Ivermectin Treatment in Patients With Onchocerciasis-associated Epilepsy: A Randomized Clinical Trial

Introduction

Many studies have reported an association between epilepsy, including nodding syndrome (NS), and onchocerciasis. A meta-analysis of African population-based surveys showed a variation in epilepsy prevalence consistent with onchocerciasis prevalence, with epilepsy prevalence being increased, on average, by 0.4% for each 10% increase in onchocerciasis prevalence. NS is an epileptic disorder occurring in children in onchocerciasis (river blindness) endemic regions, initially only observed in South Sudan, Uganda and Tanzania. NS occurs in previously health children, aged mainly between 5-18 years and is characterized by head-nodding, an atonic epileptic seizure. Individuals may also develop other types of seizures and stunted growth. NS should be considered part of a spectrum of onchocerciasis associated epileptic (OAE) disorders. We recently suggested that these epileptic disorders share etiological factors related to Onchocerca volvulus (OV) infection and therefore considered Ivermectin, used to treat Onchocerciasis, as a treatment option for OAE.

One dose of Ivermectin eliminates microfilariae very rapidly. A mathematical model predicted that microfilariaedermia would be reduced by half 24 h after the intake of Ivermectin. Therefore, if the microfilariae load plays an important role in causing OAE, it may be that Ivermectin also has a rapid effect on the frequency of seizures.

Ivermectin treatment may decrease seizure frequency in patients with OAE In a study in Kabarole district in Uganda in 1992, 34/91 (37%) patients reported some decrease in either the frequency or severity of seizures after one dose of Ivermectin (150 µg/kg). After being treated with Ivermectin, 13 (14%) individuals had no seizures for 3.7 months (on average). Seizures were unchanged in 51 (56%), and worsened in 6 (7%). In a recent trial in the DRC, comparing Moxidectin (an anti-OV experimental drug with a longer half-life than Ivermectin) with Ivermectin, 6 (80%) out of 7 OV infested patients with epilepsy became seizure free after treatment with Moxidectin or Ivermectin (the randomization code has not been broken yet). In one person seizure frequency was significantly reduced over the 18 month follow-up period. In this person, microfilariae remained present in skin snips, though at a lower level than before the onchocerciasis treatment. In all subjects who became seizure free, the skin snips too became microfilaria free.

To assess whether Ivermectin treatment may reduce the frequency of seizures and leads to seizure freedom, we intend to conduct a short proof of concept randomized clinical trial to compare immediate Ivermectin treatment with delayed (after 4 months) Ivermectin treatment in onchocerciasis infested persons with epilepsy. The primary outcome is seizure freedom at 4 months. Reducing the burden of epilepsy will have a major impact on quality of life and socio-economic status of families with affected members in Africa. If we are able to demonstrate an effect of Ivermectin on the frequency of seizures, this would be an extra argument that Onchocerciasis is causing epilepsy and that therefore we should increase our efforts to eliminate onchocerciasis.