Onchocerciasis-associated epilepsy: an update and future perspectives.

Onchocerciasis-associated epilepsy (OAE) is an important neglected public health problem in areas with high ongoing onchocerciasis transmission. The risk that children in such areas develop epilepsy is related to their Onchocerca volvulus microfilarial (mf) load. Before the implementation of mass treatment with ivermectin, microfilariae were detected in cerebrospinal fluid (CSF). More recently, neither O. volvulus microfilariae nor DNA were detected in CSF or brain tissue; however, these samples were obtained years after seizure onset. It is possible that during fever-induced increased blood-brain barrier permeability, microfilariae enter the brain and, upon dying, cause an inflammatory reaction inducing seizures. Including OAE in the onchocerciasis disease burden estimation may mobilise extra resources for onchocerciasis disease elimination and treatment/care of OAE-affected persons/families.

Impact of a bi-annual community-directed treatment with ivermectin programme on the incidence of epilepsy in an onchocerciasis-endemic area of Mahenge, Tanzania: A population-based prospective study.

BACKGROUND: Community-directed treatment with ivermectin (CDTi) is used to eliminate onchocerciasis. However, despite 25 years of annual CDTi in Mahenge, Tanzania, the prevalence of onchocerciasis and onchocerciasis-associated epilepsy remained high in certain rural villages. Therefore, in 2019, bi-annual CDTi was introduced in the area. This study assessed the impact of the programme on the incidence of epilepsy in four villages. METHODOLOGY: Door-to-door epilepsy surveys were conducted prior to (2017/18) and after (2021) implementing a bi-annual CDTi program. All household members were screened for epilepsy symptoms using a validated questionnaire, and suspected cases were examined by a medical doctor to confirm/reject the diagnosis of epilepsy. The prevalence and annual incidence of epilepsy, including nodding syndrome, were calculated with 95% Wilson confidence intervals with continuity correction. The latter was also done for CDTi coverage in 2016 and 2021. RESULTS: Precisely 5,444 and 6,598 persons were screened for epilepsy before and after implementing the intervention. The CDTi coverage of the overall population was 82.3% (95%CI: 81.3-83.2%) in 2021 and sustained in both distribution rounds (81.5% and 76.8%). The coverage was particularly high in children and teenagers aged 6 to 18 years (93.2%, 95%CI: 92.1-94.2%). The epilepsy prevalence remained similar: 3.3% (95%CI: 2.9-3.9%) in 2017/18 versus 3.1% (95%CI: 2.7-3.5%) in 2021. However, the incidence of epilepsy declined from 177.6 (95%CI: 121.2-258.5) in 2015-2017 and 2016-2018 to 45.5 (95%CI: 22.2-89.7) in 2019-2021 per 100,000 persons-years. The incidence of probable nodding syndrome varied from 18.4 (95%CI: 4.7-58.5) to 5.1 (95%CI: 0.3-32.8). None of the nine incidence cases of epilepsy for which information on ivermectin intake was available took ivermectin in the year they developed their first seizures. CONCLUSION: A bi-annual CDTi programme should be implemented in areas with high prevalence of onchocerciasis and epilepsy. High CDTi coverage among children is particularly important to prevent onchocerciasis-associated epilepsy.

Onchocerciasis-associated epilepsy in Maridi, South Sudan: Modelling and exploring the impact of control measures against river blindness.

BACKGROUND: Onchocerciasis, also known as "river blindness", is caused by the bite of infected female blackflies (genus Simuliidae) that transmit the parasite Onchocerca volvulus. A high onchocerciasis microfarial load increases the risk to develop epilepsy in children between the ages of 3 and 18 years. In resource-limited settings in Africa where onchocerciasis has been poorly controlled, high numbers of onchocerciasis-associated epilepsy (OAE) are reported. We use mathematical modeling to predict the impact of onchocerciasis control strategies on the incidence and prevalence of OAE. METHODOLOGY: We developed an OAE model within the well-established mathematical modelling framework ONCHOSIM. Using Latin-Hypercube Sampling (LHS), and grid search technique, we quantified transmission and disease parameters using OAE data from Maridi County, an onchocerciasis endemic area, in southern Republic of South Sudan. Using ONCHOSIM, we predicted the impact of ivermectin mass drug administration (MDA) and vector control on the epidemiology of OAE in Maridi. PRINCIPAL FINDINGS: The model estimated an OAE prevalence of 4.1% in Maridi County, close to the 3.7% OAE prevalence reported in field studies. The OAE incidence is expected to rapidly decrease by >50% within the first five years of implementing annual MDA with good coverage (≥70%). With vector control at a high efficacy level (around 80% reduction of blackfly biting rates) as the sole strategy, the reduction is slower, requiring about 10 years to halve the OAE incidence. Increasing the efficacy levels of vector control, and implementing vector control simultaneously with MDA, yielded better results in preventing new cases of OAE. CONCLUSIONS/SIGNIFICANCES: Our modeling study demonstrates that intensifying onchocerciasis eradication efforts could substantially reduce OAE incidence and prevalence in endemic foci. Our model may be useful for optimizing OAE control strategies.

