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Chorea

Article in CONTINUUM Lifelong Learning in Neurology · August 2016

DOI: 10.1212/CON.0000000000000349

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 Review Article

Chorea
Address correspondence to
Dr Tiago A. Mestre,
Parkinson’s Disease and
Movement Disorders Centre,
Civic Campus, The Ottawa Tiago A. Mestre, MSc, MD
Hospital, 1053 Carling Ave,
Rm 2174, Ottawa,
ON K1Y 4E9, Canada,
tmestre@toh.on.ca.
Relationship Disclosure:
ABSTRACT
Dr Mestre receives personal Purpose of Review: This article reviews the clinical approach to the diagnosis of
compensation for serving on adult patients presenting with chorea, using Huntington disease (HD) as a point of
the scientific advisory board
of AbbVie, for speaking reference, and presents the clinical elements that help in the diagnostic workup.
engagements for Teva Principles of management for chorea and some of the associated features of other choreic
Pharmaceutical Industries Ltd, syndromes are also described.
and for educational events
for WebMD. Dr Mestre Recent Findings: Mutations in the C9orf72 gene, previously identified in families
receives grant support from with a history of frontotemporal dementia, amyotrophic lateral sclerosis, or both,
the Parkinson Study have been recognized as one of the most prevalent causes of HD phenocopies in the
Group/Parkinson Disease
Foundation. white population.
Unlabeled Use Summary: The diagnosis of chorea in adult patients is challenging. A varied number
of Products/Investigational of associated causes require a physician to prioritize the investigations, and a detailed
Use Disclosure: history of chorea and associated findings will help. For chorea presenting as part of a
Dr Mestre reports
no disclosure. neurodegenerative syndrome, the consideration of a mutation in the C9orf72 gene is
* 2016 American Academy a new recommendation after excluding HD. There are no new treatment options for
of Neurology. chorea, aside from dopamine blockers and tetrabenazine. There are no disease-
modifying treatments for HD or other neurodegenerative choreic syndromes.

Continuum (Minneap Minn) 2016;22(4):1186–1207.

INTRODUCTION
HuntingtOn disease (HD) is the mOst
frequent cause Of a hereditary neurO-
degenerative chOreic syndrOme. HD
has a wOrldwide distributiOn with sOme
geOgraphic variability in its prevalence.
In NOrth America and EurOpe, the
average prevalence is 5 per 100,000
inhabitants.1 In patients with HD, the
initial symptOms Occur mOre fre-
quently between the ages Of 30 and
50, althOugh Onset can range frOm
childhOOd/adOlescence (juvenile fOrm,
alsO known as the Westphal variant) tO
individuals Older than 70 years Of age.
HD can present tO the clinician with
Supplemental digital content:
Videos accompanying this ar- One Of three symptOm cOmplexes class-
ticle are cited in the text as ically described in this cOnditiOn
Supplemental Digital Content.
Videos may be accessed by (mO- tOr, cOgnitive, and
clicking on links provided in the neurOpsychiatric) Or in cOmbinatiOn.
HTML, PDF, and app versions
of this article; the URLs are
The mOtOr symptOms include chOrea,
provided in the print version. Video dystOnia, and tics. ChOrea has been
legends begin on page 1204. classically used as the reference
manifestatiOn fOr a clin-
1186 www.ContinuumJournal.com
ical diagnosis. ParkinsOnism usually
develOps later in the cOurse Of the
disease. The juvenile fOrm Of HD pre-
sents as a predOminantly hypOkinetic
mOvement disOrder with parkinsOnism
but alsO myOclOnus. Of impOrtance, as
many as 7% Of subjects with a
clinical presentatiOn cOmpatible with
HD are fOund tO have a negative
genetic test
fOr HD and have been cOined ‘‘HD
2
phenocOpies.’’ Spinocerebellar ataxia
(SCA) type 17 (SCA17), alsO referred
tO as HuntingtOn diseaseYlike (HDL)
syndrOme type 4 (HDL4), and C9orf72-
related HD phenocOpy in pOpulatiOns
Of white individuals are cOnsidered the
3,4
mOst frequent alternative diagnoses.
The mOtOr and nonmOtOr elements
that help in the diagnostic wOrkup Of
HD phenocOpies in the adult will be
dis- cussed later in this article, and a
cOre de- scriptiOn of
neurOdegenerative chOreic syndrOmes
is prOvided in Table 8-1.
August 2016

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TABLE 8-1 Clues for Diagnosis and Investigations of Adult-Onset Neurodegenerative
Diseases With Chorea

Neurodegenerative
Relevant
Conditions
Demographics Core Features Useful Investigations
Most common neurodegenerative choreic syndromes
Huntington
Estimated prevalence Chorea (onset); Caudate atrophy (MRI),
disease (HD)
is 5/100,000 (with depression, apathy, genetic test (HTT gene,
geographic variation); irritability, cognitive CAG repeat expansion
modal age group for impairment, parkinsonism, 935)
onset is 30Y50 years of and dystonia (later
age stages)
Huntington
diseaseYlike (HDL) Ataxia in an Caudate and cerebellar
Common cause HD phenocopy atrophy, putaminal rim
syndrome
for HD-negative enhancement (MRI),
type 4 (HDL4)/
neurodegenerative genetic test (TBP gene,
Spinocerebellar
chorea CAA/CAG repeat
ataxia (SCA)
(white populations) expansion 942)
type 17 (SCA17)
C9orf72-related
HD phenocopy HD phenocopy, ataxia, Genetic test (C9orf72
Common cause parkinsonism, and upper gene, GGGGCC/G4C2
for HD-negative motor neuron signs, hexanucleotide repeat
neurodegenerative phenotypic heterogeneity expansion 960 are
chorea (white in families definitely pathogenic)
populations)
HDL2 Exclusive to
HD phenocopy Caudate atrophy (MRI),
sub-Saharan
acanthocytosis (fresh
African descendants
blood film) in about
10% of patients, genetic
test (JPH3 gene, CTG
repeat expansion 940,
fully penetrant)
Rare neurodegenerative syndromes, chorea as a classic prominent feature
Chorea-acanthocytosis
Estimated prevalence of Chorea, dystonia Acanthocytosis (fresh
(Levine-Critchley
1000 cases worldwide; (orofacial involvement, blood film), elevated
syndrome)
young adult onset tongue protrusion), creatine kinase, chorein
tics, self-mutilation, absent in red blood cells,
seizures, sensorimotor predominant atrophy of
axonal polyneuropathy, the head of caudate
hepatomegaly, splenomegaly (MRI), genetic test
(VPS13A gene)
McLeod syndrome Rarer than
Chorea, dystonia, Acanthocytosis (fresh blood
chorea-acanthocytosis;
parkinsonism, psychiatric film), antigen Kell absent/
exclusive to males and
features, seizures, reduced in red blood cells,
with a later onset (after
sensorimotor axonal elevated creatine kinase
fourth decade)
neuropathy, cardiomyopathy, and liver function test,
hepatosplenomegaly, genetic test (XK gene)
hemolytic anemia
Continued on page 1188

Continuum
(Minneap Minn)

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1187

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 Chorea

TABLE 8-1 Clues for Diagnosis and Investigations of Adult-Onset Neurodegenerative

