Journal of the association of physicians of india july 2013 VOL.

61 35

Review Article

Chorea
Sanjay Pandey*

Abstract
Chorea is an involuntary movement disorder characterised by flowing and rhythmic in nature. Hyperkinetic
movement disorders such as myoclonus may be mistaken for chorea. Pathogenesis of chorea is complex and results
from dysfunction of network between motor nucleus of thalamus and subcortical nuclei including globus pallidus
interna. There are genetic and non genetic causes of chorea. Huntingtons disease is most common genetic cause
of chorea. Clinical manifestations of Huntingtons disease are mainly neurological and psychiatric. Recently non
neurological clinical manifestations of this disease have been described. Genetic test for Huntingtons disease is
available which may be done for diagnosis and detection of family members at risk of developing disease. Other
genetic causes of chorea are neuroacanthocytosis and Wilsons disease. Treatment of genetic causes of chore is
usually symptomatic with exception of Wilsons disease. Sydenhams chorea is a neurological manifestation of
acute rheumatic fever and most important cause of chorea seen in paediatric population. Treatment includes
penicillin prophylaxis and drugs such as sodium valproate and carbamazepine. Diagnosis of chorea is mainly
clinical. Family history is very important in diagnosis of genetic causes of chorea. In other patients a detailed work
up is required before a final diagnosis is made. Hematological and blood chemistry investigations are helpful in
diagnosis of some of the patients. Neuro imaging may also be useful mainly in Huntingtons disease patients.
Metabolic disorders and drugs are very important causes of non genetic chorea. Early diagnosis is important
because majority of the patients respond to the treatment.

Introduction (GPe), caudate nuclei, subthalamus and thalamus.1,5 There are

inhibitory GABAergic projections from GPi to motor nucleus
T he word Chorea is derived from Greek word meaning
dance. It is characterised by involuntary rhythmic movement
which is random and brief.1 Chorea may involve face, tongue,
of thalamus. Dysfunction of these inhibitory inputs leads to
hyperkinetic choreform movements. However this model is not
so straightforward. In Parkinsons disease patients pallidotomy
neck, trunk, upper extremities and lower extremities. 2 Very leads to abolition of chorea raising a question mark over this
severe chorea with predominant proximal distribution is labelled model.
as ballismus. Unilateral chorea is called hemichorea and if
associated with ballismus it is called choreoballistic movement.
Description of chorea has been available in literature since 14th
Clinical Symptoms
century when epidemic dancing mania was described.3 Thomas Movements in chorea may be simple or complex. Sometimes
Sydenham described post infectious chorea for the first time. they are superimposed with voluntary actions leading to a bizarre
character. It may be mistaken for myoclonus but a flowing nature
Chorea can be hereditary or acquired. Most common form of
of chorea is most characteristic. Another difference is speed of
hereditary chorea is Huntingtons disease. Most common causes
movement which is more in case of myoclonus in comparison
of non genetic chorea are autoimmune, infectious, vascular, drug
with chorea. Hypotonia is a consistent feature and knee jerks may
and metabolic.4
be pendular. Hung-up reflex may be seen due to a combination
of choreic movement with reflex.
Pathogenesis
Many clinical methods have been described to elicit chorea,
Chorea originates from dysfunction of a neuronal network like milkmaids grip (while squeezing examiners fingers
between motor cortex and basal ganglia which includes irregular contractions of hand muscles), piano sign (when
subcortical nuclei like globus pallidus interna (GPi) and externa arms are extended repeated hand spooning and pronation),
tongue movement (worm like movement on protrusion) and
Table 1 : Genetic and non genetic causes of chorea
handwriting (to demonstrate motor impersistence).
Genetic causes Non genetic causes
Huntingtons Disease Sydenhams chorea Causes of Chorea
Neuroacanthocytosis Metabolic causes Chorea may result from genetic or nongenetic causes (Table1).
Benign hereditary chorea Chorea gravidarum Most common genetic cause is Huntingtons disease. Non
Wilsons disease Drug induced chorea genetic causes of chorea include metabolic, infectious disorders
Dentatorubropallidoluysian atrophy Senile chorea and stroke.
