New Article

[LNN]

I got an alert that this article has just been published, but the link doesn't work. Does anyone have access?

 

 

Streptococcal Upper Respiratory Tract Infections and Exacerbations of Tic and Obsessive-Compulsive Symptoms: A Prospective Longitudinal Study

James F. Leckman, Robert A. King, Donald L. Gilbert, Barbara J. Coffey, Harvey S. Singer, Leon S. Dure, Heidi Grantz, Liliya Katsovich, Haiqun Lin, Paul J. Lombroso, Ivana Kawikova, Dwight R. Johnson, Roger M. Kurlan, Edward L. Kaplan, Journal of the American Academy of Child & Adolescent Psychiatry, 50:2:108-118.e3 (February 2011)

 

http://www.jaacap.com/article/S0890-8567(10)00816-6/abstract

[SarahJane]

Gilbert's on there. Wonder if he's thinking zebra now. Hmmmm.

[AmbersMommy]

I got an alert that this article has just been published, but the link doesn't work. Does anyone have access?

 

 

Streptococcal Upper Respiratory Tract Infections and Exacerbations of Tic and Obsessive-Compulsive Symptoms: A Prospective Longitudinal Study

James F. Leckman, Robert A. King, Donald L. Gilbert, Barbara J. Coffey, Harvey S. Singer, Leon S. Dure, Heidi Grantz, Liliya Katsovich, Haiqun Lin, Paul J. Lombroso, Ivana Kawikova, Dwight R. Johnson, Roger M. Kurlan, Edward L. Kaplan, Journal of the American Academy of Child & Adolescent Psychiatry, 50:2:108-118.e3 (February 2011)

 

http://www.jaacap.com/article/S0890-8567(10)00816-6/abstract

 

Hi, It's about 9:20 AM. I got the link to work. I think in a nut-shell they are saying that strep doesn't cause exacerbations of tic/OC symptoms in children diagnosed with PANDAS. I hope I am wrong, but this is a very curious result if I have interpreted the abstract correctly. The full-text version costs $12.00. I may spring for a copy. If anyone else reads the full article or has a different interpretation of the results please post!! Thanks.

[browneyesmom]

I might via my PubMed subscription... lemme check... brb

[browneyesmom]

Got it!! Thanks for posting the heads up... I haven't read it yet, but here is the article so we can all have a look:

 

Streptococcal Upper Respiratory Tract Infections and Exacerbations of Tic and Obsessive-Compulsive Symptoms: A Prospective Longitudinal Study

 

Journal of the American Academy of Child and Adolescent Psychiatry - Volume 50, Issue 2 (February 2011) - Copyright © 2011 American Academy of Child and Adolescent Psychiatry - About This Journal Remove Journal Issue Alert Add Journal Issue Alert

 

MDC Extra Article: This additional article is not currently cited in MEDLINE®, but was found in MD Consult's full-text literature database.

 

 

 

PDF version of article

New research

Streptococcal Upper Respiratory Tract Infections and Exacerbations of Tic and Obsessive-Compulsive Symptoms: A Prospective Longitudinal Study

 

 

James F. Leckman, M.D.a,⁎icon_mail

Robert A. King, M.D.a

Donald L. Gilbert, M.D.b

Barbara J. Coffey, M.D., M.S.c

Harvey S. Singer, M.D.d

Leon S. Dure , IV, M.D.e

Heidi Grantz, M.S.W.a

Liliya Katsovich, M.B.A.a

Haiqun Lin, M.D., Ph.D.f

Paul J. Lombroso, M.D.a

Ivana Kawikova, M.D., Ph.D.a

Dwight R. Johnson, B.S.g

Roger M. Kurlan, M.D.h

Edward L. Kaplan, M.D.g

 

a Child Study Center and the Yale Center for Clinical Investigation, Yale University School of Medicine

b Division of Neurology at the Cincinnati Children's Hospital Medical Center and the University of Cincinnati, School of Medicine

c Child Study Center at New York University School of Medicine and the Nathan Kline Institute for Psychiatric Research

d Johns Hopkins University School of Medicine

e Division of Child Neurology at the University of Alabama at Birmingham

f Yale University School of Medicine

g University of Minnesota Medical School

h Atlantic Neuroscience Institute, Overlook Hospital in Summit, NJ

* Correspondence to James Leckman, M.D., Child Study Center, Yale University School of Medicine, 230 South Frontage Road, New Haven, CT 06520-7900

E-mail address: james.leckman@yale.edu

 

Manuscript accepted November 5, 2010

 

 

This article was reviewed under and accepted by Ad Hoc Editor Daniel S. Pine, M.D.

This research was funded in part by the Tourette Syndrome Association and the National Institutes of Health, grants (R01MH061940 (J.F.L.); K05 MH076273 (J.F.L.); K02 MH01527 (P.J.L.); M01RR006022; and RR00125).

