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We investigated urinary N-acetyltyramine-O,&beta ; -glucuronide (NATOG) levels as a biomarker for active Onchocerca volvulus infection in an onchocerciasis-endemic area in the Democratic Republic of Congo with a high epilepsy prevalence. Urinary NATOG was measured in non-epileptic men with and without O. volvulus infection, and in O. volvulus-infected persons with epilepsy (PWE). Urinary NATOG concentration was positively associated with microfilarial density (p < ; 0.001). The median urinary NATOG concentration was higher in PWE (3.67 µ ; M) compared to men without epilepsy (1.74 µ ; M), p = 0.017 ; and was higher in persons with severe (7.62 µ ; M) compared to mild epilepsy (2.16 µ ; M) ; p = 0.008. Non-epileptic participants with and without O. volvulus infection had similar NATOG levels (2.23 µ ; M and 0.71 µ ; M, p = 0.426). In a receiver operating characteristic curve analysis to investigate the diagnostic value of urinary NATOG, the area under the curve was 0.721 (95% CI: 0.633&ndash ; 0.797). Using the previously proposed cut-off value of 13 µ ; M to distinguish between an active O. volvulus infection and an uninfected state, the sensitivity was 15.9% and the specificity 95.9%. In conclusion, an O. volvulus infection is associated with an increased urinary NATOG concentration, which correlates with the individual parasitic load. However, the NATOG concentration has a low discriminating power to differentiate between infected and uninfected individuals.

We investigated urinary N-acetyltyramine-O,beta-glucuronide (NATOG) levels as a biomarker for active Onchocerca volvulus infection in an onchocerciasis-endemic area in the Democratic Republic of Congo with a high epilepsy prevalence. Urinary NATOG was measured in non-epileptic men with and without O. volvulus infection, and in O. volvulus-infected persons with epilepsy (PWE). Urinary NATOG concentration was positively associated with microfilarial density (p < 0.001). The median urinary NATOG concentration was higher in PWE (3.67 mu M) compared to men without epilepsy (1.74 mu M), p = 0.017; and was higher in persons with severe (7.62 mu M) compared to mild epilepsy (2.16 mu M); p = 0.008. Non-epileptic participants with and without O. volvulus infection had similar NATOG levels (2.23 mu M and 0.71 mu M, p = 0.426). In a receiver operating characteristic curve analysis to investigate the diagnostic value of urinary NATOG, the area under the curve was 0.721 (95% CI: 0.633-0.797). Using the previously proposed cut-off value of 13 mu M to distinguish between an active O. volvulus infection and an uninfected state, the sensitivity was 15.9% and the specificity 95.9%. In conclusion, an O. volvulus infection is associated with an increased urinary NATOG concentration, which correlates with the individual parasitic load. However, the NATOG concentration has a low discriminating power to differentiate between infected and uninfected individuals.

We investigated urinary N-acetyltyramine-O,β-glucuronide (NATOG) levels as a biomarker for active Onchocerca volvulus infection in an onchocerciasis-endemic area in the Democratic Republic of Congo with a high epilepsy prevalence. Urinary NATOG was measured in non-epileptic men with and without O. volvulus infection, and in O. volvulus-infected persons with epilepsy (PWE). Urinary NATOG concentration was positively associated with microfilarial density (p < 0.001). The median urinary NATOG concentration was higher in PWE (3.67 µM) compared to men without epilepsy (1.74 µM), p = 0.017; and was higher in persons with severe (7.62 µM) compared to mild epilepsy (2.16 µM); p = 0.008. Non-epileptic participants with and without O. volvulus infection had similar NATOG levels (2.23 µM and 0.71 µM, p = 0.426). In a receiver operating characteristic curve analysis to investigate the diagnostic value of urinary NATOG, the area under the curve was 0.721 (95% CI: 0.633–0.797). Using the previously proposed cut-off value of 13 µM to distinguish between an active O. volvulus infection and an uninfected state, the sensitivity was 15.9% and the specificity 95.9%. In conclusion, an O. volvulus infection is associated with an increased urinary NATOG concentration, which correlates with the individual parasitic load. However, the NATOG concentration has a low discriminating power to differentiate between infected and uninfected individuals.

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.

