One of the problems that has perplexed many Australian government officials and veterans advocates in recent years is the disproportionately high number of Australian Defence Force (ADF) East Timor veterans who have been diagnosed with post-traumatic stress disorder (PTSD). PTSD is a mental health disorder that can develop after a person is exposed to a traumatic event or events. The types of traumatic events specified in the PTSD diagnostic criteria are “death, threatened death, actual or threatened serious injury, or actual or threatened sexual violence.”
PTSD is one of the most commonly diagnosed, service-related health conditions among East Timor veterans. The number of PTSD claims accepted by the Department of Veterans Affairs (DVA) from East Timor veterans is very similar to the number from Afghanistan veterans. Although the duration and numbers of personnel involved in each of those military commitments was similar, the nature of the conflicts and health exposures were quite different, leading respected veterans advocates such as former SAS officer John Burrows to speculate on the disproportionately high PTSD numbers among East Timor veterans:
Mr Burrows was contacted by News Corp Australia to explain an apparent statistical anomaly that shows the 1999 operations to liberate East Timor from Indonesia had produced more sufferers of post-traumatic stress disorder than either the Iraq or Afghanistan wars.
This was despite the fact that few ADF personnel came close to serious combat action in East Timor.
… Mr Burrows also said that while few — if any — service person in East Timor lived with dodging air strikes, rocket-propelled grenades, cannon fire or even sustained firefights, DVA initially took the view that it had to process all claims quickly.
This was because the government had failed so many veterans in its last major action, in Vietnam 27 years earlier, and was initially nervous of repeating its mistake.
Added to that, said Mr Burrows, many serving in the ADF in its initial commitment to Timor were not acquainted with the realities of conflict.
“It was a Defence Force that hadn’t been to war for many years and many had an overwhelming feeling they were in imminent danger anywhere in the operational zone,” said Mr Burrows, even though the expected battles with the Indonesian military and citizen forces did not eventuate.
… “In Afghanistan, I believe from my dealings with veterans who have served there, is that the numbers of enemy being contacted is much higher and the intensity much greater than was the case in most actions in Vietnam,” he said.
Along with PTSD, two of the three most prevalent, service-related health conditions among East Timor veterans are tinnitus (ringing in the ears) and sensori-neural hearing loss, which are commonly associated with noise exposure. The disproportionate DVA figures among East Timor veterans in comparison to those from Afghanistan also led Burrows to speculate on this, in the same article quoted above:
Likewise, claims for both tinnitus and sensori-neural hearing loss from East Timor veterans far exceed claims from Iraq and Afghanistan, where combat forces routinely experienced close proximity to loud and damaging live fire.
… Timor vets with accepted claims for tinnitus (892) and sensori-neural hearing loss (882) far outnumber those from Afghanistan and Iraq.
… Mr Burrows said many hearing disorders from East Timor vets likely came from live firing exercises.
This speculation overlooks the most plausible explanation for the high prevalence of these disorders among East Timor veterans, which is the extensive use of the anti-malarial drugs mefloquine and tafenoquine in the ADF during the early years of this military operation. There is a high likelihood that a large proportion of those personnel have simply been misdiagnosed with PTSD and/or suffer from hearing problems, as a result of the toxicity of these drugs.
Mefloquine and tafenoquine were administered to at least 2,842 ADF personnel in a series of drug trials conducted by the Army Malaria Institute (AMI) in Bougainville and East Timor from 1998-2002. Excluding the Bougainville tafenoquine trials but including a conservative estimate of East Timor veterans given mefloquine (which had been in use as the ADF’s second line anti-malarial since 1993) beyond those trials, brings the East Timor figure to approximately 2,500, if not significantly greater.
