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The objective of this blinded, prospective longitudinal study was to determine whether new group A beta hemolytic streptococcal (GABHS) infections are temporally associated with exacerbations of tic or obsessive-compulsive (OC) symptoms in children who met published criteria for Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections (PANDAS). A group of children with Tourette syndrome and/or obsessive-compulsive disorder without a PANDAS history served as the (non-PANDAS) comparison group.
Consecutive clinical ratings of tic and OC symptom severity were obtained for 31 PANDAS subjects and 53 non-PANDAS subjects. Clinical symptoms and laboratory values (throat cultures and streptococcal antibody titers) were evaluated at regular intervals during a 25 month period. Additional testing occurred at the time of any tic or OC symptom exacerbation. New GABHS infections were established by throat swab cultures and/or recent significant rise in streptococcal antibodies. Laboratory personnel were blinded to case or control status, clinical (exacerbation or not) condition, and clinical evaluators were blinded to the laboratory results.
No group differences were observed in either the number of clinical exacerbations or the number of newly diagnosed GABHS infections. On only six occasions out of a total of 51 (12%) a newly diagnosed GABHS infection was followed, within two months, by an exacerbation of tic and/or OC symptoms. In every instance, this association occurred in the non-PANDAS group.
This study provides no evidence for a temporal association between GABHS infections and tic/OC symptom exacerbations in children who meet the published PANDAS diagnostic criteria.
Tourette syndrome (TS) and pediatric-onset obsessive-compulsive disorder (OCD) are chronic, familial neuropsychiatric disorders that affect from 0.3 to 3% of the pediatric population.1,2 They are chronic disorders that are often associated with impairment and disability.
The etiologies of these disorders are unknown. It has been hypothesized that some individuals develop these disorders as a result of post-infectious autoimmune processes.3 As in Sydenham’s chorea (SC), autoimmune responses following infections with group A beta hemolytic streptococci (GABHS) have been hypothesized to be responsible.3 Swedo et al. have identified this subgroup with the acronym PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections).3 However, subsequent clinical and laboratory-based studies have failed to provide uniform support for this proposed subgroup.4–37
A major shortcoming of the PANDAS hypothesis has been the very small number of adequately designed prospective studies examining any temporal relationship between antecedent bona fide GABHS infections and the onset or exacerbations of tic and obsessive-compulsive (OC) symptoms.5–8 To determine whether there is such a specific relationship we conducted an intensive, blinded clinical and laboratory prospective cohort study that included PANDAS as well as non-PANDAS comparison subjects. We hypothesized that, if PANDAS is a unique clinical entity, then PANDAS cases would have more clinical exacerbations temporally linked to antecedent GABHS infections than non-PANDAS comparison subjects. The non-PANDAS subjects were diagnosed with either TS or pediatric-onset OCD and had no existing evidence of a prior association between GABHS infections and symptom onset or exacerbations as stated in the published criteria.3
All of the subjects were sequentially enrolled at one of six clinical settings (Yale University, Cincinnati Children’s Hospital Medical Center, the New York University Child Study Center, Johns Hopkins University School of Medicine, the University of Alabama at Birmingham, and the University of Rochester School of Medicine) during a four and a half year period from July 2002 to December 2006. Approval by the Institutional Review Boards was obtained at all sites.
Case subjects met all five of the published diagnostic criteria for PANDAS described by Swedo et al.3: (1) the presence of OCD and/or a chronic tic disorder (Tourette disorder, chronic motor or vocal tic disorder), defined as meeting lifetime Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), diagnostic criteria;38 (2) age at onset between 3 years and the beginning of puberty; (3) clinical course characterized by the abrupt onset of symptoms or by a pattern of dramatic recurrent symptom exacerbations and remissions; (4) temporal relationship between GABHS infection and the clinical course of illness (onset and/or exacerbations) as reported by the subject or parent; and (5) at least one of the following symptoms appeared or became noticeably worse: motoric hyperactivity, choreiform movements, jerks of the hands, arms or legs, clumsiness, slurred speech, impaired dexterity or more difficulty drawing.
