<<Slide>> Cognition and Multiple Sclerosis (MS): What Does Every Neurologist Need to Know?

Speaker 1 (https://www.rev.com/transcript-editor/Edit?token=BHlekhZ8QMMzEWHXccPLUKGAvEpG3CisTBGlqBb_yEhpgNUio4H-wALBgeo7ppawBxdWL4FkLGw9NJhtM31MrQojvu0&loadFrom=DocumentDeeplink&ts=3.27">00:03):

This program was is presented by Medscape Education Global. (NOTE: change was not made; not sure how noticeable it is.)

Iris-Katharina Penner, PhD ("https://www.rev.com/transcript-editor/Edit?token=Ay26QRQfdh_oR8Zi73sSIIZIILUNc-_Eqoaur4LwI5NIC1ThsaDJGZwbitShGVIjpMRkH3RY-qz1PNR9bO7szHWJxy0&loadFrom=DocumentDeeplink&ts=9.97">00:0):

Hello. I'm Iris-Katharina Penner. I'm a professor of neuropsychology and cognitive neuroscience at the Heinrich-Heine-Universität in Düsseldorf in Germany. I would like to welcome you to this program entitled Cognition and Multiple Sclerosis: What Does Every Neurologist Need To Know?

Iris-Katharina Penner, PhD ("https://www.rev.com/transcript-editor/Edit?token=ySxwOFS3NIGS7UUAzHiezHry_tfm3JOW_5dJlzJloXHjAWlFHP48_s2GzzM8aTyGBESocnAJh3nINuYw6XC9sXbCi7s&loadFrom=DocumentDeeplink&ts=29.95">00:29):

So first of all, I would like to welcome my esteemed colleague, John DeLuca, who is Senior Vice President for Research at Kessler Foundation in New Jersey.

John DeLuca, PhD:

Yeah. Hello Iris. Good to be with you.

Iris-Katharina Penner, PhD:

Thank you. Same here.

<<Slide>> Overview of Cognitive Impairment (CI) in MS

So both of us, we know that cognitive impairment is a major feature of multiple sclerosis; however, it is still underrecognized by many doctors, mainly neurologists, but also practitioners from other disciplines. So we know that cognitive impairment can start very early on in the disease. Already it can be present at the stage of a clinically isolated syndrome or at the stage of a radiologically isolated syndrome and so I think we have to be very aware that these kinds of symptoms can happen in our patients [Penner 2017]. This is important for the patient because it has a huge impact on the daily lives of the patients. It impacts their ability to work, for example, but also their social activities and their independence [Rao et al., 1991; Kavaliunas et al., 2019].

Iris-Katharina Penner, PhD (01:39):

So therefore, both of us, John and I, think we are let's say the pioneers in the field to enhance the awareness that these kind of symptoms have to be taken into account when having patients with MS in front of you. So John, let me ask you, what kind of domains are typically affected in multiple sclerosis?

<<Slide>> Broad Spectrum of Cognitive Deficits in MS

John DeLuca, PhD (02:16):

Thank you, Iris. Obviously, in MS patients, it's a very individualized disease. So we can see general patterns, but they can vary a lot by individual. But in general, slowed information processing speed is the primary problem that one sees across the spectrum with persons with MS. It really to me represents an inefficient brain processing. The brain is just working more slowly and the patients really feel that there's a slow processing speed and there are really good data to show that.

John DeLuca, PhD (02:50):

The other area of major problems in persons with MS is problems of learning and memory. Patients will often complain of problems with learning and memory as their primary problem, even though it may be more representative of slow processing speed.

John DeLuca, PhD:

And the third major area that I would say is areas of executive functioning such as planning and organization, initiation. Patients typically don't say I have a problem with executive function. They'll say I have a problem with learning and memory. And I think the important thing is for the clinicians to understand the nature of the problem that patients are complaining about. They may say I have a problem with my memory, but in fact, it could be a problem with executive function or processing speed or all of the above. So I think it's really important to recognize at least these.

<TP slide 7>

<<Slide>> Frequency of CI Tends to Increase Over MS Course

John DeLuca, PhD (03:47):

And as you mentioned earlier, approximately two-thirds of patients with MS have cognitive impairment, but that's not equally distributed along the time course. So as you mentioned, even in a clinically isolated syndrome, approximately a third of those patients already show cognitive impairment. When you go to relapsing and remitting, now you're talking about 50% on average of patients that are showing cognitive problems. But now when you get to the progressive forms, 80-90% of those patients are exhibiting cognitive impairment.

