I. Pezone, S. Vendemmia, M. Vendemmia
Institution: ASL Caserta, San Giuseppe Moscati Hospital, Pediatric Unit
Correspondence to:
ABSTRACT
Sydenham's chorea (SC), also known as chorea minor, is a major manifestation of acute rheumatic fever (ARF) and represents one of the few causes of acquired chorea in children and adolescents. While its incidence has decreased in high-income countries due to improved treatment of Streptococcus pyogenes pharyngitis, it remains a public health issue in low-resource settings. This review summarizes current understanding of the epidemiology, pathogenesis, clinical features, diagnostic approach, and treatment strategies of SC, with a focus on recent advances in neuroimmunology and potential therapeutic targets.
INTRODUCTION
Sydenham’s chorea is a post-infectious movement disorder that classically occurs several weeks to months after group A streptococcal (GAS) pharyngitis, as part of the spectrum of acute rheumatic fever. First described by Thomas Sydenham in 1686, the condition is characterized by involuntary, rapid, purposeless movements, emotional lability, and hypotonia. While self-limiting in most cases, SC may recur and can be associated with long-term neuropsychiatric sequelae. Understanding the immunopathological mechanisms of SC is essential for developing targeted therapies and for guiding management of ARF.
EPIDEMIOLOGY
The global burden of rheumatic fever remains significant, especially in sub-Saharan Africa, South Asia, and parts of Latin America. SC affects approximately 10–30% of patients with ARF. Girls are disproportionately affected, and the peak incidence is between 5 and 15 years of age. The latency between streptococcal infection and the onset of chorea, which can range from 1 to 6 months, often complicates diagnosis.
PATHOGENESIS
The current model supports a molecular mimicry mechanism: antibodies generated against GAS antigens cross-react with basal ganglia neuronal antigens, particularly lysoganglioside GM1 and tubulin. These autoantibodies can modulate neuronal signaling, particularly through effects on dopamine receptors (notably D1 and D2). This neuroimmune interaction results in the dysregulation of motor circuits involving the striatum, thalamus, and cortex.
Recent studies using functional neuroimaging (e.g., SPECT, fMRI) have identified hypermetabolism in the basal ganglia during acute SC, supporting this model. Moreover, elevated anti-basal ganglia antibodies (ABGA) have been proposed as a potential biomarker, although their clinical utility remains debated.
CLINICAL FEATURES
Sydenham’s chorea presents insidiously with:
- Chorea: Rapid, involuntary movements, often asymmetric, affecting limbs, face, and trunk.
- Motor impersistence: Inability to sustain voluntary muscle contraction (e.g., "milkmaid’s grip").
- Hypotonia: Floppy posture and poor muscle tone.
- Emotional lability: Irritability, anxiety, and even psychosis in severe cases.
- Cognitive symptoms: Attention deficits and learning difficulties, which may persist after resolution of motor symptoms.
The course is typically monophasic, with spontaneous resolution over weeks to months. However, relapses can occur, especially during pregnancy (chorea gravidarum).
DIAGNOSTIC APPROACH
SC is a major criterion in the Jones criteria (revised 2015) for the diagnosis of ARF. Diagnosis is clinical, but investigations aim to support evidence of prior streptococcal infection and to rule out mimickers
Investigations include:
- Throat culture or rapid antigen test for Streptococcus pyogenes.
- Antistreptolysin-O (ASO) and anti-DNase B titers (may be normal due to long latency).
- MRI brain: Often normal; may show nonspecific T2 hyperintensities in basal ganglia.
- EEG: Occasionally abnormal but nonspecific.
- ABGA testing: Investigational, not yet standard of care.
Differential diagnosis includes other causes of pediatric chorea: autoimmune (e.g., SLE), infectious (e.g., PANDAS, post-viral), metabolic (e.g., Wilson disease), and drug-induced.
TREATMENT
The management of Sydenham’s chorea (SC) involves a multifaceted approach that targets both symptom control and the underlying immune response, as well as prevention of recurrence. While the condition is often self-limiting, treatment can significantly reduce the duration and severity of symptoms and improve quality of life, particularly in moderate to severe cases.
Symptomatic treatment is usually the first step, especially when involuntary movements interfere with daily functioning. Medications such as valproic acid and carbamazepine are commonly used due to their relatively favorable side-effect profiles and effectiveness in reducing choreiform movements. These antiepileptic drugs modulate neuronal excitability and are generally well-tolerated in children and adolescents.
For more severe or refractory cases, antipsychotic agents like haloperidol or risperidone may be employed. These medications work by antagonizing dopamine receptors, particularly in the basal ganglia, but their use is limited by potential extrapyramidal side effects. They are typically reserved for patients who do not respond to first-line agents or whose symptoms are causing significant distress or disability.
Benzodiazepines, such as clonazepam, may be useful as adjunctive therapy. Their anxiolytic and muscle-relaxant properties can help manage both chorea and the emotional lability that often accompanies it.
In addition to symptomatic control, immunomodulatory therapy is considered in patients with moderate to severe SC or when symptoms persist beyond the expected time frame. Corticosteroids, such as oral prednisone, are frequently used and have been shown to reduce symptom duration and severity. The proposed mechanism is suppression of the autoimmune response that targets basal ganglia neurons.
In particularly severe or treatment-resistant cases, intravenous immunoglobulin (IVIG) or plasmapheresis may be considered, although evidence supporting their use is limited and based largely on case reports or small series. These interventions are typically reserved for patients with disabling chorea who have not responded to conventional therapies.
Importantly, all patients diagnosed with SC should begin secondary prophylaxis with intramuscular benzathine penicillin G, administered every 3 to 4 weeks. This is a cornerstone of treatment aimed at preventing recurrent group A streptococcal infections and, consequently, further episodes of rheumatic fever and SC. The duration of prophylaxis depends on several factors, including age, the presence or absence of carditis, and the number of previous rheumatic fever episodes. In general, prophylaxis should be continued for at least 10 years after the last episode or until the patient is 21 years old, whichever is longer.
Finally, supportive care is essential. Education of the patient and family, reassurance regarding the usually benign prognosis, and coordination with schools and mental health providers are important aspects of comprehensive management. Because emotional and cognitive disturbances can persist beyond resolution of motor symptoms, long-term follow-up and neuropsychological support may be necessary.
PROGNOSIS
Most patients recover fully within 6 months. However, up to 30% may experience relapses or persistent neuropsychiatric symptoms. Long-term follow-up, especially in children with recurrent episodes or emotional/cognitive disturbances, is essential. The risk of developing rheumatic carditis is independent of SC but must be assessed periodically.
FUTURE DIRECTIONS
Emerging research into the neuroimmune basis of SC suggests potential roles for targeted immunotherapies. Studies on monoclonal antibodies, anti-inflammatory agents, and neuroprotective drugs are ongoing. Improved biomarkers (e.g., ABGA subtypes, cytokine profiles) may enhance diagnostic accuracy. Moreover, understanding the overlap between SC and related disorders like PANDAS may clarify shared pathophysiological pathways.
CONCLUSION
Sydenham’s chorea remains a clinically important and fascinating manifestation of rheumatic fever, exemplifying the intersection of infection, autoimmunity, and neuropsychiatry. Early recognition, appropriate symptomatic and immunological treatment, and long-term prophylaxis are key to optimizing outcomes. Continued research is needed to refine diagnostic tools and develop targeted therapies.
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