Understanding infection, inflammation and MS progression

Professor Galea explains the links between infection and inflammation. And he talks about the relationship between the body and the spinal cord. He compares inflammation in the body to a storm. The spinal cord, protected but not completely separate, can feel the distant effects of that storm. We also hear about how this research we funded fits into the bigger picture of MS research past and present.  

Thanks for talking to us, Ian. Could you start by giving a quick summary of what your study found? 

Our research showed that when people with progressive MS had increased inflammation in their body, a little later they had damage in their spinal cord. In scientific terms we’d say that ‘systemic inflammation was associated with loss of spinal cord substance’. The substance that’s lost includes nerve cells. And losing nerve cells is what happens when MS progresses – when it gets worse over the years.  

Because we saw that the inflammation happens first and then the damage, you might think one causes the other. And that’s a possibility. We do know from laboratory studies that inflammation causes nerve cell loss. 

But I choose my words very carefully. In our results there’s an ‘association’ between the inflammation and the damage. We haven’t proved the inflammation causes it. They might for example both change independently of each other, and be affected by other things we haven’t measured. 

But what I think we’ve done is build on decades of work done in laboratories. And found that yes, this link between inflammation in the body and damage in the spinal cord could be the case in humans. 

And is there a link between infections and inflammation?

Yes, we measured inflammation in our study. And one of the big causes of inflammation in the body is infection. For example, being exposed to a virus or a bacteria may cause inflammation even when you have no symptoms.

Tell us more about how you measured that inflammation. 

We used weekly urine tests, but we weren’t just looking for urine infections. We were looking for something called neopterin. It’s a chemical the body makes when there’s inflammation. It shows up in urine wherever the infection is in the body. But the amount of neopterin in urine is not affected by MS inflammation. That happens deep inside the brain or spinal cord. So we know we’re measuring inflammation in the rest of the body with this test. 

The people with MS who took part in the study provided urine samples every week – for two and a half years! I forever thank them for their perseverance with that. We sent reminders and stayed in touch, and they took the samples at home and brought them in. These were all things we had to think about when we consulted with people with MS to design the study. 

We developed this particular test a few years ago and it’s used in other research studies. It’s useful because when you need to test often and for a long time, it’s much easier for people than a blood test. Neopterin also shows up very quickly in urine, so we can see changes in inflammation as they happen. 

Delay between inflammation and MRI changes

You mentioned that people did these tests for two and a half years. Why for so long? 

There are two main reasons we wanted to run the study for so long.

One is what’s called the ‘sample size’. That's the number of people taking part in the study. To be confident in the results of research like this, you need to involve either a huge number of people, or fewer people for longer. 

We enrolled 50 people. If we ran the study for, say, six months, we’d expect to find only small changes in the brain or spinal cord and we'd need many more participants. Two and a half years gives us time to see bigger changes and be confident in the results with fewer people. 

The second reason for the two and half years is that, based on laboratory studies, we expected a delay between inflammation in the body and MRI signs of change in the brain or spinal cord. It turns out the delay was 30 weeks on average. Some people had longer or shorter delays than that. We designed the study to be long enough to take account of this time lag and pick up changes on the MRI.

Why is there a delay between what happens in the body and what happens in the brain and spinal cord? 

Well there are a number of reasons. An important one which people might have come across is the blood-brain barrier. That’s a thin layer between our blood and our brain. It selects what can pass through the barrier and it's designed to keep lots of things out of the brain which could be harmful. Our spinal cords have a similar barrier. But these barriers can be a bit leaky, especially in MS, so things in the body can have an effect. 

Imagine there’s a storm in the body. You’re in the middle of this storm and there’s a gale force wind and a very rough sea. But far away in the brain or spinal cord, you can just feel a breeze and a swell in the ocean. The effect gets through, but it takes a while to get there and it’s harder to detect. 

Measuring changes in the brain and spinal cord

Why did people need to do the urine tests every week? 

That's because inflammation levels can go up and down. We’d studied neopterin before and we knew people’s levels change quite a lot. That’s true for people who don’t have MS too. We’re being exposed to infections all the time. Even if we don’t know it. So we wanted to be able to track these changes and see if they corresponded to changes in the brain or spinal cord. And in the spinal cord, they did. 

Ah yes, and perhaps we can get into why not the brain in a moment. Before we do, can you explain how you measured what was happening in the brain and spinal cord?  

We used MRI at the start and the end of the study – so two and a half years apart. In those scans, we looked for shrinkage in the brain and the spinal cord. And as I said before, one of the things that’s lost with this shrinkage is nerve cells. 

The medical term for this shrinkage is ‘atrophy’. It’s one of the best ways to detect MS progression. We need to lose quite a lot of nerve cells before the effects on symptoms are noticeable. So measuring the shrinkage with MRI means we can see changes earlier than if we measured symptoms. 

Losing brain and spinal cord tissue is a normal part of ageing. But it happens quicker with MS. If you have a scan to monitor your MS, atrophy is one of the things your neurologist might look for. In this study we were measuring it very accurately so we could compare the scans at the start and end of the study. In the future, computer software that’s being developed might mean neurologists can measure these kinds of changes in their usual scans with patients. 

Spinal cord inflammation and progressive MS 

You mentioned you only found damage in the spinal cord, not in the brain. Do you know why? 

Well, there are many possible reasons, and it’s likely there’s more than one reason. In fact, there wasn't enough space to discuss all of them in the published research paper. There are limits to how much you can write in a paper!

But one very possible reason is that the 50 people in our study all happened to have MS mainly affected by changes in the spinal cord rather than the brain. Over the two and a half years, most of their symptom progression affected their legs or arms, not their memory or thinking. That suggests bigger changes in the spinal cord than in the brain. We need more studies with a more varied population of people with MS to know for sure.

