Malaria Prevention, Mefloquine Neurotoxicity, Neuropsychiatric Illness, and Risk-Benefit Analysis in the Australian Defence Force

Abstract

The Australian Defence Force (ADF) has used mefloquine for malaria chemoprophylaxis since 1990. Mefloquine has been found to be a plausible cause of a chronic central nervous system toxicity syndrome and a confounding factor in the diagnosis of existing neuropsychiatric illnesses prevalent in the ADF such as posttraumatic stress disorder and traumatic brain injury. Overall health risks appear to have been mitigated by restricting the drug's use; however serious risks were realised when significant numbers of ADF personnel were subjected to clinical trials involving the drug. The full extent of the exposure, health impacts for affected individuals, and consequences for ADF health management including mental health are not yet known, but mefloquine may have caused or aggravated neuropsychiatric illness in large numbers of patients who were subsequently misdiagnosed and mistreated or otherwise failed to receive proper care. Findings in relation to chronic mefloquine neurotoxicity were foreseeable, but this eventuality appears not to have been considered during risk-benefit analyses. Thorough analysis by the ADF would have identified this long-term risk as well as other qualitative risk factors. Historical exposure of ADF personnel to mefloquine neurotoxicity now also necessitates ongoing risk monitoring and management in the overall context of broader health policies.

Mefloquine for preventing malaria during travel to endemic areas

“…Several recently published reviews regarding the safety of mefloquine have been narrative, and included little or no description of methods applied and a lack of clearly defined and prespecified outcomes ( McCarthy 2015 ; Nevin 2015 ; Schlagenhauf 2010 ). McCarthy 2015 and Nevin 2015 discuss the policy implications of mefloquine use by the military which was beyond the scope of this Cochrane Review.…”

Accidental hydroxychloroquine overdose resulting in neurotoxic vestibulopathy

“…This phenomenon is well documented in the literature with another antimalarial drug mefloquine, known by the trade name Lariam. Mefloquine, also a member of the drug class quinolines, is a synthetic antimalarial originally developed in the 1970s to treat Plasmodium falciparum malaria resistant to chloroquine in Southeast Asia 11. Mefloquine was first discovered to exhibit neurotoxic properties in 2006 and is known to cause or exacerbate neuropsychiatric conditions 12.…”

“…In 2013–2014, mefloquine was postulated to induce a chronic toxicity syndrome in the central nervous system due to injury of the neuronal cells of the vestibular system and brainstem 13 14. The symptoms include tinnitus, hearing loss, vertigo, dizziness, headache, paresthesias, neuropathy and disrupted balance and are usually irreversible due to the poor regenerative potential of the nervous system 11. This collection of symptoms best characterises a neurotoxic vestibulopathy, which results from the neurotoxic potential of quinoline antimalarial drugs to accumulate in the neuronal cells of the vestibular nuclei, brain and brainstem 12 14 15.…”

Rational Risk-Benefit Decision-Making in the Setting of Military Mefloquine Policy

“…As described elsewhere [ 13 ], even independent of these considerations—and although mefloquine clearly remains indicated for prophylaxis in every jurisdiction in which it was originally licensed—owing to the high rate of preexisting contraindications to its use and to the high rate of induced contraindications with use of the drug, convenient and safe use of mefloquine on a widespread basis as a “drug of choice” is now prohibitive in most military settings. While such considerations alone should preclude the mass prescribing of mefloquine as a first-line agent, use of the drug may still be considered by some militaries as a second- or third-line agent [ 55 ], in spite of the broader concerns identified in this review, on an individualized basis among those with contraindications or intolerance to preferred alternative antimalarials.…”

“…Although the initial US drug label had advised that owing to concerns of “neuropsychiatric reactions” “caution should be exercised” while “piloting airplanes,” “driving,” and “operating machines” [ 16 ], in contrast to concerns over its use in aviation personnel, with limited exceptions [ 55 ], these warnings did not contribute to particular recommendations against use of the drug in other military occupational settings—for example, among drivers or machine operators. Although early research would demonstrate that dizziness and “lightheadedness” were not infrequently reported [ 32 ], other research suggested, somewhat counterintuitively, that mefloquine either had no significant effect on [ 56 ] or could even improve psychomotor performance, including performance on certain driving tests [ 57 ].…”