Hunti ngton Di sease

and Other Choreas

Francisco Cardoso, MD, PhD
Chorea is a syndrome characterized by brief, abrupt involuntary movements resulting
from a continuous flow of random muscle contractions. The pattern of movement may
sometimes seem playful, conveying a feeling of restlessness to the observer. When
choreic movements are more severe, assuming a flinging, sometimes violent, char-
acter, they are called ballism. Regardless of its cause, chorea has the same features.
1
There are genetic and nongenetic causes of chorea, listed in Box 1. Nongenetic
causes include vascular choreas, autoimmune choreas, metabolic and toxic choreas,
and drug-induced choreas. Although there are few community-based studies avail-
able regarding the prevalence and incidence of choreas, there is information regarding
the situation in tertiary care centers. Huntington disease (HD) is the most frequent
cause of genetic chorea with reported prevalence rates in North America and Europe
ranging from 3 to 7 per 100,000.
1
The other genetic conditions causing chorea are
rare. According to a recent study fromPennsylvania, Sydenham chorea (SC) accounts
for almost 100%of acute cases of chorea seen in children.
2
In contrast, the situation is
more distinct in adult patients. Although no published data are available, it is likely that
levodopa-induced chorea in patients with Parkinson disease (PD) is the most common
cause of chorea seen by neurologists. One study of consecutive patients seen at
a tertiary hospital found that stroke accounted for 50% of all cases, drug abuse
was identified in one third of the patients, and the remaining patients had chorea
related to AIDS and other infections and metabolic problems.
3
The aim of this article is to provide an overview of the main causes of chorea. The
clinical features, causes, pathogenesis, and management are discussed.
HUNTINGTON DISEASE
HD is an autosomal-dominant, progressive neurodegenerative disorder typically char-
acterized by a movement disorder, including chorea, cognitive decline, and behavioral
changes leading to relentlessly increasing disability and ultimately death. Patients
usually develop the first symptoms in their mid-30s to mid-40s. However, the onset
Internal Medicine Department, The Federal University of Minas Gerais, Av Pasteur 89/1107,
30150-290 Belo Horizonte, MG, Brazil
E-mail address: cardosofe@terra.com.br
KEYWORDS

Chorea

Ballism

Huntington disease

Neuroacanthocytosis

Sydenham chorea

Vascular chorea
Neurol Clin 27 (2009) 719736
doi:10.1016/j.ncl.2009.04.001 neurologic.theclinics.com
0733-8619/09/$ see front matter 2009 Elsevier Inc. All rights reserved.
Box1
Causes of Chorea
Genetic causes
Huntington disease
Huntington disease-like illnesses
Neuroacanthocytosis
McLeod syndrome
Wilson disease
Benign hereditary chorea (BHC)
Spinocerebellar atrophy type 2
Spinocerebellar atrophy type 3
Spinocerebellar atrophy type 17
Dentatorubropallidoluysian degeneration
Ataxia-telangiectasia
Ataxia associated with oculomotor apraxia
Neuroferritinopathy
Pantothenate kinase associated degeneration
Leigh disease and other mitochondriopathies
Lesch-Nyhan disease
Immunologic
Sydenham chorea (SC) and variants (chorea gravidarum and contraceptive-induced chorea)
Systemic lupus erythematosus
Antiphospholipid antibody syndrome
Paraneoplastic syndromes
Acute disseminated encephalomyelopathy
Celiac disease
Drug-related
Amantadine
Amphetamine
Anticonvulsants
Carbon monoxide
Central nervous system (CNS) stimulants (methylphenidate, pemoline, cyproheptadine)
Cocaine
Dopamine agonists
Dopamine-receptor blockers
Ethanol
Levodopa
Levofloxacin
Lithium
Sympathomimetics
Theophylline
Cardoso 720
Tricyclic antidepressants
Withdrawal emergent syndrome
Infections
AIDS-related (toxoplasmosis, progressive multifocal leukoencephalopathy, HIV encephalitis)
Bacteria
- Diphtheria
- Scarlet fever
- Whooping cough
Encephalitis
- B19 parvovirus
- Japanese encephalitis
- Measles
- Mumps
- West Nile River encephalitis
- Others
Parasites
- Neurocysticercosis
Protozoan
- Malaria
- Syphilis
Endocrine-metabolic dysfunction
Adrenal insufficiency
Hyper/hypocalcemia
Hyper/hypoglycemia
Hypomagnesemia
Hypernatremia
Liver failure
Vascular
Post-pump chorea (cardiac surgery)
Stroke
Subdural hematoma
Miscellaneous
Anoxic encephalopathy
Cerebral palsy
Kernicterus
Multiple sclerosis
Normal maturation (less than 12 months old)
Nutritional (eg, B12 deficiency)
Posttraumatic (brain injury)
Choreas 721
in a small proportion of subjects is before the age of 20 years (Westphal variant) or
after the age of 70 years.
