Evidence of meeting #118 for Veterans Affairs in the 42nd Parliament, 1st session. (The original version is on Parliament’s site, as are the minutes.) The winning word was australia.
A recording is available from Parliament.
Liberal
The Chair Liberal Neil Ellis
Good afternoon. I call to order this meeting of the Standing Committee on Veterans Affairs, the 42nd Parliament, 1st session, on the effects of mefloquine use among Canadian veterans.
Today we have Dr. Jane Quinn, associate dean, school of animal and veterinary services, Charles Sturt University, by teleconference; and Dr. Edward Sellers, professor emeritus, University of Toronto.
Dr. Quinn, we'll start with you. Thank you.
Professor Jane Quinn Associate Dean for Research, Faculty of Science, Charles Sturt University, As an Individual
Thank you very much for inviting me to speak to the committee.
I have prepared a short statement. Is it okay to read it?
Prof. Jane Quinn
My name is Dr. Jane Quinn. I'm an associate professor and associate dean for research in the faculty of science at Charles Sturt University. I'm also a co-founder of the Australian Quinoline Veterans and Families Association.
My background relevant to this inquiry is 30 years of experience in comparative biomedical research. I'm a Ph.D.-qualified neuroscientist and undertake research on the impact of toxins in whole animal systems and tissues, specifically the brain. Of relevance to this inquiry, I have personal lived experience of the adverse effects of mefloquine, also known as Lariam, as my late husband committed suicide after taking mefloquine for overseas exercises with the British military.
There is no doubt that there are many thousands of veterans globally whose lives have been significantly impacted by taking mefloquine for military service. These are genuine people who have suffered for many years without necessarily understanding their symptoms, why they did not go away with treatment or continued to get worse over time, some to the point of severe cognitive impairment; radical sleep disorders; severe anxiety and mood disturbances, such as bipolar disorder; or in some cases, they succumbed to suicidal ideation and suicidal completion.
Mefloquine causes permanent neurological and neuropsychiatric changes in a significant minority of those who take it. Many of these veterans have been told they have treatment-resistant post-traumatic stress disorder, without it being acknowledged that their symptoms were actually caused by an ongoing neurological brain injury. Some have been subjected to treatment regimes with multiple drugs, including antipsychotics, and in some cases their brain is further exposed to injury through ECT without ever having received a true or complete diagnosis.
As you have heard from other witnesses to this inquiry, the neurological and neuropsychiatric side effects of mefloquine and other quinoline antimalarials have been well-known for many decades. It is a key question as to why it has taken so long for the impact of this drug to be acknowledged in military veterans. Recognition that mefloquine causes long-term brain injury and other systemic medical conditions is a first and necessary step to getting effective and appropriate treatment, and ongoing medical support for those impacted.
You've heard from a number of experts who have suggested this is not the case, that their brain injury does not exist, but their arguments are not supported by a veteran's experience nor that of the emerging literature, when mefloquine exposure is taken into account.
One of the witnesses to this committee commented that the medical condition caused by exposure to mefloquine cannot be diagnosed. This is not the case. The spectrum of symptoms commonly observed in individuals who have suffered a severe or lasting reaction to this family of drugs is quite discrete. It includes insomnia, sleep disturbances, vivid dreams, depression, anxiety, paranoia, cognitive impairment and memory loss, tinnitus, vestibular dysfunction, peripheral neuropathies, gastrointestinal frequency or chronic diarrhea, and can include seizures, suicidal ideation and attempted and completed suicide.
The disease cannot be identified by name in a diagnostic manual under a discrete code in either DSM-5 or ICD-10, but this is not the same as the condition not existing.
There is a syndrome that has a consistent pattern of comorbid symptoms that can be identified in response to mefloquine exposure, very similar to the diagnostic process used to identify lupus or, indeed, post-traumatic stress disorder. Therefore, is this a condition that exists? Absolutely, yes.
Chronic or acute mefloquine toxicity syndrome, which has been shortened by some to the term “quinism”, is the condition we are talking about today.
Can the particular set of symptoms associated with mefloquine toxicity be confirmed by a discrete diagnostic process, creating a differential to other specific neurological or neuropsychiatric conditions? The answer to that is yes.
The science behind the syndrome is complex. Mefloquine is a pan-neuronal drug with broad activity within the brain. It's highly lipophilic and able to cross the blood brain barrier. It can, therefore, have broad reaching impacts across the central nervous system.
