Correspondence
Artesunate and Cerebellar Dysfunction in Falciparum Malaria
N Engl J Med 1997; 337:792-793September 11, 1997
- Article
To the Editor:
Miller and Panosian (May 1 issue)1 report an association between artesunate and a post-treatment cerebellar syndrome in falciparum malaria. As they state, no overt neurotoxicity has been reported in over a million patients with malaria who were treated with artemisinin derivatives. We treated two patients who had undergone splenectomy with prolonged courses of artesunate, artemisinin, or both to achieve parasite clearance (total doses, 165 mg per kilogram of body weight and 46 mg per kilogram over periods of 12 and 11 days, respectively), without neurotoxicity in either.2 Postmortem examination of the brain stem from another patient with complicated malaria treated with quinine and single-dose artesunate showed no abnormalities.3
Differentiation between the delayed neurologic effects of malaria and the effects of its treatment can be difficult. Although Miller and Panosian maintain that cerebellar dysfunction is highly unusual in malaria, their patient's features and the time course (acute onset after treatment and resolution over a period of months) are consistent with those in a large series of chloroquine-treated Sri Lankan patients.4 The findings of more frequent seizures and longer coma during artemether therapy than during quinine treatment in Gambian children5 bear an uncertain relation to their case.
Given the potential importance of artemisinin-related neurotoxicity, it would be vital to establish as far as possible whether the patient actually took artesunate,6 other medications, or alcohol and other recreational drugs. Knowledge of his vitamin B12 status and serologic studies for syphilis would have complemented the neuroimaging and cerebrospinal fluid analysis performed a month after symptoms started. Even if attributable to artemisinin, neurotoxicity in this case would appear to be a rare and reversible adverse effect of a valuable and increasingly used group of antimalarial drugs.
6 ReferencesTimothy M.E. Davis, M.D.
University of Western Australia, Fremantle 6160, WA, AustraliaGeoffrey O. Edwards, Ph.D.
University of Liverpool, Liverpool L69 3GE, United KingdomJames S. McCarthy, M.D.
University of Western Australia, Fremantle 6160, WA, Australia1
Miller LG ,Panosian CB . Ataxia and slurred speech after artesunate treatment for falciparum malaria. N Engl J Med 1997;336:1328-1328
Full Text | Web of Science | Medline2
Thu LTA, Davis TME, Binh TQ, et al. Delayed parasite clearance in a splenectomized patient with falciparum malaria treated with artemisinin derivatives. Clin Infect Dis (in press).
3
Davis TM ,Breheny FX ,Kendall PA , et al. Severe falciparum malaria with hyperparasitaemia treated with intravenous artesunate. Med J Aust 1997;166:416-418
Web of Science | Medline4
Senanayake N ,de Silva HJ . Delayed cerebellar ataxia complicating falciparum malaria: a clinical study of 74 patients. J Neurol 1994;241:456-459
CrossRef | Web of Science | Medline5
van Hensbroek MB ,Onyiorah E ,Jaffar S , et al. A trial of artemether or quinine in children with cerebral malaria. N Engl J Med 1996;335:69-75
Full Text | Web of Science | Medline6
Land T . Combating counterfeit drugs. Nature 1992;355:192-192
Web of Science | Medline
To the Editor:
Miller and Panosian report a well-documented case of neurotoxicity due to artesunate. The neurotoxicity of artesunate and related compounds, artemether and arteether, is becoming a major concern. Artemisinin derivatives have followed an unorthodox path of drug development. More than 2 million patients with malaria have been treated with these drugs, although preclinical and pharmacologic studies did not meet the requirements of Western and international drug-regulating agencies.1
The neurotoxicity of artemisinin derivatives has been clearly demonstrated in vivo in dogs and rats and, very recently, in monkeys and appears to be dose-dependent, involving the caudal brain stem in animal models.1-3 Moreover, brain-stem histologic changes have been seen in rats in the absence of neurologic signs or deficits in behavioral performance.1 As in monkeys,3 neurologic dysfunction occurred too late to be a useful indicator of neurotoxicity. Toxicity has been confirmed in vitro in both neuroblastoma cell lines and primary cultures of fetal-rat neuronal cells.1,2,4 The mechanism of neurotoxicity of artemisinin derivatives is similar in many respects to the mechanism of antimalarial action: the cleavage of the endoperoxide bridge of these sesquiterpene lactones is catalyzed by complexes of iron or protein-bound iron and generates free-radical intermediates that cause oxidative damage to neuronal cells.1,2,4
Despite all the experimental data, there is limited evidence of neurotoxicity of artemisinin compounds in humans. In addition to the Gambian study cited by Miller and Panosian,5 another large trial published in the same issue of the Journal suggested the occurrence of reversible neurotoxicity in Vietnamese patients with severe malaria treated with artemether.6 The possibility that repeated administration of artemisinin compounds will result in cumulative neurologic damage cannot be ruled out. This is most likely to occur in persons living in areas in which the disease is endemic, who require several courses of antimalarial drugs each year. Had the patient described by Miller and Panosian previously received any artemisinin derivative?
Until we know more about the toxicity of these antimalarial drugs, we believe that their use must be restricted to areas where quinine resistance is demonstrable and that repeated use should be avoided. The identification of the molecular mechanisms of neurotoxicity may lead to the synthesis of artemisinin analogues with better activity and less toxicity.
6 ReferencesBertrand Gachot, M.D., Ph.D.
Muriel Eliaszewicz, M.D.
Bertrand Dupont, M.D.
