Epilepsy affects more than fifty million people globally. Nearly 80% of people with epilepsy (PWE) live in low- and middle-income countries, where rates of epilepsy prevalence and incidence are higher than in high-income countries (1) and less than one in four PWE has access to adequate care (1, 2). In Africa, the prevalence of epilepsy is estimated to be between 0.5 to 10%, with higher rates in rural areas compared to urban areas (1). There is an important epilepsy diagnosis and treatment gap, leading to a high mortality and case fatality rate (3). Disability-adjusted life years (DALYs) attributed to epilepsy in Africa were estimated at 3.9 million DALYs in 2017 (4).

The only published data on epilepsy in South Sudan are from onchocerciasis-endemic areas in the Western Equatoria state (5–12), and more recently from the Lakes state (13). A significant proportion of epilepsy in these states was found to be associated with onchocerciasis (5–10). There is no data on epilepsy in the area of Deim Zubeir in the Western Bahr El Ghazal state.

Onchocerciasis, a neglected tropical disease caused by the nematode Onchocerca volvulus, remains a major health burden worldwide (14). The Global Burden of Disease Study estimated that in 2017 at least 220 million people were in need of preventive chemotherapy against onchocerciasis, 14.6 million presented with skin disease, and 1.15 million with loss of vision (15). More than 99% of those infected live in African countries, including South Sudan (14). South Sudan is highly endemic with almost 49% of the country affected (16), mostly Western Equatoria, followed by Northern and Western Bahr El Ghazal. Deim Zubeir in Raga County is an onchocerciasis endemic area in Western Bahr El Ghazal State.

Onchocerciasis is known to induce skin and eye disease (17). Increasing epidemiological evidence suggests that onchocerciasis can also induce epilepsy (18–20). A high prevalence of epilepsy was observed in several onchocerciasis-endemic areas in South Sudan, e.g. in Maridi (6), Mundri East and West (21) and Mvolo (10). Many people with epilepsy in these areas present with the characteristics of onchocerciasis-associated epilepsy (OAE) (5, 22). The first seizures in persons with OAE usually occur in previously healthy children between the ages of 3-18 years with no other obvious cause of epilepsy (5, 22, 23). Onchocerciasis-associated epilepsy includes a wide spectrum of seizure types (24, 25). Nodding and Nakalanga syndromes are two phenotypic severe forms of OAE observed only in areas with very high ongoing or past O. volvulus transmission, and mainly in households living close to blackfly breeding sites (20, 26). Nodding syndrome is characterized by head nodding seizures often during periods of reduced consciousness and frequently accompanied by cognitive impairment (26–28). Nakalanga syndrome presents with growth retardation, delayed secondary sexual development, often with morphological deformities and seizures (25, 29).

Recent retrospective (30–32) and prospective (8, 9, 33) population-based studies showed that strengthening onchocerciasis elimination programs decreased the incidence of OAE. The main strategy for onchocerciasis elimination is Community-Directed Treatment with Ivermectin (CDTI) (34, 35). However, ivermectin only eliminates microfilaria in the skin and only temporarily sterilizes female adult worms without killing them (35). Consequently, to eliminate onchocerciasis, mass drug administration with ivermectin needs to be given for at least 15 years, the lifespan of the adult worms (14), and with a CDTI coverage of at least 80% of people in the targeted community (36). People who develop epilepsy (whether OAE or other forms of epilepsy) will often require lifelong treatment with antiseizure medications.

Deim Zubeir is known as an onchocerciasis-endemic area with a high number of PWE and blindness, but a prevalence survey had never been done ¹ . During a health assessment by the Health Department of the Catholic Diocese of Wau in 2021, many parishes in Deim Zubeir reported a high number of PWE. During meetings with PWE, a high level of stigma and discrimination was reported; about half of the PWE had been chased away from their family homes due to the misconception that epilepsy is contagious, and some mentioned that they feared to go to public places, including attending health facilities, because of stigma. In 2017, the parish priest of Deim Zubeir convinced the Catholic health facilities to provide him with antiseizure medication and to give him guidance on the management of epilepsy. In 2017, the first 30 PWE received antiseizure medication in Deim Zubeir.

