to be the most
gene (C9orf72) dementia-amyotrophic lateral common cause
sclerosis of Huntington
disease
Pyramidal features (hyperreflexia)
phenocopies

SCA17 (HDL-4) Autosomal TBP (TATA-box binding Ataxia, dystonia The second most
dominant protein) common cause of
Cognitive impairment,
Huntington
neuropsychiatric features
disease
phenocopies after
C9orf72 disease

Huntington Autosomal CTG/CAG repeat African ancestry Acanthocytes can

disease–like dominant expansion in JPH3 be present in 10%
Can also present with
2 (HDL-2) (junctophilin 3) of patients
parkinsonism without chorea
Neuropsychiatric features

CONTINUED ON PAGE 1013

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CONTINUED FROM PAGE 1012

Pattern of Gene (Protein Selected Clinical Clues

Disorder Inheritance Encoded) (Other Than Chorea) Remarks/Caveats
Neuroacanthocytosis Special technique
syndromes required to detect
acanthocytes in
peripheral blood
smear
Acanthocytes not
specific to these
disorders (refer to
TABLE 6-3)

Chorea- Autosomal VPS13A (chorein) Dystonia with predilection

acanthocytosis recessive to lower cranial region
Characteristic “feeding”
(tongue protrusion) dystonia
Self-mutilation: lip and
tongue biting (mimicking
Lesch-Nyhan syndrome)
Myopathy (with elevated
creatine kinase), neuropathy,
seizure
Psychiatric features (depression,
anxiety, obsessive-compulsive
disorder)
Head drop, rubber man gait
Compared to Huntington disease
(anecdotally), delayed saccade
initiation is less impaired at the
same stage of neuropsychiatric
abnormalities
MRI: atrophy of caudate nuclei,
similar to Huntington disease

McLeod syndrome X-linked XK (Kx antigen) Cardiomyopathy in two-thirds Patients can

benefit from
Seizure, neuropathy, myopathy
autologous blood
Feeding dystonia rare banking because
of the risk of
transfusion
reaction

CONTINUED ON PAGE 1014

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CHOREA

CONTINUED FROM PAGE 1013

Pattern of Gene (Protein Selected Clinical Clues

Disorder Inheritance Encoded) (Other Than Chorea) Remarks/Caveats
Dentatorubral- Autosomal ATN1 (atrophin 1) Generally manifests with High prevalence in
pallidoluysian atrophy dominant choreoathetosis if age at Japan but can also
onset >20 years be seen in other
populations
Adult-onset: ataxia, dystonia,
parkinsonism, dementia Reported as “Haw
River syndrome” in
Childhood-onset: epilepsy,
an African
myoclonus
American family in
MRI: pontocerebellar atrophy, North Carolina
white matter T2 hyperintensities

Neurodegeneration Pantothenate
with brain iron kinase–associated
accumulation neurodegeneration
is rarely reported to
cause chorea

Neuroferritinopathy Autosomal FTL (ferritin light chain) Dystonia with predilection to lower
dominant cranial region
Low serum ferritin (not all cases)
MRI gradient recalled echo
(GRE), or susceptibility-weighted
imaging (SWI): cystic degeneration
in caudate and putamen; “pencil
sign” (cortical lining of iron) has
also been reported

Aceruloplasminemia Autosomal CP (ceruloplasmin) Dystonia, ataxia, diabetes mellitus,

recessive retinal degeneration, anemia
Absent serum ceruloplasmin (as
opposed to low level in Wilson
disease)
Iron accumulation on GRE or SWI MRI
sequences in the striatum, thalami,
and dentate nuclei

HDL = Huntington disease–like; MRI = magnetic resonance imaging; SCA17 = spinocerebellar ataxia type 17.
a
Modified with permission from Termsarasab P.11 © 2017 American Academy of Neurology.

1014 AUGUST 2019

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 Genetic testing in HD is a complex and sensitive issue. Genetic results can
impact not only a patient but also an entire family; therefore, great caution
should be exercised before ordering genetic testing. Appropriate counseling
should be performed by geneticists or genetic counselors, especially for
predictive genetic testing in asymptomatic individuals.25,26
The current clinical and research diagnostic criteria of HD are based on the
presence of unequivocal motor symptoms and signs including chorea, not solely
on the number of CAG repeats. However, attempts have been made to
incorporate cognitive and more subtle motor features to identify patients with
HD at a prodromal stage.27 Identification of individuals at premanifest and
prodromal stages may be useful for subject recruitment into natural history

An 83-year-old woman presented with an 18-month history of abnormal CASE 6-2

movements. The movements initially started in both her hands and feet,
later spreading to the proximal arms and legs. The movements were
absent during sleep. In addition, in the past 8 months, her family
members noted she had developed irritability and inappropriate
jocularity. She denied memory problems, depression, or suicidal
ideation. She had no significant family history.
Examination revealed moderate generalized chorea with choreic gait
(VIDEO 6-5, links.lww.com/CONT/A355). Upper facial chorea, seen as
activation of the frontalis muscle and eyebrow wiggling, was also
present. She demonstrated impulsivity and frontal disinhibition, including
making inappropriate jokes during the examination. She had delayed
initiation of saccades, more prominent in the horizontal than vertical
directions, and blinked her eyes or thrust her head to generate saccades.
Antisaccade tasks were also abnormal. She also had motor impersistence
including inability to maintain tongue protrusion and milkmaid’s grip.
Hung-up jerks, demonstrated as prolonged knee extension upon
quadriceps reflex testing, were present.
She was initially diagnosed with “senile chorea.” Complete blood cell
count, thyroid function tests, serum calcium, and parathyroid hormone
were normal. CT of the brain revealed mild to moderate bilateral caudate
atrophy. After appropriate genetic counseling, genetic testing was
performed, revealing 40 CAG repeats in the HTT gene. Risperidone
0.5 mg/d was initiated for symptomatic control of chorea.

A chronic course (longer than 1 year) is suggestive of a genetic etiology of COMMENT

chorea, the most common of which in adults is Huntington disease (HD). HD
manifests not only with chorea but also cognitive and neuropsychiatric
features that can sometimes be more debilitating than the chorea itself.
Senile chorea, which she had previously been diagnosed with, should
not be used as a diagnosis, and an underlying etiology, such as HD,
hyperthyroidism, or autoimmune causes should be sought. An individual
with a low number of expanded CAG repeats in the HTT gene typically has
a late-onset presentation, as in this patient.

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CHOREA

studies and clinical trials for disease-modifying therapies; however, ethical issues
and impact on patients and families should be taken into consideration.

Huntington Disease Phenocopies

HD phenocopies refers to a group of disorders with clinical features like HD. Given
the much higher prevalence of HD compared to HD phenocopies, HD is often
excluded by genetic testing in these patients before HD phenocopies are
considered.
C9ORF72 DISEASE. According to studies in Europe, the most common HD
phenocopy is C9orf72 disease, followed by SCA17.8,28 However, these data
cannot be simply applied to other populations since the prevalence of these
choreic disorders may differ among various ethnic groups. In addition to chorea,
other movement disorders in C9orf72 disease include ataxia and myoclonus. One
important diagnostic clue is upper motor neuron signs or pyramidal features.
Pathologic studies revealed transactive response DNA-binding protein 43
(TDP-43) pathologies in this disorder. Of note, these repeat expansion disorders
can be missed in next-generation sequencing techniques. Therefore, when
suspecting these disorders, clinicians should ensure that the test panels and
genetic techniques used cover these disorders appropriately.
SPINOCEREBELLAR ATAXIA TYPE 17. SCA17 (also known as Huntington
disease–like 4 [HDL4]) is due to CAG/CAA repeat expansion in the TBP gene
encoding TATA-box binding protein. In addition to ataxia and chorea, patients can
also have psychiatric features or cognitive impairment. Of note, chorea can also
be a presentation in SCA1, SCA2, SCA3, SCA8, and SCA12. However, these SCAs
are less common than SCA17 among HD phenocopies.

FIGURE 6-4
Relationship between CAG repeat length and Huntington disease phenotype.
Figure courtesy of Thananan Thammongkolchai, MD.

1016 AUGUST 2019

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DENTATORUBRAL-PALLIDOLUYSIAN ATROPHY. Dentatorubral-pallidoluysian KEY POINTS
atrophy (DRPLA), an autosomal dominant disorder due to CAG repeat expansion in
● Genetic counseling
the ATN1 gene encoding atrophin 1, can also present with chorea. The prevalence is should be considered
high in Japan, but it has also been reported in other populations. In the United States, before ordering genetic
DRPLA was initially reported in an African American family in North Carolina and testing for Huntington
was called Haw River syndrome29; it has almost exclusively been seen in patients with disease.
African ancestry. In an early-onset form (younger than 20 years of age), patients
● Autosomal recessive
with DRPLA usually have epilepsy and myoclonus, whereas chorea, ataxia, ataxia syndromes can
dystonia, parkinsonism, and dementia are features of the late-onset form. present with a variety of
hyperkinetic movement
AUTOSOMAL RECESSIVE ATAXIA SYNDROMES. In addition to the autosomal disorders, including chorea.
dominant SCAs mentioned above, several autosomal recessive ataxia syndromes
with typical onset in childhood can present with a variety of hyperkinetic movement
disorders, including chorea, dystonia, and myoclonus.30 Examples include Friedreich
ataxia, ataxia-telangiectasia, ataxia with oculomotor apraxia types 1 and 2,
abetalipoproteinemia, and ataxia with vitamin E deficiency.

HUNTINGTON DISEASE–LIKE 2. HDL2 (VIDEO 6-6, links.lww.com/CONT/A356) is

an autosomal dominant disorder due to CTG/CAG repeat expansion in the JPH3
gene encoding junctophilin 3. Clinical features, including neuropsychiatric
features and cognitive impairment, can be similar to HD. Ethnicity is an
important diagnostic clue, as it is almost exclusively seen in patients with African
ancestry. Parkinsonism can be a presentation in some patients. Interestingly,
acanthocytes can be found in about 10% of patients with HDL2. Of note, HDL1
and HDL3 are even rarer than HDL2. HDL1 is a prion disease, and HDL3 has been
reported in only a few families.

NEUROFERRITINOPATHY AND ACERULOPLASMINEMIA. Among all

neurodegeneration with brain iron accumulation disorders, chorea is more
commonly seen in neuroferritinopathy and aceruloplasminemia. Chorea is, in
fact, rare in pantothenate kinase–associated neurodegeneration, the most
common neurodegeneration with brain iron accumulation disorder, which
typically presents with pure dystonia without chorea. Serum ferritin (reduced in
neuroferritinopathy) and ceruloplasmin (absent, not just reduced, in
aceruloplasminemia) can be helpful in the diagnosis. MRI can also be a useful
diagnostic clue (eg, bilateral symmetric cystic change in the basal ganglia or
“cortical pencil lining” in neuroferritinopathy [FIGURE 6-532–34]).

NEUROACANTHOCYTOSIS SYNDROMES. Acanthocytes can be present in a

number of movement disorders 35 :
u Chorea-acanthocytosis
u McLeod syndrome
u HDL2 (in approximately 10% of patients)
u Pantothenate kinase–associated neurodegeneration (in approximately 10% of patients)
u Abetalipoproteinemia (Bassen-Kornzweig syndrome)
u Aceruloplasminemia

The two main disorders in this group are chorea-acanthocytosis and McLeod
syndrome. Chorea-acanthocytosis is due to mutations in the VPS13A gene

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CHOREA

FIGURE 6-5
Neuroimaging in choreic disorders. A, Axial T2* MRI shows hypointensity in the bilateral
striatum (red arrows), thalami (yellow arrowheads), and cortical surface (green arrow),
representing iron accumulation in a patient with aceruloplasminemia. B, Axial T2-weighted
MRI shows cystic degeneration of the bilateral basal ganglia (blue arrows) and hyperintense
signal with a hypointense rim at the bilateral thalami (red arrowheads) in a patient with
neuroferritinopathy. C, Axial susceptibility-weighted imaging (SWI) shows “cortical pencil
lining” representing superficial iron accumulation in a patient with neuroferritinopathy.
Panel A reprinted with permission from Fujita K, et al, Neurology.32 © 2013 American Academy of Neurology.
Panel B reprinted with permission from Ohta E, Takiyama Y, Neurol Res Int.33 © 2012 The Authors. Panel C
reprinted with permission from Batla A, et al, Neurology.34 © 2015 American Academy of Neurology.

encoding for chorein. However, because of the large size of the gene with 76 exons,
gene sequencing is not feasible. Using Western blot to detect chorein deficiency is
another diagnostic method. McLeod syndrome is due to mutations in the XK gene
on the X chromosome encoding for the Kx antigen on the surface of red blood
cells. The mutations lead to absent Kx antigen and reduced Kell antigen. Kx is not a
part of the Kell antigen system, but molecular structural interaction between these
two proteins leads to reduction of Kell protein when Kx antigen is absent. The
McLeod phenotype can be discovered in blood banks during blood screening and
can be detected by using anti-Kx and anti-Kell antibodies.
While acanthocytes are a hallmark of these disorders, three caveats are
important to note here. First, acanthocytes are not specific to these two disorders
and can also be seen in others as noted above. These disorders have also been
included under the umbrella of neuroacanthocytosis syndromes.36 Second, a
special technique using a wet unfixed preparation of an isotonically diluted blood
sample, as described in detail by Storch and colleagues,37 is required for higher
sensitivity of acanthocyte detection in peripheral blood smear. Although the yield
of acanthocyte detection from routine peripheral blood smear is lower, it should
still be examined, with an understanding of its limitations. Third, even with the
appropriate technique, acanthocytes can be absent in neuroacanthocytosis
syndromes; thus, the absence of acanthocytes on peripheral blood smear does not
exclude these disorders.
In chorea-acanthocytosis, dystonia has a predilection to involve the lower
cranial region, and feeding dystonia is one of the characteristic features. This can
lead to poor nutritional status. Lip and tongue biting can be due to feeding
dystonia and possibly coexisting obsessive-compulsive behaviors. Intermittent

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head drop has been observed.31 Delayed saccade initiation, similar to HD, can be KEY POINTS
a feature of chorea-acanthocytosis but anecdotally appears or becomes more
● In addition to chorea-
obvious in the later stages as compared to HD.23 The classic “rubber man” gait is acanthocytosis and McLeod
characterized by intermittent truncal flexion, extension spasms, and, sometimes, syndrome, acanthocytes
knee flexion during walking. The phenomenology of this gait appearance can also be seen in 10% of
remains unclear, but dystonia has been proposed.38,39 Similar to HD, chorea can Huntington disease–like
2 and pantothenate
gradually be replaced by parkinsonian features in the later stages of the disease
kinase–associated
(CASE 6-3). neurodegeneration as well
Clinical features of chorea-acanthocytosis and McLeod syndrome include not as abetalipoproteinemia and
only motor features but also neuropsychiatric features similar to HD, including aceruloplasminemia.
depression, anxiety, and obsessive-compulsive behaviors.
● Patients with McLeod
Associated medical and neurologic features can be helpful diagnostic clues in syndrome can benefit from
neuroacanthocytosis syndromes. Coexisting neuropathy, myopathy, and seizures cardiac surveillance and
can be seen in both chorea-acanthocytosis and McLeod syndrome. Serum creatine autologous blood
kinase and nerve conduction studies and EMG are useful investigations. Elevated transfusion.
serum creatine kinase is suggestive of coexisting myopathy, and nerve conduction ● Caudate atrophy is not
studies and EMG may show evidence of neuropathy or myopathy, or both. specific to Huntington
One of the major clinical differences between chorea-acanthocytosis and disease and can also be seen
McLeod syndrome is that in the latter, cardiomyopathy can be present in more in other disorders, such as
chorea-acanthocytosis and
than 70% of patients but feeding dystonia is rare. Recognition of McLeod
Huntington disease–like 2.
syndrome is of particular importance, since patients can benefit from cardiac
surveillance and autologous blood transfusion. Allogeneic blood transfusion can ● Benign hereditary chorea
potentially lead to severe life-threatening blood transfusion reaction, since syndromes can be due to
antibodies to Kx and Kell antigens are produced after the first exposure of these multiple mutations; the
classic benign hereditary
antigens to blood without the McLeod phenotype. chorea is due to NKX2-1
Atrophy of the caudate nuclei on neuroimaging is not specific to HD and (TITF) mutations. Some
can also be seen in other disorders, including chorea-acanthocytosis and patients with NKX2-1–
HDL2 (FIGURE 6-631). related benign hereditary
chorea can paradoxically
respond to levodopa.
Benign Hereditary Chorea Syndromes
Benign hereditary chorea is the most common genetic cause of chorea in children
(TABLE 6-3). The “classic” benign hereditary chorea is an autosomal dominant
disorder due to mutations in the NKX2-1 (formerly known as TITF-1) gene
encoding thyroid transcription factor-1. Chorea usually begins in infancy or early
childhood, and usually no or minimal progression occurs, with plateauing in
adulthood; rare remission is seen. Other associated clinical features include
ataxia, dystonia, hypotonia, and delayed motor milestones. Cognitive function
is usually normal, but intellectual disability can occur. Given that the NKX2-1
gene also has a role in lung and thyroid development, neonatal respiratory
distress, interstitial lung disease, congenital hypothyroidism, or thyroid agenesis
can coexist and serve as useful diagnostic clues. NKX2-1–related benign
hereditary chorea is also called brain-lung-thyroid syndrome; however,
involvement of all three organs is seen in only 30% to 40% of the patients
(CASE 6-4).40,41
Although indicated in the name as “benign,” it is not always benign. Some
patients may have learning disabilities, attention deficit hyperactivity disorder,
pituitary cysts, recurrent pulmonary infection, pulmonary fibrosis, and
malignancies, such as lung cancer, bladder cancer, or leukemia.42
In addition to the NKX2-1 gene, benign hereditary chorea or benign
hereditary chorea–like phenotypes have been reported in other genes,

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CHOREA

CASE 6-3 A 36-year-old woman presented for an evaluation of her progressive

neurologic symptoms. At age 22, she had developed generalized
tonic-clonic seizures that required multiple antiepileptic medications to
control, including lamotrigine, gabapentin, and zonisamide. During one
episode, she spilled boiling water on herself and required a burn unit
admission and skin graft placement. At age 32, she developed speech
and swallowing problems. She said that her tongue involuntarily pushed
food out when eating, and she also had frequent choking, once requiring
the Heimlich maneuver. She bit her lips and tongue and wore a bite block
24 hours per day. Her family had difficulty understanding her speech over
the phone. At age 35, she developed flinging movements of her arms,
trunk, and legs. She had difficulty walking and experienced multiple falls.
She had developed depression, memory loss, and irritability around age
22 but denied obsessive-compulsive behavior. Family history was
negative.
Examination revealed a mild parkinsonian appearance with facial
dystonia, especially in the lower facial region (VIDEO 6-7, links.lww.com/
CONT/A357). She had moderate dysarthria. Eye examination revealed
delayed initiation of vertical saccades with more limited range of
downgaze than upgaze. She had mild intermittent chorea in her
extremities and trunk as well as some dystonic posturing of the left arm.
Her gait was complex and partially composed of choreic and dystonic
components. She had some hyperextension and circumduction of the left
leg when walking. Deep tendon reflexes were absent throughout.
Acanthocytes were found on a routine peripheral blood smear. Her
creatine kinase was 790 U/L. A previous MRI brain reportedly showed no
caudate atrophy but was not available for review. Western blot of her
blood sample revealed absence of chorein protein. The diagnosis of
chorea-acanthocytosis was confirmed. Her care was managed by a
multidisciplinary team, including physical, occupational, and speech
therapists.

COMMENT Chorea, along with feeding dystonia, seizures, and coexisting neuropathy
or myopathy (evidenced by absent or reduced deep tendon reflexes and
elevated creatine kinase) are very suggestive of chorea-acanthocytosis, an
autosomal recessive form of neuroacanthocytosis syndromes. Although
present in this patient, acanthocytes in the peripheral blood smear are not
always seen even with a special technique using a wet unfixed preparation
of an isotonically diluted blood sample. Delayed initiation of saccades,
similar to that seen in Huntington disease, can be seen in chorea-
acanthocytosis; however, it usually comes in the later stages compared to
Huntington disease. Vertical supranuclear gaze palsy is an unusual feature
in chorea-acanthocytosis. Therapies for choreic disorders are not
restricted to the treatments of chorea. Although specific therapies are not
yet available, and symptomatic treatment is not required if chorea is mild
and nonbothersome, patients such as this one could benefit from
multidisciplinary care by a physical medicine and rehabilitation specialist
and physical, occupational, and speech therapists.

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FIGURE 6-6
Choreic disorders with bilateral caudate atrophy on neuroimaging. A, CT scan showing bilateral
caudate atrophy in Huntington disease (white arrowheads). B, Coronal T1-weighted MRI in a
patient with Huntington disease–like 2 (red arrowheads). C, Axial fluid-attenuated inversion
recovery (FLAIR) MRI in a patient with chorea-acanthocytosis (yellow arrowheads).
Panel B reprinted with permission from Margolis RL, Holmes SE, Clin Neurosci Res.31 © 2001 Nature Press.

including ADCY5,43,44 PDE10A,45,46 GNAO1,47 and SLC16A2 (associated with

Allan-Herndon-Dudley syndrome).48 Therefore, benign hereditary chorea
represents the clinical syndromes, rather than one specific disorder. The term
benign hereditary chorea syndromes has been used to represent the entire group
of patients with clinical features compatible with or similar to benign hereditary
chorea as described above regardless of the underlying genetic defects, whereas
the term classic benign hereditary chorea specifically denotes NKX2-1–related benign
hereditary chorea. While no consensus definition or distinct clinical boundary of
benign hereditary chorea syndromes exists, this term may be useful for searching
for other underlying genetic defects when encountering patients with clinical
pictures similar to or mimicking NKX2-1–related benign hereditary chorea.
Unfortunately, this terminology has not been consistently used in the literature or
clinical practice; thus, whether benign hereditary chorea represents only the classic
form or the benign hereditary chorea syndromes should always be clarified.
In addition to general symptomatic therapies for chorea, patients with
NKX2-1–related benign hereditary chorea can paradoxically respond to levodopa
for unknown reasons. In the author’s experience, this responsiveness can be
seen in some, but not all, patients.
ADCY5-related dyskinesia, previously known as familial dyskinesia with facial
myokymia,49 is an autosomal dominant disorder due to mutations in the ADCY5
gene encoding adenylate cyclase 5. Patients may have clinical features mimicking
NKX2-1–related benign hereditary chorea, but mixed movement disorders,
including chorea, dystonia, and myoclonus, often occur.43,44 One diagnostic
clue is facial dyskinesia, which cannot be perfectly categorized into any
previously described movement disorder phenomenology. Facial myokymia
was a misnomer, since subsequent electrophysiologic studies did not reveal
evidence of myokymia.50 Other clinical features include hypotonia, delayed
motor milestones, and exacerbation of dyskinesia during transitions between
wakefulness and sleep including drowsiness and sleep arousal.51 In some patients,
the movements may be paroxysmal.

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CHOREA

TABLE 6-3 Genetic Causes of Chorea That Primarily Present in Childhooda

Selected Clinical
Pattern of Gene (Protein Clues (Other
Disorder Inheritance Encoded) Than Chorea) Remarks/Caveats

Choreoathetoid NA NA Dystonia often Included in this

cerebral palsy coexists with chorea table as it is likely
composed of a
Flowing component
mixed bag of
may sometimes be
genetic/
difficult to
neurometabolic
differentiate
disorders, in
between dystonia
addition to hypoxic
and choreoathetosis
brain injury, which
Dystonic hand have to be ruled out
posturing typically carefully before
not painful; it is making this diagnosis
unique and difficult
for healthy person to
mimic

Benign hereditary Can be due to

chorea syndromes mutations in several
genes, including
NKX2-1, ADCY5,
PDE10A, GNAO1,
SLC16A2 (Allan-
Herndon-Dudley
syndrome)

Classic benign Autosomal NKX2-1 (formerly Also called Some may have
hereditary chorea dominant known as TITF-1) brain-lung-thyroid paradoxical
syndrome or gene (thyroid syndrome (or BLT response to
NKX2-1–related transcription factor-1) syndrome) levodopa
benign hereditary
Hypothyroidism and
chorea
pulmonary disease
(eg, respiratory
distress or interstitial
lung disease) can
coexist
Typically
nonprogressive, but
not always benign
(considered
relatively more
benign, compared to
Huntington disease)
Patients may have
developmental
delay or short
stature

CONTINUED ON PAGE 1023

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CONTINUED FROM PAGE 1022

Selected Clinical
Pattern of Gene (Protein Clues (Other
Disorder Inheritance Encoded) Than Chorea) Remarks/Caveats

ADCY5-related Autosomal ADCY5 (adenylate Phenotypic Previously called

dyskinesia dominant cyclase 5) variability familial dyskinesia
with facial
Mixed movement
myokymia, but the
disorders, including
facial movements
chorea, dystonia,
are, in fact, not
myoclonus
myokymia, based on
Movements can be EMG studies
paroxysmal

Lesch-Nyhan X-linked HPRT1 (hypoxanthine- Often associated Females can less

syndrome recessive guanine with dystonia with commonly be
phosphoribosyltransferase) predominant lower affected because of
cranial involvement skewed inactivation
of X chromosome
Self-mutilation
May resemble
chorea-
acanthocytosis, but
age group is typically
younger in Lesch-
Nyhan syndrome
Hyperuricemia

Wilson disease Autosomal ATP7B (ATP7B) Varieties of

recessive movement
disorders, including
dystonia,
parkinsonism, ataxia,
tremor (including
classic wing-beating
tremor, a form of
cerebellar tremor
but not common)
Kayser-Fleischer
rings (pay attention
to upper and lower
corneal limbi); when
in doubt, refer for
slit-lamp examination
Low serum
ceruloplasmin, low
serum copper, high
24-hour urine copper

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CHOREA

CONTINUED FROM PAGE 1023

Selected Clinical
Pattern of Gene (Protein Clues (Other
Disorder Inheritance Encoded) Than Chorea) Remarks/Caveats

Autosomal Most autosomal

recessive ataxia recessive ataxias
with onset in
childhood can
present with
hyperkinetic
movement
disorders, including
dystonia, chorea,
and myoclonus

Friedreich ataxia Autosomal FXN due to GAA Dystonia, ataxia, pes

recessive repeat expansion cavus, hyporeflexia,
and/or mutations diabetes mellitus,
(frataxin) cardiomyopathy,
scoliosis
Eye movement
examination:
macrosaccadic
oscillations,
hypermetric
saccades
Relatively preserved
cerebellar size on
MRI until late stages
Variants (these two
overlap):
Friedreich ataxia
with retained reflex
or hyperreflexia,
often late onset
Late-onset
Friedreich ataxia

Ataxia with Autosomal APTX (aprataxin) Oculomotor apraxia Differential

oculomotor apraxia recessive (delayed initiation of diagnoses of
type 1 (AOA1) saccades) oculomotor apraxia
associated with
Neuropathy
ataxia include ataxia-
Low serum albumin, telangiectasia, AOA1
high cholesterol and AOA2

Ataxia with Autosomal SETX (senataxin) Age group is α-Fetoprotein can

oculomotor apraxia recessive typically older than also be elevated in
type 2 (AOA2) AOA1 ataxia-telangiectasia
(almost all cases)
Oculomotor apraxia
Neuropathy
High α-fetoprotein in
almost all cases

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CONTINUED FROM PAGE 1024

Selected Clinical
Pattern of Gene (Protein Clues (Other
Disorder Inheritance Encoded) Than Chorea) Remarks/Caveats

Metabolic disorders Autosomal Multiple Can also present Differential

(eg, organic recessive with dystonia diagnoses include
acidemia) methylmalonic
Hyperintense signals
acidemia and
at bilateral lentiform
glutaric aciduria type
nuclei on T2-
I, among others
weighted MRI
Check plasma amino
acids and urine
organic acids

Mitochondrial Mitochondrial or Mitochondrial/nuclear May also present Start by checking for

disorders (eg, Leigh autosomal gene mutations with dystonia high lactate level in
syndrome or MELAS) recessive (if serum and CSF
MRI in Leigh
attributed to
syndrome:
nuclear
hyperintense signal
mutations)
at bilateral basal
ganglia and/or
brainstem on T2-
weighted sequences
MELAS can have
basal ganglia
calcification (CT is
useful to
demonstrate)

CSF = cerebrospinal fluid; CT = computed tomography; EMG = electromyography; MELAS = mitochondrial encephalomyopathy, lactic acidosis,
and strokelike episodes; MRI = magnetic resonance imaging; NA = not applicable.
a
Modified with permission from Termsarasab P.11 © 2017 American Academy of Neurology.

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CHOREA

Other rarer genes related to benign hereditary chorea syndromes are discussed
here only briefly. PDE10A mutations can be either autosomal dominant or
recessive. The dominant forms or de novo mutations typically present with
chorea at around 5 to 10 years of age and show bilateral striatal hyperintense
signals on MRI (hence, also called childhood-onset bilateral striatal necrosis), but
no intellectual impairment is seen.45 The recessive forms are more severe.
Clinical features include infantile-onset chorea and motor and language
developmental delay but, interestingly, no striatal hyperintensity on MRI.46
Gain-of-function mutations in the GNAO1 gene can present with chorea,47
whereas loss-of-function mutations cause Ohtahara syndrome, a form of early
infantile epileptic encephalopathy. Relatively new genes reported in chorea
associated with epilepsy include FOXG1 (in which patients can have prominent
orofacial chorea/dyskinesia),52 GRIN153,54 and FRRS1L.55

CASE 6-4 A 6-year-old boy came to the clinic for follow-up of his choreic disorder.
He was born full term without any prenatal and perinatal complications.
However, during the first 2 years of life, he was diagnosed with
hypothyroidism and “asthma.” Around 4.5 years of age, he was evaluated
in the movement disorder clinic because of abnormal movements
compatible with generalized chorea, which had gradually become more
noticeable in the past 1.5 years. Multiple family members on his maternal
side had thyroid problems and asthma; however, no abnormal movement
was reported in these family members. The diagnosis of benign
hereditary chorea was suspected, and it was confirmed by the mutation
in the NKX2-1 (formerly known as TITF-1) gene. He had mild intellectual
disability and had participated in a special school program. His chorea
had been stable in the past 2 years. He was trialed on levodopa at the age
of 6 years up to 5 mg/kg/d for symptomatic control of chorea. However,
because no improvement was seen, it was subsequently discontinued.
Examination revealed mild to moderate generalized chorea involving
all extremities, trunk, neck, and lower facial region, as well as mild
bilateral foot dystonia demonstrated as mild foot inversion when
walking. The dystonic component was much less prominent than chorea.
Treatment options, including tetrabenazine, were discussed with his
parents.

COMMENT This patient’s chronic temporal profile is suggestive of a genetic cause of

chorea, the most common of which in children is benign hereditary chorea.
Benign hereditary chorea syndrome can be due to several mutations. The
“classic” benign hereditary chorea syndrome is due to NKX2-1 (TITF-1)
mutations, which can also cause lung and thyroid problems (hence the term
brain-lung-thyroid syndrome), as in this patient. While seen in this patient,
involvement of all three organs is present in only 30% to 40% of patients.
Benign hereditary chorea is not always “benign”; for example, this patient
has intellectual disability. Some, but not all, patients with this disorder can
respond to levodopa.

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CHOREA IN PAROXYSMAL MOVEMENT DISORDERS
This special group of disorders can be divided into two main categories: primary
and secondary paroxysmal dyskinesias. Based on the triggers, primary
paroxysmal dyskinesias can be further classified into paroxysmal kinesigenic
dyskinesia, paroxysmal nonkinesigenic dyskinesia, and paroxysmal exercise-
induced dyskinesia. Although dystonia is common during the paroxysmal
attacks, chorea can also be seen. When encountering patients with paroxysmal
chorea, these disorders should be considered. Paroxysmal kinesigenic dyskinesia
typically has exquisite response to low-dose antiepileptic medications, especially
carbamazepine. In patients with paroxysmal exercise-induced dyskinesia,
glucose transporter 1 deficiency syndrome, which is treatable, should be
excluded. With advances in genetics, the number of genes associated with each
phenotype has been expanding.56–58 A detailed discussion about paroxysmal
movement disorders is beyond the scope of this article.

TREATMENT
The first question before initiating treatment is “Does chorea need to be treated?”
(TABLE 6-4). When chorea is mild and nonbothersome and does not interfere
with a patient’s daily activities, symptomatic treatment is not required. In some
choreic disorders, such as HD, lack of awareness of the deficit by patients as a
possible coexisting neuropsychiatric feature may limit evaluation of chorea
severity solely from patients’ reports. Thus, the clinician’s and family’s
evaluation of chorea severity should also be incorporated into clinical decisions.
When clinicians decide to treat, two main categories of therapies should be
considered: specific therapies and symptomatic therapies (TABLE 6-5).

Specific Therapies
Many acquired choreas are treatable, so correct diagnosis of these “don’t-miss”
disorders is a crucial step before using corresponding specific therapies.
Examples include blood sugar control in nonketotic hyperglycemia, phlebotomy
and hydroxyurea in polycythemia vera, antibiotics in central nervous system
(CNS) infection such as CNS toxoplasmosis, and immunotherapies in
autoimmune choreas, including systemic lupus erythematosus.

Symptomatic Therapies
Symptomatic therapies include pharmacologic treatment and deep brain
stimulation (DBS).

Principles of Chorea Treatment TABLE 6-4

Step 1: Does chorea need to be treated? When it is mild and nonbothersome, treatment is not
required.
Step 2: Is specific treatment available?
Step 3: If chorea is not controlled by specific treatment or specific treatment is not available,
what symptomatic therapies should be selected?
Step 4: Are there any other symptoms than chorea that require treatment or surveillance?
Patients can benefit from multidisciplinary approach.
Step 5: Does any family member need further evaluation or genetic counseling?

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CHOREA

TABLE 6-5 Therapeutic Options in Chorea

Specific Therapies
◆ Blood sugar control in nonketotic hyperglycemia
◆ Phlebotomy and hydroxyurea in polycythemia vera
◆ Treatment for hyperthyroidism
◆ Immunotherapies in autoimmune choreas
Symptomatic Therapies
◆ Pharmacologic therapies
◇ Presynaptic dopamine depletors
→ Tetrabenazine and reserpine
→ New-generation vesicular monoamine transporter 2 inhibitors
– Deutetrabenazine
– Valbenazine
◇ Postsynaptic dopamine receptor blockers (dopamine receptor blocking agents,
neuroleptics or antipsychotics)
→ Typical antipsychotics
– Haloperidol
→ Atypical antipsychotics
– Olanzapine
– Risperidone
– Quetiapine
– Clozapine
◇ Others
→ Antiepileptics
– Valproic acid
– Carbamazepine
Deep Brain Stimulation
◆ Reported in Huntington disease, chorea-acanthocytosis, and some acquired choreas
Multidisciplinary Approach
◆ Psychiatrist; physical medicine and rehabilitation specialist; physical, occupational, and
speech therapists
◆ Geneticist, genetic counselor
◆ Social worker

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PHARMACOLOGIC THERAPIES. As a general principle, the “start low, go slow” KEY POINTS
strategy should be followed. Medications should be started at a low dose and
● Patients with choreic
gradually titrated over time to reach the effective dose to avoid side effects. If disorders can benefit from a
side effects occur, tapering the medications and monitoring are required. If multidisciplinary approach.
medications need to be discontinued for any reason, slow tapering should be Associated features and
considered to avoid withdrawal side effects. comorbidities, such as
cognitive and
Given a hyperdopaminergic state as a general hypothesis of the pathophysiology
neuropsychiatric features,
of chorea, the strategy for symptomatic therapies is to reduce the amount of should be taken into
dopamine or its effect within the CNS. The main pharmacologic targets are consideration when treating
dopaminergic synapses, either at presynaptic or postsynaptic sites (FIGURE 6-7). chorea. Mild and
nonbothersome chorea
MEDICATIONS TARGETING THE PRESYNAPTIC SITE (PRESYNAPTIC DOPAMINE- does not require treatment.
DEPLETING AGENTS). Presynaptic dopamine-depleting agents include Immunotherapies are
treatment options in
tetrabenazine and reserpine. Both drugs inhibit vesicular monoamine Sydenham chorea.
transporter (VMAT) 2 in the CNS, thereby preventing packaging of dopamine
into presynaptic vesicles. Dopamine is then degraded by a monoamine oxidase B ● The main pharmacologic
enzyme. Tetrabenazine is a selective VMAT2 inhibitor, whereas reserpine also targets of chorea are
dopaminergic synapses,
inhibits VMAT1 in the peripheral nervous system and can lead to hypotension.
either at presynaptic or
Tetrabenazine is widely used in clinical practice and was approved by the US postsynaptic sites
Food and Drug Administration (FDA) for chorea associated with HD in 2008,
based on the TETRA-HD (Efficacy, Safety, and Dose Tolerability of

FIGURE 6-7
Sites of action of the main pharmacologic therapies in chorea. 1, Presynaptic dopamine-
depleting agents are vesicular monoamine transporter 2 (VMAT2) inhibitors. 2, Postsynaptic
dopamine receptor blocking agents (DRBAs) act by blocking mainly D2 receptors.
Figure courtesy of Thananan Thammongkolchai, MD.

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CHOREA

Tetrabenazine for Chorea in Huntington Disease) study.59 In addition to HD,

tetrabenazine has been used off-label for other indications, including chorea
from other etiologies and various hyperkinetic movement disorders such as tics
and Tourette syndrome.60,61 Because of presynaptic monoamine depletion, side
effects include parkinsonism, depression, and akathisia. Because of the potential
risks of depression and suicidality, tetrabenazine carries an FDA boxed warning.
Its active metabolites are degraded by the CYP2D6 enzyme. When the dose is
greater than 50 mg/d, CYP2D6 enzyme testing is currently recommended to
determine whether patients are poor, intermediate, or extensive metabolizers.
Extensive metabolizers may require higher doses.
The new-generation selective VMAT2 inhibitors include deutetrabenazine and
valbenazine. Deutetrabenazine was approved by the FDA for chorea associated
with HD in April 2017 and for tardive dyskinesia in August 2017, based on the
FIRST-HD (First Time Use of SD-809 in Huntington Disease)62 and AIM-TD
(Addressing Involuntary Movements in Tardive Dyskinesia)63 studies, respectively.
Six hydrogen atoms in tetrabenazine are replaced by deuterium or “heavy
hydrogen” atoms in deutetrabenazine. This leads to pharmacokinetic advantages,
including longer plasma half-life (9 to 10 hours for deutetrabenazine compared to
5 to 7 hours for tetrabenazine) and less plasma level fluctuation of the drug, and
thus fewer side effects, especially sedation. In addition, deutetrabenazine can be
administered 2 times a day, instead of 3 times a day as with tetrabenazine. Despite
no statistical difference in depression and suicidality between the treatment and
control groups in the FIRST-HD study, deutetrabenazine carries an FDA boxed
warning for depression and suicidality in patients with HD.
Valbenazine is a prodrug of one of the isomeric metabolites of tetrabenazine.
It is slowly metabolized into (+)-α-dihydrotetrabenazine. The pharmacokinetic
advantage of valbenazine and its metabolite is long plasma half-life (16 to
22 hours), so the medication can be administered once daily. It was approved
for tardive dyskinesia in adults in April 2017, based on the KINECT-3 (A Phase
3 Study of NBI-98854 for the Treatment of Tardive Dyskinesia) study.64
Valbenazine has not been studied in chorea associated with HD. Side effects
of valbenazine include sedation, headache, and QTc prolongation. It is
contraindicated in patients with underlying congenital prolonged QT
syndrome or arrhythmias with prolonged QT interval.
α-Methyl-p-tyrosine (metyrosine) depletes presynaptic dopamine by
inhibiting tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis.
However, this drug is not available in the United States and most other countries.

MEDICATIONS TARGETING THE POSTSYNAPTIC DOPAMINERGIC SITES. Medications

that target the postsynaptic dopaminergic sites are mainly dopamine receptor
blocking agents (also called antipsychotics or neuroleptics). The dopamine
receptor blocking agents effective for treatment of chorea typically have a
mechanism of action at the D2 receptor, which also contributes to the risk of
developing tardive dyskinesia. The “cleaner” dopamine receptor blocking
agents, such as clozapine and quetiapine, have also been used but may not be as
effective as dopamine receptor blocking agents with higher affinity to D2
receptors, such as the typical antipsychotics, in particular, haloperidol, and
atypical antipsychotics such as olanzapine and risperidone While clozapine is
relatively the “cleanest” with regard to the risk of tardive dyskinesia, the need
for frequent blood monitoring limits its use, especially in the setting of

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coexisting cognitive impairment or poor compliance, which may not be
uncommon in patients with chorea. Because of the risks of tardive dyskinesia,
many clinicians, especially clinicians in the United States, prefer the presynaptic
dopamine-depleting agents to dopamine receptor blocking agents. According to
a 2011 international survey,65 treatment preferences for chorea in HD differed
between Europe and America. In Europe, clinicians preferred antipsychotics to
tetrabenazine, whereas in the United States, preferences were roughly equally split
between antipsychotics and tetrabenazine. However, there may be a trend to use
more presynaptic dopamine-depleting agents in current clinical practice.66
Other associated clinical features or comorbidities should be taken into
consideration when selecting treatment for chorea. Antipsychotics may be
preferable to presynaptic dopamine-depleting agents when one or more of the
following exists: (1) coexisting psychosis or aggression, which can be seen in
some choreic disorders such as HD and chorea-acanthocytosis; (2) coexisting
depression and suicidal risks that preclude the use of presynaptic dopamine-
depleting agents; and (3) noncompliance.65 Given the higher cost of presynaptic
dopamine-depleting agents and their limited availability, antipsychotics remain
the only or more preferable choice in many regions of the world.
Dopamine receptor blocking agents, especially olanzapine and risperidone,
can cause metabolic syndromes, including weight gain, which can be a beneficial
effect in patients with significant weight loss and poor nutritional status.
Blood chemistries, including lipid profile and glucose, should be monitored
periodically. Other symptomatic therapies for chorea include antiepileptic drugs
such as valproic acid and carbamazepine (eg, in Sydenham chorea), and
levodopa (in benign hereditary chorea).
Treatment of Sydenham chorea deserves some specific discussion here. For
symptomatic treatment of the chorea, antiepileptic drugs, including valproic acid
and carbamazepine, have been found to be effective.67 Antipsychotics can pose
risks of drug-induced parkinsonism in Sydenham chorea and thus have to be
used with caution, typically as second-line treatment.68 Immunomodulatory
therapies (which serve as specific rather than symptomatic therapies), including
IVIg, IV steroids, and plasma exchange, have been increasingly employed in
Sydenham chorea,69 although more evidence from clinical trials is needed. This
option can be considered in patients with severe Sydenham chorea such as chorea
paralytica or as second-line treatment in patients with inadequate response to
conventional symptomatic therapies.

DEEP BRAIN STIMULATION. DBS in chorea remains a moving target. Most studies
have been done in HD70 and chorea-acanthocytosis.71 These are mostly case
reports or small case series,72 which can pose some biases, as cases with poor
outcome are unlikely to be reported. The most common target is the globus
pallidus internus (GPi), and stimulation at the ventral GPi is known to have an
antidyskinetic effect from extensive DBS experience in Parkinson disease.
Further clarification on DBS efficacy, candidacy, and appropriate targets can be
elucidated from future studies and randomized controlled trials.
Factors other than chorea also should be considered when selecting DBS as a
treatment. First, coexisting cognitive and neuropsychiatric features can even be
more debilitating than chorea and other motor features and are unlikely to be
responsive to DBS. Secondly, chorea in HD and chorea-acanthocytosis can
gradually be replaced by parkinsonism in the later stages of the diseases. Thus, the

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CHOREA

natural history of the disease can contribute to chorea reduction, and different
stimulation or programming strategies may be required in different stages (eg, more
dorsal electrodes in GPi to control parkinsonism). Experimental genetic therapies,
especially huntingtin-lowering treatment, are under active investigation,73,74
and more data will be required before application to clinical practice.
A holistic approach is also crucial in the care of patients with chorea. Many patients
with chorea experience not only motor symptoms but also cognitive and
neuropsychiatric features as well as psychosocial issues. A multidisciplinary team
approach that includes psychiatrists, physical medicine and rehabilitation specialists,
physical therapists, occupational therapists, speech therapists, social workers, and
geneticists and genetic counselors can be beneficial. Furthermore, in some disorders,
especially HD, the unit of treatment is an entire family rather than an individual patient.
Caregiver burden and the stress of at-risk family members should also be supported.

CONCLUSION
The etiology of chorea can be categorized into acquired and genetic causes.
Among the most useful features in the diagnostic approach are time course, age
group, and known prevalence in the population. Other clinical diagnostic clues
can help guide the investigation. Genetic counseling should be considered before
sending genetic testing in chorea. Management should include not only
symptomatic treatment of chorea but also other associated medical, neurologic,
and psychiatric aspects. Family and caregiver support should be also taken into
consideration when caring for patients with chorea.

VIDEO LEGENDS
VIDEO 6-1 VIDEO 6-4
Hemiballism secondary to central nervous system Sydenham chorea. Video shows an 8-year-old boy
toxoplasmosis. Video shows a 54-year-old man with Sydenham chorea who presented with an
with left hemiballism exhibiting large-amplitude acute temporal profile of severe generalized
movements involving the predominantly proximal chorea. He also displays hypotonia and milkmaid’s
arm and leg. On MRI, fluid-attenuated inversion grip. He is unable to stand unassisted.
recovery (FLAIR) images show numerous multifocal links.lww.com/CONT/A354
hyperintense lesions that also involve the basal
ganglia. Reproduced with permission from Frucht SJ.17
links.lww.com/CONT/A351 © 2013 Springer Science+Business Media.

Courtesy of Steven Frucht, MD.

© 2019 American Academy of Neurology. VIDEO 6-5
Huntington disease. Video shows the 83-year-old
VIDEO 6-2 woman described in CASE 6-2. She has Huntington
Hemichorea secondary to nonketotic disease and exhibits generalized chorea including
hyperglycemia. Video shows the 77-year-old upper and lower facial involvement, parakinesia,
woman described in CASE 6-1. She has hemichorea motor impersistence involving the tongue,
secondary to nonketotic hyperglycemia and milkmaid’s grip, and choreic gait. Hung-up knee jerk
demonstrates left hemichorea involving the face, is also shown.
arm, and leg as well as hemichoreic gait. links.lww.com/CONT/A355
links.lww.com/CONT/A352
© 2019 American Academy of Neurology.
© 2019 American Academy of Neurology.

VIDEO 6-3
Lupus chorea. Video shows a 29-year-old woman
with acute generalized chorea and encephalopathy
as her first presentation of systemic lupus
erythematosus. Both chorea and her mental status
improved after 3 days of treatment with IV steroids
and tetrabenazine 75 mg/d.
links.lww.com/CONT/A353
Courtesy of Steven Frucht, MD.
© 2019 American Academy of Neurology.

1032 AUGUST 2019

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VIDEO 6-6 VIDEO 6-7
Huntington disease–like 2. Video shows a Chorea-acanthocytosis. Video shows the
56-year-old woman exhibiting generalized chorea 36-year-old woman with chorea-acanthocytosis
and tongue impersistence. She is originally from described in CASE 6-3. The first video segment
Barbados with African ancestry. Genetic testing for demonstrates severe tongue protrusion and
Huntington disease is negative, and she is feeding dystonia. In the second segment, she
genetically confirmed to have mutations in JPH3 exhibits a mild parkinsonian appearance and lower
diagnostic of Huntington disease–like 2. facial and left arm dystonia, but only mild truncal
links.lww.com/CONT/A356 chorea. She walks with stutter steps and has
circumduction of the left leg.
Courtesy of Steven Frucht, MD. links.lww.com/CONT/A357
© 2019 American Academy of Neurology.
© 2019 American Academy of Neurology.

REFERENCES

1 Morris JGL, Jankelowitz SK, Fung VSC, et al. 11 Termsarasab P. Hyperkinetic movement disorders:
Athetosis I: historical considerations. Mov Dis videodiagnosis and treatment. Presented at:
2002;17:1278–1280. doi:10.1002/mds.10267. 69th Annual Meeting of the American Academy
of Neurology; April 22–28, 2017; Boston, MA.
2 Postuma RB, Lang AE. Hemiballism: revisiting a
classic disorder. Lancet Neurol 2003;2:661–668. 12 Damato V, Balint B, Kienzler AK, Irani SR. The
doi:10.1016/S1474-4422(03)00554-4. clinical features, underlying immunology, and
treatment of autoantibody-mediated movement
3 Cosentino C, Torres L, Nunez Y, Suarez R,
disorders. Mov Disord 2018;33(9):1376–1389.
Velez M, Flores M. Hemichorea/hemiballism
doi:10.1002/mds.27446.
associated with hyperglycemia: report of
20 cases. Tremor Other Hyperkinet Mov (N Y) 13 Varley JA, Webb AJS, Balint B, et al. The
2016;6:402. doi:10.7916/D8DN454P. movement disorder associated with NMDAR
antibody-encephalitis is complex and characteristic:
4 Lew J, Frucht SJ, Kremyanskaya M, et al.
an expert video-rating study. J Neurol Neurosurg
Hemichorea in a patient with JAK2V617F blood
Psychiatry 2018;pii:jnnp-2018–318584. doi:10.1136/
cells. Blood 2013;121(7):1239–1240. doi:10.1182/
jnnp-2018-318584.
blood-2012-12-468751.
14 Sabater L, Gaig C, Gelpi E, et al. A novel non-
5 Ryan C, Ahlskog JE, Savica R. Hyperglycemic
rapid-eye movement and rapid-eye-movement
chorea/ballism ascertained over 15 years at a
parasomnia with sleep breathing disorder
referral medical center. Parkinsonism Relat
associated with antibodies to IgLON5: a case
Disord 2018;48:97–100. doi:10.1016/j.
series, characterisation of the antigen, and post-
parkreldis.2017.12.032.
mortem study. Lancet Neurol 2014;13(6):575–586.
6 Walker RH. Untangling the thorns: advances doi:10.1016/S1474-4422(14)70051-1.
in the neuroacanthocytosis syndromes.
15 Gaig C, Graus F, Compta Y, et al. Clinical
J Mov Disord 2015;8(2):41–54. doi:10.14802/
manifestations of the anti-IgLON5 disease.
jmd.15009.
Neurology 2017;88(18):1736–1743. doi:10.1212/
7 Fekete R, Jankovic J. Upper facial chorea in WNL.0000000000003887.
Huntington disease. J Clin Mov Disord 2014;1:7.
16 Gelpi E, Höftberger R, Graus F, et al.
doi:10.1186/2054-7072-1-7.
Neuropathological criteria of anti-IgLON5-
8 Hensman Moss DJ, Poulter M, Beck J, et al. related tauopathy. Acta Neuropathol 2016;132(4):
C9orf72 expansions are the most common 531–543. doi:10.1007/s00401-016-1591-8.
genetic cause of Huntington disease
17 Frucht SJ, editor. Movement disorder
phenocopies. Neurology 2014;82(4):292–299.
emergencies. 2nd edition. New York, NY:
doi:10.1212/WNL.0000000000000061.
Humana Press, 2013.
9 Van Mossevelde S, van der Zee J, Gijselinck I,
18 Cardoso F, Vargas AP, Oliveira LD, et al.
et al. Clinical evidence of disease anticipation in
Persistent Sydenham's chorea. Mov Disord 1999;
families segregating a C9orf72 repeat expansion.
14(5):805–807. doi:10.1002/1531-8257(199909)14:
JAMA Neurol 2017;74(4):445–452. doi:10.1001/
5<805::AID-MDS1013>3.0.CO;2-P.
jamaneurol.2016.4847.
19 Robottom BJ, Weiner WJ. Chorea gravidarum.
10 Krause A, Mitchell C, Essop F, et al. Junctophilin 3
Handb Clin Neurol 2011;100:231–235. doi:10.1016/
(JPH3) expansion mutations causing Huntington
B978-0-444-52014-2.00015-X.
disease like 2 (HDL2) are common in South
African patients with African ancestry and a 20 Termsarasab P, Frucht SJ. The “stutter-step”: a
Huntington disease phenotype. Am J Med Genet peculiar gait feature in advanced Huntington's
B Neuropsychiatr Genet 2015;168(7):573–585. disease and chorea-acanthocytosis. Mov Disord
doi:10.1002/ajmg.b.32332. Clin Pract 2018;5:223–224. doi:10.1002/
mdc3.12586.