Hôpital de l'Institut Pasteur, 75724 Paris CEDEX 15, France1
Meshnick SR ,Taylor TE ,Kamchonwongpaisan S . Artemisinin and the antimalarial endoperoxides: from herbal remedy to targeted chemotherapy. Microbiol Rev 1996;60:301-315
Medline2
Kamchonwongpaisan S ,McKeever P ,Hossler P ,Ziffer H ,Meshnick SR . Artemisinin neurotoxicity: neuropathology in rats and mechanistic studies in vitro. Am J Trop Med Hyg 1997;56:7-12
Web of Science | Medline3
Petras JM ,Kyle DE ,Gettayacamin M , et al. Arteether: risks of two-week administration in Macaca mulatta. Am J Trop Med Hyg 1997;56:390-396
Web of Science | Medline4
Smith SL ,Fishwick J ,McLean WG ,Edwards G ,Ward SA . Enhanced in vitro neurotoxicity of artemisinin derivatives in the presence of haemin. Biochem Pharmacol 1997;53:5-10
CrossRef | Web of Science | Medline5
van Hensbroek MB ,Onyiorah E ,Jaffar S , et al. A trial of artemether or quinine in children with cerebral malaria. N Engl J Med 1996;335:69-75
Full Text | Web of Science | Medline6
Hien TT ,Day NPJ ,Phu NH , et al. A controlled trial of artemether or quinine in Vietnamese adults with severe falciparum malaria. N Engl J Med 1996;335:76-83
Full Text | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: Dr. Davis and colleagues question whether malaria itself, a second drug, or a coexisting medical condition, rather than artesunate, caused the acute neurologic illness in our patient. This seems unlikely, since he was a well-nourished, athletic 36-year-old man who drank only one to two beers daily, used no recreational or medicinal drugs (including malaria prophylaxis), and tested seronegative for human immunodeficiency virus, human T-cell lymphotropic virus type I, and syphilis. In addition, his symptoms began within 48 hours after he completed artesunate therapy and were severely disabling for several months. This clinical pattern is distinctly different from that described in Sri Lankan patients with delayed-onset postinfective cerebellar ataxia after falciparum malaria treated with chloroquine. In that report, the median interval between defervescence and neurologic symptoms was 13 days, and ataxia was maximal at 2 to 14 days.1
Gachot et al. review the mounting evidence of severe, dose-dependent brain-stem neurotoxicity in animals treated with artemisinin, which was most recently demonstrated in rhesus monkeys treated for 14 days with arteether.2 Before his acute illness, our patient had no known exposure to any artemisinin compound. However, we share the concern of Gachot et al. regarding repeated or empirical use of these drugs, since one new trend recently reported to us by American and European expatriates in Tanzania is recurrent, self-administered courses of empirical dihydroartemisinin for malaria-like illness. This practice should be strongly discouraged by physicians, because of both the potential neurotoxicity and the likelihood of recrudescent Plasmodium falciparum parasitemia after single-drug treatment with artemisinin agents.3
Given the increasing prevalence of multidrug-resistant falciparum malaria and artemisinin's increasing role in its treatment, additional clinical and pharmacologic research is urgently needed to establish a clear therapeutic index for every artemisinin derivative marketed for human use.
3 ReferencesLoren G. Miller, M.D.
Claire B. Panosian, M.D., D.T.M.&H.
UCLA Medical Center, Los Angeles, CA 900951
Senanayake N ,de Silva HJ . Delayed cerebellar ataxia complicating falciparum malaria: a clinical study of 74 patients. J Neurol 1994;241:456-459
CrossRef | Web of Science | Medline2
Petras JM ,Kyle DE ,Gettayacamin M , et al. Arteether: risks of two-week administration in Macaca mulatta. Am J Trop Med Hyg 1997;56:390-396
Web of Science | Medline3
de Vries PJ ,Dien TK . Clinical pharmacology and therapeutic potential of artemisinin and its derivatives in the treatment of malaria. Drugs 1996;52:818-836
CrossRef | Web of Science | Medline
- Citing Articles (6)
Citing Articles
1
Qigui Li, Mark Hickman. (2011) Toxicokinetic and toxicodynamic (TK/TD) evaluation to determine and predict the neurotoxicity of artemisinins. Toxicology 279:1-3, 1-9
CrossRef2
Raymond F. Genovese, Donald B. Newman. (2008) Understanding artemisinin-induced brainstem neurotoxicity. Archives of Toxicology 82:6, 379-385
CrossRef3
O.A. Busari, G. Oligbu. (2008) Chorea in a 29-year-old Nigerian following antimalarial treatment with artesunate. International Journal of Infectious Diseases 12:2, 221-223
CrossRef4
Toufigh Gordi, Eve-Irene Lepist. (2004) Artemisinin derivatives: toxic for laboratory animals, safe for humans?. Toxicology Letters 147:2, 99-107
CrossRef5
Paul N. Newton, Brian J. Angus, Wirongrong Chierakul, Arjen Dondorp, Ronatrai Ruangveerayuth, Kamolrat Silamut, Pramote Teerapong, Yupin Suputtamongkol, Sornchai Looareesuwan, Nicholas J. White. (2003) Randomized Comparison of Artesunate and Quinine in the Treatment of Severe Falciparum Malaria. Clinical Infectious Diseases 37:1, 7-16
CrossRef6
B. Kevin Park, Paul M. O’Neill, James L. Maggs, Munir Pirmohamed. (1998) Safety assessment of peroxide antimalarials: clinical and chemical perspectives. British Journal of Clinical Pharmacology 46:6, 521-529
CrossRef