In this study, we describe the results of a population-based epilepsy prevalence survey conducted in Deim Zubeir in July 2023, in prelude to the implementation of preventive and treatment actions for PWE in that area.

Ethical approval was obtained from the ethics committee of the Ministry of Health of South Sudan (January 2018, MOH/ERB50/2019) and from the ethics committee of the Antwerp University Hospital, Belgium (April 2019, B300201940004). Community engagement meetings were organized before the start of the survey. Written informed consents were obtained from the head of households and PWE and carers who participated in the study. For children up to 11 years of age, the parents/caretakers provided consent, while adolescents between the ages of 12-17 years provided assent before parental consent.

While current estimates suggest an important burden of OAE in many South Sudanese villages, a prevalence survey had never been conducted in Deim Zubeir, a remote, onchocerciasis-endemic area of South Sudan where a high number of patients with epilepsy has been reported. This paper presents the results of the first epilepsy household survey conducted in Deim Zubeir to the best of our knowledge, with the aim to estimate the prevalence of epilepsy in that area.

This household survey documents the very important burden of epilepsy in Deim Zubeir and surrounding villages. A high prevalence of epilepsy and blindness, a high epilepsy mortality rate, and a high epilepsy case-fatality rate were documented. The crude mortality rate for the entire population was 11.9 per 1,000 persons per year, very similar to the World Bank estimate of 11.05 for South Sudan in 2021 (43). PWE were more than six times more likely to die and did so at a much younger age (21 vs 41 years) compared to those without epilepsy. The prevalence of epilepsy was highest among young adults, blindness was three times higher among PWE compared to people without epilepsy; more than one third of PWE had siblings with epilepsy, and a quarter had skin lesions compatible with onchocerciasis, a pattern that is typical of OAE (21).

Our study confirms the strong epidemiological link between onchocerciasis and epilepsy. However, the pathogenesis of OAE still remains to be elucidated. Several pathophysiological mechanisms were proposed but remain unproven (20). Before the widespread use of ivermectin, microfilariae have been identified in the cerebrospinal fluid (CSF) of persons with onchocerciasis without epilepsy (44). In more recent studies, neither microfilariae nor O. volvulus DNA was detected in CSF but CSF was obtained many years after the onset of seizures (45–47). Therefore, it is possible that parasites had already been eliminated by the central nervous system immune system. One of the hypotheses for OAE-inducing mechanisms is immune mediated inflammation (46). Parasitic tolerance in children exposed to filariae in utero is another potential co-factor (48). Recently, a virus associated with O. volvulus, Onchocerca volvulus RNA virus 1 (OVRV1), was found to elicit antibody responses from infected or exposed humans (49). However, it is not known whether OVRV1 plays a role in the pathophysiology of OAE.

In a large, recent meta-analysis, the prevalence of active epilepsy in Africa was estimated at 9 per 1,000 persons (95% CI 8.0-9.9 per 1,000 persons) with wide regional variations, peaking at 30.2 per 1,000 persons (95%CI 6.2 to 66.7) in the Central Africa subregion (50). Our estimate of 23.1 per 1,000 persons is in line with this figure.

In another systematic review, the epilepsy mortality rate and case fatality rate in Africa were estimated at 342.9 per 100,000 person-years and 57.0 per 1,000 PWE in onchocerciasis high-risk sites, compared to 10.0 per 100,000 person-years and 26.6 per 1,000 PWE in non-onchocerciasis endemic sites (3). The estimated mortality rate in Deim Zubeir of 182.4 per 100,000 person-years and epilepsy case fatality rate of 64.1 deaths per 1,000 PWE are comparable with mortality rates observed in other onchocerciasis endemic areas.

Only about half of the study population took ivermectin during the last CDTI round in 2022, a proportion that is insufficient to control ongoing O. volvulus transmission (51). However, significantly more PWE took ivermectin treatment compared to the general population, with over 80% coverage in this group. This could be related to the fact that ivermectin treatment has been associated with fewer seizures (52–54); hence PWE may be more likely to take ivermectin to reduce their seizure frequency and not necessarily for onchocerciasis elimination purposes.

