Review Article

Diagnosis and
Address correspondence to
Dr Vicki Shanker, Mount Sinai
Beth Israel, Phillips Ambulatory
Care Center, 10 Union Square

Management of East, Suite 5H, New York, NY

10003, vshanker@chpnet.org.
Relationship Disclosure:

Dystonia Dr Shanker reports no

disclosure. Dr Bressman
receives personal compensation
for serving on the scientific
Vicki Shanker, MD; Susan B. Bressman, MD, FAAN advisory boards of the
Bachmann-Strauss Dystonia &
Parkinson Foundation, Inc and
the Michael J. Fox Foundation
ABSTRACT and for serving on the editorial
Purpose of Review: This article highlights the clinical and diagnostic tools used to board of Movement Disorders.
assess and classify dystonia and provides an overview of the treatment approach. Dr Bressman receives
research/grant support from
Recent Findings: In the past 4 years, the definition and classification of dystonia the Michael J. Fox Foundation.
have been revised, and new genes have been identified in patients with isolated Unlabeled Use of
hereditary dystonia (DYT23, DYT24, and DYT25). Expanded phenotypes were reported Products/Investigational
Use Disclosure:
in patients with combined dystonia, such as those with mutations in ATP1A3. Treatment Drs Shanker and Bressman
offerings have expanded as there are more neurotoxins, and deep brain stimulation discuss the unlabeled/
has been employed successfully in diverse populations of patients with dystonia. investigational use of oral
medications for the treatment
Summary: Diagnosis of dystonia rests upon a clinical assessment that requires of dystonia, none of which are
the examiner to understand the characteristic disease features that are elicited approved by the US Food and
through a careful history and physical examination. The revised classification system Drug Administration.
uses two distinct nonoverlapping axes: clinical features and etiology. A growing * 2016 American Academy
of Neurology.
understanding exists of both isolated and combined dystonia as new genes are
identified and our knowledge of the phenotypic presentation of previously reported
genes has expanded. Genetic testing is commercially available for some of these
conditions. Treatment options for dystonia include pharmacologic therapy, chemo-
denervation, and surgical intervention. Deep brain stimulation benefits many patients
with various types of dystonia.

Continuum (Minneap Minn) 2016;22(4):12271245.

INTRODUCTION dated classification system character-

Dystonia is characterized by sustained
or intermittent muscle contraction caus-
ing abnormal, often repetitive move-
ments, postures, or both. Recognition
of the patients historical and clinical
features is essential to achieving the
diagnosis. Once identified, classification
is necessary to guide further evaluation
and treatment. This article reviews the
key clinical features of dystonia, the cur-
rent system of classification of dystonia,
and the current approach to treatment.
DIAGNOSIS OF DYSTONIA
An understanding of dystonia phenom-
enology is vital to an accurate and
thorough patient assessment. An up-
izes dystonia on two axes, the first of
which is dependent on the clinical
presentation, and the second of which
is dependent on etiology as defined by
supportive testing. Both the phenom-
enology and classification system are
reviewed in the following sections.
Phenomenology
Dystonia is a hyperkinetic movement
disorder characterized by involuntary Supplemental digital content:
Videos accompanying this ar-
muscle contractions often initiated or ticle are cited in the text as
worsened by voluntary action. The mus- Supplemental Digital Content.
Videos may be accessed by
cles involved in the action (eg, writing, clicking on links provided in the
foot tapping) are typically the same HTML, PDF, and app versions
of this article; the URLs are pro-
muscles affected by dystonia, but dys- vided in the print version. Video
tonic contractions can occur distant legends begin on page 1241.

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 Dystonia
KEY POINTS
h Dystonia is a from the action as overflow (eg, foot
hyperkinetic movement tapping on the right produces dysto-
disorder characterized nia in the resting left foot). When con-
by involuntary muscle tractions are sustained, they produce
contractions often twisted or abnormal postures. These
initiated or worsened by postures have a characteristic direction-
voluntary action. ality, referred to as patterning. When
h In 2013 a consensus contractions are intermittent, they fre-
document presented a quently produce tremorlike activity or
revised classification jerky movements.1 The amplitude of
that categorized dystonic tremors is enhanced when the
dystonia into two affected area is positioned against the
nonoverlapping axes. direction of the pull (ie, turning the neck
Axis I categorizes to the right in a patient with left cervical
dystonia by the clinical
dystonia). Likewise, dystonic movements
features and axis II
may subside when the affected area is
by etiology.
placed in the maximum direction of the
h DYT-TOR1A and pull. This placement is identified as the
DYT-THAP1 are the
null point. Another characteristic, but
most common genetic
not universal, feature in dystonia is the
causes of isolated
dystonia, and commercial
sensory trick, or geste antagoniste, which
testing is available describes a tactile or proprioceptive
for both. maneuver performed to minimize the
dystonic movement.2 For example, plac-
ing a scarf around the neck may de-
crease cervical dystonia. Even the
thought of performing the trick can
reduce the dystonic movement.3 Pa-
tients may have several tricks, and tricks
may vary among individuals.
Classification
Classification schemas for dystonia have
evolved since first formulated in the
1980s. In 2013 a consensus document
presented a revised classification that
categorized dystonia into two nonover-
lapping axes.1 Axis I categorizes dysto-
nia by the clinical features and axis II
by etiology. Clinical features in axis I
include the age of onset, affected body
region, temporal pattern, and associ-
ated features, as defined in Table 10-1.
Axis II delineates the etiology of the
dystonia and contains two approaches
to etiology: (1) Is there neuropathology
(degeneration, static/structural, or nei-
ther)? (2) Is there a cause (genetic, ac-
quired, or neither [idiopathic])? The
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group characterized as idiopathic is
fluid, as causative genes may be dis-
covered, and patients will subsequently
be recategorized.
Diagnostic evaluation, including ge-
netic testing, requires an understanding
of the clinical phenotypes associated
with specific etiologies; this presents a
daunting challenge as we discover new
genetic etiologies and as we learn about
the variation in clinical expression of a
genotype. DYT-TOR1A and DYT-THAP1
are the most common genetic causes of
isolated dystonia, and commercial test-
ing is available for both. DYT-TOR1A
has autosomal dominant inheritance
with reduced penetrance estimated at
30%. One recurring TOR1A mutation,
a deletion of one of a pair of GAG triplets
coding for glutamic acid, is responsible
for almost all dystonia associated with
this gene. TOR1A encodes the protein
torsinA that resides in the endoplasmic
reticulum system. Its normal biological
function is still under study and thought
to involve protein trafficking; further-
more, recent work using TOR1A mutant
models demonstrated a loss of normal
function with activation of endoplasmic
reticulum stress and discrete neurode-
generation.4 TOR1A dystonia is more
common in the Ashkenazi Jewish pop-
ulation, which has a carrier mutation
frequency of 1:1000 to 1:3000, approx-
imately sixfold higher than the general
population. The mean age of onset is
13 years of age with an initial presen-
tation typically in an arm or a leg; leg
onset is often younger than arm onset
(mean of 9 years versus 15 years of age).
Spread to other limbs often occurs, al-
though almost one-fourth of affected
patients remain as focal dystonia; fur-
thermore, the cranial muscles are usu-
ally spared. DYT-THAP1 is also autosomal
dominant with reduced penetrance ap-
proximated at 60% and is caused by
mutations in THAP1 (Thanatos-associated
protein domain containing apoptosis
August 2016
 KEY POINT

TABLE 10-1 New Axis I Dystonia Classifications h Since the advent of

next-generation
b Age of Onset sequencing, three
additional genes have
Infancy (birthY2 years) been reported to cause
Childhood (3Y12 years) isolated adult-onset
dystonia: DYT-CIZ1,
Adolescence (13Y20 years)
DYT-ANO3, and
Early adulthood (21Y40 years) DYT-GNAL.
Late adulthood (940 years)
b Affected Body Region
Focal: One body region
Segmental: Two or more contiguous regions
Multifocal: Two or more noncontiguous regions
Hemidystonia: Multiple regions on one body side
Generalized: Trunk and two or more body regions (with or without leg)
b Temporal Pattern
Static
Progressive
Variability
Persistent dystonia
Action specific
Diurnal: Symptom occurrence and severity fluctuates with circadian variation
Paroxysmal: Self-limited episodes
b Associated Features
Isolated: Dystonia with or without tremor
Combineda:
Dystonia with other movement disorders (ie, myoclonus, parkinsonism)
Dystonia with other neurologic manifestations (ie, ataxia, dementia)
Dystonia with systemic manifestations (ie, organomegaly)
a
These groups are not mutually exclusive.

