Evaluation and Treatment of Obsessive Compulsive and Related Disorders

强迫症及相关疾病的评估和治疗

• 批准号: 10008843
• 负责人: Susan Swedo
• 金额: $ 62.91万
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10008843
• 关键词: Acute; Adolescent; Affect; Aggressive behavior; Animal Model; Antibodies; Antibody Formation; Antigens; Anxiety; Archives; Attention; Autoantibodies; Autoimmune Diseases; Autoimmune encephalitis; Awareness; Basal Ganglia; Behavior; Behavioral; Biological Assay; Biological Markers; Blood; Blood - brain barrier anatomy; Brain; Case-Control Studies; Cell Wall; Cells; Cerebrospinal Fluid; Child; Childhood; Classification; Clinical; Clinical Protocols; Clinical Research; Clinical Trials Database; Cognitive; Comorbidity; Compulsive Behavior; Convalescence; Data; Deterioration; Development; Diagnosis; Disease; Distress; Eating; Eating Disorders; Electroencephalography; Emotional; Enuresis; Etiology; Evaluation; Family; Future; Genetic Materials; Goals; Health Services Accessibility; Human; Immunoglobulins; Immunotherapy; Impairment; Improve Access; Increased frequency of micturition; Individual; Infection; Intramural Research Program; Intravenous Immunoglobulins; Investigation; Knowledge; Laboratories; Lentiform nucleus structure; Literature; Lymphoid Tissue; Magnetic Resonance Imaging; Measures; Mediating; Mental Depression; Microglia; Motor; Mus; National Institute of Mental Health; Neuraxis; Neuroimmune; Neurologic Symptoms; Neurons; Nose; Obsession; Obsessive compulsive behavior; Obsessive-Compulsive Disorder; Olfactory Nerve; Patients; Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus Infections; Performance; Personality; Pharyngeal structure; Placebos; Plasmapheresis; Polysomnography; Population Study; Positron-Emission Tomography; Prevention; Prevention strategy; Problem behavior; Reporting; Research; Research Personnel; Research Project Grants; Resistance; Resources; Rheumatic Fever; Rheumatic Heart Disease; Role; Sampling; Scarlet Fever; Schools; Sensory; Separation Anxiety; Signs and Symptoms; Site; Sleep disturbances; Steroids; Streptococcal Infections; Streptococcus; Streptococcus pyogenes; Subgroup; Sydenham Chorea; Symptoms; Syndrome; T-Lymphocyte; Testing; Therapeutic; Thinking; Tic disorder; Tissues; Work; acronyms; base; biobank; brain research; caudate nucleus; clinical care; clinical diagnostics; cognitive change; cognitive function; cross reactivity; design; effective therapy; improved; interest; member; micturition urgency; neuroinflammation; neuropsychiatric disorder; neuropsychiatric symptom; neuropsychiatry; novel; novel therapeutic intervention; prospective; treatment group

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.