Spinocerebellar ataxia type 2 Vascular chorea
McLeod syndrome Infective causes
Huntingtons Disease (HD)
Hereditary form of chorea was first described by Walters
Associate Professor Neurology, Department of Neurology, GB Pant
*
in 1842. However first detailed description and genetic mode
Hospital, Delhi of transmission was described by George Huntington in 1872.
Received: 06.07.2011; Accepted: 19.08.2011
Since Huntington was first to give a detailed description of this

JAPI july 2013 VOL. 61 471

36 Journal of the association of physicians of india july 2013 VOL. 61
Table 2 : Major presenting symptoms of Huntingtons
disease patients
Neurological Psychiatric Cognition Non-
neurological
Chorea Depression Speech difficulty Muscle and
testicular
atrophy
Dystonia Mania Executive Weight loss
dysfunction
Rigidity Psychosis Short term Osteoporosis
memory loss
Gait abnormality Anxiety Poor attention Impaired
glucose
tolerance test
Eye movement Suicidal Poor calculation Heart failure
abnormality tendency
disorder it is known as Huntingtons disease (HD). Huntington
described three peculiarities of this disorder; hereditary
character, suicidal tendency and adult onset. Prevalence rate of
HD is 3to7 per 100,000 population in North America and Europe
and annual incidence is between 2to 7 per million.1
Huntingtons disease symptom may start any time between
1 to 80 years of age. But usual age of onset is in fourth decade of
life in most of the families.6 Onset of symptoms mainly depends
upon number of CAG repeats. Earlier onset in subsequent
generation is known as anticipation, which is a hallmark of all
trinucleotide repeat disorders. Before the symptom onset there
is a presymptomatic phase which is characterised by personality
and cognitive changes. Early and late onset HD patients have
more parkinsonian features than chorea and they progress faster.
Clinical features may start with neurological or psychiatric
features alone or simultaneously. In patients presenting
with psychiatric features anxiety, anger and irritability are
most common symptoms. They may be wrongly diagnosed
as psychiatric patients till they have motor manifestations.
Other psychiatric manifestations may be in form of irritability,
aggressive behaviour, depression, anxiety and suicidal tendency.
Impulsive behaviour may lead to criminal activities. Impaired
cognition in form of speech difficulty and poor executive function
are most characteristic. Dementia is quite common in HD
patients but is more frequent in Juvenile HD. In some patients
motor impersistence may be the only initial manifestation.
Neurological features may be in form of chorea, dystonia or
gait abnormality. Gradually chorea is replaced by rigidity and
bradykinesia. In some patients upper motor neuron signs in form
of spasticity and hyper-reflexia may be seen. Different types of
eye movements have been described in HD. Slow saccade is most
consistent abnormality seen. Up gaze restriction and frequent
blinking are other characteristic ocular features.7 Progression
of disease is usually slow but can be rapid in juvenile and late
onset cases. Neuropathology studies have revealed that striatal
medium neurons are most vulnerable and interneurons are
generally spared.8 Nuclear and cytoplasmic inclusions containing
huntingtin and polyglutamate have been reported.9 Cause of
death may be a complication of psychiatric symptoms leading
to suicide or because of poor nutrition or aspiration pneumonia.
Non neurological manifestations of HD have been widely
reported in the literature (Table 2). Major non neurological
features include weight loss, muscle atrophy, testicular atrophy
and heart failure.
Huntingtons disease may not always present with typical
472 JAPI july 2013 VOL. 61
history of chorea, psychiatric and cognitive impairment.
Different variations have been reported in the literature.
Juvenile Huntingtons Disease
Juvenile form of HD is having onset before 20 years of age.
Major clinical features are bradykinesia, rigidity and dementia.
Progression is rapid in comparison to HD patients.
Huntingtons Disease without Chorea
Some cases of HD have been reported where cognitive
dysfunction and dementia are the major manifestation and
chorea is minimal or absent.
Huntingtons Disease without Dementia
Chorea without dementia or psychiatric symptoms has
been reported in some families. On pathology there has been
predominant involvement of basal ganglia with sparing of cortex.
Huntington disease like 2 (HDL2) : It is caused by Junctophilin
-3 mutation and exclusively reported from African community.
Clinical features are similar to HD patients.
Genetics and Huntingtin Protein
Huntingtons disease gene has been located on short arm of
chromosome 4. This gene is responsible for CAG repeats.
