“New Treatment Options for Demyelinating Diseases 
Of the Central Nervous System”

It is with great pleasure that I would like to introduce our next speaker, Dr. Brian Weinshenker. He is the professor of neurology at Mayo Medical School and a consultant in neurology at the clinic in Rochester, Minn.

Dr. Weinshenker completed his medical school training in Manitoba and did a residency in internal medicine there and then in neurology did a residency at the University of Minnesota. He has done research training in neuroimmunology at the University of Western Ontario. His major research interests are directed at understanding demyelinating diseases of the central nervous system, especially multiple sclerosis.

He has authored a series of papers that have been published in the magazine Brain, describing the natural history of multiple sclerosis, and he has published recently “Randomized trials with the plasma exchange in severe inflammatory demyelinating disease.”

Thanks very much for the introduction and for the invitation. It is a pleasure to talk to you today about new treatment options for multiple sclerosis and other demyelinating diseases of the central nervous system. As I went through the pamphlet, I saw that the mission statement…are you hearing me okay? Raise it up a bit? Okay. The mission statement of the organization is to improve health outcomes of catastrophic and/or chronic illnesses. Multiple sclerosis really presents both types of problems. It is a chronic illness.

Many patients with it develop progressive neurological disability but, as I will talk to you in the second half of my presentation today, the trial that we did with plasma exchange was specifically for patients with acute catastrophic events that did not respond to standard treatment. Fortunately, we were able to show, in what we feel is a conclusive way, that plasma exchange can benefit at least 40 percent of patients with this type of catastrophic event who fail standard treatments.

I am sure this is a bit of a cliché slide, after the talks that you have heard. This does seem like occupies a great part of my day, the days of my colleagues, and I am sure this applies not only for multiple sclerosis, but for artificial assists of cardiac failure and many other illnesses, and I guess it all depends which perspective you’re in.

This scene is taken from the movie Gladiator. I haven’t seen the movie, but I imagine this is the good guy and this is the bad guy, and I am sure that all my colleagues feel that we’re the good guys and the people that question our practices are the bad guys but I’m sure they view themselves as defending themselves from people like us that prescribe expensive therapies and see themselves as the good guys and us as the bad guys. It becomes a matter of perspective.

I will be talking to you about two types of treatments, as I mentioned, one for the chronic forms of MS that apply to a lot of patients. These are treatments that often don’t produce an immediate benefit and are given largely to prevent future disability. In the second part of my presentation, I will be talking about the acute catastrophic disability that occurs rarely in some patients, that do not respond to standard treatment.

To start, I have to give you a slight introduction to what multiple sclerosis is. Of course, often, when we give the diagnosis to patients, MS, they don’t know what that is. It is often mixed up with muscular dystrophy, which is an entirely different illness. It gets mixed up with ALS and other conditions. MS is a family of diseases that are idiopathic, that is of uncertain cause, they are characterized by inflammation and demyelination, damage to the myelin sheath that lines axons in the central nervous system. So that is the clinical manifestations related to involvement to the optic nerves, the brain and the spinal cord.

These disorders can be classified, based on the time, in which they evolve, or their chronicity and their severity. The severity is determined by two things -- how extensive the inflammation is in the central nervous system, what area is involved and how severe the pathology is, because MS is caused, we believe in most cases, by an autoimmune reaction.

That is immune cells, not all the immune cells, but a small group of them, get mixed up and they sneak into the brain through the blood vessels and start up inflammation. After, it becomes chronic and eventually leads to nerve deterioration. In some acute fulminate forms of demyelinating disease, the inflammation can be so severe as to wipe out the axons or nerve fibers and produce immediate severe disability.

This is a schema that we came up with a couple of years back and, in the center, the large group of MS patients begin with attacks and remission, attacks of neurological disability and recovery, but ultimately, over time, when you rip off the myelin or when the disease process rips off the myelin off the nerve fibers, and this happens repeatedly, eventually the nerve fibers start to degenerate and patients go into what is called a secondary progressive or SP course.

What you will see is a series of circles which all overlap with this prototype. The most benign extreme are patients who have isolated attacks that seem like attacks of MS but, over prolonged periods of observation, do not seem to develop other symptoms.

Unfortunately there is never a guarantee that future attacks will not occur, but these syndromes are called isolated syndromes. In general, these do not prove to be a problem except, insofar, as they create anxiety in the patients’ minds and in the physician’s mind about whether this is the first symptom of MS.

As I will point out to you, we now seem to have some treatments that are partially effective in isolated syndromes in at least delaying, if not preventing, the advent of a second episode that leads us to a definite diagnosis of MS. We do not diagnosis MS until a second episode occurs, because MS is almost as much of a diagnosis as a prognosis. It is an indication that one believes that there is going to be recurrent attacks of inflammation.

This is going to be the group of disorders that I talk about in the second part of my talk, the catastrophic forms of demyelinating diseases or MS. They go by a number of names Marburg’s variant of MS, acute disseminated encephalomyelitis, villous concentric sclerosis. It’s not important to know all these eponyms except, insofar, as to say they are also inflammatory demyelinating diseases. They develop abruptly. It they are very diffuse, they can present with coma.

Often they are multifocal, in which case, they present with multiple symptoms such as blindness in one or both eyes, paralysis on one side, on both sides, arms, legs can all be involved. Urinary retention and there can be any spectrum, from coma on the one side, to these multifocal involvements or both in these conditions.

