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Chorea, Athetosis, and Ballism
Introduction and Overview
This chapter discusses diseases and disorders where chorea, athetosis, and ballism are prominent. Chorea, athetosis, and ballism are nonpatterned, hyperkinetic movement disorders which overlap and cannot be defined precisely as mutually exclusive phenomena. However, they are characterized by some salient features. Some authors place these hyperkinetic disorders on a continuum based on amplitude, velocity, and distribution: ballism → chorea → athetosis.
In practice, many children with hyperkinetic movement disorders have a combination of chorea, athetosis, or ballism. To complicate matters, other phenomenologies such as dystonia, myoclonus, ataxia, or tics may also be present. Moreover, the relative predominance of one type of phenomenology may be state-dependent. For example, athetosis or chorea may evolve into ballism when children are stimulated, excited, or experiencing febrile illness.
Anatomically, c horea classically results from disturbances in the striatum. It can also originate from structural or physiological perturbations in the cerebellum, whose outputs modulate activity in cortical-striatal-pallidal-thalamic circuits, or in other locations projecting to striatum. Ballism often localizes to subthalamic nucleus but may be associated with subcortical lesions outside the subthalamic nucleus. Athetosis often accompanies basal ganglia diseases that also produce chorea or dystonia. Thus, despite phenomenological distinctions, clinicians may use the presence of any of these dyskinetic movements as key factors in directing diagnostic and therapeutic decision making toward the basal ganglia initially, while recognizing that other nodes in motor circuits may play a role.
Definitions of Chorea, Athetosis, and Ballism
Chorea refers to a disorder with an ongoing, random-appearing sequence of one or more discrete involuntary movements or movement fragments, with variability in timing, duration, rate, direction, or anatomic location. Some movements may be rapid, similar to ballism or myoclonus, or flowing, slower or jerkier. All body parts may be involved, with certain distributions being more characteristic of distinct diseases or disorders. Choreic movements usually worsen during attempted voluntary action. Individuals with chorea may exhibit so-called parakinesias, semivolitional movements that attempt to mask the involuntary choreic movements or incorporate them into seemingly purposeful movements, such as touching the face.
Ballism refers to involuntary, high amplitude, flinging movements typically generated by proximal muscles. These movements may be brief or continual and may occur in conjunction with chorea. Often, one side of the body is affected, that is, hemiballism, and/or hemichorea-hemiballism . In many cases, ballism emerges abruptly in the context of a vascular event or hyperglycemia. Acute onset hemiballism may resolve or become milder, evolving into chorea, athetosis, or dystonia. Severe continuous ballism can cause rhabdomyolysis.
Athetosis is defined as slow, writhing, continuous, involuntary movements. This may be historically referred to as choreoathetosis, a term that clinicians also use to describe phenomenology intermediate between chorea and athetosis. In contrast to dystonia, in which there is a sustained, twisting, patterned movement, athetosis is typically a continual, nonsustained form of movement. Athetosis sometimes occurs as part of a mixed spastic, hyperkinetic movement disorder in children with static encephalopathy (cerebral palsy). Some experts view athetosis as on a spectrum with dystonia and chorea.
Clinical Characteristics—Phenomenology of Chorea, Athetosis, and Ballism in Children
Chorea
History: In childhood, the onset of chorea is usually acute or subacute, and thus parents can describe the onset and the way in which the child's speech and purposeful movements have changed from baseline. Acquired chorea usually interferes with purposeful movement, causing functional impairment. In subtle cases, particularly in young children with underdeveloped motor coordination or speech articulation, a caregiver's report that coordination or speech has changed must be relied on.
In contrast, however, when chorea occurs as a late, stable, or minor feature of chronic neurologic disease, parents may not accurately report chorea onset. Chronic chorea may be one symptom in a syndrome with a global encephalopathy with intellectual disability, other movement disorders, and/or seizures. Diagnostically, the presence of chorea may have some localizing and etiologic value.
Examination: The child with chorea may have generalized or localized adventitious movements, but usually the face and upper limbs are involved. There is an appearance of restlessness and randomness as fragments of movement flow continually around the body. Some of these inserted fragments of movement may have a dystonic phenomenology. Speech may be slurred or slow because of involvement of tongue and facial muscles. Involvement of upper limbs is usually bilateral but also may be asymmetric. Choreic movements can occur in both proximal and distal muscles.