John DeLuca, PhD (04:25):

So not only is it important to recognize the types of impairments, but also the stage of the disease.

<<Slide>> CI by Age and Physical Disability

And the last point from my perspective, Iris, is that the relationship with physical disability is not necessarily a close one. A person can have problems early in the disease which are cognitively impaired, but no physical disability and vice versa. A person can have no cognitive impairment and a lot of physical disability. So the relationship is not clear. It's important that we know what these are and they can occur anywhere and they're very individualized.

Iris-Katharina Penner, PhD (05:08):

I think the last point is very important to underline again that in multiple sclerosis, we typically assess the physical ability of the patient via the EDSS, for example, and a lot of neurologists, they look solely on the EDSS and think if I have a patient with an EDSS of 2, for example, then this patient is one who cannot have cognitive problems. And I think that's the point. So even in these kind of patients with EDSS 0-3, for example, we can observe patients having cognitive decline. And I think that is already one very important take home message for the audience that physical disability is not directly related to the cognitive problems of the patients.

John DeLuca, PhD (06:01):

Yeah. A really important point absolutely. The reliance on EDSS in practice can be important, but its over-reliance with respect to cognition is really not something that we should really recommend.

<TP slide 9>

<<Slide>> Negative Effects of CI on Daily Function and QoL

John DeLuca, PhD (06:16):

So obviously, these cognitive impairments have a very significant impact on the everyday life of the patients and not just the patient, but the family and socially and even at work. So cognitive impairment even without physical disability, cognitive impairment can have a significant impact on employment, on driving behavior, social activities, household activities such as cooking and financial management, shopping. Cognitive impairment alone has a significant impact on income, overall quality of life. Again, these are beyond the physical disability alone. So the impact on everyday life is very significant and therefore, must be assessed early on in the disease and throughout the disease for its impact on everyday life and it's critically important.

<<Slide>> Importance of Early Detection of CI

Iris-Katharina Penner, PhD (07:17):

Maybe I would like to elaborate a little bit more on the early detection of cognitive impairment because there is good data showing that cognitive impairment when it happens at the very beginning of the disease, let's say at the time of diagnosis already, that these are patients with a bad prediction for the overall evolution of the disease, meaning that cognitive status might be a kind of predictor for the overall outcome of a patient. Do you think that this might be a point to finally convince the neurologists that it should be done from the very beginning on, so that at least at the time of diagnosis you have one cognitive status of the patient that gives you some hint on whether this is a patient with a more aggressive pathology, for example.

John DeLuca, PhD (08:15):

That's a very important point and I really want to emphasize that point, Iris. We know from the literature that early cognitive impairment, even at the time of diagnosis has significant predictive value. For example, even in CIS, the presence of cognitive impairment is predictive of conversion to definite MS. We know that early cognitive impairment predicts worse and more rapid future cognitive decline, so early detection already predicts that there'll be a future cognitive decline. Interestingly, it also predicts faster disability progression and importantly, early cognitive impairment shows a faster prediction to transfer into secondary progressive course. So again, the early cognitive impairment can predict that possibly the change in the progressive forms will be more rapid. It predicts things such as cortical thinning. And we know, also, that gray matter volume early in the disease, decreased changes in gray matter volume is a significant predictor of future cognitive decline. And of course all of this affects their everyday life.

John DeLuca, PhD:

So this really means that it's really important at the time of diagnosis that the assessment for cognition be a major part of the patient's assessment. And I think that's not the case these days.

<<Slide>> MRI Metrics Linked to Cognitive Decline in MS

Iris-Katharina Penner, PhD (09:51):

Now I would like to move a little bit to the pathophysiology because many colleagues are asking can you tells us something about the reasons why cognitive decline finally happens in multiple sclerosis?

<TP slide 11>

And if we take a closer look at MRI data, it was thought I would say 20 years ago now that the simple number of the lesions in the brain finally defined whether the patient will become a cognitively impaired person. Of course we know now much better that it is not the simple number of the lesions, but it is the location of the lesions.

Iris-Katharina Penner, PhD (10:32):

That is not only true for the lesions located in the white matter of the brain, but also in the cortex, so we are now also able to look for these kinds of cortical lesions. And you mentioned the cortical thinning. This is also, I think, one aspect that is important to mention that the gray matter pathology is mostly related to the cognitive status and therefore, the MRI images give us finally, also, some hint whether the patient in front of us is probably a person that is likely to have cognitive decline. So I'm talking a little bit or would like to talk about the brain atrophy, for example.