1
Clinical Features
HDis characterized by a triad of movement disorder, cognitive decline, and behavioral
changes. Although chorea is the prototypical movement disorder in HD and is usually
present with middle-age or elderly onset, the full spectrum of motor impairment in HD
includes eye movement abnormalities, parkinsonian features and dystonia (particu-
larly in juvenile HD), myoclonus, tics, ataxia, dysarthria and dysphagia, and spasticity
with hyperreflexia and extensor plantar responses.
48
With progressing illness, chorea
is often superseded by dystonia or akineto-rigid parkinsonian features. One study
demonstrated that dystonia is found in more than 90% of patients with HD,
9
although
rarely it becomes as prominent as in idiopathic dystonias. A recent study demon-
strated that falls are an important clinical problem in HD, occurring in 60% of patients,
and are correlated with motor deficits, cognitive decline, and behavioral changes.
10
Behavioral impairment is universal in HD and may occasionally antedate motor
manifestations. Major depression is common, diagnosed in more than 40% of
subjects, and responsible for increased suicide rates in HD. The spectrum of behav-
ioral abnormalities in HD is broad and includes anxiety or panic attacks, obsessive
compulsive symptoms, manic features, psychosis, irritability and aggressive behavior,
sexual disinhibition, and apathy.
1117
In a prospective study of a large cohort (681) of
subjects with presymptomatic HD, significantly more psychiatric symptoms (specially
depression, anxiety, and obsessive-compulsiveness) were reported than for the
controls.
18
Similarly, psychiatric difficulties are indicators of juvenile HD onset.
19
Patients with HD universally go through cognitive decline, mental slowing, impaired
problem-solving abilities, and other signs of a frontal dysexecutive syndrome, and
they eventually become demented. These patients present with the prototype of so-
called subcortical dementia.
2022
Cognitive decline also heralds the juvenile onset of
HD.
19
A recent investigation has demonstrated that asymptomatic carriers of the
HD gene have decreased phonemic fluency.
23
HD is relentlessly progressive with death occurring 15 to 20 years after symptom
onset with particularly rapid progression in the juvenile Westphal variant. Patients
with end-stage HD are typically rigid and akinetic, demented, and mute. Immobility
and dysphagia often lead to aspiration pneumonia, the most common cause of death
in these patients.
2426
Etiology and Pathogenesis
HD is caused by a trinucleotide (CAG) repeat expansion in the gene encoding for
huntingtin on chromosome 4p16.3; the exact function of normal huntingtin is still
unknown, and it is widely expressed in the human brain.
27,28
The normal CAG repeat
length in the HD gene is 35 or lower; expansions of 40 or more cause HD with
complete penetrance. Individuals with 36 to 39 repeats may also develop HD but
penetrance is incomplete.
29
A CAG repeat range between 27 and 35 is considered
normal allele with particular risk for expansion into the HD range in the paternal germ-
line.
30,31
However, there is a report showing that 1 patient with 34 repeats developed
HD.
32
The mutant protein has been shown to form nuclear aggregates but how this
leads to neurodegeneration remains unclear. Current evidence suggests that forma-
tion of aggregates of huntingtin is not primarily responsible for neuronal loss in HD.
Alternative hypotheses suggested include transcriptional dysregulation, excitotoxic-
ity, altered energy metabolism, impaired axonal transport, and altered synaptic trans-
mission.
33,34
Neurodegeneration in HD affects most prominently the striatum with loss
Cardoso 722
of medium spiny neurons and layers III, IV, and V of the cortex with loss of large
neurons, and is characterized by the presence of intranuclear inclusion bodies
consisting of amyloid-like fibrils that contain mutant huntingtin, ubiquitin, synuclein,
and other proteins.
