Episode 105      32 min 51 sec

Multiple Sclerosis: an Updated Look

Multiple Sclerosis: an Updated Look

SHANE HUNTINGTON
I'm Dr Shane Huntington. Thanks for joining us.
Multiple sclerosis, or MS, is a condition of the nervous system that has a profoundly debilitating effect on sufferers all over the world. Many of our most important physical functions are disrupted by this disease and there remains many questions about its cause and how best to treat patients.
Trevor Kilpatrick, a professor of neurology who heads the scientific group that encompasses laboratories in the Howard Florey Institute and the Centre of Neuroscience at the University of Melbourne, as well as the Clinical Research Facility at the Royal Melbourne Hospital is working to unlock some of the mysteries surrounding MS. Professor Kilpatrick is the director of the Melbourne Neuroscience Institute. Trevor joins us today on Up Close to update our understanding on MS and outline some of the latest and most promising research in the field.
Welcome to Up Close, Trevor.

TREVOR KILPATRICK
Good morning, Shane.

SHANE HUNTINGTON
Now, MS - or multiple sclerosis, as it's properly termed - is a particularly debilitating disease. Can you describe what exactly the disease is?

TREVOR KILPATRICK
Sure. It's the commonest disease affecting young adults in our community, a neurological disease. Basically, it's a very unfortunate disease because it strikes people at the prime of their life; in early, young adult life. It's a disease which has basically two phases: the first phases is one which involves short downturns in neurological function which can affect vision, can affect mobility, can affect the senses, can affect your ability to think on occasions. Usually those downturns improve over a matter of weeks to months, but ultimately, after about 10 to 15 years, the person with multiple sclerosis is faced with a phase of cumulative disability; inexorable downturn in neurological function. That's the worst aspect of the disease which everyone fears.

SHANE HUNTINGTON
What's actually occurring in the brain? I understand it involves the myelin sheaths that exist in the brain.

TREVOR KILPATRICK
Basically, the core of the disease is demyelination and that, as you say, is loss of the myelin sheath coating the nerves or neurons.
But there's a second very important component of that and that is that there's an infiltration of immune cells into the brain from the periphery, from the vascular circulation. And the consensus is that those cells - the inflammatory cells - are actually what's driving the disease, causing the demyelination; the loss of the myelin.
From there, basically two important things are happening. The first is that the nerve cells themselves can't conduct impulses throughout the brain efficiently, and that's a very important feature of our ability to react in a very efficient and nimble way to the environment.
The second is that the consequence of the loss of myelin is that ultimately it also leads to degeneration of the nerve cells themselves. So not only do they initially lose their capacity to conduct information efficiently, they themselves are eventually also lost and we believe that that is the ultimate determinant of the disability which occurs later in the disease, this inexorable phase of decline.

SHANE HUNTINGTON
Is this conductivity and electrical conductivity limitation, that's being put in place in the brain, as a result of the loss of that protective coating?

TREVOR KILPATRICK
Yes. So basically, as we evolved, we developed a capacity to be able to conduct information through nerves more quickly. An unmyelinated nerve conducts but it conducts slowly. Myelin allows us to conduct information at about 50m per second through nerves. So the loss of that myelin puts us back into a phase whereby these axons can't conduct the information so efficiently.

SHANE HUNTINGTON
Are we talking about a slowdown in that case or a complete termination of the signal?

TREVOR KILPATRICK
It's a combination of the two. So basically, if a nerve survives it might be able to conduct information or it might be that there's a conduction block. The information reaches a certain area of the nerve where it can't conduct the information any further and that's called conduction block. But ultimately that nerve may die and so therefore it obviously can't conduct the information in that context. They're the three phases of problems that we're facing in terms of transmission of information through the brain: inefficient conduction; loss of conduction; inability to conduct anything because the nerve itself is lost.

SHANE HUNTINGTON
We hear about redundancies in the brain that help stroke victims and the like recover certain functionality. Is there no redundancy in this case with regards to the conduction of these impulses and these signals?

