Clinical factors associated with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections

Clinical Factors Associated with Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections Tanya K. Murphy, MD1, Eric A. Storch, PhD1, Adam B. Lewin, PhD1, Paula J. Edge, BS2, and Wayne K. Goodman, MD3 Objective To explore associated clinical factors in children with pediatric autoimmune neuropsychiatric disordersassociated with streptococcal infections (PANDAS).
Study design Children with tics, obsessive-compulsive disorder, or both (n = 109) were examined with personaland family history, diagnostic interview, physical examination, medical record review, and measurement of baselinelevels of streptococcal antibodies.
Results Significant group differences were found on several variables, such that children in whom PANDAS (ver-sus without PANDAS) were more likely to have had dramatic onset, definite remissions, remission of neuropsychi-atric symptoms during antibiotic therapy, a history of tonsillectomies/adenoidectomies, evidence of group Astreptococcal infection, and clumsiness.
Conclusion The identification of clinical features associated with PANDAS should assist in delineating risks forthis subtype of obsessive-compulsive disorder/tics. (J Pediatr 2012;160:314-9).
ThetermPANDAS(pediatricautoimmuneneuropsychiatricdisordersassociatedwithstreptococcalinfections)refersto a disorder in children who manifest symptoms of obsessive-compulsive disorder (OCD), tic disorders, or both associatedwith a distinctive course, a temporal association with group A streptococcal (GAS) infection, and evidence of concurrent neurologic abnormalities (ie, severe hyperactivity, fine motor skill loss [handwriting deterioration], or adventitious movementssuch as choreiform movemeThe distinctive course is defined by prepubertal onset of symptoms, episodic symptomseverity, and a range of other psychiatric symptoms (eg, irritability, frequent mood changes, separation anxiety, hyperactivity,late-onset attention problems, personality change, oppositional behaviors), sleep disturbances, and deterioration in math skillsand handwriting.
Distinguishing PANDAS from other presentations of OCD or tics and, occasionally, from Sydenham chorea (SC) confounds researchers and clinicians, making it difficult to establish practical treatment protocols. Currently, careful delineation of theneuropsychiatric course offers the best framework with which to study the proposed GAS association. A core feature ofPANDAS has been a dramatic onset and a fluctuating course, with course characteristics (eg, episodic, sawtooth, remitting,progressing, chronic) likely varying with age of onset, illness duration, pattern of co-morbidity, and the patient’s sex. Althoughboth tic and OCD have the potential to manifest a chronic and disabling course, only tic disorder nosology acknowledges thepotential for an episodic course. Perhaps less recognized, OCD often has an episodic with some individuals sponta-neously remWhether children with a PANDAS subtype typically will go on to remission or progress to a more chroniccourse of illness is not known. The symptom course that is characteristic of PANDAS may not differ from the typical course ofOCD and tics early in the illness.
With the exception of children with an explosive onset of OCD/tics occurring simultaneously with GAS, the timing and the type of GAS association to makea definitive argument for PANDAS has not been well defined. The main issue From the 1Department of Pediatrics, University of SouthFlorida, St. Petersburg, FL; 2Department of Psychiatry, is the differentiation of a true inciting GAS infection, whether clinical or subclin- University of Florida, Gainesville, FL; and 3Department of ical, from GAS carrier states. Even further uncertainty exists on how much Psychiatry, Mount Sinai School of Medicine, New York,NY importance to ascribe to GAS exposure from close contacts. How synchronous Supported by National Institute of Mental Health (R01 the temporal association between GAS infection (or exposure) and symptom- MH063914 and K23 MH01739). T.M. received researchfunding from National Institutes of Health/National Insti- onset has thus far been undefined. It has been proposed that neuropsychiatric tute of Mental Health, Center for Disease Control,Tourette Syndrome Association, Otsuka Pharmaceuti-cals, Forest Pharmaceuticals, and Ortho-McNeill Jans-sen Pharmaceuticals. E.S. receives funding fromNational Institutes of Health/National Institute of MentalHealth, National Institutes of Health/National Institute ofChild Health and Human Development, The Brain andBehavior Research Fund, Otsuka Pharmaceuticals, Anti-group A streptococcal carbohydrate antigen Foundation for Prader-Willi Research, Tourette Syn- drome Association, All Children’s Hospital Research Foundation, and Ortho-McNeill Janssen Pharmaceuti-cals. A.L. receives funding from NARSAD, the Interna- tional Obsessive-Compulsive Disorder Foundation, the University of South Florida Research Council, OtsukaPharmaceuticals, and the Joseph Drown Foundation.
