What is MS and what causes it?

Dr Michael Barnett from the University of Sydney and the Royal Prince Alfred Hospital talks about what is MS and what causes it?

Transcript of Presentation

Okay, so there are couple facts that I’ll just mention at the outset and these are going to be elaborated on by the other speakers subsequent to me. We know that MS is an inflammatory disease that affects the brain and the spinal cord. We know it’s very common in young adults as a cause of neurological disability. Prevalence of the disease has gone up over the years, so there’s about 70 per 100 000, so this is a very old slide from Professor Jim McLeod at the University of Sydney from 1981, and the prevalence you’ll see in NSW has doubled in that time. We know it affects females more than males, like most disorders that affect the immune system. And it has an average age of onset of about 34 years, which of course is in the prime of peoples’ life, and often impacts severely on their working capacity.

As I said, others after me are going to address these factors in much more detail, but we don’t really know what's causes its disease. We do know from twin studies that there is a strong genetic component to the disease. So if you have MS and your twin identical sister asks you what her chance of getting MS is, its somewhere in the order of twenty-five, thirty percent; whereas that drops down dramatically if its a non-twin of even a dizygotic twin; a non-identical twin. There are, however, a large number of susceptibility genes that have been identified, which as I say will be elaborated on by Professor Booth after me.

But it’s not just your genetic makeup, it’s also some factor in the environment. And the most striking feature of MS epidemiology that points to a factor in the environment for this condition is this so called latitudinal gradient , that in this hemisphere was again best described by Jim Mcleod, where the prevalence of the disease is much greater in the more temperate climates of Hobart than it is in say Northern Queensland. And you can see this difference is six/seven times the prevalence rate down here in the colder climates of Tasmania. What explains that – we don’t really know. A number of factors have postulated. You’ll all have heard about Vitamin D, exposure to certain viruses, such as Epstein bar virus at particular ages; but really, we haven’t proven these factors and hopefully in the next two to three years, we’re going to see a number of large clinical trials come to fruition, which will help examine factors such as Vitamin D.

What we do know, as I said before, is that the prevalence and incidence of this disease is increasing. Part of that might be explained by the fact that people are more likely to be sent to a neurologist these days; people are more likely to get an MRI, so the diagnosis is more likely to be made. And there’s obviously a group of patients with very mild MS out there, who previously would never have been diagnosed, that are being diagnosed now.

Having said that, even taking that into account, it does look like there is a true increase in prevalence, and it looks like it’s almost a linear increase over the last thirty years, at least in this country. And it looks like that the increased prevalence is accounted for largely by increased incidence in females. Again, we really don’t know why.

So that's just some basic background. I'm going to move on now to, what is MS from a pathological point of view? And here you’ll see an image from a lithograph from 1838 by this chap, who was an English pathologist called Carswell, showing typical plaques of MS affecting the spinal cord, and the brain; this part of the brain is the cerebellum, responsible for balance and a number of other factors.

Not to be outdone, the French one year later; this is Creavallier, released a very similar picture in an atlas that he published in 1839. But it was really this chap, Charcot, who synthesised the clinical and pathological features of this disease.

So if you were able to look inside a chronic MS lesion, one that had been there for several years, what would it look like? This is a very typical MS lesion; you can see this punched out area; its stained for myelin, which is of course the fatty sheath that surrounds the nerve fibres in the brain and spinal cord. And this punched out area is completely devoid of myelin. And if you were to look at this under a very high powered microscope, you’d see all these little round circles, which are the nerve fibres, which in this case are largely preserved. But the myelin which should be around them as a dark blue line is completely gone, and it’s been replaced by this, what we call “gliosis” or scar tissue in between the nerve fibres. And that’s a sort of very classical MS plaque, as was described by Charcot over a hundred years ago.

We now know that MS doesn't just cause lesions in the white matter of the brain; we know that it also affects the cortex; the layer of neurons over the surface of the brain. This slide here shows this orange line showing affected cortex all around the brain in the patient with long standing secondary progressive MS.

