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Article |

Does Group A β-Hemolytic Streptococcal Infection Increase Risk for Behavioral and Neuropsychiatric Symptoms in Children? FREE

Eliana Miller Perrin, MD, MPH; Marie Lynd Murphy, MD; Janet R. Casey, MD; Michael E. Pichichero, MD; Desmond K. Runyan, MD, DrPH; William C. Miller, MD, PhD, MPH; Lisa A. Snider, MD; Susan E. Swedo, MD
[+] Author Affiliations

From the Division of General Pediatrics and Adolescent Medicine, Department of Pediatrics (Drs Perrin and Runyan), the Department of Social Medicine (Dr Runyan), and the Division of Infectious Diseases, Department of Medicine, School of Medicine and the Department of Epidemiology, School of Public Health (Dr Miller), University of North Carolina at Chapel Hill, Chapel Hill; Elmwood Pediatric Group, Rochester, NY (Drs Murphy, Casey, and Pichichero); the Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester (Dr Pichichero); the Pediatrics and Developmental Neuropsychiatry Branch, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Md (Drs Snider and Swedo).


Arch Pediatr Adolesc Med. 2004;158(9):848-856. doi:10.1001/archpedi.158.9.848.
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Published online

Objective  To determine whether group A β-hemolytic streptococcal infections increase the risk of developing symptoms characteristic of the diagnosis pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS).

Design  Prospective cohort study.

Methods  Children (N = 814) aged 4 to 11 years seen for sore throat or well-child care in a large pediatric practice in Rochester, NY, were enrolled from October 2001 to June 2002 (group A β-hemolytic streptococcal [GAS] infected, n = 411; GAS uninfected, n = 403, of whom 207 had a sore throat of presumed viral etiology and 196 were well children). Symptomatic children with GAS infection (n = 399) were treated with antibiotics. At baseline and 2 and 12 weeks following baseline, all parents completed a 20-item questionnaire about the presence/absence of recent PANDAS symptoms in their children, and capable children answered 10 items about worries, obsessions, and compulsions. The relative risk of developing a "mild PANDAS variant" (≥ 2 new PANDAS symp-toms) by illness type (GAS positive, presumed viral, or well child) and by parent and child report was determined and adjusted for potential covariates.

Results  By parent report, ill children more frequently manifested several PANDAS symptoms at baseline than well children. However, neither new symptoms nor the risk of developing a mild PANDAS variant developed during the subsequent 12 weeks more commonly in children with GAS infection than in those with presumed viral illness or in well children by parent or child report.

Conclusions  Ill children with GAS infection, treated for their GAS infection, were not at increased risk for developing PANDAS symptoms or a mild PANDAS variant compared with children with presumed viral illness or well children. The role of antibiotics in the prevention or treatment of PANDAS as well as the investigation of PANDAS in the asymptomatic, infectious host deserves future research.

Figures in this Article

Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection, or PANDAS, is hypothesized to describe a subset of children with sudden onset obsessive-compulsive disorder (OCD) and tic disorders that occur in the weeks following a group A β-hemolytic streptococcal infection ("strep throat" or GAS).1 Swedo et al1 at the National Institute of Mental Health, Bethesda, Md, identified 5 diagnostic criteria for PANDAS in 1998: (1) presence of OCD and/or tics; (2) pediatric onset of symptoms (from age 3 until puberty); (3) abrupt onset and/or episodic course of symptom severity; (4) exacerbations associated with GAS infection (confirmed by positive culture and/or elevated antistreptococcal titers); and (5) associated neurological abnormalities (eg, choreiform movements). The children in the PANDAS subgroup of children with childhood-onset OCD and tic disorders also have been documented to have a high frequency of comorbid neuropsychiatric symptoms. Increased frequencies of comorbid attention-deficit/hyperactivity disorder, oppositional defiant disorder, major depression, separation anxiety disorder, overanxious disorder, and enuresis have been reported.1

Epidemiologic tenets for causality between a risk factor and disease suggest a link between GAS and PANDAS.2 Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection is biologically plausible and has an appropriate analogy in another poststreptococcal illness. It resembles in some ways the well-described component of acute rheumatic fever, Sydenham chorea.3 There is consistency of reports in the PANDAS literature.47 Several case-control studies report the following relevant relationships: between antistreptococcal titers and tics8,9; antineuronal antibodies and movement disorders9,10; antistreptococcal antibody titers and basal ganglia volumes and OCD, chronic tic disorder, and attention-deficit/hyperactivity disorder11; antistreptococcal antibody titers and Tourette syndrome10; and caudate, putamen, and globus pallidum size and streptococcus-associated OCD and/or tics.12 Some studies explored the tenet of reversibility in that they found that experimental treatments of immunomodulatory agents such as intravenous immunoglobulin and plasma exchange yielded benefits.13 One randomized controlled trial did not demonstrate reversibility of PANDAS symptoms with penicillin prophylaxis, though this was not surprising since the penicillin failed to prevent GAS.14 More recently, Murphy and Pichichero15 reported from their observational prospective analysis of 12 children with PANDAS that PANDAS-related symptoms declined following antibiotic treatment.

