Transcript of Episode 2 with Dr. Barbara Koppel
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Host – Dan Keller
Hello, and welcome to Episode Two of Multiple Sclerosis Discovery, the Podcast of the MS Discovery Forum. I’m your host, Dan Keller.
This week’s Podcast features an interview with Dr. Barbara Koppel, whose recent review of published studies concluded that certain forms of medical cannabis can be helpful in treating some symptoms of multiple sclerosis. But first, here is a brief summary of some of the topics we’ve been covering on the MS Discovery Forum at msdiscovery.org.
First, predicting MS risk. Cardiologists can use the Framingham risk assessment tool to predict the likelihood that one of their patients will develop heart disease. But what about MS? Given that researchers have now found 110 genes related to MS risk, are we close to a formula that can predict who will develop MS and what course it will take? Disappointingly, the answer is probably not. Reporter Emily Willingham writes that “Decoding MS risk factors is less like fitting together a jigsaw puzzle and more like balancing a Jenga tower, with layer upon layer of complex interactions and unpredictable outcomes if something changes.” For those of you who may not be familiar with Jenga, it’s a children’s game popular around the world that involves balancing wooden blocks in the form of a tall tower; our article includes a helpful photo.
Next, what does the nose know about MS? Maybe a lot. Many people with MS lose their sense of smell, and now a new study involving postmortem brain samples appears to show that, contrary to earlier studies, the olfactory system is the site of significant demyelination and axonal loss. Could it be that the olfactory system is an important link between environmental exposures and MS? Stay tuned.
Finally, we’ve just posted our newest data visualization. This one is a scientific literature treemap that makes it easy to zoom in on peer-reviewed articles or clinical trial listings describing randomized, double-blind MS trials. Our own extensively researched drug development pipeline provided the source material for this visualization.
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Now, onto the interview. Dr. Barbara Koppel is Chief of Neurology at Metropolitan Hospital in New York and Professor of Clinical Neurology at New York Medical College. Along with Dr. Gary Gronseth of the University of Kansas School of Medicine, she conducted a systematic review of the literature on treating MS and other neurological diseases with medical marijuana. I caught up with Dr. Koppel at the annual meeting of the American Academy of Neurology in Philadelphia.
MSDF
First of all, let me ask you why do you use the term marijuana? Most people around the world use cannabis?
Dr. Koppel
There is a difference, there’s a technical difference. Cannabis, I think, only refers to some of the derivatives, and we thought medical marijuana, more people would connect with that, they would know what we were talking about; the current buzzword, but it also refers to both pills and smoked and everything else.
MSDF
And what did you look at in review, what forms of medical marijuana or compounds?
Dr. Koppel
The reviews went back to studies since 1948, and the compounds that were used were pills, an oral mucosal spray that’s called nabiximols that I’d never heard of but it’s used in England, and then a few of the studies covered smoked marijuana which were marijuana cigarettes basically.
MSDF
And what did you find, specifically the use of it for multiple sclerosis?
Dr. Koppel
There is symptoms that it helped. It was most efficacious in spasticity, in reducing spasticity – more on the patient-related scales than the doctor Ashforth scale – but in depending on which study we looked at, the pills helped and the spray would help. It was also useful in reducing pain levels, either pain from spasms or pain from central causes – you know, burning numbness type of pain – and it reduced the number of voids, bladder voids, but some of the other bladder symptoms it had no effect on. It didn’t help tremor, which is also good to know because now we have to keep looking for other things for tremor in MS. Then we looked at other diseases, but most of the work has been done in MS.
MSDF
Right now in the US there’s only one form, a pill form, approved. Do you think that you had sufficient data to make any conclusions or recommendations?
Dr. Koppel
The pill forms that are available here, they’re not approved for anything other than chemotherapy-induced nausea and appetite in AIDS patients, so they were used in some of the studies and they were useful for spasticity, again, and painful spasms. The problem is that the pills are primarily THC rather than cannabinoid, so it’s hard to get up to a dose that’s working without the toxicity that comes along with THC; they they weren’t all that great. The one study using smoked marijuana was in the US, and they used marijuana cigarettes which trended towards efficacy, but the study didn’t have enough power to make any conclusions from; there weren’t enough patients basically.
