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

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.

Nodding syndrome (NS) is a devastating epileptic encephalopathy of an unknown cause affecting thousands of children in Africa. Our goal is to understand the pathogenesis and develop specific interventions. The objective is to examine if NS is a neuro-inflammatory disorder induced by Onchocerca volvulus or its symbiotic bacteria, Wolbachia and whether doxycycline may be used as treatment. The specific aims are:

Aim 1: Determine the relationship between NS, antibodies to host neuron surface proteins (NSPs) or leiomodin and O.volvulus. I hypothesise that NS is an O.volvulus or Wolbachia-induced epileptic encephalopathy with antibodies against O.volvulus or specific sero-groups and variant species of Wolbachia cross-reacting with host NSPs/leiomodin. We will recruit 165 cases and 165 sibling controls, obtain blood and CSF (cases only) and examine: a) the relationship between NS and antibodies to leiomodin, the voltage-gated potassium channel complex and other surface proteins; b) in cases, examine for neuro-inflammation in CSF; c) determine the relationship between these antibodies and inflammatory markers, microfilaria density, Wolbachia sero-groups and disease severity, epileptiform discharges on EEG and structural changes on brain MRI.

Aim 2: Conduct a pilot study to examine the role of Onchocerca by targeting the adult worm. There is no routine treatment for adult Onchocerca. However, antibiotic depletion of Wolbachia results in marked reduction in microfilaria density, sterilisation and premature death of the adult worm. I hypothesise that this will lead to reduced markers of inflammation and potential subsequent clinical improvement. In a proof of principle pilot study I will randomise 152 patients to either doxycycline or placebo and determine the effect on levels of antibodies to NSPs or leiomodin, disease severity, inflammatory markers, microfilaria density and Wolbachia load at 6 and 24 months.

The proposed project is taking a major stride in understanding the pathogenesis of nodding syndrome and is the first attempt at a specific treatment intervention. It is an important study with societal and individual patient and family benefits, and benefits for the wider affected community and the Ministries of Health of the affected countries.
a. Patients and families
To date, nodding syndrome remains a poorly understood disease with only limited descriptions. The aetiology, natural history and mechanisms of disease that would allow development of evidence based treatment are all unknown. This is the first large prospective study of pathogenesis. The main benefit, a better understanding of the disease, is societal. For patients and their families, this information is crucial for counselling: the study will provide physicians with tools and information to counsel patients and families on the disease. The study of pathogenesis may lay the ground of developing evidence based therapies.
b. The wider affected Community
A poor understanding of the syndrome, the debilitating nature and severe disability associated with it has created so much anxiety about nodding syndrome, self blame and stigma in the community. Neighbourhood parents are unsure if their child is next. This study will hopefully provide the community with a better understanding of the disease; facilitate community education and reduce anxiety. The study results may also help reduce stigma which is currently hindering treatment access.
c. Ministries of Health of affected countries, clinical and public health interventions
The study we propose will contribute to the understanding of pathogenesis and morbidity factors. A description of the early features of disease will allow prompt recognition and may be intervention to prevent progression. The current guidelines were developed on limited evidence and only a small range of symptomatic treatments is offered. Knowledge of the types, progressive development of symptoms and severity of co-morbidities will allow the Ministry of Health develop better treatment plans which may include anticipation of morbidities and planning for interventions, putting in place the required human resource for patient care and developing plans for secondary disability prevention. The Ministry of Health in the other affected countries, in particular South Sudan, has limited human resource capacity and has benefited from collaboration with the Ministry of Health, Uganda. Results of this the trial may have immediate impact and may guide the changes in treatment policies.
This project will also build local capacity in critical areas clinical research and care in Uganda. In addition, we will continue to work with policy makers in the Ministries of Health of affected countries, the World Health Organization and US Centers of Disease Control and input in management guidelines for patient care.