TREVOR KILPATRICK
There is significant redundancy actually and this is what spares us for some time. So basically, one of the common presentations in multiple sclerosis is a condition called optic neuritis. This is a condition in which patients lose vision over a period of hours to days. They may have a loss of colour vision; they may have what we call a central scotoma: inability to see the middle part of the vision. That usually improves either spontaneously or with the assistance of medications called steroids and usually improves over a period of days to weeks, occasionally months.
Now, the majority of people then feel they make a complete recovery, but we can detect persistent changes in the optic nerve even though the clinical recovery is complete. So if we look with an ophthalmoscope at the back of the eye - called fundoscopy - and we look at the optic nerve, it looks pale. There's continuing loss of myelin. In addition, if we look at the electrical impulses in the nerves, we find that the amplitude of the impulse or the time for the impulse to track from the nerve through to the occipital cortex may be delayed. This indicates that there's persistent damage.
Now, what that means is that if there's another attack of optic neuritis the reserve is reduced. So the likelihood of a permanent sequelae to the event becomes greater the more events you have. That's one of the key issues facing people with multiple sclerosis.
Another aspect of it as well is that when we trial medications in this disease we've got to be very careful, because we might be thinking that the medication has no effect is the placebo group recovers clinically as well as the group receiving the active agent. But we have to, in that context, develop the concept of paraclinical markers to actually more directly interrogate the residual pathology and whether the treatment influences that residual pathology. That's a key area of research and development in the multiple sclerosis field at this point of time.

SHANE HUNTINGTON
Trevor, you've mentioned the optical problems that occur for patients. What other early stage symptoms do we see in patients when they're first starting to present with the disease?

TREVOR KILPATRICK
There are three classical types of presentation. The first is the optic nerve dysfunction, which we've talked about. The second is a spinal cord presentation. That basically, usually involves problems with sensation, usually in the feet and legs but it may ultimately also affect the arms if the involvement is in the cervical spinal cord in the neck. That sometimes then progresses to weakness and problems with bowel and bladder dysfunction. So that's the second typical or classical type of presentation in the early phase.
The third is a brain stem presentation where there can be involvement of an area of the brain called the cerebellum or its connections and that often leads to problems with ataxia, or imbalance, but it also may lead to problems directly within the brain stem with involvement of the eye movement centre. So you can have double-vision or diplopia, as we call it, or it might affect the vestibular centre, for example. And there, there can be problems with what we call vertigo, a sense of rotation of imbalance, or it might result in nausea or vomiting as a consequence of that.

SHANE HUNTINGTON
When patients present themselves are we able to test directly for MS or is it inferred from these particular symptoms that they have?

TREVOR KILPATRICK
There's no actual specific diagnostic test for multiple sclerosis. So even in 2010 it remains a clinical diagnosis. There are features of the presentation which make us think of multiple sclerosis and in particular whether there's a relapsing remitting component to the disease and whether there are events dissociated both in space and time. By that I mean that ultimately there is a series of events - and that's the sine qua non of multiple sclerosis - and that it affects different parts of the nervous system either in a single event or at different times.
We now have the benefit of ancillary tests as well and the most important test which we routinely use is magnetic resonance imaging. This is a technique which allows us to gain very detailed information concerning the structure of the parenchyma of the brain. In MS typically, there is an increasing water content in focal areas of the brain, the areas which are normally mylenated - the deep white matter tracts. So typically one will see a number of white spots in these deep white matter tracts, in a person who has multiple sclerosis.
But we have to be careful here because there are other causes of increasing water content within the deep white matter. For example, small vessel disease can also produce a similar pattern or similar change on the MRI scan and ultimately we have to rely on the pattern of spots - the distribution of spots within the brain - which, by experience, we know - and with correlation with pathology - is more likely to relate to multiple sclerosis than other conditions. So it's building up a probability factor which ultimately leads us to the diagnosis.

SHANE HUNTINGTON
I'm Shane Huntington, you host for this episode of Up Close, coming to you from the University of Melbourne. Today we're talking to Professor Trevor Kilpatrick about his understanding and latest research on multiple sclerosis.
Trevor, I'd like to move now to the issue of what's actually causing multiple sclerosis. Do we know at this point what the core cause of this particular condition is?