Rapid diagnostic testing for onchocerciasis in Maridi (South Sudan) before and after improving elimination strategies: a repeated cross-sectional survey.

Background: Maridi County is an onchocerciasis-endemic area in South Sudan. Annual community-directed treatment with ivermectin (CDTi) was instituted in Maridi since the early 2000s, but with low coverage. In 2021, the CDTi programme was strengthened to a six-monthly programme. Additionally, the community-based vector control strategy "Slash and Clear" has been implemented since 2019 at the Maridi Dam, the only blackfly breeding site in the area. This study assessed the effect of these reinforced onchocerciasis elimination interventions on the Onchocerca volvulus seroprevalence among young children, an indicator of ongoing transmission. Methods: Baseline and follow-up serosurveys were conducted in Maridi in 2019 (prior to strengthening onchocerciasis elimination efforts) and 2023, respectively. During both surveys, children aged three to nine years were recruited from five study sites situated at different distances from the Maridi Dam. Ov16 antibodies were detected via rapid diagnostic tests (RDTs) using whole blood obtained by finger-pricking the participants. Baseline and follow-up Ov16 prevalence rates were calculated and compared. Results: In 2019, the Ov16 seroprevalence among children aged three to nine years was 24.5% compared to 30.6% in 2023 (p=0.22). Both surveys found a particularly high Ov16 seroprevalence in the study site closest to the Maridi Dam (35.0% in 2019 and 44.0% in 2023, p=0.52). The Ov16 seroprevalence had a non-significant decreasing trend in the three-year-old children, from 12.5% (3/24) in 2019 to 8.8% (3/34) in 2023 (p=0.65). Conclusion: The persistent Ov16 RDT seropositivity among three-year-old children in 2023 indicates ongoing O. volvulus transmission. Therefore, further strengthening of the onchocerciasis elimination programme is required. The study highlights the utility of RDTs in monitoring onchocerciasis transmission in highly endemic settings.

Onchocerciasis-associated epilepsy: an explorative case-control study with viral metagenomic analyses on Onchocerca volvulus.

Background: A high prevalence of onchocerciasis-associated epilepsy (OAE) has been observed in onchocerciasis-endemic areas with high ongoing Onchocerca volvulus transmission. However, the pathogenesis of OAE remains to be elucidated. We hypothesise that the O. volvulus virome could be involved in inducing epilepsy. With this study, we aim to describe the O. volvulus virome and identify potential neurotropic viruses linked to OAE. Methods: In Maridi County, an onchocerciasis endemic area in South Sudan with a high prevalence of OAE, we will conduct an exploratory case-control study enrolling 40 persons aged 12 years and above with palpable onchocerciasis nodules. Cases will be participants with OAE (n=20), who will be age- and village-matched with controls without epilepsy (n=20). For each study participant, two skin snips at the iliac crest will be obtained to collect O. volvulus microfilariae, and one nodulectomy will be performed to obtain adult worms. A viral metagenomic study will be conducted on microfilariae and adult worms, and the O. volvulus virome of persons with and without OAE will be compared. The number, size, and localisation of onchocerciasis nodules in persons with and without OAE will be described. Moreover, the pre- and post-nodulectomy frequency of seizures in persons with OAE will be compared. Ethics and dissemination: The protocol has been approved by the Ethics Committee of the University of Antwerp and the Ministry of Health of South Sudan. Findings will be disseminated nationally and internationally via meetings and peer-reviewed publications. Registration: ClinicalTrials.gov registration NCT05868551 ( https://clinicaltrials.gov/study/NCT05868551). Protocol version: 1.1, dated 09/05/2023.

