The modern medical literature implicates malaria, and particularly the potentially fatal form of cerebral malaria, with a risk of neurocognitive impairment. Yet historically, even milder forms of malaria were associated in the literature with a broad range of psychiatric effects, including disorders of personality, mood, memory, attention, thought, and behaviour. In this article, the history of psychiatric effects attributed to malaria and post-malaria syndromes is reviewed, and insights from the historical practice of malariotherapy in contributing to understanding of these effects are considered. This review concludes with a discussion of the potentially confounding role of the adverse effects of anti-malarial drugs, particularly of the quinoline class, in the unique attribution of certain psychiatric effects to malaria, and of the need for a critical reevaluation of the literature in light of emerging evidence of the chronic nature of these adverse drug effects.

Mefloquine is a quinoline derivative antimalarial which demonstrates promise for the treatment of schistosomiasis. Traditionally employed in prophylaxis and treatment of chloroquine-resistant Plasmodium falciparum malaria, recent changes to the approved European and U.S. product labeling for mefloquine now warn of a risk of permanent and irreversible neurological sequelae including vertigo, loss of balance and symptoms of polyneuropathy. The newly described permanent nature of certain of these neurological effects challenges the conventional belief that they are due merely to the long half-life of mefloquine and its continued presence in the body, and raises new considerations for the rational use of the drug against parasitic disease. In this opinion, it is proposed that many of the reported lasting adverse neurological effects of mefloquine are consistent with the chronic sequelae of a well characterized but idiosyncratic central nervous system (CNS) toxicity syndrome (or toxidrome) common to certain historical antimalarial and antiparasitic quinolines and associated with a risk of permanent neuronal degeneration within specific CNS regions including the brainstem. Issues in the development and licensing of mefloquine are then considered in the context of historical awareness of the idiosyncratic CNS toxicity of related quinoline drugs. It is anticipated that the information presented in this opinion will aid in the future clinical recognition of the mefloquine toxidrome and its chronic sequelae, and in informing improved regulatory evaluation of mefloquine and related quinoline drugs as they are explored for expanded antiparasitic use and for other indications.

The antimalarial drug mefloquine (MQ) is associated with neuropsychiatric adverse reactions, some of which may predict the development of more serious effects. Although prescribing guidance in the United States drug label (DL) recommends to discontinue MQ at the onset of neuropsychiatric symptoms, only certain reactions are listed in both the DL and the corresponding patient medication guide with a recommendation to discontinue or to consult a physician should they occur. To identify possible prodromal reactions for which there is complete or partial agreement in prescribing and patient recommendations, a systematic comparison of international drug safety labeling was performed.

The well-studied C677T variant in the methylenetetrahydrofolate reductase (MTHFR) enzyme is a biologically plausible genetic risk factor for seizures or epilepsy. First, plasma/serum levels of homocysteine, a pro-convulsant, are moderately elevated in individuals with the homozygote TT genotype. Furthermore, the TT genotype has been previously linked with migraine with aura—a comorbid condition—and with alcohol withdrawal seizures. Finally, several small studies have suggested that the TT genotype may be overrepresented in epilepsy patients. In this study, we consider whether the MTHFR C677T or A1298C variants are associated with risk of epilepsy including post-traumatic epilepsy (PTE) in a representative military cohort. Study subjects were selected from the cohort of military personnel on active duty during the years 2003 through 2007 who had archived serum samples at the DoD Serum Repository, essentially all active duty personnel during this time frame. We randomly selected 800 epilepsy patients and 800 matched controls based on ICD-9-CM diagnostic codes. We were able to isolate sufficient genetic material from the archived sera to genotype approximately 85% of our study subjects. The odds of epilepsy were increased in subjects with the TT versus CC genotype (crude OR=1.52 [1.04–2.22], p=0.031; adjusted OR=1.57 [1.07–2.32], p=0.023). In our sensitivity analysis, risk was most evident for patients with repeated rather than single medical encounters for epilepsy (crude OR=1.85 [1.14–2.97], p=0.011, adjusted OR=1.95 [1.19–3.19], p=0.008), and particularly for PTE (crude OR=3.14 [1.41–6.99], p=0.005; adjusted OR=2.55 [1.12–5.80], p=0.026). Our early results suggest a role for the common MTHFR C677T variant as a predisposing factors for epilepsy including PTE. Further exploration of baseline homocysteine and folate levels as predictors of seizure risk following traumatic brain injury is warranted.

To estimate the number of undocumented incident traumatic brain injuries (TBIs) among active component US military personnel serving in Iraq and Afghanistan prior to policy changes implemented in late 2006 and 2010 that improved TBI documentation. Negative binomial regression was used to model monthly incident TBI counts between December 2010 and June 2012 (N = 19) and then estimate expected monthly counts of incident TBIs during 2 periods: January 2003-October 2006 and November 2006-November 2010. Monthly amputation counts from Department of Defense surveillance data were used as a proxy for changing injury rates. Monthly active component deployment estimates derived from the Congressional Research Service, Brookings Institution, and Defense Manpower Data Center were used to estimate the size of the at-risk population each month. The difference between expected monthly incident TBI counts and reported counts is presented as the estimated number of undocumented incident TBIs. The full model estimates that 21 257 active component military personnel experienced undocumented incident TBIs while deployed in Iraq or Afghanistan between January 2003 and October 2006, more than 4 times the 5272 incident TBIs documented during that period. A sizeable majority of Iraq and Afghanistan combat veterans who experienced incident TBI while deployed prior to November 2006 are likely to have had their injuries undocumented, creating challenges for clinical care, disability evaluation, and future research.