We also know that in addition to this fatty sheath, the myelin being targeted in MS; even in the earliest phases of the disease, nerve fibres are being damaged. And this is a slide, again from a hundred years ago, showing that nerves have been cut, or transected, and resulted in these so called little ‘retraction bulbs’ where the nerve retracts upon itself into a little ball. And this is an acute MS lesion, worked by a very famous neuropathologist in the US, Bruce Traper; showing that up to eleven thousand of these nerves per cubic millimetre can be cut or transected in an acute MS lesion. And that's happening from the word ‘go’. And its one of the reasons, or it’s an impetus to start treatment early in this disease.

Finally, in addition to myelin being lost and axons, or nerve fibres; the actual nerves themselves, the nerve cells in the cortex of the brain are also lost relatively early in MS. And part of that loss, which is only really a recently recognised phenomenon, accounts for the reason people get problems with their memory, in their thinking, and other features which Dr Lechner-Scott is going to talk to you about shortly.

Our own interest has been what happens not at that end of the disease; what happens toward the beginning of the disease. And this is a patient of mine with a fairly typical scan, showing these lesions on a MRI scan; patches of inflammation, and one of them, this bright one, lights up with the injection of the contrast agent which we give to patients with MS, called ‘gadolinium’ and that indicates that this lesion is a very active, acute lesion in which the barrier between the blood and brain is broken down, and that ‘gadolinium’, that contrast has crossed the blood-brain barrier and leached into the brain.

What would happen if you looked inside a lesion like that? So if you were to be able to look under a microscope, this is what you’d see. Not that sort of chronic, punched out area, but you’d still see myelin shown in blue, sitting on the nerve fibres. So those long linear profiles you see are the nerve fibres, and there’s some myelin left on them. And between these nerve fibres, there’s these cells here; four little blue dots (I'm not sure how well that projects) but those little blue dots are dots of the myelin that have been eaten up, or digested in part by these cells called macrophages.

The traditional hypothesis for the cause, the pathological cause for Ms, is that these cells, these macrophages are attacking normal myelin, striping the myelin off and damaging it. That sort of activity, where you get these acute active lesions, like the one I just showed you; is much more prevalent in the early phases of the condition, where people get quite a lot of attacks, as opposed to the other end of the disease, when there’s often just a gradual progression of disability, but none of these acute attacks.

And we now know that probably a lot of this is going on even before patients are diagnosed. So when a patient now presents with their first episode of MS, we can now make the diagnosis almost on day one, on the basis of current published criteria for the disease. And because we know that there’s all of this damage that’s probably gone on for some time before, there is an increasing trend to be a little but more aggressive with our treatments in this disease; and you’ll hear all about that from Dr Hodgkinson, who has just arrived.

This is a very busy slide, and I don’t want you to worry about this slide. I'm not going to go through it in any detail. It is just to reiterate that most authorities still believe that MS is an autoimmune disease; it’s a disease in which your own immune system is responsible for generating an attack on your own brain constituents; the myelin and the nerve fibres, as I just described.

Why this is occurs, we don’t know. Perhaps it is because there is a so called loss of ‘tolerance’ to our own nerves and myelin, perhaps it is due to some virus that initiates the immune response, and t-cells are thought to be the prime drivers of this response. So t-cells are able to cross the blood-brain barrier in normal people, but if those t-cells have a specificity, or are directed towards, their attack is directed towards myelin or nerve fibres, and they cross the blood-brain barrier, they can damage your own tissue.

This is a very simplistic sort of diagram, but we now know that in addition to t-cells being important, we know that other parts of the immune system, the b-cells, which produce antibodies, are very important, and different types of t-cells are important. And perhaps from our own work, there is some problem not just coming from the outside into the brain where the immune system attacks the brain, but perhaps there some intrinsic problem with the brain in the form of a primary problem with the cells that make that myelin, the Oligodendrocytes.

And this is just to show you (I'm not sure how that projects); this is a section of brain showing lots of MS lesions, but some of them, these little ones here with the arrows, are very recently active lesions. And when we looked inside of these areas, we found the Oligodendrocytes there, the cells that make the myelin, the fatty sheath, had died (and you can see them here) even before immune cells fluxed into the brain to cause this damage. So perhaps there is also some intrinsic problem in the brain as well as an immune attack, and I don’t think that's necessarily agreed upon by most researchers, but certainly it was the implications from our own studies.

