Abstract
BackgroundMefloquine has historically been considered safe and well-tolerated for long-term malaria chemoprophylaxis, but prescribing it requires careful attention in order to rule out contraindications to its use. Contraindications include a history of certain neurological conditions that might increase the risk of seizure and other adverse events. The precise pathophysiological mechanism by which mefloquine might predispose those with such a history to seizure remains unclear.Presentation of the hypothesisStudies have demonstrated that mefloquine at doses consistent with chemoprophylaxis accumulates at high levels in brain tissue, which results in altered neuronal calcium homeostasis, altered gap-junction functioning, and contributes to neuronal cell death. This paper reviews the scientific evidence associating mefloquine with alterations in neuronal function, and it suggests the novel hypothesis that among those with the prevalent EPM1 mutation, inherited and mefloquine-induced impairments in neuronal physiologic safeguards might increase risk of GABAergic seizure during mefloquine chemoprophylaxis.Testing and implications of the hypothesisConsistent with case reports of tonic-clonic seizures occurring during mefloquine chemoprophylaxis among those with family histories of epilepsy, it is proposed here that a new contraindication to mefloquine use be recognized for people with EPM1 mutation and for those with a personal history of myoclonus or ataxia, or a family history of degenerative neurologic disorder consistent with EPM1. Recommendations and directions for future research are presented.
Highlights
Mefloquine has historically been considered safe and well-tolerated for long-term malaria chemoprophylaxis, but prescribing it requires careful attention in order to rule out contraindications to its use
Testing and implications of the hypothesis: Consistent with case reports of tonic-clonic seizures occurring during mefloquine chemoprophylaxis among those with family histories of epilepsy, it is proposed here that a new contraindication to mefloquine use be recognized for people with EPM1 mutation and for those with a personal history of myoclonus or ataxia, or a family history of degenerative neurologic disorder consistent with EPM1
Historically the long-term use of mefloquine for malaria chemoprophylaxis has been considered safe and well-tolerated [1,2], careful prescribing is needed to minimize the potential for severe neurological adverse events, including myoclonus and seizure, for which individuals with certain neurological histories appear to be at highest risk [3]
Summary
Mefloquine (Lariam®) is a commonly prescribed antimalarial. historically the long-term use of mefloquine for malaria chemoprophylaxis has been considered safe and well-tolerated [1,2], careful prescribing is needed to minimize the potential for severe neurological adverse events, including myoclonus and seizure, for which individuals with certain neurological histories appear to be at highest risk [3]. The prevalence of EPM1 homozygosity is as high as four per 100,000 in some western populations [44], which suggests that the genotypic frequency of EPM1 heterozygosity under Hardy-Weinberg equilibrium could exceed one percent Such underlying prevalence might be consistent with the incidence of observed neurologic adverse events with mefloquine prophylaxis, when coupled with an as-yet-unclear population prevalence of either MDR1 polymorphisms, co-administration of medication which may further inhibit P-gp function, or other conditions such as liver dysfunction which may decrease metabolism and, lead to increases in neuronal mefloquine concentrations. ATP: Adenosine Triphosphate; CSTB: Cystatin B; Cx: Connexin; EPM1: Progressive Myoclonic Epilepsy; Type 1; ER: Endoplasmic Reticulum; GABA: Gamma Aminobutyric Acid; IP3: Inositol-1,4,5-Phosphat; IP3-R: IP3 Receptor; μM: Micro Molar; ug/mL: Microgram per Militer; mg/kg: Miligrams per Kilogram; MDR1: Multi-Drug Resistance 1 Gene; P-gp: P-Glycoprotein; ULD:Unverricht-Lundborg Disease; U.S.: United States
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