Download Acute and Chronic Chorea in Childhood

Acute and Chronic Chorea in Childhood
Donald L. Gilbert, MD, MS
This review discusses diagnostic evaluation and management of chorea in childhood.
Chorea is an involuntary, hyperkinetic movement disorder characterized by continuous,
jerky, or flowing movement fragments, with irregular timing and direction. It tends to be
enhanced by voluntary actions and generally causes interference with fine motor function.
The diagnostic evaluation begins with accurate classification of the movement disorder
followed by consideration of the time course. Most previously healthy children presenting
with acute/subacute chorea have an autoimmune etiology. Chronic chorea usually occurs
as part of encephalopathies or diseases causing more global neurologic symptoms. We
review the management of acute/subacute and chronic choreas, with special emphasis on
Sydenham chorea and benign hereditary chorea.
Semin Pediatr Neurol 16:71–76 © 2009 Published by Elsevier Inc.
C
horea is a nonpatterned, involuntary, hyperkinetic
movement disorder. It is continuous, variable in speed,
unpredictable in timing and direction, and flowing or jerky in
appearance.1 Chorea may be accompanied by athetosis or
ballism. Athetosis is also continuous but the rate is slower.
Athetosis often accompanies dystonia or occurs in symptomatic chorea and may be referred to as choreoathetosis. Ballism
designates larger amplitude, flinging, proximally generated
movements. It rarely occurs in isolation in children but can
accompany chorea.
Anatomically, chorea classically most often results from
disturbances in the caudate or putamen.2 Occasionally, the
source may be thalamic/subthalamic.3 A number of neurodegenerative ataxias can also present with prominent chorea.
Because of the vulnerability of the basal ganglia and its
connections to a wide variety of pathologies, the differential
diagnosis of acute and chronic chorea is very large. Genetic
and metabolic diseases, endocrine disturbances, autoimmune disorders, infections, cerebrovascular disease, neoplasms, neurodegenerative diseases, toxins, and trauma can
all result in chorea. A detailed review of the entire spectrum
of these diseases would exceed space limitations for this article. This review will discuss acute and chronic chorea, emphasizing clinical diagnosis and management. Sydenham
chorea, the most common acute/subacute acquired chorea in
childhood, and benign hereditary chorea, a rare but primary
From the Movement Disorders Clinics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH.
Address reprint requests to Donald L. Gilbert, MD, MS, Division of Neurology, Cincinnati Children’s Hospital Medical Center ML 11006 and Neurology, 3333 Burnet Avenue, Cincinnati OH. E-mail: donald.gilbert@
cchmc.org
1071-9091/09/$-see front matter © 2009 Published by Elsevier Inc.
doi:10.1016/j.spen.2009.03.009
genetic chorea, will be emphasized. Paroxysmal movement
disorders involving chorea will not be discussed but are reviewed elsewhere.4 As the phenomenology of chorea overlaps in acute and chronic choreas, most features of the neurologic examination will be discussed under acute chorea.
Acute Chorea
Clinical Characteristics
of Acute/Subacute Chorea
History of Present Illness
In childhood, chorea is most often acquired acutely or subacutely. It interferes with purposeful movements and often
with speech. Parents can describe the hour, day, or week of
onset and the way in which the child’s speech and purposeful
movements have changed. In subtle cases, parents will report
that coordination or speech has been affected in ways that
may not be apparent to the examiner. When the observable,
choreic movements are being discussed in clinic, children
with mature communication and awareness should be able to
describe the subjective nature of the movements, that is, the
movements are involuntary, nonsuppressible, and not performed in response to an urge or sensation. They may describe that the movements make them clumsy and that their
speech is slurred or slow. The movements generally cause
functional interference. This can be gauged by asking about
difficulties with activities of daily living.
A careful history of possible antecedents to acute chorea is
critical. As the most common etiology is autoimmune and
poststreptococcal, a careful history of known or possible upper respiratory infections or other illnesses should be sought.
Exposures to and doses of psychiatric and other medications,
71
D.L. Gilbert
72
Table 1 Neurologic Examination in the Child With Chorea
Neurologic Examination
Mental status
Cranial nerve
Motor examination
Sensory examination
Cerebellar and gait
Key Findings
Emotional changes may be present as part of or in response to the disease. Note that the
presence of involuntary facial movements that do not match the child’s mood or meaning
may confound assessment.
May be normal. Slurring of speech due to motor control problems of face and tongue, and
not due to brainstem or cranial nerve pathology.
Bulk and reflexes may be normal; tone may be normal or low. Strength may appear weak due
to motor impersistence, ie, involuntary relaxations or choreic intrusions on sustained motor
output. Classic examples include “milk maid’s grip” during sustained grip and “darting
tongue” during sustained tongue protrusion.
