Section III

Hyperkinetic disorders

C H A P T ER 15
Chorea, ballism, and athetosis

Chapter contents
Introduction 335
Dentatorubral-pallidoluysian atrophy and HD-like Other choreas 345
disorders 335
Other Huntington disease-like disorders 337
Neuroacanthocytosis 339
Neurodegeneration with brain iron accumulation 341
Other familial choreas 342
Infectious chorea 343
Postinfectious and autoimmune choreas 343
Other autoimmune choreas 344
Treatment of chorea 346
Ballism 346
Treatment of ballism 347
Athetosis 347
Treatment of athetosis 348
Appendix 349

Introduction Cardoso etal., 2006; Jankovic and Fahn, 2009) (Tables 15.1
and 15.2, Fig. 15.1). Chorea may be seen in normal infants,
but these movements usually disappear by age 8 months,
Chorea consists of involuntary, continual, abrupt, rapid,
and some of these movements may be purposeful (Van der
brief, unsustained, irregular movements that flow randomly
Meer etal., 1995).
from one body part to another. Patients can partially and
In this chapter we will briefly mention HD, but the focus
temporarily suppress the chorea and frequently camouflage
will be on non-HD causes of chorea, as HD-like phenotypes
some of the movements by incorporating them into semi-
without the HD genotype are increasingly being described
purposeful activities (parakinesia). The inability to maintain
and must be recognized. Several neurodegenerative disor-
voluntary contraction (motor impersistence), such as manual
ders, some with expanded trinucleotide repeats, have been
grip (milkmaid grip) or tongue protrusion, is a characteristic
reported as phenocopies of HD, including spinocerebellar
feature of chorea and results in dropping of objects and
atrophy, particularly SCA2 and SCA3 (Kawaguchi etal.,
clumsiness. Chorea should be differentiated from pseudo-
1994), pure cerebello-olivary degeneration (Fox etal., 2003),
choreoathetosis, a movement disorder that is phenomeno-
and dentatorubral-pallidoluysian atrophy (DRPLA) (see
logically similar to chorea or athetosis (slow chorea) due to
below) (La Spada etal., 1994; Ikeuchi etal., 1995; Komure
loss of proprioception (Sharp etal., 1994). Muscle stretch
etal., 1995; Warner etal., 1995; Ross etal., 1997; Rosenblatt
reflexes are often hung-up and pendular. Affected
etal., 1998; Wild etal., 2008). In a study of 285 patients
patients typically have a peculiar, irregular, and dance-like
with clinical features consistent with HD, but who tested
gait. The pathophysiology of chorea is poorly understood,
negative for HD by a DNA analysis, the following diagnoses
but in contrast to parkinsonism, dystonia, and other move-
were identified: five cases had Huntington disease-like type
ment disorders, intracortical inhibition of the motor cortex
4 (HDL4), one had HDL1, one had HDL2, and one patient
is normal in chorea (Hanajima etal., 1999). In addition,
had Friedreich ataxia (Wild etal., 2008).
semiquantitative analysis of single photon emission com-
puted tomography in patients with hemichorea due to
various causes suggests that there is an increase in activity in
the contralateral thalamus, possibly due to disinhibition as
Dentatorubral-pallidoluysian atrophy and
a result of loss of normal pallidal inhibitory input (Kim HD-like disorders
etal., 2002).
Chorea may be a manifestation of a primary neurologic Dentatorubral-pallidoluysian atrophy (DRPLA) is an auto-
genetic disorder, such as Huntington disease (HD), or it may somal dominant neurodegenerative disorder that is particu-
occur as a neurologic complication of systemic, toxic, or larly prevalent in Japan, but it has been also identified in
other disorders (Rosenblatt etal., 1998; Cardoso, 2004; Europe and in African-American families (Haw River
2011 Elsevier Ltd, Inc, BV
DOI: 10.1016/B978-1-4377-2369-4.00015-9
 15 Chorea, ballism, and athetosis
Table 15.1 Differential diagnosis of chorea
Developmental choreas
Physiologic chorea of infancy
Chorea minima
Idiopathic choreas
Buccal-oral-lingual dyskinesia and edentulous orodyskinesia
In older adults, senile chorea (probably several causes)
Hereditary choreas
Huntington disease
Benign hereditary chorea (TITF1 gene)
Neuroacanthocytosis (VPS13A gene)
Other heredodegenerations: Huntington disease-like (HDL) disorders
(e.g., prion protein PRNP, junctophilin or JPH3 genes), dentatorubral-
pallidoluysian atrophy (c-Jun NH-terminal kinase, JNK gene),
spinocerebellar ataxias (SCA2, SCA17), ataxia telangiectasia, ataxia
with oculomotor apraxia type 1 (aprataxin gene), ataxia with
oculomotor apraxia type 2 (due to mutations in the senataxin gene),
tuberous sclerosis of basal ganglia, pantothenate kinase associated
neurodegeneration, other neurodegenerations with brain iron
accumulation (HallervordenSpatz disease), Wilson disease,
neuroferritinopathy, infantile bilateral striatal necrosis (IBSN)
Neurometabolic disorders
LeschNyhan syndrome, lysosomal storage disorders, amino acid
disorders, Leigh disease, porphyria; glucose transporter type 1
deficiency syndrome (Prez-Dueas etal., 2009)
Drugs
Neuroleptics (tardive dyskinesia, withdrawal emergent syndrome),
dopaminergic drugs, anticholinergics, amphetamines, cocaine,
tricyclics, oral contraceptives
Toxins
Alcohol intoxication and withdrawal, anoxia, carbon monoxide,
manganese, mercury, thallium, toluene
Metabolic and endocrine disorders
Hypernatremia, hyponatremia, hypomagnesemia, hypocalcemia,
hypoglycemia, hyperglycemia (nonketotic)
Hyperthyroidism, hypoparathyroidism
syndrome) (Burke etal., 1994; Thomas and Jankovic,
2001; Wardle etal., 2009) (Table 15.3). Usually beginning
in the fourth decade, the disorder may occur as an early-
onset DRPLA (before 20 years of age), manifested by a
variable combination of myoclonus, epilepsy, and mental
retardation, or late-onset DRPLA (after 20 years of age),
manifested by cerebellar ataxia, choreoathetosis, dystonia,
rest and postural tremor, parkinsonism, and dementia
(Video 15.1).
Unstable CAG expansion has been identified as the muta-
tion in the DRPLA (or ATN1) gene on chromosome 12p13.31
(Koide etal., 1994; Komure etal., 1995; Warner etal., 1995;
Becher etal., 1997; Ross etal., 1997). The DRPLA gene codes
for protein that has been identified as a phosphoprotein,
c-Jun NH(2)-terminal kinase, one of the major factors
involved in its phosphorylation. In DRPLA, this protein
appears to be slowly phosphorylated; thus, it may delay
a process that is essential in keeping neurons alive
336
Pregnancy (chorea gravidarum)
Acquired hepatocerebral degeneration
Renal failure
Nutritional (e.g., ketogenic diet, beriberi, pellagra, vitamin B1 and B12
deficiency, particularly in infants)
Infectious and postinfectious
Sydenham chorea
Encephalitis lethargica
Various other infectious and postinfectious encephalitis, Creutzfeldt
Jakob disease, Lyme disease, mycoplasma
Immunological
Systemic lupus erythematosus
HenochSchnlein purpura
Acquired immunodeficiency disease
Acute disseminated encephalomyelitis (ADEM)
Vascular
Infarction or hemorrhage
Arteriovenous malformation, moyamoya disease
Polycythemia rubra vera
Antiphospholipid syndrome
Migraine
Following cardiac surgery with hypothermia and extracorporeal
circulation in children (choreathetosis and orofacial
dyskinesia, hypotonia, and pseudobulbar signs or CHAP
syndrome)
Tumors
Trauma
Other secondary choreas
Cerebral palsy (anoxic), kernicterus, sarcoidosis, multiple sclerosis,
disease, Behet disease, polyarteritis nodosa, mitochondrial
disorders
Miscellaneous
Paroxysmal dyskinesias (choreoathetosis), familial dyskinesia, and facial
myokymia
(Okamura-Oho etal., 2003). Similar to HD, there is an
inverse correlation between the age at onset and the number
of CAG repeats (Ikeuchi etal., 1995). The early onset of
DRPLA is associated with greater number of CAG repeats
(6279) as compared to the late-onset type (5467 repeats)
(Ikeuchi etal., 1995). Testing for the various gene mutations
will undoubtedly lead to better recognition and appreciation
of the spectrum of clinical and pathologic changes associ-
ated with these disorders. For example, a family with spastic
paraplegia, truncal ataxia, and dysarthria, but without other
clinical features of DRPLA, has been found to show homozy-
gosity for an allele that carries intermediate CAG repeats in
the DRPLA gene (Kuroharas etal., 1997). The DRPLA gene
is expressed predominantly in neurons, but neurons that are
vulnerable to degeneration in DRPLA do not selectively
express the gene (Nishiyama etal., 1997).
Neuroimaging studies in patients with DRPLA often show
evidence of cortical, brainstem, and cerebellar atrophy and
 Other Huntington disease-like disorders