For criterion 4 above, we used a more exacting criterion. Specifically, we required documentation in the patient’s medical record that there was a temporal relationship between an antecedent GABHS infection and the onset of the disorder as well as at least one exacerbation or that there was a temporal relationship between an antecedent GABHS infection and at least two exacerbations. We used time windows of 9 months for onset and 4 weeks for exacerbations. In addition, all PANDAS cases were required to be ≤16 years of age. Informed consent had to be provided by a parent or guardian and assent provided by the subject. Exclusion criteria for “PANDAS cases” included the following: (1) Sydenham’s chorea or a history of rheumatic fever; (2) presence of severe intellectual disability IQ<75, autism, or a secondary tic disorder other than PANDAS (e.g., drug induced or neuroacanthocytosis); (3) a psychiatric illness other than OCD or a tic disorder or ADHD that is the primary focus of treatment; (4) a major neurological disease (other than a tic disorder); (5) a CNS autoimmune disorder (e.g., multiple sclerosis, systemic lupus erythematosus, Behcet’s) or a documented infection associated with neuropsychiatric symptoms (Lyme disease); (6) patient treated with corticosteroids, IVIG or plasma exchange during the prior 3 months; and/or (7) patient treated with antibiotics in the past 1 month.
Inclusion criteria for non-PANDAS comparison subjects were: (1) the presence of OCD and/or a chronic tic disorder by DSM-IV criteria; (2) age at onset between 3 and 14 years; (3) currently ≤16 years of age; (4) following a review of the medical records and focused parental interviews, the clinical site director found no evidence that subject’s clinical course of neuropsychiatric symptoms (onset or exacerbations) was temporally related to GABHS infections; and (5) informed consent provided by parent or guardian and assent provided by the subject. The same exclusion criteria for PANDAS case subjects were also applied to control subjects.
When a family entered the study, information concerning the patient was collected in a two-stage process.5,7,8 Initially the families, in conjunction with experienced clinicians, completed the Yale Global Tic Severity Scale (YGTSS)39] and the Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS). 40 Symptom severity in other domains was assessed using the DSM-IV Attention-Deficit/Hyperactivity Disorder (ADHD) Rating Scale,41 and the Child Global Assessment Scale for global functioning.42 The parent completed rating scales for ADHD (Conners’ Abbreviated Symptom Questionnaire-Parent [ASQ-P]),43 and the child completed self-report ratings of depression (Child Depression Inventory-Short Version [CDI-SV])44 and anxiety (Multidimensional Anxiety Scale for Children [MASC]).45 The assessments for ADHD, depression, and anxiety symptoms were included to determine whether clinical exacerbations in association with GABHS infection are specific for tics and OCD or whether worsening is nonspecific and involves other childhood behavioral problems.
Clinical ratings were performed by assessors who were members of the existing clinical teams at each site with at least a masters-level degree. They were trained to reliability prior to the initiation of the study using videotaped assessments. Inter-rater reliability was maintained by periodic (every three to six months) co-rating among clinicians administering the C-YBOCS and YGTSS.
Comorbid psychiatric diagnoses, including ADHD, were made by three expert clinicians (JFL, RAK, and PJL) after reviewing all available information including data from the Schedule for Affective Disorders and Schizophrenia for School-Age Children.46 The same diagnostic panel used the PANDAS criteria to confirm cases as PANDAS or non-PANDAS.3
Tic and OC symptom severities were assessed by an expert evaluator at the approximately monthly telephone contacts using the YGTSS and the CY-BOCS. Clinical evaluators were blinded to the results of streptococcal laboratory tests. However, they were not blinded with regard to the child’s status as a PANDAS or non-PANDAS case. In-person visits occurred approximately every three months for monitoring of neuropsychiatric and collection of throat cultures for GABHS and blood samples for ASO and ADB titers. The parents were also asked to report any history of “sore throats”, “colds”, or other illnesses (especially those suggestive of streptococcal infections) that their child experienced during each three month interval. In addition, parents and/or subjects completed the self-report scales (ASQ-P; CDI-SV; and the MASC) every 4 weeks.