associated protein 1). The mean age of
onset is 16 years, and the usual site of
onset involves brachial, cervical, or cra-
nial muscles, and unlike DYT-TOR1A,
speech is often affected. DYT-THAP1
dystonia may remain as a focal dystonia;
however, more commonly, it becomes
segmental or generalized.
Since the advent of next-generation
sequencing, three additional genes have
been reported to cause isolated adult-
onset dystonia: DYT-CIZ1, DYT-ANO3,
and DYT-GNAL. Prior to these discov-
eries, little was known about the cause
of isolated adult-onset dystonia. All three
conditions have autosomal dominant
inheritance. Commercial testing is not
currently available for these mutations.
CIZ1 (cyclin-dependent kinase inhib-
itor 1AYinteracting zinc finger protein 1)

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 Dystonia

KEY POINT
h The most common cause
of dopa-responsive
dystonia is mutations in
GCH1, which encodes
the rate-limiting enzyme
in the biosynthesis of
tetrahydrobiopterin.
was identified in a large white kindred
with adult-onset cervical dystonia.4
Subsequent screens have identified rare
or no pathogenic variants, suggesting
this gene very rarely underlies dysto-
nia.5,6 ANO3 (anoctamin 3) mutations
manifest as tremor-predominant cervi-
cal dystonia. Dystonia may also begin
or spread to involve brachial, laryngeal,
or facial muscles. Some patients have
myocloniclike jerks in the head or arms
and the age of onset is broad, ranging
from childhood (4 to 5 years of age) to
adulthood (40 years of age).7 GNAL mu-
tations were first identified in two fam-
ilies and then confirmed in about 15
additional families; this disorder is in-
herited in an autosomal dominant fash-
ion and produces a phenotype usually
marked by adult-onset cervical and cra-
nial dystonia (either focal or segmental,
with rare early onset or generalization).
The GNAL (G protein subunit alpha L)
encoded protein (G"olf) couples the
dopamine D1 receptor of the direct
pathway and adenosine A2A receptor
of the indirect pathway to the activation
of adenylate cyclase type 5 (ADCY5), re-
sulting in adenosine 3,5-cyclic mon-
ophosphate (cAMP) production.8 With
population screening, the mutation
accounts for only a very small propor-
tion (1% to 2%) of cervical dystonia in
adults. The full phenotypic spectrum and
penetrance requires additional study.8,9
Many of the combined dystonias have
identified genes as well. Dopa-responsive
dystonia is due to deficiencies in en-
zymes involved in the biosynthesis of
dopamine. The most common cause
of dopa-responsive dystonia is muta-
tions in GCH1, which encodes the rate-
limiting enzyme in the biosynthesis of
tetrahydrobiopterin. Commercially
available DNA tests include gene se-
quencing and also testing for deletions
and duplications. CSF analysis and
phenylalanine loading testing are sup-
plementary tests that can assist in
making the diagnosis. Most often,
GCH1mutations cause a childhood
onset disorder that is inherited domi-
nantly with reduced penetrance.
Symptoms are predominantly dystonic
and often diurnal. Mean age of onset
ranges between 6 and 12 years of age,
with larger studies favoring an older age
of onset.10 Girls are more likely to be
affected. Case 10-1 illustrates a case of
dopa-responsive dystonia. Younger

Case 10-1
An 11-year-old girl presented for gait evaluation. Her mother had had a
normal pregnancy, and there were no complications at birth. The patient
walked at 9.5 months but her parents noted that her gait was clumsy and her
toes pointed inward. She walked better in the morning than in the evening.
Prior assessments included a diagnosis of femoral anteversion from a pediatric
orthopedist and cerebral palsy from a neurologist. When she was 6 years old,
she developed clenching of her left hand. The patient had a normal MRI of
her brain and spine. At the time of presentation, her parents noted new right
hand clenching and retrocollis when walking. Family history was significant
for a paternal grandfather with Parkinson disease. Neurologic examination
was pertinent for increased patellar reflexes. While sitting, there was mild
retrocollis and intoeing of both feet. There was dystonic posturing in both
arms (left greater than right) and legs when performing activities in the
limbs. Dystonic posturing was noted in all limbs when walking. She was
started on one-half of a 25 mg/100 mg tablet of carbidopa/levodopa per
day, and she was slowly increased to a whole 25 mg/100 mg tablet 2 times per
Continued on page 1231

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 KEY POINTS
Continued from page 1230 h Rapid-onset
day and became asymptomatic. A diagnosis of dopa-responsive dystonia was
dystonia-parkinsonism is
made and was ultimately confirmed with genetic testing. Her examination
another combined
pre- and postlevodopa is shown in Supplemental Digital Content 10-1,
dystonia associated with
links.lww.com/CONT/A198.
parkinsonian features
Comment. Dopa-responsive dystonia should be considered in the evaluation with an identified
of all children presenting with dystonic symptoms. Clinical clues of genetic origin: mutations
dopa-responsive dystonia in this patient included diurnal variation and a in ATP1A3.
family history of parkinsonism. Levodopa therapy can completely eliminate
symptoms in the majority of cases. Early intervention can make a significant h Myoclonus-dystonia is
impact in the quality of the patients life. a syndrome most
commonly associated
patients often develop segmental or tions in sepiapterin reductase (SPR) are with mutations in the
generalized dystonia with greatest se- another cause of dopa-responsive dys- sarcoglycan epsilon
verity in the lower extremities; tonia. Onset is usually in the first year gene (SGCE).
hyperreflexia may be present. Chil- of life. Up to 75% of patients have an
dren may manifest parkinsonian fea- oculogyric crisis in the first 10 months
tures such as bradykinesia and rigidity, of life. Dystonia is not universally pres-
and presentation in adults may mimic ent in patients with SPR mutations.
Parkinson disease. Patients are also Parkinsonism may be seen as well.
more likely to have comorbid psychiat- Rapid-onset dystonia-parkinsonism
ric conditions such as obsessive-com- is another combined dystonia associ-
pulsive disorder, depression, or anxiety. ated with parkinsonian features with
Atypical presentations, which include an identified genetic origin: mutations
oculogyric crisis, tics, and myoclonus, in ATP1A3. The phenotype is marked
have been reported. Autosomal reces- by generalized or segmental dystonia
sive GCH1 deficiency was reported; it and parkinsonism; usually the bulbar
causes more severe symptoms, such as muscles are most severely affected. A
truncal hypotonia, diffuse spasticity, or hallmark feature present in most but
oculogyric episodes. Tyrosine hydroxy- not all is rapid onset or worsening of
lase deficiency is a rare, autosomal symptoms over hours to days, often
recessive cause of dopa-responsive dys- after an emotional or physical trigger.
tonia due to mutations to the TH gene Patients are generally poorly responsive
on chromosome 11. Patients have an to oral medications, including levo-
age of onset ranging from weeks after dopa. Alternating hemiplegia of child-
birth until 6 years of age. A range of hood and cerebellar ataxia, areflexia,
phenotypes exists, from a dopa- pes cavus, optic atrophy, and sensori-
responsive dystoniaYlike phenotype neural hearing loss (CAPOS) syndrome
with dystonia and mild parkinsonism are also caused by mutations in ATP1A3.
responsive to levodopa, to severe dis- Alternating hemiplegia of childhood,
ease seen in those with onset in infancy CAPOS syndrome, and rapid-onset
where there may be a progressive dystonia-parkinsonism differ in certain
encephalopathy and a variable re- clinical features, including age of onset,
sponse to levodopa. Clinical features in but also share features consistent with
severe cases include truncal hypotonia, their shared genetic etiology.11
severe hypokinesia, oculogyric crises, Myoclonus-dystonia is a syndrome
ptosis, and paroxysmal periods of leth- most commonly associated with mu-
argy associated with increased sweating tations in the sarcoglycan epsilon gene
and drooling as well as a marked delay (SGCE). Patients typically present in
in motor development. Biallelic muta- childhood and inheritance is autosomal