Iris-Katharina Penner, PhD (11:22):

If you had to take a look at the brain image of one of your patients and you see that there is huge brain atrophy, overall cortical atrophy, then I think we can say that the probability that this is a patient also having cognitive problems is larger than having images from a patient who is not showing this kind of cortical pathology. Would you agree on that?

<<Slide>> Limitations of MRI in Assessing CI

Because we here in Germany, we always make some kind of double examinations. We do the neuropsych testing and then we look at the MRI images just to get an impression whether there is a fit between the brain image and the cognitive test result.

<TP slide 12>

John DeLuca, PhD (12:06):

This is a really important point, also. We know from the literature, as I mentioned, that early gray matter volume loss is a strong predictor of future cognitive decline. But I also like to say that looking at a brain scan tells you nothing about behavior. There's no behavior in it. It's a picture of the brain and so it can give a potential hint. And I certainly would look at it and say the person is having significant brain pathology that among other kinds of things one might think about, cognition would be one.

John DeLuca, PhD (12:47):

But it's also important to look at things more broadly. The brain imaging is a hint, but part of the neuropsychological understanding of the patient is what's going on in their lives, what is their cognitive reserve level, and the psychiatric aspects, putting all that together is as important, if not more, than just a brain scan alone.

John DeLuca, PhD (13:13):

So looking at the brain scan is the first point to ask a question what else should I be looking at in this patient? And that's where the neuropsychological aspects of what's going on become critical.

Iris-Katharina Penner, PhD (13:27):

I'm really glad that you elaborated on that point because I think at the moment the idea is that if I have a patient not showing any cortical pathology on a brain image, then this is not a patient who has to undergo neuropsychological testing and I think that's completely wrong. So it's also the other way around that is not true. I can also have a patient not showing any pathology, huge pathology in an MR image, but nevertheless, having problems with information processing speed or episodic memory.

Iris-Katharina Penner, PhD (14:05):

And I think that's also a learning point for the doctor that purely looking at an image is not enough and that we are not treating images, but patients. And you mentioned, also, the psychiatric symptoms. I think depression, fatigue, anxiety, these are also contributing factors to the cognitive status of the patient. So therefore, I'm really glad that we both agree here that at the moment there are several aspects that can be improved from the clinical point of view.

John DeLuca, PhD:

Without a doubt. We need to treat the whole patient.

<TP slide 13>

<<Slide>> Thalamus Atrophy and MS-Related CI

Iris-Katharina Penner, PhD (14:47):

Yes. Absolutely. Broadly, one additional aspect concerning the MR images. Normally we only have these kind of general sequences, so T1 and T2 images that are acquired by the radiologist. But at least in our country it is the case that nobody is looking, for example, thalamus atrophy. And we have learned, also, from a couple of studies that obviously the thalamus gets atrophic from the beginning on in the disease and we know that the thalamus is some kind of integrative structure in the brain and highly important for cognitive functionality. How is that managed in the US? Do you have radiologists who are specifically looking for thalamic atrophy when you send them for MR investigation?

John DeLuca, PhD (15:45):

I think that you're right about thalamic atrophy and its close relationship to cognition and cognitive decline. I think the only way that radiologists are going to look at specific aspects of thalamic atrophy, for example, is if the neurologist or the referring physician makes a particular point about it. That is not an automatic kind of thing, I believe, in practice today, but that should be something to look at specifically and in other aspects, too. Hippocampal lesions obviously are very critical, not just in MS, but it clearly affects learning and memory in other aspects, too.

John DeLuca, PhD (16:27):

So I think it's really up to the clinician to have a keen sense of the literature, not just global atrophy, and how it relates to cognition specifically. And I think people are not that aware of this literature. So thalamic atrophy is a key aspect, I agree.

Iris-Katharina Penner, PhD (16:48):

I think we agree that imaging, brain imaging in terms of diagnosis or the diagnostic process in multiple sclerosis is very important; however, it is not, let's say, a kind of biomarker for the cognitive status of the patient. So we need to assess the patient cognitively and we have some kind of neuropsychological batteries available. Maybe you can tell us something about the assessment tools that are typically used in multiple sclerosis?

