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 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 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.

horea is a nonpatterned, involuntary, hyperkinetic genetic chorea, will be emphasized. Paroxysmal movement Cmovement disorder. It is continuous, variable in speed, disorders involving chorea will not be discussed but are re- unpredictable in timing and direction, and flowing or jerky in viewed elsewhere.4 As the phenomenology of chorea over- appearance.1 Chorea may be accompanied by or laps in acute and chronic choreas, most features of the neu- ballism. Athetosis is also continuous but the rate is slower. rologic examination will be discussed under acute chorea. Athetosis often accompanies or occurs in symptom- atic chorea and may be referred to as . Ballism designates larger amplitude, flinging, proximally generated Acute Chorea movements. It rarely occurs in isolation in children but can accompany chorea. Clinical Characteristics Anatomically, chorea classically most often results from of Acute/Subacute Chorea disturbances in the caudate or .2 Occasionally, the History of Present Illness source may be thalamic/subthalamic.3 A number of neurode- In childhood, chorea is most often acquired acutely or sub- generative can also present with prominent chorea. acutely. It interferes with purposeful movements and often Because of the vulnerability of the and its with speech. Parents can describe the hour, day, or week of connections to a wide variety of pathologies, the differential onset and the way in which the child’s speech and purposeful diagnosis of acute and chronic chorea is very large. Genetic movements have changed. In subtle cases, parents will report and metabolic diseases, endocrine disturbances, autoim- that coordination or speech has been affected in ways that mune disorders, infections, , neo- may not be apparent to the examiner. When the observable, plasms, neurodegenerative diseases, toxins, and trauma can choreic movements are being discussed in clinic, children all result in chorea. A detailed review of the entire spectrum with mature communication and awareness should be able to of these diseases would exceed space limitations for this ar- describe the subjective nature of the movements, that is, the ticle. This review will discuss acute and chronic chorea, em- movements are involuntary, nonsuppressible, and not per- phasizing clinical diagnosis and management. Sydenham formed in response to an urge or sensation. They may de- chorea, the most common acute/subacute acquired chorea in scribe that the movements make them clumsy and that their childhood, and benign hereditary chorea, a rare but primary speech is slurred or slow. The movements generally cause functional interference. This can be gauged by asking about difficulties with activities of daily living. From the Movement Disorders Clinics, Cincinnati Children’s Hospital Med- A careful history of possible antecedents to acute chorea is ical Center, Cincinnati, OH. critical. As the most common etiology is autoimmune and Address reprint requests to Donald L. Gilbert, MD, MS, Division of Neurol- ogy, Cincinnati Children’s Hospital Medical Center ML 11006 and Neu- poststreptococcal, a careful history of known or possible up- rology, 3333 Burnet Avenue, Cincinnati OH. E-mail: donald.gilbert@ per respiratory infections or other illnesses should be sought. cchmc.org Exposures to and doses of psychiatric and other medications,

1071-9091/09/$-see front matter © 2009 Published by Elsevier Inc. 71 doi:10.1016/j.spen.2009.03.009 72 D.L. Gilbert

Table 1 Neurologic Examination in the Child With Chorea Neurologic Examination Key Findings Mental status 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. Cranial nerve May be normal. Slurring of speech due to motor control problems of face and tongue, and not due to brainstem or cranial nerve pathology. Motor examination 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. Sensory examination Typically normal. Significant sensory hypersensitivity suggests rather than chorea. Cerebellar and gait 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 his- Diagnostic Approach tory, recent psychological stressors, and review of systems The critical component is identifying and classifying the should be routinely obtained. movement disorder. Once established that the problem is General and Neurologic Examination acute chorea, the history should point to a relatively limited During the process of taking the history, the clinician will number of categories of disease, and from there the testing generally observe that the child’s trunk appears restless and is can be targeted. Selected etiologies are listed in Table 2. 