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 Dystonia
KEY POINTS
h The movement disorder dominant with imprinting (the epige-
examination is crucial to netic process that leads to inactivation
identifying dystonia of a paternal or maternal allele) with
phenomenology and preferential expression of the paternal
includes several allele. Myoclonus (which is the promi-
elements not routinely nent feature) and dystonia are most
included in the frequently present in the cervical area
neurologic examination. and the upper extremities. Symptoms
h Additional studies such often improve with alcohol. However,
as genetic testing and patients are at risk for developing
neuroimaging may be alcohol dependence, which is seen in
required to characterize approximately one-fourth of manifest-
a patient with dystonia ing carriers. Comorbid psychiatric diag-
along axis II of the noses are common with social and
classification system.
specific phobias present in one-third
of manifesting carriers. An excess of
major affective disorder and obsessive-
compulsive disorder have been re-
ported.12 A missense mutation in
CACNA1B was recently identified in
one family with myoclonus-dystonia
and may also be associated with car-
diac arrhythmias. Painful limb cramps
and continuous high-frequency leg my-
oclonus were also present in some of
this population.13
Paroxysmal kinesigenic dyskinesia
is a condition where frequent brief
(seconds to minutes) hyperkinetic
movements, including dystonia, are
triggered with activity. Attacks are often
preceded with a sensory warning. Mu-
tations in PRRT2 (proline-rich trans-
membrane protein 2) on chromosome
16 can cause the disease state, which is
usually autosomal dominant.14,15 This
mutation is also associated with infan-
tile convulsions with choreoathetosis
with or without paroxysmal kinesigenic
dyskinesia, benign familial infantile
seizures, episodic ataxia, hemiplegic
migraine, and benign paroxysmal tor-
ticollis of infancy. Paroxysmal exertionY
induced dyskinesia and epilepsy can be
caused by mutations in SLC2A1, the
gene that encodes the glucose trans-
porter 1 (GLUT1) of the blood-brain
barrier.16 Paroxysmal nonkinesigenic dys-
kinesia is associated with mutations in
1232 www.ContinuumJournal.com
Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
PxMD-PNKD.17 Patients develop acute
dystonia, chorea, or ballistic movements
lasting minutes to hours. Attacks are
infrequent and are commonly triggered
by alcohol, caffeine, or stress.
All of the axis I features of dystonic
syndromes are obtained clinically. His-
tory should include a careful screen
for exposure to causative agents and a
detailed family history for movement
disorders. Patients should be asked
about the presence of any ameliorat-
ing or exacerbating features including
sensory tricks. The presence of depres-
sion and anxiety, which may be comor-
bid with many forms of dystonia, should
be assessed as well. The movement
disorder examination is crucial to iden-
tifying dystonia phenomenology and
includes several elements not routinely
included in the neurologic examina-
tion. Table 10-2 supplies features of
patient history and examination find-
ings that are helpful to the diagnosis.
Case 10-2 illustrates the importance
of clinical assessment in achieving the
correct diagnosis and treatment plan.
Additional studies may be required
to characterize the etiology of a pa-
tients dystonia, as listed in axis II of
the revised classification system. Aside
from neurologic signs, the clinical eval-
uation should include an ophthalmic
and general medical examination that
may point to a specific etiology (eg,
Kayser-Fleischer rings and Wilson dis-
ease). When concern exists for vocal
cord involvement, ear, nose, and throat
referral is recommended for fiberoptic
laryngoscopy. MRI of the brain or spinal
cord should be ordered if the history or
examination suggests an underlying
etiology associated with structural pa-
thology. In cases where the diagnosis of
dystonia due to a parkinsonian condition
is considered, a dopamine transporter
scan may be helpful. If the dopamine
transporter scan shows reduced striatal
dopamine terminals, Parkinson disease
August 2016
TABLE 10-2 Associated Clinical Features of Dystonia
Site of Assessment
Eyes (blepharospasm)
Vocal cords (laryngeal dystonia/ Change in voice quality; vocal tremor;
spasmodic dysphonia)
Neck (cervical dystonia)
Arms/hands (limb dystonia)
Legs/feet (limb dystonia)
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Historical Features Clinical Examination
18
Photophobia (common) ; other eye Stereotyped bilateral and synchronous
problems (ie, blepharitis, iritis, corneal orbicularis oculi spasms inducing
disease, or conjunctivitis); eyelid narrowing/closure of the eyelids19;
opening apraxia (rare) increased blinking
Have the patient sustain ahh or e
complaints of cough, paroxysmal sound for 7 seconds, listening for
sneezing, hiccups, or dyscoordinate phonatory breaks; Adductor
breathing (typically seen when involvement: Constant harsh or tight
vocal cords are one of many areas voice, intermittent pitch and voice
of involvement)20 breaks in the middle of a word, or
glottal stops with tremor in the
middle of the word21; Abductor
involvement: Constant whispering,
intermittent breathiness with
consonants at the beginnings of
words, or voice tremor with breathy
breaks at 4 Hz to 5 Hz in the middle
of words
Neck pain22,23; isolated neck tremor24 Look for muscle hypertrophy; examine
the neck in multiple positions (ie,
head to each shoulder, complete head
turn, chin to chest, head tilted
upward); ask the patient to close eyes
and allow the neck to move in the
direction it feels most comfortable
Cramping or tightness in the hand Writing tasks (ie, drawing spirals,
while writing or during prolonged drawing loops across a page, writing
activity of the limb; involuntary a sentence in cursive), may show a
hand movements tight grip of the pen, unusual
posturing of the hand that may
progress as the patient continues to
write, breaks in the writing, dystonic
mirroring/overflow in another limb,
and involvement of more proximal
muscles; with tremor, observe for
directionality and examine the arms
in positions to look for null point
Cramping of feet; toe curling; Observe leg movements including
involuntary foot/leg/hip movements stomping movements, toe tapping,
and rapid alternating movements
(heel/toe); look for torsion in limb as
well as overflow; movements may
be slow but will not diminish in
amplitude; symptoms improve when
walking backward
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 Dystonia

Case 10-2
A 65-year-old ambidextrous woman presented with a chief complaint of
head tremor, which developed when she was 30 years old. The tremor was
associated with an uncomfortable tightness in her neck muscles. She was
never exposed to dopamine-blocking medications prior to symptom onset.
The patients symptoms improved if she lightly touched her cheek and
when she turned her head to the left. She never had tremor in her voice or
in her limbs, and she denied symptoms of writers cramp. Her mother had a
neck tremor as an adult. The patient had been previously diagnosed with
essential tremor, and propranolol had been prescribed but did not improve
symptoms. On examination, there was hypertrophy in both sternocleidomastoid
muscles. She had a jerky, multidirectional neck tremor, notable for a null
point with head turn to the left and neck flexed. There was no tremor in the
arms (Supplemental Digital Content 10-2, links.lww.com/CONT/A199). She
was diagnosed with cervical dystonia with dystonic tremor. Symptoms improved
with botulinum toxin injections that were initially placed in the right
sternocleidomastoid muscle and left splenius cervicis muscle with EMG guidance.
Later injections sets were modified to include bilateral splenii muscles as
well as the right semispinalis capitis and right longissimus muscles.
Comment. The presence of a tremor in the neck is often associated with
essential tremor. However, essential tremor never presents with isolated
neck tremor. The presence of isolated neck tremor should raise suspicion
for an alternate diagnosis. In this case, the patient had a sensory trick, muscle
pain, muscle hypertrophy, and a null point, all suggestive of a diagnosis of
cervical dystonia. Early misdiagnosis led to an ineffective treatment plan.
Careful attention to history and the physical examination will allow the
clinician to offer effective treatments early in the disease.

or an atypical parkinsonian condition is fending agents that may cause or ex-

the likely diagnosis. However, a dopa-
mine transporter scan does not have
100% specificity or sensitivity, and
further follow-up of the patient will
be required.25
TREATMENT OF DYSTONIA
The approach to dystonia management
is often multidisciplinary and may in-
clude physical and psychological therapy.
Consideration of the patients age, symp-
tom location, symptom severity, and the
side effect profile of the proposed inter-
vention is vital when developing a man-
agement plan. Treatment can be classified
into oral medications, chemodenervation,
and surgical intervention.
Oral Medications
It is helpful to first review the patients
current medications to assess for of-
1234 www.ContinuumJournal.com
acerbate symptoms. Dopamine-blocking
medications are common offenders and
include some antiemetics (ie, prochlor-
perazine, metoclopramide) and antipsy-
chotics including newer generation and
atypical agents (ie, risperidone, olanza-
pine, ziprasidone, and aripiprazole)
as well as older, typical, agents. Rarely,
dystonia may be due to selective se-
rotonin reuptake inhibitors (SSRIs) such
as fluoxetine and serotonin norepi-
nephrine reuptake inhibitors (SNRIs),
including venlafaxine and duloxetine.26,27
Tapering and discontinuation of these
drugs often require coordinated care
with a psychiatrist or primary care phy-
sician as alternate medications may be
needed for underlying conditions.
Aside from drug-induced dystonia,
targeted, disease-specific treatments are
increasing as our understanding of
August 2016

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the etiology for the combined/complex
dystonia syndromes expands (eg,
GLUT1 deficiency, cerebrotendinous
xanthomatosis, manganese transport
disorder, Wilson disease).27,28 These
etiologies are rare, and a comprehen-
sive screening approach has yet to be
established (although this will no
doubt evolve with the increased ac-
cessibility to exome and genome se-
quencing). Table 10-3 reviews these
conditions and their treatments. One
targeted therapy that has been incor-
porated into clinical diagnostic practice
is treating children and adolescents,
especially those with diurnal variation,