Actions enhance chorea. With arms outstretched horizontally, hands pronated, and fingers
spread wide, there may be hyperextension at the metacarpophalangeal joints (a dystonic
posture referred to as “spooning”) and irregular distal movements. The “touchdown sign”
is an inability to maintain hands and arms fully extended and supinated over head due to
chorea. Additional tasks, such as talking or protruding tongue, may magnify hand/arm
findings.
Typically normal. Significant sensory hypersensitivity suggests akathisia rather than chorea.
Important and sometimes challenging to discern. Cerebellar dysfunction on finger to nose
and gait/tandem gait testing should be fairly regular. In contrast, basal ganglia dysfunction
results in interference due to irregularly timed choreic intrusions on the trajectory of limb
movements, causing the finger to miss the target or the gait to lurch. In some diseases,
cerebellar and basal ganglia dysfunction co-occur.
exposure to toxins, detailed medical and developmental history, recent psychological stressors, and review of systems
should be routinely obtained.
General and Neurologic Examination
During the process of taking the history, the clinician will
generally observe that the child’s trunk appears restless and is
moving continuously in a random manner that is distinct
from titubation seen in ataxias. The child with acute chorea
may have generalized or localized dyskinetic movements.
Usually, there is prominent involvement of the face and 1 or
both arms and hands. Irregularly flowing or jerking, continuous movements give an appearance of restlessness. Facial
and tongue chorea may slur or slow speech. Marked asymmetry of upper limb chorea may occur.
The general examination is important for other signs of
illnesses, particularly those indicating autoimmune diseases
and infections. Skin, heart, joints, and lymph nodes should
be emphasized. Identifying an integral non-neurologic feature of a disease narrows the differential diagnosis of the
movement disorder. For example, the presence of joint inflammation or a systolic cardiac murmur supports an autoimmune etiology.
The neurologic examination should be thorough, emphasizing portions of the examination related to basal ganglia
and cerebellar function. The clinician should carefully observe
the child’s motor system at rest as well as while performing
sustained movements and common actions. Videotaping the
examination is helpful to allow reviewing phenomenology and
assessing severity over time. Key findings of the neurologic examination are described in Table 1.
Finally, it is important to note that fairly continuous, frequent myoclonus, particularly with dystonia, may lead to a
movement disorder that appears identical to chorea.
Diagnostic Approach
The critical component is identifying and classifying the
movement disorder. Once established that the problem is
acute chorea, the history should point to a relatively limited
number of categories of disease, and from there the testing
can be targeted. Selected etiologies are listed in Table 2.
Table 2 Etiology of Acute Chorea in Childhood: Categories
and Selected Examples
Etiologic
Category
Autoimmune
Other infections
and
encephalitides
Vascular/hypoxic
ischemic
Mitochondrial
disease
Toxins
Iatrogenic
Psychogenic
Examples
Poststreptococcal, Sydenham chorea5
Systemic lupus erythematosis6
Antiphospholipid antibody syndrome7
Herpes simplex virus,8 Mycoplasma9
Stroke; post cardiac transplantation—
“post pump chorea” in infants10
Static damage in dyskinetic cerebral
palsy, markedly exacerbated
dyskinesia with febrile illness11
Mitochondrial encephalopathy with
lactic acidosis and stroke (MELAS):
acute basal ganglia injury12
Carbon monoxide13
Dopamine receptor blocking agents/
neuroleptics/antipsychotics: acute,
tardive, withdrawal-emergent14
Psychostimulants
Anticonvulsants
Conversion disorder15
Acute and chronic chorea in childhood
73
Diagnostic Testing
Laboratory Testing. A subacute course is most common
and supports an inflammatory disease, most commonly poststreptococcal. Documenting a positive culture for group A
␤-hemolytic streptococcal (GABHS) infection in the throat,
during the previous 6 months, helps confirm a diagnosis of
Sydenham chorea (SC).16 Otherwise, blood testing for elevations in streptococcal antibodies, anti-streptolysin O (ASO)
and anti-DNAse B (ADB), should be obtained, tested in an
experienced laboratory, and compared against childhood
normative levels for that laboratory. It should be noted that
GABHS infections are highly prevalent and therefore elevated
antibody titers are nonspecific. If ASO and ADB are not elevated, it is important to test for systemic lupus erythematosus
and anti-phospholipid antibody syndrome. Referral to a
department of rheumatology may be considered. Chorea
caused by other infections, such as herpes simplex, Lyme
disease, human immunodeficiency virus, mycoplasma pneumonia, or Legionnaire disease may be considered in the appropriate clinical setting, but this is extremely rare.
Neuroimaging. Obtaining a brain MRI scan to rule out brain
structural causes should be considered as part of the evaluation of any child presenting with acute/subacute chorea.