Action and certain postures usually exacerbate or enhance chorea, and therefore, chorea usually interferes with execution of purposeful movements. In children who are dependent on caregivers or who have severe intellectual impairments, chorea may interfere with caregiver tasks such as dressing or bathing the child.
Differentiating chorea from ataxia, jerky dystonia, or myoclonus can be challenging. The motor function problems in chorea should be generally distinguishable from ataxia. Choreic movements during, for example, finger to nose testing should intrude upon the planned movement trajectory in unpredictable ways. This usually appears different from findings in ataxia such as dysmetria of the limbs, intention tremor, or balance difficulties while sitting or walking accompanied by brief postural corrections. Thus, when chorea involves the legs, for example, the child may lurch intermittently due to choreic leg movements when walking, but there is not the consistent broad-based or unsteady gait seen in ataxia. In addition, ataxia does not manifest in body parts that are at rest (supported against gravity). Chorea may diminish in body parts at rest, but typically does not abate. A mixed movement disorder with chorea as one component may be challenging to characterize.
Children with chorea, particularly Sydenham's chorea (SC) (see later discussion), often have motor impersistence, described by Gowers in 1888 as “unintended relaxation.” Motor impersistence is the inability to maintain a posture or motor command. The appearance is one of intermittent interruption of the intended, sustained signal from motor cortex to muscle. For example, two classic signs in SC are “darting tongue” caused by inability to keep the tongue protruded and “milkmaid's grip” caused by inability to maintain a steady grip force. In both cases, in response to the examiner's command, the cooperative patient reactivates the muscles repeatedly, leading to back-and-forth activation/relaxation patterns. Choreic intrusions, unintended relaxations, or both may contribute to the difficulty of maintaining a steady grip. The abnormal movements, while irregular in appearance, tend to occur reproducibly during attempts to maintain certain postures. They cannot be entrained, which helps distinguish them from functional (previously referred to as psychogenic) chorea. ,
Additional findings may include hypotonia and “hung up” reflexes occurring when a choreic movement is superimposed on the reflex jerk.
Ballism
Ballismus or ballism refers to involuntary, large amplitude, flinging movements typically generated by proximal muscles. These movements may be brief or continual and may occur in conjunction with chorea. In childhood, ballism usually does not occur in isolation. It can occur in children with static encephalopathies, congenital brain malformations such as pontocerebellar hypoplasias, or choreoathetoid cerebral palsy. Such children have action-induced choreoathetoid movements at baseline but may develop severe, forceful, flinging, high amplitude movements during febrile illnesses. In severe cases, these movements can lead to rhabdomyolysis, renal failure, and death. Hemiballismus is occasionally described as the result of an acute process such as a vascular insult or hyperglycemia, although this is much more common in adults. Flinging, ballistic movements sometimes occur in SC.
Athetosis
The child with slow, writhing, athetoid movements may have a more stereotyped phenomenology. If the athetosis is symptomatic of a chronic global encephalopathy with very low intellectual function, the movement alone usually causes little functional difficulty, relative to the encephalopathy. If the athetosis is acquired acutely or subacutely, the functional interference related solely to athetosis may be more prominent. Athetosis is common in dyskinetic cerebral palsy.
Localization and Pathophysiology
Neuroanatomy of Chorea, Athetosis, Ballism
Based on many examples of localized genetic, metabolic, vascular, and hereditary neurodegenerative lesions, it is reasonable to conclude that the primary substrate for chorea is disturbance in structure or function of nodes or pathways involving cortical striatal pallidal thalamic circuits. These neuroanatomic pathways from cortex, through striatum to globus pallidus and thalamus are described in more detail in Chapter 1 . Imaging studies using a variety of modalities across multiple diseases support this anatomic link. A case–control study of persons with SC showed subtle increases in size of caudate, putamen, and globus pallidus, suggesting an inflammatory process in the basal ganglia. Other forms of autoimmune chorea also show preferential involvement of striatum. In adults, degeneration of the caudate and putamen in Huntington disease (HD) is associated with chorea, probably due to preferential vulnerability of indirect pathway neurons. , This is also true for juvenile-onset HD, which becomes apparent in later teenage years; however, less selective degeneration is present in childhood-onset HD, the Westphal variant, usually manifests with parkinsonism, dementia, myoclonus, and seizures rather than chorea.
Extrastriatal lesions can also influence chorea. For example, one postmortem study showed loss of cerebellar cortex Purkinje cells, not striatal neuropathology, correlated with motor symptoms in HD. Chorea has also been observed in ataxia telangiectasia (AT), spinocerebellar ataxia type 3, and ataxia with oculomotor apraxia. In children, lesions in the parietal cortex or thalamus, and static and degenerative diseases in cerebellum may also be associated with chorea.
