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Treatment of Chorea in Childhood

  • Sanem Yilmaz
    Affiliations
    Department of Neurology, University of Rochester Medical Center, Rochester, New York

    Division of Pediatric Neurology, Department of Pediatrics, Ege University Medical Faculty, Izmir, Turkey
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  • Jonathan W. Mink
    Correspondence
    Communications should be addressed to: Mink; Frederick A. Horner, MD Endowed Professor in Pediatric Neurology; Professor of Neurology, Neuroscience, and Pediatrics; Chief Division of Child Neurology; Vice Chair Department of Neurology; University of Rochester Medical Center; 601 Elmwood Ave., Box 631; Rochester, NY 14642.
    Affiliations
    Department of Neurology, University of Rochester Medical Center, Rochester, New York

    Department of Neuroscience, University of Rochester Medical Center, Rochester, New York

    Department of Pediatrics, University of Rochester Medical Center, Rochester, New York
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      Abstract

      Chorea is a movement disorder characterized by ongoing random-appearing sequences of discrete involuntary movements or movement fragments. Chorea results from dysfunction of the complex neuronal networks that interconnect the basal ganglia, thalamus, and related frontal lobe cortical areas. The complexity of basal ganglia circuitry and vulnerability of those circuits to injury explains why chorea results from a wide variety of conditions. Because etiology-specific treatments or effective symptomatic treatments are available for causes of chorea, defining the underlying disease is important.
      The treatment of chorea can be considered in three main categories: (1) terminating or modifying exposure to the causative agent, (2) symptomatic treatment of chorea, and (3) treatment targeting the underlying etiology. Symptomatic treatment decision of chorea should be based on the functional impact on the child caused by chorea itself. There have been no reported randomized, placebo-controlled trials of symptomatic treatment for chorea in childhood. Thus the recommendations are based on clinical experience, case reports, expert opinions, and small comparative studies. Better knowledge of mechanisms underlying childhood chorea will provide more etiology-based treatments in the future.

      Keywords

      Definitions and phenomenology

      Chorea is a movement disorder characterized by ongoing random-appearing sequences of discrete involuntary movements or movement fragments. The movements appear random because of unpredictable timing, duration, direction, or anatomic location. The duration of the individual movements is brief, typically in the range of 50 to 300 ms.
      • Marsden C.D.
      • Obeso J.A.
      • Rothwell J.C.
      Clinical neurophysiology of muscle jerks: myoclonus, chorea, and tics.
      Although there is some overlap in duration, the movements of chorea are typically less sustained than those of dystonia and are more sustained and less “shock-like” than those of myoclonus. The presence of chorea often gives the child a “fidgety” appearance with an apparent inability to remain still.
      When choreic movements are especially large in amplitude, forceful, and involve more proximal joints, resulting in flinging or flailing movements of the limbs, the term ballism is often used. Ballism is part of the spectrum of chorea and involves similar pathophysiologic mechanisms. When ballism effects one side of the body, it is called hemiballism. Hemiballism is the classical manifestation of injury affecting the subthalamic, nucleus but it can be associated with lesions in other parts of the basal ganglia.
      • Sanger T.D.
      • Chen D.
      • Fehlings D.L.
      • et al.
      Definition and classification of hyperkinetic movements in childhood.
      Involuntary movements that result in slow, continuous, involuntary, nonforceful, and sinuous movements of distal body parts that prevent maintenance of a stable posture are called athetosis. The lack of identifiable movement fragments and the involvement of same body parts repeatedly distinguish athetosis from chorea. In children, athetosis rarely occurs in isolation and often accompanies chorea or dystonia. The term choreoathetosis is commonly used by clinicians to describe movements that are difficult to fully classify as chorea or athetosis. Athetosis is most often observed in children with dyskinetic cerebral palsy and in many cases accompanies dystonia as a coexisting movement disorder.
      • Sanger T.D.
      • Chen D.
      • Fehlings D.L.
      • et al.
      Definition and classification of hyperkinetic movements in childhood.
      • Mink J.W.
      • Zinner S.H.
      Movement disorders ii: chorea, dystonia, myoclonus, and tremor.
      • Singer H.S.
      • Mink J.W.
      • Gilbert D.L.
      • Jankovic J.
      Chorea, athetosis, and ballism.
      Athetosis is a distinct movement disorder, but the spatiotemporal characteristics make it appear as if on a continuum between dystonia and chorea.
      The term choreiform is often used in reference to very-low-amplitude choreic movements. We prefer the term minimal chorea as a more precise term that also conveys the slightness of the movements. Minimal chorea is often noted in children who are otherwise healthy or in those who have neurobehavioral disorders, particularly when arms are held in outstretched position.
      • Sanger T.D.
      • Chen D.
      • Fehlings D.L.
      • et al.
      Definition and classification of hyperkinetic movements in childhood.
      • Mink J.W.
      • Zinner S.H.
      Movement disorders ii: chorea, dystonia, myoclonus, and tremor.

      Pathophysiology

      Chorea classically results from dysfunction of the complex neuronal networks that interconnect the basal ganglia (striatum, globus pallidus, subthalamic nucleus, substantia nigra), thalamus, and related frontal lobe cortical areas.
      • DeLong M.R.
      • Wichmann T.
      Circuits and circuit disorders of the basal ganglia.
      The inputs to the basal ganglia from the cerebral cortex are glutamatergic and excitatory. The majority of intrinsic basal ganglia circuitry is GABAergic and inhibitory, with modulation by peptide neurotransmitters and dopamine, and the output from the basal ganglia to the thalamus and brainstem targets is entirely GABAergic and inhibitory.
      • Mink J.W.
      The basal ganglia and involuntary movements: impaired inhibition of competing motor patterns.
      Structural or functional lesions that result in decreased inhibitory output from the basal ganglia can cause chorea, regardless of the specific focus of that abnormality. Lesions causing chorea are most likely to be located in the striatum or the subthalamic nucleus.
      • Mink J.W.
      The basal ganglia and involuntary movements: impaired inhibition of competing motor patterns.
      • Cardoso F.
      • Seppi K.
      • Mair K.J.
      • Wenning G.K.
      • Poewe W.
      Seminar on choreas.
      Based on the known pathophysiology and the critical roles of γ-aminobutyric acid (GABA) and dopamine, most pharmacotherapies for chorea target GABAergic or dopaminergic neurotransmission.
      • Singer H.S.
      • Mink J.W.
      • Gilbert D.L.
      • Jankovic J.
      Chorea, athetosis, and ballism.
      Cholinergic transmission is typically intact, so anticholinergic medications are rarely effective for chorea. In some types of chorea, dysregulated neuronal discharge in basal ganglia circuits may be present, and this may explain the efficacy of antiseizure medications in some cases.

      Etiologies

      The complexity of basal ganglia circuitry and vulnerability of those circuits to injury explains why chorea results from a wide variety of conditions.
      • Singer H.S.
      • Mink J.W.
      • Gilbert D.L.
      • Jankovic J.
      Chorea, athetosis, and ballism.
      • Cardoso F.
      • Seppi K.
      • Mair K.J.
      • Wenning G.K.
      • Poewe W.
      Seminar on choreas.
      • De Gusmao C.M.
      • Waugh J.L.
      Inherited and acquired choreas.
      • Gilbert D.L.
      Acute and chronic chorea in childhood.
      • Mencacci N.E.
      • Carecchio M.
      Recent advances in genetics of chorea.
      • Bashir H.
      • Jankovic J.
      Treatment options for chorea.
      Because of the wide diversity of etiologies for chorea, attempts have been made to develop classification systems to guide clinicians in the approach for differential diagnosis, and none of them is without shortcomings.
      • Mink J.W.
      • Zinner S.H.
      Movement disorders ii: chorea, dystonia, myoclonus, and tremor.
      • Singer H.S.
      • Mink J.W.
      • Gilbert D.L.
      • Jankovic J.
      Chorea, athetosis, and ballism.
      • De Gusmao C.M.
      • Waugh J.L.
      Inherited and acquired choreas.
      • Gilbert D.L.
      Acute and chronic chorea in childhood.
      • Mencacci N.E.
      • Carecchio M.
      Recent advances in genetics of chorea.
      • Bashir H.
      • Jankovic J.
      Treatment options for chorea.
      Traditionally, chorea has been classified as primary and secondary. The term primary was used interchangeably with “idiopathic” or “genetic,” and secondary was used to mean that the chorea resulted from a known underlying disorder. This classification has diminishing utility given the rapid advances in understanding the genetic etiologies of movement disorder. Another approach classifies choreas based on the time course of symptom onset and evolution, e.g., acute, subacute, paroxysmal, chronic static, and chronic progressive. However, this is also unsatisfactory because of the phenotypic spectrum within individual disorders and lack of specificity of time course for predicting underlying cause. Similar to the etiologic classification of dystonia by Albanese et al.,
      • Albanese A.
      • Bhatia K.
      • Bressman S.B.
      • Delong R.M.
      • Fahn S.
      • Fung V.S.C.
      Phenomenology and classification of dystonia: a consensus update.
      it may be more useful to classify chorea as acquired (known specific cause), inherited (proven genetic origin), and idiopathic (unknown cause). However, even with that scheme there is some lack of specificity because some causes of “acquired” chorea may have a genetic component.
      In clinical practice, age and rapidity of onset are two important factors for prioritizing the differential diagnosis of chorea. Chorea in children most often presents with acute or subacute onset due to an acquired cause. Because etiology-specific treatments or effective symptomatic treatments are available for causes of chorea, defining the underlying disease is important. Table 1., Table 2. briefly summarize the expanding etiologic classification of childhood-onset choreas.
      Table 1.Common Acquired Causes of Childhood-Onset Chorea
      • Structural: Basal ganglia lesions
        • Stroke
        • Moyamoya disease
        • Vascular malformations
        • Hemorrhage
        • Postpump chorea
        • Mass lesions
        • Choreoathetoid cerebral palsy
        • Trauma
      • Parainfectious: Autoimmune disorders
        • Sydenham chorea
        • Chorea associated with antibody-mediated disorders (anti-NMDA receptor encephalitis, basal ganglia encephalitis)
        • Antiphospholipid antibody syndrome
        • Systemic lupus erythematosus
        • Acute disseminated encephalomyelitis
        • Behçet disease
        • Celiac disease
      • Infectious disorders
        • Human immunodeficiency virus encephalopathy
        • Viral encephalitis (herpes simplex virus, mumps, varicella, parvovirus B19, measles)
        • Legionella, mycoplasma
        • Lyme disease
        • Toxoplasmosis
      • Metabolic
        • Hypo/hyperglycemia
        • Hypo/hypernatremia
        • Hypo/hypercalcemia
        • Hyperthyroidism
      • Drug-induced
        • Direct mechanism (dose-dependent)
          • Psychostimulants
          • Sodium channel blockers (phenytoin, carbamazepine, tiagabine)
          • Calcium channel blockers
          • Antimuscarinics
          • Others (baclofen, steroids, cyclosporine, propofol)
        • Indirect mechanism (due to receptor supersensitivity)
          • Dopamine-blocking agents (withdrawal or tardive syndrome)
          • Antiparkinsonian drugs with acute/chronic treatment (l-dopa-induced dyskinesia)
        • Others
          • Oral contraceptives
          • Polypharmacy for psychiatric conditions or epilepsy
          • Selective serotonin reuptake inhibitors
          • Valproate
      • Toxin-induced
      • Carbon monoxide
      • Carbon disulfide
      • Methanol
      • Manganese
      • Toluene
      • Psychogenic
      Table 2.Common Inherited Causes of Childhood-Onset Chorea
      DiseaseInheritanceAssociated Gene
      Chorea as the core or initial feature
       Benign hereditary choreaAD/de novoNKX2-1
       ADCY5-related dyskinesiaAD/de novoADCY5
       PDE10A-related hyperkinetic disorderDe novo/ARPDE10A
       Adolescent-onset Huntington diseaseADCAGn in HTT
       Huntington disease-like 3ARLinked to 4p15.3
       Huntington disease-like 4 (spinocerebellar ataxia 17)ADCAGn or CAAn in TBP
       Ataxia telangiectasiaARATM
       Ataxia telangiectasia-like disorderARMRE11A
       Ataxia with oculomotor apraxia 1 and 2ARAPTX
       Friedreich ataxiaARGAAn in FRDA
       Idiopathic basal ganglia calcification, childhood onsetAR and ADSLC20A2-PDGFRB
       ChoreoacanthocytosisARVPS13A
       Paroxysmal nonkinesigenic dyskinesiaADMR1
      Chorea as a common additional feature
       GLUT1 deficiency syndromeADSLC2A1
       Cerebral creatine deficiency syndrome 2ARGAMT
       Pyruvate dehydrogenase E1-alpha deficiencyX-linkedPDHA1
       Dopamine transporter deficiency syndromeARSLC6A3
       Infantile bilateral striatal necrosisARNUP62
       Congenital Rett syndromeADFOXG1
       Chorea associated with epilepsy or developmental delayAD