TABLE 10-3 Treatment of Dystonia in Conditions With Disease-Modifying Therapies

Common Age of Onset Disease State Treatment

Infancy Aromatic L-amino acid
decarboxylase deficiency
Biotinidase deficiency
Cobalamin deficiencies
(inherited subtypes AYG)
Cerebral creatine deficiency
type 3
Guanidinoacetate
methyltransferase deficiency
Pyruvate dehydrogenase
deficiency
Early childhood to adolescence Cerebral folate deficiency
Propionic aciduria
Early childhood to adulthood Glutaricaciduria type 1
Niemann-Pick C disease
Wilson disease
Childhood Dystonia with brain
manganese accumulation
Homocystinuria
Maple syrup urine disease
Methylmalonic aciduria
Childhood to adulthood Abetalipoproteinemia
Ataxia with vitamin E deficiency
Cerebrotendinous
xanthomatosis
Galactosemia
Any age Coenzyme Q10 deficiency
Dopamine agonists, monoamine oxidase
inhibitors
Biotin
Cobalamin derivatives, protein restriction,
or both
Creatine
Arginine restriction, creatine, and ornithine
Thiamine, ketogenic diet, dichloroacetate
Folinic acid
Protein restriction, avoid or treat aggressively
any intercurrent illness
Lysine restriction, avoid or treat aggressively
any intercurrent illness
N-Butyldeoxynojirimycin (miglustat)
Zinc, penicillamine, trientine
Chelation therapy
Methionine restriction
Leucine restriction, thiamine
Protein restriction, avoid or treat
aggressively any intercurrent illness
Vitamin E, reduced-fat diet
Vitamin E
Chenodeoxycholic acid
Lactose restriction
Coenzyme Q10

Continuum (Minneap Minn) 2016;22(4):12271245 www.ContinuumJournal.com 1235

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

 Dystonia
KEY POINTS
h Targeted, disease-specific
treatments are increasing
as our understanding of
the etiology for the
combined/complex
dystonia syndromes
expands (eg,
GLUT1 deficiency,
cerebrotendinous
xanthomatosis,
manganese transport
disorder, Wilson disease).
h For most patients with
multifocal and
generalized dystonia,
oral medical therapy is
the first-line approach.
TABLE 10-4 Common Oral Medications Used in Treatment of Dystonia
Therapeutic Class and
Medication
Anticholinergic
Trihexyphenidyl
Benzodiazepine
Clonazepam
Diazepam
Dopamine precursor
Carbidopa/levodopa
Dopamine-depleting agents
Tetrabenazine
+-Aminobutyric acid B
(GABA-B) agonist
Baclofen
1236 www.ContinuumJournal.com
Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
with low-dose levodopa for possible
dopa-responsive dystonia (see the
following section on dopaminergic
medications).
For most patients with multifocal and
generalized dystonia, oral medical ther-
apy is the first-line approach. Medica-
tion options include carbidopa/levodopa,
anticholinergics (ie, trihexyphenidyl),
benzodiazepines, baclofen, and
dopamine-depleting agents. A sum-
mary of these medications, along with
common doses and side effects, are
listed in Table 10-4. With the exception
of a few special circumstances, no
controlled or randomized studies are
available to guide clinicians to choose
one drug over another.
Dopaminergic medications.
Carbidopa/levodopa is the standard
of care treatment for dopa-responsive
dystonia as patients characteristically
Therapeutic Daily Dose
(Typically Divided Into
2Y4 Times a Day Dosing)
6Y40 mg
1Y4 mg
10Y40 mg
75 mg/300 mgY500 mg/2000 mg
12.5Y100 mg
40Y120 mg
have a significant and sustained improve-
ment to low-dose therapy. A gradual
titration starting at 25 mg/d to 50 mg/d
of levodopa for children and 50 mg/d
to 100 mg/d of levodopa for adults is
recommended. Slow titration reduces
the risk of side effects such as nausea
and transient dyskinesias. Usually, a ro-
bust response occurs with 200 mg/d
to 300 mg/d but, in rare cases, higher
doses up to 1000 mg/d are needed.29
Wearing-off symptoms and motor fluc-
tuations are not commonly seen in re-
sponse to long-term use as they are
in patients with Parkinson disease. Pa-
tients with nonYdopa-responsive dys-
tonia, whether idiopathic, genetic, or
acquired, may also have a partial clin-
ical response to levodopa. Some cases
of dystonic tremor worsen with levo-
dopa.30 Patients with cerebral palsy may
not benefit from levodopa.31
Common Side Effect Profile
Blurry vision, confusion, constipation,
urinary retention, xerostomia
Drowsiness, fatigue, aspartate transaminase,
and alanine transaminase elevation
Drowsiness, fatigue
Nausea
Akathisia, anxiety/nervousness, depression/
suicidality, neuroleptic malignant syndrome,
parkinsonism, sleepiness
Drowsiness, fatigue, nausea, muscle weakness
August 2016