MSDF
Is the oral spray – which isn’t available in the US – a different composition, and does it have any differences in effect or advantages?
Dr. Koppel
It has a big advantage because it’s a combination of cannabinoid – which is the part of the cannabis that you want to reduce symptoms – and THC. And the psychoactive side effects usually come from the THC as opposed to the cannabinoid, although it does have some psychoactivity as well. So the main advantages that I could find is that patients could self-titrate; they could use up to a certain numbers of pumps a day. But if they felt better with two or three pumps, they could stay at that dose. If it didn’t work at that dose, they could go up to six or seven – I forgot – the maximum. So I think that was found to be more effective, just because patients could take a dose that was adequate. It is going to be studied here, it’s the company has got testing sites mostly for epilepsy now, but it will become available here.
MSDF
Have you found either in practice or from any studies whether patients were reporting self-medicating, especially with smoked form?
Dr. Koppel
Yeah. The We couldn’t use those studies to make this systematic review because no one really examined them and they’re just basically testimonials or questionnaires, but there was a lot of literature that included that. And, in fact, one of the earlier papers from England, that’s why they began looking at more suitable forms of cannabis, because their patients were self-medicating by smoking, you know, just regular old marijuana and reporting that to their doctors, and and then the doctors tried to translate that into a pill form or a spray form that could be looked at more rigorously. And my patients in New York, you know, they they’re not shy. I don’t have a big MS practice, so my patients are more likely to be seizure patients. It’s not that they use it for their seizures. Every once in a while they’ll ask me if it’s okay, if it’s going to cause seizures or withdrawal, like alcohol withdrawal can cause seizures. And I can now tell them, no, it’s safe enough from that point of view.
MSDF
I think you had mentioned in a news conference that there were 2 out of something like 623 patients who had did have seizure that might be attributed to use of the drug, so I take it that does not concern you. Are those small numbers, especially since you’re dealing with patients with epilepsy?
Dr. Koppel
Yeah, those are small numbers. And what I’ve found is that they used to say patients with MS didn’t get seizures, but they do. There were actually four seizures that were reported, and two they didn’t blame on the drug; so they were either in the placebo group or they were patients that already had seizures. But it’s always something to worry about, but it’s such a small number that I wasn’t concerned.
MSDF
While we’re on the subject, what other adverse effects did the studies you reviewed note?
Dr. Koppel
The common ones that appeared in at least two two papers were things like nausea, fatigue, dizziness, fainting. In some of the studies that used the more potent forms that had more THC, they had hallucinations and depression and suicidal thoughts, but no one actually did commit suicide during the studies.
MSDF
Is this a problem in MS since some of these types of symptoms or problems occur with the disease itself, could these be exacerbating it or are they directly related, do you think, to use of the drug?
Dr. Koppel
That makes it complicated and that’s why you need kind of rigorous studies so that you can compare dose effects and things like that. But if a patient already has cognitive impairment, they may have trouble dealing with the side effects that, you know, that I mentioned. It’s easy to confuse that issue with the heavy users, the recreational users who end up with cognitive impairment that can be permanent. These were doses that were nothing like what people use for fun.
MSDF
If this works out that it would be a useful form of drug if testing shows validity, who do you see it being recommended for? People refractory to certain other medications, or how would it be used?
Dr. Koppel
That was the case with all the studies, they were allowed to try everything there was up to that point and kind of added this marijuana as a last-ditch effort. So I would say if a patient’s got uncontrolled spasticity or too much pain, they should try it. I wouldn’t really recommend it for bladder issues because it wasn’t that successful, and I definitely wouldn’t recommend it if tremor was the symptom they were trying to get rid of. So it just depends on what the patient’s telling you is bothering them the most. And, obviously, the patient has to be willing to assume all the side effects. I think one of the good things about this is some of the stigma is possibly going away so that… There’s a lot of people who assume that patients that want to try it, it’s just because they want an excuse to, you know, use recreational marijuana and get high, and it it really wasn’t the case in the studies.