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 Syndrome 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. Dr. Kurlan has received research support from the National Institutes of Health, the Centers for Disease Control, the Michael J. Fox Foundation, Neurologix, 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, Ms. Grantz, Mr. Johnson, and Ms. Katsovich report no biomedical financial interests or potential conflicts of interest.

 

PII S0890-8567(10)00816-6

 

Objective

 

The objective of this blinded, prospective, longitudinal study was to determine whether new group A β 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 OC disorder without a PANDAS history served as the comparison (non-PANDAS) group.

Method

 

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.

Results

 

No group differences were observed in the number of clinical exacerbations or the number of newly diagnosed GABHS infections. On only six occasions of a total of 51 (12%), a newly diagnosed GABHS infection was followed, within 2 months, by an exacerbation of tic and/or OC symptoms. In every instance, this association occurred in the non-PANDAS group.

Conclusions

 

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.

 

 

Key Words

 

obsessive-compulsive disorder

Tourette syndrome

group A β hemolytic streptococci

streptococcal infections

pediatric neuropsychiatric disorders associated with streptococcal infections (PANDAS)

 

 

Tourette syndrome (TS) and pediatric-onset obsessive-compulsive disorder (OCD) are chronic, familial neuropsychiatric disorders that affect 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 postinfectious autoimmune processes.[3] As in Sydenham chorea, autoimmune responses after infections with group A β hemolytic streptococci (GABHS) have been hypothesized to be responsible.[3] Swedo et al.[3] 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] , [5] , [6] , [7] , [8] , [9] , [10] , [11] , [12] , [13] , [14] , [15] , [16] , [17] , [18] , [19] , [20] , [21] , [22] , [23] , [24] , [25] , [26] , [27] , [28] , [29] , [30] , [31] , [32] , [33] , [34] , [35] , [36] , [37]

 

A major shortcoming of the PANDAS hypothesis has been the very small number of adequately designed prospective studies examining any temporal relation between antecedent bona fide GABHS infections and the onset or exacerbations of tic and OC symptoms. [5] , [6] , [7] , [8] To determine whether there is such a specific relation, we conducted an intensive, blinded, clinical and laboratory prospective cohort study that included PANDAS and 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 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]

Method

 

Subjects

 

All subjects were sequentially enrolled at one of six clinical settings (Yale University, Cincinnati Children's Hospital Medical Center, New York University Child Study Center, Johns Hopkins University School of Medicine, University of Alabama at Birmingham, and University of Rochester School of Medicine) during a 4-year 6-month 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 DSM-IV diagnostic criteria;[38] 2) age at onset from 3 years to 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 relation 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, we used a more exacting criterion. Specifically, we required documentation in the patient's medical record that there was a temporal relation between an antecedent GABHS infection and the onset of the disorder and at least one exacerbation or that there was a temporal relation between an antecedent GABHS infection and at least two exacerbations. We used time points of 9 months for onset and 4 weeks for exacerbations. In addition, all PANDAS cases were required to be no older than 16 years. Informed consent had to be provided by a parent or guardian and assent provided by the subject. Exclusion criteria for PANDAS cases included: 1) Sydenham chorea or a history of rheumatic fever; (2) presence of severe intellectual disability with an IQ lower than 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 attention-deficit/hyperactivity disorder (ADHD) that is the primary focus of treatment; 4) a major neurologic disease (other than a tic disorder); (5) a central nervous system autoimmune disorder (e.g., multiple sclerosis, systemic lupus erythematosus, Behçet syndrome) or a documented infection associated with neuropsychiatric symptoms (Lyme disease); 6) treatment with corticosteroids, intravenous immunoglobulin, or plasma exchange during the previous 3 months; and/or 7) treatment with antibiotics in the previous 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 from 3 to 14 years; 3) currently no older than 16 years; 4) after a review of the medical records and focused parental interviews, the clinical site director found no evidence that a subject's clinical course of neuropsychiatric symptoms (onset or exacerbations) was temporally related to GABHS infections; and 5) informed consent provided by a parent or guardian and assent provided by the subject. The same exclusion criteria for PANDAS case subjects were applied to control subjects.

Clinical Assessments

 

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.[40] Symptom severity in other domains was assessed using the DSM-IV 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),[43] and the child completed self-report ratings of depression (Child Depression Inventory–Short Version)[44] and anxiety (Multidimensional Anxiety Scale for Children).[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 before the initiation of the study using videotaped assessments. Inter-rater reliability was maintained by periodic (every 3 to 6 months) co-rating among clinicians administering the Children's Yale-Brown Obsessive Compulsive Scale and YGTSS.

