Correspondence

Central Anticholinergic Syndrome with the Antimalarial Drug Mefloquine

N Engl J Med 1994; 331:57-58July 7, 1994

Article

To the Editor:

The neuropsychiatric side effects of the antimalarial drug mefloquine are well documented1,2. They include anxiety, depression, hallucinations, acute psychosis, and seizures. The incidence of these side effects is 1 in 13,000 with prophylactic use and 1 in 250 with therapeutic use2. The mechanism of action is unknown1.

A 47-year-old, previously healthy Japanese tourist was admitted to our hospital because of severe falciparum malaria with parasitemia of 24 percent after a trip to Zaire without any antimalarial chemoprophylaxis. Treatment consisted of 750 mg of quinine per day and 450 mg of clindamycin three times daily for five days. Blood glucose and serum quinine levels were closely monitored. The initial course was uneventful. The parasitemia cleared within five days. The patient was fully alert and busily writing letters. On the sixth day, he received 750 mg of mefloquine, followed by 500 mg and 250 mg after 6 and 12 hours, respectively. Within a few hours after the last dose, a severe neurologic syndrome developed, with agitation, progressive delirium, and generalized rigors. Because of repeated aspiration, he was intubated and mechanically ventilated. Flumazenil in a cumulative dose of 1.5 mg had no effect on the patient's neurologic state. After five days of mechanical ventilation, a central anticholinergic syndrome was suspected because of the persistence of stupor and rigors together with mydriasis and hyperpyrexia up to 38.9 °C. Two milligrams of physostigmine was given intravenously. The patient immediately became alert and fully oriented. Rigors and hyperpyrexia disappeared, and he was successfully extubated just one hour later. No neurologic disturbances were observed during the following weeks.

The close temporal correlation between the administration of mefloquine and the occurrence of the neurologic disorder and its prompt disappearance after the administration of physostigmine suggest that the side effects were due to a central anticholinergic syndrome3. Although the patient received other drugs acting on the central nervous system, their use did not correlate with the clinical course. These other drugs included a single 2.5-mg dose of morphine and several 5-mg doses of metoclopramide, which had been given two days before the occurrence of delirium, and midazolam, given for sedation during ventilation. All three drugs were given again, without any side effects, after the patient had undergone a full neurologic recovery. A single 15-mg dose of levopromazine was administered two days after the onset of the neurologic disturbances. A rechallenge with mefloquine was thought to be inappropriate.

In conclusion, we believe that this prolonged neurologic syndrome in our patient was induced by mefloquine and that it was probably due to a central anticholinergic syndrome. The long duration of the syndrome can readily be explained by the half-life of mefloquine, which is 15 to 30 days4. A trial with physostigmine should be considered in patients with severe mefloquine-induced neuropsychiatric side effects.

Rudolf Speich, M.D.
Alois Haller, M.D.
University Hospital of Zurich, CH-8091 Zurich, Switzerland

4 References

1. 1

   Patchen LC, Campbell CC, Williams SB. Neurologic reactions after a therapeutic dose of mefloquine. N Engl J Med 1989;321:1415-1416
   Full Text | Web of Science | Medline

2. 2

   Weinke T, Trautmann M, Held T, et al. Neuropsychiatric side effects after the use of mefloquine. Am J Trop Med Hyg 1991;45:86-91
   Web of Science | Medline

3. 3

   Duvoisin RC, Katz R. Reversal of central anticholinergic syndrome in man by physostigmine. JAMA 1968;206:1963-1965
   CrossRef | Web of Science | Medline

4. 4

   Mimica I, Fry W, Eckert G, Schwartz DE. Multiple-dose kinetic study of mefloquine in healthy male volunteers. Chemotherapy 1983;29:184-187
   CrossRef | Web of Science | Medline

Citing Articles (14)

Citing Articles

1. 1

   Alan L. Peterson, Robert A. Seegmiller, Libby S. Schindler. (2011) Severe Neuropsychiatric Reaction in a Deployed Military Member after Prophylactic Mefloquine. Case Reports in Psychiatry 2011, 1-4
   CrossRef

2. 2

   Stephen Toovey. (2009) Mefloquine neurotoxicity: A literature review. Travel Medicine and Infectious Disease 7:1, 2-6
   CrossRef

3. 3

   Franco Giovanetti. (2007) Travel medicine interventions and neurological disease. Travel Medicine and Infectious Disease 5:1, 7-17
   CrossRef

4. 4

   2006. Mefloquine. , 2232-2238.
   CrossRef

5. 5

   Douglas V. Brown, Floyd Heller, Robert Barkin. (2004) Anticholinergic Syndrome After Anesthesia: A Case Report and Review. American Journal of Therapeutics 11:2, 144-153
   CrossRef

6. 6

   O. Kukoyi. (2003) Curses, Madness, and Mefloquine. Psychosomatics 44:4, 339-341
   CrossRef

7. 7

   Philip R. Fischer, Eric Walker. (2002) Myasthenia and Malaria Medicines. Journal of Travel Medicine 9:5, 267-268
   CrossRef

8. 8

   Chukwuemeka S. Okereke. (1999) Management of HIV-infected pregnant patients in malaria-endemic areas: Therapeutic and safety considerations in concomitant use of antiretroviral and antimalarial agents. Clinical Therapeutics 21:9, 1456-1496
   CrossRef

9. 9

   ANTHONY T. DUGBARTEY, MARGARET T. DUGBARTEY, MATTHEW Y. APEDO. (1998) Delayed Neuropsychiatric Effects of Malaria in Ghana. The Journal of Nervous &amp Mental Disease 186:3, 183-186
   CrossRef

10. 10

    A. M. Ronn, J. Ronne-Rasmussen, P. C. Gotzsche, I. C. Bygbjerg. (1998) Neuropsychiatric manifestations after mefloquine therapy for Plasmodium falciparum malaria: comparing a retrospective and a prospective study. Tropical Medicine and International Health 3:2, 83-88
    CrossRef

11. 11

    J. Link, G. Papadopoulos, D. Dopjans, I. Guggenmoos-Holzmann, K. Eyrich. (1997) Distinct central anticholinergic syndrome following general anaesthesia. European Journal of Anaesthesiology 14:1, 15-23
    CrossRef

12. 12

    Nguyen Thi Hoang Mai, Nicholas PJ Day, Ly Van Chuong, Deborah Waller, Nguyen Hoan Phu, Delia B Bethell, Tran Tinh Hien, Nicholas J White. (1996) Post-malaria neurological syndrome. The Lancet 348:9032, 917-921
    CrossRef

13. 13

    J. Link. (1996) After Transdermal Fentanyl. Anesthesiology 85:2, 436
    CrossRef

14. 14

    &NA;. (1994) Mefloquine. Reactions Weekly &NA;:510, 8
    CrossRef