Figs. 10.1–10.5 demonstrate several anatomic localizations and etiologies of chorea in children.
Neurophysiology of Chorea, Athetosis, Ballism
Peripheral and central nervous system physiological studies can provide biological insights but are not clinically used in diagnosis or treatment decisions for chorea, athetosis, or ballism. Electromyography of muscle shows that muscle activity differs in chorea versus normal voluntary movement. The normal initial agonist burst in a voluntary movement usually lasts less than 100 msec. However, in SC and in ballism, the initial burst duration may be longer. , In SC, routine EEGs show at most nonspecific abnormalities which are not helpful for diagnosis or treatment. If the chorea occurs as part of an epileptic encephalopathy or with suspected encephalitis, , then EEG may have diagnostic value.
Diseases and Disorders
Etiologic Categories of Diseases Producing Chorea, Athetosis, Ballism
This section reviews some of the more common or important conditions causing chorea in children. Choreiform, athetoid, or ballistic movements can emerge as a consequence of autoimmune diseases, genetic and metabolic diseases, cerebrovascular disease, infections, trauma, toxins, and neoplasms. The cells and structures in the basal ganglia are vulnerable to a wide variety of pathologies. In many of these diseases, the hyperkinetic movement disorder is not the sole or predominant neurologic problem. Table 10.1 shows key etiologic categories and important diagnoses. Prioritization of this list in clinical practice typically involves consideration of the rapidity of onset and the child's age. Acquired/secondary chorea is discussed first, as this is more common. More detailed information is provided about the more common genetic conditions involving chorea in the remainder of the section.
Table 10.1
Etiological Categories of Choreas and Prominent Examples With Childhood Onset
| Categories and subcategories | Disorders and diseases |
|---|---|
| Physiologic Choreas | Infantile benign chorea |
| Choreiform movements in neurobehavioral disorders | |
| Primary/Heritable Choreas a | Diseases with chorea as a prominent feature |
| Diseases with chorea as a generally minor feature in childhood Early onset ataxias Structural brain malformations Huntington and Huntington-disease-like chorea Neuro-acanthocytosis syndromes Epilepsy/dyskinesia spectrum disorders Neurodegenerative diseases Paroxysmal chorea/dyskinesia b |
|
| Secondary/Acquired Choreas | |
| Autoimmune | Acute disseminated encephalomyelitis (ADEM) |
| Anti-NMDA receptor encephalitis/other antibody-mediated encephalitides | |
| Antiphospholipid antibody syndrome (APS)—associated | |
| Sydenham chorea (SC) | |
| Endocrine | Hyperglycemia-induced, diabetic nonketotic acidosis |
| Thyroid disease/hyperthyroidism | |
| Iatrogenic/drug-induced b | Anticholinergic medications |
| Anticonvulsants | |
| Dopamine agonists | |
| Dopamine 2-receptor blocking agents (D2RBs)—withdrawal or tardive syndrome | |
| Selective serotonin reuptake inhibitors | |
| Stimulants | |
| Neuropsychiatric polypharmacy | |
| Oral contraceptives | |
| Infections | Human immunodeficiency virus |
| Mycoplasma | |
| Viral encephalitis (herpes, measles, mumps, parvovirus B19, varicella) | |
| Toxin-induced | Carbon monoxide |
| Manganese | |
| Methyl alcohol | |
| Toluene | |
| Vascular/Hypoxic-ischemic | Dyskinetic cerebral palsy—pre/perinatal hypoxic ischemic encephalopathy |
| Hemorrhage—trauma; vascular | |
| Moyamoya disease | |
| Postpump chorea (postcardiac surgery) | |
| Stroke | |
| Functional Neurological Disorder With Abnormal Movement b | |
a Inherited choreas are discussed below.
b Paroxysmal movement disorders manifesting with chorea are discussed in Chapter 9 . Drug-induced movement disorders are discussed in Chapter 22 . Functional movement disorders are discussed in Chapter 23 .
Physiologic Chorea
Chorea in Infancy
The decomposed or immature movements of infants may sometimes be described as choreiform. These do not generally indicate neurologic disease. In the context of a normally developing child with normal head circumference, these movements can be monitored through regular follow up clinic visits. Brain MRI imaging, metabolic and genetic testing may be deferred.