I won’t talk much about these diseases of restrictive distribution. The most important one is a disease called the Vick syndrome, which is another area of great interest for me. In this situation, only the optic nerves and spinal cord are involved. The brain is not involved, either clinically or based on MRI studies.

In the Vick syndrome, in particular, the attacks are severe and recurrent. The spinal cord attacks are so severe that the often produce an necrosis of the upper spinal cord, respiratory failure, and have a significant death rate, directly from these attacks, which is not generally true for multiple sclerosis. In general, most of these prototypic cases of MS are not associated with significant excess mortality and, mainly, they affect quality of life in the long term.

The next group is the progressive forms of MS. I put this as being less severe because they develop insidiously but, although they develop insidiously, they tend to progress and so, after five, ten, fifteen years, they do cause substantial disability. Most commonly affect mainly the spinal cord. This is seen mainly in older age of onset patients, typically patients over the age of 40. The average age of onset of multiple sclerosis is 25-30.

Finally there is a form called benign MS, which seems to be a subset of prototypic MS. In this situation, patients have recurrent attacks but never seem to enter this progressive form of the disease.

MS is classified mainly based on this temporal course and I have referred to, much of this in the previous slide, relapsing remitting disease characterized by attacks. This subset never goes on to develop progressive disease, but about half or more of patients after time, presumably because they have developed repeated injury to the nerve fibers, will enter a progressive course. That’s called secondary progressive.

Primary progressive patients, again the older onset patients, never report attacks, but insidiously and gradually develop a myelopathy of spinal cord deterioration and present with imbalance, weakness of the legs, bladder dysfunction, and it becomes progressive. Occasionally there may be a super imposed attack.

Those schematics don’t offer figures about what is the proportion of patients who become disabled. There have been a number of studies, some that we conducted some years ago. This study was reported in 1993 from Sweden. The results are almost identical with what we reported from Canada and basically this shows that within 15 years, about 50 percent of patients would have reached this level of disability which is DSS6. DSS6 means that one would need a cane to walk a distance of half a block.

This is death due to MS and you can see that the mortality rate due to MS is not very great and in fact there is only a very slight excess mortality due to the typical garden variety of MS. That is typically due to advanced disability, being predisposed to pneumonia, nor direct death due to MS unlike some of those fulminate forms that we talked about.

This all seems complicated, relapsing, remitting, secondary, progressive, is there any way to put all this together into a schema that we can understand? This type of schema has evolved really over the past ten years, but there are multiple lines of evidence that would suggest that, and I mentioned to you that multiple sclerosis is an inflammatory demyelinating disease and it seems like that the two hallmarks of the disease are inflammation, which is usually how it starts, and axonal degeneration.

The inflammation targets the myelin predominantly, the lining around the nerve fiber. Whereas, axonal degeneration refers to the actual death of the nerve fibers, which is irreversible. So we go from reversible inflammation to irreversible axonal degeneration.

Inflammation, the typical clinical manifestation, is attacks of disability that do recover usually over weeks to months. As this axonal degeneration develops, there may be gradual progression of disability. We know that this is not always true. Inflammation may be silent.

We know, from clinical trials in following patients serially with MRIs and measuring how active the disease is with the various treatments that I will be talking to you about in a minute, for every ten times that there are new spots that we see on the MRI indicating that the disease is active, in only one out of ten times will the patient report new symptoms. Is it important that the patient is developing spots on the MRI even though they don’t have symptoms? We think that it is. We suspect that this build up of lesions in so-called silent or non-eloquent areas in the brain may eventually lead to a progressive axonal degeneration and permanent progressive disability. It may be too late to treat at that point.

Not all the proofs that we would like for that hypothesis and theory are in place, but increasingly this is gaining favor and there is considerable evidence that would support that this concept of the disease is correct. What are our goals of treatment? For patients who have attacks, we want to shorten their attacks and promote recovery. Difficult thing to study, because most patients we know, with or without treatment, will recover substantially and in many cases fully. Hard to show benefit when you know, that regardless of treatment, patients are likely to improve.

Now this is true for 80 percent of the attacks. However, if you take the worst 20 percent that I will talk to you about or the worst five percent in the second half of my presentation, when they don’t respond to treatment, there is plenty of evidence that those patients are not going to recover and respond and their prognosis is very different.

Treatment of residual symptoms or progressive symptoms, and, until 1993, this was the cornerstone of treatment. We couldn’t do much about the developing disability. We would encourage a healthy lifestyle. This seems to help to some extent, but we would end up treating fatigue, pain, weakness, bladder dysfunction, spasticity and the complications of the disease.

In recent years, we have partially effective treatments that have been shown to reduce the frequency of attacks. We are all hopeful, although this is not proven yet, that this will ultimately reduce the number of patients with late progressive disease.

The first of these treatments, as I will tell you, Betaseron was just approved by the FDA in 1993 in the United States. It wasn’t approved in Europe until late 1995. We don’t have years and years of experience and multiple sclerosis is, in general, a chronic disease that evolves over decades. It will take us decades to get a substantial idea about how our new partially effective treatments are working.

I will go into this in much more detail. As I alluded to and I will show you some slides, there are some recent data that would suggest that, in patients with a first symptom, that sounds like an MS symptom, but before we can diagnose them as definitely having MS, starting them on some of these treatments may delay, it’s very much conjecture, further symptoms that would lead to a definite diagnosis of MS. Is this just a delay or prevention? I think we cannot answer that fully, but I will show you some data about that in a minute.

