Circa 2007
A funny thing happened on the way to San Francisco. ABILITY editor-in-chief Chet Cooper planned to fly up from LAX for a few hours to meet with one of the foremost authorities on multiple sclerosis: Dr. Douglas S. Goodin. But it turned out Cooper was grounded.
“May I have your attention, please?” a voice came over the P.A. system as he sat in the boarding area. “Flight 293 to San Francisco has been cancelled.” That was followed by more good news: “There are no more flights to San Francisco today.”
After a few passengers had full-on tantrums, the airline put them on the local, flying them into San Jose, and then shuttle-busing them through Palo Alto and San Mateo up to San Francisco, 45 minutes away.
It was a bumper to bumper ride. But all was not lost. As sometimes happens, Cooper got a good seatmate: Melanie Jameson. He told her he was in town to talk with neurologists at UCSF’s Multiple Sclerosis Center. “What a weird coincidence,” she replied. “I have MS myself!” She’d recently relocated from New York to Northern California, and had yet to find a local doctor. So he took her along to the interview. Her questions would be as good as his own, if not better, he reasoned. Jameson would bring a patient’s perspective to the conversation about the causes, treatment, and possible cures of MS, which affects roughly 400,000 people in the United States.
Chet Cooper: How would you describe MS?
Dr. Goodin: MS is an inflammatory disorder of the nervous system that tends to occur in episodes. So people get symptoms of neurologic dysfunction: blindness, numbness, weakness, imbalance, trouble with bowel and bladder. It lasts for a period of weeks to months and they typically remit at the beginning, and then later on, over the course of the illness, many patients experience a more steady and insidious progression of their disability, which is where we call the transition from remitting/relapsing MS to secondary progressive MS. A few people, not very many, have progressive MS right from the get-go. But by and large, we think of MS as being these recurrent inflammatory episodes that affect the brain in a relatively random way.
CC: How would a doctor evaluate someone’s symptoms and diagnose MS? There are a lot of symptoms that could be due to something else.
DG: Well, potentially, any symptom in the nervous system could be due to MS. As I said, it could be blindness, numbness, weakness, a whole variety of things. The key to making a diagnosis is that usually MS patients are young, the typical age of onset is between the ages of 20 and 40, so that takes it away from some of the other diseases of the nervous system, like strokes, which tend to affect an older age group. So if a person comes in and they’re young, it’s more likely that you’re dealing with something like MS. This recurrence and then remission, that pattern of illness, is very characteristic of MS. If a person comes in with that, that ought to at least be on your mind. We’re obviously also helped out by laboratory tests, MR scans. Now we can image the person’s brain and actually get a very clear picture of what is going on in their central nervous system. Similarly, spinal fluid can provide us with information that would not be present in some of the other neurological problems.
CC: Can you take us through a little bit of the standard procedure for treating MS?
DG: It’s not usually that the person has been suffering from something or having symptoms for years. They come in with these episodes, so they may come in with an episode where they, for instance, can’t see out of their left eye, or they can see very little out of their left eye, and it’s come on over the course of a week, and now they’re coming to us and asking our opinion or asking for treatment, or both. And then we will take a history and say, “Have you ever had anything like this before?” And they’ll say, “Well, there was that one time in college 20 years ago or 10 years ago or five years ago when I woke up in the morning and my whole left side had gone to sleep. I couldn’t feel anything in my arm or leg. It was there for a week and it went away. I was told by the doctors that it was stress and finals. I didn’t think anything more about it.” That would be an important event for us to know about that would help us make the diagnosis of MS. But usually, in the interim they have not had any problems. They usually will be functionally normal.
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CC: What’s your opinion of the typical drugs used to treat MS? Avonex, Betaseron, Copaxone—the “ABC” drugs.
DG: Well, I think all of us have our own take on the ABC drugs—which ones are more effective, or less effective. My own view is that the interferons as a class, of which there are three, Avonex (Biogen), Betaseron (Berlex), and Rebif (Serono), have better evidence of being effective than Copaxone (Teva). That doesn’t mean that Copaxone doesn’t work as well, it just means that it hasn’t been studied as thoroughly, so I have less confidence. That makes me use Copaxone relatively less. Other people are impressed by the fact, and it’s certainly true, that Copaxone is very well-tolerated and, in fact, is probably better tolerated than the interferons. They’re not as disturbed by the fact that there’s less evidence of it being effective, they like the side-effect profile and they’re more likely to use Copaxone. I think there’s a lot of individual physician variability on that.