However, in most cases where the clinical diagnosis is SC,
neuroimaging does not guide management.5 MRI findings
would also point toward diagnoses of mitochondrial/metabolic diseases, degenerative, neoplastic, and other inflammatory diseases targeting the basal ganglia.
Neurophysiology. Electroencephalography, central motor
neurophysiological assessment with transcranial magnetic
stimulation, and electromyography are of interest in the
field of research. These studies do not routinely guide
management.
Sydenham Chorea
Clinical Features
SC is an autoimmune disease. Chorea in isolation or accompanied by other organ involvement is considered a manifestation of rheumatic disease, a group of sequelae of GABHS
infections, based on Jones criteria.17 GABHS are Gram-positive bacteria that colonize or invade the upper respiratory
tract. In selected cases, possibly due to molecular mimicry,
an autoimmune response is triggered. The relationship of
GABHS to SC is supported by epidemiologic observations,
including the reduction in cases in the post-antibiotic era and
common co-occurrence of chorea and other manifestations
of rheumatic disease, particularly carditis and arthritis.5
Chorea in SC develops over hours to days. Symptom severity varies widely but generally there is difficulty with fine
motor tasks. Parents often report personality changes, including inattention, anxiety, obsessive compulsiveness, paranoia, and reluctance to speak.18-22 Interestingly, children
with rheumatic fever not only commonly develop obsessive
compulsive symptoms, they also have a higher than expected
prevalence of these symptoms in first-degree relatives.23 Because SC is a form of rheumatic disease, it is critical to assess
the child carefully for the presence of a systolic heart murmur
or of arthritis or arthralgia.5
The term SC should not be used interchangeably with the
term pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). Key distinguishing features are listed in Table 3.
Further discussion of PANDAS lies outside the scope of
this review, but a number of recent studies are of interest.24-26
Management
Management involves education about the diagnosis and decisions about medical treatment. There is typically no role for
occupational or physical therapy.
Secondary Prevention of Group A ␤-Hemolytic Streptococcal Infections. The standard of care for all children diagnosed with SC, even in cases of isolated chorea with no carditis or arthritis, is secondary prevention with penicillin or
comparable agents17 to reduce the risk of future GABHS infections causing permanent cardiac valvular damage.27
Chorea Symptom Suppression. This treatment is elective.
Chorea symptom suppressing medication is effective and
may be used when chorea interferes with important daily
Table 3 Differences Between Sydenham Chorea (SC) and Pediatric Autoimmune Neuropsychiatric Disorder Associated With
Streptococcal Infections (PANDAS)
Feature
Prevalence
Cardiac involvement
SC
PANDAS
Rare
Controversial
Carditis/valvular disease occurs prior, during, No current evidence that this occurs; published
or after chorea if GABHS infections recur
case series negative for cardiac disease
Time course and
Self-limited, generally resolves in < 1 year
Explosive onset/exacerbations on 2 or more
prognosis
occasions, chronic symptoms may persist to a
milder degree between episodes, long-term tics
and/or OCD common
Effect of antibiotics on
No suppression of symptoms reported
Clinicians/families often report antibiotics directly
current neurologic or
suppress the tics or OCD but no currently
psychiatric symptoms
published clinical trials support this
Role of immune therapies No accepted standard
Controversial
Role of antibiotics for
Standard of care, until age 21
Controversial
secondary prevention
D.L. Gilbert
74
activities. Beneficial chorea suppression in SC has been described in small case series with benzodiazepines and several
anticonvulsants, most commonly valproic acid.28,29 Some
consider dopamine receptor blocking agents to be the treatment of choice, as these are usually highly effective at low
doses.1,22,30 The expected course of treatment is brief, that is,
weeks to months. Therefore, long-term tardive risks are insignificant. Anticholinergic agents should not be used.
Immune Modulation. This treatment is not established. On
the basis of pathophysiology of SC, it is reasonable to consider immune-modulating therapies, for example, steroids or
intravenous immuneglobulin (IVIG), to shorten the course of
illness in severe cases. The most compelling evidence for
benefit from steroids comes from a recent randomized,
blinded placebo-controlled study.31 Relative to placebo, a
2-mg/kg daily oral dose of prednisone over 4 weeks, followed
by a taper, reduced the duration of chorea and accelerated the
reduction in symptoms. Weight gain was substantial, so a
shorter treatment course may be more reasonable. Supportive evidence also comes from a clinical trial comparing prednisone to IVIG and plasmapheresis.32 There was no placebo
group in that study. Other reports from uncontrolled, retrospectively ascertained data are difficult to interpret.
Chronic Chorea
Clinical Characteristics of Chronic Chorea
History of Present Illness
Most children with chronic chorea have a mixed movement
disorder secondary to a static or progressive encephalopathy.
