Aetiologies and therapies of nodding syndrome: a systematic review and meta-analysis

Abstract

# Background Nodding syndrome (NS) is a childhood epileptic disorder of unknown aetiology confined to parts of South Sudan, Uganda and the United Republic of Tanzania. Patients suffer from atonic seizures that result in characteristic head nodding, and may develop other neurological, endocrinological and psychiatric manifestations. The objective of this study was to adopt a non-judgemental approach to review the hypothesised aetiologies and therapeutic options available for NS. To explore the reported association between NS and *Onchocerca volvulus* (OV) a meta-analysis of the prevalence of OV among NS cases and controls was performed. # Methods Systematic searching of five electronic databases yielded 26 articles that addressed potential aetiologies of NS and 12 that explored the treatment of NS. # Results Nine articles contained data about the prevalence of OV in NS cases that was suitable for inclusion in the meta-analysis. Four broad aetiological themes were identified. 1) Nutritional associations included biomarkers of malnutrition and conflicting reports regarding the consumption of some foodstuffs. 2) Regional conflict and the associated psychological trauma have led to consideration of psychiatric aetiologies. 3) There is a strong epidemiological association between NS and *Onchocerca volvulus*. The meta-analysis in this study revealed that 68.0% (95% confidence interval (CI)=45.2-87.0) of 416 NS patients were OV+, compared to 46.6% (95% CI=16.4-78.1) of 321 controls. Heterogeneity among both cases (*I^2^*=95.5%, 95% CI=93.3-97.0) and controls (*I^2^*=97.1%, 95% CI=95.5-98.2) was high. The difference of 21.4% in OV prevalence between the pooled populations was significant (*P*\<0.0001). It is thought that NS represents a form of onchocerciasis-associated epilepsy, however there are also reported associations with *Mansonella pestans* and measles virus. 4) Autoantibodies against leiomodin-1 and the voltage-gated potassium channel have been associated with NS. Molecular mimicry between leiomodin-1 and *O. volvulus* tropomyosin is a recently suggested aetiology. Without a clear aetiology treatment is symptomatic and patients have been shown to improve with a combination of anti-epileptic medication and supportive therapy. # Conclusions The aetiology of NS remains unclear. The leading theory is that NS represents a form of onchocerciasis-associated epilepsy secondary to autoimmunity driven by molecular mimicry. Alternatively, it has been suggested that NS may represent a post-infectious sequelae of measles virus infection. However, each theory currently leaves some questions unanswered. It remains important to understand the aetiology of NS to better prevent or treat future outbreaks.