The entity of PANDAS, however, remains controversial. Some postulate that the relationship between GAS infection, an extremely common illness in children, and neuropsychiatric symptoms may merely be an "epiphenomenon."1618 Skeptics have pointed to limitations of some previous PANDAS research, including lack of prospective and controlled studies17; small numbers of study subjects19; and failure to identify whether subjects were preselected for having had "recent, recurrent, or chronic" GAS tonsillopharyngitis.11 Furthermore, most PANDAS studies focus on patients with severe neuropsychiatric illness, and no studies have included comparison groups derived from outpatient pediatric populations.

To date, no large prospective cohort study of children with and without GAS exposure has been performed to determine the risk of GAS exposure on the development of PANDAS or its milder symptoms. Therefore, we sought to conduct a prospective cohort study following 2 groups of children (those with and without GAS infection) for 12 weeks in an outpatient pediatrics practice to determine if children with GAS infection are more likely than children without GAS (those with presumed viral infection and well children) to develop symptoms that have been reported to occur in the typical PANDAS subgroup of children with OCD and tics and their comorbid conditions. We hypothesized that although PANDAS that meets all criteria1 may be rare, milder variants of the disorder with more transient symptoms might be captured in a large, prospective outpatient study.

We used a prospective cohort study design and followed 2 distinct cohorts of children for 12 weeks: children with GAS infection and children without GAS infection. While cohort studies are not traditionally used to investigate the risks of rare disorders such as PANDAS, we hypothesized that a "mild PANDAS variant" would be more common and would be identifiable in a cohort study. We defined a mild PANDAS variant a priori as the development of 2 or more new PANDAS-related symptoms during 12 weeks.

We recruited 4- to 11-year-old English-speaking children and their parents from the Elmwood Pediatric Group, a large suburban practice in Rochester, NY, during 1 GAS season (October 2001 through June 2002). While PANDAS criteria indicate children must be at least age 3 years, we believed that by beginning enrollment at age 4 years, we might more likely have children who could reliably report psychological symptoms. The upper limit of age 11 years was chosen because in the clinical description of the first 50 cases, the upper age limit for the onset of PANDAS was 11 years for girls and 12 years for boys.1 Written informed consent was obtained from parents and written assent from the children. Because we were interested in incident symptoms, children were excluded from participation if they had any previously diagnosed psychiatric or neurological problem, including attention-deficit/hyperactivity disorder, autism, depression, OCD, pervasive developmental delay, mental retardation, and Tourette or other tic disorders. Children were also excluded from participation if they were taking any psychotropic medications (including medication for attention-deficit/hyperactivity disorder or selective serotonin reuptake inhibitors) or had any history of closed head injury with loss of consciousness or seizures.

Children enrolled in the GAS-infected cohort had a throat culture positive for GAS and symptoms of GAS infection including a sore throat and other symptoms such as fever or headache. The GAS-uninfected cohort of children was divided, roughly in half, with patients who were seen with illness symptoms (ie, fever, sore throat, or headache) and presumed viral infection and with patients who were seen for routine well-child care.

PARTICIPANT COHORTS

Of the 814 children who received throat cultures at the outset of the study, 411 had GAS infection and 403 did not have GAS infection. Among the 411 who had GAS infection, 399 had come to the practice with symptoms of illness. Because the practice is open 7 days per week for sick care and because patients who had positive results by initial rapid streptococcal testing (later confirmed by culture) were given a prescription at the time of initial examination, there were unlikely to be significant delays in onset of treatment. Symptomatic patients with GAS infection were treated according to the practice's previously established consensus on treatment of GAS. Children were treated with a twice-daily, weight-based regimen of amoxicillin. Penicillin-allergic patients, those with recurrent streptococcal illness, or those with demonstrated previous amoxicillin resistance were treated with a cephalosporin antibiotic.

Twelve (<2%) of the patients seen for well-child care who had throat cultures because of study protocol were found to be GAS positive but were symptom free. They were believed to be carriers and excluded prior to data analysis because carriers usually do not mount an immunological response to infection. The other 403 participants were GAS negative. This group consisted of 196 children seen for well-child care and 207 children with nonstreptococcal acute respiratory illnesses, which included sore throat. We refer to this latter group as the "presumed viral group" (Figure 1). Children without GAS infection had not had previous GAS infection during that streptococcal season (October 2001 to June 2002).

Place holder to copy figure label and caption

Flow diagram of participants. GAS indicates group A β-hemolytic streptococcal infection.

Graphic Jump Location

All parents and children were encouraged to speak with their pediatricians about symptoms of concern rather than to assume problems would be brought to attention as a result of the study. All procedures were compliant with and the study was approved by the University of North Carolina at Chapel Hill School of Medicine institutional review board.