Pediatric autoimmune neuropsychiatric disorders associated with The other authors declare no conflicts of interest.
0022-3476/$ - see front matter. Copyright symptom-onset that occurs 1 to 6 months after GAS infection movement assessment.Videotapes were scored by an expe- could be a chance association.However, in cases of pure SC rienced rater (P.E.) blinded to subjects’ clinical and serologic (no evidence of carditis), an infection triggered etiology gen- status. In the choreiform segment, subjects were assessed with erally is presumed by the presence of GAS antibody elevations arms/hands outstretched in pronated and supinated posi- that can be observed after a lag between the suspected inciting tions (20 seconds each), then rated for severity of distal (fin- infection and the onset of symptoms. GAS antibody eleva- gers and wrist) and proximal (arms, elbows, and shoulders) tions observed within weeks of the onset of OCD or tics is choreiform (quick, jerky) movements. Movements were not enough in the current state of the field to establish scored with Touwen 0 to 3 scale: 0 = no movement visible during the 20 seconds; 1 = 2 to 5 isolated twitches; 2 = 6 to Unfortunately, PANDAS criteria and associated clinical 10 twitches; 3 = continuous twitching.
features that may serve to differentiate PANDAS from The Immune-Related OCD/TS Evaluation, an evaluation OCD/tics disorders without PANDAS are not well estab- tool devised by the first author, was completed by the physi- lished. The purpose of this study was to examine which cian with the parent of each subject. The use of this core features of PANDAS (eg, OCD/tic symptom course, instrument with patients assumes a diagnosis of OCD or GAS infection history, neurologic symptoms, and immune tics. The Immune-Related OCD/TS Evaluation elicited infor- history) provide the most meaningful differentiation mation germane to the diagnosis of immunologic conditions, between subjects with and without a PANDAS classification infections, rheumatic fever, SC, and other movement disor- and which additional clinical factors best exemplify the ders. Detailed descriptions about the course of neuropsychi- PANDAS presentation to advance the understanding of risks atric symptoms were obtained as were examination of the presence of PANDAS operational criteria developed bySwedo,age of onset of symptoms, symptom characteristics,and parental impression of symptom course. This instrument also screened for family history of autoimmune illnesses,recent stresses, and effect of medications on illness course.
A total of 109 patients with childhood-onset OCD, tics, orboth, ages 4 to 17 years, were asked to participate in the study. The study inclusion criterion was meeting the Diag- This study was approved by the institution’s human subjects nostic and Statistical Manual of Mental Disorders, Fourth Edi- review board. Study procedures were explained, the informed tion criteria for OCD, a tic disorder, or both. Recruitment consent was reviewed, and parents/subjects were given the op- was weighted to enrolling children with history of any portunity to ask questions. Before participation, parents gave infection-related symptom flare-ups or history of dramatic written consent, and subjects gave oral assent, and when age- onset of either OCD or tics, although children not meeting appropriate ($7 years), written assent. After participation, sub- these criteria also were included. Age of symptom-onset jects participated in the baseline assessment with the measures was determined by using all available information, including aforementioned. All assessments were conducted either by the pediatrician records, reports from parents and teachers, and first author or by a trained clinician with experience in pediatric self-reports from the child. Patients with a psychotic disor- OCD and tic disorders. Ratings were based on patient and par- der, significant medical illness, or non-tic neurologic disor- ent response, clinician judgment, and behavioral observation.
der at baseline were excluded from the study. Patients onstable doses of psychotropic medication for their condition Participant diagnostic information, symptoms, and familyhistory of autoimmune disorders were obtained through clin- ical interview, medical records, baseline laboratory tests in- The Schedule for Affective Disorders and Schizophrenia for cluding streptococcal antibodies, and psychological ratings.