With the advent of these treatments, the question has arisen whether patients who have the progressive forms of MS, who are more disabled, might benefit from those treatments as well. Initially, the clinical trials were restricted to patients with early active inflammatory MS. In some of the patients with the late progressive forms, yes they probably have axonal deterioration, but do they have ongoing inflammation? Might they also benefit? There have been a number of trials reported just within the last year in that group of patients, and I will refer to some of those results as well.

What was treatment? What’s old, that is pre-1993? We had steroids to treat acute attacks or ATCH. Basically, also a form of steroid therapy rarely used anymore. We had symptomatic management that I referred to. That was the state prior to 1993.

Treatment, what’s new? Now I’m going to talk about treatments between 1993 and 1998. As you will see 1999 has been a hallmark year. There have been a number of new studies that have come out, but there are three FDA-approved treatments. Two of them are essentially the same interferon beta treatments; this is Beta 1B which is produced in bacteria. This is Beta 1A which is produced in hamster cells.

The interferon is a recombinant protein, so the Beta 1A is virtually identical chemically to human beta interferon. I will talk a bit about the mechanism of actions but these are indicated for relapsing, remitting forms of MS. The early attack remission forms of MS to reduce the number of attacks. That is what they are proven conclusively to do. The cost, as you can see, is considerable -- $15,000 a year for Betaseron and close to $12,000 for Avonex.

A third drug was proved in 1996, with a different mechanism of action. I will show you in the next slide what is believed to be the mechanism of action. It’s called Copaxone, essentially for the same indication.

There is a fourth drug that I’ll mention, and I will show you some results, which has been approved, but not allowed to be marketed in the US. It is on the market in Europe and Canada called Rebif. It is identical with Avonex. The only difference is the dose. The dose is several-fold higher for Rebif than for Avonex.

Currently there is a national study, in which we are participating, comparing Rebif, versus Avonex to get at the answer whether the higher doses of interferon may be superior. There is considerable evidence that suggests that, from previous clinical trials, that included more than one dose, but there has been no direct head-to-head comparison of these different products to show that one is superior to the other but that is ongoing.

Interferon Beta, as I mentioned, is a human protein, a cytokine, that is a protein that immune cells use to communicate with other cells, that has many actions. It is an antiviral agent, and really interferon was discovered because of its antiviral properties.

When you develop the flu, you produce interferon, and this helps your cells fight off viral infections. It has many immunomodulatory properties and, although we don’t understand which of these properties is most critical in the treatment of MS, we suspect that these immunomodulatory properties are the important ones. They inhibit the proliferation of lymphocytes.

The block the production of and antagonize the actions of certain other cytokines which are deleterious in MS, especially interferon gamma. We know, for interferon beta, it can inhibit certain enzymes called metalloproteinases that the lymphocytes use to dissolve through the blood-brain barrier and to get in from the systemic circulation of the blood into the brain.

Glatiramer acetate or Copaxone, which is produced by Tebba pharmaceuticals, has a different mechanism of action. It is believed to interfere by mimicking certain myelin proteins to the immune system. It may interfere with the generation of the immune response, as well as stimulating other cells, which may produce more favorable anti-inflammatory cytokines. There is some evidence for that. Essentially different mechanism of action and one of the things that is being considered now is whether addition of the two drugs, two partially effective treatments with different mechanisms of actions, may add extra benefit. There are some pilot trials at least ongoing there.

What do we know about these new treatments that ABC (Avonex, Betaseron, and Copaxone) treatments? These are the results from the pivotal clinical trials and these results show the benefits compared to the control group. Now you will see some, apparently major, differences between the drugs, suggesting one might be more effective than the other. I caution you not to make those interpretations because the behavior of the control groups was somewhat different.

The trend is really in the same direction. Attacks reduced by about 30 percent. You can see that relative to the control group, the percentage of patients who start on these drugs who, at two years, will say, “I have not experience any further attack,” is up almost by double for Betaseron and up by 46 percent for Avonex and 26 percent for Copaxone.

The time that it takes until a patient gets their next relapse, the median time to first relapse, comparably increased substantially. For Betaseron, in the Betaseron trial, attack severity was also evaluated. It also seems to reduce attack severity and one of the major arguments in terms of quality of life and cost effectiveness in this study, hospitalizations were studied, and this was a randomized, blinded study.

Patients were, except insofar, as the side effects told them what they were getting, were blinded. This is often looked at as a fairly objective major. Forty-three percent decreased hospitalizations in the group that were receiving interferon.

These are short-term benefits. The important thing, when patients start on these treatments, is to educate them that we are not giving them these treatments to have them feel better. These are not more symptomatic treatments. Often patients with MS, after they have recovered from their attacks, say they are feeling quite well. These drugs all do have some side effects.

Fortunately, they are generally well-tolerated, but the interferons typically produce flu-like symptoms, myalgias and low grade fever, particularly in the first three months the patients go on them.

Why do I want to take this treatment in the long term when I am feeling quite well right now? These long-term treatments do not treat symptoms. They treat disease activity.

We see the disease activity best on an MRI. This is a patient I saw just two weeks ago, a young girl, 19-years old, first symptoms of MS. She didn’t have many symptoms referable to her brain. All of the symptoms suggested spinal cord involvement, which we did see, but on her brain scan she had multiple lesions including some large lesions.

We know now that the number of lesions at the very first presentation, first symptom, is very strongly predictive of the future course. Seeing all of these lesions, including large ones, on the first scan and this patient with the first symptoms of MS, does tend to suggest she is at higher risk in the long-term for disability.

My feeling is that this is ultimately going to be the critical test of what we do. We certainly want to decrease hospitalizations and decrease attacks, but we only decrease them by 30 percent. If it were 100 percent elimination, there would be no question that these treatments are highly beneficial.

