Doxycycline for the treatment of nodding syndrome (DONS); the study protocol of a phase II randomised controlled trial

Abstract

Background Nodding syndrome is a poorly understood neurological disorder of unknown aetiology, affecting several thousand children in Africa. There has been a consistent epidemiological association with infection by the filarial parasite, Onchocerca volvulus and antibodies to leiomodin and DJ-1, cross-reacting with O.volvulus proteins, have been reported. We hypothesized that nodding syndrome is a neuro-inflammatory disorder, induced by antibodies to O.volvulus or its symbiont, Wolbachia, cross-reacting with human neuron proteins and that doxycycline, which kills Onchocerca through effects on Wolbachia, may be used as treatment. Methods This will be a two-arm, double-blind, placebo-controlled, randomised phase II trial of doxycycline 100 mg daily for six weeks in 230 participants. Participants will be patients’ ages≥8 years with nodding syndrome. They will receive standard of care supportive treatment. All will be hospitalised for 1–2 weeks during which time baseline measurements including clinical assessments, EEG, cognitive and laboratory testing will be performed and antiepileptic drug doses rationalised. Participants will then be randomised to either oral doxycycline (Azudox®, Kampala Pharmaceutical Industries) 100 mg daily or placebo. Treatment will be initiated in hospital and continued at home. Participants will be visited at home at 2, 4 and 6 weeks for adherence monitoring. Study outcomes will be assessed at 6, 12, 18 and 24-month visits. Analysis will be by intention to treat. The primary efficacy outcome measure will be the proportion of patients testing positive and the levels or titires of antibodies to host neuron proteins (HNPs) and/or leiomodin at 24 months. Secondary outcome measures will include effect of the intervention on seizure control, inflammatory markers, cognitive function, disease severity and quality of life. Discussion This trial postulates that targeting O. volvulus through drugs which kill Wolbachia can modify the pathogenic processes in nodding syndrome and improve outcomes. Findings from this study are expected to substantially improve the understanding and treatment of nodding syndrome. Trial registration Registered with clinicaltrials.gov ID: NCT02850913 on 1st August, 2016.

Onchocerca volvulus and epilepsy: A comprehensive review using the Bradford Hill criteria for causation

“…There is also weaker evidence for causality concerning the criteria: specificity, plausibility, coherence, and analogy. Until now, there is little experimental evidence, and this is identified as an important research gap that needs further in vivo, in vitro, and epidemiological studies such as those discussed here [ 92 , 107 , 118 , 119 ]. However, consideration of the Bradford Hill criteria suggests that there is consistent evidence that O .…”

Household poverty, schooling, stigma and quality of life in adolescents with epilepsy in rural Uganda

“…This was a cross sectional study describing the socio-economic status, household poverty, attendance of formal education, and QoL of adolescents with epilepsy compared to age-matched normal community children in northern Uganda. The study was nested in a large project studying the pathogenesis and treatment of a devastating neurologic disorder in this region, the nodding syndrome, and Onchocerca volvulus associated epilepsy [30]…”

Neuroimmunology of Common Parasitic Infections in Africa

“…The pathological mechanisms by which Onchocerca may led to neurological sequalae remain poorly understood and under investigation ( 266 ). Several hypotheses have however been proposed with conflicting results: 1) Direct Invasion of CNS by the parasite or pathogenic proteins/metabolites ( 267 , 268 ), 2) An O. volvulus –induced immune response through an inflammatory process or auto antibodies against neuron surface proteins ( 269 – 272 ), 3) A Wolbachia spp., dependent pathway ( 273 ), and finally, a tauopathy, manifesting as aggregates of tau protein in the brain ( 274 , 275 ).…”