Causes/Pathophysiology

Acute rheumatic fever (ARF) is a delayed inflammatory reaction in response to a streptococcal bacterial infection (i.e., with group A beta-hemolytic streptococci). Members of certain families appear to have an increased risk of ARF and rheumatic heart disease. In addition to possible hereditary factors, certain environmental factors, including overcrowded living conditions and malnutrition, are also thought to play some role in increasing susceptibility to streptococcal infections as well as the risk of subsequent ARF. Also, as mentioned previously, some investigators suggest that sex hormones (e.g., the female hormone estrogen) may be a contributing factor in some instances of Sydenham's chorea. This is based upon various findings, including the fact that females are more commonly affected than males, particularly in the years around puberty, and that recurrences have been associated with estrogen therapy or pregnancy.

The specific underlying mechanism(s) responsible for development of ARF remain unknown. However, evidence suggests that the disorder may result from an abnormal immune reaction in which antibodies produced in response to the invading bacterium act against certain of the body's own cells. For example, according to such a theory (sometimes known as "autoimmune mimicry"), a foreign protein (antigen) from a particular bacterium may be similar to one of the body's own proteins; as a result, the human immune system may be unable to distinguish between its "self" protein and that of the invading microorganism, potentially triggering an inappropriate autoimmune response. The symptom-free period between recovery from sore throat (pharyngitis) to the onset of symptoms associated with ARF (i.e., latent period) may lend support to the theory of an abnormal immune mechanism resulting in tissue damage.

In addition, experts suggest that Sydenham's chorea appears to result from such an autoimmune response. Evidence indicates that certain streptococcal proteins or antigens (streptococcal M proteins) induce the body's production of antibodies (i.e., antineuronal antibodies) that "crossreact" against the body's own cells in certain regions of the brain. (Group A streptococcal M protein has been shown to contain some of the same amino acid sequences as within certain human tissues.) Furthermore, some researchers have reported detecting certain antibodies (e.g., immunoglobulin G [IgG] antibodies) in children with Sydenham's chorea that interacted with certain cellular proteins (i.e., neuronal antigens) in the basal ganglia, such as the caudate nuclei and subthalamic nucleus. The basal ganglia are paired nerve cell clusters deep within the brain that play an essential role in initiating and regulating movement.

In another study, researchers determined that, during acute attacks, 80 percent of patients with ARF had antibodies against cardiolipin (anticardiolipin antibodies). Cardiolipin is a fatty compound (i.e., phospholipid) located within human mitochondrial inner membranes and bacterial cellular membranes. There was not a significant difference in the percentage of patients with antibodies who did or did not have Sydenham's chorea.

As mentioned above, Sydenham's chorea appears to result from an autoimmune or antibody-mediated inflammatory response involving certain regions of the basal ganglia. Experts indicate that the results of certain neuroimaging studies may provide further information concerning underlying disease processes (i.e., pathophysiology) involved in Sydenham's chorea. For example, such studies have demonstrated abnormally increased metabolism (hypermetabolism) in certain regions of the brain, findings that may reflect the autoimmune process. More specifically, positron emission tomography (PET) scanning has shown increased glucose metabolism within major substructures of the basal ganglia (i.e., striatum), a finding that was reversed with clinical improvement. This is in marked contrast to Huntington's disease (HD) and other hereditary forms of chorea, in which PET demonstrates decreased glucose and oxygen metabolism. In addition, magnetic resonance imaging (MRI) of patients with Sydenham's chorea has shown abnormally increased size of the 3 major substructures that form the basal ganglia, including the caudate nuclei, the globus pallidus, and the putamen, possibly providing evidence of an inflammatory process.

	Diagnosis