School-Age Children-Present and Lifetimeis a structured Specific areas of interest were: participant diagnosis of immu- clinical interview to assess the presence of Diagnostic and nologic conditions, infections, rheumatic fever, SC and other Statistical Manual of Mental Disorders, Fourth Edition diag- movement disorders; course of neuropsychiatric symptoms; noses in children. The Children’s Yale-Brown Obsessive age of symptom-onset; details about co-morbid presenta- Compulsive Scaleis a clinician-rated, semi-structured inter- tions; extent of GAS infection and exposure, other infectious view that assesses the severity of OCD symptoms; strong triggers; recent stresses; and presence of PANDAS operational psychometric properties have been demonstrated. The Yale criteria as developed by Swedo et For each participant, the Global Tic Severity Scaleis a clinician-rated, semi-struc- first author assigned a classification of either ‘‘PANDAS’’ or tured interview that assesses tic severity; strong psychometric ‘‘without PANDAS’’ (course and GAS relatedness not consis- tent with PANDAS) on the basis of putative criteria described A filmed neurologic examination was conducted to record by Swedo et al. To establish inter-rater reliability of the case- any adventitious facial and limb movements, spooning or ness rating, the third author independently assessed a subsam- extension of arms, or other movements based on both the ple of 25 cases. Assessment consisted of a review of all available neurologic examination of soft signsand the choreiform data. Overall, inter-rater reliability was high (intraclass THE JOURNAL OF PEDIATRICS correlation coefficient = 0.86). These data were designed to with c2 test; risk ratios were calculated to report likeli- assimilate an impression of PANDAS at an initial presenta- hood of subjects with PANDAS to present with a particular tion during a clinical assessment by the child’s pediatrician criterion. No statistical correction for multiple tests was or psychiatrist without any prospective observation.
deoxyribonuclease B, and anti-A carbohydrate (anti-ACHO), A total of 109 patients (66.6% males) were asked to partic- were collected in 99 of the 109 children. The use of 3 anti- ipate in the study. Average age was 9.2 Æ 2.4 years; average bodies reduces the false-negative rate of a single test from age of onset of disorder was 5.7 Æ 2.5 years. Demographic 20% to approximately 5% to 10%. All streptococcal antibody data are presented in . Of the 109 subjects, 41 tests were performed in the University of Florida’s strepto- were classified as having PANDAS (28 male; mean age at coccal antibody laboratory. To minimize assay variability and to maximize the ability to detect individual’s changes PANDAS (n = 68) had a mean age of 9.36 years (SD, 2.3) with time, the full complement of samples from the same and 38 were male. Subjects in the PANDAS group were patient was assayed in the same run. The Sure-Vue ASO test kit (Fister Scientific, Pittsburgh, Pennsylvania)was used. Reagents used, technique, reading, and interpretation dramatic onset of symptoms; (3) have definite remissions; of the anti-deoxynuclease B (anti-DNaseB) and anti-ACHO assays have been described previously.
during antibiotic therapy; (5) have elevated streptococcal Earlier studies have established that a significant antibody titers; (6) have episodes of fever/sore throat at onset/flare rise can be detected approximately 2 weeks after an acute up; (7) show positive GAS culture results with symptom streptococcal infection (ie, pharyngitis) and that the antibody onset/flare up; and (8) present with clumsiness. Risk response typically peaks 3 to 4 weeks after that infection.A ratios and inferential statistics are presented in .
child was classified as having elevated titers when any one of Duration of illness was shorter in subjects classified as the 3 levels obtained at the baseline visit was higher than the having PANDAS. No notable group differences were set threshold. Thresholds used were $200 for antistreptoly- sin O (ASO), $240 for the anti-DNASeB, and $2.76 for symptoms, OCD, tic disorder, or separation anxiety.
the anti-ACHO antibody levels. These levels were not age ad- Although not statistically significant, 61% of subjects with justed and may have resulted in some false-negative results PANDAS had attention-deficit hyperactivity disorder versus 46% of subjects without PANDAS. An elevation ofone or more streptococcal titers was found in all the subjects with PANDAS (by case definition), especially Descriptive statistics were calculated for study variables.
ASO antibody (). With stringent criteria for Group differences (in PANDAS caseness) were examined GAS association (documented GAS culture or rising Table I. Subject demographics by group classification ADHD, attention-deficit hyperactivity disorder; CYBOCS, Children’s Yale-Brown Obsessive Compulsive Scale; YGTSS, Yale Global Tic Severity Scale.
*Duration of illness was significantly shorter for those youth meeting PANDAS caseness versus youth who did not (t [107] = À2.27, P < .025).