As previously described in detail, tic and/or OC symptom exacerbations were identified by using a two-stage algorithm.7,47 If an exacerbation occurred, the patient was immediately re-evaluated and scheduled for two in-person visits when additional throat culture and serum specimens were collected (an “exacerbation” visit was scheduled as soon as possible and “follow-up” visit was scheduled eight weeks after the exacerbation visit). Most families completed their regularly scheduled encounters. The mean time between consecutive staff-family encounters, across all patients, was 31.5 days (SD, 12.5). In six instances the time interval between visits exceeded 100 days.
At the initial visit, duplicate throat swabs (collected simultaneously) and blood samples for ASO and ADB titers were obtained. All of the samples were sent by overnight courier to the Streptococcal Reference Laboratory at the University of Minnesota Medical School, Department of Pediatrics. In addition, parental authorization was obtained to contact each subject’s pediatrician or primary care physician at the time of enrollment. These professionals then collected the monthly duplicate throat swabs that were obtained between the onsite study visits and sent the specimens directly to the Streptococcal Reference Laboratory. Laboratory personnel were blinded to case or control status and clinical status (i.e., clinical exacerbation visits).
Throat culture processing, streptococcal serogrouping, T-protein agglutination characterization, opacity factor determination, and M typing and/or emm-gene sequence typing were performed in the streptococcus laboratory.48,49 Rapid antigen detection tests were not used. All of the β-hemolytic streptococci, not only group A, were serogrouped. The interval between throat swabs averaged 33.1 days (14.6) (range 3–156 days). Subsequently, duplicate throat swabs were obtained approximately monthly (mean days = 33.1 [SD 14.6], range: 3–156) by either the primary care clinicians or the study investigators
Blood was collected in tubes with a clot activator and gel for serum separation (BD Biosciences, 367988). The samples were allowed to stand in room temperature for at least 30 min, after centrifugation serum was aliquoted and stored at −80°C. Tests for ASO and ADB antibodies were performed using the classical micro-titer plate methods with a dilution scheme based on 0.1 log10 intervals.48 All serum samples from a given subject were tested in the same run to minimize effects of inter-test variation, and each run included appropriate “high” and “low” titer control sera. The average interval between serum specimens was approximately 13 weeks (88.7 days [SD 35.0], range: 3–156 days). Serum specimens were collected at each in-person visit (mean days = 88.7 [SD 35.0], range: 17 to 290).
In each instance, a designation of No, Possible, or a Definite new infection was made by DRJ and ELK based all available information concerning each subject and summarized in longitudinal graphs. 49 The criteria used to identify a “Definite” new GABHS infection were the isolation of a GABHS strain with a corresponding log10 rise (of ≥ 0.20) in either ASO and/or ADB antibody titers. For both the ASO and the ADB tests, an increase in titer of ≥ 0.2 log10 between sequential specimens (~13 week intervals) was considered to be significant.4 In order to satisfy the positive culture requirement, the prior culture had to be either negative or positive for a different strain of GABHS. The criteria used to identify a “Possible” new GABHS infection were either: 1) the isolation of a new GABHS strain without a corresponding rise in antibody titers; or 2) a temporally related log10 ASO or ADB titer increase of ≥0.20.
If requested by the subject’s primary care clinician, the results of the throat cultures were sent directly from the streptococcal laboratory by facsimile to his or her office. Approximately two-thirds of the practitioners asked to receive this information. Any clinical decisions by the primary care physicians concerning the use of antibiotics were recorded for later analysis. This information was not shared with the study evaluators at the six clinical sites or at the laboratory.
