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The tau hypothesis is that the cause of NS is unknown but that the pathophysiology of the disease results in tau pathology, which explains the seizures and other clinical hallmarks of NS. Nodding syndrome (NS) was first described in the Mahenge mountains in Tanzania, where it exists in an endemic form of epilepsy [[1]]. More specifically, the presence of tau pathology in NS does not exclude OV as a cofactor in NS. The OV hypothesis suggests that OV somehow causes seizures, and the seizures secondarily result in tau deposition in the brain (Fig 1B). [Extracted from the article]

Previous studies have described the association of onchocerciasis (caused by Onchocerca volvulus) with epilepsy, including nodding syndrome, although a clear etiological link is still missing. Cases are found in different African countries (Tanzania, South Sudan, Uganda, Democratic Republic of the Congo, Central African Republic and Cameroon). In our study we investigated immunological parameters (cytokine, chemokine, immunoglobulin levels) in individuals from the Mahenge area, Tanzania, presenting with either epilepsy or nodding syndrome with or without O. volvulus infection and compared them to O. volvulus negative individuals from the same endemic area lacking neurological disorders. Additionally, cell differentiation was performed using blood smears and systemic levels of neurodegeneration markers, leiomodin-1 and N-acetyltyramine-O, β-glucuronide (NATOG) were determined. Our findings revealed that cytokines, most chemokines and neurodegeneration markers were comparable between both groups presenting with epilepsy or nodding syndrome. However, we observed elevated eosinophil percentages within the O. volvulus positive epilepsy/nodding syndrome patients accompanied with increased eosinophilic cationic protein (ECP) and antigen-specific IgG levels in comparison to those without an O. volvulus infection. Furthermore, highest levels of NATOG were found in O. volvulus positive nodding syndrome patients. These findings highlight that the detection of distinct biomarkers might be useful for a differential diagnosis of epilepsy and nodding syndrome in O. volvulus endemic areas. Trial-registration:NCT03653975. Author summary: A lot of epidemiological studies suggest that an infection with the filarial nematode Onchocerca volvulus is a risk factor for a certain form of epilepsy which includes the nodding syndrome. The seizures occur suddenly in previously healthy children between the ages of 3 and 18 years and the disease is an important public health problem in onchocerciasis-endemic regions with inadequate or lacking onchocerciasis elimination programmes. So far, no exact pathophysiological mechanisms were detected that shed light on how the parasite can trigger the seizures, although many factors have been investigated. However, most studies lack an accurate determination of an active/chronic O. volvulus infection; rather, they rely on the presence of circulating antibodies, which is only evidence of previous exposure to the parasite (and therefore positive in most people living in endemic areas. Within our study, we included participants from the Mahenge area, Tanzania, who were displaying epilepsy/nodding syndrome in absence or presence of a PCR-determined O. volvulus infection. We could show that the group of O. volvulus infected patients displayed higher levels of eosinophils, antigen-specific immunoglobulin levels as well as increased levels of a worm-related metabolic product (NATOG), which might be used as a potential diagnostic biomarker of the disease in future studies. [ABSTRACT FROM AUTHOR]