 

Comorbid psychiatric diagnoses, including ADHD, were made by three expert clinicians (J.F.L., R.A.K., and P.J.L.) 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]

Longitudinal Evaluations

 

Tic and OC symptom severities were assessed by an expert evaluator at the approximately monthly telephone contacts using the YGTSS and the Children's Yale-Brown Obsessive Compulsive Scale. Clinical evaluators were blinded to the results of streptococcal laboratory tests. However, they were not blinded to a child's status as a PANDAS or non-PANDAS case. In-person visits occurred approximately every 3 months for neuropsychiatric monitoring 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 3-month interval. In addition, parents and/or subjects completed the self-report scales (Conners' Abbreviated Symptom Questionnaire–Parent, Child Depression Inventory–Short Version, and the Multidimensional Anxiety Scale for Children) every 4 weeks.

 

As previously described in detail, tic and/or OC symptom exacerbations were identified 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 the “follow-up” visit was scheduled 8 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 days). In six instances the interval between visits exceeded 100 days.

Throat Cultures and Serum Specimens

 

At the initial visit, duplicate throat swabs (collected simultaneously) and blood samples for ASO and ADB titers were obtained. All 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 β-hemolytic streptococci, not only group A, were serogrouped. Subsequently, duplicate throat swabs were obtained approximately monthly (mean = 33.1 days, SD = 14.6 days, range = 3-156 days) by the primary care clinicians or the study investigators.

 

Blood was collected in tubes with a clot activator and gel for serum separation (BD Biosciences, San Jose, CA, 367988). The samples were allowed to stand in room temperature for at least 30 minutes; after centrifugation serum was stored in aliquots at −80°C. Tests for ASO and ADB antibodies were performed using classic microtiter 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 days, range = 3-156 days). Serum specimens were collected at each in-person visit (mean = 88.7 days, SD = 35.0 days, range = 17-290 days).

GABHS Infections

 

In each instance, a designation of “no,” “possible,” or “definite” new infection was made by D.R.J. and E.L.K. based on 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 increase (of ≥0.20) in ASO and/or ADB antibody titers. For the ASO and the ADB tests, an increase in titer of at least 0.2 log10 between sequential specimens (∼13-week intervals) was considered significant.[4] To satisfy the positive culture requirement, the prior culture had to be negative or positive for a different strain of GABHS. The criteria used to identify a possible new GABHS infection were 1) the isolation of a new GABHS strain without a corresponding increase in antibody titers or 2) a temporally related log10 ASO or ADB titer increase of at least 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.

Medication Status

 

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 physicians, and the clinicians responsible for the treatment of the child's neuropsychiatric symptoms. Records were kept and coded concerning the use of antibiotics and 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.

Statistical Analysis

 

The baseline demographic and clinical data for cases and controls and for PANDAS and non-PANDAS subjects were compared using 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 symptoms[7] 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 noninfection 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 previous 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 when the exacerbation occurred during the 2-week period before the GABHS infection was first diagnosed (infection period = 10 weeks). Second, based on a previous report by Kurlan et al.,[7] we used a second infection period that extended from 2 weeks before to 5 months after diagnosis of a new GABHS infection (infection period = 22 weeks).

Results

 

Description of Study Cohort

 

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 and control comparisons included age as a covariate.

 

TABLE 1 -- Demographic and Clinical Characteristics at Baseline

Variable n PANDAS Patients (n = 31) n Non-PANDAS Patients (n = 53)

Age (years), mean ± SD (range)[⁎] 31 9.6 ± 1.9 (6.0-13.2) 53 10.5 ± 1.8 (6.6-13.9)

Girls (%) 31 19% 53 26%

Caucasian (%) 31 100% 53 94%

Parent education (years), mean ± SD 30 15.5 ± 2.5 53 15.1 ± 2.7

Primary diagnoses (%)

TS (including chronic tics) 26 84 49 92

OCD 22 71 35 66

Age of onset (years), mean ± SD (range)

TS (including chronic tics) 26[a] 5.8 ± 2.1 (2-9) 49[a] 6.1 ± 1.9 (3-10)

OCD 22 6.6 ± 2.2 (2-10) 35 6.6 ± 1.8 (3-10)

Baseline symptom severity by diagnosis, mean ± SD

TS (including chronic tics)[c] 26[a] 18.5 ± 9.1 49[a] 17.5 ± 8.8

OCD[d] 22 10.9 ± 8.4 35 12.2 ± 5.9

Other DSM-IV diagnoses (%)

ADHD 31 42 53 53

Separation anxiety 31 13 53 11

Specific phobia 31 3 53 11

Major depression 31 6 53 11

Symptom severity, mean ± SD

ADHD rating scale[e] 31 18.6 ± 13.9 53 22.2 ± 14.3

ASQ–P[f] 31 8.7 ± 7.4 53 10.5 ± 8.2

CDI[g] 31 5.8 ± 6.5 53 5.8 ± 6.3

MASC[h] 31 46.4 ± 14.1 53 46.7 ± 19.4

CGAS–Investigator 31 77 ± 12.9 53 75.2 ± 12.9

Positive family history[j] (%)

Tics 31 37 53 42

OCD 31 40 53 38

ADHD 31 40 53 37

Anxiety disorder 31 52 53 42

Major depression 31 60 53 38

Rheumatic fever 31 20 53 8

 

Note: PANDAS = pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections.