      AD or AR

      AR
      GNAO1, SCN8A, SYT1

      GRIN1

      FRRS1L, GPR88
      Chorea sometimes present
       Dentatorubropallidoluysian atrophyADCAGn in atrophin-1
       Alternating hemiplegia of childhoodARATP1A-3
       Pantothenate kinase-associated neurodegenerationARPANK2
       Wilson diseaseARATP7B
       Lesch-Nyhan diseaseX-linkedHPRT
       PhenylketonuriaARPAH
       Biopterin-deficient hyperphenylalaninemiaUsually ARMultiple genes
       Nonketotic hyperglycinemiaARGLDC, GCST or GCSH
       Glutaric aciduria type 1ARGCDH
       3-Methylglutaconic aciduria type III (Costeff syndrome)AROPA3
       Succinate semialdehyde dehydrogenase deficiencyARALDH5A
       GM1-GM2 gangliosidosisARGLB1-HEXA
       Paroxysmal kinesigenic dyskinesiaADPRRT2
       Paroxysmal exercise-induced dyskinesiaADSLC2A1
      Abbreviations:
      AD = Autosomal dominant
      AR = Autosomal recessive

      Treatment

      The treatment of chorea can be considered in three main categories: (1) terminating or modifying exposure to the causative agent, (2) symptomatic treatment of chorea, and (3) treatment targeting the underlying etiology. Etiology-specific treatment is the ultimate goal for most conditions causing chorea in children, but at this time it is available only in a minority of conditions.

      Terminating or modifying exposure to the causative agent

      Several drugs have been reported to cause chorea in childhood. Some of these cause chorea as a dose-dependent side effect, whereas the others interact with pre-existing basal ganglia network dysfunction. Examples of the latter include dopamine receptor supersensitivity or presynaptic dysfunction of dopamine neurons. A classic example is levodopa-induced dyskinesia (LID) in Parkinson disease (PD). LID may also occur in patients with tyrosine hydroxylase (TH) deficiency and other inherited disorders of dopamine synthesis despite the lack of nigrostriatal degeneration.
      • Roser P.
      • Syrengelas D.
      • Youroukos S.
      • et al.
      Levodopa-induced dyskinesias in tyrosine hydroxylase deficiency.
      Unlike LID in PD, LID in TH deficiency occurs within a few days or months of treatment onset.
      Another disorder that is thought to be related to dopamine D2 receptor supersensitivity is tardive dyskinesia (TD), which occurs in some patients after chronic treatment with dopamine receptor antagonists. TD is rare in children but a related disorder; withdrawal-emergent dyskinesia is more common. In that condition, rapid discontinuation of dopamine receptor antagonists is thought to result in transient overstimulation of dopamine D2 receptors.
      • Singer H.S.
      • Mink J.W.
      • Gilbert D.L.
      • Jankovic J.
      Chorea, athetosis, and ballism.
      • Cardoso F.
      • Seppi K.
      • Mair K.J.
      • Wenning G.K.
      • Poewe W.
      Seminar on choreas.
      Estrogen-containing oral contraceptives may also induce chorea in patients with previous Sydenham chorea (SC), chorea gravidarum, antiphospholipid antibody syndrome (APS), and systemic lupus erythematosus (SLE).
      • Singer H.S.
      • Mink J.W.
      • Gilbert D.L.
      • Jankovic J.
      Chorea, athetosis, and ballism.
      When chorea is caused by an exogenous toxin that is not used for therapeutic purposes, eliminating exposure is the logical course of action. When drug-or toxin-induced chorea occurs, withdrawal or dose modification of the offending agent may not always result in resolution of the symptoms. Specific pharmacologic treatments for persistent drug-induced chorea are discussed below.

      Symptomatic treatment of chorea in children

      Symptomatic treatment decision of chorea should be based on the functional impact on the child caused by chorea itself. If chorea is impairing, then the next step is to decide which treatment would fit the patient best. There are limited studies of symptomatic treatment for chorea in adults, and even fewer studies of childhood chorea treatment. To date, there have been no reported randomized, placebo-controlled trials of symptomatic treatment for chorea in childhood. Thus, our recommendations are based on clinical experience, case reports, expert opinions, and small comparative studies. Most of these published reports concern SC. The medications described below may be effective in multiple forms of chorea, but individual patient factors should be considered in prioritizing the choices. Table 3., Table 4. summarize the drugs used for the symptomatic treatment of chorea in children.
      Table 3.Drugs Used in the Medical Treatment of Childhood Chorea Due to a Variety of Conditions (see Text for Specific Comments)
      DrugDoseSide EffectsContraindicationsSpecial PointsEvidence
      Dopamine-depleting agents
       TetrabenazineInitial dose: 6.5-12.5 mg daily, increase by 12.5 mg/day every 3-5 days

      Usual effective dose: 50-150 mg/day, divided into three doses

      Maximum recommended dose: 200 mg/day
      Parkinsonism, drowsiness, fatigue, sedation, anxiety, depression, akathisia, tremor, nausea, vomiting, insomnia, orthostatic hypotension, suicidality, neuroleptic malignant syndromeHistory of depression, suicidality, parkinsonism, hepatic impairment

      Should be discontinued promptly at the first signs of depression
      Children may require higher doses than adults

      Do not initiate therapy within 14 days of MAO inhibitor use
      Retrospective studies, case series, case reports
      • Jain S.
      • Greene P.E.
      • Frucht S.J.
      Tetrabenazine therapy of pediatric hyperkinetic movement disorders.
      • Chatterjee A.
      • Frucht J.
      Tetrabenazine in the treatment of severe pediatric chorea.
      • Voung K.H.C.
      • Mejia N.
      • Jankovic J.
      Safety and efficacy of tetra-benazine in childhood hyperkinetic movement disorders.
      • Ananth A.L.
      • Robichaux-Viehoever A.
      • Kim Y.-M.
      Clinical course of six children with GNAO1 mutations causing a severe and distinctive movement disorder.
      • Hawkes C.H.
      • Nourse C.H.
      Tetrabenazine in Sydenham’s chorea.
      • Lance E.I.
      • Kronenbuerger M.
      • Cohen J.S.
      • Furmanski O.
      • Singer H.S.
      • Fatemi A.
      Successful treatment of choreo-athetotic movements in a patient with an EEF1A2 gene variant.
      • Jankovic J.
      • Caskey T.C.
      • Stout J.T.
      • Butler I.J.
      Lesch-Nyhan syndrome: a study of motor behavior and cerebrospinal fluid neurotransmitters.
      • Baizabal-Carvallo J.F.
      • Stocco A.
      • Muscal E.
      • Jankovic J.
      The spectrum of movement disorders in children with anti-NMDA receptor encephalitis.
      • Gras D.
      • Jonard L.
      • Roze E.
      • Chantot-Bastaraud S.
      • Koht J.
      • Motte J.
      Benign hereditary chorea: phenotype, prognosis, therapeutic outcome and long term follow-up in a large series with new mutations in the TITF1/NKX2-1 gene.
      • Patel N.J.
      • Jankovic J.
       ReserpineInitial dose: 0.25 mg/day Increase by 0.25 mg/day every few days

      Can be given in dosages of 1-9 mg/day, three times daily
      Sedation, orthostatic hypotension, depression, drug-induced parkinsonism, insomnia, anxiety, akathisia, cardiac arrhythmiaDepression, Parkinson disease, orthostatic hypotension, and pregnancyUsually reserved for patients with severe tardive dyskinesia and hemiballismus Should not be used concurrently with MAO inhibitorsCase reports for Sydenham chorea
      • Naidu S.
      • Narasimhachari N.
      Sydenham’s chorea: a possible presynaptic dopaminergic dysfunction initially.
      • Raffaele R.
      • Patti F.
      • Sciacca A.
      • Palmeri A.
      Effects of short-term reserpine treatment on generalized and focal dystonic-dyskinetic syndromes.
      Potent D2 receptor blockers (typical antipsychotics)
       HaloperidolInitial dose: 0.25-0.5 mg/day (evening)

      Increase 0.25-0.5 mg weekly, one or two times daily

      Total daily dose ranges: 0.75-5 mg
      Extrapyramidal reactions, neuroleptic malignant syndrome, parkinsonism, tardive dyskinesia, drowsiness, agitation, insomnia, confusion, headache, seizuresProlonged QT syndrome, narrow-ankle glaucoma, parkinsonism, severe cardiac or liver disease, severe CNS depression, history of extrapyramidal symptoms or neuroleptic malignant syndromePossible increased sensitivity in SC and NMDAR-encephalitis

