Epileptogenic potential of mefloquine chemoprophylaxis: a pathogenic hypothesis

Studies 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.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. Recommendations and directions for future research are presented.Mefloquine (Lariam？) is a commonly prescribed anti-malarial. Although 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]. In particular, case-report [4], case-series [5], and retrospective cohort [6,7] studies define a well-characterized pattern of increased susceptibility to seizure and other movement disorders including nystagmus and ataxia [4] with use of mefloquine among those with a personal [4-6] or family history [7] of such conditions. Additional case-reports describe, in the absence of personal or family history, the occurrence of multifocal myoclonus [8], convulsions, and seizures following both therapeutic [9] and prophy