ubiquitin (Becher and Ross, 1998). Subsequent studies have

Table 15.2 Differential diagnosis of inherited and demonstrated accumulation of mutant atrophin-1 in the
sporadic choreas neuronal nuclei, rather than neuronal intranuclear inclu-
Inherited disorders Sporadic disorders sions, as the predominant pathologic feature in this neuro-
degenerative disorder (Yamada etal., 2001).
HD Static encephalopathy (CP)
HDL1, HDL2, HDL3 Essential (senile) chorea
DRPLA Sydenham chorea Other Huntington disease-like disorders
Neuroacanthocytosis Vascular chorea
SCA2, 3, 17 Polycythemia vera
An autosomal dominant HD-like neurodegenerative disor-
NBIA Sporadic CreutzfeldtJakob der, now classified as HDL1 and mapped to chromosome
Pantothenate kinase disease
20p (Xiang etal., 1998), is a familial prion disease with an
associated Systemic lupus
expanded PrP. A 192-nucleotide insertion in the region of
neuodegeneration (PKAN), erythematosus
neuroferritinopathy,
the prion protein gene (PRNP) encoding an octapeptide
Antiphospholipid syndrome
aceruloplasminemia, repeat in the prion protein, was found in a single family with
Hyperthyroidism
infantile neuroaxonal HD phenotype, suggesting that PRNP mutations can result
AIDS
dystrophy in HD phenocopies (Moore etal., 2001).
Tardive dyskinesia Another disorder, termed HDL2, is characterized by onset
Benign hereditary chorea
Metabolic encephalopathy in the fourth decade, involuntary movements such as chorea
Wilson disease
Hepatolenticular and dystonia as well as other movement disorders (bradyki-
Mitochondrial disorders
degeneration nesia, rigidity, tremor), dysarthria, hyperreflexia, gait abnor-
Ataxia with oculomotor
Nonketotic hyperglycemia mality, psychiatric symptoms, weight loss, and dementia
apraxia (types 1 and 2)
Hypoglycemia with progression from onset to death in about 20 years
Ataxia telangiectasia
Renal failure (Margolis etal., 2001, 2004; Walker etal., 2003a). The dis-
Ketogenic diet order appears to be present exclusively or predominantly in
individuals of African origin. The neuroimaging and neu-
ropathologic findings are very similar to those in HD, except
that there appears to be more severe involvement of the
Table 15.3 Clinical features of dentatorubral-pallidoluysion
occipital cortex (Greenstein etal., 2007), and the intranu-
atrophy (DRPLA) clear inclusions stain with 1C2 but not with anti-huntingtin
Early onset Late onset antibodies. Unlike the family linked to chromosome 20p,
<20 years >20 years
seizures are not present in the HDL2 family. All 10 affected
family members had a CAG repeat expansion of 5060 tri-
Mildmoderate Moderatesevere
plets. The gene was later mapped to chromosome 16q24.3
Myoclonus Ataxia (severe)
and was found to encode junctophilin-3, a protein of the
Epilepsy Choreoathetosis
junctional complex linking the plasma membrane and the
Mental retardation Dystonia
endoplasmic reticulum (Holmes etal., 2001). Although
6279 CAG repeats Rest and postural tremor
acanthocytosis was emphasized by Walker and colleagues
Parkinsonism (2002, 2003b) in their initial report and in one of three
Dementia patients reported subsequently (Walker etal., 2003b), we
MRI white matter changes have not been able to confirm the presence of acanthocytes
5467 CAG repeats in one member of the original family or in the other members
when we carefully examined the peripheral smear.
The mutation associated with HDL2 has been identified
widespread white matter changes (Koide etal., 1997; Muoz as a CTG/CAG trinucleotide repeat expansion within the
etal., 1999, 2004). Neuropathologic findings consist chiefly junctophilin-3 (JPH3) gene. In the normal population, the
of degeneration of the dentatorubral system, globus pallidus repeat length ranges from 6 to 27 CTG triplets, whereas
externa (GPe), subthalamic nucleus, and, to a lesser extent, affected individuals have 4158 triplets. One family,
striatum, substantia nigra, inferior olive, and thalamus previously described as autosomal dominant chorea
(Warner etal., 1994) as well as demyelination and reactive acanthocytosis with polyglutamine-containing neuronal
astrogliosis in the cerebral white matter (Muoz etal., inclusions (see later) (Walker etal., 2002), was subse-
2004). Involvement of oligodendrocytes in autopsied brains quently found to have the triple nucleotide expansion of
and an increased number of affected glia, as well as larger HDL2 (Stevanin etal., 2003; Walker etal., 2003b). The CTG
expansions in CAG in these glia, in transgenic mice might repeat expansion at the HDL2 locus has been found to be
explain the widespread demyelination (Yamada etal., 2002). responsible for 2% of patients with typical features of HD
Several pathologic reports have noted widespread deposition but without expanded CAG repeats in the IT15 gene and
of lipofuscin. Similar to HD and other diseases associated 0.2% of all HD families, again providing evidence that HD
with CAG repeat expansions, DRPLA has also been associ- is clinically and genetically heterogeneous (Stevanin etal.,
ated with the formation of perinuclear aggregates that can 2002). This group later analyzed 252 patients with an HDL
be prevented by the use of transglutaminase inhibitors such phenotype, including 60 with typical HD, who had tested
as cystamine and monodansyl cadaverine (Igarashi etal., negative for pathologic expansion in the IT15 gene and
1998). These intranuclear inclusions stain intensely with found two patients that had an abnormal CTG expansion in

337
 15 Chorea, ballism, and athetosis

DIAGNOSTIC EVALUATION OF CHOREA

History Neurological Laboratory

examination tests

Age at onset Family Time Drug Distribution Associated Blood Hematology Antibody Molecular
(childhood vs. history course exposure of chorea neurological chemistry (acanthocytosis) screen genetic
adult choreas) findings testing

Genetic Metabolic/ CHAC HD

Childhood choreas: Drug- Focal or
choreas endocrine MLS HDL2
autoimmune induced hemichorea
chorea HDL2 SCA2,3, 17
-SC chorea
PKAN DRPLA
-SLE AT
-Postvaccinal AOA1,2
-Infectious Structural PKAN
Genetic basal ganglia Wilson
-BHC lesions disease
-AT, ATLD BHC
-AOA1,2
-PKC, ICCA
-Wilson disease >Anti-streptococcal
-PKAN >Anti-phospholipid
Drug-induced >Antinuclear
Intermittent Static Progressive Ataxia Dementia PerIpheral
Static encephalopathy >ABGA (currently only
or fluctuating neuropathy
-Athetotic cerebral available in research
palsy settings)
-Bilirubin encephalopathy
Metabolic Metabolic Structural Neuro- SCA2,3, 17 HD CHAC Autoimmune
Basal ganglia tumors Drug-induced BG lesions degenerative DRPLA HDL2 MLS choreas
PKC BHC disease AT, ATLD DRPLA AT
Autoimmune AOA1,2 SCA17 AOA1,2
SCA3 Imaging

CT/MRI PET/SPECT

Subcortical Changes
pathology in basal
Vascular ganglia
Neoplastic metabolism
Inflammatory and
Neuro- perfusion in
degenerative degenerative
and
autoimmune
choreas

Figure 15.1 Evaluation of chorea.

the JPH3 gene and two other patients with abnormal CAG
expansion in the gene coding for TATA-binding protein
(TBP/SCA17), important in initiation of transcription
(Stevanin etal., 2003; Toyoshima etal., 2004; Schneider
etal., 2006). SCA17, categorized as HDL4, has many clinical
features that overlap with HD (Schneider etal., 2007; Bech
etal., 2010). Thus, the frequency of mutation in either the
JPH3 gene or TBP gene among patients with HDL phenotype
is about 3%. Initially, the TBP expansion was found in the
family with SCA17, characterized clinically by intellectual
deterioration, cerebellar ataxia, epilepsy, and chorea. CUG
repeat-containing RNA foci, resembling myotonic dystrophy
type 1, were detected in neurons of HDL2 brains, suggesting
that RNA toxicity may play a role in the pathogenesis of this
neurodegenerative disorder (Rudnicki etal., 2007). HLD2
resembles HD clinically and pathologically more than any
other disease (Rudnicki etal., 2008).
While the majority of genetic forms of chorea are inherited
in an autosomal dominant pattern, a novel autosomal reces-
sive neurodegenerative HDL disorder has been described
(Kambouris etal., 2000). Beginning at 34 years of age and
manifested by chorea, dystonia, ataxia, gait disorder, spastic-
ity, seizures, mutism, intellectual impairment, and bilateral
frontal and caudate atrophy, this neurodegenerative disorder
has been linked to 4p15.3, different from the 4p16.3 HD
locus, but confirmation of this finding is lacking. Although
classified as HDL3, because of its AR inheritance and clinical
features atypical for HD, it should not be categorized as
HDL. In fact the HDL terminology should be replaced with
specific disorders in which genetic mutation has been
identified.
Some cases of neuronal intranuclear inclusion disease,
caused by expanded CAG repeats and characterized by the
combination of extrapyramidal signs, lower motor neuron