A 30 percent decrease in attacks in the short-term, how valuable is that in terms of what we are asking patients to do? Take injection treatments because all of these treatments are administered parenterally, and do this regularly and, in some cases, put up with side affects.

What we want to do is prevent the situation evolving to this. This is a patient with more advanced MS who has brain atrophy, these are what we call “black holes” where there is actual frank tissue destruction and axonal loss and this woman has dementia from her MS. All those individual lesions don’t cause many symptoms but when they build up they can cause significant permanent cognitive impairment as well as this woman had a great deal of difficulty walking. This is what we are trying to prevent in the long term.

Here are some results from the fourth drug that I have listed there, Rebif. They are essentially very similar to what I could show you with the other two interferon produces. This is from the four-year follow-up in the study conducted in Europe, the Prism Study, and this shows the cumulative, what we call burden of disease, or accumulation of that white stuff in the brain measured in cubic millimeters, and over four years patients in the high dose Rebif group showed an actual reduction in the cumulative burden of disease.

Whereas, patients on the low dose showed a modest increase, about a three percent increase, and these two bars both represent placebo, the only difference was this was a three-year study and, at the end of three years, patients were switched to open label therapy and they were either switched to the high dose here, 44 micrograms three times a week or the low dose 22 micrograms three times a week.

You can see, in both cases, substantially more lesion burden. It seemed like those that were switched to the higher dose had a somewhat lower accumulation than those that were switched to the low dose. That was one of the points of the slide. This is one of the reasons for the clinical trial that I mentioned, that is ongoing. Now to look at the difference between the dose and the differential effectiveness. A substantial decrease in accumulation of these lesions, will that translate into fewer wheelchairs down the line? This is what we are all most interested and we don’t know yet.

If we look at progression of disability, this is what we typically measure. We measure slight differences in a disability scale that is very sensitive to walking or, as most concentrates on walking, which is the major permanent disability that most MS have. You can see that even in the short-term of four years, there is a clear difference between the high dose, 44 micrograms, the low dose, 22 micrograms, and these two placebo groups, depending on whether they switched over at three years to the low dose or high dose. The difference is small.

Thirty-eight percent had not worsened in this high dose, versus 50 percent had not worsened in the placebo group. Yes, a significant difference, but still, how important is that difference? Patients, even in the high dose over the short term seemed to be worsening. We haven’t eliminated progression of disease. I guess the big question is, if instead of looking over four years, one looked over twenty years, because we know MS evolves over decades, would this difference widen? Would the effects become more substantial or might they not? Might these two curves drift together? This is obviously something that we have to learn.

That is what we knew as of the end of 1998. What is new since 1999? The first point is, as I mentioned, there have been two trials. One conducted in Europe called the Etoms Trial with Rebif and one conducted in North American called the Champs Trial. Both were designed very similarly. They identified patients with first symptoms, such as optic neuritis, losing vision in the eye, some eye pain, vision goes blurry, may progress to complete visual loss and recovers over several weeks.

You hear that story in a young person probably suggests that demyelinating disease. The question is, is this going to be the only evident or will there be recurrences? We know that, if we follow patients long enough -- 30 years -- 75 percent are going to develop further symptoms suggestive of MS.

Recently, it has been found that, if we look at the first MRI of the head, if there are other spots on the brain, the risk goes up to 90 percent. If there are no other lesions in the brain, the risk goes down to ten percent after ten years.

A big difference, based on whether the MRI is normal or abnormal, all patients in these trials were admitted because they had at least two spots on the brain that suggested MS, as well as their clinical symptoms, most commonly optic neuritis, but also isolated brain stem clinical symptoms or spinal cord symptoms that were suggestive of a first event of MS. I will show you the results in a minute.

The second new advance, several studies reported within the last year. Two from Europe, one of Rebif and one of Betaseron studied in Europe. One just announced a Betaseron in North America looking at patients who had developed this secondary progressive form of MS asking the question, is there a benefit in patients who have this secondary progressive form of MS? Would they benefit as well? I will show you the results in the coming slide.

Here is the Etom’s result. This is Rebif and those patients with the isolated demyelinating events suggestive of MS. Here they were followed two years and looked at the proportion of patients who developed a second clinical event, which lead to a diagnosis of MS. It was 45 percent in the placebo group, 34 percent in the Rebif group, a 24 percent relative reduction. It is positive.

I still feel that it is unclear in my mind in these patients who are feeling quite well and a substantial of proportion of which may never develop further symptoms, whether we gain something by early treatment. Its one of those trials that I had some reservations about even before it was conducted, because I said, “Even if its positive, and shows this kind of reduction, I’m still not sure it’s not worth waiting.”

Did this prevent or just delay what was going to happen anyway? Is that delay sufficiently important to take a patient who may not have a recurrence, a very first event of optic neuritis? This is a common occurrence in a young person, and put them on indefinite injection treatments that are expensive. I think, although the results are positive and probably indicate some benefit. The question is whether the practical aspects of that benefit warrant this kind of very early treatment.

I don’t know the answer to it and there are different opinions, some feel definitely that it does. As I said, I think we are relatively conservative and I think, at this point, unless the tide of clinical practice across the country forces us into using this treatment, we are probably going to hold off.

This is one of the studies conducted in secondary progressive forms of MS. Patients who have gone into this progressive form of MS, and this shows the time to worsening in terms of this disability scale that we measured, and it was disappointing. It showed that there was no difference. 