CONTINUUMJOURNAL.COM 1033

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

CHOREA

21 Bates GP, Dorsey R, Gusella JF, et al. Huntington 36 Peikert K, Danek A, Hermann A. Current state of
disease. Nat Rev Dis Primers 2015;1:15005. knowledge in chorea-acanthocytosis as core
doi:10.1038/nrdp.2015.5. neuroacanthocytosis syndrome. Eur J Med Genet
2017;61(11):699–705. doi:10.1016/j.ejmg.2017.12.007.
22 McColgan P, Tabrizi SJ. Huntington's disease: a
clinical review. Eur J Neurol 2018;25(1):24–34. 37 Storch A, Kornhass M, Schwarz J. Testing for
doi:10.1111/ene.13413. acanthocytosis: a prospective reader-blinded
study in movement disorder patients. J Neurol
23 Termsarasab P, Thammongkolchai T, Rucker JC,
2005;252(1)84–90. doi:10.1007/s00415-005-0616-3.
Frucht SJ. The diagnostic value of saccades in
movement disorder patients: a practical guide 38 Schneider SA, Lang AE, Moro E, et al.
and review. J Clin Mov Disord 2015;2:14. doi: Characteristic head drops and axial extension in
10.1186/s40734-015-0025-4. advanced chorea-acanthocytosis. Mov Disord
2010;25(10):1487–1491. doi:10.1002/mds.23052.
24 Gusella JF, MacDonald ME, Lee JM. Genetic
modifiers of Huntington's disease. Mov Disord 39 Bhidayasiri R, Jitkritsadakul O, Walker RH. Axial
2014;29(11):1359–1365. doi:10.1002/mds.26001. sensory tricks in chorea-acanthocytosis: insights
into phenomenology. Tremor Other Hyperkinet
25 MacLeod R, Tibben A, Frontali M, et al.
Mov (N Y) 2017;7:475. doi:10.7916/D8PV6RWW.
Recommendations for the predictive genetic
test in Huntington's disease. Clin Genet 2013; 40 Gras D, Jonard L, Roze E, et al. Benign hereditary
83(3):221–231. doi:10.1111/j.1399-0004.2012.01900.x. chorea: phenotype, prognosis, therapeutic
outcome and long term follow-up in a large
26 Nance MA. Genetic counseling and testing for
series with new mutations in the TITF1/NKX2-1
Huntington's disease: a historical review. Am J
gene. J Neurol Neurosurg Psychiatry 2012;83(10):
Med Genet B Neuropsychiatr Genet 2017;174(1):
956–962. doi:10.1136/jnnp-2012-302505.
75–92. doi:10.1002/ajmg.b.32453.
41 Peall KJ, Lumsden D, Kneen R, et al. Benign
27 Reilmann R, Leavitt BR, Ross CA. Diagnostic
hereditary chorea related to NKX2.1: expansion
criteria for Huntington's disease based on natural
of the genotypic and phenotypic spectrum.
history. Mov Disord 2014;29(11):1335–1341. doi:
Dev Med Child Neurol 2014;56(7):642–648.
10.1002/mds.26011.
doi:10.1111/dmcn.12323.
28 Schneider SA, Bird T. Huntington's disease,
42 Peall KJ, Kurian MA. Benign hereditary chorea: an
Huntington's disease look-alikes, and benign
update. Tremor Other Hyperkinet Mov (N Y) 2015;
hereditary chorea: what's new? Mov Disord Clin
5:314. doi:10.7916/D8RJ4HM5.
Pract 2016;3:342–354. doi:10.1002/mdc3.12312.
43 Mencacci NE, Erro R, Wiethoff S, et al. ADCY5
29 Burke JR, Wingfield MS, Lewis KE, et al. The
mutations are another cause of benign
Haw river syndrome: dentatorubropallidoluysian
hereditary chorea. Neurology 2015;85(1):80–88.
atrophy (DRPLA) in an African–American family.
doi:10.1212/WNL.0000000000001720.
Nat Genet 1994;7(4):521–524. doi:10.1038/
ng0894-521. 44 Chen DH, Méneret A, Friedman JR, et al. ADCY5-
related dyskinesia: broader spectrum and genotype-
30 Pearson TS. More than ataxia: hyperkinetic
phenotype correlations. Neurology 2015;85(23):
movement disorders in childhood autosomal
2026–2035. doi:10.1212/WNL.0000000000002058.
recessive ataxia syndromes. Tremor Other
Hyperkinet Mov (N Y) 2016;6:368. doi:10.7916/ 45 Mencacci NE, Kamsteeg EJ, Nakashima K, et al.
D8H70FSS. De novo mutations in PDE10A cause
childhood-onset chorea with bilateral striatal
31 Margolis RL, Holmes SE. Huntington’s
lesions. Am J Hum Genet 2016;98(4):763–771.
disease–like 2: a clinical, pathological, and
doi:10.1016/j.ajhg.2016.02.015.
molecular comparison to Huntington’s disease.
Clin Neurosci Res 2003;3(3):187–196. 46 Diggle CP, Sukoff Rizzo SJ, Popiolek M, et al.
doi.org/10.1016/S1566-2772(03)00061-6. Biallelic mutations in PDE10A lead to loss of
striatal PDE10A and a hyperkinetic movement
32 Fujita K, Osaki Y, Harada M, et al. Brain and
disorder with onset in infancy. Am J Hum Genet
liver iron accumulation in aceruloplasminemia.
2016;98(4):735–743. doi:10.1016/j.ajhg.2016.03.015.
Neurology 2013;81(24):2145–2146. doi: 10.1212/01.
wnl.0000437304.30227.bd. 47 Saitsu H, Fukai R, Ben-Zeev B, et al. Phenotypic
spectrum of GNAO1 variants: epileptic
33 Ohta E, Takiyama Y. MRI findings in
encephalopathy to involuntary movements with
neuroferritinopathy. Neurol Res Int 2012;2012:
severe developmental delay. Eur J Hum Genet
197438. doi: 10.1155/2012/197438.
2016;24(1):129–134. doi:10.1038/ejhg.2015.92.
34 Batla A, Adams ME, Erro R, et al. Cortical pencil
48 Kurian MA, Jungbluth H. Genetic disorders of
lining in neuroferritinopathy: a diagnostic cluc.
thyroid metabolism and brain development.
Neurology 2015;84(17):1816–1818. doi: 10.1212/
Dev Med Child Neurol 2014;56(7):627–634.
WNL.0000000000001511.
doi:10.1111/dmcn.12445.
35 Jung HH, Danek A, Walker RH.
49 Fernandez M, Raskind W, Wolff J, et al. Familial
Neuroacanthocytosis syndromes. Orphanet J
dyskinesia and facial myokymia (FDFM): a novel
Rare Dis 2011;6:68. doi:10.1186/1750-1172-6-68.
movement disorder. Ann Neurol 2001;49(4):
486–492. doi:10.1002/ana.98.

1034 AUGUST 2019

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

50 Tunc S, Brüggemann N, Baaske MK, et al. Facial 62 Huntington Study Group, Frank S, Testa CM, et al.
twitches in ADCY5-associated Effect of deutetrabenazine on chorea among
disease - Myokymia or myoclonus? An electro- patients with Huntington disease: a randomized
myography study. Parkinsonism Relat Disord clinical trial. JAMA 2016;316(1):40–50. doi:10.1001/
2017;40:73–75. doi:10.1016/j. jama.2016.8655.
parkreldis.2017.04.013.
63 Anderson KE, Stamler D, Davis MD, et al.
51 Chang FC, Westenberger A, Dale RC, et al. Deutetrabenazine for treatment of involuntary
Phenotypic insights into ADCY5-associated movements in patients with tardive dyskinesia
disease. Mov Disord 2016;31(7):1033–1040. (AIM-TD): a double-blind, randomised,
doi:10.1002/mds.26598. placebo-controlled, phase 3 trial. Lancet
Psychiatry 2017;4(8):595–604. doi:10.1016/
52 Papandreou A, Schneider RB, Augustine EF, et al.
S2215-0366(17)30236-5.
Delineation of the movement disorders
associated with FOXG1 mutations. Neurology 64 Hauser RA, Factor SA, Marder SR, et al. KINECT 3:
2016;86(19):1794–1800. doi:10.1212/WNL. a phase 3 randomized, double-blind,
0000000000002585. placebo-controlled trial of valbenazine for
tardive dyskinesia. Am J Psychiatry 2017;174(5):
53 Lemke JR, Geider K, Helbig KL, et al. Delineating
476–484. doi:10.1176/appi.ajp.2017.16091037.
the GRIN1 phenotypic spectrum: a distinct
genetic NMDA receptor encephalopathy. 65 Burgunder JM, Guttman M, Perlman S, et al. An
Neurology 2016;86(23):2171–2178. doi:10.1212/ international survey-based algorithm for the
WNL.0000000000002740. pharmacologic treatment of chorea in
Huntington's disease. PLoS Curr 2011;3:RRN1260.
54 Zehavi Y, Mandel H, Zehavi A, et al. De novo
doi:10.1371/currents.RRN1260.
GRIN1 mutations: an emerging cause of severe
early infantile encephalopathy. Eur J Med Genet 66 Bashir H, Jankovic J. Treatment options for
2017;60(6):317–320. doi:10.1016/j. chorea. Expert Rev Neurother 2018;18(1):51–63.
ejmg.2017.04.001. doi:10.1080/14737175.2018.1403899.
55 Madeo M, Stewart M, Sun Y, et al. Loss-of- 67 Genel F, Arslanoglu S, Uran N, Saylan B.
function mutations in FRRS1L lead to an Sydenham's chorea: clinical findings and
epileptic-dyskinetic encephalopathy. Am J comparison of the efficacies of sodium
Hum Genet 2016;98(6):1249–1255. doi:10.1016/ valproate and carbamazepine regimens.
j.ajhg.2016.04.008. Brain Dev 2002;24(2):73–76. doi:10.1016/
S0387-7604(01)00404-1.
56 Erro R, Sheerin UM, Bhatia KP. Paroxysmal
dyskinesias revisited: a review of 500 genetically 68 Cardoso F. Sydenham's chorea. Curr Treat
proven cases and a new classification. Options Neurol 2008;10(3):230–235. doi:10.1007/
Mov Disord 2014;29(9):1108–1116. doi:10.1002/ s11940-008-0025-x.
mds.25933.
69 Dean SL, Singer HS. Treatment of Sydenham’s
57 Erro R, Bhatia KP, Espay AJ, Striano P. The chorea: a review of the current evidence. Tremor
epileptic and nonepileptic spectrum of Other Hyperkinet Mov (N Y) 2017;7:456.
paroxysmal dyskinesias: channelopathies, doi:10.7916/D8W95GJ2.
synaptopathies, and transportopathies.
70 Wojtecki L, Groiss SJ, Hartmann CJ, et al.
Mov Disord 2017;32(3):310–318. doi:10.1002/
Deep brain stimulation in Huntington's
mds.26901.
disease—preliminary evidence on
58 Erro R, Bhatia KP. Unravelling of the paroxysmal pathophysiology, efficacy and safety.
dyskinesias. J Neurol Neurosurg Psychiatry 2018; Brain Sci 2016;6(3); pii: E38. doi:10.3390/
pii:jnnp-2018-318932. doi:10.1136/jnnp-2018- brainsci6030038.
318932.
71 Liu Z, Liu Y, Wan X, et al. Pallidal deep brain
59 Huntington Study Group. Tetrabenazine as stimulation in patients with chorea-
antichorea therapy in Huntington disease: a acanthocytosis. Neuromodulation 2018;21(8):
randomized controlled trial. Neurology 2006; 741–747. doi:10.1111/ner.12763.
66(3):366–372. doi:10.1212/01.wnl.
72 Smith KM, Spindler MA. Uncommon applications
0000198586.85250.13.
of deep brain stimulation in hyperkinetic
60 Chen JJ, Ondo WG, Dashtipour K, Swope DM. movement disorders. Tremor Other Hyperkinet
Tetrabenazine for the treatment of hyperkinetic Mov (N Y) 2015;5:278. doi:10.7916/D84X56HP.
movement disorders: a review of the literature.
73 Wild EJ, Tabrizi SJ. Therapies targeting DNA
Clin Ther 2012;34(7):1487–1504. doi:10.1016/j.
and RNA in Huntington's disease. Lancet
clinthera.2012.06.010.
Neurol 2017;16(10):837–847. doi:10.1016/S1474-
61 Jankovic J. Dopamine depleters in the treatment 4422(17)30280-6.
of hyperkinetic movement disorders. Expert
74 Tabrizi SJ, Leavitt BR, Landwehrmeyer GB, et al.
Opin Pharmacother 2016;17(18):2461–2470.
Targeting Huntington expression in patients with
doi:10.1080/14656566.2016.1258063.
Huntington's Disease [published online May 6,
2019]. N Engl J Med 2019. doi:10.1056/
NEJMoa1900907.

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 REVIEW ARTICLE


Ataxia
C O N T I N UU M AUDIO By Sheng-Han Kuo, MD
INTERVIEW AVAILABLE
ONLINE


VIDEO CONTENT ABSTRACT
A VA I L A B L E O N L I N E PURPOSE OF REVIEW: This
article reviews the symptoms, laboratory and
neuroimaging diagnostic tests, genetics, and management of cerebellar
ataxia.

RECENT FINDINGS:Recent advances in genetics have led to the identification

of novel genetic causes for ataxia and a more comprehensive
understanding of the biological pathways critical for normal cerebellar
function. When these molecular pathways become dysfunctional, patients
Downloaded from http://journals.lww.com/continuum by BhDMf5ePHKbH4TTImqenVA9Bu/kT98wMVr3YF8MvrsXMDXbs4YWeuR7t2+BPOx7j on 08/03/2019

CITE AS:
CONTINUUM (MINNEAP MINN) develop cerebellar ataxia. In addition, several ongoing clinical trials for
2019;25(4, MOVEMENT DISORDERS): Friedreich ataxia and spinocerebellar ataxia will likely result in novel
1036–1054.
symptomatic and disease-modifying therapies for ataxia. Antisense
Address correspondence to oligonucleotides for spinocerebellar ataxias associated with CAG repeat
Dr Sheng-Han Kuo, 650 West
168th St, Room 305, New York,
expansions might be a promising therapeutic strategy.
NY 10032, [email protected].
SUMMARY: Cerebellar ataxias include heterogeneous disorders affecting
RELATIONSHIP DISCLOSURE:
Dr Kuo has received personal
cerebellar function, leading to ataxic symptoms. Step-by-step diagnostic
compensation for serving on the workups with genetic investigations are likely to reveal the underlying
medical advisory board of the causes of ataxia. Some disease-specific therapies for ataxia exist, such as
International Essential Tremor
Foundation and on the research vitamin E for ataxia with vitamin E deficiency and thiamine for Wernicke
advisory board of the National encephalopathy, highlighting the importance of recognizing these forms of
Ataxia Foundation. Dr Kuo has
ataxia. Finally, genetic diagnosis for patients with ataxia will accelerate
received research/grant support
from the American Brain clinical trials for disease-modifying therapy and will have prognostic value
Research Training Fellowship, and implications for family planning for these patients.
American Parkinson Disease
Association, International
Essential Tremor Foundation, the
Louis V. Gerstner Jr Scholarship, INTRODUCTION

T
Continued on page 1054
he causes of cerebellar ataxia are diverse, ranging from infectious and
immune mediated to degenerative. In addition, many genetic causes
UNLABELED USE OF
PRODUCTS/INVESTIGATIONAL of cerebellar ataxia exist. Therefore, the workup for cerebellar ataxia
USE DISCLOSURE: usually poses significant challenges to neurologists. In addition, the
Dr Kuo discusses the unlabeled/
treatment for cerebellar ataxia has been traditionally thought to be
investigational use of
amantadine, baclofen, ineffective, leaving many patients with ataxia untreated. Moreover, nonmotor
chlorzoxazone, and riluzole for symptoms, such as depression and mood disorders, are common in patients with
the treatment of cerebellar ataxia;
4-aminopyridine for the treatment
ataxia and are often underrecognized and undertreated.
of episodic ataxia type 2; deep To circumvent these challenges of the diagnosis and treatment for patients
brain stimulation for the with ataxia, this review provides step-by-step approaches and an overview for
treatment of spinocerebellar
ataxia type 2; miglustat for the ataxia. This review does not cover ataxia caused by strokes, tumors, or multiple
treatment of Niemann-Pick sclerosis since these lesion-related ataxias are easily identified by neuroimaging
disease type C; and varenicline and are discussed in other issues within the Continuum curriculum. The section
for spinocerebellar ataxia type 3.
on ataxia genetics only briefly covers the most common causes of ataxia and
© 2019 American Academy
does not provide a complete list of ataxic genes, which can be found in other
of Neurology. comprehensive reviews.1–3

1036 AUGUST 2019

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 Finally, this article also discusses the medications that have been studied KEY POINTS
and used to treat ataxia symptoms. This review also highlights important
● Determining the etiology
developments in therapies for ataxia, both symptomatic and disease modifying. of cerebellar ataxia is
complex; however,
SIGNS AND SYMPTOMS OF ATAXIA step-by-step approaches
Ataxia is a physical finding on examination that is often linked to the disease of can streamline the
diagnostic workflow.
the cerebellum. However, abnormal sensory inputs into the cerebellum, such as
diseases involving the proprioceptive system/dorsal columns, can also result in ● Key questions regarding
ataxia. Hence, ataxia might have both motor and sensory components, and not all difficulty running, trouble
patients with ataxia have disease pathology in the cerebellum. walking in high heels or
The first step to approaching patients with cerebellar ataxia is to recognize gait barefoot on the beach, and
veering toward one side can
imbalance, which is often the first symptom for patients with ataxia.4 Often, be helpful in identifying the
patients will have difficulty going upstairs and downstairs and will have to hold subtle gait abnormality
on to the railing. Other common early symptoms include difficulty running, associated with ataxia.
trouble walking in high heels or barefoot on the beach, and veering toward one
● Patients with ataxia can
side. “Do you walk as if you are drunk?” is a useful question, and some patients have a variety of eye
do show sensitivity to a small amount of ethanol. In the later stage of the disease, movement abnormalities,
frequent falling is frequently encountered. In the early stage, patients with ataxia including nystagmus,
sometimes have double vision when turning their heads quickly. Blurry vision, hypermetric or hypometric
saccades, and
resulting from transient and mild double vision, is also common. Slurred speech
ophthalmoplegia.
can develop, making some words difficult to be understood. Patients can also
have loss of hand dexterity with bad handwriting and difficulty performing
delicate hand tasks.
Once the symptoms of ataxia are established, it is important to further investigate
the timing of ataxia development (acute, subacute, chronic, episodic), which
will provide important diagnostic clues. TABLE 7-1 lists the common causes for
ataxia with different chronicity.
Although recognizing ataxia is an important first step, the associated symptoms
in addition to ataxia often can point toward the diagnosis. Therefore, questioning
about symptoms of peripheral neuropathy, parkinsonism, sleep dysfunction,
autonomic symptoms, seizures, hearing loss, and a family history of ataxia and
other balance problems is also an important part of history taking. In addition, a
history assessing for toxin and medication exposures will also be helpful in
identifying the cause.

NEUROLOGIC EXAMINATION FOR ATAXIA

The neurologic examination of ataxia can be divided into several domains: eyes,
speech, hands, legs, and gait.
Several abnormalities of eye movements could be associated with different
types of ataxia: (1) saccadic intrusion in fixed gaze (ie, square-wave jerks), which
can be seen especially in Friedreich ataxia,3 (2) horizontal or vertical end-gaze
nystagmus, which occurs in many types of ataxia, among which down-beat
nystagmus can often been seen in spinocerebellar ataxia (SCA) type 6 (SCA6),
(3) hypometric or hypermetric saccades, which can be observed in many types of
ataxia, (4) breakdown of smooth pursuit, often encountered in SCA3,5 (5) slow
saccades, typical for SCA2,5 (6) ophthalmoplegia/ophthalmoparesis, which can
be observed in sensory ataxic neuropathy, dysarthria, and ophthalmoparesis
(SANDO), and (7) ptosis, which can occur in SANDO and ataxia associated with
mitochondrial genome mutations.6 Among these signs, nystagmus and
hypometric or hypermetric saccades are commonly shared by ataxic disorders;

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ATAXIA

therefore, these signs are helpful in differentiating cerebellar ataxia from sensory
ataxia, especially in the early stages of the disease when no cerebellar atrophy is
found on neuroimaging.
Patients with ataxia usually have scanning speech (ie, words are broken up
into separate syllables with disrupted normal speech patterns). The speed of
speech could become slow, and the volume of speech could be variable.
The three commonly used tasks for ataxic hand examination include (1)
finger-nose-finger test (the patient points repeatedly with his or her index finger
from his or her nose to the examiner’s finger), (2) finger chase (the patient’s
index finger follows the examiner’s moving index finger as precisely as possible),
and (3) fast alternating movements (the patient performs cycles of repetitive

TABLE 7-1 Acute, Subacute, Chronic, and Episodic Causes of Cerebellar Ataxia

Acute Causes of Cerebellar Ataxia (Minutes to a Few Days)

◆ Vascular causes: ischemic or hemorrhagic cerebellar strokes
◆ Ethanol intoxication
◆ Toxins (mercury, thallium, toluene, solvents)
◆ Medication (phenytoin, carbamazepine, phenobarbital, lithium)
◆ Multiple sclerosis
◆ Meningitis, particularly basilar meningitis
◆ Viral cerebellitis
◆ Cerebellar abscess
◆ Wernicke encephalopathy/thiamine deficiency
Subacute Causes of Cerebellar Ataxia (Weeks to Months)
◆ Paraneoplastic cerebellar degeneration
◆ Brain tumors
◆ Creutzfeldt-Jakob disease
◆ Superficial siderosis
◆ Anti–glutamic acid decarboxylase ataxia
Chronic Causes of Cerebellar Ataxia (Months to Years)
◆ Ataxia associated with gluten sensitivity
◆ Genetic ataxia
◆ Mitochondrial disease
◆ Multiple system atrophy
◆ Idiopathic late-onset cerebellar ataxia
Episodic Causes of Cerebellar Ataxia
◆ Genetic episodic ataxia
◆ Psychogenic ataxia
◆ Mitochondrial disease
◆ Multiple sclerosis

1038 AUGUST 2019

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alternation of pronation and supination of the hand on the thigh). Patients with KEY POINTS
ataxia will overshoot in the finger-chase test, have intention tremor on the
● The gait abnormality
finger-nose-finger test as the tremor becomes more prominent when closer to the associated with cerebellar
target, and have variable rhythm and speed in alternating movements. In ataxia can change over the
heel-to-shin tests, patients with ataxia are asked to straighten one leg and to use the course of the disease.
heel of the other leg to slide down the shin from the knee smoothly and precisely
● After establishing the
but will have difficulty making the heel stay on the shin.
signs of cerebellar ataxia,
Next, patients should be asked to stand in a natural position so the clinician look for other neurologic
can observe any truncal sways. Then the patient is instructed, if able to do so, to signs (eg, tremor, dystonia,
stand with feet together in the tandem stance, to stand on either foot, or to hop parkinsonism, motor neuron
on either foot. These maneuvers are used to test for subtle balance abnormalities signs) as clues to the cause
of ataxia.
associated with cerebellar dysfunction. A useful variation is to ask the patient to
close his or her eyes while doing these maneuvers; a considerable worsening in ● Laboratory evaluation can
balance during this test will indicate the contribution of sensory neuropathy. Gait be helpful in identifying
examination should focus on the observation of variable stride length and nutritional and immunologic
causes of cerebellar ataxia.
direction, and an ataxic gait might change characteristics at different disease
stages. In mild ataxia, the gait might be narrow based but veering toward one
direction, and missteps are often observed. Turning can often bring out the gait
deficits in patients with ataxia. In moderate ataxia, the gait becomes wide
based to compensate for the imbalance. In more advanced ataxia, the stride
length can be shortened in addition to a wide-based gait to allow for further
compensation. VIDEO 7-1 (links.lww.com/CONT/A358) demonstrates the gait
abnormality in different degrees of ataxia. For patients who have difficulty
walking upstairs and downstairs or running, observing them performing such
tasks usually will yield additional information for the diagnosis.
Once the neurologic examination establishes the presence of ataxia, other
associated signs can be critical in pointing toward specific diagnoses. Special
attention should be paid to signs of parkinsonism, tremor, dystonia, myoclonus,
sensory neuropathy, hyperreflexia, and extensor plantar reflexes. Other signs
during the physical examination can possibly aid in diagnosis, including
telangiectasia (for ataxia telangiectasia), splenomegaly (for Niemann-Pick
disease type C), scoliosis, and pes cavus (for Friedreich ataxia). CASE 7-1
illustrates a case of pathologically confirmed multiple system atrophy with
features of cerebellar ataxia and parkinsonism.

LABORATORY TESTS FOR ATAXIA

Serum biomarkers are useful for nutritional and immune-mediated causes of
ataxia. Blood levels of vitamin B12 and vitamin E can be tested for vitamin
deficiency–associated ataxias. Although blood vitamin B1 levels and associated
red blood cell transketolase activity can be measured, it is not clear whether these
measurements accurately reflect the brain levels. High clinical suspicion and
empiric treatment with thiamine for patients with ataxia with altered mental
status and nystagmus are important in treating Wernicke encephalopathy.
Serum antibody levels can indicate specific immune-mediated ataxia
(eg, anti–glutamic acid decarboxylase [GAD] antibody). Serum anti–gliadin
antibodies and tissue transglutaminase antibodies are associated with ataxia with
gluten sensitivity.7 Anti–thyroperoxidase antibody can indicate ataxia associated
with steroid-responsive encephalopathy. Paraneoplastic antibodies should also
be examined when encountering patients with subacute cerebellar ataxia.
Whether these antibodies are pathogenic for ataxia is still not entirely clear.

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ATAXIA

Lumbar puncture should be performed in patients with acute or subacute

ataxia. CSF analysis for cell counts, glucose, and protein levels, immunoglobulins,
and bacterial and viral studies can help identify inflammatory and infectious
causes of ataxia. CSF examination can also aid in the diagnosis of Creutzfeldt-
Jakob disease.8 Low CSF glucose levels might indicate ataxia with glucose
transporter type 1 deficiency. If acquired causes of cerebellar ataxia have been
excluded or if the patient has a family history of ataxia, particularly in
first-degree relatives, genetic tests should be ordered, which are detailed below.

NEUROIMAGING FOR ATAXIA

Patients with ataxia should have a brain MRI to identify any structural and
vascular lesions, including brain tumors, abscesses, ischemic and hemorrhagic
strokes, or multiple sclerosis. Cerebellar atrophy is the most common
neuroimaging finding. Neurologists should assess the degree of cerebellar
atrophy in the vermis, paravermis, and hemispheric regions (FIGURE 7-1A–D).
The foliation of cerebellar lobules becomes obvious as the cerebellum
degenerates. The part of the cerebellum that is important for motor control is
predominantly located in the anterior lobules, and atrophy in this region is
often associated with ataxia. However, atrophy of the posterior lobules of the
cerebellum might be related to the nonmotor features of cerebellar dysfunction,
such as depression and emotional lability.9,10 Vermal atrophy might be associated
with truncal and gait ataxia whereas paravermal atrophy might be more related
to appendicular ataxia. Some forms of ataxia may not be associated with
cerebellar atrophy, especially in the early stage.3 These ataxias are the result of a

CASE 7-1 A 56-year-old woman presented because of imbalance, difficulty walking

upstairs and downstairs, and slurred speech that had developed over 4 years.
On examination, she had nystagmus and prominent cerebellar ataxia with
finger dysmetria, impaired rapid alternating movements, and inability to
perform a tandem walk.
Within 1 year, she had fallen several times and started to use a walker. She
also developed two syncopal episodes due to orthostatic hypotension. A
repeat neurologic examination revealed marked slowing in hand and leg
movements with hypomimic facial expression in addition to worsening of
ataxia. Her gait became wide based with a short stride length and no heel
strikes (VIDEO 7-2, links.lww.com/CONT/A359). She also fell back in a pull test.
Her postmortem pathologic examination demonstrated glial cytoplasmic
inclusions, the hallmarks for multiple system atrophy.

COMMENT This case illustrates a typical presentation of multiple system atrophy,

cerebellar type, for which cerebellar ataxia develops first followed by
parkinsonism and autonomic features. The symptomatic treatment for
such patients should focus on the domain-specific dysfunction (eg, riluzole
for ataxia, levodopa for parkinsonism, and management of orthostatic
hypotension).

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 FIGURE 7-1
Sagittal T1-weighted brain MRI demonstrates cerebellar atrophy in a patient with
spinocerebellar ataxia type 13. Note that prominent cerebellar foliation and sulci are seen
in the cerebellar vermis (A), paravermis (B), and cerebellar hemisphere (C). Prominent
cerebellar sulci are also noted in the axial fluid-attenuated inversion recovery (FLAIR)
sequence in the same patient (D). Axial T2-weighted MRI sequence shows the hot cross bun
sign in the pons of a patient with multiple system atrophy (E). Axial T2-weighted brain MRI
demonstrates hyperintensities in the bilateral inferior olivary nuclei (F, arrows) in a patient
with POLG ataxia. Axial gradient recalled echo (GRE) brain (G) and sagittal spinal cord MRI (H)
demonstrated hypointensity surrounding the brainstem, cerebellum, and spinal cord in a
patient with superficial siderosis. Sagittal T1-weighted brain MRI shows spinal cord atrophy
but no cerebellar atrophy in a patient with Friedreich ataxia (I).
Panel E is reprinted with permission from McFarland NR, Continuum (Minneap Minn).11 © 2016 American
Academy of Neurology.

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ATAXIA

predominantly sensory neuropathy, such as Friedreich ataxia and ataxia with

vitamin E deficiency, and POLG ataxia.
Aside from cerebellar atrophy, other brain MRI findings might indicate
specific diagnoses and are listed in TABLE 7-2. The hot cross bun sign (a cross sign
in the pons on T2-weighted MRI) can be seen in multiple system atrophy and
certain SCAs (FIGURE 7-1E11). T2 hyperintensities in the mammillary bodies,
periaqueductal gray, and paraventricular thalamus are changes that can be
observed in Wernicke encephalopathy. Cerebral white matter changes can be
seen in cerebrotendinous xanthomatosis and adult-onset Alexander disease. T2
hyperintensity in the bilateral inferior olivary nucleus, indicating hypertrophic
neuronal degeneration, could occur in POLG ataxia, adult-onset Alexander
disease, and ataxia with gluten sensitivity (FIGURE 7-1F). Other special MRI
sequences can be helpful for specific types of ataxia. For instance, the gradient
recalled echo sequence (GRE) can be used to identify superficial siderosis

TABLE 7-2 Brain MRI Findings Associated With Specific Forms of Ataxia

Associated Findings and

Brain MRI Findings Pathology Associated Ataxia
No cerebellar atrophy No obvious structural Friedreich ataxia, ataxia with vitamin E
cerebellar cortical deficiency, abetalipoproteinemia,
degeneration immune-mediated ataxia

Hot cross bun sign Pontine atrophy Multiple system atrophy,

spinocerebellar ataxia type 2

Cervical spinal cord atrophy Cervical spinal cord atrophy Friedreich ataxia

T2 hyperintensity in the middle cerebellar Degeneration/ Multiple system atrophy, fragile X

peduncles demyelination of middle tremor-ataxia syndrome
cerebellar peduncles

T2 hyperintensity in the mammillary bodies, Possibly petechial Wernicke encephalopathy

periaqueductal gray, and paraventricular hemorrhages in these brain
thalamus regions

T2 hyperintensity in the bilateral inferior olivary Hypertrophic degeneration POLG ataxia, adult-onset Alexander
nuclei of the neurons in the inferior disease, ataxia with gluten sensitivity
olivary nuclei

Dentate nucleus calcification (CT)a Dentate nucleus calcification Spinocerebellar ataxia type 20

T2 hyperintensity in the white matter Leukoencephalopathy Cerebrotendinous xanthomatosis,

adult-onset Alexander disease

Medullary atrophy Medullary atrophy Adult-onset Alexander disease

T2 gradient recalled echo showing linear Iron deposition on the Superficial siderosis
hypointensity around the cerebellum and surface of the brain
brainstem parenchyma

Diffusion-weighted imaging hyperintensity Spongiform degeneration Creutzfeldt-Jakob disease

in the cerebral cortex, basal ganglia, or thalamus

CT = computed tomography; MRI = magnetic resonance imaging.

a
This particular finding is best seen on the CT scan.

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(FIGURE 7-1G–H),12 and diffusion-weighted imaging can be useful in diagnosing KEY POINTS
Creutzfeldt-Jakob disease.8 Other than the cerebellum, special attention should
● Aside from cerebellar
be paid to the spinal cord because spinal cord atrophy could be seen in patients atrophy, specific changes
with Friedreich ataxia (FIGURE 7-1I). on MRI associated with
different forms of
OTHER TESTS FOR ATAXIA cerebellar ataxia can
provide important
Other associated tests to confirm the extracerebellar symptoms might aid
diagnostic clues.
the diagnosis. If multiple system atrophy is suspected, assessment for
orthostatic hypotension or urinary disturbance and a sleep study ● The spinocerebellar
demonstrating rapid eye movement sleep behavior disorder might be ataxia nomenclature relates
necessary. A dopamine transporter scan can be used to determine whether to the autosomal dominant
causes of ataxia.
there is presynaptic dopamine terminal loss. Sensory neuropathy could be
evaluated by nerve conduction studies. If Creutzfeldt-Jakob disease is in the
differential diagnosis, EEG should be performed to look for the typical
periodic sharp-wave complexes.

DIAGNOSTIC ALGORITHM FOR ATAXIA

The previous sections covered the history, neurologic examination, and
diagnostic tests for cerebellar ataxia. As illustrated in FIGURE 7-2, and using the
information mentioned above, the following is a step-by-step algorithm for the
evaluation of cerebellar ataxia.
In patients with a balance problem, the first step is to confirm the presence of
cerebellar ataxia. Other causes of balance disorders should be considered,
including parkinsonism, sensory neuropathy, vestibular problems, muscle
weakness, and orthopedic issues. Once ataxia is confirmed, the next step is to
assess the acquired causes of ataxia, such as toxin exposures, nutritional
deficiency, immune-mediated causes (anti-GAD or ataxia associated with gluten
sensitivity), and paraneoplastic causes. Brain MRI should be performed, and
variable degrees of cerebellar atrophy should be expected. However, certain
forms of cerebellar ataxia with prominent sensory neuronopathy might not have
cerebellar atrophy, as mentioned above. Special attention should be paid to
specific changes in MRI, as listed in TABLE 7-2.
For patients with a family history of ataxia, the diagnostic flow can be divided
into autosomal dominant ataxia, autosomal recessive ataxia, X-linked ataxia, and
mitochondrial disorders, depending on the pattern of inheritance. If no family
history of ataxia is present and the disease onset occurs when the patient is older
than 60 years of age, degenerative causes are likely. In this group, multiple
system atrophy is associated with parkinsonism, rapid eye movement sleep
behavior disorders, and autonomic dysfunction, whereas idiopathic late-onset
cerebellar ataxia usually presents solely as cerebellar ataxia.

GENETICS OF ATAXIA
Genetic causes of ataxia are many. The Online Mendelian Inheritance in Man
(OMIM) can serve as a useful resource for up-to-date ataxia genetics.13 Following
is an overview of ataxia genetics based on the pattern of inheritance.

Autosomal Dominant Ataxia

For autosomal dominant cerebellar ataxia, there is designated SCA nomenclature,
from type 1 to type 48 to date. Among these, cerebellar ataxia caused by the
CAG-repeat expansions, including SCA1, SCA2, SCA3, SCA6, SCA7, and

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ATAXIA

FIGURE 7-2
The diagnostic workflow for cerebellar ataxia.
AD = autosomal dominant; AR = autosomal recessive; FXTAS = fragile X tremor-ataxia syndrome; GAD =
glutamic acid decarboxylase; ILOCA = idiopathic late-onset cerebellar ataxia; MRI = magnetic resonance
imaging; MSA = multiple system atrophy; REM = rapid eye movement; SCA = spinocerebellar ataxia.

SCA17, are the most common,14 constituting approximately half of all

dominantly inherited ataxias. Other repeat-associated ataxia disorders often
have repeat expansions in the noncoding regions of the genes, such as SCA8,
SCA10, and SCA12. The rest of the relatively rare SCAs are often associated
with the sequence alterations in the coding region.1 Note that whole exome
sequencing is best to detect sequence alterations but not repeat expansions.
Therefore, determining repeat expansions in the common SCA genes is the
first step for SCA genetics. If no repeat expansions are found, sequencing
methods should be the next step.15
Each SCA has distinct but overlapping clinical features as listed in TABLE 7-3.
Patients with SCA1 have early dysphagia and dysarthria. Patients with SCA2
often have slow saccades, truncal titubation, hyporeflexia, and tremor. Patients
with SCA3 commonly have dystonia, depression, restless legs syndrome, and
parkinsonism. Patients with SCA6 classically have only cerebellar ataxia without
other extracerebellar symptoms. Patients with SCA7 have vision loss due to
pigmentary retinal degeneration. Patients with SCA17 have dementia, chorea,

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and dystonia. Although these clinical symptoms are helpful in pinpointing the
correct genetic diagnosis, there is a strong ethnic predilection. For example,
SCA2 is very common in Cuba, whereas SCA3 is most common in China,
Portugal, and Brazil.2 Different types of CAG-repeat SCAs have different rates of
disease progression. For example, SCA1 progresses most quickly, followed by
SCA3 and SCA2. SCA6 has the slowest rate of progression among these
subtypes.16,17 CASE 7-2 and CASE 7-3 demonstrate typical clinical presentations of
SCA2 and SCA3, respectively.
The proposed pathomechanism of the common CAG-repeat SCAs is the
polyglutamine, and the associated repeats exert toxic effects on the neurons or
cause the loss of the normal function of respective proteins.1 Intraneuronal
inclusions can be observed in CAG-repeat SCAs.24 However, the pathomechanism
of SCAs of non–CAG repeats in the noncoding regions is proposed to be primarily
due to RNA toxic gain of function. Finally, SCAs associated with sequence
alterations are often due to disturbed protein function from the genetic mutations.25

Autosomal Recessive Ataxia

Autosomal recessive ataxia can be divided into three categories: (1) cerebellar
ataxia with predominant sensory neuronopathy, (2) cerebellar ataxia with
sensorimotor axonal neuropathy, and (3) cerebellar ataxia without sensory
neuropathy (TABLE 7-4). Therefore, the characteristics of associated neuropathy
are key to the examination in recessive ataxia. The prototypical disease for the
category of cerebellar ataxia with predominant sensory neuronopathy is
Friedreich ataxia, which is the most common recessive ataxia. Patients with
Friedreich ataxia have an age of onset from childhood to the third decade and
might also have pes cavus, scoliosis, square-wave jerks, and hyporeflexia. About
15% of Friedreich ataxia cases are adult onset, which could be associated with
prominent spasticity and hyperreflexia.3 Diabetes mellitus and cardiomyopathy

Common Autosomal Dominant Ataxias Associated With Repeat Expansions TABLE 7-3

Disease Gene Alterations Associated Clinical Features and Notes

SCA1 CAG repeats in ATXN1 Dysphagia, dysarthria, pyramidal signs

SCA2 CAG repeats in ATXN2 Slow saccades, truncal sways, hyporeflexia,

postural and rest tremor, parkinsonism

SCA3 CAG repeats in ATXN3 Abnormal smooth pursuit, depression, restless

legs syndrome, dystonia, parkinsonism

SCA6 CAG repeats in CACNA1A Pure cerebellar ataxia

SCA7 CAG repeats in ATXN7 Vision loss/pigmentary retinal degeneration

SCA8 CTG repeats in ATXN8 and Hyperreflexia

ATXN8OS

SCA10 ATTCT repeats in ATXN10 Epilepsy

SCA17 CAG repeats in TBP Dementia, chorea, dystonia

SCA = spinocerebellar ataxia.

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ATAXIA

are also common in Friedreich ataxia. Friedreich ataxia is caused by intronic GAA
repeat expansions of the FXN gene, which result in inefficient production of
frataxin protein and lead to disturbed mitochondrial function. About 5% of
patients with Friedreich ataxia have one allele carrying a point mutation in the
FXN gene and another allele with repeat expansions. Therefore, a neurologist
should still have a high suspicion of Friedreich ataxia if the expanded repeats are
detected in only one allele in patients with otherwise classical Friedreich ataxia.

CASE 7-2 A 55-year-old woman presented for evaluation of progressive gait

difficulty. She had initially noted difficulty walking downstairs and
running at the age of 47. Her imbalance problems became progressively
worse over the years, and she developed slurred speech, transient
double vision while turning her head quickly, and loss of hand dexterity.
She had frequent falls and needed to use a walker. She had an extensive
family history of cerebellar ataxia, affecting her mother and brother.
On examination, she had slurred speech and slow saccadic eye
movements without nystagmus or hypermetric or hypometric saccades.
She had dysmetria on finger-nose-finger tests and overshoot in finger-
chase tests. She also had impaired rapid alternating movements. She had a
hypomimic facial expression and bradykinesia. Her gait showed variable
stride length and was wide based (VIDEO 7-3, links.lww.com/CONT/A360).
Brain MRI showed pontocerebellar atrophy. Genetic tests for repeats
revealed pathologic CAG expansions of the ATXN2 gene of 38 repeats
(normal <32), confirming the diagnosis of spinocerebellar ataxia type
2 (SCA2).
The patient was treated with riluzole 50 mg 2 times a day,18 which
provided modest benefits for her speech. Physical therapy helped with
her balance. Carbidopa/levodopa 25 mg/100 mg, 3 times a day, improved
her parkinsonism by increasing the speed of her movements.
During the follow-up visit, she described depressive symptoms with
suicidal ideation. She was treated with duloxetine 30 mg/d, which helped
with her mood. She was also treated with zinc 50 mg/d because zinc has
been shown to potentially help patients with SCA2.19
Five years later, her symptoms progressed, and she needed to use a
wheelchair. She had ophthalmoparesis, particularly in vertical gaze, and
her saccadic eye movements became very slow (VIDEO 7-3, links.lww.com/
CONT/A360).

COMMENT This case demonstrates that determination for repeat expansions is the
first step for autosomal dominant ataxia. Slow saccades are the key feature
for SCA2. Other than treating ataxia symptoms, parkinsonism in patients
with ataxia can sometimes respond to carbidopa/levodopa. Finally,
depressive symptoms are very common in patients with cerebellar ataxia,9
possibly due to the cerebellar cognitive affective syndrome,10 and should
be treated with antidepressants.

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 Another relatively common recessive ataxia is SANDO syndrome, caused by
POLG mutations. The age of onset is in adulthood with ophthalmoplegia, ptosis,
myoclonus, and epilepsy.6 Bilateral inferior olivary nucleus T2 hyperintensity
could sometimes be observed on brain MRI (FIGURE 7-1F).
Another group of autosomal recessive ataxias is cerebellar ataxia with
sensorimotor axonal neuropathy. Within this group, the common types are
ataxia telangiectasia and ataxia with oculomotor apraxia type 1 and type 2.
In addition to neuropathy, chorea, dystonia, and spasticity are common
symptoms in this group. α-Fetoprotein levels are elevated in ataxia
telangiectasia and ataxia with oculomotor apraxia type 2, which sometimes
could be used as a screening tool for these diseases. Patients with ataxia
telangiectasia have increased risks of cancer and infection, in addition to
sensitivity to radiation.
The third category for recessive ataxia is ataxia without sensory neuropathy,
among which autosomal recessive cerebellar ataxia type 1 is usually adult onset

A 49-year-old man presented for evaluation of a 5-year history of CASE 7-3

progressive slowness of movements, decreased facial expression, and
shuffling gait. Further questioning revealed that his sister also had an
imbalance problem, which had started at 36 years of age.
On examination, he had a hypomimic facial expression, bradykinesia, a
parkinsonian gait, and mild cerebellar ataxia with a variable step length.
The neurologic examination of his sister, at the age of 51, showed
prominent cerebellar ataxia. Both the patient’s and his sister’s brain MRI
showed pontocerebellar atrophy. The patient’s dopamine transporter
scan showed decreased uptake in the bilateral striatum.
He was treated with carbidopa/levodopa up to 25 mg/250 mg 3 times a
day, which significantly improved his symptoms. The patient’s genetic
test for repeat expansions revealed pathologic expansions of 73 in ATXN3
(normal <50). He later developed painful peripheral neuropathy in his
legs, and his cerebellar ataxia became more prominent. He also had
depressive symptoms and felt hopeless and helpless.
In addition to levodopa, the patient was also prescribed varenicline
1 mg 2 times a day,20 which improved his gait to a modest degree. He was
treated with 2000 mg/d of coenzyme Q10 based on retrospective data.21
His depression was treated with citalopram 20 mg/d.

This case exemplifies the clinical heterogeneity of monogenic ataxia, COMMENT

ranging from levodopa-responsive parkinsonism to peripheral neuropathy
and cerebellar ataxia. Spinocerebellar ataxias (SCAs) should be in the
differential diagnosis of young-onset parkinsonism. Although the majority
of the treatment options for SCAs lack large-scale randomized controlled
clinical trials, neurologists still should try different therapies based on
published data.22 For example, citalopram has been shown to decrease
ataxin-3 aggregation in animal models of SCA323; thus, it might provide
additional benefits to patients with SCA3.

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ATAXIA

with upper or lower motor neuron signs, pes cavus, and scoliosis.26 Patients
with Niemann-Pick disease type C have characteristic vertical supranuclear
ophthalmoplegia (VIDEO 7-4, links.lww.com/CONT/A361)27 in addition to mental
retardation, dystonia, and cognitive decline.

X-linked Ataxia
The most common X-linked ataxia is fragile X tremor-ataxia syndrome, which is
caused by CGG repeat expansions within the FMR1 gene, leading to RNA toxic
function. A longer repeat expansion of the FMR1 gene, as the result of
anticipation, will lead to premature ovarian failure in the patients’ daughters and
mental retardation in patients’ grandsons. Thus, fragile X tremor-ataxia
syndrome should be considered in the context of a family history of mental
retardation and premature ovarian failure. Parkinsonism and autonomic
dysfunction can also occur; therefore, fragile X tremor-ataxia syndrome should
be in the differential diagnosis for multiple system atrophy. T2 hyperintensity in
the middle cerebellar peduncles and corpus callosum on brain MRI are
characteristics of fragile X tremor-ataxia syndrome and can help with the
diagnosis (FIGURE 7-3).28

TABLE 7-4 Common Causes of Autosomal Recessive Ataxia

Disease Genetic Mutations Age at Onset Associated Clinical Features

Cerebellar Ataxia With Predominant Sensory Neuronopathy

Friedreich ataxia Repeat expansions in From childhood Pes cavus, scoliosis, square-wave jerks,
intron 1 of FXN gene to third decade hyporeflexia, spasticity (adult onset)

Sensory ataxic neuropathy, POLG mutations 20–60 years Ophthalmoplegia, dysarthria, ptosis,
dysarthria, and myoclonus, epilepsy
ophthalmoparesis (SANDO)

Cerebellar Ataxia With Sensorimotor Axonal Neuropathy

Ataxia telangiectasia ATM mutations <5 years Telangiectasia, chorea, dystonia,

susceptibility to infections and cancer,
radiosensitivity, elevated α-fetoprotein

Ataxia with oculomotor apraxia APTX mutations <20 years Oculomotor apraxia, chorea, dystonia
type 1

Ataxia with oculomotor apraxia SETX mutations From childhood Oculomotor apraxia, chorea, dystonia,
type 2 to third decade elevated α-fetoprotein

Cerebrotendinous CYP27 mutations Childhood Spasticity, mental retardation, tendon

xanthomatosis xanthoma, chronic diarrhea, premature cataract

Cerebellar Ataxia Without Sensory Neuropathy

Autosomal recessive cerebellar SYNE1 mutations From second to Spasticity, lower motor neuron signs
ataxia type 1 fifth decade

Autosomal recessive cerebellar ADCK3 mutations <10 years Mental retardation, myoclonus, epilepsy,
ataxia type 2 exercise intolerance

Niemann-Pick disease type C NPC1 and NPC2 From first to Vertical supranuclear ophthalmoplegia,
mutations third decade splenomegaly, dystonia, cognitive decline

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Mitochondrial Ataxia KEY POINTS
Mitochondrial DNA mutations
● Autosomal recessive
can also cause ataxia. The ataxia can be divided into
common causes are Kearns- three categories: (1)
Sayre syndrome, myoclonic cerebellar ataxia with
epilepsy with ragged red fibers predominant sensory
neuronopathy, (2) cerebellar
(MERRF), and mitochondrial
ataxia with sensorimotor
encephalopathy, lactic acidosis, axonal neuropathy, and (3)
and strokelike episodes cerebellar ataxia without
(MELAS). Because of the tissue- sensory neuropathy.
specific mitochondrial defects
● Fragile X tremor-ataxia
(ie, heteroplasmy), muscle FIGURE 7-3 syndrome is the most
biopsy should be performed Fragile X tremor-ataxia syndrome. Axial T2- common cause of X-linked
because mitochondrial defects weighted MRI of a 76-year-old man with fragile X ataxia.
are more likely to be detected tremor-ataxia syndrome showing symmetric
increased signal within the middle cerebellar ● The first approach to the
in the non-dividing cells, such genetics of ataxia is to
peduncles (arrow).
as muscles. Reprinted with permission from Hagerman PJ, Hagerman RJ, investigate for repeat
Nat Clin Pract Neurol.28 © 2007 Nature Publishing Group. expansions, which are the
Episodic Ataxia common causes of
autosomal dominant,
Episodic ataxia (types 1 to 8) recessive, and X-linked
constitutes a group of genetic causes for intermittent ataxia attacks, lasting from ataxia.
minutes to days. There might be underlying progressive ataxia in addition to
episodic attacks. Some forms of episodic ataxias can be triggered by exertion.29
The genetic mutations associated with episodic ataxia are often in the ion
channels or membrane proteins important to neuronal excitability. Other major
differential diagnostic considerations for episodic ataxia are multiple sclerosis
and psychogenic ataxia.

A Rational Approach to the Diagnosis of Genetic Ataxia

Despite the rapid advancement of whole exome and genome sequencing
technologies, the first approach to the diagnosis of hereditary ataxia is to test for
repeat expansions because these repeat-associated ataxias are most common
(autosomal dominant: SCA1, SCA2, SCA3, SCA6; autosomal recessive: Friedreich
ataxia; X-linked ataxia: fragile X tremor-ataxia syndrome), and repeat-length
alterations will not be detected by the sequencing methods. After excluding the
repeat-related ataxias, whole exome sequencing can be very useful in determining
sequence alterations.15 Another limitation of whole exome sequencing for
ataxia is that this method is not sensitive for large chromosomal deletions or
duplications, such as in SCA20, or for ataxia associated with mitochondrial
genome mutations, or for repeat expansions in the noncoding regions. A genetic
diagnostic test for ataxia should be coupled with the clinical presentation for
appropriate genetic tests.
Investigators have performed sequencing analysis in a large cohort of patients
with ataxia without a family history. It turns out that autosomal recessive
cerebellar ataxia type 1 with SYNE1 mutation is the most common and, thus,
should be kept in mind in adult-onset ataxia with variable motor neuron signs
such as hyperreflexia, extensor plantar responses, muscle atrophy, or
fasciculations.15 It has also been recently recognized that genetic mutations for
spastic paraplegia can sometimes cause cerebellar ataxia. While these genetic
mutations are not traditionally categorized into SCAs or recessive ataxias,

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ATAXIA

clinicians should still keep these genes in mind. One example is the SPG7 mutation,
which has been observed in patients with idiopathic cerebellar ataxia.30

DEGENERATIVE ATAXIA
Degenerative forms of ataxia usually occur in patients who are older than
60 years of age and have no family history of ataxia. In this category, multiple
system atrophy and idiopathic late-onset cerebellar ataxia are the two most
common diseases.
Multiple system atrophy is characterized by cerebellar ataxia, parkinsonism,
autonomic instability (orthostatic hypotension; impotence; and urinary
frequency, urgency, and incontinence), and pyramidal signs.31 Depending on
the predominant features, multiple system atrophy can also be divided into
multiple system atrophy–parkinsonism type or multiple system atrophy–cerebellar
type. Multiple system atrophy–cerebellar type constitutes approximately 30% of
all multiple system atrophy cases.31 Patients with multiple system atrophy with
predominant cerebellar ataxia generally have a slower disease progression than
those with predominant parkinsonism. In the early stage of the disease, patients
might present with relatively isolated cerebellar ataxia. Therefore, the history
and examination should focus on searching for any signs of parkinsonian
features, autonomic dysfunction, and upper motor neuron signs. Rapid eye
movement sleep behavior disorder is often present, which can be very helpful
in indicating an underlying synucleinopathy associated with multiple system
atrophy.31 Respiratory stridor and obstructive sleep apnea sometimes are
present. Therefore, for patients with cerebellar ataxia onset later in life,
autonomic tests and sleep studies can provide additional evidence to support the
diagnosis of multiple system atrophy when clinical symptoms are not yet
evident. Brain MRI in patients with multiple system atrophy may show the hot
cross bun sign; this sign might not be evident in the early stage of the disease but
can show up later after the disease progresses.
Multiple system atrophy is a disease with a relatively fast progression. However,
idiopathic late-onset cerebellar ataxia is a disease with a slow progression,
and it usually does not compromise the life span. Patients with idiopathic
late-onset cerebellar ataxia usually will not develop other neurologic features
such as hyperreflexia or parkinsonism.
Practically, the presence of parkinsonism and autonomic dysfunction in
elderly patients with ataxia usually indicates a poor prognosis because the
diagnosis is likely to be multiple system atrophy. If no parkinsonism or
autonomic dysfunction is seen within 5 years after the onset of ataxia, these
patients are likely to follow a benign clinical course with the diagnosis of
idiopathic late-onset cerebellar ataxia.

TREATMENT OF ATAXIA
The treatment for ataxia can be divided into symptomatic and disease-modifying
therapies. Disease-modifying therapy exists for some causes of ataxia, especially
for acquired cases (eg, thiamine for Wernicke encephalopathy,32 gluten-free diet
for ataxia associated with gluten sensitivity, and IV immunoglobulin and plasma
exchange for anti-GAD ataxia and paraneoplastic ataxia). Disease-modifying
therapies for genetic ataxias include vitamin E replacement for ataxia associated
with vitamin E deficiency and abetalipoproteinemia, miglustat for Niemann-Pick
disease type C, and ketogenic diet for glucose transporter type 1 deficiency.33

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 There is a pipeline of therapy development for Friedreich ataxia, which KEY POINT
includes medications that could improve mitochondrial function and reduce
● Patients with multiple
oxidative stress, modulate frataxin-controlled metabolic pathways, serve as system atrophy can have
frataxin stabilizers or enhancers, or increase FXN gene expression.34 The detailed cerebellar ataxia,
stages of development in each drug are listed on the Friedreich’s Ataxia Research parkinsonism, autonomic
Alliance website.35 dysfunction, and pyramidal
signs.
For symptomatic therapy of cerebellar ataxia, in general, a recently published
comprehensive review should be used as a guide.22 The following are several
selectively highlighted commonly used treatment options among ataxia experts.
Riluzole 50 mg 2 times a day has been shown to improve dysarthria and gait
ataxia18 and can be tried in patients with ataxia. Monitoring liver function is
necessary while patients are treated with riluzole. Varenicline 1 mg 2 times a
day has been shown to be helpful in patients with SCA3.20 The side effect of
depression should be closely monitored. 4-Aminopyridine 15 mg/d has been
shown to be effective to suppress the number of attacks in patients with episodic
ataxia type 2,36 and it is sometimes useful in treating nystagmus.37 Other
medications, such as amantadine,38 baclofen, and chloroxazone,39 can also be
used to treat ataxia. Symptoms other than ataxia, such as tremor, dystonia, and
depression, should be identified and treated with conventional symptomatic
therapy. For instance, postural tremor can be treated with primidone or
propranolol, dystonia with botulinum toxin, and depression with
antidepressants.
Exercise can provide benefit for patients with ataxia because exercise has been
shown to dramatically enhance the life span of SCA1 mouse models.40
Coordinated training has been demonstrated to provide long-standing benefits
for patients with ataxia,41 and these exercises focus on core strength and balance.
Whether aerobic and other forms of exercise also have additional benefits remain
to be tested.
Some evidence indicates that dietary supplementation might be helpful in
treating ataxia. For example, coenzyme Q10 supplementation might be beneficial
for SCAs21 or multiple system atrophy. Rare mutations of COQ2, a gene that
encodes an enzyme essential for coenzyme Q10 biosynthesis, have been identified
in patients with multiple system atrophy,42 and patients with idiopathic multiple
system atrophy also have decreased brain coenzyme Q10 levels.43 A clinical trial
has been initiated to test MSA-01, a variant of coenzyme Q10 that has more
bioavailability to the brain, for patients with multiple system atrophy.44 Zinc
supplementation might also be helpful for patients with SCA2.19
The development of ataxia therapy is an exciting area of neurology research.
With the advancement of our understanding of cerebellar physiology, ion
channel modulation of cerebellar circuitry can present an opportunity for
symptomatic therapy for ataxia. Small-conductance calcium-activated potassium
channels are enriched within Purkinje cells and can regulate the firing patterns of
these neurons. In addition, cerebellar physiology can potentially be modulated by
the speed of glutamate uptake in astrocytes. Therefore, medications regulating
these mechanisms are currently being tested in patients with genetically
confirmed SCA.45 Deep brain stimulation for patients with ataxia has had
variable success, but the most consistent benefit is in tremor of patients with
SCA2.46 Further exploration of new stimulation targets and the stimulation
parameters are likely to identify ways of improving ataxia symptoms. Finally,
antisense oligonucleotides have been shown to knock down the toxic protein

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ATAXIA

levels and to improve the symptoms of mouse models of SCA2 and SCA3.47,48
These studies formulate a strong scientific rationale to test antisense
oligonucleotides in patients with ataxia in the near future.

