Pediatrics

Sydenham chorea

OVERVIEW: What every practitioner needs to know

Are you sure your patient has Sydenham chorea? What are the typical findings for this disease?

  1. Generalized chorea (hemichorea in about 20%)

  2. Motor impersistence (tongue darting, milkmaid, and pronator signs); hypometric saccades

  3. Neuropsychiatric signs (emotional lability, obsessive-compulsive behaviors, anxiety, inattention) often precede the chorea.

  4. Reduced muscle tone, tics, grimacing, clumsiness, dysarthria, weakness.

Sydenham chorea (SC) is the most common form of immune chorea. Despite its decline in frequency worldwide, it remains the most prevalent form of chorea in children, even in developed areas. Sydenham chorea is one of the major diagnostic criteria of rheumatic fever caused by the group A beta-hemolytic streptococcus (GABHS). SC is present in 10%-30% of patients with rheumatic fever. Findings include the following:

Clinical Features

Chorea is characterized by rapid, random, continual, abrupt, unpredictable, nonstereotyped actions that are usually bilateral and generalized (although hemichorea occurs in 20%-35% of patients). The timing, direction and distribution of movements varies from moment to moment. Chorea usually worsens during attempted voluntary action.

Patients often display other neurological and non-neurological symptoms and signs:

The muscle tone is usually diminished, and in severe cases may be so pronounced that the patient becomes bedridden (“chorea paralytica”).

Tics are common, although it may be difficult to distinguish tics from fragments of chorea.

Dysarthria is frequent, and patients may present with a reduction of verbal frequency (“disinclination to speak”).

Alterations of speech may also include prosody (prosody is diminished, with a monotone speech), decreased vocal pitch, and increased duration of speech.

Behavioral abnormalities are common, usually precede the onset of chorea, and can lead to major dysfunction.

Obsessive-compulsive behaviors have been reported in 20%-70% of subjects, with about 20% having obsessive-compulsive disorder.

Attention deficit hyperactivity disorder (ADHD) has been found in about 30%.

Relation to Rheumatic Fever

The current diagnostic criteria for SC represents a modification of the Jones criteria first formulated in 1944 by the American Heart Association.

Chorea, of acute or sub-acute onset, must lack clinical and laboratory evidence of an alternative etiology.

The diagnosis is further supported by the presence of additional major or minor manifestations of rheumatic fever (Table I).

Table I.

Revised Jones Criteria for diagnosis of rheumatic fever
Major criteria Minor criteria
Polyarthritis Fever
Carditis Arthralgia
Subcutaneous nodules Elevated acute phase reactants
Erythema marginatum Prolonged P-R interval on ECG
Sydenham chorea Previous episode of rheumatic fever

Cardiac involvement, especially mitral value dysfunction, is reported in 60%-70% of cases with SC.

The association with arthritis is less common and is seen in about 30% of patients with SC.

Chorea is the sole manifestation of rheumatic fever in about 20% of cases.

Differential diagnosis:

The following conditions may present with findings similar to those of SC:

  • Systemic lupus erythematosus

  • Primary antiphospholipid antibody syndrome

  • Acute encephalitides

  • Drug intoxication

  • Wilson disease

  • Familial chorea

  • Metabolic (hyperglycemia)

  • Endocrine (hyperthyroidism)

What caused this disease to develop at this time?

  • The usual age of onset of Sydenham chorea is 8-9 years of age, but some patients have developed chorea during the third decade of life.

  • Patients develop SC 4-8 weeks after an episode of group A beta-hemolytic streptococcus (GABHS) pharyngitis.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

  • Selected tests should be performed to identify evidence for a streptococcal infection and to identify possible alternative etiologies.

    Specific laboratory tests should include:

    Throat culture

    Anti-streptolysin O titer

    Anti DNAse B titer

    Antinuclear antibody studies

    Anticardiolipin antibody

    Antiphospholipid tests

    Thyroid function tests

    Renal function tests

    Hepatic function tests

    Ceruloplasmin concentration

    Erythrocyte sedimentation rate

    C-reactive protein

    Spinal fluid analysis

EEG can be considered

Evaluations for other aspects of rheumatic fever (i.e., echocardiogram) should be performed.

Interpretation of laboratory tests:

  • Laboratory studies assist in eliminating alternative causes of chorea, but do not confirm the diagnosis of SC.

  • Throat cultures may confirm a preceding GABHS infection, but cultures are positive in only a minority of cases.

  • Acute-phase reactants (erythrocyte sedimentation rate and C-reactive protein) are usually normal in SC, since the interval between the group A beta-hemolytic streptococcus (GABHS) infection and onset of chorea is relatively long.

  • The antistreptolysin-O titer peaks 3-5 weeks and the anti-DNA B titer 8-12 weeks post infection. The percentage of patients with elevated antistreptococcal titers has ranged from about 15%-30%.

  • A single sample is insufficient evidence to determine whether the titer is rising or declining.

  • Several investigators have reported the presence of anti-basal ganglia antibodies in patients with SC, although their biological and diagnostic value remains unproven.

  • Cerebrospinal fluid analysis is often normal.

  • EEG is usually normal.

  • There is no specific biological marker for SC.

Would imaging studies be helpful? If so, which ones?

  • Imaging is primarily recommended to rule out other causes of chorea.

  • MRI imaging studies are usually normal in SC, but have sometimes demonstrated have basal ganglia enlargement and increased T2 intensity during the acute phase.

  • Positron emission tomography and single-photon emission computed tomography have identified transient increases in basal ganglia metabolism.