There was the high-dose treatment group, the low-dose, and the placebo groups and essentially no difference. It wasn’t entirely negative. Firstly, in terms of the MRI accumulation of new lesions, it looked very similar to what I showed you in relapsing-remitting MS before.

There was a substantial reduction in the accumulation of new T2 lesions. When they broke down the results into those patients, who were continuing to have clinical attacks when they were enrolled in the study, would have pre-study relapses, no benefit at all.

However, when they looked at the groups that did have attacks, so they had progressive disability but they still reported, “I’m getting attacks and needing steroids,” and this was also done by looking at the number of patients who had spots that were picking up dye on MRI scans, indicating that there was still active inflammation and, here it seemed that there was some benefit.

Again, the benefit was modest, but some benefit. Again, the question would be, if that carried out, would those curves get wider and wider apart or would they come together indicating no benefit at all?

What is the bottom line of the first part of my talk? These new treatments interferon and Copaxone definitely reduce the number of attacks, but are only partially effective, 30 percent, roughly, reduction. They definitely reduce MRI lesions. In the case of Rebif and Betaseron, up to 80 percent reduction of new MRI lesions.

They probably reduce disability in the short term modestly. They probably have significantly less impact on the later progressive forms of MS, secondary progressive MS, but perhaps they may help if there is still ongoing activity, manifested by MRI lesions, developing or clinical attacks, in spite of the fact that they have progressive disease.

It is clear that these treatments are most effective when used early. But the question is how early is early? Is it that patient with the very first symptom? Should we consider it in all patients at that point or should we monitor the patients, both clinically and MRI, to decide after doing so, which patients really need the treatments? There is still a lot we don’t know. Do they clearly improve disability?

There have been some reports that patients actually get some improvement of disability. That has been reported with Copaxone. I don’t think that that is entirely clear. Does that benefit become more or less obvious after five years? We know that there are certain interferon treatments that neutralizing antibodies develop. That is, antibodies that, at least in the test tube, will neutralize the activity of the interferon. Will this interfere with the effectiveness of the drug?

There is some suggestion that that may be the case, but this is not entirely clear. Often these antibodies do disappear. That was true for insulin therapy as well. Many patients developed antibodies to insulin and they found, if you just increase the insulin dose, the antibodies go away.

Very similar issues have been raised with interferon therapy and MS. Obviously the big question is if we count wheelchairs in the next decade or two decades down the line, will the treatments we institute now have a substantial impact on that, because no treatment that we have had, prior to 1993, even possibly approached having an impact on that.

The second half of my talk, I would like to talk about the catastrophic variety of demyelinating disease, treatment of acute devastating attacks that don’t respond to standard treatment. These are results that we presented on Sept. 17, 1999. We are published in the December issue [a trade journal].

Some of you, who were involved in this certifying patients for treatment, may recall that there was a tremendous amount of national publicity about this clinical trial. For someone who is a great enthusiast, obviously being the principle investigator and I am obviously quite convinced with the results, I do spend about 95 percent of my time that I speak with patients, I am trying to discourage from using it, because most commonly the patients that I get called about are patients that have been in wheelchairs for some time and have progressive disability and want to know if this can restore their function.

There is no evidence that that is the case. In fact all evidence is to the contrary. I am frequently called from a patient’s hospital room and they will say, “You know, I have been trying this plasma exchange, it doesn’t work at all,” and I will say, “Gee, I’m sorry to hear that. Can you tell me a bit about how you got started on this treatment?”

They are off 500 miles away or a 1000 miles away in some hospital and they say, “Well, I heard about this on the news and, although I have been in a wheelchair for some years, I just thought it might help. My doctor ordered it for me and it’s not helping.”

Well, we have done everything that we could: websites, mailings to patients that ask for information and, I think, in the published article and in everything we have said, it’s very clear. It’s only for acute recent catastrophic deterioration. I think, when you see our inclusion and exclusion criteria, it will make it very clear. It’s a very small group of patients we are talking about, but unlike the interferon treatments or Copaxone, where you can’t see the benefit, you’re kind of hoping the patient is getting benefit.

It is only large clinical trials that give you a hint of benefit. Here the benefit, as I will show you in videotape, evolves in front of your eyes and there can almost be no question. Obviously, what I am going to be presenting to you is a randomized control trial. We felt it was very important to do it in that way, but I think the results of the trial were unequivocal.

In the way of background, as I mentioned to you, MS can result in acute attacks of neurological disability. Rarely these attacks can be severe and fail to respond. The fulminate syndromes I mentioned to you commonly result in these severe devastating attacks that lead to permanent disability.

Although this is rare, at Mayo Clinic, this is a common situation for us, because a very common scenario is a patient comes in to hospital with one of these episodes in a peripheral hospital or other medical center, they fail, and they ask their neurologist, “I want a referral to the Mayo Clinic.”

The patients are sent to us and we end up with a fairly large accumulation of these patients, which allowed us to conduct this kind of clinical trial. There had been no control trial that targeted this group of patients before. The exact group that we studied had not been targeted by any specific controlled investigation.

However, and the way that I got into this, is I arrived at Mayo Clinic in 1992 and my colleague, Dr. Rodriguez, who is the senior member of our group, had tried plasma exchange in a number of patients. He reported this, in 1993, that six consecutive patients that he had treated all had dramatic recoveries, even though they had failed steroids.

Several of the patients were ventilator-dependent. They had patients in comas and they recovered. Frankly, I was very skeptical. I had just arrived at Mayo and I was skeptical. The first thing to do was to see if this was a unique experience to Dr. Rodriguez or had others in fact observed this.