Background: Nodding syndrome (NS) has been consistently associated with onchocerciasis. Nevertheless, a positive association between NS and a Mansonella perstans infection was found in South Sudan. We aimed to determine whether the latter parasite could be a risk factor for NS in Mahenge. Methods: Cases of epilepsy were identified in villages affected by NS in Mahenge, Tanzania, and matched with controls without epilepsy of the same sex, age and village. We examined blood films of cases and controls to identify M. perstans infections. The participants were also asked for sociodemographic and epilepsy information, examined for palpable onchocercal nodules and onchocerciasis-related skin lesions and tested for anti-Onchocerca volvulus antibodies (Ov16 IgG4) by ELISA. Clinical characteristics of cases and controls, O. volvulus exposure status and relevant sociodemographic variables were assessed by a conditional logistic regression model for NS and epilepsy status matched for age, sex and village. Results: A total of 113 epilepsy cases and 132 controls were enrolled, of which, respectively, 56 (49.6%) and 64 (48.5%) were men. The median age in cases and controls was 28.0 (IQR: 22.0–35.0) and 27.0 (IQR: 21.0–33.3) years. Of the persons with epilepsy, 43 (38.1%) met the probable NS criteria and 106 (93.8%) had onchocerciasis-associated epilepsy (OAE). M. perstans infection was absent in all participants, while Ov16 seroprevalence was positively associated with probable NS (odds ratio (OR): 5.05, 95%CI: 1.79–14.27) and overall epilepsy (OR: 2.03, 95%CI: 1–07–3.86). Moreover, onchocerciasis-related skin manifestations were only found in the cases (n = 7, p = 0.0040), including persons with probable NS (n = 4, p = 0.0033). Residing longer in the village and having a family history of seizures were positively correlated with Ov16 status and made persons at higher odds for epilepsy, including probable NS. Conclusion: In contrast to O. volvulus, M. perstans is most likely not endemic to Mahenge and, therefore, cannot be a co-factor for NS in the area. Hence, this filaria is unlikely to be the primary and sole causal factor in the development of NS. The main risk factor for NS remains onchocerciasis. Author summary: Nodding syndrome (NS) is a rare and severe form of epilepsy that mainly affects children. The syndrome has only been found in onchocerciasis-endemic areas, and epidemiological studies suggest that it may be one of the forms of onchocerciasis-associated epilepsy caused by the parasite Onchocerca volvulus. Nevertheless, other causes have been considered, such as an infection with Mansonella perstans. To identify a main causal factor for NS, it needs to be present in all sites where the syndrome is found. Hence, our team explored 113 people with epilepsy and 132 healthy controls in Mahenge, Tanzania, to determine if M. perstans could be behind the epidemic of NS in the area. Over a third of the epilepsy cases in the study met the criteria for probable NS. None of the participants was diagnosed with an M. perstans infection. However, those exposed to onchocerciasis and with onchocerciasis-associated skin lesions were more likely to have epilepsy, including probable NS. In conclusion, onchocerciasis remains the most likely main risk factor for NS. [ABSTRACT FROM AUTHOR]

Background: Nodding syndrome (NS) is a progressive neurological disease that has been described in several sub-Saharan African counties, but South Sudan is considered the most affected. However, knowledge about the exact burden and the epidemiological risk factors of NS in South Sudan is lacking. Objective: To determine the prevalence, distribution and epidemiological risk factors of NS in the Greater Mundri area, the epicenter of NS in South Sudan. Methods: A NS prevalence house-to-house survey was conducted in multiple villages between February 2018 and November 2019. Geographical distribution and clustering of NS cases was identified using spatial and binomial regression analysis. Epidemiological risk factors of NS were identified using univariate and multivariate models. Results: Of the 22,411 persons surveyed in 92 villages, 607 (2.7%) persons with NS were identified, of which 114 (19%) were new-onset cases. The highest prevalence was found in Diko village with a prevalence of 13.7%. NS showed a significant spatial pattern with clustering of cases between adjacent households and along rivers. Risks factors for NS include all behaviors around rivers (drinking, cooking, handwashing and bathing) and exposure to poultry. On the other hand, ownership of mobile phone decreased the risk of NS. Many other factors, including prior ivermectin treatment and internal displacement were not associated with NS. Conclusion: Our study demonstrates a very high burden of the NS disease in the Greater Mundri area, strengthens the association with rivers, and identified possible new clues for an underlying cause. Author summary: Nodding syndrome (NS) is a neglected and progressive neurological disorder that is disabling and of unknown cause. The Greater Mundri area in South Sudan is currently considered to be the epicenter of new cases. In this study, we evaluated the prevalence, spatial pattern and epidemiological risks of NS. We found that the prevalence of NS is very high–more than one in five households affected–in the Greater Mundri area, which is comparable with the previously reported rates within smaller populations in the same area, but higher than the rates reported in all the other NS-endemic countries. We found that NS cases significantly cluster between adjacent households but we could not find clustering within the same household. In addition, we prove that living near the rivers, as well as using river water for drinking, cooking, handwashing and bathing strongly increased the risk of having a NS case in households. We further identified a new association of NS with ownership of poultry. [ABSTRACT FROM AUTHOR]