CC: Can you tell me about the trials that you’re doing at UCSF?
DG: UCSF is actually involved in a lot of trials. One of the trials that I’m doing is looking at Betaseron, which is one of the interferons, in its current dose, doubling the dose and comparing it to Copaxone. That trial’s actually almost over. We’re about to take on a couple of trials with some novel agents that are not currently approved by the FDA but have very promising results in phase two. One of them has the very catchy name of FTY720, which just rolls off your tongue. I think it will have another name when it’s marketed, though.
FTY720 looks very promising in phase two, and it’s an oral treatment, so it would avoid the injection, so that would be great. There’s another one that is called Rituximab (Genentech), which is also being used as an anticancer drug, so we have some information on the safety of that. The nice thing about Rituximab is that it also has great phase two data, but the really nice thing is, you only inject it once every nine months to a year. So both those drugs, if they work, which I hope they will, will actually be a major step forward.
Melanie Jameson: How do these two drugs compare to Tysabri?
DG: Tysabri (Biogen) has some problems, because of the two people that got a rare, usually fatal brain infection called multifocal leukoencephalopathy during the study. That’s made some people a little nervous. The idea of putting a 22-year old on a drug that could kill him doesn’t sound like a good choice. [i](laughs)[i] So it’s going to be two or three years before I’m going to feel really comfortable with Tysabri’s safety profile.
By that time, I think these other two drugs are going to be on the market. It’s usually very hard to know in phase two how they’re going to look in phase three. One of the things that was really impressive with Tysabri was that the phase two study was a big study—involving almost 200 patients—and gave us a really good clue as to what we were going to see in phase three.
The same size study has been done on these two new drugs, and they have, at least in phase two, similar efficacy to Tysabri. But they probably have a better side-effect profile. In other words, FYT720 has actually been used in kidney transplants, so we have a fair amount of at least short-term data on FTY720, and Rituximab’s currently FDA approved for treatment of some cancers, whereas with Tysabri we really didn’t know. It was brand new. But we’ll see. Both of the drugs are very potent. I mean, the fact that you only have to use Rituximab once every nine months means that it works for a long time. There’s no take-backs. You can’t go, “Oops!”
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MJ: Do patients go into permanent remission?
DG: Yeah. I think benign MS, or MS that doesn’t really become progressive, is a lot more common than most people give it credit for. People claim the amount of benign cases is only 10 percent, or even fewer than that. But there are a lot of things that would argue against that. For instance, in optic neuritis, which is really an MS disease, it’s linked to the same genes and it’s got the same worldwide distribution as MS. Only about 50 to 60 percent of patients ever have a second neurological event. That means that 40 percent of those people are, by definition, pretty benign. If you look at data of people sort of randomly autopsied at the age of 90, about one in a 1,000 have MS, unsuspected, at least from the ’60s. This is out of approximately 32,000 autopsies. Well, one in a 1,000 rivals the prevalence of MS in the population, one to two per 1,000. Which would mean that 30 to 50 percent of patients that have this disease never even have symptoms. So I think there’s a lot more benign MS out there.
MJ: My doctor suspects that I have benign MS. I’ve been diagnosed for three years. My question is If you suspect at some point in time that your patient is benign, do you still continue treatment with drugs?
DG: That’s a great question. All these things ultimately are the decision of the patient, not of the doctor. But I think it’s very hard to know how to advise patients. I would not put somebody who had a first clinical event on therapy, which puts me sort of at the far end of the bell curve, because everybody else is trying to start these people out immediately. But I don’t know whether they’re going to be benign or not. So if I don’t put them on therapy, it has two advantages. One, it gives them six months to sort of digest the fact that they’ve got a disease that is potentially disabling, and also to think about the therapies without feeling the pressure of having to start them. But I will always see them again at six months, get a scan, and if there are new lesions or they’ve had new attacks, then I recommend they go on therapy.
