The Mefloquine Intoxication Syndrome: A Significant Potential Confounder in the Diagnosis and Management of PTSD and Other Chronic Deployment-Related Neuropsychiatric Disorders

Acute mefloquine intoxication may produce vivid, hyper-realistic nightmares that may precede a manic, paranoid, dissociative or confusional psychosis, often marked by horrific auditory and visual hallucinations. Courtesy of Allison Stroh Rabin.

Mefloquine intoxication has significant but previously overlooked relevance in military and veteran populations. Since the early 1990s, mefloquine has been widely used as an antimalarial prophylaxis during large-scale military operations, particularly in Somalia, Iraq, and Afghanistan [1]. However, only recently has intoxication with mefloquine been recognized as potentially confounding the diagnosis and management of certain deployment-related neuropsychiatric disorders , including posttraumatic stress disorder (PTSD) [2]. In this chapter, a well-publicized case of missed diagnosis of mefloquine intoxication is presented as background to frame a discussion of the symptomatology of acute mefloquine intoxication and its chronic sequelae.

The chapter discusses methods for the appropriate prevention, diagnosis, and management of this condition in military and veteran populations potentially exposed to this neurotoxic drug [3].

The chapter then discusses the relevance of recent insights [4] into the lasting and even permanent nature of many of the sequelae of mefloquine intoxication for the evaluation and care of exposed veterans, and concludes by considering the possibility that even mild subclinical intoxication may have similar chronic effects.

Given the prior widespread use of the drug in military and veteran populations , the chapter concludes with a recommendation that health-care providers screen for mefloquine exposure, particularly when assessing a patient who appears to have PTSD or other chronic neuropsychiatric disorders whose diagnosis may be plausibly confounded by prior intoxication.

19.1 Case Presentation¹

In September 2003, a 33-year-old male soldier presented to a combat stress control unit in Iraq complaining of the acute onset 4 days earlier of symptoms of marked anxiety , paranoia, auditory and visual hallucinations, delusions of persecution, and confusion, with worsening physical complaints of photophobia and dizziness. The soldier was a newly arrived member of the US Army Special Forces unit based in a small team house in Samarra.

The night his symptoms began, he reported being awakened by a terrifying and “hyperrealistic” nightmare in which his room was exploding in a giant fireball as if under attack. Fearing the enemy was infiltrating his team house, the soldier quickly donned his combat gear and grabbed his weapon, and conducted a tactical room-to-room search. He was horrified to perceive the peacefully sleeping members of his unit as mangled corpses; eerily similar to the mangled corpse of an Iraqi insurgent he had seen the evening prior while on a mission. The soldier returned to his room experiencing visual and auditory hallucinations, unable to sleep, helpless, anxious, and paranoid.

The next day, his hallucinations continued. He perceived his team members as horrific “talking skeletal remains” and he heard nearby muffled voices plotting his death. He reluctantly informed his immediate supervisor of his hallucinations and anxiety and stated his fears that he was experiencing a “nervous breakdown.” However, his concerns were initially attributed to cowardice and he was advised to return to duty.

His sense of helplessness and persecutory delusions worsened the following day. After finally insisting on medical care, and fearing for their safety, his unit members disarmed and confined him while they awaited his transport to a nearby combat stress control unit where he received an evaluation 2 days later.

On evaluation, his medical history was significant only for an episode of concussion in his mid-teens, for which he was briefly hospitalized and from which he had no residual symptoms. He had no family or personal history of mental illness. He was serving as an interrogator and human intelligence collector and had been granted a top secret security clearance after passing a full background investigation.

His only medication was mefloquine, which he had begun approximately 2 weeks prior to his departure to Iraq. He had taken his third 250-mg weekly dose 2 days prior to the onset of his symptoms. He had consumed a modest amount of alcohol with meals while awaiting air transport to Iraq, but none following his arrival. In the days prior to the acute onset of his psychosis, he recalls having experienced no vivid dreams, change in personality, anxiety, restlessness, depression, or confusion.