MSDF
It seems like it’s long past due to be rigorously testing these things.
Dr. Koppel
Yes, I I agree. It has been tested in other disease states, this is just a piece of the pie where marijuana is used. It’s been used on patients with intractable pain from cancer or people with glaucoma have benefited from it; there’s usage out there. And the states that have legalized it, they don’t care which condition it’s being prescribed for. So I think it’s just neurology’s kind of lagged behind because it’s been so hard to do research on it in this country. Even in England where a lot of the studies were done, they put into their reports that it wasn’t easy to get approval. It’s not legal there either, but I guess they just were more persistent in studying it.
MSDF
Since in most of the studies that you reviewed, it was used sort of as a last resort or an add-on later, would you see that as its primary role or could it take a more prominent role?
Dr. Koppel
As I said, I usually treat seizures, and what I try to do is not pile on one pill after another pill. If something seems to work, I’ll take away something that wasn’t working. So I think that’s the role for it, because if you take everything you’re going to definitely accumulate the side effects and then you really have trouble functioning. So I think if this works better than some of the existing treatments, there’s no reason to take both of them. Let me just add, it still shouldn’t be your first-line treatment, you you should still try the traditional ones first. And mon many of these trials only lasted 8 weeks; you don’t need forever to decide if something’s helping or not.
MSDF
What would be the message to physicians who contemplate advising patients about medical marijuana?
Dr. Koppel
I can’t tell them to go ahead and prescribe it because – for two reasons – I don’t really love the form that’s available here because it’s all THC, and it’s not FDA-approved for these conditions, so they’re still taking a chance on breaking that rule. I would advise physicians to find trials or to do a trial rather than just tell patients… even in the states where a doctor can give a card that says they agree with using medical marijuana, you you lose control of the dose and how much how much the patient smokes, and all that. So I would encourage some more traditional pills and sprays to be studied so that then they could be prescribed.
MSDF
Should these prescriptions, or recommendations, really come with either informal or formal informed consent about side effects and possible things to avoid doing, like driving?
Dr. Koppel
We should probably do that on a lot more pills that we’re currently prescribing. I I don’t always routinely do it, but the pharmacy tends to hand out a list of dos and don’ts, and some of the bottles are labeled don’t drive. It’s not that different from other CNS-depressing drugs, but it’s worth warning people. And, actually, I think it shows up in their urine, so if they’re going to go somewhere where a tox screen might get done, they they should have a card or a prescription that shows that it was prescribed.
MSDF
This systematic review is being published in the Journal of Neurology on April 29th, and also, I guess, it’s already been endorsed by certain societies, medical societies?
Dr. Koppel
They sent a summary of the findings to, I guess, other other societies that deal with the same conditions, because in addition to MS, we studied Parkinson’s and Huntington’s and Tourette’s and seizures, even though there were only two studies for that. So some of the other societies have not confirmed it but endorsed it in the sense that they agree with what we found.
MSDF
I appreciate it.
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Thank you for listening to Episode Two of Multiple Sclerosis Discovery. This Podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations.
Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.
We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.
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Multiple Sclerosis Discovery: The Podcast of the MS Discovery Forum
Transcript of Episode 1 with Dr. Timothy Vollmer
[intro music]
Host – Dan Keller
Hello, and welcome to Episode One of Multiple Sclerosis Discovery, the Podcast of the MS Discovery Forum. I’m your host, Dan Keller.
This week’s Podcast features an interview with Dr. Timothy Vollmer, who discusses strategies for maximizing brain health in people with MS. But first, here is a brief summary of some of the topics we’ve been covering on the MS Discovery Forum at msdiscovery.org.
First, oral contraceptives. According to a retrospective study published in the journal Fertility and Sterility, women with relapsing remitting MS who used combined oral contraceptives tended to have less severe disease, and they were less likely to move on to secondary progressive MS. On the other hand, this study showed no association between oral contraceptives and annualized relapse rates or EDSS scores. An intriguing set of associations, but correlation does not imply causation.
