This transcript has been edited for clarity.
Anne Cross, MD: Hello. I am Dr Anne Cross and welcome to Medscape's InDiscussion series on multiple sclerosis (MS). Today we'll be discussing cognitive dysfunction in MS. Let me introduce my guest and good friend, Dr Lauren Krupp. Dr Krupp is a professor of neurology at NYU Grossman School of Medicine, and she directs the Multiple Sclerosis Comprehensive Care Center at NYU Langone Health. Welcome to InDiscussion. And as I often do with guests, I'd like to ask you, what is it that brought you to work on MS? Can you give us a little background on yourself?
Lauren Krupp, MD: Sure. It's a real pleasure to be here today. I found MS fascinating because of the immunology. I thought immunology was interesting and challenging and complicated. But I'm also very interested in the brain and the mind and behavior and thinking. And although there are a variety of neuroimmune disorders that affect the nervous system, MS was the perfect marriage between neuroimmune processes and the central nervous system. Of course, there was not a whole lot we could do to intervene when I first started in MS. But it's dramatically changed in so many wonderful ways that it's been a very exciting time to live through.
Cross: Dr Krupp, you are an expert on cognitive dysfunction in MS. I'll start off by asking you, what do you mean when you say cognitive impairment in the MS population?
Krupp: Cognitive impairment is a term that people often use somewhat loosely. When a person complains of brain fog or challenges with concentration and attention, the conclusion sometimes is, oh, they have cognitive impairment. But in fact, cognitive impairment specifically refers to a deviation from normal performance on neuropsychological tests, and different authors will use different criteria. It's typically a deviation from normal functioning in more than one domain. In MS, the areas most affected include cognitive processing speed, visual and verbal memory to a lesser degree, verbal fluency — not a big issue there, visual-spatial is sometimes a problem for many people, and planning and executive functioning.
Cross: How common is cognitive dysfunction, and what effects does it have on the day-to-day life of our patients?
Krupp: It's common. I think it's more common in individuals who have had a longer disease duration and a more progressive form of MS. In looking at the overall population of people with MS, the impairment frequency people state ranges anywhere from 50% to 75%. If you look at people early in their MS disease course and early in relapsing-remitting MS, the impairment frequency is much less. But for people with secondary progressive MS, for example, the impairment frequency is on the higher end of that range. And the challenges people have can be dramatic. I recall a patient who kept on forgetting to pick up her daughter from daycare because she couldn't remember it was one of her responsibilities. The effects of dysfunction in these different cognitive domains can be very dramatic. They can include problems at work, problems dealing with multitasking at home, and problems with interacting with their spouse or significant other.
Cross: Yes. This is what I'm running into with a lot of patients, too. In the busy clinic, I'm always challenged with how to ferret out cognitive problems in our patients when they're there. We don't have too much time with them, and we're dealing with a bunch of other things, too.
Cross: How do you screen for cognitive dysfunction in your clinic?
Krupp: There's no great solution to this challenge of how to screen because nobody has the time to do the full assessments that are probably necessary to truly screen for cognitive difficulties. There is a Brief International Cognitive Assessment in Multiple Sclerosis set of measures that's called BICAMS. And the three cognitive tests that it involves are verbal memory, visual memory, and cognitive processing speed, but it takes a good 20 minutes or more to administer it, and most people don't have the time or staff to do it. We tend to just rely on the Symbol Digit Modalities Test (SDMT), and it's a very much a screening test. There are people who don't do well on it who are not cognitively impaired. And performance can be affected by how hard you're trying or how easily you're distracted. But it is sensitive in most cases. We sometimes use it in addition to the sense that I get from the exam and what we hear from the family. It can be difficult to rely exclusively on a patient's report because when people complain of trouble finding their car or trouble remembering names, these complaints correlate with symptoms of mood more than actual cognitive performance. But if the spouse is saying they notice their wife is getting lost when she's driving or is having difficulties in the kitchen, that's something that has a lot more correlation with impaired performance on neuropsychological testing.
Cross: What about mood? How often would depression, if ever, masquerade as cognitive dysfunction in the clinic?
