Obsessive-compulsive disorder (OCD) affects 1-2% of children and adolescents, causing significant distress and impairments from the unrelenting obsessional thoughts and compulsive behaviors. In some cases, childhood-onset OCD appears to arise as a consequence of common childhood infections, including Group A beta-hemolytic streptococcal (GABHS) infections (""""""""strep throat"""""""" and Scarlet fever). Children whose symptoms begin or exacerbate following GABHS infections may belong to a subgroup of neuropsychiatric disorders identified by the acronym PANDAS (for Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections). The PANDAS subgroup shares several common clinical characteristics and may share a common pathophysiology for their symptoms. The postulated etiology for the PANDAS subgroup is that specific strains of group A beta hemolytic streptococi (GABHS), in genetically susceptible individuals, elicit the production of cross-reactive antibodies which recognize antigens not only on the GABHS cell wall, but also in the host brain tissue, eliciting obsessions, compulsions, tics and other neuropsychiatric symptoms. The cross-reactive antibodies have been shown to correlate with other anti-streptococcal antibodies and also with neuropsychiatric symptom severity, with highest titers seen in children acutely ill with Sydenham chorea or PANDAS symptomatology. A recent report by Yaddanapudi et al (Mol Psychiatry advance on-line publication, 11 Aug 2009;doi10.1038/mp.2009.77)demonstrated that passive transfer of these cross-reactive antibodies resulted in stereotypies and other neurologic symptoms in the recipient mice. This paper adds to the results of more than 15 years of research at the NIMH intramural program and elsewhere, demonstrating that: the PANDAS subgroup has a specific and identifiable symptom course (marked most notably by the acute, abrupt, overnight onset of symptoms (""""""""zero to sixty in less than 24 hours"""""""");the cross-reactive antibodies correlate with both GABHS infection status and neuropsychiatric symptom severity;prevention of GABHS infections through antibiotic prophylaxis results in prevention of neuropsychiatric symptom exacerbations;and, treatment of acutely ill children with immunomodulatory therapies (specifically, intravenous immunoglobulin IVIGor plasmapheresis) results in dramatic reductions in symptom severity. This line of research is unusual, in that it reversed the typical """"""""bench to bedside"""""""" progression and took clinical observations and experiences into the laboratory in search of information about etiopathogenic mechanisms. The results proved exciting, as the cross-reactive antibodies identified antigenic targets in the CNS which might provide new targets for therapeutic interventions. The PANDAS research represents a collaborative relationship among this branch (Dr. Swedo) and Dr. James Leckman and colleagues at the Yale University Child Study Center and Dr. Madeleine Cunningham of the University of Oklahoma Health Sciences Center. Drs. Swedo, Leckman, and Cunningham were the joint recipients of an NIH """"""""Bench to Bedside"""""""" award which is helping to fund a multi-site placebo-controlled trial of intravenous immunoglobulin (IVIG) for severely ill children with PANDAS. Up to 50 children (3-12 yrs old) willl be enrolled in the trial and randomly assigned to receive an infusion of IVIG or placebo. In addition to the information provided about the utility of IVIG treatment for PANDAS, the trial will generate biological samples to be analyzed by Dr. Cunningham and others, with the goal of further delineating the pathologic role of the cross-reactive antibodies, as well as potentially developing biomarkers for disease activity and treatment response. The trial is currently enrolling subjects. Screening is done by teams at Yale and at NIH, but all clinical interactions take place at the NIH Clinical Center. More information about the study is available at: http://clinicaltrials.gov/ct2/show/NCT01281969?term=bethesda%2C+MD+%2B+PANDAS&rank=1

Project Start
Project End
Budget Start
Budget End
Support Year
19
Fiscal Year
2011
Total Cost
$529,453
Indirect Cost
Name
U.S. National Institute of Mental Health
Department
Type
DUNS #
City
State
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Zip Code
Grant, Paul; Farmer, Cristan; Song, Jane et al. (2017) Riluzole Serum Concentration in Pediatric Patients Treated for Obsessive-Compulsive Disorder. J Clin Psychopharmacol 37:713-716
Swedo, Susan E; Frankovich, Jennifer; Murphy, Tanya K (2017) Overview of Treatment of Pediatric Acute-Onset Neuropsychiatric Syndrome. J Child Adolesc Psychopharmacol 27:562-565
Hommer, Rebecca E; Swedo, Susan E (2017) Anorexia and Autoimmunity: Challenging the Etiologic Constructs of Disordered Eating. Pediatrics 140:
Thienemann, Margo; Murphy, Tanya; Leckman, James et al. (2017) Clinical Management of Pediatric Acute-Onset Neuropsychiatric Syndrome: Part I-Psychiatric and Behavioral Interventions. J Child Adolesc Psychopharmacol 27:566-573
Gaughan, Thomas; Buckley, Ashura; Hommer, Rebecca et al. (2016) Rapid Eye Movement Sleep Abnormalities in Children with Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS). J Clin Sleep Med 12:1027-32
Williams, Kyle A; Swedo, Susan E; Farmer, Cristan A et al. (2016) Randomized, Controlled Trial of Intravenous Immunoglobulin for Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections. J Am Acad Child Adolesc Psychiatry 55:860-867.e2
Williams, Kyle A; Swedo, Susan E (2015) Post-infectious autoimmune disorders: Sydenham's chorea, PANDAS and beyond. Brain Res 1617:144-54
Kovacevic, Miro; Grant, Paul; Swedo, Susan E (2015) Use of intravenous immunoglobulin in the treatment of twelve youths with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. J Child Adolesc Psychopharmacol 25:65-9
Latimer, M Elizabeth; L'Etoile, Nathan; Seidlitz, Jakob et al. (2015) Therapeutic plasma apheresis as a treatment for 35 severely ill children and adolescents with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. J Child Adolesc Psychopharmacol 25:70-5
Toufexis, Megan D; Hommer, Rebecca; Gerardi, Diana M et al. (2015) Disordered eating and food restrictions in children with PANDAS/PANS. J Child Adolesc Psychopharmacol 25:48-56

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