Next, the blood brain barrier. A study in PLOS ONE showed that when cultured blood-brain barrier cells are treated with serum from MS patients the cells decrease their production of tight junction molecules and increase their production of cell adhesion molecules that promote cell migration. Breakdown of the blood-brain barrier is an early feature of MS, and this allows activated leukocytes to migrate into the brain. Understanding this process is important in its own right, but the study also raises questions about the safety of blood donations from people with MS. Does this study suggest that people with MS should be barred from donating blood? Let us know your opinion in the comments.
Finally, we hope you’ll check out our new data visualization section, which will allow you to see MS-related data in new ways. Our first visualization is a bubble chart presenting data from 106 MS clinical trials published between 1986 and April 2014 involving 44,606 patients. You can easily sort the data by compound, by trial phase, by dose, by year, by funding, or by population. Please let us know if you discover something unexpected or particularly striking in the data.
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Now, onto the interview. Dr. Timothy Vollmer is a practicing neurologist specializing in MS. He’s also professor and director of clinical research at the University of Colorado Denver. Bob Finn, our executive editor, caught up with Dr. Vollmer at the annual meeting of the American Academy of Neurology in Denver.
Interviewer – Bob Finn
This is Bob Finn from the MS Discovery Forum. I'm here with Dr. Timothy Vollmer of the University of Colorado Denver Rocky Mountain MS Center, who among other things is interested in how to maximize lifelong brain health in people with MS. Dr. Vollmer, welcome.
Interviewee – Timothy Vollmer
Thank you.
MSDF
Why is now a good time to ask about maximizing brain health?
Dr. Vollmer
Well two reasons: one is because recent research has indicated that there are both medical ways and lifestyle ways to actually improve brain health, and the the data suggests that if we do that that's going to improve people's function later in life and allow them to be the grandparents that they want to be or other things that they want to do later in life. And the second reason is is that we now have nine FDA approved therapies to alter the course of MS by inhibiting the inflammation that causes the damage in the brain. And our challenge is figuring out how to use those most effectively.
MSDF
So how do you measure a concept as broad as brain health?
Dr. Vollmer
The easiest measure is actually the size of the brain. One of the unfortunate consequences of multiple sclerosis – as is true with hypertension, cardiovascular disease, strokes, dementia, and other things – is that neurons are dying. So MS is not just a disease of myelin; it's a disease of the entire brain, and it affects neurons and cells called astrocytes and cells called oligodendrocytes that make up the bulk of what the brain is. The result of of loss of these neurons is the brain has less and less flexibility in terms of shifting function around from areas that are not working well to areas that are working well. That ability to switch, or shift function around, is something that we do automatically throughout life. Every time we bump our head and get a little bit of bruising in the brain the brain can compensate by shifting function around. This is the same issue that the NFL is dealing with with its football players and mothers are worried about with their kids in contact sports. The problem of multiple sclerosis is that most of the disease activity is actually below the radar – it's not presenting as relapses – and you don't see it unless you're doing regular MRIs, or you're doing a a more modern MRI technique called a volumetric MRI where you can actually measure the three-dimensional volume of the brain. And we do that routinely in studies, and we know that in MS the brain is shrinking at a rate of about six times faster than the normal healthy controls. That's the fundamental problem in terms of maximizing lifelong activity is we're losing brain function too fast in the early phase of the disease.
MSDF
So how does this concept help guide treatment?
