Veterans Affairs Committee on May 13th, 2019

[Doug Eyolfson, Liberal, Charleswood—St. James—Assiniboia—Headingley, MB]

Thank you both for coming.

This is very useful to us, and likewise, Dr. Quinn, thank you for coming forward and for your candour about your struggles. I know this must make things much more difficult for you.

We're talking about the diagnosis of mefloquine toxicity. Right now, we are dealing with a lot of literature that says there are some associations. I haven't been able to pin down anyone for an answer as to how I can look at patient X and say this patient's symptoms are mefloquine toxicity. An Australian committee report tabled in March of 2019 specifically says, “There is no specific way to diagnose chronic mefloquine toxicity effects as many symptoms are shared with other conditions such as PTSD.”

How do we reconcile a statement like that?

[Prof. Jane Quinn]

I think that statement is somewhat simplistic. A set of diagnostic criteria includes both neurological as well as neuropsychiatric symptoms.

[Doug Eyolfson, Liberal, Charleswood—St. James—Assiniboia—Headingley, MB]

Okay. Sorry to interrupt. I have very limited time.

Where can we find these diagnostic criteria published? Are these generally accepted by the medical profession as diagnostic criteria?

[Prof. Jane Quinn]

I think that's what I said, namely, that it doesn't appear in any of the diagnostic manuals. However, the accumulation of symptoms has been published on numerous occasions, both in case reports and in articles that have taken broader populations into account.

[Doug Eyolfson, Liberal, Charleswood—St. James—Assiniboia—Headingley, MB]

I understand that, but that doesn't necessarily mean this is defined by diagnostic criteria if part of the literature describes it in a number of case reports. If it's not in any diagnostic manual, how do I as a physician know that a patient who came back and deployed and took mefloquine is suffering from mefloquine toxicity versus PTSD?

[Prof. Jane Quinn]

There are a number of specific differentials, one of which is vestibular disorder and central vestibular disorder. The others are the particularly vivid dreaming states and the decline observed in patients suffering from after-exposure to mefloquine.

The other key diagnostic indicator is whether or not a person had a reaction at the time to taking the drug. In other words, they had a different health status prior to and immediately prior to taking mefloquine and their health status changed at the point at which they took the drug. That's a key critical indicator to identify those who had been directly affected.

I think Professor Sellers will probably have something to add to that as well.

[Doug Eyolfson, Liberal, Charleswood—St. James—Assiniboia—Headingley, MB]

Dr. Sellers.

[Dr. Edward Sellers]

Yes. I think that Professor Quinn is nudging up to what you have to do. It's really the assessment of whether the drug has caused a reaction. In this case, we know the natural history that an acute reaction is associated with a probability of a longer term reaction. So you need to know, was the drug given? What dose was given? Was it taken? How long was it taken? What are the individual's risk factors? What is the uniqueness of their symptomatology? What's their past history of anxiety, depression and so forth? And if you do that systematically, you can determine whether mefloquine was involved in the evolution of the symptomatology. It's nice to have a diagnostic category, but with neuropsychiatric kinds of issues, you're going to have a mixture of signs and symptoms.

[Doug Eyolfson, Liberal, Charleswood—St. James—Assiniboia—Headingley, MB]

Okay. Thank you.

I'd like to refer to a paper published in the American Journal of Tropical Medicine and Hygiene in 2018. This was data collected from approximately 19,500 U.S. veterans, many who were deployed and many who were not. It looked at the mental health outcomes between anti-malarials—whether or not people received anti-malarials. Again, this is a very large study in a peer-reviewed scientific journal. The summary says, “once deployment and combat exposure were added to the multivariable models... No significant associations were found between mefloquine and mental health measures.” It goes on to say, “These data suggest that poor physical and mental health outcomes reported in this study population are largely because of combat deployment exposure.”

This is a very large study in a peer-reviewed journal that's fairly recent, which basically says that they cannot find any definitive relationship between this drug and these symptoms.

What do we have to counter that? Are there peer-reviewed scientific journal articles of similar power that will refute this?

[Prof. Jane Quinn]

There have been a number of studies done over time.

Sorry, go ahead.