 

a Number of subjects within group who had Tourette syndrome (TS) (including chronic tics).

b Number of subjects within group who had obsessive-compulsive disorder (OCD).

c Total tic severity score on the Yale Global Tic Severity Scale (YGTSS).[39]

d Total score on the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS).[40]

e Total score on the DSM-IV attention-deficit/hyperactivity disorder (ADHD) rating scale.[41]

f Total score on the Conners' Abbreviated Symptom Questionnaire - Parent (ASQ-P).[43]

g Total score on the Children's Depression Inventory (CDI).[44]

h Total score on the Multidimensional Anxiety Scale for Children (MASC).[45]

i Total score on the Child Global Assessment Scale for Global Functioning.[42]

j Proportion of families reporting at least one first- or second-degree relative with the disorder.

⁎ p < .05.

 

Exacerbations

 

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 per year; Table 2). The relative risk for PANDAS versus non-PANDAS after controlling for age was 1.27 (95% confidence interval = 0.75-2.13, nonsignificant). Of the 25 exacerbations identified in the PANDAS group, only six (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%.

 

TABLE 2 -- Clinical Exacerbations of Tic and/or Obsessive-Compulsive Symptoms (OC)

PANDAS (n = 31) Non-PANDAS (n = 53) Total

Total number of exacerbations 25 34 59

Number of subjects with exacerbations 16 20 36

Number of subjects with multiple exacerbations 6 7 13

Maximum number of exacerbations per subject 3 5 5

Tic exacerbations 14 18 32

Number of subjects with tic exacerbations 10 16 26

OC exacerbations 8 14 22

Number of subjects with OC exacerbations 6 8 14

Combined tic + OC exacerbations 3 2 5

Number of subjects with tic + OC exacerbations 3 2 5

 

Note: PANDAS = pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections.

 

 

GABHS Infections

 

The number of biological specimens collected is presented in a supplemental table (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 per year). Controlling for age, the relative risk for newly diagnosed GABHS infections was not increased in the PANDAS group compared with the non-PANDAS contrast group (Table 4).

 

TABLE 3 -- Newly Diagnosed Group A β Hemolytic Streptococcal (GABHS) Infections

Group Period of Observation (months) Newly Diagnosed Definite GABHS Infections (infections per person per year) Newly Diagnosed Possible GABHS Infections (infections per person per year) Newly Diagnosed Definite + Possible GABHS Infections (infections per person per year)

All patients (N = 84) 1646.4 26 (0.19) 26 (0.19) 52 (0.38)

PANDAS patients (n = 31) 663.1 7 (0.13) 13 (0.23) 20 (0.36)

Non-PANDAS patients (n = 53) 983.3 19 (0.23) 13 (0.16) 32 (0.39)

 

Note: No significant differences were observed comparing the rates of infections. PANDAS = pediatric autoimmune disorders associated with streptococcal infections.

 

 

 

TABLE 4 -- Relative Risks for Newly Diagnosed Group A β Hemolytic Streptococcal (GABHS) Infections Controlling for Age

PANDAS/Non-PANDAS Relative Risk 95% CI

Relative risk for definite GABHS infections 0.50 0.20-1.22

Relative risk for possible GABHS infections 1.19 0.54-2.65

Relative risk for definite + possible GABHS infections 0.81 0.45-1.43

 

Note: None of the relative risks were statistically significant. CI = confidence interval; PANDAS = pediatric autoimmune disorders associated with streptococcal infections.

 

 

Antibiotic Treatment

 

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 with 28% (9/32) in the non-PANDAS group. The proportion of treated GABHS infections in PANDAS subjects was significantly higher than in non-PANDAS subjects (χ21 = 5.2, p = .02).

Hits

 

Within the first infection period (10 weeks, see Methods), only six hits (10.1%) were observed of a total of 59 clinical exacerbations of tics and/or OC symptoms. All 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, Multidimensional Anxiety Scale for Children, or Child Depression Inventory–Short Version scores.