3537
Management
To date there is no effective treatment to modify the relentlessly progressive course of
HD.
38
Symptomatic treatment of chorea is needed if it causes functional disability or
social embarrassment. One principle that generally guides the choice of antichoreic
agents is their ability to powerfully block D2 receptors. With the exception of amanta-
dine (see later discussion), all drugs effective in providing symptomatic improvement
of chorea have high affinity toward this family of dopamine receptors, which explains
why atypical agents, such as quetiapine and clozapine, often used to treat psychosis
in patients with movement disorders, are usually ineffective in controlling chorea.
Atypical antipsychotics such as olanzapine, quetiapine or risperidone may sufficiently
and at least transiently reduce choreic movements but are generally less potent than
typical neuroleptics. If the neuroleptics are effective in reducing chorea, they are often
associated with unacceptable side effects such as sedation, acute dystonic reaction,
tardive dyskinesia, and parkinsonism. Parkinsonism can be a problem in patients with
HD; with progression of the illness there is a tendency for development of rigidity and
dystonia.
39
Mild to moderate chorea in HD may also respond to glutamate antagonists
such as amantadine.
40,41
Recent controlled data have confirmed that tetrabenazine,
a presynaptic dopamine depletory, is efficacious in controlling chorea in HD.
42,43
This agent has now been approved by the Food and Drug Administration for symp-
tomatic control of chorea in HD. In a recent open-label study, aripiprazole was found
to have efficacy comparable to tetrabenazine in the control of chorea in HD. Further
studies are required to confirm this observation.
44
Levodopa may be required in
patients with Huntington disease with advanced illness and severe rigidity.
38
Atypical
neuroleptics may also be useful in the management of emotional irritability, aggres-
siveness, and other forms of erratic behavior.
17,45
Depression may respond to classic
antidepressants such as selective serotonin reuptake inhibitors (SSRIs) or antimuscar-
inic drugs, or to newer antidepressants such as mirtazapine, reboxatine, or venlafaxin,
but there are no formal trial data to assess the relative efficacy and safety of these
agents in HD.
17
Occasional reports have claimed mild beneficial effects of treatment
with cholinesterase inhibitor to reduce cognitive dysfunction in HD, but there are no
adequate studies to support their use.
46,47
Surgery to treat chorea is rarely needed.
Pallidotomy and pallidal stimulation have also been used in a few patients with
HD.
48,49
Several patients with Huntington disease have been treated with fetal cell
implantation in the striatum. Despite a few positive reports, in most cases no improve-
ment has been observed. Autopsy studies have shown that the grafts survive but do
not integrate with host striatum.
50,51
OTHER GENETIC CHOREAS
Approximately 3% of patients with an HD phenotype test negative for this condition.
Cohort studies have established that, although most phenocopy patients remain undi-
agnosed, in those patients in whom a genetic diagnosis is reached the commonest
causes are neuroacanthocytosis, SCA17, Huntington disease-like syndrome 2, familial
prion disease, andFriedreich ataxia. Other causes of HDphenocopies include Hunting-
ton disease-like syndrome 1, Huntington disease-like syndrome 3, other spinocerebel-
lar ataxias, dentatorubral-pallidoluysian atrophy, and iron accumulation disorders.
52,53
Choreas 723
Neuroacanthocytosis causes chorea combined with dystonia (especially a self-
mutilating oro-mandibullingual dyskinesia), tics, parkinsonism, dementia, seizures,
and head of caudate atrophy on neuroimaging studies.
54
Several conditions can
cause the combination of chorea and acanthocytosis: autosomal recessive chorea-
acanthocytosis, X-linked McLeod syndrome, Huntington disease-like 2, panthotenate
kinaseassociated neurodegeneration, and Bassen-Kornzweig disease.
55
A study of
several patients with McLeod syndrome, including the subject of the original report,
demonstrated that their phenotype is similar to the clinical features of patients with
HD, with the myopathic findings overtaken by chorea and dementia.
56
Another genetic cause of chorea that has received increased attention is benign
hereditary chorea (BHC). Not long ago, the existence of this condition was ques-
tioned.
57
Now it is well established as an autosomal dominant illness, with a mutation
in the TITF-1 gene, which codes for a transcription factor essential for the organogen-
esis of the lungs, thyroid, and basal ganglia.
