Etiology and Types of MS: Current Concepts and Outcomes

There has been considerable research into the causes of MS in recent years. Could you recap what we know are potential causes of MS and which of the suspected causes have not been shown to have an impact?

Dr. Kantor: MS research is exciting. In just a little over 2 decades, we’ve gone from having no treatments that were FDA approved, or Food and Drug Administration approved, to now having 13 separate branded products, 1 branded generic, and 2 unbranded generics. That’s an amazing leap forward. It is faster than everything else in neurology and most things in medicine.

The question is has our research into the cause of MS kept up with our research into how to treat MS, and the answer is somewhat. We still give that same answer that we gave 20 years ago, which is that MS is a combination of some sort of genetic background and then there is some sort of an environmental trigger that makes a person who is predisposed to have Multiple Sclerosis end up having those symptoms. The problem is we don’t fully understand the genetics and we don’t fully understand the environmental trigger. Anybody who figures out one or the other, or both, is going to be having a nice trip to Scandinavia to win a Nobel Prize, but we do know a lot more than we knew 5 years ago, 10 years ago, 20 years ago.

We now have about 200 genes that are called gene-wide associations, so meaning these aren’t genes that if you have it, you have MS, and if you don’t have it, you don’t have MS. But having MS means you’re more likely to have some of those genes than to have other ones, but even if you have those genes doesn’t mean you’re going to have MS. So if you have an identical twin with MS and you have only a 30% chance of having MS. That’s not fully genetic, but that’s not fully non-genetic. So the question is what is that trigger and that’s where we’ve looked a lot for environmental triggers.

The viral theory of MS has been around for a long time and it’s sort of getting a resurgence and this idea of the most prevalent virus we talk about is the mononucleosis, or the Epstein-Barr, or EBV, virus. When you look at people with MS 100% of them have been exposed to that virus, but when you look at people without MS 80% of us have been exposed to it. So that just means that it’s very common to have the kissing virus, the mono virus, out there, but why is it that we see it in some people and not in other people, and that’s still what we don’t fully understand.

So there are certain researchers who look at one type of virus versus another type of virus, and there’s some people that don’t believe in the viral theory. What I think is most fascinating right now, and we really were excited just several months ago, when we were at the largest MS meeting ever at ECTRIMS, or the European Committee on Treatment and Research in MS in 2017 in beautiful Paris, France, and we heard in a late-breaking session we heard about a medicine that was being developed. A monoclonal antibody, meaning it sticks to something else, that was directed against what we call the HERV W envelope protein.

Now why is this important? Why is this not just like all the other research? Well it’s important because it turns out that 8 to 10% of our DNA is actually not human DNA originally. It’s actually foreign DNA that millions of years ago got incorporated into the human genome and that’s important because it allows us to, for example, have implantation during fertilization and have babies. All of that DNA is not originally human. It’s actually viral DNA, but also that viral DNA may be pathogenic and we call that pathogenic human endogenous retroviruses, and 8 to 10% of our DNA is like that, and it turns out there may be a portion that gets transactivated and derepressed by actually the Epstein-Barr Virus, forms what’s called the envelope protein.

This envelope protein then goes and stimulates something called TLR4. TLR4 has two effects. It causes neuro-inflammation with the immune cells and it causes neurodegeneration with the OPCs, or oligodendracyte progenitor cells, and those are the cells that eventually become oligodendracytes, which are the cells that form myelin, and remember that in MS, demyelination is the problem.

It may be that we’ve come so much closer to figuring out the true cause of MS and we may eventually see a treatment that actually targets that. This research is very exciting and it’s ongoing, but what that means is we’re getting much, much closer into understanding what is the cause, or what isn’t the cause of Multiple Sclerosis. Long ago we thought it was humors out in the environment. Then we thought it was heavy metals. All of that’s been disproven. More recently there’s been an Italian doctor who talked about your veins being skinny and that caused it. That’s been shown to not be true as well.

But this idea that somehow your immune system gets angry and starts to attack you looks like that probably is the cause of MS. The question is why did your immune system get angry at you. Was there something that happened first, or not, and that’s what we’re trying to figure out.

Are any of these causes modifiable, especially once a diagnosis has been established?

Dr. Kantor: It used to be that we couldn’t talk about modifiable or unmodifiable risk factors for multiple sclerosis. We can do that for heart disease. If you lose some weight, if you reduce your cholesterol, you stop smoking that’s better for your heart disease. For MS we’re finally able to talk about that too. The number one modifiable risk factor for MS is to stop smoking cigarettes. Often when I ask patients that question they say well Vitamin D is the most common modifiable risk factor and then I say to the group of patients, I say, how may of you are on Vitamin D, and everyone raises their hand, and I say how many of you are cured of MS, and everyone’s hand goes down.