At the time of his initial evaluation at the combat stress control unit, his symptoms were attributed to a panic attack stemming from his initial encounter with the deceased Iraqi insurgent. The symptoms were deemed consistent with a combat stress reaction. Although combat stress control had recommended he should receive local treatment, his unit had elected to initiate legal proceedings for his earlier behavior. He was subsequently returned to the USA to be charged with cowardice by the Army under Article 99 of the Uniformed Code of Military Justice (UCMJ), a crime that carries a maximum penalty of death.

The possibility that the patient’s symptoms could represent an adverse reaction to mefloquine was not initially suspected either by his command or medical personnel, nor the soldier himself. Although the soldier had been issued the drug some months after the US Food and Drug Administration (FDA) first required issuance of a medication guide “wallet card” [5], he neither received this card nor verbal or other written instructions describing under what conditions to discontinue the drug.

Unaware of the information contained in the approved drug labeling to discontinue the medication at the onset of symptoms of “anxiety , depression , restlessness, or confusion,” he continued to take mefloquine for two additional weeks after the onset of his symptoms, for a total of five doses.

Following his discontinuation of the drug, his psychiatric symptoms gradually improved and he subsequently received a diagnosis of PTSD. Meanwhile, his physical symptoms including photophobia, accommodative dysfunction, vertigo, and disequilibrium became more prominent. On subsequent evaluation, an ear, nose, and throat specialist documented nystagmus, and he was diagnosed with a vestibular injury and “likely [mefloquine] toxicity.” Brainstem injury was suspected.

Upon learning that mefloquine could have been the cause of the soldier’s behavior, the legal team proposed exposure to the drug as a defense against the charges of cowardice. The soldier’s use of mefloquine was initially challenged by the US Army owing to lack of documentation of its prescription (an unfortunately common occurrence). However, the US Army conceded exposure to the drug when the soldier was able to demonstrate possession of his remaining tablets.

On being informed of the diagnosis of vestibular injury, in June 2004 the US Army terminated all legal action against the soldier.

Although causal attribution to mefloquine was never formally acknowledged, in April 2005 the soldier was temporarily medically retired. In August 2006, he was formally medically retired for his vestibular disorder and with a diagnosis of PTSD.

In subsequent years, many of his chronic symptoms of disequilibrium gradually improved following physical and vestibular rehabilitation, but over a decade after onset, he complains of being occasionally short-tempered and irritable and experiencing intermittent vertigo and photophobia.

19.2 Diagnostic Challenges

This case, widely covered in the contemporary media [6–9], vividly illustrates the challenges faced in correctly diagnosing acute mefloquine intoxication, given that its symptoms may readily mimic those of acute stress reaction or other disorders attributable to deployment stressors. To avoid missed diagnosis, mefloquine intoxication or its prodrome must be considered in any psychiatric differential diagnosis where mefloquine exposure is a possibility. As no available biomarkers, imaging, or objective testing modality has sufficient sensitivity to identify mefloquine intoxication in every setting, clinicians must be prepared to rely on details of history, clinical presentation, and the ruling out of other similar disorders for diagnosis.

In particular, in order to avoid a delayed or missed diagnosis and to minimize the risk of continued dosing seen in this case, providers should become familiar with the full range of symptoms associated with acute intoxication and its prodrome, and if these are observed, be prepared to immediately discontinue the medication and consider additional steps in management to mitigate the risk of lasting sequelae.

In retrospective cases, diagnosis may be aided through additional testing and specialist referrals as necessary, which may reveal objective and convergent evidence of chronic sequelae. Certain of these tests may be difficult to obtain except at specialized clinics, therefore frequently necessitating tertiary referral. While the chronic sequelae of mefloquine intoxication may potentially confound diagnosis of PTSD and other chronic neuropsychiatric disorders, particularly with the benefit of specialized testing certain presentations may provide sufficient specificity so as to confidently permit assigning the diagnosis even in the presence of these and other comorbidities, as described below.