INSTRUMENTS

Because no standardized instruments to assess PANDAS symptoms exist, we developed 2 instruments for our outcome measures. The first instrument was a questionnaire administered to parents that asked about the recent onset of 20 unusual behaviors reported frequently by children in the PANDAS subgroup. These behaviors included the 2 primary neuropsychiatric findings in this subgroup of children with childhood-onset OCD and tic disorders—namely, OCD symptoms (such as checking, hoarding, washing, fixation with order, or unusual religiosity and were adapted from the Children's Yale-Brown Obsessive Compulsive Scale20) and tics. They also encompassed the associated comorbid neuropsychiatric symptoms of attention-related problems; separation anxiety and "clinginess"; more generalized worries and fears; negativity; obsessive toilet paper wiping and unusual bathroom routines; and unusual urinary problems such as urgency and enuresis. The symptoms of toileting and urinary problems were included because new-onset enuresis or daytime urinary frequency were found in 6 (12%) of 50 of the initial PANDAS sample described by Swedo et al,1 and compulsive daytime urinary urgency, frequency, and wiping were noted in 7 (58%) of 12 of the PANDAS sample evaluated by Murphy and Pichichero.15

Following these questions, parents were asked: "Which of the following statements represents your feelings about your child's recent behaviors? (a) Recent behaviors have not been a problem; (b) Recent behaviors have been a little bit of a problem; (c) Recent behaviors have been a moderate problem; and, (d) Recent behaviors have been a severe problem and have meant that we have had to change our routine at school or home to compensate." They were also asked: "Which of the following statements is true? (a) My child and/or our family has had a significant life event recently; or (b) My child and/or our family has NOT had a significant life event recently." For choice "a," parents were given a series of examples of significant life events such as death of a family member or a recent move. Finally, parents answered demographic questions about their children, themselves, and their partners (age of child, sex of child, ethnicity, sex of responding parent, education of responding parent, education of spouse/significant other, marital status).

Children who were able (n = 682) privately completed a 10-item written questionnaire about internalizing or anxious thoughts and obsessive-compulsive symptoms that might not be known by parents.2023 For children who were not able to read, a study nurse read questions to them and they verbally answered "yes" or "no." These replies were then marked on a separate form. Study nurses also demonstrated to parents how to administer this questionnaire in a private manner for follow-up surveys so that parents would not be aware of children's responses. Children who were not able to read the questionnaire themselves or understand directions for completing the nonliteracy-dependent version (as assessed by our study nurses) were not given questionnaires (n = 122), though their parents were still invited to participate.

To assess development of new symptoms as they emerged 2 and 12 weeks after enrollment, parents and children were sent surveys identical to the baseline instruments. If their responses to the follow-up mailings were not received within 2 weeks, another mailing was sent and study nurses telephoned to remind parents to respond. Questionnaires were considered in the analysis if they were complete or nearly complete (no more than 2 of 32 questions missing answers). A random 10% of the sample was rechecked for data entry reliability.

OUTCOME MEASURES AND ANALYSIS

We assessed 4 main outcome measures. First, we examined the prevalence of individual parent- or child-endorsed symptoms at baseline (time of enrollment) in the GAS-infected and presumed viral groups vs the well-child group. We hypothesized that a higher percentage of children with GAS infection and their parents would endorse individual symptoms than those with presumed viral infections or well children. We used Fisher exact tests for categorical variables. For these symptoms' comparisons, we used an α level of .01 because of the use of multiple comparisons. We also calculated the prevalence odds ratios (ORs) with exact 95% confidence intervals (CIs) to determine if either children with GAS infection or children with presumed viral infection had an increased prevalence of symptoms when compared with the referent of well children.

Second, we assessed the incidence of individual symptoms endorsed by either parents or children across time in the 3 comparison groups. χ2 tests for categorical variables were determined using α = .01. Incidence ORs were then calculated with exact 95% CIs to determine if either children with GAS infection or children with presumed viral infection had a greater incidence of symptoms than well children.

We also considered a mild PANDAS variant, defined a priori as 2 or more changed PANDAS symptoms (not endorsed at baseline but endorsed 2 or 12 weeks later) on parent or child questionnaires. We postulated that the new onset of 2 or more symptoms from one point to the next would be more clinically meaningful than a single symptom and yet prevalent enough by sample size calculations to be able to detect a difference by GAS exposure in our sample size. We determined a necessary sample size of 275 based on a power of 90%, α = .05, and an estimated 10% difference in proportions.

We calculated unadjusted and adjusted relative risks for the development of a mild PANDAS variant by exposure to GAS at 2 weeks, 12 weeks, and overall (2 or 12 weeks). We used generalized linear models with binomial distribution and log link (binomial or multiplicative risk regression) to determine the relative risk of developing a mild PANDAS variant by illness type (children with GAS infection and children with presumed viral infection were compared with well children). Adjusted models accounted for potential confounders of the relationship. The potential confounding variables were identified a priori and included the child's age (≥7 vs <7 years), sex, and race (white vs nonwhite), as well as the responding parent's sex, educational attainment (<college degree vs ≥college degree), and endorsement of a recent significant life event (yes vs no).

The final outcome measure was a dichotomous variable representing whether behavior worsened across time as reported by parents on a behavior scale across the 3 time points (from 1, "not a problem" to 4, "a severe problem"). The relative risk for developing more problematic behavior from time point 1 (baseline) to time point 2 (2 weeks following baseline) or time point 3 (12 weeks following baseline) by illness type (those with GAS infection, those with presumed viral syndrome, and those who were well) was calculated. We used a generalized linear model with binomial distribution and log link (binomial regression or multiplicative risk regression) to determine the relative risk relationship between worsening of behavior and GAS exposure status, adjusted for the potential confounders listed earlier, in 3 possible combinations: (1) "transiently" worse (behavior worsened from time point 1 to time point 2 but returned to baseline by time point 3); (2) "lastingly" worse (behavior at time point 3 worse than behavior at time point 1); and (3) "ever" worse (combines those whose behavior at any 1 of the time points was worse than at the other time points).

