Role of Streptococcal Infection in Tourette Syndrome and Other Neuropsychiatric Disease
abstracts & commentary
Sources: Singer HS, et al. Antibodies against human putamen in children with Tourette syndrome. Neurology 1998;50:1618-1624; Kurlan R. Tourette’s syndrome and PANDAS.’ Neurology 1998;50:1530-1534; Garvey MA, et al. PANDAS: The search for environmental triggers of pediatric neuropsychiatric disorders. Lessons from rheumatic fever. J Child Neurol 1998;13:413-423; Hall MC, et al. Acute disseminated encephalomyelitis-like syndrome following group A beta-hemolytic streptococcal infection. J Child Neurol 1998;13:354-356; DiFazio MP, et al. Acute myoclonus secondary to group A beta-hemolytic streptococcus infection: A PANDAS variant. J Child Neurol 1998;13:516-518; Sanberg PR, et al. Treatment of Tourette’s syndrome with mecamylamine. Lancet 1998;352:705-706.
Since the original description of sydenham’s chorea (sc) many decades ago, a growing appreciation has emerged of the complexity of neurologic disease that may be related to streptococcal infection. The acronym PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection) is a relatively new diagnostic construct to describe this spectrum of disease.
Several investigators have presented converging lines of evidence for a role of streptococcal infection in triggering Tourette syndrome (TS), obsessive-compulsive disorder (OCD) and other neuropsychiatric disease. Using standard ELISA and Western blot techniques, Singer and colleagues tested serum from 41 patients with TS (33 boys, 8 girls; mean age 11.3 years) and 39 controls (22 boys, 17 girls; mean age 12.1 years) for immune reactivity against human caudate, putamen, and globus pallidus. TS patients generated a significant increase in antineuronal antibodies, largely against putamen and caudate, compared to controls. Markers for streptococcal infection such as antistreptolysin O (ASO) titers were often equivocal.
DiFazio and colleagues reported three male patients, ages 5, 10, and 12 years, who developed a variety of myoclonic movement disorders associated with occult streptococcal infection. Only one patient was culture positive, but all had high ASO and anti-DNAase B titers. The myoclonus was effectively treated with erythromycin or penicillin, and recurred with subsequent reinfection with streptococcus. Similarly, Hall et al reported a case of an 11-year-old boy who, one week following group A beta-hemolytic streptococcal pharyngitis, developed paraparesis with a post-infectious encephalomyelitis. The patient responded well to antibiotics and corticosteroids.
Sanberg et al reported a retrospective case series of 13 Tourette’s patients treated with the nicotinic antagonist mecamylamine 2.5-5 mg/d, alone or in combination with haloperidol or sertraline. Four were adults (one female; mean age 34 years) and nine were children (one female; mean age 14 years). Eleven of the 13 improved significantly in motor and vocal tics, as well as behavioral complaints such as irritability and aggression.
Garvey et al and Kurlan provide excellent reviews of TS, tic disorders, and associated behavioral disturbance such as OCD that appear to arise from post-infectious autoimmune mechanisms. Thus, in addition to genetic factors that may determine a predisposition to TS, there appear to be important environmental triggers. An immune response generated against streptococcal antigens may crossreact with neuronal epitopes in the basal ganglia to cause neurological dysfunction. Trifiletti and colleagues at Cornell University Medical College have preliminarily identified a 83-kd brain protein by immunoblot analysis that seems to be recognized by antibodies in the serum of TS and OCD patients (Ann Neurol 1998;44:561).
The clinical therapeutic significance of these findings is important. Physicians now recognize the importance of penicillin prophylaxis for group A beta-hemolytic streptococcal infections in avoiding neurologic as well as cardiac complications. Undiagnosed streptococcal infection should always be considered in young patients presenting with new TS, OCD, SC, or other unusual movement disorders. Rather than using harsh neuroleptics for symptomatic management of TS or OCD, investigators are using immunomodulatory therapies such as corticosteroids, IVIG, and plasmapheresis with suggestion of benefit in small uncontrolled trials. Larger numbers of patients in carefully conducted studies will be required to assess the efficacy of these immune approaches that carry significant risks. Until then, pharmacologic agents such as the nicotinic drug mecamylamine may provide better symptomatic control.