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大脑疾病，但人们对此知之甚少，正影响着非洲数千名儿童。它的特点是点头，并伴有其他癫痫发作、精神障碍、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。疾病的原因和机制尚不清楚，但与导致河盲症的寄生虫螺旋体有很强的联系。没有特定的治疗方法；可用的治疗方法只会减轻一些患者的症状。我们想要回答什么问题？我们的目标是确定病因，了解点头综合症的发生机制，并制定具体的治疗和预防措施。我们想要回答以下问题：1.扭转盘尾丝虫在世界各地都有发现，但点头综合征只在非洲有报道。在患者的大脑中也没有检测到这种寄生虫。那么它会如何导致疾病呢？2.第二，靶向丝虫成虫能否在治疗中发挥作用？我们将进行哪些研究活动？我们假设，点头综合症是由针对螺旋丝虫或沃尔巴克氏菌(丝虫携带的细菌)的抗体与人类神经元表面的蛋白质发生交叉反应引起的。在第一项研究中，我们将招募165名患有点头综合征的儿童和165名未受影响的兄弟姐妹：a)对不同疾病阶段的患者进行详细的临床和脑成像测试，并描述点头综合征的早期特征；b)从病例中获取皮肤样本、成对的血液和脊液样本，以及来自对照组的血液样本，并测试这些样本是否存在螺旋体螺旋体感染，是否有针对人类神经元的抗体，以及对一种名为leiomodin-1的人类蛋白的抗体，该蛋白与一种名为leiomodin-1的蛋白有相似之处，乌干达的初步研究表明，这种蛋白在疾病中可能是重要的；C)确定大脑中是否有炎症的证据，并调查这与点头综合征、螺旋体或其沃尔巴克氏菌感染之间的关系，并将这些炎症反应与疾病严重程度以及脑电和脑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，给他们服用多西环素胶囊(一种通过杀死成虫所含细菌来攻击成虫的药物)或每天服用安慰剂，为期六周。患者将在2周、4周和6周以及3个月时由家访人员探望，以确保依从性并记录药物反应。参与者将在六个月后再次住院，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，可能会考虑免疫调节治疗，特别是在新患者身上。点头综合症和盘尾丝虫病之间的明确联系将使治疗和预防工作逐步升级。如果试点研究的数据是积极的，多西环素提供了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.