Chorea Minor/Chorea in Neurobehavioral Disorders
Mild chorea, referred to as “chorea minima or chorea minor” (as opposed to chorea major) typically manifests in hands and fingers when arms are held in an outstretched position in front of the body, may be seen in typically developing children. Children diagnosed with neurobehavioral disorders such as attention-deficit/hyperactivity disorder (ADHD) are more likely to manifest some subtle difficulties with motor control, including motor overflow and mild choreiform movements. These movements can also occur in typically developing children.
Secondary (Acquired) Choreas
Immunologic/Autoimmune Diseases
The majority of childhood-onset diseases where chorea is the predominant movement disorder are acquired, with acute or subacute onset, and have an inflammatory, autoimmune etiology (see Chapter 18 ). SC is the most common acquired chorea in children ages 5–15 years. Chorea associated with systemic lupus erythematosus (SLE), antiphospholipid antibody syndrome (APS), and mitochondrial diseases may manifest similarly. The majority of acquired chorea in childhood is self-limited. Diagnostic workup may need to be expanded in cases that recur or become chronic.
Sydenham's Chorea
Description
SC is considered a manifestation of rheumatic disease, a group of sequelae of group A β-hemolytic streptococci (GABHS) infections. GABHS are Gram-positive bacteria that colonize or invade the upper respiratory tract. Surface M proteins are important for virulence and have different subtypes with varying levels of immunogenicity (See also Chapter 18 on autoimmune diseases). Cytolytic toxins, including streptolysin O, induce antibody responses. Elevated measurements of both antistreptolysin O (ASO) and anti-DNAse B (ADB) titers in blood are markers of prior infections, but do not provide specificity for the timing of prior infection.
Epidemiology
The relationship of GABHS to SC is supported by epidemiologic observations, including the reduction in cases in the postantibiotic era and common cooccurrence of chorea and other manifestations of rheumatic disease, particularly carditis, and arthritis. The chorea appears the same, whether or not carditis and arthritis occur. In the proper setting, chorea-only following GABHS is also classified as rheumatic disease. That is, children that manifest with subacute chorea, with or without carditis or arthritis/arthralgia, weeks or months after GABHS infections, can meet the Jones Criteria for Rheumatic Disease. GABHS is the etiologic agent of “strep throat,” a highly prevalent bacterial infection that occurs one or more times in many children. Most infections are uncomplicated, responding readily to penicillin or other appropriate antibiotics with few sequelae, and many infections are self-limited, resolving without antibiotics. Infections may also be asymptomatic, so that affected individuals do not seek medical attention.
SC is rare in the United States , , but remains common elsewhere. The presence of markers of GABHS infection is nonspecific due to the high prevalence of GABHS infections. Further, single antibody titer measures can be misleading, as these may remain elevated for months to years after infections. Therefore in atypical or recurrent cases or those with chorea but no cardiac or joint symptoms, the possibility of Systemic Lupus Erythematosus (SLE) and APS should be considered, as discussed later in this chapter. Consultation with a rheumatologist may be considered in cases involving joints or multiple body systems, or when antibody testing results do not confirm SC.
Clinical Features
Chorea in SC develops over hours to days. Parents and children can often identify the day or week and sometimes may remember the hour of onset. Symptom severity varies widely. Difficulty with activities of daily living and fine motor tasks, particularly writing, is common. Patients may describe that they are clumsy or weak, often dropping items in their hands. Abnormal movements diminish or cease during sleep.
In addition to abnormal involuntary movements, cognitive and emotional symptoms, including inattention, emotional lability, anxiety, obsessive compulsiveness, paranoia, and reluctance to speak, may cooccur and often precede chorea. , , Interestingly, children with rheumatic fever (RF) not only commonly develop obsessive-compulsive symptoms, they also have a higher than expected prevalence of these symptoms prior to diagnosis , and in first-degree relatives.
On examination, affected children appear restless or fidgety while sitting. There may be a paucity of speech and facial movements, combined with inappropriate adventitious facial expressions or facial tics. Speech articulation may be slurred. Coordination is often poor with erratic performance of finger-to-nose testing and intermittent lurching while walking. Falls are not common. Delirium is rare.
There are four classic neurologic signs. These are nonspecific and may be present in chorea due to other causes, but they nearly always occur together and support the diagnosis of SC:
- 1.