      Should be reserved for severe cases and used with caution
      Retrospective comparison studies, retrospective case series, case reports
      • Axley J.
      Rheumatic chorea controlled with haloperidol.
      • Shenker D.M.
      • Grossman H.J.
      • Klawans H.L.
      Treatment of Sydenham’s chorea with haloperidol.
      • Demiroren K.
      • Yavuz H.
      • Cam L.
      • Oran B.
      • Karaaslan S.
      • Demiroren S.
      Sydenham’s chorea: a clinical follow-up of 65 patients.
      • Pena J.
      • Mora E.
      • Cardozo J.
      • Molina O.
      • Montiel C.
      Comparison of the efficacy of carbamazepine, haloperidol and valproic acid in the treatment of children with Sydenham’s chorea: clinical follow-up of 18 patients.
      • Tumas V.
      • Caldas C.T.
      • Santos A.C.
      • Nobre A.
      • Fernandes R.M.
      Sydenham’s chorea: clinical observations from a Brazilian movement disorder clinic.
      • Gherpelli J.L.D.
      • Azeka E.
      • Riso A.
      • Atik E.
      • Ebaid M.
      • Barbero-Marcial M.
      Choreoathetosis after cardiac surgery with hypothermia and extracorporeal circulation.
      • Cervera R.
      • Asherson R.A.
      • Font J.
      • et al.
      Chorea in the antiphospholipid syndrome. Clinical, radiologic, and immunologic characteristics of 50 patients from our clinics and the recent literature.
      • Arisaka O.
      • Obinata K.
      • Sasaki H.
      • Arisaka M.
      • Kaneko K.
      Chorea as an initial manifestation of systemic lupus erythematosus. A case report of a 10-year-old girl.
       PimozideInitial dose: 0.5-1 mg/day (evening), may be increased every 5-7 days

      Usual range: 2-4 mg/day, two times daily

      Do not exceed 10 mg/day
      Sedation, dysphoria, constipation, dry mouth, cognitive blunting, school refusal, acute anxiety with somatizations, personality change, weight gain, orthostatic hypotension, blurred visionHistory of cardiac arrhythmias, prolonged QT syndrome, neuroleptic malignant syndrome, tardive dyskinesia, CNS depression or Parkinson diseaseAn ECG should be done at baseline and periodically during the dose adjustment

      Avoid consumption of grapefruit juice

      Use smallest dose with shortest duration
      Retrospective comparison study

      Case reports
      • Demiroren K.
      • Yavuz H.
      • Cam L.
      • Oran B.
      • Karaaslan S.
      • Demiroren S.
      Sydenham’s chorea: a clinical follow-up of 65 patients.
      • Harries-Jones R.
      • Gibson J.G.
      Successful treatment of refractory Sydenham’s chorea with pimozide.
      • Shannon K.M.
      • Fenichel G.M.
      Pimozide treatment of Sydenham’s chorea.
      • Yakinci C.
      • Durmaz Y.
      • Korkut M.
      • Aladag A.
      • Onal C.
      • Aydinli M.
      Cavernous hemangioma in a child presenting with hemichorea: response to pimozide.
      • Osari S.
      • Muranaka H.
      • Kojima T.
      • Kimura Y.
      Persistent chorea following cardiac surgery for congenital heart disease.
      • Hama A.
      • Furune S.
      • Nomura K.
      • Takada Y.
      • Matsushima Y.
      A case of unilateral moyamoya disease presenting with hemichorea.
       ChlorpromazineInitial: 0.5 mg/kg/dose every 4-6 hours as needed

      Maximum recommended daily doses: Children <5 years: 40 mg/day, IM or 50 mg/day orally Children ≥5 years: 75 mg/day IM or 200 mg/day orally
      Anticholinergic effects, sedation, somnolence, CNS depression, extrapyramidal side effects, hypotension, QT prolongation, blood dyscrasiasHypersensitivity to phenothiazines, concomitant use with large amounts of CNS depressants, comatose statesUse with caution in patients with cardiovascular disease, avoid use in patients suspected to have Reye syndromeRetrospective comparison, case reports
      • Tumas V.
      • Caldas C.T.
      • Santos A.C.
      • Nobre A.
      • Fernandes R.M.
      Sydenham’s chorea: clinical observations from a Brazilian movement disorder clinic.
      • Lewenfisz-Wojnarowska T.
      • Popielarska A.
      • Grzybowska J.
      Largactil administration in chorea in children.
      • Gillot F.
      • Sendra L.
      • Dalaut J.J.
      • Legeais G.
      • Guenoun M.
      34 Cases of acute chorea in children observed in the Children’s Hospital of Algiers; etiological conclusions and current therapeutic methods.
      • Teixeira A.L.
      • Cardoso F.
      • Maia D.P.
      • Cunningham M.C.
      Sydenham’s chorea may be a risk factor for drug induced parkinsonism.
      • Lopez-Munoz F.
      • Alamo C.
      • Cuenca E.
      • Shen W.
      • Clervoy P.
      • Rubio G.
      History of the discovery and clinical introduction of chlorpromazine.
      • Weiner S.G.
      • Normandin P.A.
      Sydenham chorea.
      Atypical antipsychotics
       RisperidoneInitial dose: 0.25 or 0.5 mg/day (evening) and titrate up to 2-4 mg/day gradually, two times dailyHypotension, somnolence, weight gain, hyperglycemia, akathisia, parkinsonism, tremor, neuroleptic malignant syndrome, headache, seizuresHistory of QT prolongation, use of other drugs known to prolong QT interval, caution is recommended when there is concern for hyperglycemia and diabetesUse smallest dose with shortest durationProspective open-label study, expert opinion
      • Cardoso F.
      Sydenham’s chorea.
      • Kamate M.
      • Mittal N.
      • Metgud D.
      Effect of risperidone on the motor and functional disability in children with choreoathetoid cerebral palsy.
      Antiepileptic drugs
       Valproic acidInitial dose: 10-15 mg/kg/day or 125 mg, two times daily

      Increase by 5 to 10 mg/kg weekly up to 25-30 mg/kg/day or 1000 mg/day
      Nausea, vomiting, weight gain, drowsiness, tremor, ataxia, hyperammonemia, nystagmus, alopecia hepatic injury, pancreatitis, Stevens–Johnson syndrome, bone marrow suppression, polycystic ovary diseaseHepatic dysfunction, urea cycle disorders, children younger than 2 yearsLiver function tests should be monitored

      Avoid use of sodium valproate in women of childbearing age
      Prospective and retrospective comparison studies, case series, case reports
      • Pena J.
      • Mora E.
      • Cardozo J.
      • Molina O.
      • Montiel C.
      Comparison of the efficacy of carbamazepine, haloperidol and valproic acid in the treatment of children with Sydenham’s chorea: clinical follow-up of 18 patients.
      • McLachlan R.S.
      Valproic acid in Sydenham’s chorea.
      • Chandra V.
      • Spunt A.L.
      • Rusinowitz M.S.
      Treatment of post-traumatic choreo-athetosis with sodium valproate.
      • Alvarez L.A.
      • Novak G.
      Valproic acid in the treatment of Sydenham chorea.
      • Dhanaraj M.
      • Radhakrishnan A.R.
      • Srinivas K.
      • Sayeed Z.A.
      Sodium valproate in Sydenham’s chorea.
      • Giroud M.
      • Dumas R.
      Valproate sodium in postanoxic choreoathetosis.
      • Steinberg A.
      • Reifen R.M.
      • Leifer M.
      Efficacy of valproic acid in the treatment of Sydenham’s chorea.
      • Daoud A.S.
      • Zaki M.
      • Shakir R.
      • al-Saleh Q.
      Effectiveness of sodium valproate in the treatment of Sydenham’s chorea.
      • Kulkarni M.L.
      Sodium valproate controls choreoathetoid movements of kernicterus.
      • Davutoglu V.
      • Kilinc M.
      • Dinckal H.
      • Soydinc S.
      • Sezen Y.
      Sydenham’s chorea-clinical characteristics of nine patients.
      • Sabui T.K.
      • Pant P.
      Sodium valproate in the treatment of Sydenham’s chorea.
      • Genel F.
      • Arslanoglu S.
      • Uran N.
      • Saylan B.
      Sydenham’s chorea: clinical findings and comparison of the efficacies of sodium valproate and carbamazepine regimens.
       CarbamazepineInitial dose: 7-10 mg/kg/day, two times daily

      Usual dose range: 10-30 mg/kg/day, three times daily
      Dizziness, nausea, drowsiness, fatigue, unsteadiness, blurred vision, weight gain, rash, hepatotoxicity, pancreatitis, and hyponatremia

      Serious side effects: bone marrow suppression and skin reactions
      History of bone marrow suppression or known hypersensitivity to tricyclic antidepressantsParoxysmal dyskinesias typically respond to doses less than necessary for seizure control

      Need to monitor liver function tests, complete blood count, sodium levels
      Prospective and retrospective comparison studies, case series, case reports
      • Pena J.
      • Mora E.
      • Cardozo J.
      • Molina O.
      • Montiel C.
      Comparison of the efficacy of carbamazepine, haloperidol and valproic acid in the treatment of children with Sydenham’s chorea: clinical follow-up of 18 patients.
      • Waln O.
      • Jankovic J.
      Paroxysmal movement disorders.
      • Mink J.W.
      Treatment of paroxysmal dyskinesias in children.
      • Sun W.
      • Li J.
      • Zhu Y.
      • Yan X.
      • Wang W.
      Clinical features of paroxysmal kinesigenic dyskinesia: report of 24 cases.
      • Roig M.
      • Montserrat L.
      • Gallart A.
      Carbamazepine: an alternative drug for the treatment of nonhereditary chorea.
      • Harel L.
      • Zecharia A.
      • Straussberg R.
      • Volovitz B.
      • Amir J.
      Successful treatment of rheumatic chorea with carbamazepine.
      Abbreviations:
      CNS = Central nervous system
      ECG = Electroencephalography
      IM = Intramuscular
      MAO = Monoamine oxidase
      NMDAR = N-methyl-d-aspartate receptor
      SC = Sydenham chorea
      Table 4.Drugs Reported to be Effective in the Medical Treatment of Childhood Chorea Due to Specific Conditions
      DrugDoseSide EffectsContraindicationsSpecific EtiologyEvidence
      OlanzapineInitial dose: 2.5 mg/day (evening), escalate gradually as necessary up to 5-10 mg/day, two times dailyHypotension, somnolence, weight gain, dizziness, hyperglycemia, akathisia, parkinsonism, neuroleptic malignant syndrome, seizuresCaution is recommended when there is concern for hyperglycemia and diabetesSydenham choreaCase series
      • Sethi S.
      • Setiya R.
      • Lallar K.
      Successful treatment of Sydenham chorea with olanzapine.
      LevetiracetamInitial dose: 15-20 mg/kg/day or 250-500 mg/day, two times daily

