Inflammatory marker profiles and seizure control in children with Nodding syndrome on antiepileptic drug therapy

Abstract

Background Nodding syndrome (NS) is a neurological disorder afflicting patients in Africa. The disease progresses from a prodromal stage to head nodding (its distinctive feature). Thereafter, convulsive seizures, worsening cognitive, psychiatric, nutritional, growth and physical decline ensure. Despite antiepileptic therapy, many individuals continue to experience seizures. It is unclear why seizure resolution is achieved in only a fraction of patients. This study hypothesized that in patients with NS, 1) poor seizure control is associated with elevated levels of inflammatory markers in cerebrospinal fluid (CSF) and plasma; 2) such high levels are possibly induced by infection by Onchocerca volvulus or another unknown contagion. The objective of the study was to determine the relationship between levels of plasma and CSF inflammatory markers and seizure control in NS patients receiving anti-epileptic drug therapy. Methods This was a case-control study nested within a larger cohort evaluating the pathogenesis and treatment of nodding syndrome in Kitgum district, Uganda. Participants were children (>8 years) with NS as defined by WHO receiving Sodium valproate as anti-epileptic therapy. A full clinical history and physical examination including the number of seizures in the past month was documented. Blood and CSF were collected from all participants. CSF and plasma levels of inflammatory markers were determined using a customized multiplex magnetic microsphere immunoassay and a commercial ELISA kit. In a proportion of patients, mass spectrometry was used to examine CSF for the presence of any contagion proteins. Results A total of 240 participants were recruited. The mean age was 15.6(SD 2.0) years and 138/240 (57.5%) were male. Overall, 101(42.1%) had good seizure control. In CSF, levels of C-Reactive protein were significantly higher and of A proliferation-inducing ligand (APRIL) lower in patients with poor seizure control vs those with good seizure control. Similarly, in plasma, the concentrations of both IL-6 and CRP were significantly higher in children with poor seizure control compared to those with good control. There was a linear correlation between the number of seizures in the past month and the concentrations of CRP (r = 0.12, p-value=0.04) in CSF. In Plasma both CRP (r =0.16, p-value =0.013) and IL-6 (r =0.16, p-value =0.012) also showed a positive correlation with the number of seizures. Nine peptides of O.volvulus and a comparatively xii lower abundance of 8 Trypanosoma like peptides were identified in 29 CSF samples tested by mass spectrometry. Conclusion The study suggests that in patients with NS, poor seizure control may be associated with a dysregulation in inflammatory processes, particularly CRP. Further, the presence of O.volvulus and T.brucei proteins in CSF suggest that these parasites may be involved in the causation of NS. If these findings are replicated in larger prospective studies, incident cases of NS may possibly benefit from specific anti-parasitic treatment and immunomodulatory therapies.