19.2.1 Symptomatology

Accumulated experience suggests that where the presentation of mefloquine intoxication is not fulminant as in this case, intoxication may begin with a subtle prodrome that may present with a sense of unease [10] or impending doom and restlessness [11, 12], personality change [10], agoraphobia [13], or other phobias [14]. Prodromal symptoms of intoxication may also include vivid dreams [15], nightmares [15], or sleep disturbances [16], including hypersomnia and often-severe insomnia [17]. Such symptoms may not be easily recognized, or may be misattributed to other causes including common stressors [18].

Over time these prodromal symptoms may progress to a more acute intoxication. Commonly reported symptoms of acute mefloquine intoxication include anxiety [19], paranoia [19] and persecutory mania [20–24], panic attacks [25–27], emotional lability [12], and aggression [28]. Patients may also experience symptoms of psychosis [29] including magical thinking [30] and grandiose [31], persecutory [32] or religious [17, 33] thoughts and delusions, and auditory [10, 20, 33, 34], visual [15, 19, 34–36], and olfactory [37] hallucinations, although as with the case, not infrequently with some degree of preserved insight.

Where insight is preserved, certain patients, particularly within military or other occupational settings, may initially fail to report even very severe symptoms of psychosis, out of concern for stigma, loss of fellow unit members’ confidence, or as demonstrated in this case, concern for legal or administrative repercussions, such as potential loss of security clearance.

Acute intoxication may also manifest as depression [15, 19, 25, 38, 39], with sadness [32], tearfulness [32], fatigue [17], malaise and lethargy [40], confusion [15, 19. 34, 41], and a sense of helplessness, hopelessness, or pessimism [32]. In certain cases, those suffering intoxication may also experience dissociative symptoms[13, 42] including derealization [10, 37, 43] and depersonalization [36, 43, 44].

Acute mefloquine intoxication may also manifest with temporospatial disorientation [10, 15, 36, 45–47], and explicit memory impairment, including retrograde and anterograde amnesia [48], and particularly with impairment of short-term, working, and verbal memory [19, 42], with corresponding disturbances in attention or concentration.

With implicit memory typically preserved [48], those affected by explicit memory impairment from mefloquine intoxication may nonetheless be able to continue to participate in complex learned actions [49]. In certain cases, patients may even demonstrate improved performance during certain rote tasks [50], but may later experience profound amnesia to their actions or to events occurring during their period of intoxication [48]. Symptoms of memory impairment may also limit the reliability and completeness of reporting of prodromal symptoms preceding acute intoxication, or limit the reliability of history on initial examination [36].

In certain patients, symptoms of intoxication may quickly progress to a profound delirium [51], which may result in the patient requiring intensive medical care. Intoxication may also present in a fulminant manner as seizures [52]. Each presentation may potentially mask other psychiatric symptoms of intoxication [53].

This accumulated experience with its symptomology further suggests that on initial presentation, those suffering from mefloquine intoxication may often appear to be suffering from a potentially bewildering range of plausible disorders spanning the psychiatric nosology, including acute anxiety, dissociative, depressive, manic, bipolar, psychotic, personality, conversion, and factitious disorders [1, 10, 54].

Rather than reflecting a purely psychiatric disorder triggered or unmasked by the drug, these symptoms of mefloquine intoxication and its prodrome should be considered as organic manifestations of an underlying progressive toxic encephalopathy affecting particularly the limbic system and brainstem [10]. While potentially acutely reversible, this encephalopathy may be associated with a risk of chronic psychiatric effects [30, 55] as well as additional neurological effects likely due to central nervous system (CNS) injury [4].

These neurological effects most typically include dizziness, vertigo, and nystagmus, but not uncommonly also include sleep disorders, photophobia, accommodative disorders, dysesthesias, paresthesias, and occasionally myoclonus or dyskinesias, dysarthrias, dysautonomias, central apnea, and esophageal and gastrointestinal dysmotility, many of which have been observed from brainstem toxicity in closely related quinoline-based drugs [4].

Recognition of these chronic sequelae, through the use of appropriate specialist referrals where necessary, may aid the psychiatrist in disentangling symptoms due to mefloquine from those due to common confounding and comorbid psychiatric disorders that may be prevalent in military and veteran populations.