CONCLUSION
The causes of cerebellar ataxia are many and can present as diagnostic challenges.
This article provides a step-by-step diagnostic guide for patients with ataxia. The
acquired causes of ataxia should first be considered, followed by genetic and
degenerative forms of ataxia. If genetic ataxia is suspected, pathologic repeat
expansions in the ataxic genes should be determined first, followed by assessing
for sequence alterations. Among late-onset cerebellar ataxias, multiple system
atrophy is most common and should be considered. Although the treatment for
cerebellar ataxia remains only modestly effective, several novel therapies are
currently being tested, including pharmacologic therapy, brain stimulation, and
antisense oligonucleotides.

USEFUL WEBSITES
ONLINE MENDELIAN INHERITANCE IN MAN (OMIM) FRIEDREICH’S ATAXIA RESEARCH ALLIANCE
The OMIM website provides useful guidance for This website discusses therapy development for
genetic mutations associated with cerebellar ataxia. Friedreich ataxia.
omim.org curefa.org/pipeline

VIDEO LEGENDS
VIDEO 7-1 VIDEO 7-3
Different degrees of gait ataxia. The first video Spinocerebellar ataxia type 2. The first video
segment shows an 18-year-old man with ataxia with segment shows the 55-year-old woman discussed
oculomotor apraxia type 2. Mild gait ataxia can in CASE 7-2 with spinocerebellar ataxia type 2. She
manifest with variable step length, side steps, and has limited upward gaze and slow saccadic eye
veering toward one side without a marked wide movements without nystagmus or hypermetric or
base. The second video segment shows a 37-year- hypometric saccades. She has dysmetria on finger-
old man with idiopathic cerebellar ataxia. In patients nose-finger tests and an overshoot in finger chase
with moderate ataxia, the gait becomes wide tests. She also has impaired rapid alternating
based with obvious variable stride lengths. The third movements. Her facial expression is hypomimic,
video segment shows a 32-year-old woman with and her gait is wide based and shows variable stride
spinocerebellar ataxia type 2. In the advanced length. The second video segment shows the
stages of ataxia, a wide-based gait is more evident, same patient 5 years later. Her symptoms have
and the stride length becomes shorter to progressed. She has ophthalmoparesis, particularly
compensate for ataxia. in vertical gaze, and her saccadic eye movements
links.lww.com/CONT/A358 have become very slow.
© 2019 American Academy of Neurology. links.lww.com/CONT/A360
© 2019 American Academy of Neurology.
VIDEO 7-2
Multiple system atrophy, cerebellar type. VIDEO 7-4
Video shows the 56-year-old woman discussed in Niemann-Pick disease type C. Video shows a
CASE 7-1 who developed imbalance and walked “as 30-year-old man with Niemann-Pick disease type C.
if she were drunk.” She veered toward one side He has relatively preserved smooth pursuit in the
while walking, had two episodes of syncope, horizontal direction without end-gaze nystagmus.
and her speech and hand dexterity were He can perform upward pursuit, but his downward
subsequently involved. On examination, she has pursuit movements are extremely slow. He also has
hypomimic facial expression, hypermetric relatively preserved horizontal saccades and has
saccades, dysmetria on finger-nose-finger tests, great difficulty in vertical saccades, particularly in
bradykinesia in finger taps, and ataxic gait with the downward direction.
variable footsteps. Her postmortem brain links.lww.com/CONT/A361
pathology demonstrated glial cytoplasmic © 2019 American Academy of Neurology.
inclusions along with olivopontocerebellar
atrophy, confirming the diagnosis of multiple
system atrophy, cerebellar type.
links.lww.com/CONT/A359
© 2019 American Academy of Neurology.

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REFERENCES

1 Ashizawa T, Öz G, Paulson HL. Spinocerebellar 15 Fogel BL, Lee H, Deignan JL, et al. Exome
ataxias: prospects and challenges for therapy sequencing in the clinical diagnosis of sporadic
development. Nat Rev Neurol 2018;14(10): or familial cerebellar ataxia. JAMA Neurol
590–605. doi:10.1038/s41582-018-0051-6. 2014;71(10):1237–1246. doi:10.1001/jamaneurol.
2014.1944.
2 Schöls L, Bauer P, Schmidt T, et al. Autosomal
dominant cerebellar ataxias: clinical features, 16 Ashizawa T, Figueroa KP, Perlman SL, et al.
genetics, and pathogenesis. Lancet Neurol 2004; Clinical characteristics of patients with
3:291–304. doi:10.1016/S1474-4422(04)00737-9. spinocerebellar ataxias 1, 2, 3 and 6 in the US; a
prospective observational study. Orphanet J
3 Anheim M, Tranchant C, Koenig M. The autosomal
Rare Dis 2013;8:177. doi:10.1186/1750-1172-8-177.
recessive cerebellar ataxias. N Engl J Med 2012;
366(7):636–646. doi:10.1056/NEJMra1006610. 17 Jacobi H, Bauer P, Giunti P, et al. The natural
history of spinocerebellar ataxia type 1, 2, 3, and
4 Luo L, Wang J, Lo RY, et al. The initial symptom
6: a 2-year follow-up study. Neurology 2011;77(11):
and motor progression in spinocerebellar
1035–1041. doi:10.1212/WNL.0b013e31822e7ca0.
ataxias. Cerebellum 2017;16(3):615–622.
doi:10.1007/s12311-016-0836-3. 18 Romano S, Coarelli G, Marcotulli C, et al. Riluzole
in patients with hereditary cerebellar ataxia: a
5 Moscovich M, Okun MS, Favilla C, et al. Clinical
randomised, double-blind, placebo-controlled
evaluation of eye movements in spinocerebellar
trial. Lancet Neurol 2015;14(10):985–991.
ataxias: a prospective multicenter study.
doi:10.1016/S1474-4422(15)00201-X.
J Neuroophthalmol 2015;35(1):16–21. doi:10.1097/
WNO.0000000000000167. 19 Velázquez-Pérez L, Rodríguez-Chanfrau J,
Garcia-Rodríguez JC, et al. Oral zinc sulphate
6 Kuo PH, Lo RY, Tanji K, Kuo SH. Clinical reasoning:
supplementation for six months in SCA2
a 58-year-old man with progressive ptosis and
patients: a randomized, double-blind, placebo-
walking difficulty. Neurology 2017;89(1):e1–e5.
controlled trial. Neurochem Res 2011;36(10):
doi:10.1212/WNL.0000000000004064.
1793–1800. doi:10.1007/s11064-011-0496-0.
7 Lin CY, Wang MJ, Tse W, et al. Serum antigliadin
20 Zesiewicz TA, Greenstein PE, Sullivan KL, et al. A
antibodies in cerebellar ataxias: a systematic
randomized trial of varenicline (Chantix) for the
review and meta-analysis. J Neurol Neurosurg
treatment of spinocerebellar ataxia type 3.
Psychiatry 2018;89(11):1174–1180. doi:10.1136/
Neurology 2012;78(8):545–550. doi:10.1212/
jnnp-2018-318215.
WNL.0b013e318247cc7a.
8 Tee BL, Longoria Ibarrola EM, Geschwind MD.
21 Lo RY, Figueroa KP, Pulst SM, et al. Coenzyme Q10
Prion diseases. Neurol Clin 2018;36(4):865–897.
and spinocerebellar ataxias. Mov Disord 2015;
doi:10.1016/j.ncl.2018.07.005.
30(2):214–220. doi:10.1002/mds.26088.
9 Lo RY, Figueroa KP, Pulst SM, et al. Depression
22 Zesiewicz TA, Wilmot G, Kuo SH, et al. Comprehensive
and clinical progression in spinocerebellar
systematic review summary: treatment of cerebellar
ataxias. Parkinsonism Relat Disord 2016;22:87–92.
motor dysfunction and ataxia: report of the
doi:10.1016/j.parkreldis.2015.11.021.
Guideline Development, Dissemination, and
10 Hoche F, Guell X, Vangel MG, et al. The cerebellar Implementation Subcommittee of the American
cognitive affective/Schmahmann syndrome Academy of Neurology. Neurology 2018;90(10):
scale. Brain 2018;141(1):248–270. doi:10.1093/ 464–471. doi:10.1212/WNL.0000000000005055.
brain/awx317.
23 Ashraf NS, Duarte-Silva S, Shaw ED, et al.
11 McFarland NR. Diagnostic approach to atypical Citalopram reduces aggregation of ATXN3 in a
parkinsonian syndromes. Continuum (Minneap YAC transgenic mouse model of Machado-Joseph
Minn) 2016;22(4, Movement Disorders):1117–1142. disease. Mol Neurobiol 2019;56(5):3690–3701.
doi:10.1212/CON.0000000000000347. doi:10.1007/s12035-018-1331-2.
12 Kuo PH, Kuo SH, Lo RY. Deferiprone reduces 24 Seidel K, Siswanto S, Brunt ER, et al. Brain pathology
hemosiderin deposition in superficial siderosis. of spinocerebellar ataxias. Acta Neuropathol
Can J Neurol Sci 2017;44(2):219–220. doi:10.1017/ 2012;124(1):1–21. doi:10.1007/s00401-012-1000-x.
cjn.2016.329.
25 Paulson HL, Shakkottai VG, Clark HB, Orr HT.
13 Online Mendelian Inheritance in Man: an online Polyglutamine spinocerebellar ataxias—from
catolog of human genes and genetic disorders. genes to potential treatments. Nat Rev Neurosci
omim.org. Updated April 23, 2019. Accessed 2017;18(10):613–626. doi:10.1038/nrn.2017.92.
June 4, 2019.
26 Mademan I, Harmuth F, Giordano I, et al.
14 Durr A. Autosomal dominant cerebellar ataxias: Multisystemic SYNE1 ataxia: confirming the high
polyglutamine expansions and beyond. Lancet frequency and extending the mutational and
Neurol 2010;9(9):885–894. doi:10.1016/S1474- phenotypic spectrum. Brain 2016;139(pt 8):e46.
4422(10)70183-6. doi:10.1093/brain/aww115.

CONTINUUMJOURNAL.COM 1053

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

ATAXIA

27 Gupta DK, Blanco-Palmero VA, Chung WK, Kuo 38 Botez MI, Botez-Marquard T, Elie R, et al.
SH. Abnormal vertical eye movements as a clue Amantadine hydrochloride treatment in
for diagnosis of Niemann-Pick type C. Tremor heredodegenerative ataxias: a double blind
Other Hyperkinet Mov (N Y) 2018;8:560. study. J Neurol Neurosurg Psychiatry 1996;61(3):
doi:10.7916/D8XS7BGD. 259–264. doi:10.1136/jnnp.61.3.259.
28 Hagerman PJ, Hagerman RJ. Fragile X-associated 39 Bushart DD, Chopra R, Singh V, et al. Targeting
tremor/ataxia syndrome–and older face of the potassium channels to treat cerebellar ataxia.
fragile X gene. Nat Clin Pract Neurol 2007;3(2): Ann Clin Transl Neurol 2018;5(3):297–314.
107–112. doi:10.1038/ncpneuro0373. doi:10.1002/acn3.527.
29 Jen JC, Wan J. Episodic ataxias. Handb Clin 40 Fryer JD, Yu P, Kang H, et al. Exercise and genetic
Neurol 2018;155:205–215. doi:10.1016/B978-0-444- rescue of SCA1 via the transcriptional repressor
64189-2.00013-5. Capicua. Science 2011;334(6056):690–693.
doi:10.1126/science.1212673.
30 Pfeffer G, Pyle A, Griffin H, et al. SPG7 mutations
are a common cause of undiagnosed ataxia. 41 Ilg W, Brötz D, Burkard S, et al. Long-term effects
Neurology 2015;84(11):1174–1176. doi:10.1212/WNL. of coordinative training in degenerative cerebellar
0000000000001369. disease. Mov Disord 2010;25(13):2239–2246.
doi:10.1002/mds.23222.
31 Fanciulli A, Wenning GK. Multiple-system
atrophy. N Engl J Med 2015;372(3):249–263. 42 Multiple-System Atrophy Research
doi:10.1056/NEJMra1311488. Collaboration. Mutations in COQ2 in familial and
sporadic multiple-system atrophy. N Engl J Med
32 Kuo SH, Debnam JM, Fuller GN, de Groot J.
2013;369(3):233–244. doi:10.1056/NEJMoa1212115.
Wernicke's encephalopathy: an underrecognized
and reversible cause of confusional state in 43 Barca E, Kleiner G, Tang G, et al. Decreased
cancer patients. Oncology 2009;76(1):10–18. coenzyme Q10 levels in multiple system atrophy
doi:10.1159/000174951. cerebellum. J Neuropathol Exp Neurol 2016;75(7):
663–672. doi:10.1093/jnen/nlw037.
33 Braga Neto P, Pedroso JL, Kuo SH, et al. Current
concepts in the treatment of hereditary ataxias. 44 UMIN Clinical Trials Registry. Clinical trial
Arq Neuropsiquiatr 2016;74(3):244–252. UMIN000031771. upload.umin.ac.jp/cgi-open-
doi:10.1590/0004-282X20160038. bin/ctr_e/ctr_view.cgi?recptno=R000036134.
Updated July 27, 2018; Accessed June 4, 2019.
34 Aranca TV, Jones TM, Shaw JD, et al. Emerging
therapies in Friedreich's ataxia. Neurodegener 45 ClinicalTrials.gov. NCT02960893. clinicaltrials.
Dis Manag 2016;6(1):49–65. doi:10.2217/nmt.15.73. gov/ct2/show/NCT02960893. Updated
August 8, 2018. Accessed June 4, 2019.
35 Friedreich’s Ataxia Research Alliance. Research
pipeline. curefa.org/pipeline. Accessed June 4, 46 Hashimoto T, Muralidharan A, Yoshida K, et al.
2019. Neuronal activity and outcomes from thalamic
surgery for spinocerebellar ataxia. Ann Clin Transl
36 Strupp M, Kalla R, Claassen J, et al. A randomized
Neurol 2018;5(1):52–63. doi:10.1002/acn3.508.
trial of 4-aminopyridine in EA2 and related
familial episodic ataxias. Neurology 2011;77(3): 47 Scoles DR, Meera P, Schneider MD, et al.
269–275. doi:10.1212/WNL.0b013e318225ab07. Antisense oligonucleotide therapy for
spinocerebellar ataxia type 2. Nature 2017;
37 Tsunemi T, Ishikawa K, Tsukui K, et al. The effect
544(7650):362–366. doi:10.1038/nature22044.
of 3,4-diaminopyridine on the patients with
hereditary pure cerebellar ataxia. J Neurol Sci 48 McLoughlin HS, Moore LR, Chopra R, et al.
2010;292(1–2):81–84. doi:10.1016/j.jns.2010.01.021. Oligonucleotide therapy mitigates disease in
spinocerebellar ataxia type 3 mice. Ann Neurol
2018;84(1):64–77. doi:10.1002/ana.25264.

DISCLOSURE
Continued from page 1036
National Ataxia Foundation, for the National Institute
of Environmental Health Sciences pilot grant
ES009089, as principal investigator for studies from
the National Institute of Neurological Disorders and
Stroke (R01 NS104423, K08 NS083738), Parkinson’s
Foundation, and the Rare Disease Clinical Research
Network (RC1NS068897).

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 Myoclonus REVIEW ARTICLE


By John N. Caviness, MD, FAAN 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

ABSTRACT
PURPOSE OF REVIEW: This
article offers clinicians a strategic approach for
making sense of a symptom complex that contains myoclonus. The article
presents an evaluation strategy that highly leverages the two major
classification schemes of myoclonus. The goal of this article is to link
evaluation strategy with diagnosis and treatment of myoclonus.

RECENT FINDINGS: Thegrowth of medical literature has helped better define

myoclonus etiologies. Physiologic study of myoclonus types and etiologies
Downloaded from http://journals.lww.com/continuum by BhDMf5ePHKbH4TTImqenVBosEKX31uF9Xrl5zJqiRIzEiZ0bzbwBKM6MljL6CEtn on 08/03/2019

with electrophysiologic testing has provided greater clarity to the

pathophysiology of the myoclonus in various diseases. Although studies
have been limited, the role of newer treatment agents and methods has
made progress.

SUMMARY: Myoclonus has hundreds of different etiologies. Classification

is necessary to evaluate myoclonus efficiently and pragmatically. The
classification of myoclonus etiology, which is grouped by different
clinical presentations, helps determine the etiology and treatment of
the myoclonus. The classification of myoclonus physiology using
electrophysiologic test results helps determine the pathophysiology of
CITE AS:
the myoclonus and can be used to strategize symptomatic treatment
CONTINUUM (MINNEAP MINN)
approaches. Both basic ancillary testing (including EEG and imaging) 2019;25(4, MOVEMENT DISORDERS):
and more comprehensive testing may be necessary. Treatment of the 1055–1080.

underlying etiology is the ideal approach. However, if such treatment is not

Address correspondence to
possible or is delayed, symptomatic treatment guided by the myoclonus Dr John N. Caviness, Department
physiology should be considered. More controlled study of myoclonus of Neurology, Mayo Clinic 13400 E
treatment is needed. Further research on myoclonus generation Shea Blvd, Scottsdale, AZ 85259,
[email protected].
mechanisms should shed light on future treatment possibilities.
RELATIONSHIP DISCLOSURE:
Dr Caviness reports no
disclosure.

INTRODUCTION UNLABELED USE OF

M
yoclonus is defined as a sudden, brief, lightninglike muscle PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
contraction.1 Myoclonus may occur from an increase in Dr Caviness discusses the
contraction activity (positive myoclonus) or inhibition unlabeled/investigational use of
of contraction activity (negative myoclonus).1 To recognize anticholinergic medications,
botulinum toxin,
the visual appearance of a myoclonic jerk, the clinician should carbamazepine, clonazepam,
consider the quickest movement that can be performed with that body part. deep brain stimulation,
Indeed, the brief movement of myoclonus does not slow down, pause, or “hang levetiracetam, sodium oxybate,
and tetrabenazine for the
up.” Dystonic spasms or dyskinetic jerks may be sudden, but they are not treatment of myoclonus.
lightning brief. A tremor discharge may be brief but does not result in a jerk or
sudden movement. Indeed, the myoclonus phenotype is both a jerk (sudden) © 2019 American Academy
and the most transient (brief ) compared with any other movement disorder of Neurology.

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MYOCLONUS

phenotype. Although this definition has been quoted for decades, a study
found only moderate agreement on labeling a movement as myoclonus when
presented with a mixture of myoclonus, tics, and psychogenic jerks.2
The incidence of myoclonus in the clinic setting is estimated at 1.3 cases per
100,000 person-years, with a prevalence of 8.6 cases per 100,000 in the overall
population.3 These numbers are probably an underestimate because myoclonus
is most often secondary to another disorder. However, no single etiology or even
a small group of etiologies accounts for most of the cases. Indeed, myoclonus
has a bewildering number of types and etiologies.
To efficiently evaluate a patient with an unknown etiology for myoclonus,
clinicians must have an organized approach to myoclonus evaluation.
Fortunately, an efficient and pragmatic strategy exists to best define the
diagnosis, physiology, and treatment approach for a specific myoclonus case.
Central to this strategy are myoclonus classification schemes. Myoclonus has
popular classification schemes based on clinical presentation and etiology and a
separate scheme based on physiology.1,4
This article first covers the overall evaluation strategy for myoclonus. Second,
the physiologic classification of myoclonus is discussed. Next, clinical
presentation and etiologic classification and myoclonus types are reviewed.
Finally, symptomatic treatment strategies are discussed. This article focuses
on the connection between the evaluation (including classification) and
symptomatic treatment of myoclonus.

AN EFFICIENT AND PRAGMATIC EVALUATION OF MYOCLONUS

The evaluation is organized into three steps.

Step One: History and Examination With Clinical Presentation Classification

A comprehensive history and examination are the critical first steps. Events
coincident or close to the myoclonus onset are important clues, including
comorbid medical conditions. For example, the starting of a new medication
may implicate that medication as the myoclonus etiology. A subacute onset of
the myoclonus should trigger a targeted evaluation of infectious/postinfectious,
inflammatory/immune, paraneoplastic, and toxic-metabolic etiologies.
Chronic onset of diffuse or multifocal myoclonus is commonly caused by
neurodegenerative and genetic etiologies. Chronic onset of focal myoclonus
can suggest a neoplastic etiology. A family history of myoclonus may suggest a
genetic cause, including epileptic syndromes. A history of concomitant
symptoms, especially neurologic symptoms, is important to document.
The examination should characterize the amplitude, distribution, and
activation characteristics of the myoclonus because various etiologies may
have typical examination findings. Thus, the examination may be used to
corroborate the etiology of the myoclonus. Equally important is the
documentation of the involvement of other neurologic signs. For example,
dementia commonly implicates a cortical disease. Moreover, myoclonus in a
patient with dementia is likely to have a cortical physiology. Myoclonus
commonly occurs in a variety of neurodegenerative disorders, so the history
and physical examination may define the overall diagnosis (eg, multiple system
atrophy, corticobasal syndrome, dementia with Lewy bodies). A similar
concept can be appreciated with ataxic, parkinsonian, dystonic, and even
peripheral disorders.

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 After the comprehensive history and physical examination, the clinical KEY POINTS
presentation classification of myoclonus should occur as described below, ie,
● The brief, lightninglike
physiologic, essential, epileptic, or symptomatic. Such classification can then muscle contraction defines
guide further evaluation by allowing the clinician to narrow the diagnostic it as myoclonus.
possibilities under the clinical classification category.
● Myoclonus is a symptom
or sign, not a diagnosis. It
Step Two: Basic Ancillary Testing occurs in multiple diseases
Ancillary testing of a patient with myoclonus is recommended if the myoclonus and conditions.
etiology is not determined with a comprehensive history and physical
● Evaluation for
examination. Even if an etiology is suspected, basic testing is useful in confirming myoclonus begins with a
that common or easily treatable etiologies are ruled out. The following basic comprehensive history and
testing for myoclonus should be considered: neurologic examination
that allows the clinical
presentation classification
u Electrolytes (including calcium and magnesium) into a physiologic, essential,
u Glucose epileptic, or symptomatic
category.
u Renal and hepatic function tests
u Drug and toxin screen (including bismuth) ● EEG should be the initial
electrophysiologic testing
u EEG for myoclonus without a
u Brain imaging (eg, CT, MRI, functional imaging)/other imaging determined etiology.

This testing evaluates for basic electrolyte and metabolic disorders known to
cause myoclonus. Although a metabolic etiology may present in the outpatient
clinic, metabolic and drug causes are particularly relevant in the hospital setting.
Moreover, myoclonus may appear after initial hospitalization because new
medications and progression of medical problems commonly occur during the
hospital course.
EEG should be performed in all cases of myoclonus unless the myoclonus
etiology is obvious since myoclonus most commonly arises from either cortical
or cortical-subcortical physiology, including seizures. The EEG also constitutes
the first step in the electrophysiologic evaluation of the myoclonus. For more
electrophysiologic definition, adding surface EMG channels to the EEG or
performing multichannel recording by using an EMG machine is recommended.
As discussed in the section on the physiologic classification of myoclonus, the
EMG discharge duration and pattern of myoclonus provide more exact
physiologic classification of the myoclonus.
Consideration of brain imaging is recommended, especially for symptomatic
presentations. If the distribution of myoclonus could be consistent with a
segmental or peripheral physiology or with propriospinal (nonsegmental)
myoclonus, then spinal cord or peripheral imaging, or both, should be considered.
The combination of these two steps will lead to the etiology of the myoclonus
in most cases. Moreover, if non–myoclonus signs and symptoms are present,
then appropriate evaluation for a unifying diagnosis should be undertaken. Only
after that evaluation should more comprehensive testing for the suspected
etiology of the myoclonus be undertaken.

Step Three: More Comprehensive Testing if Needed

If the above testing does not reveal the etiology of myoclonus, then other testing
may be required. Further testing should be strongly guided by the evaluation

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MYOCLONUS

results of steps one and two. Because myoclonus is caused by so many potential
etiologies, considering the best diagnosis when taking into account the
nonmyoclonus clinical features and all test evidence may be useful. To define the
physiology of the myoclonus, more electrophysiologic testing may be needed.
The list of eligible tests for more comprehensive testing is vast, which
reinforces the need for a targeted strategy and, ideally, a stepwise evaluation if
numerous tests are being considered. The broad categories of additional testing
may include specific genetic tests, whole exome sequencing, neuronal specific
antibodies (including paraneoplastic), additional specific toxins, and CSF
examination, among others.

CLASSIFICATION OF MYOCLONUS PHYSIOLOGY BY USING

ELECTROPHYSIOLOGIC TEST RESULTS
Physiologic classification requires testing in a clinical neurophysiology
laboratory. Modern digital EMG and EEG have the capability to allow for
different testing modes (eg, multichannel surface EMG recording) and the use of
extra (or substituted) positions for EEG with EMG recordings or vice versa.
Individual cases need tailored testing, and the neurophysiologist should be
comfortable with interpretation.
In this scheme, the classification focuses on the pathophysiologic genesis of
the myoclonus, regardless of its clinical presentation. Indeed, different
myoclonus physiologies exist within the same clinical presentation classification
category and may be cortical, subcortical, or segmental. Also, myoclonus may
have the same physiology (eg, segmental) but a different anatomical location
(eg, brainstem or spinal cord). Thus, physiologic information is complementary
and not redundant to the clinical presentation classification. The determination
of physiology category is based on findings from electrophysiologic tests.
Because symptomatic treatment strategy closely parallels the abnormal
physiology being treated, the combination of both clinical and physiologic
classification gives the clinician a strategy for treatment of myoclonus.4
The physiologic classification of myoclonus is outlined below with basic
electrophysiologic test findings of the major categories. Methodologies and
complete description details are available.5

Cortical Myoclonus
The classification of cortical myoclonus implies that intrinsic cortical
hyperexcitability is the major driver of the genesis of the patient’s myoclonus.
The abnormally excessive motor cortical activity occurs at any one instant in a
relatively small part of the motor homunculus. The excitation occurs in one part
of the homunculus, then in another, usually correlating with a multifocal
distribution of the myoclonus in the limbs. However, excitability spread is
common, subsequently activating adjacent muscles almost synchronously or
even bilateral muscles bisynchronously when the discharge transmits through
the corpus collosum. Myoclonus EMG discharges are brief (25 ms to 100 ms) in
duration and usually spread to antagonist and other contiguous muscle groups
(FIGURE 8-1A).
Chronic posthypoxic myoclonus (Lance-Adams syndrome) is a well-known
type of cortical myoclonus. The myoclonus in disorders classified as progressive
myoclonus epilepsy such as Unverricht-Lundborg disease and mitochondrial
conditions are classically cortical. Neurodegenerative illnesses affecting the

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 cortex, such as Alzheimer disease KEY POINTS
and dementia with Lewy bodies,
● Cortical myoclonus
commonly have cortical physiology is best defined
myoclonus. Certain drugs, such by brief (<50 ms) EMG
as lithium, will have myoclonus discharges and a focal EEG
that is cortical. correlating with the
myoclonus. Enlarged
EEG may show epileptiform
cortical somatosensory
activity correlating with the evoked potential wave,
myoclonic EMG discharges, abnormal long-latency EMG
either grossly or with back reflex, and increased
corticomuscular coherence
averaging. If this is
are supportive but not
demonstrated, cortical confirmatory.
myoclonus is confirmed.6
EEG-EMG back averaging can ● Cortical-subcortical
show a cortical correlate even if myoclonus physiology is
best defined by generalized
no EEG discharge is grossly epileptiform discharges that
apparent on the EEG occur with the myoclonus. It
(FIGURE 8-1B). Supportive most commonly takes the
evidence for a cortical physiology form of EEG generalized
spike-and-wave discharges.
may include enlarged cortical
waves in the somatosensory
FIGURE 8-1 evoked potential (FIGURE 8-2A)
Electrophysiology of cortical myoclonus from a and enhanced long-latency EMG
patient with dementia with Lewy bodies. A, reflexes to peripheral nerve
Surface EMG polygraphy of right wrist muscles
showing myoclonus EMG discharges (arrows). stimulation (FIGURE 8-2B).
Note the brief-duration myoclonus EMG
discharges. B, EEG showing back-averaged Cortical-Subcortical
correlate maximal over the left central scalp Myoclonus
region in the C3 EEG electrode. The averaged
This myoclonus physiology
trigger EMG waveform is in the lower left corner.
occurs with primary generalized
seizures, such as myoclonic
seizures in juvenile myoclonic epilepsy and myoclonus associated with absence
seizures. Generalized spike-and-wave discharges on EEG that correlate with the
myoclonus confirm this category of physiology.7,8 The abnormal excessive
neuronal activity is spread between cortical and subcortical circuits, producing
the diffuse excitation. As such, this physiology is dissimilar from localized
cortical myoclonus and thus is in a different physiology category. Because this
excitation over the sensorimotor cortex is simultaneously widespread, the
myoclonus is commonly generalized. Myoclonus EMG discharges are brief
(25 ms to 100 ms). Enlarged cortical waves in the somatosensory evoked
potential can be seen but are not typical. Enhanced long-latency EMG reflexes
are not associated with this physiology of myoclonus.

Subcortical/Nonsegmental Myoclonus
Two major patterns are seen in subcortical/nonsegmental myoclonus. In the first
pattern, the initial myoclonus EMG discharge corresponds to the subcortical
nidus level (at the brainstem or spinal cord) followed by simultaneous rostral and
caudal recruitment spread of muscle involvement. One example is brainstem
reticular myoclonus in which the first discharge arises in the cranial nerve XI
brainstem innervated muscles (trapezius and sternocleidomastoid). As the

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MYOCLONUS

excitation spreads rostrally,

cranial nerve VII (facial) and
then V (masseter) muscles jerk.
At the same time, the caudally
spreading excitation recruits
bilateral arm muscles and then
leg muscles, thereby producing
their jerking. Trunk muscles
activate progressively in the
caudal direction. To the
observer, the jerk is generalized.
These discharges can be brief
FIGURE 8-2
but more often are more than
Electrophysiologic exaggerated reflex features 100 ms in duration. Another
in cortical myoclonus due to Huntington disease. example is propriospinal
Many cases of cortical myoclonus will show myoclonus, which has its nidus
electrophysiologic evidence of exaggerated
responses to somatic stimulation. This is believed
in the cervical or thoracic spinal
to be hyperexcitability in cortical sensory areas cord and then a similar
that parallels the hyperexcitability in cortical bidirectional muscle recruitment
motor areas. A, Enlarged cortical somatosensory up and down the spinal muscle
evoked potential. B, Enhanced long-latency EMG
segments.9 The myoclonus type
reflex from median nerve stimulation averaged
with rectified (absolute value) signal. Note that may be caused by a variety of
the averaged discharges after 50 ms are of spinal lesions, or it may occur
abnormally long latency. FC3/FC4 (frontocentral) during sleep transition.
and CP3/CP4 (centroparietal) refer to the
In the second subcortical/
standard 10-20 EEG electrode positions.
Modified with permission from Caviness JN.5 nonsegmental myoclonus
© 2003 Elsevier. pattern, myoclonus EMG
discharges are also longer than
100 ms in duration, but a
multifocal pattern is observed. The myoclonus in myoclonus-dystonia is an
example of this pattern, and the electrophysiologic findings have been classically
defined by Roze and colleagues.10 In both patterns, EEG shows no consistent
correlate, and usually the EEG is unremarkable. Somatosensory evoked potential
and long-latency EMG reflexes are normal.

Segmental Myoclonus
In segmental myoclonus the myoclonus EMG discharges usually last longer
than 100 ms and are highly rhythmic. By definition, the discharges are limited
to a few contiguous segments of the brainstem or spinal cord.11 The discharges
are either simultaneous with the other segments or at least time locked. The
discharges are fairly persistent and not usually affected by stimuli or exogenous
factors. Palatal segmental myoclonus is the most common location of segmental
myoclonus. Palatal segmental myoclonus is divided into essential and
symptomatic clinical types.12 Different types of focal lesions of the spinal cord
can cause spinal segmental myoclonus.12

Peripheral Myoclonus
The term peripheral myoclonus should be reserved for instances where the
movement phenotype is myoclonus, although it may coexist with other phenotypes
as well. However, the distribution is defined by one or more peripheral nervous

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system elements (eg, root, nerve). Myoclonus EMG discharges have a variable KEY POINTS
duration and appearance in a given muscle.13 The duration of these discharges
● Subcortical-nonsegmental
may range from 50 ms to 200 ms or longer. Often discharges are simultaneous or myoclonus physiology is
time locked between muscles in the same peripheral nerve distribution. Needle defined by one of two
EMG may prove extremely useful in demonstrating the discharges within small patterns: (1) initiation from
muscles of the same peripheral nerve distribution as well as differential diagnosis the brainstem or spinal cord
followed by simultaneous
of the movement itself (eg, myokymia). The mechanism of peripheral
rostral and caudal EMG
myoclonus is controversial in many cases.14 Although association with a recruitment or (2) multifocal
peripheral nervous system lesion is found, central reorganization of motor myoclonus EMG discharges.
pathways may be a required event for peripheral myoclonus to occur.15 Both patterns show EMG
discharges of more than
However, this is difficult to confirm.
100 ms.

CLASSIFICATION OF MYOCLONUS ETIOLOGY GROUPED BY ● Segmental myoclonus

CLINICAL PRESENTATION physiology is defined by
In this classification scheme, the etiologies of myoclonus are organized around low-frequency rhythmic
myoclonus EMG discharges
the clinical presentation. In the mid-20th century, comprehensive reviews of that persist almost
myoclonus showed that etiologies of myoclonus were associated with certain continuously, with more
clinical circumstances. This concept was used in the long-established clinical than 100 ms duration EMG
classification scheme of Marsden and colleagues1 (TABLE 8-1). The main discharges confined to a
few contiguous muscle
categories in this classification scheme are physiologic, essential, epileptic, and segments.
symptomatic. Each category reflects the elements of characteristic syndrome
presentations, and the various etiologies listed below each category most closely ● Peripheral myoclonus
fit with the clinical presentation reflected by that category. The list of etiologies physiology is defined by a
highly variable myoclonus
in TABLE 8-1 has been modified to reflect current literature.
EMG discharge duration
confined to a specific root,
Physiologic Myoclonus plexus, or peripheral nerve.
Physiologic myoclonus refers to myoclonic jerks that occur as normal phenomena,
and they occur in almost all people. This myoclonus may occur with different ● Physiologic myoclonus is
a normal phenomenon.
frequency and prominence among normal individuals and may not even be Education and reassurance
noticed when it occurs. Physiologic myoclonus is commonly noticed by a are usually the best
concerned observer, such as a spouse. Jerks occurring in sleep or sleep transition treatments.
are common examples (CASE 8-1).16 Normal startle response and hiccups are also
physiologic myoclonus examples. However, it should be realized that some
phenotypes of physiologic myoclonus may be part of a clinical syndrome or
disorder. In these instances, clinical symptoms are caused by the myoclonus
being disruptive or excessive. A prime example is hyperekplexia, in which an
otherwise normal startle response is nonfatigable and symptomatic. As such,
hyperekplexia is considered a pathologic disorder.

Essential Myoclonus
The clinical presentation of essential myoclonus is characterized by a chronic and
relatively stable course in which myoclonus is a prominent or the only symptom.
The jerks interfere with coordination and may become moderate, but the patient
usually compensates without disability (CASE 8-2).17 Nonmovement neurologic
systems are usually not affected, but they occur in some patients.18

HEREDITARY. Myoclonus-dystonia syndrome is the most cited example of

hereditary essential myoclonus.10 As the name indicates, the coexistence of
myoclonus and dystonia is characteristic, although the relative proportion of
myoclonus and dystonia is variable. Autosomal dominant genetic transmission

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MYOCLONUS

TABLE 8-1 Classification of Myoclonus Etiology Grouped by Clinical Presentationa,b

Physiologic Myoclonus (Normal Phenomenon, Healthy Individuals)

1 Sleep-associated myoclonus (eg, hypnic jerks)
2 Anxiety induced
3 Exercise induced
4 Hiccup (singultus)
5 Benign infantile myoclonus with feeding
6 Startle reflex
Essential Myoclonus (Primary Symptom, Mild or Nonprogressive History)
1 Hereditary (myoclonus-dystonia syndrome, autosomal dominant)
2 Sporadic
Epileptic Myoclonus (Seizures Predominate, Part of Chronic Seizure Disorder)
1 Fragments of epilepsy
A Focal motor seizures (including epilepsia partialis continua)
B Myoclonus patterns within a seizure
i Myoclonic-tonic-clonic
ii Myoclonic-atonic
iii Atonic
C Isolated epileptic myoclonic jerks
D Idiopathic stimulus-sensitive myoclonus
E Photosensitive myoclonus
F Myoclonus during absence seizures
i Petit mal epilepsy
ii Eyelid myoclonia
2 Myoclonic seizures
A Infantile spasms
B Myoclonic astatic epilepsy (Lennox-Gastaut syndrome)
C Cryptogenic myoclonus epilepsy (Aicardi syndrome)
D Myoclonic epilepsy
i Infancy
ii Early childhood
iii Juvenile
iv Adult
Symptomatic Myoclonus (Secondary, Progressive, or Static Encephalopathy Predominates)
1 Progressive myoclonic epilepsy syndromes
A Lafora body disease
B GM2 gangliosidosis (late infantile, juvenile)
C Tay-Sachs disease

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CONTINUED FROM PAGE 1062

D Gaucher disease (noninfantile neuronopathic form)

E Krabbe leukodystrophy
F Ceroid lipofuscinosis (Batten disease)
G Sialidosis (cherry-red spot) (types 1 and 2)
H Unverricht-Lundborg disease (Baltic myoclonus disease)
I Action myoclonus-renal failure syndrome
2 Spinocerebellar degenerations
A Idiopathic progressive myoclonic ataxia (dyssynergia cerebellaris myoclonica [also
known as Ramsey Hunt syndrome])
B Friedreich ataxia
C Ataxia-telangiectasia
D Other spinocerebellar degenerations
3 Basal ganglia degenerations
A Wilson disease
B Torsion dystonia
C Neurodegeneration with brain iron accumulation (NBIA)
D Progressive supranuclear palsy
E Huntington disease
F Parkinson disease
G Multiple system atrophy
H Corticobasal degeneration
I Dentatorubral-pallidoluysian atrophy
4 Dementias
A Creutzfeldt-Jakob disease
B Alzheimer disease
C Dementia with Lewy bodies
D Frontotemporal dementia
E Rett syndrome
5 Inflammation (infectious, postinfectious, antibody-mediated, paraneoplastic)
A Opsoclonus-myoclonus syndrome
i Idiopathic
ii Paraneoplastic
iii Infectious
iv Other
B Subacute sclerosing panencephalitis
C Encephalitis lethargica
D Arbovirus encephalitis

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MYOCLONUS

CONTINUED FROM PAGE 1063

E Herpes simplex encephalitis

F Human T-lymphotropic virus I
G HIV
H Miscellaneous bacteria (streptococcus, clostridium, other)
I Malaria
J Syphilis
K Cryptococcus
L Lyme disease
M Progressive multifocal leukoencephalopathy
N Antibody-mediated
i Anti–N-methyl-D-aspartate (NMDA) receptor encephalitis
ii Voltage-gated potassium channel antibody (LGI1 and CASPR2)
O Paraneoplastic encephalopathies
6 Metabolic
A Hyperthyroidism
B Hepatic failure
C Renal failure
D Dialysis syndrome
E Hyponatremia
F Hypoglycemia
G Nonketotic hyperglycemia
H Multiple carboxylase deficiency
I Biotin deficiency
J Mitochondrial dysfunction
K Hypoxia
L Metabolic alkalosis
M Vitamin E deficiency
7 Toxic and drug-induced syndromes (see TABLE 8-2)
8 Physical encephalopathies
A Posthypoxia (acute and chronic [Lance-Adams syndrome])
B Posttraumatic
C Heat stroke
D Electric shock
E Decompression injury
9 Focal nervous system damage
A Central nervous system
i Poststroke

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CONTINUED FROM PAGE 1064

ii Postthalamotomy
iii Tumor
iv Trauma
v Inflammation (eg, multiple sclerosis)
vi Moebius syndrome
vii Developmental
B Peripheral nervous system
i Trauma
ii Hematoma
iii Tumor/infiltration
10 Malabsorption
A Celiac disease
B Whipple disease
11 Eosinophilia-myalgia syndrome
12 Exaggerated startle syndrome
A Hereditary
B Sporadic
13 Hashimoto encephalopathy (steroid-responsive encephalopathy associated with
autoimmune thyroiditis [SREAT])
14 Multiple system degenerations (genetic disorders not falling into another category)
A Allgrove syndrome
B DiGeorge syndrome
C Angelman syndrome
D Familial cortical myoclonic tremor and epilepsy
15 Primary progressive myoclonus of aging
16 Myoclonus associated with sleep
A Generalized
B Propriospinal
17 Unknown

HIV = human immunodeficiency virus; LGI1 = leucine-rich glioma inactivated protein 1; CASPR2 = contactin-
associated proteinlike 2.
a
Modified with permission from Marsden CD, et al, Movement Disorders.1 © 1982 Butterworths.
b
The genetics and clinical details of these etiologies are complex and are not given in detail.

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MYOCLONUS

occurs, and onset is usually early. ε-Sarcoglycan mutations are known to be

associated with this syndrome, but other genes are also involved.19 The clinical
spectrum of these mutations is complex. Other clinical symptoms have been
reported for some patients, and some patients with myoclonus-dystonia have
little or almost insignificant myoclonus. Psychiatric symptoms may be
significant, but other symptoms vary markedly between families.

SPORADIC. Cases of sporadic essential myoclonus are very heterogeneous with

regard to clinical characteristics, including timing, distribution, and exacerbating
factors among other examination findings. Sporadic essential myoclonus likely
includes heterogeneous yet undiscovered etiologies of myoclonus and instances
of false-negative family history.

Epileptic Myoclonus
Epileptic myoclonus occurs in syndromes that are traditionally considered to
be epilepsy (ie, a chronic seizure disorder).7 In most instances, the myoclonus
is the seizure itself and is called a myoclonic seizure. Less commonly, the

CASE 8-1 A 53-year-old man presented for evaluation of whole-body jerks. He was
accompanied by his wife, who reported that her spouse sometimes had
violent whole-body jerks as he was falling asleep. These may have been
going on for years but seemed more apparent recently. He had recently
been diagnosed with diabetes mellitus, and his wife was worried that
these jerks were related to his diabetes mellitus. His current medications
were insulin, losartan, atorvastatin, and aspirin. The patient denied
trouble with falling asleep, insufficient sleep, or excessive daytime
somnolence. He had no other neurologic concerns, and his examination
was normal. His EEG was normal.
He was diagnosed with hypnic jerks presenting as physiologic sleep
myoclonus. The patient and his wife were told that this jerking was of no
concern at that time. They were instructed to return to clinic if any jerks
were disrupting his sleep or preventing her from sleeping. Reassurance
was given that this is a normal phenomenon that varies in occurrence and
size among the healthy population.

COMMENT The patient in this case has myoclonus symptoms characteristic of the
physiologic clinical presentation category. Myoclonus occurs normally
in humans. In this patient, no disabling or functional consequence
accompanied the myoclonus. In fact, from the standpoint of the patient,
the myoclonus was asymptomatic. There was no connection to the
diagnosis of diabetes mellitus or any medication that the patient was
taking. It is typical that the patient or patient’s family expresses concern
about the myoclonus and its possible associations. The evaluation should
be guided by associated symptoms, the neurologic examination, and
plausible differential diagnosis. The EEG was ordered to rule out seizures,
since such generalized jerks may be epileptic in nature.

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myoclonus is just one component of the whole seizure manifestation and is called
a fragment of the seizure or epileptic syndrome. An example of this is when eyelid
myoclonus occurs with an absence seizure. As phenomena related to seizures,
these myoclonic jerking episodes are most often paroxysmal and unpredictable
(CASE 8-3).
Juvenile myoclonic epilepsy is the most common and typical example of an
epileptic myoclonus syndrome.8 It represents generalized epilepsy, and the
myoclonic seizure produces the jerk. The myoclonus is most often generalized

A 24-year-old woman presented with a history of “jerking as far back as I CASE 8-2
can remember.” She experienced bilateral jerking of the arms with
muscle activation and random jerks of the neck. Although these
movements were bothersome, she related only mild disability with
using her hands and arms for handwriting, eating, and other hand
movements. She reported no other symptoms. Rare alcohol
consumption decreased the jerking. She had been previously diagnosed
with essential tremor, and the patient was being treated with propranolol
with modest effect. The patient was adopted, her family history was
unknown, and she worked as a graduate student.
Her examination revealed myoclonic continuous small-to-moderate
multifocal jerking in random directions occurring unpredictably in
bilateral proximal upper extremities during muscle activation. A slight left
torticollis was present. Postural activation of the left arm showed mild
hyperpronation of the forearm. The rest of the examination was normal.
Laboratory evaluation showed no electrolyte disturbance or other toxic-
metabolic or inflammatory abnormality. Imaging and EEG were normal.
She was diagnosed with myoclonus-dystonia syndrome presenting as
essential myoclonus (classified as subcortical-nonsegmental physiology).
Propranolol was discontinued with only a mild detrimental effect, and
clonazepam 1 mg twice daily decreased the myoclonic jerking by more than
50% per patient report.

Some patients, like the one described here, can have repetitive rhythmic COMMENT
myoclonic movements of the upper limbs resembling the postural tremor
of essential tremor. The fact that the myoclonus was the primary symptom
and was chronic with little disability makes essential myoclonus the correct
clinical classification category. The reference to myoclonus-dystonia
means that both myoclonus and dystonia coexist in the patient. However,
in some cases, there may be mostly myoclonus or mostly dystonia.
Although no genetic testing was done, an ε-sarcoglycan or another gene
mutation could have been found in this patient. However, currently, such
genetic testing would not affect treatment, although it affords a more exact
diagnosis and possible future treatment implications. If symptoms become
severe and not adequately controlled with medication (see the section on
treatment for subcortical myoclonus), deep brain stimulation could be
considered.

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MYOCLONUS

but may not be perfectly symmetrical. Although often occurring in the early
morning hours, the seizures arise unpredictably regardless of the muscle state,
relaxation, or activation. Other types of generalized seizures (eg, tonic-clonic)
are common in patients with juvenile myoclonic epilepsy. There may be
photosensitivity and predisposing factors such as sleep deprivation, alcohol use,
and other stresses.

Symptomatic Myoclonus
This category comprises the most common clinical presentation category and
the largest list of myoclonus etiologies.3 In this category, myoclonus is secondary
to a medical or neurologic illness. Seizures may be a significant part of the
patient’s illness, but the seizure is not the major myoclonus phenotype as in
epileptic myoclonus. Other neurologic systems are typically affected and may

CASE 8-3 A 57-year-old woman presented for evaluation of episodes of left arm
jerking. The patient stated that these symptoms had occurred for
decades as sporadic jerking episodes lasting a few seconds. Recently,
they were occurring as a series of repetitive jerks occurring for 15 to
45 seconds on most days. These episodes were unpredictable, and the
jerks disabled the use of the arm while they were occurring. She reported
no other symptoms. Her past medical history revealed no known history
of seizures, and her family history was unremarkable.
Her examination was unremarkable except for a witnessed jerking spell
characterized by abrupt repetitive moderate-to-large myoclonus of the
left arm, at a frequency of about a 1 time per second. Multiple muscles
were involved. After several seconds, the jerks became less frequent and
abruptly stopped.
Her laboratory evaluation was normal. Imaging was normal. Interictal EEG
findings were normal, but EEG during a jerking spell showed rhythmic,
sharply contoured theta activity occurring over the right central head region.
She was diagnosed with focal motor seizures presenting as epileptic
myoclonus (cortical physiology). She was treated with carbamazepine,
resulting in nearly complete remission of the jerking episodes.

COMMENT These episodes presented as unpredictable myoclonus from rest and likely
represented focal motor seizures with epileptic myoclonus as the correct
clinical presentation classification category. The lack of an interictal EEG
abnormality should not dissuade a clinician from a seizure diagnosis. The
gross EEG cortical correlate during a jerking episode confirmed a cortical
physiology for this myoclonus. It is important to define the electrophysiologic
pattern as much as possible. Because these were focal seizures,
carbamazepine was a reasonable treatment option in this patient;
however, it should be noted that myoclonic seizures with generalized spike
and wave may become worse with carbamazepine. This highlights the
importance of distinguishing myoclonus etiologies within the epileptic
myoclonus category with assistance from the EEG pattern.

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involve cognition, parkinsonism, ataxia, sleep dysfunction, autonomic KEY POINTS
symptoms, upper motor neuron findings, and even peripheral nerve
● Essential myoclonus is
dysfunction. Almost all the major medical pathophysiologic processes can pathologic but chronic with
include myoclonus as a symptom, including metabolic, degenerative, toxic, little or no disability. It is
structural lesion, infectious, and inflammatory (CASE 8-4). not common.

● Epileptic myoclonus
PROGRESSIVE MYOCLONIC EPILEPSY SYNDROMES. Various storage diseases
etiologies are chronic
fall under the clinical syndrome of progressive myoclonic epilepsy.22 Progressive seizure disorders that have
myoclonic epilepsy is a chronic, progressive, neurologic syndrome that manifests myoclonus as a prominent
as some combination of myoclonus, seizures, ataxia, and dementia. These phenomenon.
disorders usually affect younger individuals and are often fatal. Several clinical
● Symptomatic myoclonus
differences exist between individual storage diseases in their age of onset, rate is secondary to another
of progression, details of clinical expression, and other clinical manifestations. disorder, neurologic or
The neuropathology in the brain is widespread. Genetic testing is used for an non-neurologic. Multiple
increasing number of etiologies. other symptoms and signs
are usually present or tied to
definable pathology.
NEURODEGENERATION. Myoclonus occurs in chronic degenerative disorders,
including spinocerebellar disorders, basal ganglia disorders, and dementing
diseases. The syndrome dyssynergia cerebellaris myoclonica (also known as
Ramsey Hunt syndrome) refers to an idiopathic progressive myoclonic ataxia.23
Progressive myoclonic ataxia can appear similar to progressive myoclonic
epilepsy, but progressive myoclonic ataxia involves ataxia more than the
seizures that are seen in progressive myoclonic epilepsy. A variety of
progressive myoclonic conditions have been noted to have a predominant
progressive myoclonic ataxia rather than progressive myoclonic epilepsy
phenotype.24 Thus, distinguishing between a progressive myoclonic epilepsy
and progressive myoclonic ataxia phenotype can assist with differential
diagnosis.
Cortical myoclonus occurs across the spectrum of Lewy body disorders.25 The
myoclonus in Parkinson disease is small amplitude and may be confused with
tremor.26 In dementia with Lewy bodies, the myoclonus is larger and occurs in
about 58% of patients.27 The myoclonus that occurs in patients with dementia
with Lewy bodies is more likely to occur at rest than the myoclonus in
Parkinson disease.
Multiple system atrophy manifests as varying degrees of parkinsonism, ataxia,
and autonomic dysfunction. In the parkinsonian presentation, postural
activation triggers small-amplitude myoclonus in about 36% of patients, whereas
a stimulus-induced myoclonus to touch or muscle stretch is not uncommon in
the cerebellar presentations.28
Myoclonic jerks, both action and stimulus sensitive, commonly occur in
corticobasal degeneration. The reported range of the prevalence of myoclonus
in corticobasal degeneration is wide but previously thought to occur in the
majority of clinical cases. However, an autopsy series yielded 27%, suggesting
a smaller occurrence in pathologically confirmed cases.29 The distribution
of the myoclonus in corticobasal degeneration is either asymmetric or
focal and is similar in distribution to the other clinical manifestations of
the disease.
Myoclonus occurs in about 43% of patients with Alzheimer disease.27 The
usual appearance is small multifocal distal jerking, but widespread or generalized
jerks may be present. Myoclonus is a hallmark of Creutzfeldt-Jakob disease and

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MYOCLONUS

CASE 8-4 A 76-year-old man presented for evaluation of symptoms of myoclonus

and confusion that he had experienced over the past few months. His
past medical history included hypertension, diabetes mellitus controlled
by diet, and back surgery. His social history revealed no smoking and only
occasional alcohol use. He was a farmer and ran his farm with his
children, who had become concerned about his bizarre behavior,
confusion, and involuntary movements. A referral was made to neurology
with concerns about a diagnosis of Creutzfeldt-Jakob disease.
On examination, he was awake and alert, but he was disoriented to
location and time. He scored poorly on a short test of mental status.
Multifocal mild-to-moderate myoclonus in all four extremities was
present at rest and was markedly exacerbated with muscle activation.
Quick stretching of his right thumb evoked a local, mild myoclonic jerk.
No reflex sensitivity was present. His gait was moderately unsteady. The
remainder of the neurologic examination was unremarkable.
Laboratory testing showed no electrolyte disturbance or other toxic-
metabolic abnormalities, and there was no evidence of infection or
inflammation.
Brain imaging was unremarkable, and EEG demonstrated significant
generalized slowing; no sharp waves or any epileptiform abnormality was
present. No gross EEG correlate was seen during elicited myoclonus.
Movement neurophysiology revealed short-duration (<50 ms) myoclonus
surface EMG discharges that were synchronous between agonist,
antagonist, and contiguous muscle groups. EEG back averaging of 108
rectified (absolute value) signal myoclonus EMG discharges yielded a
time-locked cortical transient 22 ms before the averaged myoclonus
EMG discharge. Somatosensory evoked potential showed no enlarged
cortical components. Abnormal long-latency EMG reflexes were not
present. A paraneoplastic blood panel showed significantly elevated
voltage-gated potassium channel complex antibodies.
The patient was diagnosed with autoimmune encephalitis secondary
to voltage-gated potassium channel complex antibodies presenting
as symptomatic myoclonus. Treatment with a 5-day course of
methylprednisolone 1 g IV/d yielded a dramatic improvement in
myoclonus as well as his cognitive status.

COMMENT The subacute onset and presence of abnormal mental status suggest that
this patient’s presentation was consistent with symptomatic myoclonus as
the correct clinical presentation classification category. Antibodies to the
voltage-gated potassium channel complex include the subtypes leucine-
rich glioma inactivated protein 1 (LGI1) and contactin-associated proteinlike
2 (CASPR2). Such antibodies may cause multiple neurologic syndromes.20 It
should be realized that this syndrome may present similarly to Creutzfeldt-
Jakob disease, but once discovered, it may be treatable with
immunosuppressive therapy.21 In this case, the patient responded to
treatment of the autoimmune encephalitis, and no symptomatic treatment
of the myoclonus was necessary.

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can occur with rest, voluntary muscle activation, or stimuli.30 When the
myoclonus in Alzheimer disease is large and widespread, it may be confused with
Creutzfeldt-Jakob disease.
Various syndromes of frontotemporal dementia had an overall cumulative
prevalence of myoclonus of 23% in one series.27 An idiopathic progressive
syndrome with cortical action myoclonus as the main symptom has been
described in older individuals as primary progressive myoclonus of aging.31 The
clinical course resembles a chronic neurodegenerative syndrome, but the cause
is unknown.

