Parasitic, bacterial, viral, immune-mediated, metabolic and nutritional factors associated with nodding syndrome

Arthur W D Edridge, Gasim Abd-Elfarag, Martin Deijs, Melissa H Broeks, Cosimo Cristella, Brandon Sie, Frédéric M Vaz, Judith J M Jans, Job Calis, Hans Verhoef, Ayse Demir, Sven Poppert, Beatrice Nickel, Alje van Dam, Boy Sebit, Maarten J Titulaer, Jaco J Verweij, Menno D de Jong, Tom van Gool, Brian FaragherNanda M Verhoeven-Duif, Stephen J Elledge, Lia van der Hoek, Michael Boele van Hensbroek

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Abstract

Nodding syndrome is a neglected, disabling and potentially fatal epileptic disorder of unknown aetiology affecting thousands of individuals mostly confined to Eastern sub-Saharan Africa. Previous studies have identified multiple associations-including Onchocerca volvulus, antileiomodin-1 antibodies, vitamin B 6 deficiency and measles virus infection-yet, none is proven causal. We conducted a case-control study of children with early-stage nodding syndrome (symptom onset <1 year). Cases and controls were identified through a household survey in the Greater Mundri area in South Sudan. A wide range of parasitic, bacterial, viral, immune-mediated, metabolic and nutritional risk factors was investigated using conventional and state-of-the-art untargeted assays. Associations were examined by multiple logistic regression analysis, and a hypothetical causal model was constructed using structural equation modelling. Of 607 children with nodding syndrome, 72 with early-stage disease were included as cases and matched to 65 household- and 44 community controls. Mansonella perstans infection (odds ratio 7.04, 95% confidence interval 2.28-21.7), Necator americanus infection (odds ratio 2.33, 95% confidence interval 1.02-5.3), higher antimalarial seroreactivity (odds ratio 1.75, 95% confidence interval 1.20-2.57), higher vitamin E concentration (odds ratio 1.53 per standard deviation increase, 95% confidence interval 1.07-2.19) and lower vitamin B 12 concentration (odds ratio 0.56 per standard deviation increase, 95% confidence interval 0.36-0.87) were associated with higher odds of nodding syndrome. In a structural equation model, we hypothesized that Mansonella perstans infection, higher vitamin E concentration and fewer viral exposures increased the risk of nodding syndrome while lower vitamin B 12 concentration, Necator americanus and malaria infections resulted from having nodding syndrome. We found no evidence that Onchocerca volvulus, antileiomodin-1 antibodies, vitamin B 6 and other factors were associated with nodding syndrome. Our results argue against several previous causal hypotheses including Onchocerca volvulus. Instead, nodding syndrome may be caused by a complex interplay between multiple pathogens and nutrient levels. Further studies need to confirm these associations and determine the direction of effect.

Original languageEnglish
Article numberfcad223
Pages (from-to)1-12
JournalBrain communications
Volume5
Issue number5
DOIs
Publication statusPublished - 2023

Keywords

  • Mansonella perstans
  • nodding syndrome
  • Onchocerca volvulus
  • encephalopathy

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