TREVOR KILPATRICK
In a nutshell, we don't. We've learnt a lot in recent years but there's still a lot of research which needs to be undertaken. It's a complex disease and we know that there are both genetic and environmental factors which lead to a predisposition and we also believe that probably there are stochastical random factors which are involved as well.
In a nutshell, we know that Caucasians - or people of European descent - are more likely to develop the disease. This has led us to a view that there is a genetic component to the disease. We also know that people in high latitudes are more likely to develop the disease. Now, you may say that Caucasians, by definition, are more likely to live in high latitude zones. But independent of that we know that migrants have variable susceptibility to the disease as well, such that if you go from an area of high prevalence to an area of low prevalence before the age of 15, most studies suggest that one tends to take on the prevalence rate of the country to which one emigrates. Now, there are a lot of confounders here, but this suggests that there is an environmental component to the disease.
Another key factor in this has been work which has been done in the 1960s to 1980s from Professor James McLeod here in Australia. He and co-workers were able to show that, in fact, there's a seven-fold latitudinal gradient along the Eastern Seaboard in Australia, with the highest prevalence in Tasmania and the lowest in Northern Queensland. This - in an environment where the majority of migration until the last 25 years was from Northern European countries - suggests to us, once again, that there must surely be an environmental factor which is important in transforming predisposition to ultimately extant disease.
So that has led us an others to think deeply about what might be the environmental factors which drive this latitudinal gradient. The obvious, in terms of field affect, is exposure to ultraviolet light. We would see that there's a very, very strong inverse correlation between ambient UVR and risk of multiple sclerosis. In fact, the strength of that negative correlation is stronger than the positive correlation between UVR and malignant melanoma.
On the back of that, we've conducted a number of studies to look at this particular hypothesis. Perhaps the best and most definitive has been a study called the Ausimmune Study, in which we have, in four regions of Australia, attempted to recruit every person who had their first central demyelinating event and to match those with controls and understand the life events for those individuals. In addition, we've taken blood samples from those individuals.
What we've found is that from the compositive information, there appears to be a reduction in key exposures to UVR in earlier life for these people who have a central demyelinating event. On average, the vitamin D levels are lower amongst those with a clinical presentation. In addition, if we look at actinic damage to the skin on sun exposed areas by taking silicone casts, there's been some evidence in patients with extant disease that the level of damage is lower than in controls, suggesting that there may be a reduction in lifelong exposure to UVR amongst those that developed MS. Now, this has to controlled for the level of melanin in the skin, but when we do that the result is still the same.
So the hypothesis at the moment is that UVR and, as a consequence, vitamin D might be relevant to susceptibility to MS. There may be a second element to UVR independent of vitamin D which drives this as well.
The other aspect of this is that there's been a debate, which has been a topical debate in recent years, as to whether this is fundamentally an autoimmune disease in which the body's own immune cells inappropriately attack a target tissue, in this instance the central nervous system, or whether it's an example of a neurodegenerative disease, in which the primary phenomenon is actually within the brain and the immune attack is secondary.
Now, the majority of people continue to favour the former hypothesis and I think the results of the genetic studies which have come out from 2007 to 2010 would suggest that the genetic susceptibility is affecting our immune responsiveness. So I think that as of 2010, the predominant view would be autoimmunity. But many people still believe that the nervous system response is a key determinant of severity and that nature of the neurodegeneration which ultimately occurs some years down the track.

SHANE HUNTINGTON
Trevor, do we know for sure that UV exposure susceptibility that we're seeing is a direct one towards MS? Is there any possibility that the other health impacts of low UV exposure that we see in the population are then themselves leading to the MS susceptibility problem?

TREVOR KILPATRICK
It's a really important question and ultimately we try to deal with confounders - you know, the associations - and that's done through multivariate analysis. But in any association study there's always this niggling doubt. The only way of ultimately testing this is to look at the relevant factor and to replace that relevant factor in susceptible populations and ultimately to determine whether the prevalence of the disease is reduced.
Now, the obvious factor to hone in on here would be vitamin D. We don't want to suggest that people willy-nilly go out and expose themselves to the sun, because there potentially will be negative health consequences of that, in terms of skin cancer, et cetera. But we believe that ultimately vitamin D represents a possibility of a safe intervention to reduce susceptibility to MS.
There are, however, major barriers in terms of testing this scientifically. Basically, at the end of the day, multiple sclerosis is a moderately uncommon disease - the prevalence is about one in 1000 - so one has to ultimately, potentially stratify the population and identify who is at higher rather than lower risk, and to concentrate on those people who are at higher risk of developing the disease.
Also, we're finding that in the community people have taken-up our research and that of other groups and, to some extent, are also already supplementing themselves with vitamin D, which may be good news for them, but, at the end of the day, makes it difficult to either confirm or refute the hypothesis. As scientists, we have to recognise that we ultimately shouldn't be going on hunches; we should be going on hard facts, in terms of what we recommend to the community and to our patients.

SHANE HUNTINGTON
You're listening to Up Close, coming to you from the University of Melbourne, Australia. I'm Shane Huntington and our guest today is Professor Trevor Kilpatrick, on multiple sclerosis.
Trevor, let's talk now about the ways in which we're dealing with the particular disease and helping patients. You mentioned before that MS primarily seems to be an inflammatory problem potentially. Can this be halted using normal, anti-inflammatory medications and the like?