You can imagine that if the cell that makes the myelin, here’s one of the Oligodendrocytes, dies, then the myelin, which in actual fact is just an extension of that cell. So if you look at the cell, all of that stuff that wraps around and around these nerves is actually just the myelin; the myelin sheath is really just part of the so called ‘plasma membrane’ of the cell. So you can imagine if this cell dies, all of that myelin might also die with it. And another explanation for those cells I showed you, which have been thought to attack the normal myelin; they might just be cleaning up dead myelin, but again that's just a hypothesis.

Whatever is the case of this, we do know that the immune system is extremely important; and we know that not just from hypotheses and animal models, we know that from treatment. If you treat a patient with a treatment like Tysabri, which prevents t-cells crossing the blood-brain barrier, you will dramatically abrogate the activity of the disease.

So this is just a cartoon to show you what happens. This is normal white matter in a brain. Blue is myelin. These little fried-egg-like appearing cells are the myelin forming cells; the oligodendrocytes. This is normal. For one reason or another, is would appear that these cells would become dark and die. At that point, these macrophages more in and either attack or clean, depending on your viewpoint. The myelin, you can see the macrophages full of those little dots of blue, which is bits of myelin.

Eventually, within a matter of weeks already, even though the myelin is being digested, and this is now turned into fat; this is a stain for fat, called oil-red #o, already you can see hopefully, very thin lines like tram tracks on the sides of these nerves. This is new myelin being laid down already. So the body is intrinsically capable of repairing these MS lesions, especially in the earlier phases of the disease. And eventually, within a matter of months, under a microscope at high power, these areas that were previously damaged can look almost normal.

I’ve showed you this picture at the start of this punched-out lesion, and you might say, ‘well if the body’s repairing the myelin, what have we got to worry about? How does it possibly end up like this when there’s all this repair going on?’ For some reason this process of remyelination of the capacity of the body to repair, is progressively diminished with duration of the disease, and no one knows why that happens. There are a lot of molecular pathways that are being elucidated that might explain it, but we are a long way off from any therapy that promotes this intrinsic repair mechanism.

All of our current therapies, as I say, are directed at the immune response and therefore are really only applicable in the earlier phases of the disease when people are getting a lot of active inflammation.

I will say though, that in early disease, there is this loss of axons. I have talked a lot about myelin, but the nerve fibres themselves are damaged early in the disease, and it is irreversible. There is no mechanism that the brain has that repair injured nerve fibres; only the fatty sheath around them. And because these are being lost early in the disease, and that most researchers believe that there is an intrinsic relationship between the inflammation and the damage to the nerves, our only treatment option at the moment is to try and turn that inflammation off early in the disease, when these are going to be effective.

So, MS might be an autoimmune disease, as I’ve said. Could it be an infectious disease? Well a lot of work has been done on this over the last fifty to one hundred years. Multiple agents have been implicated, none of them have been corroborated. Probably the agent with the most evidence, and you’ll hear some more about this later, is Epstein Barr Virus. But again, it appears to be relating to patients susceptibility to develop the disease, rather than being a causative factor.

I’ve shown there’s some evidence to point to an intrinsic problem in the brain; some form of neuro-degenerative problem, rather than just an immune response. And then of course there’s this old paradigm of how much of this is genetics, how much is environment, and I think really it’s still to be worked out. So although my task today was to tell you what the cause of MS is, I'm afraid I’ve failed and I would just leave you by saying that MS is a complex disorder, possibly with no one single cause.

Just to leave you today, I’ll show you some famous people who’ve had the disease. This is Augustus D’est, the illegitimate grandchild of George III, who wrote the first personal account of MS. This actually isn’t Freud’s nanny, it’s his granddaughter, but Freud’s nanny had MS, and he attributed her disease to hysteria and treated her with psychotherapy; a little bit better than the treatment that Augustus D’est got which was electrocution and urethral dilatation. And of course, this is Jacqueline Dupre. And Jacqueline Dupre of course grew up and had her illness in an era when we had none of the modern therapies available.

So, I think really we’re in very exciting times at the moment because unlike these poor people, we’re in an era now where effective therapies are really coming into their own. And for researchers like myself, I think there’s not really a better time to be in the business of MS research. Thanks very much.