Spooning sign. The examiner asks the child to extend both arms straight forward, horizontally from the shoulders, with hands pronated (palms down) and fingers spread wide. Children with SC tend to hyperextend at the metacarpophalangeal joint. This “spooning” is dystonic posturing. This maneuver also tends to induce more chorea in proximal and distal arm muscles. Often, the movements are asymmetric. These movements may worsen further if an additional task is added, such as protruding the tongue.
- 2.
Touchdown ( or “ three-point shot ”, “ goal-post ”) sign. The examiner asks the child to extend both arms up vertically from the shoulders with palms facing each other. This induces choreiform movements and results in hand pronation and elbow flexion, again often asymmetric.
- 3.
Milkmaid's grip. The examiner offers her or his index and middle fingers together, both hands, for the child to squeeze. The child attempts to squeeze both hands and typically is unable to persist in squeezing due to choreic intrusions. This is motor impersistence. The cooperative child, each time the grip releases, tries to squeeze again. As this happens repeatedly, this resembles “milking” the examiner's fingers. Even in cases where hand and arm signs one and two are highly asymmetric, in SC there is usually some degree of grip impersistence in the less involved hand.
- 4.
Darting tongue. The examiner asks the child to stick out his or her tongue. The child attempts to cooperate but the tongue protrusion cannot be maintained, resulting in a “darting tongue.”
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. The presence of a systolic murmur in this setting, particularly if the parents believe a murmur was not previously reported to them by their primary physician, is virtually pathognomonic for rheumatic chorea. Carditis is typically mild.
Long-term prognosis of SC is generally good, with resolution of symptoms in greater than 90% of cases within 1 year. , , , In some cases, chorea may persist chronically. Chorea may also recur in up to 20% of children, despite secondary prevention with penicillin. Recurrence appears to be more common in women at the time of pregnancy. A long-term follow-up case series from Brazil reported a chorea gravidarum rate of 75%, with a higher than expected rate of miscarriages. Oral contraceptives also induced recurrent chorea in these women. In addition, a high proportion of adults who had SC in childhood appear to have a mild degree of bradykinesia and executive dysfunction in adulthood.
The high prevalence of psychiatric symptoms, as well as tics, in SC has led to a great deal of important clinical, epidemiological, and immunological research devoted to determining whether there is a parallel but distinct acquired condition in which GABHS induces tics and OCD symptoms but no (or minimal) chorea. This entity has been called pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). Based on the original operational definition of PANDAS, which emphasized tics and required observation of temporal association between GABHS and neuropsychiatric symptoms on two or more occasions, prospective studies were undertaken. These failed to support PANDAS as a discrete diagnostic entity. To date, attempts to identify and compare antibrain antibodies identified in SC, PANDAS, and Tourette Syndrome have had mixed results, possibly related to differences in antibodies tested and assays utilized.
Recently, the relationship between GABHS and non-SC neuropsychiatric symptoms was reconceptualized and renamed PANS, pediatric acute-onset neuropsychiatric syndrome. The new diagnostic criteria deemphasize tics. The cardinal symptoms are now psychiatric: OCD and eating disorders. A causal link with GABHS was eliminated in PANS; a specific etiology was not proposed but is asserted to have an inflammatory pathophysiology.
The relationship between GABHS infection and tics is addressed in greater detail in Chapter 7, Chapter 18 . The terms PANDAS and SC should not be used interchangeably.
Pathophysiology
Although the clinical phenomenology of SC has been recognized for centuries, a causal relationship with GABHS infection was not established until the 1950s. Antibodies to the caudate and subthalamic nucleus have been identified in children with SC. The identification of M proteins on streptococci that can evoke antibodies that cross-react with human brain suggested that molecular mimicry may play a role. Preliminary studies of antibodies administered via passive transfer to rodents appear to support an effect of SC antibodies on dopaminergic activity. It is important to point out that some antibasal ganglia antibodies were found elevated in HD and Parkinson disease, as well as in lower proportions of healthy people, so these findings are not specific and may in some cases be epiphenomena or effects, rather than causes. In addition, studies generally find elevated titers of antibrain antibodies in healthy control groups. This suggests that GABHS infection may induce circulating antibodies which may in turn require a variety of additional processes to gain access to brain and disrupt neuronal signaling. Some of these processes may result from factors inducing susceptibility in selected hosts.