Huntingtin protein is mostly found in mammals in brain and
is involved in transcriptional process.10 It has also been found
in other tissues like testes, liver, heart and lung. In normal
individuals less than 36 CAG repeats are seen in Huntingtin
protein. But in mutant huntingtin protein number of repeats are
more than 39. Mutant huntingtin protein is toxic in nature and
leads to impaired transcriptional process leading to apoptosis.
More repeats are associated with early onset of symptoms,
known as anticipation. Genetic test in family members of HD
patients can predict the disease in advance and is an important
tool for diagnosis in preclinical stage. Certain group of
individuals having suicidal thoughts should be excluded from
this test. Worldwide only 5-10% such individuals go for this test
because of fear and anxiety.11Major reason of anxiety is losing job
and medical insurance. Recently some European countries have
banned disclosure clause for genetic test in health insurance.
This step is needed by other countries also to motivate people
for getting genetic test done.
Neuroacanthocytosis: Similar to HD neuroacanthocytosis also
starts in younger or middle age individuals. Characteristic
features include chorea, self-mutilation, peripheral neuropathy
and dystonia. Gait in neuroacanthocytosis is very typical and
some authors have labelled this as rubber man syndrome.
Demonstration of acanthocytes on peripheral blood smear
examination is crucial for the diagnosis. Neuropathological
studies have demonstrated atrophy and gliosis of caudate
nuclei and putamen without involvement of other part of brain.
Mcleod neuroacanthocytosis syndrome is a multisystem disorder
characterised by central nervous system (CNS), neuromuscular,
and hematologic manifestations in males. McLeod blood group
phenotype results from abnormal expression of Kell surface
antigens on the erythrocyte.
Benign hereditary chorea (BHC): Benign hereditary chorea is
also known as essential chorea. It is inherited in an autosomal
dominant pattern and starts in first decade of life with a peak
in second decade. Characteristic features include chorea and
ataxia. BHC is non progressive and sometimes improves with
age. Mutation in thyroid transcription factor -1(TITF-1) on
chromosome 14q is diagnostic.
Journal of the association of physicians of india july 2013 VOL. 61 37
Table 3 : Drugs causing chorea
Antiepileptic drugs Phenytoin, carbamazepine,
valproate, benzodiazepines
Drugs used in Parkinsons disease Levodopa, dopamine agonists
Stimulants Cocaine, amphetamines
Hormones Oestrogens
Others Lithium, baclofen, phenothiazine,
flunarazine
Wilsons Disease
Wilsons disease is characterised by autosomal recessive
inheritance and mutation in chromosome 13q14.3. Clinical
features include tremor, dystonia, chorea and Kayser-Fleischer
rings (KF rings). In neurological cases diagnosis is made by
serum ceruloplasmin level (<300 mg/l), 24 hour urinary copper
excretion (>100 mg/day) and presence of KF ring. Treatment
includes chelating agent such as penicillamine and zinc.
Dentatorubrolpallidoluysian Atrophy
(DRPLA)
DRPLA has been commonly reported from Japan. It is
an autosomal dominant inheritance disorder and caused by
trinucleotide repeat with gene location at chromosome 12.
Clinical features include chorea, ataxia, seizure, myoclonus
and mental retardation. Magnetic resonance imaging brain in
DRPLA patients have revealed cerebellar and midbrain atrophy.
Paroxysmal Chorea
Paroxysmal chorea may manifest in two different ways;
paroxysmal kinesogenic choreoathetosis (PKC) or paroxysmal
dystonic choreoathetosis (PDC). Symptoms start in first decade
of life and episodes starts with exercise or physical activity.
Majority of the patients respond to antiepileptic drugs.
Sydenhams Chorea
Sydenhams chorea (SC) is one of the neurological
manifestations of acute rheumatic fever. It usually starts in first
decade of life and is more common in girls. Manifestation of
chorea in acute rheumatic fever is late and occurs in 10-30% of
patients usually in absence of other symptoms. Associate carditis
is seen in 40-80% patients and arthritis in 10-30% patients of
Sydenhams chorea.12 In a study of 50 patients with rheumatic
fever; arthritis was more common in patients without chorea
(84%) than patients with chorea (31%).13 Predominantly head
and upper limbs are involved. Typically chorea appears after 4-5
weeks of streptococcal infection when other manifestations of
rheumatic fever are not seen. Twenty percent patients may have
asymmetrical onset of chorea and may present as hemi chorea.