TREVOR KILPATRICK
There's been an absolute revolution in the management of multiple sclerosis since 1993, so that over the last 17 years we've been able to translate abject despair to concrete hope for a very significant proportion of people who are suffering from multiple sclerosis. The key here has been the development of immunomodulatory agents. These agents basically alter the repertoire of the immune response and they affect elements such as the blood brain barrier, or affect the egress of cells into the central nervous system, or potentially change the repertoire of key cytokines which might otherwise cause damage to nerves.
What we found initially was that the agents which were found to have benefit were partially effective. For example, beta interferon - which has been the workhorse, in terms of the clinic, for many years - reduces relapse rate by about 30 per cent and it reduces severe relapses by the order of 50 per cent. Now, it was uncertain for many years as to whether this might translate into long-term endurable benefit, in relation to either delaying or reducing the rate of progression in the progressive phase of the disease I mentioned.
With time, the bulk of evidence is suggesting that these agents have some benefit at this phase of the disease as well, but indirectly. If we start the agents once the neurodegeneration has really demonstrably become established, it's too late. So there's been the mantra now of treating early and treating effectively and this has really influenced the way neurologists are treating multiple sclerosis as of 2010.
The next development has been a whole range of second generation agents - immunomodulatory agents - which are coming to the fore over the last four to five years. The best example of that is an agent called Tysabri which influences the ability of white cells - inflammatory cells - to cross the blood brain barrier. The suggestion is that these agents might be even more potent in reducing that immune component of disease.
There is a flip side, however, and with potency comes some increased risk. For the future we're going to find challenges in terms of balancing risk versus benefit for individual patients. Some of these agents cause or occasionally are associated with nasty consequences, such as a condition called progressive multifocal leukoencephalopathy in which there is reactivation of a virus within the brain which stands latent for most of us. So this is rare - it only occurs in about one in 1000 of patients who are treated with tysabri - but nevertheless it's providing new challenges with us, in terms of how we mix and match patients and therapy.
The other aspects of the therapeutics of the disease are that, to date, these agents have had to be delivered by injections, but we're now just on the cusp of having agents which can be taken orally. The absolute challenge, though, is how to deal with a neurodegenerative phase of the disease. Here there are two additional elements that we need to consider which are, at this point of time, still couched in research.
The first is neuroprotection, and that is how to protect nerves which are otherwise likely to be damaged. Now, at one level you may say that turning off inflammation is part of that - and it is. But in addition there's a second component, and that is directly assisting the nerves to maintain viability in the context of ongoing damage - or ongoing insult, should I say. There, we're on the cusp of being able to test a number of agents in the clinic, although that provides specific challenge.
The final element is regeneration and this is a very important element for the millions of people with MS around the world who already have damage, whose nerves have been lost and immune therapies are really going to have little to no benefit. Here there's the promise ultimately of stem cell research.

SHANE HUNTINGTON
Trevor, with regards to the use of stem cells, presumably even if you were to get them to work to regenerate the cells that are needed, the underlying condition would still be there and still be attacking those new cells as well. Would that be an issue we would have to deal with first?

TREVOR KILPATRICK
Absolutely and I think that it's always going to be part of a two, if not three-pronged attack. That is to reduce the inflammation, to protect the nerves, and ultimately to try and replace the neural cells which have been lost as a consequence of the damage.
Now, in MS there are two particular components that we can think of in relation to the regeneration. The first are the cells which actually are responsible for producing the myelin and that works locally. The cells put out short processes, they insheathe the nerve cells. It's applicable to think about how that might be done, in other words, how a stem cell might be induced to differentiate and take on that function.
The second problem is more difficult - and that's one I alluded to earlier - whereby as a consequence of the damage not only the ensheathing cells, but ultimately the nerves themselves which are responsible for transmitting the impulses might be lost. There, the challenge is not only to replace that nerve but ultimately to get that nerve to put out processes and for those processes to make appropriate connections with other nerves or with other cells. That's a tremendously difficult task and one which I don't see we were going to have the capacity to solve in the immediate future.
But in MS I think we do have potential capacity to replenish the myelin-producing cells - the so-called oligodendrocyte - and there are two ways we might think about that. The simple way which most people are thinking about this is actually to grow cells in the petri dish and to inject those cells. The problem there is that in MS we're dealing with a multifocal disease, which affects the whole neuraxis from the bottom of the spinal cord right through to the cerebral cortex potentially. So therefore one would either have to think of a pin cushion-type technique, in terms of injecting the cells, or ultimately to rely on great mobility - or motile capacity - of those cells, which are both significant challenges either from the technical or from the understanding of migration perspectives.
The second aspect of it is to understand that there are also precursor cells within the brain. There are two sources of those precursor cells. The first are committed progenitor cells which are halfway along the way to becoming mature oligodendrocytes or myelin-producing cells. They're throughout the whole central nervous system and we know that they're exploited by the brain itself, normally in terms of the repair which is undertaken after an episode of demyelination in MS. It's just that that becomes more inefficient with time.
The second source of cells are actually bone fide stem cells. Over the last 15 years we have identified that there are two areas of the brain where these stem cells persist into adult life. One of the challenges is to understand how those cells might be recruited to become the oligodendrocyte cell and also to migrate into the relevant areas to ultimately affect the myelination which we know need to occur.