      Anticonvulsant dose range: 20-60 mg/kg/day
      Somnolence, dizziness, headache, emotional irritability, depression/suicidality, psychosis, pancreatitis, pancytopeniaHypersensitivity, lower doses should be used in patients with impaired renal functionDyskinetic cerebral palsy, Sydenham chorea, paroxysmal nonkinesigenic dyskinesiaCase reports
      • Sahin S.
      • Cansu A.
      A new alternative drug with fewer adverse effects in the treatment of Sydenham chorea: levetiracetam efficacy in a child.
      • Vles G.F.
      • Hendriksen J.G.
      • Visschers A.
      • Speth L.
      • Nicolai J.
      • Vles J.S.
      Levetiracetam therapy for treatment of choreoathetosis in dyskinetic cerebral palsy.
      TopiramateInitial dose: 25 mg/day, titrate slowly

      Usual effective dose range: 5-9 mg/kg/day or 50-300 mg/day, two times daily
      Confusion, cognitive impairment, paresthesias, ataxia, diplopia, somnolence, weight loss, nephrolithiasis, oligohidrosis, hyperthermiaUse lower doses in renal impairmentParoxysmal kinesigenic choreoathetosis and GNAO1-related choreaOpen-label prospective study, case report
      • Kurian M.A.
      SLC6A3-Related dopamine transporter deficiency syndrome.
      • Gauquelin L.
      • Tran L.T.
      • Chouinard S.
      • Bernard G.
      The movement disorder of brain-lung-thyroid syndrome can be responsive to methylphenidate.
      ClonazepamInitial dose: 0.25-0.5 mg at bedtime

      Usual dose: 1-4 mg/day, three times daily
      Sedation, somnolence, fatigue, confusion, cognitive impairment, hyperactivity, ataxiaSignificant liver dysfunction, respiratory depression, acute narrow-angle glaucomaParoxysmal nonkinesigenic dyskinesias, SLC6A3-related choreaCase reports
      • Fourcade G.
      • Roubertie A.
      • Doummar D.
      • Vidailhet M.
      • Labauge P.
      Paroxysmal kinesigenic dyskinesia: a channelopathy? Study of 19 cases.
      • Fernandez M.
      • Raskind W.
      • Wolff J.
      • et al.
      Familial dyskinesia and facial myokymia (FDFM): a novel movement disorder.
      • Carecchio M.
      • Mencacci N.E.
      • Iodice A.
      • et al.
      ADCY5-related movement disorders: frequency, disease course and phenotypic variability in a cohort of paediatric patients.
      GabapentinInitial dose: 10-15 mg/kg/day, three times daily

      Usual dose: 50-300 mg/day
      Sedation, dizziness, weight gain, vision changes, depression, suicidal behavior, ideationHypersensitivityHemichorea/hemiballismusCase report
      • Kothare S.V.
      • Pollack P.
      • Kulberg A.G.
      • Ravin P.D.
      Gabapentin treatment in a child with delayed-onset hemichorea/hemiballismus.
      AcetazolamideInitial dose: 125-250 mg/day divided into two to four daily doses

      Daily dose may range 1000-2000 mg
      Drowsiness, dizziness, fatigue, paresthesias, tinnitus, electrolyte imbalance, Stevens–Johnson syndromeHyponatremia, hypokalemia, hyperchloremic acidosis, adrenocortical insufficiencyParoxysmal kinesigenic dyskinesia and ADCY-5-related dyskinesiaCase reports
      • Waak M.
      • Mohammad S.S.
      • Coman D.
      • et al.
      GNAO1-related movement disorder with life-threatening exacerbations: movement phenomenology and response to DBS.
      • Koy A.
      • Cirak S.
      • Gonzalez V.
      • et al.
      Deep brain stimulation is effective in pediatric patients with GNAO1 associated severe hyperkinesia.
      • Elia A.E.
      • Bagella B.F.
      • Ferr F.
      • Zorzi G.
      • Calandrella D.
      • Romito L.M.
      Deep brain stimulation for dystonia due to cerebral palsy: a review.
      MethylphenidateInitial dose: 10 mg/day, two or three times daily (30 minutes before meals)

      Usual dose: 10-60 mg/day
      Tachycardia, hypertension, palpitations, sweating, irritability, anorexia, tremors, seizuresMAO inhibitor use, structural heart defects, hyperthyroidism, history of drug abuseBenign hereditary chorea and ADCY5-related choreaCase reports
      • Gauquelin L.
      • Tran L.T.
      • Chouinard S.
      • Bernard G.
      The movement disorder of brain-lung-thyroid syndrome can be responsive to methylphenidate.
      • Friederich R.L.
      Benign hereditary chorea improved on stimulant therapy.
      • Devos D.
      • Vuillaume I.
      • Becdelievre A.D.
      • et al.
      New syndromic form of benign hereditary chorea is associated with a deletion of TITF-1 and PAX-9 contiguous genes.
      • Tubing J.
      • Bohnenpoll J.
      • Spiegler J.
      • et al.
      Methylphenidate can improve chorea in NKX2.1 and ADCY5 mutation-positive patients—a report of two children.
      LevodopaInitial dose: 1 mg/kg/day, three times daily

      Usual dose: 4-5 mg/kg/day (30 minutes before meals)
      Nausea, vomiting, confusion, dizziness, somnolence, orthostatic hypotension, dry mouth, constipation, depression, insomniaMAO inhibitor use, narrow-ankle glaucoma, melanomaBenign hereditary choreaCase reports
      • Gras D.
      • Jonard L.
      • Roze E.
      • Chantot-Bastaraud S.
      • Koht J.
      • Motte J.
      Benign hereditary chorea: phenotype, prognosis, therapeutic outcome and long term follow-up in a large series with new mutations in the TITF1/NKX2-1 gene.
      • Asmus F.
      • Horber V.
      • Pohlenz J.
      • et al.
      A novel titf-1 mutation causes benign hereditary chorea with response to levodopa.
      • Fons C.
      • Rizzu P.
      • Garcia-Cazorla A.
      • et al.
      TITF-1 gene mutation in a case of sporadic nonprogressive chorea. Response to levodopa treatment.
      AmantadineInitial dose: 50 mg/day

      Increase 50 mg twice a day after 1-2 weeks

      Usual dose: 50 mg 2-3 times/day

      Alternative dose: 5-7 mg/kg/day
      Anticholinergic-type side effects including dry mouth, nose, and throat; blurred vision; nausea; constipation; confusion; sedationHypersensitivity, use with caution in patients with congestive heart failure and renal insufficiency, dementia, psychosisAtaxia telangiectasiaOpen-label prospective study
      • Nissenkorn A.
      • Hassin-Baer S.
      • Lerman S.F.
      • Levi Y.B.
      • Tzadok M.
      • Ben-Zeev B.
      Movement disorder in ataxia-telangiectasia: treatment with amantadine sulfate.
      l-ThyroxineDepends on age, usual dose for adolescents: 1-3 μg/kg/day (once before breakfast)Fatigue, weight loss, headache, hyperactivity, tremor, muscle weakness, palpitations, tachycardiaOveractive thyroid glandBenign hereditary choreaCase report
      • Shiohama T.
      • Ohashi H.
      • Shimizu K.
      • et al.
      L-Thyroxine-responsive drop attacks in childhood benign hereditary chorea: a case report.

      Dopamine-depleting agents

      These agents act by reversibly and selectively inhibiting presynaptic vesicular monoamine transporter type 2 (VMAT2), which results in degradation of dopamine by monoamine oxidases before uptake into synaptic vesicles, causing dopamine depletion.
      • Jankovic J.
      • Clarence-Smith K.
      Tetrabenazine for the treatment of chorea and other hyperkinetic movement disorders.
      Although the use of dopamine-depleting agents in choreas other than Huntington disease (HD) and TD is still off-label in the United States, the advantage of dopamine depletors not causing TD with fewer side effects has led them to be preferred to antidopaminergic drugs by many clinicians.

      Tetrabenazine

      Tetrabenazine (TBZ) was the first dopamine-depleting agent approved by the US Food and Drug Administration (FDA) for the treatment of chorea related to HD. TBZ has a five to seven hour half-life that requires three times daily dosing in most patients, and has potential side effects including depression, parkinsonism, and akathisia.
      • Bashir H.
      • Jankovic J.
      Treatment options for chorea.
      Deutetrabenazine and valbenazine are other currently available dopamine depletors with longer half-lives of nine to 10 hours and 15 to 22 hours, respectively.
      • Anderson K.E.
      • Stamler D.
      • Davis M.D.
      • et al.
      Deutetrabenazine for treatment of involuntary movements in patients with tardive dyskinesia (AIM-TD): a double-blind, randomised, placebo-controlled, phase 3 trial.
      • Hauser R.A.
      • Factor S.A.
      • Marder S.R.
      • et al.
      Kinect 3: a phase 3 randomized, double-blind, placebo-controlled trial of valbenazine for tardive dyskinesia.
      These drugs may cause fewer side effects due to lower peak-dose concentrations with comparable “area under the curve.” Deutetrabenazine has been approved by the FDA both for HD and TD; valbenazine is FDA-approved for TD only. Neither of these longer-acting forms has been studied in childhood chorea.
      TBZ can suppress chorea even when dopamine receptor antagonists are ineffective. In a study evaluating the effect of TBZ therapy in pediatric hyperkinetic movement disorders resistant to other medications, 18 of 31 children with hyperkinetic movement disorders had chorea, nine of whom had isolated chorea.
      • Jain S.
      • Greene P.E.
      • Frucht S.J.
      Tetrabenazine therapy of pediatric hyperkinetic movement disorders.
      Fourteen of 18 (78%) showed an improvement with TBZ. Sedation was the most common side effect, occurring in 50% of those treated, followed by behavioral changes (21%), depression (7%), oculogyria (7%), drooling (7%), nausea, and vomiting (7%). In that study, no TD occurred and parkinsonism occurred in one patient (3%) in a dose-dependent manner. The most significant finding in this study was that they used TBZ at higher doses (average 107 mg/day) than used in most adult studies (75 mg/day or less) with better apparent tolerability. In another study,
      • Chatterjee A.
      • Frucht J.
      Tetrabenazine in the treatment of severe pediatric chorea.
      five children with severe chorea responded to TBZ with complete resolution in three. In that report, as much as 250 mg total daily dose of TBZ was administered (17 mg/kg/day) with a mean dose of 190 mg/d (14 mg/kg/day). Thus, TBZ may be tolerated by children in doses higher than those used in adults.
      TBZ has been reported to be effective in specific etiologic subgroups of childhood-onset chorea including various genetic, metabolic, and immune etiologies.
      • Voung K.H.C.
      • Mejia N.
      • Jankovic J.
      Safety and efficacy of tetra-benazine in childhood hyperkinetic movement disorders.
      • Ananth A.L.
      • Robichaux-Viehoever A.
      • Kim Y.-M.
      Clinical course of six children with GNAO1 mutations causing a severe and distinctive movement disorder.
      • Hawkes C.H.
      • Nourse C.H.
      Tetrabenazine in Sydenham’s chorea.
      • Lance E.I.
      • Kronenbuerger M.
      • Cohen J.S.
      • Furmanski O.
      • Singer H.S.
      • Fatemi A.
      Successful treatment of choreo-athetotic movements in a patient with an EEF1A2 gene variant.
      • Jankovic J.
      • Caskey T.C.
      • Stout J.T.
      • Butler I.J.
      Lesch-Nyhan syndrome: a study of motor behavior and cerebrospinal fluid neurotransmitters.
      • Baizabal-Carvallo J.F.
      • Stocco A.
      • Muscal E.
      • Jankovic J.
      The spectrum of movement disorders in children with anti-NMDA receptor encephalitis.
      TBZ has also been suggested as a first-line drug for benign hereditary chorea (BHC), the most common cause of childhood-onset genetic chorea, due to TITF1/NKX2-1 gene mutations.
      • Gras D.
      • Jonard L.
      • Roze E.
      • Chantot-Bastaraud S.
      • Koht J.
      • Motte J.
      Benign hereditary chorea: phenotype, prognosis, therapeutic outcome and long term follow-up in a large series with new mutations in the TITF1/NKX2-1 gene.
      • Patel N.J.
      • Jankovic J.
      • To achieve effective treatment with TBZ while minimizing side effects in childhood chorea, start at a low dose (6.25 mg to 12.5 mg per day), increase gradually in a three times per day dosing schedule, and base maximum daily dosing on magnitude of benefit and side effects.