Krupp: As an example, I can say when I can't find where I parked my car that I'm an absent-minded professor; of course I can't remember such inconsequential things. I say that if I'm feeling good about myself. But if I'm feeling very anxious and worried about myself and if I have Alzheimer's disease, I better get myself to a neuropsychologist. The symptoms people report don't always reflect cognitive deficit. And so a lot of symptoms of not remembering things, feeling brain fog, and whatnot may reflect a mood issue without there being significant deficits on testing.
Sometimes the neuropsychological testing can be very reassuring. On the other hand, a severely depressed person, in the presence of MS or not, can have pseudodementia and be withdrawn, not communicative, and appear to be very cognitively impaired. And the degree to which that individual will do poorly on neuropsychological testing is variable. Sometimes what you find is this variability in performance where they do worse on some of the easy tests and better on some of the hard tests. It happens. Mood problems, fatigue, and cognitive challenges — they blend together, and in people with more advanced disease, they've got all the problems. Sometimes it's easier to treat the mood issues than it is to treat anything else. I always try to start with that before going to fatigue issues or even cognitive problems if there's a big mood component.
Cross: Speaking of fatigue, you also have written extensively on that topic. And as an aside, I'm just wondering, what are you doing these days in terms of assessing fatigue when people complain of it and treating it?
Krupp: When we saw interferon beta-1a injections being used, the day afterward, there would be cytokine changes and fatigue and flu-like symptoms. So we know there's an immune basis to the problem. There's also a lot of correlations with brain volume changes and white matter changes. What we have learned is that pharmacologic management really doesn't work. I emphasize things like exercise, mindfulness, and a healthy diet. A lot of what fatigue is, or some part of what it is, is feeling out of control. You feel overwhelmed, out of control, and don't know why you can't do this or that, and you have a sense of having no energy.
The trick is to help the person feel in control and organize their day in such a way that the most demanding tasks are in the morning, so they can manage the afternoon with less stress. There are a lot of very practical energy conservation techniques and then amazingly, things like mindfulness, yoga, and exercise — those things really help fatigue. But they require more discipline than just taking a pill, so you have to motivate the person.
Cross: Yes. Back to cognitive dysfunction. I'm wondering, if you do an SDMT in your clinic and the results are abnormal, do you immediately send them for further testing, or do you repeat the test?
Krupp: I want to see the test results a few times because there's a certain amount of jumping around that can happen. I also want to make sure that if it's not me who administered the test, I speak to the person who did to make sure the patient was engaged and trying. One of the reasons the SDMT is so sensitive is that it's not only capturing cognitive processing speed. What you do is give the person a paper with symbols on it, and at the top of the page is a key that assigns a number to each symbol. You ask the person to look at the piece of paper, follow a symbol with their hand and with their finger, and read out the number that corresponds to that symbol. To some extent, the test is getting eye tracking, concentration, and the speed in which the person can go from looking at the key to looking at the symbol to giving you an answer. It's getting multiple aspects of neurologic function. If somebody tried and did poorly, and I see them again and their results are still poor, then I might dive into it a little bit.
It also depends on what's happening with them. How is this affecting or not affecting their interactions in the office or at home or socially? That is a tough one. It's not an easy thing to help people with because we don't have a medication that will turn it around. If you engage in neuropsychological testing to confirm what you think is present — a problem with cognitive functioning — and you refer them to a neuropsychologist if you can, and you see that they have MS-associated impairments, what do you do? There's not a pill that will turn that around. There are several options, right? Some of what you can do can be borrowed from the Alzheimer's world. There's the Mind Diet, which is avoiding saturated fats and eating things such as fruits and vegetables and berries. There's exercise, and the data are mixed on how much exercise enhances cognition. It certainly improves quality of life. There are also computer-assisted cognitive games that get harder the better you do, and these are powerful for enhancing cognitive processing. In some places, you can get an occupational therapist or even a neuropsychologist to do cognitive retraining with someone who is motivated to do it and wants to really work on the problem.
Cross: I was just thinking that I, personally, have this battery of things I go through that might be causing cognitive dysfunction or fatigue, such as thyroid dysfunction and obstructive sleep apnea. Do you have such a list of things you go through in your mind?