Most study participants in this upstate, suburban practice were non-Hispanic white and their parents were highly educated; only 24% had less than a college degree, and 33% completed some graduate education (Table 1). The GAS-infected, presumed viral, and well-child cohorts differed by percentage of children younger than or equal to age 7 years and percentage of parental respondents who were women. Mean age at enrollment, child's sex, educational level of the responding parent, educational level of the responding parent's significant other or spouse, and marital status of the responding parent were similar between cohorts.

Table Graphic Jump LocationTable 1. Selected Child and Parent Characteristics

At 2 weeks, 676 (84%) of 803 enrollment participant parents returned complete questionnaires. At 12 weeks, 625 (78%) returned complete questionnaires. Child response rates were as follows: at 2 weeks, 548 (80%) of 682 (able to complete questionnaires) returned complete questionnaires, and at 12 weeks, 508 (74%) of 682 returned complete questionnaires.

At baseline, parents of ill children vs parents of well children reported the recent onset of several PANDAS symptoms more frequently, including harder time paying attention, increased fidgetiness/restlessness, unusual clinginess/harder time with separation, unusual noises such as throat clearing or barking, trying to stop a behavior the child always repeats, unusual urinary problems, and seeming more negative than usual (Table 2). However, none of these symptoms was significantly more commonly reported for those with GAS exposure than for those with presumed viral infection. Being more sick with worry and having upsetting, intruding thoughts were more commonly reported for those with viral syndrome compared with well children but not for those with GAS exposure (Table 2). Considering symptoms reported by the children, no PANDAS symptoms were more commonly reported by children with GAS infection or with presumed viral infections when compared with the well cohort. The obsessive-compulsive symptom of needing to dress in a certain way each day was significantly less frequently endorsed by children with GAS infection (Table 3).

Table Graphic Jump LocationTable 2. Parents' Endorsements of Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections Symptoms in Their Children at Time of Enrollment by Illness Type (N = 802)
Table Graphic Jump LocationTable 3. Children's Endorsements of Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections Symptoms in Themselves at Time of Enrollment by Illness Type (N = 682)

We also examined change in symptom endorsement across time by illness status. No differences in the onset of incident symptoms were reported among the GAS, viral, and well cohorts from enrollment to 2 or 12 weeks at the P<.01 significance level for either parents or children (Table 4 and Table 5). However, parents of children with GAS infection were 4 times as likely to report that their children were "more sick with worry" than parents of well children (OR, 4.2 [95% CI, 1.1-undefined]), and parents of children with presumed viral infection were nearly 9 times as likely to report unusual fears than parents of children who were well (OR, 8.7 [95% CI, 1.4-undefined]).

Table Graphic Jump LocationTable 4. Parents' Endorsements of New Symptoms Across the Subsequent 12 Weeks Not Present at Time of Enrollment (Incident) by Illness Type
Table Graphic Jump LocationTable 5. Children's Endorsements of New Symptoms Across the Subsequent 12 Weeks Not Present at Time of Enrollment (Incident) by Illness Type (N = 682)

Children with GAS infection were not at increased risk for development of a mild PANDAS variant based on parental or child report when compared with well children across 2 or 12 weeks or overall (Table 6 and Table 7).

Table Graphic Jump LocationTable 6. Unadjusted and Adjusted Relative Risk (RR) for Developing a Mild Pediatric Autoimmune Neuropsychiatric Disorder Associated With Streptococcal Infections Variant (New Endorsement of ≥2 Symptoms) by Illness Type Where Children With Group A β-Hemolytic Streptococcal (GAS) and Children With Presumed Viral Infection are Each Compared With Well Children as the Referent
Table Graphic Jump LocationTable 7. Relative Risk (RR) for Developing a Mild Pediatric Autoimmune Neuropsychiatric Disorder Associated With Streptococcal Infections Variant (New Endorsement of ≥2 Symptoms) by Illness Type Where Children With GAS and Children With Presumed Viral Infection Are Each Compared With Well Children as the Referent

Finally, parents of the GAS-infected cohort did not report significantly more transient, lasting, or ever worse behavior than parents of children without GAS infection in multivariate analyses. The adjusted relative risk for reporting behavior that worsened transiently was 1.76 (95% CI, 0.47-6.51) for children with GAS infection and 2.00 (95% CI, 0.50-8.02) for children with presumed viral infection compared with well children. For reporting behavior that worsened and persisted throughout time, the relative risk was 1.67 (95% CI, 0.71-3.93) for children with GAS infection and 0.92 (95% CI, 0.33-2.55) for children with presumed viral infection compared with well children. Similar findings were observed for reporting behavior that was worse at any point in the study (adjusted relative risk for children with GAS infection, −1.16 [95% CI, 0.76-1.78]); with presumed viral infection, 0.99 (95% CI, 0.62-1.63); referent, well children).