Assessing Onchocerca volvulus Intensity of Infection and Genetic Diversity Using Mitochondrial Genome Sequencing of Single Microfilariae Obtained before and after Ivermectin Treatment.

Onchocerciasis is a neglected tropical disease targeted for elimination using ivermectin mass administration. Ivermectin kills the microfilariae and temporarily arrests microfilariae production by the macrofilariae. We genotyped 436 microfilariae from 10 people each in Ituri, Democratic Republic of the Congo (DRC), and Maridi County, South Sudan, collected before and 4-5 months after ivermectin treatment. Population genetic analyses identified 52 and 103 mitochondrial DNA haplotypes among the microfilariae from DRC and South Sudan, respectively, with few haplotypes shared between people. The percentage of genotype-based correct assignment to person within DRC was ~88% and within South Sudan ~64%. Rarefaction and extrapolation analysis showed that the genetic diversity in DRC, and even more so in South Sudan, was captured incompletely. The results indicate that the per-person adult worm burden is likely higher in South Sudan than DRC. Analyses of haplotype data from a subsample (n = 4) did not discriminate genetically between pre- and post-treatment microfilariae, confirming that post-treatment microfilariae are not the result of new infections. With appropriate sampling, mitochondrial haplotype analysis could help monitor changes in the number of macrofilariae in a population as a result of treatment, identify cases of potential treatment failure, and detect new infections as an indicator of continuing transmission.

First description of Nodding Syndrome in the Central African Republic.

BACKGROUND: The term Nodding Syndrome (NS) refers to an atypical and severe form of childhood epilepsy characterized by a repetitive head nodding (HN). The disease has been for a long time limited to East Africa, and the cause is still unknown. The objective of this study was to confirm the existence of NS cases in Central African Republic (CAR). METHODOLOGY/PRINCIPAL FINDINGS: This was a cross-sectional descriptive study in the general population. The identification of NS cases was conducted through a door-to-door survey in a village near Bangui along the Ubangui River. Based on Winkler's 2008 and the World Health Organization (WHO)'s 2012 classifications, the confirmation of cases was done by a neurologist who also performed the electroencephalograms. No laboratory tests were done during this investigation. Treatment was offered to all patients. A total of 6,175 individuals was surveyed in 799 households. After reviewing the cases, we identified 5 NS cases in girls aged between 8 and 16. The age of onset of the seizures was between 5 and 12 years of age. Two cases were classified as "HN plus" according to Winkler's 2008 classification. Four NS cases were classified as probable and one as confirmed according to the WHO's 2012 classification. Three of them presented with developmental delay and cognitive decline, and one had an abnormally low height-for-age z-score. Electroencephalographic abnormalities were found in four patients. CONCLUSIONS/SIGNIFICANCE: Nodding Syndrome cases were described in CAR for the first time. Despite certain peculiarities, these cases are similar to those described elsewhere. Given that only a small part of the affected area was investigated, the study area along the Ubangui River needs to be expanded in order to investigate the association between Onchocerca volvulus and NS and also evaluate the real burden of NS in CAR.

OV16 Seroprevalence among Persons with Epilepsy in Onchocerciasis Endemic Regions: A Multi-Country Study.

There is growing epidemiological evidence that onchocerciasis may induce epilepsy. High prevalence of onchocerciasis has been reported in onchocerciasis-meso and hyper-endemic regions. We aimed to determine the OV16 antibody prevalence in persons with epilepsy (PWE) in four onchocerciasis-endemic regions. PWE were identified during studies in Mahenge area (Tanzania), Kitgum and Pader districts (Uganda), the Mbam and Sanaga river valleys (Cameroon), and the Logo health zone (Democratic Republic of Congo). Exposure to Onchocerca volvulus was assessed by testing PWE for OV16 IgG4 antibodies using a rapid diagnostic test. The OV16 seroprevalence among PWE in the four onchocerciasis-endemic study sites ranged from 35.2% to 59.7%. OV16 seroprevalence increased with age until the age of 39 years, after which it decreased drastically. Our study suggests that, in onchocerciasis-endemic regions, epilepsy in young people is often associated with onchocerciasis, while epilepsy in older persons seems unrelated to O. volvulus exposure.