19.2.2 Biomarkers

Notwithstanding previous creative theories to the contrary [56,57], neither abnormal liver enzymes, thryoid hormone levels, nor levels of certain common metabolites reliably correlate with risk of intoxication.

Although dose-dependent mefloquine CNS toxicity may be predicted on theoretical grounds based on an abundance of in vivo and in vitro data [58, 59−63], no studies have directly correlated CNS effects with concentrations in brain, nor have threshold toxic CNS concentrations been clinically identified, although physiologically relevant effects may be expected even at the low CNS concentrations that may result from administration of as little as a single tablet.

Additionally, as would be expected of a drug with highly variable neuropharmacokinetics [64], both blood [65, 66] and cerebrospinal fluid [67] (CSF) levels of the drug correlate poorly with those in CNS, and blood levels of mefloquine are not strongly correlated with risk of intoxication [45, 68−70].

For these reasons, quantitative determination of mefloquine concentrations in body fluids, including blood and CSF, should be considered useful only in ruling in exposure [54]. Owing to the extreme lipophilicity of the drug [71, 72], the relative quantitative insensitivity of many assays, and the drug’s tendency to pool in organ tissue including brain [62, 73, 74] relative to body fluids, a negative mefloquine serum level may not rule out current or recent intoxicating concentrations in CNS.

Conversely, measurement of mefloquine metabolite levels in blood is not directly relevant clinically, as systemic metabolism may not directly predict CNS concentrations of the drug [74, 75]. Similarly, although genotyping, particularly of drug metabolic and transport enzyme genes [76], may be clinically useful to guide pharmacotherapy in the management of mefloquine intoxication, the genetic epidemiology of intoxication remains uncertain [54], and no gene, genotype or haplotype has yet been linked in confirmatory analysis to a risk of intoxication, despite promising early studies [77] and anecdotal clinical observations [78] implicating possible involvement of the MDR1 (ABCB1) gene in predicting susceptibility.

19.2.3 Imaging

No imaging modality has yet been identified that can reliably diagnose mefloquine intoxication [54]. Conventional neuroimaging such as computed tomography (CT) and magnetic resonance imaging (MRI) will typically be normal during acute intoxication [10, 54], although there is insufficient published evidence with functional MRI (fMRI) to rule out this modality being of utility [79]. Limited published evidence also suggests advanced imaging techniques such as single-photon emission tomography (SPET) or positron emission tomography (PET) may reveal evidence of abnormal brain functioning during acute intoxication [30, 80].

In retrospective diagnoses, particularly in cases with neurological sequelae where brain or brainstem injury may be suspected, structural imaging including higher-resolution MRI may eventually hold promise, although neurohistopathological evidence from animal models [63] and from earlier experience with related quinoline drugs [81] suggests neurotoxic injury from mefloquine, when it occurs, is likely to be microscopic and may affect only scattered regions of the CNS, possibly in a cell-type specific manner [4]. Normal results on routine brain imaging should therefore not be considered as ruling out prior intoxication or its chronic sequelae.

19.2.4 Neuropsychological Testing

Although clearly difficult to administer during acute intoxication, detailed neuropsychological testing may be useful in the differential diagnosis of prodromal symptoms of intoxication, and in retrospective diagnoses where chronic psychiatric neurocognitive sequelae may be predominant. Absent baseline testing prior to exposure, the interpretation of single test results either during the prodrome, acute intoxication, or most commonly in retrospective diagnosis, may prove challenging. Serial testing, particularly during the subacute period, may demonstrate mild improvements, although with potentially lasting deficits in tests of attention and concentration, auditory and visual memory, information processing speed, coordination, construction, verbal learning, and productivity [10, 15, 19].