A high burden of epilepsy is observed in Africa where parasitological infections are endemic. In 2016, in an Onchocerciasis endemic area in the Logo health zone, in Ituri province in the Democratic Republic of Congo, a door-to-door study showed an epilepsy prevalence of 4.6%, and 50.6% of persons with epilepsy were infected with Onchocerca volvulus. In the current study, the serum of 195 people infected with O. volvulus persons with epilepsy were tested to determine the proportion of co-infections with Taenia solium, Toxocara canis and Strongyloides. These proportions were, respectively, 8.2, 18.5 and 12.8%. Persons with a T. solium co-infection were older than those without co-infection (p = 0.021). In six (37.5%) of the T. solium co-infected persons, the first seizures appeared after the age of 30 years compared to three (2.1%) persons without a co-infection (p < 0.0001). Our study suggests that an O. volvulus infection is the main parasitic cause of epilepsy in the Ituri province, but in some persons, mainly in those with late onset epilepsy and with focal seizures, the epilepsy may be caused by neurocysticercosis. As the population in the area rears pigs, activities to limit T. solium transmission should be implemented.

Onchocerciasis is diagnosed by detecting microfilariae in skin snips or by detecting OV16 IgG4 antibodies in blood by either enzyme linked immunosorbent assay (ELISA) or a rapid diagnostic test (RDT). Here, we compare the sensitivity and specificity of these three tests in persons with epilepsy living in an onchocerciasis endemic region in the Democratic Republic of Congo. Skin snips and blood samples were collected from 285 individuals for onchocerciasis diagnosis. Three tests were performed: the OV16 RDT (SD Bioline) and the OV16 ELISA both on serum samples, and microscopic detection of microfilariae in skin snips. The sensitivity and specificity of each test was calculated with the combined other tests as a reference. Microfilariae were present in 105 (36.8%) individuals, with a median of 18.5 (6.5–72.0) microfilariae/skin snip. The OV16 RDT and OV16 ELISA were positive in, respectively, 112 (39.3%) and 143 (50.2%) individuals. The OV16 ELISA had the highest sensitivity among the three tests (83%), followed by the OV16 RDT (74.8%) and the skin snip (71.4%). The OV16 RDT had a higher specificity (98.6%) compared to the OV16 ELISA (84.8%). Our study confirms the need to develop more sensitive tests to ensure the accurate detection of ongoing transmission before stopping elimination efforts.

Onchocerciasis is diagnosed by detecting microfilariae in skin snips or by detecting OV16 IgG4 antibodies in blood by either enzyme linked immunosorbent assay (ELISA) or a rapid diagnostic test (RDT). Here, we compare the sensitivity and specificity of these three tests in persons with epilepsy living in an onchocerciasis endemic region in the Democratic Republic of Congo. Skin snips and blood samples were collected from 285 individuals for onchocerciasis diagnosis. Three tests were performed: the OV16 RDT (SD Bioline) and the OV16 ELISA both on serum samples, and microscopic detection of microfilariae in skin snips. The sensitivity and specificity of each test was calculated with the combined other tests as a reference. Microfilariae were present in 105 (36.8%) individuals, with a median of 18.5 (6.5&ndash ; 72.0) microfilariae/skin snip. The OV16 RDT and OV16 ELISA were positive in, respectively, 112 (39.3%) and 143 (50.2%) individuals. The OV16 ELISA had the highest sensitivity among the three tests (83%), followed by the OV16 RDT (74.8%) and the skin snip (71.4%). The OV16 RDT had a higher specificity (98.6%) compared to the OV16 ELISA (84.8%). Our study confirms the need to develop more sensitive tests to ensure the accurate detection of ongoing transmission before stopping elimination efforts.

The current serological test for human onchocerciasis relies on IgG4 reactivity against the parasite Ov-16 antigen, with reported sensitivities of only 60&ndash ; 80%. As control programs move from control to elimination, it is imperative to identify novel molecules that could improve the serodiagnosis reliability of this disease. In this study we compared the sensitivity of total IgG against OvMANE1&mdash ; a chimeric antigen previously identified as a potential biomarker of human onchocerciasis&mdash ; with that of an Ov-16 antibody test to detect an Onchocerca volvulus infection in persons presenting with microfilaria in skin snips. One hundred and ninety serum samples were obtained from persons with epilepsy in an onchocerciasis-endemic area at Ituri in the Democratic Republic of Congo where ivermectin has never been distributed. Fifty-nine (31.1%) samples were from individuals with a positive skin snip test ; 41 (69.5%) of these 59 samples were positive with the OvMANE1 test and 41 (69.5%) with the Ov-16 test ; 30 (50.8%) samples were positive for both tests and in 52 (88.1%) at least one of the tests was positive. Testing the 131 sera from persons with a negative skin snip result revealed that 63 (48.1%) were positive exclusively with the OvMANE1 test, 13 (9.9%) exclusively with the Ov-16 test and 25 (19.1%) with both tests. Nine European samples from individuals without past travel history in onchocerciasis endemic zones and 15 samples from Rwanda, a hypoendemic country for onchocerciasis were all negative for the OvMANE1 and Ov-16 tests. However, the specificity of both tests was difficult to determine due to the lack of a gold standard for antibody tests. In conclusion, the tandem use of OvMANE1 and Ov-16 tests improves the sensitivity of detecting Onchocerca volvulus seropositive individuals but, the OvMANE1 test needs to be further evaluated on samples from a population infected with other helminths to cautiously address its specificity.