SHANE HUNTINGTON
Trevor, when we talk about stem cells there's obviously many positives that people are talking about, in terms of the future application of them. But what about the negatives; are there some potential risks for things like tumour development and the like when we start using stem cells to generate other cells in the body that we need?

TREVOR KILPATRICK
There are. One has to be careful about the sort of stem cell you're talking about when one looks at these risks. In relation to the endogenous cells I talked about - the adult neural precursor cells - those risks don't apply. Those cells have already become neural cells and there's really no effective risk of tumour development. This risk, however, is very germane to embryonic stem cells and also to a new technology called induced pluripotential stem cells, where you can take so-called fibroblasts from just underneath the skin, and by a variety of molecular tricks induce those cells to become precursors, and then ultimately induce those cells to become another mature type of cell.
In both of those instances there is risk of the reprogramming of the cells being such that they might produce multiple lineages and might ultimately become uncontrolled and produced so-called teratomas. So people are very aware of this risk and this has been one of the impediments in terms of application of the field.

SHANE HUNTINGTON
Trevor, just finally, we've talked about many of these amazing possibilities that are coming out in the future, in terms of potential treatments for MS sufferers. What about people who have the disease at the moment; what's sort of timeframe are we talking about for the full progression of the disease, in terms of a person's life cycle?

TREVOR KILPATRICK
The thing about MS is that it's, in general, a disease of disability rather than shortening lifespan. A very unfortunate small subset of people have aggressive disease where mortality is an issue, but for the majority of people it's basically a lifelong disease, ultimately leading to accumulative disability. So the average lifespan after diagnosis of MS is well over 30 years. Now, that's not to say that there might not be some shortening of lifespan in general, but unequivocally the major problem we have in MS is the disability factor. So that's where our attention needs to be drawn.
But it also produces certain challenges for us, paradoxically. If you look at cancer, where there's unequivocally mortality in the short-term, basically it's worth taking significant risk and this has been the whole mantra of aggressive chemotherapy. For MS we're dealing with potential or emergent disability and at times we've been thinking about using chemotherapies similar to what have been used in cancer. But for us, the risk-benefit equation is different because it's not backs-to-the-wall in relation to the risk of mortality. It's about quality of life rather than life itself. That's influenced the way we have approached the management of the disease, both in the past and in the future.
But inexorably, we are having to face this question in more concrete ways with time, as the efficacy of the therapies which we have available increases. But the risks might also be ratcheted up a little bit as well, commensurate with the potentiated efficacy.

SHANE HUNTINGTON
Professor Trevor Kilpatrick, Director of the Melbourne Neuroscience Institute here at the University of Melbourne, we thank you very much for being our guest on Up Close today and wish you the very best of luck with this research.

TREVOR KILPATRICK
Thank you very much, Shane.

SHANE HUNTINGTON
Relevant links, a full transcript and more info on this episode can be found at our website at upclose.unimelb.edu.au.  Up Close is brought to you by marketing and communications of the University of Melbourne, Australia.  This episode was recorded on 24 June 2010. Our producers for this episode were Kelvin Param and Eric van Bemmel; audio engineering by Ben Loveridge; background research for this episode was conducted by Dr Christine Bailey. Up Close was created by Eric van Bemmel and Kelvin Param.
I'm Dr Shane Huntington, until next time, goodbye.

VOICEOVER
You've been listening to Up Close.  For more information visit upclose.unimelb.edu.au. Copyright 2010, the University of Melbourne.