During the study, subjects were allowed to take their usual psychotropic medications for OCD, tics, or other conditions. Such treatment could be modified by the site investigator according to standard clinical practice. Consequently, each subject’s medication history was monitored at each encounter. This information was collected from the parents, primary care physician, and the clinicians responsible for the treatment of the child’s neuropsychiatric symptoms. Records were kept and coded concerning the use of antibiotics as well as specific classes of psychotropic agents (adrenergic agonists, neuroleptics, serotonin reuptake inhibitors and other antidepressants, mood stabilizers, psychostimulants, benzodiazepines, and other agents). Apart from antibiotics prescribed by pediatricians or other primary care clinicians, no immune-modifying or prophylactic and/or active antibiotic therapy specifically directed at PANDAS was given during the course of the study.
The baseline demographic and clinical data for cases and controls as well as PANDAS and non-PANDAS subjects were compared using either t-tests or Fisher Exact tests, as appropriate. Poisson regression model was used to compare rates of infections in the PANDAS and non-PANDAS groups.
The primary focus of this study was to determine the number of times a clinical exacerbation of tic and/or OC symptoms7 occurred in association with a newly diagnosed GABHS infection. Under the null hypothesis of no temporal association between infections and exacerbations, exacerbations were expected to be randomly distributed between the infection periods and the non-infection periods. For each subject, the expected number of “hits” (exacerbations that are temporally associated with documented GABHS infections) under the null hypothesis was calculated as the number of exacerbations experienced by the subject multiplied by the proportion of time that the subject spent in an infection period. This quantity was summed across subjects in each group of subjects (PANDAS or non-PANDAS cases) to obtain the total number of “hits” that would be expected by chance alone. Under the null hypothesis there would be no temporal association between infections and exacerbations.
Based on the results of earlier studies using similar methodologies,5,7 we selected two infection periods. First, we identified the exacerbations that occurred within 8 weeks after a newly diagnosed GABHS infection. We also included instances where the exacerbation occurred during the two week period prior to when the GABHS infection was first diagnosed (infection period = 10 weeks). Second, based on the previous report by Kurlan et al.,7 we also used a second infection period that extended from 2 weeks prior to five months following diagnosis of a new GABHS infection (infection period = 22 weeks).
Apart from age, the PANDAS cases and the non-PANDAS comparison group had similar demographic and clinical characteristics (Table 1). As a consequence, all case vs. control comparisons included age as a covariate.
The PANDAS cases and the non-PANDAS cases had very similar rates of tic and/or OC symptom exacerbations (PANDAS: 0.45 per person per year; non-PANDAS: 0.42 per person/year) (Table 2). The relative risk for PANDAS to Non-PANDAS after controlling for age was 1.27 with a 95% confidence interval 0.75, 2.13 (non-significant). Of the 25 exacerbations identified in the PANDAS group only 6 (24%) were associated with a simultaneous sudden increase (≥25%) in anxiety, depression and/or ADHD symptoms. In the non-PANDAS group the rate was slightly lower at 18%.
The number of biological specimens collected is presented a supplemental table (See Table S1, available online). As presented in Table 3, the PANDAS cases and the non-PANDAS cases had very similar rates of newly diagnosed GABHS infections (Definite infection + Possible infection) (PANDAS: 0.36 per person per year; non-PANDAS: 0.39 per person/year). Controlling for age, the relative risk for newly diagnosed GABHS infections was not increased in the PANDAS group relative to the non-PANDAS contrast group (Table 4).
Of the 52 Definite and Possible new GABHS infections, 21 episodes were treated by the primary care clinician with a variety of appropriate antibiotics. In the PANDAS group 60% (12/20) of the newly diagnosed GABHS infections were treated compared to 28% (9/32) in the non-PANDAS group. The proportion of treated GABHS infections among PANDAS subjects was significantly higher than among non-PANDAS subjects (Chi-square (1)=5.2, p=0.02).