      Reserpine

      Reserpine inhibits VMAT1 (peripheral) and VMAT2 (central) at the presynaptic membrane, resulting in the depletion of the synaptic pool of monoamines. This drug was used before 1990s for the treatment of SC in children.
      • Naidu S.
      • Narasimhachari N.
      Sydenham’s chorea: a possible presynaptic dopaminergic dysfunction initially.
      • Raffaele R.
      • Patti F.
      • Sciacca A.
      • Palmeri A.
      Effects of short-term reserpine treatment on generalized and focal dystonic-dyskinetic syndromes.
      However, the higher incidence of peripheral side effects including orthostatic hypotension, cardiac arrhythmia, and gastric intolerance due to its nonspecificity regarding central and peripheral VMAT receptors and the introduction of new drugs with safer profiles has limited its use in children more recently. Reserpine should be reserved for patients with severe TD or dystonia that is unresponsive to other treatments.

      Dopamine D2 receptor-blocking agents

      These agents have been known to be effective in pediatric chorea since the 1950s.
      • Lewenfisz-Wojnarowska T.
      • Popielarska A.
      • Grzybowska J.
      Largactil administration in chorea in children.
      • Gillot F.
      • Sendra L.
      • Dalaut J.J.
      • Legeais G.
      • Guenoun M.
      34 Cases of acute chorea in children observed in the Children’s Hospital of Algiers; etiological conclusions and current therapeutic methods.
      • Lanza I.
      • Morbidelli R.
      Treatment of chorea minor with prednisone and prednisone with chlorpromazine.
      However, there have been no placebo-controlled trials of either typical or atypical antipsychotic agents in childhood chorea; their use is still based on retrospective studies and case series.
      There are two major groups of D2 receptor-blocking agents: (1) typical or first-generation antipsychotics that are potent D2 receptor blockers (neuroleptics) and (2) atypical or second-generation antipsychotics that are dopamine-serotonin antagonists, with high affinity for 5-hydroxytryptamine 2A receptors.
      General principles for D2 receptor-blocking agents can be summarized as follows:
      • More potent D2 receptor-blocking action is associated with greater antichoreic efficacy
      • More potent D2 receptor-blocking action is associated with a higher risk of developing TD.
      Contrary to the historical thought that the percentage of D2 receptor occupation is related to the risk of TD, it appears that strength of binding to the D2 receptor better explains why atypical neuroleptics have fewer side effects despite their high D2 occupancy.
      • Seeman P.
      • Tallerico T.
      Antipsychotic drugs which elicit little or no parkinsonism bind more loosely than dopamine to brain D2 receptors, yet occupy high levels of these receptors.
      • Feinstein E.
      • Walker R.
      An update on the treatment of chorea.

      Potent D2 receptor-blocking agents (typical antipsychotics)

      Agents such as haloperidol, pimozide, and chlorpromazine were the most common therapeutic agents used to treat SC before the 1980s.
      • Axley J.
      Rheumatic chorea controlled with haloperidol.
      • Shenker D.M.
      • Grossman H.J.
      • Klawans H.L.
      Treatment of Sydenham’s chorea with haloperidol.
      • Lewenfisz-Wojnarowska T.
      • Popielarska A.
      • Grzybowska J.
      Largactil administration in chorea in children.
      • Gillot F.
      • Sendra L.
      • Dalaut J.J.
      • Legeais G.
      • Guenoun M.
      34 Cases of acute chorea in children observed in the Children’s Hospital of Algiers; etiological conclusions and current therapeutic methods.
      • Lanza I.
      • Morbidelli R.
      Treatment of chorea minor with prednisone and prednisone with chlorpromazine.
      However, their unacceptable side effects such as acute dystonic reactions, akathisia, TD, parkinsonism, prolonged QT, sedation, and cognitive impairment limited their use in children.
      • Teixeira A.L.
      • Cardoso F.
      • Maia D.P.
      • Cunningham M.C.
      Sydenham’s chorea may be a risk factor for drug induced parkinsonism.
      • Dean S.L.
      • Singer H.S.
      Treatment of Sydenham’s chorea: a review of current evidence.
      After the 1980s, they became less preferred with the rapid discovery of effective and more reliable drugs.

      Haloperidol

      Haloperidol is a butyrophenone first-generation antipsychotic agent. The clinical experience of its use in children is mostly based on patients with SC with one prospective comparison study, one retrospective comparison study, several case series, and case reports.
      • Axley J.
      Rheumatic chorea controlled with haloperidol.
      • Shenker D.M.
      • Grossman H.J.
      • Klawans H.L.
      Treatment of Sydenham’s chorea with haloperidol.
      • Demiroren K.
      • Yavuz H.
      • Cam L.
      • Oran B.
      • Karaaslan S.
      • Demiroren S.
      Sydenham’s chorea: a clinical follow-up of 65 patients.
      • Pena J.
      • Mora E.
      • Cardozo J.
      • Molina O.
      • Montiel C.
      Comparison of the efficacy of carbamazepine, haloperidol and valproic acid in the treatment of children with Sydenham’s chorea: clinical follow-up of 18 patients.
      • Tumas V.
      • Caldas C.T.
      • Santos A.C.
      • Nobre A.
      • Fernandes R.M.
      Sydenham’s chorea: clinical observations from a Brazilian movement disorder clinic.
      In 2007, Tumas et al.
      • Tumas V.
      • Caldas C.T.
      • Santos A.C.
      • Nobre A.
      • Fernandes R.M.
      Sydenham’s chorea: clinical observations from a Brazilian movement disorder clinic.
      retrospectively analyzed the medical charts of 100 patients with SC. Of the 100 patients 82 received haloperidol with benefit and no reported significant side effects. However, Pena et al.
      • Pena J.
      • Mora E.
      • Cardozo J.
      • Molina O.
      • Montiel C.
      Comparison of the efficacy of carbamazepine, haloperidol and valproic acid in the treatment of children with Sydenham’s chorea: clinical follow-up of 18 patients.
      compared haloperidol, valproic acid, and carbamazepine in 18 individuals with SC prospectively and reported that two of six patients who received haloperidol developed serious side effects such as excessive somnolence and dystonic reaction, whereas no side effects were recorded with the other drugs. In a retrospective study by Demiroren et al.,
      • Demiroren K.
      • Yavuz H.
      • Cam L.
      • Oran B.
      • Karaaslan S.
      • Demiroren S.
      Sydenham’s chorea: a clinical follow-up of 65 patients.
      it was concluded that haloperidol not only seemed to be more effective than pimozide but also caused more frequent and serious adverse effects like dystonia, parkinsonism, sleepiness, and forgetfulness. Haloperidol has been reported to be effective in various other types of chorea including APS, SLE, and postpump chorea.
      • Gherpelli J.L.D.
      • Azeka E.
      • Riso A.
      • Atik E.
      • Ebaid M.
      • Barbero-Marcial M.
      Choreoathetosis after cardiac surgery with hypothermia and extracorporeal circulation.
      • Cervera R.
      • Asherson R.A.
      • Font J.
      • et al.
      Chorea in the antiphospholipid syndrome. Clinical, radiologic, and immunologic characteristics of 50 patients from our clinics and the recent literature.
      • Arisaka O.
      • Obinata K.
      • Sasaki H.
      • Arisaka M.
      • Kaneko K.
      Chorea as an initial manifestation of systemic lupus erythematosus. A case report of a 10-year-old girl.
      Potential extrapyramidal side effects of haloperidol explain why reports of haloperidol use in childhood chorea were mainly published before 2000. Despite the disadvantages, given its efficacy for chorea, haloperidol should still be considered an option for treating childhood chorea particularly in resistant cases. Careful monitoring for potential side effects is essential.

      Pimozide

      Pimozide is a diphenylbutylpiperidine first-generation antipsychotic drug. There is one retrospective comparison study and a few case reports for the use of pimozide in children with SC.
      • Demiroren K.
      • Yavuz H.
      • Cam L.
      • Oran B.
      • Karaaslan S.
      • Demiroren S.
      Sydenham’s chorea: a clinical follow-up of 65 patients.
      • Harries-Jones R.
      • Gibson J.G.
      Successful treatment of refractory Sydenham’s chorea with pimozide.
      • Shannon K.M.
      • Fenichel G.M.
      Pimozide treatment of Sydenham’s chorea.
      The retrospective study compared haloperidol and pimozide with respect to their efficacy and side effects.
      • Demiroren K.
      • Yavuz H.
      • Cam L.
      • Oran B.
      • Karaaslan S.
      • Demiroren S.
      Sydenham’s chorea: a clinical follow-up of 65 patients.
      Haloperidol provided a significantly faster improvement in chorea but was associated with more withdrawals due to side effects, compared with pimozide. Pimozide was also reported to be effective in moyamoya disease, cavernous hemangioma, and postpump-related chorea.
      • Yakinci C.
      • Durmaz Y.
      • Korkut M.
      • Aladag A.
      • Onal C.
      • Aydinli M.
      Cavernous hemangioma in a child presenting with hemichorea: response to pimozide.
      • Osari S.
      • Muranaka H.
      • Kojima T.
      • Kimura Y.
      Persistent chorea following cardiac surgery for congenital heart disease.
      • Hama A.
      • Furune S.
      • Nomura K.
      • Takada Y.
      • Matsushima Y.
      A case of unilateral moyamoya disease presenting with hemichorea.
      The extrapyramidal side effects of pimozide are fewer than those of haloperidol, but potential cardiac side effects of prolonged QT and arrhythmia limit its use in children.

