Neurological Dysfunction Following Malaria: Disease- or Drug-Related?

SIR—The artemisinin derivatives are very important new antimalarial drugs, which are being used increasingly throughout the world. The possibility that these otherwise extremely well tolerated and highly effective drugs may damage the CNS is of great concern. Unfortunately, the case report by Elias et al. [1] contains unjustified speculation on this subject that may cause unnecessary alarm. The authors described a 55-year-old expatriate patient who was treated with an inadequate course (5 days) of artemether (parenteral? oral?) for acute falciparum malaria in Ghana and, when recrudescence of the infection occurred 3 weeks later, was again treated with artemether. He developed tremors of the hands and unsteadiness, neurological sequelae of acute malaria which are well described [2–5]. However, the authors chose to ascribe this to the artemether treatment rather than to the malaria and, as evidence to support their hypothesis, misquote a reference describing 74 patients with cerebellar dysfunction following malaria [6] (of whom none had received artemisinin derivatives and 11 had not received any antimalarial treatment at all). Some antimalarial drugs are potentially neurotoxic. Mefloquine is associated with a self-limiting syndrome characterized by psychosis or encephalopathy, with an incidence of ∼1 in 10,000 in healthy individuals, 1 in 200–1000 among people who have had uncomplicated malaria, and 1 in 20 among people who have had cerebral malaria [7]. Chloroquine may also (rarely) produce neuropsychiatric reactions. In contrast, large clinical trials that have involved 17000 patients, in which detailed neurological evaluations were performed, have failed to show any evidence of CNS dysfunction after treatment with artemisinin derivatives [8–10]. A variety of neurological deficits following acute falciparum malaria have been reported and are considered to be a result of the disease rather than the treatment. These are more common following cerebral malaria but may also occur after uncomplicated infections, as is likely in this case. Tremor has been described most commonly in adults, with an overall incidence ranging from !0.1% to 3% of all cases of acute falciparum malaria [1, 7]. Self-limiting tremor has been reported to occur before or after treatment with chloroquine, quinine, mefloquine, and (in this case) artemether, which suggests strongly that it is a result of the disease rather than its treatment. Different types of tremor have been observed: (1) as part of a Parkinsonian syndrome; (2) rarely, in association with the well-described delayed cerebellar ataxia that may follow acute falciparum malaria; and (3) sometimes in isolation. It is highly likely that the neurological abnormalities in this case resulted from malaria and not artemether. However, instead of discussing this probable explanation, Elias et al. have provided unjustified and misleading recommendations that would unnecessarily restrict the use of artemisinin derivatives for the treatment of malaria.