Understanding artemisinin-induced brainstem neurotoxicity

Artemisinins are fast-acting and highly efficacious antimalarials. There has been a rapid increase in their use in response to increasing drug resistance and further increases in their use are anticipated as they continue to replace existing therapies. In laboratory studies, artemisinins can produce relatively specific brainstem neurotoxicity. Select nuclei in the medulla, pons and mesencephalon are usually found to be most vulnerable. Species-specific differences in the vulnerability of nuclei may also exist. While not yet completely understood, occurrence of the lesion seems to be dependent upon a sustained, rather than peak, level of circulating drug or metabolite. With daily administrations, the onset of signs of brainstem neurotoxicity frequently develops abruptly and sometimes is observable only at the end of, or after, a regimen of administration. Behavioral correlates of brainstem neurotoxicity in laboratory animals include ataxic symptoms such as tremor, gait impairment and balance disturbance. Symptoms may also include auditory impairment. Screening and diagnostic procedures to guard against artemisinin-induced brainstem neurotoxicity in humans need to be based on the available, albeit limited, data from laboratory studies. Substantial and fundamental gaps in our understanding of artemisinin brainstem neurotoxicity exist including the mode of action of neurotoxicity and the specific conditions under which it occurs. Further, the possibility of increased vulnerability from age-related factors, drug interactions and cumulative administration regimens has not yet been investigated. Substantial progress addressing these issues is needed to maintain appropriate pharmacovigilance as the use of these powerful and life-saving antimalarials increases.