In this series from the London school of hygiene and Tropical Medicine, a retrospective survey of adverse effects in 1214 individuals on mefloquine chemoprophylaxis was compared to adverse effects in 1181 individuals on chemoprophylaxis with chloroquine/proguanil. Individuals accessing a well-respected pay-per-minute travel health line were retrospectively contact by mail questionnaire and asked to self-grade the severity of any of 12 specified adverse events on a scale from 1 to 4. The authors then contacted by telephone individuals stating neuropsychiatric adverse events of grade 3 (medical attention sought) or grade 4 (requiring hospital attention). Symptoms were subjectively rated using the authors’ own unvalidated criteria in a blinded fashion as to whether the adverse effects were "severely disabling" or not.
In the self-reporting questionnaires, no differences between the two groups occurred in the frequency of any adverse event (41.4% vs 40.6%) at any grade of severity, gastrointestinal side effects of grade 2 or more, of individuals stopping or changing their malaria chemoprophylaxis (5.8% vs 6.5%), or of individuals admitted to hospital (6/1214 vs 5/1181). Mefloquine users had significantly more (31/1214) grade 3 or 4 neuropsychiatric side effects such as anxiety, vivid dreams, headache, insomnia, or depression when compared to the chloroquine/proguanil users (12/1181).
In the authors’ subjective assessment of the 43 individuals self-reporting grade 3 or 4 neuropsychiatric side effects, it was concluded that these were "severely disabling" in nine mefloquine users (overall rate, 0.7%) and in one chloroquine/proguanil user (overall rate, 0.09%).
COMMENT BY DAVID O. FREEDMAN, MD
The controversy over the true incidence of neuropsychiatric side effects of mefloquine is one that just won’t go away. A class action lawsuit by more than 500 individuals in Britain claiming permanent neurological damage after mefloquine chemoprophylaxis and a great deal of hyperbole in the lay press worldwide have done much to intimidate patients prior to their arrival at our offices. Were mefloquine not unquestionably the only highly effective malarial chemoprophylactic drug left for many areas of the world, I have no doubt that the current hysteria would have been enough by now to force the drug onto the sidelines.
The lack of definitive data is due to the lack of large, well-designed prospective studies with proper control groups. The high quality studies to date, including a survey of more than 140,000 Swiss travelers (Lancet 1993;341:1299) and a review of the Peace Corps experience (Lancet 1993;341:848) have included appropriate comparison groups but have, like the present study, been completely retrospective and, thus, dependent on study subjects’ recollections. Perhaps more importantly has been a complete lack of agreement among investigators as to what constitutes a neuropsychiatric side effect and how to define and grade what are ultimately subjective complaints into categories such as disabling, severe, moderate, mild, or trivial. From the earlier studies, rates of overt psychosis or seizures of approximately one in 10,000 have been found.
For definition of the worst outcomes, the earlier studies have relied either on hospitalization rates, which did not differ between patient groups in the present study, or on internationally recognized diagnostic criteria for psychiatric illness, which are not reported here. From the case descriptions presented here, none of the present study subjects in either group manifests an acute psychotic reaction.
The present authors defined their worst neuropsychiatric outcome, "severely disabling," according to subjective criteria defined mostly in terms of whether the patient was able to complete the activities that were the purpose of the journey. This definition is open to interpretative bias both on the part of the patient and on the part of the assessor but, nevertheless, can be quite helpful to the practicing physician reading the paper in being able to provide information to his or her patients.
Adverse reactions of varying severity can and do occur with any drug. In the present study, highly disturbing but not life-threatening side effects such as anxiety, depression, or subjective feelings of dissociation occurred in somewhere well below 1% of mefloquine users. This rate of serious but not life-threatening complications due to a drug known to be the most highly effective in preventing a life-threatening condition would probably be considered acceptable for most other diseases. The authors’ emphatically featured (abstract, discussion, "Key Messages" inset box) figure of 0.7% for severely disabling neuropsychiatric events is not corrected for a potential bias in the retrospective sample where individuals with complaints may be more likely to respond to a survey. Of 1102 non-respondents to the mail questionnaire, mefloquine had been recommended for 792 during their telephone call to the health line as compared to only 310 to whom chloroquine/proguanil had been recommended. In addition, the study did not control for alcohol intake, and the quoted rates for neuropsychiatric adverse effects due to mefloquine do not correct for background levels of similar neuropsychiatric symptoms in the general population.
Overall, to me the most helpful and least subjective statistic in this study is the finding that the drug cessation rate didn’t differ between the two patient groups. Of course, we are obliged to discuss with patients the possibility of what is an infrequent CNS event, but we should continue to have no hesitation in prescribing this highly effective drug when it is indicated.
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