Postinfectious Inflammation, Autoimmunity, and Obsessive-Compulsive Disorder: Sydenham Chorea, Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infection, and Pediatric Acute-Onset Neuropsychiatric Disorder.

Postinfectious neuroinflammation has been implicated in multiple models of acute-onset obsessive-compulsive disorder including Sydenham chorea (SC), pediatric acute-onset neuropsychiatric syndrome (PANS), and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS). These conditions are associated with a range of autoantibodies which are thought to be triggered by infections, most notably group A streptococci (GAS). Based on animal models using huma sera, these autoantibodies are thought to cross-react with neural antigens in the basal ganglia and modulate neuronal activity and behavior. As is true for many childhood neuroinflammatory diseases and rheumatological diseases, SC, PANS, and PANDAS lack clinically available, rigorous diagnostic biomarkers and randomized clinical trials. In this review article, we outline the accumulating evidence supporting the role neuroinflammation plays in these disorders. We describe work with animal models including patient-derived anti-neuronal autoantibodies, and we outline imaging studies that show alterations in the basal ganglia. In addition, we present research on metabolites, which are helpful in deciphering functional phenotypes, and on the implication of sleep in these disorders. Finally, we encourage future researchers to collaborate across medical specialties (e.g., pediatrics, psychiatry, rheumatology, immunology, and infectious disease) in order to further research on clinical syndromes presenting with neuropsychiatric manifestations.

Impact of PANS and PANDAS Exacerbations on Occupational Performance: A Mixed-Methods Study.

OBJECTIVE: Pediatric acute-onset neuropsychiatric syndrome (PANS) includes pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections and involves sudden-onset neuropsychiatric symptoms, including obsessions, compulsions, sensory difficulties, and dysgraphia after infection or other triggers. Our objective was to identify problems with areas of occupation, body functions, and performance skills during exacerbations. METHOD: In this online retrospective study, based on the Occupational Therapy Practice Framework: Domain and Process (2nd ed.), we surveyed parents of 111 children with PANS. RESULTS: Activities of daily living, math, handwriting, extracurricular activities, free play, organized sports, community and family social participation, higher level thinking, attention, memory, sequencing, emotional coping, and energy and drive were commonly affected during exacerbations. During exacerbations, children often required assistance and adaptation to remain functional or were unable to function at a typical level. CONCLUSION: Children with PANS present with pervasive occupational performance needs during exacerbation. Children and families may benefit from accommodations to maximize function during this turbulent period.

Treatment of Pediatric Acute-Onset Neuropsychiatric Disorder in a Large Survey Population.

OBJECTIVE: The goal of this study was to investigate treatment histories and outcomes in a large community sample of youth with Pediatric Acute-onset Neuropsychiatric Syndrome (PANS), and, where appropriate, to examine the impact of immune deficiency on treatment outcomes. METHODS: A comprehensive internet-based survey was completed by parents or guardians of youth who had received physician diagnoses of PANS, or by young adults (age 18+) who had themselves been diagnosed by a physician (N = 698). Data regarding the treatment histories of these patients, including the variety of medical and psychological treatments employed and the caregiver- or self-reported response to each, are presented. RESULTS: The PANS patients in this study had commonly been treated with antibiotic (N = 675), anti-inflammatory (N = 437), and/or psychotropic therapy (N = 378). Response to antibiotic treatment was best when treatment was relatively aggressive, with broad-spectrum antibiotics and courses of >30 days generally producing the best results (i.e., up to 52% of patients achieving a "very effective" response). For immune-deficient patients (caregiver-reported laboratory studies below normal limits; N = 108), use of broad-spectrum antibiotics appeared to be particularly desirable. Anti-inflammatory therapies, including over-the-counter medications such as ibuprofen, were at least "somewhat effective" for most patients. Intravenous immunoglobulin (IVIG) had been used to treat PANS in 193 (28%) of the patients and was at least "somewhat effective" for 89%, although for 18% of these, the effect was not sustained. The highest rate of sustained response to IVIG treatment was seen in immune-deficient patients who received doses of at least 0.8 g/kg IVIG on a regular basis. Psychotropic medications, most commonly SSRIs (38% reported a trial), were commonly employed, but were often ineffective (e.g., 44% found SSRIs "somewhat" to "very effective"). Many patients (N = 473) had received some form of psychotherapy with some benefit, with cognitive behavioral therapy found to be at least somewhat effective in a majority of those treated with this modality. CONCLUSION: Among the PANS patients represented in this study, relatively aggressive treatment courses targeted at eradicating infection and modulating the inflammatory response appeared to provide the best caregiver-reported therapeutic results, and to be generally well tolerated. Given its relative efficacy and tolerability, treatment targeting the inflammatory response may represent an underutilized approach in this population. The results of this study should be considered in light of the limitations inherent in a self-selected and administered online survey.

A Survey of Pediatric Acute-Onset Neuropsychiatric Syndrome Characteristics and Course.

OBJECTIVE: To date, studies in the area of pediatric acute-onset neuropsychiatric syndrome (PANS; including pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection [PANDAS] and pediatric infection-triggered neuropsychiatric disorder [PITAND]) have been relatively small and hence unable to comprehensively address questions of disease heterogeneity (e.g., by age, gender), comorbidities, and progression. In this study, we investigated an internet survey sample to more fully characterize the phenotypic traits; medical, family, and developmental history; functional challenges; and clinical course associated with PANS. METHODS: Six hundred and ninety-eight patients with clinical diagnoses of PANS were included in this study. Participants, who included parents and legal guardians (for minors) or the PANS patients themselves (for those ages 18 and older), were asked to complete a 146-question survey designed to ascertain medical, developmental, and family history; PANS symptomatology; medical and nonmedical interventions for PANS; PANS course; PANS outcomes; and access to PANS care. RESULTS: Our results agree with previous findings concerning the core symptoms of PANS as well as its male predominance (65% in this survey) and infection-triggered onset, thus validating the study population. Infection was implicated as the primary inciting factor in 65% of patients; 54% of patients reported an association with group A streptococcus specifically. The results of this survey also revealed new findings, including a surprisingly strong impact of gender and pubertal status on symptom course and chronicity, a high rate of medical comorbidity suggesting generalized immune dysfunction, a profound impact of PANS episodes on functional status, and a role for early resolution of infection through antibiotic treatment in disease course. CONCLUSIONS: This study serves as the first survey of its size to provide insight into the global clinical picture and range of phenotypes of PANS patients. Significant results included the impact of gender and pubertal status on phenotype, affirmation of the role of the immune system in PANS pathology, and the role of timely resolution of infection in clinical outcomes. Understanding how PANS presents in a broad population-based sample, within the limitations of a self-selected and administered online survey, is an important step toward improving diagnosis, creating more targeted treatment options, educating the clinical and research community, and generating hypotheses for future prospective research.