Others have questioned the role of a brain stem lesion in mefloquine toxicity syndrome. We must be mindful in making sweeping statements about the area of the brain impacted by mefloquine that both deep brain areas, such as the brainstem, Raphe nuclei and ascending reticular activation system, or subcortical areas impacting emotion and those controlling learning and memory, such as the hippocampus, all are impacted by exposure to mefloquine. Definitive biological studies in humans to confirm this would be simply unethical.
The broad mode of action is reflected in the variety, but consistency, of symptoms that mefloquine toxicity can show, impacting both superficial and deep brain regions. It does not just cause seizures and psychosis, which are indicative of higher cortical to subcortical effects, but also emotional and behavioural changes controlled by the amygdala and other subcortical regions.
Tinnitus and vestibular disorders can be both central and peripheral, and this is where the brain stem can be involved. As such, a description of mefloquine as a brain stem injury and, therefore, simply looking for cellular impacts in the brain stem would be conferring a simplicity to this syndrome that is not reflected in its symptomatology.
You have heard from a number of other witnesses that mefloquine can cause both short-term and long-term neuropsychiatric and neurological side effects, but these are not the only health impacts associated with mefloquine. They can include severe gastrointestinal disease, joint pain and peripheral neuropathies, so there is a spectrum of ill health associated with a reaction to mefloquine, all of which can have a significant life-changing impact on the sufferer and last for many decades post-exposure.
Perhaps some of the most compelling arguments to support this statement that exposure to mefloquine causes long-term health deficits are findings in a recent study commissioned by the Australian Department of Defence and Department of Veterans' Affairs. This study reviewed health surveys undertaken by Australian soldiers who had been given mefloquine or another anti-malarial treatment during active service in Bougainville or East Timor. This was, therefore, a study comparing like with like, apart from their drug exposure, and included exposure to battle conditions. Although it was based an opportunistic retrospective dataset, this analysis identified that the personnel who had been given mefloquine were more likely to have poorer health scores in the long term than those who had received doxycycline or another anti-malarial.
As an analysis, commissioned by Defence, of scientists who were trusted Defence research partners, this evidence could not be overlooked. Perhaps on the basis of this finding, the Australian government accepted in principle all of the recommendations of the recent Senate inquiry into the use of mefloquine and tafenoquine in the Australian Defence Force, and committed $2.1 million Australian dollars to a treatment and rehabilitation program currently being implemented by the Department of Veterans' Affairs in conjunction with its counselling service, Open Arms.
I'm proud to say that I sit on the steering committee for this program, and I hope it will provide significant assistance to the group of veterans who have, to date, been left without assistance by the organizations meant to help and treat them.
Acceptance that mefloquine causes long-term harm is critical to resolving the health issues for those affected, and I believe that this evidence is not in doubt. The question is what the next steps are for those individuals and what strategies can be implemented to help them.
Comprehensive neurocognitive screening should be applied to all veterans to determine their neurocognitive, as well as psychological, health status. A 360-degree health review should be implemented to look holistically at the health and well-being of these veterans and their families, and appropriate support strategies should be applied, including access to occupational therapists, psychologists, psychiatrists or other health care professionals as appropriate.
Pharmacogenomics screening, particularly for metabolic enzymes of the cytochrome oxidase P450 family and for pharmacogenetics markers that have been shown to be required for mefloquine metabolism, should become mandatory for all military personnel prior to their being prescribed any anti-malarial drugs to ensure both efficacy and safety, as well as the efficacy and safety of other treatments that they may be given during their military service or after.
This screening should also be applied to all veterans, particularly those affected by mefloquine, to ensure that any drugs now being prescribed are not going to cause further complications.
I would urge this committee to look to the future to ask the question “What is the best assistance that can be given to the veterans suffering from long-term health impacts from mefloquine for military service?” and to look to programs currently being designed in Australia to go at some of their outcomes.
I very much appreciate being invited to speak to this committee, and I am happy to answer any questions.
Liberal
The Chair Liberal Neil Ellis
Thank you.
Dr. Sellers, can you hear me, or do we have to go to the screen?
Dr. Edward Sellers Professor Emeritus, University of Toronto, As an Individual
No. I can hear you.
Liberal
Professor Emeritus, University of Toronto, As an Individual
I'll make a few brief comments.
I'm a professor emeritus of pharmacology and toxicology, psychiatry and medicine at the University of Toronto. I've been involved in research, teaching, and clinical care, involving psycho-pharmacology—that is drugs that act on the brain—for over 40 years.
