We thank Colebunders et al. for their critical comments on our systematic review [1, 2]. They would like to draw our attention to the potential causal role of onchocerciasis in the occurrence of Nodding Syndrome (NS) and other epilepsies that show some degree of association with onchocerciasis, i.e., onchocerciasis-associated epilepsies (OAE), of which the authors argue NS is part. They mention that recent articles [3‒6], suggesting a “causal” link between onchocerciasis and NS/OAE, have not been taken into account in our systematic review. The cut-off date for the inclusion of articles in our systematic review was November 2021, which is why the first articles [3, 4] were included and not the other two, which were published in 2023. We are therefore well aware of these studies and do not question the strong epidemiological link between onchocerciasis and NS. The meta-analysis we carried out confirmed this link (OR = 8.8 [4.8, 15.9]) [1]. However, the decline in the incidence of NS following the introduction of onchocerciasis elimination programmes in certain areas does not necessarily mean that onchocerciasis is the cause of NS. In addition to the problematic epidemiological definition of a “causal link” itself [7, 8], there are still uncertainties in the investigation of a relationship between NS and onchocerciasis.

In some onchocerciasis-endemic areas, notably the Mahenge area of Ulanga district (south-eastern Tanzania) [9] and the Aketi health zone (northern Democratic Republic of the Congo) [10], the use of onchocerciasis elimination programmes has failed to significantly reduce the prevalence and incidence of epilepsy (including NS) after 14 years in the Democratic Republic of the Congo and 20 years in Tanzania. If onchocerciasis were the cause of NS, or at least the only factor involved in the occurrence of NS in endemic areas, then elimination programs would have to work systematically everywhere. Moreover, it has been recognized for a number of years that one of the major epidemiological counter-arguments to the causal role of Onchocerca volvulus in NS is the fact that O. volvulus is endemic in many areas where NS has not been reported [11‒13]; according to some authors, the most obvious explanation that onchocerciasis does not cause NS [14].

Although our meta-analysis led to a significant OR for the onchocerciasis – NS relationship [1], it is important to mention that some studies [15, 16], including a very recent one [14], found no association between NS and O. volvulus. Indeed, in this latest case-control study, which took place in 181 children (72 cases and 109 controls) living in the Greater Mundri region (Western Equatoria State of South Sudan) between February 2018 and November 2019, the association between NS and O. volvulus was not found. Numerous other infectious, nutritional, and immunological factors were tested. The authors hypothesize that some factors (higher concentrations of vitamins A and E, low history of viral exposure, and Mansonella perstans infection) directly or indirectly modify the risk of NS, while others (lower vitamin B12 concentration, Necator americanus infection, and malaria exposure) may result from having NS. None of these associations were strong enough to suggest a unifactorial cause [14].

Microfilariae of O. volvulus were previously found in the cerebrospinal fluid (CSF) of patients suffering from onchocerciasis [17, 18]. Colebunders et al. explain the absence of O. volvulus genetic material in the CSF of NS and OAE patients [19] by previous use of ivermectin during onchocerciasis control programs [20]. In our opinion, the two studies that found O. volvulus microfilariae in patients’ CSF provided some evidence that this pathogen could potentially cross the blood-brain barrier and cause neurological signs/symptoms in NS; thus, the absence of microfilariae in NS patients may support the idea that O. volvulus is not (or at least not directly) responsible for neurological signs/symptoms in NS. Indeed, even if previous use of ivermectin was put forward as the explanation for the absence of microfilariae in CSF, we believe that at least dead microfilariae should have been found in CSF of NS patients in areas of active transmission if O. volvulus were the direct cause. Other researchers believe that if there had been contact between the parasite and the CSF, and yet the CSF PCR was negative, individuals with intrathecal antibody production, and therefore a positive CSF/serum antibody index, should have been found [19]. It should be noted that the same authors, who studied people suffering from epilepsy (PWE) and NS in Tanzania, in which genetic material of O. volvulus had not been found, reported that, at the time, ivermectin distribution seemed irregular and that most people had no recollection of receiving the treatment, even though Mahenge (study area) had been part of the African Programme for Onchocerciasis Control (APOC) since 1997. Later on, another study in Sudan [21] still failed to find any trace of O. volvulus microfilaria in the CSF of patients.

Colebunders et al. [20] also hypothesize that NS and OAE only appear after a certain level of microfilaria infestation has been reached, and that this is the reason why “the peaks in head nodding appearance in April and June do not correlate with black fly biting activity in humans”. Indeed, they argue that, just as blindness takes 20 years to develop in people with onchocerciasis, the development of NS or other OAEs could also take time and may be linked to an accumulation of microfilariae in the body. However, the exact pathomechanism remains unclear. Indeed, pathological studies of children who died during NS revealed evidence of a degenerative process, so that a connection with a previous direct brain infection without CSF evidence [22] is rather unlikely. An immunological indirect relationship, however, may be possible, as has been discussed for cross-reacting leiomodin antibodies between O. volvulus and neuronal structures, although the results here are also contradictory [23‒25].

In addition to the infectious pathway, other factors should be considered and further investigated in the occurrence of NS and OAE, such as food shortages or, more generally, nutritional status [1, 26]. Indeed, previous results reported that certain foods were associated with the occurrence of NS [12, 27‒29]. A very recent study looking at the long-term clinical evolution and treatment results of people with NS in Mahenge, Tanzania, revealed that food shortages have consistently been present in the history of people with NS, and that affected individuals often present a certain degree of undernourishment [26]. Furthermore, the study by Gazda and Kitara in 2018 reported that a combined treatment based on a high-quality, regular, local diet, anti-seizure medication, and regular monitoring could reduce or completely stop epileptic seizures in children suffering from NS [30].

To date, there are no biological or pathophysiological arguments to support the claim that O. volvulus is the cause of NS or other OAEs. However, there seems to be a rather robust epidemiological association between onchocerciasis and NS and other OAEs. We put forward some hypotheses which could explain the association between onchocerciasis in the occurrence of NS and other OAE:

  • 1.

    Onchocerciasis could be associated with the causal pathway of another as yet unknown infectious agent or other causative factor.

  • 2.

    Onchocerciasis could share the same environmental niche and risk factors as another agent which so far has not been researched.

  • 3.

    NS/OAE is the result of an accumulation of several risks that are not necessarily known (including genetic, parasitic, environmental, and dietary risk factors).

  • 4.

    NS/OAE could be the cause of immunological factors that so far have not been identified or at least not consistently proven to be related with NS as is the case with leiomodin antibodies.

There is therefore a need for further research into NS/OAE to try to explain the role of onchocerciasis, avoiding bias or claims that onchocerciasis is “the cause of NS”. Finally, as mentioned in our review [1], particular care must be taken when using the term OAE, as many other risk factors for epilepsy such as perinatal asphyxia, road traffic accidents, malaria and other parasitic diseases can be the underlying cause for epilepsy independently of the presence of O. volvulus. In recent literature, this point of view is well defended with various arguments [31].

The authors have no conflicts of interest to declare.

This study was not supported by any sponsor or funder.

S.M.: drafting the work. A.S.W.: reviewing it critically for important intellectual content. S.M. and A.S.W.: final approval of the version to be published and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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