Rarely chorea may be very severe leading to chorea paralytics.
Hypotonia is a common feature. Other motor findings like tics
are very common. Association with migraine, papilloedema,
seizure and central retinal artery occlusion has also been seen.
Patients may have psychiatric manifestations like hyperactivity,
irritability and learning disorders. In Sydenhams chorea
individual muscle contractions are longer (>100 msec) than HD
patients (50-100 msec).14 Activities of daily living, motor function
and behavioural disorders can be measured by Universidade
Federal de Minas Gerais Sydenham choreaRating Scale. 15 It has
27 items each having 0 (no symptom or disability) to 4 (severe
symptom, sign or disability) score. Most likely pathogenesis
is molecular mimicry between central nervous system and
JAPI july 2013 VOL. 61 473
streptococcal antigen. Diagnosis is mainly presumptive and
clinical. Anti-basal ganglia antibodies, antistreptolysin-o titre,
throat culture and erythrocyte sedimentation ratio helps in
diagnosis. Neuroimaging may be helpful in some patients. In a
study of Sydenhams chorea patients 3 out of 19 had alteration in
caudate nucleus on Magnetic resonance imaging (MRI).16 Jones
criteria is helpful in diagnosis of patients.17 Other causes of chorea
such as Wilsons disease, drugs, systemic lupus erythematosus
and benign hereditary chorea should be ruled out. In majority
of the patients penicillin prophylaxis is recommended.
Chorea Gravidarum
Chorea occurring during pregnancy is known as chorea
gravidarum. Many such patients have previous history of
Sydenhams chorea also. Other conditions such as systemic lupus
erythematosus (SLE), antiphospholipid antibody syndrome
(APLS),
Syphilis and encephalitis have been associated with
chorea gravidarum.18 There have been association with use
of oral contraceptive pills (OCP) also. Patients should also be
investigated for collagen disorders and management includes
stoppage of oral contraceptive pills. Clinical symptoms usually
develop in first trimester and majority of the patients have
remission after delivery.
Drugs causing chorea: There are many drugs which may
cause chorea (Table3). Drug induced chorea may be seen
during acute phase of treatment or may appear after some time.
Antiparkinsonian and anti epileptic drugs are most important
causes of chorea. Levodopa induced chorea is most common
cause of chorea in adults. Treatment includes withdrawal of
the offending drug. It may take days to months before patient is
free from symptoms. In difficult cases drugs like tetrabenazine
has been tried.
Metabolic chorea: Hyperthyroidism, hypoglycaemia, chronic
acquired hepatolenticular degeneration and renal failure
may manifest as chorea. Transitory chorea may be seen in
hyperosmolar hyperglycaemia and hyponatremia. Majority of
the patients recover after correction of underlying metabolic
abnormality.
Vascular chorea: Another important cause of chorea in middle
age group and elderly is stroke. But chorea is usually unilateral
in this setting. Most common site of insult is subcortical;
predominantly in basal ganglion, caudate, thalamus, and
subthalamic nucleus. Chorea is also seen in approximately 1%
patients of polycythemia vera. Pathophysiology includes chronic
hyperviscosity leading to hypoxia and ischemia of basal ganglia
region. Patients may require repeated venesection.
Infective causes: Most common infectious causes of chorea are
human immunodeficiency virus and opportunistic infections
associated with it. Lymphoma, toxoplasma, progressive
multifocal leukoencephalopathy and tuberculoma are
most common. Rarely tuberculoma and neurocysticercosis
may involve caudate nucleus and may lead to chorea in
immunocompetent persons.
Senile Chorea
Sporadic chorea with onset after 50 years of age is termed as
senile chorea. Its exact pathogenesis is not clear. Causes of senile
chorea include drugs, stroke, metabolic and genetic.