I must say, Mr. Chairman, I was somewhat surprised to be invited to meet with the committee because it wasn't entirely evident to me what you expected. I suspect it may have something to do with my very broad background in basic and clinical neuroscience and my involvement in pharmacal kinetics and risk factors for drugs. One area that I have worked in that might of particular use to the committee is the causality assessment of drug-related events. That is the determination of whether a drug has actually caused a particular adverse event.
One of my papers, for which I was the senior and supervising author, is probably particularly relevant to the work of the committee. This paper was called “A method for estimating the probability of adverse drug reactions”. It is a systematic algorithm for looking at all the factors and rating the likelihood that a drug actually caused a reaction and to take into account the relative contribution that the drug might have had in the face of other factors that may bear on a joint risk between the drug and the particular adverse event.
I agree with Professor Quinn's characterization of the evidence that there are acute and chronic, often serious, adverse events of administering mefloquine. I've used this particular algorithm in many settings, from single patients and groups of patients to literature reviews and so forth. Several years ago, I used this particular way of assessing causality to apply to a non-military individual who in error dispensed mefloquine instead of Malarone and had a profound, acute, and chronic, neurotoxic reaction.
Professor Quinn has outlined some of the issues around diagnosis. Of course, it's very tempting to try and fit what happens after a drug is given into a very tight box. You give penicillin; you get a rash, and it seems fairly straightforward.
In the case of chronic neuropsychiatric toxicity, it's not really that simple because a drug that has such reaction interacts with the individual's past history, their concurrent history, if they have mental disorders or are subject to other stresses. It's not surprising that the manifestations are quite diverse. I have heard people sort of argue, “How could a drug cause such a broad kind of effects?” Anyone who's involved in behavioural science and neuroscience doesn't find it surprising, really, because very many different parts of the brain can be affected by drugs that can bind to different receptors in different parts of the brain. The way the adverse event shows up—it's phenotype, as we call it—is determined by antecedent and concurrent factors.
A problem that frequently comes up is that often the information that's available is incomplete. Many of the studies alleging that the neuropsychiatric consequences of mefloquine are very rare are really done from data sets that are very weak. In those that have been designed properly, prospectively or with matched controls—mefloquine has even been given to healthy, normal volunteers—indicate that it has a very narrow margin of safety. You can raise the dose two-fold or three-fold, and you'll have 40% or 50% of the healthy, normal volunteers having acute effects from the drug.
The acute effects sometimes get passed off as if they're not important, but we're talking about a drug that's used for prophylaxis in people who don't have the disease. When you give the drug to normal volunteers and you see vivid dreams, disassociation, and effects on cognition, this is a warning sign that this drug has potentially serious toxicity.
One issue that comes up with mefloquine is that the toxicity doesn't seem to be entirely predictable. Now, it is true that higher dosages give rise to greater frequency of adverse events, and some of them are very unpleasant. However, it's not so clear with the onset of chronic neurotoxicity. Often, an acute event after taking the drug is a warning that the individual has some risk factor, that the drug is interacting and is going to cause a problem.
What we find is that there are other things that must be afoot. For example, we know that mefloquine gets out of the brain by a particular transport protein. There are individuals who lack this transport protein, so mefloquine can reach very high concentrations in their brains, and that puts them at particular risk. It's really the mefloquine in the brain—amount or concentration—that's important.
The final comment I would make is to endorse the systematic approach that Professor Quinn has urged. It is extremely important that individuals who are to receive any drug that has risk be explicitly warned and that there be careful documentation, and that individuals who have the risk factors don't receive certain drugs.
I know that there's been interest in this particular field in drug labelling, but drug labelling is not a good way to inform patients or even physicians about what the problems are. The surgeon general's review identified a lack of proper documentation among military individuals with respect to having even received this drug, and identified individuals who received the drug who had contraindications.
There's something clearly not right, and I think Professor Quinn outlines a very reasonable, systematic and probably long overdue approach.
Having said that, I think that the current practice of not prescribing this drug is entirely appropriate. I noticed in some of the material I looked at before today that somehow patients are given an option that they can indicate they would be prepared to take the drug. I think we're past that. I don't think this is a drug—except in situations where there is extremely careful monitoring and very knowledgeable individuals are prescribing the drug—that somebody can say, “Well, yes, I'd like to take mefloquine”. There's an implication here that is outside of the normal medical world that I work in.
My recommendation is that you take this assessment of causality, this strategy, and apply it systematically to cases that are either emergent ones or retrospectively.... This involves two steps: applying the algorithm to assess causality, and then assessing what information is missing that makes it difficult to make the assessment of causality. Just because it looks like it's not likely the drug doesn't mean there isn't a reaction caused by the drug. It's usually because the information is not available to make the assessment. This is the problem in most of the literature that people point to when they're trying to support that this is a very rare kind of thing, or that it doesn't happen at all and so forth. That's not the real situation.
