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(4 0f 4) In the final of our series of conversations with Dr. Kornguth, he talks about the symptoms of multiple sclerosis, the differences in susceptibility across geographical regions and the higher incidence among females. He explores the historical understanding of the disease and how it relates to sense-making in medicine, and he discusses change in our understanding of stressors leading to the disease. We look at change on an individual level - in terms of disease progression - and we consider the sociohistorical dimension as we explore the complicated rhythm of exacerbation and remission associated with MS and other autoimmune diseases. We revisit the cost-benefit analysis of the tradeoffs of effective treatments and the associated  side effects. As always, each treatment presents negative consequences along with positive benefit for the patient.

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Karen French: We're back again with Dr. Steven Kornguth for a fourth and final podcast. Today we're talking about the most prevalent autoimmune disease impacting the central nervous system. This is multiple sclerosis.

Karen: Steve, what are the symptoms of multiple sclerosis and what are the susceptibility factors?

Steven Kornguth: It's a fascinating disease; it affects people in the prime of their life, typically 15 to 40 years of age. It affects women twice as frequently as it affects men. Two-thirds of the patients are women with women and comes a bit earlier. You have a sudden change in the wellness of the patient as they walk in. The sudden change can occur over a period of hours from full fitness to compromised function and compromised cognitive ability and various symptoms that can be divided into clinical signs and they can be divided into what I'll call a physiological signs. So the patient walks in and the difficulties that they are perceiving is slurred speech often visual difficulties... tremor. These are the three classic signs that are manifested with MS in the patient, there are a whole variety of other signs which appear and that includes weakness and that includes sensitivity to heat. So taking a bath of an MS patient when they're in the illness phase, we call that exacerbation, suddenly weak (tremendously in going into a hot bath) can't stand up again or there's tremor there's communication difficulty or visual problems that they're going to have the difficulty standing up difficulties performing tasks they normally do with a change happening in a very short period of time. So it's noticeable to the patient in terms of the physiological changes that we see, there is a weakness which is related to loss of myelin. Myelin allows nerves to conduct impulses very quickly. So if you take a look at the detection, an ability of the patient to perceive what's going on there a mixed signal processing going on in the brain because of the loss of myelin. That's a characteristic that we going to be looking at. In addition, you have other sorts of features. You have a high incidence of multiple sclerosis in Northern climates. So depending where you live geographically, there's going to be if you're in the Northern climate, Northern Europe, Northern United States - The incidence of the disease is roughly 70 to 80 or 90 persons per 100,000. If you're living in the southern climates, typically it's going to be 15 to 20 persons per 100,000. Very big difference in incidence. So you have a disease that affects people in onset in the prime of their life depending where they are living much more prevalent in women than in men and this gives the challenge of what we call sense-making and doing the differential diagnosis saying, "Is this multiple sclerosis, or some other disease?" and the ability to name. We call it classify or stratify the patient by the disease name tells us how we can begin to define treatment and management of that patient because the treatment is essentially an understanding of what the mechanism or etiology of the disease is.

Karen: Thinking about that name - you're saying the treatment and the name. What does that name tell us about the disease itself. So multiple sclerosis, what does that mean? What does it tell us about it?

Steve: Great question. So multiple sclerosis. The name multiple. It means that there are multiple areas in the brain that are affected, and there have to be multiple areas of brain affected to be called multiple sclerosis. So it could be vision. It could be hearing it could be speech. It could be tremor. It could be bladder control. It could be inability to stand so the site and the clinical symptom are going to be involved. The site is for instance… the vision. So it's the eye processing - vision processing - system. The sclerosis refers to the hardening; replacement of myelin by astrocytes. Astrocytes are a type of a cell and they have fibrillar material within that cell. When you touch that region of the brain that's affected by the multiple sclerosis is hard, harder than surrounding tissue. So that is sclerotic: hardening. So multiple sclerosis refers to the multiple regions of the brain affected and the texture of the lesion that is giving rise to the clinical symptom.

Karen: So there are multiple plaques in the brain, and depending on where those plaques are, they have that have different symptoms.

Steve: Different clinical symptoms because the clinical symptoms reflect the loss of the myelin and the loss of the conduction velocity to detect... for the brain to detect what's going on.

Karen: So will different patients have different symptoms? At different times in their..?

Steve: Oh, yes, absolutely!