INFLAMMATION. Opsoclonus-myoclonus syndrome presents with subacute

opsoclonus (irregular, rapid eye movements) and multifocal or generalized
myoclonus.32 Opsoclonus-myoclonus in adults may be due to an infectious,
autoimmune, paraneoplastic, or drug-induced etiology.
Neuroblastoma is a major paraneoplastic etiology consideration in children
with opsoclonus-myoclonus. In adults, a wider variety of tumors are associated
with paraneoplastic cases (eg, ovarian, lung, breast, kidney). The number of
discovered idiopathic autoimmune syndromes with myoclonus and associated
antibodies is growing.33 One example is anti–N-methyl-D-aspartate (NMDA)
receptor encephalitis, which can be seen in children and adults. Antibodies
to the voltage-gated potassium channel complex can be associated with a
variety of neurologic presentations, but prominent myoclonus is seen in
some cases.20

METABOLIC CONDITIONS. Myoclonus often occurs in the hospital setting in

patients with metabolic abnormalities, frequently with mental status changes.
The myoclonus may be multifocal and subtle or generalized and almost
constant as in myoclonic status epilepticus. The prognosis in such cases depends
on the severity and reversibility of the underlying metabolic process. Organ
dysfunction and electrolyte abnormalities are common acquired metabolic
etiologies. Asterixis, which is known as negative myoclonus, is a well-known
characteristic of toxic and metabolic encephalopathy. It is characterized by
brief lapses in postural tone usually observed during postural activation with
the patient’s arms outstretched and wrists extended and is particularly common
in kidney and liver failure.

DRUG-INDUCED. In a patient with myoclonus, all drugs, either in isolation or

combination, must be scrutinized for a potential causative role in the myoclonus.
Drug-induced myoclonus can be due to a wide variety of agents (TABLE 8-2).
This myoclonus is potentially fully treatable because it is almost always reversible
on withdrawal of the offending agent or agents. A spectrum of lithium-induced
myoclonus exists with regard to different clinical manifestations of motor
cortex hyperexcitability. At therapeutic levels or mild lithium toxicity cortical
action myoclonus can be associated with a mildly slower EEG background
rhythm. Instances of greater lithium toxicity can demonstrate motor seizures
and generalized convulsions. Liver or kidney dysfunction may elevate the levels
of certain myoclonus-causing drugs or their metabolites, thereby contributing
to myoclonus. Withdrawal of certain medications, such as sedatives and
anti-seizure agents, may cause myoclonus.

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MYOCLONUS

POSTHYPOXIA. Myoclonus is known to occur after hypoxia that is significant

enough to cause coma.35 Acute myoclonus after hypoxia presents as spontaneous
or stimulus-triggered generalized jerks. Recent literature has suggested
that this myoclonus possibly arises from the brainstem.36 Chronic posthypoxic
myoclonus (Lance-Adams syndrome) occurs after some recovery of mental
status.36 Multifocal action myoclonus dominates the clinical picture. Chronic
posthypoxic myoclonus can be present in facial muscles and affect speech and
swallowing. Some patients also have cerebellar ataxia and negative myoclonus,
which can cause sudden falls. Patients with either acute or chronic posthypoxic
myoclonus may also have seizures from the hypoxic damage.

MYOCLONUS TYPES
Certain myoclonus entities have characteristic presentations on examination and
are ingrained in the vernacular of clinicians, and have designations that are long
ingrained in the literature. These entities may be idiopathic or have variable

TABLE 8-2 Drug Classes and Examples of Drugs Associated With Myoclonusa

Psychiatric Medications
◆ Cyclic antidepressants
◆ Selective serotonin reuptake inhibitors (SSRIs)
◆ Monoamine oxidase inhibitors
◆ Lithium preparations
◆ Antipsychotic agents (including tardive syndrome)
Anti-infectious Agents
◆ Penicillins
◆ Carbapenem classes
Narcotics
◆ Morphine
◆ Fentanyl
Anticonvulsants
◆ Phenytoin
◆ Valproic acid
Anesthetics
◆ Lidocaine
◆ Midazolam
Contrast Media
Cardiac Medications
◆ Antiarrhythmics (eg, amiodarone, flecainide)
Calcium Channel Blockers

a
Modified with permission from Caviness JN, Brown P, Lancet Neurol.34 © 2004 Elsevier.

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classification, and have distinctive examination findings that are used to coin a
term for them. These major myoclonus types are discussed below.

Palatal Myoclonus
The term palatal myoclonus coincides with a segmental distribution of and
around the soft palate. Expectedly, the physiologic classification is segmental.
It is the most common cause of segmental myoclonus and a common cause of
myoclonus in general.3 Some experts prefer the term palatal tremor. However,
a literature search reveals that palatal myoclonus is used in the majority of cases.
It is recommended that the determination be based on the phenotypic
appearance of the repetitive movement. Some examples do have a very rhythmic
and continuous sinusoidal cadence, and it is reasonable to refer to this as
palatal tremor. For movements that are jerky or somewhat irregular, palatal
myoclonus is the correct term.
Palatal myoclonus can be due to a variety of etiologies.37 Essential palatal
myoclonus parallels the characteristics of an essential myoclonus clinical
presentation. In essential palatal myoclonus, the muscle agonist is the tensor
veli palatini, and the myoclonus is frequently associated with an ear-clicking
sound, and often disappears with sleep (CASE 8-5). In the more common
symptomatic palatal myoclonus, the palatal movement is due to contractions
of the levator veli palatini, has other symptoms related to the causative lesion,
and is more persistent. Symptomatic palatal myoclonus is believed to arise from
disruption within the Guillain-Mollaret triangle, a pathway connecting the red
nucleus to the inferior olivary nucleus (central tegmental tract), the inferior
olivary nucleus to the dentate nucleus (inferior cerebellar peduncle), and the
dentate nucleus to the red nucleus (superior cerebellar peduncle). Essential
cases are idiopathic with or without a family history. Symptomatic cases are most
often due to a structural lesion (eg, stroke).

Propriospinal Myoclonus
Propriospinal myoclonus was described by Brown and colleagues9 in 1991. It
arises from a subcortical-nonsegmental physiology within the spinal cord in
which the trigger then travels rostrally and caudally simultaneously via slow
propriospinal pathways. Extension or flexion trunk jerks may occur (CASE 8-6).
Cases may be idiopathic, but lesions are common. Multiple reports exist of
propriospinal myoclonus occurring during transition into sleep, when waking,
or both.39

Orthostatic Myoclonus
Orthostatic myoclonus manifests as leg shaking when the patient is standing,
similar to orthostatic tremor. In contrast to orthostatic tremor, orthostatic
myoclonus produces much more difficulty with gait and has a much higher
prevalence of associated neurologic problems.40 It can be difficult to distinguish
between these two orthostatic movement disorders because of significant clinical
overlap on history and examination. However, the surface EMG pattern in the
lower extremities appears to be different between orthostatic tremor and
orthostatic myoclonus. Instead of the rhythmic 13-Hz to 16-Hz surface EMG
discharges that are seen with orthostatic tremor, orthostatic myoclonus shows
lower frequency and more discharge duration variability with many brief

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MYOCLONUS

discharges (<100 ms). A variety of disorders have been associated with

orthostatic myoclonus, including Parkinson disease.

Cortical Tremor
The myoclonus type known as cortical tremor was first described in 1990.41
It has the classic features of cortical physiology, including enlarged cortical
somatosensory evoked potentials. However, the myoclonus EMG discharges
occur rhythmically or semirhythmically at 6 Hz to 9 Hz, which mimics a
nonspecific muscle activation tremor. Cortical tremor can occur from different
etiologies. A particular syndrome, familial autosomal dominant cortical tremor,
myoclonus, and epilepsy, is now a defined syndrome.42

Minipolymyoclonus
Minipolymyoclonus is a form of multifocal myoclonus and is characterized by
small jerks in different locations.43 This term has also been used to describe
small-amplitude jerks in patients with spinal muscular atrophy. Hence, the

CASE 8-5 A 33-year-old woman presented because of “an obnoxious sound” in her
ears. When it began 5 to 7 years ago, she thought that it was simply
“ringing in her ears” from listening to loud music and just a nuisance.
Lately, the sounds were distracting her. She had no other symptoms. Her
past medical, surgical, and family history were unremarkable.
Examination revealed audible clicking from both ears. Inspection of
the soft palate showed that the roof of the soft palate was rhythmically
moving. She had no other movements of the mouth, face, or elsewhere.
The rest of her neurologic examination was normal. Laboratory testing
was unremarkable. Brain MRI was normal. She was diagnosed with
essential palatal myoclonus (tremor) presenting as essential myoclonus
with a segmental physiology. Treatment with clonazepam was started but
did not change the clicks. Botulinum toxin injection into the tensor veli
palatini muscle eliminated the clicks.

COMMENT The clinical course in this patient, without other signs and symptoms and
the relative slow progression, was most consistent with the clinical
presentation of essential myoclonus. Symptomatic myoclonus begins
more abruptly but may be delayed after an acute lesion, nevertheless. In
addition, symptomatic palatal myoclonus often involves other areas of the
mouth or face. Another distinction is that cases of essential palatal
myoclonus have the click as the primary symptom, whereas cases of
symptomatic cases mostly have other symptoms from the lesion, such as
dysphagia, numbness, and ataxia. Essential palatal myoclonus/tremor
usually shows a rhythmic movement that resembles tremor, justifying the
label of essential palatal tremor. Evidence in the literature supports
botulinum toxin as a viable treatment option.38 However, the potential risks
must be clearly delineated. In many centers, the injection is performed by
an otolaryngologist for safety reasons.

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evaluation may need to assess for lower motor neuron disorders through
needle EMG to distinguish from small myoclonus. It is not exactly clear when
myoclonus is small enough to use this term. Hence, it is advisable to avoid using
this term all together, describing these jerks as small and multifocal in a
certain distribution.

TREATMENT OF MYOCLONUS
The etiology of the patient’s disorder should be the most important consideration
when deciding on treatment because symptomatic treatment has limitations.
If treatment of the etiology is not possible or is delayed, then symptomatic
treatment can be considered. Some treatments of myoclonus may worsen
cognitive status or movement coordination; therefore, the treatment of
myoclonus must be weighed against likely side effects. Moreover, if

A 72-year-old woman presented for evaluation of lower thoracic jerking CASE 8-6
that had slowly increased over many months. These jerks caused her to
arch her back and were emanating from her lower thoracic spine. She
stated that this caused a very uncomfortable sensation that would run up
and down her spine; this sensation was just as unsettling as, if not more
than, the movement itself. She had a long history of aching back and neck
pain. Her past medical history included hypertension and esophageal
reflux.
Examination showed trunk extension myoclonus that was worse when
she was sitting than when recumbent or standing. Sensitivity to tactile
stimulation in the lower thoracic spine was present but inconsistent. There
were no upper motor neuron signs.
Brain and cervical spine MRI and EEG were normal. MRI of the thoracic
spine showed a herniated disc at T10 which caused mild edema at that level
of the spinal cord.
She was diagnosed with a T10 central herniated disk producing
propriospinal myoclonus presenting as symptomatic myoclonus with a
subcortical-nonsegmental physiology. The thoracic disk herniation was
repaired surgically, and the myoclonus was not present a few weeks after
the operation.

Propriospinal myoclonus may have a definable causative lesion in one-third COMMENT

of cases. In this patient, the herniation of the thoracic disk was presumed
to have caused the progressive extension jerks of the trunk. The
importance of treating the underlying etiology cannot be overemphasized,
and this justifies the evaluation to discover that etiology. In this patient, no
symptomatic treatment of the myoclonus was necessary in the long term.
The patient was treated with clonazepam before the surgery, which
resulted in only about 50% improvement and with some sedation. The
clonazepam was discontinued postoperatively because the jerks
disappeared over a few weeks.

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MYOCLONUS

symptomatic treatment is started, therapeutic benefit must be weighed

against side effects just after beginning therapy and longitudinally.
It is acknowledged that very little controlled evidence exists for specific
symptomatic treatments for myoclonus. Thus, recommendations are based on
small studies, case reports, and experience. This is not ideal, and evidence-based
reviews become problematic with so few studies reaching criteria for inclusion.
Standard titration schedules for these medications can be applied. However, for
patients with multiple medical problems and medications, slower titrations may
be necessary. The dosages mentioned below are for adults, and dosages may have
to be modified with other concomitant medications or liver/kidney dysfunction.
Treatment of neuropsychiatric comorbidities, such as depression, should also
garner attention. Physical and occupational therapy should be considered within
the myoclonus treatment strategy.
The best symptomatic treatment strategy is formulated on the basis of the
physiology of the patient’s myoclonus.4 Physiologic classification best predicts
symptomatic treatment response to the various antimyoclonus medications.
Ideally, electrophysiologic testing is used to define physiology as in the above
section. However, if electrophysiologic testing is incomplete or unavailable, then
the myoclonus physiology that is typically associated with a defined etiology can
be applied. Examples include chronic posthypoxic myoclonus with a presumed
cortical physiology, juvenile myoclonic epilepsy with a cortical-subcortical
physiology, and segmental pathology and localization associated with a
segmental myoclonus physiology. However, if treatment fails, then more
definition of the physiology may be useful to better define the treatment strategy.
If neither the etiology nor the physiology can be defined, then treatment effect is
left to chance and may be more precarious. The following treatment guidelines
are discussed under each physiologic classification category.

Cortical Myoclonus
Levetiracetam is usually the first-line treatment of cortical myoclonus. This
drug is chemically related to piracetam, an older drug used previously for
posthypoxic myoclonus in countries where it was available. Levetiracetam
(1000 mg/d to 3000 mg/d divided into 2 daily doses) has shown effectiveness in
a few small studies where cortical physiology is present.44–47 Clonazepam
(1 mg/d to 3 mg/d divided into 2 or 3 daily doses) or valproic acid (500 mg/d to
2000 mg/d divided into 2 or 3 daily doses) may be used if levetiracetam is
discontinued for any reason or in combinational therapy for myoclonus.48–50
Sodium oxybate has shown some efficacy in case reports.51 Brivaracetam, a drug
with structural similarity to levetiracetam, has not shown consistent efficacy for
cortical myoclonus.52 Perampanel has shown efficacy in cortical myoclonus,
including in a study with 12 patients with Unverricht-Lundborg disease.53
Initially, deep brain stimulation was met with some skepticism for cortical
myoclonus. However, more reported cases with positive results suggest a
controlled trial is needed to determine case-based efficacy and the best site
for stimulation.54

Cortical-Subcortical Myoclonus
The primary generalized epilepsy syndromes that produce myoclonus (eg,
juvenile myoclonic epilepsy, absence syndromes) usually receive valproic acid
(500 mg/d to 2000 mg/d divided into 2 or 3 daily doses) as the initial antiseizure

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drug.32,55 Besides controlling other seizure manifestations in a generalized KEY POINTS
epilepsy syndrome, the myoclonus will also respond. Lamotrigine or
● A determined etiology
levetiracetam are agents used when valproic acid is not successful or cannot be for the myoclonus will allow
given, as in the case of women of childbearing age.56,57 In rare instances, the clinician to decide
lamotrigine may worsen myoclonic seizures, so close monitoring is necessary. whether the underlying
Brivaracetam may be useful when levetiracetam cannot be tolerated in myoclonus cause is
treatable or curable.
cortical-subcortical myoclonus.57
● If treatment of the
Subcortical-Nonsegmental Myoclonus etiology of myoclonus is not
The therapies for this category vary more when compared with either cortical or possible or is delayed, then
cortical-subcortical myoclonus and are almost purely based on anecdotal symptomatic treatment
should be considered if
literature evidence. Clonazepam is a good first choice, including reticular reflex overall improvement is
myoclonus, myoclonus-dystonia, opsoclonus-myoclonus, and propriospinal possible when weighing
myoclonus.17,34,36,58 Zonisamide (300 mg/d to 500 mg/d divided into 1 or 2 daily potential side effects.
doses) and anticholinergics are used as well.17 It must be emphasized that
● Symptomatic treatment
consistent evidence for efficacy is much less than it is for the agents discussed best aligns with the
above in the cortical and cortical-subcortical categories. In myoclonus-dystonia myoclonus physiology
syndrome, the subcortical myoclonus has been known to respond to deep brain classification. An agent that
stimulation therapy.59 An experienced center should be consulted if this therapy suppresses a specific
myoclonus physiology can
is considered and the risks and benefits of surgery carefully considered.
potentially do that for all
myoclonus cases with that
Segmental Myoclonus common physiology.
This physiologic type of myoclonus is notorious for its lack of responsiveness to
treatment. Clonazepam and other antiseizure medications are tried most often.11 ● Cortical myoclonus
treatments are also
For palatal myoclonus, botulinum toxin injections (dosage variable according to antiseizure agents and are
muscle) have been reported as effective in some cases.38 For the ear clicking in able to reduce the
essential palatal myoclonus, the tensor veli palatini muscle is injected, but other hyperexcitability of the
muscles may be appropriate depending on the symptom targeted. In spinal cortex, resulting in
suppression of cortical
segmental myoclonus, botulinum toxin therapy may help with the discomfort of myoclonus.
the myoclonic muscle contractions.60 In all these cases, the potential adverse
effect of botulinum toxin injections should be carefully considered. ● Subcortical myoclonus
agents operate at the
subcortical movement areas
Peripheral Myoclonus
such as the basal ganglia
The twitching in hemifacial spasm is the most famous example of peripheral and brainstem.
myoclonus. Botulinum toxin injections (dosage variable according to muscle)
usually help both the quick phasic contractions as well as the more sustained ● Deep brain stimulation
spasms.61 Other cases of peripheral myoclonus may respond to botulinum toxin has been used successfully
for the myoclonus-dystonia
injection.13 Antiseizure medications, such as carbamazepine, were mostly used syndrome.
before botulinum toxin was available. Such medications can still be tried if
botulinum toxin is not preferred in a particular patient. ● Botulinum toxin injections
have been used for
segmental and peripheral
TRENDS myoclonus.
Three prominent trends in myoclonus should be mentioned. First, an increasing
number of myoclonus etiologies that have complex genetics have been
discovered and defined. This applies to both established and newly discovered
etiologies of myoclonus. At this time, if justified, a targeted search for a genetic
basis may be reasonable. In the future, whole genome sequencing may provide
the best way to find a variety of genetic etiologies that are difficult to diagnose or
confirm otherwise. Electrophysiology is being better defined for more etiologies,
presentations, and types of myoclonus. This has driven more rational treatment

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MYOCLONUS

strategies by using physiologic classification. Last, in the future, the assumption

that myoclonus arises from a single area of the nervous system will likely be
challenged. Local area networks and even distributed networks may be operant
in the genesis of myoclonus.

CONCLUSION
The many types and etiologies of myoclonus may at first seem confusing. An
efficient and pragmatic evaluation of myoclonus that uses the clinical
presentation classification scheme offers the best approach to define the etiology.
Further evaluation that results in physiologic classification can lead to further
understanding of the myoclonus. Combining the information from the etiology
with the determined or presumed physiology is used to develop the best
treatment strategy. Treatment is often unsatisfactory, and more research into
treatment and controlled clinical studies are desperately needed. Rather than
presuming that myoclonus arises from a single area, it may be that a network
abnormality produces myoclonus in some syndromes. Further research on
myoclonus generation mechanisms should shed light on future treatment
possibilities.

REFERENCES

1 Marsden CD, Hallett M, Fahn S. The nosology and 8 Genton P, Thomas P, Kasteleijn-Noist Trenité DG,
pathophysiology of myoclonus. In: Marsden CD, et al. Clinical aspects of juvenile myoclonic
Fahn S, editors. Movement disorders. London, epilepsy. Epilepsy Behav 2013;28(suppl 1):S8–S14.
United Kingdom: Butterworths, 1982:196–248. doi:10.1016/j.yebeh.2012.10.034.
2 van der Salm SM, de Haan RJ, Cath DC, et al. The 9 Brown P, Thompson PD, Rothwell JC, et al. Axial
eye of the beholder: inter-rater agreement myoclonus of propriospinal origin. Brain 1991;
among experts on psychogenic jerky movement 114(pt 1A):197–214. doi:10.1093/oxfordjournals.
disorders. J Neurol Neurosurg Psychiatry 2013; brain.a101857.
84(7):742–747. doi:10.1136/jnnp-2012-304113.
10 Roze E, Apartis E, Clot F, et al. Myoclonus-
3 Caviness JN, Alving LI, Maraganore DM, et al. The dystonia: clinical and electrophysiologic pattern
incidence and prevalence of myoclonus in related to SGCE mutations. Neurology 2008;
Olmsted County, Minnesota. Mayo Clin Proc 70(13):1010–1016. doi:10.1212/01.wnl.0000297516.
1999;74(6):565–569. doi:10.4065/74.6.565. 98574.c0.
4 Caviness JN. Treatment of myoclonus. 11 Caviness JN. Segmental Myoclonus. In: Albanese
Neurotherapeutics 2014;11(1):188–200. doi: A, Jankovic J, editors. Hyperkinetic movement
10.1007/s13311-013-0216-3. disorders. West Sussex, United Kingdom:
Wiley-Blackwell, 2012:221–236.
5 Caviness JN. Clinical neurophysiology of myoclonus.
In: Hallett M, editor. Movement disorders. 12 Deuschl G, Mischke G, Schenck E, et al.
Handbook of clinical neurophysiology. Vol 1. Symptomatic and essential rhythmic palatal
Amsterdam, the Netherlands: Elsevier, 2003: myoclonus. Brain 1990;113(pt 6):1645–1672.
521–548. doi:10.1093/brain/113.6.1645.
6 Avanzini G, Shibasaki H, Rubboli G, et al. 13 Bono F, Salvino D, Sturniolo M, et al. Botulinum
Neurophysiology of myoclonus and progressive toxin is effective in myoclonus secondary to
myoclonus epilepsies. Epileptic Disord 2016; peripheral nerve injury. Eur J Neurol 2012;19:
18(S2):11–27. doi:10.1684/epd.2016.0835. e92–e93. doi:10.1111/j.1468-1331.2012.03780.x.
7 Caviness JN. Epileptic myoclonus. In: Sirven JI, 14 Rose Russell AL, Knight W, Oware A, Fuller GN.
Stern JM, editors. Atlas of video-EEG monitoring. A unique case of peripheral myoclonus. J Neurol
New York, NY: McGraw-Hill Medical, 2011: Neurosurg Psychiatry 2012;84(1):117–118. doi:
309–328. 10.1136/jnnp-2012-303795.

1078 AUGUST 2019

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

15 Shin HW, Ye BS, Kim J, et al. The contribution of 28 Okuma Y, Fujishima K, Miwa H, et al. Myoclonic
a spinal mechanism in developing peripheral tremulous movements in multiple system
myoclonus: a case report. Mov Disord 2007; atrophy are a form of cortical myoclonus.
22(9):1350–1351. doi:10.1002/mds.21418. Mov Disord 2005;20(4);451–456. doi:10.1002/
mds.20346.
16 Frauscher B, Gabella D, Mitterling T, et al.
Motor events during healthy sleep: a quantitative 29 Grijalvo-Perez AM, Litvan I. Corticobasal
polysomnographic study. Sleep 2014;37(4): degeneration. Semin Neurol 2014;34(2):160–173.
763–773. doi:10.5665/sleep.3586. doi:10.1055/s-0034-1381734.
17 Chokroverty S, Manocha MK, Duvoisin RC. A 30 Iwasaki Y. Creutzfeldt-Jakob disease.
physiologic and pharmacologic study in Neuropathology 2017;37(2):174–188.
anticholinergic-responsive essential myoclonus.
31 Alvarez M, Caviness JN. Primary progressive
Neurology 1987;37(4):608–615. doi:10.1212/
myoclonus of aging. Mov Disord 2008;23(12):
WNL.37.4.608.
1658–1664. doi:10.1002/mds.22085.
18 Asmus F, Salih F, Hjermind LE et al.
32 Sweeney M, Sweeney Matthew, Soldan MMP,
Myoclonus-dystonia due to genomic deletions in
Clardy SL. Antineuronal nuclear autoantibody
the epsilon-sarcoglycan gene. Ann Neurol 2005;
type 1/Anti-Hu-associated opsoclonus
58(5):792–797. doi:10.1002/ana.20661.
myoclonus and epilepsia partialis continua:
19 Marras C, Lang A, van de Warrenburg BP, et al. case report and literature review. Pediatr Neurol
Nomenclature of genetic movement disorders: 2016;65:86–89. doi:10.1016/j.pediatrneurol.
recommendations of the international Parkinson 2016.08.024.
and movement disorder society task force.
33 Honorat JA, McKeon A. Autoimmune movement
Mov Disord 2016;31(4):436–457. doi:10.1002/
disorders: a clinical and laboratory approach.
mds.26527.
Curr Neurol Neurosci Rep 2017;17(1):4. doi:10.1007/
20 Tan KM, Lennon VA, Klein CJ, et al. Clinical s11910-017-0709-2.
spectrum of voltage-gated potassium channel
34 Caviness JN, Brown P. Myoclonus: current
autoimmunity. Neurology 2008;70(20):1883–1890.
concepts and recent advances. Lancet Neurol
doi:10.1212/01.wnl.0000312275.04260.a0.
2004;3(10):598–607. doi:10.1016/S1474-4422(04)
21 Geschwind MD, Tan KM, Lennon VA, et al. 00880-4.
Voltage-gated potassium channel autoimmunity
35 Gupta HV, Caviness JN. Post-hypoxic myoclonus:
mimicking Creutzfeldt-Jakob disease. Arch
current concepts, neurophysiology, and
Neurol 2008;65(10):1341–1346. doi:10.1001/
treatment. Tremor Other Hyperkinet Mov (N Y)
archneur.65.10.1341.
2016;6:409. doi:10.7916/D89C6XM4.
22 Michelucci R, Pasini E, Riguzzi P, et al. Myoclonus
36 Ong MT, Sarrigiannis PG, Baxter PS. Post-anoxic
and seizures in progressive myoclonus epilepsies:
reticular reflex myoclonus in a child and
pharmacology and therapeutic trials. Epileptic
proposed classification of post-anoxic
Disord 2016;18(2):145–153. doi:10.1684/epd.
myoclonus. Pediatr Neurol 2017;68:68–72.
2016.0861.
doi:10.1016/j.pediatrneurol.2016.12.014.
23 Marsden CD, Harding QE, Obeso JA, Lu CS.
37 Deuschl G, Wilms H. Palatal tremor: the
Progressive myoclonic ataxia (the Ramsay Hunt
clinical spectrum and physiology of a rhythmic
syndrome). Arch Neurol 1990;47(10):1121–1125.
movement disorder. In: Fahn S, Frucht SJ,
doi:10.1001/archneur.1990.00530100091019.
Hallett M, Truong D, editors. Myoclonus and
24 Charlesworth G, Balint B, Mencacci NE, et al. paroxysmal dyskinesias. Advances in neurology.
SLC25A46 mutations underlie progressive Volume 89. New York, NY: Lippincott Williams &
myoclonic ataxia with optic atrophy and Wilkins, 2002:115–130.
neuropathy. Mov Disord 2016;31(8):1249–1251.
38 Slengerik-Hansen J, Ovesen T. Botulinum toxin
doi:10.1002/mds.26716.
treatment of objective tinnitus because of
25 Caviness JN, Adler CH, Beach T, et al. Myoclonus essential palatal tremor: a systematic review.
in Lewy body disorders. In: Fahn S, Frucht SJ, Otol Neurotol 2016;37(7):820–828. doi:10.1097/
Hallett M, Truong D, editors. Myoclonus and MAO.0000000000001090.
paroxysmal dyskinesias. Advances in neurology.
39 Antelmi E, Provini F. Propriospinal myoclonus: the
Volume 89. New York, NY: Lippincott Williams &
spectrum of clinical and neuro physiological
Wilkins, 2002:23–30.
phenotypes. Sleep Med Reviews 2015;22:54–63.
26 Sifoglu A, Gunduz A, Kiziltan G. Dopaminergic doi:10.1016/j.smrv.2014.10.007.
medication unrelated myoclonus is less related
40 Hassan A, van Gerpen JA. Orthostatic tremor
to tremor in idiopathic Parkinson’s disease.
and orthostatic myoclonus: weight-bearing
Neurol Sci 2017;38(4):679–682.
hyperkinetic disorders: a systematic review, new
27 Beagle AJ, Darwish SM, Ranasinghe KG, et al. insights, and unresolved questions. Tremor Other
Relative incidence of seizures and myoclonus in Hyperkinet Mov (N Y) 2016;6:417. doi:10.7916/
Alzheimer’s disease, dementia with Lewy bodies, D84X584K.
and frontotemporal dementia. J Alzheimers Dis
2017;60(1):211–223.

CONTINUUMJOURNAL.COM 1079

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

MYOCLONUS

41 Ikeda A, Kakigi R, Funai N, et al. Cortical tremor: a 52 Kälviäinen R, Genton P, Andermann E, et al.
variant of cortical reflex myoclonus. Neurology Brivaracetam in Unverricht-Lundborg disease
1990;40(10):1561–1565. doi:10.1212/WNL.40.10.1561. (EPM1): results from two randomized,
double-blind, placebo-controlled studies.
42 Coppola A, Santulli L, Del Gaudio L, et al. Natural
Epilepsia 2016;57(2):210–221. doi:10.1111/epi.13275.
history and long-term evolution in families with
autosomal dominant cortical tremor, myoclonus, 53 Crespel A, Gelisse P, Tang NP, Genton P.
and epilepsy. Epilepsia 2011;52(7):1245–1250. Perampanel in 12 patients with Unverricht-
doi:10.1111/j.1528-1167.2011.03017.x. Lundborg disease. Epilepsia 2017;58(4):543–547.
doi:10.1111/epi.13662.
43 Wilkins DE, Hallett M, Erba G. Primary generalized
epileptic myoclonus: a frequent manifestation of 54 Ramdhani RA, Frucht SJ, Kopell BH. Improvement
minipolymyoclonus of central origin. J Neurol of post-hypoxic myoclonus with bilateral pallidal
Neurosurg Psychiatry 1985;48(6):506–516. deep brain stimulation: a case report and review
of the literature. Tremor Other Hyperkinet Mov
44 Genton P, Gélisse P. Antimyoclonic effect of
(N Y) 2017;7:461. doi:10.7916/D8NZ8DXP.
levetiracetam. Epileptic Disord 2000;2(4):
209–212. 55 Nevitt SJ, Sudell M, Weston J, et al. Antiepileptic
drug monotherapy for epilepsy: a network
45 Striano P, Manganelli F, Boccella P, et al.
meta-analysis of individual participant data.
Levetiracetam in patients with cortical myoclonus:
Cochrane Database of Systematic Reviews
a clinical and electrophysiological study.
2017;(12):CD011412. doi:10.1002/14651858.CD011412.
Mov Disord 2005;20(12):1610–1614. doi:10.1002/
pub3.
mds.20530.
56 Buchanan N. The use of lamotrigine in juvenile
46 Frucht SJ, Louis ED, Chuang C, Fahn S. A pilot
myoclonic epilepsy. Seizure 1996;5:149–151.
tolerability and efficacy study of levetiracetam in
doi:10.1016/S1059-1311(96)80110-5.
patients with chronic myoclonus. Neurology
2001;57(6):1112–1114. doi:10.1212/WNL.57.6.1112. 57 Steinig I, von Podewils F, Möddel G, et al.
Postmarketing experience with brivaracetam in
47 Magaudda A, Gelisse P, Genton P. Antimyoclonic
the treatment of epilepsies: a multicenter cohort
effect of levetiracetam in 13 patients with
study from Germany. Epilepsia 2017;58(7):
Unverricht-Lundborg disease: clinical
1208–1216. doi:10.1111/epi.13768.
observations. Epilepsia 2004;45(6):678–681.
doi:10.1111/j.0013-9580.2004.56902.x. 58 Caviness JN, Forsyth PA, Layton DD, McPhee TJ.
The movement disorder of adult opsoclonus.
48 Goldberb MA, Dorman JD. Intention myoclonus:
Mov Disord 1995;10(1):22–27. doi:10.1002/
successful treatment with clonazepam. Neurology
mds.870100106.
1976;26(1):24–26. doi:10.1212/WNL.26.1.24.
59 Rocha H, Linhares P, Chamadoira C, et al. Early
49 Fahn S. Posthypoxic action myoclonus: review of
deep brain stimulation in patients with
the literature and report of two new cases with
myoclonus-dystonia syndrome. J Clin Neurosci
response to valproate and estrogen. Adv Neurol
2016;27:17–21. doi:10.1016/j.jocn.2015.08.034.
1979;26:49–84.
60 Rath JJ, Tavy DL, Snoeck-Streef I, Contarino MF.
50 Obeso JA, Artieda J, Rothwell JC, et al. The
Sustained remission of segmental myoclonus
treatment of severe action myoclonus. Brain
due to peripheral nerve injury after treatment
1989;112(pt 4):765–777. doi:10.1093/brain/
with onabolinumtoxinA. Parkinsonism Relat
112.3.765.
Disord 2015;21(9):1111–1112. doi:10.1016/j.
51 Arpesella R, Dallocchio C, Arbasino C. A patient parkreldis.2015.07.001.
with intractable posthypoxic myoclonus
61 Chaudhry N, Srivastava A, Joshi L. Hemifacial
(Lance–Adams syndrome) treated with sodium
spasm: the past, present and future. J Neurol Sci
oxybate. Anaesth Intensive Care 2009;37:
2015;356(1–2):27–31. doi:10.1016/j.jns.2015.06.032.
314–318.

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 Tardive Syndromes REVIEW ARTICLE


By Joseph H. Friedman, MD, FAAN, FANA 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


ABSTRACT VIDEO CONTENT
PURPOSE OF REVIEW: This
article reviews the history, nosology, clinical A V AI L A B L E O N L I N E

features, epidemiology, and treatment of tardive syndromes.

RECENT FINDINGS: Themajor advance in the field of tardive syndromes has

been the development and US Food and Drug Administration (FDA)
approval of two vesicular monoamine transporter type 2 inhibitors,
valbenazine and deutetrabenazine, for treating tardive syndromes. These
Downloaded from http://journals.lww.com/continuum by BhDMf5ePHKbH4TTImqenVE5wmW8EcRnjrAzg21f18Yjf5gZ6bkyNKeX5acgOUaRW on 08/03/2019

medications are derivatives of tetrabenazine and reduce dyskinetic

movements by reducing dopamine stimulation. Treatment is not curative,
and the medications reduce, or “mask,” symptoms but presumably without
adding to the long-term risk of increased involuntary movements believed
to accrue from suppressive treatment with dopamine receptor–blocking
drugs. A confounding advance has been the accumulation of data finding
that second-generation antipsychotics, also known as atypical CITE AS:
CONTINUUM (MINNEAP MINN)
antipsychotics, may not be safer than first-generation antipsychotics in 2019;25(4, MOVEMENT DISORDERS):
causing tardive syndromes. The public health risk of tardive syndromes 1081–1098.
may actually have increased as some second-generation antipsychotics,
widely promoted to both doctors and patients, are increasingly used as Address correspondence to
Dr Joseph H. Friedman, 345
antidepressants. Blackstone Blvd, Butler Hospital,
Providence, RI 02906,
[email protected].
SUMMARY: Tardive syndromes remain a public health risk. Second-generation
antipsychotics have not been proven to have less risk than first-generation RELATIONSHIP DISCLOSURE:
drugs in causing tardive syndromes and are nevertheless being used more Dr Friedman has received
honoraria from Cambridge
widely to treat depression, bipolar disease, and insomnia. Symptomatic University Press, MedLink, and
treatment for tardive syndromes is available, although expensive. Springer Press. He has received
research/grant support as site
investigator of clinical studies
for the Michael J. Fox
Foundation for Parkinson’s
INTRODUCTION Research and the National

T
Institutes of Health.
he first antipsychotic drug, chlorpromazine, was introduced in France
in 1952 and in the United States in 1954. Acute and subacute motor UNLABELED USE OF
side effects were recognized early, but the first report of a tardive PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
syndrome was first published in 1957.1,2 More cases came to light, and Dr Friedman discusses the
the condition, initially thought rare or nonexistent, was recognized as unlabeled/investigational use of
a significant problem.1,2 The term tardive dyskinesia, referring to the late onset, α-methyl-para-tyrosine,
botulinum toxin, clozapine,
was coined in 1964 and caught on.3 deep brain stimulation,
The reasons for doubting that a tardive syndrome was the result of a drug reserpine, and tetrabenazine for
the treatment of tardive
effect were much more understandable at the time than they seem in
syndromes.
retrospect. A wide spectrum of abnormal movements had been associated with
psychiatric disorders by psychiatrists of the early 20th century,4 raising the question
of whether the movements were part of the disease. In that era, little clarity for © 2019 American Academy
diagnoses existed, and a large percentage of people in psychiatric asylums had of Neurology.

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TARDIVE SYNDROMES

tertiary syphilis and other disorders, including forms of autism and other behavioral
disorders that could be associated with movement disorders.5 The second
observation was that the purported side effects, usually oral-buccal-lingual
dyskinesias, improved when the offending drug dose was increased and worsened
when the drug was decreased. These observations conflicted with canonical
thinking about drug side effects, which assumed that higher doses of a drug
that causes a side effect should result in more, not fewer, side effects. A third
observation was the variable nature of the movements, the variable time to
onset, and the lack of an apparent dose-effect relationship. It should be noted that
the relationship between drugs and tardive disorders rests on epidemiology, as
no mechanism has yet been elucidated (refer to the following section on
pathophysiology).

CLINICAL ASPECTS
The tardive syndromes may include overlapping signs, but there are often very
clear discriminating features that allow for distinct categorization. The signs,
symptoms, and nosology are important because treatments may be different for
each tardive syndrome.

Nosology
The term tardive dyskinesia is commonly used in two ways. It is often used
as an umbrella term to include all the tardive syndromes as well as the
most commonly recognized syndrome, oral-buccal-lingual dyskinesia. In this
article the term tardive syndrome6 will be used as the inclusive umbrella term,
and tardive dyskinesia will refer to the various choreoathetoid or stereotypic
movements, including oral-buccal-lingual dyskinesias. The American Psychiatric
Association’s Diagnostic and Statistical Manual of Mental Disorders, Fifth
Edition (DSM-5) defines tardive dyskinesia as: “involuntary athetoid or
choreiform movements (lasting at least a few weeks)… developing in association
with the use of a neuroleptic medication for at least a few months. Symptoms
may develop after a shorter period of medication use in older persons.”7 It
is a modification of the definition from the Diagnostic and Statistical Manual
of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR), which
required continuous exposure to a neuroleptic for at least 3 months for those
younger than 60 years of age and continuous exposure for 1 month or more
for those older than 60 years of age, and the movement disorder needed
to develop either while the patient was on the drug or within 4 weeks of
stopping it. Rare cases caused by much shorter exposure have been described.8
The diagnoses of tardive dystonia and tardive akathisia are also listed in
the DSM-5.
Although some authors have embraced the idea that drugs that do not
block dopamine receptors may also cause clinical syndromes identical to a tardive
syndrome, this is uncertain.9 Almost all cases of tardive syndromes have occurred
in patients who developed symptoms after another psychoactive drug was added
to a dopamine receptor–blocking drug, in patients who had a history of dopamine
receptor–blocking drug use, or in patients whose history had not specifically
excluded exposure to dopamine receptor–blocking drugs. In many cases, the
movement disorder lasted only a brief time after the non–dopamine receptor–
blocking drug was discontinued and therefore did not meet clinical criteria for a
tardive syndrome. In a review of this topic, D’Abreu and colleagues9 asserted

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that the non–dopamine receptor–blocking drug brought out a latent movement KEY POINTS
disorder induced via an unknown priming process induced by the dopamine
● The relationship between
receptor–blocking drugs.9,10 tardive dyskinesia and
antipsychotics took several
Phenomenology of Tardive Syndromes years to establish and was
Although the DSM-5 defines only choreoathetoid movements, dystonia, and initially thought to be rare.
akathisia as tardive, these as well as several other syndromes that can be included
● All definitions of tardive
in this category are discussed below.11 Note that this article uses the term tardive dyskinesia or tardive
dyskinesia to refer to the two most common tardive syndromes discussed first syndromes require at least
below, the choreoathetoid or stereotypic movement disorder, because their several weeks exposure to a
phenomenology and pharmacotherapy are very similar. drug preceding the
development of a new
movement disorder that
TARDIVE DYSKINESIA. Tardive dyskinesia is defined by the presence of persists for several weeks
choreoathetoid movements, which most commonly involve the tongue, lips, while on the drug, or off the
mouth, and jaw and cause chewing movements, tongue writhing (often with drug, and is not better
explained by an alternative
protrusion), lip puckering, and lip smacking, but may also cause choreic etiology.
and athetoid movements of the limbs or trunk (CASE 9-1 and CASE 9-2).
Respiratory changes may occur causing huffing, hyperventilation, or irregular
or loud breathing.

TARDIVE STEREOTYPY. Stereotypy is a term used to connote repeated voluntary

movements that are purposeless. Stereotypies are frequently present in people
with autism in the form of clapping or flapping, but the term is also used to
describe the frequent nonchoreic and nonathetoid movements seen as a tardive
syndrome in people who wring their hands, cross and uncross their legs, smile or
frown, and rock from side to side or forward and backward while denying any
sense of restlessness or distress (VIDEO 9-3, links.lww.com/CONT/A364).

TARDIVE AKATHISIA. Tardive akathisia exactly mimics acute akathisia, a sense of

uncomfortable restlessness that causes continuous voluntary movements to
relieve distress (CASE 9-3). Patients will rock in place while seated, shift weight,
pace, or march in place when standing, which may be more uncomfortable than
the psychosis itself. When minor, patients may have difficulty distinguishing this
feeling from anxiety and may perceive it as jitteriness. Some patients appear very
restless, squirming or rocking when sitting or swaying and marching in place
when standing, yet deny feeling restless. Since akathisia is defined by the
sensation of restlessness, this syndrome is defined as pseudoakathisia. These
patients often also have tardive stereotypy.

TARDIVE DYSTONIA. Dystonia is a sustained or transiently abnormal posture,

usually of a twisting nature. Tardive dystonia may be focal, restricted to a single
body part such as the neck or one limb; segmental, restricted to adjoining body
parts such as the neck, shoulder, and arm; or generalized, involving a larger part
of the body. It may be intermittent, as with jaw opening or jaw closing dystonia
or blepharospasm, or sustained, as usually seen in torticollis or spasmodic
dysphonia. Truncal hyperextension (opisthotonos) may rarely be seen
(VIDEO 9-6, links.lww.com/CONT/A367).

TARDIVE MYOCLONUS. Tardive myoclonus is a rare tardive disorder that more

commonly affects the arms than other body parts. Since some medications,

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TARDIVE SYNDROMES

CASE 9-1 A 77-year-old man presented for a neurologic evaluation for symptoms
of parkinsonism consisting of resting tremor, soft speech, slower
movements, and imbalance. He had been taking aripiprazole 5 mg/d for
3 years for bipolar disorder. It was the only neuroleptic he had ever taken.
A previous trial off aripiprazole had lasted only 2 weeks because of
worsened depression. His tremors had improved during that time.
His initial neurologic examination was normal aside from parkinsonism,
manifest by masked facial expression, resting tremor, bradykinesia,
and typical gait. He had a Unified Parkinson’s Disease Rating Scale,
part III, score of 36 and a Hoehn and Yahr stage of 2.5. His Abnormal
Involuntary Movement Scale (AIMS) score was 0. A dopamine transporter
scan was normal.
Aripiprazole was discontinued 11 days before his next follow-up
4 months later. Off his neuroleptic, his AIMS score was 4 but he was not
bothered by his symptoms.
Eight months later he returned for follow-up (VIDEO 9-1, links.lww.com/
CONT/A362). He and his wife reported that involuntary mouth
movements had worsened 1 month prior. The patient had continuous
chewing movements and tongue writhing. His jaw moved up and down
but also laterally. His lips appeared to not be involved but because of the
continuous tongue movements, it was difficult to be certain. The rest of
his face was not involved. He had stereotypic rubbing movements of his
fingers and dyskinetic movements of both legs, left greater than right.
The mouth movements were unlikely to be due to his being edentulous
because he was not rubbing his gums together and had the other
movements that are typical of oral, buccal, and lingual tardive dyskinesia.
His AIMS score was 13 with a severity rating of 4 (severe), and his Unified
Parkinson’s Disease Rating Scale motor score was 13.

COMMENT Several weeks after aripiprazole was stopped, this patient’s parkinsonism
improved but involuntary movements in his mouth developed. He was
edentulous, which may have contributed to the movements. The
emergence of a tardive syndrome when the offending drug is stopped is
not uncommon. When evaluating any patient on a neuroleptic, the
physician must evaluate both for parkinsonism and for a tardive syndrome.
Any patient on a neuroleptic is supposed to have an AIMS evaluation on a
regular basis, but the possibility of a tardive syndrome being masked by the
neuroleptic must always be kept in mind. It is also important to recognize
that second-generation antipsychotics may cause both parkinsonism and
tardive syndrome.
The patient was not treated for the movements because of medical and
psychiatric issues so the “natural history” of the disorder (ie, 19 months off
dopamine-blocking drugs) was evident, with improved parkinsonism and
minimal change in the tardive syndrome.

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 A 64-year-old woman presented for a neurologic evaluation for CASE 9-2
involuntary mouth movements. She had been diagnosed with bipolar
disease 13 years earlier and had been treated with neuroleptic
medications for the last 10 years; she had been started on olanzapine but
switched to aripiprazole after a few months. She had required two
psychiatric hospitalizations in the preceding 5 years and had received
electroconvulsive therapy twice since in the last 3 years. Aripiprazole had
been stopped 2 years prior due to the development of involuntary mouth
and tongue movements recognized as tardive dyskinesia. After stopping
the aripiprazole, her movements worsened over the following year until
reaching a plateau. She frequently had sores on her tongue from its
rubbing her teeth. She stated that the movements also hurt her teeth and
that her mouth felt “like I chewed on some razor blades.” She noted that
her eyes closed involuntarily, but that this did not bother her because she
was blind from macular degeneration. When initially seen, she was taking
lithium 900 mg/d and oxybutynin 5 mg/d.
Her examination revealed moderately severe blepharospasm; oral,
buccal, and lingual dyskinesias; and possible torticollis (VIDEO 9-2, links.
lww.com/CONT/A363). She had no signs of parkinsonism. She did not
exhibit any other adventitious movements. She was treated with
tetrabenazine after consultation with the psychiatrist over the possibility
of worsening the depression. Oxybutynin was stopped due to concern
about anticholinergic action worsening mouth movements due to dryness
as well as to movement effects. She was started on tetrabenazine 12.5 mg
2 times daily and gradually titrated over 12 weeks to 50 mg 3 times daily.
Her tardive movements resolved, and she had no signs of parkinsonism.
However, 5 months later, on the same regimen, minimal signs of
parkinsonism emerged, and the tardive dyskinesia was not resolved.
Six months after this, her parkinsonism became severe, with prominent
tremor, slowness, and gait dysfunction, and tetrabenazine was reduced
to 37.5 mg 3 times a day.
Over the next year, parkinsonism remained a significant problem and
tardive dyskinesia recurred as her tetrabenazine was reduced. Trials of
deutetrabenazine 24 mg 2 times daily and then valbenazine 80 mg
allowed the parkinsonism to improve, but did not resolve. Her Abnormal
Involuntary Movement Scale (AIMS) score increased to 21. She opted to
try deep brain stimulation of globus pallidus internus.

This patient was treated with tetrabenazine before the drugs approved by COMMENT
the US Food and Drug Administration (FDA) were available. Tetrabenazine
was initially very helpful but required a high dose, which eventually caused
severe parkinsonism. As her parkinsonism lessened, with the reduction in
tetrabenazine then the trials of deutetrabenazine and valbenazine, her
tardive dyskinesia reemerged. Having failed all three drugs, she was
referred for globus pallidus internus deep brain stimulation.

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TARDIVE SYNDROMES

particularly clozapine, may cause asterixis, which is the “negative” form of

myoclonus, and may be difficult to clinically distinguish from myoclonus, other
potential causes should be excluded.

TARDIVE TICS. Vocal and motor tics may mimic Tourette syndrome. Unlike
Tourette syndrome, the syndrome of tardive tics is late in onset and develops
only after chronic exposure to dopamine receptor–blocking drugs. It is rare, and
at least one case with coprolalia has been reported (CASE 9-4).

TARDIVE TREMOR AND TARDIVE PARKINSONISM. The categories of tardive tremor

and tardive parkinsonism are contentious, as the duration of parkinsonian side
effects of the dopamine receptor–blocking drugs is highly variable and may
last for several years. Essential tremor may develop at any age, regardless of
medications. Improvement in parkinsonism or tremor with increased doses of the
dopamine receptor–blocking drugs needs to be observed to confirm this diagnosis.
These reports involve parkinsonian types of tremor (resting and postural).

CASE 9-3 A 45-year-old woman was intially referred for evaluation of severe
restlessness. She had been diagnosed with schizoaffective disorder at
age 30 and was treated with several first-generation antipsychotic drugs,
including haloperidol, chlorpromazine, thioridazine, and others. She
reported being extremely uncomfortable due to her restlessness and
could not keep from moving. She denied feeling anxious. She stated that
this had been present for about 4 years. It did not vary significantly during
the day, but resolved during sleep. She denied paresthesia or abnormal
sensations in her legs. Her husband did not report leg movements during
sleep. Although her antipsychotics had been altered during that time, her
movements had persisted. She had not improved with benztropine or
amantadine. She had no history of thyroid disease, substance abuse, or
medical problems. Her psychotic symptoms were controlled but she felt
helpless and depressed.
At the time of her initial neurologic evaluation, she was taking
haloperidol 2 mg/d and nortriptyline 100 mg/d. Other than the findings
shown in the video (VIDEO 9-4, links.lww.com/CONT/A365), her neurologic
examination was normal except for mild oral, buccal, and lingual
dyskinesias. She did not have parkinsonian signs.
She was diagnosed with akathisia. At the time of her initial evaluation,
the only drugs available to treat this were reserpine and α-methyl-para-
tyrosine. Tetrabenazine and its derivatives were not then available. It was
recommended that she be treated with clozapine once it became available
6 years later, which replaced her haloperidol. Her akathisia resolved
completely when the haloperidol was replaced by the clozapine, but the
dyskinetic mouth movements were unchanged.
VIDEO 9-5 (links.lww.com/CONT/A366) shows the same patient on
follow-up 33 years later. She has continuous writhing movements of her
tongue as well as continuous lip and jaw movements.

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TARDIVE PAIN. Tardive pain is rarely mentioned and is not strictly a
movement disorder; however, it has been described as the central symptom in
patients who also had a typical tardive movement syndrome and in whom
extensive testing for the pain was unrevealing.12 In patients with tardive pain,
the pain improves as the movement disorder improves. The pain has mostly
been described in the mouth and the pelvis. Unexplained pain in the absence
of a tardive movement syndrome should not be considered tardive in origin.
TABLE 9-1 lists the tardive syndromes.

APPROACH TO THE PATIENT

Several aspects need to be considered in evaluating patients with suspected
tardive syndromes. Most patients have chronic psychiatric disorders, primarily
schizophrenic disorders, or bipolar disease. Their histories may not be
reliable but must always be taken seriously and, when suspect, should be
confirmed with the treating physicians, other health care professionals, or
caregivers. The patient’s history of medication use over the previous year or

This patient’s movements reflect akathisia, an uncomfortable sense of COMMENT

restlessness, which forces people to move. By definition, akathisia reflects
a sensation of restlessness, which is not associated with stereotypies,
which are semivoluntary movements (ie, movements that occur with some
degree of volition, but without conscious thought). The movements are not
choreic jerks or athetoid serpentine or slow movements and were not
present during sleep. When mild, the signs and symptoms of akathisia can
be confused with anxiety. Unlike restless legs syndrome, there was no
diurnal variation. She had no thyroid abnormalities, and the problem had
been present for several years. There was no history to suggest drug
intoxication.
It is not clear why clozapine should have been helpful in this patient;
clozapine is thought to have no extrapyramidal side effects and would
have been assumed to have possibly made the akathisia worse, by
lessening the dopamine D2 blocking effect of the haloperidol. Akathisia
sometimes can occur as a persistent disorder, developing acutely but
persisting for long periods if the patient remains on the offending drug, but
little has been written about this. This is a possible explanation here;
however, the occurrence of the akathisia, in concert with the classic mouth
dyskinesias and the development of the akathisia after a long exposure,
suggests that a tardive explanation is likely.

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TARDIVE SYNDROMES

CASE 9-4 A 61-year-old woman with schizoaffective disorder was referred for
management of a movement disorder. She was unaware of her
movements, which her family noticed only within the past year. Once
pointed out to her, they did not bother or concern her. She did not
think that they attracted attention.
She had been treated with neuroleptics for 13 years, including
haloperidol, perphenazine, risperidone, aripiprazole, ziprasidone, and
brexpiprazole and was currently taking lurasidone. She liked being on
lurasidone because it controlled her auditory hallucinations and made
her feel better than she had on any of the other antipsychotics. She and
her family denied her having tics as a child and she had no family
history of tics or other movement disorders. She did not have
compulsive behaviors. Her identical twin had no tics or other
movement disorders. She had no history of other neurologic problems.
She was treated for hypertension, hypothyroidism, and increased
cholesterol. Her thyroid hormone levels had been therapeutic. Her
medications included lurasidone 40 mg/d.
Her neurologic examination showed mild parkinsonism, with mild facial
masking, a mildly stooped posture, and absent arm swing; her tics
manifested by sudden extension or flexion of either knee while sitting
VIDEO 9-7 (links.lww.com/CONT/A368), and she exhibited facial tics.

COMMENT This patient’s movements were tics. They primarily involved her legs, right
more than left. She also had facial tics, more commonly seen on the right,
affecting both the upper and lower face. It is unusual that she did not
perceive the movements, as most tics are associated with an urge to move.
Her lack of concern for attracting attention may reflect her social isolation,
her psychiatric disorder, or her personality. The standard approach to
treating the tardive tics would be replace her lurasidone with quetiapine
and then treat the tics with either valbenazine or deutetrabenazine. If the
quetiapine did not adequately control her psychotic symptoms, then
clozapine would be instituted. However, both drugs are associated with
weight gain, which was a major concern for this patient. She spontaneously
remarked how happy she had been on lurasidone, in contrast to the many
drugs she’s failed, and was very reluctant to change. In addition, she was
not aware of her movements, other than for being told about them, and did
not care about them. Since the natural history of these movements was
unknown, and may not worsen, the recommendation was to not alter
medications and simply follow her. Her movements, had they been
bothersome, could have been treated by adding valbenazine or
deutetrabenazine to her regimen of lurasidone.

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so is especially important as recent dose escalations or decreases may strongly
affect the severity of the movements, possibly masking them entirely.
The medication lists that patients carry with them sometimes do not include
neuroleptic medications that are injected every few weeks. Unless the
clinician is also taking responsibility for treating the patient’s psychiatric
disorder, it should generally be assumed that advice will need to be provided
to the patient’s psychiatrist, and that recommendations may not be followed.
What may be ideal for the movement disorder may not be ideal for the
psychiatric disorder.
Since most movement disorders vary significantly in relation to anxiety, do
not assume that marked changes in severity between how the patient appeared in
the waiting room versus the office reflects a “psychogenic” disorder, rather than
increased anxiety.