Thank you.
Conservative
Cathay Wagantall Conservative Yorkton—Melville, SK
I really appreciate that both of you, Professor Quinn and Dr. Sellers, are here today. Your testimony has already been very beneficial to us.
Dr. Quinn, I want to express my deep concern and sympathy for what you've been through personally. You have a unique environment, in that you have suffered one of the greatest losses you could in relation to this drug, and you also have such expertise in this field. Thank you so much for being willing to be here with us today.
One of the answers we get here related to veterans seeking care for the effects of mefloquine toxicity, which is not recognized here in Canada as a medical condition, is that if they have a diagnosis consistent with the warnings listed for the drug, then they only need to bring that diagnosis to VAC, and VAC will treat the veteran for the condition but will not recognize that the condition is due to mefloquine. If veterans are reporting nausea, vomiting, diarrhea, abdominal pain, dizziness, vertigo, loss of balance, or neuropsychiatric events such as headaches, lack of sleep, or sleep disorders, they could be treated for these conditions but with no recognition that they might be due to taking mefloquine.
I would really like to know your perspective on whether that is appropriate or whether it should be considered as a major factor in their diagnosis.
Prof. Jane Quinn
Yes, I definitely think it should be considered as a major factor. If you have a clear causal relationship—and this is what we've just been discussing—then it is common sense that there needs to be a validation of that causality within the diagnosis.
One of the significant issues that veterans have faced is the fact that the role of the drug in their ongoing medical conditions has not been formally acknowledged and has therefore not been allowed to be taken into account in their treatment and in the consideration of the life circumstances around how their particular medical condition arose.
There has been a significant amount of money, for example, focused on PTSD research, which is a very valid cause, but this is an equally valid cause with an equally well-described and well-contained disease status.
Prof. Jane Quinn
Those veterans with validation through a PTSD diagnosis gain considerable benefit in their mental well being, and that needs to be applied for—
Conservative
Cathay Wagantall Conservative Yorkton—Melville, SK
Right. So it's not just a matter of recognizing the conditions. PTSD and mefloquine toxicity should receive the same kind of attention.
I'm curious. I was at the Invictus Games in 2017. CIMVHR held a big seminar on taking care of the families of our armed forces and veterans. Your minister of Veterans Affairs at the time—I'm forgetting his name—was there. We had a good conversation around mefloquine. He said that our new Minister of Veterans Affairs, Mr. Seamus O'Regan, had indicated to him that he would really like to work with him on studying and dealing with this particular issue.
Are you aware of any collaboration at all between Australia and Canada, with the research that you have been doing?
Prof. Jane Quinn
I'm not clear that there has been a direct collaboration. Certainly Australia and Canada are both part of the Five Eyes on mental health, a broad initiative around military veterans' mental health, particularly. But the direct collaboration—
Conservative
Prof. Jane Quinn
I know that there is international oversight of what's occurring globally, but I'm not sure that there's a specific initiative.
Conservative
Cathay Wagantall Conservative Yorkton—Melville, SK
So they should definitely be aware of it, if nothing else—the research that's been done.
Conservative
Cathay Wagantall Conservative Yorkton—Melville, SK
In March of this year, as you mentioned, Australia announced a $2.1 million initiative to support veterans who had taken mefloquine. From what I understood, part of that came from the fact that they had a whole year to come and testify, and that was in itself traumatic. It includes a comprehensive health assessment, and concern for those who took mefloquine.
From what you said, you have a major role to play in Open Arms. Where do you see the value in something like this coming forward for our Canadian veterans? As of today, the surgeon general has changed how mefloquine is distributed. It's no longer used the way it was. Its use has gone way down. But we have many veterans who have suffered under this drug. What is your view on transferring that type of program to other countries, including Canada?
Prof. Jane Quinn
First, I'm on the steering committee, so I'm not formally employed by either the Department of Veteran Affairs or Open Arms, but I sit very much as an external adviser on that committee and part of the team that has formulated how that program should look.
It would hardly be applicable. It would be immediately transferable. It's a treatment design program that aims to give an assessment and treatment strategy for personnel who suffer from any kind of neurocognitive, neurological disorder. So it's not necessarily specific only to mefloquine and tafenoquine veterans in Australia, but can take account of more broadly acquired brain injury in mild traumatic brain injury or degenerative brain conditions for all the veterans as well.
It would be easily transferable to any other jurisdiction.
Conservative