[Dr. Edward Sellers]

The issue here is that large doesn't make good. That's a particular retrospective kind of study that suffers from failure to document, record and have an accurate estimate, and the kind of symptoms that often get reported never show up in medical records, so—

[Doug Eyolfson, Liberal, Charleswood—St. James—Assiniboia—Headingley, MB]

If I may, the paper is very detailed. It has a number of symptoms and quite a rigorous medical evaluation of these people who were deployed. Again, I've done some medical research. I practised medicine for 20 years. I have to admit, that's the first time I've ever heard the phrase regarding scientific studies that “large doesn't make good”. One of the problems with scientific studies is that the smaller your studies, the more difficult it is to basically ascribe significance to them.

[The Chair, Liberal, Neil Ellis]

Thank you.

Ms. Blaney.

[Rachel Blaney, NDP, North Island—Powell River, BC]

Dr. Sellers, I would be very happy to hear your response to that question.

[Dr. Edward Sellers]

The basis of my little clip there that “large doesn't make good” is that it really depends on the source of the data. That kind of study is very typical of retrospective epidemiologic studies. The universal weakness of those studies is that one does not have information about all the things you really want to have.

You want to know what the subjective symptoms and behaviours were that were exhibited. What you often end up with is little things in a chart; you have a diagnosis, but you don't know when it started, so you end up basically with an inference that that particular study is at odds with what we know from other studies that have been properly controlled.

Professor Quinn referred to one such study, but there are others. In the literature as a composite, going back as early as the 1970s, it is clear that drugs that have this chemical structure are associated with this again and again and again.

When you see somebody leaving a bank, and the money isn't there, you say “woah”. It happens the next day. There's a robber. Something is going on. This is a repetitive pattern with this drug.

[Rachel Blaney, NDP, North Island—Powell River, BC]

Thank you so much. I really appreciate that.

Dr. Quinn, I will turn to you. Right now in Canada there's no real process for Veterans Affairs or even National Defence to reach out to people who have taken mefloquine. There's no process for them to screen, so one of the concerns that I have as we do this study is how many people are undiagnosed in this country. Are they getting the proper supports and treatment they need?

You also spoke to the reality that sometimes treatment for post-traumatic stress disorder—which may be part of the diagnosis, but not the fulsome diagnosis—can be a problem for them in getting the support they need.

I'm just wondering if you could speak to the parts of the following question. How can we explain to this government that we need to be reaching out to these folks to make sure they get properly diagnosed? What happens if they're undiagnosed and only being treated for post-traumatic stress disorder? What kind of harm could that bring?

Thank you.

[Prof. Jane Quinn]

This was very much the position that we came into when designing the neurocognitive health program for Australia. We knew there was a cohort of veterans out in the community who were suffering from long-term neuropsychiatric and neurological health impacts, as well as other health impacts, that had impacted their family members and their very broad existence. We knew they were very disenfranchised from treatment modalities through the Department of Veterans' Affairs, because those have often been highly unsuccessful.

One key remit was to have an open strategy that allowed them to re-engage with that process without fear of coming into conflict with previous diagnoses, and also to allow a full and open neurocognitive assessment and holistic assessment of their current health status and health needs. One key thing that needs to occur prior to those veterans coming back into those treatment programs is the validation that their condition could be related to the drugs they have taken. An acknowledgement by the Australian government—and now through the findings of the senate inquiry—that it is a tangible and real event that has impacted their lives in a very longitudinal manner is something that is extremely important to re-engage those veterans who have been lost from treatment programs in the past.

I think these are key strategies, and an active outreach program that is very focused on improving overall quality of life, not just making a series of short-term diagnoses and therefore short-term treatment outcomes.

[Rachel Blaney, NDP, North Island—Powell River, BC]

Thank you so much. Definitely what we've heard from many veterans across Canada is that piece about being acknowledged and that their feelings of stress and disenfranchisement are because their having this disorder is not not being acknowledged.

Dr. Sellers, is there anything you would like to add to that part about the treatment of post-traumatic stress disorder without the proper diagnosis of mefloquine toxicity. So you have anything about doing the outreach and actually connecting with people who may have this and do not have the proper diagnosis here in Canada?

[Dr. Edward Sellers]

Of course, this goes far beyond PTSD because the neuropsychiatric consequences of mefloquine can involve depression, psychosis and a whole range of different kinds of symptoms. As a clinical pharmacologist, the kind of thing I would do is look for an index of exposure. I would try to find all individuals who were alleged to have been prescribed. In my opening comments, I made the point that prescribing, dispensing and taking are all quite different. We have examples of mefloquine being taken every day when it's meant...and so forth. All these strange kinds of things happen.