In reviewing the literature of plasma exchange treatment of MS, I came across twelve series and, in those twelve series, were 29 patients with symptoms, with similar syndromes.

Typically, they were mixed in with other patients who had chronic MS and they were treated and clearly, if there was any benefit in that group, it was not very clear and, in that, there would be a much more rare patient with an acute attack, who seemed to do dramatically well. When I called all of these series out, it seemed that, if you just picked out those patients who had the acute severe attacks, they seemed to do very well.

Now obviously there is publication bias. People report their positive results. How many patients had been treated with this treatment and had no improvement? We had no way of knowing that. There had been one controlled study of plasma exchange for acute attacks of MS conducted for the same reason. Because, I am sure Dr. Weiner was aware of the same series and probably, in his institution, they would have fewer patients with these acute very severe attacks, so what they did is they enrolled all patients with attacks of MS.

As I mentioned, most of those are going to recover on their own and that’s what he found. The control group did very well. He treated all of the patients in this study with Cytokine, which is a chemotherapy drug, which is not at all a standard treatment for an acute attack of MS plus ATCH. On top of that, he randomized them to receive plasma exchange or sham exchange. So, looking to see whether plasma exchange gives a boost on top of Cytokine on top of ATCH.

Basically, there was no convincing difference, although he did say that maybe in the most severe attacks, there might be a benefit. Not at all convincing, I don’t have the slide here but we looked at the impact of this on the number of plasma exchange studies being performed in Canada, because Canada has a registry of plasma exchange, and how often that’s done.

There is no such registry in the US, and the practice is fairly similar in Canada to the US, in general. It was clear that there was really no pick up of the use of plasma exchange as a result of this study, which essentially was negative. That wasn’t surprising, but we were still faced with this observation that Dr. Rodriguez had made, and I found these 29 other patients and these 12 case reports suggesting dramatic benefits.

So we said, “We have to do a control study that directly addresses the group of patients Dr. Rodriguez studied.”

I tried to set up the clinical trial to look at exactly that same group and choose inclusion criteria accordingly. This was a randomized double-masked, sham-controlled trial of plasma exchange in patients with acute severe attacks who failed steroid treatment. The inclusion criteria, I won’t go through in detail, but they all had to have MS. In some of these fulminate cases, we were concerned they may have other diseases: lymphoma, gliomatosis, there’s a broad differential diagnosis, and at Mayo we commonly do biopsies to be certain where there is uncertainty.

They all had to have corticosteriod treatment, and we had to watch them for two weeks. We waited two weeks to see if there was any significant improvement before enrolling them. The inclusion criteria are probably not important, but we did not use any other immunotherapy. The only treatment we gave them was plasma exchange. Dr. Rodriguez had found plasma exchange alone worked, and we said that was the only thing we’re going to evaluate. No other treatment.

For patients who received the active treatment -- I don’t know how familiar you are with plasma exchange – but, essentially, this is a machine that is very simple. Blood is circulated into the machine. There is a centrifuge, which separates the liquid portion of the blood, the plasma from the cells.

An artificial plasma, which is an albumin solution, is mixed in with the cells and returned to the patient. It’s that simple. It’s a very simple procedure. For the sham, everything was done identically. The blood went into the same machine, the cells were separated and centrifuged, except, instead of replacing the plasma with an artificial plasma, we just mixed the cells and plasma back together and returned them to the patient.

How was it masked? Well, there are no side affects related to that separation. The only side affects from plasma exchange are because the blood is going out in the machine that can lower the blood pressure. It’s mixed with a citrate anticoagulant. That was done equally in the active and sham treatment.

The procedure, although I think you would have to be very sophisticated to tell the difference of what was going on, was hidden by a curtain and the study was double-masked, neither the patient nor either of the physicians or the nurse coordinator knew which treatment the patient was receiving.

As you see the blinding was excellent. Only the statistician and the aphaeresis staff administering it knew. This is our curtain. Patient was here, this is an older version of our plasma exchange machine, but that is essentially how the blinding occurred, and this was the treatment protocol.

Patients were randomized to receive either active or sham treatment for seven treatments over fourteen days, after which, we decided if success occurred. If they did, they were finished and we followed them six months. If not, they crossed over and received the opposite treatment.

Why did we create this crossover? Primarily, because we were asking patients to come from 500 miles, typically paraplegic or quadriplegic acutely, and we would never have achieved enrollment if we said you had a 50-50 chance of not receiving the active treatment. Practically, it would have been impossible to do this trial without offering this crossover.

So they knew, if they failed after two weeks, they would crossover. We would not tell them what they had, if they had active, they would get sham, if they would get sham they would get active. We would not know. The code was not broken until the very end of the whole trial. Not after each patient, but at the end of the whole trial. But they knew that, either in the first treatment of if they failed the second treatment, they were going to get the active treatment.

We felt this might increase the power and it did because, as I will show you, there were a number of patients who were on sham, as the case in the videotape I will show you, patient failed. No improvement. Actually got worse and then crossed over and within days had dramatic improvement.

Those proved to be the most informative patients. They were all followed for six months. We were interested in a robust outcome. We were not interested in a treatment, these patients typically were paralyzed, couldn’t wiggle their toes, no movement, unable to stand, typically unable to sit. We were not interested in a treatment that would let them wiggle their toes. Dr. Rodriguez had claimed there was marked improvement and that’s what we were going to look for.