Both drugs are known to be neurotoxic. Mefloquine, along with several other synthetic quinoline antimalarials including 8-aminoquinolines (tafenoquine is an 8-aminoquinoline) has been found to be a cause of a central nervous system toxicity syndrome resulting in chronic neuropsychiatric symptoms. Many of these psychiatric symptoms mimic those of PTSD, to the extent that the U.S. Centres for Disease Control (CDC), the U.S. Army Surgeon General, and researchers from the U.S. Walter Reed Army Institute of Research (WRAIR) have acknowledged that mefloquine toxicity can confound the diagnosis of PTSD, particularly in military veterans:
Intoxication with the antimalarial drug mefloquine (previously marketed as Lariam) is a potentially life-threatening condition marked by changes in affect, behavior, cognition, and thought that may be associated with a risk of central nervous system (CNS) neuronal injury as well as chronic neurological and psychiatric sequelae. The acute symptoms of mefloquine intoxication may mimic and be mistaken for a number of acute psychiatric disorders including posttraumatic stress disorder (PTSD). Particularly in deployed settings, this may delay the correct diagnosis of mefloquine intoxication, risking subsequent morbidity. As the subacute and chronic psychiatric and neurologic sequelae of acute mefloquine intoxication may also confound the later diagnosis and management of PTSD, as well as other chronic neuropsychiatric disorders prevalent among deployed cohorts, health-care providers must screen for prior mefloquine exposure and consider the diagnosis of mefloquine intoxication in patients with appropriate history and findings on clinical evaluation.
The conclusion of a recent report describing a case of mefloquine toxicity in a U.S. military veteran authored by WRAIR (the research institute that originally developed mefloquine) researchers found:
This case documents the potential long-term and varied mefloquine-induced neuropsychiatric side effects, ranging from a central vestibulopathy to significant behavioral changes and sleep disorders. Especially pertinent to the military population, it demonstrates the difficulty in distinguishing from possible mefloquine-induced toxicity versus PTSD, and raises some questions regarding possible linkages between the two diagnoses.
Mefloquine is also a known ototoxicant, i.e. a toxic substance able to cause problems including tinnitus and hearing loss. Although there is less published research on the toxicity of tafenoquine, researchers from WRAIR (which also developed tafenoquine) found in 2009 that “tafenoquine is more neurotoxic than mefloquine.”
A large proportion of East Timor veterans administered these two drugs have been diagnosed with PTSD, without having experienced the traumatic exposures required for this diagnosis, as well as tinnitus, sensori-neural hearing loss and other neuropsychiatric disorders symptomatic of quinoline neurotoxicity. Many of them are included in the above DVA figures, although others who were medically discharged from the ADF have had their claims perversely rejected by the Veterans Review Board on the basis that they were not involved in combat. Having met with a group of these veterans and families at a forum in Townsville earlier this year, the Surgeon General of the ADF is fully aware of these concerns.
This situation has developed despite Defence and DVA having poured literally tens of millions of dollars into extensive research on neuropsychiatric illness among East Timor and Bougainville veterans, including studies of PTSD, tinnitus and sensori-neural hearing loss. These studies have examined a variety of health factors while systematically excluding exposures to neurotoxic anti-malarial drugs that are fully documented in files held at AMI, for example:
- A. McGuire et al., Bougainville Health Study, Centre for Military and Veterans Health, 2009.
- A. McGuire et al., East Timor Health Study, Centre for Military and Veterans Health, 2009.
- D. Dunt, Independent study into suicide in the ex-service community, 2009.
- D. Dunt, Review of mental health care in the ADF and transition through discharge, 2009.
- A. McFarlane et al., 2010 ADF Mental Health Prevalence and Wellbeing Study, University of Adelaide, 2011.
- A. McGuire et al., Review of PTSD group treatment programs, Centre for Military and Veterans Health, 2011.
- K. Kirk et al., Self-reported tinnitus and ototoxic exposures among deployed Australian Defence Force personnel, Military Medicine, vol. 176, no. 4, 2011.
- J. Bleier et al., Risk of adverse health outcomes associated with frequency and duration of deployment with the Australian Defence Force, Military Medicine, vol. 176, no. 2, 2011.
- M. Waller et al., Traumatic events, other operational stressors and physical and mental health reported by Australian Defence Force personnel following peacekeeping and war-like deployments, BMC Psychiatry, vol. 12, no. 88, 2012.
- Australian Centre for Posttraumatic Mental Health, Australian peacekeepers: Long-term mental health status,
health service use, and quality of life, University of Melbourne, 2013.
