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

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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.