Antidopaminergic medications. Tetra-
benazine is an inhibitor of the vesicular
monoamine transporter type 2 in
the central nervous system, depleting
dopamine in addition to norepineph-
rine and serotonin. Tetrabenazine is
used off-label for the treatment of
dystonia. It may be most helpful in
patients with tardive dystonia, with
one retrospective chart review
reporting that 70% of patients with
tardive dystonia had moderate to excel-
lent response to the drug.32 A case
report described two siblings with
myoclonus-dystonia and SGCE muta-
tions who improved while taking
tetrabenazine 25 mg 3 times per
day.33 Dosing typically begins with
one-half of a 25 mg tablet and is slowly
titrated by 12.5 mg doses every 3 to
5 days to efficacy, with most patients
taking 50 mg to 100 mg divided into
2 or 3 daily doses. Reserpine is another
dopamine-depleting agent that has an
additional mechanism of action causing
irreversible inhibition of the vesicular
monoamine transporter type 1 in the
peripheral nervous system, which can
lead to peripheral side effects of diz-
ziness and gastrointestinal upset. For
this reason, tetrabenazine is the pre-
ferred dopamine-depleting agent. Pa-
tients taking dopamine-depleting agents
should be monitored for akathisia, par-
kinsonism, and depression.
In addition to the dopamine-depleting
agents, trials of clozapine, a D4 receptor
blocker, have shown moderate bene-
fits in various types of dystonia.34 Pa-
tients taking clozapine must enter a
registry and are monitored closely for
signs of developing agranulocytosis.
Patients with tardive dystonia may also
benefit when quetiapine replaces the
formerly used antipsychotic.35
Anticholinergic medications. Anti-
cholinergic medications are considered
first-line treatment in patients with gen-
eralized dystonia. Trihexyphenidyl is the
Continuum (Minneap Minn) 2016;22(4):12271245
Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
KEY POINTS
preferred anticholinergic agent and the h Carbidopa/levodopa is
only oral medication studied in a pro- the standard of care
spective double-blinded fashion for treatment for
the treatment of dystonia.36 Trihexy- dopa-responsive
phenidyl is considered a first-line dystonia as patients
therapy for dystonic tremor.37 The characteristically
proposed active mechanism is block- have a significant and
age of muscarinic acetylcholine recep- sustained improvement
tors in the basal ganglia and is usually to low-dose therapy.
started at a 1 mg/d dose (one-half of a h Tetrabenazine may be
2 mg tablet) and slowly titrated to most helpful in patients
efficacy or side effects. The medication with tardive dystonia,
is divided into doses given 2 to 4 times a with one retrospective
day. Typical therapeutic dosing ranges chart review reporting
that 70% of patients
from 4 mg/d to 40 mg/d, with adults
with tardive dystonia
usually tolerating only the lower end of
had moderate to
that range, whereas generally children excellent response
tolerate higher dosages, up to 100 mg/d. to the drug.
Patients should be counseled on the
h Trihexyphenidyl is the
potential side effects of this medication,
preferred anticholinergic
which include dry mouth, constipation, agent and the only oral
urinary retention, blurry vision, and medication studied
gastrointestinal upset. Potential central in a prospective
effects include confusion, memory im- double-blinded fashion
pairment, hallucinations, and fatigue. for the treatment
Patients should not receive anticholin- of dystonia.
ergics if they have a history of closed-
angle glaucoma. Pyridostigmine (30 mg/d
to 120 mg/d) is often prescribed con-
currently when patients reach higher
doses of trihexyphenidyl to counteract
the peripheral anticholinergic effects.
+-Aminobutyric acidYrelated drugs.
Despite the lack of double-blind and
controlled studies, benzodiazepines
such as clonazepam and diazepam
are commonly used in the treatment
of dystonia. These drugs are pos-
itive allosteric modulators of the
+-aminobutyric acid A (GABA-A) recep-
tor and are thought to amplify trans-
mission through the GABA receptors.
Retrospective studies have reported
benefit in tremor-predominant forms
of dystonia, myoclonus-dystonia, ble-
pharospasm, dystonia associated with
spasticity, and paroxysmal dyskinesias
with prominent dystonia.38Y40 Clo-
nazepam is commonly used for the
www.ContinuumJournal.com 1237
 Dystonia
KEY POINTS
h Baclofen is a
+-aminobutyric acid B
receptor agonist
reported in several
retrospective studies to
demonstrate benefit in
dystonia management,
especially in children
with comorbid dystonia
and spasticity.
h Chemodenervation with
botulinum neurotoxin is
first-line therapy for
most patients with focal
and segmental dystonia.
1238 www.ContinuumJournal.com
Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
treatment of paroxysmal nonkinesigenic
dyskinesia. Dosing is usually twice daily,
although, when initiated, often begins
with evening doses to offset possible
sedation. Titration should be slow. Im-
paired mentation and nausea are com-
mon side effects. Patients are instructed
to avoid sudden discontinuation of the
medication as cessation of large doses
can cause seizures and delirium.
Baclofen is a GABA-B receptor ago-
nist reported in several retrospective
studies to demonstrate benefit in dys-
tonia management, especially in chil-
dren with comorbid dystonia and
spasticity. Because of its mild side effect
profile, oral baclofen is frequently tried
in adults as well. Patients are often
started on 10 mg/d to 15 mg/d given in
2 to 3 equally divided doses per day and
effective doses range from 30 mg/d to
120 mg/d. Common side effects include
sedation, nausea, dizziness, hypotonia,
and impaired cognition. Continuous in-
trathecal baclofen is an alternative de-
livery method considered for children
with dystonia and leg spasticity or
cerebral palsy.41 Prior to surgical im-
plementation, a trial is conducted where
patient response to baclofen delivered
through a temporary catheter is as-
sessed. Intraventricular baclofen has
shown benefit in patients with symp-
tomatic generalized dystonia who are
refractory to oral medications. Patients
taking baclofen can also develop sei-
zures, delirium, rebound muscle rigid-
ity, rhabdomyolysis, hyperpyrexia, and
organ failure with abrupt discontinua-
tion of the baclofen; a slow taper off
the medication is recommended.
Sodium oxybate is the sodium salt
of +-hydroxybutyrate, a metabolite of
the neurotransmitter GABA. It is ap-
proved for use in cataplexy and exces-
sive daytime sleepiness in narcolepsy.
However there are reports that it is
helpful in myoclonus-dystonia and spas-
modic dysphonia.42,43 Effective doses
range from 1 g/d to 7.6 g/d. Sodium oxy-
bate is a Schedule III controlled substance,
which can cause significant central ner-
vous system and respiratory suppression.
Pharmacologic treatment in spe-
cial circumstances. Antiepileptic drugs
have variable benefit in dystonia. Car-
bamazepine is the exception, shown to
be beneficial in cases of paroxysmal
kinesigenic dyskinesia. In Wilson dis-
ease, a disorder of copper metabolism,
copper chelators such as peni-
cillamine and trientine are typically
first-line therapy. For more information,
refer to the article Wilson Disease by
Ronald F. Pfeiffer, MD, FAAN,44 in this
issue of Continuum. Acute medication-
induced dystonic reactions are dystonic
movements that can occur within mi-
nutes to hours of receiving a medi-
cation that causes a nigrostriatal D2
dopamine blockade. These episodes
are terminated commonly with the anti-
histamine diphenhydramine (25 mg to
50 mg IV or IM) or the anticholinergic
benztropine (1 mg to 2 mg IV or IM).
Chemodenervation
Chemodenervation with botulinum neu-
rotoxin is first-line therapy for most
patients with focal and segmental dys-
tonia. Patients with generalized dysto-
nia can also receive therapy to targeted
areas. Botulinum neurotoxin is a neu-
rotoxic protein that is produced by the
bacterium Clostridium botulinum. The
toxin is injected into the affected
muscle(s) and taken up into associated
motor neurons. The toxin then blocks
the vesicular release of acetylcholine
into the neuromuscular junction, ulti-
mately reducing the involuntary activity
of the affected muscles. Although
seven distinct serotypes (A to G) exist,
only types A and B are used commer-
cially and have US Food and Drug Ad-
ministration (FDA) approval for clinical
use. Serotype A is available as onabotu-
linumtoxinA, abobotulinumtoxinA, and
August 2016

incobotulinumtoxinA. Another type A
toxin has completed phase 3 trials and
is similar to incobotulinumtoxinA in
that it lacks complexing proteins.45
All three available serotype A toxins
are FDA approved for use in cervical
dystonia. OnabotulinumtoxinA and
incobotulinumtoxinA are FDA approved
for blepharospasm. OnabotulinumtoxinA,
abobotulinumtoxinA, and incobotuli-
numtoxinA are approved by the FDA
for upper limb spasticity and onabotu-
linumtoxinA is approved for lower limb
spasticity, but not specifically for limb
dystonia. Serotype B is available as
rimabotulinumtoxinB, which is ap-
proved for the use in patients with
cervical dystonia.
In 2016, the American Academy of
Neurology (AAN) released updated
guidelines for the use of botulinum
toxin in dystonia. The committee re-
ported that abobotulinumtoxinA and
rimabotulinumtoxinB are established
as effective and should be offered for the
treatment of cervical dystonia (Level A).
In addition, onabotulinumtoxinA and
incobotulinumtoxinA are probably ef-
fective and should be considered
(Level B) for use in cervical dystonia.
Level B evidence exists that onabotu-
linumtoxinA and incobotulinumtoxinA
are probably effective and should
be considered for blepharospasm.
AbobotulinumtoxinA is possibly effec-
tive and may be considered (Level C)
for blepharospasm.46 There were no
recommendations made for limb,
oromandibular, or laryngeal dystonia.
In 2013, an expert panel performed
a literature review and made recom-
mendations for the use of botulinum
toxin in dystonia.47,48 The committee
gave a Level B recommendation for
the use of abobotulinumtoxinA and
onabotulinumtoxinA for limb dystonia
and Level C recommendations for the use
of these toxins in oromandibular dystonia.
They reported a Level C recommendation
Continuum (Minneap Minn) 2016;22(4):12271245
Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
KEY POINT
for the use of onabotulinumtoxinA for h Selection of the specific
laryngeal dystonia. botulinum toxin may
Patients may begin to have symp- have to do with outside
tomatic benefit as early as 2 days after factors including
treatment, and maximum benefit is medication cost,
typically reported 2 to 6 weeks after physician experience
injection, after which a tapering off with toxin, and office
of efficacy occurs. Treatment benefit access to refrigeration.
usually persists for 2 and one-half to
4 months, such that most patients re-
quire treatments three to four times
per year. Injections should start at the
lowest doses in the recommended
range to decrease the risk of deleteri-
ous side effects. Side effects are typi-
cally local and occasionally are due to
diffusion of the toxin to unintended
locations adjacent to the intended
target. Patients injected for blepharo-
spasm may report dry eyes, focal
hematoma at the injection site, ptosis,
and rare diplopia. Patients with cervi-
cal dystonia may report dry mouth, ex-
cessive neck weakness, and, occasionally,
dysphagia. Patients with anterocollis
are more susceptible to developing
dysphagia due to the location of the
injections. Patients injected for limb
dystonia may develop weakness in the
injected limbs. Injections for vocal cord
adduction can cause hypophonia or
hoarseness. On rare occasions, patients
report dysphagia.
Typically, treatment for dystonia be-
gins with botulinum neurotoxin A;
however, comparison between the two
strains has not shown a marked differ-
ence in efficacy or side effects.49 Thus,
selection of toxin may have to do with
outside factors including medication
cost, physician experience with toxin,
and office access to refrigeration. EMG
or ultrasound are often used to assist
injections, especially in lower face,
neck, and limbs. A systematic review of
the literature, performed to assess the
impact of EMG and ultrasound on the
effectiveness of botulinum toxin type A,
reported Level I evidence that either
www.ContinuumJournal.com 1239
 Dystonia