19.2.5 Neurological, Neuro-Otologic, and Neuro-Optometric Testing

Although similarly difficult to administer during acute intoxication, when symptoms dictate, careful evaluation by specialists either during the prodromal period or more commonly during retrospective diagnosis may reveal objective evidence consistent with focal CNS toxic injury. Although gross neurologic motor and sensory evaluation by neurologists in most cases of intoxication is typically normal, evaluation by neuro-otologists, neuro-optometrists, neuro-ophthalmologists, or otorhinolaryngologists may reveal objective evidence consistent with central vestibular or oculogyric dysfunction [10].

Similarly, while surface electroencephalography (EEG) is typically normal after administration of mefloquine [82] and may even be normal in acute intoxication [36], there may be evidence of deep epileptiform or other abnormal activity [46, 83−85]. Similarly, advances in quantitative EEG and deep brain or limbic EEG modalities may hold promise in identifying changes in electrical activity during the prodrome, or associated with possible seizure foci related to neurotoxic injury to the brainstem and subcortical regions in retrospective diagnosis [86].

19.2.6 Additional Testing

When indicated, particularly during retrospective diagnosis, sleep studies may reveal evidence of central apnea or parasomnias [15]. Similarly, in patients with altered speech [15] or esophageal dysmotility, evaluation by speech language pathologists may be appropriate. Insufficient evidence exists to recommend routine neuroendocrine screening, although the drug’s accumulation [74] and physiological activity on the hypothalamus [87] provides a plausible mechanism for certain chronic endocrine disorders that may develop after mefloquine exposure.

19.2.7 Coding and Documentation

Acute mefloquine intoxication does not yet have a unique diagnostic code, either in the International Classification of Diseases (ICD) version 9 Clinical Modification (ICD-9-CM) or version 10 Clinical Modification (ICD-10-CM), creating challenges both for the proper coding and documentation of the disorder, and in its surveillance using administrative data systems, such as those commonly used in the military [88].

In the ICD-10 coding system, the series of codes T37.2X5 (“Adverse effect of antimalarials and drugs acting on other blood protozoa”), including T37.2X 5S (“sequela”), are technically accurate as primary diagnoses both for acute and subacute intoxication and its chronic effects, but each code may fail to adequately communicate the clinical nature of the intoxication. This lack of specificity may require additional coding to specify the effects of mefloquine acting as a psychoactive substance. Owing to the complexity of the ICD-10 coding system, particularly for drug adverse event reporting [89], further discussion of or recommendations for such coding is deferred.

In contrast, in legacy coding systems, any of the small range of ICD-9-CM codes specified under ICD-9-CM series 292 (“Drug-induced mental disorders”) may be appropriate for use as a primary diagnosis, depending on the nature of observed symptoms. For example, ICD-9-CM 292.84 (“Drug-induced mood disorder”) or ICD-9-CM 292.11 (“Drug-induced psychotic disorder with delusions”) may each be appropriate for diagnosis, depending on the presentation of the acute intoxication. Similarly, subacute or chronic effects may be specified through the use of ICD-9-CM 909.5 (“Late effect of adverse effect of drug, medicinal or biological substance”).

However, as these codes are not specific to antimalarials or to mefloquine, in order to aid in surveillance, and to acknowledge the imperfectly specified nature of existing diagnoses assigned to the condition, the ICD-9-CM E-code E931.4 (“Antimalarials and drugs acting on other blood protozoa causing adverse effects in therapeutic use”) should also be considered for patients in whom intoxication is suspected.

Although many of the symptoms of mefloquine intoxication may mimic a range of psychiatric disorders, regardless of the coding system used, care should be taken in documentation to not to assign a secondary psychiatric diagnosis where this is excluded by current criteria. For example, a significant change to the diagnostic criteria for PTSD in DSM-5 now excludes the diagnosis if it may be “attributable to the physiological effects of a substance (e.g., medication, alcohol) or another medical condition” [90]. As many of the acute and chronic effects of mefloquine intoxication may mimic almost perfectly this condition [1], the psychiatrist should only consider documenting the diagnosis of PTSD if there is clear evidence of an adequate external traumatic etiology separate from the frequently traumatic effects of mefloquine intoxication.

