Evaluation and Treatment of Obsessive Compulsive and Related Disorders

强迫症（OCD）影响1-2%的儿童和青少年，从无情的强迫思想和强迫行为中造成显着的痛苦和损害。 在某些情况下，儿童期发作的强迫症似乎是由于常见的儿童感染而引起的，包括A组β-溶血性链球菌（GABHS）感染（“链球菌性咽喉炎”和猩红热）。在GABHS感染后症状开始或恶化的儿童可能属于由首字母缩略词PANDAS（与链球菌感染相关的儿童自身免疫性神经精神疾病）确定的神经精神疾病亚组。PANDAS亚组具有几个共同的临床特征，并且可能具有共同的症状病理生理学。 PANDAS亚组的假定病因是A组β溶血性链球菌（GABHS）的特定菌株在遗传易感个体中引起交叉反应性抗体的产生，这些抗体不仅识别GABHS细胞壁上的抗原，而且识别宿主脑组织中的抗原，引起强迫症、强迫症、抽搐和其他神经精神症状。 交叉反应性抗体已被证明与其他抗链球菌抗体相关，也与神经精神症状的严重程度相关，在患有Sydenham舞蹈病或PANDAS舞蹈病的儿童中观察到最高滴度。 Yaddanapudi等人最近的报告（Mol Psychiatry advance on-line publication，2009年8月11日; doi 10.1038/mp. 2009. 77）证明，这些交叉反应性抗体的被动转移导致受体小鼠中的刻板和其他神经症状。 本文增加了超过15年的研究结果，在NIMH内部计划和其他地方，表明：PANDAS亚组有一个特定的和可识别的症状过程（最显著的特征是症状的急性、突然、过夜发作（“在不到24小时内从0到60”）;交叉反应性抗体与GABHS感染状态和神经精神症状严重程度相关;通过抗生素预防GABHS感染可预防神经精神症状恶化;用免疫调节疗法（特别是静脉注射免疫球蛋白IVIG或血浆置换）治疗急性病儿童可显著降低症状严重程度。 这一系列研究是不寻常的，因为它扭转了典型的“从实验室到床边”的进展，并将临床观察和经验带入实验室，以寻找有关病因机制的信息。 结果令人兴奋，因为交叉反应性抗体鉴定了CNS中的抗原靶点，这可能为治疗干预提供新的靶点。 PANDAS的研究代表了该分支（Swedo博士）与耶鲁大学儿童研究中心的James Leckman博士及其同事以及俄克拉荷马州健康科学中心的Madeleine Cunningham博士之间的合作关系。 Swedo，Leckman和Cunningham博士是NIH“Bench to Bedside”奖的联合获得者，该奖项有助于资助一项针对PANDAS重症儿童的静脉注射免疫球蛋白（IVIG）的多地点安慰剂对照试验。 多达50名儿童（3-12岁）将参加试验，并随机分配接受IVIG或安慰剂输注。 除了提供关于IVIG治疗PANDAS的实用性的信息外，该试验还将产生生物样本，由坎宁安博士和其他人进行分析，目的是进一步描述交叉反应抗体的病理作用，以及潜在地开发疾病活动和治疗反应的生物标志物。该试验目前正在招募受试者。筛查由耶鲁大学和NIH的团队完成，但所有临床互动都在NIH临床中心进行。有关该研究的更多信息，请访问：http://clinicaltrials.gov/ct2/show/NCT01281969? term=bethesda%2C+MD+%2B+PANDAS&rank=1

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