Table II. Frequency of symptom item adherence by cases with PANDAS Onset new and significant but not dramatic Elevated ASO/DNAseB/ACHO titers (of 99 with baseline data) Remission of neuropsychiatric symptoms during antibiotic therapy Fever and/or clinical sore throat without GAS confirmed Frequent GAS infections before 7 years of age History of tonsillectomies/adenoidectomies Rising titers or + GAS culture + dramatic onset Rising titers or + GAS culture + definite remissions Rising titers or + GAS culture + dramatic onset + definite remissions *c2 could not be determined, because at least one expected cell frequency was <5 (Fisher exact probability test indicated P > .05).
†P < .05.
{P < .001.
**Percentages are based on available data. A number of cases were missing titer information necessary to categorize as rising/not rising, and (to a lesser degree) as high/not high.
antibodies) at onset or flare up with course features that antibodies between time of onset to 4 to 8 weeks later included dramatic onset and definite remissions, 46% of was found in only a minority of subjects (on the basis of the PANDAS group met this requirement versus 10% in the without PANDAS group. The remaining 54% of subjects with PANDAS had dramatic onset with GAS(n = 15), This study was conducted to determine the strength of coreand associated clinical factors with PANDAS cases. Although limitations of the study included the subjective assessment of raters on the basis of original features of PANDAS and the ac-curacy of recall of symptoms and onset by parents, significant study strengths include the use of objective laboratory values and extensive review of factual medical records. As defined by the putative PANDAS criteria and supported by the clinician’s impression of PANDAS caseness, GAS correlation, dramatic onset, and definite remission were strong predictors. Al- though nearly all of our subjects were prepubertal at symptomonset, those having a shorter duration of illness were more of- *On the basis of collected samples at baseline visit.
ten associated with a PANDAS presentation. One possibility is †c2 could not be determined, because at least on expected cell frequency was <5 (Fisher exactprobability test indicated P > .05).
that patients examined earlier in their course of illness have Clinical Factors Associated with Pediatric Autoimmune Neuropsychiatric Disorders Associated with THE JOURNAL OF PEDIATRICS a higher reporting of GAS association and are more likely to both local and general changes in immunologic parameters.
have an episodic course with more definitive remissions.
Both humoral (immunoglobulin A, G, M levels) and cellular Whether this observation is related to the etiology of onset (CD3+, CD4+, CD8+ lymphocyte counts) immune factors or is a clinical coincidence will need further investigation.
decreased significantly postoperatively, but 6 months post- We did not find specificity for some characteristics operatively, findings are normal. The effect of a transient, thought to distinguish PANDAS, namely dramatic flare- immune modulation associated with surgical removal of ups and choreiform movements. Another observation that the tonsils, adenoids, or both on the development of autoim- was more specific to the PANDAS group was remission or partial remission of symptoms while taking antibiotics. The Approximately one-half our subjects had multiple strepto- design of the two published studies has precluded drawing coccal infections before the age of 7 years (49% of group a definitive conclusion on the efficacy of antibiotic use for overall, 56% of those with PANDAS). Recent PANDAThe safety, efficacy, dosing, and duration of suggest risk associated with repeat GAS infections in children antibiotic use for purported cases of PANDAS needs further who have neuropsychiatric symptoms. For example, a history of multiple GAS infections within a 12-month period was At least one streptococcal antibody level was elevated in associated with increased risk for Tourette syndrome most patients regardless of group assignment. Although (OR = 13.6).26 Another source found a number of earlier many of the patients were recruited in this study because GAS infections to be positively related to severity of course they had some features of PANDAS (ie, flare-ups, frequent and incidence of relapseA school study examining motoric streptococcal infections, etc.), this finding is not surprising.
signs and behavior while obtaining monthly GAS cultures on ASO antibody level was the only antibody significantly asso- 693 schoolchildren found that those with repeated GAS ciated with cases versus non-cases (59% versus 37%, respec- infections during the 8-month study had more frequent neu- tively; P = .03). Streptococcal antibody tests provide evidence ropsychiatric In our study, we were specifically only for an antecedent streptococcal infection. Elevations in interested in children with frequent GAS infections at an these antibodies are not diagnostic of PANDAS, but require early age. Vulnerability to neuropsychiatric sequelae may careful consideration of the clinical history and examination.
