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Anne Haney Cross, MD, Professor of Neurology at Washington University St. Louis
talks about M.S.
and the possible benefits from intermittent fasting and intermittent energy reduction
in the studies they are currently conducting.
Interview conducted by Ivanhoe Broadcast News in May 2019.
What are some of the most troublesome symptoms of someone living with M.S.?
CROSS: M.S. is a neurological disorder and it can affect many different things related to neurological function in the body. So, in different people, it can affect all sorts of things. But some of the most troublesome things I hear are weakness, visual dysfunction, and sensory problems, including; pain, fatigue, bladder and bowel control problems, sexual dysfunction, sensory problems, and numbness in coordination.
So this is kind of all encompassing?
Is it progressive?
CROSS: In some people it is progressive. We divide it into people who have a relapsing, remitting course and people who have a progressive course which may have plateaus in it. It doesn’t have to be downhill the entire time. The more we learn about the disease the more we’re realizing that many people who have this relapsing remitting course actually have an underlying progression that maybe is masked by plasticity.
Are the treatments so far treating just the symptoms where you’re not treating the underlying cause? Or are there treatments like that too?
CROSS: No, actually our subspecialty of neurology is one of the few that treats the underlying disease process. We certainly have treatments for symptoms too but at least for relapsing M.S. patients we have disease modifying treatments that slow the disease process.
So, patients will get those treatments as well as treatments for symptoms?
CROSS: That is correct.
Are a lot of those treatments medication, pills, or do they have to take shots?
CROSS: Many of them are medications for the symptoms but not all of them. There’s stretching and exercise for fatigue and plasticity which is stiffness due to a central nervous system cause. In terms of disease modification, there’s two types of underlying pathologies. It’s much more of a spectrum rather than two individual pathologies. But we think of it with this inflammatory relapsing remitting course where the relapses are inflammatory, and cells come in from the bloodstream into the central nervous system and cause the relapses. Then there’s this underlying progression in many people – probably not all, but many – where there’s a continual drop out of nerve fibers. That tends to occur more prominently later in the course when people hit – middle age. We don’t have good disease modifying therapies for that portion of the pathology disease yet, but we do for the relapses.
OK. So people are on lots of medications and it’s different for everybody. Some people might progress faster or decline sooner?
CROSS: That’s right.
How does this affect their day to day life?
CROSS: Well it really depends on the person and what their symptoms are. Some people are not affected much day to day and actually live a pretty normal life and have a normal lifespan. Other people are plagued by fatigue, pain, weakness, visual problems, swallowing problems, bladder problems or the side effects of the medications they’re taking to try to reduce their relapses.
I’ve read a little bit about how people have tried – this is for a lot of different diseases – people have tried different diets to see if that can affect it.
Are there lots of different diets that have been tried?
CROSS: The first one that really came to the forefront was by Roy Swank. He advocated a very low saturated fat diet in his patients way back in the 1970s I believe. He followed a lot of those patients over the years and found that those that actually abided by his low saturated fat recommendations did better overall. Now that is not a what we would call scientific – certainly not a randomized prospective trial like we do these days. But that’s one of the first ones.
Tell me about intermittent fasting and why was this even thought that it might be beneficial.