KEY POINT
h Substantial data
suggest that patients
with DYT1 and isolated
non-DYT1 generalized
dystonia are most
responsive to deep brain
stimulation intervention.
instrument significantly improved injec-
tion outcomes.50
In the future, mapping of muscle
endplates may improve efficacy and re-
duce the side effects of toxin injection. A
study using high-density surface EMG
found that patients with cervical dysto-
nia had equal clinical benefit when
toxin was injected at half dose in the
motor unit endplates of the splenius
capitis or sternocleidomastoid mus-
cles compared to normal doses during
the patients traditional injections.51
Surgical Intervention
In 2003, deep brain stimulation (DBS)
received a humanitarian exemption by
the FDA for use in dystonia. Since this
time, it has emerged as first-line sur-
gical therapy for dystonia. The globus
pallidus internus (GPi) is the target for
most surgeries. In 2006, the first sham
study, including a group of 40 patients
with isolated segmental or generalized
dystonia, was published.52 Patients
receiving true stimulation had signifi-
cant improvement when compared to
the sham. Substantial data suggest that
patients with DYT1 and isolated non-
DYT1 generalized dystonia are most
responsive to DBS intervention.53 How-
ever, patients with DYT6 dystonia may
not have as robust of a response.54
More recent studies have shown im-
provement in patients with isolated
cervical dystonia resistant to chemode-
nervation, combined dystonia such as
myoclonus-dystonia, and dystonia in
other identified genetic and central
nervous system diseases.55,56 Case 10-3

Case 10-3
A 51-year-old man presented with a chief complaint of involuntary tongue
protrusion, dysphagia, increased salivation, and impaired speech progressing
over a 1-year period. He had not been exposed to dopamine-blocking
medication prior to symptom onset. On physical examination he had severe
dysarthria and hypometric saccades on vertical gaze. Motor examination
was pertinent for involuntary tongue protrusion with improvement when a
tongue depressor rested on the tongue, diffuse rigidity, dystonic posturing
of all four limbs, and truncal tilt to the right with retropulsion when walking.
Imaging was normal, as was video laryngoscopy. There was no significant
clinical response to trihexyphenidyl or clonazepam. Genetic testing revealed
a mutated allele (T) at DSC3 and a mutated allele (G) at DSC12 on his X
chromosome. This confirmed a diagnosis of X-linked dystonia-parkinsonism
(DYT3). The patient received bilateral globus pallidus internus (GPi) deep
brain stimulation (DBS). Early improvements were seen in the limbs. Two
years after surgery the patient had no involuntary tongue protrusion,
improved dysarthria and dysphagia, no limb involvement, and improved
truncal movements. Supplemental Digital Content 10-3, links.lww.com/
CONT/A200 illustrates this case pre- and post-DBS.
Comment. X-linked dystonia-parkinsonism is a condition that typically
presents in adulthood. The disease is also called Lubag disease from first
descriptions of the disease in subjects from the island of Panay in the
Philippines. Patients may have a focal onset, but dystonia typically generalizes.
This case demonstrates clinical improvement in a patient with DYT3 dystonia.
A recent case report and review of the literature found significant clinical
improvement in other patients with DYT3 dystonia.57 Benefits of DBS for
DYT1 are well reported. However, growing evidence suggests that other
genetic forms of dystonia may improve with surgical intervention.