People whose MS is benign may ultimately have their condition controlled with the medicines, but I think they are at high risk for having continued activity if they don’t do something. On the other hand, if they haven’t had any new lesions and they haven’t had any attacks and they’ve done just fine over the six months, then I’ll scan them again a year later. And there are a fair number of people who I am now following who’ve never been on therapy. So that’s easy. I can say, “Nothing’s happened in three years and you’ve been off therapy and I think you’re fine.”
It’s much harder when you put them on therapy, because now you don’t know whether they’re doing well because of the therapy or in spite of the therapy. I think it’s very tough. If somebody came to me and said, “Look, I’ve been on disease-modifying therapies for three years and I’ve had absolutely nothing”—maybe the drug’s really, really working. It’s hard to tell.
MJ: What kind of treatment do you use for patients who’ve had debilitating MS for years? Do any of these treatments help them?
DG: The treatments actually seem to be more effective early on. If you look at the size of the therapeutic benefit that you get from the drugs, it seems that they’re better in the very early stages than they are in the relapsing/remitting stage, and better in that stage than in the secondary progressive stage. By the time you get to very progressed MS, I don’t think these treatments have any benefit at all, and they’re not even approved by the FDA in that setting. I mean, the insurance companies oftentimes still pay, but they’re not indicated for non-relapsing forms of MS.
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CC: Do you believe that stem cell research could be effective in treating MS?
DG: Well, stem-cell research is obviously one of the approaches that is being explored in MS. We have therapies that actually lower the biological activity and slow down the disease process. We have therapies that can help specific symptoms, which are like putting Band Aids on cuts. They don’t do anything about the underlying biology, but they make people feel better.
We have a major gap in treatments that actually promote repair of the nervous system–remyelination, axonal sprouting, that kind of thing. The stem cells could theoretically help with remyelination and repair. There are a lot of people who are looking into that. The difficulty I see is that there are a whole lot of theoretical difficulties. They don’t carry flags—how do you know that a cell is a myelin cell?
CC: You ask them?
DG: (laughs) Right. You can ask. Provided you know what you’re listening to. But you’re putting cells that have a lot of growth potential into unusual places, and who knows, they may become cancer. So that’s a potential problem. In MS, the disease tends to be spread out all over the place. It’s in the brain, the spinal cord, the left hemisphere, the right hemisphere. How do you get the myelin cells to where they ought to be? That doesn’t mean that stem cells are a bad idea. I just think they have a lot of challenges to overcome. It turns out that the lesions in the brain have myelin precursor cells already there. They’re just sitting there, not doing anything. They have myelin precursor cells already sitting near the areas of demyelination. In other words, they have the cells already in place, they’re just not dividing, they’re not repairing things. So to me, it makes a whole lot more sense to try and find out what the chemical stop signal is that they’re getting, and find something that interferes with that, rather than trying to transplant stem cells. But all that is guesswork. That’s not to say that we shouldn’t pursue both avenues at the same time.
The idea of stem cells is that when you start life, you start as a fertilized egg, and that’s one cell, but that one cell is going to ultimately become everything: eyes, nose, mouth, intestines. So it’s got potential to become anything. And then over time they gradually split off into their finer and finer branches off the tree, and then they get more committed. A brain cell is not going to turn into a kidney cell, because it’s too far along the brain cell pathway. So stem cells are really just cells that are early along on that path, where you can direct it to what kind of a cell you want it to become.
They’re doing this down at USC. I’ve seen some of their preliminary data. They have a 12-step process, kind of like Alcoholics Anonymous, and they think they’re at step six in terms of how you get there. So they have a bunch of cells that look like, under the microscope, myelin cells. What does “look like myelin cells” mean? I don’t know. What are those cells? We don’t have any treatments at the moment that are reparative in that sense. I think we need to pursue different ideas. My guess is that stem cells won’t turn out to be the answer, but I would have told you that interferon wasn’t going to work, too. So I don’t have a crystal ball.
CC: Are there surgical procedures available to treat MS?
DG: Not really. People do occasionally do bone-marrow transplants. It’s not really surgery. It’s a pretty aggressive therapy, but there’s really not anything surgical that can be done.