We obviously did not want to be so conservative that we were going to miss an important treatment and what we required was a moderate to marked improvement -- minimal, obvious and impacts on function or major functional improvement. Slight, but definite improvement, we were going to consider a failure.

Two neurologists evaluated the patients at various points. Neurologist B, who was the critical one on whom the results of the study hinged, although the agreement was excellent between the two neurologists. There was only one instance, in one patient at one point, that they disagreed. One said mild and one said moderate, which mild was failure. Moderate was success. The critical evaluations were at day zero, 14 and 28.

Neurologist A saw the multiple more times, so we could get some idea of the course of improvement. The study was overseen by a number of committees. An internal safety committee that we appointed, plus NIH, which sponsored this study appointed a patient safety monitoring board that was chaired by Dr. Richard Rudick at the Cleveland Clinic. They visited us once a year and every six months did reviews.

Here are the results of the study. We enrolled as we planned 22 patients. That’s what we said we’d do and that’s what we did. Eleven were randomized to active treatment first and eleven to sham first. The average age was 42 years. Seven men, fifteen women, twelve of the 22 had MS, equally divided between the two groups, and the other ten had other demyelinating diseases.

These other fulminant diseases, the most common of which was acute transverse myelitis, which would manifest as paraplegic typically, in some cases quadriplegic. These were their neurological deficits. All of the patients had hemiplegia, paraplegia or quadriplegia. In addition, two patients were aphasic and one patient was in coma.

This summarizes what happened in the study and the results. It took us 165 patients to screen to get the 34 patients who were eligible. Most of the ones who were not eligible either didn’t have MS or had significant recovery on steroids that we judged had responded to steroids. We took only patients who had minimal or no response to steroids. Most of the patients who were eligible were enrolled.

The ones who weren’t enrolled just felt that they could not travel to the Mayo Clinic. We had offered them enrollment, but they said, “I just can’t come. I have no one to come with me and I am paraplegic and I can’t get transportation and I can’t do it.” But we did enroll most of the eligible patients.

Let’s start with this on the left side, the purple background boxes. Eleven received active exchange. Five improved and reached that moderate to marked improvement. Six failed. Of those who failed, all six crossed over to sham, there were no successes -- followed up for six months.

Of those who were randomized to sham, we had only one success that reached moderate to marked improvement on sham. As I will tell you later, on further follow-up she rapidly redeveloped neurological disability and did very poorly in the long term.

We had two patients who died in the first treatment phase. The lady who was in coma developed progressive cerebral herniation and died of her disease. [She] had a postmortem, which confirmed fulminant demyelinating disease. The other patient, unfortunately, developed a rare complication of heparin called heparin-associated thrombosthenin and developed a severe pulmonary embolus and died.

Of the eight remaining patients, who had failed and were alive, they all crossed over to active and three of those patients in the second treatment phase, were successes in the second treatment phase. All went into the follow-up. There was no method statistically to analyze…this was a unique study in that only patients who failed crossed over.

This was a novel statistical challenge but my college, Dr. Peter O’Brien, who is an expert statistician, developed a very simple and easy to understand method to analyze the results. This was developed well ahead of the study. It’s very simple to understand.

There were two treatment groups; active first and sham first, and there were three possible outcomes. Either there were successes in the first phase, they didn’t crossover or they failed and they crossed over and they succeed, or they failed the first treatment, failed the second treatment and continued to be observed. The same three outcomes in both groups.

Here is the distribution of patients. The five patients succeeded, no crossover in the active first. Six patients failed in the sham first, one, three, seven. We compared the difference in distribution of these, if the treatment were perfect, all patients would have been in this category.

We would have had eleven here and none in the others. In the sham first, they would have all failed at the beginning and succeeded here. We would have all the patients in this category. Obviously it wasn’t perfect. I don’t think we expected it to be perfect, but this difference in distribution was 0.01, which is highly significant. To otherwise summarize it to you, nine out of the 22 patients enrolled were successes and, of those, eight out of nine were receiving active treatment when they got better.

So success occurred in 42 percent of the time that we administered a course of active treatment and, in only one case out of 17, 5.9 percent of the times that we administered a sham treatment.

I think statistics alone don’t show fully what we experienced. So I am going to show you one brief videotape of a 36-year old woman. She is from Milwaukee, in 1991, developed right-sided weakness, had a lesion on the left side of the brain. Something we don’t commonly do for a diagnosis of MS, she did have a brain biopsy in Milwaukee, was diagnosed as having MS.

In 1994, had vertigo, probably related to her MS, although hard to be sure, she was treated with steroids and recovered. She was free of symptoms between 1994 and 1998 but then, in January 1998, after the flu, she developed numbness and severe weakness of her right side to the point that she a great deal of difficulty walking.

She was treated in Milwaukee, with intravenous Methylprednisolone, with minimal improvement. She went to a rehab facility and, about a month later, developed severe weakness of both legs, which we will show you, right worse than left, and the MRI showed an enhancing, that is dye leaking into the lesion at T4 in the spinal cord. Let’s go to the videotape.

[Videotape is playing.]

So, after this, she started on the first course of treatment and as you will see the left leg got a tad better, but no improvement at all in the right leg. She developed some weakness in her right arm and she also developed double vision. We had no idea and she had no idea what treatment she was receiving.

She also developed a lesion on her buttock, which was aspirated and was positive for herpes, which is why she’s in an isolation facility, as you will see. She is on a Clinitron bed so it’s kind of noisy. There was essentially no improvement at all in her right leg. This was two weeks later, after she had completed the first course of treatment. So a little more movement in the left foot that had no significant functional impact, so we judged that this was in our terms failure. We decided to cross her over. She was wiggling her toes but really, as I said, no functional impact. Still unable to sit.