More parents of ill children who were both GAS positive and GAS negative reported inattentiveness, fidgetiness, clinginess, and unusual noises (barking, throat clearing) among their children at baseline. These findings are consistent with reports noting associations between illness (even in nonhospitalized children) and behavioral problems and tic exacerbations.2427 However, from this prospective cohort study of 802 patients in an outpatient pediatrics practice, using parent- and child-reported data, children infected with and treated for GAS do not appear to be at increased risk over children with presumed viral syndrome for development of PANDAS symptoms or a mild PANDAS variant, defined in our study as the new onset (<2 weeks) of 2 or more symptoms that characterize PANDAS. Because all participants with GAS infection were treated with appropriate antibiotics, intervention may have prevented or altered the natural history of mild PANDAS symptoms as at least 1 report suggests15 and as is true for the analogous rheumatic fever.

This is the largest prospective study of PANDAS symptoms to date. Nevertheless, sample size and ascertainment bias may have played a role in our negative results. The prospective study by Murphy and Pichichero15 identified only 12 children manifesting PANDAS among approximately 4000 patients infected with GAS across a 3-year period in the same practice, suggesting the rarity of the entity in its classical manifestation. While based on these numbers we would only expect to detect 2 to 3 patients with PANDAS by classic, explosive manifestation in this prospective study of 800 patients, we expected to identify individual incident symptoms and subclinical manifestation with more frequent incidence. We were cautious throughout to label our findings of greater than 2 new-onset symptoms by parents or children a mild PANDAS variant. Because of our limited sample size and symptom measures, our study cannot provide relative risks or incidence figures for PANDAS itself in this population. Our study was powered to detect a 10% difference in the proportions of number of symptoms endorsed by GAS exposure (with 90% power and a 2-tailed α of .05). If there was a difference in proportions of even subclinical manifestations below this level, our study might not have detected that.

We relied on parent and child subjective responses to serve as a proxy for symptom development, but this approach has limitations. Previous studies, for example, have demonstrated that parents may underreport tics in children when compared with direct observation,28 and children may hide obsessive-compulsive symptoms from their parents too.21 Our child queries revealed high rates of symptom endorsement. These rates were unexpected given the known rates of obsessive-compulsive symptoms and may have obscured between-group differences. The questionnaire may have been worded in such a way that the "symptoms" endorsed by parents or children did not reflect problematic behaviors. In fact, the lack of impairment related to these symptoms suggests that the frequency of endorsement on this questionnaire may have been a reflection of normal childhood concerns rather than symptoms of psychopathology. To determine the validity of our questionnaire will require further research.

Because some patients with sore throat and a positive GAS culture may have had viruses and merely be carriers of GAS, there may have been misclassification bias. This would have biased our results to the null hypothesis. In some patients with pharyngitis, a culture positive for GAS represents a carrier state in which the oropharynx is colonized with GAS. There is not a true GAS infection since there is not an immune response. In those instances, the positive culture is an incidental finding and not a reflection of a GAS pharyngitis. Since there is not an immune response to the GAS colonization, the carrier cannot have poststreptococcal autoimmune sequelae. Twelve children were considered GAS carriers in the present study and were not included in the original analyses to avoid misclassification bias. When the 12 carriers were included in a reanalysis of the data, the results did not differ.

Of more importance, the present study did not capture children with asymptomatic GAS infections. These children were not included in the GAS-positive group as they were not seen at the clinic for evaluation of pharyngitis; if they happened to be there for a well-child visit, they would have been excluded from the healthy control group because of their positive GAS culture. The literature has shown that asymptomatic GAS infections are a frequent cause of post-GAS sequelae. For example, the recent rheumatic fever epidemics in Utah demonstrated that 83% of children with rheumatic carditis did not have a history of sore throat or other symptoms of GAS pharyngitis.29 Asymptomatic GAS infections also appear to play an important role in triggering neuropsychiatric symptoms, such as OCD and tics. Murphy et al30 found that the majority of the children meeting criteria for the PANDAS subgroup were initially seen for "behavior conferences" and did not have complaints of sore throat or fever, although their throat cultures were positive for GAS and they demonstrated rising antibody titers. Future research studies should be designed to capture children with asymptomatic infections, as this may be the group with the highest yield for GAS-related neuropsychiatric symptoms.

The study occurred during only 1 GAS season. It is possible that, just as there are rheumatogenic GAS strains, there may also be "PANDAS-genic" GAS strains. Looking at only 1 year of streptococcal data might have missed such strain-specific occurrences.31 Since we asked parents at baseline for endorsement of symptoms with recent onset and then used strict epidemiologic methods to base relative risks only on change from baseline to 2 or 12 weeks, our study design might have underestimated the relative risk of GAS-related acute behavioral/neuropsychiatric problems in our population. This would be the case if symptoms were present at baseline but only had been present for a brief period. We have no data about child or parental perceptions of behavior or neuropsychiatric symptoms prior to enrollment, and it is possible that we started our study effectively too late. However, we did exclude patients with known psychiatric disease at enrollment.

In conclusion, this is the first prospective cohort study to examine the risk of behavioral symptoms associated with GAS infections. We found no evidence to support the notion that symptomatic, treated GAS tonsillopharyngitis confers significant risk toward the development of most neuropsychiatric symptoms or mild PANDAS variants. While it is possible that there is no relationship between GAS and OCD and tic disorders, other explanations for our negative findings are that mild PANDAS variants may be an uncommon manifestation of GAS tonsillopharyngitis, related to specific GAS strains, or occur only in untreated or predisposed hosts.