So some patients their very first symptom can be sudden change in vision. Another patient can be bladder - loss of bladder control, a third patient can be not able to stand up, even though they're great athletes and were able to run marathons. So it's a sudden change in something the first episode that occurs. That episode gets worse. We call that exacerbation, and then gets better, and we call that remission. That phenomenon of increasing incapacity or difficulty and then getting better - not necessarily recovering to the full state, but getting worse getting better, this periodic episode is characteristic of multiple sclerosis. And the second event that may happen to that person which is required for MS diagnosis can be the same area that was affected initially, but most often it's a different region of the brain that's affected, and then you have a third episode, and that's now again another region of the brain that is affected. Now when one is doing the clinical signs, there is still some evidence of compromised function, even when the first sign recovered. If you can think of it that the brain is essentially historically having compromised function in every region of the brain where there was the first episode, a second episode, a third episode, and that change is going to be visible by the diagnostic tools we have today in 2018.

Karen: So you're saying... I might have vision problems, and then I might have tremor; and then I might have something else. Part of it gets worse. It gets better. It gets worse. It’s get better. When it gets better, does that part of the brain heal, or does it stay the same?

Steve: No, it heals. It recovers but then there are compensatory mechanisms. The brain is wonderful organ, because there are multiple different pathways that a given information processing can occur, and we call that compensation and that compensation allows you to function in essentially a relatively normal way, even though there is an existing lesion remaining in that brain.

Karen: So the lesion stays.

Steve: The lesion can improve slightly but yes that lesion still leaves a mark further on.

Karen: But the function can get better, right.

Steve: Differentiate the pathology - namely what's changing in specific brain region - from the function of the clinical ability of the patient to operate. They're different.

Karen: So thinking about this with 2018 we can look in like an MRI or something and look in a brain and see what's happening. How long have we known about a MS? And what did we think about it before because there's somebody does this sort of gets better get to work to get to the better it gets worse. You can't really see what's happening before we could see into a brain and see what was happening. This is an unusual behavior.

Steve: Yes, very good.

Karen: How did they, and I...

Steve: Let's think about how this thing evolved, right?

Karen: Yeah, that would be..

Steve: How our understanding was… and the understanding evolves depending on the tools, you have to look at the patient and your understanding of how the brain is working. So the first what I would call diagnosis of a disease we now understand as multiple sclerosis was in 1380. This was by Saint Lidwina from Holland, a young woman, and she had sudden onset of vision difficulties followed also by tremor and by falling (tripping), they recovered in each of these episodes. And then she went on to develop reading difficulties and so on it, and it was not clear at that time, whether it was a property of the brain that was going on, or just a wellness state. Because there was no neurology at that point. No tools to understand function and nobody dissecting the brain or anything of that sort to look for particular tools. So the first... have to jump forward now...

Karen: Back to St Lidwina, when that happened to her, they attributed it to...

Steve: An illness.

Karen: An illness. Okay. We're not sure

Steve: She had the symptoms… but In her diary. which is what the extant material is in her diary. That’s how we know. She describes the falling and the visual problems. So you now have to fast forward to 1868 the father of Neurology, Charcot. So, Charcot was at Salpêtrière in Paris... famous-famous diagnostician. So he was able to see and they had a ward of patients - almost all women, and he was looking at the way they were acting and they will have this common both psychiatric (as we would call today and neurological symptoms) and visions. They had difficulties in tremor so on. And he did autopsies on the brains of the individuals who passed away. Is it is1868 and as he dissected the brain he noticed that there are areas absent myelin - fatty areas - and when you touched it it felt hard. And so you have multiple sclerosis in the time Charcot. Now what's interesting about this, because it has to do how do you understand what the cause is.

So Charcot was 10 to 15 years after Koch, a German pathologist. And Koch was the one who defined characteristics of viral and bacterial caused illness.

And how do you understand the illness? Well, you have to have an agent that caused disease, you have to be able to isolate that agent inject into another animal in Koch's case and come down with the same illness that the animal had to begin with.

This is within 15 years of Charcot recognizing that there's this change in the brain which gets correlated at that time with MS. So the first notion that came up was it is probably an infectious disease. Just imagine the times, when you go from no understanding of disease of an infectious nature to a sudden understanding of a change in the brain of an individual with multiple sclerosis. So the notion of a viral or bacterial agent was present at that time. Now, you have to go fast forward from that point to another great scientist Pasteur.

