R Idro, Makerere University - The pathogenesis and treatment of nodding syndrome

什么是点头综合症？点头综合症是一种毁灭性的，但人们对它知之甚少的脑部疾病，它影响着非洲成千上万的儿童。它的特点是头点头，并伴有其他癫痫发作、精神困难、营养不良、认知和身体衰退。研究表明，这是一种独特的癫痫类型。该病的病因和发病机制尚不清楚，但与引起河盲症的盘尾丝虫病有密切联系。没有具体的治疗方法；现有的治疗方法只能减轻部分患者的症状。我们想要回答什么问题？我们的目标是确定病因，了解点头综合征发展的机制，并制定具体的治疗和预防措施。我们想回答以下几个问题：1。盘尾丝虫在世界上许多地方都有发现，但点头综合症只在非洲有报道。在患者的大脑中也未发现这种寄生虫。那么它怎么会引起疾病呢？2. 其次，靶向盘尾丝虫病成虫能否起到治疗作用？我们将进行哪些研究活动？我们假设点头综合症是由针对盘尾丝虫或沃尔巴克氏体（盘尾丝虫携带的细菌）的抗体与人类神经元表面的蛋白质交叉反应引起的。在第一项研究中，我们将招募165名患有点头综合症的儿童和165名未患病的兄弟姐妹，并：a)对不同疾病阶段的患者进行详细的临床和脑成像检查，并描述点头综合症的早期特征；(b)获取病例的皮肤样本、配对血液和脊髓液样本以及对照组的血液样本，并检测是否存在盘尾丝虫感染、针对人类神经元的抗体和针对一种称为leiomotin -1的人类蛋白质的抗体，这种蛋白质与盘尾丝虫蛋白质有相似性，乌干达的初步研究表明，这种蛋白质可能对疾病很重要；c)确定大脑中是否有炎症的证据，并调查其与点头综合征、盘尾丝虫感染或其沃尔巴克氏菌之间的关系，并将这些炎症反应与疾病严重程度以及脑电图和脑MRI扫描的变化进行比较。在第二项研究中，我们将从第一项研究中招募152名8岁或以上的患者，并每天给他们服用强力霉素胶囊（一种通过杀死其含有的细菌来攻击成年蠕虫的药物）或安慰剂，持续六周。患者将在第2周、第4周和第6周以及第3个月时接受家访，以确保依从性并记录药物反应。六个月后，参与者将再次住院，为期一周，以评估治疗对被认为是由蠕虫或其细菌引起的炎症标志物的影响，以及对儿童临床症状的影响。这项研究将补充什么？如果我们发现异常炎症的证据，免疫调节治疗可能会被考虑，特别是对新患者。点头综合征和盘尾丝虫病之间的明确联系将允许治疗和预防的升级。如果初步研究的数据是积极的，强力霉素将提供一种廉价的干预措施，将在更大的研究中进行测试。

What is nodding syndrome? Nodding syndrome is a devastating but poorly understood brain disorder that is affecting thousands of children in Africa. It is characterised by head nodding and complicated by other seizures, psychiatric difficulties, malnutrition, cognitive and physical decline. Studies suggest that this is a distinct epilepsy type. The cause and mechanisms of disease are unknown but there has been a strong association with the parasite Onchocerca volvulus, the cause of river blindness. There is no specific treatment; available treatments only reduce symptoms in some patients. What questions do we want to answer?Our goal is to determine the cause, understand the mechanisms by which nodding syndrome develops and to develop specific interventions for treatment and prevention. We want to answer the following questions:1. Onchocerca volvulus is found in many places around the world but nodding syndrome has only been reported in Africa. The parasite has also not been detected in the brain in patients. How then would it cause disease? 2. Secondly, can targeting Onchocerca adult worms play a role in treatment? What research activities will we perform?We hypothesise that nodding syndrome is caused by antibodies against Onchocerca volvulus or Wolbachia (the bacteria which Onchocerca worms carry along) cross reacting with proteins on the surface of human neurons. In the first study, we will recruit 165 children with nodding syndrome and 165 unaffected siblings and: a) Perform detailed clinical and brain imaging tests for patients in different stages of disease and describe the early features of nodding syndrome; b) Obtain skin samples, paired blood and spinal fluid samples from cases and blood samples from the controls and test these for the presence of Onchocerca volvulus infection, for antibodies against human neurons and for antibodies to a human protein called leiomodin-1 which has similarities with an Onchocerca protein and which preliminary studies in Uganda suggest may be important in disease; c) Determine if there is evidence of inflammation in the brain and investigate the relationship between this and nodding syndrome, infection by Onchocerca volvulus or its Wolbachia bacteria and also compare these inflammatory responses with disease severity and changes on EEG and brain MRI scans.In the second study, we will recruit 152 cases 8 years or older from the first study and administer to them capsules of either doxycycline (a drug that attacks the adult worm by killing bacteria it contains) or a placebo daily for six weeks. Patients will be visited by a home visitor at 2, 4 and 6 weeks and at 3 months to ensure compliance and to document drug reactions. Participants will be hospitalised again after six months for a week to assess the effects of the treatment on markers of inflammation thought to be casued by the worm or its bacteria and on clinical symptoms of the children. What will this research add?If we find evidence of abnormal inflammation, immune-modulatory therapies may be considered especially in new patients. A definitive association between nodding syndrome and onchocerca volvulus will allow escalation of treatments and prevention. If data from the pilot study is positive, doxycycline offers a cheap intervention that will be tested in a larger study.