CROSS: So over 10 years ago here, we were doing an experiment with animals that get M.S. disease, like mice. One of our mice had abnormal teeth and couldn’t eat really well and was sort of the runt of the group, so to speak. And we immunized them all to develop this disease that’s like M.S, and that particular mouse that couldn’t eat well didn’t get it. And Dr. Laura Pico and Dr. Jen Stark who were my fellows at the time – they noticed that. And then we showed this mouse to the vets and they said why don’t you clip the front teeth and the mouse will eat better. So, they clipped the front teeth and the mouse started gaining weight and developed this model. So, when the mouse wasn’t eating well, getting fewer calories, it was not developing the disease. That set off a light bulb in all of us thinking that maybe we should do a real experiment with calorie restriction to see what would happen. And sure enough, when we calorie restricted our mice, they didn’t develop this model called EAE. That sort of got us going on it. We discovered there was another group that had done this in rats right around the same time. We published around the same time and we tried to figure out what it was about a low-calorie diet that was making these mice not get sick. We found a couple of things. One was the elevation of adiponectin. Another was a decrease in adiponectin’s called leptin. And these mice also had increased endogenous steroid formation. So, all those things might have contributed to the mice that were calorie restricted not getting EAE. Fast forward a little bit and we’re thinking that it would be hard to do a chronic calorie restriction for life, kind of experiment in humans, and that it might ruin the quality of life of a lot of people. So, we realized that intermittent fasting had been advocated as sort of another way to approach calorie restriction where you would have one day eating normally, hopefully not over normally, and then the next day off. Or two days on and one day of not eating or maybe eating maybe 500 calories a day and good things under a nutritionist. So that’s what we are doing now in humans. But first of course we did that in mice and we found some really interesting things. I mean, one is that it reduced – it delayed onset of this animal model. It reduced the severity. The mice had much less pathology. They had less nerve fiber loss; the mice had a different microbiome that’s really sort of trendy popular scientific issue right now in many different diseases. But when you look at the stool of the mice and you determine what bacteria was in there even though the mice were eating the exact same chow. Just one group was getting it every other day and the other was getting it every day. Their microbiome, their bacteria in their gut, changed.
Wow. So, everything else was the same? One group was just eating more, and one group was eating every other day?
And you saw all those changes?
CROSS: Yeah, and the mice that ate every other day had lower weight in general. Their weight would kind of go up and down with the day that they were eating or not, but still they were less than the mice that were getting fed daily. But it was the same exact chow and they had different bacteria. The pattern of the bacteria in the ones that got every other day feeding was a less inflammatory pattern of bowel bacteria or microbiome. It seemed to change their immune system. All these things led us to do a small trial of intermittent fasting in humans with M. S. who were having relapses.
How long ago did this one start?
CROSS: I’m guessing around five years ago, something like that. It was a pilot trial. Basically, patients would come in and they would get randomized to either doing every other day fasting or regular eating, but both under the supervision of a nutritionist for about 15 days. And this was around the time of their relapse. Then they would come back in and we were drawing their blood and checking their clinical exams. But this was certainly not a blinded trial. The patients knew what they were doing. We knew what they were doing. We tried to blind the exams and of course we could blind the assessment of their blood levels of adequate kinds, it was kind of encouraging. After the initial couple of weeks, the patients who were in that trial were invited to undergo intermittent fasting or intermittent energy reduction.
OK. So, were they doing 500 calories every other day?
CROSS: It’s not really calorie total restriction, but certainly energy reduction.
What did you see? What were the results?
CROSS: Well the pattern of adipokine was more like an anti-inflammatory pattern. There was a reduction of leptin levels and a relative rise in adiponectin levels which is an adipokine.
And when you say the leptin levels, what’s that mean? How does that benefit them?
CROSS: So, leptin is an adipokine made by adipose tissue that is required for the mouse model. So, leptin is sort of a pro inflammatory – considered a pro inflammatory adipokine. Relatively speaking that was reduced in these people, so that was encouraging. Then Dr. Laura Pico who’s an Associate Professor here wrote a grant to the National M.S. Society of the United States and got it funded to do a trial on people with MS – a much larger trial and the patients wouldn’t necessarily be having an attack when this happened. And that’s ongoing now. We don’t have results, but it’s close to being fully enrolled.
And when did you start rolling for that one?
CROSS: I think it was about a year ago, it may be slightly less.
So, is this considered kind of like a phase two, as it were?
OK. And you have roughly how many people in this study? Or how many will be? When you’ve finished complete enrollment, what’s the rough number?
CROSS: That I don’t recall.
I just wondered is it 500 or is it?
CROSS: No, it’s more like 40.
How is it thought that having an anti-inflammatory response can help people’s symptoms?
CROSS: We think that the anti-inflammatory effects of intermittent fasting may be more helpful to tone down the immune system to help reduce relapses and the disease process itself, not so much the symptoms but the actual disease process, which is inflammatory.
OK. I think I misunderstood that I think I thought it was for symptoms. So, this is actually an even bigger deal?
CROSS: It’s intended to reduce the disease pathogenesis in the CNS and in the periphery and the immune system. So intermittent fasting reduces the inflammatory profile in the blood and possibly in the central nervous system. It certainly did in the central nervous system of mice.
