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

Lead Research Organisation: University of Oxford
Department Name: Tropical Medicine


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.

Technical Summary

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.

Planned Impact

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.


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Description Biomarkers in the pathogenesis and diagnosis of nodding syndrome 
Organisation Wellcome Trust
Department KEMRI-Wellcome Trust Research Programme
Country Kenya, Republic of 
Sector Multiple 
PI Contribution One of the secondary aims of the project is to identify biomarkers of potential value in determining the aetiology (and therefore of diagnostic value) and pathogenesis of nodding syndrome. We worked with the Drs James Njunge, Abdi and Evelyn Gitau at KEMRI Welllcome Trust to develop a protocol to study this by mass spectrometry. The grant is availing to the collaboration the clinical and biological samples for testing. We have also paid for part of the reagents for this testing. In addition, one of the project Research Assistants travelled to Kenya to work on the samples with the Kenya team. Preliminary sample preparations are complete and testing is taking place.
Collaborator Contribution The KEMRI Wellcome Trust team is providing the laboratory space, equipment (mass spectrometry), time and personnel (led by Drs Njunge and Abdi) to conduct the biomarkers study.
Impact None as yet.
Start Year 2016
Description Community engagement in nodding syndrome research 
Organisation University of Oxford
Department Ethox Centre
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution We applied Jointly with Dr Dorcus Kamunyu of the Ethox Centre/KEMRI Wellcome Programme to the Africa - Oxford Programme to support the initiation of a Community Engagement Programme at our Research Site in Kitgum. The objective was to initiate a new collaboration around community engagement, travel to Kilifi and learnt best practices and obtain technical support form the Drs Kamunyu and Noni in initiating a similar programme in Uganda. A team of four travelled to Kenya and over a week worked with the community engagement team in Kenya and learnt hands on, the processes around community engagement.
Collaborator Contribution The Ethox Centre and KEMRI availed staff (4) to help guide us in initiating the programme. As above, the provided us with a practical experience of one week in Kenya and later this year, will come to Uganda to help establish a similar programme in Uganda.
Impact 1. We have submitted a SEED application to the community engagement programme of the MRC to support the initial stages of the programme. 2. Already, rudimentary engagement programmes including monthly radio programmes, (village) community dialogues before each recruitment drive in each village are ongoing.
Start Year 2016
Description Host Genetics in Nodding Syndrome and other Rare Epilepsy Disorders in Uganda 
Organisation University College London
Department Institute of Neurology
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution We are conducting detailed clinical, EEG and brain imaging examinations and collecting biological (blood) samples from patients with nodding syndrome and other epilepsy as part of the study. These resources will be made available to the Neurogenetics Lab of Prof Henry Houlden at the UCL Institute of Neurology.
Collaborator Contribution Prof Houlden's group is providing us with additional sample collection materials and will dedicate the time of one PhD student and a Post Doctoral Student to conduct a detailed Genetics Study of patients with nodding syndrome.
Impact None as yet.
Start Year 2017
Description An update on the progress of nodding syndrome research to members of Uganda Medical Association 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact I wrote an update on the progress of nodding syndrome research and in particular, the aetiology and progress on the treatment trial and what this means. The update was on a social media platform - talkUMA - a Uganda Medical Association discussion forum for all the approximately 5000 doctors registered in Uganda (whether practicing in the country or not). This dicussion lasted about a week. A formal presentation is planned for the annual Grande Doctors Conference in August 2017.
Year(s) Of Engagement Activity 2017
Description Community dialogue on research 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact This community dialogues targeted carers, community members and the local leaership of cultural chiefs and local council leaders at village, parish and sub-county level in the study area.

The objectives were to:
1. Initiate community entry by introducing the study to village members
2. Collate and address community concerns on undertaking this study
3. Obtain local village support to conduct research
4. Conduct outreach screening for eligible study participants

Between 18th November 2016 to Feb 6th 2017, we had 5 community sensitization meetings in 5 areas. Each was attended by close to 90 residents. The activities were:
1. Introduced research, research in to nodding syndrome, why research and summarized the purpose of the new research in nodding syndrome and processes involved in recruitment of participants to conduct study specific and standard of care assessments
2. Using a question-answer approach, study staff responded to questions from community members concerning skepticism and optimism about our study and recruiting their children into the study.

1. A total of 432 community members educated for a better understanding of nodding syndrome and other epilepsies and why we need their support in screening and recruitment of their eligible children
2. Disseminated appropriate and relevant information to improve their awareness of the study, our recruitment approach using both door-to-door and community screening in outreaches and health facilities
3. Identified key community concerns, perceptions and practices towards our study in order to guide approaches used in our trial conduct.
4. Updated community on the study progress since start of recruitment
5. Awareness raised to allay anxiety about invasive procedures and their purpose for collecting human subject samples for tests.
6. Local leaders made commitments to support mobilization efforts and encouraging participation in selected villages.
7. Potential demand created for the conduct of more open discussions involving community members
Year(s) Of Engagement Activity 2016,2017
Description Engagement of administrative and political leadership of Kitgum and Pader Districts 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Policymakers/politicians
Results and Impact Met with and had indepth discussions with In-depth discussions with the Assistant District Health Officer, Deputy District Chairperson and Resident District Commissioner - Pader district and also with the District Chairperson, Resident District Commissioner, Chief Administrative Officer and the Community Development Officer of Kitgum district.

The objective was to:
1. To seek support of the political and administrative support of the selected district leadership
2. To discuss challenges and opportunities for the nodding syndrome outbreak response in the respective districts

The main outputs were:
The six district leaders made commitments to support the process of trial site activation, created a liaison with sub-county, parish and village leaders for the study team to guide community entry and study implementation.
Year(s) Of Engagement Activity 2016,2017
Description Meetings (dialogue) and group discussions with Village Health Teams and facility based clinicians 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Other audiences
Results and Impact Between 18th Nov 2016 and 4th Feb 2017 we held 5 sensitization meetings with small groups of Village Health Teams (total of 115) in different villages in the study area on the study objectives and procedures purpose. This was in the form of short presentations followed by interactive in-depth discussions with a question-answer approach were conducted. We also interacted with the health unit clinicians (22) in the same villages discussing the study.
Year(s) Of Engagement Activity 2016,2017