 

TABLE 5 -- Observed Versus Expected Number of Hits When a Newly Diagnosed Group A β Hemolytic Streptococcal (GABHS) Infections Occurred in a 10-Week Window Surrounding a Tic and/or Obsessive-Compulsive Symptom Exacerbation[a]

Infection Classification Number of Hits Expected Number of Hits by Chance 95% CI

All subjects

Definite GABHS infections 3[c] 2.3 0.62-8.77

Possible GABHS infections 3[c] 1.5 0.62-8.77

Definite or possible GABHS infections 6[c] 3.8 2.2-13.1

PANDAS only

Definite GABHS infections — 0.5 —

Possible GABHS infections — 0.5 —

Definite or possible GABHS infections — 1.0 —

Non-PANDAS

Definite GABHS infections 3[c] 1.8 0.62-8.77

Possible GABHS infections 3[c] 1.0 0.62-8.77

Definite or possible GABHS infections 6[c] 2.8 2.2-13.1

 

Note: CI = confidence interval; OC = obsessive-compulsive; PANDAS = pediatric autoimmune disorder associated with streptococcal infections.

 

a For each subject, the expected number of “hits” 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 2 weeks before the detection of a new GABHS infection plus 8 weeks after the detection of a new GABHS infection. This quantity was summed across subjects in each group (PANDAS or control) to obtain the total number of “hits” that would be expected by chance alone. See text for the rationale for including the 2-week interval before a new GABHS infection was diagnosed. Table S2 (available online) presents a similar analysis for a second infection interval defined as 2 weeks before the detection of a new GABHS infection plus 20 weeks after the detection of a new GABHS infection. This longer interval was considered in an exploratory analysis because of the findings reported by Kurlan et al.[7]

b See text.

c In one non-PANDAS subject, two exacerbations occurred within 2 months after definite GABHS infection and one exacerbation after a possible GABHS infection.

 

Similar results were seen for the second infection period interval (22 weeks, see Methods) during which only eight hits (13.6%) were observed of a total of 59 clinical exacerbations of tics and/or OC symptoms (Table S2, available online).

 

In addition to considering the number of hits, we examined the magnitude of the subsequent changes in tic and OC symptom severity after a new GABHS infection. This analysis also failed to detect significant differences between the PANDAS and non-PANDAS groups even when a patient's antibiotic treatment status was taken into account (Supplement 1 and Table S3, available online).

Discussion

 

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 larger in the non-PANDAS cases than in the PANDAS cases, although this difference was not statistically significant. Our findings support those from earlier previous prospective, blinded, case-control study in which more 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 methodologic differences, because each of six sites participating in this study were also sites for the previous study[7] 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 >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 after a newly diagnosed GABHS infection were conducted. These analyses also failed to support a link between any documented GABHS infections and symptom exacerbations (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 with 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 (Table S3, available online).

 

Contrary to projections based on the retrospective study of Swedo et al.,[3] the PANDAS cases identified in this study had 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 previous prospective longitudinal studies [5] , [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 study by Kurlan et al.,[7] has shown 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 subject. 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 health care 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 for tic or OC symptoms. This may have affected our results.[51] However, only two of the sites were based in child psychiatry programs where patients with tic and OCD are routinely referred for cognitive-behavioral therapy so that the actual number of such cases is likely to have been relatively small.

 

Fourth, the total number of clinical exacerbations and the total number of GABHS infections were smaller than that had been estimated, raising the possibility that this study was underpowered.

 

Fifth, although the investigators in this study and the study by Kurlan et al.[7] 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 includes (James Leckman, M.D., personal communication, July 2010) 1) eliminating cases in which there was a sudden onset of a tic disorder in the absence of a 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 to 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 interval as the OC symptoms.

 

Next, it is 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 previous studies conducted at National Institutes of Health Clinical Center. [3] , [27] , [28] In our view, future studies should focus in part on the new-onset cases because 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 Sydenham chorea.

 

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, sinusitis, and the common cold). [24] , [52] , [53] , [54] , [55] , [56] , [57] , [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, 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 subjects after these symptoms are established. During the prospective course of 2 years of intensive observation and care, no documentable differences emerged to suggest that GABHS infections were temporally related to 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 there is no 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, when there is clinical evidence of the abrupt onset or sudden worsening of OC and other neuropsychiatric symptoms.

 

The authors thank the study families and participants for taking part in this study. They also acknowledge Ms. Nancy Thompson, Ms. Virginia Eicher, Barbara Peterson-Cremer, M.D., Deborah Katz, and Matthew Monteiro at the Child Study Center at Yale University; Tara D. Lipps, R.N., C.N.P., with the Division of Neurology at the Cincinnati Children's Hospital Medical Center; Matthew Schrock, Tracey Rawls, M.A., and Adeena Gabriel with the New York University Child Study Center; Dana Bridges, M.S., with the Department of Neurology at the Johns Hopkins University School of Medicine; Donna Peneley, P.N., with the Children's Hospital of Alabama; and Peter Como, Ph.D., and Pam Mapstone, M.S.N., P.N.P., with the Department of Neurology at the University of Rochester Medical Center for their valuable assistance in completing this study. They also thank Cheryl Kunde and Amy Van Gheem, M.D., 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.