Diseases With Chorea Continued from page 1187

Neurodegenerative
Relevant
Conditions
Demographics Core Features Useful Investigations
HDL1 Very rare (four
Chorea, ataxia, prominent Atrophy of basal ganglia,
families reported5)
psychiatric features, cerebellum, frontal and
myoclonus, seizures temporal lobes (MRI),
genetic test (PRNP gene,
eight octapeptide
repeat insertions)
Dentatorubral-
pallidoluysian Most common in Ataxia, chorea, myoclonus, Atrophy of cerebellum,
atrophy Japan (1/208,000), rare dementia, seizures brainstem, cerebrum;
in non-Japanese hyperintensity in
populations periventricular white
matter (MRI), genetic test
(ATN1 gene, CAG
repeat expansion 947,
fully penetrant)
Neuroferritinopathy Reported in Cumbria,
Chorea/dystonia with Hypointensity in dentate
United Kingdom, and
orofacial involvement, nuclei, red nuclei, basal
France; estimated
nontremulous parkinsonism ganglia, thalami, rolandic
prevalence of
(less frequent), maintained cortex (T2*), bilateral
G1/1 million (very rare)
asymmetrical features, pallidal necrosis with cystic
ataxia (rarer), late degeneration (MRI), low
neuropsychiatric and serum ferritin, genetic test
cognitive symptoms (FTL gene)
(later feature)
Aceruloplasminemia Estimated prevalence
Dystonia (craniocervical), Low serum ceruloplasmin
of 1/1 million to
parkinsonism, chorea and and high ferritin,
1/1.2 million (very rare);
ataxia, depression, cognitive hypointensity in the
onset at middle age
dysfunction, anemia, striatum, thalamus, and
diabetes mellitus, retinal dentate nucleus (T2* MRI),
degeneration preceding genetic test (CP gene)
neurologic manifestations
Neurodegenerative syndromes, chorea as a rare manifestation
SCA1 Rare chorea-athetosis,
Cerebellar atrophy (MRI),
ataxia, dystonia, dementia,
genetic test (ATXN1 gene,
early hyperreflexia,
triplet repeat expansion
late neuropathy
939, fully penetrant)
SCA2 Rare chorea-athetosis,
Cerebellar atrophy (MRI),
ataxia, hyperreflexia,
genetic test (ATXN2 gene,
earlier slow saccades,
CAG/CAA repeat expansion
levodopa-responsive,
932, fully penetrant)
parkinsonism, dystonia,
dementia, early neuropathy

Continued on page 1189

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TABLE 8-1 Clues for Diagnosis and Investigations of Adult-Onset Neurodegenerative
Diseases With Chorea Continued from page 1188

Neurodegenerative
Conditions
SCA3
Wilson disease
Pantothenate
kinaseYassociated
neurodegeneration
Friedreich ataxia
Pallidonigroluysian
atrophy
Lubag disease (TAF1)
MRI = magnetic resonance imaging.
a
Diagnostic features of pantothenate kinaseYassociated neurodegeneration, but not documented in the case report.
Relevant
Demographics Core Features Useful Investigations
Rare chorea-athetosis,
Cerebellar atrophy (MRI),
ataxia, levodopa-responsive,
genetic test (ATXN3 gene,
parkinsonism, dystonia,
triplet repeat expansion
hyperreflexia/spasticity,
951, fully penetrant)
late neuropathy
Chorea is relatively rare,
Kayser-Fleischer rings
predominantly parkinsonism
(slit-lamp examination),
and dystonia (with risus
eye-of-the-panda sign,
sardonicus), ataxia,
variable white matter
psychiatric symptoms,
lesions in brainstem,
seizures can occur (G10%),
cerebellum (MRI), low
KayserYFleischer rings,
serum ceruloplasmin, high
arthropathy, hemolytic
urine copper (24-hour
anemia
urine), high liver copper
content on biopsy,
genetic test (CP gene)
Single case with Head and upper limb Bilateral hypointensity in
chorea reported, chorea with later the putamen, caudate,
onset at age 766 generalization, imbalance substantia nigra, and
dentate nuclei,
eye-of-the-tiger signa (MRI),
acanthocytosis (fresh blood
film) in about 10% of
patients,a genetic test
(PANK2 gene)a
Single case with
Ataxia, chorea, cognitive Genetic test (FXN gene,
chorea reported3
impairment (at GAA repeat expansion 965,
presentation), dysphagia fully penetrant)
and dysarthria (later stages)
Very rare7 Chorea (20% of cases), gait Postmortem diagnosis
or balance disturbance
Filipino origin Dystonia-parkinsonism,
Genetic test (TAF1 gene)
chorea is a very rare
feature (also reported in
female carriers)

Acquired causes Of chOrea are im-
pOrtant tO take intO cOnsideratiOn since
a few can be treated. Certain elements
in the clinical presentatiOn of
acquired causes Of chOrea help in the
differential diagnosis. ChOrea
secOndary tO strOke and drug-induced
chOrea are amOng the mOst prevalent
causes Of spOradic
chOrea that a clinician shOuld cOnsider
in the apprOpriate setting.8 Other spO-
radic fOrms Of chOrea are brOadly
divided intO immune-mediated, infec-
tiOus, metabOlic/endOcrine, vascular, and
Others causes (Table 8-2). This article
cOvers the apprOach tO adult-Onset chO-
rea. As such, cOnditiOns with a classic

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 Chorea

TABLE 8-2 Nongenetic Causes of Chorea

b Drugs
Antiemetics (dopamine antagonists)
Antiepileptic drugs (eg, phenytoin, carbamazepine, valproic acid)
Antihistamines
Baclofen
Calcium channel blockers
Digoxin
Fluoroquinolones
Levodopa, dopamine agonists (levodopa-induced
dyskinesia) Lithium
Methotrexate, cyclosporine
Neuroleptics (tardive dyskinesia)
Oral contraceptives, estrogen replacement therapy (often with a history of
previous Sydenham chorea)
Psychostimulants (eg, cocaine, amphetamines)
Steroids
Theophylline
Tricyclic antidepressants
b Immune Mediated
Antibody associated (paraneoplastic or idiopathic)9
Associated with neoplasia: collapsin response mediator protein-5 (CRMP5)
(small cell lung carcinoma and thymoma), Hu (small cell lung carcinoma), Yo,
antineuronal nuclear antibody (ANNA) type 1 and type 2, N-methyl-D-
aspartate (NMDA) subunit NR1 (ovarian tumor)
Idiopathic: NMDA subunit NR1 (45% of cases), leucine-rich, glioma
inactivated 1 (LgI1), contactin-associated proteinlike 2 (CASPR2),
glutamic acid decarboxylase 65 (GAD65), IgLON family member 5
(IgLON5), pediatric autoimmune neuropsychiatric disorders associated
with streptococcal infections (PANDAS)
Behçet disease
Celiac disease
Demyelinating disease (rare, hemiballismus reported)10
Sjo¨ gren syndrome
Systemic lupus erythematosus/antiphospholipid syndrome

Continued on page 1191

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 TABLE 8-2 Nongenetic Causes of Chorea Continued from page 1190

b Infectious
Encephalitis (West Nile virus, mumps, measles, varicella zoster)
Human immunodeficiency virus (HIV) (eg, secondary focal lesion due to
toxoplasmosis, primary central nervous system lymphoma, HIV encephalitis)
Tuberculosis, cysticercosis, borreliosis, neurosyphilis, diphtheria
Variant Creutzfeldt-Jakob disease
b Metabolic/Endocrine
Acquired hepatolenticular degeneration (advanced liver disease)
Electrolyte imbalance (hypoglycemia/hypercalcemia, hypomagnesemia,
hyponatremia)
Hyperthyroidism
Hypoglycemia/hyperglycemia (nonketotic)
Vitamin B12 deficiency (more frequently found as a cause of
chorea in children)
b Vascular
Essential thrombocythemia (one case reported)11
Ischemic/hemorrhagic stroke
Polycythemia rubra vera (elderly, primarily females)
Posterior reversible encephalopathy syndrome
Postpump chorea (more frequent in children)
b Other Causes
Carbon monoxide intoxication
Hydrocephalus
Postanoxic/cerebral palsy
Psychogenic chorea

Onset in the pediatric age grOup will CLINICAL APPROACH TO AN

not be discussed in detail, and brief
references will be given when pertinent.
Examples Of these cOnditiOns include
acquired pOstinfectiOus Sydenham
chOrea, benign hereditary chOrea, pan-
tOthenate kinaseYassOciated neurO-
degeneratiOn, Lesch-Nyhan syndrOme,
and autOsOmal recessive ataxias in
which chOrea has alsO been described,
such as apraxia with OculOmOtOr
apraxia type 1 and 2 and ataxia
telangiectasia.
ADULT PATIENT WITH CHOREA
Physicians treating adult patients pre-
senting with chOrea shOuld carry Out a
detailed and fOcused histOry and ex-
aminatiOn that cOnsider the multiple
causes Of chOrea and its presentatiOns.
The data cOllected by the physician
give impOrtant clues tOward the mOst
likely cause Of the presenting chOrea
and the selectiOn of the mOre perti-
nent investigatiOns.