In these cases, chorea is just 1, not necessarily predominant,
symptom. Chronic chorea may emerge gradually in infancy
but more commonly becomes apparent after age 1 year.
Children with chronic, early-onset choreas may have subnormal motor skills and function. In most conditions, it is
more widespread central nervous system abnormalities, and
not chorea per se, that are interfering with normal neurologic
function. As in Sydenham chorea, children with mature communication and awareness should be able to describe the
subjective nature of the movements, that is, the movements
are involuntary, nonsuppressible, and not performed in response to an urge or sensation. However, awareness of the
movements on an ongoing basis may be low.
A careful developmental history is critical. Progressive loss
of skills requires a detailed evaluation to attempt to identify a
genetic/molecular diagnosis. Although at present this will
most likely not have a specific treatment, precise molecular
diagnoses give families a feeling of knowledge and more control, and these may allow participation in advocacy and support groups. Problems with learning and mood should be
systematically assessed as well, as these commonly co-occur.
The presence of seizures with chorea generally indicates a
diffuse, serious central nervous system disease.
General and Neurologic Examination
Many diseases cause a relatively small number of types of
movement disorders. The general examination can reveal
findings, for example growth parameters or dysmorphic features that narrow the differential diagnosis.
The neurologic examination should be thorough, emphasizing portions of the examination related to basal ganglia
and cerebellar function. Assessment of head growth, cognitive function, speech, and cortical spinal tract function are
also important, as chronic neurologic conditions with chorea
often involve multiple neurologic systems.
Key findings of the neurologic examination related to
chronic choreas are discussed in Table 1.
Diagnostic Approach
A constellation of neurologic and non-neurologic symptoms
and signs can be used effectively to narrow the differential
diagnosis. Selected diseases are discussed in Table 4.
Diagnostic Testing
Neuroimaging with brain MRI is usually a diagnostic test of
choice. Decisions about genetic and metabolic testing, particularly for progressive, inherited diseases, can be informed
with on-line resource, such as on-line Mendelian inheritance
in Man (http://www.ncbi.nlm.nih.gov/omim) and Genetests
(http://www.genetests.org).
Benign Hereditary Chorea
Clinical Features
Benign hereditary chorea (BHC) is a rare, autosomal dominant, static disorder characterized by onset of chorea before
age 5.38 “Atypical” clinical features are common and there is
substantial overlap in phenomenology with myoclonus dystonia.39 The severity of the chorea varies substantially within
and between families.40,41 Otherwise, chorea is isolated. Features supporting this diagnosis include normal general examination with no dysmorphic features, broadly normal intellectual development with no regression or loss of cognitive
Table 4 Etiology of Chronic Chorea in Childhood: Categories
and Selected Examples
Etiologic
Category
Primary
Secondary
Vascular/hypoxic
ischemic
Choreas in
neurodegenerative
diseases and
severe
encephalopathies
Diseases with
chorea as a minor
or late feature
Chorea in ataxias
Examples
Benign hereditary chorea (including
syndrome of choreoathetosis,
hypothyroidism, neonatal
respiratory distress)
Stroke/third trimester or pregnancy
or perinatal hypoxic ischemic
injuries leading to choreoathetoid
cerebral palsy
Lesch–Nyhan syndrome33
Nonketotic hyperglycinemia34
Phenylketonuria35
Ceroid-lipofuscinosis36
Ataxia telangiectasia37
Acute and chronic chorea in childhood
skills, absence of other significant neurologic disturbances,
such as epilepsy, and, with the exception of chorea, normal
neurologic examination findings. As is often true in movement disorders, it is important to examine other family members in addition to taking a multigeneration history. The
presence of mild symptoms in a parent would support the
presence of autosomal dominant inheritance in BHC. Some
symptom improvement may occur in adulthood.
In the absence of a family history, other diagnoses to consider in a child presenting under age 5 with chorea include
ataxia telangiectasia (AT),37 which is autosomal recessive.
The characteristic telangiectasias lag behind the neurologic
symptoms.42 Initial diagnostic testing for a young child with
chorea, dystonia, or ataxia emerging between 12 and 36
months of age should include serum alpha-fetoprotein,
which is elevated in AT.
Diagnosis. MRI is usually normal.43 BHC is caused in some,
but not all pedigrees, by mutations in the NKX2.1 gene encoding TITF1.44,45 Commercial diagnostic testing is available.
Management. There is no symptomatic treatment shown to
be beneficial in genetically confirmed BHC. Interestingly,
there is a report of improvement with levodopa treatment.46
Conclusions
The presence of acute or chronic chorea suggests disordered
neural transmission or structural pathology in the basal ganglia or occasionally in other structures. The most common
causes of acute chorea in children are autoimmune, especially poststreptococcal, SC. In chronic encephalopathies,
chorea usually occurs in conjunction with other neurologic
symptoms.
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