Neurotoxicity: The Risk of Malaria Misdiagnosed and Treated
Neurotoxicity: The Risk of Malaria Misdiagnosed and Treated
Abstract and Commentary
By Maria D. Mileno, MD
Director, Travel Medicine, The Miriam Hospital, Associate Professor of Medicine and Infectious Diseases, Director, International Travelers’ Clinic, Emory University School of Medicine
Dr. Mileno is a consultant for GlaxoSmithKline, and is involved in research with Merck.
Synopsis: Readers are alerted to a case report published in Clinical Infectious Diseases which illustrates the degree of potential toxicity that could occur with use of antimalarial medications. In this case the malaria was also misdiagnosed.
Source: Franco-Paredes C, et al. Neurotoxicity Due to Antimalarial Therapy Associated with Misdiagnosis of Malaria. Clin Infect Dis. 2005;40:1710-1711.
A 39-year-old man who traveled to sierra Leone presented with tremors, lack of coordination, poor concentration, and severe anxiety upon return to the United States. He received treatment for malaria while abroad that included artesunate therapy (5 10-day courses and one 10-day course of chloroquine) for treatment of 3 separate episodes of fever, chills, and malaise. However, he had been fully adherent to his malaria chemoprophylaxis with doxycycline.
His physical examination was significant for tremors, restlessness, hyperreflexia, and spasticity. Laboratory evaluation was normal, as were a chest radiograph and brain MRI. Immunofluorescent antibody testing for detection of antibodies to each human Plasmodium species showed antibody titers < 1:16, consistent with no previous malaria exposure.
Commentary
Fortunately, this patient's symptoms improved markedly after discontinuation of his antimalarial therapy. Fever in travelers to malaria-endemic regions should produce a high index of suspicion for malaria. Each of the 4 human Plasmodium species cause serious febrile illness, and P. falciparum is responsible for substantial mortality, primarily for infants and children in holoendemic regions of sub-Saharan Africa. There is a dictum in the field of infectious diseases that "the first 10 diagnostic possibilities for the cause of fever in a traveler are malaria until proven otherwise." In this case, multiple repeat courses of artemisinin derivatives were given to a patient who simply never had malaria!
Treatments given empirically to travelers who become ill when they are abroad can pose a serious threat to any traveler's well being. Trade in pharmaceutical agents is not always regulated, and there could be insufficient or inactive ingredients present in labeled products. Staff with little formal training may be responsible for taking care of patients. Safety and tolerability of the available antimalarials are outlined in Table 2, obtained from a recent review of antimalarial medications in the New England Journal of Medicine.2
The artemesinins are potent compounds derived from the Chinese wormwood plant Artemesia annua. They have rapid antiparasitic activity, and can reduce the malaria parasitemia burden 4-fold within each cycle. However, significant neurotoxicity had been documented in rats during early studies of these compounds.3 Currently, they are used widely in southeast Asia for malaria, given daily for 7 days. They have been combined with other agents as well. Artesunate-clindamycin therapy in 46 Gabonese children with uncomplicated malaria was found to be comparable to quinine-clindamycin in 48 Gabonese children treated for malaria, in the analysis of cure rates, safety, and tolerability.4 The only neuropsychiatric symptom noted was headache found in small numbers in both groups. Artesunate-clindamycin and other artemisinin-based combinations will likely achieve more use in those regions where the rate of malaria transmission is high. Interest in their approval for use in the United States is increasing. This study by Franco-Paredes and colleagues is an important observation that perhaps delineates some limits of artemisinin compounds and their potential to confer significant neurotoxicity during the management of malaria.
References
- Franco-Paredes C, et al. Neurotoxicity Due to Antimalarial Therapy Associated With Misdiagnosis of Malaria. Clin Infect Dis. 2005;40:1710-1711.
- Baird JK. Effectiveness of Antimalarial Drugs. N Engl J Med. 2005;352:1565-1577.
- Mileno MD. Artemisinin: An Alternative Malaria Therapy? Travel Medicine Advisor. Update 7:No. 3 (May/June) 21-23, 1997.
- Ramharter M, et al. Artesunate-Clindamycin Versus Quinine-Clindamycin in the Treatment of Plasmodium falciparum Malaria: A Randomized Controlled Trial. Clin Infect Dis. 2005;40:1777-1784.
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