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 Table 2 Etiology of Acute Chorea in Childhood: Categories both arms and hands. Irregularly flowing or jerking, contin- and Selected Examples uous movements give an appearance of restlessness. Facial Etiologic and tongue chorea may slur or slow speech. Marked asym- Category Examples metry of upper limb chorea may occur. Autoimmune Poststreptococcal, Sydenham chorea5 The general examination is important for other signs of Systemic erythematosis6 illnesses, particularly those indicating autoimmune diseases Antiphospholipid antibody syndrome7 and infections. Skin, heart, joints, and lymph nodes should Other infections Herpes simplex virus,8 Mycoplasma9 be emphasized. Identifying an integral non-neurologic fea- and ture of a disease narrows the differential diagnosis of the encephalitides movement disorder. For example, the presence of joint in- Vascular/hypoxic ; post cardiac transplantation— 10 flammation or a systolic cardiac murmur supports an auto- ischemic “post pump chorea” in infants Static damage in dyskinetic cerebral immune etiology. palsy, markedly exacerbated The neurologic examination should be thorough, empha- with febrile illness11 sizing portions of the examination related to basal ganglia Mitochondrial Mitochondrial with and cerebellar function. The clinician should carefully observe disease lactic acidosis and stroke (MELAS): the child’s motor system at rest as well as while performing acute basal ganglia injury12 sustained movements and common actions. Videotaping the Toxins Carbon monoxide13 examination is helpful to allow reviewing phenomenology and Iatrogenic Dopamine receptor blocking agents/ assessing severity over time. Key findings of the neurologic ex- neuroleptics/: acute, amination are described in Table 1. tardive, withdrawal-emergent14 Finally, it is important to note that fairly continuous, fre- Psychostimulants quent , particularly with dystonia, may lead to a Psychogenic Conversion disorder15 movement disorder that appears identical to chorea. Acute and chronic chorea in childhood 73

Diagnostic Testing infections, based on Jones criteria.17 GABHS are Gram-posi- Laboratory Testing. A subacute course is most common tive bacteria that colonize or invade the upper respiratory and supports an inflammatory disease, most commonly post- tract. In selected cases, possibly due to molecular mimicry, streptococcal. Documenting a positive culture for group A an autoimmune response is triggered. The relationship of ␤-hemolytic streptococcal (GABHS) infection in the throat, GABHS to SC is supported by epidemiologic observations, during the previous 6 months, helps confirm a diagnosis of including the reduction in cases in the post-antibiotic era and Sydenham chorea (SC).16 Otherwise, blood testing for eleva- common co-occurrence of chorea and other manifestations tions in streptococcal antibodies, anti-streptolysin O (ASO) of rheumatic disease, particularly carditis and arthritis.5 and anti-DNAse B (ADB), should be obtained, tested in an Chorea in SC develops over hours to days. Symptom se- experienced laboratory, and compared against childhood verity varies widely but generally there is difficulty with fine normative levels for that laboratory. It should be noted that motor tasks. Parents often report personality changes, in- GABHS infections are highly prevalent and therefore elevated cluding inattention, anxiety, obsessive compulsiveness, para- antibody titers are nonspecific. If ASO and ADB are not ele- noia, and reluctance to speak.18-22 Interestingly, children vated, it is important to test for systemic lupus erythematosus with not only commonly develop obsessive and anti-phospholipid antibody syndrome. Referral to a compulsive symptoms, they also have a higher than expected department of rheumatology may be considered. Chorea prevalence of these symptoms in first-degree relatives.23 Be- caused by other infections, such as herpes simplex, Lyme cause SC is a form of rheumatic disease, it is critical to assess disease, human immunodeficiency virus, mycoplasma pneu- the child carefully for the presence of a systolic heart murmur monia, or Legionnaire disease may be considered in the ap- or of arthritis or arthralgia.5 propriate clinical setting, but this is extremely rare. The term SC should not be used interchangeably with the term pediatric autoimmune neuropsychiatric disorders asso- Neuroimaging. Obtaining a brain MRI scan to rule out brain ciated with streptococcal infections (PANDAS). Key distin- structural causes should be considered as part of the evalua- guishing features are listed in Table 3. tion of any child presenting with acute/subacute chorea. Further discussion of PANDAS lies outside the scope of However, in most cases where the clinical diagnosis is SC, this review, but a number of recent studies are of interest.24-26 neuroimaging does not guide management.5 MRI findings would also point toward diagnoses of mitochondrial/meta- Management bolic diseases, degenerative, neoplastic, and other inflamma- Management involves education about the diagnosis and de- tory diseases targeting the basal ganglia. cisions about medical treatment. There is typically no role for Neurophysiology. Electroencephalography, central motor occupational or physical therapy. neurophysiological assessment with transcranial magnetic Secondary Prevention of Group A ␤-Hemolytic Streptococ- stimulation, and electromyography are of interest in the cal Infections. The standard