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

Background: The possibility that onchocerciasis may cause epilepsy has been suggested for a long time, but thus far, an etiological link has not been universally accepted. The objective of this review is to critically appraise the relationship between Onchocerca volvulus and epilepsy and subsequently apply the Bradford Hill criteria to further evaluate the likelihood of a causal association. Methods: PubMed and gray literature published until September 15, 2020, were searched and findings from original research were synthesized. Adherence to the 9 Bradford Hill criteria in the context of onchocerciasis and epilepsy was determined to assess whether the criteria are met to strengthen the evidence base for a causal link between infection with O. volvulus and epilepsy, including the nodding syndrome. Results: Onchocerciasis as a risk factor for epilepsy meets the following Bradford Hill criteria for causality: strength of the association, consistency, temporality, and biological gradient. There is weaker evidence supporting causality based on the specificity, plausibility, coherence, and analogy criteria. There is little experimental evidence. Considering the Bradford Hill criteria, available data suggest that under certain conditions (high microfilarial load, timing of infection, and perhaps genetic predisposition), onchocerciasis is likely to cause epilepsy including nodding and Nakalanga syndromes. Conclusion: Applying the Bradford Hill criteria suggests consistent epidemiological evidence that O. volvulus infection is a trigger of epilepsy. However, the pathophysiological mechanisms responsible for seizure induction still need to be elucidated. Author summary: There is growing epidemiological evidence that an infection with Onchocerca volvulus (the parasite causing onchocerciasis or river blindness) can trigger epilepsy, including nodding and Nakalanga syndromes. We studied the association between onchocerciasis and epilepsy using previously proposed criteria for causality and found strong arguments in favor of a causal relationship. The risk for children to develop epilepsy seems to be determined by the O. volvulus microfilarial load. However, the mechanism by which the O. volvulus parasite is able to trigger seizures remains to be elucidated. This form of epilepsy, called onchocerciasis-associated epilepsy (OAE), is an important public health problem in onchocerciasis-endemic regions with nonexistent or suboptimal onchocerciasis elimination programs. OAE is often characterized by sudden seizure onset in previously healthy children, between 3 to 18 years, without any other obvious cause of epilepsy. On the basis of the findings presented in this paper, it appears that onchocerciasis control may be able to prevent OAE. This further highlights the importance to eliminate onchocerciasis, particularly in areas with a high burden of epilepsy.