Within the first infection period (10 weeks, see methods) only 6 hits (10.1%) were observed out of a total of 59 clinical exacerbations of tics and/or OC symptoms. All of the hits occurred in non-PANDAS cases (Table 5). Remarkably, three of the six observed hits occurred in the same non-PANDAS case, an 11 year old boy diagnosed at entry with TS, OCD, ADHD and Generalized Anxiety Disorder. At his baseline (entry) assessment, no association between prior GABHS infections and tic worsening was documented. At each of these exacerbations his OC symptoms increased, but there was no sudden increase in his YGTSS, MASC, or CDI-SV scores.
Similar results were seen for the second infection period interval (22 weeks, see Methods) during which only 8 hits (13.6%) were observed out of a total of 59 clinical exacerbations of tics and/or OC symptoms (see Table S2, available online).
In addition to considering the number of ‘hits’, we also examined the magnitude of the subsequent changes in tic and OC symptom severity following a new GABHS infection. This analysis also failed to detect significant differences between the PANDAS and non-PANDAS groups even when the patient’s antibiotic treatment status was taken into account (see Supplement 1 and Table S3, available online).
In this prospective, blinded, case-control study of children who met published diagnostic criteria for PANDAS, there was no temporal association between clinical exacerbations and antecedent GABHS infections documented by microbiologic and/or immunologic criteria. The number of “hits” was higher in the non-PANDAS cases than in the PANDAS cases, although this difference was not statistically significant. Our findings support those from an earlier prospective, blinded, case-control study in which greater than 75% of clinical exacerbations were not temporally related to infections. However, in that study, the only “hits” occurred in the PANDAS cases, and PANDAS cases were significantly more likely to meet criteria for a new GABHS infection.7 The basis for this apparent difference is unlikely to be due to methodological differences, as each of six sites participating in this study were also sites for the earlier study7 and a virtually identical protocol was used in selecting and monitoring the PANDAS and non-PANDAS cases. Taken together, the implication from these two intensive, prospective studies (involving more than 160 unique subjects) is that there is no convincing evidence for an ongoing causal association between GABHS infections and tic/OC symptom exacerbations in children who meet the published PANDAS diagnostic criteria.
Given the binary nature of exacerbations (Yes or No), secondary analyses designed to determine if symptom severity worsening occurred following a newly diagnosed GABHS infection were also conducted. These analyses also failed to support a link between any documented GABHS infections and symptom exacerbations (See Supplement 1, available online). The one significant difference was that the PANDAS cases were significantly more likely to receive a course of antibiotics during episodes of pharyngitis from their primary care clinicians compared to the non-PANDAS cases. This may reflect the practice of many community-based practitioners to prescribe antibiotics once a diagnosis of PANDAS has been made.50 On average, the use of these antibiotics did not influence subsequent changes in tic or OC symptom severity (see Table S3, available online).
Contrary to projections based on the retrospective study of Swedo et al.3 the PANDAS cases identified in this study experienced a lower rate of clinical exacerbations and documented bona fide new GABHS infections than expected. In addition, they did not typically show (during periods of tic or OC symptom exacerbation) a sudden increase in the severity of neuropsychiatric comorbidity including: emotional lability, intense anxiety, cognitive deficits, oppositional behaviors, motoric hyperactivity, choreiform movements, jerks of the hands, arms or legs, clumsiness, slurred speech, impaired dexterity or more difficulty drawing.
Another important potentially confounding issue in almost all of the earlier prospective longitudinal studies5,8 is that the criteria used to determine whether or not a new GABHS infection had occurred may have been flawed. In-depth analysis of prospectively and frequently collected culture and antibody data from this study, in conjunction with the earlier Kurlan et al. study7 has revealed that a single point or widely spaced cultures and/or only “elevated” ASO or ADB titers are often times misleading.49 Indeed, some cases had repeated positive throat cultures for the same strain of GABHS and their titers remained elevated over the entire 25 months of this study.49
These findings must be interpreted in light of several limitations of the study.37 First, although the expert clinical evaluators were blinded to the results of streptococcal laboratory tests and the decisions made by the patients’ primary care clinicians to treat or not to treat GABHS infections, they were not blinded to the presumptive PANDAS status of the case. This lack of blindness could have influenced the clinical ratings leading to more or fewer exacerbations being detected.
