Evaluation and Treatment of Obsessive Compulsive and Related Disorders

National Institute Of Mental Health

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Abstract

Obsessive-compulsive disorder (OCD) affects 1-2% of children and adolescents, causing significant distress and impairments from the unrelenting obsessional thoughts and compulsive behaviors. Approximately 1/4 of children with OCD report an abrupt, dramatic onset of their symptoms. When these symptoms are accompanied by other behavior problems, cognitive changes and somatic symptoms, the child may qualify for a diagnosis of Pediatric Acute-onset Neuropsychiatric Syndrome (PANS). PANS is characterized by the sudden onset of OCD and/or eating disorder, accompanied by at least two of the following seven comorbidities: 1) Anxiety; 2) Emotional lability and/or depression; 3) Irritability, aggression and/or severely oppositional behaviors; 4) Behavioral (developmental) regression; 5) Deterioration in school performance; 6) Sensory or motor abnormalities; 7) Somatic signs and symptoms, including sleep disturbances, enuresis or urinary frequency and others. (Swedo, Leckman, Rose Pediatr Therapeutics 2:1-8, 2012) For some children with PANS, symptoms appear to arise as a consequence of common childhood infections, including Group A streptococcal (GAS) infections (strep throat and Scarlet fever). Children whose symptoms begin or exacerbate following GAS infections may belong to a subgroup of neuropsychiatric disorders identified by the acronym PANDAS (for Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections) (Swedo et al, AJP 1998). Three decades of research has revealed that PANDAS represents a post-streptococcal neuroinflammatory disorder, similar to Sydenham chorea (the neurologic manifestation of acute rheumatic fever). Five lines of evidence support an etiologic role for GAS infections in PANDAS: 1) Case-control, population-based studies, and school-based observational investigations have shown increased rates of OCD and tic disorders among children with recent GAS infections. 2) Prospective, longitudinal evaluations of children with acute-onset OCD reveal symptom exacerbations following GAS infection or exposure 3) Prompt treatment of GAS infections can ameliorate OCD and other neuropsychiatric symptoms among children newly ill with PANDAS 4) Prevention of GAS infections reduces neuropsychiatric symptom exacerbations (similar to results for rheumatic heart disease or Sydenham chorea) 5) Repeated GAS infections in the nasal-associated lymphoid tissue of mice produce neuroimmune activation via GAS-specific T-cells which enter the brain via the olfactory nerve In PANDAS, symptoms appear to arise when certain rheumatogenic GAS infect genetically vulnerable individuals and provoke the production of antibodies recognizing antigens not only on the GAS cell wall, but also on cells within the human central nervous system. These cross-reactive antibodies produce neuroinflammation of the basal ganglia, resulting in the abrupt onset of neuropsychiatric symptoms which characterize PANDAS. An emerging literature supports the classification of PANDAS as a post-infectious (autoantibody-mediated) autoimmune encephalitis; supportive lines of research include: 1) Prospective, longitudinal clinical observations documenting multiple symptom domains, including abnormalities of emotional, behavioral, motor, sensory, somatic and cognitive functions 2) Abnormalities on clinical laboratory assays, including quantitative immunoglobulins, as well as on paraclinical tests, such as polysomnography or electroencephalography 3) Demonstration of cross-reactive antibodies that recognize both components on the GAS cell wall and human neuronal tissue; titers of these cross-reactive antibodies are higher during acute illness than during convalescence in the cerebrospinal fluid (CSF) as well as blood of affected individuals 4) In animal models, passive transfer of the cross-reactive antibodies produces behavioral abnormalities and restricted food intake 5) Positron emission tomography (PET) studies reveal activated microglia (a sign of neuroinflammation) in the caudate and lentiform nucleus of acutely ill PANDAS patients; these abnormalities resolve with successful immunotherapy 6) Immune therapies, including steroids, intravenous immunoglobulin (IVIG) and therapeutic plasmapheresis, have been reported to improve neuropsychiatric symptoms (although a 2016 NIMH/Yale trial of IVIG failed to show superiority of IVIG over placebo for 35 children with PANDAS) To replicate the findings in PANDAS and extend investigations to the larger group of children with PANS, Dr. Swedo assembled and led a nationwide consortium of clinicians and researchers with interest in PANS/PANDAS. The goals of the collaborative clinical research network are to: (1) improve recognition, diagnosis, and treatment of acute onset neuropsychiatric syndromes, (2) conduct research which improves understanding of etiologic factors, host vulnerability, and disease mechanisms, and c) increase awareness and recognition of PANDAS, PANS, and related disorders in order to improve access to care. Members of the Consortium met at the NIMH in February 2019 to discuss clinical and research issues, including approaches to clinical care of treatment-resistant cases. Consortium members are collaborating on a number of research projects, including efforts to identify specific antigen-antibody interactions; document neuroinflammation through the use of PET or magnetic resonance imaging (MRI); evaluate the impact of the cross-reactive antibodies on the blood-brain barrier and evaluate the efficacy of novel therapeutic interventions. In parallel to these clinical-laboratory investigations, Dr. Swedo has launched a nationwide effort to obtain prospective, longitudinal clinical information, samples and genetic material from children with PANS and their families. Although the project closed in April 2019 in the intramural program several academic sites remain interested in continuing this project, with plans to collect data and samples using common measures that will permit cross-site comparisons. Samples collected at NIMH have been archived in the NIMH Biorepository and data are stored in NIMHs Clinical Trials Database. The archived material will be a rich resource for future investigations of disease mechanism, treatment and prevention of acute-onset neuropsychiatric disorders in children. Work was conducted under clinical protocols NCT01281969, NCT03507218, NCT01778504.