58
The clinical picture of these patients is
characterized by a variable combination of chorea, mental retardation, congenital
hypothyroidism, and chronic lung disease, hence the term brain-thyroid-lung
syndrome, proposed for this disease.
59,60
The movement disorder of these patients
is differentiated from the hyperkinesia seen in myoclonus dystonia by its continuous
nature; in myoclonus dystonia the movements are triggered by motion.
61
New studies
with clinical-genetic correlation have helped to demonstrate that the clinical spectrum
of BHC is wider than previously believed, and includes psychosis and short
stature.
62,63
The phenotype of BHCand hypothyroidismhas been shown to be caused
by a novel NKX2.1 mutation.
64
Moreover, a new locus on 8q21.3 q23.3 is associated
with adult-onset, pure, slowly progressive chorea.
65
The list of genetic causes of chorea is long and growing.
1
It is beyond the scope of
this article to review all of them. Recently, however, there has been interest in a few
additional conditions in which progress has been made. For example, paroxysmal
nonkinesigenic dyskinesia, Mount-Reback Syndrome, is now known to be caused
by mutations of myofibrillogenesis regulator 1 (MR-1) gene mutations, located on
2q35.
66,67
Patients with this condition develop episodes of chorea or other movement
disorders unrelated to exercise but often in association with the use of nicotine and
alcohol.
68
A new study showed that there is a defect in the MR-1 mitochondrial target-
ing sequence.
69
Other paroxysmal dyskinesias in which chorea is part of the clinical
picture map to genes on 16p12-q12 and 10q22.
70
There are no controlled studies of treatment of other genetic causes of chorea.
Overall, the principles discussed for HD apply to these conditions. However, there
are peculiarities in some cases. A substantial proportion of patients with chorea-acan-
thocytosis present with a self-mutilating tongue-biting dystonia. This dyskinesia can
be disabling, preventing these patients from eating properly and resulting in severe
injuries. In the authors experience, injections of botulinum toxin in the genioglossus
muscle can provide substantial and lasting relief. Another clinical feature common in
this condition is seizure disorder, requiring the use of antiepileptic drugs. The kinesi-
genic paroxysmal dyskinesias are sensitive to low doses of antepileptic drugs,
whereas Mount-Reback syndrome responds to benzodiazepines.
68,71
Finally, there
is one report suggesting that levodopa can be effective in the treatment of BHC.
72
SYDENHAM CHOREA
SC, the most common form of autoimmune chorea worldwide, is a major feature of
acute rheumatic fever (ARF), a nonsuppurative complication of group A b-hemolytic
Streptococcus infection. Despite the decline of ARF, it remains the most common
Cardoso 724
cause of acute chorea in children in the United States and a major public health
problem in developing areas of the world. Clinically, it is characterized by a combina-
tion of chorea, other movement disorders, behavioral abnormalities, and cognitive
changes.
1,2
Clinical Features
The usual age at onset of SC is 8 to 9 years, but there are reports of patients who
developed chorea during the third decade of life. In most series, there is a female
preponderance.
73
Typically, patients develop this disease 4 to 8 weeks after an
episode of group A b-hemolytic streptococcal pharyngitis. It does not occur after
streptococcal infection of the skin. The chorea spreads rapidly and becomes general-
ized, but hemichorea persists in 20%of patients.
73,74
Patients display motor impersis-
tence, particularly noticeable during tongue protrusion and ocular fixation. The muscle
tone is usually decreased; in severe and rare cases (8% of all patients seen at the
Movement Disorders of the Federal University of Minas Gerais, Brazil), this is so
pronounced that the patient may become bedridden (chorea paralytica).
Patients often display other neurologic and nonneurologic symptoms and signs.
There are reports that tics are a common occurrence in SC. However, it is virtually
impossible to distinguish simple tics from fragments of chorea. Even vocal tics, found
in 70% or more of patients with SC in one study, are not a simple diagnosis in patients
with hyperkinesias.
75
In a cohort of 108 patients with SC who were carefully followed
up at our unit, vocalizations were identified in just 8% of subjects. The term tic was
avoided because there was no premonitory sign or complex sound and, conversely,
the vocalizations were associated with severe cranial chorea. These findings suggest
that involuntary sounds present in a few patients with SC result from choreic contrac-
tions of the upper respiratory tract muscles rather than true tics.
