Background High onchocerciasis transmission predisposes endemic communities to a high epilepsy burden. Retrospective studies suggest that adequate onchocerciasis control would decrease the epilepsy burden, but this has never been assessed prospectively. The 4.4% (95% CI: 4.1–4.7%) epilepsy prevalence documented in 2018 in the onchocerciasis focus in Maridi, South Sudan, prompted the strengthening of onchocerciasis elimination measures. We evaluated the effect of these interventions on the incidence of epilepsy, including nodding syndrome (NS). Methods Community-directed treatment with ivermectin (CDTi) was implemented annually in 2017, 2018 and 2019, interrupted in 2020 and re-implemented biannually in 2021. Additionally, a community-based “Slash and Clear” vector control method was initiated in 2019 at the Maridi dam, the main blackfly breeding site. Community-based surveys were conducted in Maridi in 2018 (baseline) and 2022 (follow-up) to investigate changes in epilepsy incidence following onchocerciasis elimination interventions. Epilepsy was confirmed via a two-stage approach: the house-to-house screening of all residents followed by confirmation of the epilepsy diagnosis by trained clinicians. Results The baseline and follow-up surveys included 17,652 and 14,402 individuals, respectively. When biannual CDTi was initiated in 2021, CDTi coverage rose by 15.7% (95% CI: 14.6–16.8%); still, only 56.6% of the population took ivermectin in 2021. Between 2018 and 2022, epilepsy incidence decreased from 348.8 (95% CI: 307.2–395.8) to 41.7 (95% CI: 22.6–75.0) per 100,000 person-years. Similarly, the incidence of NS decreased from 154.7 (95% CI: 127.6–187.3) to 10.4 (95% CI: 2.7–33.2) per 100,000 person-years. Living closer to the Maridi dam, being aged 6–40 years, not taking ivermectin and being male constituted risk factors for epilepsy. Conclusions In onchocerciasis-endemic areas with high epilepsy prevalence, strengthening onchocerciasis elimination interventions can decrease the incidence of epilepsy, including NS. Additional efforts are needed to increase CDTi coverage and sustain blackfly control in Maridi.
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