Dr. Vollmer
Well it turns out that there actually are three components to a treatment plan that wants to maximize brain health over a lifetime. The first one in multiple sclerosis is obviously to try to prevent further damage to the brain by using the immunological therapies that we have in the most effective way possible. And that's a a bit challenging, but the fact is we have a lot of opportunities now that we've never had before. And this is an issue for the medical field. The second aspect is it turns out that more and more research – including that presented here at the American Academy of Neurology meeting – suggests that if you exercise and are intellectually and physically active that increases your brain reserve. It does that because as you fire neurons by doing something – learning a language, volunteering, going to church, reading, whatever – that causes the nerve cells to put out new branches called neurites. And those neurites randomly connect with other neurons in the vicinity. If you do something to activate that pathway, then you make it permanent. If you don't do something to activate that pathway, it breaks automatically within 24 to 48 hours. So you need to be active on a daily basis really to try to maximize those connections. And what you're doing you're just creating this three-dimensional network of connections between nerve cells that gives the brain the flexibility of shifting function around. And it was reported at this meeting – and it's been reported in the literature a number of times – that people who are intellectually active actually have less disability controlling for all other factors than people who are not intellectually active. And we now know that that's also true by being physically active. And again, this cuts across multiple diseases, but it's just as important in MS as it is in other ones. And then, the third factor is diet. The reason for that is not that there's a specific MS diet; there isn't. But we know that if you develop other dietary related diseases, that substantially increases your risk of disability from MS. So for example, just developing diabetes almost doubles your risk of being disabled from MS than just having MS alone. So just having high blood pressure, just being overweight or obese increases your risk of disability. So that means if we want to maximize lifelong outcomes then we prevent injury by using the drugs as effectively as we can; we get people to exercise and be intellectually active to create more connections with brain, create more cognitive and brain reserve; and we also help them develop a healthy lifestyle from a nutrition aspect, as well, to prevent them from developing other diseases that would compromise neurological health.
MSDF
Well all of this sounds interesting, but it sounds completely obvious to me. What is controversial about this subject?
Dr. Vollmer
There are two things. One is that the medical profession is just now beginning to evolve in the direction of trying to think about global health and chronic diseases. Primary care physicians have been thinking about this for some time, in general, but in terms of applying it to chronic diseases this is a a relatively new concept, and how to do it is still a challenge. The second reason is that regulatory agencies, in other countries, and then in this country, health insurance organizations, prevent us from doing this. So for example, in early phase disease for patients who don't carry a virus called JC virus, a drug called natalizumab or a drug called fingolimod might be actually be the best drugs for them. But the insurance companies, even Medicare and Medicaid, make it very difficult for us to use them in the patients. They tend to approve the old drugs first because they perceive them as cheaper usually through sweetheart deals made by the private insurance companies or just because of concerns of cost on the part of Medicaid. And they prevent us from using more effective drugs earlier; they don't understand this concept of preserving brain volume and brain health in terms of trying to maximize lifelong outcomes.
MSDF
Is there any proof though that starting with fingolimod or natalizumab – starting with the "heavy hitters" – will prevent the the long, slow progression?
Dr. Vollmer
Yes and no. The problem is the gold standard would be a 50-year study looking at 10,000 people. That's never going to be done partly because the target is constantly moving as new therapies come into the marketplace, but also it's just not practical. However, having said that, published both in the peer reviewed literature and at the American Academy of Neurology meeting are a number of relatively large studies done at centers around the world – most not funded by drug companies – that have reported that patients on fingolimod or natalizumab are significantly better off after two years of treatment than patients using interferons or glatiramer acetate. And at this meeting, specifically they compared in an open-label way patients who were started on fingolimod versus patients started on interferons or GA or switched, and again they showed a 50% reduction in relapse rate. And in the literature for natalizumab, there have been reports since 2010 of the fact that if you're treating relapsing MS patients over two years period of time, on average, that group is improving in function. And that includes fatigue, cognition, mobility, employability. So with highly effective therapies, we do have evidence, substantial evidence, that slowing down brain volume is important, and that results in better function and often resolution of symptoms – patients actually get better on these highly effective therapies. And we've not seen that with interferons and glatiramer in most patients.
MSDF
As a physician, can you recommend strategies for making the argument to third party payers?