Much recent research has been devoted to identifying individual or groups of antibodies that are syndrome specific or which reflect specific pathophysiological processes. For example, elevated immunoglobulin G (IgG) antibodies to neuronal tubulin in blood and cerebrospinal fluid (CSF) have been reported in SC. In addition, it has been reported that the acute chorea sera induced calcium/calmodulin-dependent protein kinase II activity in human neuronal cells. Some research suggests the presence of elevated titers of antibodies that bind to neuronal cell surface antigens may reflect pathophysiological processes associated with SC but not tic disorders. In a study comparing healthy children, children diagnosed with SC, Tourette Syndrome, or PANDAS, and children with basal ganglia encephalitis (presenting with chorea, dystonia, or parkinsonism but without anti-N-methyl- d -aspartate receptor [NMDA] receptor antibodies), antibodies to D2 receptors were measured. Elevated D2 receptor antibody titers were reported in 70% (12/17) of children with basal ganglia encephalitis, 33% (10/30) of children with SC, 9% (4/44) children with TS, but none in children diagnosed with PANDAS (n = 22) or in healthy controls (n = 40).
Diagnostic Approach
The diagnosis of SC starts with recognition that the child's movement disorder is chorea. Identification on physical examination of signs of carditis, such as a systolic murmur, or arthritis, strongly supports the diagnosis, although RF can present with only chorea. Although the differential diagnosis of chorea is large, fortunately, only a few categories of disease need to be considered in a school-age, previously healthy child when chorea develops over a period of hours to days. Most such children will have SC. , , After careful history, family history, and examination, diagnostic evaluation can therefore often focus on GABHS and rheumatic disease.
The clinician should keep in mind other etiologies that may trigger subacute or acute chorea. Other inflammatory etiologies include APS and SLE. In some circumstances, drug-induced choreic movements may be considered (See also Chapter 18, Chapter 22 ). In toddlers, this may result from accidental ingestions. Common offenders are stimulants used to treat ADHD. In older children and teens, stimulant overdose, cocaine, or abrupt withdrawal of high-potency dopamine receptor blocking agents such as risperidone may present with hyperkinetic movements. Chorea caused by endocrine disorders such as hyperthyroidism, hyperparathyroidism, and hyperglycemia may also be considered in the appropriate clinical setting and ruled out with laboratory testing. Hyperthyroidism can cause chorea, but usually tachycardia, diarrhea, and skin changes should also be present. Vascular diseases are unlikely in childhood to produce solely chorea because of the low prevalence of small vessel intracranial disease, although Moyamoya disease can present with chorea. Vascular causes should be considered in cases of acute, thunderclap onset of unilateral chorea or ballism, or when careful neurologic examination suggests a constellation of symptoms in a distribution supporting vascular disease (see Fig. 10.4 ). Mitochondrial diseases may selectively affect basal ganglia and produce chorea (see Fig. 10.5 ). These may be accompanied by characteristic findings of signal change on MRI or basal ganglia lactate elevation on magnetic resonance spectroscopy. Functional neurological symptoms disorders may have a choreic phenomenology. ,
Laboratory Testing
Chorea with a subacute course, with gradual evolution of symptoms over minutes to hours or days, is typical of an inflammatory disease and thus this category of illness should be the focus of laboratory investigations. GABHS is the most common antecedent of subacute chorea in otherwise healthy children. Obtaining a history of infection during the prior 6 months with headache, fever, and sore throat is important. Documenting a prior positive throat culture for GABHS is generally confirmatory. The presence of a positive throat culture at chorea presentation is not needed for the diagnosis of SC and in fact often the throat culture will be negative. Even in the absence of this information, with the proper time course, physical, and neurological examination, SC is the most likely diagnosis.
This high pretest probability is important for interpreting the results of confirmatory SC testing with antistreptococcal antibodies. In the presence of a typical history and examination, if there is no documented antecedent GABHS infection, blood testing for both antistreptolysin O (ASO) and ADB should be obtained. Case series in the United States, 40 years apart, found the sensitivity when both ASO and ADB were tested was 87% and 90%. If only ASO is utilized, the true positive rate may be lower, closer to 60%. A further important consideration is specificity. Because GABHS infections are so common, and antibody titers may remain elevated for months and may be even higher in some geographic regions, streptococcal antibody testing can easily generate false positives. Thus, the diagnosis of SC remains clinical, based on phenomenology and history.
As SC is a manifestation of RF, other testing recommended as part of RF guidelines should also be obtained. Blood testing should include ESR or CRP. Levels supportive of RF depend on population risk.
Chorea caused by other inflammatory diseases or other infections, such as Lyme disease, human immunodeficiency virus, mycoplasma pneumonia, or Legionnaire's disease, parvovirus B19 may be considered, in the appropriate clinical setting.