One of the above studies, published in 2012, compared traumatic events and “other operational stressors” between 1,704 Bougainville veterans and 1,333 East Timor veterans and examined subsequent health outcomes:
Two cross sectional studies of the Australian Defence Force were used to contrast the prevalence of exposures reported by a group deployed on a peacekeeping operation (Bougainville, n = 1704) and those reported by a group deployed on operations which included warlike and non-warlike exposures (East Timor, n = 1333). A principal components analysis was used to identify groupings of non-traumatic exposures on deployment. Multiple regression models were used to assess the association between self-reported objective and subjective exposures, stressors on deployment and subsequent physical and mental health outcomes.
The study found that 7.2% of East Timor veterans had symptoms of PTSD and 6.9% had a high level of psychological distress, while the corresponding numbers in the Bougainville group were 5.9% and 5.5% respectively. These findings were based on self-reported DSM-IV symptoms of PTSD:
The Post-Traumatic Stress Disorder Checklist Civilian Version (PCL-C) was also used. This is a self-report rating scale for assessing 17 symptoms of PTSD. A cut-off of 50 on the PCL-C has previously been used as an indicator of PTSD prevalence in military populations.
Despite the fact that approximately 3,000 ADF personnel were administered mefloquine and tafenoquine during these deployments, this factor was not considered during the study. A 2014 paper on mefloquine and PTSD published by the U.S. Army Surgeon General highlights the questionable validity of this research, finding that many of the symptoms of mefloquine toxicosis may “be erroneously deemed as meeting [DSM-IV] diagnostic criteria”:
In deployed settings where US military personnel may have been exposed to mefloquine, the ubiquity of potentially traumatic experiences may have had the effect of significantly reducing the specificity of DSM- IV diagnostic criteria. For example, in an early study of returning service members from Afghanistan and Iraq, encompassing the period of widespread mefloquine use, between one-quarter and one-half of subjects reported feeling “in great danger of being killed;” more than one-third to one-half reported witnessing individuals wounded or killed, consistent with DSM-IV criteria of experiencing, witnessing, or being confronted by events involving “actual or threatened death or serious injury” (criterion A1). Similarly, intense fear, helplessness, or horror (criterion A2), while seemingly specific to external traumatic stressors, may be readily confounded by the onset of panic attacks or certain symptoms of psychosis, which may solely result from mefloquine’s effects but whose specific symptoms may reflect fearful or horrific content that may risk being attributed to an external stressor in the context of military deployment.
Other symptoms of mefloquine intoxication may also closely mimic many criteria B (re-experiencing) and C (avoidant/numbing) symptoms. For example, intrusive recollections (criterion B1), possibly reflecting the effects of daytime or hypnopompal hallucinations, are a common feature of case reports. Similarly, distressing nightmares (criterion B2), frequently described as “vivid” and “terrifying,” are a pervasive feature of intoxication, affecting more than one-third of military users during prophylactic dosing. Similarly, again possibly reflecting the effects of hallucinations, symptoms consistent with flashbacks (criterion B3) are commonly reported with reports of directed actions in response to perceived threats. As the symptoms of mefloquine intoxication may present independent of a specific external traumatic stressor, individuals suffering from its effects may not exhibit psychological distress or physiological reactivity specifically in response to traumatic reminders (criteria B4 and B5), but instead may experience such reactions unpredictably and without obvious triggers. In certain environments, where traumatic reminders are prevalent or where ascertainment or recall bias may identity these preferentially on examination, such symptoms may be erroneously attributed to traumatic reminders, which confounds diagnosis.
Similarly, while the effects of mefloquine intoxication may result in nonspecific avoidance behaviors, these may risk being similarly misattributed to an external traumatic stressor (criteria C1 and C2) on examination. Conversely, because of the lasting effect of mefloquine on memory and its association with anterograde amnesia, the inability of those suffering intoxication to recall specific aspects of a presumed trauma (criterion C3) coincident with dosing may—in some contexts—be erroneously deemed as meeting diagnostic criteria.
Another of the Australian studies published in 2011 specifically examined tinnitus and ototoxic exposures in a sample of 4,175 veterans of Bougainville and East Timor:
The objective of this study was to investigate the effect of chemical and environmental exposures during deployment on tinnitus among Australian Defence Force personnel previously deployed to Bougainville and East Timor. Participants were asked to self-report recent occurrence and severity of “ringing in the ears,” and identify any chemical and environmental exposures during their deployment. Self-reported exposure to loud noises, heavy metals, intense smoke, engine exhaust, solvents and degreasing agents, and chemical spills increased the risk of self-assessed moderate or severe tinnitus.