Dr. Vollmer
Yes. There is a lot of research data that proves that brain volume or gray matter volumes or the number of neurons that you have in your brain is the most powerful predictor of what's going to happen to you in terms of disability over your lifetime, and this is not an arguable point. However, regulators tend to look at relapse rate reduction and gadolinium-enhancing MRI lesion reduction, which are not very good at predicting long-term outcomes. So we need to reeducate health insurers and third-party payers that if you really want to optimize patients' lifelong health you need to make the investment upfront in highly effective therapies to prevent them from developing more disability. We know there are a number of studies reporting that total healthcare costs are less if you're using highly effective therapy like natalizumab or fingolimod over time than they are with interferon and and glatiramer acetate. So this has been published in many different ways; there's more than a dozen papers in the literature on this. The problem is is that any one study is relatively small, and it's easy to criticize it. But the field needs to step back and look at the overall literature. And the overall literature is consistent; we consistently demonstrate that if there's an effect the effect is in favor of using more effective therapies as early as possible in the disease course.
MSDF
Aside from brain volumetrics, what are what are some other good ways of measuring brain health?
Dr. Vollmer
Well you can look at the number of what are called T2 lesions that are developing on the MRI; so your neurologist can look at that, and they can compare you to other patients of a similar age and try to determine are you on the good end of the spectrum or or the more worse end of the spectrum. You can look at what's called T1 black holes; it's a typical MRI measure that's always done. But T1 black holes are more correlated with worse long-term outcomes, and so if you have more T1 black holes you really should be thinking about being on a more effective therapy. And certainly, if somebody is on a therapy and they continue to have any evidence of disease activity – which means a relapse, a change in the MRI or progressive disability – they should probably be thinking about being on a more effective therapy, and they should be discussing that with their physician.
MSDF
I'm a little surprised that you didn't mention any cognitive measures.
Dr. Vollmer
It’s only because I assume automatically that they're very important, and, in fact, most of the data on brain reserve is focused on cognitive function. However, I would argue that the same principles apply for mobility, for sensation, for vision, for creativity. And so, MS is a disease of the central nervous system, so it attacks the very core of what it is to be human. We tend to focus on the bipedal nature of human behavior, but that's not the most important thing. The most important thing is maintaining your interaction with your family, with your friends, with your profession, being able to progress and learn, etc. We can deal with mobility issues, but we don't have a way to recover cognitive function yet.
MSDF
Are you yourself conducting any studies in this area?
Dr. Vollmer
Yes. We have a number of studies; we actually have 28 clinical studies going on in MS. But two of the ones that I think are very relevant to this particular issue is we have been funded to be able to look at the changes on MRI in patients that have been on either fingolimod or natalizumab for two years or longer. And we're comparing them to age matched healthy controls. And what we're asking is is the rate of brain volume change, which all of us suffer, but is the rate of that change in those patients now similar to what it is in healthy controls versus patients who have MS? And as I said, we know that the percent change in brain volume for healthy people is about 0.1% per year; in MS it averages about 0.6% per year. So we're we're doing this study now to see the patients who are doing well – they're coming into the clinic, they're saying I'm feeling good, I feel like I'm as good or better than I was last year – is their brain now normalized in terms of its very modest loss of brain volume over time as a result of normal aging?
MSDF
And you said there was a second one that that is particularly relevant.
Dr. Vollmer
The second one is is to take and ask patients, it's called patient reported outcomes – where we actually ask the patient about how they're doing in cognition, how they're doing with energy, how they're doing with mobility, how they're doing with sexual function, you know, the things that are important to us – and we're asking how that is changing over time on these therapies, and we're trying to correlate that back with what's happening to their brain MRI in terms of brain volume.
MSDF
Dr. Vollmer, I've come to the end of my prepared questions. Is there anything else you'd like to add or any questions I didn't ask that I should have asked?
Dr. Vollmer
Two things. As I said, one is it's very important for patients and the healthcare profession to really begin to understand that MS is a disease of the entire central nervous system, and its impact on neurons is actually the most important aspect of this of this disease. The second one is that healthcare providers working with MS patients and MS patients and families need to advocate to the healthcare system to allow healthcare providers to use the most effective therapy that works best for that patient based on individual assessments of safety and efficacy.
MSDF
Well thank you very much.
Dr. Vollmer
Thank you. Appreciate the interest.
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Host – Dan Keller
Well that’s it for Episode One of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum—MSDF--the premier source of independent news and information on MS research, Robert Finn, executive editor. MSDF is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is the Vice President of Scientific Operations.
MSDiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.
We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.
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