<<Slide>> Objective Assessment of CI Is Critical

John DeLuca, PhD (17:26):

I think I'll start first by saying that there is literature that neurologists’ judgment of cognitive impairment is no greater than chance. So just simple interview or basic neuro examination is not predictive of cognitive impairment. The clinical interview alone is also not predictive and the patient's self-report is not necessarily predictive of actual objective cognitive impairment. The patient's self-report tends to be related more to emotional distress rather than actual cognitive impairment.

So think about it. You go to a clinic. You meet your neurologist, you have an interview, a neurologic exam. You listen to the patient and you make a determination as to whether it is a cognitive problem. All of that may be wrong. You have to have the objective assessment.

Iris-Katharina Penner, PhD (18:26):

May I just interrupt you and ask why is the self-report of the MS patient not really correlated to the actual cognitive status? Is it because they have no self-insight or is it an over or an underestimation?

John DeLuca, PhD (18:46):

Yeah. It's a really tough question and this is something that as a clinician, we have to really be sensitive to. But there are patients who will be reacting emotionally, emotional distress under changes in their lives, for example. So they may be having difficulty at work which may not necessarily be related to cognition, but feel like I'm not as smart as I used to be. Therefore, my learning and my memory is a problem. But it may be that they're really talking about I'm upset about what's going on at work or at home and that comes across as a potential cognitive problem. There may be one, but the patient's self-report alone is not enough and I think that's a big part of it.

The family report tends to be a little better, more predictive than the patient report of objective cognitive impairment, but nothing ... you have to do the testing and I think we're going to get into a little bit about how we do that.

Iris-Katharina Penner, PhD (19:46):

You can elaborate a little bit more on the assessment tools that are typically used in MS.

<<Slide>> Screening for CI in Patients With MS Is Suboptimal

John DeLuca, PhD (19:54):

Again, in the United States, a report in 2012 showed that more than half of clinics do no assessment for cognitive impairment. About another 20% only ask patients in self-report. Less than a third do any type of testing. So what's happening in the clinic is not reflective of the research and what happens in Germany, for example.

Iris-Katharina Penner, PhD (20:23):

It's exactly the same situation. It's not in the focus even in the MS specialist centers and I think there is still need to improve that situation.

<<Slide>> National MS Society Guidelines for Cognitive Care

John DeLuca, PhD (20:37):

So to deal with this in the United States, the National MS Society has come up with guidelines for cognitive care because of the data I just reported and most clinics really don't do much. Let me just briefly go over these. This is really important. This is the National MS Society guidelines for cognitive care. So number one, they say there should be a cognitive screening at baseline, at diagnosis. There should be a cognitive, at least a screening and they're pretty specific, a screening with a Symbol Digit Modalities Test (SDMT) or a similarly validated instrument in all individuals 8 years old or greater. Very specific.

John DeLuca, PhD (21:27):

They also say that there should be annual reassessment with the same instrument so that cognitive processing can be followed annually. And the third important point is that there should also be an annual, yearly depression screening and they're very specific about the instruments to utilize in this depression screening. And the reason for that is to get back to the point I was saying about the patient's emotional distress versus their actual cognitive problems and cognitive complaints.

Doing this at baseline and annually can give the clinician at least a good sense of what are the actual cognitive problems as a screen and what's going on emotionally in the everyday life of the patient? And in the last part of this is that if the screening shows significant problems, then the National MS Society recommends a comprehensive neuropsychological evaluation to see exactly what's going on.

So this is the recommendation in the United States. I don't think we're there yet, but coming from the National MS Society, I think that this becomes really, really important and something that we need to strive to get to.

<<Slide>> Rapid Screening Tools Validated in the MS Population

Iris-Katharina Penner, PhD (22:51):

I really appreciate this kind of guideline. At the moment, we do not have these kind of guidelines in Germany, for example. Nevertheless, I think that the SDMT alone is probably not sufficient. So I would rather go for an initial testing with more tests and more elaborate testing because otherwise, you will not get any information on how memory, or memory and learning are developing over time or what you mentioned in the beginning, the executive functions are completely missing here.

John DeLuca, PhD (23:29):

Iris, you're absolutely right. Obviously, this was a compromise. It does take some time to do cognitive testing, although, which if it deserves, it also takes a lot of time to do an MRI. But if you have a problem and you're really serious about the impact of cognition in everyday life, you need to do the assessment. SDMT doesn't take much time at all. It just takes a couple minutes.

