Genetics of childhood disorders: XXXI. Autoimmune disorders, part 4: is Sydenham chorea an autoimmune disorder?

For many years Sydenham chorea (SC) has been considered the prototype of an autoimmune disorder triggered by an infectious agent. Nevertheless, despite its description more than 300 years ago by Thomas Sydenham, its defined association with rheumatic fever in 1838, and linkage to a preceding group A β-hemolytic streptococcal (GABHS) infection, there are numerous unanswered questions about the underlying pathology and pathophysiology of SC. Recently, clarification of the underlying mechanism in SC has assumed renewed importance as the disorder has been proposed as a model for a spectrum of childhood neurobehavioral disorders, including tics and obsessive-compulsive disorder, termed PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection). The distinguishing clinical manifestation of SC is the presence of spontaneous, involuntary choreiform movements affecting the face and extremities that typically persist for several months before subsiding. Diagnosis is made strictly on clinical observation. No confirmatory laboratory test for SC is available, although an elevated titer against antistreptolysin O, anti-deoxyribonuclease B, or anti-nicotinamide adenine dinucleotidase is demonstrated in 80% of SC patients. Onset is usually between ages 5 and 15 years, and a female predominance is observed in most studies. Associated neurological symptoms may include dysarthria, hypometric saccades, hypotonia, weakness, hemiballismus, and gait disturbances that correlate with severity of chorea. Affected individuals may present with behavioral or emotional difficulties that predate the motoric abnormalities by weeks to months. For example, most patients have concomitant psychological dysfunction presenting as personality changes, emotional irritability, distractibility, and age-regressed behaviors. Studies have also shown a higher frequency of obsessive-compulsive symptoms in children with SC or nonchoreic rheumatic fever. Motor or vocal tics and oculogyric crises have also been reported in patients with SC. Despite a relatively common occurrence of EEG abnormalities, seizures are uncommon. Rheumatic valvular cardiac disease is seen in about one third of patients, although echocardiogram screenings suggest a higher prevalence. Arthritis is uncommon. The outcome in SC is quite favorable. Most cases resolve in 1 to 6 months. Some investigators have identified residual abnormal EEGs, minor lingering motor abnormalities, persistent neuropsychiatric problems, and future development of valvular heart disease. About 20% to 60% of cases have recurrent episodes of chorea, usually within 1 to 2 years after the original event. An individual may have multiple attacks with reactivation precipitated by a GABHS infection or by another environmental stimulus. Pregnancy and oral contraceptives may stimulate the reappearance of chorea after many years of quiescence. Magnetic resonance imaging (MRI) and functional imaging studies in SC have localized acute changes to the basal ganglia. In an MRI study evaluating the size of the basal ganglia in 24 patients with SC and 48 matched controls, children with SC had a 10% increase in size of the caudate and a 7% increase in size of both putamen and globus pallidus. A limited number of postmortem brain studies have demonstrated Genetics of Childhood Disorders: XXXI. Autoimmune Disorders, Part 4: Is Sydenham Chorea an Autoimmune Disorder?