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 Chorea

KEY POINTS
■ Chorea may present as an
isolated symptom or as a
syndrome with a variable
combination of a mixed
movement disorder,
behavioral and cognitive
symptoms, seizures,
or polyneuropathy.
■ Most of the cases of
senile chorea
correspond to cases of
late-onset Huntington
disease.
Chorea as Symptom
ChOrea can present as an isOlated
symptOm Or a mixed mOvement dis-
Order and can be assOciated with
behaviOral and cOgnitive symptOms,
seizures, Or symptOms suggestive Of
pOlyneurOpathy. The different symp-
tOm cOmplexes identified with a clin-
ical interview can give the first clues
fOr a diagnosis and priOritizatiOn of
investigatiOns. ChOrea is frequently
noticed first by a third persOn and
not by the patient; cOnsequently, the
infOrmatiOn prOvided by a caregiver
Or family member is particularly im-
pOrtant fOr a mOre rigorOus histOry Of
chOrea. As with Other neurOlOgic
symp- tOms, the age Of Onset (adult
versus elderly), the acute versus
prOgressive mOde Of Onset, and the
type Of dis- ease cOurse (remitting,
parOxysmal, Or cOntinuOus) can favOr
a specific syn-
drOme. In terms Of age Of Onset,
there is the particular case Of senile
chOrea defined as an idiOpathic spO-
radic fOrm Of chOrea with Onset in the
elderly in the absence Of dementia
(Supplemental Digital Content 8-1,
links.lww.com/CONT/A188).12 The ad-
vent Of a genetic diagnosis fOr HD
has shOwn that mOst Of these cases
are, in fact, late-Onset HD (Case 8-
1).13 In terms Of mOde Of Onset, a
rela- tively acute Onset Of chOrea
can be the manifestatiOn of strOke,
and alsO Other causes such as
nonketOtic hy- perglycemia, chOrea
gravidarum, Or drug-induced chOrea
(Table 8-2). A subacute cOurse
Over a few days Or weeks may be
the manifestatiOn of infectiOus
prOcess Or autOimmune
chOrea, including a paraneOplastic
syndrOme, but dOes not exclude a
metabOlic cause.14 In sOme cases Of
drug-induced chOrea, a gradual Onset
may Occur, such as in lev O d O pa-
induced dyskinesia in ParkinsOn dis-
ease (Supplemental Digital Content
8-2, links.lww.com/CONT/A189) Or
neurOleptic-induced dyskinesia.15 A
mOre prOtracted cOurse Of mOnths tO
years is usually assOciated with a neu-
rOdegenerative cOnditiOn. In terms Of
the time cOurse Of chOrea, a slOwly

Case 8-1
An 88-year-old woman presented with a 6- to 8-year history of progressive
involuntary movements and imbalance, for which she had to use a walker.
The involuntary movements were described as ‘‘shaking’’ and were
increasingly embarrassing to the patient. She had also noticed swallowing
air when eating. The patient did not endorse cognitive or mood
symptoms, and she lived independently at a retirement home. The patient
did not have a family history of chorea. Her examination was remarkable
for pronounced generalized chorea involving the limbs, trunk, and face,
as well as an inability to walk unaided. A diagnosis of senile chorea was
made. The investigations at that time included a head CT, renal and liver
function tests, serum glucose, thyroid-stimulating hormone (TSH), as well
as anticardiolipin, antiphospholipid, and antinuclear antibodies. All
investigations were normal. Genetic testing for Huntington disease (HD)
showed a CAG repeat of 39, confirmatory of a diagnosis of late-onset HD.
Two years later, the patient died at age 90 with complications from
dysphagia and dehydration.
Comment. This case is demonstrative of how to approach a case of
senile chorea and how late in life a diagnosis of HD can be made. In a
case of senile chorea, a diagnosis of HD has implications for a patient’s

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remitting hemichOrea is Often a case
Of vascular chOrea secOndary tO a
strOke Or nonketOtic hyperglycemia.
The particular case Of parOxysmal
recurrent chOrea suggests a cOm-
pletely different set Of diagnoses with
cOnsideratiOn of parOxysmal dyskine-
sias when multiple and shOrt-lived
episOdes Of chOrea are repOrted.
Three fOrms are classically described:
par- Oxysmal kinesigenic dyskinesia,
par- Oxysmal nonkinesigenic
dyskinesia,
and parOxysmal exertiOn-induced (Or
exercise-induced) dyskinesia. AlthOugh
chOrea can present in isOlatiOn, the
parOxysmal dyskinesias manifest mOst
cOmmOnly with bOth dystOnia and
chOrea in abOut 60% tO 65% Of
genet- ically prOven cases Of
parOxysmal kinesigenic dyskinesia
(Supplemental Digital Content 8-3,
links.lww.com/ CONT/A190) and
parOxysmal non- kinesigenic
dyskinesia and in abOut 95% Of
genetically prOven cases Of
parOxysmal exertiOn-induced dyski-
nesia.16 These cOnditiOns have been
distinguished On a clinical basis, mainly
with respect tO the trigger Of the
episOdes, and have been further
characterized by the age Of Onset,
duratiOn and
frequency Of episOdes, and respOnse
tO treatment. In recent years, there
has been a significant breakthrOugh
in finding the genetic basis Of these
cOnditiOns (fOr mOre infOrmatiOn, refer
tO the fOllOwing sectiOn on investiga-
tiOns and Table 8-3). PsychOgenic
chOrea is rarely repOrted as a cause
Of psychOgenic mOvement disOrders
and typically presents in the f Orm
Of a par O xysmal m O vement dis-
Order.17 Recurrent chOrea can alsO
Occur in patients with a histOry Of
chOrea gravidarum Or Sydenham chO-
rea whO develOp chOrea when expOsed
tO drugs such as Oral cOntraceptives
Or phenytOin, althOugh these cases
can assume a distinctive pattern of
lOnger- lasting episOdes separated, at
times, by
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
KEY POINTS
years.18 The presence Of chOrea in ■ Chorea secondary to
specific bOdy regiOns alsO prOvides stroke has an acute
impOrtant clues fOr the differential onset and will, most
diagnosis. In fOrms Of often, improve
neurOdegenera-
tive chOrea, OrOfacial chOrea frequently over time.
assOciated with dystOnia is suggestive ■ Recurrent episodes of
Of a classic neurOacanthOcytOsis chorea, frequently in
syndrOme (ie, chOrea-acanthOcytOsis association with dystonia,
(Case 8-2 and Supplemental Digital suggest a form of
Con- tent 8-4, paroxysmal dyskinesia.
links.lww.com/CONT/A191) and, less ■ Orofacial chorea is
cOmmOnly, McLeOd syn- drOme).19 suggestive of a classic
OrOfacial chOrea can alsO
be an early feature Of the rare neurO- neuroacanthocytosis
ferritinopathy, a late-Onset fOrm Of syndrome.
neurOdegeneratiOn with brain irOn ac-
cumulatiOn.20 The dystOnic prOtrusiOn
Of the tOngue with an assOciated
difficulty maintaining ingested fOOd
in the mOuth (feeding dystOnia) has
been classically described in chOrea-
acanthOcytOsis, but can alsO be fOund
in other cOnditiOns cOnsidered in the
differential diagnosis Of chOrea, such
as McLeOd syndrOme, tardive dyskine-
sia, pantOthenate kinaseYassOciated
neurOdegeneratiOn, and Lesch-Nyhan
syndrOme.21 In additiOn, the presence
Of head drOps and truncal/cervical
extensiOn is recOgnized as a distinc-
tive feature Of advanced chOrea-
acanthOcytOsis, but is alsO described in
McLeOd syndr O me and advanced
HD.22Y24 The presence Of tics can be
fOund in HD, but alsO in the classic
neurOacanthOcytOsis syndrOmes, par-
ticularly in chOrea-acanthOcytOsis. The
presence Of significant behaviOral
symptOms in additiOn tO cOgnitive de-
teriOratiOn strOngly suggests a neurO-
degenerative chOreic syndrOme, namely
HD. In an HD pOpulatiOn, apathy is
cOnsidered the mOst prevalent behav-
iOral symptOm (28.1%), fOllOwed by
depressiOn, irritability/aggressiveness,
and Obsessive/cOmpulsive behaviOrs.25
PsychOsis is less prevalent and can
affect as little as 1.2% Of the HD
pOpulatiOn.25 BehaviOral symptOms can
precede the Onset Of mOtOr symptOms
and, at the
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 Chorea

