NSETHIO, project funded by ERC, Horizon 2020

Nodding Syndrome: a trans-disciplinary approach to identify the cause and decrease the incidence of river epilepsy


Prof. Dr. R. Colebunders

Research description

Nodding syndrome (NS) is a neurological, incurable syndrome, currently affecting mainly children between 5 and 18 years of age in South Sudan, Uganda and Tanzania. https://www.youtube.com/watch?v=5S7QLocaS0M. Since 1950, when NS was first described, its cause has remained a mystery. NS is characterized by head-nodding (an atonic form of epilepsy), often followed by clonic - tonic seizures, developmental retardation and faltering growth. In the affected regions, NS is a major public health problem associated with severe socio-economic consequences.  In South Sudan, in the West Equatoria State, in Mvolo, we found that one in six children had epilepsy and at least one in two families had at least one child with epilepsy.

In many onchocerciasis endemic areas a high prevalence of epilepsy is found. We hypothesize that NS is part of a spectrum of different types of seizures in onchocerciasis endemic areas, and that several of the different types most likely have a related etiology as a direct and/or indirect (potentially immune mediated) consequence of OV infection. We propose to call this form of epilepsy associated with onchocerciasis “river epilepsy”.

We recently discovered a high prevalence of epilepsy in several onchocerciasis endemic areas in the Democratic Republic of the Congo (DRC) (e.g. in the Oriental Province, Ituri, and Katanga). In Titule in Bas Uélé region, Orientale Province the epilepsy prevalence was 2.3%.  A case control study showed that, daily bathing in the local rivers was an important risk factor for epilepsy (OR 3.07, 95% CI 1.19-7.93). 

Recently, others found that serum autoantibodies against leiomodin-1, (a protein present in the human brain), were more likely to be present in NS cases than in controls. These antibodies were also present in the cerebrospinal fluid of certain patients with NS, and were found to be neurotoxic in vitro, and cross-reacting with OV-specific proteins. Whether these antibodies are instrumental in the pathogenesis of NS and epilepsy and/or are a consequence of damage to the central nervous system caused by OV, or an OV endosymbiont such as Wolbachia, or an unknown neurotropic agent transmitted by blackflies, needs to be investigated.

The African Programme for Onchocerciasis Control estimates there are currently 36 million people with onchocerciasis.  Therefore, if 1% (equivalent to the approximate excess prevalence over non-endemic areas) were to develop epilepsy, the number of excess cases of epilepsy due to onchocerciasis would be on the order of 360,000. We hypothesize that most of this excess in prevalence of epilepsy is potentially preventable by increasing the coverage of ivermectin treatment and larviciding rivers, and by maintaining it over many years. If it is confirmed that OV increases the risk of epilepsy, this will be an additional argument to strengthen onchocerciasis elimination plans.   

NETSIO aims to study NS and river epilepsy in South Sudan, Uganda, Tanzania, Cameroon and the DRC using a trans-disciplinary approach including clinical-epidemiological, post-mortem, eco-entomological, and metagenomic studies. In a population based trial we will investigate whether increasing the coverage of ivermectin with or without larviciding rivers will decrease the incidence of river epilepsy. So far a multi-country study on NS and river epilepsy was never done and nearly all previous studies were cross-sectional, carried out during short country visits. With this long term research plan we hope to finally discover the cause of NS and river epilepsy and detect an effective control strategy to decrease the incidence of epilepsy in onchocerciasis endemic areas.