I suspect the military must have really good records of who actually was prescribed this. That would be a starting point to identify what we would call an index case, and to then go and assess that individual with respect to some of the things I outlined in this causality process. That involves establishing that it was taken, that the sequence was right, what dose it was and what concurrent issues were.... It's a systematic way of taking an individual and making an assessment.

It's convenient to talk about how the drug causes it all, but it's always a little more complicated than that when you're dealing with these kinds of disorders. The drug can very well be an important contributor, and that is just as important to determine as those rare cases when it was the only antecedent factor that caused it.

For the case that I mentioned that I assessed, it was clearly just a dose issue. Seven times the proper dose was given to a businessman, and he had a profound acute effect and a very profound neuropsychiatric consequence. You have to have the information and get the data.

[The Chair, Liberal, Neil Ellis]

Ms. Ludwig.

[Karen Ludwig, Liberal, New Brunswick Southwest, NB]

Thank you both for your testimony today.

My first question is for Professor Quinn. Dr. Sellers talked about records of who was prescribed mefloquine. We know from previous witnesses before this committee that we don't have thorough records here in Canada, unfortunately.

In Australia, have records been taken, in terms of who was prescribed and when that was prescribed?

[Prof. Jane Quinn]

Yes, to some extent. We have an interesting situation and it's somewhat comparable to Canada's in that there were a number of veterans who received mefloquine during clinical trials carried out by defence during the late 1990s and early 2000s.

Interestingly, because they were exposed to the drugs during a clinical trial regime, that exposure wasn't documented in their main military records. It was held separately. What became apparent when we were first investigating the situation here in Australia was that those individuals were not aware that they had been exposed to mefloquine or another experimental drug, tafenoquine, because that was not documented in their general medical records. Those medical records had been held separately. So accessing those medical records became extremely important.

What is unique, slightly, about the Australian situation is that those individuals are therefore extremely well documented, and the retrospective study that I talked about in my opening statement actually was cross-referencing between some of those data sets, because there were individuals who could be discretely identified. We know quite precisely the number who were exposed during clinical trials—it's around 4,500—to the two experimental drugs, one of which was mefloquine, and then there has been some detailed documentation kept since about 2010 that allows us to know that there were at least another 500 individuals exposed after that.

There is a paucity of information from the late 1980s through to about 2000, when more detailed electronic medical records were kept, so it's an open book as to who exactly was taking mefloquine and who wasn't. That's a very similar situation to that in the U.K., the U.S. and Canada, where there's been a period of time prior to electronic medical record-keeping when it is actually very difficult to know exactly who took the drug and who didn't. What we do know is who was deployed to regions where it was the drug of first choice, so individuals deployed to those locations could almost be guaranteed to have taken that drug.

However, as Dr. Sellers says, one of the key things that need to be done is to actually interrogate those personnel to find out if that was the case, because recollections of whether a drug was taken daily or weekly can certainly give a very strong indication for those who were exposed during that period of time as to whether they were likely to be taking—

[Karen Ludwig, Liberal, New Brunswick Southwest, NB]

Professor Quinn, I'm just going to jump in to add to that. I'm going to take a turn on this one.

I'm wondering, Dr. Sellers, if you could speak a little bit to that. For example, Professor Quinn is talking about digging deeper into people's pasts in terms of who may or may not have taken it. When you talk about the neuropsychiatric symptoms, how familiar would health care professionals be in Canada on the neuropsychiatric symptoms possibly associated with mefloquine, if veterans went in to see their family doctor?

[Dr. Edward Sellers]

I think the reality is that it wouldn't work out all that well. I think most primary care physicians would not be very familiar with.... We know that the management of mental health is a problem in our health care system anyway. Problems aren't recognized. This is getting very deep into a very specialized kind of problem, so I think that the kind of approach that involves a targeted kind of approach with special capabilities to do the assessments....

I take the point that sometimes the records are just dreadful, so you can't really tell whether something's actually been prescribed, but you probably do have a pretty good record of who was deployed into a zone in which prophylaxis would have been given. Then you can go to the individuals and ask. Many, many individuals will tell you exactly, “Oh yes, they gave me this pill, but I never took it”, or they'll say, “Oh yes, well I thought maybe I should take some extras”. They'll tell you more or less what's going on. You don't go crazy putting weight on it, but it gives you something that you may not find in the record, because they can tell you.

[Karen Ludwig, Liberal, New Brunswick Southwest, NB]

Right.

Do I have more time?