338

Table 15.4 Clinical and genetic features of neuroacanthocytosis
Neuroacanthocytosis coined to replace LevineCritchley
syndrome and choreoacanthocytosis and to draw attention to the
heterogeneous presentation with a variety of hyperkinetic and
hypokinetic movement disorders in addition to other neurologic
deficits and abnormal laboratory findings
Choreaacanthocytosis (ChAc, MIM 200150)
Autosomal recessive
VPS13A gene (9q21, 73 exons); 100 different mutations
Encodes a large protein, chorein (3174 amino acids)
Chorein required for trafficking of proteins between cell
organelles; interferes with membrane functions
It is widely expressed in various tissues, but its expression is
absent or severely reduced in ChAc
Absence of expression of chorein (Western blot) in RBC
membrane is strongly suggestive of a diagnosis of ChAc
(www.naadvocacy.org)
signs, and cognitive and behavioral abnormalities resulting
in death by the third decade, also show intranuclear
aggregates, similar to the other CAG disorders (Lieberman
etal., 1998).
Neuroacanthocytosis
After HD, neuroacanthocytosis is perhaps the most common
form of hereditary chorea (Table 15.4). Previously also
referred to as choreaacanthocytosis, it is now recognized
that this multisystem, neurodegenerative disorder can be
expressed by a wide variety of clinical and laboratory abnor-
malities, hence the term neuroacanthocytosis (Spitz etal.,
1985; Danek etal., 2005; Walker etal., 2006, 2007; Thomas
and Jankovic, 2006) (Table 15.5). The term was coined by
Jankovic etal. (1985) to replace the old term Levine
Critchley syndrome choreoacanthocytosis to draw attention
to the heterogeneous presentation with a variety of hyperki-
netic (chorea, dystonia, tics) and hypokinetic (parkinson-
ism) movement disorders in addition to other neurologic
deficits and abnormal laboratory findings. Symptoms usually
first begin in the third and fourth decades of life (range:
862 years) with lip and tongue biting followed by orolin-
gual (eating) dystonia, motor and phonic tics, generalized
chorea, and stereotypies (Video 15.2). Other features include
cognitive and personality changes, seizures, dysphagia, dys-
arthria, vertical ophthalmoparesis, parkinsonism, amyotro-
phy, areflexia, evidence of axonal neuropathy, and elevated
serum creatine kinase without evidence of myopathy. Hardie
and colleagues (1991) reviewed the clinical, hematologic,
and pathologic findings in 19 patients (10 males and 9
females) with a mean age of 32 years (range: 862 years)
with more than 3% acanthocytes on peripheral blood smear.
Twelve of these patients with neuroacanthocytosis were
familial, and seven were sporadic; two had the McLeod phe-
notype (see later). In their series, Hardie and colleagues
(1991) found a variety of movement disorders, including
chorea (58%), orofacial dyskinesia (53%), dystonia (47%),
vocalizations (47%), tics (42%), and parkinsonism (34%).
Although lip and tongue biting was observed in only 16%
Neuroacanthocytosis
Table 15.5 Classification of neuroacanthocytosis
I. Normal lipids
1. Autosomal dominant
a. Without inclusions
b. With polyglutamine-containing neuronal inclusions (Walker
etal., 2002)
2. Autosomal recessive: 9q21 (73 exons)
a. Multiple mutations in the chorea acanthocytosis gene coding
for chorein (Rampoldi etal., 2001; Ueno etal., 2001)
3. Sporadic
II. Hypobetalipoproteinemia (Mars etal., 1969)
III. Abetalipoproteinemia (Bassen and Kornzweig,
1950)
IV. Aprebetalipoproteinemia (Bohlega etal., 1998)
V. Hypoprebetalipoproteinemia
1. HARP syndrome: Hypoprebetalipoproteinemia, acanthocytosis,
retinitis pigmentosa, and pallidal degeneration: similar to NBIA-1
(HSD)
VI. X-linked (McLeod syndrome) (Allen etal., 1961)
Xp21
1. Neuroacanthocytosis: http://www.naadvocacy.org
of the patients, this is a characteristic feature of neuroacan-
thocytosis and when present, it strongly suggests the diagno-
sis. The use of a mouth guard has been reported to be
effective in the treatment of oral self-mutilation associated
with neuroacanthocytosis (Fontenelle and Leite, 2008).
Besides movement disorders other associated features
included dysarthria (74%); absent or reduced reflexes (68%);
dementia (63%); psychiatric problems such as depression,
anxiety, and obsessive-compulsive disorder (58%); dys-
phagia (47%); seizures (42%); muscle weakness and wasting
(16%); and elevated creatine phosphokinase (CK) in 58%.
Magnetic resonance volumetry and fluorodeoxyglucose posi-
tron emission tomography (PET) show striatal atrophy in
patients with neuroacanthocytosis (Jung etal., 2001).
Although autosomal dominant, X-linked recessive, and
sporadic forms of neuroacanthocytosis have been reported,
the majority of the reported families indicate autosomal
recessive inheritance. Genome-wide scan for linkage in 11
families with autosomal recessive inheritance showed a
linkage to a marker on chromosome 9q21, indicating a
single locus for the disease (Rubio etal., 1997). Ueno and
colleagues (2001) carried out a linkage-free analysis in the
region of chromosome 9q21 in the Japanese population and
identified a 260bp deletion in the EST (expressed sequence
tags) region K1AA0986 in exon 60, 61 that was homozygous
in patients with neuroacanthocytosis and heterozygous in
their parents. Further sequencing has identified a polyade-
nylation site with a protein with 3096 amino acid residues
that has been named chorein by the authors. This deletion
is not found in normal Japanese and European populations
(Ueno etal., 2001). In another study by Rampoldi and col-
leagues (2001) in European patients, a novel gene encoding
a 3174-amino-acid protein on chromosome 9q21 with 73
exons was identified. They identified 16 mutations in the
339
 15 Chorea, ballism, and athetosis
chorea acanthocytosis (ChAc) gene, later renamed VPS13A
gene. These mutations were identified in various exons. They
suggested that chorea acanthocytosis encodes an evolution-
arily conserved protein that is involved in protein sorting
(Rampoldi etal., 2002). Other single heterozygous muta-
tions have been identified in this gene (Saiki etal., 2003).
Molecular analysis by screening all 73 exons of the VPS13A
gene showed marked genotypephenotype heterogeneity
(Lossos etal., 2005). The function of the protein product,
chorein, is not yet fully understood, but it is probably
involved in intracellular protein trafficking. Using anti-
chorein antisera, the expression of chorein in peripheral red
blood cells has been found to be absent or markedly reduced
in patients with neuroacanthocytosis, but not with McLeod
syndrome or with HD (Dobson-Stone etal., 2004). Loss
of chorein expression, measured by Western blot analysis
has been found to be a reliable diagnostic test for
neuroacanthocytosis.
Walker and colleagues (2002) described a family with
chorea or parkinsonism as well as cognitive changes, inher-
ited in an autosomal dominant pattern. At autopsy, there
was marked degeneration of the striatum and intranuclear
inclusion bodies immunoreactive for ubiquitin, expanded
polyglutamine CGG repeats, and torsinA. Interestingly, one
of the patients had fragile X syndrome, and two had expanded
trinucleotide repeats at permutation range, previously asso-
ciated with postural/kinetic tremor, parkinsonism, ataxia,
and cognitive decline (Hagerman etal., 2001). The family
reported by Walker and colleagues (2002) turned out to have
the trinucleotide repeat expansion associated with HDL2,
but subsequent analysis of the family shed doubt on the
presence of acanthocytes as a feature of the HDL2 syndrome
(Walker etal., 2003a).
Two patients from the original study by Rubio and col-
leagues (1997) were found to have the McLeod phenotype,
an X-linked (Xp21) recessive form of acanthocytosis associ-
ated with depression, bipolar and personality disorder, and
neurologic manifestations, including chorea, involuntary
vocalizations, seizures, motor axonopathy, hemolysis, liver
disease, and high creatine kinase levels (Witt etal., 1992;
Danek etal., 2001a, 2001b). Neuroimaging usually reveals
caudate and occasionally cerebellar atrophy with a rim of
increased T2-intensity in the lateral putamen. Functional
neuroimaging studies show evidence of downregulation of
D2 dopamine receptors. In contrast to the autosomal reces-
sive form of neuroacanthocytosis linked to mutations in
VPS13A gene on chromosome 9, patients with McLeod syn-
drome usually do not exhibit lip-biting or dysphagia. This
multisystem disorder is associated with low reactivity of Kell
erythrocyte antigens (weak antigenicity of red cells) due
to absence of XK, a 37kDa, 444-amino-acid, membrane
protein that forms a complex with the Kell protein. The
disorder is caused by different mutations in the XK gene
encoding for the XK protein (Ho etal., 1996; Danek etal.,
2001a; Jung etal., 2001). Mutations identified by various
authors include frame shift mutations in exon 2 at codon
151, deletion at codon 90 in exon 2 and at codon 408 in
exon 3, and splicing mutations in intron 2 of the XK gene
(Dotti etal., 2000; Ueyama etal., 2000; Danek etal., 2001a;
Jung etal., 2001). Rarely, neuroacanthocytosis may be asso-
ciated with abetaliproteinemia due to mutations in the
microsomal triglyceride transfer protein (Sharp etal., 1993).
340
In addition to acanthocytosis, the patients exhibit retinopa-
thy; malabsorption, including that of vitamin E; low serum
cholesterol levels; and abnormal serum lipoprotein electro-
phoresis. Aprebetalipoproteinemia can also cause move-
ment disorders and acanthocytosis (Bohlega etal., 1998).
An examination of wet blood or Wright-stained, fast dry,
blood smear usually reveals over 15% of red blood cells as
acanthocytes. In mild forms of acanthocytosis, scanning
electron microscopy might be required to demonstrate the
red blood cell abnormalities (Feinberg etal., 1991). In a
recent study of two patients with pathologically proven neu-
roacanthocytosis, Feinberg and colleagues (1991) noted that
the yield in demonstrating acanthocytosis may be increased
by using a coverslip because the contact with glass causes the
fragile cells to undergo morphologic changes. Diluting the
blood with normal saline, incubating the Wright-stained
smear with EDTA, using a scanning electron microscope, and
other techniques designed to increase echinocytotic stress
are also helpful (Feinberg etal., 1991; Orrell etal., 1995).
The characteristic acanthocytic appearance of red blood cells
has been attributed to abnormalities in transmembrane
glycoprotein band 3 that can be demonstrated on gel elec-
trophoresis. It is not yet clear how the gene mutation leads
to the abnormal morphology of the red cells.
By using high-performance liquid chromatography, fatty
acids of erythrocyte membrane proteins were analyzed in six
patients with neuroacanthocytosis (Sakai etal., 1991). In
comparison with normal controls and patients with HD,
erythrocytes of patients with neuroacanthocytosis showed a
marked abnormality in the composition of covalently bound
fatty acids: an increase in palmitic acid (C16:0) and a
decrease in stearic acid (C18:0).
Brain magnetic resonance imaging (MRI) in patients with
neuroacanthocytosis usually shows caudate and more gen-
eralized brain atrophy, but some cases also show extensive
white matter abnormalities (Nicholl etal., 2004). Caudate
hypometabolism and atrophy have been demonstrated by
PET studies and by neuroimaging. Similar to the findings in
Parkinson disease, PET scans in six patients with neuro
acanthocytosis showed a reduction to 42% of normal
in [18F]dopa uptake in the posterior putamen; in contrast to
Parkinson disease, however, there was a marked reduction in
the striatal [11C]raclopride (D2) receptor binding (Brooks
etal., 1991).
Neuronal loss and gliosis were particularly prominent in
the striatum and pallidum but may also affect the thalamus,
substantia nigra, and anterior horns of the spinal cord
(Rinne etal., 1994b). The neuronal loss in the substantia
nigra is most evident in the ventrolateral region, similar to
Parkinson disease, but the nigral neuronal loss is more wide-
spread in neuroacanthocytosis (Rinne etal., 1994a). The
preservation of the cerebral cortex, cerebellum, subthalamic
nucleus, pons, and medulla may serve to differentiate patho-
logically between neuroacanthocytosis, HD, and DRPLA.
Brain biochemical analyses showed low substance P in
the substantia nigra and striatum and increased levels of
norepinephrine in the putamen and pallidum (DeYebenes
etal., 1988).
Unfortunately, there is no effective treatment for patients
with neuroacanthocytosis. The associated parkinsonism
rarely improves with dopaminergic therapy, probably
because there is loss of postsynaptic dopamine receptors. We