76,77
There is evidence
that many patients with active chorea have hypometric saccades, and a fewalso show
oculogyric crisis. Dysarthria and impairment of verbal fluency are common. In a case
control study of patients, a pattern of decreased verbal fluency was described that
reflected reduced phonetic, but not semantic, output.
78
This result is consistent
with dysfunction of the dorsolateral prefrontal basal ganglia circuit. Studying adults
with SC, the authors have extended this finding, showing that many functions depen-
dent on the prefrontal area are impaired in these patients. The conclusion of this study
is that SC should be included among the causes of dysexecutive syndrome.
79
The
prosody is also affected in SC. In an investigation of 20 patients with SC, decreased
vocal tessitura and increased duration of the speech were shown.
80,81
These findings
are similar to those observed in Parkinson disease.
82
In a recent survey of 100 patients
with rheumatic fever, half of whom had chorea, migraine was found to be more
frequent in SC (21.8%) than in normal controls (8.1%, P 5 .02).
83
This is similar to
what has been described in Tourette syndrome (TS).
84
In the older literature, there
are also references to papilledema, central retinal artery occlusion, and seizures in
a few patients with Sydenham chorea.
Attention has also been drawn to behavioral abnormalities. Swedo and colleagues
85
found obsessive-compulsive behavior in 5 of 13 SCpatients, 3 of whommet criteria for
obsessive-compulsive disorder, whereas no patient of the rheumatic fever group
presented with obsessive-compulsive behavior. In another study of 30 patients with
SC, Asbahr and colleagues
86
demonstrated that 70% of the subjects presented
with obsessions and compulsions, whereas 16.7% of them met criteria for obses-
sive-compulsive disorder. None of the 20 patients with ARF without chorea had
obsessions or compulsions. These results were roughly replicated by a more recent
study in which patients with ARF without chorea were found to have more obsessions
Choreas 725
and compulsions than healthy controls.
87
This study also tackled the issue of hyper-
activity and attention deficit disorder in SC and found that 45% of their 22 patients
met criteria for this condition. Recently, Maia and colleagues
88
investigated behavioral
abnormalities in 50 healthy subjects, 50 patients with rheumatic fever without chorea,
and 56 patients with Sydenham chorea. The investigators found that obsessive-
compulsive behavior, obsessive-compulsive disorder, and attention deficit and hyper-
activity disorder were more frequent in the SC group (19%, 23.2%, 30.4%) than in the
healthy controls (11%, 4%, 8%) or in the patients with ARF without chorea (14%, 6%,
8%). In this study, the investigators demonstrated that obsessive-compulsive
behavior displays little degree of interference in the performance of the activities of
daily living. Another study compared the phenomenology of obsessions and compul-
sions of patients with SC with subjects diagnosed with tic disorders. The investigators
demonstrated that the symptoms observed among the SCpatients were different from
those reported by patients with tic disorders but were similar to those previously noted
among samples of pediatric patients with primary obsessive-compulsive disorder.
89
A recent investigation comparing healthy controls with patients with rheumatic fever
showed that obsessive-compulsive behavior is more commonly seen in patients
with Sydenham chorea with relatives who also have obsessions and compulsions.
90
This study makes clear that there is interplay between genetic factors and the environ-
ment in the development of behavioral problems in SC. The authors recently reported
that, although rare, SC may induce psychosis or trichotillomania during the acute
phase of the illness.
91,92
An investigation demonstrated that the peripheral nervous system is not targeted in
Sydenham chorea.
93
SC is a major manifestation of rheumatic fever. Sixty percent to
80% of patients display cardiac involvement, particularly mitral valve dysfunction, in
SC, whereas the association with arthritis is less common, seen in 30% of patients;
however, in approximately 20% of patients, chorea is the sole finding.
73,94
A prospec-
tive follow-up of patients with SC with and without cardiac involvement in the first
episode of chorea suggests that the heart remains spared in those without lesion at
the onset of the rheumatic fever.
95
The current diagnostic criteria of SC are a modification of the Jones criteria: chorea
with acute or subacute onset and lack of clinical and laboratory evidence of an
alternative cause are mandatory findings. The diagnosis is further supported by the
presence of additional major or minor manifestations of ARF.