The ototoxic exposures considered in this study included heavy metals, intense smoke, engine exhaust, solvents/degreasing agents, chemical spills and pesticides. Quinoline anti-malarial drugs were excluded from consideration in this study despite the fact that mefloquine and tafenoquine were administered to approximately 3,000 ADF personnel during these deployments.
During the recent Senate inquiry into ADF mental health, a serving Army officer testified that PTSD has become a “diagnosis of convenience” that is preventing many veterans receiving appropriate health care. The same inquiry also heard evidence from neuroscientist Dr Jane Quinn, emphasising the importance of correct diagnosis:
“Proper diagnosis is key. It is important that mefloquine toxicity is recognised as being a significant and identifiable neuropsychiatric disease state, because this has a severe impact on the way personnel need to be dealt with in terms of psychiatric treatment. Drugs that are administered for standard post-traumatic stress disorder can often exacerbate the clinical symptoms of mefloquine toxicity due to the underlying neurological damage. Therefore, a correct diagnosis is key. Implementation of an institutional recognition of mefloquine toxicity in the defence force is critically required and, further, a program to identify, assist and treat appropriately those who have suffered.”
One of the key recommendations from this inquiry was for Defence and DVA to implement an outreach program for veterans affected by quinoline toxicity, to ensure they receive proper health care:
4.79 The committee recommends that Defence and DVA contact ADF members and veterans who have been administered mefloquine hydrochloride (mefloquine) during their service to advise them of the possible short-term and long-term side effects and that all ADF members and veterans who have been administered mefloquine during their service be given access to neurological assessment.
The Australian government has thus far refused to implement this recommendation. This situation poses serious questions about the validity of tens of millions of dollars worth of veterans health research and the resulting inadequate support being provided to seriously ill veterans and their families. Many of these veterans remain at risk of suicide. Health care professionals, researchers and government officials involved in veterans affairs need to urgently rectify this situation with appropriate follow up studies and other necessary support for those affected.
*The manufacturer of tafenoquine, GlaxoSmithKline, has requested those affected by the toxicity of the drug to contact them on 1800 033 109.*
R. L. Nevin and E. C. Ritchie, FDA black box, VA red ink? A successful service-connected disability claim for chronic neuropsychiatric adverse effects from mefloquine, Federal Practitioner, in press, 2016.
J. Livezey, T. Oliver and L. Cantilever, Prolonged neuropsychiatric symptoms in a military service member exposed to mefloquine, Drug Safety: Case Reports, vol. 3, no. 7., 2016.
S. McCarthy, Malaria Prevention, Mefloquine Neurotoxicity, Neuropsychiatric Illness and Risk-Benefit Analysis in the Australian Defence Force, Journal of Parasitology Research, vol. 2015 , Article ID 368064, 2015.
J. C. Quinn, Complex Membrane Channel Blockade: A Unifying Hypothesis for the Prodromal and Acute Neuropsychiatric Sequelae Resulting from Exposure to the Antimalarial Drug Mefloquine, Journal of Parasitology Research, vol. 2015 , Article ID 368064, 2015.
R. L. Nevin, Idiosyncratic quinoline central nervous system toxicity: historical insights into the chronic neurological sequelae of mefloquine, International Journal for Parasitology: Drugs and Drug Resistance, vol. 4, no. 2, pp. 118-125, 2014.
R. L. Nevin, Mefloquine and post-traumatic stress disorder, in Elspeth C. Ritchie (ed.), Forensic and Ethical Issues in Military Behavioural Health, Borden Institute, Surgeon General U.S. Army, Falls Church, 2014.
E. C. Ritchie, J. Block and R. L. Nevin, Psychiatric side effects of mefloquine: applications to forensic psychiatry, Journal of the American Academy of Psychiatry and the Law, vol. 41, no. 2, pp. 224-235, 2013.
R. L. Nevin, Limbic encephalopathy and central vestibulopathy caused by mefloquine: A case report, Travel Medicine and Infectious Disease, vol. 10, no. 3, pp. 144-151, 2012.