      Chlorpromazine

      Chlorpromazine was the first antipsychotic drug discovered in 1950 and is considered as one of the greatest advances of the twentieth century medicine. The use of this drug in children with SC was first published in 1956.
      • Lopez-Munoz F.
      • Alamo C.
      • Cuenca E.
      • Shen W.
      • Clervoy P.
      • Rubio G.
      History of the discovery and clinical introduction of chlorpromazine.
      Following this report, chlorpromazine was used in a few studies with inadequate information on dosing and efficacy.
      • Lewenfisz-Wojnarowska T.
      • Popielarska A.
      • Grzybowska J.
      Largactil administration in chorea in children.
      • Gillot F.
      • Sendra L.
      • Dalaut J.J.
      • Legeais G.
      • Guenoun M.
      34 Cases of acute chorea in children observed in the Children’s Hospital of Algiers; etiological conclusions and current therapeutic methods.
      • Machado A.
      • Cerqueira J.
      • Rodrigues M.
      • Soares-Fernandes J.
      Is methylphenidate-induced chorea responsive to chlorpromazine?.
      In the study by Tumas et al.,
      • Tumas V.
      • Caldas C.T.
      • Santos A.C.
      • Nobre A.
      • Fernandes R.M.
      Sydenham’s chorea: clinical observations from a Brazilian movement disorder clinic.
      among 100 cases with SC, only one received chlorpromazine and responded well. Teixiera et al.
      • Teixeira A.L.
      • Cardoso F.
      • Maia D.P.
      • Cunningham M.C.
      Sydenham’s chorea may be a risk factor for drug induced parkinsonism.
      compared the side effect profile of chlorpromazine between patients with SC and those with Tourette syndrome with the hypothesis of increased susceptibility of patients with SC for extrapyramidal side effects. The investigators concluded that individuals with SC were more prone to develop extrapyramidal side effects, but the limited demographic data of the groups made it difficult to comment on this result. In 2007, Weiner and Normandin
      • Weiner S.G.
      • Normandin P.A.
      Sydenham chorea.
      reported a nine-year-old girl with SC who improved with 50 mg three times daily dosing of chlorpromazine. Chlorpromazine may be effective in childhood chorea, but it has no obvious superiority over other potential treatments.

      Atypical (second-generation) antipsychotics

      These drugs were first introduced with clozapine in 1990
      • Crilly J.
      The history of clozapine and its emergence in the US market a review and analysis.
      ; they are often preferred due to their lower risk of TD. However, the lower risk of TD may correspond to lower efficacy for chorea. Agents with higher potency at D2 receptors are more likely to be effective. Olanzapine and risperidone have been recommended for the treatment of SC.
      • Cardoso F.
      Sydenham’s chorea.
      • Sethi S.
      • Setiya R.
      • Lallar K.
      Successful treatment of Sydenham chorea with olanzapine.
      Recently, Kamate et al.
      • Kamate M.
      • Mittal N.
      • Metgud D.
      Effect of risperidone on the motor and functional disability in children with choreoathetoid cerebral palsy.
      studied the effect of risperidone on 30 children with choreoathetoid cerebral palsy. The investigators reported a statistically significant decline in abnormal movements, improvement in quality of life and positive change in behavior without significant side effects. Although the limited number of reports makes it difficult to comment on their use in childhood chorea, atypical antipsychotics may be considered as a treatment option and prioritized in children with behavioral comorbidities. We recommend the following considerations:
      • Haloperidol is an effective antichoreic agent with high potential for side effects; therefore it should be reserved for severe cases and used with caution.
      • Pimozide has fewer neuropsychiatric side effects but has a higher risk for cardiac side effects of arrhythmia and prolongation of the QTc interval.
      • Atypical antipsychotic agents may also be effective and may be preferred in children with psychiatric comorbidities including FDA-approved indications.

      Levodopa (L-dopa)

      l-Dopa is the immediate precursor to dopamine in the synthetic pathway. Despite the fact that treatment with l-dopa worsens chorea in most conditions and may cause LID, treatment with l-dopa, may be effective in BHC due to TITF1/NKX2-1 gene mutations.
      • Gras D.
      • Jonard L.
      • Roze E.
      • Chantot-Bastaraud S.
      • Koht J.
      • Motte J.
      Benign hereditary chorea: phenotype, prognosis, therapeutic outcome and long term follow-up in a large series with new mutations in the TITF1/NKX2-1 gene.
      • Asmus F.
      • Horber V.
      • Pohlenz J.
      • et al.
      A novel titf-1 mutation causes benign hereditary chorea with response to levodopa.
      • Fons C.
      • Rizzu P.
      • Garcia-Cazorla A.
      • et al.
      TITF-1 gene mutation in a case of sporadic nonprogressive chorea. Response to levodopa treatment.
      BHC is possibly the only form of chorea that is likely to respond to l-dopa. Although the mechanism is unclear, a lack of functional TITF-1 protein might impair developmental maturation of the dopamine pathways in the basal ganglia.
      • Kawano H.
      • Horie M.
      • Honma S.
      • Kawamura K.
      • Takeuchi K.
      • Kimura S.
      Aberrant trajectory of ascending dopaminergic pathway in mice lacking Nkx2.1.

      Antiepileptic drugs

      These drugs are commonly used for the treatment of hyperkinetic movement disorders in children
      • Siniscalchi A.
      • Gallelli L.
      • De Sarro G.
      Use of antiepileptic drugs for hyperkinetic movement disorders.
      ; their primary mechanism of action is thought to be increasing brain GABA levels either with sodium channel blockage or with a GABA agonist effect.
      • Feinstein E.
      • Walker R.
      An update on the treatment of chorea.
      Valproic acid and carbamazepine are the two most common antiepileptic drugs used to treat childhood chorea associated with various diseases such as SC, kernicterus, vascular, hypoxic, and traumatic chorea.
      • Axley J.
      Rheumatic chorea controlled with haloperidol.
      • Shenker D.M.
      • Grossman H.J.
      • Klawans H.L.
      Treatment of Sydenham’s chorea with haloperidol.
      • Shannon K.M.
      • Fenichel G.M.
      Pimozide treatment of Sydenham’s chorea.
      • Yakinci C.
      • Durmaz Y.
      • Korkut M.
      • Aladag A.
      • Onal C.
      • Aydinli M.
      Cavernous hemangioma in a child presenting with hemichorea: response to pimozide.
      • Osari S.
      • Muranaka H.
      • Kojima T.
      • Kimura Y.
      Persistent chorea following cardiac surgery for congenital heart disease.
      • Hama A.
      • Furune S.
      • Nomura K.
      • Takada Y.
      • Matsushima Y.
      A case of unilateral moyamoya disease presenting with hemichorea.
      • Teixeira A.L.
      • Cardoso F.
      • Maia D.P.
      • Cunningham M.C.
      Sydenham’s chorea may be a risk factor for drug induced parkinsonism.

      Valproic acid

      Valproic acid was first used for the treatment of chorea in a 19-year-old-patient with SC in 1981.
      • McLachlan R.S.
      Valproic acid in Sydenham’s chorea.
      In the following years, several cases and case series reporting efficacy of valproate for chorea related to various etiologies were published.
      • Chandra V.
      • Spunt A.L.
      • Rusinowitz M.S.
      Treatment of post-traumatic choreo-athetosis with sodium valproate.
      • Alvarez L.A.
      • Novak G.
      Valproic acid in the treatment of Sydenham chorea.
      • Dhanaraj M.
      • Radhakrishnan A.R.
      • Srinivas K.
      • Sayeed Z.A.
      Sodium valproate in Sydenham’s chorea.
      • Giroud M.
      • Dumas R.
      Valproate sodium in postanoxic choreoathetosis.
      • Steinberg A.
      • Reifen R.M.
      • Leifer M.
      Efficacy of valproic acid in the treatment of Sydenham’s chorea.
      • Daoud A.S.
      • Zaki M.
      • Shakir R.
      • al-Saleh Q.
      Effectiveness of sodium valproate in the treatment of Sydenham’s chorea.
      • Kulkarni M.L.
      Sodium valproate controls choreoathetoid movements of kernicterus.
      • Davutoglu V.
      • Kilinc M.
      • Dinckal H.
      • Soydinc S.
      • Sezen Y.
      Sydenham’s chorea-clinical characteristics of nine patients.
      • Sabui T.K.
      • Pant P.
      Sodium valproate in the treatment of Sydenham’s chorea.
      In a retrospective comparison study by Pena et al.,
      • Pena J.
      • Mora E.
      • Cardozo J.
      • Molina O.
      • Montiel C.
      Comparison of the efficacy of carbamazepine, haloperidol and valproic acid in the treatment of children with Sydenham’s chorea: clinical follow-up of 18 patients.
      valproic acid was found to be more effective than carbamazepine and haloperidol. Genel et al.
      • Genel F.
      • Arslanoglu S.
      • Uran N.
      • Saylan B.
      Sydenham’s chorea: clinical findings and comparison of the efficacies of sodium valproate and carbamazepine regimens.
      prospectively compared valproic acid and carbamazepine and reported that they are equally effective and safe. As a result, valproic acid is one of the first-line therapeutic options for the treatment of chorea in childhood. However, its long-term side effects on bone metabolism, increased risk of polycystic ovary syndrome, and teratogenic effects should be kept in mind in children and adolescents, particularly the ones who may require longer treatment duration.

      Carbamazepine

      Carbamazepine is the treatment of choice in chorea associated with paroxysmal kinesigenic dyskinesia (PKD).
      • Waln O.
      • Jankovic J.
      Paroxysmal movement disorders.
      • Mink J.W.
      Treatment of paroxysmal dyskinesias in children.
      • Sun W.
      • Li J.
      • Zhu Y.
      • Yan X.
      • Wang W.
      Clinical features of paroxysmal kinesigenic dyskinesia: report of 24 cases.
      In addition to the comparison studies of carbamazepine use in SC described above, the efficacy and safety of carbamazepine in SC is supported by other case reports and case series.
      • Roig M.
      • Montserrat L.
      • Gallart A.
      Carbamazepine: an alternative drug for the treatment of nonhereditary chorea.
      • Harel L.
      • Zecharia A.
      • Straussberg R.
      • Volovitz B.
      • Amir J.
      Successful treatment of rheumatic chorea with carbamazepine.
      These findings make carbamazepine one of the more preferred antichoreic agents in childhood chorea along with TBZ and valproate.