of care for all children diag- field of research. These studies do not routinely guide nosed with SC, even in cases of isolated chorea with no car- management. ditis or arthritis, is secondary prevention with penicillin or 17 Sydenham Chorea comparable agents to reduce the risk of future GABHS in- fections causing permanent cardiac valvular damage.27 Clinical Features SC is an autoimmune disease. Chorea in isolation or accom- Chorea Symptom Suppression. This treatment is elective. panied by other organ involvement is considered a manifes- Chorea symptom suppressing medication is effective and tation of rheumatic disease, a group of sequelae of GABHS 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 SC PANDAS Prevalence Rare Controversial Cardiac involvement 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 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 74 D.L. Gilbert activities. Beneficial chorea suppression in SC has been de- findings, for example growth parameters or dysmorphic fea- scribed in small case series with benzodiazepines and several tures that narrow the differential diagnosis. anticonvulsants, most commonly valproic acid.28,29 Some The neurologic examination should be thorough, empha- consider dopamine receptor blocking agents to be the treat- sizing portions of the examination related to basal ganglia ment of choice, as these are usually highly effective at low and cerebellar function. Assessment of head growth, cogni- doses.1,22,30 The expected course of treatment is brief, that is, tive function, speech, and cortical spinal tract function are weeks to months. Therefore, long-term tardive risks are in- also important, as chronic neurologic conditions with chorea significant. Anticholinergic agents should not be used. often involve multiple neurologic systems. Key findings of the neurologic examination related to Immune Modulation. This treatment is not established. On chronic choreas are discussed in Table 1. the basis of pathophysiology of SC, it is reasonable to con- sider immune-modulating therapies, for example, steroids or Diagnostic Approach intravenous immuneglobulin (IVIG), to shorten the course of A constellation of neurologic and non-neurologic symptoms illness in severe cases. The most compelling evidence for and signs can be used effectively to narrow the differential benefit from steroids comes from a recent randomized, diagnosis. Selected diseases are discussed in Table 4. 31 blinded placebo-controlled study. Relative to placebo, a Diagnostic Testing 2-mg/kg daily oral dose of prednisone over 4 weeks, followed Neuroimaging with brain MRI is usually a diagnostic test of by a taper, reduced the duration of chorea and accelerated the choice. Decisions about genetic and metabolic testing, par- reduction in symptoms. Weight gain was substantial, so a ticularly for progressive, inherited diseases, can be informed shorter treatment course may be more reasonable. Support- with on-line resource, such as on-line Mendelian inheritance ive evidence also comes from a clinical trial comparing pred- in Man (http://www.ncbi.nlm.nih.gov/omim) and Genetests 32 nisone to IVIG and plasmapheresis. There was no placebo (http://www.genetests.org). group in that study. Other reports from uncontrolled, retro- spectively ascertained data are difficult to interpret. Benign Hereditary Chorea Clinical Features Chronic Chorea Benign hereditary chorea (BHC) is a rare, autosomal domi- nant, static disorder characterized by onset of chorea before Clinical Characteristics of Chronic Chorea age 5.38 “Atypical” clinical features are common and there is History of Present Illness substantial overlap in phenomenology with myoclonus dys- Most children with chronic chorea have a mixed movement tonia.39 The severity of the chorea varies substantially within disorder secondary to a static or progressive encephalopathy. and between families.40,41 Otherwise, chorea is isolated. Fea- In these cases, chorea is just 1, not necessarily predominant, tures supporting this diagnosis include normal general exam- symptom. Chronic chorea may emerge gradually in infancy ination with no dysmorphic features, broadly normal intel- but more commonly becomes apparent after age 1 year. lectual development with no regression or loss of cognitive Children with chronic, early-onset choreas may have sub- normal motor skills and function. In most conditions, it is more widespread central abnormalities, and Table 4 Etiology of Chronic Chorea in Childhood: Categories not chorea per se, that are interfering with normal neurologic and Selected Examples function. As in Sydenham chorea, children with mature com- Etiologic munication and awareness should be able to describe the Category Examples subjective nature of the movements, that is, the movements are involuntary, nonsuppressible, and not performed in re- Primary Benign hereditary chorea (including sponse to an urge or sensation. However, awareness of the syndrome of choreoathetosis, hypothyroidism, neonatal movements on an ongoing basis may be low. respiratory distress) A careful developmental history is critical. Progressive