a
TABLE 8-3 Clinical Features of Paroxysmal Dyskinesia

Paroxysmal
Paroxysmal Paroxysmal Exertion-Induced
Kinesigenic Dyskinesia Nonkinesigenic Dyskinesia
Age of onset Childhood/adolescence Dyskinesia Variable (depending
(majority of cases) Childhood/adolescence on cause)
(majority of cases)
Episodes
Triggers Sudden movements or
Coffee, tea, alcohol Prolonged exertion
intention to move
(more consistent), anxiety, (more frequently),
excitement, fatigue fasting, stress, anxiety
Duration Brief, majority of episodes
Typically more prolonged, Episode ends with rest
G1 minute
10 minutes to 4 hours
Frequency Up to hundreds of episodes
Weekly episodes Dependent on triggers
a dayb
more commonb
Treatment Good response to
Avoid triggering factors; Avoid triggering factors,
antiepileptics; carbamazepine
poor response to treat underlying cause
is drug of choice
benzodiazepines, phenytoin, when applicable
acetazolamide, levodopa
Etiology
Gene associated
Proline-rich transmembrane Myofibrillogenesis Glucose transporter 1
with primary
protein 2 (PRRT2) regulator 1 (MR-1)d (SLC2A1)e (in 20Y25%
formc
of cases)
Secondary causes Secondary to brain
Secondary to brain injury, Parkinson disease,
injury (vascular,
symptomatic cases are rare dopa-responsive dystonia
trauma, multiple
sclerosis)
a
Data from Erro R, et al, Mov Disord.16 onlinelibrary.wiley.com/doi/10.1002/mds.25933/abstract.
b
Frequency has a tendency to decrease with age.
c
Genotype-phenotype correlation is incomplete, and overlap of forms of paroxysmal dyskinesia may exist.
d
Potassium calcium-activated channel, subfamily M alpha member 1 (KCNMA1) has been described in one family with cases of paroxysmal
nonkinesigenic dyskinesia and epilepsy.
e
Mutations in the gene SLC2A1 can also cause benign familial infantile seizures, familial infantile convulsions with paroxysmal choreoathetosis, and
hemiplegic migraine.

1194 www.ContinuumJournal.com
Case 8-2 August 2016

A 28-year-old man presented with a 1-year history of difficulty chewing

and abnormal gait. In order to eat, the patient swallowed food in big
chunks without chewing it. There was no history of seizures, and he was
otherwise healthy. There was a known family history of chorea-
acanthocytosis in his brother and two paternal cousins. Examination was
remarkable for a left gum ulcer, dystonic protrusion of the tongue when
ingesting food or speaking, as well as jaw-opening dystonia and recurrent
sniffing. He had mild generalized chorea and slight weakness in his hands
and feet. Ankle reflexes were absent. Gait was abnormal with hesitations,
namely with turns. The investigations identified elevated creatine kinase
(422 units/L) and acanthocytes (more than 10%) in the blood. He was
started on

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

 KEY POINTS
Continued from page 1194 ■ In chorea-acanthocytosis,
trihexyphenidyl for jaw-opening dystonia with benefit. The patient did not seizures can occur in about
return for follow-up. 50% of cases.
Comment. This case shows features suggestive of chorea- ■ Huntington diseaseYlike
acanthocytosis, including the presence of oromandibular dyskinesia with syndrome type 2 is most
feeding dystonia, tics, as well as signs of peripheral neuropathy. The prevalent in patients with
documented family history of chorea-acanthocytosis and the laboratory a sub-Saharan African
findings of elevated creatine kinase and presence of more than 10% of ancestry.
acanthocytes in the blood facilitated the diagnosis.

time Of a diagnosis based On mOtOr
features, deficits in cOgnitive functiOn
can be elicited in fOrmal testing.26
Suicidal ideatiOn is relatively frequent
(8% tO 10%) and shOuld be actively
lOOked fOr, especially in patients with
active depressiOn and a previOus
suicidal attempt.27
HD phenocOpies in which behav-
iOral Or cOgnitive symptOms are part
Of the clinical presentatiOn include
HDL2, chOrea-acanthOcytOsis, and
dentatOrubral-pallidOluysian atrOphy
(DRPLA).28Y30 In McLeOd syndrOme,
behaviOral prOblems are mOre cOm-
mOn and cOgnitive difficulties are
milder.29 Self-mutilatiOn of the lip and
tOngue is a clinical manifestatiOn of
chOrea-acanthOcytOsis, but is uncOm-
mOn in McLeOd syndrOme.31 Lesch-
Nyhan syndrOme is an X-linked genetic
cOnditiOn in which patients can have
self-mutilating behaviOrs but the Onset
Occurs in childhOOd.
ChOrea gravidarum, antiphOsphO-
lipid syndrOme, Or systemic lupus
erythematOsus are amOng nondegen-
erative causes Of chOrea that can
present with cOncOmitant behaviOral
sympt O ms, including pers O nality
changes, depressiOn, psychOtic symp-
tOms, and cOgnitive impairment.18
The Occurrence Of seizures is a dif-
ferentiating feature Of sOme HD
phenocOpies, Occurring in abOut 50%
Of the cases in chOrea-acanthOcytOsis
(30% as presenting feature) and
McLeOd syndrOme, as well as in DRPLA
and HDL1, an exceedingly rare entity
in which the majOrity Of the cases have
seizures.5,19,30,32 In DRPLA, it is useful
tO recOgnize that when the age Of
Onset Overlaps the mean age Of Onset
Of the adult fOrm Of HD, seizures rarely
Occur, and mOre cOmmOn presenting
features are chOrea, in additiOn tO dys-
tOnia, parkinsOnism, and psychOsis.
When the clinician is cOnsidering
a genetic chOreic syndrOme, it is
helpful tO recOgnize that certain causes
have a higher incidence, in particular,
geOgraphic areas Or ethnic Origins
and, thus, shOuld be priOritized when-
ever applicable. FOr example, HDL2
has been repOrted almOst exclusively
in subjects with a sub-Saharan African
ancestry, namely African Americans
and black SOuth Africans, and in the
rare cases Of a presumed non-African
Origin, an African ancestOr cOuld not
be ruled Out.33 NeurOferritinopathy
has been mOstly described in families
frOm the United KingdOm (Cumbria
regiOn), with a few cases repOrted in
France and One single case in NOrth
America.34 DRPLA is mOst frequent in
Japan, althOugh it is not exclusive tO
that cOuntry, with rare cases repOrted
in EurOpean and NOrth American pOp-
ulatiOns Of non-Japanese ancestry.35
The Haw River syndrOme cOrrespOnds
tO a family Of African Americans Orig-
inally frOm NOrth CarOlina, and has
been repOrted as a fOrm Of DRPLA.36
Past Medical History
The presence Of acute hemichOrea
Or hemiballismus in a patient with