Similarly, while other formal psychiatric diagnoses without such clear exclusion criteria may appear appropriate, assigning certain of these diagnoses risks confusion in communicating etiology, which may result in inappropriate or ineffective attempts at treatment. Until consensus is achieved in defining formal diagnostic criteria for the intoxication syndrome , the psychiatrist evaluating a patient with mefloquine intoxication or its chronic sequelae should select only those additional psychiatric diagnoses (frequently, those “not otherwise specified”) that adequately describe the observed phenomenology while emphasizing its organic etiology.

19.3 Prevention

Presumably in recognition of the lasting risks associated with acute intoxication, ever since the drugʼs initial licensing in 1989, the US mefloquine product insert has included language warning that “if signs of unexplained anxiety, depression, restlessness, or confusion are noticed, these may be considered prodromal to a more serious event,” and has cautioned that should these prodromal symptoms occur, “[i]n these cases, the drug must be discontinued” [54].

Certain users of mefloquine will discontinue use of the drug at the onset of the unsettling prodromal symptoms of intoxication, thus minimizing the number of cases of acute intoxication experienced during prophylactic use. However, as documented rates of discontinuation in military cohorts are significantly lower than the proportion reporting prodromal symptoms [91], military cohorts may be at particular risk of acute intoxication and its chronic sequelae.

For example, among those with a history of certain preexisting neuropsychiatric disorders [92], these symptoms may be erroneously attributed to such disorders or be obscured or confounded by psychotropic drug use [15]. Since 2002, mefloquine has therefore been absolutely contraindicated among those with a current or recent history of psychiatric illness [93], as these users may be at greater risk of failing to discontinue mefloquine as the product insert directs. The manufacturer has similarly cautioned that mefloquine “should not be prescribed for prophylaxis in patients with active depression, a recent history of depression, generalized anxiety disorder, psychosis, or schizophrenia or other major psychiatric disorders” [94]. However, in a recent military cohort, the prevalence of these and other neuropsychiatric contraindications to mefloquine use was approximately one in ten [92], and among these, approximately one in seven may have nonetheless been prescribed the drug [95].

Even among those without contraindications, patients must be clearly informed that neuropsychiatric symptoms that develop during mefloquine use could be evidence of a progressive intoxication that requires the immediate discontinuation of the drug. Prior to the black box warning, such neuropsychiatric symptoms were commonly attributed by influential authorities to other causes and not always appreciated as evidence of toxicity [18, 96−99]. However, even often subtle or overlooked symptoms such as nightmares or vivid dreams [100, 101], and sleep disturbance or insomnia [102] have been listed on various mefloquine product inserts or prescribing guidance as requiring the immediate discontinuation of the medication. Current US guidance makes it clear that “if psychiatric or neurologic symptoms occur, the drug should be discontinued” [103].

According to recent guidance provided by the manufacturer [104], symptoms of abnormal dreaming or disturbed sleep may occur in greater than 10 % of the users, and symptoms of depression or anxiety may occur in 1–10 % of the users. In randomized controlled trials, neuropsychiatric symptoms that were consistent with prodromal symptoms of intoxication occurred in 29 % of the users [105]. In contrast, military guidance as recently as 2009 erroneously stated, the risk of “psychiatric symptoms” with mefloquine use was only “1 per 2000–13,000 persons” [106], or over 1000 times lower than the true value, further complicating compliance with product insert guidance in military settings.

As symptoms of mefloquine intoxication or its prodrome may progress to include anxiety and paranoia [10], in settings such as the military where drug adherence has traditionally been emphasized, such symptoms of anxiety and paranoia may heighten fear of malaria or of judicial and nonjudicial penalties for nonadherence. As a result, even patients who have received adequate education who experience intoxication may fail to comply with product insert guidance to discontinue the medication, and may continue taking the drug despite the awareness of toxicity.

Similarly, as symptoms of confusion may make remembering and complying with mefloquine product insert guidance challenging [48], in military settings, the prescribing clinician should complement patient counseling by ensuring that the patient’s military chain of command, particularly those individuals in the deployed environment, is trained in the recognition of the signs and symptoms of mefloquine intoxication, which in prior military settings, as illustrated in the case, have been incorrectly attributed to cowardice or to potentially stigmatizing conditions.