The idea of the bone-marrow transplant is that there’s something wrong with the immune system. So if you wipe out the immune system and put back in the stem cells that are immune stem cells, which are actually present in our blood, when the immune system comes back again, it’ll come back in a different state and won’t have the same properties that it had before.
The problem with bone-marrow transplants is that some people die from it. You give them massive chemotherapy. It’s not totally benign. And it’s not clear to me that it has any real benefit. But it really hasn’t been tried. I mean that kind of therapy would presumably be more effective with a 22-year-old who just had her first episode, than with a person who’s already in a wheelchair. Mostly it’s been done at the very end stages, which is where you’d expect that it wouldn’t be effective anyway. But you’re a little hesitant to do it with a 22-year-old that’s otherwise healthy and running track.
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MJ: I was told that most people with MS are diagnosed when they’re around 30.
DG: Twenty to 40 is the vast majority of people.
MJ: Are you finding any of them to be younger?
DG: The youngest case that I know of is a year and a half.
MJ: What kind of symptoms does a year-and-a-halfyear-old have?
DG: They’re the same kinds of things. The one that I remember that was part of a legal case was a child who walked at nine months, and then at 15 months she was unable to walk for a period of three months, and finally was able to walk again.
MJ: Do you have any feelings on women with MS taking the “ABC” drugs during pregnancy?
DG: I don’t think any of them are recommended during pregnancy, though Copaxone is probably safer than the others.
MJ: How do you feel about the risks of women with MS getting pregnant in general?
DG: I think getting pregnant’s fine. If you look at the pregnancy year as nine months of pregnancy and three months postpartum, your risk of getting MS attacks is less in the nine months of pregnancy and greater in the three months postpartum. But if you look at the entire pregnancy year, it’s about the same. I don’t think there’s any downside to getting pregnant and having a family, but I think that you need to make sure that you have the wherewithal to take care of the child when it’s born. It could be that the person has a mate who’s willing to do that, but one needs to think of that.
MJ: I have a couple of friends with MS who have gotten pregnant. They haven’t had symptoms before and they weren’t on any drugs, but after they gave birth, they had full episodes.
DG: Right. You’re at increased risk in the postpartum period, so then the question is, how do you manage that? Do you breastfeed? We at least recommend that you don’t use the drugs during breastfeeding. I would say most of the immune benefits that the baby gets are probably during the first two or three weeks anyway, and you can breastfeed for the first two weeks to a month and then shift onto your drugs. It’s not usually that big a deal. But there is a risk in the postpartum period.
CC: Can you calculate when you’re more likely to have an attack? Going on and off your meds, is that a roll of the dice?
DG: I think it’s basically just a roll of the dice, yeah. I think your propensity, your likelihood for having an attack varies from person to person, and also probably varies over the course of the year, but we don’t know how to predict that. I think a year off, or six months, and your attack rate is once a year, you have a 50-50 chance of having the attack during that period.
MJ: I know some people say MS is more prevalent in the northern hemisphere than south of the equator. Do you believe this?
DG: There’s no question that that’s true. The disease is more prevalent the farther you go north or south of the equator, less prevalent in the equatorial regions. So the question is, why is that? Part of the answer could be environmental. I mean, there’s less sunlight in the more northern exposures, it could be related to vitamin D. People are interested in that. Some people believe that that is the answer.
A lot of the equatorial regions are populated with people of non-European descent, and they tend to have less susceptibility to MS than Europeans do, for whatever reason. That obviously plays a role. I think we’re trying to figure out all those things, but it’s been very, very difficult.
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CC: So there’s a genetic disposition?
DG: There is a genetic predisposition. If you ask what is the likelihood of getting MS in the general population, it’s one to two in a 1,000. If you ask what is the likelihood if you have MS, that your child will get MS, it’s probably one to two in a 100. If you ask what is the likelihood of your sister or brother having MS if you have MS, it’s probably 2 percent to 4 percent. If you ask what is the likelihood of your identical twin getting MS if you have MS, it’s 30 percent. So clearly there’s a genetic predisposition. But if it were all genetic, the identical twins would have an identical risk, right? Thirty percent is far away from 100 percent, so there’s obviously something in the environment. There has to be something genetic. It’s not a terribly strong genetic trait. It’s probably multiple genes, and in fact we have good evidence that it’s multiple genes, not a single gene, not a simple Mendelson inheritance pattern.