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 Chorea
KEY POINTS
■ In the Western world,
chorea gravidarum has
become a rare cause of
chorea.
■ In C9orf72-related
Huntington disease,
phenocopies present with
significant phenotypic
heterogeneity
and have, in most of
the cases, a positive
family history.
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
significant vascular risk factOrs sug-
gests strOke as a cause, while in a pa-
tient with diabetes mellitus, a primary
diagnosis Of nonketOtic
hyperglycemia has tO be cOnsidered
in additiOn. Re- current miscarriages,
migraine, and thrOmbOtic events are a
clue fOr the presence Of an
antiphOsphOlipid syn- drOme Or
systemic lupus erythema-
tOsus. HemOdialysis, alcOhOlism, and
malnutritiOn can pOint tO extrapOntine
myelinolysis, and the presence Of
human immunodeficiency virus (HIV)
risk factOrs prOvide clues tO the clini-
cian fOr HIV-assOciated causes Of chO-
rea (eg, O pp O rtunistic infecti O ns
including tOxOplasmOsis, prOgressive
multifOcal leukOencephalOpathy, and
HIV encephalitis).
The Occurrence Of chOrea in a preg-
nant wOman shOuld raise the pOssibility
Of chOrea gravidarum. In the Western
wOrld, chOrea gravidarum is increas-
ingly rare; currently, its mOst cOmmOn
causes are antiphOsphOlipid
syndrOme and systemic lupus
erythematOsus.18 In the past,
rheumatic fever was the mOst
prevalent cause fO r chOrea
gravidarum,
but it decreased sharply with the
wide-
spread use Of penicillin.18
Family History
A clear pattern of inheritance will help
the clinician priOritize genetic causes
Of chOrea in the differential diagnosis.
HOwever, it is impOrtant tO recOgnize
that the absence Of a family histOry
dOes not exclude a genetic disOrder
fOr many pOssible reasOns, including
nonpaternity, de novO mutatiOns (in-
cluding unstable trinucleOtide
repeats),
premature death Of asymptOmatic
carriers, as well as partial penetrance
and phenotypic variability. In fact, ge-
netic causes fOr chOrea are frequently
fOund in spOradic cases (Case 8-1).
In the presence Of a family his-
SCA17, C9orf72-related HD pheno-
cOpy, HDL2, as well as DRPLA, neurO-
ferritinopathy, SCA1, SCA2, SCA3, SCA7,
and HDL1.37 In SCA17, mOst Of the
cases repOrted are spOradic Or isOlated
subjects in a family with an ataxic syn-
drOme. AlthOugh a family with a
SCA17 mutatiOn and multiple members
pres- enting an HD-like phenotype
shOw
that phenotypic hOmOgeneity may
exist, this is exceedingly rare.38 FOr
C9orf72-related HD phenocOpies,
available data suggest a higher preva-
lence Of a pOsitive family histOry,
althOugh with phenotypic heterOge-
neity within the known spectrum Of
C9orf72-related clinical presentatiOns.4
The prevalence Of C9orf72-related
HD phenocOpies shOuld be further
assessed as in the initial case series,
Only three Of the 10 cases repOrted
had chOrea in their presentatiOn.4
An autOsOmal recessive inheritance
pattern is cOmpatible with chOrea-
acanthOcytOsis and
acerulOplasminemia. HDL3 alsO has an
autOsOmal recessive inheritance
pattern but has Only been described in
a Saudi Arabian family.
The Onset Of symptOms is in early
childhOOd, and its presentatiOn re-
sembles the HD Westphal variant.39
An X-linked recessive inheritance
pat- tern is cOmpatible with McLeOd
syn-
drOme, althOugh rare female cases
have been repOrted.40
EXAMINATION
The ObservatiOn of chOrea, Other
mOvement disOrders, and additiOnal
neurOlOgic Or systemic signs prOvides
clues fOr the differential diagnosis.
Phenomenology of Chorea and
Related Movement Disorders
ChOrea is One Of the hyperkinetic
mOvement disOrders. ChOrea (derived
frOm the Greek wOrd horos, meaning
 tOry, an autOsOmal dOminant inheri- dance) is characterized by invOluntary,
tance pattern is cOmpatible with HD, brief, irregular, randOm mOvements
1196 www.ContinuumJournal.com August 2016

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(Supplemental Digital Content 8-5,
links.lww.com/CONT/A192; Supple-
mental Digital Content 8-6, links.
lww.com/CONT/A193). Ballismus (de-
rived frOm the Greek wOrd ballismos,
meaning jumping abOut) is cOnsidered
a fOrm Of chOrea characterized by high-
amplitude mOvement Of a limb in a
flinging or flailing mOtiOn, including
the mOst prOximal segments
(Supplemen- tal Digital Content 8-7,
links.lww. com/CONT/A194). AthetOsis
(derived frOm the Greek wOrd athetos,
meaning not fixed) is classically a slOw,
randOm, invOluntary, writhing
mOvement Of the distal regiOn of the
limbs and is now recOgnized tO be a
manifestatiOn of underlying dystOnia,
namely in cases Of cerebral palsy, and
will not be addressed in this article
(Supplemen- tal Digital Content 8-8,
links.lww. com/CONT/A195).
Chorea Distribution
Particular lOcatiOns Of chOrea are sug-
gestive Of specific etiOlOgies; aside
frOm the diagnostic value Of prOmi-
nent OrOlingual and truncal/cervical
chOrea-dystOnia previOusly described,
the presence Of hemichOrea or hemi-
ballismus suggests a fOcal structural
brain lesiOn secOndary tO a vascular
event, nonketOtic hyperglycemia, and,
mOre rarely, an oppOrtunistic infectiOn
in HIV. Nevertheless, instances Occur
in which hemichOrea is a presenting
fea- ture Of Other cOnditiOns withOut
a repOrts Of
dOcumentable fOcal brain lesiOn, ex-
amples Of which are autOimmune
chO-
rea including Sydenham chOrea and
paraneOplastic syndrOmes as well as
variant Creutzfeldt-JakOb disease.9,15,41
COnversely, cOnditiOns such as non-
ketOtic hyperglycemia can present as
generalized chOrea42 (Case 8-3).
Other Movement Disorders
The presence Of Other mOvement dis-
Orders can help with the diagnosis Of a
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
KEY POINTS
particular chOrea syndrOme. DystOnic ■ Hemichorea or
features can be present in HD and in hemiballismus suggest
the mOst prevalent HD phenocOpies the presence of a focal
such as HDL2, SCA17, but alsO in brain lesion.
chOrea-acanthOcytOsis, DRPLA, and ■ The combination of other
neurOferritinopathy (OrOfacial dystO- movement disorders can
nia), amOng others. ParkinsOnism is a help with the diagnosis of
late feature Of adult-Onset HD at a stage a particular chorea
in which chOrea is less intense. NOn- syndrome.
tremulOus parkinsOnism has been de-
scribed in neurOferritinopathy, but it
is a less cOmmOn presenting feature
(7.5%) cOmpared with chOrea (50%)
and fOcal limb dystOnia (47.5%).20
MOre prOminent ataxic features,
including eye mOvement abnormalities
(saccadic pur- suit, dysmetric saccades,
gaze-evOked nystagmus), limb
incOOrdinatiOn, and wide-based gait
with imbalance shOuld make the
clinician suspect an SCA, SCA17
being a mOre frequent cause. DRPLA
can alsO be cOnsidered, and,
mOre rarely, WilsOn disease can be
cOnsidered when ataxia is part Of a
chOrea syndrOme. In SCA17, althOugh
ataxia is mOst Often present, marked
phenotypic heterOgeneity Occurs, and
the presence Of a pure chOreic syn-
drOme dOes not exclude this diagno-
sis.38 It is wOrthwhile mentiOning that
chOreic mOvements are exceptiOnal
in other SCAs, such as the example Of
SCA1, SCA2, SCA3, and SCA7.37,44 In
these cases, ataxia is predOminant,
and the descriptiOn of chOrea best fits
with chOreOathetOsis. Very rare
chOrea in other SCAs can be fOund in
the literature: hand chOreic mOve-
ments have been described in SCA14
(PRKCG gene) and in SCA8 (ATXN8/
ATXN8OS gene) gene expansiOn, al-
thOugh the pathOlOgic rOle Of an ex-
pansiOn in the ATXN8/ATXN8OS gene
remains a matter Of discussiOn.45,46
Apart frOm eye mOvement
abnormalities cOnsistent with an ataxia
syndrOme, Other changes can be
dOcumented when ex- amining a
patient with chOrea. Difficulty
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 Chorea

Case 8-3
A 73-year-old woman presented to the emergency department with an 8-day history of generalized chorea with an acute onset
There was no relevant past medical history, no family history of chorea, and no known use
of neuroleptic drugs. Her examination was remarkable for orofacial dyskinesias and generalized chorea. The investigations for
Chorea persisted beyond the normalization of the patient’s hyperglycemia. She died 32 days after admission as a result o
Comment. This case shows that nonketotic hyperglycemia may be a cause of acute-onset chorea presenting in a generalized fo
The MRI findings highlighted in this case are typical of the syndrome of chorea in the setting of nonketotic hyperglycemia.
Case modified with permission from Mestre TA, et al, J Neurol Neurosurg Psychiatry.43
B 2007 BMJ Publishing Group Ltd. .