loss Secondary of skills requires a detailed evaluation to attempt to identify a Vascular/hypoxic Stroke/third trimester or pregnancy genetic/molecular diagnosis. Although at present this will ischemic or perinatal hypoxic ischemic most likely not have a specific treatment, precise molecular injuries leading to choreoathetoid diagnoses give families a feeling of knowledge and more con- cerebral palsy trol, and these may allow participation in advocacy and sup- Choreas in Lesch–Nyhan syndrome33 port groups. Problems with learning and mood should be neurodegenerative Nonketotic hyperglycinemia34 systematically assessed as well, as these commonly co-occur. diseases and Phenylketonuria35 The presence of with chorea generally indicates a severe diffuse, serious central nervous system disease. encephalopathies Diseases with Ceroid-lipofuscinosis36 General and Neurologic Examination chorea as a minor Many diseases cause a relatively small number of types of or late feature Chorea in ataxias telangiectasia37 movement disorders. The general examination can reveal Acute and chronic chorea in childhood 75 skills, absence of other significant neurologic disturbances, 11. PeBenito R, Talamayan RC: Fever-induced protracted ballismus in cho- such as , and, with the exception of chorea, normal reoathetoid cerebral palsy. Clin Pediatr (Phila) 40:49-51, 2001 neurologic examination findings. As is often true in move- 12. Wong LJ, Naviaux RK, Brunetti-Pierri N, et al: Molecular and clinical genetics of mitochondrial diseases due to POLG mutations. Hum Mutat ment disorders, it is important to examine other family mem- 29:E150-E172, 2008 bers in addition to taking a multigeneration history. The 13. Park S, Choi IS: Chorea following acute carbon monoxide poisoning. presence of mild symptoms in a parent would support the Yonsei Med J 45:363-366, 2004 presence of autosomal dominant inheritance in BHC. Some 14. Gilbert DL: Drug-induced movement disorders in children. Ann N Y symptom improvement may occur in adulthood. Acad Sci 1142:72-84, 2008 In the absence of a family history, other diagnoses to con- 15. Isaacs KM, Kao E, Johnson MD, et al: Precipitating events and signifi- cant life stressors of pediatric patients diagnosed with a psychogenic sider in a child presenting under age 5 with chorea include movement disorder, in 37th Annual Meeting of the International Neu- 37 ataxia telangiectasia (AT), which is autosomal recessive. ropsychological Society, Atlanta, GA, 2009 The characteristic telangiectasias lag behind the neurologic 16. Ayoub EM, Wannamaker LW: Streptococcal antibody titers in Syden- symptoms.42 Initial diagnostic testing for a young child with ham’s chorea. Pediatrics 38:946-956, 1966 chorea, dystonia, or ataxia emerging between 12 and 36 17. American Academy of Pediatrics: Group A streptococcal infections, in months of age should include serum alpha-fetoprotein, Pickering LK, Baker CJ, Long SS, et al (eds): Red Book. Report of the which is elevated in AT. Committee on Infectious Diseases. 27th ed. Elk Grove, IL: American Academy of Pediatrics; 2006:610-620 Diagnosis. MRI is usually normal.43 BHC is caused in some, 18. Maia DP, Teixeira AL Jr, Quintao Cunningham MC, et al: Obsessive compulsive behavior, hyperactivity, and attention deficit disorder in but not all pedigrees, by mutations in the NKX2.1 gene en- Sydenham chorea. 64:1799-1801, 2005 44,45 coding TITF1. Commercial diagnostic testing is available. 19. Freeman JM, Aron AM, Collard JE, et al: The emotional correlates of Sydenham’s chorea. Pediatrics 35:42-49, 1965 Management. There is no symptomatic treatment shown to 20. Asbahr FR, Ramos RT, Negrao AB, et al: Case series: Increased vulner- be beneficial in genetically confirmed BHC. Interestingly, ability to obsessive-compulsive symptoms with repeated episodes of there is a report of improvement with levodopa treatment.46 Sydenham chorea. J Am Acad Child Adolesc Psychiatry 38:1522-1525, 1999 21. Swedo SE, Rapoport JL, Cheslow DL, et al: High prevalence of obses- Conclusions sive-compulsive symptoms in patients with Sydenham’s chorea. Am J Psychiatry 146:246-249, 1989 The presence of acute or chronic chorea suggests disordered 22. Ridel KR, Lipps TD, Gilbert DL: The prevalence and severity of OCD neural transmission or structural pathology in the basal gan- and ADHD in children diagnosed with Sydenham’s Chorea: A long- glia or occasionally in other structures. The most common term follow-up of a community based sample, in American Academy of causes of acute chorea in children are autoimmune, espe- Neurology Meeting, Chicago, IL, April 17, 2008 23. Hounie AG, Pauls DL, do Rosario-Campos MC, et al: Obsessive-com- cially poststreptococcal, SC. In chronic encephalopathies, pulsive spectrum disorders and rheumatic fever: A family study. Biol chorea usually occurs in conjunction with other neurologic Psychiatry 61:266-272, 2007 symptoms. 24. Kurlan R, Johnson D, Kaplan EL: Streptococcal infection and exacer- bations of childhood tics and obsessive-compulsive symptoms: A pro- spective blinded cohort study. 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