We know certain genes are linked to MS. We know, for instance, one of the immune molecules that gets put on the immune cells and helps the immune cells to recognize their targets, there is a specific gene that’s related to that system which is linked to MS. So that’s sort of intriguing. But that’s the only thing that we’ve been able to find. We’ve done full genome screens, and we can’t find anything else that’s reliable.
CC: And you say race is also a factor?
DG: Right. Africans tend to have a very low risk of MS relative to European Americans. Native Africans have a lower risk than African Americans. Eskimos I think may have zero risk.
CC: But they’re north.
DG: Right, but they’re Eskimos. Asians in general, and they obviously come from Asian stock—
CC: Could it be because they kiss with their noses?
DG: (laughs) Could be. Or maybe it’s because the igloos are really good places to live. I’d forgotten they kiss with their noses. But Japanese and Asians tend to have a lower prevalence of MS as well. There are some areas of the world where MS seems to be getting more prevalent. Actually, in many places in the world it seems to be getting more prevalent. But some places, like Iran, which we’re actually very interested in, used to have a very low prevalence of MS, and now it’s skyrocketing. Other areas are also experiencing the same thing.
CC: Are they just becoming more and more aware?
DG: No, they’re not. Many of the neurologists have been trained in the U.S., and they know what MS is. It’s their impression, despite knowing MS pretty well, that it’s changed in Tehran.
MJ: Is there still the impression that MS occurs more often in women than in men?
DG: Well, there are more women than men diagnosed with MS. Interestingly, I think the sex ratio is changing. Around the turn of the century, it was more like one-toone. For a long time it was said to be two-to-one, and now it’s closer to four-to-one. So it’s becoming more and more prevalent in women, which is interesting, because that can’t be genetic, right? That’s got to be something in the environment. It could be an interaction between genes and the environment.
MJ: So right now, the research still is on treatment and not detection?
DG: Or prevention. No, I wouldn’t say that. It’s easier for us to recognize MS once it’s happened. It’s harder for us to recognize MS before it’s happened.
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CC: Were you talking about screening as well?
DG: There are people that are interested in prevention. For instance, as a simple possibility, which I don’t think is going to probably turn out, because nothing in life is ever so simple, it might be that it’s a vitamin D deficiency or something like that during the in utero experience of the child. It might be that you could prevent MS in a person at age 20, by treating that person’s mother with vitamin D, in the same way that we treat with a bunch of other prenatal vitamins. There are people who are interested in that.
CC: So if you are pregnant, take vitamin D just in case?
MJ: I’ve read that in terms of diet, red meats are good.
DG: There are as many therapies for MS as you can imagine. High-fat, low-fat, no-fat diets, vitamin this, vitamin that, snake venom, bee stings, mercury amalgam, tooth fillings.
CC: And it all comes in one jar.
DG: (laughs) There are a lot of them. And what they share is that no one has ever really looked at them in any kind of credible scientific way. The diet that most people are interested in is a diet called the Swank Diet. Roy Swank was a neurologist up in Oregon who followed a group of a couple hundred patients but based his observations on some epidemiological studies he’d done in Scandinavia. What he thought he noticed, and I think that in the ‘50s, which is when he was setting up his diet, I don’t think we were very good at epidemiology, so I’m not sure how reliable the observations are, but what he thought he observed was that in the inland areas of Scandinavia, where they had a lot of milk products and animals, the prevalence of MS was much higher than on the coast, where they had very little in the way of animal fat, and they had a lot of fish oils and all of that. So he then based a diet that is a typical 1950s diet. Have you ever looked at the Swank Diet? It’s very proscriptive. Half an ounce of cod liver oil every Thursday, Saturday, and Sunday.
CC: At 3:35. DG: (laughs) Exactly. A typical sort of ‘50s diet, without any basis that I can think of, other than the fact that he picked cod liver oil. I mean, this is just pulled out of the hat. Having said that, in that group of 200 people that he followed, they seemed to do very well. So some people have been very interested in the Swank Diet ever since. I don’t know that there’s any good evidence that the diet is helpful, but it probably lowers your risk of heart disease even if it doesn’t affect the MS.