peer-reviewed ; Onchocerciasis-associated epilepsy (OAE) is a devastating childhood disorder occurring in areas with high Onchocerca volvulus transmission. Despite epidemiological evidence showing the association between O. volvulus and epilepsy, the underlying mechanism remains unknown. Since high levels of serotonin are known to induce seizures, we investigated serotonin levels in persons with OAE and controls selected from the Democratic Republic of Congo. Serum serotonin levels were determined by ELISA in 19 persons with OAE, 32 persons with epilepsy without O. volvulus infection, 18 with O. volvulus infection but without epilepsy, and 35 with neither O. volvulus infection nor epilepsy. O. volvulus infection was diagnosed by skin snip testing and/or OV16 antibody detection. Serum serotonin levels were significantly decreased in persons with OAE compared to persons with O. volvulus infection and no epilepsy. In conclusion, an increased serotonin level is unable to explain the pathogenesis of OAE. Other hypotheses to identify the causal mechanism of OAE will need to be investigated.

A clinical trial performed in the Democratic Republic of Congo (DRC), among persons with epilepsy (PWE) infected with Onchocerca volvulus treated with anti-seizure medication suggested that ivermectin reduces the seizure frequency. We assessed the effect of ivermectin treatment on seizure frequency in PWE with and without anti-seizure medication in three onchocerciasis endemic areas (Maridi, South Sudan; Aketi, DRC; and Mahenge, Tanzania). Pre- and 3-5 months post-ivermectin microfilariae densities in skin snips and seizure frequency were assessed. After ivermectin, the median (IQR) percentage reduction in seizure frequency in the study sites ranged from 73.4% (26.0-90.0) to 100% (50.0-100.0). A negative binomial mixed model showed that ivermectin significantly reduced the seizure frequency, with a larger decrease in PWE with a high baseline seizure frequency. Mediation analysis showed that ivermectin reduced the seizure frequencies indirectly through reduction in microfilariae densities but also that ivermectin may have a direct anti-seizure effect. However, given the short half-life of ivermectin and the fact that ivermectin does not penetrate the healthy brain, such a direct anti-seizure effect is unlikely. A randomized controlled trial assessing the ivermectin effect in people infected with O. volvulus who are also PWE on a stable anti-seizure regimen may be needed to clarify the causal relationship between ivermectin and seizure frequency. ; European Research Council (ERC 671055) and VLIR-UOS. ; VLIR-UOS ; Dusabimana, A; Colebunders, R (corresponding author), Univ Antwerp, Global Hlth Inst, Doornstr 331, B-2610 Antwerp, Belgium. alfred.dusabimana@uantwerpen.be; swafula@musph.ac.ug; Stephen.Jada@amref.org; josephnelson.siewefodjo@uantwerpen.be; dan.bhwana@nimr.or.tz; floritepage@yahoo.fr; gasim4u83@gmail.com; an.hotterbeekx@uantwerpen.be; steven.abrams@uantwerpen.be; robert.colebunders@uantwerpen.be

A clinical trial performed in the Democratic Republic of Congo (DRC), among persons with epilepsy (PWE) infected with Onchocerca volvulus treated with anti-seizure medication suggested that ivermectin reduces the seizure frequency. We assessed the effect of ivermectin treatment on seizure frequency in PWE with and without anti-seizure medication in three onchocerciasis endemic areas (Maridi, South Sudan; Aketi, DRC; and Mahenge, Tanzania). Pre- and 3–5 months post-ivermectin microfilariae densities in skin snips and seizure frequency were assessed. After ivermectin, the median (IQR) percentage reduction in seizure frequency in the study sites ranged from 73.4% (26.0–90.0) to 100% (50.0–100.0). A negative binomial mixed model showed that ivermectin significantly reduced the seizure frequency, with a larger decrease in PWE with a high baseline seizure frequency. Mediation analysis showed that ivermectin reduced the seizure frequencies indirectly through reduction in microfilariae densities but also that ivermectin may have a direct anti-seizure effect. However, given the short half-life of ivermectin and the fact that ivermectin does not penetrate the healthy brain, such a direct anti-seizure effect is unlikely. A randomized controlled trial assessing the ivermectin effect in people infected with O. volvulus who are also PWE on a stable anti-seizure regimen may be needed to clarify the causal relationship between ivermectin and seizure frequency.