have seen some patients whose condition remained static for
several years, followed by further progression and an even-
tual demise as a result of aspiration pneumonia or other
complications of chronic illness.
Neurodegeneration with brain
iron accumulation
A group of neurodegenerative disorders, formerly known as
HallervordenSpatz disease, has been receiving increasing
attention as the genetic and pathogenic mechanisms of the
various subtypes become elucidated. Because of Haller-
vordens terrible past and his shameless involvement in
active euthanasia (Shevell, 2003), this group of disorders has
been renamed neurodegeneration with brain iron accumula-
tion (NBIA). The prototype form of NBIA consists of an
autosomal recessive disorder characterized by childhood-
onset progressive rigidity, dystonia, choreoathetosis, spastic-
ity, optic nerve atrophy, and dementia, and has been
associated with acanthocytosis (Malandrini etal., 1996;
Racette etal., 2001; Thomas etal., 2004). Although chorea
is not a typical feature of NBIA, senile chorea has been
described in a patient with pathologically proven NBIA
type1 (NBIA-1) (Grimes etal., 2000).
The most classic NBIA, NBIA-1, is the pantothenate kinase-
associated neurodegeneration (PKAN). Linkage analyses
initially localized the NBIA-1 gene on 20p12.3p13; subse-
quently, a 7bp deletion and various missense mutations
were identified in the coding sequence of the PANK2
gene, which codes for pantothenate kinase (Zhou etal.,
2001; Hayflick etal., 2003). Pantothenate kinase is an essen-
tial regulatory enzyme in coenzyme A biosynthesis. It has
been postulated that as a result of phosphopantothenate
deficiency, cysteine accumulates in the globus pallidus of
brains of patients with NBIA-1. It undergoes rapid auto-
oxidation in the presence of nonheme iron that normally
accumulates in the globus pallidus interna (GPi) and sub-
stantia nigra, generating free radicals that are locally neuro-
toxic. Interestingly, atypical subjects were found to be
compound heterozygotes for certain mutations for which
classic subjects were homozygous. The disorder with the
clinical phenotype of NBIA associated with mutations in the
PANK2 gene is now referred to as pantothenate kinase-
associated neurodegeneration or PKAN (Thomas etal.,
2004). On the basis of an analysis of 123 patients from 98
families with NBIA-1, Hayflick and colleagues (2003) found
that classic HallervordenSpatz syndrome was associated
with PANK2 mutation in all cases and that one-third of
atypical cases had the mutations within the PANK2 gene.
Those who had the PANK2 mutation were more likely to
have dysarthria and psychiatric symptoms, and all had the
typical eye-of-the-tiger abnormality on MRI with a specific
pattern of hyperintensity within the hypointense GPi
(McNeill etal., 2008).
Neuroacanthocytosis and NBIA may overlap in some clini-
cal features. While PKAN may be associated with acanthocy-
tosis, another neuroacanthocytosis syndrome, linked to
PKAN, is the hypoprebetalipoproteinemia, acanthocytosis,
retinitis pigmentosa, and pallidal degeneration (HARP) syn-
drome (Orrell etal., 1995). This disorder is associated with
dystonia, particularly involving the oromandibular region,
Neurodegeneration with brain iron accumulation
Table 15.6 Differential diagnosis of neurodegeneration with
brain iron accumulation (NBIA)
Pantothenate kinase-associated neurodegeneration
Neuroferritinopathy
Aceruloplasminemia
Infantile neuroaxonal dystrophy (NBIA-2)
Karak syndrome
PLAN (PLA2G6-associated neurodegeneration). The PLA2G6
gene encodes a calcium-independent phospholipase A2
enzyme that catalyzes the hydrolysis of glycerophospholipids;
early-childhood-onset axial hypotonia, spasticity, bulbar
dysfunction, ataxia, and dystonia
PLAN without iron deposition; adult-onset, levodopa-
responsive dystoniaparkinsonism
rather than chorea and self-mutilation. Indeed, a homozygous
nonsense mutation in exon 5 of the PANK2 gene that creates
a stop codon at amino acid 371, found in the original HARP
patient, establishes that HARP is part of the pantothenate
kinase-associated neurodegeneration disease spectrum
(Ching etal., 2002; Houlden etal., 2003).
The classification of NBIA is continuously being revised as
our understanding of this group of disorders is improving.
In addition to PKAN, other forms of NBIA include neurofer-
ritinopathy, infantile neuroaxonal dystrophy, and acerulo-
plasminemia, and PLA2G6-associated neurodegeneration
(PLAN), with mutations in the PLA2G6 gene, on chromo-
some 22q13.1 (Schneider etal., 2009) (Table 15.6, Fig.
15.2). These disorders are chiefly manifested by childhood-
onset axial hypotonia, spasticity, bulbar dysfunction, ataxia,
dystonia, and choreoathetosis, as well as MRI changes indic-
ative of iron deposition in the globus pallidus and substantia
nigra (Kurian etal., 2008). Previously diagnosed as infantile
neuroaxonal dystrophy, now classified as NBIA-2, PLAN may
also present as adult-onset, levodopa-responsive dystonia
parkinsonism without iron on brain imaging (McNeill etal.,
2008; Paisan-Ruiz etal., 2008; Schneider etal., 2009).
Another gene, FA2H, when mutated, has been found to cause
not only leukodystrophy and hereditary spastic paraplegia,
but also NBIA (Kruer et al., 2010). The FA2H-associated
neurodegeneration (FAHN) is characterized by childhood-
onset gait impairment, spastic paraparesis, ataxia, and dys-
tonia (Kruer et al., 2010; Schneider and Bhatia, 2010). FA2H
is involved in lipid and ceramide metabolism. Another form
of NBIA was highlighted by a report of 11 children with a
biochemical profile suggestive of dopamine transporter defi-
ciency syndrome (Kurian et al., 2011). Presenting in infancy,
this disorder is usually characterized by severe parkinson-
ism-dystonia syndrome, but chorea, oculomotor deviations,
and spasticity may also dominate the clinical phenotype. The
CSF ratio of homovanillic acid to 5-hydroxyindoleacetic acid
is usually increased. This autosomal recessive disorder has
been attributed to homozygous or compound heterozygous
SLC6A3 mutations and complete loss of dopamine trans-
porter activity in the basal nuclei (indicated by abnormal
DAT Scan SPECT). Regression of symptoms after 6 months
of iron chelation with deferiprone has been reported in
some patients with NBIA (Forni etal., 2008).
341
 15 Chorea, ballism, and athetosis

BRAIN IRON HOMEOSTASIS AND NEURODEGENERATIVE DISEASE Figure 15.2 The role of iron in
neurodegenerative disorders.
Neuron
Frataxin

End-foot
process Fe/S

Endosome
Blood Mitochondria

Fe3+ Ceruloplasmin

H+ Astrocyte
Fe2+
Transferrin

Transferrin
DMT1 ATP Ferritin
receptor 1
citrate
(TfR1)
?
Brain Ferroportin
endothelial cell
NTBI

?
Oligodendrocyte
Synaptic terminal

progresses until the second decade, after which time it

Table 15.7 Clinical features of benign hereditary chorea
Onset in early childhood
Progresses until second decade static or spontaneously
improves (may persist >60)
No dementia or other abnormalities
MRI normal, but may show hypoplastic pallidum, lack of
differentiation of medial and lateral components, and bilateral
signal hyperintensities on T2-weighted images
No pathologic changes, but may have reduced number of striatal
and neocortical interneurons
Autosomal dominant associated with mutation in TITF1 gene on
chromosome 14q13q21.1
TITF1 gene mutation should be considered in patients with
chorea, mental retardation, chronic lung disease and congenital
hypothyroidism, hence the term brainlungthyroid (BLT)
syndrome
May improve markedly with levodopa
Other familial choreas
Besides HD and neuroacanthocytosis, genetically transmitted
choreas include benign hereditary chorea (BHC), a nonpro-
gressive chorea of childhood onset (Wheeler etal., 1993;
Kleiner-Fisman and Lang, 2007; Adam and Jankovic, 2010)
(Table 15.7). BHC usually starts in early childhood and
remains static or even spontaneously improves. The patients
may have a slight motor delay because of chorea, slight
gait ataxia, and their handwriting may be impaired, but the
disorder is self-limiting after adolescence in most cases,
although it may persist as a mild chorea beyond age 60 years.
Inherited as an autosomal dominant disorder, BHC has been
linked to a marker on chromosome 14q13.1q21.1 (de Vries
etal., 2000; Fernandez etal., 2001; Breedveld etal., 2002)
and a novel single nucleotide substitution in the TITF1
gene (also referred to as TTF, Nkx2.1, and T/ebp), coding for
a transcription essential for the organogenesis of the
lung, thyroid, and basal ganglia, has been identified in
one Canadian family (Kleiner-Fisman etal., 2003; Kleiner-
Fisman and Lang, 2007; Ferrara etal., 2008) (http://
www.ncbi.nlm.nih.gov/sites/GeneTests/). This syndrome has
been also described in patients with deletion of not only the
TITF1 gene but also the contiguous PAX9 gene (Devos etal.,
2006). These mutations should be considered in children
and adults with chorea, mental retardation, congenital
hypothyroidism, and chronic lung disease, hence the term
brainlungthyroid syndrome proposed for this disease
(Willemsen etal., 2005; Devos etal., 2006). MRI has been
generally reported to be unremarkable but some cases showed
hypoplastic pallidum, lack of differentiation of medial and
lateral components, and bilateral signal hyperintensities on
T2-weighted MRI images (Kleiner-Fisman and Lang, 2007).

