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

Abstract

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.

High Prevalence of Epilepsy in an Onchocerciasis-Endemic Area in Mvolo County, South Sudan: A Door-To-Door Survey

“…In recent years, the association between onchocerciasis and epilepsy has been clearly established in many epidemiological studies [ 19 ]. Moreover, these studies showed the usefulness of the OAE case definition for identifying hotspots of high ongoing O. volvulus transmission [ 20 ].…”

Nodding syndrome research revisited

“…While the above studies suggest that O. volvulus infection is able to trigger epilepsy (Colebunders et al, 2021), the data do not demonstrate causality. Therefore, the involvement of an alternative pathogen cannot be excluded (Table 1).…”

“…A recent systematic review using the Bradford Hill criteria for causality identified O. volvulus as the most likely trigger of nodding syndrome and other forms of onchocerciasis-associated epilepsy (OAE) (Colebunders et al, 2021). Indeed, high prevalence of OAE is observed in onchocerciasis-endemic areas with high rates of O. volvulus transmission and low (Mukendi et al, 2019) or no (Lenaerts et al, 2018) coverage of community-directed treatment with ivermectin (CDTI).…”

“…While relatively understudied, blackflies are known to be infected with many viruses (Kraberger et al, 2019), and are most notably vectors of the New Jersey serotype of vesicular stomatitis virus to cattle, horses and swine (Smith et al, 2009). Many epidemiological studies now suggest that O. volvulus is able to trigger epilepsy (Colebunders et al, 2021), but the pathophysiological mechanism remains elusive. Neither O. volvulus microfilariae nor DNA have been detected in the brain or cerebrospinal fluid of persons with OAE (Hotterbeekx et al, 2019(Hotterbeekx et al, , 2020.…”

The World Health Organization road map for neglected tropical diseases 2021–2030: implications for onchocerciasis elimination programs

“…However, so far mental health problems caused by onchocerciasis-associated epilepsy have not been internationally recognized. Given the strong epidemiological evidence for the association between onchocerciasis and epilepsy, onchocerciasis-associated epilepsy should be considered as one of the clinical presentations of onchocerciasis [ 12 ]. For those who still do not want to recognize this, onchocerciasis-associated epilepsy should be considered as new NTD because it only occurs in tropical areas and is a neglected public health problem.…”