FIGURE 8-1 Brain MRI of the patient in Case 8-3 with bilateral chorea-related nonketotic

hyperglycemia exhibiting putaminal hyperintensity in T1-weighted imaging.

Reprinted with permission from Mestre TA, et al. J Neurol Neurosurg Psychiatry.43 B 2007 BMJ Publishing Gro

in initiating saccades is classically de- disturbances, and behaviOral changes

scribed in HD.
Other assOciated neurOlOgic signs
may suggest a particular diagnosis: In
chOrea-acanthOcytOsis (Case 8-2) and
McLeOd syndrOme, areflexia (Achilles
reflex absent in 90% Of patients) and
limb weakness tOgether with muscle
wasting are suggestive Of an axOnal
pOlyneurOpathy and, in sOme cases, a
my-
Opathy has alsO been dOcumented.19,47
Patients with SCA1, SCA2, and SCA3
can alsO have a pOlyneurOpathy. In
paraneOplastic syndrOmes, mOre cOm-
mOnly there will be Other neurOlOgic
signs, including peripheral
neurOpathy, visual disturbances,
ataxia, OculOmOtOr
with a subacute presentatiOn.9,48
Systemic Features in Choreic
Syndromes
Classic neurOacanthOcytOsis syndrOmes
are recOgnized as multisystemic disOr-
ders. McLeOd syndrOme is assOciated
with a cardiOmyOpathy with atrial fib-
rillatiOn in 60% Of the cases, in additiOn
tO hemOlytic anemia, hepatOmegaly,
and splenomegaly. 1 9 In ch O rea-
acanthOcytOsis, hepatOmegaly and
splenomegaly are alsO fOund.32 The
presence Of a phOtOsensitive malar rash
and arthritis is suggestive Of systemic
lupus erythematOsus. Signs Of thyrOid

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disease suggest the presence Of under- KEY POINTS
lying thyrOid dysfunctiOn. Anemia, dia- cOnsidered, including cases withOut a ■ In neuroacanthocytosis
betes mellitus, and retinal degenerati Onknown family histOry fOr chOrea and syndromes, the
are fOund in acerulOplasminemia. withOut an apparent cause after a first clinical multisystemic
Stigma of chrOnic liver failure can sug- rOund Of investigatiOns. In the presence involvement is characteristic
Of a symptOm cOmplex that pOints tO a and has
gest acquired hepatOcerebral degen- specific, albeit rare, cause Of chOrea, diagnostic and
eratiOn, in which patients can present these neurOdegenerative cOnditiOns management implications.
with OrObuccal chOrea resembling can alsO be cOnsidered in a first ■ Huntington disease is
rOund
tardive dyskinesia, in additiOn tO dys- Of investigatiOns (Table 8-1). the most frequent genetic
tOnia, parkinsOnism, and ataxia, as well FOr HD, a trinucleOtide cytOsine- cause of chorea.
as cOgnitive and behaviOral prOblems.49 adenosine-guanine (CAG) equal tO Or
Kayser-Fleischer rings are Observed in greater than 36 repeats is diagnostic
WilsOn disease. in the presence Of characteristic
symptOms. In the special case Of
INVESTIGATIONS asymptOmatic carriers, a result
An initial panel Of investigatiOns between 36 and 39 CAG repeats
shOuld cOrrespOnds tO incOmplete
be used tO cOnsider treatable causes penetrance and uncertainty abOut
Of chOrea and include rOutine hema- phenocOnversiOn in life. As with Other
tOlOgy and blOOd biOchemistry tests, neurOdegenerative cOnditiOns caused
in additiOn tO brain MRI and autOanti- by a trinucleOtide expansiOn, a larger
bOdy testing tO identify antiphOs- number Of repeats is assOciated with
phOlipid syndrOme and systemic lupus an earlier age Of Onset, and a tendency
erythematOsus (Table 8-4). MOst Of exists fOr the number Of repeats tO
these treatable causes have an acute increase frOm generatiOn tO genera-
Or subacute Onset, which is in striking tiOn, manifesting in the fOrm Of an
cOntrast with a mOre prOtracted anticipatiOn phenomenon fOr the age
cOurse Of HD and HD phenocOpies. Of Onset. CAG repeats in the interme-
As HD is the mOst prevalent genetic diate range Of 27 and 35 CAG repeats
cause Of chOrea, testing fOr a that have been described in rare case
pathOlOgic repeat expansiOn in the repOrts cOmpatible with symptOmatic
HTT gene shOuld be

TABLE 8-4 Initial Panel of Investigations in Patients With Chorea

1. Test for thyroid function, renal and liver function, electrolytes,

erythrocyte sedimentation rate, antinuclear antibodies, antiYdouble-
stranded DNA antibodies, anticardiolipin antibodies, and lupus
anticoagulant.
2. Perform brain MRI.
3. If inconclusive or known family history of chorea, perform genetic test
for Huntington disease. If the latter genetic test is negative, consider
spinocerebellar ataxia type 17 and C9orf72 in white individuals, and
Huntington diseaseYlike syndrome type 2 in subjects with black
African ancestry.
4. Test for acanthocytes in peripheral fresh blood film. A single negative test
is not sufficient to rule out the presence of acanthocytes and should be
done in a laboratory with appropriate expertise; perform three assays.
DNA = deoxyribonucleic acid; MRI = magnetic resonance imaging.

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Continuum (Minneap Minn) 2016;22(4):1186–1207 www.ContinuumJournal.com 1199

