Treatment and prevention of epilepsy in onchocerciasis-endemic areas is urgently needed.

BACKGROUND: There is increasing epidemiological evidence supporting the association between onchocerciasis and seizures, reinforcing the concept of onchocerciasis-associated epilepsy (OAE). The aim of this paper is to provide an update on the new knowledge about OAE and to propose recommendations to the World Health Organization how to address this public health problem. MAIN TEXT: During the 2nd International Workshop on OAE held on 19-21 September, 2023, in Antwerp, Belgium, participants recognised OAE as a substantial yet neglected public health problem, particularly in areas of sub-Saharan Africa where onchocerciasis remains hyperendemic. Evidence from prospective population-based studies suggest that strengthening onchocerciasis elimination efforts leads to a significant reduction of OAE incidence. There is a need to validate an OAE case definition to estimate the burden of disease and identify onchocerciasis-endemic areas requiring intensification of onchocerciasis elimination programmes and integration of epilepsy care. It is expected that raising awareness about OAE will boost the population uptake of ivermectin. The implementation of a community-based epilepsy treatment programme offering free anti-seizure medications (ASMs) has shown high effectiveness in reducing the frequency of seizures and improving the overall quality of life of people with epilepsy. CONCLUSIONS: To reduce OAE burden, enhanced collaboration between onchocerciasis and mental health programmes at community, national, and international levels is required. Urgent efforts are needed to ensure the uninterrupted provision of free ASMs in onchocerciasis-endemic areas. Furthermore, OAE should be included in the quantification of the onchocerciasis disease burden.

Persistence of onchocerciasis and associated dermatologic and ophthalmic pathologies after 27 years of ivermectin mass drug administration in the middle belt of Ghana.

OBJECTIVES: There is a pressing need to regularly evaluate the progress of onchocerciasis elimination programmes to timely identify and mitigate potential risks hindering the reaching of the 2030 targets proposed by the World Health Organization (WHO) in its roadmap on neglected tropical diseases (NTDs). We determined the prevalence of onchocerciasis and associated dermatological and ophthalmological manifestations in six endemic communities in the Bono Region of Ghana after 27 years of ivermectin mass treatment. METHODS: In a cross-sectional study, 564 participants aged ≥5 years were enrolled (49.1% females), with a median age of 26 (range: 5-89) years. In 54% and 47%, skin-snip microscopy and Ov16 rapid diagnostic tests were performed, respectively. Skin disease was determined using the WHO Skin NTD App. Visual function assessments included tests of visual acuity. RESULTS: The overall microfilarial prevalence was 12.5% (38/305) and Ov16 seroprevalence was 24.2% (64/265). Severe itching was recorded in 24.3%, acute papular onchodermatitis in 52.8%, chronic papular onchodermatitis in 12.5%, lichenified onchodermatitis in 0.7%, skin atrophy in 11.3%, depigmentation in 1.7% and palpable nodules in 5.3%. Of the 301 persons in which visual acuity was examined, 17% were visually impaired and 5.3% were blind and 47.3% presented with cataract. Chronic papular onchodermatitis, lichenified onchodermatitis, depigmentation and visual impairment were significantly associated with the presence of skin microfilariae and Ov16 seropositivity. CONCLUSIONS: The persistence of Onchocerca volvulus infection and onchocerciasis-associated dermatological and ophthalmological pathologies after prolonged treatment is of concern. There is a need to include morbidity management in onchocerciasis elimination programmes and understand better patterns of treatment coverage, adherence and actual intake of ivermectin.

The onchocerciasis hypothesis of nodding syndrome.

Nodding syndrome (NS) is a phenotypic presentation of onchocerciasis-associated epilepsy (OAE). OAE is an important public health problem in areas with high ongoing Onchocerca volvulus transmission. OAE, including NS, is preventable by strengthening onchocerciasis elimination programs. The presence of tau in OAE postmortem brains could be the consequence of neuroinflammation directly or indirectly induced by O. volvulus. Omics research is needed to investigate whether O. volvulus worms contain a neurotropic virus.