What This Study Adds

Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections is the diagnosis applied to a subgroup of children with new-onset neuropsychiatric and behavioral problems following GAS infection. While much evidence indicates an association between GAS infections and PANDAS symptoms, no large prospective cohort studies exist to determine if GAS increases the risk for PANDAS symptoms.

Our study determined that GAS infection was not associated with the development of a mild PANDAS variant (which we had defined a priori as 2 or more new-onset PANDAS symptoms). Ours is the first large prospective study of PANDAS symptoms. Since the entity of PANDAS is controversial, this negative study is important. While there was no relationship between GAS and OCD or tic disorders in this study, it remains possible that antibiotic treatment (which patients in our study received for symptomatic GAS infections) prevents or treats PANDAS symptoms, that PANDAS occurs more frequently in patients with asymptomatic yet infectious GAS, or that even mild PANDAS variants occur at a rate too rare to identify by our sample size.

Correspondence: Eliana Miller Perrin, MD, MPH, Division of General Pediatrics and Adolescent Medicine, Department of Pediatrics, University of North Carolina at Chapel Hill, CB 7220, 200 Mason Farm Rd, 5th floor, Chapel Hill, NC 27599-7220 (eliana_perrin@med.unc.edu).

Accepted for publication April 14, 2004.

This study was funded by The Robert Wood Johnson Clinical Scholars Program, Princeton, NJ (Dr Perrin), and grant HD01441 from the National Institutes of Health K12 University of Carolina Building Interdisciplinary Research Careers in Women's Health Career Development Program, Bethesda, Md (Dr Perrin).

Dr Perrin was a research fellow of The Robert Wood Johnson Clinical Scholars Program during the conception and analysis of this research.

We thank Anne Francis, MD; Steven Marsocci, MD; William Hoeger, MD; Carolyn Cleary, MD; Ann Sorrento, MSN, PNP; Kathleen White-Ryan, MSN, PNP; Juli Miller, RN, CCRC; Traci Stanton, AAS; Doreen Francis, RN, CCRC; Sally Thomas, LPN, CCRC; and Melissa Maschoff, RN, of the Elmwood Pediatric Group, Rochester, NY, without whom this study would not have been possible. We thank Nikki Rogers, BS, and Halle Amick, BFA, for tireless help with data entry and administrative support and Carol Porter, BS, and Andrew Perrin, PhD, for help with data management. We appreciate the parents and children who participated in this study. We thank Joanne Garrett, PhD, and Robert Hamer, PhD, for advice on statistical analysis and David Ransohoff, MD, for advice on epidemiological methods.

This study was presented in part at the Pediatric Academic Societies Annual Meeting; May 5, 2003; Seattle, Wash, and at The Robert Wood Johnson Clinical Scholars Program National Meeting; November 7, 2002; Ft Lauderdale, Fla.

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Peterson  BSLeckman  JFTucker  D  et al.  Preliminary findings of antistreptococcal antibody titers and basal ganglia volumes in tic, obsessive-compulsive, and attention deficit/hyperactivity disorders. Arch Gen Psychiatry. 2000;57364- 372
PubMed Link to Article
Giedd  JNRapoport  JLGarvey  MAPerlmutter  SSwedo  SE MRI assessment of children with obsessive-compulsive disorder or tics associated with streptococcal infection. Am J Psychiatry. 2000;157281- 283
PubMed Link to Article
Perlmutter  SJLeitman  SFGarvey  MA  et al.  Therapeutic plasma exchange and intravenous immunoglobulin for obsessive-compulsive disorder and tic disorders in childhood. Lancet. 1999;3541153- 1158
PubMed Link to Article
Garvey  MAPerlmutter  SJAllen  AJ  et al.  A pilot study of penicillin prophylaxis for neuropsychiatric exacerbations triggered by streptococcal infections. Biol Psychiatry. 1999;451564- 1571
PubMed Link to Article
Murphy  MLPichichero  ME Prospective identification and treatment of children with pediatric autoimmune neuropsychiatric disorder associated with group A streptococcal infection (PANDAS). Arch Pediatr Adolesc Med. 2002;156356- 361
PubMed Link to Article
Shulman  ST Pediatric autoimmune neuropsychiatric disorders associated with streptococci (PANDAS). Pediatr Infect Dis J. 1999;18281- 282
PubMed Link to Article
Kurlan  RKaplan  EL The pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) etiology for tics and obsessive-compulsive symptoms: hypothesis or entity? practical considerations for the clinician. Pediatrics. 2004;113883- 886
PubMed Link to Article
Kaplan  E PANDAS? or PAND? or both? or neither? assessing a (possible?) temporal or pathogenic relationship with the Group A streptococcal diseases complex. Contemp Pediatr. 2000;881- 96
Singer  HS PANDAS and immunomodulatory therapy. Lancet. 1999;3541137- 1138
PubMed Link to Article
Scahill  LRiddle  MAMcSwiggin-Hardin  M  et al.  Children's Yale-Brown Obsessive Compulsive Scale: reliability and validity. J Am Acad Child Adolesc Psychiatry. 1997;36844- 852
PubMed Link to Article
Rapoport  JLInoff-Germain  GWeissman  MM  et al.  Childhood obsessive-compulsive disorder in the NIMH MECA study: parent versus child identification of cases: Methods for the Epidemiology of Child and Adolescent Mental Disorders. J Anxiety Disord. 2000;14535- 548
PubMed Link to Article
Klein  RG Parent-child agreement in clinical assessment of anxiety and other psychopathology: a review. J Anxiety Disord. 1991;5187- 198
Link to Article
Achenbach  TMMcConaughy  SHHowell  CT Child/adolescent behavioral and emotional problems: implications of cross-informant correlations for situational specificity. Psychol Bull. 1987;101213- 232
PubMed Link to Article
Shrand  H Behavior changes in sick children nursed at home. Pediatrics. 1965;36604- 607
PubMed
Mattsson  AWeisberg  I Behavioral reactions to minor illness in preschool children. Pediatrics. 1970;46604- 610
PubMed
Borowsky  IWMozayeny  SIreland  M Brief psychosocial screening at health supervision and acute care visits. Pediatrics. 2003;112 (pt 1) 129- 133
PubMed Link to Article
Silva  RRMunoz  DMBarickman  JFriedhoff  AJ Environmental factors and related fluctuation of symptoms in children and adolescents with Tourette's disorder. J Child Psychol Psychiatry. 1995;36305- 312
PubMed Link to Article
Snider  LASeligman  LDKetchen  BR  et al.  Tics and problem behaviors in schoolchildren: prevalence, characterization, and associations. Pediatrics. 2002;110 (pt 1) 331- 336
PubMed Link to Article
Veasy  LGTani  LYHill  HR Persistence of acute rheumatic fever in the intermountain area of the United States. J Pediatr. 1994;1249- 16
PubMed Link to Article
Murphy  MLCasey  JRPichichero  ME PANDAS in primary care practice: presenting complaints, clinical and lab findings of 25 patients with new onset PANDAS [abstract]. Pediatr Res. 2002;51277A
Inoff-Germain  GRodriguez  RSTorres-Alcantara  SDiaz-Jimenez  MJSwedo  SERapoport  JL An immunological marker (D8/17) associated with rheumatic fever as a predictor of childhood psychiatric disorders in a community sample. J Child Psychol Psychiatry. 2003;44782- 790
PubMed Link to Article

