Urinary N-acetyltyramine-O,β-glucuronide in Persons with Onchocerciasis-Associated Epilepsy

Hotterbeekx, An; Dusabimana, Alfred; Mandro, Michel; Abhafule, Germain; Deogratias, Wonya'Rossy; Fodjo, Joseph Nelson Siewe; Abrams, Steven; Colebunders, Robert

doi:10.3390/pathogens9030191

Cited by 9 publications

(13 citation statements)

References 17 publications

(29 reference statements)

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“…Onchocerciasis elimination efforts, which lead to reductions in microfilarial prevalence and load, have been shown to decrease the incidence of epilepsy/NS [78,79]. Recent studies in the DRC showed that high seizure frequency was associated with increasing microfilarial density [71] and increasing levels of urinary N-acetyltyramine-O,β-glucuronide (NATOG), a biomarker for onchocerciasis [90]. Furthermore, a randomized trial in the DRC, comparing a single versus a multiple dose of ivermectin treatment regimen in O. volvulus-infected persons with epilepsy treated with phenobarbital showed that the multiple dose ivermectin regimen was associated with a reduced frequency of seizures [91].…”

Section: Biological Gradient (Dose Response)mentioning

confidence: 99%

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

et al. 2021

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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.

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Section: Biological Gradient (Dose Response)mentioning

confidence: 99%

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

et al. 2021

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“…Recently, Hotterbeekx et al [ 16 ] conducted a further study on the viability of NATOG as a biomarker for onchocerciasis. The mean amounts of NATOG were elevated in infected (9.7 ± 1.4 µM, n = 117) compared with non-infected individuals (3.2 ± 0.9 µM, n 55).…”

Section: Discussionmentioning

confidence: 99%

“…1 a). In Table 6 of their manuscript, Hotterbeekx et al [ 16 ] compiled the results of NATOG measurements in urine samples of the previous studies. The maximal amounts of NATOG in samples of all non-infected individuals, of all Mp-infected and Ll + Mp-infected individuals was < 80 µM (the only exception being Ll-infected), while the groups of O. volvulus -infected individuals (Ov and co-infection; Ov infection with/without epilepsy) contained data points with NATOG levels > 80 µM [ 13 , 16 ].…”

Section: Discussionmentioning

confidence: 99%

“…In Table 6 of their manuscript, Hotterbeekx et al [ 16 ] compiled the results of NATOG measurements in urine samples of the previous studies. The maximal amounts of NATOG in samples of all non-infected individuals, of all Mp-infected and Ll + Mp-infected individuals was < 80 µM (the only exception being Ll-infected), while the groups of O. volvulus -infected individuals (Ov and co-infection; Ov infection with/without epilepsy) contained data points with NATOG levels > 80 µM [ 13 , 16 ]. A high level for NATOG could therefore be used to conduct larger epidemiological investigations to determine whether onchocerciasis is still prevalent in a certain area and could even specify a threshold for the elimination on this basis, provided that the results are confirmed, including in areas with lower onchocerciasis endemicity.…”

Section: Discussionmentioning

confidence: 99%

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Urine metabolites for the identification of Onchocerca volvulus infections in patients from Cameroon

et al. 2021

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Background The tropical disease onchocerciasis (river blindness), caused by Onchocerca volvulus filarial nematodes, is targeted for elimination by mass treatment with nematocidal and antimicrobial drugs. Diagnosis of O. volvulus infections is based on counts of skin-borne microfilariae, but additional diagnostic tools, e.g. worm- or host-derived small RNAs, proteins or metabolites, are required for high-throughput screening. N-acetyltyramine-O,β-glucuronide (NATOG) was suggested as a biomarker for onchocerciasis but its viability as diagnostic tool has been challenged. Methods We performed a screening program of urine samples from individuals from Cameroon infected with O. volvulus, Loa loa, Mansonella perstans or a combination thereof. Urine metabolites were measured by liquid chromatography–mass spectrometry (LC-MS). Principle component analysis (PCA) revealed that onchocerciasis causes complex changes of the urine metabolome. Results The mean NATOG content was elevated in urine of O. volvulus-infected compared with non-infected individuals, but NATOG levels showed considerable variation. However, 13.8% of all O. volvulus-infected individuals had high NATOG levels never reached by individuals without filarial infections or only infected with L. loa or M. perstans. Therefore, the identification of individuals with high NATOG levels might be used to screen for the elimination of onchocerciasis after mass drug application. Additional metabolites, including a compound identified as cinnamoylglycine, had high PC1/PC2 loadings in the data set. Mean levels of cinnamoylglycine were increased in O. volvulus-infected individuals, and 17.2% of all O. volvulus individuals had elevated cinnamoylglycine levels not reached by the controls. Conclusions On an individual level, NATOG alone had poor discriminative power distinguishing infected from non-infected individuals. However, 13.8% of all O. volvulus-infected individuals had NATOG levels never reached by individuals without filarial infections or infected with only L. loa or M. perstans. Discrimination of O. volvulus infections from controls or individuals suffering from multiple infections was improved by the measurement of additional metabolites, e.g. cinnamoylglycine. Thus, measuring a combination of urine metabolites may provide a way to assess onchocerciasis on the population level. This provides the possibility to design a strategy for large-scale onchocerciasis epidemiological screening programs based on urine rather than invasive techniques. Graphical abstract

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“…Persons with OAE were selected among participants from previously described studies in South Sudan [ 27 ] and the DRC [ 28 ]. Characteristics of the study participants are shown in Table 1 .…”

Section: Methodsmentioning

confidence: 99%

Cytokines and Onchocerciasis-Associated Epilepsy, a Pilot Study and Review of the Literature

Vieri

Hotterbeekx

Raimon³

et al. 2021

Pathogens

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Neuro-inflammation may be associated with onchocerciasis-associated epilepsy (OAE) but thus far very few immunological studies have been performed in children with this form of epilepsy. In a pilot study we measured the cytokine levels in cerebrospinal fluid (CSF) of persons with OAE from Maridi, South Sudan, and from Mosango, Democratic Republic of the Congo (DRC) and compared these results with cytokine levels in CSF of Africans with non-OAE neurological disorders, and Europeans with epilepsy or other neurological conditions. The following cytokines were studied: IL-6, TNF-α, IL1-β, IL-5, IL-4, IL-13, CCL3 (Mip-1α), VEGF-C, VCAM-1. No cytokine was significantly associated with OAE, although a lower IL-13 level was observed in CSF of persons with OAE compared to African controls. Observed cytokine profiles and neuro-inflammation may be the consequence of long-standing epilepsy, concomitant infections and malnutrition. Ideally cytokine levels should be determined in a prospective study in serum and CSF collected at the time of onset of the first seizures.

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Urinary N-acetyltyramine-O,β-glucuronide in Persons with Onchocerciasis-Associated Epilepsy

Cited by 9 publications

References 17 publications

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

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

Urine metabolites for the identification of Onchocerca volvulus infections in patients from Cameroon

Cytokines and Onchocerciasis-Associated Epilepsy, a Pilot Study and Review of the Literature

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