Evaluation and Treatment of Obsessive Compulsive and Related Disorders

强迫症(OCD)影响着1-2%的儿童和青少年，由无情的强迫思想和强迫行为造成显著的痛苦和损害。在某些情况下，儿童期发病的强迫症似乎是由常见的儿童期感染引起的，包括A组β-溶血性链球菌(GABHS)感染(“链球菌咽喉炎”和猩红热)。感染GABHS后症状开始或加重的儿童可能属于首字母缩写PANAS(与链球菌感染相关的儿科自身免疫性神经精神障碍)确定的神经精神障碍的一个亚组。大熊猫亚群有几个共同的临床特征，并且它们的症状可能有共同的病理生理。大熊猫亚群的假设病因学是，在遗传易感个体中，A组β溶血性链球菌(GABHS)的特定菌株会引发交叉反应抗体的产生，这种抗体不仅识别GABHS细胞壁上的抗原，而且还识别宿主脑组织中的抗原，引发强迫症、抽搐和其他神经精神症状。交叉反应抗体已被证明与其他抗链球菌抗体相关，也与神经精神症状严重程度相关，最高滴度出现在患有Sydenham舞蹈症或大熊猫症状的急性疾病儿童中。Yaddanapudi等人最近的一份报告(摩尔精神病学进展在线出版物，2009年8月11日；doi10.1038/mp.2009.77)表明，被动转移这些交叉反应抗体会导致受体小鼠出现刻板印象和其他神经症状。这篇论文补充了NIMH内部项目和其他机构超过15年的研究结果，证明：大熊猫亚组有一个特殊的和可识别的症状过程(最显著的特征是急性、突然、一夜之间出现症状(“在不到24小时内从0到60”)；交叉反应抗体与GABHS感染状态和神经精神症状严重程度都相关；通过抗生素预防感染GABHS可以防止神经精神症状恶化；对急性疾病儿童进行免疫调节治疗(特别是静脉注射免疫球蛋白IVIGI或血浆置换)可显著减轻症状严重程度。这一系列的研究是不寻常的，因为它逆转了典型的“从板凳到床边”的发展过程，并将临床观察和经验带入实验室，以寻找关于病因机制的信息。结果被证明是令人兴奋的，因为交叉反应抗体识别了中枢神经系统中的抗原靶点，这可能为治疗干预提供新的靶点。 熊猫研究代表了该分支(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大学健康科学中心的Madeleine Cunningham博士之间的合作关系。斯威多博士、莱克曼博士和坎宁安博士共同获得了美国国立卫生研究院“长凳到床边”奖，该奖项帮助资助了一项针对患有大熊猫的重病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)将被纳入试验，并随机分配接受静脉注射免疫球蛋白或安慰剂。除了提供有关IVIG治疗大熊猫的效用的信息外，这项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，并可能开发疾病活动和治疗反应的生物标记物。这项试验目前正在招募受试者。筛查是由耶鲁大学和NIH的团队进行的，但所有的临床互动都是在NIH临床中心进行的。有关这项研究的更多信息，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