78,96,97
The first validated
scale to rate SC was published recently. The Universidade Federal de Minas Gerais
Sydenham Chorea Rating Scale was designed to provide a detailed quantitative
description of the performance of the activities of daily living, behavioral abnormalities,
and motor function of patients with SC. It comprises 27 items, and each is scored from
0 (no symptom or sign) to 4 (severe disability or finding).
98
Etiology and Pathogenesis
Taranta and Stollerman established the casual relationship between infection with
group A b-hemolytic streptococci and the occurrence of SC.
99
Based on the assump-
tion of molecular mimicry between streptococcal and central nervous system
antigens, it has been proposed that the bacterial infection in genetically predisposed
subjects leads to formation of cross-reactive antibodies that disrupt the basal ganglia
function. Several studies have demonstrated the presence of such circulating
antibodies in 50% to 90% of patients with Sydenham chorea.
100,101
A specific epitope
of streptococcal M proteins that cross-reacts with basal ganglia has been identi-
fied.
102
In one study, all patients with active SC had antibasal ganglia antibodies
demonstrated by ELISA and Western blot. In subjects with persistent SC (duration
Cardoso 726
of disease greater than 2 years despite best medical treatment), positivity was about
60%.
103
Recently, neuronal tubulin was found to be the target of antineuronal
antibodies.
104
The biologic value of the antibasal ganglia antibodies remains to be
determined. One study suggests that they may interfere with neuronal function,
however. Kirvan and colleagues
105
demonstrated that IgMof 1 patient with Sydenham
chorea induced expression of calcium-dependent calmodulin in a culture of neuro-
blastoma cells. Our finding that there is a linear correlation between the increase in
intracellular calcium levels in PC12 cells and antibasal ganglia antibody titer in the
serum from SC patients further strengthens the hypothesis that these antibodies
have a pathogenic value.
106
Although some investigations suggest that susceptibility to rheumatic chorea is
linked to human leukocyte antigen-linked antigen expression,
107
some studies have
failed to identify any relationship between SC and human leukocyte antigen class I
and II alleles.
108
However, an investigation has shown that there is an association
between HLA-DRB1*07 and recurrent streptococcal pharyngitis and rheumatic heart
disease.
109
The genetic marker for ARF and related conditions would be the B-cell
alloantigen D8/17.
110
Despite repeated reports of the group who developed the assay
claiming its high specificity and sensitivity,
111,112
findings of other investigators
suggest that the D8/17 marker lacks specificity and sensitivity.
1
Another suggested
genetic risk factor for development of ARF but not SC are polymorphisms within the
promoter region of the tumor necrosis factor-a gene.
113
Because of the difficulties with the molecular mimicry hypothesis in accounting for
the pathogenesis of SC, some studies have addressed the role of immune cellular
mechanisms in this condition. Investigating sera and cerebrospinal fluid (CSF)
samples from patients of the Movement Disorders of the Federal University of Minas
Gerais, Church and colleagues
114
found elevation of cytokines that take part in the Th2
(antibody-mediated) response, interleukins 4 (IL-4) and 10 (IL-10), in the serum of
patients with acute SC in comparison with persistent SC. They also described inter-
leukin 4 in the CSF of 31% of patients with acute SC, whereas just interleukin 4 was
raised in the CSF of patients with persistent SC. The investigators concluded that
SC is characterized by a Th2 response. However, as they have found elevated levels
of interleukin 12 in patients with acute SC and, more recently, Teixeira and colleagues
described an increased concentration of chemokines CXCL9 and CXCL10 in the
serum of patients with acute SC,
115
it can be concluded that Th1 (cell-mediated)
mechanisms may also be involved in the pathogenesis of this disorder.
Currently, the evidence suggests that the pathogenesis of SC is related to circu-
lating cross-reactive antibodies. Streptococcus-induced antibodies have been shown
to be associated with a form of acute disseminated encephalomyelitis characterized
by a high frequency of dystonia and other movement disorders as well as basal
ganglia lesions on neuroimaging.
116
Antineural and antinuclear antibodies have also
been found in patients with TS but their relationship with prior streptococcus infection
remains equivocal.
117
Management
In the past, physicians emphasized the need for bed rest for the treatment of SC.
Currently there is no place for this measure. Because SC results from autoimmune,
and not direct bacterial attack against the CNS, quarantine to prevent contamination
of others is usually unnecessary.