      Other antiepileptic drugs

      Other antiepileptic drugs are known to be effective in different etiologic subgroups of chorea. Other than carbamazepine, phenytoin, phenobarbital, gabapentin, topiramate, oxcarbazepine, valproic acid, and lamotrigine have also been used in PKD.
      • Waln O.
      • Jankovic J.
      Paroxysmal movement disorders.
      • Mink J.W.
      Treatment of paroxysmal dyskinesias in children.
      • Sun W.
      • Li J.
      • Zhu Y.
      • Yan X.
      • Wang W.
      Clinical features of paroxysmal kinesigenic dyskinesia: report of 24 cases.
      • Palau-Bargues J.
      • Rubio-Agusti I.
      • Burguera J.A.
      • Vilchez-Padilla J.J.
      • Villanueva V.E.
      Familial idiopathic paroxysmal kinesigenic dyskinesia: its natural history and a descriptive study in three Spanish families.
      • Iglesias-Gómez S.
      • Vadillo-Olmo F.J.
      • Abella-Corral J.
      • et al.
      Oxcarbazepine in the treatment of kinesigenic paroxysmal choreoathetosis.
      • Huang Y.G.
      • Chen Y.C.
      • Du F.
      • et al.
      Topiramate therapy for paroxysmal kinesigenic choreoathetosis.
      Levetiracetam has been reported to be effective in one individual with SC and two patients with choreoathetoid cerebral palsy
      • Sahin S.
      • Cansu A.
      A new alternative drug with fewer adverse effects in the treatment of Sydenham chorea: levetiracetam efficacy in a child.
      • Vles G.F.
      • Hendriksen J.G.
      • Visschers A.
      • Speth L.
      • Nicolai J.
      • Vles J.S.
      Levetiracetam therapy for treatment of choreoathetosis in dyskinetic cerebral palsy.
      ; it has also been reported effective in two children with genetically confirmed paroxysmal nonkinesigenic dyskinesia (PNKD).
      • Szczałuba K.
      • Jurek M.
      • Szczepanik E.
      • et al.
      A family with paroxysmal nonkinesigenic dyskinesia: genetic and treatment issues.
      Gabapentin has been reported to be effective for hemichorea/hemiballismus.
      • Kothare S.V.
      • Pollack P.
      • Kulberg A.G.
      • Ravin P.D.
      Gabapentin treatment in a child with delayed-onset hemichorea/hemiballismus.
      In one individual with GNAO1-related resistant chorea, topiramate significantly reduced the frequency of chorea episodes.
      • Sakamoto S.
      • Monden Y.
      • Fukai R.
      • et al.
      A case of severe movement disorder with GNAO1 mutation responsive to topiramate.
      Mutations in several genes (e.g., PRRT2, GNAO1, FOXG1, SCN8A, GRIN1) have been associated with both chorea and epilepsy.
      • Papandreou A.
      • Schneider R.B.
      • Augustine E.F.
      • et al.
      Delineation of the movement disorders associated with FOXG1 mutations.
      • Larsen J.
      • Carvill G.L.
      • Gardella E.
      • et al.
      The phenotypic spectrum of SCN8A encephalopathy.
      • Lemke J.R.
      • Geider K.
      • Helbig K.L.
      • et al.
      Delineating the GRIN1 phenotypic spectrum: a distinct genetic NMDA receptor encephalopathy.
      • Saitsu H.
      • Fukai R.
      • Ben-Zeev B.
      • et al.
      Phenotypic spectrum of GNAO1 variants: epileptic encephalopathy to involuntary movements with severe developmental delay.
      The increasing awareness of this association may favor the use of antiepileptic drugs in childhood chorea to treat two different conditions with a single drug to prevent multidrug use and related side effects. However, evidence is still lacking to determine whether this is the best approach.
      Although antiepileptic drugs may be effective for treating chorea, these drugs, especially at high doses or in combination, may also cause chorea. A significant increased risk is described with the combined use of phenytoin and lamotrigine.
      • Zaatreh M.
      • Tennison M.
      • D’Cruz O.N.
      • Beach R.L.
      Anticonvulsants-induced chorea: a role for pharmacodynamic drug interaction?.
      • Shanmugam S.
      • Daniel L.
      • Ahamed J.
      Meta-analysis of antiepileptic drugs induced choreoathetosis in paediatric patients.
      This possibility should be kept in mind in the setting of acute-onset chorea in individuals with newly initiated antiepileptic medication either alone or combination.
      Although there is no consensus for the use of antiepileptic medications in childhood chorea, we provide the following recommendations:
      • Valproic acid and carbamazepine may be preferred first-line agents for treating chorea, especially SC.
      • Carbamazepine is the treatment of choice in PKD.
      • The coexistence of epilepsy and chorea in an individual patient may be a reason to consider antiepileptic drugs as first-line agents for treating the chorea.

      Benzodiazepines

      Benzodiazepines, especially clonazepam, may be beneficial for treating chorea due to a variety of causes. Most of the published reports of clonazepam for treating chorea are in patients with PNKDs.
      • Waln O.
      • Jankovic J.
      Paroxysmal movement disorders.
      • Mink J.W.
      Treatment of paroxysmal dyskinesias in children.
      • Sun W.
      • Li J.
      • Zhu Y.
      • Yan X.
      • Wang W.
      Clinical features of paroxysmal kinesigenic dyskinesia: report of 24 cases.
      • Bruno M.K.
      • Lee H.Y.
      • Auburger G.W.
      • Friedman A.
      • Nielsen J.E.
      • Lang A.E.
      Genotype-phenotype correlation of paroxysmal nonkinesigenic dyskinesia.
      • Yeh T.H.
      • Lin J.J.
      • Lai S.C.
      • et al.
      Familial paroxysmal nonkinesigenic dyskinesia: clinical and genetic analysis of a Taiwanese family.
      SLC6A3-related dopamine transporter deficiency syndrome is another disorder for which benzodiazepines may be beneficial to reduce chorea and other dyskinesias.
      • Kurian M.A.
      SLC6A3-Related dopamine transporter deficiency syndrome.

      Acetazolamide

      Acetazolamide is a carbonic anhydrase inhibitor that has been reported to be effective for reducing symptoms in paroxysmal disorders such as episodic ataxia, periodic paralysis, and spinocerebellar ataxia type 6. Although treatment of paroxysmal dyskinesias has been less beneficial, acetazolamide has been reported to be effective to some extent in patients with chorea secondary to PKD, paroxysmal exertional dyskinesia (PED), and ADCY-5 related dyskinesia.
      • Fourcade G.
      • Roubertie A.
      • Doummar D.
      • Vidailhet M.
      • Labauge P.
      Paroxysmal kinesigenic dyskinesia: a channelopathy? Study of 19 cases.
      • Fernandez M.
      • Raskind W.
      • Wolff J.
      • et al.
      Familial dyskinesia and facial myokymia (FDFM): a novel movement disorder.
      • Carecchio M.
      • Mencacci N.E.
      • Iodice A.
      • et al.
      ADCY5-related movement disorders: frequency, disease course and phenotypic variability in a cohort of paediatric patients.
      • Anheim M.
      • Maillart E.
      • Vuillaumier-Barrot S.
      • et al.
      Excellent response to acetazolamide in a case of paroxysmal dyskinesias due to GLUT1-deficiency.
      • Ramm-Pettersen A.
      • Nakken K.O.
      • Skogseid I.M.
      • et al.
      Good outcome in patients with early dietary treatment of GLUT-1 deficiency syndrome: results from a retrospective Norwegian study.

      Methylphenidate

      Methylphenidate is a dopamine reuptake blocker that increases synaptic concentrations of dopamine. It may seem illogical that methylphenidate might reduce choreas, but it has been reported to be effective in BHC.
      • Friederich R.L.
      Benign hereditary chorea improved on stimulant therapy.
      Similar to the effect of l-dopa on NKX2-1/TITF1 gene disorders, the exact mechanism of its benefit remains unknown.
      • Gauquelin L.
      • Tran L.T.
      • Chouinard S.
      • Bernard G.
      The movement disorder of brain-lung-thyroid syndrome can be responsive to methylphenidate.
      • Devos D.
      • Vuillaume I.
      • Becdelievre A.D.
      • et al.
      New syndromic form of benign hereditary chorea is associated with a deletion of TITF-1 and PAX-9 contiguous genes.
      In a recent study by Tubing et al.,
      • Tubing J.
      • Bohnenpoll J.
      • Spiegler J.
      • et al.
      Methylphenidate can improve chorea in NKX2.1 and ADCY5 mutation-positive patients—a report of two children.
      methylphenidate was found effective in two patients with NKX2-1 and ADCY-5 gene-related chorea with additional attention-deficit/hyperactivity disorder. These findings raise the possibility that methylphenidate may be a treatment option in patients with chorea and concomitant attention-deficit/hyperactivity disorder.

      Amantadine

      Amantadine is a noncompetitive N-methyl-d-aspartic acid (NMDA) receptor antagonist acting as an antiglutamatergic agent. The mechanism of action of this drug on dopaminergic system is not well understood. In adults, amantadine is the treatment of choice for LID in PD. In childhood, it was used with some benefit in a single study of ataxia telangiectasia with motor impairment including chorea.
      • Nissenkorn A.
      • Hassin-Baer S.
      • Lerman S.F.
      • Levi Y.B.
      • Tzadok M.
      • Ben-Zeev B.
      Movement disorder in ataxia-telangiectasia: treatment with amantadine sulfate.

      l-Thyroxine

      This drug was recently reported in a single individual with BHC, asymptomatic hypothyroidism, and arm chorea. Discontinuation of l-thyroxine after a long period of euthyroid status resulted in drop attacks and reemergence of upper limb chorea. These symptoms resolved after reinitiation of l-thyroxine replacement therapy.
      • Shiohama T.
      • Ohashi H.
      • Shimizu K.
      • et al.
      L-Thyroxine-responsive drop attacks in childhood benign hereditary chorea: a case report.

      Deep brain stimulation

      Deep brain stimulation (DBS) has been used to treat a variety of movement disorders for the past two decades. Although DBS is more commonly and effectively used in childhood for primary dystonia, it may be an effective alternative treatment for medically intractable chorea. DBS treatment has been reported in dyskinetic cerebral palsy, ADCY-5-related dyskinesia, and GNAO1-related severe choreoathetosis, with variable outcomes.
      • Waak M.
      • Mohammad S.S.
      • Coman D.
      • et al.
      GNAO1-related movement disorder with life-threatening exacerbations: movement phenomenology and response to DBS.
      • Koy A.
      • Cirak S.
      • Gonzalez V.
      • et al.
      Deep brain stimulation is effective in pediatric patients with GNAO1 associated severe hyperkinesia.
      • Sato K.
      • Nakagawa E.
      • Saito Y.
      • et al.
      Hyperkinetic movement disorder in a child treated by globus pallidus stimulation.
      • Dy M.E.
      • Chang F.C.
      • Jesus S.D.
      • et al.
      Treatment of ADCY5-associated dystonia, chorea, and hyperkinetic disorders with deep brain stimulation: a multicenter case series.
      • Lin J.P.
      • Kaminska M.
      • Perides S.
      • et al.
      Bilateral globus pallidus internus deep brain stimulation for dyskinetic cerebral palsy supports success of cochlear implantation in a 5-year old ex-24 week preterm twin with absent cerebellar hemispheres.
      Uncertainty of case selection criteria, optimal age at procedure for the best benefit, and outcome-predicting factors require additional research.
      • Elia A.E.
      • Bagella B.F.
      • Ferr F.
      • Zorzi G.
      • Calandrella D.
      • Romito L.M.
      Deep brain stimulation for dystonia due to cerebral palsy: a review.
      • Koy A.
      • Timmermann L.
      Deep brain stimulation in cerebral palsy: challenges and opportunities.