Second, out of respect for the well being of the subjects in the study the primary healthcare providers were informed of the results of throat cultures. As a result, the patients’ primary clinicians were free, if they chose to prescribe antibiotics for symptomatic or asymptomatic patients with positive cultures. This practice could have potentially limited the number of exacerbations observed.6
Third, we did not systematically monitor whether a child was referred for cognitive behavioral therapy (CBT) for either their tic or OC symptoms. This may have affected our results.51 However, only two of the sites were based in child psychiatry programs where tic and OC patients are routinely referred for CBT so that actual number of such cases is likely to have been relatively small.
Fourth, both the total number of clinical exacerbations and the total number of GABHS infections were lower than that had been estimated, raising the possibility that this study was underpowered.
Fifth, although the investigators in both this study and the earlier Kurlan et al. study7 prospectively identified PANDAS cases based on the published criteria, only a small minority of the clinical exacerbations recorded were consistent with the descriptions of PANDAS exacerbations in which the period of increased tic or OC symptom severity was associated with a sudden increase in the severity of psychiatric comorbidity.3 Consequently, if indeed PANDAS exists as a valid clinical entity, the diagnostic criteria may need to be strengthened. One set of proposed suggestions include (James Leckman, personal communication, July 2010): (1) eliminating cases where there was a sudden onset of a tic disorder in the absence of the sudden onset of OCD; (2) specifying that the acuity of symptom onset/exacerbation must be severe, dramatic, and proceeded from no/minimal symptoms to maximum severity within 24–48 hours; and (3) requiring that the onset/exacerbation of OC symptoms is accompanied by at least three (rather than just one) of the seven PANDAS associated symptoms (markedly increased level of anxiety; emotional lability, irritability, aggressive behavior; sudden difficulties with concentration or learning; developmental regression (loss of abilities); sleep disorder; sudden onset of motor dysfunction [dysgraphia, motoric hyperactivity, tics]; and/or urinary frequency or an increased urge to urinate) and that the acuity of the co-occurring symptoms must occur in the same sudden time interval as the OC symptoms.
Next, it is also worth noting that true PANDAS cases may be relatively rare so that it may be necessary to use a national referral base to recruit an adequate number of PANDAS cases as was true of the earlier studies conducted at NIH Clinical Center. 3,27,28 In our view, future studies should focus in part on the new onset cases as this was not addressed in this study and it is a key element of the PANDAS hypothesis. However, if the focus is just on the treatment of new onset cases, this may leave in doubt whether PANDAS is chronic relapsing and remitting polyphasic illness if the intervention is efficacious. It will also be critical to exclude cases of SC.
Finally, although GABHS infections have been postulated as the main initial autoimmune response-inciting event contributing to the sudden onset of severe neuropsychiatric symptoms in a subgroup of patients, it is well documented that sudden OC and tic symptom onset or worsening can be triggered by other infectious agents (e.g. herpes simplex virus, varicella zoster virus, human immunodeficiency virus, Borrelia burgdorferi, Mycoplasma pneumoniae, as well as sinusitis, and the common cold).24,52–58 It will be important for clinicians and scientists to continue to work together across the disciplines of pediatrics, family medicine, neurology, child and adolescent psychiatry and immunology and microbiology to advance our knowledge and improve our understanding and care of these children regardless of the diagnostic label they carry.