118
The first aimof the treatment of SCis to provide control of the chorea and behavioral
problems often associated with this condition. Regardless of the choice of agent for
symptomatic control, the physician should attempt a gradual decrease in the dosage
Choreas 727
of the medication (25% reduction every 2 weeks) after the patient remains free of the
symptom for at least 1 month. In some patients symptoms are so mild that they do not
cause meaningful disability. In these cases, it is possible to avoid any pharmacologic
intervention, because spontaneous remission of SCis the rule.
97,119
The second aimis
prophylaxis of newbouts of ARF. Although it remains unproved whether prophylaxis of
streptococcus infection prevents recurrences of SC,
120
clearly it decreases the
development of new cardiac lesions, which are the source of the most important
disability in rheumatic fever.
There are no controlled studies of symptomatic treatment of SC and all the recom-
mendations mentioned are off-label use of the cited drugs.
118
The first choice is
valproic acid at an initial dosage of 250 mg/d that is increased over a 2-week period
to 250 mg 3 times a day. If the response is not satisfactory, dosage can be increased
gradually up to 1500 mg/d. As this drug has a slowonset of action, a period of 2 weeks
should elapse before concluding that the regimen is ineffective. Valproic acid is usually
well tolerated although some patients may develop dyspepsia and diarrhea at the
beginning of the treatment. Chronic exposure may be associated with action tremor
of the hands and, more rarely, liver toxicity. An open-label study demonstrated that
carbamazepine (15 mg/kg/d) is as effective as valproic acid (2025 mg/kg/d) to induce
remission of chorea.
121
If the patient fails to respond to valproic acid, or, as first line
treatment in patients who present with chorea paralytica, the next option is to
prescribe neuroleptics. Risperidone, a potent dopamine D2 receptor blocker, is
usually effective in controlling the chorea. The initial regimen is usually 1 mg twice
a day. If, 2 weeks later, the chorea is still troublesome, the dosage can be increased
to 2 mg twice a day. Haloperidol and pimozide are also occasionally used in the
management of chorea in SC. However, they are less well tolerated than risperidone.
Dopamine D2 receptor blockers must be used with great caution in patients with SC.
After observation of development of parkinsonism, dystonia, or both in patients
treated with neuroleptics, we performed a casecontrol study comparing the
response to these drugs in patients with SC and TS. Five percent of 100 patients
with chorea developed extrapyramidal complications, whereas these findings were
not seen among patients with tics matched for age and dosage of neuroleptics.
121
Other potential side effects of these agents are sedation, depression, and tardive
dyskinesia. There are no published guidelines concerning the discontinuation of anti-
choreic agents. Our policy is to attempt a gradual decrease of the dosage (25%reduc-
tion every 2 weeks) after the patient remains at least free of chorea for 1 month. Finally,
the most important measure in the treatment of patients with SC is secondary
prophylaxis.
Because of the presumably autoimmune origin of SC, there have been attempts to
treat patients with rheumatic chorea with corticosteroids. However, this is a controver-
sial area. Despite mentions of effectiveness of prednisone in suppressing chorea, this
drug is only used when there is associated severe carditis. We recently reported that
methylprednisolone 25 mg/kg/d in children and 1 g/d in adults for 5 days followed by
prednisone 1 mg/kg/d is an effective and well-tolerated treatment regimen for patients
with SC refractory to conventional treatment with antichoreic drugs and peni-
cillin.
98,122
At least one other group has replicated our findings of a good response
to steroids in selected patients with SC.
123
In one of the few randomized controlled
trials in SC, the investigators compared oral prednisone (2 mg/kg/d) and placebo in
a double-blind fashion. Simultaneous use of haloperidol was allowed. They concluded
that steroid accelerates the recovery but the rate of remission and recurrence is similar
in both groups.
124
However, this study has some limitations: haloperidol use was not
controlled in both groups; it remains uncertain whether the development of side
Cardoso 728
effects such as weight gain and moon face in the steroid group could have potentially
compromised the blinding of the study (this is of particular concern considering the
high dosage of prednisone); the investigators used a nonvalidated scale to rate the
severity of chorea. The current recommendation is to reserve steroids for patients
with persistent disabling chorea refractory to antichoreic agents or those who develop
unacceptable side effects with other agents. Finally, one open, controlled study of
a small number of patients reported that plasma exchange or intravenous immuno-
globulin are as effective as oral prednisone to control the severity of chorea in
SC.