强迫症（OCD）影响了1-2％的儿童和青少年，从而造成了无情的痴迷思想和强迫行为的严重困扰和损害。大约有1/4的强迫症儿童报告了他们的症状突然发作。当这些症状伴随着其他行为问题，认知改变和躯体症状时，儿童可能有资格诊断儿科急性发作神经精神综合征（PANS）。盘子的特征是强迫症和/或饮食失调突然发作，并伴有以下七种合并症中的至少两种：1）焦虑； 2）情绪不稳定和/或抑郁； 3）烦躁，侵略和/或严重的对立行为； 4）行为（发展）回归； 5）学校表现恶化； 6）感觉或运动异常； 7）体征和症状，包括睡眠障碍，遗传或尿频等。 （Swedo，Leckman，Rose Pediatr Therapeutics 2：1-8，2012） 对于某些患有PANS的儿童，症状似乎是由于常见的儿童感染而引起的，包括A组链球菌（气体）感染（“链球菌喉咙”和Scarlet Fever）。气体感染后症状开始或加剧的儿童可能属于通过缩写旁nym缩写pandas鉴定的神经精神疾病的亚组（用于与链球菌感染相关的小儿自身免疫性神经精神疾病（Swedo等，Swedo等，AJP 1998）。三十年的研究表明，大熊猫代表了链球菌神经炎症性疾病，类似于Sydenham Chorea（急性风湿热的神经系统表现）。五条证据支持大熊猫气体感染的病因学作用： 1）病例控制，基于人群的研究以及基于学校的观察性研究表明，最近气体感染儿童的强迫症和TIC疾病发生率提高。 2）对急性发作OCD儿童的前瞻性，纵向评估揭示了气体感染或暴露后的症状 3）迅速治疗气体感染可以改善强迫症和其他熊猫病儿童的神经精神症状 4）预防气体感染会减少神经精神症状的恶化（类似 5）小鼠鼻相关淋巴组织中反复的气体感染通过气体特异性T细胞产生神经免疫性激活，这些T细胞通过嗅觉神经进入大脑 在熊猫中，当某些风湿性气体感染遗传易受伤害的个体并引起识别抗原抗原不仅在燃气细胞壁上，而且在人类中枢神经系统内的细胞上识别抗原的抗体的产生时，似乎会出现症状。这些交叉反应性抗体会产生基底神经节的神经炎症，导致突然发作是熊猫的神经精神症状。新兴文献支持大熊猫作为感染后（自身抗体介导的）自身免疫性脑炎的分类；支持的研究线包括： 1）前瞻性，纵向临床观察，记录了多个症状领域，包括情绪，行为，运动，感觉，体细胞和认知功能的异常 2）临床实验室测定的异常，包括定量免疫球蛋白以及旁流胶测试，例如多摄影或脑电图 3）证明交叉反应性抗体，这些抗体识别燃气细胞壁和人类神经元组织上的两个成分；急性疾病期间这些交叉反应性抗体的滴度高于脑脊液（CSF）的康复期间的滴度以及受影响个体的血液 4）在动物模型中，交叉反应性抗体的被动转移会产生行为异常和限制食物摄入量 5）正电子发射断层扫描（PET）研究揭示了急性病熊猫患者的尾状核和垒核中活化的小胶质细胞（神经炎症的迹象）；这些异常通过成功的免疫疗法解决 6）据报道，包括类固醇，静脉免疫球蛋白（IVIG）和治疗性静脉曲张的免疫疗法可改善神经精神症状（尽管IVIG的2016年NIMH/YALE试验未能显示出35名pandas患有安慰剂的优势） 为了复制熊猫中的发现，并将调查扩展到较大的锅儿童群体，瑞典博士组建了一个临床医生和研究人员，并领导了一个对锅/熊猫感兴趣的临床医生和研究人员。协作临床研究网络的目标是：（1）提高对急性发作神经精神综合征的识别，诊断和治疗，（2）进行研究，以提高人们对病因学因素，宿主脆弱性和疾病机制的理解，以及C）提高对Pandas，Pans，Pans，Pans和Ressace Disorders in Corper care care care care care care care in Care in Care in care的认识和认识。该财团的成员于2019年2月在NIMH开会，讨论了临床和研究问题，包括对抗治疗病例的临床护理方法。 财团成员正在进行许多研究项目，包括识别特定抗原抗体相互作用的努力；通过使用PET或磁共振成像（MRI）来记录神经炎症；评估交叉反应性抗体对血脑屏障的影响，并评估新型治疗干预措施的功效。与这些临床实验室研究并行，Swedo博士发起了一项全国性的努力，以获取有Pans及其家人的儿童的前瞻性纵向临床信息，样本和遗传物质。尽管该项目于2019年4月在壁内计划中关闭，几个学术地点仍然有兴趣继续该项目，并计划使用常用措施收集数据和样品，以允许跨站点比较。 在NIMH收集的样品已存档在NIMH生物库中，数据存储在NIMHS临床试验数据库中。 存档的材料将是对疾病机制，治疗和预防儿童急性神经精神疾病的未来研究的丰富资源。 工作是根据临床方案NCT01281969，NCT03507218，NCT01778504进行的。

项目成果

Children with obsessive-compulsive disorder: are they just "little adults"?

• DOI: 10.1172/jci37563
• 发表时间: 2009-04-01
• 期刊: JOURNAL OF CLINICAL INVESTIGATION
• 影响因子: 15.9
• 作者: Kalra, Simran K.;Swedo, Susan E.
• 通讯作者: Swedo, Susan E.

Executive and attention functioning among children in the PANDAS subgroup.

PANDAS 亚组儿童的执行和注意力功能。

• DOI: 10.1080/09297040802186899
• 发表时间: 2009
• 期刊: Child neuropsychology : a journal on normal and abnormal development in childhood and adolescence
• 作者: Hirschtritt,MatthewE;Hammond,ChristopherJ;Luckenbaugh,David;Buhle,Jason;Thurm,AudreyE;Casey,BJ;Swedo,SusanE
• 通讯作者: Swedo,SusanE