Figures

Place holder to copy figure label and caption

Flow diagram of participants. GAS indicates group A β-hemolytic streptococcal infection.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Selected Child and Parent Characteristics
Table Graphic Jump LocationTable 2. Parents' Endorsements of Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections Symptoms in Their Children at Time of Enrollment by Illness Type (N = 802)
Table Graphic Jump LocationTable 3. Children's Endorsements of Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections Symptoms in Themselves at Time of Enrollment by Illness Type (N = 682)
Table Graphic Jump LocationTable 4. Parents' Endorsements of New Symptoms Across the Subsequent 12 Weeks Not Present at Time of Enrollment (Incident) by Illness Type
Table Graphic Jump LocationTable 5. Children's Endorsements of New Symptoms Across the Subsequent 12 Weeks Not Present at Time of Enrollment (Incident) by Illness Type (N = 682)
Table Graphic Jump LocationTable 6. Unadjusted and Adjusted Relative Risk (RR) for Developing a Mild Pediatric Autoimmune Neuropsychiatric Disorder Associated With Streptococcal Infections Variant (New Endorsement of ≥2 Symptoms) by Illness Type Where Children With Group A β-Hemolytic Streptococcal (GAS) and Children With Presumed Viral Infection are Each Compared With Well Children as the Referent
Table Graphic Jump LocationTable 7. Relative Risk (RR) for Developing a Mild Pediatric Autoimmune Neuropsychiatric Disorder Associated With Streptococcal Infections Variant (New Endorsement of ≥2 Symptoms) by Illness Type Where Children With GAS and Children With Presumed Viral Infection Are Each Compared With Well Children as the Referent