Recognition of a Tardive Syndrome

Early studies have demonstrated that tardive dyskinesia was frequently
overlooked by psychiatry residents.13,14 In one study involving 101 patients, 26%
of patients were identified as having tardive dyskinesia by faculty but only 11%
by residents.14 A previous smaller study revealed that psychiatry residents
missed 90% of tardive cases.13 While these studies were published 3 decades
ago, no further studies on this topic have been published. It is likely that the
common belief that second-generation antipsychotics have lowered the risk
of a tardive syndrome has translated into a decreased sensitivity to the problem.

Tardive Syndromes TABLE 9-1

Tardive Syndrome Characteristics

Tardive dyskinesia Choreoathetoid or stereotypic movements, which can affect any body part, but most
commonly the oral, buccal, lingual region

Tardive dystonia Dystonia, a sustained, involuntary muscle contraction, often writhing in nature, producing
an abnormal posture; this may cause torticollis, blepharospasm, jaw opening or closing
dystonia, or affect other body parts

Tardive akathisia An uncomfortable feeling of restlessness causing movements such as marching in place,
pacing, rocking in place while seated, and rubbing hands

Pseudoakathisia Overlaps with or may be considered stereotypy: patients are in constant motion as if
restless but deny the feeling of restlessness

Tardive stereotypy Repetitive, purposeless movements, such as rocking, crossing legs, rubbing hands when
not feeling restless

Tardive tics Usually motor and not vocal

Tardive tremor and tardive A debated syndrome since many authorities believe that cases reported as tardive tremor
parkinsonism or tardive parkinsonism really had essential tremor or idiopathic Parkinson disease.

Tardive pain A pain disorder associated with one of the above disorders that is not directly caused by
the movements themselves

Tardive myoclonus Myoclonic lightninglike jerk affecting isolated muscles causing an obvious limb or trunk
jerk or vocalization

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TARDIVE SYNDROMES

TABLE 9-2 Differential Diagnosis of Tardive Syndromesa

Tardive Dyskinesia
◆ Idiopathic oral facial dyskinesias of the elderly
◆ Stereotypic chewing in the edentulous
◆ Stereotypies in patients with autism
◆ Teeth, gum, tongue, mouth disorders (loose dentures)
◆ Chorea (inherited, metabolic, inflammatory, structural)
◆ Drug toxicity (eg, phenytoin, lithium)
◆ Levodopa-induced dyskinesias in a patient with Parkinson disease
◆ Psychogenic
◆ Tics
Tardive Stereotypies
◆ Behaviors unrelated to drugs
◆ Sensory neuropathies (“piano playing fingers”)
◆ Tactile hallucinations
◆ Anxiety
◆ Obsessive-compulsive disorder
◆ Tics
Tardive Akathisia
◆ Anxiety
◆ Drug withdrawal/drug intoxication
◆ Psychotic/other psychogenic internal stimuli
◆ Chorea
Tardive Dystonia
◆ Inherited or brain injury
◆ Peripheral injury
◆ Psychogenic
◆ Presenting feature of Parkinson disease or other neurodegenerative disorder
Tardive Myoclonus
◆ Tics
◆ Toxic or metabolic disorders
Tardive Tics
◆ Tourette syndrome

a
This table lists disorders that may be confused with the tardive syndromes.

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Self-Perception of Tardive Syndromes KEY POINT
It is commonly observed that patients with some tardive syndromes, particularly
● There are several
choreoathetosis and stereotypy, minimize or even fail to perceive their different tardive syndromes.
movements. While this is often believed to reflect the underlying psychiatric Dyskinesia and stereotypies
or cognitive disorder,15 much of this is likely due to the nature of the are very similar, while
movement disorder itself, as chorea is often underperceived by the patient, akathisia and dystonia are
very different. The others
regardless of the cause of the chorea or the patient’s cognitive and behavioral
are rare. Patients may have
capabilities.16,17 The mechanism for this agnosia is unknown but is hypothesized more than one syndrome. It
to reflect a “feed forward” process in which motor and sensory circuits are is important to note that
simultaneously stimulated.16 patients often have more
than one tardive syndrome.

Evaluation
The Abnormal Involuntary Movement Scale (AIMS) has become the standard
evaluation tool for tardive syndrome studies. The AIMS is focused on
choreoathetoid movements and stereotypies. It does not capture akathisia,
which is usually measured with the Barnes Akathisia Rating Scale.18 The
usual clinical research criteria for diagnosing tardive dyskinesia are the
Schooler-Kane19 criteria, which require scores of 2 (mild) or greater in at
least two body parts or one score of 3 (moderate) or greater in one body part,
while meeting the contemporary DSM-5 criteria for onset and duration.
TABLE 9-2 lists the differential diagnosis of the tardive syndromes.

Reversibility and Natural History

The natural history of tardive syndromes is not known. To determine natural
history, the clinician would need to stop the neuroleptic when a tardive
syndrome is identified, allowing for long-term follow-up; however, the vast
majority of patients taking these drugs require life-long neuroleptics. Since
these drugs generally mask the movement disorder, patients remaining on them
often have a syndrome masked by the same drug that caused the problem.
A 1982 meta-analysis of 285 treatment trials reported remission in 37% of
participants, but this remission percentage has not been borne out by more
recent studies.20 The largest chart review of patients with a tardive syndrome
who had stopped their dopamine receptor–blocking drugs involved 108 patients
who were followed for a mean duration of 3.1 years.21 Only 13.9% of participants
had complete resolution. Outcome was no better if patients had only taken
second-generation drugs. Younger age at onset, shorter duration of therapy, and
faster withdrawal appeared to improve outcomes. Most patients improved only
mildly. Other studies report conflicting results with stopping the neuroleptic,
with 11 of 12 patients improving in one report22 to 1 of 49 patients improving in
another.23 A 2018 Cochrane Review of 13 randomized controlled trials involving
771 subjects compared antipsychotic discontinuation versus continuing
antipsychotic treatment, or lowering dose or switching to an alternative
antipsychotic, and found only low-level evidence showing benefit to any
intervention.24 Fernandez and colleagues25 completed a 14-year follow-up of
patients in a long-term psychiatric hospital and found that in patients who
continued taking neuroleptics, the tardive syndrome improved, as measured
by AIMS assessments, but parkinsonism worsened. Medications were not
recorded, but the results suggest that tardive dyskinesia was likely masked,
not resolved.

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TARDIVE SYNDROMES

Unfortunately, the limited data suggest that there is no clear benefit to

stopping the offending drugs to allow “natural healing,” or that switching to
antipsychotics of lower potency will be beneficial long-term, although this is
done routinely.

PATHOPHYSIOLOGY
The pathophysiology of tardive syndrome is unknown. The most “popular” and
clearly the most heuristically appealing theory of tardive syndrome is the dopamine
receptor supersensitivity, or “up-regulation” theory.8,11,26 The hypothesis presumes
that, in some patients, long-term exposure to dopamine receptor–blocking drugs
causes an increase in D2 receptors or in their sensitivity. This is based largely on the
observation that dopamine receptor–blocking drugs or drugs that reduce dopamine
stimulation reduce the movements. The theory is further supported by rodent
studies showing that dopamine receptor–blocking drugs do cause receptor
hypersensitivity, but human studies have produced mixed results,27,28 and
long-term exposure of dopamine receptor–blocking drugs in rodents also do not
support this hypothesis. Alternative hypotheses include structural changes in the
synapse26,29 or the presynaptic dopamine-secreting neuron29 due to direct toxic
effects of the drugs, or indirectly via oxidative stress, genetic anomalies affecting
dopamine receptors, and alterations of RNA production affecting other
neurotransmitters induced by dopamine receptor–blocking drugs.
The synaptic plasticity hypothesis rests on the observation that synapses in the
human neocortex are altered by dopamine receptor–blocking drugs, as well as
in the striatum of rodents, and that abnormal plasticity is found in animal models
of hyperkinetic human disorders.26 The theory posits that the movements are
generated by abnormal signal processing.
Another hypothesis proposes that dopamine receptor–blocking drugs cause a loss
of dopamine-secreting cells in the substantia nigra, which, in turn, causes
“denervation supersensitivity and tardive dyskinesia.”30 However, data on loss of
neurons in the human substantia nigra in patients on chronic antipsychotics are
conflicting.31,32 An oxidative stress theory proposes an increase in hydrogen
peroxide and free radicals as a result of increased dopamine turnover resulting from
dopamine receptor blockade. Many human genetic studies reveal correlations
between tardive syndromes and a large number of dopamine, serotonin, and other
neurotransmitter receptors, suggesting the possibility that the genetics of a number
of different neuroreceptor subtypes may explain both the risk of developing a
syndrome and the type and severity of the disorder. Animal studies have revealed
changes in gene expression in the brains after chronic dopamine receptor–blocking
drug exposure, raising a question as to whether this may occur in humans as well.

EPIDEMIOLOGY
In American nursing homes, 20% of residents take antipsychotics. In addition,
some neuroleptics are also approved in the United States for treating depression
and are among the best-selling drugs in the country. As the elderly are at greatest
risk for the development of a tardive syndrome, having a fivefold greater risk
than younger patients,33 it is likely that many instances of tardive dyskinesia go
unnoticed in nursing homes.
The development of second-generation antipsychotics was thought to herald
the beginning of the end of tardive syndromes. Clozapine, the first “atypical”
antipsychotic, has not been linked to a tardive disorder except when there has

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been prior exposure to a dopamine receptor–blocking drug. Although the KEY POINT
impression persists that tardive syndromes are less common with second-
● While widely believed to
generation antipsychotics, the National Institutes of Health–supported CATIE represent dopamine
(Clinical Antipsychotic Trials of Intervention Effectiveness) trial upended that supersensitivity, the
conviction.34 The CATIE study, involving 1493 subjects seen at 57 sites, evaluated pathophysiology of tardive
subjects who were treated either with the first-generation antipsychotic, syndromes remains
unknown, and no
perphenazine, or one of the second-generation drugs (risperidone, olanzapine,
explanation explains the
ziprasidone, or quetiapine) found no differences in any extrapyramidal side variety of tardive
effects between subjects assigned to perphenazine versus any of three syndromes.
second-generation antipsychotics. Unfortunately, 74% of subjects did not
complete the 18 months of treatment that had been planned, confounding
interpretation. One meta-analysis of 31 randomized controlled trials involving
2230 subjects reported that, among the second-generation drugs, only clozapine
was safer.35 Another meta-analysis reported a 3.5-fold lower risk with second-
generation drugs,36 while a third reported a reduction in incidence from 5.5% to
3.9%31 and a change in point prevalence of 32.4% with first-generation drugs
to 13.1% with second-generation drugs. Conversely, a 30-month study found
no difference between tardive syndrome incidence with first-generation or
second-generation drugs.37 Before second-generation drugs were developed,
the risk of a tardive syndrome was thought to be 32% after 1 year, 57% after
15 years, and 68% after 25 years.38 A recent meta-analysis of 41 studies
involving 11,493 patients had a mean prevalence of 25.3%, with 20.7%
attributed to second-generation drugs and 30% with first generation.39
Why are there such conflicting results on tardive syndrome incidence and
prevalence? Inherent difficulties exist in interpreting any study of a tardive
syndrome while patients remain on drugs that both cause and mask the condition.
The vast majority of patients with a tardive syndrome are treated for primary
psychotic disorders, which are life-long. These patients therefore cannot stop
antipsychotic drugs, which, although they cause the problem, also mask it. Thus,
patients who harbor a tardive syndrome may have no adventitious movements
and will reveal their disorder only when their dopamine receptor blockade is
lessened. Some of these patients develop a tardive syndrome within days of
discontinuation, called withdrawal emergent dyskinesia, but most will have a
delayed onset as dopamine receptor–blocking drugs bind avidly to the dopamine
receptor while also being extremely lipid soluble, remaining in the brain for a very
long time. Thus, while their serum half-life is relatively short, the parkinsonian
side effects, which mask the tardive syndrome, may last several months. The
previously cited study on the natural history of tardive syndromes noted that
patients followed up after 14 years in a state psychiatric hospital had fewer rather
than more tardive disorders in association with a higher level of parkinsonism.25
Another caveat is a 2018 report indicating that almost all published cases of
purported tardive syndrome not caused by dopamine receptor–blocking drugs
had, at some point, been treated with a dopamine receptor–blocking drug, raising
the hypothesis that any exposure to a dopamine receptor–blocking drug may
produce a priming effect that increases the risk of a latent movement disorder
developing on drugs not known to cause a tardive syndrome.9

RISK FACTORS
Most reports on risk factors for tardive syndromes have not been confirmed.
Older age as a risk factor has the most support. In cohorts of older versus

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TARDIVE SYNDROMES

younger patients exposed to neuroleptics for the same period of time, the older
patients are more likely to develop a tardive syndrome. Other cited factors are
not so reliable. Presumed racial differences may be explained by different
prescribing and diagnosing patterns. African Americans are thought to have a
higher risk than white Americans, but this is confounded by the observation that
African Americans generally received higher doses of antipsychotics, and racial
distinctions may not be scientifically accurate. It could also be argued that this
higher dosing might actually mask the syndrome, reducing the perceived risk. A
history of early-onset extrapyramidal side effects such as acute dystonic
reactions, akathisia, or parkinsonism has been suggested but not confirmed as
risk factors for later onset of a tardive syndrome. Brain damage has also been
suggested as a risk factor, but this is a difficult risk factor to quantify. The
presence of an affective disorder has been proposed to increase the risk. Female
gender, duration of antipsychotic use, dose of the antipsychotic, dementia,
diabetes mellitus, HIV infection, intellectual disability, brain damage, and
anticholinergic use all have soft support for being risk factors.40

TREATMENT
Anticholinergic drugs were commonly used when neuroleptics were initiated
to reduce the acute extrapyramidal side effects, particularly acute dystonic
reactions, and they were effective for this purpose. They were also commonly
used to treat parkinsonian side effects, with much less clear benefit. This
common use was expanded so that they have frequently been used to treat
tardive syndromes, particularly dyskinetic ones, although no evidence
supports their utility, and it is likely that they worsen the tardive syndromes,
as anticholinergic drugs worsen choreic movements in general; additionally,
for patients with oral, buccal, lingual movements, the dry mouth caused by
anticholinergics increases the discomfort and the movements themselves.
Only two treatments approved by the US Food and Drug Administration
(FDA) exist for tardive syndromes: valbenazine and deutetrabenazine, both
of which are tetrabenazine-related drugs. They are similar to the previous
standard therapies, reserpine, tetrabenazine, and α-methyl-para-tyrosine,
in that they reduce dopamine stimulation. They, like tetrabenazine, are
selective vesicular monoamine transporter inhibitors type 2, which reduce the
incorporation of dopamine (as well as histamine, serotonin, and norepinephrine)
into vesicles, hence reducing dopamine stimulation. Deutetrabenazine has a
deuterated hydrogen atom, while valbenazine is a prodrug of the most active isomer
of tetrabenazine, both of which have significantly longer serum half-lives than
tetrabenazine, leading to a more sustained pharmacokinetic profile, possibly
explaining their much reduced side effects, avoiding depression and parkinsonism41
in particular. Unfortunately, these two drugs cost between $65,000 and $100,000
each year.
Four Class I trials of both drugs41 have shown significant reductions in
AIMS scores, the primary outcome variable, and no depression or parkinsonism
within the 6 to 12 week study and open-label extensions. The studies did not
distinguish the various types of tardive syndromes, however. The drugs
probably are more effective for dyskinesias, stereotypies, and akathisia than
dystonia or myoclonus. Interestingly, patients were less impressed by their
improvement than the blinded raters. These drugs have not been compared head
to head either with each other or with the older remedies.

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 Tardive dystonia should be considered separately from the other tardive KEY POINTS
disorders, which all share a similar response to pharmacotherapy. No approved
● Tardive syndromes
treatment exists for tardive dystonia, but numerous reports and series support remain a major problem
the use of botulinum toxin for focal dystonia, particularly blepharospasm and for patients treated with
torticollis, and deep brain stimulation of the globus pallidus internus in severe dopamine receptor–
cases.41 Both of these interventions are nonspecific interventions for dystonia blocking drugs. While there
are data to suggest that
regardless of cause. In addition, there are several reports of clozapine being
second-generation
helpful specifically for tardive dystonia, treating both the psychosis and the antipsychotics are less likely
movement disorder, when used at the dose required to control psychosis, which is to cause a tardive syndrome
generally in the 300 mg/d to 900 mg/d range. Whether the benefit was due to than first-generation
antipsychotics, these data
stopping the prior neuroleptic or specifically due to the effect of clozapine
are not convincing, and the
is uncertain. largest study performed to
The underlying question in treating a tardive syndrome is what to do about answer this question did not
the antipsychotic medication. Where the dopamine receptor–blocking drug find a difference.
is being used as an antidepressant or for nausea or gastroparesis, the answer is to
● Deutetrabenazine and
try alternatives that do not block dopamine receptors, if at all possible. Both valbenazine are approved
doctors and patients are appropriately reluctant to use electroconvulsive therapy, treatments for tardive
but this is often very helpful in treating depression refractory to medications, syndromes, and probably
allowing patients to be kept in remission on doses of antidepressants that had work best for nondystonic
disorders. Replacing the
previously not been helpful. Electroconvulsive therapy has been widely reported neuroleptic with clozapine
to improve mobility in patients with Parkinson disease, but its effect on choreic at a dose to treat the
disorders, dystonia, and tardive syndromes is uncertain. psychosis may be very
In the more common case of a tardive syndrome occurring in a patient who helpful, especially for
dystonic syndromes.
requires an antipsychotic, the usual recommendation is to switch to either clozapine
or quetiapine. These two drugs rarely, if ever, cause extrapyramidal disorders. This ● Botulinum toxin is likely to
comes as close as possible to drug withdrawal, hence the term “passive healing,” in be helpful for all focal
which the tardive syndrome hopefully reverses when the dopamine receptor– dystonias, including tardive
blocking drug is stopped. This is often not possible as patients may have failed dystonias. Deep brain
stimulation, with globus
these drugs. In such cases, the usual recommendation is to switch to aripiprazole. pallidus internus as the
However, it is unclear if this strategy is at all useful.42,43 target, may be helpful for
When the disorder is bothersome, either deutetrabenazine or valbenazine is dystonic or choreoathetoid
used,41 with a slow upward titration. No data imply the superiority of either drug. tardive disorders.
Valbenazine is given once daily and deutetrabenazine twice daily. Valbenazine
has only two strengths, while deutetrabenazine can be titrated over several
dosages. Since occasional cases will remit, attempts at slow reduction of doses
should be considered.
Three double-blind trials of gingko biloba, used as a presumed antioxidative
agent, have been conducted. There were 299 subjects reported in the three
12-week trials comparing antipsychotic plus gingko biloba versus antipsychotic
with placebo, reporting a benefit in the AIMS similar to that reported with the
tetrabenazinelike drugs, but the follow-up was limited.42 While many drugs have
been considered promising for treating tardive syndromes, most have fallen by
the wayside. Of the current crop, amantadine is of interest since it has been
approved for treating levodopa-induced dyskinesias in Parkinson disease, a
phenomenologically similar syndrome to tardive dyskinesia, and is a useful drug
for treating neuroleptic-induced parkinsonism, thus offering the possibility of
treating both disorders, which are commonly both present. Only one small
crossover trial has been published. Drugs thought to have possible utility to treat
tardive syndromes include tetrabenazine, clonazepam, gingko biloba, and
amantadine.41 A small number of reports support the use of botulinum toxin for

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TARDIVE SYNDROMES

focal tardive dystonias, and deep brain stimulation, generally targeting the
globus pallidus internus segment, for uncontrolled dyskinesias and dystonia.

CONCLUSION
Tardive dyskinesia reduces quality of life and remains a major public health
issue.44 Second-generation antipsychotics have not been shown to decrease the
risk of tardive syndromes, and their increasing use for nonpsychotic indications
is likely to increase the prevalence. Our understanding of tardive syndrome
pathophysiology is not significantly better than it was decades ago. Two bright
spots have been the emergence of effective and safe symptomatic treatment for
tardive syndrome and the possibility that antipsychotic drugs that do not involve
dopamine are being developed.45 Meanwhile, there is a continued need for
vigilance in our use of dopamine receptor–blocking drugs and a need for
better treatments.

VIDEO LEGENDS
VIDEO 9-1 VIDEO 9-5
Tardive dyskinesia and stereotypy. Video Classic tardive dyskinesia. Video shows a
shows the 78-year-old man discussed in CASE 9-1 78-year-old woman with symptoms of classic
exhibiting involuntary mouth movements indicative tardive dyskinesia, involving oral, buccal, and lingual
of tardive dyskinesia and stereotypy. Exposure to a movements. She is the same patient discussed in
second-generation antipsychotic drug at usual CASE 9-3, 33 years later. She has continuous writhing
doses may result in tardive syndromes in a patient movements of her tongue as well as continuous lip
with no risk factors other than age. and jaw movements.
http://links.lww.com/CONT/A362 http://links.lww.com/CONT/A366
© 2019 American Academy of Neurology. © 2019 American Academy of Neurology.

VIDEO 9-2 VIDEO 9-6

Tardive dyskinesia and tardive dystonia. Mild, segmental tardive dystonia with
Video shows the 64-year-old woman discussed in associated tachypnea. Video shows a
CASE 9-2 exhibiting continuous chewing movements, 70-year-old man with mild, segmental tardive
lip puckering, blepharospasm, and left leg dystonia exhibiting irregular contractions of the
stereotypies indicative of tardive dyskinesia and corners of his mouth, asymptomatic tachypnea,
tardive dystonia. Her posture reveals moderate and a masked facial expression. The mouth
torticollis, with her head rotated to her right and the movements are dystonic in nature, and he has no
right shoulder mildly elevated. The patient’s other signs of a tardive syndrome. He had been
movement disorder is generalized, involving face, treated with chlorpromazine, risperidone, and
neck, and trunk. other antipsychotics for several decades. His
http://links.lww.com/CONT/A363 movements developed when risperidone was
© 2019 American Academy of Neurology. changed to quetiapine. At the time of this video,
the patient was taking risperidone 0.5 mg twice
daily and tetrabenazine 12.5 mg twice daily.
VIDEO 9-3
http://links.lww.com/CONT/A367
Leg stereotypies or dystonia. Video shows the
legs of a 95-year-old woman exhibiting bilateral leg © 2019 American Academy of Neurology.
movements that may be classified as stereotypies or
dystonia. The patient also exhibits tachypneic breathing, VIDEO 9-7
which is a symptom of the tardive syndrome. Tardive tics. Video shows the 61-year-old
http://links.lww.com/CONT/A364 woman described in CASE 9-4 exhibiting tardive tics
© 2019 American Academy of Neurology. primarily involving her legs, right more than left.
Tardive tics are uncommon, and these are
VIDEO 9-4 particularly unusual in that the patient is unaware of
Tardive akathisia. Video shows the 45-year-old them and is not bothered by them.
woman described in CASE 9-3 with tardive akathisia http://links.lww.com/CONT/A368
exhibiting severe restlessness. The patient also has © 2019 American Academy of Neurology.
oral, buccal, and lingual dyskinesias (not shown).
http://links.lww.com/CONT/A365
© 2019 American Academy of Neurology.

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REFERENCES

1 Friedman JH. Historical perspective on 16 Shenker JI, Wylie SA, Fuchs K, et al. On-line
movement disorders. J Clin Psychiatry 2004; anosognosia: unawareness for chorea in real
65(suppl 9):3–8. time but not on videotape delay. Neurology
2004;63(1):159–160. doi:10.1212/01.WNL.
2 Caroff SN, Ungvari GS, Cunningham Owens DG.
0000131901.46303.65.
Historical perspectives on tardive dyskinesia.
J Neurol Sci 2018;389:4–9. doi:10.1016/j. 17 Vitale C, Pellecchia MT, Grossi D, et al.
jns.2018.02.015. Unawareness of dyskinesias in Parkinson’s and
Huntington’s diseases. Neurol Sci 2001;22(1):
3 Faurbye A, Rasch PJ, Petersen PB, et al.
105–106. doi:10.1007/s100720170066.
Neurological symptoms in pharmacotherapy of
psychoses. Acta Psychiatr Scand 1964;40(1): 18 Barnes TR. A rating scale for drug-induced
10–27. doi:10.1111/j.1600-0447.1964.tb05731.x. akathisia. Br J Psychiatry 1989;154:672–676.
doi:10.1192/bjp.154.5.672Pu.
4 Fenton WS. Prevalence of spontaneous
dyskinesia in schizophrenia. J Clin Psychiatry 19 Schooler NR, Kane JM. Research diagnoses for
2000;61(suppl 4):10–14. tardive dyskinesia. Arch Gen Psychiatry 1982;
39(4):486–487. doi:10.1001/archpsyc.1982.
5 Shah BB, Lang AE. Acquired neurosyphilis
04290040080014.
presenting as movement disorders. Mov Disord
2012;27(6):690–695. doi:10.1002/mds.24950. 20 Jeste DV, Wyatt RJ. Therapeutic strategies against
tardive dyskinesia. Two decades of experience.
6 Frei K, Truong DD, Fahn S, et al. The nosology of
Arch Gen Psychiatry 1982;39(7):803–816.
tardive syndromes. J Neurol Sci 2018;389:10–16.
doi:10.1001/archpsyc.1982.04290070037008.
doi:10.1016/j.jns.2018.02.008.
21 Zutshi D, Cloud LJ, Factor SA. Tardive syndromes
7 American Psychiatric Association. Diagnostic and
are rarely reversible after discontinuing
statistical manual. 5th ed. Washington, DC:
dopamine receptor blocking agents: experience
American Psychiatric Association, 2013.
from a university-base movement disorder clinic.
8 Marsden CD, Jenner P. The pathophysiology of Tremor Other Hyperkinet Mov (N Y) 2014;4:282.
extrapyramidal side-effects of neuroleptic doi:10.7916/D8MS3R8C.
drugs. Psychol Med 1980;10(1):55–72. doi:10.1017/
22 Quitkin F, Rifkin A, Gochfeld L, Klein DF. Tardive
S003329170003960XPu.
dyskinesia: are first signs reversible? Am J
9 D'Abreu A, Akbar U, Friedman JH. Tardive Psychiatry 1977;134(1):84–87. doi:10.1176/
dyskinesia: epidemiology. J Neurol Sci 2018;389: ajp.134.1.84.
17–20. doi:10.1016/j.jns.2018.02.007.
23 Glazer WM, Morgenstern H, Schooler N, et al.
10 Fishbain DA, Dominguez M, Goldberg M. Predictors of improvement in tardive dyskinesia
Dyskinesia associated with fluoxetine use: case following discontinuation of neuroleptic
report. Neuropsychiatry Neuropsychol Behav medication. Br J Psychiatry 1990;157:585–592.
Neurol 1992;5(2):97–100. doi:10.1192/bjp.157.4.585.
11 Aquino CC, Lang AE. Tardive dyskinesia 24 Bergman H, Rathbone J, Agarwal V, Soares-
syndromes: current concepts. Parkinsonism Weiser K. Antipsychotic reduction and/or
Relat Disord 2014;20(suppl 1):S113–S117. cessation and antipsychotics as specific
doi:10.1016/S1353-8020(13)70028-2. treatments for tardive dyskinesia. Cochrane
Database Syst Rev 2018;2:CD000459.
12 Ford B, Greene P, Fahn S. Oral and genital tardive
doi:10.1002/14651858.CD000459.pub3.
pain syndromes. Neurology 1994;44(11):2115–2119.
doi:10.1212/WNL.44.11.2115. 25 Fernandez HH, Krupp B, Friedman JH. The course
of tardive dyskinesia and parkinsonism in
13 Weiden PJ, Mann JJ, Haas GE, et al. Clinical
psychiatric inpatients: 14-year follow-up.
nonrecognition of neuroleptic-induced
Neurology 2001;56(6):805–807. doi:10.1212/
movement disorders: a cautionary study. Am J
WNL.56.6.805.
Psychiatry 1987;144(9):1148–1153. doi:10.1176/
ajp.144.9.1148. 26 Teo JT, Edwards MJ, Bhatia K. Tardive dyskinesia
is caused by maladaptive synaptic plasticity: a
14 Hansen TE, Brown WL, Weigel RM, Casey DE.
hypothesis. Mov Disord 2012;27(10):1205–1215.
Under recognition of tardive dyskinesia and
doi:10.1002/mds.25107.
drug-induced-parkinsonism by psychiatry
residents. Gen Hosp Psychiatry 1992;14(5): 27 Adler CM, Malhotra AK, Elman I, et al.
340–344. Amphetamine-induced dopamine release
and post-synaptic specific binding in
15 Correll CU, Schenk EM. Tardive dyskinesia and
patients with mild tardive dyskinesia.
new antipsychotics. Curr Opin Psychiatry 2008:
Neuropsychopharmacology 2002;26(3):295–300.
21(2);151–1516. doi:10.1097/YCO.0b013e3282f53132.
doi:10.1016/S0893-133X(01)00309-8.

CONTINUUMJOURNAL.COM 1097

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

TARDIVE SYNDROMES

28 Silvestri S, Seeman MV, Negrete JC, et al. 37 Woods SW, Morgenstern H, Saksa JR, et al.
Increased dopamine D2 receptor binding after Incidence of tardive dyskinesia with atypical and
long-term treatment with antipsychotics in conventional antipsychotic medications: a
humans: a clinical PET study. Psychopharmacology prospective cohort study. J Clin Psychiatry 2010;
(Berl) 2000;152(2):174–180. doi:10.1007/ 71(4):463–473. doi:10.4088/JCP.07m03890yel.
s002130000532.
38 Glazer WM, Morgenstern H, Doucette JT.
29 Seeman P, Tinazzi M. Loss of dopamine neuron Predicting the long-term risk of tardive dyskinesia
terminals in antipsychotic-treated schizophrenia; in outpatients maintained on neuroleptic
relation to tardive dyskinesia. Prog medications. J Clin Psychiatry 1993;54(4):133–139.
Neuropsychopharmacol Biol Psychiatry 2013;44:
39 Carbon M, Hsieh C-H, Kne JM, et al. Tardive
178–183. doi:10.1016/j.pnpbp.2013.02.011.
dyskinesia prevalence in the period of
30 Chen S, Seeman P, Liu F. Antipsychotic drug second-generation antipsychotic use: a
binding in the substantia nigra: an examination of meta-analysis. J Clin Psychiatry 2017;78(3):
high metoclopramide binding in the brains of e264–e278. doi:10.4088/JCP.16r10832.
normal, Alzheimer’s disease, Huntington’s
40 Solmi M, Pigato G, Kane JM, Correll CU. Clinical
disease, and multiple sclerosis patients, and its
risk factors for the development of tardive
relation to tardive dyskinesia. Synapse 2011;65(2):
dyskinesia. J Neurol Sci 2018;389:21–27.
119–24. doi:10.1002/syn.20825.
doi:10.1016/j.jns.2018.02.012.
31 Shuaib UA, Rajput AH, Robinson CA, Rajput A.
41 Bhidayasiri R, Jitkritsadakul O, Friedman JH, Fahn
Neuroleptic-induced parkinsonism:
S. Updating the recommendations for treatment
clinicopathological study. Mov Disord 2016;31(3):
of tardive syndromes: a systematic review of
360–365. doi:10.1002/mds.26467.
new evidence and practical treatment algorithm.
32 Christensen E, Moller JE, Faurbye A. J Neurol Sci 2018;389:67–75. doi:10.1016/j.
Neuropathological investigation of 28 brains jns.2018.02.010.
from patients with dyskinesia. Acta Psychiatr
42 Bergman H, Rathbone J, Agarwal V, Soares-
Scan 1970;46(1):14–23. doi:10.1111/j.1600-0447.1970.
Weiser K. Antipsychotic reduction and/or
tb02097.x.
cessation and antipsychotics as specific
33 Kane J, Woerner P, Weinhold P, Wegner J. Results treatments for tardive dyskinesia. Cochrane
from a prospective study of tardive dyskinesia Database Syst Rev 2018;2:CD000459.
development: preliminary findings over a 2-year doi:0.1002/14651858.CD000459.pub3.
period. Psychopharmacol Bull 1982;18:82–83.
43 Mentzel CL, Bakker PR, van Os J, et al. Effect of
34 Swartz MS, Stroup TS, McEvoy JP, et al. What antipsychotic type and dose changes on tardive
CATIE found: results from the Schizophrenia dyskinesia and parkinsonism severity in patients
Trial. Psychiatr Serv 2008;59(5):500–506. with a serious mental illness: the Curaçao
doi:10.1176/ps.2008.59.5.500. extrapyramidal syndromes study XII. J Clin
Psychiatry 2017;78(3):e279–e285. doi:10.4088/
35 Leucht S, Wahlbeck K, Hamann J, Kissling W. New
JCP.16m11049.
generation antipsychotics versus low-potency
conventional antipsychotics: a systematic review 44 Browne S, Roe M, Lane A, et al. Quality of life in
and meta-analysis. Lancet 2003;361(9369): schizophrenia: relationship to sociodemographic
1581–1589. doi:10.1016/S0140-6736(03)13306-5. factors, symptomatology and tardive dyskinesia.
Acta Psychiatr Scand 1996;94(2):118–124.
36 Correll CU, Leucht S, Kane JM. Lower risk for
doi:10.1111/j.1600-0447.1996.tb09835.x.
tardive dyskinesia associated with second-
generation antipsychotics: a systematic review 45 Cummings J, Isaacson S, Mills R, et al.
of 1-year studies. Am J Psychiatry 2004;161(3): Pimavanserin for patients with Parkinson’s
414–425. doi:10.1176/appi.ajp.161.3.414. disease psychosis: a randomised, placebo-
controlled phase 3 trial. Lancet 2014;383(9916):
533–540. doi:10.1016/S0140-6736(13)62106-6.

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 Movement Disorders REVIEW ARTICLE


in Children C O N T I N U UM AUDIO
INTERVIEW AVAILABLE
ONLINE
By Toni S. Pearson, MBBS; Roser Pons, MD

ABSTRACT
PURPOSE OF REVIEW: This article provides an overview of the clinical features
and disorders associated with movement disorders in childhood. This
article discusses movement disorder phenomena and their clinical
presentation in infants and children and presents a diagnostic approach to
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suspected genetic disorders with a focus on treatable conditions.

RECENT FINDINGS: Technologic advances in molecular genetic testing over the

past decade continue to lead to the discovery of new diseases. This article
discusses the clinical presentation and early experience with treatment
for several recently described genetic forms of infantile-onset and
childhood-onset dystonia and chorea.
CITE AS:
CONTINUUM (MINNEAP MINN)
SUMMARY: The clinical spectrum of pediatric movement disorders is broad 2019;25(4, MOVEMENT DISORDERS):
and heterogeneous, ranging from acute or transient self-limited conditions 1099–1120.

to conditions that cause profound lifelong motor disability. Most

Address correspondence to
movement disorders in childhood are chronic, and the large number of Dr Toni S. Pearson, Department
rare, genetic conditions associated with pediatric movement disorders can of Neurology, Washington
pose a significant diagnostic challenge. Recognition of distinctive University School of Medicine,
660 S Euclid Ave, CB 8111,
diagnostic clues in the history and examination can facilitate the diagnosis St. Louis, MO 63110,
of potentially treatable disorders. [email protected].

RELATIONSHIP DISCLOSURE:
Dr Pearson has received
research/grant support from
the National Institutes of
INTRODUCTION Health/National Institute of

M
ovement disorders in childhood encompass a range of Neurological Disorders and
neurologic syndromes that are characterized by abnormalities Stroke. Dr Pons has received
personal compensation for
of tone, posture, the initiation or control of voluntary serving as a consultant for and
movements, or unwanted involuntary movements. Movement on the scientific advisory board
disorders are conventionally divided into two main categories: of Biogen, for serving as a
consultant for Guidepoint on a
hyperkinetic (involuntary movements such as dystonia, chorea, myoclonus, and rare metabolic disorder, and for
tremor) and hypokinetic (parkinsonism). In contrast to adults, children often serving as a speaker for Biogen
and for PTC Therapeutics.
present with mixed movement disorders rather than pure syndromes. Also,
symptoms may evolve over time as brain development interacts with the UNLABELED USE OF
underlying disease process so that different motor symptoms emerge at different PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
ages along the course of a given disease. Drs Pearson and Pons report
This article describes the approach to clinical evaluation and diagnosis of no disclosures.
movement disorders that cause dystonia, chorea, ataxia, myoclonus, and
parkinsonism in infancy and childhood. This article focuses on genetic disorders © 2019 American Academy
and highlights rare, treatable disorders that present in infancy. For information of Neurology.

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MOVEMENT DISORDERS IN CHILDREN

on tics and stereotypies, refer to the article “Tics and Tourette Syndrome” by
Harvey S. Singer, MD, FAAN,1 in this issue of Continuum.

MOVEMENT DISORDER PHENOMENOLOGY IN CHILDREN

The terminology used to describe movement disorder phenomena in childhood is
the same as that used in adults, but some specific features relevant to the
manifestation of each type of movement disorder in children are considered
briefly here.

Dystonia
Dystonia is one of the most common movement disorders in children and is
defined as abnormal often repetitive movements or postures that are caused by
sustained or intermittent involuntary muscle contractions. Numerous conditions
are associated with dystonia in children. Dystonic cerebral palsy associated with
brain injury due to complications of prematurity, stroke, or hypoxic ischemic
encephalopathy is the most common cause. Dystonia is also a feature of many
genetic disorders and may occur either in isolation or as part of a complex
neurologic syndrome. In contrast to dystonia in adults, isolated dystonia in
children is more likely to progress to generalized or multifocal dystonia than
remain focal.

Chorea
Chorea, ballism, and athetosis are hyperkinetic movement disorders that often
coexist in the same patients and are viewed as part of a continuum. Chorea is
characterized by an ongoing random-appearing sequence of one or more discrete
involuntary movements or movement fragments.2 Chorea is frequently
associated with athetosis (choreoathetosis), which is characterized by slow,
continuous, involuntary distally predominant writhing movements that prevent
maintenance of a stable posture. Ballism is defined as chorea that affects
proximal joints such as shoulder or hip joints and leads to large-amplitude
movements of the limbs. In children, acute chorea due to postinfectious/
autoimmune conditions is the most frequent cause of chorea, while dyskinetic
cerebral palsy is the most frequent cause of chronic chorea. In general, genetic
chorea is chronic, develops gradually, and tends to be generalized and
symmetric, whereas acquired chorea often manifests acutely or subacutely and,
when related to brain injury, can be asymmetric or unilateral.

Ataxia
Ataxia refers to impaired muscle control or coordination of voluntary
movements that cannot be attributed to weakness or involuntary movements
(eg, dystonia, chorea, or myoclonus).3 On examination, children with ataxia may
exhibit a variety of clinical signs, depending on the underlying pathology.
Signs include eye movement abnormalities (saccade dysmetria, nystagmus,
oculomotor apraxia), slow speech with impaired articulation (cerebellar
dysarthria), poor accuracy and coordination of voluntary reaching movements
(dysmetria, intention tremor), poor stability of head and trunk position during
sitting (titubation), and an unsteady, broad-based, or veering gait (gait ataxia).
Young children with ataxia may habitually walk quickly or run to compensate
for their balance difficulties and minimize falls.

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 Acute or subacute ataxia usually has an underlying toxic, autoimmune, KEY POINTS
traumatic, or neoplastic etiology. Intermittent ataxia may be a feature of inborn
● Many causes of childhood
errors of metabolism or a genetic episodic ataxia. Chronic nonprogressive ataxia ataxia exist that may be
may be a manifestation of congenital cerebellar malformations or genetic broadly divided into acute,
neurodevelopmental disorders, while chronic progressive ataxia usually occurs in intermittent, and chronic
the context of a genetic, neurodegenerative disease process. categories.
Some practical points are worth bearing in mind when evaluating a child who
● Myoclonus can be
has been referred with suspected ataxia. The first is to question whether ataxia is physiologic (hypnic
in fact the main motor disturbance. For example, a young child with clumsiness myoclonus), or it can be
and balance problems caused by chorea or dystonia may sometimes be the manifestation of a
mischaracterized as ataxic. Similarly, multifocal myoclonus can produce the broad range of systemic
disorders and metabolic
appearance of action tremor, leading to a mislabel of dysmetria during reaching derangements.
movements. Careful observation for involuntary movements and specific
characterization of the ataxic features will help to ensure accurate ● Parkinsonism in infants
characterization of the motor syndrome. A second point is that ataxia in children and young children differs
from parkinsonism in adults,
often occurs in combination with other motor abnormalities, such as spasticity often manifesting as
and dystonia. A child with a spastic-ataxic gait may have a normal or narrow bradykinesia/hypokinesia,
base, rather than a wide base, walk on his or her toes, and have leg stiffness in dystonia, and axial hypotonia;
addition to gait unsteadiness. tremor is often absent.

Myoclonus
Myoclonus is defined as the “sequence of repeated, often nonrhythmic, brief
shock-like jerks due to sudden involuntary contraction or relaxation of one or
more muscles.”2 Myoclonus is associated with abnormal neuronal excitability of
cortical or subcortical gray matter; it can be classified based on distribution of
the movements (focal, multifocal, segmental, generalized) or on the etiologic
location (cortical, subcortical, spinal). While myoclonus in adults is often a
benign sign associated with metabolic disturbances, myoclonus in children is
often an ominous manifestation that can be caused by tumors, metabolic
diseases, neurodegenerative disease, or encephalitis and is often associated with
seizures and encephalopathy. Benign forms of myoclonus can occur in children
as well.2 Myoclonus can be physiologic (hypnic myoclonus) or it can be the
manifestation of a broad range of systemic disorders and metabolic
derangements, the adverse effect of multiple drugs, and the symptom of a broad
range of neurologic disorders. In pediatric patients, neurologic conditions
manifesting with myoclonus include inflammatory/autoimmune disorders (ie,
opsoclonus-myoclonus-ataxia syndrome), severe hypoxic injury, encephalitis,
and focal mass lesions or dysplasias (often manifesting as epilepsia partialis
continua).4,5

Parkinsonism
Parkinsonism is characterized by the combination of bradykinesia and one or
more of the following cardinal signs: rigidity, resting tremor, and postural
instability. Parkinsonism is rare in children, especially in infancy, and the clinical
manifestations in children differ from adults in several important ways. First,
tremor is often, but not always, absent. Second, dystonia is a common
accompanying feature; hence, childhood-onset parkinsonism is frequently
referred to as parkinsonism-dystonia.6 Third, infants with parkinsonism typically
have marked hypotonia as the primary baseline disturbance of tone.

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MOVEMENT DISORDERS IN CHILDREN

Tremor
Tremor refers to oscillating, rhythmic movements about a fixed point, usually a
joint, producing a regular back-and-forth movement. Common causes of acute
tremor in children include drug-induced tremor and psychogenic tremor.
Essential tremor, characterized by a chronic, slowly progressive, isolated postural
and action tremor, may begin in childhood. Many secondary tremors occur in
conjunction with other movement disorders, such as dystonia and ataxia.
Parkinsonian resting tremor is uncommon in children.

BENIGN TRANSIENT DEVELOPMENTAL MOVEMENT DISORDERS

OF INFANCY
Neonates, infants, and toddlers may manifest with a number of abnormal
movements that are benign and typically display complete resolution over time.
The abnormal movements may appear as myoclonus, dystonia, or tremor and are
often paroxysmal. They are thought to be a manifestation of central nervous
system immaturity and disappear with brain maturation. Typically,
psychomotor development and neurologic function are normal.

TABLE 10-1 Common Acute Movement Disorder Presentations in the Previously

Healthy Child

Movement
Disorder Etiologies Comments

Chorea Poststreptococcal (Sydenham Movement disorder often mixed (dystonia, stereotypies) in

chorea), other autoimmune anti–N-methyl-D-aspartate (NMDA) receptor and other
encephalitis autoimmune encephalitis; treatment: immunomodulatory
therapy for autoimmune encephalitis

Drug induced Anticholinergics, dopaminergic medications (acute chorea);

dopamine receptor blockers (tardive: often mixed syndrome
with akathisia, dystonia; withdrawal-emergent dyskinesia:
hyperkinetic movement disorder with ataxia)

Dystonia Acute dystonic reaction Caused by dopamine receptor–blocking medications, including

antipsychotics and antiemetics (eg, metoclopramide); treatment
of acute episode: anticholinergic medication

Myoclonus Opsoclonus-myoclonus-ataxia May be accompanied by ataxia, sleep disruption, irritability; often

syndrome associated with neuroblastoma; treatment: immunosuppression
with goal of inducing remission of symptoms, limiting long-term
motor and intellectual disability

Ataxia Postinfectious cerebellar ataxia May follow infectious illness or vaccination; onset is usually very
acute, 90% recover completely over period of 2 to 3 months

Drug ingestion For example, antiepileptics, benzodiazepines, antihistamines;

typically accompanied by mental status changes

Parkinsonism Drug induced Caused by dopamine receptor–blocking medications

Autoimmune encephalitis Rare; associated with inflammatory lesions of the basal ganglia

Tremor, dystonia, Psychogenic movement disorder Clinical clues: sudden onset of dystonia with fixed posture, episodic
gait disturbance tremor; treatment may include physical therapy and management
of comorbid mood symptoms with medication or psychotherapy

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 Benign transient conditions with myoclonic appearance include benign KEY POINTS
neonatal sleep myoclonus, which occurs during sleep and disappears by waking up
● Neonates, infants, and
the baby, and benign myoclonus of infancy, which resembles the infantile spasms toddlers may manifest with
of West syndrome. Tremor appearance includes jitteriness, a generalized tremor a number of benign and
that is highly stimulus sensitive and occurs in neonates; shuddering that resembles transient movement
shivering and occurs during infancy or early childhood; and spasmus nutans, disorders such as
myoclonus, dystonia, or
which occurs in late infancy and is characterized by the triad of head nodding,
tremor; development is
nystagmus, and head tilt. In the case of spasmus nutans, neuroimaging is indicated normal, and treatment is
because it has occasionally been associated with optic pathway gliomas.7,8 not required.
Benign transient conditions with dystonic appearance include benign
paroxysmal torticollis of infancy, which is a putative infantile migraine variant ● The most common
etiologies underlying acute
that manifests with periodic episodes of head tilt and may be associated with movement disorders in a
pallor, vomiting, irritability, or ataxia. Benign idiopathic dystonia of infancy is previously healthy child are
characterized by segmental dystonia at rest, usually of one arm, that disappears autoimmune, drug-induced,
with volitional movement. Sandifer syndrome is characterized by torticollis or and psychogenic.
opisthotonic posturing associated with gastroesophageal reflux, and infantile
masturbation manifests by stereotyped posturing of the lower limbs. Finally,
paroxysmal tonic upgaze of infancy is characterized by episodes of sustained
conjugate upward deviation of the eyes resembling ocular dystonia and is often
accompanied by neck flexion.7,8
Treatment for these benign transient infantile conditions is not required, but it
is important to recognize them so that parental anxiety and unnecessary
investigations can be avoided.

ACUTE MOVEMENT DISORDERS

The acute onset of movement disorder symptoms in a previously healthy,
developmentally normal child will often prompt a request for urgent neurologic
evaluation, either in the office or in the emergency department. It is helpful to
be familiar with the conditions that typically present in an acute fashion
(TABLE 10-1). Autoimmune, drug-induced, and psychogenic etiologies are
the predominant conditions in this context.9 Accurate diagnosis is important as
many of these are treatable conditions. Treatment is directed at the
underlying cause.
Acute-on-chronic movement disorder presentations may also occur in
children with a preexisting neurologic disorder. A common example is the acute
worsening of dystonia (status dystonicus) in a child with dystonic cerebral palsy
due to a documented history of brain injury. Another example is the acute onset
of severe chorea and ballismus in a child with GNAO1 encephalopathy, a genetic
disorder that may initially manifest nonspecifically with hypotonia and
developmental delay. In both of these situations, management in an intensive
care setting is frequently required.

CHRONIC MOVEMENT DISORDERS

Most movement disorders in childhood are chronic and may be either acquired
or genetic.

Dyskinetic Cerebral Palsy

Cerebral palsy is the single most prevalent cause of childhood movement
disorders. Cerebral palsy is an umbrella term that describes a motor disorder
resulting from a nonprogressive lesion or dysfunction of the developing brain.

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MOVEMENT DISORDERS IN CHILDREN

While no single etiology is specified, the term cerebral palsy usually implies an
underlying acquired etiology, such as brain lesions associated with complications
of prematurity, neonatal hypoxic ischemic encephalopathy, perinatal stroke, or
chronic sequelae of meningoencephalitis. Dyskinetic cerebral palsy is the
phenotypic classification applied to the 10% to 15% of children with cerebral
palsy whose motor syndrome is predominated by involuntary movements.
Children with dyskinetic cerebral palsy typically have a combination of dystonia
and athetosis, often accompanied by axial hypotonia with or without spasticity
in the limbs.
Dyskinetic cerebral palsy is classically associated with injury to the basal
ganglia. In practice, dystonia is a relatively common finding in children with
other cerebral palsy phenotypes, including spastic hemiplegia, diplegia, and
quadriplegia, who have injury to brain structures other than the basal ganglia.
Normal brain imaging has been reported in approximately one-third of patients
with a diagnosis of dyskinetic cerebral palsy,10 suggesting that etiologies other
than brain injury may underlie the diagnosis of cerebral palsy in a significant
proportion of children with a diagnosis of dyskinetic cerebral palsy.

Approach to Clinical Evaluation and Diagnosis

When evaluating a young child with motor developmental delay and abnormal
movements, a frequent diagnostic question is whether the child has a syndrome
compatible with a diagnosis of cerebral palsy or whether the child may have an
underlying genetic disorder. The diagnosis of a genetic disorder has important
implications for genetic counseling for the family. In some cases, the diagnosis
also has important treatment implications because some metabolic diseases
have available treatment that targets the primary disease process rather than
control of symptoms, and early initiation of the disease-specific treatment may
dramatically improve the long-term outcome (eg, the disorders of monoamine
neurotransmitter synthesis and glucose transporter type 1 [GLUT1] deficiency
syndrome). In older children who present with progressive symptoms
suggesting a neurodegenerative disease, the identification of a rare treatable
disorder, such as Wilson disease or ataxia with vitamin E deficiency, is
similarly important.

Diagnostic Approach for a Suspected Genetic Disorder

The rarity, phenotypic diversity, and large number of genetic disorders that may
cause movement disorders pose a diagnostic challenge even for experienced
specialists. On occasion, distinctive features in the history and neurologic
examination strongly suggest a well-defined disease. In many cases, however, the
clinical features may be nonspecific or atypical, making definitive clinical
diagnosis difficult.
As a first step, the clinical evaluation aims to capture key features of the
history and construct an accurate characterization of the neurologic and systemic
features of the clinical syndrome. Factors of particular importance in the
history include the presence of possible perinatal risk factors for brain injury
(prematurity, complicated delivery, neonatal intensive care admission), age of
onset of symptoms, family history, and developmental history (developmental
delay or regression). With regard to the motor symptoms themselves, it is
important to inquire specifically about the time course of symptoms: are they
persistent, intermittent, or fluctuating (eg, diurnal variation, worsened by stress,

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illness, or exercise); or are they stable or progressive? In addition to the general
and neurologic examination, ophthalmologic evaluation should be strongly
considered. Eye findings, such as Kayser-Fleischer rings (associated with Wilson
disease), or pigmentary retinopathy or optic atrophy (both associated with some
forms of neurodegeneration with brain iron accumulation, for example) may
provide important diagnostic clues. An accurate and complete characterization
of the clinical syndrome both informs the choice of genetic testing and is likely, at
a later stage, to aid in the interpretation of genetic test results.
Brain imaging with MRI is usually indicated early in the course of
investigation. Brain imaging may detect an acquired structural lesion as the cause
of a cerebral palsy sydrome. Alternatively, the finding of specific brain lesions or
structural abnormalities may narrow the differential diagnosis of potential
genetic disorders. Imaging may be considered an important component of
the phenotype.
In the past decade, the advent of next-generation sequencing technology for
molecular genetic analysis has had a huge impact on the approach to diagnostic
testing and the yield of genetic testing in child neurology. In this context, what
is the current role of biochemical laboratory investigations in the workup of
children with suspected genetic or metabolic disease? The authors of this article
argue that there remains a role for screening biochemical investigations, although
lengthy and exhaustive metabolic testing procedures prior to genetic testing are
now rarely performed. Biochemical markers can provide rapid and unequivocal
evidence for some treatable metabolic conditions, facilitating prompt initiation
of treatment (TABLE 10-2). Even for disorders without a disease-specific
treatment, the finding of a positive biomarker may narrow the differential
diagnosis so that a more focused (and therefore time-saving and cost-saving)
genetic testing strategy can be pursued. Analysis of selected biochemical markers
may also be performed after genetic testing to evaluate the pathogenicity of
genetic variants of unknown significance that are detected using next-generation
sequencing methods.
The appropriate genetic testing strategy will depend on the diagnostic
impression of the clinician based on clinical, radiological, and biochemical
findings as outlined above. If a clear and specific syndrome emerges,
confirmatory molecular genetic testing may be directed at a small number of
genes. In many cases, however, a more comprehensive testing approach is
appropriate. Comparative genomic hybridization microarray analysis to detect
copy number variants should always be considered, particularly if the syndrome
includes intellectual disability, dysmorphism, or multiple systemic abnormalities
suggesting a contiguous gene syndrome. Next-generation sequencing
techniques, including multigene panels and whole exome sequencing, should
then be pursued if available. The diagnostic accuracy of next-generation
sequencing tests depends upon the interpretation of findings in relation to the
patient’s syndrome, so thoughtful clinical characterization remains vital.

GENETIC MOVEMENT DISORDERS THAT USUALLY PRESENT

IN INFANCY
Many of the genetic movement disorder syndromes that present in infancy or
early childhood are nonprogressive disorders that impair motor development
and may be accompanied by other neurologic symptoms including seizures and
intellectual disability. It is common for these disorders to manifest with mixed

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MOVEMENT DISORDERS IN CHILDREN

movement disorders (eg, dystonia in combination with chorea, ataxia, or

myoclonus). These patients may be misdiagnosed with dyskinetic cerebral palsy
because of the early age of onset and nonprogressive course of their
motor symptoms.
Neurodevelopmental disorders often present initially with fairly nonspecific
motor features such as hypotonia and developmental delay. It is common for
motor symptoms to evolve with age as the brain develops, even when the
underlying pathology is nonprogressive. Involuntary movements and ataxia
often become more apparent as the child begins to attempt to sit, stand, walk,

TABLE 10-2 Treatable Metabolic Disorders Associated With Movement Disorders in

Infancy or Childhood

Condition Gene(s) Age of Onset Key Clinical Features

Monoamine GCH, TH, PTS, Infancy, Hypotonia, dystonia, oculogyric crises, ptosis, autonomic
neurotransmitter disorders QDPR, SPR, childhood dysfunction (dopa-responsive dystonia: dystonia, spastic
DDC, DNAJC12 paraplegia with diurnal variation)

Glucose transporter type 1 SLC2A1 Infancy, Ataxia, spasticity, dystonia, paroxysmal exertional
(GLUT1) deficiency childhood dyskinesia, seizures, intellectual disability
syndrome

Cerebral folate deficiency FOLR1a Infancy, Hypotonia, developmental delay, irritability, ataxia,
childhood spasticity, chorea, dystonia, seizures

Thiamine deficiency SLC19A3 Infancy, Recurrent acute encephalopathy, dystonia, spasticity,

syndromes childhood ataxia, seizures

Pyruvate dehydrogenase PDHA1, DLAT, Infancy, Ataxia (may be intermittent in milder cases), hypotonia,
complex deficiency others childhood intellectual disability, seizures, paroxysmal exertional
dyskinesia (rare)

Biotinidase deficiency BTD Infancy, Ataxia, hypotonia, seizures, eczematous skin

childhood rash, alopecia

Coenzyme Q10 deficiency COQ8A, Infancy to Ataxia, may have encephalopathy, spasticity, seizures,
PDSS2, others adulthood myopathy, intellectual disability, sensorineural deafness

Creatine deficiency GAMT Childhood, Dystonia, chorea, ataxia, intellectual disability,

adolescence hyperactivity, self-injurious behavior

Ataxia with vitamin E TTPA Childhood, Ataxia, dystonia, head tremor, may have peripheral
deficiency adolescence neuropathy, decreased vibration sense

Wilson disease ATP7B Childhood, Dystonia, parkinsonism, tremor, liver disease

adolescence

Hypermanganesemia SLC30A10 Childhood, Dystonia, parkinsonism, polycythemia, liver disease

adulthood

CSF = cerebrospinal fluid; GAA = guanidinoacetate; MRI = magnetic resonance imaging.

a
Note that FOLR1 mutations are a rare cause of cerebral folate deficiency. The most common cause is blocking autoantibodies against the folate
receptor.