Effect of onchocerciasis elimination measures on the incidence of epilepsy in Maridi, South Sudan: a 3-year longitudinal, prospective, population-based study.

BACKGROUND: High onchocerciasis transmission predisposes endemic communities to a high epilepsy burden. The 4·4% epilepsy prevalence documented in 2018 in Maridi, South Sudan, prompted the strengthening of onchocerciasis elimination measures. Community-directed treatment with ivermectin was implemented annually in 2017, 2018, and 2019, interrupted in 2020, and re-implemented biannually in 2021. We aimed to assess the effect of these interventions, along with slash and clear vector control on the incidence of epilepsy, including nodding syndrome. METHODS: In this longitudinal, prospective, population-based study, we did a two-stage house-to-house epilepsy survey before (May 10-30, 2018) and after (March 9-19, 2022) the strengthening of onchocerciasis elimination interventions in South Sudan. Strengthening also included the implementation of a community-based slash and clear vector control method that we initiated in 2019 at the Maridi dam (the main blackfly breeding site). Eight sites were surveyed near the Maridi dam and inclusion required residence in one of these sites. All household residents were first screened by community workers, followed by confirmation of the epilepsy diagnosis by trained clinicians. The primary outcome was epilepsy incidence, including nodding syndrome, which was assessed via self-reported new-onset epilepsy in the previous 4 years of each survey, confirmed by clinician assessment. FINDINGS: The preintervention survey included 17 652 people of whom 736 had epilepsy (315 female and 421 male), and the post-intervention survey included 14 402 people of whom 586 had epilepsy (275 female and 311 male). When biannual community-directed treatment with ivermectin was initiated in 2021, the intervention's coverage rose by 15·7% (95% CI 14·6-16·8); although only 56·6% of the population took ivermectin in 2021. Between 2018 and 2022, epilepsy incidence decreased from 348·8 (307·2-395·8) to 41·7 (22·6-75·0) per 100 000 person-years. Similarly, the incidence of nodding syndrome decreased from 154·7 (127·6-187·3) to 10·4 (2·7-33·2) per 100 000 person-years. The identified risk factors for epilepsy were: living closer to the Maridi dam, being aged between 6 and 40 years, not taking ivermectin, and being male. INTERPRETATION: In onchocerciasis-endemic areas with high epilepsy prevalence, strengthening onchocerciasis elimination interventions can decrease the incidence of epilepsy, including nodding syndrome. Additional efforts are needed to increase community-directed treatment with ivermectin coverage and sustain blackfly control in Maridi. FUNDING: Research for Health in Humanitarian Crisis, European Research Council, Research Foundation-Flanders, Research Foundation-Flanders, the Italian Agency for Development Cooperation, and La Caixa Foundation.

Genome diversity of Leishmania aethiopica.

Leishmania aethiopica is a zoonotic Old World parasite transmitted by Phlebotomine sand flies and causing cutaneous leishmaniasis in Ethiopia and Kenya. Despite a range of clinical manifestations and a high prevalence of treatment failure, L. aethiopica is one of the most neglected species of the Leishmania genus in terms of scientific attention. Here, we explored the genome diversity of L. aethiopica by analyzing the genomes of twenty isolates from Ethiopia. Phylogenomic analyses identified two strains as interspecific hybrids involving L. aethiopica as one parent and L. donovani and L. tropica respectively as the other parent. High levels of genome-wide heterozygosity suggest that these two hybrids are equivalent to F1 progeny that propagated mitotically since the initial hybridization event. Analyses of allelic read depths further revealed that the L. aethiopica - L. tropica hybrid was diploid and the L. aethiopica - L. donovani hybrid was triploid, as has been described for other interspecific Leishmania hybrids. When focusing on L. aethiopica, we show that this species is genetically highly diverse and consists of both asexually evolving strains and groups of recombining parasites. A remarkable observation is that some L. aethiopica strains showed an extensive loss of heterozygosity across large regions of the nuclear genome, which likely arose from gene conversion/mitotic recombination. Hence, our prospection of L. aethiopica genomics revealed new insights into the genomic consequences of both meiotic and mitotic recombination in Leishmania.

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.

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.

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.