Supplement 1

 

Analyses of Relation Between Newly Occurring Group A Beta Hemolytic Streptococcal (GABHS) Infection and Subsequent Changes in Tic and Obsessive-Compulsive Symptom Severity

 

Of the 52 definite or possible new GABHS infections, one infection occurred at the last patient visit. Therefore, scores on tic and OC symptom severity from the visit after an infection are available for 51 instances. The following results are based on those 51 infections for which the subsequent clinical and laboratory data were available. Considering the 51 instances of a “definite” or “possible” new GABHS infection, half the time (51%, 26/51) the combined tic and OC symptom severity scores (Yale Global Tic Severity Scale total tic score + Children's Yale-Brown Obsessive Compulsive Scale score) increased and half the time (49%, 25/51) the total symptom level decreased at the time of the next encounter (Table S3, available online). There were also 1,450 encounters when no new infection was identified. On 856 of these occasions (59%), there was no change or an improvement in the level of overall symptom severity versus 41% of the occasions when there was a “worsening” of symptoms. This difference was not significant (χ21 = 2.04, p = .15).

 

The average increase in the combined tic and OC symptom severity scores after a “definite” or “possible” new GABHS infection was 5.4 ± 4.7, which was slightly lower than the scores after no new infection (5.8 ± 5.2) but this difference was not statistically significant (t618 = 0.37, p = .71). There was a 7.4 ± 6.9 point worsening of the total symptom score if the newly diagnosed GABHS infection was treated with antibiotics and just a 4.3 ± 2.6 point increase if the newly diagnosed infection was not treated. The difference in worsening of the total symptom score was not significant (t24 = 1.67, p = .11). In the PANDAS group, the magnitude of the increase in symptom severity scores at the next encounter was slightly greater after a new infection (7.2 ± 6.9) than when no new infection was detected (5.9 ± 5.4; Table S2, available online). However, the difference in the mean increases of symptom severity was not statistically significant (t254 = 0.71, p = .48). Likewise, no significant differences were seen in the non-PANDAS group (Table S3, available online).

Appendix

 

 

TABLE S1 -- Numbers of Biological Specimens and Rates of Infection

Variable PANDAS Patients Non-PANDAS Patients

Number of subjects 31 53

Total number of sera samples collected 267 380

Mean number of sera samples per subject (range) 8.6 (2-12) 7.2 (1-12)

Total number of throat cultures collected 650 947

Mean number of throat cultures per subject (range) 21 (5-27) 18 (2-26)

Total number of definite GABHS infections 7 19

Number of subjects with definite GABHS infections 7 17

Number of subjects with multiple definite GABHS infections 0 2

Maximum number of definite GABHS infections per subject 1 2

Total number of possible GABHS infections 13 13

Number of subjects with possible GABHS infections 10 11

Number of subjects with multiple possible GABHS infections 3 2

Maximum number of possible GABHS infections per subject 2 2

Total number of definite + possible GABHS infections[a] 20 32

Number of subjects with definite + possible GABHS infections 15 23

Number of subjects with multiple definite + possible GABHS infections 4 6

Maximum number of definite + possible GABHS infections per subject 3 3

Total number of definite + possible GABHS infections treated with antibiotics 12 9

Number of β hemolytic streptococcal positive cultures not group A (rate of positive cultures per person per year) 5 ± 0.09 14 ± 0.17

Number of other illnesses including pharyngitis symptoms, flu, and/or upper respiratory infections with negative culture and no antibody increase (rate of other illnesses per person per year) 139 ± 2.52 130 ± 1.59

 

Note: Sixteen Group A Beta Hemolytic Streptococcal (GABHS) infections (4 in pediatric autoimmune disorder associated with streptococcal infections (PANDAS) group and 12 in non-PANDAS group) were identified based on positive throat cultures at the baseline visit but were not counted as new infections because it would be impossible to evaluate the date of possible acquisition of GABHS without prebaseline sera and cultures.

 

a Twenty positive throat cultures for group A were found in the PANDAS group and 29 positive throat cultures for group A were found in the non-PANDAS group.