342

Two autopsied brains from patients with BHC due to TITF1
showed no pathologic abnormalities (Asmus etal., 2005),
but specific immunochemical investigations suggested
reduced number of striatal and neocortical interneurons,
consistent with a defect in migration normally mediated by
the TITF1 gene (Kleiner-Fisman etal., 2005).
Adult-onset, autosomal dominant, benign chorea without
dementia, initially reported in Japan, in which HD, HDL1,
HDL2, DRPLA, SCA17, and mutations in the TITF1 gene
were excluded, revealed linkage to a novel locus on chromo-
some 8q21.3q23.3 in two Japanese families with benign
hereditary chorea type 2 (BHC2) (Shimohata etal., 2007).
Surprisingly, BHC may improve markedly with levodopa
(Asmus etal., 2005). The existence of BHC has been ques-
tioned because many patients who were initially diagnosed
with the disorder were later found to have some other diag-
nosis, such as myoclonic dystonia, hereditary essential myo-
clonus, tics, and HD (Schrag etal., 2000).
Essential chorea is a form of adult-onset, nonprogressive
chorea without family history of chorea or other symptoms
suggestive of HD and without evidence of striatal atrophy
on neuroimaging studies. Sometimes referred to as senile
chorea, essential chorea usually has its onset after age 60,
and in contrast to HD, it is not associated with dementia or
positive family history. Some cases of senile chorea, however,
have been reported to have pathologic changes identical to
HD; others have had predominant degeneration of the
putamen rather than the caudate (Friedman and Ambler,
1990). The CAG repeat length should, by definition, be
normal, but Ruiz and colleagues (1997) found abnormal
CAG expansion in three of six clinically diagnosed cases of
senile chorea. Although the authors suggest that some
patients with senile chorea have a sporadic form of HD, the
term essential (or senile) chorea should be reserved for those
patients with late-onset chorea without family history,
without dementia, without psychiatric problems, and
without CAG expansion. These criteria are necessary in order
to separate senile or essential chorea from HD. Hereditary
chorea without dementia and with a benign course has been
also described (Behan and Bone, 1977).
Choreoathetosis, along with developmental regression,
mental retardation, pendular nystagmus, optic atrophy, dys-
phagia, dystonia, spasticity, and severe bilateral striatal
atrophy with response to biotin, is a feature of familial infan-
tile bilateral striatal necrosis (IBSN) (Straussberg etal., 2002;
Basel-Vanagaite etal., 2006). IBSN, an autosomal recessive
neurodegenerative disorder, was found to be associated with
mutation of nup62 on chromosome 19q13.3213.41 (Basel-
Vanagaite etal., 2006).
Ataxia telangiectasia, an autosomal recessive multisystem
disease, is another disorder often associated with chorea. In
a retrospective analysis of the clinical characteristics in 18
adult patients with ataxia telangiectasia from 9 families
and 6 unrelated adults documented with elevated alpha-
fetoprotein, chromosomal instability, and mutations in the
A-T mutated (ATM) gene and measurements of ATM protein
expression and kinase activity, choreaathetosis was present
in 14/18 (78%) cases (Verhagen etal., 2009). Other common
abnormalities included dysarthria, oculomotor apraxia, dys-
tonia, rest tremor, neuropathy, immunodeficiency, restricted
respiratory function, and malignancies. Not all affected indi-
viduals have telangiectasia.
Postinfectious and autoimmune choreas
Another disorder, rarely considered in the differential diag-
nosis of chorea, is familial dyskinesia and facial myokymia
(FDFM), characterized by childhood-onset adventitious
movements and perioral or periorbital myokymia. These
movements may be paroxysmal in early stages, increase in
frequency and severity, and become constant in the third
decade, without intellectual impairment or shortening of
lifespan. Frontotemporal dementia, particularly associated
with TAR-DNA binding protein (TDP)-43 abnormalities due
to TARDBP mutations, may be associated not only with
amyotrophic lateral sclerosis, but also supranuclear gaze
palsy and chorea (Kovacs etal., 2009).
Infectious chorea
A variety of infections that affect the central nervous system
have been associated with chorea. Acute manifestations of
bacterial meningitis, encephalitis, tuberculous meningitis,
and aseptic meningitis include movement disorders such as
chorea, athetosis, dystonia, or hemiballismus (Alarcon etal.,
2000). Human immunodeficiency virus (HIV) has also been
reported to cause chorea and other features of HD, either as
the result of human immunodeficiency virus encephalitis
(Sevigny etal., 2005) or as the result of focal opportunistic
infections such as toxoplasmosis (Nath etal., 1987; Gallo
etal., 1996; Pardo etal., 1998; Piccolo etal., 1999).
Postinfectious and autoimmune choreas
Sydenham disease
Occasionally still referred to as St Vitus chorea or St Vitus
dance (Krack, 1999), Sydenham chorea was described origi-
nally by Thomas Sydenham, an English physician, in 1686.
Considered an autoimmune disorder, a consequence of
infection with group A -hemolytic streptococcus (GABHS),
the phenomenology has broadened to include not only
chorea but also a variety of other neurologic, psychiatric,
cardiac, rheumatologic, and other disorders (Swedo, 1994;
Cardoso etal., 1997; Cardoso, 2004) (Videos 15.3 and
15.4). Since chorea is only one of many neurologic and non-
neurologic manifestations, the term Sydenham disease is pre-
ferred, rather than Sydenham chorea, but the latter is used so
frequently in the literature that its usage will be difficult to
change. Osler, in his seminal paper On Chorea and Chorei-
form Affections, published in 1894, drew attention to the
distinction between Sydenham disease and HD (Goetz,
2000). Although the majority of the patients have bilateral
involvement, the distribution of chorea is usually asymmet-
rical, and pure hemichorea can be seen in 20% of all Syden-
ham disease patients. The individual contractions are slightly
longer in Sydenham disease (>100ms) compared to those
in HD (50100ms) (Hallett and Kaufman, 1981). Other
features of Sydenham disease include dysarthria and
decreased verbal output, hypometric saccades, oculogyric
crisis, papilledema, central retinal artery occlusion, and sei-
zures. Similar to Tourette syndrome (Kwak etal., 2003b),
migraine is more common in children with Sydenham
disease than in controls (Teixeira etal., 2005). Unlike arthri-
tis and carditis, which occur soon after streptococcal infec-
tion, chorea and various neurobehavioral symptoms may be
343
 15 Chorea, ballism, and athetosis
delayed for 6 months or longer and may be the sole mani-
festation of rheumatic fever (Stollerman, 1997). In 50 con-
secutive patients with rheumatic fever, 26% developed
chorea, but arthritis was more frequent in patients without
chorea (84%) than in those with chorea (31%) (Cardoso
etal., 1997).
Some features of Sydenham disease overlap with those of
Tourette syndrome. Although tics are often differentiated
from chorea by the presence of premonitory sensation,
reported by more than 90% of patients with Tourette syn-
drome (Kwak etal., 2003a), some patients with chorea also
report sensory symptoms (Rodopman-Arman etal., 2004).
There is controversy as to whether pediatric autoimmune
neuropsychiatric disorders associated with streptococcal
infections (PANDAS), discussed in more detail in Chapter
16, which may be associated with motor and phonic tics, is
a variant of Sydenham disease or a separate entity (Kurlan,
2004; Kurlan etal., 2008; Singer etal., 2008).
Behavioral problems associated with Sydenham disease
include irritability, emotional lability, obsessive-compulsive
disorder, hyperactivity, learning disorders, and other behav-
ioral problems that are typically observed in patients with
Tourette syndrome. One study compared 56 patients with
Sydenham disease with 50 rheumatic fever patients and 50
healthy subjects and found that obsessive-compulsive behav-
ior was present in 19%, obsessive-compulsive disorder in
23.2%, and attention deficit-hyperactivity disorder in 30.4%,
all significantly more frequently than in the rheumatic fever
or healthy controls (Maia etal., 2005). The neurobehavioral
symptoms usually begin within 24 weeks after the onset of
the choreic movements. The disorder tends to resolve spon-
taneously in 34 months but may persist in half of the
patients during a 3-year follow-up (Cardoso etal., 1999).
Female gender and the presence of carditis might be risk
factors for persistent disease. In some cases of Sydenham
disease, the chorea recurs during pregnancy (chorea gravi-
darum) or when the patient is exposed to estrogen. Syden-
ham disease, once relatively common, is now encountered
relatively rarely in developed countries (Eshel etal., 1993).
Recurrences of Sydenham disease are not associated with
anti-basal ganglia antibodies (Harrison etal., 2004).
In addition to occasionally elevated titers of antistrep-
tolysin O (ASO), which is not specific for GABHS infection
as it can also reflect group G, the majority of patients with
Sydenham disease have been found to have IgG antibodies
reacting with neurons in the caudate and subthalamic nuclei
(Kiessling etal., 1993; Swedo etal., 1993). These antineuro-
nal antibodies are found in nearly all patients with Syden-
ham disease (Swedo, 1994; Abraham etal., 1997; Mittleman,
1997). The rheumatic B-cell alloantigen D8/17 is also fre-
quently found in patients with rheumatic chorea, but it is
not clear whether this could be used as a diagnostic test
(Feldman etal., 1993). Anti-basal ganglia antibodies have
been identified in patients with acute and persistent Syden-
ham disease, providing further evidence that the disease is
an antibody-mediated disorder (Church etal., 2002).
MRI is usually normal in patients with Sydenham disease
except for selective enlargement of the caudate, putamen,
and globus pallidus (Giedd etal., 1995). In contrast to other
choreic disorders, PET scans in patients with Sydenham
disease indicate increased rather than decreased striatal
glucose consumption (Weindl etal., 1993).
344
The standard of care for all children diagnosed with Syden-
ham disease, even in cases of isolated chorea, is secondary
prevention with penicillin to reduce the risk of recurrences
of chorea but especially to reduce the likelihood that future
GABHS infections could cause carditis and permanent
valvular damage (Panamonta etal., 2007; Cardoso, 2008).
Current recommendations in the United States are for treat-
ment until age 21 years with either monthly intramuscular
or daily oral penicillin. Although cephalosporins are equally
effective, penicillin, 5001000mg of penicillin G four times
per day or one intramuscular injection of 600000 to 1.2
million units of benzathine penicillin, is considered the drug
of choice for pharyngitis caused by GABHS infection (Garvey
and Swedo, 1997). Despite an adequate (10-day) course, the
bacteriologic failure rate is as high as 15%, and some patients
develop rheumatic fever. Therefore, oral rifampin 20mg/kg
every 24 hours for four doses is recommended during the
last 4 days of the 10-day course of penicillin therapy. Alter-
natively, oral rifampin 10mg/kg can be given every 12 hours
for eight doses with one dose of intramuscular benzathine
penicillin G. Another alternative is oral clindamycin 20mg/
kg/day in three doses for 10 days. The best prevention of
rheumatic fever is accurate diagnosis and adequate treatment
of the initial acute pharyngitis. Penicillin prophylaxis is
advisable in all patients for at least 10 years after rheumatic
fever. Symptomatic treatment usually consists of anti-
dopaminergic drugs such as tetrabenazine, valproic acid, and
carbamazepine until the condition resolves spontaneously.
A double-blind, placebo-controlled study of prednisone
showed beneficial effects on Sydenham disease (Paz
etal., 2006).
Other autoimmune choreas
Besides Sydenham disease, another poststreptococcal disor-
der which may include chorea, but more commonly is char-
acterized by parkinsonism and dystonia is poststreptococcal
acute disseminated encephalomyelitis (PSADEM), associ-
ated with the anti-basal ganglia antibodies (Dale etal.,
2001). Although both Sydenham disease and PSADEM are
associated with MRI T2 hyperintensities, the lesions described
in PSADEM had normal T1 sequences and the white matter
and brainstem are additionally involved. Chorea has been
also recognized in a variety of other autoimmune processes,
such as systemic lupus erythematosus (SLE). Chorea occurs
in 2% of patients with SLE, and choreic movements precede
the diagnosis of SLE in 22% of these cases. Choreic move-
ments associated with pregnancy (chorea gravidarum) and
with birth control pills probably result from a common
pathogenesis, and chorea gravidarum may be the first mani-
festation of SLE or may represent as a variant of Sydenham
disease. Chorea in SLE has been associated with the presence
of antiphospholipid antibodies, a heterogeneous group of
antibodies that produce platelet endothelial dysfunction and
promote thrombogenesis. The primary antiphospholipid
syndrome is characterized by the presence of antiphospholi-
pid antibodies in patients who have autoimmune phenom-
ena but insufficient clinical or serologic features to be
classified as having SLE. Antiphospholipid antibody syn-
drome is defined by a clinical event of thrombosis or miscar-
riage in the setting of persistently present and sufficiently