1240 www.ContinuumJournal.com August 2016

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


illustrates the benefits of DBS in a pa-
tient with X-linked dystonia-parkinsonism.
MRI and intraoperative single-unit mi-
croelectrode as well as local field po-
tential recordings are used to ensure
proper placement. Placement of neu-
rostimulators in the chest and connec-
tion of the extension cables to the
neurostimulators are usually done in a
separate surgery under sedation. Patients
may have two single lead channels placed
bilaterally or one neurostimulator with
two channels leading to either side.
The surgical risks for all patients
who undergo DBS, including those with
Parkinson disease and essential tremor,
are reported as a 0.4% risk of death
in 30 days, a 1% risk of morbidity, and a
3% risk of intracranial bleed (many of
which are asymptomatic). However, it is
hypothesized that those with dystonia
have fewer complications as they typi-
cally undergo surgery at a younger age.53
It is estimated that hardware malfunc-
tion or infections may occur in as many
as 10% of patients over the course of a
lifetime.58 A 2014 randomized, sham-
controlled trial of pallidal stimulation in
patients with medication refractory
cervical dystonia reported adverse events
in 34% (n = 11) of those receiving
neurostimulation. Most events resolved
without sequelae, and five events were
serious and related to the placement of
the device or the device itself.59
Patients stimulators are programmed
in the office approximately 2 weeks
after the final stage of surgery. Children
with dystonia who receive GPi stimu-
lation may respond to low frequencies
(60 Hz to 80 Hz) while higher frequen-
cies (130 Hz to 180 Hz) are often used
in adults. Low frequency has an addi-
tional benefit of preserving battery life.
The pulse width used in dystonia ranges
between 60 2s to 210 2s.58,60 The initial
voltage is determined in the office and
is chosen based on physician prefer-
ence and the side effects experienced
Continuum (Minneap Minn) 2016;22(4):12271245
Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
KEY POINT
by the patient on testing. Patients with h Children with dystonia
dystonia often have a delayed response who receive globus
to stimulation with improvement be- pallidus internus
ginning in weeks to months. Initial stimulation may respond
programming is often modified every to low frequencies
few weeks during initial sessions, and (60 Hz to 80 Hz) while
intervals between later appointments higher frequencies
are lengthened to every few months. (130 Hz to 180 Hz) are
Mood and cognition do not appear to often used in adults.
worsen postsurgically.61,62 Speech does
not predictably worsen either.63
CONCLUSION
Dystonia is a hyperkinetic movement
disorder characterized by patterned sus-
tained or intermittent muscle contrac-
tions that can cause abnormal postures
or tremorlike movements. It is diag-
nosed clinically and characterized under
a recently revised classification system
designed to reflect the growing knowl-
edge of genetic etiologies. The approach
to treatment depends on the extent of
muscle involvement. In addition to phar-
macologic therapy, surgical intervention
is a treatment option for an increasing
group of affected patients. Growing un-
derstanding of the etiology and patho-
physiology of dystonia will allow more
targeted therapies in upcoming years.
VIDEO LEGENDS
Supplemental Digital
Content 10-1
Dopa-responsive dystonia pre-
treatment and posttreatment with
levodopa. Video shows an 11-year-old
girl who presented with generalized
dystonia that started with clumsy gait
and toe walking, which worsened in the
evening. On examination, dystonic pos-
turing in both arms, left greater than
right, and legs was present. When
walking, dystonic posturing was noted
in all limbs. She was prescribed
carbidopa/levodopa 25 mg/100 mg and
slowly increased to 500 mg/d of levodopa
in divided doses and became asymptom-
atic after treatment.
www.ContinuumJournal.com 1241
 Dystonia
links.lww.com/CONT/A198
B 2016 American Academy of Neurology.
Supplemental Digital
Content 10-2
Cervical dystonia misdiagnosed as
essential tremor. This video shows a
65-year-old woman who presented with
a 35-year history of head tremor that
was previously diagnosed as essential
tremor but was unresponsive to
medication for essential tremor. She
did not experience hand tremor, but
experienced neck tightness and en-
dorsed a sensory trick where tremor
improved when she lightly touched her
cheek. On examination, hypertrophy was
present in both sternocleidomastoid
muscles. She had a jerky, multidirec-
tional neck tremor, notable for a null
point with head turn to the left. Symp-
toms improved with botulinum toxin
injections, performed with EMG guid-
ance, in the bilateral sternocleidomastoid
muscles and bilateral splenius capitis
muscles. Further improvement was
later seen adding injections into the
right semispinalis capitis and right
longissimus muscles.
links.lww.com/CONT/A199
B 2016 American Academy of Neurology.
Supplemental Digital
Content 10-3
X-linked dystonia-parkinsonism
(Lubag disease) improved after
globus pallidus internus deep brain
stimulation. This video shows a 51-
year-old man with X-linked dystonia-
parkinsonism who presented with 1
year of progressive involuntary tongue
protrusion, dysphagia, increased saliva-
tion, and impaired speech. Motor exam-
ination was pertinent for involuntary
tongue protrusion, diffuse rigidity, dys-
tonic posturing of all four limbs, and
truncal tilt to the right with retropulsion
when walking. The patient received
1242 www.ContinuumJournal.com
Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
bilateral globus pallidus internus deep
brain stimulation. Two years after
surgery the patient had no involuntary
tongue protrusion, improved dysar-
thria and dysphagia, no limb involve-
ment, and improved truncal
movements as demonstrated in this
video showing the examination
pretreatment and posttreatment.
links.lww.com/CONT/A200
B 2016 American Academy of Neurology.
USEFUL WEBSITES
American Dystonia Society. The
American Dystonia society advocates
for veterans, Hispanics, and young
adults with dystonia and promotes gen-
eral public and governmental aware-
ness of the condition.
www.dystoniasociety.org
Bachmann-Strauss Dystonia &
Parkinson Foundation, Inc. The
Bachmann-Strauss Dystonia & Par-
kinson Foundation, Inc is a nonprofit
organization dedicated to finding bet-
ter treatments and cures for dystonia
and Parkinson disease. The organiza-
tion has a collaborative research alliance
with the Michael J. Fox Foundation for
Parkinsons Research.
www.dystonia-parkinsons.org
Benign Essential Blepharospasm
Research Foundation. The Benign
Essential Blepharospasm Research
Foundation searches for the cause and
cure of benign essential blepharo-
spasm and other related disorders.
www.blepharospasm.org
Dystonia Medical Research Foun-
dation. The Dystonia Medical Research
Foundation is dedicated to finding
a cure for dystonia while providing
support for individuals affected by
the condition.
www.dystonia-foundation.org
August 2016
National Center for Biotechnology
Information GeneReviews: Dystonia.
GeneReviews are expertly written dis-
ease descriptions and information
related to the diagnosis, management,
and genetic counseling of patients with
these conditions. This listing specifically
refers to dystonia.
www.ncbi.nlm.nih.gov/books/
NBK1155
National Institute of Neurological
Disorders and Stroke: Dystonia Fact
Sheet. The National Institute of Neuro-
logical Disorders and Stroke provides
information on the symptoms, classifi-
cation, and treatment of dystonia.
www.ninds.nih.gov/disorders/
dystonias/detail_dystonias.htm
National Spasmodic Torticollis Asso-
ciation. The National Spasmodic Torti-
collis Association supports individuals
and families affected by the condition,
promotes awareness, and advances
research for treatment.
www.torticollis.org
Spasmodic Torticollis Dystonia. The
Spasmodic Torticollis Dystonia organiza-
tion provides information and research
on the condition as well as doctor and
patient opinions on various treatments.
www.spasmodictorticollis.org
REFERENCES
1. Albanese A, Bhatia K, Bressman SB, et al.
Phenomenology and classification of dystonia:
a consensus update. Mov Disord 2013;28(7):
863Y873. doi:10.1002/mds.25475.
2. Deuschl G. Dystonic tremor. Rev Neurol
(Paris) 2003;159(10 pt 1):900Y905.
3. Greene PE, Bressman S. Exteroceptive and
interoceptive stimuli in dystonia. Mov Disord
1998;13(3):549Y551. doi:10.1002/mds.
870130329.
4. Liang CC, Tanabe LM, Jou S, et al. TorsinA
hypofunction causes abnormal twisting
movements and sensorimotor circuit
neurodegeneration. J Clin Invest 2014;124(7):
3080Y3092. doi:10.1172/JCI72830.
Continuum (Minneap Minn) 2016;22(4):12271245
Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
5. Dufke C, Hauser AK, Sturm M, et al.
Mutations in CIZ1 are not a major cause for
dystonia in Germany. Mov Disord 2015;30(5):
740Y743. doi:10.1002/mds.26198.
6. Ma L, Chen R, Wang L, et al. No mutations in
CIZ1 in twelve adult-onset primary cervical
dystonia families. Mov Disord 2013;28(13):
1899Y1901. doi:10.1002/mds.25542.
7. Charlesworth G, Plagnol V, Holmstrom KM,
et al. Mutations in ANO3 cause dominant
craniocervical dystonia: ion channel implicated
in pathogenesis. Am J Hum Genet 2012;91(6):
1041Y1050. doi:10.1016/j.ajhg.2012.10.024.
8. Fuchs T, Saunders-Pullman R, Masuho I, et al.
Mutations in GNAL cause primary torsion
dystonia. Nat Genet 2013;45(1):88Y92.
doi:10.1038/ng.2496.
9. Balint B, Bhatia KP. Isolated and combined
dystonia syndromesVan update on new
genes and their phenotypes. Eur J Neurol
2015;22(4):610Y617. doi:10.1111/ene.12650.
10. Wijemanne S, Jankovic J. Dopa-responsive
dystoniaVclinical and genetic heterogeneity.
Nat Rev Neurol 2015;11(7):414Y424.
doi:10.1038/nrneurol.2015.86.
11. Sweney MT, Newcomb TM, Swoboda KJ. The
expanding spectrum of neurological
phenotypes in children with ATP1A3 mutations,