If you are able to confirm that the patient has Sydenham chorea, what treatment should be initiated?

  • The treatment of patients with SC should include the triad of primary therapy, symptomatic therapy and supportive care.

  • Primary Therapy:

    • Despite the fact that most patients do not have active GABHS infections at the onset of chorea, it is generally recommended that penicillin therapy be given (10-day course of oral penicillin V or benzathine penicillin G injection).

  • Treatment of chorea:

    • No large, placebo controlled, randomized, blinded studies have been performed, and most recommendations are based on case reports.

    • Several studies have suggested that valproate, pimozide, risperidone, haloperidol, tiapride, tetrabenazine and carbamazepine may be effective. In view of the side effects associated with dopaminergic antagonists, valproic acid is the drug of choice. The optimal dose is 20-25 mg/kg per day administered in three daily doses.

    • Irrespective of the choice of medication, once the patient has become symptom-free for at least one month, consideration should be given to gradually reducing the dosage.

    • Use of immunomodulatory therapies: Recognizing the autoimmune nature of SC, intravenous immunoglobulin (IVIG), plasma exchange, and oral prednisone have been used in small studies. In a study comparing oral prednisone (2mg/kg/day) to placebo, the addition of steroid accelerated recovery but did not alter the rate of remission and recurrence.

      The current recommendation is to reserve steroids for patients with refractory chorea i.e., the patient has been unsuccessfully treated with other antichorea medications. In this instance, IV methylprednisolone (25mg/kg/day) is given for 5 days followed by 1mg/kg/day of prednisone. Medication is gradually tapered after control of symptoms for 1 month.

      A small, controlled, open-label study found that IVIG or plasma exchange were equally as effective as oral prednisone in reducing chorea severity. In general, however, recognizing the effectiveness of other medications, the potential complications of IVIG and plasma exchange, their high cost, and limited trials, these treatments remain investigational.

    • Treatment of neuropsychiatric signs:

      • Psychiatric signs are usually short-lived.

      • Selective serotonin reuptake inhibitors are effective for obsessive-compulsive behaviors, benzodiazepines are used for anxiety, and in some patients antidepressants are required.

  • Prophylaxis of rheumatic fever:

    • The recommendation of the World Health Organization is the regular use of secondary prophylaxis with penicillin G benzathine (1.2 million units IM every 21 days). Allergic patients are treated with oral sulfa drugs, such as sulfadiazine, 500 mg every 6 hours.

What are the adverse effects associated with each treatment option?

N/A

What are the possible outcomes of Sydenham chorea?

In contrast to existing beliefs that SC is a self-limited condition, it has been suggested that in up to half of patients, chorea continues to be active 2 years after the acute onset. Further, in many cases, recurrences occur despite the use of penicillin prophylaxis. In multiple instances, a return in symptoms is not associated with a GABHS infection or change in antineuronal antibodies.

What causes this disease and how frequent is it?

  • Sydenham chorea is proposed to be a group A beta-hemolytic streptococcal (GABHS)-induced autoimmune disorder secondary to polyreactive antibodies against streptococci that also recognize neuronal extracellular surface or intracellular antigens. After binding to the normal protein, through the process of molecular mimicry, clinical symptoms may be secondary to altered cell signaling, cellular toxicity, or other mechanisms.

  • Support for an antineuronal antibody proposal in SC is based in part on the documentation of serum autoreactive antibodies against human basal ganglia or rat striatum. In acute rheumatic fever, cross reactive antibodies against the streptococcal group A carbohydrate antigen N-acetyl-beta-D-glucosamine (GlcNAc) and cardiac muscle have been associated with rheumatic carditis. In studies using monoclonal antibodies derived from acute SC patients, cross reactivity has been identified between GlcNAc and mammalian lysoganglioside GM1, tubulin, and the dopamine D1 and D2 receptors. SC monoclonal antibody and acute sera activate CaM kinase II release in human neuroblastoma cells. Despite the aforementioned, the microinjection of SC antibodies into rodent striatum does not alter motor behavior or cause detectable cellular changes.

How do these pathogens/genes/exposures cause the disease?

N/A

Other clinical manifestations that might help with diagnosis and management

N/A

What complications might you expect from the disease or treatment of the disease?

N/A

Are additional laboratory studies available; even some that are not widely available?

N/A

How can Sydenham chorea be prevented?

See above recommendations regarding prophylactic use of anti-streptococcal antibiotics.

What is the evidence?

Selected References:

Oosterveer, DM, Overweg-Plandsoen, WC, Roos, RA. "Sydenham's chorea: a practical overview of the current literature". Pediatr Neurol. vol. 43. 2010. pp. 1-6.

(A review of practical aspects of Sydenham chorea with diagnostic and treatment flow charts)

Cardoso, F. "Sydenham's chorea". Curr Treat Options Neurol. vol. 10. 2008. pp. 230-5.

(Quality review of multiple treatment options in Sydenham chorea)

Walker, KG, Wilmshurst, JM. "An update on the treatment of Sydenham's chorea: the evidence for established and evolving interventions". Ther Adv Neurol Disord. vol. 3. 2010. pp. 301-9.

(Thorough review of therapeutics in Sydenham chorea, with excellent summarization of major treatment studies)

Barash, J, Margalith, D, Matitiau, A. "Corticosteroid treatment in patients with Sydenham's chorea". Pediat Neurol. vol. 32. 2005. pp. 205-7.

(Case review of children treated with corticosteroids)

Ongoing controversies regarding etiology, diagnosis, treatment

N/A

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