38 Journal of the association of physicians of india july 2013 VOL. 61
Fig. 1 : Head CT scan of a Huntingtons disease patient showing
bilateral caudate head atrophy altering the configuration of frontal
horn of lateral ventricle known as Box sign
Approach to Chorea
History taking and clinical examination
Most important part of history taking is to differentiate
between genetic and non genetic causes of chorea. Family
history suggestive of autosomal dominant pattern is very
much suggestive of Huntingtons disease. Wilsons disease is
also characterised by positive family history but inheritance
pattern is autosomal recessive type. Other conditions where
family history may be very significant is benign hereditary
chorea, neuroacanthocytosis, spinocerebellar ataxia and
McLeod syndrome. Recent history of streptococcal infection
is very important especially in paediatric age group as it may
be an evidence of Sydenhams chorea. History of any recent
drug exposure, metabolic impairment and worsening during
pregnancy may be an important clue towards final diagnosis.
On neurological examination it is important to look for
associated findings like presence of KF rings, ataxia, peripheral
neuropathy and dementia which may give important clues
regarding aetiology of chorea. Distribution of chorea is also very
important. Sudden onset, very severe and unilateral chorea may
be a feature of vascular chorea. Similarly in children hemichorea
may be seen in 20% of Sydenhams chorea patients.
Investigations
Haematological investigations should be done including liver
and kidney function tests. Acanthocytes may be seen on general
blood picture. Antinuclear antibodies and antistreptolysin-o titre
are also quite helpful in diagnosis. Other investigations include
thyroid function test, test for human immunodeficiency virus
and neuroimaging in selected patients. Caudate atrophy is a
consistent feature in HD patients on neuro- imaging. Progression
of disease and preclinical diagnosis in at risk patients have been
correlated with caudate atrophy and inter caudate atrophy on
CT scan and MRI.7 Because of caudate atrophy bilateral frontal
horns of lateral ventricle gives an impression of box known
as Box Sign (Figure 1). Electroencephalogram (EEG) and
electromyography (EMG) have been found to be useful in some
474 JAPI july 2013 VOL. 61
patients. Diminished alpha activity is the most common EEG
finding in HD patients and their clinically healthy relatives.19
Motor impersistence is a unique feature of HD and can be
demonstrated on EMG by using surface disc electrodes. Genetic
studies should be done after narrowing down the possibilities
at the end of history and neurological examinations.
Treatment
Chorea does not require treatment if it is mild. But many
times patients and their family members seek treatment because
of cosmetic reasons. Most of the drug studies have been done
on Huntingtons disease patients. Neuroleptic drugs were first
to be used but they carry significant extrapyramidal side effects
in form of parkinsonian features, so they are least preferred.
Nongenetic causes of chorea which are secondary to infection,
metabolic disorders and drugs respond to the treatment of
underlying cause. Sydenhams chorea is usually treated by
sodium valproate in a dosage starting from 250 mg/day and
gradually increasing to 250 mg three times a day. A maximum
dosage of 1500 mg/day has also been tried. Other alternatives
are carbamazepine, haloperidol, risperidone and pimozide.20
Steroids have also been tried but its use remains controversial.
Treatment of HD is mainly symptomatic. For chorea most
potent drug is Tetrabenazine which has been found to be
quite effective.21 Behavioural symptoms may be treated with
antidepressants and anxiolytics. For psychotic symptoms
atypical neuroleptics are preferred. Surgical treatments like
pallidotomy and deep brain stimulation have been tried.22,23
Progression of disease can be monitored by using unified
Huntington disease rating scale.24 Many experimental drugs
like creatine, minocycline and lithium have been tried. Different
genetic animal models (mouse, drosophila and caenorhabditis
elegans) have been used for development of drugs which may be
effective in preclinical stage and may prevent further progression
of the disease. YAC 72 and YAC 128 is the most common mouse
model used.
Supportive treatments like physical, speech and occupational
therapy with adequate nutrition is very important. Patients
should be counselled for disability benefits and life planning.
Care givers should also be counselled regarding physical and
emotional need of the patient.
Conclusion
Chorea is an important movement disorder seen in adult and
paediatric neurology. Huntingtons disease is most common
genetic causes of chorea, whereas Sydenhams chorea is usually
seen in paediatric population, especially in Indian subcontinent.
Metabolic disorders like hyperthyroidism, Wilsons disease and
hyperglycaemia are important reversible causes. Many infectious
and vascular disorders may also lead to chorea. Treatment is
usually symptomatic. More research is needed to understand
the pathogenesis of chorea.
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