So Pasteur was in France, and he came down with a wonderful discovery of the rabies vaccine. And the rabies vaccine was taking the rabies virus injecting it into rabbit brain, which would weaken the rabies virus. It turned out when you take that material which includes the brain which contains now the virus that's attenuated and injected into a patient is human as he did that person now becomes immune to the rabies virus. The problem that came in a significant number of patients, that were not written up directly in the open literature, was they came down with a demyelinating disease which looked very much like multiple sclerosis.

That disease was called allergic encephalomyelitis. And today we quoted experimental allergic encephalomyelitis giving rise to the notion that it probably is immune, but in the 1890s, we didn't have a good understanding of immune processing. Fast forward again, it turns out in the twenties and thirties it was recognized that the lesions in the multiple sclerosis brain were always around blood vessels - small blood vessels we call that perivascular lesions. So Putnam at Columbia University said, "Ah, This is like a stroke, because you have a lesion around the blood vessel. Maybe something plugging up the blood vessel." So he injected little materials, particles, into the brain of animals and they came down with what looked like multiple sclerosis lesions perivascular lesions, and so Putnam's argument at that point was the disease was a vascular disorder like a stroke - a mini stroke, and now you go forward which is really the exciting thing to me and it turns out in the sixties and seventies. It was recognized that there are three proteins in myelin, which if you inject them into an animal will cause a demyelinating disease, and you produced antibodies reacting with any one of these three proteins, and now the notion of an autoimmune disease came to the floor forward . So there were several different notions of mechanism and etiology and the challenge with multiple sclerosis then is how do I make sense of which one of these is prevalent and the most likely one? So you now I have to begin to say well if it's a stroke, what do I have to do to treat that; if it's a virus I have to be able to isolate a virus from the brain of the individual, or I have to give an antiviral or an antibacterial to control it. And if it's an autoimmune disease, that then I have to give an anti-inflammatory or an antibody against the antibody that is causing the disease in the first place. Have to block that immune response. And so everything we know today and we can get into a little detail on that is completely consistent and confirmatory of an immune process rather than an infectious process or a stroke-like process that's involved and causative in the case of the multiple sclerosis.

Karen: We've come a long way since 1380.

Steve: Since 1380, we've come a long way. Yes.

Karen: So, where is it? Now? What is our understanding of the process?

Steve: Our understanding today is that there is an immune event, which causes cells in the body to make antibodies and cells that affect negatively (breakdown) myelin. The myelin is the sheath that permits rapid conduction velocity of an axon. And what we are talking about is going from 150 meters per second to 5 to 10 meters per second.

Karen: Wow!

Steve: That's a huge loss, and imagine that it's not every nerve which is reduced, but you have a bundle and some of them are markedly reduced and others are not reduced and their conduction velocity. And now you have mixed signals coming depending on how far and how long it takes the nerve to talk to its target. So that gives the difficulty with speech, the difficulty with vision, and the tremor. So we understand it as an immune disease now in 2018, and this is been the case really since the 70s. So because it's that we have a variety of therapeutics which have great utility in managing the patient, and the first of these was cortisone. So cortisone was recognized in 1951 as an anti-inflammatory agent, which means if you gave cortisone the patient's interval between the exacerbation and remission would increase and the severity would decrease. So the patients were doing better. There's a problem with cortisone, and this is going to be another aspect via MS is so instructive - and that is such a trade off. Every medicine we have has an adverse effect at a beneficial effect (cost benefit ratio). And in terms of the benefit, longer wellness (that is longer periods between exacerbation and remission and severity) are very big pluses. However, there are depression, psychiatric depression that goes along with the cortisone administration... there are susceptibilities to other agents because you're knocking out the inflammatory response, you're knocking out protection against invading bacteria and viruses. So that's your trade off; go far forward from there. The next period and great discovery was interferon-beta. This is a naturally occurring material in your body which when you give it again extends the period between exacerbations number one and gives longer function with much less frequent severity, than when you haven't got interferon, but the interferon is an immune suppressor. And so now again, you are more susceptible to viral infections, bacterial infections, on the interferon and there other side effects as well that are undesirable. In the 2000s with the advent of what we called monoclonal antibody production you can take clinically antibodies that will suppress the immune response in the patient and because it's autoimmune, a treatment generally is to suppress the immune response. So you have got less of the cells that are going to cause demyelination than normal. So the patient does much better. And the first of these that were really exciting was Tysabri and it is used today. Tysabri gave much longer intervals between the exacerbation. The problem is there is a virus which is resident in many people. JC virus is called… John Cunningham is the name for that, and that virus is kept in check by your immune system. Not the MS, but in general people in a small but significant number of MS people on Tysabri that virus control is diminished because you've suppress immune system. And what happens is it is a fulminant viral consequence called progressive multifocal leukoencephalopathy which leads to death. And so the trade-off is long-term survival and in some individuals coming down with the PML. To get beyond that, there's another drug now which also suppresses the immune system antibody and that's called Lemtrada and Lemtrada hits again B-cells and T-cells and inhibits their production which is where your antibodies are being made and the Lemtrada increases the wellness state of the patient, but without the consequences of the PML that we see with the Tysabri and there are a lot of other drugs today being developed which has minimal negative side effects with a longer extension of time in wellness and so forth. Again, we're talking about young people - for the women, typically coming down between 15 and 30-35; for the men it's typically between 25 and 40-45. Women typically somewhat more severe than men. Both men and women in the prime of life having clinical significant difficulties on a long-term progressive basis.

