Childhood epilepsy disorders are particular frequent in low income countries and especially common in the area around Mahenge, Ulanga region, southern Tanzania, with an epilepsy prevalence of up to 39 per 1000 inhabitants. Therefore, in 1959 Prof. Louise Jilek-Aall founded the Mahenge Epilepsy Clinic to provide basic care to people suffering from convulsive disorders and to enable further in-depth investigations regarding epilepsy. In the summer of 2005, a multinational a team of researchers including the founder of the clinic, Prof. Louise Jilek-Aall, Prof. Erich Schmutzhard, Dr. Andrea Winkler and Prof. William Matuja performed several in-depth etiological investigations. In intensive field research they were able to examine a large number of clinic patients and healthy controls, perform electro-encephalographic and magnetic resonance studies and collect biological materials, such as blood, cerebrospinal fluid (CSF) and skin samples for further sophisticated laboratory tests in Europe. Among others, the studies confirmed the presence of a new type of childhood epilepsy with repetitive head nodding episodes and often progressive cognitive dysfunction. Even though the disease termed Nodding Syndrome (NS) affects thousands in Tanzania, Uganda and South-Sudan, clinical, metabolic and EEG phenotypes are still imprecisely described, and etiology and pathogenesis remain obscure. The high familial occurrence and clustering within circumscribed villages and tribes suggests that genetic traits might play a role. Epidemiological associations with Onchocerca volvulus and Mansonella spp. were noted at different African sites. Despite lacking evidence for the presence of O. volvulus in the CSF the association to NS remains robust.

This is basis for the present study where the investigators aim to examine if and how O. volvulus and/or Mansonella spp. contribute to the pathology of NS, elucidate associated genetic traits, further specify the clinical, metabolic and EEG phenotypes. The investigators will use a cross-sectional observational design including children with NS and epilepsy in order to describe the clinical characteristics and a case-control design to evaluate associated factors.

It is intended to enroll 250 patients and controls between 3 and 18 years of age (I: people with NS, n=50 (inclusion according to the WHO case definition from the first "International Conference on Nodding Syndrome", Kampala, Uganda, July 2012); II: people with epilepsy (PWE) and onchocerciasis, n=50; III: PWE without onchocerciasis, n=50; IV: controls with onchocerciasis but otherwise healthy, n= 50; healthy controls without evidence for onchocerciasis, n= 50). Patients with cardiovascular or renal comorbidities, a history of birth or traumatic brain injuries, lacking or withdrawing consent will be excluded. Groups II to V will be matched to Group I for age, gender and social status.

The investigators intend to analyze the filarial infection and host immune response in affected children compared to unaffected controls. PCR assays will be performed to characterize Onchocerca and Mansonella spp. strains found in patients with NS/PWE and determine Wolbachia loads and features. A novel unique biomarker, N-acetyltyramine-O,ß-glucuronide (NATOG) will be determined to quantify infection with O. volvulus and correlated with other markers that define the host immune response and immune regulation (e.g. regulatory T cells (Treg), cytokines). As polymorphisms in the multidrug-resistance gene 1 (MDR-1) that alter p-glycoprotein expression or function may enhance neurotoxicity of widely used antihelmintic drugs, single nucleotide polymorphism (SNP)-arrays will be determined to investigate if specific polymorphisms might be associated with NS. In addition, the investigators aim to define the clinical picture and course of NS and conduct further EEG investigations and validated neuropsychological tests, follow up patients of previous studies and perform metabolic analyses to specify the metabolic characteristics of NS. A genetic workup that includes whole-exome sequencing (WES) to identify traits predisposing to epilepsy, NS or specific immune responses is scheduled.

In summary, the study aims to elucidate factors that contribute to the high prevalence of NS and epilepsy in the Mahenge area in Southern Tanzania. Also, the research project will have immediate benefits for the population under investigation as people newly diagnosed with epilepsy will be offered treatment at the Mahenge Epilepsy Clinic and staff, patients and relatives will receive further education regarding epilepsy, thereby contributing to sustainability of a standardized approach to care for children with NS and PWE. Conclusions drawn from our study will not only relate to the Mahenge area, but may be applicable to vast numbers of children with NS (northern Uganda and South Sudan) and PWE in other areas. Dissemination of the data through scientific meetings and publications may stimulate further research regarding risk factors for epilepsy in the low income countries.