What could this mean for patients? I’m not going to say it’s easy because on the 500-calorie day it isn’t necessarily easy. But you do get to eat normal on the other days.
How could they adjust to it?
CROSS: Right, so this interment or every other day or maybe two days a week depending upon the person’s underlying body mass index – it’s not easy, as you say. It’s hard. I’ve tried it myself. It’s not easy. It would be an adjunct, I think, to using some of the disease modifying therapies that we have that are clearly proven in double blinded, randomized prospective trials. We’re trying to make this one as blinded as possible. Certainly, the patients know what they’re doing, but the people evaluating them doing the exams don’t know which diet the person was assigned to and then the blood work that’s being done as part of the outcome measures is blinded. So how would this work? Well I think it could probably have a lot of different health benefits, not even just on the M.S. process. A number of studies have shown that chronic energy deprivation or chronic fasting but in a nutritionally sound way – can prolong the lifespan – hasn’t been shown for humans, but for most other animal forms, it has. So, I think there’s a lot of potential benefits, not just on the MS. And we now know, thanks to a number of investigators including Helen Trimlett and Ed Murray in particular that comorbidities in M.S. can make the disease worse or seem worse. If you happen to have diabetes and M.S, your outcomes are worse. If you happen to have heart disease and M.S, your outcomes are worse, neurologically speaking. So, if we can improve any of the other comorbid conditions that people might have, that may have a benefit on the outcome of MS.
How are the patients reacting? Are they saying yes, I’ll try anything or like oh this isn’t easy? I don’t know if I could stick with this. What’s their reaction to it?
CROSS: Not every patient wants to do it. I think that the people that have enrolled have been motivated. So, they’re interested in doing it. I’m a blinded investigator and I’m a blinded backup investigator even. So, I don’t really talk to them a whole lot. I talk to my patients sometimes about whether they’re interested in joining it if they seem to fit the inclusion exclusion criteria. And I certainly encourage them because I think it’s probably a healthy thing to do. And we have a nutritionist supervising it.
They don’t all say yes?
CROSS: No, not by any means.
I think that seems hard. I think eating 500 calories. And it probably changes. If they’re a very small person, they might be eating less than 500 calories.
CROSS: Well now, as far as I know it’s always the same.
What’s the next step? I guess what’s coming next?
CROSS: Well I think we have to see the results of this first. And we have to see the findings from the blood work, the exams and how patients do and how adherent they are to the diet. Of course, everybody’s going to have lapses. That’s expected. But we want to see how adherent people can be. And go from there. If we get the results, we’ll obviously want to do a larger study – a multi-center trial.
If you do get good results and the larger study happens and these results are repeated, what could that mean for the future of M.S? We’re not talking about a drug. We’re talking about a lifestyle. But what could that mean for patients?
CROSS: Well I think it would give people control and I think that’s one thing that I hear from my patients a lot, which is they want to have control of their disease. And I would not venture to say that this would ever replace the therapies that we have now. I would say it would be an adjunctive kind of thing, but to hopefully improve the outcomes. And people seem to want control. That seems natural.
Is there anything else you want to say? Did I miss anything?
CROSS: If we take this further, if we get good results, I mean, the next trial would have MRI as an outcome too. We’d be looking at the volume of the grey matter and the white matter and the brain. Possibly the circumference of the spinal cord, things like that, to try to get more objective data to show whether this is effective or not.
How long will this take before you have results? Are we a year out still?
CROSS: Yeah at least a year out. I guess I also failed to mention that we get stool samples from patients too, just like we did in the mice, to see if there’s a change in the microbiome.
OK. Are you seeing any changes?
CROSS: Everything’s blinded. And we’re looking at T cells and other immune cells in the blood flow cytometry to see if there’s changes in the activity level and the phenotypes of the T cells because there’s different types of immune cells. Some are what one might call good and some are what one might call bad. Some are regulatory, meaning they modulate the immune system in a good way. We’re trying to look to see if there’s a change in that such that the regulatory cells are increasing in the people who are on intermittent fasting.
There’s clear objective measure. It isn’t just, oh, they had they didn’t relapse, or they feel that?
CROSS: Right. Because there’s a huge placebo effect in medicine in general in studies, so can’t go by what people say.
END OF INTERVIEW
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