Vitamin D is important but it may also just be a marker for disease. For example if you have Parkinson’s disease, not related to MS, you also have lower vitamin D. You have heart disease not related to MS. You also have a lower vitamin D. There are some studies that look at supplementing with Vitamin D and it may be helpful, but it may be a little bit too little, too late. We also have to be cautious in not taking too much vitamin D. Remember that the American Endocrinology Society says that patients should not take more than 4 thousand international units of vitamin D a day without the supervision of a physician in order to check for kidney stones and other sorts of laboratory abnormalities.

We’re also learning about other risk factors. The team out of Southern California at University of Southern California in Los Angeles found that when you live closer to the highway versus living a little further out, the same social background, the same ethnic background, the people who live closer to the highway had more MS than the people who lived further away. What that might be telling us is that living close or far from the highway is a marker of environmental pollution, and being exposed to environmental pollution along with the wrong DNA together is going to lead to a trigger that is going to lead to multiple sclerosis.

So it’s probably not just one hit. There’s probably multiple steps that need to be in place and it doesn’t mean that every time you go driving in the car you’re putting yourself at risk for MS, but it does mean that there is something about our environment that can actually interplay with our genes and can lead to diseases such as multiple sclerosis.

Could you give us an overview from initial diagnosis of the different types of MS?

Dr. Kantor: In 2013, we talked about different subtypes of multiple aclerosis. We talked about clinically isolated syndrome. We talked about relapsing remitting MS. We talked about secondary progressive MS. We talked about progressive relapsing MS, and primary progressive MS. The 4 subtypes, the RRMS, SPMS, PRMS, and PPMS were really the hallmark of MS.

You had that 85% of people started out with a relapsing form of MS. They may later go on and in fact before there were treatments probably 50%, or half our patients, went on to develop secondary progressive MS. But 15% of patients said what are you talking about getting better and getting worse, relapses and remissions? I’ve been getting worse from the beginning. We call that type of MS primary progressive MS, but then more recently what we’ve found out is that people with primary progressive MS may start out with disability progression, but may actually have relapses in between as well.

And so now, the terminology is we talk about whether a person is going to be having relapsing happening, whether they are going to have progression happening, and whether they are going to have activity, or not. So, for example, if somebody with primary progressive MS goes on and starts having attacks, relapses, they are called primary progressive MS with activity as opposed to just saying they are primary progressive MS and they happen to have relapses, and so you can talk about whether they are progressing or not, and you can talk about whether they are relapsing or not. Whether they’re having activity, or whether they’re not having activity, and that’s changed the terminology.

Recently we presented a poster that had to do with how patients look at this terminology and it turns out that patients may not have caught up to where the physician and nursing community is. Patients may not love us talking about progression of MS. They may find it confusing. They may be scared that they’re going to be taken off their disease modifying therapies that have changed their lives because they now have a new label attached to them, and so it turns out that perhaps we should be having two forms of terminology, or we should do a better job in the MS community of educating the patient community about the new terminology that we’re having.

While we’re talking about terminology, though, I do want to make a big point about the word jargon. Jargon has no space in an office visit. It’s a fancy word that means fancy words. It shouldn’t be used by us as physicians and it shouldn’t be used by patients, and you may be curious why would a patient every use jargon. All the time I see patient who walk in and they think they are going to help me by saying I have neuropathy.

What they probably mean is that they have pain, or that they have numbness, or they have tingling, but when I as a neurologist here neuropathy I think peripheral neuropathy, and when I think peripheral neuropathy I think diabetes, diabetes, diabetes. I’m not thinking about Multiple Sclerosis, and this person was just trying to describe their pain so that I could help them but instead they’ve confused me, and confused themselves, and taken up some of their valuable time in talking about jargon.

So it’s a good idea for patients not to use it, but it’s equally a good idea for us not to talk over our patients and to make sure that we explain what we’re talking about. Remember that the word doctor actually comes from the Latin for docere, which actually means teacher, and our job as doctors is first and foremost to do no harm, but then also to be valued teachers.

How does this picture differ in the pediatric population?

Dr. Kantor: When we talk about multiple sclerosis, we often talk about people in their 20s to 40s. The truth is that 5% of people with MS are actually diagnosed before the age of 18, and more than that probably started out with symptoms. They were in their teenage years, they were a cheerleader, they had some blurry vision, and some numbness and people said oh you’re just numb in your hands because you’re a cheerleader, and you’re just not sleeping enough, or drinking too many Red Bulls, or coffees, but those people actually had multiple sclerosis way back then.

Until recently doctors didn’t used to talk about it much and pediatricians weren’t aware of this idea there could be multiple sclerosis. The reason for that is MS doesn’t affect that many people in the United States. We used to talk about 400 to 450 thousand. The new numbers look closer to a million that we just saw at a recent presentation, but the point is still those are small numbers compared to everything else that we think about in life, and so it’s a good idea not for our pediatrician to every time see a patient and think, "Oh my God, maybe they have MS."