1106 AUGUST 2019

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and make purposeful arm movements. Some neurodegenerative diseases may
also present in infancy or early childhood. In these cases, a history of significant
developmental regression (not only of developmental delay) is a red flag that
should alert the clinician to this possibility.
Treatable metabolic conditions that may present during infancy include the
primary monoamine neurotransmitter disorders, GLUT1 deficiency syndrome,
organic acidurias, thiamine deficiency syndromes, pyruvate dehydrogenase
deficiency, coenzyme Q10 deficiency, cerebral folate deficiency, creatine
deficiency syndromes, and biotinidase deficiency. Therefore, metabolic

Brain MRI Findings Laboratory Investigations Treatment

Usually normal Disease-specific abnormalities of CSF Neurotransmitter precursor replacement,

monoamine neurotransmitter metabolites may have tetrahydrobiopterin, folinic acid
and pterins (some disorders: elevated (selected disorders)
blood phenylalanine on newborn screening)

Usually normal Low CSF glucose, normal serum glucose, Ketogenic diet
low-normal CSF lactate

Frontotemporal atrophy, Low CSF 5-methyltetrahydrofolate Folinic acid

periventricular white matter T2
hyperintensity; may be normal

T2 hyperintensity in basal ganglia, High CSF lactate, abnormal urine organic Thiamine, biotin supplementation
brainstem acids profile

Ventriculomegaly, corpus callosum High lactate, pyruvate (plasma, CSF) normal Ketogenic diet, thiamine
dysgenesis, T2 hyperintensity in lactate to pyruvate ratio
basal ganglia, brainstem

Cerebral volume loss, white High serum ammonia, high lactate, may Biotin
matter T2-hyperintensity have abnormal urine organic acids profile;
low serum biotinidase activity

May have cerebellar atrophy High plasma lactate, low coenzyme Q10 Coenzyme Q10 (ubiquinone)

T2 hyperintensity in globus High GAA, low creatine (urine and plasma) Arginine restriction, creatine and ornithine
pallidus; may be normal supplements

May have cerebellar atrophy (half Low plasma vitamin E Vitamin E

of reported patients)

T2 hyperintense lesions in basal Low or normal serum copper, Zinc, tetrathiomolybdate

ganglia, midbrain, pons, may have ceruloplasmin; high urine copper
T1 hyperintensity in globus pallidus

T1 hyperintensity of basal ganglia, High whole-blood manganese Chelation with disodium calcium edetate;
sparing thalamus iron

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MOVEMENT DISORDERS IN CHILDREN

screening investigations, including CSF analysis, should be strongly considered

in this age group (TABLE 10-2), particularly if the clinical history reveals marked
fluctuation of motor symptoms, symptom exacerbation in the context of illness
or other catabolic stress, or encephalopathy. Some of the treatable and more
common disorders are highlighted below.

Primary Monoamine Neurotransmitter Disorders

The primary monoamine neurotransmitter disorders comprise defects of
enzymes, cofactors, and transporters that are involved in the metabolism and
homeostasis of the catecholamines (dopamine, norepinephrine, and epinephrine)
and serotonin. The majority of these disorders are inherited in an autosomal
recessive fashion. These disorders manifest clinically with infantile dystonia-
parkinsonism (CASE 10-1). Onset is usually within the first months of life with

CASE 10-1 A 6-month-old girl was brought by her parents for evaluation of
hypotonia and developmental delay. She had been born full term after an
uneventful pregnancy, delivery, and neonatal period. Her parents had
begun to be concerned at around the age of 4 months because of the lack
of motor development and the occurrence of daily episodes of tonic
upward eye deviation of several minutes duration that resolved with
sleeping. She often had nasal congestion and sweated profusely.
On examination she was alert and interactive but was easily distressed.
She showed poor facial expression and minimal spontaneous movements.
She had dystonic posturing of all limbs and dystonic tremor of the upper
limbs. She had prominent axial hypotonia. Appendicular tone was decreased
when relaxed and increased when manipulated or distressed. Tendon
reflexes were brisk, and her toes were spontaneously up (striatal toes).
Brain MRI was normal. CSF analysis of biogenic amines disclosed
decreased concentration of the dopamine metabolite homovanillic acid.
Molecular analysis of the gene encoding tyrosine hydroxylase revealed a
homozygous pathogenic mutation (c.707T>C). These findings were
consistent with tyrosine hydroxylase deficiency.
She was started on treatment with levodopa 0.5 mg/kg/d that was
followed by gradual psychomotor development. The oculogyric crises
decreased in frequency and gradually disappeared. Her hyperhidrosis and
nasal congestion resolved completely.

COMMENT This case illustrates the typical motor and autonomic symptoms of infantile
dystonia-parkinsonism associated with congenital disorders of monoamine
neurotransmitter synthesis: oculogyric crises, hypokinesia, hypotonia, and
dystonia, in conjunction with excessive sweating and nasal congestion.
CSF examination readily detected a low concentration of the dopamine
metabolite homovanillic acid, and diagnosis was confirmed with molecular
genetic testing. The patient had an excellent response to treatment with
levodopa.

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hypotonia, developmental delay, decreased spontaneous movements, rigidity, KEY POINTS
and dystonia. Oculogyric crises are a common feature and are characterized by
● In a child with a dyskinetic
sustained, tonic conjugate, typically upward deviation of the eyes lasting from cerebral palsy phenotype,
seconds to hours that may also be associated with axial or appendicular dystonic absent risk factors for
posturing.11 In addition, approximately half of patients may have tremor.12 As a perinatal brain injury, and
result of the deficiency of dopamine and other catecholamines, patients often normal brain MRI,
investigation for an
manifest signs of autonomic dysfunction (ptosis, sweating, nasal congestion),
underlying genetic disorder
sleep disturbance, and prominent dysphoric mood. The findings of profound should be considered. Some
hypotonia, hypokinesia, and ptosis may lead to misdiagnosis of a neuromuscular genetic disorders have
disease. The important distinguishing features to recognize are the associated disease-specific treatment
that improves symptoms
oculogyric crises and dystonia, which will lead to accurate clinical diagnosis of a
and developmental
neurotransmitter disorder. Neuroimaging is usually normal, and diagnosis is outcome.
confirmed with molecular analysis and with the analysis of monoamine
neurotransmitter metabolites and pterins in CSF.11,12 ● The primary monoamine
neurotransmitter disorders
comprise defects of
Glucose Transporter Type 1 Deficiency Syndrome enzymes, cofactors, and
transporters involved in the
GLUT1 deficiency syndrome is a neurodevelopmental disorder that usually metabolism and
presents in infancy and has both persistent and paroxysmal neurologic homeostasis of the
symptoms. The two most common initial symptoms reported in infants with catecholamines and
GLUT1 deficiency syndrome are seizures and characteristic episodes of repetitive serotonin.
eye-head movements consisting of apparently involuntary multidirectional shifts
● In biogenic amine
of gaze. Ataxia is often a prominent component and usually becomes evident as disorders, neuroimaging is
the child begins to stand and walk. In this disorder, a typical feature is the usually normal, and
fluctuating severity of ataxia with worsening in the context of exercise, illness, or diagnosis is confirmed with
the analysis of monoamine
fasting (eg, ataxia first thing in the morning upon waking). The full neurologic
neurotransmitter
syndrome consists of variable combinations of ataxia, spasticity, dystonia, metabolites and pterins in
seizures, and intellectual disability. A variety of episodic neurologic phenomena CSF and with molecular
may also occur, including paroxysmal exertional dyskinesia, migraines, analysis.
dysphoria, and hemiparesis or quadriparesis (refer to the section on paroxysmal
dyskinesia). CSF analysis can provide a rapid diagnostic clue with the finding of a
low CSF glucose concentration in the setting of normoglycemia. The majority of
patients have a heterozygous variant in SLC2A1, which encodes the GLUT1
transporter. Treatment with the ketogenic diet typically leads to a dramatic
improvement in the paroxysmal and fluctuating symptoms (including ataxia,
seizures, and paroxysmal dyskinesia) and may improve long-term developmental
outcome. (CASE 10-2)

NKX2-1–Related Disorders (Brain-Thyroid-Lung Syndrome)

NKX2-1–related disorders are autosomal dominant movement disorders that
result from mutations of the NK2 homeobox 1 gene (NKX2-1), encoding a
transcription factor that is essential for the development of lung, thyroid, and
basal ganglia. In NKX2-1–related disorders, chorea occurs in association with
variable thyroid and respiratory involvement (brain-thyroid-lung syndrome).
Thyroid involvement may range from subclinical elevation of thyroid-stimulating
hormone (TSH) to severe congenital hypothyroidism causing failure to thrive in
early infancy, while lung involvement may manifest with neonatal respiratory
distress, recurrent pulmonary infections, asthma, and lung cancer.
Patients usually present with hypotonia, delayed walking, and generalized
chorea. Chorea improves in adolescence and stabilizes or resolves completely in

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MOVEMENT DISORDERS IN CHILDREN

CASE 10-2 A 5-year-old boy presented for evaluation following his first seizure. He
had a history of unsteady gait. He had been a healthy neonate and had
been born at term without perinatal complications. His parents had
become concerned about his motor development when he was 12 months
old. He often fell when trying to stand. He walked independently at age
16 months, but his gait always appeared unsteady. His parents noticed
that he was much stiffer and less steady in the mornings immediately
after waking, with subsequent improvement by midmorning after eating
breakfast. His balance also worsened whenever he was sick.
At 4 years of age he had several brief episodes, typically 10 to
15 minutes in duration, of involuntary stiffening and jerking movements of
both legs following periods of running or active play. At age 5 years, he
presented to the hospital following a single, brief generalized tonic-
clonic seizure.
On examination, he was observed to be alert and cooperative but
distractible. His speech was dysarthric. He had moderate lower limb
spasticity and abnormally brisk lower limb reflexes with several beats of
bilateral ankle clonus. He had mild upper limb dysmetria and a spastic-
ataxic gait pattern characterized by a narrow but variable base, toe
walking, veering, unsteadiness, and multiple falls.
His brain MRI was normal. A lumbar puncture was performed, and his
CSF glucose was 35 mg/dL (serum glucose 92 mg/dL, with a CSF to serum
ratio of 0.38). A diagnosis of glucose transporter type 1 (GLUT1) deficiency
syndrome was confirmed with the finding of a heterozygous pathogenic
missense variant in SLC2A1.
He was started on the ketogenic diet, and on follow-up 6 months
later, he had had no further seizures or episodes of involuntary leg
movements, showed marked improvement in his ataxia, and had
improved attention at school.

COMMENT This case illustrates the typical constellation of neurologic symptoms

found in patients with GLUT1 deficiency syndrome: developmental delay,
spasticity, fluctuating ataxia that worsens during fasting and illness,
paroxysmal dyskinesia provoked by sustained physical activity, and
seizures. The CSF glucose concentration was approximately half the value
expected for the given serum glucose concentration (ratio of
approximately 1:3, instead of 2:3). Treatment with the ketogenic diet
provides an alternative brain fuel source to glucose, with resulting dramatic
symptom improvement.

1110 AUGUST 2019

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early adulthood. Approximately half of patients develop other movement KEY POINT
disorders such as dystonia, ataxia, or intention tremor. Cognition is relatively
● The epileptic-dyskinetic
preserved, and neuroimaging is normal.13 encephalopathies are a
heterogeneous group of
ADCY5-Related Dyskinesia disorders that are
ADCY5-related dyskinesia is due to heterozygous mutations in the ADCY5 gene. associated with a spectrum
of movement disorders,
Patients manifest with infantile-onset or early childhood hypotonia, motor delay,
most frequently chorea, but
and dyskinesia (chorea, ballismus, choreoathetosis). Episodic exacerbation of also dystonia and
baseline dyskinesia during drowsiness upon awakening, when falling asleep, or stereotypies.
during intercurrent illnesses, lasting minutes to hours, is characteristic.
Generalized dystonic spasms can also occur.13
Another gene associated with generalized childhood-onset chorea is PDE10A,
which may follow either dominant or recessive inheritance.13

Epileptic-Dyskinetic Encephalopathies
A recently described group of complex neurologic disorders that may manifest
with a hyperkinetic movement disorder early in life are the epileptic-dyskinetic
encephalopathies. They are a genetically and clinically heterogeneous group of
disorders characterized by a spectrum of manifestations ranging from isolated
movement disorders (most frequently chorea, but also dystonia and
stereotypies) to severe infantile epileptic encephalopathy.13 Mutations in FOXG1
cause a developmental encephalopathy manifesting in infancy or early childhood
with severe developmental delay, acquired microcephaly, profound intellectual
disability, epilepsy, and a hyperkinetic movement disorder emerging within
the first year of life that includes various combinations of chorea,
orolingual/facial dyskinesias, dystonia, myoclonus, and hand stereotypies.
Neuroimaging may show corpus callosum hypoplasia or aplasia, delayed
myelination, simplified gyration, and frontotemporal abnormalities.14 Mutations
in GNAO1 can cause a severe infantile epileptic encephalopathy or a static
encephalopathy with associated hyperkinetic movement disorder (chorea,
ballismus, dystonia, and orofaciolingual dyskinesia) (CASE 10-3). The initial
motor phenotype is often nonspecific with hypotonia, dystonia, and motor
developmental delay. Characteristic episodes of severe chorea and ballismus in
combination with autonomic dysfunction, triggered by infections or other
stressors, can last hours or days.13 Other genes associated with epileptic-
dyskinetic encephalopathies include GRIN1, SCN8A, FRRS1L, GPR88,
UNC13A, and SYT1.15 The list is likely to expand further with the discovery of
new genes.

GENETIC MOVEMENT DISORDERS THAT USUALLY PRESENT

IN CHILDHOOD
A diverse range of movement disorder syndromes may present with symptom
onset in childhood or adolescence, typically after a period of normal motor
development in infancy.

Dystonia
Dystonia is a feature of many childhood-onset genetic conditions, divided into
three main categories: (1) isolated (pure dystonia), (2) combined (dystonia
accompanied by myoclonus or parkinsonism), and (3) complex (dystonia as one
feature of a complex neurologic syndrome).

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MOVEMENT DISORDERS IN CHILDREN

ISOLATED AND COMBINED DYSTONIAS. In the isolated and combined genetic

dystonia syndromes, symptoms usually appear after a period of normal infantile
motor development. These are non-neurodegenerative diseases, but the dystonia
is typically progressive. The age of onset varies widely, from as young as 1 year of
age, to adulthood. The distribution of dystonia helps to distinguish between the
different genetic forms of isolated dystonia. Prominent cranial and bulbar
involvement is typical in DYT6-THAP1 and DYT28-KMT2B, while it is rare in
DYT1-TOR1A. Limb involvement is common to all of the disorders and usually
occurs early in the course. Progression to generalized or multifocal dystonia
occurs in more than half of patients with childhood-onset isolated genetic
dystonia, and as a general rule, the earlier the age of onset, the higher the risk of
generalization. Brain imaging is normal in DYT1 and THAP1–related dystonia,
but KMT2B-related dystonia may be associated with subtle T2 hypointensity of
the globus pallidus.

CASE 10-3 An 11-year-old girl presented to the emergency department with acute,
severe chorea and ballismus. She had been born at term following an
uncomplicated pregnancy and delivery. As a neonate she had hypotonia
and feeding difficulties, and at age 9 months she was diagnosed with
developmental delay when she was unable to sit independently. She
eventually sat at 18 months and walked with a walker at age 3 years.
On examination at age 3 years she had generalized hypotonia,
bradykinesia, dystonia in the upper and lower limbs, and slightly brisk
lower limb reflexes. Her brain imaging was normal, and a diagnosis of
atypical cerebral palsy was made.
At age 9 years she had an episode of mild chorea in the context of an
acute viral respiratory illness, which resolved spontaneously within a
few weeks.
At age 11, in the setting of another viral upper respiratory tract illness,
she developed severe acute chorea complicated by rhabdomyolysis.
This led to a prolonged intensive care unit admission. Whole exome
sequencing performed during this admission revealed a de novo
heterozygous pathogenic missense variant mutation in GNAO1.
Treatment with tetrabenazine 400 mg/d controlled the involuntary
movements. Six months later, bilateral globus pallidus internus deep
brain stimulation leads were placed, and over the next 18 months, the
tetrabenazine was tapered off without any recurrence of chorea. Her
motor function remained significantly impaired compared to baseline;
she could no longer sit independently or walk and was very hypokinetic.

COMMENT This case illustrates the characteristic clinical features of the predominant
motor phenotype of GNAO1 encephalopathy: a static neurodevelopmental
disorder consisting of hypotonia and developmental delay, with recurrent
episodes of acute chorea triggered by illness that can be severe and life-
threatening. As in this case, the hyperkinetic movement disorder has been
reported to be responsive to deep brain stimulation in several patients.

1112 AUGUST 2019

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 Dopa-responsive dystonia (DYT5) is an important diagnosis to consider in the
differential diagnosis of childhood-onset dystonia as symptoms have a dramatic
and sustained response to treatment with low-dose levodopa (2 mg/kg/d to
7 mg/kg/d). Children typically present between 5 and 9 years of age with focal
limb dystonia, involving the leg more than the arm, which has a characteristic
diurnal fluctuation of severity. Symptoms worsen in the afternoon and evening
and improve following sleep. Diurnal fluctuation is a key diagnostic clue for a
dopa-responsive dystonia and is particularly helpful in patients with atypical
presentations such as spastic paraparesis or a nonspecific gait disturbance, rather
than clear dystonia. In adulthood, patients may proceed to develop signs of
parkinsonism, including bradykinesia and postural instability.16
Dopa-responsive dystonia is most often caused by a heterozygous mutation in
GCH, the gene encoding guanosine triphosphate cyclohydrolase, resulting in
deficient brain dopamine synthesis. More complex forms of dopa-responsive
dystonia that present in infancy were discussed in the previous section on
monoamine neurotransmitter disorders.
DYT1 dystonia is the most common form of isolated genetic dystonia and is
inherited in an autosomal dominant manner with 30% penetrance. A three
base-pair deletion in TOR1A explains up to 90% of the generalized dystonias in
the Ashkenazi Jewish population and approximately 40% to 60% of cases of
generalized dystonia in the non–Ashkenazi Jewish population.17 DYT1 dystonia
often starts in childhood as a focal lower limb dystonia, usually involving the leg.
The average age of onset is 13 years but varies widely. More than 60% of patients
will progress to generalized or multifocal dystonia. DYT1 dystonia has a robust
response to globus pallidus internus deep brain stimulation (DBS), which should
be considered early if symptoms are severe.
DYT6-THAP1–related dystonia is an autosomal dominant disorder with 60%
penetrance. Half of patients initially present with cranial or cervical dystonia and
have prominent laryngeal involvement. DBS seems to be less effective for DYT6
than for DYT1 dystonia. It has been hypothesized that cranial and cervical
symptoms may be less responsive to DBS.
The KMT2B gene was identified in 2016 by two independent groups and is
the most recently described genetic cause of childhood-onset dystonia.18,19
More than 40 patients have been reported to date.20 It is an autosomal dominant
disorder and may be associated with either heterozygous intragenic KMT2B
variants or a chromosome 19 microdeletion syndrome involving the KMT2B
gene. Patients with contiguous deletions are more likely to present with a
complex syndrome, including additional neurologic and systemic findings (eye
movement abnormalities, developmental delay, microcephaly, short stature,
and mild facial dysmorphism), while those with intragenic variants typically
present with isolated dystonia.20 Dystonia usually begins in the lower limbs
before 10 years and becomes generalized over time, with prominent
involvement of cervical, oromandibular, and laryngeal regions. Patients with
chromosomal microdeletions tend to have an earlier age of onset than those
with intragenic variants. Brain MRI in many, but not all, patients demonstrates
subtle globus pallidus externus hypointensities on susceptibility-weighted
imaging (SWI).18 Reported patient response to treatment so far indicates
limited benefit from antidystonia medications such as trihexyphenidyl but
showed substantial improvement following bilateral globus pallidus internus
stimulation in 13 patients.20

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MOVEMENT DISORDERS IN CHILDREN

Rapid-onset dystonia-parkinsonism (DYT12) is associated with heterozygous

mutations in ATP1A3. In contrast to the slow and gradual symptom progression
typically observed in the genetic dystonias, the distinctive feature of rapid-onset
dystonia-parkinsonism is the acute onset of dystonia over a period of days to
months, often triggered by an emotional or physical stress. Prominent
involvement of the lower cranial and bulbar region, in addition to the limbs, is
common. Dystonia in rapid-onset dystonia-parkinsonism typically has limited
responsiveness to levodopa, antidystonia medications, or DBS, making this a
challenging condition to treat.

COMPLEX DYSTONIA SYNDROMES. Dystonia may be a component of numerous

genetic neurodegenerative diseases. In these cases, dystonia is progressive and is
typically accompanied by other neurologic abnormalities. Clinical red flags include
cranial-onset or cervical-onset dystonia, rapid dystonia progression, eye movement
abnormalities such as supranuclear gaze palsy, associated hearing or vision loss,
associated parkinsonism, and progressive cognitive decline or behavioral symptoms.
A review of these conditions may be found in other sources.21–23
Importantly, treatable neurodegenerative conditions that may present in
childhood or adolescence with dystonia include disorders of heavy metal
accumulation (eg, Wilson disease, manganese transporter deficiency) and ataxia
with vitamin E deficiency (TABLE 10-2).
Chorea
The prototype neurodegenerative condition manifesting with chorea is
Huntington disease, which is the most frequent form of genetic chorea in
adulthood. It is dominantly inherited and is secondary to an expansion in the
number of CAG repeats in the huntingtin (HTT) gene. Younger age at onset and
more rapid disease progression is associated with longer CAG repeats in HTT.
Huntington disease in childhood often presents with an akinetic-rigid syndrome
rather than chorea, while adolescents are more likely to present with the typical
clinical triad seen in adults: chorea, cognitive decline, and psychiatric or
behavioral disturbance.15
Neuroacanthocytosis syndromes are progressive neurodegenerative conditions
that resemble Huntington disease. Two forms may present earlier in life with
prominent facial involvement: VPS13A gene mutations (chorea-acanthocytosis,
autosomal recessive) and XK gene mutation (McLeod syndrome, X-linked recessive).14
Chorea may be a prominent feature of conditions that typically present with
other movement disorder abnormalities, including neurodegenerative disorders
with metal ion accumulation (Wilson disease and pantothenate kinase–associated
neurodegeneration), and cerebellar ataxias such as ataxia-telangiectasia and, more
rarely, ataxia with oculomotor apraxia type 1, 2, and 4, and Friedreich ataxia.14

Ataxia
Numerous genes are associated with chronic progressive ataxia, which is usually
subdivided broadly into autosomal dominant, autosomal recessive, and
spastic-ataxia subgroups.24 The autosomal recessive ataxias are collectively the
most common in childhood and include Friedreich ataxia (the most prevalent
inherited ataxia), ataxia-telangiectasia, ataxia with oculomotor apraxia types 1
and 2, and ataxia with vitamin E deficiency.25 Several genes that are more
commonly associated with complex dystonia syndromes may also present with a
predominantly ataxic phenotype, including PLA2G6 and ATP1A3. The autosomal

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dominant ataxias include a number of the spinocerebellar ataxias (SCAs), as KEY POINT
well as dentatorubral-pallidoluysian atrophy, which manifests with seizures,
● Huntington disease in
myoclonus, and dementia in addition to ataxia. childhood often presents
Most chronic progressive ataxias present later in childhood or adolescence with an akinetic-rigid
after a period of normal development in infancy and early childhood. One syndrome rather than
exception is ataxia-telangiectasia, which classically presents between the ages of 1 chorea.
and 4 years, but may rarely present in the first year of life. Clinical diagnosis can
be challenging in the initial stages because young children with ataxia-telangiectasia
may have prominent dystonia and chorea in addition to ataxia, ataxia may
appear static in the first 1 to 2 years before progression becomes evident, and
oculocutaneous telangiectasia may emerge months or years after neurologic
symptom onset (usually by 6 years of age). Ataxia-telangiectasia is a multisystem
disorder that also includes immunodeficiency and increased susceptibility to
malignancy. The immunodeficiency is characterized by low numbers of circulating
T lymphocytes and B lymphocytes, and decreased serum immunoglobulin levels,
particularly IgA, IgG2, and IgG4.26 A history of recurrent sinopulmonary infections
may precede the onset of neurologic symptoms in some children.
Friedreich ataxia is the most common autosomal recessive ataxia in white
populations. The clinical syndrome is characterized by progressive ataxia,
dysarthria, limb weakness, impaired proprioception and vibration sense,
areflexia, and extensor plantar responses. Homozygous GAA triplet repeat
expansions in exon 1 of the frataxin gene (FXN) are detected in more than 95%
of patients. The remaining patients have an abnormal GAA expansion on one
allele coupled with another pathogenic variant on the other allele.
The following general approach is a suggested guide to the evaluation of a
child with a suspected progressive genetic ataxia:

◆ Delineate the clinical syndrome, including any accompanying involuntary movements, and
associated neurologic features and systemic features. If a distinctive clinical syndrome,
such as Friedreich ataxia, is apparent, consider proceeding directly to single-gene
genetic testing.
◆ Examine the brain MRI to determine whether cerebellar atrophy is present (eg, ataxia-
telangiectasia, ataxia with oculomotor apraxia types 1 and 2) or absent (eg, Friedreich ataxia,
ataxia with vitamin E deficiency) and search for associated abnormalities including cerebral
or brainstem volume loss, white matter lesions, or basal ganglia lesions.
◆ Perform selected routine laboratory investigations to screen for treatable disorders (plasma
vitamin E, coenzyme Q10), and identify abnormal biochemical markers that may assist in
the diagnosis of a nontreatable ataxia syndrome (ataxia-telangiectasia and ataxia with
oculomotor apraxia types 1 and 2), including serum α-fetoprotein, IgG subclasses, albumin,
creatine kinase, and cholesterol panel.
◆ Perform molecular genetic testing: In cases where the clinical, biochemical, and
radiologic phenotype suggests a specific syndrome, single-gene testing may be appropriate.
Increasingly, multigene next-generation sequencing panels or whole exome sequencing
are used early in the testing process. It is important to be aware that next-generation
sequencing methods will not detect triplet repeat expansions, which is an important
consideration for a number of the genetic ataxias (selected SCAs, dentatorubral-
pallidoluysian atrophy, and Friedreich ataxia).

Myoclonus
Genetic conditions manifesting with nonprogressive myoclonus include
hereditary hyperekplexia and myoclonus-dystonia, while progressive myoclonus
is characteristic of the progressive myoclonic epilepsies. Other neurodegenerative

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MOVEMENT DISORDERS IN CHILDREN

disorders, such as ataxia-telangiectasia, may feature myoclonus as part of a

complex syndrome.
Myoclonus-dystonia is a rare movement disorder characterized by a
combination of nonepileptic myoclonic jerks and dystonia. The disorder usually
begins in childhood, with symptom onset at a mean age of 6 years. Myoclonus is
usually the presenting symptom, while dystonia may be present initially or
develop later. Both symptoms may affect any part of the body but are usually
most prominent in the upper limbs and neck. The myoclonus in myoclonus-
dystonia is present at rest; precipitated or aggravated by posture, action, and
stress; and is stimulus insensitive. Most older patients notice significant reduction
of their myoclonus in response to alcohol ingestion, but this information is not
typically available in pediatric patients. Patients have normal cognition and often
have psychiatric comorbidities including depression, anxiety, and obsessive-
compulsive disorder. Neuroimaging is normal. Severity and clinical course vary
widely and cannot be predicted. Myoclonus-dystonia is not a degenerative
disorder and is compatible with an active life and a normal life span. In some cases,
however, myoclonus-dystonia may be progressive and may lead to considerable
functional disability. Symptomatic drug therapy is usually disappointing. Some
patients benefit from anticholinergic drugs and benzodiazepines, which are
occasionally effective for both myoclonus and dystonia. Botulinum toxin can be
used to treat focal dystonia. In patients with severe and disabling myoclonus-
dystonia, DBS of the globus pallidus internus is safe and can be effective.27
The syndrome of myoclonus-dystonia is genetically heterogeneous. SGCE
mutations are detected in 30% to 50% of cases. Inheritance is autosomal
dominant with reduced penetrance because of imprinting and subsequent
silencing of the maternal allele. Transmission is therefore paternal.28 Myoclonus-
dystonia has also been reported to be associated with mutations in other genes
including ADCY5, KCTD17, CACNA1B, and RELN. However, in these cases, the
clinical phenotype is distinct from the phenotype usually observed in myoclonus-
dystonia due to SGCE mutations.27

Progressive Myoclonic Epilepsies

The progressive myoclonic epilepsies are a clinically and genetically heterogeneous
group of disorders characterized by the core features of action myoclonus,
epileptic seizures, and progressive neurologic decline (ataxia, dementia).29
Typically, myoclonus is in a focal or segmental distribution and is arrhythmic,
asynchronous, and asymmetric. Progressive myoclonic epilepsies typically present
during childhood and are often fatal. The majority of genes involved encode
lysosomal proteins, and the disorders are inherited in an autosomal recessive
pattern, including the neuronal ceroid lipofuscinoses, Unverricht-Lundborg
disease (cystatin B [CSTB]), Lafora disease (NHLRCI), and sialidosis. Children
with juvenile neuronal ceroid lipofuscinoses typically experience progressive loss
of vision due to pigmentary retinopathy. Mitochondrial disorders including
myoclonic epilepsy with ragged red fibers (MERRF), mitochondrial
encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS), and
POLG-related disorders can also manifest with progressive myoclonus.

Parkinsonism
Several degenerative conditions resemble Parkinson disease with recessive
modes of inheritance and onset of symptoms before 21 years of age.30 In these

1116 AUGUST 2019

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cases, the term juvenile parkinsonism, rather than juvenile Parkinson disease, is KEY POINTS
preferred, since the histopathologic characteristics differ.31 The genes involved,
● Myoclonus-dystonia is a
in order of frequency, are PRKN (parkin), PINK1, and DJ1. Age of onset is rare genetic movement
variable with the youngest reported patient being 5 years old.32 Dystonia is disorder characterized by a
frequently observed at onset, while tremor is less common than in adult-onset combination of nonepileptic
idiopathic Parkinson disease. Patients with parkin mutations often experience myoclonic jerks and
dystonia.
marked sleep benefit. Disease progression is slower than in idiopathic Parkinson
disease. Patients have a marked response to levodopa, although dyskinesia and ● Myoclonus-dystonia is
motor fluctuations occur early. compatible with an active
A number of genetic neurodegenerative disorders manifest with juvenile and normal life span;
parkinsonism as one component of a complex neurologic syndrome that may however, some patients
have a progressive course
feature dystonia, chorea, ataxia, gaze abnormalities, neuropsychiatric symptoms, leading to considerable
dementia, and other neurologic abnormalities. These conditions include Wilson disability. Treatment is
disease, early-onset Huntington disease (Westphal variant), SCA2 and SCA3, usually disappointing.
neurodegeneration with brain iron accumulation (PKAN, PLA2G6, ATP13A2),
● Progressive myoclonic
juvenile neuronal ceroid lipofuscinoses, and Niemann-Pick disease type C, epilepsy is characterized by
among others.22,30,31 action myoclonus, epileptic
Enhancement of dopamine transmission is the mainstay of parkinsonism seizures, and progressive
treatment. This can be achieved with levodopa, dopamine agonists, and neurologic decline. The
majority of genes involved in
monoamine oxidase inhibitors. The type of drug, response to treatment, and
progressive myoclonic
prognosis depend on the etiology. Most of the congenital disorders of epilepsy encode lysosomal
monoamine neurotransmitter synthesis, but not all, respond well to treatment. proteins and are inherited in
Levodopa should be started at a low dose (0.5 mg/kg/d to 1 mg/kg/d) and titrated an autosomal recessive
pattern. The largest group of
slowly until complete benefit or dose-limiting side effects occur33 due to the high
progressive myoclonic
prevalence of dyskinesia in all patients with pediatric parkinsonism, regardless of epilepsies are the neuronal
the underlying cause. In children who have congenital dopamine deficiency due ceroid lipofuscinoses.
to a metabolic defect of dopamine synthesis, dyskinesia is expected to gradually
improve over time so that larger doses eventually become well tolerated. In ● Juvenile parkinsonism
refers to hereditary
children with neurodegenerative diseases, dyskinesia and the behavioral side effects conditions with onset
of levodopa are frequently dose limiting. In acquired parkinsonism (ie, ischemic before the age of 21 years
lesions, tumors, encephalitis), response to treatment is variable. While presynaptic that clinically resemble
dopaminergic transmission failure can respond to dopaminergic drugs, the effect Parkinson disease but with
different histopathologic
is limited in postsynaptic failure where there is injury to the striatal targets.31 characteristics.

PAROXYSMAL MOVEMENT DISORDERS ● In juvenile parkinsonism,

A number of genetic conditions that cause episodic involuntary movements or progression is slower than in
idiopathic Parkinson disease.
ataxia typically present during childhood or adolescence. The paroxysmal
Patients have a marked
dyskinesias and episodic ataxias have traditionally been considered distinct response to levodopa,
phenotypes, but it is increasingly recognized that there is considerable although dyskinesias and
phenotypic overlap associated with these genetic disorders that encompasses motor fluctuations occur early.
movement disorders and other episodic neurologic symptoms such as migraine
● The classic genetic
and epilepsy. paroxysmal dyskinesias may
be clinically distinguished
Paroxysmal Dyskinesias from one another by the
The paroxysmal dyskinesia syndromes are a group of childhood-onset genetic episode triggers, episode
duration, and the presence
conditions that are characterized by discrete episodes of involuntary movements or absence of interictal
(dystonia, chorea, ballism, myoclonus, or a combination) lasting from seconds to neurologic features.
hours depending on the specific disorder. The most important clinical features
that distinguish the disorders from each other are the episode trigger, duration,
and the presence or absence of interictal neurologic abnormalities, rather than

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MOVEMENT DISORDERS IN CHILDREN

the precise motor phenomena that occur during the episode itself. Review of the
episodes on home video remains a valuable tool to distinguish the attacks from
seizures or another episode type. The three classic paroxysmal dyskinesia
syndromes are paroxysmal kinesigenic dyskinesia, paroxysmal exertional
dyskinesia, and paroxysmal nonkinesigenic dyskinesia.
Children with paroxysmal kinesigenic dyskinesia and paroxysmal nonkinesigenic
dyskinesia typically have a normal interictal neurologic examination. Paroxysmal
kinesigenic dyskinesia episodes are usually seconds in duration, while paroxysmal
nonkinesigenic dyskinesia episodes typically last minutes to hours. Paroxysmal
kinesigenic dyskinesia episodes are often triggered by sudden movement or the
intent to move, while paroxysmal nonkinesigenic dyskinesia episodes may be
triggered by caffeine, alcohol, and stress. Both disorders are caused by monoallelic
mutations in their respective genes, PRRT2 (for paroxysmal kinesigenic
dyskinesia) and PNKD (for paroxysmal nonkinesigenic dyskinesia), and may be
either sporadic or inherited in an autosomal dominant pattern. Paroxysmal
kinesigenic dyskinesia episodes are typically well controlled with low-dose
anticonvulsant medication, most commonly carbamazepine, while paroxysmal
nonkinesigenic dyskinesia is treated with benzodiazepines.
Episodes of paroxysmal exertional dyskinesia are triggered by sustained
exercise. Disorders that cause paroxysmal exertional dyskinesia usually have other
interictal neurologic features, including intellectual disability and persistent motor
abnormalities such as ataxia or dystonia. GLUT1 deficiency syndrome, the
prototypical cause of paroxysmal exertional dyskinesia, is one example and is an
important diagnosis to recognize as it is treatable with the ketogenic diet
(discussed in the section on GLUT1 deficiency syndrome). Paroxysmal
exertional dyskinesia has also been rarely reported as a manifestation of pyruvate
dehydrogenase deficiency, which may respond to treatment with thiamine.34
Other genetic disorders in which paroxysmal dyskinesia occurs in the context
of a complex neurologic syndrome include ADCY5-related dyskinesia (as
previously discussed) and alternating hemiplegia of childhood due to mutations
in ATP1A3. In ADCY5-related dyskinesia, a distinctive feature of the paroxysmal
attacks is that they may occur at night during drowsiness.35 Infants with
ATP1A3-related alternating hemiplegia of childhood may have episodes of
paroxysmal dystonia, typically accompanied by other classic signs including
monocular nystagmus, episodic hemiplegia or quadriplegia, and persistent
neurologic deficits, including hypotonia, ataxia, dystonia, chorea, and bulbar
dysfunction.36

Intermittent and Episodic Ataxias

The episodic ataxias are a group of autosomal dominant disorders characterized
by intermittent discrete attacks of ataxia, usually with accompanying mild
interictal neurologic findings. Age of onset ranges from 2 to 20 years. Patients
with episodic ataxia type 1 (caused by a mutation in the potassium channel gene
KCNA1) typically experience brief attacks, seconds to minutes in duration, that
may be triggered by startle or exercise, and have myokymia on examination
between attacks. Patients with episodic ataxia type 2 (the most common type
of episodic ataxia, caused by a mutation in the calcium channel subunit gene
CACNA1), have attacks lasting minutes to hours and have gaze-evoked
nystagmus between episodes. Some patients with episodic ataxia type 2
ultimately develop persistent progressive ataxia. There are other rare episodic

1118 AUGUST 2019

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ataxia subtypes, each described in one or two families so far. Treatment with
acetazolamide can be effective in preventing attacks, particularly in episodic
ataxia type 2.37
Some conditions that present with recurrent acute ataxia are treatable
metabolic disorders. These often present in infancy or early childhood, and
episodes may be accompanied by encephalopathy. Examples are organic
acidurias (eg, methylmalonic aciduria, propionic acidemia), urea cycle enzyme
defects (eg, ornithine transcarbamylase deficiency), mild forms of pyruvate
dehydrogenase deficiency, and biotinidase deficiency.

CONCLUSION
Movement disorders in infants and children are associated with a large number
of acquired and genetic disorders. Clinical characterization of (1) the course and
timing of neurologic symptoms in the context of the child’s development, and (2)
the movement disorder phenomena and associated neurologic and systemic
findings on examination are the key to accurate diagnosis. Disease-modifying
treatments exist for many movement disorders that present acutely and for
selected genetic, metabolic conditions that present with chronic symptoms. In
the current context of technologic advances in relation to genetic diagnosis and to
treatment, such as neuromodulation and gene therapy, the diagnosis and
treatment of childhood movement disorders is poised to evolve rapidly.

REFERENCES

1 Singer HS. Tics and Tourette syndrome. Continuum 9 Dale RC, Singh H, Troedson C, et al. A prospective
(Minneap Minn) 2019;25(4, Movement Disorders): study of acute movement disorders in children.
936–958. Dev Med Child Neurol 2010;52(8):739–748.
doi:10.1111/j.1469-8749.2009.03598.x.
2 Sanger TD, Chen D, Fehlings DL, et al. Definition
and classification of hyperkinetic movements 10 Krgeloh-Mann I, Cans C. Cerebral palsy update.
in childhood. Mov Disord 2010;25(11):1538–1549. Brain Dev 2009;31(7):537–544. doi:10.1016/j.
doi:10.1002/mds.23088. braindev.2009.03.009.
3 Sanger TD, Chen D, Delgado MR, et al. Definition 11 Kurian MA, Gissen P, Smith M, et al. The monoamine
and classification of negative motor signs in neurotransmitter disorders: an expanding range of
childhood. Pediatrics 2006;118(5):2159–2167. neurological syndromes. Lancet Neurol 2011;10(8):
doi:10.1542/peds.2005-3016. 721–733. doi:10.1016/S1474-4422(11)70141-7.
4 Sanger TD. Pathophysiology of pediatric movement 12 Hoffman GF, Blau N. Signs and symptoms of
disorders. J Child Neurol 2003;18(suppl 1):S9–S24. neurotransmitter disorders: approach to diagnosis
doi:10.1177/0883073803018001S0401. congenital neurotransmitter disorders a clinical
approach. New York, NY: Nova Science Publishers
5 Eberhardt O, Topka H. Myoclonic disorders. Brain
Inc, 2014:1–15.
Sci 2017;7(8):pii: E103. doi:10.3390/brainsci7080103.
13 Carecchio M, Mencacci NE. Emerging monogenic
6 García-Cazorla A, Ortez C, Pérez-Dueñas B, et al.
complex hyperkinetic disorders. Curr Neurol
Hypokinetic-rigid syndrome in children and
Neurosci Rep 2017;17(12):97. doi:10.1007/
inborn errors of metabolism. Eur J Paediatr Neurol
s11910-017-0806-2.
2011;15(4):295–302. doi:10.1016/j.ejpn.2011.04.013.
14 Mencacci NE, Carecchio M. Recent advances in
7 Bonnet C, Roubertie A, Doummar D, et al.
genetics of chorea. Curr Opin Neurol 2016;29(4):
Developmental and benign movement disorders
486–495. doi:10.1097/WCO.0000000000000352.
in childhood. Mov Disord 2010;25(10):1317–1334.
doi:10.1002/mds.22944. 15 de Gusmao CM, Waugh JL. Inherited and
acquired choreas. Semin Pediatr Neurol 2018;
8 Fernández-Alvarez E. Transient benign paroxysmal
25:42–53. doi:10.1016/j.spen.2018.01.002.
movement disorders in infancy. Eur J Paediatr
Neurol 2018;22(2):230–237. doi:10.1016/
j.ejpn.2018.01.003.

CONTINUUMJOURNAL.COM 1119

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

MOVEMENT DISORDERS IN CHILDREN

16 Mencacci NE, Isaias IU, Reich MM, et al. 27 Roze E, Lang AE, Vidailhet M. Myoclonus-
Parkinson's disease in GTP cyclohydrolase dystonia: classification, phenomenology,
1 mutation carriers. Brain 2014;137(pt 9): pathogenesis, and treatment. Curr Opin Neurol
2480–2492. doi:10.1093/brain/awu179. 2018;31(4):484–490. doi:10.1097/WCO.
0000000000000577.
17 Ozelius L, Lubarr N. DYT1 early-onset isolated
dystonia. In: Adam MP, Ardinger HH, Pagon RA, 28 Grabowski M, Zimprich A, Lorenz-Depiereux B,
et al, editors. Seattle, WA: GeneReviews, 1999. et al. The epsilon-sarcoglycan gene (SGCE),
mutated in myoclonus-dystonia syndrome, is
18 Meyer E, Carss KJ, Rankin J, et al. Mutations in the
maternally imprinted. Eur J Hum Genet 2003;11(2):
histone methyltransferase gene KMT2B cause
138–144. doi:10.1038/sj.ejhg.5200938.
complex early-onset dystonia. Nat Genet 2017;
49(2):223–237. doi:10.1038/ng.3740. 29 Kälviäinen R. Progressive myoclonus epilepsies.
Semin Neurol 2015;35(3):293–299. doi:10.1055/
19 Zech M, Boesch S, Maier EM, et al.
s-0035-1552620.
Haploinsufficiency of KMT2B, encoding the
lysine-specific histone methyltransferase 2B, 30 Puschmann A. Monogenic Parkinson's disease
results in early-onset generalized dystonia. Am J and parkinsonism: clinical phenotypes and
Hum Genet 2016;99(6):1377–1387. doi:10.1016/ frequencies of known mutations. Parkinsonism
j.ajhg.2016.10.010. Relat Disord 2013;19(4):407–415. doi:10.1016/
j.parkreldis.2013.01.020.
20 Gorman KM, Meyer E, Kurian MA. Review of the
phenotype of early-onset generalised progressive 31 Paviour DC, Surtees RA, Lees AJ. Diagnostic
dystonia due to mutations in KMT2B. Eur J considerations in juvenile parkinsonism.
Paediatr Neurol 2018;22(2):245–256. doi:10.1016/ Mov Disord 2004;19(2):123–135. doi:10.1002/
j.ejpn.2017.11.009. mds.10644.
21 Klein C, Lohmann K, Marras C, Munchau A. 32 Al-Rumayyan A, Klein C, Alfadhel M. Early-onset
Hereditary dystonia overview. In: Adam MP, parkinsonism: case report and review of the
Ardinger HH, Pagon RA, et al, editors. Seattle, literature. Pediatr Neurol 2017;67:102.e1–106.e1.
WA: GeneReviews, 2003. doi:10.1016/j.pediatrneurol.2015.06.005.
22 Kurian MA, Dale RC. Movement disorders 33 Mink JW. Dopa-responsive dystonia in children.
presenting in childhood. Continuum (Minneap Curr Treat Options Neurol 2003;5(4):279–282.
Minn) 2016;22(4 Movement Disorders):1159–1185. doi:10.1007/s11940-003-0033-9.
doi:10.1212/CON.0000000000000367.
34 Castiglioni C, Verrigni D, Okuma C, et al.
23 Meijer IA, Pearson TS. The twists of pediatric Pyruvate dehydrogenase deficiency presenting
dystonia: phenomenology, classification, and as isolated paroxysmal exercise induced
genetics. Semin Pediatr Neurol 2018;25:65–74. dystonia successfully reversed with thiamine
doi:10.1016/j.spen.2018.02.001. supplementation. Case report and mini-review.
Eur J Paediatr Neurol 2015;19(5):497–503.
24 Bird TD. Hereditary ataxia overview. In: Adam
doi:10.1016/j.ejpn.2015.04.008.
MP, Ardinger HH, Pagon RA, et al., editors.
Seattle, WA: GeneReviews, 1998. 35 Chang FC, Westenberger A, Dale RC, et al.
Phenotypic insights into ADCY5-associated
25 Anheim M, Tranchant C, Koenig M. The autosomal
disease. Mov Disord 2016;31(7):1033–1040.
recessive cerebellar ataxias. N Engl J Med 2012;
doi:10.1002/mds.26598.
366(7):636–646. doi:10.1056/NEJMra1006610.
36 Silveira-Moriyama L, Kovac S, Kurian MA, et al.
26 Nowak-Wegrzyn A, Crawford TO, Winkelstein JA,
Phenotypes, genotypes, and the management
et al. Immunodeficiency and infections in
of paroxysmal movement disorders. Dev Med
ataxia-telangiectasia. J Pediatr 2004;144(4):
Child Neurol 2018;60(6):559–565. doi:10.1111/
505–511. doi:10.1016/j.jpeds.2003.12.046.
dmcn.13744.
37 Jen JC, Wan J. Episodic ataxias. Handb Clin
Neurol 2018;155:205–215. doi:10.1016/B978-
0-444-64189-2.00013-5.

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 Psychogenic (Functional) REVIEW ARTICLE


Movement Disorders 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
By Mary Ann Thenganatt, MD; Joseph Jankovic, MD, FAAN

VIDEO CONTENT
A V AI L A B L E O N L I N E

ABSTRACT
PURPOSE OF REVIEW: This article reviews a practical approach to psychogenic
movement disorders to help neurologists identify and manage this
complex group of disorders.
CITE AS:
RECENT FINDINGS: Psychogenic movement disorders, also referred to as CONTINUUM (MINNEAP MINN)
Downloaded from http://journals.lww.com/continuum by BhDMf5ePHKbH4TTImqenVJsWiCZ2rfmURyvd+GhSb/tCduNFOQnx1h7K2U0aUH/H on 08/03/2019

2019;25(4, MOVEMENT DISORDERS):

functional movement disorders, describe a group of disorders that
1121–1140.
includes tremor, dystonia, myoclonus, parkinsonism, speech and gait
disturbances, and other movement disorders that are incongruent with Address correspondence to
patterns of pathophysiologic (organic) disease. The diagnosis is based Dr Joseph Jankovic, Parkinson’s
Disease Center and Movement
on positive clinical features that include variability, inconsistency, Disorders Clinic, Department of
suggestibility, distractibility, suppressibility, and other supporting Neurology, Baylor College of
information. While psychogenic movement disorders are often associated Medicine 7200 Cambridge,
Ste 9A, Houston, TX 77030-4202,
with psychological and physical stressors, the underlying pathophysiology [email protected].
is not fully understood. Although insight-oriented behavioral and
RELATIONSHIP DISCLOSURE:
pharmacologic therapies are helpful, a multidisciplinary approach led by
Dr Thenganatt has received an
a neurologist, but also including psychiatrists and physical, occupational, honorarium from MedLink
and speech therapists, is needed for optimal outcomes. Neurology. Dr Jankovic has
received personal
compensation for serving on the
SUMMARY: The diagnosis of psychogenic movement disorders is based advisory boards of and as a
on clinical features identified on neurologic examination, and consultant for Parexel;
Retrophin, Inc; and Teva
neurophysiologic and imaging studies can provide supporting information. Pharmaceutical Industries Ltd.
Dr Jankovic has received
personal compensation as an
editor for and has received
royalties from Cambridge
INTRODUCTION University Press, Elsevier, Future

P
sychogenic movement disorders have been described as a “crisis for Science Group, and Hodder
neurology”1 as they represent a major public health and economic Arnold. Dr Jankovic has received
research/grant support from
problem, with an estimated annual incidence of 4 to 12 cases per Allergan, CHDI Foundation,
100,000.2–4 Debate exists about the most appropriate name for this Dystonia Coalition, F.
group of disorders. The term functional movement disorders is preferred Hoffman-La Roche AG,
Huntington Study Group,
by some who argue that this term is free of stigma and does not imply a Michael J. Fox Foundation for
psychological etiology of the disorder.5 Others prefer the term psychogenic Parkinson’s Research, and the
National Institutes of Health.
movement disorders, finding the term functional vague and confusing to patients
who often see themselves as “dysfunctional” rather than “functional.”3 UNLABELED USE OF
Psychogenic movement disorders are among the most challenging movement PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
disorders to treat as they are often difficult to diagnose, the presentation is Drs Thenganatt and Jankovic
variable in terms of phenomenology and course, the pathophysiology is poorly report no disclosures.
understood, and there is no consensus of the best therapeutic approach.6 Over
the past several decades, there has been greater awareness of this disorder with © 2019 American Academy
increased efforts into understanding and treating this common neurologic of Neurology.

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PSYCHOGENIC (FUNCTIONAL) MOVEMENT DISORDERS

disorder. A study of 3781 patients who were referred to neurologic centers in

Scotland over a 1-year period identified 16% of patients as having psychogenic
or psychological symptoms, which were the second most common symptoms
after headaches.7 While psychogenic movement disorders are most common in
women, with a median age of 50 years (range of 17 to 83 years),8 they present
in all age groups, including in children.9 Out of a group of 151 patients with
psychogenic movement disorders, 33 (22%) patients were older than 60 years of
age at symptom onset, indicating that psychogenic movement disorders are
not uncommon in the elderly.10
It is important for neurologists to be familiar with the phenomenology of
psychogenic movement disorders so that a diagnosis can be made as early as
possible. Diagnosis is based on the identification of positive symptoms
characteristic of psychogenic movement disorders rather than a diagnosis of
exclusion. Neurologists are often more concerned about missing an organic
disease than identifying a psychogenic movement disorder. However, patients
with psychogenic disease can have similar or worse disability compared to those
with organic neurologic disorders. One study of more than 3000 patients found
that those with psychogenic neurologic disease had worse physical and mental
health status compared to those with organic disease.11 They were also more
likely to be unemployed because of medical issues and to be receiving
government disability benefits. Unfortunately, the prognosis of psychogenic
neurologic symptoms is generally poor, with symptoms unchanged or worse at
follow-up in most patients. A longer duration of symptoms is the greatest
predictor of poor outcome, with younger age and shorter duration associated
with overall better prognosis.12
Ancillary testing including accelerometers, EMG, EEG, as well as structural
and functional imaging can provide supporting information, but some of these
tools are mainly available on a research basis.6
In addition to making the diagnosis, the neurologist should provide ongoing
support and coordinate a multidisciplinary approach to care. Increased
awareness and research into understanding the mechanisms of disease and
effective treatment strategies will hopefully lead to improved outcomes for
patients with psychogenic movement disorders.

DIAGNOSTIC CRITERIA
The initial and most widely recognized diagnostic criteria for psychogenic
movement disorders are the Fahn-Williams13 criteria, proposed in 1988. This set
of criteria categorizes patients into four categories: documented, clinically
established, probable, and possible. For a classification of documented
psychogenic movement disorders, persistent resolution of symptoms occurs
after psychotherapy, placebo, or suggestion or when the patient is witnessed
without the abnormal movements when observed unknowingly. The clinically
established psychogenic movement disorders category is based on inconsistency
of movements or incongruence with organic movement disorders, as well as one
additional finding of other psychogenic signs, psychological disturbances, or
multiple somatizations. The probable psychogenic movement disorders category
is based on either the presence of movements inconsistent/incongruent with
organic movement disorders or on the presence of multiple psychogenic signs or
somatizations. The possible psychogenic movement disorders category only
requires the presence of an emotional disturbance.

1122 AUGUST 2019

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 Subsequently, the Shill-Gerber14 criteria placed more emphasis on historical KEY POINTS
information including pain, fatigue, and secondary gain. Gupta and Lang15
● Early diagnosis of a
proposed a combination of clinical and electrophysiologic testing primarily for psychogenic movement
tremor and myoclonus. Overall, although most patients have some evidence of disorder is important as
childhood, sexual, or other stressors, there is a trend toward less reliance on the longer duration of
presence of psychological factors to make a diagnosis. The Diagnostic and symptoms is associated with
poor outcome.
Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), has also updated
the criteria for functional neurologic symptoms, focusing on sensory and motor ● Diagnosis of a
symptoms inconsistent with organic disorders and eliminating the requirement psychogenic movement
of preceding psychological factors.16,17 disorder is based on positive
signs and symptoms and is
not just a diagnosis of
CLINICAL FEATURES exclusion.
Evaluating a patient with a suspected psychogenic movement disorder requires
familiarity with the typical clinical features of these disorders and performing a ● Psychogenic movement
detailed history and neurologic examination to identify these supporting features disorders are typically
sudden in onset and rapidly
(TABLE 11-1). While no one feature is pathognomonic, it is the entire clinical progress to severe
picture that leads to an accurate diagnosis. disability.