Karen: So they're still working on new treatments that will follow the same pattern of reducing the.. autoimmune immune response and without compromise doing so much damage.

The human function- That seems to be a theme that you've returned to through... Let's see when you're talking about um.. paraneoplasia did the same thing. This comes up again and again and again that that sort of trade-off between cost and benefits. So in all of the autoimmune diseases a way of thinking of the four lectures that we've been talking what you have is an immune process which depends upon the body's making of the proteins we call antibodies. And of cells that attack self material what you're trying to do in treatment and management is diminish the production of the antibodies that attack self and of the cells that attack self, but typically what you doing is you are decreasing the efficacy of your immune system period to attack the foreign viruses, bacteria, fungi that bedevil us in wellness. And so the trade-off is sustaining wellness by diminishing the functioning of the immune system understanding that there always has a cost associated with that at least in 2018. And the wonderful thing we can look for in the future is how to make more specific the targeting of the immune system to external threats rather than internal materials that look like external units.

Karen: So in thinking back over this series and the discussions that we've had, you change the way I thought about medicine in the way that we.. at least my understanding of sort of drug development too. I always thought of it is the goal was wiping out disease, but it's not. It's about maximizing the benefits, minimizing the costs. That's the whole point of these lectures. Yes, there is no medicine that only does good things. Every medicine we take every drug we take has an associated adverse consequence. That's what's the point is cost benefit has to be heavily in the favor of the benefit. And minimized in the cost, its not financial, but it's dysfunction of the human, right?

And so the other thing that we've talked about a lot is the notion of differential diagnosis and my understanding of sort of the role of a physician and how that's different than my understanding as a patient: my goals versus their goals.

Steve: Let me correct you. Yes, both of your goals. Of the physician and the patient is to improve your wellness. How do you understand the mechanism involved is going to be different. So the patient who has a compromise vision is going to focus on the vision, but if a compromise vision is a consequence of an immune response to cancer, then there's a trade-off, right? If you with small cell carcinoma of the lung live 3 years or 4 years longer in a well state albeit with some visual difficulties, if you have the antibodies that are hitting the tumor versus the self, the visual system that system that system, that improvement enables both the physician to want to help you (killing the tumor) and you're interested in the antibodies' (I would imagine) killing the tumor. The question is how you understand what the compromise is from the patient who can see they're concerned about seeing, number one. That's a complaint. From the physician, the physician is trying to ask what is it that I can modify or ameliorate in your body to allow you to function, and that has to do with mechanism.

Karen: So it's not goal difference. It's perspective difference.

Steve: It's perspective difference, exactly right.

And the more I can understand where they're coming from, the more effective our communication is, and that the physician can understand where you're coming from. Because it's patient's decision. The cost-benefit is not the physician's decision. The cost-benefit is the patient's. So you have to inform the patient what are the negative outcomes potentially, and there has to be a predictive negative outcome because it's very hard to make decisions if there's nothing predictive. So the patient has to say when the physician tells me I have choices of X Y and Z and the problem I'm going to have with X's one set, problem with Y another set and Z is a third-set.

Karen: The patient has to say which of these is more important to me? What trade-offs am I taking to improve my clinical states and wellness?

Steve: Always.. should be... the decision should be the patient’s or the patient's surrogate. Right.

Karen: And I think the final thing I've learned from the conversations with you is the notion of sense-making and the process and how that process sort of changes is informed by time, especially looking at MS and our understanding of that from 1380 to now. It's always informed by context in history.

Steve: That's right.

Karen: It has been a great conversation. Thank you so much for your time!

Steve: Thank you so much. You're so wonderful.

Karen: Thank you!