As some prodromal intoxication may be identified during early use of the drug [107], the prescribing clinician should strongly consider a “test prescription” of mefloquine by limiting initial prescription of the drug to a small number of tablets. During this period, prior to prescribing the remaining tablets for deployment [108], the patient should be evaluated regularly and carefully for the development of prodromal symptoms. Where deployment dates are known in advance, and as mefloquine can take 7–10 weekly doses to build protective and steady-state serum concentrations [109], such a period of pre-deployment dosing with careful observation should be considered both to minimize the risk that intoxication may occur and be unrecognized during remote deployments, as well as to improve the effectiveness of the drug.

Even with such precautions, both the clinician and the chain of command must be aware of the possibility that the service member may need to immediately discontinue the medication while remotely deployed. Under the current US military policy that restricts the use of mefloquine to a “drug of last resort” [110, 111], typically no other prophylactic medications would be available to switch to in the event where prodromal symptoms develop. In areas that are highly endemic for malaria, this may require the patient’s evacuation to minimize risks when mefloquine is discontinued. Although in remote malaria-endemic areas, it may seem appealing for the chain of command or the clinician to recommend continuing the use of mefloquine even in the presence of prodromal symptoms, the risks articulated in the US product insert of serious and long-lasting psychiatric symptoms and permanent neurological effects with continued dosing make such a recommendation distinctly unwise [103].

Although appropriate recognition and management of prodromal symptoms is a critical component in the prevention of acute intoxication, symptoms consistent with acute intoxication, its prodrome, and its chronic sequelae have been reported after only a single 250-mg tablet [10, 112]. Therefore, even such careful steps will merely minimize, but will not eliminate, the risk of adverse effects from the drug, and clinicians choosing to administer mefloquine must be prepared to recognize and appropriately treat and manage acute cases of intoxication when they occur.

19.4 Management

The management of acute mefloquine intoxication relies on proper diagnosis and should primarily be conservative in nature. The goals of such management should be to encourage the elimination of the drug while minimizing the risk of further acute harm that may occur through psychopolypharmacy or through inattention to appropriate care precautions. Similarly, in subacute to chronic cases, management should also be conservative, with goals focused on rehabilitation and management of disability and avoidance of inappropriate, ineffective, or potentially harmful treatments that may arise through missed diagnosis.

19.4.1 Pharmacotherapy of Acute Intoxication

There are no clinical trials reported in the medical literature investigating management of acute intoxication, although typical case reports describe attempts at treatment primarily with antipsychotic drugs [34, 37, 42, 49]. Psychotic symptoms may be the most striking observed during acute intoxication and may appear to indicate treatment with antipsychotics. However, as the most severe psychotic symptoms associated with cases of acute intoxication appear to be mostly self-limiting even without medication [28, 29, 37, 113], and as psychopolypharmacy may carry a risk of further harm, conservative management may be a more appropriate management strategy.

Specifically, the indiscriminate use of antipsychotic drugs may be problematic owing to the potential for drug–drug interactions. As growing evidence implicates abnormal mefloquine neuropharmacokinetics in the etiology of intoxication [64], drugs that may affect metabolism of mefloquine, or that may risk slowing or delaying its efflux from brain [65], may plausibly increase the risk of chronic sequelae.

For these reasons, as with intoxication with related quinoline antimalarials [114], avoidance of antipsychotics which are substrates of common CNS drug transport and metabolism enzymes appears warranted except in cases where their likely benefits clearly exceed these plausible risks.

Point-of-care pharmacogenetic testing [76], which may identify abnormal drug metabolism and transport phenotypes [115, 116], may provide clinicians information to guide the safer use of such drugs. However, as the pathophysiology of mefloquine intoxication is likely multifactorial rather than strictly limited to isolated dopaminergic dysfunction, the desire for rational drug therapy and the avoidance of psychopolypharmacy may make other treatments more desirable.

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