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 Chorea
KEY POINTS
■ The vast majority of
Huntington disease
phenocopies remain
undiagnosed.
■ Spinocerebellar ataxia
type 17 and
C9orf7-related
Huntington disease
phenocopy are the most
frequent causes for a
Huntington disease
phenocopy.
■ Caudate atrophy can be
found in Huntington
disease phenocopies,
namely in Huntington
diseaseYlike
syndrome type 2,
chorea-acanthocytosis,
and McLeod syndrome.
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
HD are assOciated with significant
behaviOral abnormalities, with impli-
catiOns fOr genetic cOunseling.50,51
Genetic testing in HD and Other
neurOdegenerative cOnditiOns with an
adult Onset not Only impacts the life Of
the individual being tested, but als O
his Or her family, especially children.
FOr family members at risk, the c Onsid-
eratiOn of predictive testing is usually
prOmpted by wishing tO know the
carrier status but alsO fOr a need tO
in- fOrm life decisiOns including
marriage, parenthOOd, Or a In mOre recent years, there has been
prOfessiOnal career. Genetic
cOunseling is fundamental in Order
fOr patients tO make a decisiOn abOut
predictive testing in a fully infOrmed
and free manner. Risks that are
assOciated with pOsitive predictive
testing need tO be discussed, includ-
ing the pOtential issues Of discrimina-
tiOn at wOrk Or fOr insurance purpOses,
tensiOn in family and persOnal
relatiOns, as well as stress On the
patient. Legisla- tiOn on prOtectiOn
against genetic dis-
criminatiOn exists but varies frOm
cOuntry tO cOuntry and, in the United
States, can change frOm state tO state.
A significant prOpOrtiOn of patients
presenting as an HD phenocOpy cur-
rently remain undiagnosed. An alterna-
tive diagnosis is fOund in as lOw as
2.8% Of the cases in tertiary m Ovement
disOrders centers.3 In an attempt tO
priOritize investigatiOns, elements
related with differentiating clinical
features,
ethnic/geOgraphic Origin, and family
histOry shOuld be cOnsidered as de-
scribed previOusly. Available clinical
data frOm case series in tertiary HD
centers frOm Western EurOpe suggest
that SCA17 and C9orf72 gene muta-
tiOns shOuld be priOritized, particularly
in white individuals.4 HDL2 shOuld be
strOngly cOnsidered in African Ameri-
cans. Of note, HDL2 may resemble HD
mOre than any Other known disease.52
In a Brazilian cOhOrt, HDL2 and SCA2
were the diagnoses fOund fOr HD
phenocOpies, and there was no diag-
nosis Of SCA17.53
AmOng rare genetic entities that
have been repOrted tO present as an
HD phe- nocOpy and have an available
diagnostic test, Friedreich ataxia was
repOrted as an adult-Onset chOreic
syndrOme in the sixth decade Of life,
in assOciatiOn with cerebellar ataxia,
and a single case Of adult-Onset
chOrea was fOund tO have typical
pathOlOgy Of pantOthenate
kinaseYassOciated neurOdegeneratiOn.3,6
a significant breakthrOugh in the ge-
netic basis Of parOxysmal dyskinesia:
the myOfibrillOgenesis regulatOr 1 (MR-
1) gene and the much less frequent
pOtassium calcium-activated channel
subfamily M alpha 1 (KCNMA1) gene
were identified in parOxysmal non-
kinesigenic dyskinesia, the prOline-
rich transmembrane prOtein 2 (PRRT2)
gene was identified in parOxysmal
kinesigenic dyskinesia, and the gluc Ose
1 transpOrter (SLC2A1 gene) was
identi-
fied in parOxysmal exertiOn-induced
(exercise-induced) dyskinesia.
MRI can be helpful in the differential
diagnosis Of a suspected neurOdegen-
erative chOreic syndrOme, with atten-
tiOn tO patterns Of atrOphy, presence
Of signal changes in T1, T2, and fluid-
attenuated inversiOn recOvery (FLAIR)
weighted images, and irOn susceptibil-
ity imaging. The hallmark feature in
clinical MRIs fOund in adult-Onset HD
is caudate atrOphy (Figure 8-2). It is
impOrtant tO emphasize that a few
adult-Onset neurOdegenerative HD
phenocOpies may not be differentiated
frOm HD based On MRI findings, exam-
ples Of which include HDL2, chOrea-
acanthOcytOsis, and McLeOd syndrOme.
Nevertheless, in chOrea-acanthOcytOsis
and McLeOd syndrOme, T2-weighted
hyperintensity in the striatum, mild gen-
eralized cOrtical atrOphy (less in
McLeOd
syndrOme), an hippOcampal sclerOsis
d
and atrOphy (in chOrea-acanthOcytOsis)
1200 www.ContinuumJournal.com August 2016

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 FIGURE 8-2 Caudate atrophy in a patient with Huntington disease documented on T2-weighted MRI.
have been described.54 Cerebellar atrO-
phy Occurs earlier and mOre severely in
SCAs; in HD, cerebellar atrOphy is a
late and mild feature.55 In DRPLA,
brain-
stem and cerebellar atrOphy can be
fOund in additiOn tO diffuse T2-
weighted
hyperintensities in the deep
subcOrtical white matter, and
increased irOn sus-
ceptibility is fOund in the cerebellum,
dentate nuclei, and basal ganglia.56,57
The presence Of a distinctive
pattern Of irOn depOsitiOn can suggest
and, at times, be diagnostic Of
neurOdegen-
eratiOn with brain irOn accumulatiOn
(Figure 8-358). In neurOferritinopathy,
hypOintensities in the dentate nuclei,
red nuclei, basal ganglia, thalami, and
the rOlandic cOrtex are fOund even in
nonmanifesting carriers.20 With
disease
prOgressiOn, a distinctive bilateral
pallidal necrOsis with cystic degenera-
tiOn is Observed (Figure 8-3).20 MRI
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
be cOnfirmatOry Of a diagnosis in spO-
radic fOrms Of chOrea; in patients with
chOrea due tO strOke, a vascular lesiOn
in the subthalamic nucleus is classically
described, but chOrea can alsO be assO-
ciated with strOkes in other basal
ganglia lOcatiOns, thalamus, and internal
capsule.59 In the variant Creutzfeldt-
JakOb disease, the bilateral hyper-
intensity in the pulvinar Of the thalamus
(hOckey stick sign), mOre frequently
fOund in FLAIR sequences, is almOst
pathOgnomOnic.60 In nonketOtic
hyper-
glycemia, T1-hyperintense lesiOns in
the putamen are Observed.43 In ac-
quired hepatOcerebral degeneratiOn, T1
hyperintense lesiOn ar fOund in the
s e
putamen and alsO in the internal cap-
sule, the mesencephalOn, and the cere-
bellum, in additiOn tO cavitatiOns Of the
is alsO helpful tO raise the suspiciOn or
basal thOught tO be secOnd- ary tO the
ganglia, depOsitiOn of manganese via a
all pOrtOsystemic shunt.49 The presence
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 Chorea
KEY POINT
■ The treatment of chorea
should aim at reducing
related disability and
improving overall
function.
FIGURE 8-3 MRI findings in neuroferritinopathy with hypointensity in T2*-weighted image involving the globus pallidus, p
nuclei (not shown). Hyperintensity in the putamen and pallidum in T2-weighted fast spin echoYweighted image found at a later
Reprinted with permission from McNeill A, et al. Neurology.58 B 2008 American Academy of Neurology.
.
Of brain calcificatiOn, better dOcu-
mented with a head CT, suggests idiO-
pathic basal ganglia calcificatiOn once
secOndary causes are excluded; hOwev-
er, chOrea is a rare presentatiOn.61 Other
investigatiOns are tO be specifically
cOnsidered fOr certain spOradic and
genetic causes (refer tO Table 8-1 and
Table 8-2), including an antibOdy panel
and search Of an occult neOplasm in
paraneOplastic chOrea.
MANAGEMENT
When chOrea is the manifestatiOn of a
treatable cOnditiOn, the main goal Of
management is treatment Of the under-
lying cOnditiOn rather than of the
chOrea itself. This includes remOval Of
the Offending drug, normalizatiOn of
glycemia, immunomOdulatOry therapy
fOr autOimmune chOrea, Or remOval Of
an underlying neOplasm.
When these apprOaches prOve tO
be insufficient Or a treatable cause is
not fOund, symptOmatic treatment is
cOnsidered fOr chOrea. Establishing
clinical criteria fOr treatment is the first
1202 www.ContinuumJournal.com
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
step in the management Of chOrea. The
clinician shOuld assess the degree Of
functiOnal incapacity Or sOcial embar-
rassment caused by chOrea in a partic-
ular individual. HOwever, the lack Of
insight frequently shOwn by a patient
with chOrea relative tO the severity Of
his Or her Own symptOms can be a
limitatiOn fOr an accurate assessment.
In fact, relatives Often request treat-
ment. Regardless Of the decisiOn, anti-
chOreic medicatiOn shOuld be used
judiciOusly as no drug has prOven tO
have a dramatic effect, and adverse
effects may have an impact On the
functiOnal capacity Of patients. Clas-
sically, neurOleptics have been used
tO treat chOrea, althOugh the evi-
dence suppOrted by randOmized cOn-
trOlled trials is scarce. The Only treatment
shOwn tO effectively treat chOrea, in-
cluding HD, is the mOnoamine de-
pleter tetrabenazine.62 Due tO the
cOst and tOlerability prOfile Of this
drug, it may be chOsen as a secOnd-
line drug after the unsuccessful trial
Of an atypical neurOleptic. MOnitOring
August 2016
Of depressiOn, suicidal ideatiOn, aka-
thisia, and parkinsOnism are manda-
tOry with tetrabenazine.
Pallidal deep brain stimulatiOn
(DBS)
has been cOnsidered as an optiOn fOr
the treatment Of pharmacOresistant
chOrea or ballismus in cases with sig-
nificant disability, as well as f Or head
drOps in chOrea-acanthOcytOsis, with
a suggestiOn of efficacy in HD and
chOrea-acanthOcytOsis.22,63
The treatment Of Other symptOms
in HD phenocOpies deserves a special
cOmment. FOr severe tOngue prO-
trusiOn, it is impOrtant tO recOgnize
that swallOwing and breathing difficul-
ties may be life-threatening. BOtulinum
tOxin injectiOns have been cOnsidered
in these cases with success, in spite Of
the risk Of tempOrary dysphagia.21
TOngue Or lip biting can alsO be treated
with bOtulinum tOxin injectiOns Or
with the use Of mOuth guards.21,64 In
McLeO syndrOme, OrthOses may be
d
useful in patients with severe
peripheral neurOpathy. Patients with
head drOps
such as th O se f O und in ch O rea-
acanthOcytOsis (but alsO in McLeOd
syn- drOme and advanced HD) can use
head prOtective gear.
M OO d sympt O ms are generally
treated as in general psychiatry, since
there are no medicatiOns specifically
apprOved fOr mOOd disOrders in HD
and Other chOreic syndrOmes. There
are no cOgnitive-enhancing medica-
tiOns with prOven efficacy fOr HD and
Other chOreic syndrOmes. FOr the
cOn-
ditiOns presenting with seizures, gen-
eral principles fOr the treatment fO
r
epilepsy apply.
In the chOreic syndrOmes that are
part Of a multisystem disOrder, manage-
ment requires the invOlvement Of dif-
ferent medical specialties. An impOrtant
example is McLeOd syndrOme, which
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
KEY POINT
NO disease-mOdifying therapies are ■ In Huntington disease
available fOr HD (althOugh several and Huntington disease
trials are Ongoing) and Other neurO- phenocopies, a
degenerative chOreic syndrOmes. In multidisciplinary
acerulOplasminemia, anecdOtal evi- management plan
dence suggests that the use Of irOn is required.
chelatOrs may mOdify disease biOlOgy.65
CONCLUSION
ChOrea is a hyperkinetic mOvement
disOrder with a vast list Of causes. Aside
frOm spOradic causes, the mOst preva-
lent cause Of chOrea in the adult is HD.
The rigorOus characterizatiOn of the
phenomenolOgy and assOciated
neurO- lOgic and systemic features will
help the clinician priOritize the
investigatiOns fOr
the differential diagnosis Of chOreic
syndrOmes. HD phenocOpies represent
a challenging diagnostic grOup; SCA17,
C9orf72 in white individuals, and HDL2
in peOple Of sub-Saharan African an-
cestry, including African Americans, are
the mOst frequent diagnoses, and apart
frOm a few Other entities, the vast ma-
jOrity Of patients currently remain
withOut
a diagnosis. The management Of chOrea
represents a challenge, and the
clinician shOuld be able tO identify the
disability secOndary tO chOrea as the
apprOpriate
indicatiOn fOr treatment. When a treat-
able cause Of chOrea is present, identi-
ficatiOn of that cause is mandatOry.
ACKNOWLEDGMENTS
The authOr wOuld like tO acknowl-
edge David Grimes, MD, FRCPC, fOr
prOvidin Supplemental Digital Con-
g
tent 8-3 and Supplemental Digital
Content 8-4, as well insightful cOm-
ments. The authOr wOuld als like tO
O
acknowledge AnthOny E. Lang, OC, MD,
FRCPC, FAAN, FCAHS, FRSC, fOr prOvid-
ing Supplemental Digital Content 8-6
and JOaquim J. Ferreira, MD, PhD, fOr
pr O viding Supplemental Digi-
requires periOdic cardiac assessment tal Content 8-5, Supplemental Digital
due tO the presence Of cardiOmyOpathy Content 8-7, and Supplemental Digital
and the risk Of cardiac sudden death. Content 8-8.
Continuum (Minneap Minn) 2016;22(4):1186–1207 www.ContinuumJournal.com 1203