      Specific paroxysmal dyskinesias

      Some of the paroxysmal dyskinesias have been shown to respond to specific medications; this is true for the most common forms of PKD, PNKD, and PED. As described above, carbamazepine is the treatment of choice in PKDs.
      • Waln O.
      • Jankovic J.
      Paroxysmal movement disorders.
      • Mink J.W.
      Treatment of paroxysmal dyskinesias in children.
      • Sun W.
      • Li J.
      • Zhu Y.
      • Yan X.
      • Wang W.
      Clinical features of paroxysmal kinesigenic dyskinesia: report of 24 cases.
      Proline-rich transmembrane protein-2 (PRRT2) gene mutations may present with a wide range of neurological conditions including benign familial infantile epilepsy, infantile convulsions and choreoathetosis, PKD, episodic ataxia, and familial hemiplegic migraine.
      • Chen W.J.
      • Lin Y.
      • Xiong Z.Q.
      • et al.
      Exome sequencing identifies truncating mutations in PRRT2 that cause paroxysmal kinesigenic dyskinesia.
      • Liu Q.
      • Qi Z.
      • Wan X.H.
      • et al.
      Mutations in PRRT2 result in paroxysmal dyskinesias with marked variability in clinical expression.
      • Ebrahimi-Fakhari D.
      • Saffari A.
      • Westenberger A.
      • Klein C.
      The evolving spectrum of PRRT2-associated paroxysmal diseases.
      • Silveira-Moriyama L.
      • Gardiner A.R.
      • Meyer E.
      • et al.
      Clinical features of childhood-onset paroxysmal kinesigenic dyskinesia with PRRT2 gene mutations.
      Huang et al.
      • Huang X.J.
      • Wang T.
      • Wang J.
      • et al.
      Paroxysmal kinesigenic dyskinesia: clinical and genetic analyses of 110 patients.
      reported that 98.4% of patients with PRRT2 mutations who received carbamazepine displayed a good response. Carbamazepine may also be effective in PKD due to other causes (secondary PKD).
      • Mink J.W.
      Treatment of paroxysmal dyskinesias in children.
      • Roig M.
      • Montserrat L.
      • Gallart A.
      Carbamazepine: an alternative drug for the treatment of nonhereditary chorea.
      PNKD typically does not respond to carbamazepine, but it has been shown to respond to benzodiazepines, with most reports specifying clonazepam.
      • Bruno M.K.
      • Lee H.Y.
      • Auburger G.W.
      • Friedman A.
      • Nielsen J.E.
      • Lang A.E.
      Genotype-phenotype correlation of paroxysmal nonkinesigenic dyskinesia.
      • Yeh T.H.
      • Lin J.J.
      • Lai S.C.
      • et al.
      Familial paroxysmal nonkinesigenic dyskinesia: clinical and genetic analysis of a Taiwanese family.
      PED due to SLC2A1 mutations (GLUT1 deficiency) does not consistently respond to either carbamazepine or clonazepam, but it may respond in some patients to acetazolamide or the ketogenic diet.
      • Anheim M.
      • Maillart E.
      • Vuillaumier-Barrot S.
      • et al.
      Excellent response to acetazolamide in a case of paroxysmal dyskinesias due to GLUT1-deficiency.
      • Ramm-Pettersen A.
      • Nakken K.O.
      • Skogseid I.M.
      • et al.
      Good outcome in patients with early dietary treatment of GLUT-1 deficiency syndrome: results from a retrospective Norwegian study.
      The response of paroxysmal dyskinesias due to other causes may be more variable.

      Other agents

      Recently, there has been growing interest in the potential for cannabinoids to treat a variety of movement disorders. Cannabinoids modulate the dopaminergic system through cannabinoid receptors (CB1), and the endocannabinoid system is involved in the basal ganglia pathways that are responsible for the generation of chorea.
      • Feinstein E.
      • Walker R.
      An update on the treatment of chorea.
      • Kluger B.
      • Triolo P.
      • Jones W.
      • et al.
      The therapeutic potential of cannabinoids for movement disorders.
      • Andrzejewski K.
      • Barbano R.
      • Mink J.
      Cannabinoids in the treatment of movement disorders: a systematic review of case series and clinical trials.
      However, in a systematic review published in 2017, the evidence to support the use of cannabinoids in childhood was found insufficient in conditions other than chemotherapy-related nausea, vomiting, and epilepsy.
      • Wong S.S.
      • Wilens T.E.
      Medical cannabinoids in children and adolescents: a systematic review.
      Thus, there is currently no evidence to support the use of cannabinoids in any movement disorders in childhood.

      Treatment targeting the underlying etiology

      Etiology-based treatment of chorea may include pharmacologic, surgical, and dietary interventions. Some specific conditions in which chorea is a prominent feature and treating the underlying disease results in resolution or improvement of chorea are discussed below. The specific treatment of inborn errors of metabolism resulting in chorea is beyond the scope of this review.

      Sydenham chorea

      The pathophysiology of SC raises the possibility of immune-modulating therapies such as corticosteroids, intravenous immunoglobulin (IVIG), plasmapheresis, and rituximab being effective. The overall clinical experience to support the use of immunomodulatory therapies in SC is limited. Steroids have the strongest data with a prospective, double-blind randomized controlled trial and prospective or retrospective case series having been reported.
      • Paz J.A.
      • Silva C.A.
      • Marques-Dias M.J.
      Randomized double-blind study with prednisone in Sydenham’s chorea.
      • Fusco C.
      • Ucchino V.
      • Frattini D.
      • Pisani F.
      • Della Giustina E.
      Acute and chronic corticosteroid treatment of ten patients with paralytic form of Sydenham’s chorea.
      • Green L.N.
      Corticosteroids in the treatment of Sydenham’s chorea.
      In an open-label randomized study by Garvey et al.,
      • Garvey M.A.
      • Snider L.A.
      • Leitman S.F.
      • Werden R.
      • Swedo S.E.
      Treatment of Sydenham’s chorea with intravenous immunoglobulin, plasma exchange, or prednisone.
      IVIG, plasma exchange (PLEX), and oral prednisone were compared. Although clinical improvements appeared to be more rapid and robust in the IVIG and PLEX groups than in the prednisone group, the between-group differences were not statistically significant. The potential side effects, the limited scientific evidence, and the fact that SC usually improves with symptomatic therapy and resolves spontaneously have led to a tendency to reserve these alternatives for difficult to manage patients such as those with chorea paralytica.
      • Dean S.L.
      • Singer H.S.
      Treatment of Sydenham’s chorea: a review of current evidence.
      • Paz J.A.
      • Silva C.A.
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      Treatment of Sydenham’s chorea with intravenous immunoglobulin, plasma exchange, or prednisone.
      However, the underlying autoimmune basis for SC provides rationale for these treatments. It should be noted that although the primary aim is to protect the heart and its effect on chorea relapses is still not clear, secondary prophylaxis of group A β-hemolytic streptococci infections with penicillin is the standard of care for all children diagnosed with SC regardless of chorea severity.

      Anti-N-methyl-d-aspartic acid receptor encephalitis

      Anti-NMDA receptor encephalitis is the prototypic antibody-mediated encephalitis associated with chorea in childhood. The clinical presentation is quite classical with subacute onset of seizures, dyskinesias, insomnia, psychiatric symptoms, and autonomic instability. The clinical awareness of the disease in the last decade led to a noteworthy increase in the number of patients diagnosed with this clinical entity. Etiology-specific treatment of anti-NMDA receptor encephalitis includes the surgical removal of the tumor if present (most commonly ovarian teratomas) and several types of immunomodulatory treatments either alone or in combination including steroids, IVIG, PLEX, rituximab, and cyclophosphamide.
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      Principle and approaches to the treatment of immune-mediated movement disorders.
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      Autoimmune and paraneoplastic movement disorders: an update.

      Antiphospholipid antibody syndrome and systemic lupus erythematosus

      Chorea is the most common movement disorder in patients with APS and SLE, and it may even be the initial presenting symptom. APS is either a primary or a secondary systemic autoimmune condition characterized by hypercoagulable state, which results in arterial and venous thrombosis and pregnancy morbidities. Anticoagulant or antiplatelet agents are the first step for chorea treatment in APS. For patients who do not respond, additional therapeutic options such as azothioprine, cyclophosphamide, IVIG, PLEX, and rituximab are reported.
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      • Antenora A.
      • De Rosa A.
      • et al.
      Antiphospholipid-related chorea.
      • Torreggiani S.
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      • Cuoco F.
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      • Corona F.
      Chorea, a little-known manifestation in systemic lupus erythematosus: short literature review and four case reports.
      SLE is the most common secondary cause of APS, and the presence of antiphospholipid antibodies in SLE is defined as a strong risk factor for the development of chorea. Antiplatelet agents may be considered in patients with SLE with antiphospholipid antibodies. Chorea usually resolves with symptomatic therapy, and immunosuppressive agents may be considered in systemic disease activity.
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      Antiphospholipid-related chorea.
      • Torreggiani S.
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      Chorea, a little-known manifestation in systemic lupus erythematosus: short literature review and four case reports.
      • Bertsias G.K.
      • Ioannidis J.P.
      • Aringer M.
      • et al.
      EULAR recommendations for the management of systemic lupus erythematosus with neuropsychiatric manifestations: report of a task force of the EULAR standing committee for clinical affairs.

      Moyamoya disease

      Moyamoya disease is a progressive occlusive disease in which 3% of affected children may present with chorea. Although resolution may take months and relapses may occur, revascularization surgery has been reported to result in improvement of chorea.
      • Singer H.S.
      • Mink J.W.
      • Gilbert D.L.
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      Chorea, athetosis, and ballism.
      • Ahn E.S.
      • Scott R.M.
      • Robertson Jr., R.L.
      • Smith E.R.
      Chorea in the clinical presentation of moyamoya disease: results of surgical revascularization and a proposed clinicopathological correlation.

      Conclusion

      Currently available options for treating childhood chorea are many but often result in less-than-complete benefit. The large number of etiologies, the complex pathophysiology, and the presence of off-target effects for most available medications contribute to the therapeutic challenges. Even with increasing knowledge about underlying etiologies for chorea, the therapeutic approach requires complex clinical reasoning that relies on knowledge of neurochemistry, neural circuitry, immunologic mechanisms, and the natural history of the disorders. With a rational and systematic approach, prioritizing treatment of chorea that causes disability, meaningful clinical benefit can often be achieved even if chorea cannot be eliminated. In the future, it is expected that more etiology-based treatments will become available as the mechanisms are understood better.

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