high titers of antibodies, either anticardiolipin IgG or IgM,
lupus anticoagulant, or anti-B2-glycoprotein 1 (Sapporo
criteria ) (Orzechowski etal., 2008). In a cohort of 1000
patients who met the Sapporo criteria for definite antiphos-
pholipid syndrome, chorea occurred in 13 (1.3%) patients.
In addition to a hypercoagulable state, a variety of neuro-
logic and movement disorders, such as chorea, ballism,
dystonia, parkinsonism and paroxysmal dyskinesias have
been associated with the antiphospholipid syndrome
(Gutrecht etal., 1991; Lang etal., 1991; Cervera etal., 1997;
Martino etal., 2006; Wu etal., 2007; Huang etal., 2008;
Orzechowski etal., 2008). Other clinical features include
spontaneous abortions, arthralgias, Raynaud phenomenon,
digital infarctions, transient ischemic attacks, and stroke
(Sanna etal., 2006). Antiphospholipid antibodies present in
patients with this syndrome include lupus anticoagulant,
anticardiolipin antibody, and anti-2-glycoprotein-I anti-
bodies. Anticardiolipin antibodies, frequently found in
SLE, are absent in patients with Sydenham disease. Contral-
ateral striatal hypermetabolism was documented by an 18F-
fluorodeoxyglucose PET scan in a 23-year-old woman with
alternating hemichorea and antiphospholipid syndrome
(Furie etal., 1994). The striatal D1 and D2 receptor binding,
measured by PET scans, was normal in one patient with SLE
(Turjanski etal., 1995).
Other choreas
One of the most common forms of chorea encountered in
a movement disorder clinic is drug-induced chorea associ-
ated with the use of dopaminergic or antidopaminergic
drugs, anticonvulsants, and other drugs (Hyde etal., 1991;
Jankovic, 1995). Levodopa-induced dyskinesia is often man-
ifested by stereotypies, dystonia, and myclonus as well as
chorea (Jankovic, 2005) (Video 15.5). Although the domi-
nant hyperkinetic movement disorder seen in patients with
tardive dyskinesia is stereotypy, some patients have associ-
ated chorea, and chorea is the chief manifestation in chil-
dren with withdrawal emergent syndrome. Chorea, often
accompanied by ataxia and deafness, has also been associ-
ated with mitochondrial DNA mutations (Nelson etal.,
1995) and other evidence of mitochondrial cytopathies,
including mutations in the POLG gene (Caer etal., 2005;
Wong etal., 2008). The disorder of early-onset ataxia with
oculomotor apraxia and hypoalbuminemia due to muta-
tions in the aprataxin gene on chromosome 19p13 has also
been associated with chorea (Shimazaki etal., 2002).
Besides vasculitis, chorea has been associated with a variety
of other vascular etiologies, but few have been documented
pathologically. The topic of vascular chorea has been
reviewed in a report of an 85-year-old woman who devel-
oped progressive dementia and chorea at age 70 (Bhatia
etal., 1994). At autopsy, her brain showed neostriatal
neuronal loss and gliosis associated with congophilic
angiopathy and atherosclerosis. Hemichorea has been also
reported following endarterectomy for carotid stenosis
(Galea etal., 2008).
During the 1980s, there was an increase in the number of
children with chorea as sequelae to cardiac surgery, but with
modification of treatment strategies during the perioperative
period, the incidence of this complication has subsequently
Other choreas
decreased (Robinson etal., 1988). This post-pump chorea
appears to be associated with prolonged time on pump,
deep hypothermia, and circulatory arrest (Medlock etal.,
1993; Newburger etal., 1993; du Plessis etal., 2002) (Videos
15.6 and 15.7). Others have suggested that hypoxia rather
than hypothermia is critical in the development of CHAP
syndrome (choreathetosis and orofacial dyskinesia, hypoto-
nia, and pseudobulbar signs) after surgery for congenital
heart disease. In most patients, the chorea persists, and fewer
than 25% improve with antidopaminergic therapy such as
haloperidol. Steroid-responsive chorea was described in a
patient after heart transplant (Blunt etal., 1994). Although
the chorea may improve, long-term studies have shown that
these children have persistent deficits in memory, attention,
and language (du Plessis etal., 2002).
A variety of systemic (Janavs and Aminoff, 1998), meta-
bolic, and neurodegenerative disorders can be associated
with chorea, such as hypocalcemia or hypercalcemia, hyper-
glycemia (Ahlskog etal., 2001; Chu etal., 2002; Oh etal.,
2002; Pisani etal., 2005; Sitburana and Ondo, 2006), hyper-
thyroidism (Pozzan etal., 1992), B12 deficiency (Pacchetti
etal., 2002), LeschNyhan syndrome (Jankovic etal., 1988;
Jinnah etal., 1994; Ernst etal., 1996), propionic acidemia
(Nyhan etal., 1999), and other metabolic disorders such as
glutaric aciduria, gluscose transporter type 1 deficiency (Prez-
Dueas etal., 2009), and GM1 gangliosidosis (Shulman
etal., 1995; Stacy and Jankovic, 1995).
Chorea (with or without associated ballism) has been
reported as the presenting feature of renal failure (Kujawa
etal., 2001) and paraneoplastic striatal encephalitis (Tani
etal., 2000; Vernino etal., 2002; Kinirons etal., 2003; Grant
and Graus, 2009; Kleinig etal., 2009). In a series of 16 patients
with paraneoplastic chorea, 11 had small-cell carcinoma, all
had CRMP-5 IgG, and 6 had ANNA-1 (anti-Hu) antibodies
(Vernino etal., 2002). Another metabolic cause of chorea is
liver disease, particularly chronic acquired hepatocerebral
degeneration (Thobois etal., 2002) (Video 15.8). Many of
the metabolic choreas are associated with abnormalities on
MRI scans. For example, hepatocerebral degeneration and
hyperglycemic chorea are often associated with high signal
intensity on T1-weighted MRI, involving the striatum and
pallidum (Ahlskog etal., 2001; Thobois etal., 2002; Sitburana
and Ondo, 2006). In a report of two patients with hyperg-
lycemic hemichoreahemiballism, Chu and colleagues (2002)
found high signal intensities on T1- and T2-weighted images
as well as on diffusion-weighted MRI accompanied by a
reduction in diffusion coefficient, suggestive of hyperviscosity,
rather than petechial hemorrhages, as the mechanism of
edema in the striatum. This is also supported by another
study of seven patients with hyperglycemic choreoathetosis
using MRI and MR spectroscopy (Kandiah etal., 2009). Inter-
estingly, the presence of high acanthocyte count may predis-
pose patients with diabetes to develop hyperglycemic chorea
(Pisani etal., 2005). Other disorders frequently associated
with this MRI abnormality include manganese toxicity, Wilson
disease, abnormal calcium metabolism, neurofibromatosis,
hypoxia, and hemorrhage. Chorea has been associated with
a variety of other causes, including cerebrospinal fluid leak
(Mokri etal., 2006).
Another disorder associated with chorea and frequently
misdiagnosed as Huntington disease is neuroferritinopathy,
a progressive but potentially treatable disorder caused by
345
 15 Chorea, ballism, and athetosis
mutations in the ferritin light chain gene (FTL1), located on
19q13.3q13.4. Patients may be initially diagnosed as
idiopathic dystonia, Parkinson disease, Huntington hemichorea/hemiballism (Krauss and Mundinger, 2000).
disease, and a variety of other disorders. In a study of 41
genetically homogeneous subjects with the 460InsA muta-
tion in FTL1, the mean age at onset was 39.4 13.3 years
(range: 1363), beginning with chorea in 50%, focal lower
limb dystonia in 42.5%, and parkinsonism in 7.5%
(Chinnery etal., 2007). The disease progressed over a 510-
year period, eventually leading to aphonia, dysphagia and
severe, often asymmetrical, motor disability, and finally
dementia in the advanced stages. A characteristic action-
specific facial dystonia was present in 65%. Serum ferritin
levels were low in the majority of males and postmenopau-
sal females, but may be normal, particularly in premenopau-
sal females. MRI typically shows gradient echo T2*
hypointensity in red nuclei, substantia nigra, and globus
pallidus; brain imaging was abnormal in all affected indi-
viduals and one presymptomatic carrier, with T1 hyperinten-
sity in the globus pallidus and posterior putamen (Chinnery
etal., 2007).
Treatment of chorea
The first step in the treatment of chorea is the identification
of a specific etiology. Chorea has been treated successfully
with drugs that interfere with central dopaminergic function,
such as the dopamine receptor-blocking drugs (neuro
leptics), reserpine, and tetrabenazine (Jankovic and Beach,
1997; Chatterjee and Frucht, 2003; Kenney and Jankovic,
2006; Sitburana and Ondo, 2006; Fasano and Bentivoglio,
2009; Jankovic, 2009). Indeed, tetrabenazine provides the
most effective relief of chorea with only minimal, dose-
related side effects, such as drowsiness, insomnia, depres-
sion, and parkinsonism. Tetrabenazine is effective not only
for the treatment of chorea associated with HD (Ondo etal.,
2002; Huntington Study Group, 2006), but also for choreatic
disorders associated with tardive dyskinesia (Ondo etal.,
1999), cerebral palsy (CP), and post-pump encephalopathy
(Chatterjee and Frucht, 2003) (Video 15.6). While some
studies have suggested that sodium valproate may be effec-
tive in the treatment of chorea (Daoud etal., 1990; Hoffman
and Feinberg, 1990), other reports have been less conclusive
(Sethi and Patel, 1990). Levetiracetam has been reported to
markedly improve a patient with CP and postinfectious
chorea (Recio etal., 2005).
There is no consensus as to the optimal management of
autoimmune chorea. Patients with Sydenham disease should
be treated with penicillin prophylactically to prevent
rheumatic fever. Symptomatic suppression of chorea with
dopamine antagonists may lessen disability. Anticoagula-
tion, immunosuppressants, and plasmapheresis have been
utilized with variable success, and the frequent occurrence
of spontaneous remissions makes the results of treatment
difficult to interpret. Until prospective therapeutic trials can
be designed, careful selection of treatment that best seems
to suit the severity of the patients illness might be indicated.
The presence of true vasculitis might require more aggressive
management. Steroids are sometimes recommended for
the treatment of autoimmune chorea, and this treatment
was found effective also in chorea associated with heart
346
transplant (Blunt etal., 1994). Stereotactic surgery is occa-
sionally needed in very severe and disabling cases of
Ballism
Chorea, athetosis, and ballism represent a continuum of
involuntary, hyperkinetic movement disorders. Ballism is a
form of forceful, flinging, high-amplitude, coarse, chorea
(Videos 15.9 and 15.10). Ballism and chorea are often inter-
related and may occur in the same patient (Harbord and
Kobayashi, 1991). The involuntary movement usually affects
only one side of the body; the term hemiballism is used to
describe unilateral ballism. Although various structural
lesions have been associated with ballism (Rossetti etal.,
2003), damage to the subthalamic nucleus and the pallido-
subthalamic pathways appears to play a critical role in the
expression of this hyperkinetic movement disorder (Guridi
and Obeso, 2001). Subthalamotomy has been found to
ameliorate the motor disturbances in human and experi-
mental parkinsonism, but the procedure can produce tran-
sient or permanent hemiballism (Bergman etal., 1990; Aziz
etal., 1991; Guridi and Obeso, 2001; Chen etal., 2002).
When caused by a hemorrhagic or ischemic stroke, the
movement disorder is often preceded by hemiparesis. Ante-
rior parietal artery stroke, without any evidence of involve-
ment of the basal ganglia, thalamus, or subthalamic nucleus,
has been associated with contralateral hemiballism and neu-
rogenic pain (Rossetti etal., 2003). This and other similar
cases suggest that the lesion associated with hemiballism may
extend beyond the contralateral subthalamic nucleus and
connecting structures into the adjacent internal capsule. Less
common causes of hemiballism include abscess, arteriov-
enous malformation, cerebral trauma, hyperosmotic hyperg-
lycemia (Ahlskog etal., 2001), multiple sclerosis, and tumor
(Glass etal., 1984). Rarely, ballism occurs bilaterally (para-
ballism), usually due to bilateral basal ganglia strokes or
calcification (Inbody and Jankovic, 1986; Vidakovic etal.,
1994). In a series of 21 patients with hemiballism, hemicho-
rea, or both, an identifiable cause was found in all (Dewey
and Jankovic, 1989). Stroke was the most common cause,
followed by tumors, abscesses, encephalitis, vasculitis, and
other causes. In a series of 23 patients with hemiballism and
2 with biballism, Vidakovic and colleagues (1994) found
ischemic and hemorrhagic strokes to be the most common
causes of hemiballism. Only two patients had pure hemibal-
lism, and only six showed a lesion in the subthalamic nucleus
on neuroimaging studies. The prognosis for spontaneous
remission was good; nine patients completely recovered, and
in seven additional patients, there was complete recovery of
the ballism, but mild chorea had persisted. While hemichorea
hemiballism is usually contralateral to a basal ganglia lesion,
ipsilateral hemichoreahemiballism has been described in
patients with contralateral hemiparesis (Krauss etal., 1999).
The mechanism of this peculiar phenomenon is unknown.
Survival rates following vascular hemiballismus are similar to
those of vascular disease, with only 32% survival and 27%
stroke-free survival 150 months following the onset of the
movement disorder (Ristic etal., 2002).
Other causes of ballism include encephalitis, Sydenham
disease, SLE, basal ganglia calcifications, tuberous sclerosis,