Alternating Hemiplegia of Childhood,
Rapid-onset Dystonia-Parkinsonism, CAPOS
and beyond. Pediatr Neurol 2015;52(1):56Y64.
doi:10.1016/j.pediatrneurol.2014.09.015.
12. Peall KJ, Dijk JM, Saunders-Pullman R, et al.
Psychiatric disorders, myoclonus dystonia
and SGCE: an international study. Ann Clin
Transl Neuro 2016;3(1):4Y11. doi:10.1002/
acn3.263.
13. Groen JL, Andrade A, Ritz K, et al. CACNA1B
mutation is linked to unique myoclonus-dystonia
syndrome. Hum Mol Genet 2015;24(4):
987Y993. doi:10.1093/hmg/ddu513.
14. Wang JL, Cao L, Li XH, et al. Identification of
PRRT2 as the causative gene of paroxysmal
kinesigenic dyskinesias. Brain 2011;134(pt 12):
3493Y3501. doi:10.1093/brain/awr289.
15. Chen GH. Five cases of paroxysmal kinesigenic
dyskinesia by genetic diagnosis. Exp Ther Med
2015;9(3):909Y912. doi:10.3892/etm.2014.2155.
16. Suls A, Dedeken P, Goffin K, et al. Paroxysmal
exercise-induced dyskinesia and epilepsy is
due to mutations in SLC2A1, encoding the
glucose transporter GLUT1. Brain 2008;131(pt 7):
1831Y1844. doi:10.1093/brain/awn113.
17. Charlesworth G, Bhatia KP, Wood NW. The
genetics of dystonia: new twists in an old
tale. Brain 2013;136(pt 7):2017Y2037.
doi:10.1093/brain/awt138.
www.ContinuumJournal.com 1243
 Dystonia
18. Peckham EL, Lopez G, Shamim EA, et al.
Clinical features of patients with blepharospasm:
a report of 240 patients. Eur J Neurol
2011;18(3):382Y386. doi:10.1111/j.1468-1331.
2010.03161.x.
19. Defazio G, Hallett M, Jinnah HA, Berardelli A.
Development and validation of a clinical
guideline for diagnosing blepharospasm.
Neurology 2013;81(3):236Y240. doi:10.1212/
WNL.0b013e31829bfdf6.
20. Payne S, Tisch S, Cole I, et al. The clinical
spectrum of laryngeal dystonia includes
dystonic cough: observations of a large
series. Mov Disord 2014;29(6):729Y735.
doi:10.1002/mds.25865.
21. Grillone GA, Chan T. Laryngeal dystonia.
Otolaryngol Clin North Am 2006;39(1):
87Y100. doi:10.1007/s00415-014-7586-2.
22. Comella C, Bhatia K. An international survey
of patients with cervical dystonia. J Neurol
2015;262(4):837Y848. doi:10.1007/
s00415-014-7586-2.
23. Charles PD, Adler CH, Stacy M, et al. Cervical
dystonia and pain: characteristics and
treatment patterns from CD PROBE (Cervical
Dystonia Patient Registry for Observation
of OnabotulinumtoxinA Efficacy). J Neurol
2014;261(7):1309Y1319. doi:10.1007/
s00415-014-7343-6.
24. Louis ED, Dogu O. Isolated head tremor: part
of the clinical spectrum of essential tremor?
Data from population-based and clinic-based
case samples. Mov Disord 2009;24(15):
2281Y2285. doi:10.1002/mds.22777.
25. Schneider SA, Edwards MJ, Mir P, et al.
Patients with adult-onset dystonic tremor
resembling parkinsonian tremor have scans
without evidence of dopaminergic deficit
(SWEDDs). Mov Disord 2007;22(15):
2210Y2215. doi:10.1002/mds.21685.
26. Hawthorne JM, Caley CF. Extrapyramidal
reactions associated with serotonergic
antidepressants. Ann Pharmacother
2015;49(10):1136Y1152. doi:10.1177/
1060028015594812.
27. Mehta SH, Morgan JC, Sethi KD. Drug-induced
movement disorders. Neurol Clin 2015;33(1):
153Y174. doi:10.1016/j.ncl.2014.09.011.
28. Jinnah HA, Factor SA. Diagnosis and treatment
of dystonia. Neurol Clin 2015;33(1):77Y100.
doi:10.1016/j.ncl.2014.09.002.
29. Thenganatt MA, Jankovic J. Treatment of
dystonia. Neurotherapeutics 2014;11(1):
139Y152. doi:10.1007/s13311-013-0231-4.
30. Hensman DJ, Bain PG. Levodopa can worsen
tremor associated with dystonia. Mov Disord
2006;21(10):1778Y1780. doi:10.1002/mds.21043.
1244 www.ContinuumJournal.com
Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
31. Pozin I, Bdolah-Abram T, Ben-Pazi H. Levodopa
does not improve function in individuals with
dystonic cerebral palsy. J Child Neurol 2014;
29(4):534Y537. doi:10.1177/0883073812473645.
32. Kenney C, Hunter C, Jankovic J. Long-term
tolerability of tetrabenazine in the treatment
of hyperkinetic movement disorders. Mov
Disord 2007;22(2):193Y197. doi:10.1002/
mds.21222.
33. Luciano AY, Jinnah HA, Pfeiffer RF, et al.
Treatment of myoclonus-dystonia syndrome
with tetrabenazine. Parkinsonism Relat
Disord 2014;20(12):1423Y1426. doi:10.1016/
j.parkreldis.2014.09.029.
34. Illowsky Karp BI, Goldstein SR, Chen R, et al.
An open trial of clozapine for dystonia. Mov
Disord 1999;14(4):652Y657. doi:10.1002/
1531-8257(199907)14:4G652::AID-
MDS101593.0.CO;2-G.
35. Gourzis P, Skokou M, Soubasi E, et al.
Treatment of tardive dystonia induced by
antipsychotics, old and new. Clin
Neuropharmacol 2015;38(4):121Y126.
doi:10.1097/WNF.0000000000000086.
36. Burke RE, Fahn S, Marsden CD. Torsion dystonia:
a double-blind, prospective trial of
high-dosage trihexyphenidyl. Neurology 1986;
36(2):160Y164. doi:10. 1212/WNL.36.2.160.
37. Fasano A, Bove F, Lang AE. The treatment of
dystonic tremor: a systematic review.
J Neurol Neurosurg Psychiatry 2014;85(7):
759Y769. doi:10.1136/jnnp-2013-305532.
38. Kinugawa K, Vidailhet M, Clot F, et al.
Myoclonus-dystonia: an update. Mov Disord
2009;24(4):479Y489. doi:10.1002/mds.22425.
39. Strzelczyk A, Burk K, Oertel WH. Treatment
of paroxysmal dyskinesias. Expert Opin
Pharmacother 2011;12(1):63Y72.
doi:10.1517/14656566.2010.513971.
40. Greene P, Shale H, Fahn S. Experience with
high dosages of anticholinergic and other
drugs in the treatment of torsion dystonia.
Adv Neurol 1988;50:547Y556.
41. Albright AL, Ferson SS. Intraventricular baclofen
for dystonia: techniques and outcomes.
Clinical article. J Neurosurg Pediatr 2009;3(1):
11Y14. doi:10.3171/2008.10.PEDS0847.
42. Frucht SJ, Bordelon Y, Houghton WH,
Reardan D. A pilot tolerability and efficacy
trial of sodium oxybate in ethanol-responsive
movement disorders. Mov Disord 2005;20(10):
1330Y1337. doi:10.1002/mds.20605.
43. Simonyan K, Frucht SJ. Long-term effect of
sodium oxybate (XyremA) in spasmodic
dysphonia with vocal tremor. Tremor Other
Hyperkinet Mov (N Y) 2013;3. doi:10.7916/
D8CJ8C5S
August 2016
44. Pfeiffer RF. Wilson disease. Continuum
(Minneap Minn) 2016;22(4 Movement
Disorders):1246Y1261.
45. Walker TJ, Dayan SH. Comparison and
overview of currently available neurotoxins.
J Clin Aesthet Dermatol 2014;7(2):31Y39.
46. Simpson DM, Hallet M, Ashman EJ, et al.
Practice guideline update summary:
botulinum neurotoxin for the treatment of
blepharospasm, cervical dystonia, adult
spasticity, and headache. Neurology
2016;86(10):1818Y1826. doi:10.1212/wnl.
0000000000002560.
47. Simpson DM, Blitzer A, Brashear A, et al;
Assessment: botulinum neurotoxin for the
treatment of movement disorders (an
evidence-based review): report of the
Therapeutics and Technology Assessment
Subcommittee of the American Academy of
Neurology. Neurology 2008;70(19):
1699Y1706. doi:10.12/01.wnl.0000311389.
26145.95.48.
48. Hallett M, et al. Evidence-based review and
assessment of botulinum neurotoxin for the
treatment of movement disorders. Toxicon
2013;67:94Y114. doi:10.1016/j.toxicon.
2012.12.004.
49. Ramirez-Castaneda J, Jankovic J. Long-term
efficacy and safety of botulinum toxin
injections in dystonia. Toxins (Basel) 2013;5(2):
249Y266. doi:10.3390/toxins5020249.
50. Grigoriu AI, Dinomais M, Remy-Neris O,
Brochard S. Impact of injection-guiding
techniques on the effectiveness of botulinum
toxin for the treatment of focal spasticity and
dystonia: a systematic review. Arch Phys
Med Rehabil 2015;96(11):2067Y2078.e1.
doi:10.1016/j.apmr.2015.05.002.
51. Delnooz CC, Veugen LC, Pasman JW, et al.
The clinical utility of botulinum toxin
injections targeted at the motor endplate
zone in cervical dystonia. Eur J Neurol
2014;21(12):1486Ye98. doi:10.1111/ene.12517.
52. Kupsch A, Benecke R, Muller J, et al.
Pallidal deep-brain stimulation in primary
generalized or segmental dystonia. N Engl J
Med 2006;355(19):1978Y1990. doi:10.1056/
NEJMoa063618.
53. Fox MD, Alterman RL. Brain stimulation for
torsion dystonia. JAMA Neurol 2015;72(6):
713Y719. doi:10.1001/jamaneurol.2015.51.
Continuum (Minneap Minn) 2016;22(4):12271245
Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
54. Bruggemann N, Kuhn A, Schneider SA, et al.
Short- and long-term outcome of chronic
pallidal neurostimulation in monogenic
isolated dystonia. Neurology 2015;84(9):
895Y903. doi:10.1212/WNL.0000000000001312.
55. Roze E, Vidailhet M, Hubsch C, et al. Pallidal
stimulation for myoclonus-dystonia: ten
years outcome in two patients. Mov Disord
2015;30(6):871Y872. doi:10.1002/mds.26215.
56. Nam TM, Cho KR, Youn J, et al. Deep brain
stimulation in a dentatorubral-pallidoluyisian
atrophy patient with myoclonic dystonia.
J Clin Neurosci 2015;22(12):1976Y1978.
doi:10.1016/j.jocn.2015.04.010.
57. Patel AJ, Sarwar AI, Jankovic J, Viswanathan A.
Bilateral pallidal deep brain stimulation for
X-linked dystonia-parkinsonism. World
Neurosurg 2014;82(1-2):241.e1Y241.e4.
doi:10.1016/j.wneu.2013.09.039.
58. Kupsch A, Tagliati M, Vidailhet M, et al.
Early postoperative management of DBS in
dystonia: programming, response to
stimulation, adverse events, medication
changes, evaluations, and troubleshooting.
Mov Disord 2011;26(suppl 1):S37YS53.
doi:10.1002/mds.23624.
59. Volkmann J, Mueller J, Deuschl G, et al.
Pallidal neurostimulation in patients with
medication-refractory cervical dystonia: a
randomised, sham-controlled trial. Lancet
Neurol 2014;13(9):875Y884. doi:10.1016/
S1474-4422(14)70143-7.
60. Kim JP, Chang WS, Park YS, Chang JW.
Effects of relative low-frequency bilateral
globus pallidus internus stimulation for
treatment of cervical dystonia. Stereotact
Funct Neurosurg 2012;90(1):30Y36.
doi:10.1159/000333839.
61. Owen T, Gimeno H, Selway R, Lin JP. Cognitive
function in children with primary dystonia
before and after deep brain stimulation.
Eur J Paediatr Neurol 2015;19(1):48Y55.
doi:10.1016/j.ejpn.2014.09.004.
62. Meoni S, Zurowski M, Lozano AM, et al.
Long-term neuropsychiatric outcomes after
pallidal stimulation in primary and secondary
dystonia. Neurology 2015;85(5):433Y440.
doi:10.1212/WNL.0000000000001811.
63. Bressman SB, de Leon D, Brin MF, et al.
Inheritance of idiopathic torsion dystonia among
Ashkenazi Jews. Adv Neurol 1988;50:45Y56.
www.ContinuumJournal.com 1245