Neuroimaging
Obtaining a brain MRI scan to rule out brain structural causes should be considered in all cases of acute- or subacute-onset chorea. However, this is not required to rule out other causes and to confirm a diagnosis of SC. Although a number of studies have reported subtle signal change or volume increase in basal ganglia nuclei, , , , in most cases where the clinical diagnosis is SC, neuroimaging does not guide further management. MRI findings may point toward diagnoses of mitochondrial/metabolic diseases, degenerative, neoplastic, vascular, and other inflammatory diseases targeting the basal ganglia. However, experienced clinicians, in the presence of a classic, unambiguous cases of SC, may elect to defer neuroimaging, because of the expense, the common need for sedation to allow for high-quality images in the presence of chorea, and the low clinical utility. Subsequently, if the patient's clinical course diverges from what is expected for SC, neuroimaging can be reconsidered and, after the acute period, some striatal changes may be present ( Fig. 10.3 ).
Metabolic imaging studies provide support for anatomic models of striatal dysfunction but are not necessary for clinical care. SPECT scans show striatal hyperperfusion, and positron emission tomography (PET) scans show hypermetabolism in basal ganglia during the acute phase of the illness. Volumetric MRI scans show increases in basal ganglia size which are statistically, though not clinically, apparent. Similarly, diffusion weighted imaging shows apparent diffusion coefficients which are lower in striatum and which increase after steroid treatment. Although informative regarding pathophysiology, these findings are nonspecific and do not guide clinical management.
Other Testing and Specialty Consultation
ECG and echocardiography/Doppler are recommended in recent guidelines for confirmed or suspected RF, irrespective of evidence from the clinical examination. Careful surveillance with a thorough cardiac examination should be emphasized at regular, early follow-up visits. In general, carditis in children with SC is mild and may resolve completely.
Treatment
There are three treatment issues to be considered: secondary prevention, chorea symptom suppression, and immune modulation.
Secondary Prevention of GABHS Infections The standard of care for all children diagnosed with SC, even in cases of isolated chorea without carditis, is secondary prevention with penicillin. , The purpose is 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. An appropriate alternative may be selected for children with penicillin allergies. Current recommendations are for treatment until age 21 years with either monthly intramuscular (IM) penicillin or daily oral penicillin. Some physicians favor monthly IM penicillin to ensure compliance. Infectious disease consultation may be considered if GABHS recurs despite prophylaxis, which is rare, or if there is concern that the individual or family members are asymptomatic GABHS carriers. Some otolaryngologists will operate to remove adenoids and tonsils in children with SC who have moderate or large tonsils, but this has not been systematically studied.
Chorea Symptom Suppression A more general discussion of pharmacologic treatment of chorea appears at the end of this chapter in the treatment section. Symptom-suppressing medication is not needed in mild cases. However, treatment is reasonable for children for whom important daily activities are impaired by chorea. As is the case for many movement disorders, there are many small, uncontrolled case series reporting benefit of many medications. These include benzodiazepines and several anticonvulsants, most commonly valproic acid, carbamazepine, and levetiracetam. , , Because chorea in SC is selflimited, it is difficult to interpret these positive reports. Many experts consider high potency dopamine receptor blocking agents, for example, haloperidol, and vesicular monoamine transporter type 2 (VMAT2) inhibitors, such as tetrabenazine and deutetrabenazine, to be the most effective chorea-suppressing agents. , , The side effect profile may favor levetiracetam over haloperidol. Although parents and some physicians may be understandably reluctant to use neuroleptics due to risks of short- and long-term side effects, it is helpful to emphasize that the effective dose is often low and the course of treatment often brief.
Anticholinergic agents such as benztropine or trihexyphenidyl should not be used to treat chorea. These agents, although helpful in some primary, lesional, and drug-induced dystonias, can make chorea worse.
Immune Modulation Based on the pathophysiology of SC, it is reasonable to consider immune-modulating therapies to shorten the course of illness. By analogy with other subacute neurologic and medical conditions, including acute inflammatory demyelinating polyneuropathy, Kawasaki's disease, and idiopathic thrombocytopenic purpura, treatment with steroids, intravenous immune globulin, or plasmapheresis may be considered. Expert opinion on management suggests four important principles: diagnose and treat as early as possible, aim to minimize disease severity, escalate treatment when the patient does not respond to initial treatment, and minimize relapses.