Objectives: To investigate the reasons for the high prevalence of epilepsy (>6%) discovered in 2015 in the Aketi health zone in the north of the Democratic Republic of the Congo. Methods: Persons with epilepsy (PWE) diagnosed in a door-to-door survey in 2015 were traced and re-examined in 2017 by a neurologist. Confirmed PWE were paired with matched controls. For onchocerciasis assessment, children 7-10 years old were tested for IgG4 Onchocerca volvulus (OV16) antibodies, a rapid epidemiological mapping of onchocerciasis (REMO) study was performed, and ivermectin coverage was investigated. Results: Forty-three (61.4%) previously diagnosed PWE were traced; the neurologist confirmed the epilepsy diagnosis in all of them. The overall OV16 positivity rate was 64.5%. Poor ivermectin coverage (55.9%) and a high prevalence of onchocercal nodules (>70%) were observed. The prevalence of epilepsy was 5.7% in Aketi rural town, with nine PWE (13.8%) experiencing head nodding seizures. A case-control study showed that PWE had lower body weight and higher ivermectin coverage in 2017 than healthy controls. Conclusions: The high prevalence of epilepsy in the Aketi health zone, despite 14 years of community-directed treatment with ivermectin (CDTI), was found to be associated with high onchocerciasis transmission and low ivermectin use. An awareness programme to increase ivermectin coverage and the introduction of a bi-annual CDTI programme should be considered. (c) 2018 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). ; We thank the Fons Peeters and the VZW Aketi for logistical assistance, and the populations of Wela, Makoko, and Aketi for their collaboration in the study. R. Colebunders received funding from the European Research Council (ERC) (grant number 671055, project title NSETHIO). The funder had no role in the study design, in the collection, analysis, and interpretation of the data, in the writing of the manuscript, or in the decision to submit the manuscript for publication.

•A high epilepsy prevalence in the Aketi health zone was observed despite 14 years of community-directed treatment with ivermectin.•The high prevalence of OV16 antibodies in children is indicative of high ongoing onchocerciasis transmission.•High onchocerciasis transmission is the consequence of high exposure to blackflies and low intake of ivermectin.•Head nodding seizures were observed in 13.8% of the persons with epilepsy.•Ivermectin coverage needs to be increased and bi-annual distribution should be considered.

Background: There is anecdotal evidence that ivermectin may decrease seizure frequency in Onchocerca volvulus-infected persons with epilepsy (PWE). Methods: In October 2017, a 12-month clinical trial was initiated in rural Democratic Republic of Congo. PWE with onchocerciasis-associated epilepsy experiencing &ge ; 2 seizures/month were randomly allocated to receive, over a one-year period, ivermectin once or thrice (group 1), while other onchocerciasis-infected PWE (OIPWE) were randomized to ivermectin twice or thrice (group 2). All participants also received anti-epileptic drugs. Data was analyzed using multiple logistic regression. Results: We enrolled 197 participants. In an intent-to-treat analysis (data from group 1 and 2 combined), seizure freedom was more likely among OIPWE treated with ivermectin thrice (OR: 5.087, 95% CI: 1.378&ndash ; 19.749 ; p = 0.018) and twice (OR: 2.471, 95% CI: 0.944&ndash ; 6.769 ; p = 0.075) than in those treated once. Similarly, > ; 50% seizure reduction was more likely among those treated with ivermectin twice (OR: 4.469, 95% CI: 1.250&ndash ; 16.620) and thrice (OR: 2.693, 95% CI: 1.077&ndash ; 6.998). Absence of microfilariae during the last 4 months increased the odds of seizure freedom (p = 0.027). Conclusions: Increasing the number of ivermectin treatments was found to suppress both microfilarial density and seizure frequency in OIPWE, suggesting that O. volvulus infection plays an etiological role in causing seizures.