and overlap between Fisher syndrome and GuillainBarr
syndrome (Odaka etal., 1999; Postuma and Lang, 2003). In
addition to structural lesions, metabolic disorders, such as
hyperglycemia (Sitburana and Ondo, 2006), nutritional
vitamin D deficiency (Fernandez etal., 2007), and certain
drugs, such as phenytoin and lamotrigine (Yetimalar etal.,
2007), have been associated with ballism.
Treatment of ballism
The frequent occurrence of spontaneous remission makes the
assessment of therapy difficult. Dopamine receptor-blocking
drugs such as haloperidol, chlorpromazine, pimozide,
and atypical neuroleptics have been used most frequently
(Dewey and Jankovic, 1989; Bashir and Manyam, 1994;
Shannon, 2005). Dopamine-depleting drugs, such as reser-
pine and tetrabenazine, have also been used successfully
(Jankovic and Beach, 1997). Tetrabenazine is our preferred
drug for its rapid onset of action and its effectiveness, without
the danger of inducing tardive dyskinesia if chronic anti-
dopaminergic treatment is needed (Sitburana and Ondo,
2006). Other drugs that are sometimes beneficial in the
treatment of ballism include sodium valproate and clon-
azepam. Finally, ventrolateral thalamotomy and other stere-
otactic surgeries may be needed to control violent and
disabling contralateral hemiballism (Cardoso etal., 1995;
Krauss and Mundinger, 2000). Although effective and rela-
tively safe, this procedure should be used only as a last resort
in patients with disabling and medically intractable move-
ment disorder.
Athetosis
Athetosis is a slow form of chorea that consists of writhing
movements resembling dystonia, but in contrast to dystonia,
these movements are not sustained, patterned, repetitive, or
painful. Originally described by Hammond in acquired
hemidystonia and by Shaw in CP, athetosis should be viewed
as a movement disorder separate from dystonia (Morris
etal., 2002a). The relationship of athetosis to chorea is high-
lighted not only by the continuously changing direction of
movement but also by the observation that chorea often
evolves into athetosis or vice versa. In some patients, particu-
larly children, chorea and athetosis often coexist, hence the
term choreoathetosis. Dystonia, particularly involving the
trunk causing opisthotonic posturing, also frequently accom-
panies athetosis, particularly in children with CP (Video
15.11). In contrast to idiopathic dystonia, athetosis associ-
ated with perinatal brain injury often causes facial grimacing
and spasms, particularly during speaking and eating, and the
bulbar function is usually impaired.
Athetosis is typically present in children with CP, but
may be caused by many various etiologies (Kyllerman, 1982;
Kyllerman etal., 1982; Foley, 1983; Murphy etal., 1995;
Goddard-Finegold, 1998; Morris etal., 2002b; Cowan etal.,
2003; Ashwal etal., 2004; Koman etal., 2004; Bax etal.,
2006; Keogh and Badawi, 2006). In a study of 431 children
diagnosed with CP, 26.2% had hemiplegia, 34.4% had
diplegia, 18.6% had quadriplegia, 14.4% had dyskinesia,
and 3.9% had ataxia (Bax etal., 2006). In a study of 1817
Athetosis
of the 2357 (77%) children born preterm (2232 weeks of
gestation) who survived at least 5 years, CP was diagnosed
in 9%, and 5% had severe, 9% moderate, and 25% minor
disability; cognitive and motor disability was most common
in children born at 2428 weeks of gestation (49%)
(Larroque etal., 2008). In addition to motor disorders man-
ifested chiefly by weakness and hypertonia (i.e., spasticity,
rigidity, athetosis, dystonia), patients with CP may also have
cognitive impairment, epilepsy, visual and hearing prob-
lems, and other neurologic deficits. Although many patients
with dyskinetic CP have well-preserved intellectual function,
most of them have a variety of comorbidities. In one study
the following comorbidities were documented: nonverbal
22.2% (54/243), active afebrile seizure disorder 16.9%
(41/243), severe auditory impairment 11.5% (28/243), corti-
cal blindness 9.5% (23/243), and gavage feeding require-
ment 7.8% (19/243) (Shevell etal., 2009). Children with
ataxic-hypotonic, spastic quadriplegic, and dyskinetic CP
subtypes experienced about five times the numerical burden
(i.e., frequency) of comorbidities compared to children with
the spastic diplegic or hemiplegic variants; dyskinetic chil-
dren had a particularly high frequency of nonverbal skills
(8/16, 50%) and auditory impairment (6/16, 38%).
As a result of hypertonia, many patients with untreated CP
develop fixed contractures. With the advent of botulinum
toxin treatment, intrathecal baclofen infusion, and selective
dorsal rhizotomy, coupled with aggressive physical therapy
and antispastic drugs, these sequelae can be largely
prevented.
Although there has been a steady decline in infant mortal-
ity, the incidence of CP has remained unchanged. Because of
the higher frequency of premature births, the frequency of
certain types of CP, such as spastic diplegia, has been increas-
ing. In one study of children born at 25 or fewer completed
weeks of gestation, half of the patients at 30 months of age
were considered disabled, 18% were diagnosed with CP, and
24% had gait difficulties (Wood etal., 2000).
Kernicterus, once a common cause of CP due to bilirubin
encephalopathy associated with neonatal jaundice, is now
quite rare, although still an important cause of childhood
disabilities in developing countries (Maisels, 2009). Besides
delayed developmental milestones and athetotic or dystonic
movements, patients with kernicterus often exhibit vertical
ophthalmoparesis, deafness, and dysplasia of the dental
enamel. Hearing abnormalities, very common in chronic
bilirubin encephalopathy, can be present as the only finding
of kernicterus. The high-frequency sensory neural hearing
loss has been attributed to damage to the cochlear nuclei
and auditory nerves, possibly as a result of bilirubins inter-
ference with intracellular calcium homeostasis (Shapiro and
Nakamura, 2001). Unconjugated bilirubin can also cause
damage to endoplasmic reticulum membranes leading to
neuronal excitotoxicity and mitochondrial energy failure.
Although improved perinatal care has reduced the fre-
quency of birth-related injuries, birth asphyxia with anoxia
is still a relatively common cause of CP (Kuban and Leviton,
1994; Cowan etal., 2003). Expression of tyrosine hydroxy-
lase was reduced in the putamen in cases of acute kernicterus
and in the globus pallidus of acute and chronic post-
kernicterus (Hachiya and Hayashi, 2008).
The cause of CP is multifactorial. Intrauterine insults,
particularly chorioamnionitis and prolonged rupture of
347
 15 Chorea, ballism, and athetosis
membranes (Murphy etal., 1995), might be responsible for
many of the cases of CP. In one study of 351 full-term
infants with neonatal encephalopathy, early seizures or
both, excluding infants with congenital malformations and
obvious chromosomal disorders, MRI showed evidence of
an acute insult in 6980% (Cowan etal., 2003). The higher
figure correlated with evidence of perinatal asphyxia. The
vast majority of children with neurologic deficits associated
with perinatal asphyxia show abnormalities within the
basal ganglia with shrinkage of the striatum. In addition,
defects in myelination are often associated with a marbled
gross appearance (hypermyelination-status marmoratus) or
dysmyelination.
The border zones between the major cerebral arteries
(watershed) is most vulnerable to asphyxia (Folkerth,
2005). In the striatum, the excitatory glutamate receptors
and GABAergic neurons are particularly sensitive to asphyxia.
Striatal neurons also die by glutamate-mediated excitotoxic-
ity in which apoptosis may be delayed over days to weeks.
Leukomalacia was the most common MRI abnormality,
found in 42.5%, followed by basal ganglia lesions in 12.8%,
cortical/subcortical lesions in 9.4%, malformations in 9.1%,
and infarcts in 7.4%. Although athetosis is usually associated
with perinatal brain injury, the neuroimaging studies often
fail to show basal ganglia pathology.
Both above-normal and below-normal weight at birth are
also significant risk factors for CP (Jarvis etal., 2003). These
data strongly suggest that events in the immediate perinatal
period are most important in the neonatal brain injury. An
analysis of 58 brains of patients with clinical diagnosis of
CP showed wide morphologic variation, but the authors
were able to classify the brains into three major categories:
thinned cerebral mantle (n = 10), hydrocephalus (n = 3), and
microgyriapachygyria (n = 45) (Tsusi etal., 1999). Of the
19 brains that were examined microscopically, four showed
heterotopic gray matter, three showed cortical folding (corti-
cal dysplasia), and three showed neuronal cytomegaly. The
majority of the examined brains showed a variable degree of
laminal disorganization in the cortex and disorientation of
neurons, suggesting impaired neuronal migration during
cortical development. Because 510% of patients with athet-
oid CP have a family history, genetic factors are considered
important in the pathogenesis of this disorder (Fletcher
and Foley, 1993). In a study based on a Swedish registry,
40% of cases of CP were thought to have a genetic basis
(Costeff, 2004).
A growing number of studies also draw attention to inflam-
mation and coagulation abnormalities in children with CP.
The increased concentrations of interleukins, tumor necrosis
factor, reactive antibodies to lupus anticoagulant, anti
cardiolipin, antiphospholipid, antithrombin III, epidermal
growth factor, and other abnormal cytokine patterns may
play an important role in the etiology of CP (Nelson etal.,
1998; Kaukola etal., 2004). Kadhim and colleagues (2001)
suggest that an early macrophage reaction and associated
cytokine production and coagulation necrosis, coupled with
intrinsic vulnerability of the immature oligodendrocyte, lead
to periventricular leukomalacia, the most common neuro
pathologic changes found in premature infants who develop
CP. Although infection and inflammation, along with free
radicals, can activate the process that leads to periventricular
leukomalacia and even to delayed progression (Scott and
348
Jankovic, 1996), the cause or pathogenesis of CP is still not
well understood.
Often referred to as static encephalopathy, the neurologic
deficit associated with CP may progress with time. Motor
development curves derived by assessing patients with the
Gross Motor Function Measure, used to prognosticate gross
motor function in patients with CP, indicate that, depending
on their level of impairment (levels I to V) 310 years after
birth, the natural course becomes static (Rosenbaum etal.,
2002). We and others, however, found that some patients
continue to progress, and others may progress after a period
of static course. In about half of the patients with CP, the
abnormal movements become apparent within the first year
of life, but in some cases, they might not appear until the
fifth decade or even later. The mechanism by which such
delayed-onset movement disorder becomes progressive
after decades of a static course is unknown, but aberrant
regeneration and sprouting of nerve fibers has been consid-
ered (Scott and Jankovic, 1996). In contrast to the other
forms of CP (e.g., diplegic or spastic and hemiplegic), the
athetoid variety, which constitutes only about a quarter of
all cases, is usually not associated with significant cognitive
impairment or epilepsy. Although here we emphasize atheto-
sis, the most common movement disorder in patients with
CP is spasticity (Albright, 1995).
Many other disorders associated with developmental delay
and intellectual disability can cause athetosis. Chromosomal
microarray has been recommended for genetic testing
of individuals with unexplained developmental delay/
intellectual disability, autism spectrum disorders, or multi-
ple congenital anomalies (Miller etal., 2010). Some are due
to errors in metabolism and include acidurias, lipidoses, and
LeschNyhan syndrome (Jankovic etal., 1988; Stacy and
Jankovic, 1995) (Table 15.1). Finally, athetotic movements,
or pseudoathetosis, can be seen in patients with severe
proprioceptive deficit (Sharp etal., 1994).
Treatment of athetosis
Athetosis usually does not respond well to pharmacologic
therapy. Because dopa-responsive dystonia is sometimes
confused with athetoid CP, it is prudent to treat all these
patients with levodopa. If levodopa fails to provide any
meaningful benefit, then anticholinergic drugs should be
tried in the same manner as when treating dystonia. Although
generally recommended, physical therapy might or might
not prevent contractures, and its role in altering the eventual
outcome is uncertain (Palmer etal., 1988). Other complica-
tions of CP, such as carpal tunnel syndrome, cervical
spondylosis with radiculopathy, and myelopathy, require
independent assessment and treatment (Hirose and Kadoya,
1984; Treves and Korczyn, 1986). Bilateral GPi deep brain
stimulation has been reported to produce about 24.4%
improvement in the BurkeFahnMarsden scale in adult
patients with dystoniachoreoathetosis associated with CP
(Vidailhet etal., 2009).
References available on Expert Consult:
www.expertconsult.com
 Appendix