 

 

TABLE S2 -- Observed Versus Expected Number of Hits when a Newly Diagnosed Group A β Hemolytic Streptococcal Infection (GABHS) Occurred in a 22-Week Window Surrounding a Tic and/or Obsessive-Compulsive (OC) Symptom Exacerbation[a]

Infection Classification Number of Hits[a] Expected Number of Hits by Chance[a] 95% CI

All subjects

Definite GABHS infections 4[c] 5.8 1.09-10.24

Possible GABHS infections 4[c] 5.8 1.09-10.24

Definite or possible GABHS infections 8[c] 9.6 3.45-15.76

PANDAS only

Definite GABHS infections 1 1.3 0.03-5.57

Possible GABHS infections — 1.2 —

Definite or possible GABHS infections 1 2.6 0.03-5.57

Non-PANDAS

Definite GABHS infections 3[c] 4.5 0.62-8.77

Possible GABHS infections 4[c] 2.5 1.09-10.24

Definite or possible GABHS infections 7[c] 7.0 2.81-14.42

 

Note: CI = confidence interval.

 

a For each subject, the expected number of hits 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 2 weeks before the detection of a new GABHS infection plus 20 weeks after the detection of a new GABHS infection. This quantity was summed across subjects in each group of subjects (pediatric autoimmune disorder associated with streptococcal infections [PANDAS] or control) to obtain the total number of hits that would be expected by chance alone. See text for the rationale for including the 2-week interval before a new GABHS infection was diagnosed.

b See text.

c In one non-PANDAS subject, two exacerbations occurred within 2 months after definite GABHS infection and one exacerbation after a possible GABHS infection.

 

 

TABLE S3 -- Relation Between Newly Occurring Group A β Hemolytic Streptococcal Infections (GABHS) and Subsequent Changes in Tic and Obsessive-Compulsive (OC) Symptom Severity

GABHS Status Encounter Type Encounters when Symptoms Worsened

Total Number of Encounters When Symptoms Worsened, n (%) Tic + OCD Score Increase, Mean ± SD Antibiotic Treatment Status Tic/OCD Score Increase, Mean ± SD

Entire cohort

Definite or possible GABHS[a] 51 26 (51) 5.4 ± 4.7 Treated 7.4 ± 6.9

Not treated 4.3 ± 2.6

No GABHS 1450 594 (41) 5.8 ± 5.2 NA NA

PANDAS cases

Definite or possible GABHS[a] 20 9 (45) 7.2 ± 6.9 Treated 9.4 ± 8.4

Not treated 4.5 ± 3.7

No GABHS 578 247 (43) 5.9 ± 5.4 NA NA

Non-PANDAS cases

Definite or possible GABHS[a] 31 17 (55) 4.5 ± 2.7 Treated 5.0 ± 4.2

Not treated 4.3 ± 2.3

No GABHS 872 347 (40) 5.7 ± 5.0 NA NA

 

Note: Tic + Obsessive-Compulsive Disorder (OCD) score (0-90) indicates the combined tic and OC symptom severity scores (Yale Global Tic Severity Scale total tic score [0-50] + Children's Yale-Brown Obsessive Compulsive Scale score [0-40]). None of the statistical comparisons (with/without GABHS or treated/not treated) were significant. NA = not applicable; PANDAS = pediatric autoimmune disorders associated with streptococcal infections.

 

a See text for definitions of “definite” or “possible” infections.

 

 

 

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[AmbersMommy]

Thank you!!!

[browneyesmom]

Hmm... ok, I see Leckman, Singer and Kurlan are all on this study... I don't have time right now to evaluate the methods used, but I wonder about the conclusions based on prior studies involving Kurlan. I'll have to look at this later; DD11 just woke.

[thereishope]

I'd like to know where their getting these kids from for these studies? Parents would need to know if their children are involved in a study and if the joint names of certain docs are part of it, I'm a little surprised diagnosed PANDAS parents would allow their children to participate.

Edited January 21, 2011 by Vickie

[thereishope]

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.

Medication Status

 

 

Of the 52 definite and possible new GABHS infections, 21 episodes were treated by the primary care clinician with a variety of appropriate antibiotics

 

Am I reading this right.....So if someone had a documented strep infection, they didn't get antibiotics if their primary didn't request results? And those that did get antibiotics, what antibiotic were they given?

Edited January 21, 2011 by Vickie

[Phasmid]

Boy, this really hurts the cause. In summary, there was no signficant causal relationship found between exacerbations and GABHS infection.