As we said earlier on, a few primary problems are processing speed -- which the SDMT is a measure of --and learning and memory. So if we added a learning and memory component to these screenings, it would only add another five or 10 minutes and it would be much more sensitive. And I agree with you on that.

<<Slide>> Pharmacologic Management of CI in MS

Iris-Katharina Penner, PhD (24:20):

I think after having elaborated on the assessments, John, I think we should now take the last couple of minutes to focus a little bit more on the therapeutic approaches or the therapeutic opportunities.

24:28 If we take a look at immunotherapies, for example, I think we both agree that of course, immunotherapies they help to protect the brain from further destruction, so by probably acting on relapse rate and also, acting on brain atrophy. We elaborated on that and also on the correlation between these kinds of changes in the brain tissue and cognition; however, there is at the moment no good evidence that immunotherapies really improve cognitive functioning and therefore, I would rather focus on symptomatic therapies and here, probably start with the symptomatic pharmacological approaches.

<TP slide 20>

John DeLuca, PhD (25:20):

First of all, I agree with you the disease modifying therapies do have an impact on protecting the brain, but again, the relationship with behavior is not very strong. So there's some evidence, but it's very minor evidence for the other therapies, for example, donepezil. Donepezil, of course is one that people use with Alzheimer's. The Cochrane review on donepezil showed no effect on persons with MS. And it may be very much because what's going on in the brain is very different in MS than it is, for example, in Alzheimer disease. So just because a drug is approved or has been shown to be effective improving memory in one context, it has no effect here on MS.

<TP slide 21>

John DeLuca, PhD (26:10):

I think the other problems with what I call observational studies is that those studies tend to have less control. They tend to not be randomized controlled trials. And when you see some of these drugs, when they've potentially shown an effect in the paper, you find that the control group is not very good. When you look at the randomized controlled trials, there is really little to no effect.

So I think it's important to keep those in mind. I think physicians can try things, but they should try things based on the literature. I think that's really the key. And the literature is not real positive on the medications. I think the difference is in the area of cognitive rehabilitation.

<<Slide>> Cognitive Rehabilitation in MS

John DeLuca, PhD (27:04):

Here we have actually good evidence, very good evidence. The older Cochrane reviews have shown that in fact, the evidence is limited and the quality of the data is not great and that's true. But more recently, there's been a number of studies which have shown class 1 evidence that behavioral interventions, cognitive rehabilitation can have a significant impact not only improving cognition, but improving everyday life and it does so through mechanisms in the brain, through neuroplasticity.

John DeLuca, PhD (27:41):

All of this data has been shown. So I think that the good news is that the cognitive rehabilitation can significantly help patients with MS. I think the problem, at least in the United States, is the limited number of people who are really qualified to deliver cognitive rehabilitation treatment. We need more therapists. We need more people trained who are familiar with MS. But that shouldn't stop the physicians from saying I have something that can help you. We've got to find out how to.

Iris-Katharina Penner, PhD (28:17):

Let me ask you one question. The title, neuropsychological rehabilitation or cognitive rehabilitation, what exactly does that mean?

<TP slide 25 partially>

John DeLuca, PhD (28:28):

That's a really, really important point. So cognitive rehabilitation in the broadest definition is helping the patient to improve their cognitive function so that it improves their everyday life. There is evidence that there are computer-based programs that can potentially improve things like processing speed and learning and memory, but that alone is not cognitive rehabilitation. That is one aspect of it. For example, you can give a person a computer-based treatment, but they go home to a dysfunctional family or they have alcoholism in the family or they're taking medications or drugs and they have all of these difficulties. That computer program is not going to do too much.

John DeLuca, PhD (29:17):

So we have evidence that there are techniques that can be utilized by an appropriate therapist. One must treat the entire patient and that includes understanding family dynamics, personal dynamics, emotional status of the patient, patient personality characteristics, all of which are part of cognitive rehabilitation, not just using a computer program. It's really important.

Iris-Katharina Penner, PhD (29:42):

In Germany, for example, when patients go to a rehabilitation center, they come back then to our center for reevaluation or for their yearly follow-up and they say, "Well, they did some cognitive rehabilitation with me." And I ask them then what did they do? And they say, "Well, I was sitting in front of a computer and just doing some games, some computer games." I think this is not cognitive rehabilitation and you elaborated on that very nicely. And I think that's very important that it is not sufficient to just play with a computer. So this is not what we mean by cognitive or neuropsychological rehabilitation.