This intensive study provides important additional and convincing evidence about the course of tic and OC symptoms in two groups of pediatric age subjects after these symptoms are established. During the prospective course of two years of intensive observation and care, no documentable differences emerged to suggest that GABHS infections were temporally related to either ongoing tic or OC symptoms or to exacerbations. The implication of this finding for patient care is that clinicians who see children who meet the published diagnostic criteria for PANDAS,3 particularly those whose exacerbations are limited to just tics or OC symptoms, typically do not need to perform throat cultures in the absence of symptoms of pharyngitis nor is there a convincing rationale for the use of prophylactic antibiotics. That said, further intensive longitudinal and treatment studies are warranted in younger children, at or close to the onset of their illness where there is clinical evidence of the abrupt onset or sudden worsening of OC and other neuropsychiatric symptoms.
This research was funded in part by the Tourette Syndrome Association and the National Institutes of Health: R01MH061940 (JFL), K05 MH076273 (JFL), K02 MH01527 (PJL), M01RR006022, and RR00125.
The authors wish to thank the study families and participants for taking part in this study. We also wish to acknowledge Ms. Nancy Thompson, Ms. Virginia Eicher, and Barbara Peterson-Cremer, MD. Deborah Katz, and Matthew Monteiro at Child Study Center at Yale University; Tara D. Lipps, RN, CNP, with the Division of Neurology at the Cincinnati Children’s Hospital Medical Center; Matthew Schrock, Tracey Rawls, MA, and Adeena Gabriel with the New York University Child Study Center; Dana Bridges, MS, with the Department of Neurology at the Johns Hopkins University School of Medicine; Donna Peneley, PN, with the Children’s Hospital of Alabama; and Peter Como, PhD, and Pam Mapstone, MSN, PNP, with the Department of Neurology at the University of Rochester Medical Center for their valuable assistance in completing this study. We also wish to thank Cheryl Kunde and Amy Van Gheem, MD, with the World Health Organization Streptococcal Reference Laboratory and the Department of Pediatrics, University of Minnesota School of Medicine for their technical assistance in processing the cultures and in the antibody determinations.
Disclosure: Dr. Leckman has received research support from the National Institutes of Health and the Tourette Syndrome Association. He has received salary support from the National Institutes of Health. He has received support from the Klingenstein Third Generation Foundation from the medical student fellowship program. He has received royalties from John Wiley and Sons, McGraw Hill, and Oxford University Press. Dr. Coffey receives research support from Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly and Co., the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, and the Tourette Syndrome Association. She has served on the advisory board for Jazz Pharmaceuticals, Eli Lilly and Co., Novartis, and the Tourette Syndrome Association. She has served on the speakers’ bureau for the Tourette Syndrom Association. Dr. Singer has received research and salary support from the National Institutes of Health. He has received royalties from Elsevier, and has served as an editor for the journal Neurolograd. Dr. Gilbert has received honoraria from the American Academy of Pediatrics, the Tourette Syndrome Association/Center for Disease Control, the Movement Disorder Society, and the American Academy of Neurology. He has served on the advisory board for the Tourette Syndrome Association. He has received research support from the National Institutes of Health, Cincinnati Children’s Hospital Research Foundation, the University of Cincinnati, and the Tourette Syndrome Association. He will receive salary support for clinical research from the Genzyme Corporation, Otsuka Pharmaceuticals, and Psyadon Pharmaceuticals, Inc. Dr. Kurlan has received research support from the National Institutes of Health, the Centers for Disease Control, the Michael J. Fox Foundation, Neauologix, Boehringer Ingelheim, and Kyowa. He has received salary support from the National Institutes of Health, Neurologix, Boehringer Ingelheim, and Kyowa. Dr. Lombroso has received research and salary support from the National Institute of Mental Health, the Institute for the Study of Aging, the American Health Assistant Foundation, and the Fragile X Foundation. Drs. King, Dure, Lin, Kawikova, and Kaplan, and Ms. Grantz, Mr. Johnson, and Ms. Katsovich report no biomedical financial interests or potential conflicts of interest.
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