 

However, the authors do a good job of describing the shortcomings of, yet again, this study. They explain that the next study really needs to focus only on newly diagnosed cases of PANDAS and that the diagnostic criteria should be broadened. Also, this statement is nearly the most important in print:

 

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, sinusitis, and the common cold). [24] , [52] , [53] , [54] , [55] , [56] , [57] , [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, immunology, and microbiology to advance our knowledge and improve our understanding and care of these children regardless of the diagnostic label they carry.<BR style="mso-special-character: line-break"><BR style="mso-special-character: line-break">

Edited January 21, 2011 by Phasmid

[SarahJane]

I can't tell if there's stuff written between the lines or if it is just damaging. The paper by Murphy, Kurlan & Leckman was more supportive...so with Leckman & Kurlan on this one, is it just a matter of a wait period for article publication and the supportive one was in print first? And is it just me or does it seem like 4 years is a long time to analyze data that seemed to be pretty basic? (Study was conducted from July 2002 to December 2006, but the suggested strengthened criteria was written July 2010--so the suggestions are likely more based on knowledge from outside sources than just the research itself maybe.) With the suggested criteria, my son would still meet it except for the 24-48 hr onset...ours was more gradual (tho' if we'd known what we were looking for, maybe I'd have seen it earlier). And they do mention other possible infectious triggers. AND despite not finding a difference between the groups, they cite possible flaws in the study & only vaguely dispute that PANDAS exists (make the suggestion that criteria be strengthened). It does seem that maybe some of the "non-PANDAS" subjects were actually PANDAS. And...who are these PANDAS people who didn't experience exacerbations over the time of the study...we've been on this treadmill for a year now & have had 2 very LONG exacerbations...both with dx'd strep. Also, there's no mention of other medical care the kids may have received (i.e. abx for sinusitis, viruses, allergy meds), and the PANDAS kids maybe got longer abx px's so that could've helped keep exacerbations to a minimum. We don't know if there were exacerbations absent of strep...is that why they mention that possibility of other triggers? And the kids could be on their psychotrophic meds during the study, which I would think were likely more prescribed from '02-'06 (when did word come that they weren't recommended?), which could have dampened symptoms. And we know Leckman is a believer.... So...I will need to read this for a third time & maybe outline it to make more sense of it.

 

 

P.S. Thanks to LLM & browneyesmom.

Edited January 21, 2011 by SarahJane

[SarahJane]

Just realized this mentions "pharyngitis" (strep throat) exclusively vs. recognizing impetigo or perianal strep. Hmmmm.

 

And can I just also add a big DUH! in response to the following statment from the article because isn't that what medicine is all about (especially the last part!):

 

"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, immunology, and microbiology to advance our knowledge and improve our understanding and care of these children regardless of the diagnostic label they carry."

 

And with all that...at least the doctors are studying PANDAS.

Edited January 21, 2011 by SarahJane

[Worried_Dad]

Sigh. Need Buster to weigh in on this, but is this just a re-publication of Singer & Kurlan's earlier study with some new notes added in by Leckman? Seems like it has the same flaws Buster has enumerated before in terms of misapplying the PANDAS criteria (different definition of "abrupt onset" and "dramatic exacerbation" than classic PANDAS cases; much less significant Y-BOCS swings, fewer symptoms, etc.) and completely skewing the results by allowing the PCP to treat with antibiotics.

 

Antibiotic Treatment

 

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 with 28% (9/32) in the non-PANDAS group. The proportion of treated GABHS infections in PANDAS subjects was significantly higher than in non-PANDAS subjects (χ21 = 5.2, p = .02).

 

So - if I'm reading this right - 60% of the PANDAS kids were treated with abx and only 28% of the non-PANDAS kids were. Then is it any surprise the PANDAS group had less exacerbations?!?

 

Maybe I'm missing something, but this seems like a rehash of earlier work with maybe a few more caveats added in about the study's limitations. Buster, please clear away the fog!

[P_Mom]

I wouldn't worry about this. Worried Dad is right...it is just a republication of the old Kurlan and Singer report. Cunningham showed me a graph of their study. (yes, Cunningham even studied their study to find out why he was getting what he got). In a nutshell...his controls were REALLY screwed up......enough to make the study invalid in Cunningham's eyes.

 

This was a poorly orchestrated study. I am sure Cunningham would be happy to back that up. I would just ignore it. (unfortunately, many won't)

[MomWithOCDSon]

I wouldn't worry about this. Worried Dad is right...it is just a republication of the old Kurlan and Singer report. Cunningham showed me a graph of their study. (yes, Cunningham even studied their study to find out why he was getting what he got). In a nutshell...his controls were REALLY screwed up......enough to make the study invalid in Cunningham's eyes.

 

This was a poorly orchestrated study. I am sure Cunningham would be happy to back that up. I would just ignore it. (unfortunately, many won't)

 

Thanks for that clarification P.Mom and WD. I was wondering if those statements about cooperation and cross-disciplinary communication were Leckman's adds; I can hear him actually saying them, as a matter of fact.

 

It sucks, though, that, on the surface, this paper will be read and interpreted by many as both new and negative. It has a November 2010 date stuck on it, for heaven's sake, even though it's old, old, old (and flawed)! Why go to the trouble to have this re-issued?!?!?! And, if that's the case, then why isn't it clearly identified as a Meta-Study or annotated re-issue or something along those lines?