HISTORY
Obtaining details regarding the onset and evolution of symptoms is important as
psychogenic movement disorders usually begin suddenly and rapidly progress to
severe disability. Although the course often fluctuates, spontaneous, albeit
transient, remissions may occur. Patients often associate symptoms with a
preceding injury or illness. In one study, 80% of patients reported a physical
event prior to the onset of their symptoms.18 In a study of 43 patients with motor
conversion disorder, 56% reported a stressful life event in the month preceding
symptom onset, compared to only 21% in patients with depression and 18% in
controls.19 These events were not identified on routine assessment and needed
more in-depth evaluation.
Symptoms are often episodic, occurring for varying periods of time and then
self-resolving. Aside from paroxysmal dyskinesias, discrete episodes of
symptoms are not typical in organic movement disorders and should suggest the
possibility of a psychogenic movement disorder. These episodes in psychogenic
movement disorders are variable either in duration, phenomenology, or body
location. The movements may be limited to certain situations such as only when
seated or lying down but not interrupting walking.
In addition to the chief complaint, patients often have other transient
symptoms such as intermittent speech disturbances, weakness, gait and balance
problems, or tunnel vision.20,21 Their level of disability is often discordant with
their physical deficits; patients may use assistive devices such as canes, walkers,
or wheelchairs or be dependent on family members for total care.
Past medical history typically includes a long list of diagnoses and surgical
procedures, often with multiple somatoform symptoms. While anxiety and
depression are common in neurologic disease in general, studies have shown
more severe depression, anxiety, and a greater number of somatizations in
patients with psychogenic movement disorders compared to those with organic
disease.22 Those with psychogenic movement disorders also report higher rates of
childhood traumas (emotional, sexual, and physical) compared to those with
organic movement disorders and healthy controls.23 Family history may reveal
other family members with similar disorders or other chronic neurologic

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PSYCHOGENIC (FUNCTIONAL) MOVEMENT DISORDERS

TABLE 11-1 Clinical Characteristics of Psychogenic Movement Disorders

History
◆ Sudden onset
◆ Rapid progression
◆ Preceding illness or injury
◆ Episodic symptoms
◆ Multiple somatizations
◆ Occupation in health care profession
General Examination
◆ La belle indifference
◆ Convergence spasm
◆ Giveway weakness
◆ Nonanatomic sensory signs
◆ Extreme effort and pain during testing
◆ Excessive slowness
◆ Excessive startle
Core Clinical Signs
◆ Variability of
◇ Movement frequency
◇ Direction
◇ Phenomenology
◇ Body location
◆ Distractibility
◇ Decrease or complete cessation of involuntary movements when engaged in mental
tasks or voluntary movements with an unaffected limb
◆ Entrainability
◇ Involuntary movement adopts the same frequency or a harmonic of the frequency of
voluntary repetitive movements performed with an unaffected limb
◆ Suggestibility
◇ Involuntary movement increases or decreases with the power of suggestion, such as the
application of a vibrating tuning fork
◆ Other
◇ Sudden onset
◇ Spontaneous remissions
◇ Dual-task interference
◇ Transient arrest of tremor by contralateral volitional ballistic movement
◇ Whack-a-mole sign

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diseases. Spending time understanding the patient’s social history can help reveal KEY POINT
the patient’s family environment and social support. Patients with psychogenic
● In patients with
movement disorders have often worked in the health care profession, acted as psychogenic tremor,
caregivers for the chronically ill, or worked in the health insurance industry. variability of tremor
Taking the time to obtain a detailed history, particularly with regard to the frequency and direction is
circumstances around the onset, and an attempt to understand the person is common, as well as
suggestibility, distractibility,
critical in arriving at the appropriate diagnosis.
and entrainability.

GENERAL CLINICAL EXAMINATION

The clinical examination requires keen observation beginning in the waiting
room and continuing during the history taking and the formal examination.
Observing the patient’s general movements, such as while he or she walks to the
examination room, hangs up his or her coat, handles papers, or takes off his or
her shoes, helps evaluate the consistency of the patient’s abnormal movements.
During the history the patient may display la belle indifference, such as smiling
and giggling despite describing severe impairment.
Convergence spasm (a dysconjugate gaze with miosis) when asking the
patient to fixate on a near object such as the examiner’s finger has been associated
with psychogenic movement disorders.20,24 During strength testing, the patient
may have giveway weakness characterized as full strength initially but associated
with a tremulousness and then a sudden loss of power. Strength testing is
often performed with excessive effort and associated with marked pain.25
Identifying nonanatomic neurologic signs can be supportive, such as decreased
vibration on one side of the forehead, or a complete loss of sensation and strength
in the legs with normal reflexes.
A group of core clinical signs are shared by most patients with psychogenic
movement disorders and should be explored when a diagnosis of psychogenic
movement disorder is suspected.26 Variability of movements is common and
may include variability of phenomenology with nonpatterned movements and
variability of frequency, direction, and body location. This variability without an
underlying pattern differs from organic involuntary movements that are
ultimately patterned despite some variability.
Distractibility refers to a decrease or cessation of movements when focusing
on mental or motor tasks with the unaffected limb. A simple task is asking the
patient to slowly tap each finger on one hand in sequence, or a more complex task
of tapping alternating fingers. Entrainability is demonstrated by asking the patient
to perform a repetitive movement in the opposite limb such as finger tapping or
wrist extension/flexion, and the movements in the other limb adopt the same
frequency or a harmonic of the voluntary movements. Entrainability can be
demonstrated with tremor and myoclonus. Suggestibility refers to the activation
or suppression of movements with the power of suggestion. This feature can be
demonstrated by applying a vibrating tuning fork, suggesting (not deceiving) that
different stimuli may alter movements, and observing a sudden appearance,
increase, or decrease of the abnormal movement.27 It is important to remember
that these features are not independently diagnostic of a psychogenic movement
disorder but should be considered in the context of the entire clinical picture.

TYPES OF PSYCHOGENIC MOVEMENT DISORDERS

Various phenomenologic presentations of psychogenic movement disorders are
discussed below.

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PSYCHOGENIC (FUNCTIONAL) MOVEMENT DISORDERS

Psychogenic Tremor
Psychogenic tremor is the most common psychogenic movement disorder,
accounting for 50% of this group of disorders.8 Variability of tremor frequency
and direction is common, such as changing from a pronation/supination tremor
to a flexion/extension tremor about the wrist,28 as well as suggestibility,
distractibility, and entrainability (VIDEO 11-1, links.lww.com/CONT/A369). A
blinded rater evaluated videos of 33 subjects with essential tremor and 12 with
psychogenic tremor; the patients with psychogenic tremor were significantly
more likely to relay a history of sudden onset (P=.03), spontaneous remissions
(P=.03), shorter duration of tremor (P=.001), greater degree of distraction with
alternate finger tapping (P=.01) and with mental concentration on serial 7s
(P=.01), and more suggestibility with a tuning fork (P=.04) compared to those
with essential tremor.29
Variability of tremor amplitude is not specific for psychogenic tremor as
organic tremor can have variable amplitudes as well,30 often increasing with
stress or anxiety. Irregular tremor of the head and limbs is also typical of dystonic
tremor but distinguishes itself from psychogenic by features such as task
specificity, a stereotyped abnormal posture, and the presence of a null point.
Psychogenic tremor may be equally present in all states (rest, posture, kinetic),
which is not typical for organic tremors such as in Parkinson disease, where
resting tremor is typical and decreases with action. One exception is Holmes

CASE 11-1 A 41-year-old woman presented to the emergency department with

sudden-onset tremor that started in her right arm. Over a period of
30 minutes it had spread to her left arm, trunk, and legs. She had retained
awareness and was able to walk. She had a past medical history of
interstitial cystitis and fibromyalgia. In the emergency department, she
was treated with diazepam 5 mg intravenously, and her movements
stopped. She was advised to follow-up with a neurologist.
She continued to have episodes of tremor on a daily basis involving an
arm, a leg, or her whole body. The episodes would vary in duration,
lasting from 5 minutes to 1 hour at a time and then resolve.
On initial examination by the neurologist, she had giveway weakness
with extreme effort on confrontation muscle testing. She had a high-
frequency postural tremor of both hands that changed from flexion/
extension to pronation/supination throughout the examination. The
tremor was distractible, resolving when performing voluntary finger
tapping with the opposite hand. The tremor was also entrainable,
adopting the frequency of voluntary movements with the opposite limb.
The remainder of her neurologic examination was normal.

COMMENT This case demonstrates features of psychogenic tremor with sudden-

onset episodic tremor that rapidly progressed to involve the patient’s
entire body. Distractibility and entrainability are features that can be
demonstrated on examination, as are associated psychogenic signs such
as giveway weakness.

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tremor, in which tremor occurs in all states and is associated with an underlying KEY POINTS
brain injury or lesion. Total body tremor is a typical manifestation of psychogenic
● Total body tremor is a
tremor, including a bobbing of the head and trunk (CASE 11-1). The whack-a- typical manifestation of
mole sign refers to the sudden appearance of tremor in another part of the body psychogenic tremor,
when the examiner suppresses the actively tremulous limb.31 This is easily including a bobbing of the
demonstrated with tremor but can be seen with other movements as well. head and trunk.
Electrophysiologic testing can be useful to analyze tremor and includes
● A rapid-onset fixed
accelerometry and surface EMG.32 Accelerometry measures tremor frequency dystonia is the typical
and amplitude, while surface EMG records the pattern and duration of muscle phenotype of psychogenic
activity. The pattern and duration of EMG bursts is typically variable in dystonia.
psychogenic tremor. Coherence analysis records EMG activity of the involuntary
movements compared to voluntary movements of the unaffected limb. Patients
with psychogenic tremor often demonstrate a high coherence of frequency
between both limbs, as they are not able to produce movements of varying
frequencies. Mass loading (weighting the limb) often results in an increase of
psychogenic tremor frequency and amplitude, seen in 70% of patients, but there
is often a reduction in the amplitude but no change in frequency of tremor in
patients with Parkinson disease or essential tremor.33
Coactivation of antagonist muscles prior to tremor onset is more commonly
detected through electrophysiologic testing in psychogenic tremor compared to
organic tremor. The stiffening of muscles around a joint triggers the onset of
tremor. Clinically this may be visualized as a generalized tightening of limb
muscles with the hand clenched in a fist. Dual-task interference testing
demonstrates difficulty accurately performing voluntary movements of the
opposite limb when the patient has psychogenic tremor in another limb.34 This
effect on voluntary tasks is not seen with organic tremor. The ballistic movement
test demonstrates a change in tremor amplitude or transient arrest in
psychogenic tremor when the patient is asked to perform a sudden movement
with the opposite limb.35 The various electrophysiologic tests to evaluate
psychogenic tremor have been validated, demonstrating an 89.5% sensitivity and
95.9% specificity, with good inter-rater and test-retest reliability.36

Psychogenic Dystonia
Psychogenic dystonia is characterized by a sudden onset, rapid progression to a
fixed dystonia, and early local pain.37 This is in contrast to organic dystonia,
which is usually mobile and action induced at onset with a fixed posture
associated with pain later on in the disease course. In psychogenic dystonia,
patients usually do not have associated sensory tricks and minimal or no
exacerbation with action. The most common phenotype is plantar flexion and
inversion of the foot, and associated weakness in the dystonic limb may be seen.
On examination, active resistance to passive range of motion often occurs
(CASE 11-2).When occurring in the hands, the typical pattern is a clenched fist
with flexion of digits two through five with sparing of the thumb or the index
finger, preserving the pincer grasp. When affecting the cervical region, the
typical phenotype is a fixed laterocollis with ipsilateral shoulder elevation and
contralateral shoulder depression, and the latter is not typically seen in organic
cervical dystonia.
A mobile phenotype of psychogenic dystonia has also been described, which
has a more jerky quality.38 In one study, patients with mobile cervical dystonia
were on average 10 years older than the fixed group, which had an average age of

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PSYCHOGENIC (FUNCTIONAL) MOVEMENT DISORDERS

onset in their thirties.38 The mobile group was more likely to have dystonic
movements limited to the neck area, while the patients with fixed dystonia had
fixed postures in the limbs as well. The mobile group was also more likely to have
periods of remission with subsequent relapses.
A controversial entity referred to as peripherally induced dystonia has been
described, which is preceded by a mild injury and results in a fixed dystonia often
associated with signs of complex regional pain syndrome.39 In one review of
patients with peripherally induced movement disorders, more than one-third
had associated complex regional pain syndrome, and nearly 15% were diagnosed
with a psychogenic movement disorder. The patients were also more likely to
have fixed dystonia and were less likely to respond to treatment with botulinum
toxin injections.40 A review of reported cases of peripherally induced dystonia
found that many, but not all, patients have clinical features consistent with
psychogenic dystonia.41

Psychogenic Myoclonus
Psychogenic myoclonus often presents as jerking movements of the limbs,
head, or trunk that, unlike organic myoclonus, is often associated with facial

CASE 11-2 A 13-year-old girl presented to the emergency department with an

abnormal posture of her foot. She had woken up the previous morning
with this symptom, and she had not experienced an injury but had
difficulty bearing weight because of pain.
Imaging of her foot was normal. She started to use crutches, which
were lying around the house after her mother’s knee surgery 1 year
previously. Over the next few weeks, she visited an orthopedist,
rheumatologist, and physical therapist without a diagnosis or treatment.
Over the next month she developed intermittent stuttering with
unintelligible speech for 30 minutes at a time, which self-resolved.
She eventually visited a neurologist 1 month after her symptoms
started, and by this time, she was using a wheelchair. During history
taking, she reported no recent stressors. She was a straight A student,
captain of the soccer team, and editor of the yearbook. Her speech was
normal during the history.
On neurologic examination, during cranial nerve testing she suddenly
developed stuttering slow speech. Her foot was in a fixed posture with
plantar flexion and inversion. When asked to actively try and move her
foot, she exhibited extreme effort with facial grimacing. She exhibited
suggestibility, with straightening her foot with the application and
suggestion of a vibrating tuning fork. Her gait was effortful with her foot
dragging along the floor.

COMMENT This case of psychogenic dystonia demonstrates features of rapid onset

to a fixed posture, pain, and severe disability. Suggestibility can be a
helpful finding when other features such distractibility are not seen.

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grimacing and forceful eyelid closure. When associated with interruptions in KEY POINTS
speech, this usually occurs between words. Psychogenic myoclonus often
● A clinical diagnosis of
occurs in episodes as opposed to the random nature of organic myoclonus. propriospinal myoclonus
Psychogenic myoclonus is typically slower than organic myoclonus, and is unreliable, and more
when stimulus-induced a long delay occurs that may be associated with than 50% of cases
an exaggerated startle. Psychogenic myoclonus may occur even before are psychogenic.
a stimulus is applied, such as before the hammer hits the knee when
● Psychogenic gait often
checking reflexes. presents as slowness and
Psychogenic myoclonus is often mistaken for propriospinal myoclonus, and buckling at the knees,
a clinical diagnosis of propriospinal myoclonus is often unreliable.42 The classic dramatic compensatory
description of propriospinal myoclonus is rhythmic flexor spasms that are often measures, and improvement
with minimal support.
stimulus-induced and worse when supine. Secondary causes are associated
with spinal cord lesions and often have other signs of spinal cord dysfunction
such as sensory or reflex abnormalities. A review of all published cases of
propriospinal myoclonus compared primary, secondary, and psychogenic
myoclonus and determined that 56% of cases were psychogenic.43 Psychogenic
myoclonus was characterized by arrhythmic, variable jerks that did not persist
during sleep and more often involved the face. When compared via
electrophysiologic testing, overlap occurred between organic and psychogenic
cases, with slow conduction velocities during polymyographic recordings seen in
more than two-thirds of organic cases and approximately 20% of psychogenic
cases. A Bereitschaftspotential, an EEG finding seen in voluntary movement,
was present in 63% of psychogenic cases. Variability of muscle recruitment was
most likely to distinguish psychogenic from organic myoclonus.43
Surface EMG in psychogenic myoclonus typically demonstrates a burst
muscle contraction duration greater than 70 ms as opposed to a shorter duration
in organic myoclonus.32 The EMG pattern of psychogenic jerks is typically a
triphasic wave, as a consequence of agonist and antagonist muscle activation,
similar to that seen in voluntary ballistic movements.33 Furthermore, the reflex
latency (the interval between a stimulus, such as sound, pinprick, or tendon tap,
and jerk) in psychogenic myoclonus is variable, often greater than 100 ms, with
shorter latencies in organic myoclonus. The Bereitschaftspotential is often seen
in psychogenic myoclonus, but its absence does not rule out the diagnosis.

Psychogenic Gait Disorder

A psychogenic gait disorder may occur in isolation but more commonly is seen in
combination with other psychogenic movements.44,45 General neurologic
examination does not show signs of spasticity, neuropathy, or cerebellar
dysfunction. Patients with psychogenic gait disorders often have normal strength
on motor testing but are unable to bear weight, needing maximal assistance
to stand.
Patients often have to exert excessive effort when walking, greater than
that seen in organic gait disorders. They may demonstrate the “huffing and
puffing sign” characterized by huffing, breath holding, moaning, and facial
grimacing.46 Common manifestations of psychogenic gait are excessive slowness,
intermittent buckling at the knees, lurching without falling, and magnetlike
attraction to the adjacent walls. Patients may have dramatic compensatory
measures such as walking with arms outstretched, referred to as “tightrope
walking.” Astasia-abasia refers to body contortions while tandem walking,
paradoxically demonstrating excellent balance (VIDEO 11-2, links.lww.com/CONT/

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PSYCHOGENIC (FUNCTIONAL) MOVEMENT DISORDERS

A370). Providing minimal support by the examiner with one finger often results in
dramatic improvement in balance.
Patients may have an exaggerated response to the pull test, with arms waving
in the air, reeling backward, or a simple collapse in the examiner’s hands
(CASE 11-3). A “fear of falling” gait, typically seen in elderly women after a fall, is
not considered a psychogenic gait disorder.47 This gait disorder is characterized
by sliding feet along the ground, as if walking on ice, holding onto walls and
furniture. Dramatic improvement occurs with suggestion and encouragement.
This gait disorder is often confused with a parkinsonian gait.48,49
One study evaluated a “chair test” in nine patients with a psychogenic gait
compared to those with an organic gait disorder.50 Eight patients with a psychogenic
gait disorder were able to propel themselves forward in a swivel chair when seated,
whereas those with an organic gait disorder had equal impairments when seated or
walking. It is important to distinguish a psychogenic gait disorder from organic
disease with a complex gait pattern. For example, a dystonic gait may be task
specific, only occurring in certain states such as walking forward, backward, or
running. Patients with organic diseases such as Huntington disease and
spinocerebellar ataxia and patients with levodopa-induced or paroxysmal
dyskinesia may have a complex, bizarre gait disorder with a combination of
choreic, dystonic, and ataxic features that may be misdiagnosed as psychogenic.51

CASE 11-3 A 54-year-old woman presented for evaluation of an abnormal gait that
had started 6 months ago. She described her gait as unsteady, and she
had started to use a walker. She had difficulty climbing up stairs but
would climb up her front porch when no one was there to help her. She
fell frequently but fortunately had had no major injuries.
Her examination showed no evidence for spasticity, neuropathy, or
parkinsonism. She had giveway weakness in her proximal leg muscles.
Upon standing, she developed a bouncing of the trunk, and her feet shook
with each step. She had difficulty with tandem gait, with her body
contorting from side to side while walking heel to toe. This improved
markedly with the assistance of the examiner’s pinky finger. On the pull
test, she reeled back, her arms flailing, and fell into the examiner’s hands.
Review of her brain MRI showed no abnormalities. On further discussion
with the patient, she was the primary caregiver for her mother with
Parkinson disease, who had passed away 6 months prior to the patient’s
symptom onset. The patient was concerned that she was developing
Parkinson disease.

COMMENT This case demonstrates one typical example of a psychogenic gait

disorder: the bouncy gait. Other signs such as astasia-abasia with tandem
gait, improvement with minimal assistance, and the exaggerated results of
the pull test can also help make the diagnosis. It is not uncommon for
patients with psychogenic movement disorders to have experience as
health care providers or caregivers for family members who are ill.

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Psychogenic Parkinsonism KEY POINTS
Psychogenic parkinsonism may be seen in isolation but can be associated with
● Psychogenic
underlying Parkinson disease.48,52 In contrast to Parkinson disease, those with parkinsonism often coexists
psychogenic parkinsonism are more commonly female and have a relatively with organic parkinsonism.
younger age at onset.52 Patients with psychogenic parkinsonism have also been
found to have higher rates of depression at the time of presentation. Patients ● Psychogenic facial
spasms are typically tonic
with depression may have symptoms that appear parkinsonian because of
contractions of the lower
associated psychomotor retardation that can mimic body bradykinesia seen face with ipsilateral
in Parkinson disease. platysma contraction and
Patients with psychogenic parkinsonism perform rapid successive movements downward deviation of
with excessive effort and slowness but without the decrement characteristic the lip.

of the bradykinesia in patients with Parkinson disease.48 Speech may be slow,

whispering, or stuttering rather than hypophonic. Tremor in psychogenic
parkinsonism typically affects the dominant hand and has the features of
psychogenic tremor described earlier, such as variability in frequency and
direction, alternating between a pronation/supination tremor and flexion/
extension tremor. The tremor is often equally present while at rest, maintaining a
posture, and performing kinetic movements, in contrast to the tremor in
Parkinson disease that decreases with action. When walking, the hand tremor
disappears whereas patients with Parkinson disease show persistent or often
increased hand tremor when walking. The gait in psychogenic parkinsonism is
also often effortful with feet sliding across the floor. Patients often have an
exaggerated response to the pull test, with arms waving and patient reeling
backward.
Dopamine transporter single-photon emission computed tomography
(SPECT) is a specialized imaging technique that measures the uptake of
the radioactive tracer ioflupane I123 at the presynaptic dopamine transporter
terminals, projecting from the substantia nigra to the striatum. Decreased
uptake is a surrogate marker of dopamine deficiency and distinguishes
neurodegenerative parkinsonism from other causes of parkinsonism such as
drug-induced, vascular, and psychogenic parkinsonism.53

PSYCHOGENIC FACIAL MOVEMENTS. In the past decade, an increasing number of

reports have drawn attention to the broad phenomenology of psychogenic facial
movements, a previously underrecognized psychogenic movement disorder.54
The largest reported series of psychogenic facial spasms included 61 patients
from 71 movement disorders centers.55 The classic phenotype is ipsilateral
platysma contraction with downward deviation of the corner of the mouth. The
contractions are usually tonic, episodic, and may alternate from side to side.
Ipsilateral jaw deviation is common and may be associated with ipsilateral tongue
deviation. Psychogenic hemifacial spasm usually begins with the lower face as
opposed to the eyelid in organic hemifacial spasm. The eyelid spasms may
alternate sides and are not synchronous with the lower facial contractions.
Patients often experience contralateral contraction of the frontalis as opposed
to ipsilateral frontalis contraction, referred to as the “other Babinski sign” in
organic hemifacial spasm.56 Psychogenic weakness in the ipsilateral limb is also
common, reported in 90% of psychogenic hemifacial spasm cases.57
Psychogenic blepharospasm typically involves bilateral contraction of the
frontalis and corrugator, resulting in narrowed palpebral fissures, without actual
contraction of the orbicularis oculi as seen in organic blepharospasm.

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PSYCHOGENIC (FUNCTIONAL) MOVEMENT DISORDERS

PSYCHOGENIC PALATAL MYOCLONUS. Palatal myoclonus, which is a rhythmic

contraction of the soft palate, also can be psychogenic with variable frequency
and amplitude and can be entrainable (VIDEO 11-3, links.lww.com/CONT/
A371).54 Patients often have associated psychogenic movements of the head and
face. In reported patients, those with psychogenic palatal myoclonus were
younger and more likely to be female than those with organic palatal myoclonus.
They also often reported a preceding event such as a sore throat.

PSYCHOGENIC SPEECH DISORDERS. Psychogenic speech disturbances are

commonly associated with other psychogenic movement disorders. In a study of
182 patients with psychogenic movement disorders, 16% of patients had
associated speech disorders.21 The most common speech disturbance was
stuttering, followed by speech arrests, foreign accent syndrome (intonation and
pronunciation resulting in an accent foreign to the patient’s primary language),
hypophonia, and dysphonia (alteration of voice quality/phonation). Of these
patients, 13% had a combination of phenotypes. Speech disturbances are often
episodic and last for minutes, hours, or days at a time.

PSYCHOGENIC TICS. Psychogenic tics are uncommon, with one study identifying
psychogenic tics in 4.8% of 184 patients with psychogenic movement disorders.58
Psychogenic tics can be difficult to distinguish from organic tics, which also
have sudden onset and distractibility. When compared to patients with Tourette
syndrome, those with psychogenic tics were more likely to be female and
had an older age at presentation (36.3 years versus 18.7 years of age).58 Patients
with psychogenic tics lacked a family history or a childhood history of tics. A
reemergence of childhood tics is the most common cause of tics in adulthood.
Patients with psychogenic tics lack an urge/premonitory sensation and are
unable to suppress their movements. They are less likely to report a history of
obsessive-compulsive disorder or attention deficit hyperactivity disorder,
which are common in patients with organic tics.59 A lack of a rostrocaudal
progression has been shown in psychogenic tics, as opposed to organic tics that
often start in the face and then spread. Blocking tics, which interfere with normal
movement, have been demonstrated in patients with psychogenic tics and are
rare in patients with organic tics. Patients with psychogenic tics also commonly
had manifestations of other psychogenic movement disorders or psychogenic
nonepileptic seizures.

PSYCHOGENIC STEREOTYPIES. Stereotypies, typically seen in patients with

autism, tardive dyskinesia, and autoimmune anti–N-methyl-D-aspartate
(NMDA) receptor encephalitis, have been also described as a manifestation of
psychogenic movement disorders. Patients with functional stereotypies have
features that may overlap with those with tardive dyskinesia, including
orolingual dyskinesia, limb and trunk stereotypies, and respiratory dyskinesia.60
Similar to tardive dyskinesia, patients with psychogenic stereotypies may have
sudden onset, prominent distractibility, and spontaneous remissions, but have a
much lower frequency of exposure to neuroleptic drugs.

Psychogenic Paroxysmal Dyskinesia

Psychogenic and organic paroxysmal dyskinesias can be challenging to
distinguish because of their episodic nature but have certain distinctive features.
A study of 26 patients with psychogenic paroxysmal dyskinesia described a mean

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age at onset of 38.6 years, much later than that typically seen in organic KEY POINTS
paroxysmal dyskinesia.61 Episodes had variable duration and phenomenology,
● Psychogenic tics typically
with 69.2% having a mixed or complex phenotype. Triggers were atypical such as lack a premonitory urge,
stress, alcohol, and loud noises. Patients generally did not respond to medications suppressibility, and often
typically used for organic paroxysmal dyskinesias. Of these patients, 34% had lack a family or childhood
psychogenic signs between episodes, such as gait disturbances, nonanatomic history of tics.
sensory disturbances, giveway weakness, and fixed dystonic posturing of the
● Psychogenic paroxysmal
feet, and 50% had other unexplained somatic symptoms. Interestingly, 19.3% had dyskinesias have variable
an additional organic movement disorder. Ultimately, it is the variability of the duration and phenomenology
episodes that distinguishes psychogenic from organic paroxysmal dyskinesias, and often have atypical
which have stereotyped episodes without interictal abnormalities. triggers.

● The neurologist’s role

MAKING THE DIAGNOSIS involves explaining the
Making the diagnosis of a psychogenic movement disorder is based not only on diagnosis, providing
exclusion of organic causes but, more importantly, on positive criteria such as educational information,
coordinating treatment and
characteristic phenomenology that is incongruent with organic movement providing neurologic
disorders. As with many neurologic disorders, the diagnosis of a psychogenic follow-up to patients
movement disorder is a clinical diagnosis without a confirmatory laboratory test. diagnosed with psychogenic
The diagnosis should be made by a neurologist, and it should not be deferred movement disorders.
to a psychiatrist.
It is important to convey the diagnostic process to the patient, otherwise
they may mistakenly conclude that “the doctor cannot find anything wrong
with me” and “the doctor does not know what is wrong with me.” Confidently
explaining the diagnosis is important for the patient’s acceptance of the
diagnosis, which is essential for positive treatment outcomes. The neurologist
should reinforce that this is a true neurologic disorder and that no one is implying
that “this is all in their head” or that they are “faking” it. Taking the time to explain
the diagnosis and answering patient questions is especially important with
psychogenic movement disorders, which are not well known to the public.
Clinicians have different styles of delivering a psychogenic movement disorder
diagnosis to patients. Some advocate that demonstrating the psychogenic features
of their disease is a valuable part of the treatment process.62 The dialogue and
vocabulary the clinician uses can have a great impact on the patient’s acceptance of
the diagnosis. While different styles of communication are possible, one current
approach to patients is described and illustrated by Carson and colleagues.63
Asking about underlying stressors or past traumatic experiences may identify
contributing factors. However, the absence of such experiences does not exclude the
diagnosis. Patients often have poor insight into underlying psychological factors,
while family members may be more cognizant of contributing factors. Providing
examples of familiar examples of physical symptoms triggered by underlying
stressors can be helpful, such as palpitations and sweaty palms that can occur during
public speaking. At the end of the visit, provide a written summary of the diagnosis
and treatment and make follow-up appointments; this will help patients feel
supported and guided through the treatment plan. Refer to the useful websites
section at the end of this article for educational information that can help patients
learn more about this common disorder and not feel alone.

TREATMENT
At this time, there is no consensus on the optimal treatment strategy for
psychogenic movement disorders. While a multidisciplinary approach is usually

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PSYCHOGENIC (FUNCTIONAL) MOVEMENT DISORDERS

advocated,64 access to centers that provide this support is often limited because
of the paucity of centers that specialize in psychogenic movement disorders
and frequent denials of insurance coverage. The treatment plan is coordinated
by the neurologist, who should provide continued follow-up and support to
the patient.
Psychiatrists may play an important role in the treatment rather than in the
diagnosis of patients with psychogenic movement disorders. Patients may
benefit from psychotherapy to identify underlying stressors, understand
potential psychodynamic factors, and develop coping mechanisms. Patients also
may benefit from psychotropic medications if they have underlying depression
or anxiety.65 The type of psychotherapy implemented is varied and can include
psychodynamic therapy, cognitive-behavioral therapy, and hypnosis. A
retrospective study of psychodynamic therapy for patients with psychogenic
movement disorders demonstrated that out of 30 patients, 60% showed
improvement.66 Cognitive-behavioral therapy is also used to identify cognitive
distortions and negative beliefs and modify one’s response to stressors. A pilot
study of cognitive-behavioral therapy for 21 patients with psychogenic
movement disorders demonstrated an improvement in motor symptoms and a
reduction in anxiety and depression.67 A 2016 study demonstrated the value of
qualitative interviews with open-ended conversations, rather than standardized
questionnaires.68 Out of 36 patients with psychogenic movement disorders,
28 were identified as having an additional diagnosis of a psychiatric disorder.
Such interviews provided insight to the patient’s experience of their symptoms.
Patients with psychogenic movement disorders have poor insight and
demonstrate dysfunctional emotional processing.
Physical therapy, focused on motor retraining, has been shown to be helpful in
most patients. Motor retraining focuses on regaining control over movement
by demonstrating that normal movements are possible. Distraction techniques
may be used to limit self-focus and allow for automatic movements.69 Avoiding
the use of canes or walkers helps decrease a patient’s reliance on such assistive
devices and dependency. A systematic review of physical therapy studies
involving 373 patients with psychogenic movement disorders demonstrated
improvement in 60% to 70% of patients.70
In 2015, a group of neurologists, neuropsychiatrists, and physical and
occupational therapists developed consensus recommendations for physical
therapy in psychogenic movement disorders.69 They advocated for specialized
physical therapy focused on a biopsychosocial approach. This involved
patient education about their illness, motor retraining focusing on normal
movements, and diverting attention away from their impairments. Other helpful
techniques include self-observation with mirrors and videos to change their
self-perception, using visualization techniques to focus on normal movements
while performing exercises, and keeping a journal to reinforce treatment
strategies and monitor progress.
Another possible rehabilitation strategy is using the feature of entrainment
or suppressibility in psychogenic tremor as a biofeedback tool to retrain
movements. A small study of 10 patients demonstrated the feasibility of this
approach; patients were asked to move their wrists at varying frequencies in
response to a stimulus, resulting in improvement of tremor at 6 months.71
Inpatient programs with a combination of physical therapy and
psychotherapy may have additional benefits over outpatient therapy,

1134 AUGUST 2019

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involving more intensive therapies and removing the external stressors from KEY POINTS
their home environment.72
● Patients with
The Motor Retraining program for psychogenic movement disorders is a psychogenic movement
1-week multidisciplinary inpatient rehabilitation program in Kentucky that disorders may benefit
focuses on motor retraining.73 A retrospective chart review of 32 patients from psychotherapy and
admitted to this program evaluated patient- and physician-rated outcomes at psychotropic medications
to treat depression and
1 week and 6 months. The mean duration of symptoms was 7.4 years, the
anxiety.
mean age was 49.1 years, and 75% of the patients were women. Treatment
included 3 hours of daily physical, occupational, and speech therapy and 1 hour of ● Specialized physical
daily psychotherapy using cognitive-behavioral techniques. Physical therapy therapy focusing on motor
began with mental visualization followed by a step-wise approach starting retraining can be helpful for
patients with psychogenic
with simple normal movements and advancing to more complex movements. movement disorders.
Based on the self-reported Clinical Global Impression Scale, 87% of patients
reported improvement at 1 week and 67% reported improvement at 6 months. ● Functional MRI studies
Physician-rated videos, using the Psychogenic Movement Disorders Rating scale, have demonstrated
impaired self-agency and
demonstrated a 59.1% improvement at 1 week compared to baseline. At 1 week, dysfunctional emotional
wheelchair use decreased from 21.9% to 3.1 % of patients. The program was processing in patients with
well received by patients, with 96% stating they would participate in the program psychogenic movement
again and 100% recommending the program to other patients. disorders.
Other therapies such as transcutaneous electrical stimulation and transcranial
magnetic stimulation have shown improvement in patients with psychogenic
movement disorders in few, and mainly uncontrolled, studies.74,75 It is unclear
whether the mechanism of action of transcranial magnetic stimulation in
patients with psychogenic movement disorders is due to neuromodulation,
cognitive-behavioral effect through suggestion, or motor learning by stimulating
normal movements.

Pathophysiology
Research efforts are increasingly dedicated to elucidating the underlying
mechanism of psychogenic movement disorders.6 Impaired self-agency (a sense
of control over voluntary actions) has been associated with psychogenic
movement disorders, with the temporoparietal junction identified as a key player
in modulating the neural circuit for self-agency.76 Functional MRI (fMRI) studies
have demonstrated decreased connectivity between the right temporoparietal
junction and bilateral sensorimotor regions in patients with psychogenic
movement disorders, supporting this concept.76 An impaired self-agency may
help explain why movements that are physiologically produced through
voluntary circuits are perceived by patients as involuntary.
Dysfunctional emotional processing has also been associated with
psychogenic movement disorders. Alexithymia, impaired emotional processing,
is manifested as the inability to identify and describe one’s emotion. A
cross-sectional study demonstrated that those with psychogenic motor disorders
had a higher proportion of alexithymia (34.5%) compared to patients with
organic movement disorders (9.1%) and healthy controls (5.9%).77 This suggests
that patients with psychogenic movement disorders may have difficulty
identifying physical symptoms such as tremor/weakness as stress-related
autonomic arousal.
fMRI studies have demonstrated abnormal functional connectivity in emotional
processing circuits in patients with psychogenic tremor and psychogenic
dystonia.78,79 When patients with psychogenic dystonia were presented with

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PSYCHOGENIC (FUNCTIONAL) MOVEMENT DISORDERS

emotional stimuli, decreased activation was seen in select motor and sensory
areas compared to subjects with organic dystonia or healthy controls.79
Overactivity of the limbic system has been demonstrated in patients with
psychogenic movement disorders. When presented with fearful and sad faces,
patients with psychogenic motor symptoms had increased activity of the
amygdala compared to healthy controls.80 This activity increased over time, with
repeated exposure to fearful faces in particular, in contrast to the healthy
controls that did not demonstrate this heightened arousal. Studies have also
demonstrated increased connectivity between the amygdala and motor
preparatory systems during states of emotional arousal,81 suggesting a
connection between this hyperarousal and movements.
Physiologic studies have tried to identify biological markers of stress in
patients with psychogenic movement disorders.6 A 2016 study evaluating the
autonomic nervous system found decreased resting parasympathetic activity
in psychogenic movement disorders cases versus controls.82 This lower vagal
tone may explain a vulnerability to stressful events in patients with psychogenic
movement disorders. Conversely, another study failed to demonstrate a
difference in circulating levels of cortisol (a marker of stress) between
patients with psychogenic movement disorders and healthy controls.83 Thus,
it may be the patient’s response to stress rather than the amount of stress
that is impaired in psychogenic movement disorders.

CONCLUSION
Psychogenic movement disorders is a burgeoning field of neurology with
increasing clinical reports and research focusing on underlying pathophysiology
and treatment approaches. Increasing familiarity with this group of disorders,
including physician training and public awareness, will help facilitate diagnosis
and treatment. As health care professionals become more knowledgeable and
comfortable treating this group of disorders, multidisciplinary treatment
programs will hopefully become more accessible to patients. Further
understanding of the various risk factors and underlying disease processes may
identify biomarkers that help with diagnosis and disease-course monitoring
and may lead to the development of more effective therapies.

USEFUL WEBSITES
FND HOPE FUNCTIONAL NEUROLOGICAL DISORDER SOCIETY (FNDS)
FND Hope is a patient advocacy organization for The Functional Neurological Disorder Society
those with functional neurologic symptoms. focuses on promoting education, research, and
Website content is provided by patients, caregivers, collaboration among health care professionals
physicians, and researchers. interested in functional neurologic disorders.
fndhope.org fndsociety.org

FUNCTIONAL NEUROLOGICAL DISORDERS (FND): A

PATIENT’S GUIDE
This website is authored by Dr Jon Stone and
provides information for patients regarding
functional neurologic disorders in general, including
psychogenic movement disorders.
neurosymptoms.org

1136 AUGUST 2019

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VIDEO LEGENDS
VIDEO 11-1 VIDEO 11-3
Psychogenic tremor. Video shows a 51-year-old Psychogenic palatal myoclonus. Video shows a
man with psychogenic tremor exhibiting involuntary 35-year-old woman with psychogenic palatal
movements of the head, neck, shoulders, arms, and myoclonus. She had an acute onset of palatal
trunk, which are intermittent, distractible, variable, movements after an uncomplicated rhinoplasty
and entrainable. The patient had an otherwise surgery. The repetitive movements of the soft
normal neurologic examination. The movements palate completely stop with distraction.
were initially severe and constant but progressively links.lww.com/CONT/A371
became intermittent and episodic, with periods of
normalcy in between. © 2019 American Academy of Neurology.
links.lww.com/CONT/A369

© 2019 American Academy of Neurology.

VIDEO 11-2
Psychogenic chorea and gait disorder. Video shows
a 47-year-old woman with psychogenic chorea and
gait disorder exhibiting jerky intermittent tremors
and choreiform movements in both of her hands,
which are distractible, variable, suggestible, and
entrainable. The gait shows the classic features of
astasia-abasia. The patient experienced a sudden
onset of tremors and imbalance after a revision
cervical spine surgery with a waxing and waning
course and periods of complete remission. The
episodes are triggered by stressful situations such
as getting assessed for job fitness.
links.lww.com/CONT/A370

© 2019 American Academy of Neurology.

REFERENCES

1 Hallett M. Psychogenic movement disorders: a 8 Factor SA, Podskalny GD, Molho ES. Psychogenic
crisis for neurology. Curr Neurol Neurosci Rep movement disorders: frequency, clinical profile,
2006;6(4):269–271. doi:10.1007/s11910-006-0015-x. and characteristics. J Neurol Neurosurg Psychiatry
1995;59(4):406–412. doi:10.1136/jnnp.59.4.406.
2 Fahn S, Olanow CW. “Psychogenic movement
disorders”: they are what they are. Mov Disord 9 Ferrara J, Jankovic J. Psychogenic movement
2014;29(7):853–856. doi:10.1002/mds.25899. disorders in children. Mov Disord 2008;23(13):
1875–1881. doi:10.1002/mds.22220.
3 Jankovic J. “Psychogenic” versus “functional”
movement disorders? That is the question. 10 Batla A, Stamelou M, Edwards MJ, et al. Functional
Mov Disord 2014;29(13):1697–1698. doi:10.1002/ movement disorders are not uncommon in the
mds.26040. elderly. Mov Disord 2013;28(4):540–543.
doi:10.1002/mds.25350.
4 Carson A, Lehn A. Epidemiology. Handb Clin
Neurol 2016;139:47–60. doi:10.1016/B978-0-12- 11 Carson A, Stone J, Hibberd C, et al. Disability,
801772-2.00005-9. distress and unemployment in neurology
outpatients with symptoms ‘unexplained by
5 Edwards MJ, Stone J, Lang AE. From psychogenic
organic disease’. J Neurol Neurosurg Psychiatry
movement disorder to functional movement
2011;82(7):810–813. doi:10.1136/jnnp.2010.
disorder: it's time to change the name.
220640.
Mov Disord 2014;29(7):849–852. doi:10.1002/
mds.25562. 12 Gelauff J, Stone J. Prognosis of functional
neurologic disorders. Handb Clin Neurol 2016;
6 Baizabal-Carvallo JF, Hallett M, Jankovic J.
139:523–541. doi:10.1016/B978-0-12-801772-
Pathogenesis and pathophysiology of functional
2.00043-6.
(psychogenic) movement disorders. Neurobiol
Dis 2019;127:32–34. doi:10.1016/j.nbd.2019.02.013. 13 Fahn S, Williams DT. Psychogenic dystonia.
Adv Neurol 1988;50:431–455.
7 Stone J, Carson A, Duncan R, et al. Who is
referred to neurology clinics?–the diagnoses 14 Shill H, Gerber P. Evaluation of clinical diagnostic
made in 3781 new patients. Clin Neurol Neurosurg criteria for psychogenic movement disorders.
2010;112(9):747–751. doi:10.1016/j.clineuro. Mov Disord 2006;21(8):1163–1168. doi:10.1002/
2010.05.011. mds.20921.

CONTINUUMJOURNAL.COM 1137

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

PSYCHOGENIC (FUNCTIONAL) MOVEMENT DISORDERS

15 Gupta A, Lang AE. Psychogenic movement 29 Kenney C, Diamond A, Mejia N, et al. Distinguishing
disorders. Curr Opin Neurol 2009;22(4):430–436. psychogenic and essential tremor. J Neurol Sci
doi:10.1097/WCO.0b013e32832dc169. 2007;263(1–2):94–89. doi:10.1016/j.jns.2007.06.008.
16 American Psychiatric Association. Diagnostic and 30 Mostile G, Fekete R, Giuffrida JP, et al. Amplitude
statistical manual of mental disorders, 5th ed fluctuations in essential tremor. Parkinsonism
(DSM-5). Washington, DC: American Psychiatric Relat Disord 2012;18(7):859–863. doi:10.1016/j.
Association, 2013. parkreldis.2012.04.019.
17 Levenson JL, Sharpe M. The classification of 31 Park JE, Maurer CW, Hallett M. The “whack-
conversion disorder (functional neurologic a-mole” sign in functional movement disorders.
symptom disorder) in ICD and DSM. Handb Clin Mov Disord Clin Pract 2015. doi:10.1002/
Neurol 2016;139:189–192. doi:10.1016/B978-0-12- mdc3.12177.
801772-2.00016-3.
32 Kamble NL, Pal PK. Electrophysiological
18 Pareés I, Kojovic M, Pires C, et al. Physical evaluation of psychogenic movement disorders.
precipitating factors in functional movement Parkinsonism Relat Disord 2016;22(suppl 1):
disorders. J Neurol Sci 2014;338:174–177. S153–S158. doi:10.1016/j.parkreldis.2015.09.016.
doi:10.1016/j.jns.2013.12.046.
33 Apartis E. Clinical neurophysiology of
19 Nicholson TR, Aybek S, Craig T, et al. Life events psychogenic movement disorders: how to
and escape in conversion disorder. Psychol diagnose psychogenic tremor and myoclonus.
Med 2016;46(12):2617–2626. doi:10.1017/ Neurophysiol Clin 2014;44(4):417–424. doi:10.1016/
S0033291716000714. j.neucli.2013.08.014.
20 Baizabal-Carvallo JF, Jankovic J. Psychogenic 34 Kumru H, Begeman M, Tolosa E, Valls-Sole J.
ophthalmologic movement disorders. Dual task interference in psychogenic tremor.
J Neuropsychiatry Clin Neurosci 2016;28(3): Mov Disord 2007;22(14):2077–2082. doi:10.1002/
195–198. doi:10.1176/appi.neuropsych.15050104. mds.21670.
21 Baizabal-Carvallo JF, Jankovic J. Speech and 35 Kumru H, Valls-Solé J, Valldeoriola F, et al.
voice disorders in patients with psychogenic Transient arrest of psychogenic tremor induced
movement disorders. J Neurol 2015;262(11): by contralateral ballistic movements. Neurosci
2420–2424. doi:10.1007/s00415-015-7856-7. Lett 2004;370(2–3):135–139. doi:10.1016/j.
neulet.2004.08.009.
22 Defazio G, Pastore A, Pellicciari R, et al.
Personality disorders and somatization in 36 Schwingenschuh P, Saifee TA, Katschnig-Winter P,
functional and organic movement disorders. et al. Validation of “laboratory-supported” criteria
Psychiatry Res 2017;257:227–229. doi:10.1016/j. for functional (psychogenic) tremor. Mov Disord
psychres.2017.07.068. 2016;31(4):555–562. doi:10.1002/mds.26525.
23 Kranick S, Ekanayake V, Martinez V, et al. 37 Schmerler DA, Espay AJ. Functional dystonia.
Psychopathology and psychogenic movement Handb Clin Neurol 2016;139:235–245. doi:10.1016/
disorders. Mov Disord 2011;26(10):1844–1850. B978-0-12-801772-2.00020-5.
doi:10.1002/mds.23830.
38 Petrović IN, Tomić A, Vončina MM, et al.
24 Fekete R, Baizabal-Carvallo JF, Ha AD, et al. Characteristics of two distinct clinical
Convergence spasm in conversion disorders: phenotypes of functional (psychogenic) dystonia:
prevalence in psychogenic and other movement follow-up study. J Neurol 2018;265(1):82–88.
disorders compared with controls. J Neurol doi:10.1007/s00415-017-8667-9.
Neurosurg Psychiatry 2012;83(2):202–204.
39 Jankovic J. Peripherally induced movement
doi:10.1136/jnnp-2011-300733. doi:10.1176/appi.
disorders. Neurol Clin 2009;27(3):821–32, vii.
neuropsych.15050104.
doi:10.1016/j.ncl.2009.04.005.
25 Espay AJ, Aybek S, Carson A, et al. Current
40 van Rooijen DE, Geraedts EJ, Marinus J, et al.
concepts in diagnosis and treatment of
Peripheral trauma and movement disorders: a
functional neurological disorders. JAMA Neurol
systematic review of reported cases. J Neurol
2018;75(9):1132–1141. doi:10.1001/jamaneurol.
Neurosurg Psychiatry 2011;82(8):892–898.
2018.1264.
doi:10.1136/jnnp.2010.232504.
26 Thenganatt MA, Jankovic J. Psychogenic
41 Ganos C, Edwards MJ, Bhatia KP. Posttraumatic
movement disorders. Neurol Clin 2015;33(1):
functional movement disorders. Handb Clin
205–224. doi:10.1016/j.ncl.2014.09.013.
Neurol 2016;139:499–507. doi:10.1016/B978-0-12-
27 Baizabal-Carvallo JF, Jankovic J. Examiner 801772-2.00041-2.
manoeuvres 'sensory tricks' in functional
42 Erro R, Bhatia KP, Edwards MJ, et al. Clinical
(psychogenic) movement disorders. J Neurol
diagnosis of propriospinal myoclonus is unreliable:
Neurosurg Psychiatry 2017;88(5):453–455.
an electrophysiologic study. Mov Disord 2013;
doi:10.1136/jnnp-2016-315120.
28(13):1868–1873. doi:10.1002/mds.25627.
28 Thenganatt MA, Jankovic J. Psychogenic tremor:
43 van der Salm SM, Erro R, Cordivari C, et al.
a video guide to its distinguishing features.
Propriospinal myoclonus: clinical reappraisal and
Tremor Other Hyperkinet Mov (N Y) 2014;4:253.
review of literature. Neurology 2014;83(20):
doi:10.7916/D8FJ2F0Q.
1862–1870. doi:10.1212/WNL.0000000000000982.

1138 AUGUST 2019

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

44 Edwards M. Functional (psychogenic) gait 58 Baizabal-Carvallo JF, Jankovic J. The clinical
disorder: diagnosis and management. Handb features of psychogenic movement disorders
Clin Neurol 2018;159:417–423. doi:10.1016/B978-0- resembling tics. J Neurol Neurosurg Psychiatry
444-63916-5.00027-6. 2014;85(5):573–575. doi:10.1136/jnnp-2013-305594.
45 Fung VS. Functional gait disorder. Handb Clin 59 Demartini B, Ricciardi L, Parees I, et al. A positive
Neurol 2016;139:263–270. doi:10.1016/B978-0-12- diagnosis of functional (psychogenic) tics. Eur J
801772-2.00023-0. Neurol 2015;22(3):527–e36. doi:10.1111/ene.12609.
46 Laub HN, Dwivedi AK, Revilla FJ, et al. Diagnostic 60 Baizabal-Carvallo JF, Jankovic J. Functional
performance of the “huffing and puffing” sign in (psychogenic) stereotypies. J Neurol 2017;264(7):
psychogenic (functional) movement disorders. 1482–1487. doi:10.1007/s00415-017-8551-7.
Mov Disord Clin Pract 2015;2(1):29–32.
61 Ganos C, Aguirregomozcorta M, Batla A, et al.
doi:10.1002/mdc3.12102.
Psychogenic paroxysmal movement disorders—
47 Kurlan R. “Fear of falling” gait: a potentially clinical features and diagnostic clues.
reversible psychogenic gait disorder. Cogn Parkinsonism Relat Disord 2014;20(1):41–46.
Behav Neurol 2005;18(3):171–172. doi:10.1097/01. doi:10.1016/j.parkreldis.2013.09.012.
wnn.0000163577.92515.11.
62 Stone J, Carson A, Hallett M. Explanation as
48 Thenganatt MA, Jankovic J. Psychogenic treatment for functional neurologic disorders.
(functional) parkinsonism. Handb Clin Neurol Handb Clin Neurol 2016;139:543–553. doi:10.1016/
2016;139:259–262. doi:10.1016/B978-0-12-801772- B978-0-12-801772-2.00044-8.
2.00022-9.
63 Carson A, Lehn A, Ludwig L, Stone J. Explaining
49 Jankovic J. Diagnosis and treatment of psychogenic functional disorders in the neurology clinic:
parkinsonism. J Neurol Neurosurg Psychiatry 2011; a photo story. Pract Neurol 2016;16(1):56–61.
82(12):1300–1303. doi:10.1136/jnnp-2011-300876. doi:10.1136/practneurol-2015-001242.
50 Okun MS, Rodriguez RL, Foote KD, Fernandez HH. 64 Jacob AE, Smith CA, Jablonski ME, et al.
The “chair test” to aid in the diagnosis of Multidisciplinary clinic for functional movement
psychogenic gait disorders. Neurologist 2007;13(2): disorders (FMD): 1-year experience from a single
87–91. doi:10.1097/01.nrl.0000256358.52613.cc. centre. J Neurol Neurosurg Psychiatry 2018;89(9):
1011–1012. doi:10.1136/jnnp-2017-316523.
51 Paramanandam V, Lizarraga KJ, Soh D, et al.
Unusual gait disorders: a phenomenological 65 Voon V, Lang AE. Antidepressant treatment
approach and classification. Expert Rev outcomes of psychogenic movement disorder.
Neurother 2019;19(2):119–132. doi:10.1080/ J Clin Psychiatry 2005;66(12):1529–1534.
14737175.2019.1562337. doi:10.4088/JCP.v66n1206.
52 Frasca Polara G, Fleury V, Stone J, et al. 66 Sharma VD, Jones R, Factor SA. Psychodynamic
Prevalence of functional (psychogenic) psychotherapy for functional (psychogenic)
parkinsonism in two Swiss movement disorders movement disorders. J Mov Disord 2017;10(1):
clinics and review of the literature. J Neurol Sci 40–44. doi:10.14802/jmd.16038.
2018;387:37–45. doi:10.1016/j.jns.2018.01.022.
67 Dallocchio C, Tinazzi M, Bombieri F, et al.
53 Rodriguez-Porcel F, Jamali S, Duker AP, Espay AJ. Cognitive behavioural therapy and adjunctive
Dopamine transporter scanning in the evaluation physical activity for functional movement
of patients with suspected Parkinsonism: a disorders (conversion disorder): a pilot, single-
case-based user's guide. Expert Rev Neurother blinded, randomized study. Psychother Psychosom
2016;16(1):23–29. doi:10.1586/14737175.2015.1120160. 2016;85(6):381–383. doi:10.1159/000446660.
54 Kaski D, Bronstein AM, Edwards MJ, Stone J. 68 Epstein SA, Maurer CW, LaFaver K, et al. Insights
Cranial functional (psychogenic) movement into chronic functional movement disorders: the
disorders. Lancet Neurol 2015;14(12):1196–1205. value of qualitative psychiatric interviews.
doi:10.1016/S1474-4422(15)00226-4. Psychosomatics 2016;57(6):566–575. doi:10.1016/
j.psym.2016.04.005.
55 Fasano A, Valadas A, Bhatia KP, et al. Psychogenic
facial movement disorders: clinical features and 69 Nielsen G, Stone J, Matthews A, et al.
associated conditions. Mov Disord 2012;27(12): Physiotherapy for functional motor disorders: a
1544–1551. doi:10.1002/mds.25190. consensus recommendation. J Neurol Neurosurg
Psychiatry 2015;86(10):1113–1119. doi:10.1136/jnnp-
56 Baizabal-Carvallo JF, Jankovic J. Distinguishing
2014-309255.
features of psychogenic (functional) versus
organic hemifacial spasm. J Neurol 2017;264(2): 70 Nielsen G, Stone J, Edwards MJ. Physiotherapy
359–363. doi:10.1007/s00415-016-8356-0. for functional (psychogenic) motor symptoms:
a systematic review. J Psychosom Res 2013;75(2):
57 Stone J, Hoeritzauer I, Tesolin L, Carson A.
93–102. doi:10.1016/j.jpsychores.2013.05.006.
Functional movement disorders of the face:
a historical review and case series. J Neurol Sci 71 Espay AJ, Edwards MJ, Oggioni GD, et al. Tremor
2018;395:35–40. doi:10.1016/j.jns.2018.09.031. retrainment as therapeutic strategy in
psychogenic (functional) tremor. Parkinsonism
Relat Disord 2014;20(6):647–650. doi:10.1016/j.
parkreldis.2014.02.029.

