Elsevier

Biological Psychiatry

Volume 45, Issue 12, 15 June 1999, Pages 1564-1571
Biological Psychiatry

Original Articles
A pilot study of penicillin prophylaxis for neuropsychiatric exacerbations triggered by streptococcal infections

https://doi.org/10.1016/S0006-3223(99)00020-7Get rights and content

Abstract

Background: Some children with obsessive-compulsive disorder (OCD) and tic disorders appear to have symptom exacerbations triggered by group A beta-hemolytic streptococcal infections in a manner that is similar to rheumatic fever and its neurologic variant, Sydenham’s chorea. Because penicillin prophylaxis has proven to be effective in preventing recurrences of rheumatic fever, it was postulated that it might also prevent streptococcal-triggered neuropsychiatric symptom exacerbations in children with Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections (PANDAS). These children are identified by five clinical characteristics: presence of OCD or tic disorder, prepubertal onset, episodic symptom course, neurologic abnormalities (i.e., choreiform movements) and streptococcal-triggered symptom exacerbations.

Methods: Thirty-seven children with PANDAS were enrolled in an 8 month, double-blind, balanced cross-over study. Patients were randomized to receive either 4 months of the active compound (twice daily oral 250 mg penicillin V) followed by 4 months of placebo, or placebo followed by penicillin V. Tic, OCD, and other psychiatric symptoms were monitored monthly. Throat cultures and streptococcal antibody titers were also obtained.

Results: There were an equal number of infections in both the active and placebo phases of the study. There was no significant change seen in either the obsessive-compulsive or tic symptom severity between the two phases.

Conclusions: Because of the failure to achieve an acceptable level of streptococcal prophylaxis, no conclusions can be drawn from this study regarding the efficacy of penicillin prophylaxis in preventing tic or OCD symptom exacerbations. Future studies should employ a more effective prophylactic agent, and include a larger sample size.

Introduction

Recent reports have provided evidence for a possible connection between group A beta-hemolytic streptococcal infections and neuropsychiatric disorders Swedo et al 1994, Swedo et al 1998, Kerbeshian et al 1990, Tucker et al 1996. In a subgroup of children with tic and/or obsessive-compulsive disorders, symptom exacerbations appear to be temporally linked to streptococcal infections Allen et al 1995, Swedo et al 1991, Kiessling 1989. This subgroup has been identified by the acronym PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections), the key features of which have been outlined in a recently published study (Swedo et al 1998). As in Sydenham’s chorea (SC) Garvey et al 1998, Swedo et al 1994, the pathogenesis of PANDAS is thought to be autoimmune. Though other major manifestations of rheumatic fever such as carditis and polyarthritis are not found in children with PANDAS (Swedo et al 1998), they do manifest some of the neuropsychiatric features that are hallmarks of SC. The most characteristic of these are abnormal movements similar to chorea (Touwen 1979), attentional difficulties, and emotional lability, all of which fluctuate with exacerbations of their OCD or tics. In both conditions, there is a strong positive correlation between antistreptococcal titers and the reappearance or exacerbation of symptoms Allen et al 1995, Stollerman 1961, Stollerman 1975, Swedo 1994, Swedo et al 1998.

Penicillin is routinely used to prevent recurrences in rheumatic fever and Sydenham’s chorea. Early reports studying the prevention of rheumatic fever (RF) using sulfanilamide or related compounds Coburn and Moore 1939, Thomas and France 1939, Stowell and Button 1941, Thomas et al 1941, Kuttner and Reyersbach 1943, Hansen et al 1942 and penicillin Maliner and Amsterdam 1947, Brick et al 1950, Evans 1950 were inconclusive but led the way towards larger studies. These established the efficacy of oral prophylactic penicillin in reducing the frequency of RF recurrences Dajani et al 1988, Miller et al 1958a, Stollerman 1954, Wood et al 1964a. Because of the postulated pathophysiologic similarities between SC and PANDAS, we hypothesized that penicillin prophylaxis would reduce neuropsychiatric exacerbations in children with PANDAS by preventing streptococcal infections. To test this hypothesis, we conducted a placebo-controlled double-blind crossover trial of oral penicillin V prophylaxis in children with a history of streptococcal related exacerbations of tics and OCD. We expected that the prophylactic penicillin dose would be effective in preventing streptococcal infections, while the placebo would not, and therefore, we anticipated fewer symptom exacerbations during the active phase.

Section snippets

Subjects

Children with a history of a sudden onset or abrupt exacerbations of tic or OCD symptoms were recruited locally for this study over a period of 3 years. Advertisements were placed in the newsletter of the local chapter of the Tourette Syndrome Association and also sent to pediatricians and psychiatrists in the Washington, DC metropolitan area. Potential subjects were screened by telephone and in person using a semi-structured interview. Children were eligible for the study if they met the

Study subjects

Over a 3-year period, 150 telephone screenings were conducted and 60 children were seen in the outpatient clinic for an in-person assessment. Fifty of these met criteria for study entry. Ten children either chose not to take part in the study (n = 3) or were excluded from study entry after the baseline evaluation (n = 7). Of the latter group, one child had an atrial septal defect requiring antibiotic prophylaxis prior to all dental procedures, five children had a primary psychiatric diagnosis

Discussion

We hypothesized that an improvement of neuropsychiatric symptoms would occur as a result of the prophylactic effect of penicillin. The presence of an equal number of streptococcal infections in both the active and placebo phases of the study indicates a failure to achieve the first aim of the study and therefore substantially decreased the chances of accomplishing the secondary aim. The number of exacerbations was similar in both phases and there were no significant changes observed in the tic

Acknowledgements

We are indebted to the many people who participated with us during this project, especially Dan Richter, Jason Zamkoff, Sara Dow, and the Pharmacy Department of the Clinical Center.

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