Another reason could be that the spinal cord is just more vulnerable to inflammation in the body than the brain. There’s evidence from other studies that our blood-spinal cord barrier is leakier than our blood-brain barrier. So the effects of systemic inflammation might be more easily felt in the spinal cord. 

Also, the spinal cord might be more vulnerable because of its shape. The spinal cord is very thin. But it runs through the spine all the way down our back, so the protective barrier around it covers a lot of area. The brain is a lot thicker, and with less surface area outside to cover. 

To use the storm analogy again, there’s more surface around the spinal cord for the storm to bash against, and less distance for the bad weather to reach the centre of the spinal cord. Even small waves getting through can damage the tiny area that’s inside. 

Background levels of inflammation 

From the urine samples, you could see a background level of inflammation as well as sudden rises. What does that tell us?

Well we knew from laboratory studies that if there's already recent or ongoing exposure to inflammation, then the response to a new trigger like an infection is going to be less dramatic. So we wanted to measure both. And in our study, people with high levels of background inflammation had a weaker association between sudden spikes in inflammation and spinal cord damage. So the spikes in inflammation didn’t have as strong an effect for those people.  

But living with high levels of background inflammation are not good either. And both types of inflammation were associated with shrinkage in the spinal cord. 

What’s causing this background inflammation, and the spikes? 

Well, for someone with MS, background inflammation could be caused by something like back-to-back bladder infections. Whereas if someone only has occasional bladder infections, that would cause a more obvious spike in inflammation. 

Vaccines, smoking, diet and infections

Are there things people with MS should do right now? 

I think it's very important to underline that this is an 'observational' study and not an 'interventional' one. So we looked at what’s happening, but we haven’t tested what actions might have an effect on that. 

But our study backs up certain things we already advise. For example, getting the flu vaccine every year. Lots of studies have shown it’s safe for people with MS. And getting flu is going to have an effect on your MS. It makes sense to get your recommended vaccinations, to avoid or minimise infections. 

It’s also good practice to treat bladder or chest infections promptly. Don’t delay in contacting your GP, continence or MS team if you think you might have an infection. 

Smoking, alcohol and an unhealthy diet can all provoke inflammation and we all know what the advice is with respect to these. If one has high blood pressure or cholesterol, or diabetes, these are also associated with inflammation, so the extra effort to keep on top of these things is worth it.

The role of healthcare professionals 

Do you have any messages for healthcare professionals?

Well, how do we expect people to take up vaccines if we don't remind them and don't talk with them about vaccines? This is something for healthcare professionals. It’s one of those things I try to talk about at every appointment. We need more time in clinic to be able to do this more regularly.

We need to explain that they’re safe and effective. But we also need to help people understand how important the vaccines are. It takes effort for someone to attend a vaccination, so they have to feel it’s worth it. If we speak about the results if this study, it can help. Inflammation is linked with MS progression, and infections are the commonest cause of inflammation. 

Future research into MS progression

How does this affect future research into MS progression?

MS is a very complex condition and there are going to be several things that drive progression. But this study has started to unpick one of them, one possible driver among many others. We need to study this further, with more people involved so we can see if there’s an effect on the brain as well as the spinal cord. 

We also need to consider how to reduce the effects of inflammation. For instance, that could be to test a well-planned strategy to avoid infections. Then see if that helps people with MS experience less progression. Another approach would be to look for targets for drug treatments. For that, we need to know what’s happening when inflammation affects the spinal cord or brain. That means looking at what’s happening in the cells – at the molecular level. 

There’s still data from our study to analyse as well. We saw people involved in the study regularly. So although the study wasn’t designed to detect clinical changes, we checked their EDSS and other scores every three or six months. We’re interested in seeing how much their neurological function went up and down. 

Because we know that even with progressive MS, the progression is not completely steady. Things can go up and down over a period of weeks or months, as well as day to day. Some people don't progress much overall yet they have pronounced dips which seriously affect their quality of life. It's important to know why this happens so we can manage it. 

So we haven’t looked at the data for this yet, but that’s something we’ll do. And hopefully be able to start picking out some of the causes for this fluctuation of MS symptoms. 

Current MS research projects

What other MS research are you involved in at the moment? 

One avenue of research is looking at the effect of bladder infections on the blood-brain barrier. Do bladder infections make it more leaky, for instance?

We’re also working on a way to measure how leaky someone’s blood-brain barrier is, using an MRI. Neurologists can already see when someone has a very leaky barrier. That shows up with a dye injection called ‘contrast’. Quite a lot of people with MS have this injection before an MRI. The dye shows up on the scan if it’s leaked through from the blood into the brain. We’re working on a scan to measure much smaller leaks. Seeing early signs like that could help predict whose MS will change quickly over say five, or ten years. And that sort of knowledge helps people considering treatment choices.

Another study is looking at the health of red blood cells. These are the blood cells that carry oxygen. The brain is one of the most oxygen dependent organs in the body. It uses 20% of all the oxygen needed by the body, even though it’s nowhere near 20% of your weight. We’ve found that inflammation damages the health of red blood cells. That might be something that speeds up the loss of nerve cells in people with MS. There are several different ways this might be happening which we’re looking into.  

We’re working to speed up results from the lumbar puncture test as well. Some people need to have a lumbar puncture to diagnose MS, which is an extra delay on top of all the other examinations and tests we need to carry out. And as we say, ‘time is brain’, so we want the process to be as fast possible. So we’re refining the test to speed it up. 

And of course we're participating in the Octopus trial.