Several case reports, case series, and small trials report benefit with immune-modulating treatment for SC. Many of these study designs were not rigorous, and interpretation of benefit is challenging given that the illness is expected to be monophasic and selflimited. The most compelling evidence for efficacy from steroids comes from a randomized, blinded, placebo-controlled study by Paz and colleagues. Relative to placebo, a 4-week 2 mg/kg daily oral dose of prednisone, followed by a taper, reduced duration of chorea and accelerated the reduction in symptoms. However, weight gain was substantial in the prednisone group by the end of 2 months, and long-term results including recurrence rates were similar in both groups. More supportive evidence comes from a clinical trial comparing a lower dose of prednisone to intravenous immunoglobulin (IVIG) and plasmapheresis. This study was not blinded, and the 4-week response to IVIG appeared to be more robust than the response to prednisone. Additional suggestive evidence comes from both small case series , and a large retrospective observational study where treatment allocation was nonrandom, and follow-up was nonstandardized and nonblinded. The estimate of treatment effects is likely imprecise because of low follow-up ascertainment. In addition, because there were substantially fewer untreated patients who were followed up, bias due to case mix (untreated patients with persistent chorea were more likely to be followed up) makes interpretation of treatment versus no-treatment effects difficult. Case reports, small case series, and small clinical trials report benefits in use of IVIG, , , and use of anti-TNF alpha therapy to reduce chorea.
Chorea in Primary Antiphospholipid Antibody Syndrome (APS) and Systemic Lupus Erythematosus (SLE)
Clinical Features
The clinical features of APS and SLE manifesting with chorea overlap with those of SC and cannot be reliably differentiated solely based on the neurological examination. APS can manifest with other neurologic signs and symptoms, such as epilepsy, which are rare in SC. Cerebrovascular disease, cognitive impairment, and transverse myelopathy can also be symptoms of APS, and SLE may have multiorgan disease. Arthralgia, arthritis, and mitral valve carditis are characteristics of SC.
Pathophysiology
As is true for SC, the pathophysiology of APS is believed to be the generation of antibodies, although the trigger is unknown. Antibodies identified in the literature include antineuronal, antibrain, NMDA, antimicrotubule-associated protein 2 (AAP-2), antineurofilament, antiganglioside, antiglial fibrillary acidic protein, as well as key systemic antibodies required for diagnosis of antiphospholipid (aPL)/cardiolipin (aDL), anti-beta2-glycoproten I, and/or lupus anticoagulant. , These aPL antibodies have been shown in animal studies to enter the brain, causing hypercoagulation and inflammation, and activating endothelial cells, leading to disruption of the blood brain barrier and facilitating entry into the brain of other pathogenic antibodies that bind to myelin sheaths and neuronal membranes, causing dysfunction such as motoric behaviors and adverse cognitive changes not associated solely with vascular damage. ,
Diagnostic Approach
SC is a much more prevalent cause of acute/subacute chorea in childhood, but both APS and SLE can manifest initially with isolated chorea and associated neuropsychiatric symptoms, particularly in children. Because of the long-term implications of these diagnoses, and differences in management, it is important to carefully consider the possibility of APS and SLE in children with new chorea. If there is clinical or laboratory evidence of prior GABHS infection and if the chorea is classic for SC, as described previously, the likelihood of SLE or APS is very low. Some authors advocate obtaining testing for lupus anticoagulant and/or anticardiolipin antibodies in all children in this clinical setting. However, as discussed previously, it may be reasonable to consider APS or SLE in some previously healthy, school-age children with acute/subacute chorea in the presence of negative antistreptococcal antibody tests. , The diagnosis of APS should also be considered in apparent SC cases which recur and if other neurological complications such as seizures, strokes, demyelination, or peripheral neuropathy are identified.
As discussed in more detail in the diagnostic approach to SC, several caveats regarding laboratory testing are needed. First, because of the high prevalence of GABHS infections, elevated antistreptococcal antibody titers are common, and these may persist for months or years in some children. Thus, a child with APS or SLE may have elevated streptococcal antibodies, unrelated to their chorea. Second, antibodies elevated in APS may also be elevated in SC, including anticardiolipin β 2 -microglobulin antibodies. Rheumatology consultation is advisable when the diagnoses of APS/SLE are under consideration.
Treatment
Treatment of SLE, a systemic, multiorgan disease, lies outside the scope of this chapter. However, in general, symptom suppressing medications plus immune-suppressive therapies will reduce chorea associated with SLE , or APS.
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