Appendix

Testing for various causes of chorea is Institute of Pathology Western blot for chorein
available at the following: Case Western Reserve University Prof. Dr Adrian Danek
2085 Adelbert Road, Room 418 Neurologische Klinik
http://www.ncbi.nlm.nih.gov/sites/ Cleveland, Ohio 44106 und Poliklinik
entrez?db=omim Telephone: (216) 368-0587 Klinikum der Universitt Mnchen,
http://www.athenadiagnostics.com/content/ Fax: (216) 368-4090 Campus Grohadern
diagnostic-ed/genetic_testing Email: cjdsurv@case.edu Marchioninistrae 15
http://www.genome.gov HDL2 Lab of Russell Margolis, MD 81377 Munich
http://www.mayomedicallaboratories.com/ Germany
Neurogenetic Testing Laboratory
testcatalog/index.html Telephone: ++ 49 89 7095 6676
Johns Hopkins University
http://www.geneticalliance.org.uk/ Fax: ++ 49 89 7095 6671
600 North Wolfe Street
http://www.genetests.org Email: adrien.danek@med.uni-muenchen.
Meyer 2-181
http://www.massgeneral.org/neurology/ de/
Baltimore, MD 21287
research/resourcelab.aspx?id=43/
Telephone: (410) 955-1349
http://www.kumc.edu/gec/ VPS13A gene testing
http://www.pdgene.org Neuroacanthocytosis Koichiro Sakai, MD, PhD
http://www.familytreedna.com/default.aspx
Loss of chorein expression has been found to Ishikawa, Japan
http://www.horizonmedicine.com/ be a reliable diagnostic test and the analysis Email: ksakai@kanazawa-med.ac.jp
http://www.diagenic.com/ by Western blot test is available without
http://www.23andme.com charge by sending 2030mL of EDTA blood
http://ccr.coriell.org/ to Dr B. Baker, Munich, Germany (Benedikt.
Bader@med.uni-muenchen.de) through the
HDL1 Lab of Pierluigi Gambetti, MD support of the Advocacy for Neuroacan-
National Prion Disease Pathology thocytosis patients (http://www.naadvocacy.
Surveillance Center org).

349