Now this is two weeks later after the second course of treatment. The improvement began within one treatment of the plasma exchange, what turned out to be the active plasma exchange. See her strength is excellent. This is the side that almost had no improvement. So a very dramatic improvement. Can we fast-forward it a little bit? I just want to show you her walking. Our criteria were that it had to have functional impact.

You see, at this point, she was not walking very well, but she was able to walk with assistance -- where she wasn’t able to sit before. If we can fast-forward it a bit more, here is a month later, she is walking not too badly, and fast-forward it a little further at the six-month follow-up point, she is walking pretty normally. That’s fine. Thank you.

In continued follow-up, and I have seen her last six months ago, she’s three and a half years now since that treatment, she has had no further attacks. She is fully employed and probably would have had to consider a nursing home or some comparable long-term care facility, if it weren’t for this. The important point is that, although we have heard about this rare complication of heparin therapy, the plasma exchange procedure is generally very well tolerated and safe.

Most patients require a central intravenous line, that’s the most potentially risk-associated aspect of this treatment, although, obviously, this is a fairly standard procedure. We had no complications of the insertion. That one patient, who had the heparin associated thrombosthenin and the clotting disorder, we had to replace the line. I guess that could have been a tip off about a coagulopathy, but otherwise, we had no complications at all and no infections, but obviously that is a risk.

We try to do it peripherally where we can. Generally speaking, in men, we are more successful than in women just because the veins are better. Anemia was a common thing that we saw, but it occurred equally, as frequently in the sham group and it was asymptomatic and cleared up very quickly.

Could we effectively mask this study? The masking we feel was excellent. As you can imagine with this kind of dramatic recovery, patients would guess that they received the active treatment and neurologists would guess that as well and they were just about always right as it turned out.

Of course we didn’t know that at the time, until the study was all over, but the question was in those patients who were getting the active treatment, who failed, would the neurologist have known or would the patient have known? Basically, in only one out of those cases, did the neurologist guess they were receiving the active treatment. So in other words, the only way that the neurologist knew they were getting the active treatment is because they got better, not from any side affects. So we feel the study was very well masked.

The patients agreed with us, in all instances, where we said they were moderately to markedly improved we asked the patient, “What do you think?”

In all cases they agreed. There was no instance where the neurologist felt they improved and the patient said no. There were a number of instances where the patient said, “Yes, I am better,” and the neurologist said, “I’m sorry, we think this is a failure.”

We didn’t say that to them, but we rated that. That was about 50-50, those patients who thought they improved, whether they were on active or sham, they couldn’t tell. Those ones, where the neurologist said they improved, the patient always agreed and they were always on active treatment.

Did this protect again future problems? And the answer was clearly, no. A number of the patients had further exacerbations in follow-up. Four out of eight who were successes on active treatment, the one patient who was a success on sham, very rapidly relapsed and the treatment failures, a number of them had further attacks. I think it simply reflects the group of patients we admitted.

We do not think this has any long-term benefit. This is a way of restoring function acutely in patients who have a devastating acute attack. As in the case of the lady I showed you on the videotape, her natural history was such, and she is on interferon treatment, but she has done very well since.

That’s true for many of these fulminate syndromes. It does not necessarily mean, if you have had a fulminant demyelinating syndrome, that you are going to have this occur repeatedly. A very important point is what about those who failed? Where they going to recover too? If we had waited six months, were they going to get better?

Two out of the twelve met the criteria for treatment success over six months. Ten out of the twelve didn’t. So we think we were dealing with a group of patients who had a poor prognosis and were unlikely to recover. I will finish up with the summaries.

So plasma exchange produced dramatic and rapid improvement in 42 percent of patients as a single treatment -- as a monotherapy -- not with cyclophosomide or any other treatment. And patients who failed standard treatments, the benefit occurred not only in MS, but in these other demyelinating syndromes and one of the major arguments to this study by reviewers who reviewed it for the journals is, “Well, you’re just treating MS you’re treating these other diseases.”

I think the point is, although we don’t know what causes any of these diseases, we’re not saying the cause is the same, but when it occurs, it seems that a common numeral that is in the liquid portion of the blood mediator propagates and continues and sustains the disability.

It doesn’t matter whether it’s MS or Marburg’s or ADEM, or ATM, acute transverse myelitis, they all seem to respond. They are all idiopathic inflammatory demyelinating diseases and there may be some common pathogenetic mechanisms. The improvement can occur anywhere up to three months from the onset. We don’t know how it works. We are working on that. I think I will leave it at that.

So we recommended that this should not be the initial treatment for acute attacks of MS or inflammatory demyelinating diseases, but only in patients who have failed standard treatment and after we are sure there isn’t any cause.

In the talk today, I have talked to you about long-term treatments that are partially effective, that apply to a lot of patients, but it’s hard for patients to know and physicians to know in the short term whether they are helping.

We are still unclear about what the long term impact is going to be. It’s difficult to know which patients to choose for these treatments. All patients with active disease, early disease or even patients into the secondary progressive phase, and I have shown you that we have a new acute treatment that we think applies, at least we have proven that it applies only to a very small segment of patients with acute devastating attacks that is effective, not in all only in 42 percent. Of course that has a margin of error, because of our small sample size, anywhere from 35 up to 50 percent, and some are interested in expanding the treatment indications that may be worth addressing but at this point we feel it is justified only in this group of patients.