References

Swedo  SELeonard  HLGarvey  M  et al.  Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases. Am J Psychiatry. 1998;155264- 271erratum appears in Am J Psychiatry 1998;155:578
PubMed
Bradford-Hill  AB The environment and disease: association and causation. Proc R Soc Med. 1965;58295- 300
PubMed
Garvey  MAGiedd  JSwedo  SE PANDAS, the search for environmental triggers of pediatric neuropsychiatric disorders: lessons from rheumatic fever. J Child Neurol. 1998;13413- 423
PubMed Link to Article
Giedd  JNRapoport  JLLeonard  HLRichter  DSwedo  SE Case study: acute basal ganglia enlargement and obsessive-compulsive symptoms in an adolescent boy. J Am Acad Child Adolesc Psychiatry. 1996;35913- 915
PubMed Link to Article
Monasterio  EMulder  RTMarshall  TD Obsessive-compulsive disorder in post-streptococcal infection. Aust N Z J Psychiatry. 1998;32579- 581
PubMed
Perlmutter  SJGarvey  MACastellanos  X  et al.  A case of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. Am J Psychiatry. 1998;1551592- 1598
PubMed
Allen  AJLeonard  HLSwedo  SE Case study: a new infection-triggered, autoimmune subtype of pediatric OCD and Tourette's syndrome. J Am Acad Child Adolesc Psychiatry. 1995;34307- 311
PubMed Link to Article
Cardona  FOrefici  G Group A streptococcal infections and tic disorders in an Italian pediatric population. J Pediatr. 2001;13871- 75
PubMed Link to Article
Kiessling  LSMarcotte  ACCulpepper  L Antineuronal antibodies in movement disorders. Pediatrics. 1993;9239- 43
PubMed
Church  AJDale  RCLees  AJGiovannoni  GRobertson  MM Tourette's syndrome: a cross sectional study to examine the PANDAS hypothesis. J Neurol Neurosurg Psychiatry. 2003;74602- 607
PubMed Link to Article
Peterson  BSLeckman  JFTucker  D  et al.  Preliminary findings of antistreptococcal antibody titers and basal ganglia volumes in tic, obsessive-compulsive, and attention deficit/hyperactivity disorders. Arch Gen Psychiatry. 2000;57364- 372
PubMed Link to Article
Giedd  JNRapoport  JLGarvey  MAPerlmutter  SSwedo  SE MRI assessment of children with obsessive-compulsive disorder or tics associated with streptococcal infection. Am J Psychiatry. 2000;157281- 283
PubMed Link to Article
Perlmutter  SJLeitman  SFGarvey  MA  et al.  Therapeutic plasma exchange and intravenous immunoglobulin for obsessive-compulsive disorder and tic disorders in childhood. Lancet. 1999;3541153- 1158
PubMed Link to Article
Garvey  MAPerlmutter  SJAllen  AJ  et al.  A pilot study of penicillin prophylaxis for neuropsychiatric exacerbations triggered by streptococcal infections. Biol Psychiatry. 1999;451564- 1571
PubMed Link to Article
Murphy  MLPichichero  ME Prospective identification and treatment of children with pediatric autoimmune neuropsychiatric disorder associated with group A streptococcal infection (PANDAS). Arch Pediatr Adolesc Med. 2002;156356- 361
PubMed Link to Article
Shulman  ST Pediatric autoimmune neuropsychiatric disorders associated with streptococci (PANDAS). Pediatr Infect Dis J. 1999;18281- 282
PubMed Link to Article
Kurlan  RKaplan  EL The pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) etiology for tics and obsessive-compulsive symptoms: hypothesis or entity? practical considerations for the clinician. Pediatrics. 2004;113883- 886
PubMed Link to Article
Kaplan  E PANDAS? or PAND? or both? or neither? assessing a (possible?) temporal or pathogenic relationship with the Group A streptococcal diseases complex. Contemp Pediatr. 2000;881- 96
Singer  HS PANDAS and immunomodulatory therapy. Lancet. 1999;3541137- 1138
PubMed Link to Article
Scahill  LRiddle  MAMcSwiggin-Hardin  M  et al.  Children's Yale-Brown Obsessive Compulsive Scale: reliability and validity. J Am Acad Child Adolesc Psychiatry. 1997;36844- 852
PubMed Link to Article
Rapoport  JLInoff-Germain  GWeissman  MM  et al.  Childhood obsessive-compulsive disorder in the NIMH MECA study: parent versus child identification of cases: Methods for the Epidemiology of Child and Adolescent Mental Disorders. J Anxiety Disord. 2000;14535- 548
PubMed Link to Article
Klein  RG Parent-child agreement in clinical assessment of anxiety and other psychopathology: a review. J Anxiety Disord. 1991;5187- 198
Link to Article
Achenbach  TMMcConaughy  SHHowell  CT Child/adolescent behavioral and emotional problems: implications of cross-informant correlations for situational specificity. Psychol Bull. 1987;101213- 232
PubMed Link to Article
Shrand  H Behavior changes in sick children nursed at home. Pediatrics. 1965;36604- 607
PubMed
Mattsson  AWeisberg  I Behavioral reactions to minor illness in preschool children. Pediatrics. 1970;46604- 610
PubMed
Borowsky  IWMozayeny  SIreland  M Brief psychosocial screening at health supervision and acute care visits. Pediatrics. 2003;112 (pt 1) 129- 133
PubMed Link to Article
Silva  RRMunoz  DMBarickman  JFriedhoff  AJ Environmental factors and related fluctuation of symptoms in children and adolescents with Tourette's disorder. J Child Psychol Psychiatry. 1995;36305- 312
PubMed Link to Article
Snider  LASeligman  LDKetchen  BR  et al.  Tics and problem behaviors in schoolchildren: prevalence, characterization, and associations. Pediatrics. 2002;110 (pt 1) 331- 336
PubMed Link to Article
Veasy  LGTani  LYHill  HR Persistence of acute rheumatic fever in the intermountain area of the United States. J Pediatr. 1994;1249- 16
PubMed Link to Article
Murphy  MLCasey  JRPichichero  ME PANDAS in primary care practice: presenting complaints, clinical and lab findings of 25 patients with new onset PANDAS [abstract]. Pediatr Res. 2002;51277A
Inoff-Germain  GRodriguez  RSTorres-Alcantara  SDiaz-Jimenez  MJSwedo  SERapoport  JL An immunological marker (D8/17) associated with rheumatic fever as a predictor of childhood psychiatric disorders in a community sample. J Child Psychol Psychiatry. 2003;44782- 790
PubMed Link to Article

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