But it’s a good idea for a pediatrician if they see someone and they are having unexplained neurological symptoms send the to a neurologist, and let the neurologist do that. There are people who are pediatric neurologists. They are trained in both pediatrics, partially, as well as neurology, and there are even pediatric neurologists who are subspecialists in demyelinating disorders and Multiple Sclerosis.

Many years ago we came out with a Delphi process where a bunch of us who also see kids came up with some ideas of how to make the diagnosis differently in children. Since that time the National MS Society has actually funded some sites of excellence where they actually focus on pediatric demyelinating disorders, and there are other pediatric demyelinating disorders, but MS is still going to be the most common one of those and so we still talk about MS when we talk about pediatric MS.

What we’ve found is that kids with MS actually have almost a better outlook for the future. If we think about prognosis of MS the younger you’re diagnosed, the better. Now that also means that you have MS for longer so it’s a little bit curious, but it may be because when you get diagnosed younger you also get started on treatment younger, but until recently we had no really good evidence about our disease modifying therapies in the pediatric population. We would use it in what we say off-label because they are approved for 18 and older.

Now there’s been a recent, a big study, that looked at children with multiple sclerosis with one of our oral medications and that’s exciting because not only did they respond, and not only did their side effect profile look pretty similar to adults, and nothing new kind of jumped up out of us, they actually responded better than adults. The response rates were much better than what we’ve even seen in young adults, and what that tells us is once again it’s good to treat MS later on. It’s even better to treat it as early as possible and the Food and Drug Administration, FDA, is requiring of pharmaceutical manufacturers to not only do studies in adults, but after they get approved to also do in children as well.

Sometimes they’ll make exceptions if there aren’t going to be enough kids of that type of MS, but generally that’s what the FDA wants, and I think that’s good because it increases research but we have to be careful. Increasing research is good if it helps patients, but if they’re going to placebo controlled trials then we’ve got to think well I could just off-label prescribe a medicine, and that’s why many of those pediatric studies certainly are going to be comparative trials, especially after we’ve recently seen, in one of our main oral medicines, that it works for kids. That might be the new comparator that the FDA requests when it has companies go and do pediatric research as well.

What do we know about disability progression in patients with RRMS as well as the more aggressive forms of MS?

Dr. Kantor: Progression of MS is something that we don’t like to talk about and there’s several reasons why we don’t like to. One is that we’re so excited that since 1993 we have so many medicines, so let’s talk about what we can do and not what we can’t do. Before there were FDA approved medicines, neurologists used to "diagnose and adios," and for progressive MS, for some neurologists, that’s still the same idea. They still say well you have progressive MS. Goodbye, there’s nothing I can do for you, where that’s not the case.

Firstly, there’s disease-modifying therapies. There’s now disease modifying therapies that aren’t only approved for relapsing forms of MS. There’s one that’s approved for aggressive relapsing remitting MS as well as secondary progressive MS. We hardly use that medicine because of some side effect profile, and then there’s a much newer medicine that’s actually approved for primary progressive forms of MS as well. There are medicines in the pipeline where we’re looking at specifically secondary progressive multiple sclerosis.

Sometimes this nomenclature can be bad for the field as well because really what we know is that we’re better at treating the relapsing aspects of MS than the progressive aspects, but we’re still able to treat the progressive aspects, and a recent research coming out of Europe actually looks at that and the Europeans and the British, specifically, looked at their data on what happens in their socialized medicine system.

Turns out that when you treat people even with progressive forms of MS, so secondary progressive MS, they still do get benefit out of our regular medications, our regular DMTs. It’s not as great a benefit as if you treat earlier, but it’s still a benefit. That’s just one aspect. Remember that when we’re treating MS, disease-modifying therapies is talked about a lot, but that’s just one arm of treatment. On the whole other side of treatment we have symptomatic management and notice I didn’t say symptomatic medications.

Most of what we do does not involve medications and when it does it’s not even FDA approved for MS. So medicine for MS pain, not approved for MS in pain. A medicine for MS and thinking is not approved for MS and thinking. A medicine for MS and fatigue is not approved for MS and fatigue. We do have some that are approved for specific symptoms of Multiple Sclerosis, but generally they’re not approved, and we use other things. Tai Chi, yoga, breathing exercises, mindful meditation, all of those can be very useful.

In fact a study from 2 years ago showed that treadmill walking, not even that aggressive exercise, treadmill walking can not only be beneficial for your physical well being, it can be beneficial for your cognitive well being as well, and what that means is that we can help our patients by helping the individual symptoms of their MS as well.

So we have disease-modifying therapies, symptomatic management, and in the middle we have rescue, or relapse treatment, and that’s when we try to reduce the amount of time that someone is having an attack of multiple sclerosis.