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After observations in vietnam and thailand that a discrete neurologic syndrome could follow recovery from falciparum malaria, a prospective study was conducted over four years at the Centre for Tropical Diseases, Ho Chi Minh City, Vietnam, to determine risks for post-malaria neurological syndrome (PMNS). Criteria for inclusion consisted of patients with recent symptomatic malaria infection with parasite clearance and clinical recovery who then developed psychiatric or acute neurologic symptoms within two months. Reinfection or relapse with malaria as well as infection with other agents was ruled out as an etiology for neurologic symptoms.
During the four-year study period, 16,970 patients with uncomplicated falciparum malaria and 1065 patient with severe malaria were enrolled. Twenty-two of these patients (19 adults and 3 children) were diagnosed subsequently as having PMNS, an incidence of 1.2 per 1000 malaria cases overall (95% CI 0.7-1.8 per 1000). Twenty-one of these 22 cases followed severe malaria, an estimated incidence after severe malaria of 18.7 (95% CI 11.5-28.8 per 1000). Clinical features of PMNS included acute confusional states, generalized convulsions, and acute psychosis. Visual hallucinations, classic catatonia, and acute mania were described. At the time of PMNS diagnosis, all patients were aparasitemic; nine patients had fever without any signs of systemic illness. The syndrome was self-limiting, with a median duration of 60 hours (range, 24-240 hours). PMNS was strongly associated with the use of oral mefloquine administered after a randomized trial of intramuscular artemether or quinine. In this randomized trial, 10 of 228 patients with severe malaria who received mefloquine developed PMNS vs. one of 210 who were randomized to receive oral quinine and Fansidar (relative risk, 9.2; 95% CI 1.2-71.3; P = 0.012).
Although the manifestations of PMNS in this series are diverse, no specific predisposing factors other than mefloquine treatment and the severity of the falciparum malaria were identified. Most patients who developed PMNS in this trial did so while in the hospital, as this prospective study was conducted within a large study recently reported describing the efficacy of artemether vs. quinine for severe falciparum malaria.1 Repeat malaria smears were performed, and infection with other endemic viruses such as Japanese encephalitis or dengue were excluded. No relation to preceding treatment with artemether or quinine was determined for PMNS; (a distinct issue since artemether was associated with prolonged coma in the larger study reported). Patients were randomized to receive either an oral regimen of single-dose mefloquine or oral quinine and Fansidar to finish their therapy. Mefloquine levels were not excessive with the single dose of mefloquine (15 mg of base per kg) administered. The authors raise the question of an immunological mechanism for PMNS, as over half the patients were febrile but had no evidence of infection. At lumbar puncture, most had a CSF lymphocyte pleocytosis and elevated protein. The relative risk of developing PMNS if mefloquine is used after treatment with quinine or artemether is unacceptable and should probably make one choose another oral regimen to finish therapy for severe malaria. One must note, however, that five patients who never received any mefloquine developed PMNS in this study.
Neurological sequelae following cerebral malaria can happen but are uncommon (estimated at 10% of children and 1-3% of adults).2 Hypoglycemia resulting from malaria and quinine treatment can also cause permanent brain damage.3 Psychosis and a delayed cerebellar syndrome following falciparum malaria have also been described without implicating drug therapy.4,5 Yet the association between treatment with mefloquine and the development of PMNS in patients with severe malaria in this report indicated synergistic neurotoxicity between the drug and the severity of disease independent of antecedent clinical features or other drug treatment. The good news is that PMNS appears to happen rapidly, is relatively uncommon, and is self-limiting without serious sequelae. Further immunopathologic studies and confirmatory studies with larger numbers of PMNS study cases are needed.
1. Hien TT, et al. A controlled trial of quinine or artemether in Vietnamese adults with severe falciparum malaria. N Engl J Med 1996;335:76-83.
2. Brewster D, et al. Neurological sequelae of cerebral malaria in children. Lancet 1990;336:1039-1043.
3. White NJ, et al. Hypoglycaemia in African children with severe malaria. Lancet 1987;i:708-711.
4. Sowunmi A. Psychosis after cerebral malaria in children. J Natl Med Assoc 1993;85:695-696.
5. Silva HJD. Delayed cerebellar ataxia following falciparum malaria: Lack of evidence for antibody mediation. Trans R Soc Top Med Hyg 1992;86:608.