Krupp: Sure. Sleep disruption is critical. One of the other things people fall into is that they often use benzodiazepines at night to help them sleep. That's not good for your cognition at all. One big challenge is to try to come up with alternative ways to help people sleep that don't involve medicines that can be detrimental to cognitive functioning.
Looking for treatable causes is always a good thing to do. Ruling out sleep apnea for sure is important. Unfortunately, you don't usually find low vitamin B12. The thyroid function tests are usually unremarkable. A patient might be anemic, but that's not going to generally have that big of an impact. There are a lot of biomarkers of cognitive impairment that are really linked to MS. They include brain volume loss in specific regions like the thalamus or the cortical gray matter or even the white matter, and things like neurofilament. In a patient who has a lot of brain volume loss, there's a good chance the cognitive deficits are going to be from MS.
Cross: Yes, I guess the horse is out of the barn at that point. You are also very involved in pediatric MS care. And I know you see lots of children with MS. Unfortunately, there are these kids with MS. Could you tell us how loss of cognition affects them?
Krupp: This is something where the history of MS treatment has really made a dramatic impact, as well as the history of understanding that kids rarely, but can, get MS. It used to be that by the time we saw a kid who had MS, they were well into their disease with multiple relapses and significant delays in getting on therapy. Papers from 2005 to 2010 described a lot of cognitive problems in these kids. But I'm very happy to say that we've found that in the current treatment era, with kids also being diagnosed and managed much more quickly, they do pretty well. They recover from relapses incredibly well compared to adults, and they also appear to have overall better cognitive functioning if you compare for disease duration. The question is, what is it about youth? Do they remyelinate? Do they have the ability to repair? Do they have better compensatory mechanisms that you might pick up on a functional MRI? When we think about what lies ahead in terms of challenges with MS, I think finding the fountain of youth as it can apply to reserve resilience and repair is a critical question that lies before us. I'm happy to say that on the cognitive front, there may be some slowing here and there. What I see more of is kids struggling with having a chronic disease when they really want to be just like everybody else. And so it's more of a psychosocial kind of thing. But that was not always the case.
Cross: Things have improved. Definitely.
Cross: What are your hopes for the future for our field?
Krupp: I would like to understand when I see a 65-year-old with MS whose MRI shows a lot of white matter disease, and they're not on any therapy because they've refused it, and they're doing well — what is their secret? Because they're not all triathlon runners. What is it that allows certain individuals to have this tremendous resilience? It's really a nervous system question. We've gotten very good at controlling the waves of inflammation in relapsing-remitting MS. We don't understand that when the demyelination has occurred and the neurons are flapping in the breeze without their myelin sheath — why is it that certain individuals can handle this so much better than others? I think that's where we need to go. Of course, the other big challenge is progressive MS and understanding that repair is critical with progressive disease. Coming up with ways of enhancing repair is important. Progressive disease and working on enhancing repair mechanisms — those, to me, are the two big challenges. I think we will get there. There's enough people working on it. After all, if you are a mouse, you have the problem licked, right? You get EAE (experimental autoimmune encephalomyelitis), you do a little remyelination, and you're as good as gold, right? Running around with your tail wagging. So, the path is there. We just have a lot of work to do to forge forward.
Cross: Well, I have certainly enjoyed this talk with you this morning, Dr Krupp. And, just to summarize, we've discussed the frequency of cognitive dysfunction in MS, which is probably well over 50% in most people but increases as they are older, living longer with the disease, and getting into the secondary progressive MS phase. We took a sidestep a little bit and discussed fatigue and its management because Dr Krupp is an expert in that area. And we ended with a little discussion of pediatric MS and cognitive dysfunction. We finished with Dr Krupp's hopes for the future. Thank you so much for joining me today, Dr Lauren Krupp from NYU. This is Dr Anne Cross for InDiscussion.
Krupp: Thank you so much. This has been a real pleasure. Thank you for inviting me.
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Cite this: In the Busy MS Clinic: Diagnosing and Treating Cognitive Dysfunction - Medscape - Oct 05, 2022.