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

 Chorea
VIDEO LEGENDS
Supplemental Digital
Content 8-1
Senile chorea. VideO shOws a man in
his seventies with a clinical diagnosis
Of senile chOrea and whO was fOund tO
have genetically prOven HuntingtOn
disease. Mild chOrea is seen in the
trunk, neck, and OrOfacial regiOns,
and an exaggerated pOut and
grimace is
seen in the OrOfacial regiOn.
links.lww.com/CONT/A188
B 2016 American Academy Of NeurOlOgy.
Supplemental Digital
Content 8-2
Levodopa-induced dyskinesia in
Parkinson disease. VideO shOws a 62-
year-Old wOman with a 10-year histOry
Of ParkinsOn disease whO now has
severe, refractOry levOdOpa-induced
dyskinesia. After an acute administra-
tiOn of levOdOpa, she exhibits predOm-
inantly chOreic dyskinesia that invOlves
the lOwer limbs, trunk, and, tO a lesser
extent, the upper limbs.
links.lww.com/CONT/A189
B 2016 American Academy Of NeurOlOgy.
Supplemental Digital
Content 8-3
Paroxysmal kinesigenic dyskinesia.
VideO shOws a man with parOxysmal
kinesigenic dyskinesia (PRRT2 gene
pOsitive) presenting with chOrea and
dystOnia. UpOn standing, a 10-secOnd
episOde Occurs invOlving the left up-
per limb with arm adductiOn, elbOw
flexiOn, hand clenching, and chOreic
mOvements Of the fingers.
links.lww.com/CONT/A190
COurtesy Of David Grimes, MD, FRCPC.
Supplemental Digital
Content 8-4
Chorea-acanthocytosis. VideO shOws
a 28-year-Old man exhibiting jaw-
1204 www.ContinuumJournal.com
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
O pening dystOnia, ch O rea of the
trunk and neck, and dystOnic prO-
trusiOn of the tOngue when eating
or speaking, but not impaired
drinking. Mild bradykinesia and
sniffing with nose clearing are
alsO Observed.
links.lww.com/CONT/A191
COurtesy Of David Grimes, MD, FRCPC.
Supplemental Digital
Content 8-5
Chorea in Huntington disease. VideO
shOws flOrid chOreic mOvements in a
man with genetically prOven Hunting-
tOn disease. He exhibits brief, irre-
gular, randOm, purpOseless, invOluntary
mOvements flOwing frOm One muscle
grOup tO the next, which are super-
impOsed On vOluntary mOtOr activity,
namely walking.
links.lww.com/CONT/A192
COurtesy Of JOaquim J. Ferreira, MD, PhD.
Supplemental Digital
Content 8-6
Chorea of the hands in Huntington
disease. VideO shOws fOcal chOrea
lOcalized tO the hands Of a man
with HuntingtOn disease. He ex-
hibits randOm piano-playing mOve-
ments Of the fingers that are brOught
abOut by finger tapping and cOunt-
ing backward.
links.lww.com/CONT/A193
COurtesy Of AnthOny E. Lang, OC, MD, FRCPC,
FAAN, FCAHS, FRSC.
Supplemental Digital
Content 8-7
Ballismus. VideO shOws a man with
right upper limb unilateral ballismus.
He exhibits characteristic high-
amplitude invOluntary flinging
mOvements invOlv- ing the mOst
prOximal segment Of the upper limb.
links.lww.com/CONT/A194
COurtesy Of JOaquim J. Ferreira, MD, PhD.
August 2016
Supplemental Digital
Content 8-8
Athetosis. VideO shOws a wOman with
cerebral palsy and athetOsis Of the right
hand. She exhibits characteristic, slOw
invOluntary writhing mOvements Of
the distal limb regiOn. Underlying
dys- tOnia is evident with prOminent
lateral deviatiOn and flexiOn of the
wrist and finger extensiOn.
links.lww.com/CONT/A195
COurtesy Of JOaquim J. Ferreira, MD, PhD.
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