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

We investigated urinary N-acetyltyramine-O,ß-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.

Ivermectin Treatment Response in Onchocerca Volvulus Infected Persons with Epilepsy: A Three-Country Short Cohort Study.

Despite a long history of community-directed treatment with ivermectin (CDTI), a high ongoing Onchocerca volvulus transmission is observed in certain onchocerciasis-endemic regions in Africa with a high prevalence of epilepsy. We investigated factors associated with higher microfilarial (mf) density after ivermectin treatment. Skin snips were obtained from O. volvulus-infected persons with epilepsy before, and 3 to 5 months after ivermectin treatment. Participants were enrolled from 4 study sites: Maridi (South Sudan); Logo and Aketi (Democratic Republic of Congo); and Mahenge (Tanzania). Of the 329 participants, 105 (31.9%) had a post-treatment mf density >20% of the pre-treatment value. The percentage reduction in the geometric mean mf density ranged from 69.0% (5 months after treatment) to 89.4% (3 months after treatment). A higher pre-treatment mf density was associated with increased probability of a positive skin snip after ivermectin treatment (p = 0.016). For participants with persistent microfiladermia during follow-up, a higher number of previous CDTI rounds increased the odds of having a post-treatment mf density >20% of the pre-treatment value (p = 0.006). In conclusion, the high onchocerciasis transmission in the study sites may be due to initially high infection intensity in some individuals. Whether the decreasing effect of ivermectin with increasing years of CDTI results from sub-optimal response mechanisms warrants further research.

Women with epilepsy in sub-Saharan Africa: A review of the reproductive health challenges and perspectives for management.

BACKGROUND: Epilepsy is one of the commonest neurological conditions affecting women of reproductive age. Epilepsy management during pregnancy is a clinical conundrum, requiring a balance between seizure control and risk minimization for the women with epilepsy (WWE) as well as for their fetuses. The objective of this comprehensive review is to explore the reproductive health challenges of WWE in sub-Saharan Africa (SSA) and ways to address them. METHOD: Relevant documentation published until June 2019 were retrieved via literature searches performed in PubMed and Google Scholar, as well as a manual search to identify grey literature. RESULTS: WWE in SSA are generally more stigmatized and sexually exploited than women without epilepsy. Contraception use among WWE was reported only in Senegal (51%) and Kenya (14.7%). Only two prospective studies (one in Senegal and one in Nigeria) investigated pregnancy outcomes for a total of 97 WWE. The prevalence of convulsive epilepsy in pregnancy was estimated at 3.33 per 1000. Among pregnant WWE treated with first line anti-epileptic drugs, 16.2% had miscarriages, 41.9% premature births, and 4.1% had babies with malformations. Carbamazepine, which is frequently prescribed to pregnant WWE in SSA, still entails a 2.1-fold increased risk of congenital malformation. No reports were found concerning pre-conceptual counseling and post-natal outcomes in WWE in SSA. CONCLUSION: Our review underscores the need for contextualized evidence-based clinical guidelines and a collaborative approach to treat WWE in SSA. High risks of congenital malformations and drug interactions with first line AED warrant the provision of safer second line alternatives.

Onchocerciasis-associated epilepsy: another piece in the puzzle from the Mahenge mountains, southern Tanzania.

In a study from the onchocerciasis-endemic area of Mahenge in southern Tanzania, Mmbando et al. [Inf Dis Poverty. 2018;7:64] demonstrate that in four selected villages the overall epilepsy prevalence was high, and significantly more elevated in the two villages of higher onchocerciasis endemicity compared to those of lower endemicity. This is replicating earlier findings from many other areas of tropical Africa. The authors are also providing data indicating that in the Mahenge focus, the prevalence of nodding syndrome may be related to that of onchocerciasis in the same way as epilepsy in general. The application of a clinical case definition for onchocerciasis-associated epilepsy (OAE) as used in the study of Mmbando et al. [Inf Dis Poverty. 2018;7:64] faces some difficulties; indeed, its precision in discerning cases of OAE from epilepsy due to other etiologies is not known, and it does not allow for a specific diagnosis in the individual patient. Because an operational surveillance tool for assessing the number of patients in the population could mean substantial advance for better estimating the burden of OAE, the proposed definition should be tried in different settings and its performance reviewed in the process.