125
Surprisingly, the investigators report the lack of side effects in all groups.
Because of the lack of additional studies to confirm the safety and effectiveness of
these treatments, their high cost and existence of alternative efficacious therapeutic
options, plasmapheresis and immunoglobulin are presently considered as investiga-
tional, and do not have a place in routine medical practice.
OTHER AUTOIMMUNE CHOREAS
Other immunologic causes of chorea are systemic lupus erythematosus (SLE), primary
antiphospholipid antibody syndrome (PAPS), vasculitis, and paraneoplastic
syndromes. SLE or PAPS are classically described as the prototypes of autoimmune
choreas.
126
However, several reports show that chorea is seen in no more than 1% to
2% of large series of patients with these conditions.
127,128
Autoimmune chorea has
rarely been reported in the context of paraneoplastic syndromes associated with
CV2/CRMP5 antibodies in patients with small-cell lung carcinoma or malignant
thymoma.
129
As these disorders are rare, chorea caused by them is uncommon.
Chorea associated with SLE or PAPS has been treated with immunosuppressive
measures, especially intravenous methylprednisolone following a dosage regimen
as described for SC, and intravenous immunoglobulin.
130
As it is accepted that
neurologic complications, including chorea, in PAPS are related to ischemic events,
antiplatelet agents and even anticoagulants are often prescribed to treat chorea in
this condition.
131
However, these recommendations are based on reports of open-
label studies involving small numbers of patients and the clinical experience of the
physicians.
1
VASCULAR CHOREAS
A study in a tertiary referral center showed that cerebrovascular disease was the most
common cause of nongenetic chorea, accounting for 21 out of 42 cases.
3
Conversely,
chorea is an unusual complication of acute vascular lesions, seen in less than 1% of
patients with acute stroke. Vascular hemichorea, or hemiballism, is usually related to
ischemic or hemorrhagic lesions of the basal ganglia and adjacent white matter in the
territory of the middle or the posterior cerebral artery. In contrast to the classic
textbook concepts of hemiballism, most patients with vascular chorea have lesions
outside the subthalamus.
132
Although spontaneous remission is the rule, treatment
with antichoreic drugs such as neuroleptics or dopamine depletors may be necessary
in the acute phase. In a fewpatients with vascular chorea, the movement disorder may
persist. These patients can be treated effectively with stereotactic surgery such as
thalamotomy or posteroventral pallidotomy.
133,134
An uncommon cause of chorea is Moyamoya disease, an intracranial vasculopathy
that presents with an ischemic lesion or, less commonly, hemorrhagic stroke of the
basal ganglia.
135
Another rare form of vascular chorea is postpump chorea,
a complication of extracorporeal circulation. The pathogenesis of this movement
disorder is believed to be related to vascular insult of the basal ganglia during the
Choreas 729
surgical procedure. The current evidence supports the notion that the long-term prog-
nosis of PC is poor. In 1 series of 8 patients, for example, 5 subjects had persistent
chorea and 1 of them died. In another study, there was a clear distinction between
those 8 patients with onset at earlier age (median 4.3 months), all of whom recovered
fully, and 11 others, who were older at onset (median age 16.8 months). Among the
latter, 4 died and only 1 of the survivors made a complete neurologic recovery.
136
SUMMARY
Huntington disease (HD), an autosomal dominant degenerative disease, is the most
common genetic cause of chorea. HD, a relentlessly progressive illness, is character-
ized by a combination of movement disorder, cognitive decline, and behavioral abnor-
malities. There is no treatment capable of stopping its progression. The most common
conditions that mimic HD are neuroacanthocytosis, SCA17, Huntington disease-like
syndrome 2, familial prion disease, and Friedreich ataxia. Sydenham chorea (SC) is
the most common cause of chorea in children worldwide. Patients with SC present
with a variable combination of chorea, obsessive-compulsive behavior, other
behavioral abnormalities, and carditis. Management of SC involves prophylaxis of
Streptococcus infections with penicillin and antichoreic agents. Stroke is the most
common sporadic cause of chorea in adults. Vascular chorea, usually a complication
of diabetes mellitus, is often a self-limited condition.
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