<<Slide>> Exercise Training and Cognition in MS

I think another very important aspect is sports, so exercise training. I know that you were also involved in a couple of studies where you looked for the effects of exercise training. Can you tell us which kind of exercise training is probably the best for MS patients?

John DeLuca, PhD (30:46):

There is good evidence that exercise can improve cognition in, for example the elderly population. There's pretty good evidence for that. In MS, the evidence is growing, but it's still not there to the point where I would say this should be standard of care. We don't know exactly what type of exercise, for what duration, for how long? And really, we don't know that yet. We do know that there's preliminary evidence that exercise can improve cognitive processing speed, for example. And it can do so by actually thalamocortical changes in activation and connectivity. But that’s very preliminary.

So right now, I think the physicians can try to prescribe exercise as one form of potentially treating cognitive impairment, but knowing that the evidence right now is still very unclear. But if it doesn't hurt, it's fine to go ahead. Cognitive rehabilitation is the area where we have good data.

Iris-Katharina Penner, PhD (32:00):

And I think just to put this picture a little bit more together, I think that we agree that cognitive rehabilitation and exercise training and also probably the treating of the so called neuropsychiatric aspects such as fatigue and depression, for example, that they probably go together with this concept of cognitive reserve, meaning that if we have a patient who is doing exercise training, who is probably participating in a lot of leisure activities, for example, then this might be a person that is more protected against what will happen in the future in terms of cognitive decline or neural degeneration.

<<Slide>> Cognitive-Stimulating Activity May Be Neuroprotective

John DeLuca, PhD (32:47):

I would agree with you and that's one point about exercise, is exercise is a neuroprotective kind of thing. It influences brain activity, but so is cognitive activity. For example, there is a study which was published that in persons with MS who went a learned a second language and that learning a second language actually improved verbal skills, verbal listening, verbal comprehension skills and it did so through improving hippocampal activity. It was a relationship with activity that was going on in the brain. (Ehling PLoS One. 2019 Dec 23 14(12) e0226525.)

So prescribing stimulating intellectual activity is really important. Playing cards is one of the things that I always tell people. Playing cards, read a book, join a book club, stimulate socially and cognitively is really something that there is evidence, at least in Alzheimer's that this can actually potentially slow down the effects of cognitive impairment. It certainly can help people even in their emotional lives to just be more social, more active. And that's not by itself cognitive rehabilitation, but it's just good brain health.

<<Slide>> Understanding Cognitive Reserve

Iris-Katharina Penner, PhD (34:08):

Yeah. I fully agree and I think our work for the future should also be and also, probably for the practitioners, the doctors, that they really inform patients about this kind of concept because patients coming in our center, they typically are not aware that there is some kind of cognitive reserve that they have probably also influence on and I think it's also important to make the point that there is self-efficacy at the side of the patient because also these patients, they suffer from their MS disease because they think oh, now I have a chronic disease and everything is lost and I cannot do anything.

So I think it's from a psychological point, very important to inform patients about this concept of cognitive reserve and that despite having this kind of disease, that they have some opportunities to improve. So this is from my point of view very important and also, one important take-home message for the audience.

John DeLuca, PhD (35:18):

I totally agree. I always think of asking the patient what is it that you like to do that you've missed? And then that's what we're going to try to help you with. Some things you can't do. I used to like to run a marathon. I can't do that anymore. Do you know what? You could become a coach. There are a number of things. What is it that you used to do that you like to do and focus on that because that improves people's mood, it improves their brain health, it improves their socialization and that's something that can be done.

<<Slide>> Conclusions

Iris-Katharina Penner, PhD (35:51):

We have to conclude unfortunately. But I hope that we could help the audience in getting some new insights into this very important topic of cognitive impairment in multiple sclerosis. I think we have made the point that cognitive impairment is highly prevalent in multiple sclerosis; however, there is still a need to increase the research in the field, not only in what we mentioned about the assessment tools, regular assessment, which kind of tests should we use, but also, in terms of therapeutic approaches. I think there is a lot to do in the future.

<<Slide>> Thank you

Iris-Katharina Penner, PhD (36:32):

I would like to thank you, John, for the great discussion.

36:36

I would like, also, to thank you for participating in this activity. I hope that you enjoyed this kind of program, that you learned a lot. Please continue on to answer the questions that follow and complete the evaluation. Thank you very much.