Similar high prevalence and mortality of epilepsy were observed in other onchocerciasis-endemic areas in Western Equatoria, South Sudan. In two large surveys in Mvolo, the prevalence of epilepsy was 51.4 per 1,000 persons in 2020 and 44.5 per 1,000 persons in 2022; 3% were blind; the median age of those with epilepsy was 20 years; 82.8% met the criteria for OAE in 2022; less than one third had taken ivermectin the year before, and only 23% were receiving antiseizure medication (9). In Maridi, the prevalence of epilepsy was 44 per 1,000 persons (6) and 85% fulfilled the OAE criteria (5); median age of PWE was 18 years; 40.8% took ivermectin the year before (5). Our study also documented a very high epilepsy case fatality rate of 64.1 per 1,000 PWE per year. This is comparable with the 62.9 per 1,000 mortality among PWE documented in Maridi (6). Slightly higher epilepsy fatality rates was found in the Wulu County (Lakes State), where it was estimated at 70.3 per 1000 PWE (13). The high epilepsy related mortality in our study and other onchocerciasis-endemic areas in South Sudan is explained by the high epilepsy prevalence and the lack of access to uninterrupted antiseizure medication in the area. The relatively low epilepsy prevalence in Deim Zubeir contrasts with this high epilepsy related mortality. Most likely because of epilepsy-related stigma, epilepsy-related symptoms were not reported in certain households and therefore the epilepsy prevalence has been underestimated. The high epilepsy mortality in onchocerciasis endemic regions with high O. volvulus transmission compared to the epilepsy mortality in most non-onchocerciasis endemic areas in Africa (3) is explained, at least in part, by the lack of access to adequate epilepsy care in these remote poor onchocerciasis endemic areas without health infrastructure, often affected by insecurity. Additionally, It was observed that persons with OAE and notably the nodding syndrome, are prone to more severe forms of epilepsy which may also worsen their prognosis (26).

Our study has several limitations, in addition to the potential for misclassification and recall bias, which are inherent to questionnaire-based household surveys. First, the diagnosis of epilepsy was not confirmed by a neurologist. The prevalence of nodding syndrome could not be determined. Head movements during seizures were described by 92.8% of family members. However, to consider these movements as head nodding seizures they should be between 5-20 head movements per minute (23). Most likely many of these head movements were part of generalized seizures. We did not perform any laboratory/imaging analysis to confirm onchocerciasis, nor an entomological study with PCR testing of blackflies to document the level of onchocerciasis transmission in the area. Moreover, we did not investigate the exact cause of death in PWE. However, given the difficulty to obtain antiseizure medication in the area, it is most likely that the PWE died of causes directly or indirectly related to seizures, as was observed in a recent clinical trial among PWE in Uganda (55).

In conclusion, the prevalence of epilepsy and the epilepsy case-fatality rate was high in the region of Deim Zubeir. More than half of the persons with epilepsy met the definition of onchocerciasis-associated epilepsy. The high prevalence of epilepsy, blindness, and skin lesions consistent with onchocerciasis, coupled with the low coverage of CDTI, suggest high ongoing O. volvulus transmission Based on study findings in onchocerciasis-endemic areas in the Western Equatoria state in 2021, the South Sudanese Neglected Tropical Disease program decided recently to switch from annual to semi-annual CDTI (19, 56). Hopefully, this will result in increased ivermectin coverage (19, 20). Strengthening the onchocerciasis elimination program in Deim Zubeir is urgently needed. To prevent children from developing OAE, it will be important that they take ivermectin at least once but ideally twice a year (19, 57).

In 2023, the Catholic diocese of Wau started an epilepsy treatment program in Deim Zubeir that included the provision of free antiseizure medication. It is expected that this will improve the health seeking behaviour of PWE and their families and, together with OAE awareness campaigns, will reduce epilepsy related stigma and discrimination (19, 20). Hopefully this program will be sustainable and curb the epilepsy-related mortality. However, more advocacy is needed to ensure the provision of uninterrupted free access to antiseizure medication to PWE in these remote impoverished areas (20).