CONTINUUMJOURNAL.COM 1139

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

PSYCHOGENIC (FUNCTIONAL) MOVEMENT DISORDERS

72 Williams DT, Lafaver K, Carson A, Fahn S. 78 Espay AJ, Maloney T, Vannest J, et al. Impaired
Inpatient treatment for functional neurologic emotion processing in functional (psychogenic)
disorders. Handb Clin Neurol 2016;139:631–641. tremor: a functional magnetic resonance imaging
doi:10.1016/B978-0-12-801772-2.00051-5. study. Neuroimage Clin 2017;17:179–187.
doi:10.1016/j.nicl.2017.10.020.
73 Jacob AE, Kaelin DL, Roach AR, et al. Motor
retraining (MoRe) for functional movement 79 Espay AJ, Maloney T, Vannest J, et al. Dysfunction
disorders: outcomes from a 1-week in emotion processing underlies functional
multidisciplinary rehabilitation program. PM R (psychogenic) dystonia. Mov Disord 2018;33(1):
2018;10(11):1164–1172. doi:10.1016/j.pmrj.2018.05.011. 136–145. doi:10.1002/mds.27217.
74 Ferrara J, Stamey W, Strutt AM, et al. 80 Aybek S, Nicholson TR, O'Daly O, et al.
Transcutaneous electrical stimulation (TENS) Emotion–motion interactions in conversion
for psychogenic movement disorders. disorder: an FMRI study. PLoS One 2015;10(4):
J Neuropsychiatry Clin Neurosci 2011;23(2): e0123273. doi:10.1371/journal.pone.0123273.
141–148. doi:10.1176/appi.neuropsych.23.2.141.
81 Voon V, Brezing C, Gallea C, et al. Emotional stimuli
75 Pollak TA, Nicholson TR, Edwards MJ, David AS. and motor conversion disorder. Brain 2010;133(pt 5):
A systematic review of transcranial magnetic 1526–1536. doi:10.1093/brain/awq054.
stimulation in the treatment of functional
82 Maurer CW, Liu VD, LaFaver K, et al. Impaired
(conversion) neurological symptoms. J Neurol
resting vagal tone in patients with functional
Neurosurg Psychiatry 2014;22(suppl 1):S153–S158.
movement disorders. Parkinsonism Relat Disord
doi:10.1136/jnnp-2012-304181.
2016;30:18–22. doi:10.1016/j.parkreldis.2016.06.009.
76 Maurer CW, LaFaver K, Ameli R, et al. Impaired
83 Maurer CW, LaFaver K, Ameli R, et al. A biological
self-agency in functional movement disorders:
measure of stress levels in patients with
a resting-state fMRI study. Neurology 2016;87(6):
functional movement disorders. Parkinsonism
564–570. doi:10.1212/WNL.0000000000002940.
Relat Disord 2015;21(9):1072–1075. doi:10.1016/j.
77 Demartini B, Petrochilos P, Ricciardi L, et al. The parkreldis.2015.06.017.
role of alexithymia in the development of
functional motor symptoms (conversion
disorder). J Neurol Neurosurg Psychiatry 2014;
85(10):1132–1137. doi:10.1136/jnnp-2013-307203.

1140 AUGUST 2019

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 Liability and Failure to MEDICOLEGAL ISSUES


Warn a Patient 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
By Joseph S. Kass, MD, JD, FAAN; Rachel V. Rose, JD, MBA

ABSTRACT
This medicolegal article examines a physician’s liability when he or she has
knowledge of adverse effects associated with a prescription medication
and suggests ways to mitigate that liability risk. The article also discusses
the circumstances under which pharmaceutical companies face liability
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for side effects such as tardive dyskinesia.

CASE
Note: This is a hypothetical case.
A 38-year-old woman presented to discuss her migraine treatment with
a new neurologist after moving to a new city. The patient had a history of
chronic migraines, took topiramate daily for migraine prophylaxis, and
used metoclopramide and sumatriptan to abort her acute migraine attacks.
CITE AS:
The patient asked the neurologist to prescribe this same effective
CONTINUUM (MINNEAP MINN)
treatment regimen. 2019;25(4, MOVEMENT DISORDERS):
The neurologist was concerned about this patient's risk of developing 1141–1144.

tardive dyskinesia from metoclopramide. The neurologist also was aware

Address correspondence to
that lawsuits had been brought over metoclopramide-related tardive Dr Joseph S. Kass, Baylor College
dyskinesia. of Medicine, One Baylor Plaza
M-210, Houston, TX 77030,
[email protected].

DISCUSSION RELATIONSHIP DISCLOSURE:

T
his article examines a physician’s liability in relation to the following Dr Kass serves as associate
editor of medicolegal issues for
issues presented in this case: Under what circumstances have physicians Continuum, as an associate
faced liability for causing metoclopramide-associated tardive dyskinesia, editor for Continuum Audio, as a
neurology section editor of
and under what circumstances have pharmaceutical companies been Ferri’s Clinical Advisor for
found liable for causing tardive dyskinesia? The article then provides Elsevier, and as co-editor of
suggestions to mitigate the risk of liability when a physician has knowledge of Neurology Secrets, Sixth Edition.
Dr Kass has received personal
adverse effects associated with a prescription medication. compensation for CME lectures
from Pri-Med LLC. Ms Rose
Malpractice Basics serves on the editorial board of
BC Advantage and receives book
The most common legal underpinning for lawsuits against physicians and royalties from the American Bar
pharmaceutical companies is an allegation of negligence. In legal terms, Association.
negligence is defined as the following:
UNLABELED USE OF
PRODUCTS/INVESTIGATIONAL
The omission to do something which a reasonable [person], guided by USE DISCLOSURE:
those considerations which ordinarily regulate the conduct of human affairs, Dr Kass and Ms Rose report no
disclosures.
would do[,] or doing something which a prudent and reasonable [person]
would not do. It must be determined in all cases by reference to the situation © 2019 American Academy
and knowledge of the parties and all the attendant circumstances.1 of Neurology.

CONTINUUMJOURNAL.COM 1141

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LIABILITY AND FAILURE TO WARN A PATIENT

A malpractice case is the typical basis for a negligence lawsuit against a

physician. To prevail in a malpractice lawsuit, a plaintiff, typically the patient or
the patient’s estate, must demonstrate to the jury that the physician had a duty to
provide care to the plaintiff and breached that duty by failing to provide the
standard of care that a reasonable physician would have provided under the same
circumstances. This breach of the standard of care harmed the plaintiff, and the
physician owes the patient damages to compensate for this harm.2 The breach
of a duty of care may be the result of misdiagnosis, inappropriate treatment, or
even inadequate informed consent. A physician who fails to obtain informed
consent by failing to disclose to a patient the well-established risks of
metoclopramide (ie, tardive dyskinesia, extrapyramidal symptoms, and
neuroleptic malignant syndrome)3 is vulnerable to a negligence suit.
According to the American Medical Association’s Code of Medical Ethics
Opinion, “[i]nformed consent to medical treatment is fundamental in both ethics
and law. Patients have the right to receive information and ask questions about
recommended treatments so that they can make well-considered decisions about
care.”4 Communication is fundamental to the process of obtaining informed
consent, which results when the physician has assessed the capacity of the patient
or surrogate decision maker to understand the relevant information, presented
the information and included a description of the diagnosis (if known), and
reviewed the purpose, risks, and expected benefits of the proposed therapy. A
statement in the medical recording documenting this discussion and including
the patient’s understanding of and consent to the intervention should always be
included in the record.4
Ehrenpreis and colleagues5 analyzed all cases involving metoclopramide and
tardive dyskinesia prior to June 2014. They searched the Westlaw legal database
for cases that included the search terms metoclopramide and tardive dyskinesia
and found the following:

u 96 cases were filed by patients

u 88.5% of cases were brought against the brand name and/or generic medicine manufacturers
as failure-to-warn claims
u 11 cases were brought against medical professionals
u 8 of the 11 lawsuits (72%) against medical professionals were dismissed, settled, or in the
process of settlement

The February 2009 US Food and Drug Administration (FDA) boxed warning
about metoclopramide-induced tardive dyskinesia resulted in an uptick in
malpractice cases filed related to this adverse effect.5 These cases related directly
to physicians’ failure to disclose the risk of tardive dyskinesia, obtain informed
consent, and record the informed consent discussion in the patient chart.
The duty to obtain informed consent resides not with the pharmaceutical
company but rather with the provider. Although physicians who fail to obtain
adequate informed consent are vulnerable to a malpractice lawsuit,
pharmaceutical companies have a duty to disclose potential medication
adverse effects as soon as these adverse effects come to light. Although the nature
of the duty of care is different for the physician and pharmaceutical company,
both parties can be found liable on different theories of negligence
(malpractice due to inadequate informed consent for the physician and failure

1142 AUGUST 2019

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of timely disclosure of known risks for the pharmaceutical company) and share
the damages settlement in proportion to their assigned responsibility.
Although the application of shared liability varies from state to state, the
premise that one or more persons may be liable for paying damages to the injured
individual is referred to as joint and several liability.6 Once liability is established,
each state has its formula for determining the portion of damages each defendant
must pay.
Today’s opioid crisis provides a contemporary example of a situation where
both pharmaceutical companies and physicians may share liability for their
actions. Pharmaceutical companies are alleged to have failed to disclose the
potency and addictive nature of their opioid drugs, and many physicians
prescribed opioids without either establishing the medical appropriateness of the
prescription of highly potent opioids or disclosing the known risks of addiction to
their patients.

CASE CONTINUED
The neurologist explained to the patient why she was reluctant to
prescribe metoclopramide, describing the risks of tardive dyskinesia,
extrapyramidal side effects, and neuroleptic malignant syndrome, and
warned her of the types of symptoms that should prompt the patient to
seek immediate medical attention. Because the patient found that this
medication, when taken in combination with sumatriptan, was the only
drug regimen that aborted severe migraines, the patient was willing to
accept these risks. The neurologist, however, was judicious in her
prescribing of metoclopramide, limiting the prescription to severe migraine
attacks only. She also documented the informed consent discussion in the
medical record.

CONCLUSION
While both physicians and pharmaceutical companies may be sued for failing to
disclose known side effects, physicians can take specific steps to mitigate their
risk of a successful lawsuit against them. First, physicians must inform their
patients about a therapy’s common side effects as well as its rare but serious
side effects, such as tardive dyskinesia. The physician should document the
informed consent discussion in the medical record, which ideally includes a
review of the risks of the medication, the rationale for prescribing the medicine,
the patient’s understanding and acceptance of the risks of treatment, and
symptoms that should prompt the patient to seek urgent medical evaluation.
Second, if a physician is an early adopter of a drug (ie, using a therapy
before a robust literature exists to support its use), the physician should
disclose this situation to the patient and include an explanation of why the
therapy is medically appropriate despite lack of strong evidence to support
its use. Of course, this discussion should also be documented in the
medical record.

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LIABILITY AND FAILURE TO WARN A PATIENT

REFERENCES

1 Black’s Law Dictionary. The law dictionary. What 4 Informed consent: code of medical ethics
is negligence? thelawdictionary.org/ opinion 2.1.1. American Medical Association.
negligence/. Accessed June 11, 2019. ama-assn.org/delivering-care/ethics/informed-
consent. Accessed June 11, 2019.
2 Rodriguez-Escobar v Goss, 392 S.W.3d 109, 113
(Tex 2013). 5 Ehrenpreis ED, Krishnan A, Alexoff A, et al. A
survey of lawsuits filed for the complaint of
3 Reglan (metoclopramide) tablets: highlights of
tardive dyskinesia following treatment with
prescribing information. United States Food and
metoclopramide. Clin Pharmacol Biopharm 2014;
Drug Administration. accessdata.fda.gov/
4(1). doi:10.4172/2167-065X.100013.1.
drugsatfda_docs/label/2017/017854s062lbl.pdf.
Accessed June 11, 2019. 6 Joint and several liability. Cornell Law School.
law.cornell.edu/wex/joint_and_several_liability.
Accessed June 11, 2019.

1144 AUGUST 2019

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 ERRATUM

In the June 2019 issue of Continuum (Multiple

Sclerosis and Other CNS Inflammatory Diseases,
Vol. 25, No. 3), the following error occurred:

In “Monitoring, Switching, and Stopping Multiple

Sclerosis Disease-Modifying Therapies” by Robert H.
Gross, MD, and John R. Corboy, MD, FAAN,
(Continuum: Lifelong Learning in Neurology
2019;25:731), the text incorrectly states, “In the
Innsbruck database, those who continued
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disease-modifying therapy after age 45 and who had

no relapses in the 4 years before stopping their
disease-modifying therapy had a 94% reduction in
risk of a new relapse compared to those discontinuers
younger than 45 or who had a relapse in the prior
4 years.” The sentence should read, “In the
Innsbruck database, those who discontinued
disease-modifying therapy after age 45 and who had
no relapses in the 4 years before stopping their
disease-modifying therapy had a 94% reduction in
risk of a new relapse compared to those discontinuers
younger than 45 or who had a relapse in the prior
4 years.”

Gross RH, Corboy JR. Monitoring, switching, and

stopping multiple sclerosis disease-modifying
therapies. Continuum (Minneap Minn) 2019;
25(3, Multiple Sclerosis and Other CNS
Inflammatory Diseases):715–735. doi:10.1212/
CON.0000000000000738.

The editors regret this error.

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Downloaded from https://journals.lww.com/continuum by juGL3SikQGgPeJhlsy5S2tR2Je1+DSLxXM5+5U0pNQ/o8Sr9B6vmzj4RAT1RqJBz5vmQ6bjYts4rZHominWNXy0H3U65GuTdNee3fZ5dQ+6XNmvYCGaBTods9Wqj4Xuj3ri08TWAIZElLKJ6PR0VGZfKDZysiBtvkDigHdXH4Tg= on 08/05/2019

Movement Disorders
Article 1: Parkinson Disease
Theresa A. Zesiewicz, MD, FAAN. Continuum (Minneap Minn). 2019; 25 (4 Movement
Disorders):896–918.

ABSTRACT
PURPOSE OF REVIEW:
Parkinson disease is a common neurodegenerative disorder that affects millions of people
worldwide. Important advances in the treatment, etiology, and the pathogenesis of Parkinson
disease have been made in the past 50 years. This article provides a review of thecurrent
understanding of Parkinson disease, including the epidemiology, phenomenology, and
treatment options.
RECENT FINDINGS:
Parkinson disease is nowrecognized to be a heterogeneouscondition marked by both motor and
nonmotor symptoms. It is composed of preclinical, prodromal, and clinical phases. New
medications with improved ease of administration have been approved for its treatment.
Innovative surgical therapies for Parkinson disease may be used when motor symptoms persist
despite optimal medical management.
SUMMARY:
Parkinson disease is a complex, heterogeneous neurodegenerativedisorder. Considerable
progress has been made in its treatment modalities, both pharmacologic and surgical. While its
cure remains elusive, exciting new research advances are on the horizon.
KEY POINTS
• A renaissance of therapeutic options for Parkinson disease have occurred in the last 50 years. Levodopa
remains the gold standard for treatment of Parkinson disease, but dopamine agonists, monoamine oxidase
type B inhibitors, catechol-O-methyltransferase inhibitors, and surgical procedures have greatly expanded
the therapeuticoptions.
• Parkinson disease affects millions of people worldwide, and its prevalence increasesgreatly with advancing
age.
• Clinical features of Parkinson disease include tremor, rigidity, akinesia (or bradykinesia), and
posturalinstability. Nonmotor symptoms are commonly experienced by patients and often negatively impact
quality of life. Premotor symptoms include constipation, anosmia, rapid eye movement sleep disorder,
and depression.
• The diagnosis of Parkinson disease is made clinically. Red flags for atypical parkinsonism include severe
dysautonomia, early-onset hallucinations and dementia, freezing, postural instability, and lack of response

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 to levodopa. Red flags for atypical parkinsonism also include early speech difficulties and imbalance, poor
response to levodopa, and symmetrical symptoms.
• Parkinson disease may be divided into preclinical, prodromal, and clinical phases. Patients generally
experience good response to levodopa for several years following their diagnosis.
• Parkinson disease is characterized by the loss of dopaminergic neurons and the presence of Lewy bodies
containing the misfolded protein α-synuclein.
• Parkinson disease remains a clinical diagnosis. Neuroimaging techniques such as dopamine transporter
single-photon emission computed tomography are helpful in differentiating between essential tremor and
tremor from parkinsoniansyndromes.
• Clinical rating scales and patient diaries are helpful inmonitoring disease progression and are useful tools in
clinical research trials.
• While levodopa is the gold standard in the treatment of Parkinson disease, it is nowavailable in several
formulations that may provide ease of administration and improved efficacy. Other available medications are
dopamineagonists, catechol-O-methyltransferase inhibitors, monoamine oxidase type B inhibitors, an
N-methyl-D-aspartate antagonist, and anticholinergic medications.
• Patients with Parkinson disease should be offered dopaminergic treatment when their symptoms are
bothersome. Patients with Parkinson disease should be encouraged to exercise, as long as it is performed
safely.
• The aim of Parkinson disease treatment is to optimize on time and reduce off time while minimizing
troublesome levodopainduced dyskinesia. Treatment of levodopa induced dyskinesia requires identifying its
occurrence in relation to levodopa dosing.
• Surgical treatment of Parkinson disease was developed for patients who, despite medication optimization,
experience motor symptoms that cannot be satisfactorily ameliorated by medication.

Article 2: Progressive Supranuclear

Palsy, Corticobasal Degeneration, and
Multiple System Atrophy
Paul Greene, MD. Continuum (Minneap Minn). August 2019; 25 (4 Movement
Disorders):919–935.

ABSTRACT
PURPOSE OF REVIEW:
Patients who have parkinsonian features, especially without tremor, that are not responsive to
levodopa, usually have one of these three major neurodegenerative disorders rather than
Parkinson disease: progressive supranuclear palsy (PSP), multiple system atrophy (MSA), or
corticobasal degeneration (CBD). Each of these disorders eventually develops signs and
symptoms that distinguish it from idiopathic Parkinson disease, but these may not be present at
disease onset. Although these conditions are not generally treatable, it is still important to
correctly diagnose the condition as soon as possible.
RECENT FINDINGS:
In recent years, it has been increasingly recognized that thesymptoms of these diseases do not
accurately predict the pathology, and the pathology does not accurately predict the clinical
syndrome. Despite this, interest has grown in treating these diseases by targetingmisfolded tau
(in thecase of PSP and CBD) and misfolded α-synuclein (in the case of MSA).

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

SUMMARY:
Knowledge of the characteristic signs and symptoms of PSP, MSA, and CBD are essential in
diagnosing and managing patients who have atypical parkinsonian syndromes.

KEY POINTS
• Patients with parkinsonian features who do not improve with levodopa usually do not have idiopathic
Parkinsondisease and often have either progressive supranuclear palsy, multiple system atrophy, or
corticobasal degeneration.
• Progressive supranuclear palsy is a likely diagnosis in patients with parkinsonian features and
earlydevelopment of a supranuclear palsy.
• Some patients with progressive supranuclear palsy do not develop a supranuclear palsy until later in the
course of the disease. Early features that suggest progressive supranuclear palsy are an angry or puzzled
look, growling speech, early development of dysphagia, and a broad-based gait with abducted arms.
• A minority of patients with the pathology of progressive supranuclear palsy may have signs and symptoms
suggesting a variety of conditions, including corticobasal degeneration and, rarely, idiopathic Parkinson
disease, primary progressive aphasia, cerebellar ataxia, frontotemporal dementia, and primary lateral
sclerosis.
• Other pathologies may produce signs and symptoms suggestive of progressive supranuclear palsy, including
Alzheimer disease, some frontotemporal dementias, Whipple disease, Niemann-Pick disease type C, and
Gaucher disease.
• The pathology of progressive supranuclear palsy is characterized by deposits of 4-repeat tau in astrocytes
and oligodendroglia in multiple regions of the basal ganglia and cortex of the brain.
• Preliminary studies of agents that interfere with the formation or spread of misfolded tau are being
conducted with the hope of stopping or slowing the progression of progressive supranuclear palsy.
• The clinical hallmarks of classic corticobasal degeneration are parkinsonism combined with unilateral
dystonia, myoclonus, and cortical deficits such as apraxia, cortical sensory loss, and alien limb phenomenon.
• As in progressive supranuclear palsy, the pathology of corticobasal degeneration also involves widespread
deposition of 4-repeat tau but also includes asymmetric cortical atrophy and neuronal, oligodendroglial, and
astrocytic deposits distinct from the deposits in progressive supranuclear palsy.
• As with progressive supranuclear palsy, multiple pathologies may mimic the signs and symptoms of
corticobasal degeneration, including progressive supranuclear palsy, Alzheimer disease, Pick disease, and
Creutzfeldt-Jakob disease. When this happens, it is known as corticobasal syndrome. Similarly, the
pathology of corticobasal degeneration may present as progressive supranuclear palsy, primary nonfluent
aphasia, Alzheimer disease, and other conditions.
• Middle-aged patients presenting with parkinsonism, autonomic insufficiency, and ataxia usually have
multiple system atrophy. However, many patients with multiple system atrophy may initially only have
symptoms in one or two of these categories, making the correct diagnosis more difficult. The development of
laryngeal stridor is a strong clue that the diagnosis is multiple system atrophy.
• Unlike progressive supranuclear palsy and corticobasal degeneration, multiple system atrophy is a
synucleinopathy, not a tauopathy. This may have implications for future treatments.
• Like progressive supranuclear palsy and corticobasal degeneration, there are widespread pathologic
abnormalities in multiple systematrophy, but the characteristic inclusions contain α-synuclein, not tau. The
first identified abnormality was a glial cytoplasmic inclusion containing α-synuclein, but neuronal inclusions
havealso been identified. Rarely, Lewy bodies are found in multiple system atrophy.
• There has been an intensive search for genetic risk factors for these conditions. Some candidate genes have
been identified, but this has not currently led to any therapeutic innovations. Some genes have been
identified thatoccasionally produce one of these syndromes, but those, so far, have been responsible for
only a small percentage of known cases.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 • The typical features of progressive supranuclear palsy (supranuclear palsy), corticobasal degeneration
(cortical myoclonus and other focal cortical deficits), and multiple system atrophy (autonomic failure and
ataxia) suggest the correct diagnosis but do not achieve both sensitivity and specificity.
• Some symptoms of progressive supranuclear palsy, corticobasal degeneration, and multiple system
atrophycan be treated, such as constipation; blepharospasm and other dystonias (with botulinum toxin
injections); orthostasis; depression; pain; pseudobulbar affect; and other symptoms.

Article 3: Tics and Tourette Syndrome

Harvey S. Singer, MD, FAAN. Continuum (Minneap Minn). August 2019; 25 (4 Movement
Disorders):936–958.

ABSTRACT
PURPOSE OF REVIEW:
The purpose of this article is to present current information on the phenomenology,
epidemiology, comorbidities, and pathophysiology of tic disorders and discuss therapy options.
It is hoped that a greater understanding of each of these components will provide physicians and
caregivers with the necessary information to deliverthoughtful and optimal care to affected
individuals.
RECENT FINDINGS:
Recent advances include the finding that Tourette syndrome is likely due to a combination of
several different genes, both low-effect and larger-effect variants, plus environmental factors.
Pathophysiologically, increasing evidence supports involvement of the cortical–basal
ganglia–thalamocortical circuit; however, the primary location and neurotransmitter remain
controversial. Behavioral therapy is first-line treatment, and pharmacotherapy is based on tic
severity. Several newer therapeutic agents are under investigation (eg, valbenazine,
deutetrabenazine, cannabinoids), and deep brain stimulation is apromising therapy.
SUMMARY:
Tics, defined as sudden, rapid, recurrent, nonrhythmic motormovements or vocalizations, are
essential components of Tourette syndrome. Although some tics may be mild, others can cause
significant psychosocial, physical, and functional difficulties that affect daily activities. In
addition to tics, most affected individuals have coexisting neuropsychological difficulties
(attention deficit hyperactivity disorder, obsessive compulsive disorder, anxiety, mood
disorder, disruptive behaviors, schizotypal traits, suicidal behavior, personality disorder,
antisocial activities, and sleep disorders) that can further impact social and academic activities
or employment.

KEY POINTS
• Tics have several characteristics that are useful in identifying their presence, including precipitating factors,
a waxing and waning pattern, admixture of new and old tics, a premonitory urge thatresolveswhen the tic
is done, reduction when engrossed, and variable severity.
• Tics can be highly variable and fluctuate, and an individual’s tic repertoire evolves over time.
• The diagnosis of a tic disorder is based on historical features and observation of the tics; no
definitivediagnostic laboratory test has yet been established.
• Simple tics are relatively common in childhood, with reports of prevalence (the number of cases in
thepopulation at a given time) being 6% to 12% (range of 4% to 24%).

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 • Most individuals with Tourette syndrome have at least one comorbid/coexisting neuropsychological problem.
• Coexisting neuropsychological issues add a significant additional burden to patients with Tourette syndrome
or chronic motor or vocal tic disorder.
• Tourette syndrome is currently classified as a polygenic inherited disorder, suggesting that a combination of
a variety of genes (some common, some with a loweffect or rare, and others having a larger effect) and
environmental factors are all involved in its transmission.
• The existence of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections
(PANDAS) and its proposed therapy are extremely controversial.
• A series of parallel cortical–basal ganglia–thalamocortical circuits provide a framework for understanding
the pathophysiology of tics and associated behaviors.
• Identification of the true primary site of anatomic abnormality in Tourette syndrome remains an area of active
discussion.
• It is important to recognize that within a multitransmitter interconnected system, a successful
pharmacotherapy does not necessarily indicate that the primary neurotransmitter abnormality is being
targeted.
• The establishment of an effective therapeutic plan for Tourette syndrome and tics requires careful
initialassessment of tics, determining the presence of co-occurring issues, and clarifying the resulting
impairment of each issue.
• The first step in treatment of Tourette syndrome is education of the patient, his/her family, and the school or
workplace about the diagnosis, its potential coexisting issues, and indications for therapy.
• Specific criteria for initiating behavioral or pharmacologic ticsuppressing therapy include the presence of
psychosocial problems, tic-induced musculoskeletal/physical difficulties, and disruption of
classroom/work settings.
• Various practice guidelines have suggested that habit reversal training, more specifically Comprehensive
Behavioral Intervention for Tics (CBIT) should be the first-line intervention for tics.
• In general, a two-tiered approach to the use of pharmacotherapy is recommended for treating tics, with use of
tier 1 medications for milder tics and use of tier 2medications reserved for more difficult to control symptoms.
• Deep brain stimulation is a stereotactic treatment that has significant potential for the treatment of tics.

Article 4: Tremor
Elan D. Louis, MD, MS, FAAN. Continuum (Minneap Minn). August 2019; 25 (4 Movement
Disorders):959–975.

ABSTRACT
PURPOSE OF REVIEW:
Tremor may be defined as an involuntary movement that is rhythmic (ie, regularly recurrent)
and oscillatory (ie, rotating around a central plane) and may manifest in a variety of ways;
accordingly, tremor has a rich clinical phenomenology. Consequently, the diagnosis of tremor
disorders can be challenging, and misdiagnoses are common. The goal of this article is to provide
the reader with straightforward approaches to the diagnosis and treatment of tremors.
RECENT FINDINGS:
Focused ultrasound thalamotomy of the ventral intermediate nucleus of the thalamus is an
emerging and promising therapy for the treatment of essential tremor.
SUMMARY:
The evaluation should start with a detailed tremor history followed by a focused neurologic
examination, which should attend to the many subtleties of tremor phenomenology. Among

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

other things, the history and examination are used to establish whether the primary tremor is an
action tremor (ie, postural, kinetic, or intention tremor) or a resting tremor. The clinician should
then formulate two sets of diagnoses: disorders in which action tremor is the predominant
tremor versus those in which resting tremor is the predominant tremor. Among the most common
of the former type are essential tremor, enhanced physiologic tremor, drug-induced tremor,
dystonic tremor, primary writing tremor, orthostatic tremor, and cerebellar tremor. Parkinson
disease is the most commondisorder of resting tremor. This article details the clinical features of
each of these disorders, as well as those of additional tremor disorders. Thediagnosis of tremor
disorders is challenging. The approach to evaluating apatientwith a tremor involves a history
and a neurologic examination that is focused on the nuances of tremor phenomenology, which
are numerous.

KEY POINTS
• Tremors are involuntary movements that are both rhythmic and oscillatory.
• An initial step in evaluating patients with tremor is to determine whether the tremor is primarily present at
rest or with activity.
• The key feature of essential tremor is kinetic tremor.
• The kinetic tremor of essential tremor is typically slightly asymmetric.
• Approximately one-half of patients with essential tremor exhibit intention tremor during the
fingernose-finger maneuver.
• The postural tremor in essential tremor is generally out of phase; this can create a seesaw effect when
thepatients’ arms are held in the wing-beat position.
• Resting tremor may occur in patients with severe or long-standing essential tremor, but it is restricted to the arms.
• Neck tremor is several times more common in women with essential tremor than in men with essential tremor.
• Neck tremor is always pathologic. It is not a feature of enhanced physiologic tremor.
• Although limb tremor may be present, head tremor should not be a feature of drug-induced action tremor.
• The tremor in dystonia may be neither rhythmic nor oscillatory.
• Dystonic head tremor often persists after the patient lies on his or her back; this is generally not true of
essential tremor.
• Primary writing tremor is a tremor that occurs mainly while writing but not during other tasks that involve
the hands.
• In some cases, orthostatic tremor may be heard when a stethoscope is placed over the affected leg; the
tremormakes a sound like a distant helicopter.
• The clinical phenomenology of tremor of cerebellar origin is heterogeneous, and it extends beyond that
ofintention tremor to include postural tremor, kinetic tremor, resting tremor, and orthostatic tremor.
• Rubral tremor is strikingly asymmetric, and it has resting, postural, and kinetic components.
• Psychogenic tremors often have an abrupt onset.
• Wing-beat tremor is considered a classic tremor in Wilson disease, but it is not the most common type of
tremor in that disease.
• Although intention tremor is common in patients with fragile X tremor-ataxia syndrome, kinetic, postural, and
resting tremorsmay also occur.
• The resting tremor in Parkinson disease is generally asymmetric.
• 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.

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Article 5: The Dystonias
H. A. Jinnah, MD, PhD. Continuum (Minneap Minn). August 2019; 25 (4 Movement
Disorders):976–1000.

ABSTRACT
PURPOSE OF REVIEW:
This article provides a summary of the state of the art in the diagnosis, classification, etiologies,
and treatment of dystonia.
RECENT FINDINGS:
Although many different clinicalmanifestations of dystoniahave been recognized for decades, it
is only in the past 5 years that a broadly accepted approach has emerged for classifying them
into specific subgroups. The new classification system aids clinical recognition and diagnosis by
focusing on key clinical features that help distinguish the many subtypes. In the past few years,
major advances have been made inthe discovery of new genes as well advances in our
understanding of the biological processes involved. These advances have led to major changes
in strategies for diagnosis of the inherited dystonias. An emerging trend is to move away from
heavy reliance on the phenotype to target diagnostic testing toward a broader approach that
involves large gene panels or whole exome sequencing.
SUMMARY:
The dystonias are a large family of phenotypically andetiologically diverse disorders. The
diagnosis of these disorders depends on clinical recognition of characteristic clinical features.
Symptomatic treatments are useful for all forms of dystonia and include oral medications,
botulinum toxins, and surgical procedures. Determination of etiology is becoming increasingly
important because the number ofdisorders is growing and more specific and sometimes
disease-modifying therapies now exist.

KEY POINTS
• Dystonic movements are not always slow; they can be rapid or jerky, or resemble tremor.
• Dystonic movements tend to be patterned, not random.
• Dystonic movements are often triggered or worsened by voluntary muscle activity.
• Identification of a geste antagoniste (sensory trick) can be a very helpful clue because it is unique to dystonia
and is important to ask patients about.
• The history and examination of patients with dystonia should focus on four areas: body region affected, age
at onset, temporal features, and ancillary neurologic problems.
• For the most common focal dystonias that emerge after 40 years of age, laboratory investigations are usually
not needed.
• For any dystonia that emerges in a child or young adult, laboratory investigations are guided by the history
and examination.
• For almost all classic inherited dystonic disorders in children, late-onset cases or less severe cases are
known to occur in adults.
• Elucidating etiology is important because specific treatments are available for several types of dystonia.
• Isolated dystonia may be the initial manifestation for neurologic disorders typically associated with more
complex syndromes.
• More than 100 known causes for dystonia exist.
• Genetic forms of dystonia should be referred to by the name of the gene, not the DYT locus name.

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 • Dystonia results from dysfunction of a motor network that includes the basal ganglia, cerebellum, and
sensorimotor cortex.
• All children and young adults with unexplained dystonia must have a trial of levodopa to rule
outdopa-responsive dystonia.
• Carbamazepine and related anticonvulsant medications may be remarkably effective at very low doses in
patients with paroxysmal kinesigenic dyskinesia.
• When treating dystonia, it is important to customize both the dose and the interval between doses for
optimal benefits with botulinum toxin.
• Botulinum toxins are the treatment of first choice for focal and segmental dystonias and sometimes the most
discomforting aspects in generalized dystonias.
• Deep brain stimulation is the most commonly offered surgical treatment for dystonia although ablative
procedures may be appropriate in some cases.
• Selection of patients with dystonia for surgical intervention should be done by experienced multidisciplinary
teams.
• Focused ultrasound is becoming more popular for ablative surgery in patients with dystonia although
experience is still limited.

Article 6: Chorea
Pichet Termsarasab, MD. Continuum (Minneap Minn). August 2019; 25 (4 Movement
Disorders):1001–1035.

ABSTRACT
PURPOSE OF REVIEW:
This article provides an overview of the approach to chorea in clinical practice, beginning with a
discussion of the phenomenologic features of chorea and how to differentiate it from other
movement disorders. The diagnostic approach, clinical features of important acquired and
genetic choreas, and therapeutic principles are also discussed. Practical clinical points and
caveats are included.
RECENT FINDINGS:
C9orf72 disease is the most common Huntington disease phenocopy, according to studies in the
European population. Anti-IgLON5 disease can present with chorea. The role of
immunotherapies in Sydenhamchorea has increased, and further clinical studiesmay be useful.
Benign hereditary chorea is a syndrome or phenotype due to mutations in several genes,
including NKX2-1, ADCY5, GNAO1, PDE10A. New-generation presynaptic dopamine-depleting
agents provide more options for symptomatic treatment of chorea with fewer adverse effects.
Deep brain stimulation has been performed in several choreic disorders, but features other than
chorea and the neurodegenerative nature should be taken intoconsideration. Studies on genetic
interventions for Huntington disease are ongoing.
SUMMARY:
Clinical features remain crucial in guiding the differentialdiagnosis and appropriate
investigations in chorea. Given the complexity of most choreic disorders, treating only the
chorea is not sufficient. A comprehensive and multidisciplinary approach is required.

KEY POINTS
• Randomness is the key phenomenologic feature of chorea.
• Chorea with quick velocities may look jerky, resembling myoclonic jerks.

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• Chorea in one of three body distributions (hemichorea, orobuccolingual involvement, and forehead chorea)
can serve as a clue to narrow down the differential diagnoses.
• Structural lesions and systemic disorders (such as nonketotic hyperglycemia and polycythemia vera) can
cause hemichorea.
• Sydenham chorea can present with hemichorea or very asymmetric involvement.
• The time course can help classify chorea into acquired and genetic etiologies.
• Age group and known prevalence are very important diagnostic clues in chorea.
• The most common acquired chorea in children is Sydenham chorea.
• The most common genetic chorea in adults is Huntington disease, followed by C9orf72 disease and
spinocerebellar ataxia type 17.
• The most common genetic chorea in children is benign hereditary chorea.
• A negative family history does not exclude genetic causes of chorea.
• Huntington disease–like 2 is almost exclusively seen in patients with African ancestry.
• Autoimmune chorea should be included in the differential diagnoses of chorea with a subacute temporal
profile.
• Neuropsychiatric features such as irritability, attention deficit hyperactivity disorder, and
obsessivecompulsive behavior can be seen in Sydenham chorea.
• It is important to search for an underlying etiology in hormonal-related chorea, including chorea gravidarum
and estrogen-induced chorea.
• Nonmotor features in Huntington disease are often more debilitating than chorea itself.
• Chorea is gradually replaced by parkinsonian features in later stages of Huntington disease; thus,the
treatment regimen requires revision periodically.
• Delayed initiation of saccades is a hallmark eye movement abnormality in Huntington disease.
• Senile chorea should not be used as a diagnosis, and an underlying etiology should be sought.
• Children with Huntington disease typically do not present with chorea but rather parkinsonism, dystonia, and
seizures.
• Age at onset in Huntington disease is determined by the number of CAG repeats, genetic modifiers, and
environmental factors.
• Genetic counseling should be considered before ordering genetic testing for Huntington disease.
• Autosomal recessive ataxia syndromes can present with a variety of hyperkinetic movement disorders,
including chorea.
• In addition to chorea-acanthocytosis and McLeod syndrome, acanthocytes can also be seen in 10% of
Huntington disease–like 2 and pantothenate kinase–associated neurodegeneration as well as
abetalipoproteinemia and aceruloplasminemia.
• Patients with McLeod syndrome can benefit from cardiac surveillance and autologous blood transfusion.
• Caudate atrophy is not specific to Huntington disease and can also be seen in other disorders, such
aschorea-acanthocytosis and Huntington disease–like 2.
• Benign hereditary chorea syndromes can be due to multiple mutations; the classic benign hereditary chorea
is due to NKX2-1 (TITF) mutations. Some patients with NKX2-1–related benign hereditary chorea can
paradoxically respond to levodopa.
• Patients with choreic disorders can benefit from a multidisciplinary approach. Associated features and
comorbidities, such as cognitive and neuropsychiatric features, should be taken into consideration when
treating chorea. Mild and nonbothersome chorea does not require treatment. Immunotherapies are
treatment options in Sydenham chorea.
• The main pharmacologic targets of chorea are dopaminergic synapses, either at presynaptic orpostsynaptic
sites.

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Article 7: Ataxia
Sheng-Han Kuo, MD. Continuum (Minneap Minn). August 2019; 25 (4 Movement
Disorders):1036–1054.

ABSTRACT
PURPOSE OF REVIEW:
This article reviews the symptoms, laboratory and neuroimaging diagnostic tests, genetics, and
management of cerebellarataxia.
RECENT FINDINGS:
Recent advances in genetics have led to the identificationof novel genetic causes for ataxia and
a more comprehensive understanding of the biological pathways critical for normal cerebellar
function.When these molecular pathways become dysfunctional, patients develop cerebellar
ataxia. In addition, several ongoing clinical trials for Friedreich ataxia and spinocerebellar ataxia
will likely result in novel symptomatic and disease-modifying therapies for ataxia. Antisense
oligonucleotides for spinocerebellar ataxias associated with CAG repeat expansions might be a
promising therapeutic strategy.
SUMMARY:
Cerebellar ataxias include heterogeneous disorders affecting cerebellar function, leading to
ataxic symptoms. Step-by-step diagnosticworkups with genetic investigations are likely to
reveal the underlying causes of ataxia. Some disease-specific therapies for ataxia exist, such as
vitamin E for ataxia with vitamin E deficiency and thiamine for Wernicke encephalopathy,
highlighting the importance of recognizing these forms of ataxia. Finally, genetic diagnosis for
patients with ataxia will accelerate clinical trials for disease-modifying therapy and will have
prognostic value and implications for family planning for these patients.

KEY POINTS
• Determining the etiology of cerebellar ataxia iscomplex; however, step-by-step approaches can streamline
the diagnostic workflow.
• Key questions regarding difficulty running, trouble walking in high heels or barefoot on the beach, andveering
toward one side can be helpful in identifying the subtle gait abnormality associated with ataxia.
• Patients with ataxia can have a variety of eye movement abnormalities, including nystagmus, hypermetric or
hypometric saccades, and ophthalmoplegia.
• The gait abnormality associated with cerebellar ataxia can change over the course of the disease.
• After establishing the signs of cerebellar ataxia, look for other neurologic signs (eg, tremor, dystonia,
parkinsonism, motor neuron signs) as clues to the cause of ataxia.
• Laboratory evaluation can be helpful in identifying nutritional and immunologic causes of cerebellar ataxia.
• Aside from cerebellar atrophy, specific changes on MRI associated with different forms of cerebellar ataxia
can provide important diagnostic clues.

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 • The spinocerebellar ataxia nomenclature relates to the autosomal dominant causes of ataxia.
• Autosomal recessive ataxia can be divided into three categories: (1) cerebellar ataxia with predominant
sensory neuronopathy, (2) cerebellar ataxia with sensorimotor axonal neuropathy, and (3) cerebellar ataxia
without sensory neuropathy.
• Fragile X tremor-ataxia syndrome is the most common cause of X-linked ataxia.
• The first approach to the genetics of ataxia is to investigate for repeat expansions, which are the common
causes of autosomal dominant, recessive, and X-linked ataxia.
• Patients with multiple system atrophy can have cerebellar ataxia, parkinsonism, autonomic dysfunction, and
pyramidal signs.

Article 8: Myoclonus
John N. Caviness, MD, FAAN. Continuum (Minneap Minn). August 2019; 25 (4
Movement Disorders):1055–1080.

ABSTRACT
PURPOSE OF REVIEW:
This article offers clinicians a strategic approach for making sense of a symptom complex that
contains myoclonus. The article presents an evaluation strategy that highly leverages the two
major classification schemes of myoclonus. The goal of this article is to link evaluation strategy
with diagnosis and treatment of myoclonus.
RECENT FINDINGS:
The growth of medical literature has helped better define myoclonus etiologies. Physiologic
study of myoclonus types and etiologies with electrophysiologic testing has provided greater
clarity to the pathophysiology of the myoclonus in various diseases. Although studies have been
limited, the role of newer treatment agents and methods has made progress.
SUMMARY:
Myoclonus has hundreds of different etiologies. Classification is necessary to evaluate
myoclonus efficiently and pragmatically. The classification of myoclonus etiology, which is
grouped by different clinical presentations, helps determine the etiology and treatment of the
myoclonus. The classification of myoclonus physiology using electrophysiologic test results
helps determine the pathophysiology of the myoclonus and can be used to strategize
symptomatic treatment approaches. Both basic ancillary testing (including EEG and imaging) and
more comprehensive testing may be necessary. Treatment of the underlying etiology is the ideal
approach. However, if such treatment is not possible or is delayed, symptomatic treatment
guided by the myoclonus physiology should be considered. More controlled study of myoclonus
treatment is needed. Further research on myoclonus generation mechanisms should shed light
on future treatment possibilities.

KEY POINTS
• The brief, lightninglike muscle contraction defines it as myoclonus.
• Myoclonus is a symptom or sign, not a diagnosis. It occurs in multiple diseases and conditions.
• Evaluation for myoclonus begins with a comprehensive history and neurologic examination that allows the
clinical presentation classification into a physiologic, essential, epileptic, or symptomatic category.
• EEG should be the initial electrophysiologic testing for myoclonus without a determined etiology.

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 • Cortical myoclonus physiology is best defined by brief (<50 ms) EMG discharges and a focal EEG correlating
with the myoclonus. Enlarged cortical somatosensory evoked potential wave, abnormal long-latency EMG
reflex, and increased corticomuscular coherence are supportive but not confirmatory.
• Cortical-subcortical myoclonus physiology is best defined by generalized epileptiform discharges that occur
with the myoclonus. It most commonly takes the form of EEG generalized spike-and-wave discharges.
• Subcortical-nonsegmental myoclonus physiology is defined by one of two patterns: (1) initiation from the
brainstem or spinal cord followed by simultaneous rostral and caudal EMG recruitment or (2) multifocal
myoclonus EMG discharges. Both patterns show EMG discharges of more than 100 ms.
• Segmental myoclonus physiology is defined by low-frequency rhythmic myoclonus EMG discharges that
persist almost continuously, with more than 100 ms duration EMG discharges confined to a few contiguous
muscle segments.
• Peripheral myoclonus physiology is defined by a highly variable myoclonus EMG discharge duration confined
to a specific root, plexus, or peripheral nerve.
• Physiologic myoclonus is a normal phenomenon. Education and reassurance are usually the best treatments.
• Essential myoclonus is pathologic but chronic with little or no disability. It is not common.
• Epileptic myoclonus etiologies are chronic seizure disorders that have myoclonus as a prominent phenomenon.
• Symptomatic myoclonus is secondary to another disorder, neurologic or non-neurologic. Multiple other
symptoms and signs are usually present or tied to definable pathology.
• A determined etiology for themyoclonus will allow the clinician to determine whether the underlying
myoclonus cause is treatable or curable.
• If treatment of the etiology of myoclonus is not possible or is delayed, then symptomatic treatment should
be considered if overall improvement is possible when weighing potential side effects.
• Symptomatic treatment best aligns with the myoclonus physiology classification. An agent that suppresses a
specific myoclonus physiology can potentially do that for all myoclonus cases with that common physiology.
• Cortical myoclonus treatments are also antiseizure agents and are able to reduce the hyperexcitability of the
cortex resulting in suppression of cortical myoclonus.
• Subcortical myoclonus agents operate at the subcortical movement areas such as the basal ganglia and
brainstem.
• Deep brain stimulation has been used successfully for the myoclonus-dystonia syndrome.
• Botulinum toxin injections have been used for segmental and peripheral myoclonus.

Article 9: Tardive Syndromes

Joseph H. Friedman, MD, FAAN, FANA. Continuum (Minneap Minn). August 2019; 25 (4
Movement Disorders):1081–1098.

ABSTRACT
PURPOSE OF REVIEW:
This article reviews the history, nosology, clinical features, epidemiology, and treatment of
tardive syndromes.
RECENT FINDINGS:
The major advance in the field of tardive syndromes has been the development and US Food and
Drug Administration (FDA) approval of two vesicular monoamine transporter type 2 inhibitors,
valbenazine and deutetrabenazine, for treating tardive syndromes. These medications are
derivatives of tetrabenazine and reduce dyskinetic movements by reducing dopamine
stimulation. Treatment is not curative, and the medications reduce, or “mask,” symptoms but
presumablywithout adding to the long-term risk of increased involuntary movements believed to

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accrue from suppressive treatment with dopamine receptor–blocking drugs. A confounding
advance has been the accumulation of data finding that second-generation antipsychotics, also
known as atypical antipsychotics, may not be safer than first-generation antipsychotics in
causing tardive syndromes. The public health risk of tardive syndromes may actually have
increased as some second-generation antipsychotics, widely promoted to both doctors and
patients, are increasingly used asantidepressants.
SUMMARY:
Tardive syndromes remain a public health risk. Second-generationantipsychotics have not been
proven to have less risk than first-generation drugs in causing tardive syndromes and are
nevertheless being used more widely to treat depression, bipolar disease, and insomnia.
Symptomatic treatment for tardive syndromes is available, although expensive.

KEY POINTS
• The relationship between tardive dyskinesia and antipsychotics took several years to establish and was
initially thought to be rare.
• All definitions of tardive dyskinesia or tardive syndromes require at least several weeks exposure to a drug
preceding the development of a new movement disorder that persists for several weeks while on the drug, or
off the drug, and is not better explained by an alternative etiology.
• There are several different tardive syndromes. Dyskinesia and stereotypies are very similar, while akathisia
and dystonia are very different. The others are rare. Patients may have more than one syndrome. It is
important to note that patients often have more than one tardive syndrome.
• While widely believed to represent dopamine supersensitivity, the pathophysiology of tardive syndromes
remains unknown, and no explanation explains the variety of tardive syndromes.
• Tardive syndromes remain a major problem for patients treated with dopamine receptor–blocking drugs.
While there are data to suggest that second-generation antipsychotics are less likely to cause a tardive
syndrome than first-generation antipsychotics, these data are not convincing, and the largest study
performed to answer this question did not find a difference.
• Deutetrabenazine and valbenazine are approved treatments for tardive syndromes, and probably work best
for nondystonic disorders. Replacing the neuroleptic with clozapine at a dose to treat the psychosis may be
very helpful, especially for dystonic syndromes.
• Botulinumtoxin is likely to be helpful for all focal dystonias, including tardive dystonias. Deep brain
stimulation, with globus pallidus interna as the target, may be helpful for dystonic or choreoathetoid tardive
disorders.

Article 10: Movement Disorders in

Children
Toni S. Pearson, MBBS; Roser Pons, MD. Continuum (Minneap Minn). August 2019; 25 (4
Movement Disorders):1099–1120.

ABSTRACT
PURPOSE OF REVIEW:
This article provides an overview of the clinical features and disorders associated with
movement disorders in childhood. This article discusses movement disorder phenomena and
their clinical presentation in infants and children and presents a diagnostic approach to
suspected genetic disorders with a focus on treatable conditions.

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RECENT FINDINGS:
Technologic advances inmolecular genetic testing over thepast decade continue to lead to the
discovery of new diseases. This article discusses the clinical presentation and early experience
with treatment for several recently described genetic forms of infantile-onset and
childhood-onset dystonia and chorea.
SUMMARY:
The clinical spectrum of pediatric movement disorders is broad and heterogeneous, ranging
from acute or transient self-limited conditions to conditions that cause profound lifelong motor
disability. Most movement disorders in childhood are chronic, and the large number of rare,
genetic conditions associated with pediatricmovement disorders can pose a significant
diagnostic challenge. Recognition of distinctive diagnostic clues in the history and examination
can facilitate the diagnosis of potentially treatable disorders.

KEY POINTS
• Many causes of childhood ataxia exist that may be broadly divided into acute, intermittent, and chronic
categories.
• Myoclonus can be physiologic (hypnic myoclonus), or it can be the manifestation of a broad range of systemic
disorders and metabolic derangements.
• Parkinsonism in children differs from parkinsonism in adults, often manifesting as bradykinesia/hypokinesia,
dystonia, and axial hypotonia; tremor is often absent.
• Neonates, infants, and toddlers may manifest with a number of benign and transient movement disorders
such as myoclonus, dystonia, or tremor; development is normal, and treatment is not required.
• The most common etiologies underlying acute movement disorders in a previously healthy child are
autoimmune, drug-induced, and psychogenic.
• In a child with a dyskinetic cerebral palsy phenotype, absent risk factors for perinatal brain injury, and normal
brain MRI, investigation for an underlying genetic disorder should be considered. Some genetic disorders
have disease-specific treatment that improves symptoms and developmental outcome.
• The primary monoamine neurotransmitter disorders comprise defects of enzymes, cofactors, and
transporters involved in the metabolism and homeostasis of the catecholamines and serotonin.
• In biogenic amine disorders, neuroimaging is usually normal, and diagnosis is confirmed with the analysis of
monoamine neurotransmitter metabolites and pterins in CSF and with molecular analysis.
• The epileptic-dyskinetic encephalopathies are a heterogeneous group of disorders that are associated with a
spectrum of movement disorders, most frequently chorea, but also dystonia and stereotypies.
• Huntington disease in childhood often presents with an akinetic-rigid syndrome rather than chorea.
• Myoclonus-dystonia is a rare genetic movement disorder characterized by a combination of nonepileptic
myoclonic jerks and dystonia.
• Myoclonus-dystonia is compatible with an active and normal life span; however, some patients have a
progressive course leading to considerable disability. Treatment is usually disappointing.
• Progressive myoclonic epilepsy is characterized by action myoclonus, epileptic seizures, and progressive
neurologic decline. The majority of genes involved in progressive myoclonic epilepsy encode lysosomal
proteins and are inherited in an autosomal recessive pattern. The largest group of progressive myoclonic
epilepsies are the neuronal ceroid lipofuscinosis.
• Juvenile parkinsonism refers to hereditary conditions with onset before the age of 21 years that clinically
resemble Parkinson disease but with different histopathologic characteristics.
• In juvenile parkinsonism disease, progression is slower than in idiopathic Parkinson disease. Patients have a
marked response to levodopa, although dyskinesias and motor fluctuations occur early.
• The classic genetic paroxysmal dyskinesias may be clinically distinguished from one another by the episode
triggers, episode duration, and the presence or absence of interictal neurologic features.

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Article 11: Psychogenic (Functional)
Movement Disorders
Mary Ann Thenganatt, MD; Joseph Jankovic, MD, FAAN. Continuum (Minneap Minn).
August 2019; 25 (4 Movement Disorders):1121–1140.

ABSTRACT
PURPOSE OF REVIEW:
This article reviews a practical approach to psychogenic movement disorders to help
neurologists identify and manage this complex group of disorders.
RECENT FINDINGS:
Psychogenic movement disorders, also referred to as functional movement disorders, describe
a group of disorders that includes tremor, dystonia, myoclonus, parkinsonism, speech and
gait disturbances, and other movement disorders that are incongruent with patterns of
pathophysiologic (organic) disease. The diagnosis is based on positive clinical features that
include variability, inconsistency, suggestibility, distractibility, suppressibility, and other
supporting information. While psychogenic movement disorders are often associated with
psychological and physical stressors, the underlying pathophysiology is not fully understood.
Although insight-oriented behavioral and pharmacologic therapies are helpful, a multidisciplinary
approach led by a neurologist, but also including psychiatrists and physical, occupational, and
speech therapists, is needed for optimal outcomes.
SUMMARY:
The diagnosis of psychogenic movement disorders is based on clinical features identified on
neurologic examination, and neurophysiologic and imaging studies can provide supporting
information.

KEY POINTS
• Early diagnosis of a psychogenic movement disorder is important as longer duration of symptoms is
associated with poor outcome.
• Diagnosis of a psychogenic movement disorder is based on positive signs and symptoms and isnot a diagnosis
of exclusion.
• Psychogenic movement disorders are typically sudden in onset and rapidly progress to severe disability.
• In patients with psychogenic tremor, variability of tremor frequency and direction is common, as well as
suggestibility, distractibility, and entrainability.
• Total body tremor is a typical manifestation of psychogenic tremor, including a bobbing of the head and
trunk.
• A rapid-onset fixed dystonia is the typical phenotype of psychogenic dystonia.
• A clinical diagnosis of propriospinal myoclonus is unreliable, and more than 50% of cases are psychogenic.
• Psychogenic gait often presents as slowness and buckling at the knees, dramatic compensatory measures,
and improvement with minimal support.
• Psychogenic parkinsonism often coexists with organic parkinsonism.
• Psychogenic facial spasms are typically tonic contractions of the lower face with ipsilateral platysma
contraction and downward deviation of the lip.
• Psychogenic tics typically lack a premonitory urge, suppressibility, and often lack a family or childhood
history of tics.

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• Psychogenic paroxysmal dyskinesias have variable duration and phenomenology and often have atypical
triggers.
• The neurologist’s role involves explaining the diagnosis, providing educational information, coordinating
treatment and providing neurologic follow-up to patients diagnosed with psychogenic movement disorders.
• Patients with psychogenic movement disorders may benefit from psychotherapy and psychotropic
medications to treat depression and anxiety.
• Specialized physical therapy focusing on motor retraining can be helpful for patients with psychogenic
movement disorders.
• Functional MRI studies have demonstrated impaired self-agency and dysfunctional emotional processing in
patients with psychogenic movement disorders.

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