occur when a cumulative threshold effect of repeat infections In some cases, particularly for very young children, limited is reached in a young child. Although the development of earlier exposures to GAS might affect likelihood of surpassing rheumatic fever is rare in children <5 years old, the effect the threshold for elevated antibody levels. Other factors such of early GAS infections on future immune response to GAS as hyperlipidemia, treatment with antibiotics, and the indi- and neuropsychiatric vulnerability is unknown. Neuroim- vidual’s ability to mount a strong immune response, are mune reactions may be non-specific to the type of infectious other potential reasons for variations in antibody levels. Fre- trigger and caused by an inherent, broader immunologic risk.
quent exposure, reinfecor stronger than typical Reasons for GAS recurrence are likely complex and numer- immune responsesto GAS are likely reasons for sustained Most of the recurrences of GAS are relapses (ie, infec- titers or the slower rate of decline in some of these children tion by the same streptococcal strain rather than new infections caused by a different strain).
An increased rate of OCD and Tourette syndrome in first- Currently, the exact prevalence of the PANDAS subtype degree family members of patients with PANDAShas been remains unknownbecause most studies of PANDAS have reported. In the case series of 54 patients with PANDAS, 39% been based on targeted recruitment, leading to difficulties had family history of tics and 23% had family history of OCD in identification of base-rates and probabilities for (when subclinical OCD cases were included) in 100 first- encountering the disorder. For example, although all our degree relatives. Currently, the prevalence of immune disor- subjects had OCD, tics, or both, our study selected for sub- ders in family members has not been examined in the jects who met two or more PANDAS criteria (ie, prepubertal PANDAS subtype of OCD or tics despite some clinical evi- onset, fluctuating course, dramatic onset, GAS association).
dence of a Family members of our subjects had Most subjects were prepubertal and many had a fluctuating a substantial prevalence of autoimmune disease compared course, but a minority met more stringent criteria for PANDAS requiring dramatic onset and clearly identifiable We found a high association between PANDAS cases and association with GAS. Despite our attempt from the outset rate of tonsillectomies and adenoidectomies. This finding to enrich the sample with PANDAS, only 38% were assigned may suggest that pre-existing infections such as otitis and the PANDAS classification. This study advances the literature pharyngitis were related to risk of the development of neuro- by validating a set of largely objective criteria compared with psychiatric symptomsor that removal of this lymphoid clinician impression. Defining risks and associated features tissue increased immunologic risksthat may be associ- will have a major impact on determining the etiology of ated with increased risk of OCD/tics.Although symptomatic this pediatric disorder and evaluating treatments. n GAS infections have been shown to decrease after tonsillec-tomy,the role of non-carrier state subclinical infections We thank Muhammad W. Sajid, MD, for his assistance in the confir- has not been documented. Recent research has shown that mation of diagnoses, physical examinations, and inter-rater assess- children with hypertrophy of adenoids and tonsils exhibit ments, P. Jane Mutch, PhD, for ratings and institutional review board administration, and Mark Yang, MD, (posthumously) for his 15. Kaplan EL, Rothermel CD, Johnson DR. Antistreptolysin O and anti- contribution in statistical design and support.
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16. Garvey MA, Perlmutter SJ, Allen AJ, Hamburger S, Lougee L, Submitted for publication Jul 29, 2010; last revision received May 24, 2011;accepted Jul 11, 2011.
Leonard HL, et al. A pilot study of penicillin prophylaxis for neuropsy-chiatric exacerbations triggered by streptococcal infections. Biol Psychi- Reprint requests: Tanya K. Murphy, MD, Professor & Rothman Endowed Chair, Department of Pediatrics, University of South Florida, 800 6th St, South,Box 7523, St. Petersburg, FL 33701. E-mail: 17. Budman C, Coffey B, Dure L, Gilbert D, Juncos J, Kaplan E, et al. Regard- ing ‘‘antibiotic prophylaxis with azithromycin or penicillin forchildhood-onset neuropsychiatric disorders.’ Biol Psychiatry 2005;58: 18. Gilbert D, Gerber AA. Regarding ‘‘antibiotic prophylaxis with azithro- 1. Swedo SE, Garvey M, Snider L, Hamilton C, Leonard HL. The PANDAS mycin or penicillin for childhood-onset neuropsychiatric disorders.’’ subgroup: recognition and treatment. CNS Spectr 2001;6:419-22. 25-6.
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Clinical Factors Associated with Pediatric Autoimmune Neuropsychiatric Disorders Associated with


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