Transcript - The Management of Fatigue and Cognitive Dysfunction Associated with Multiple Sclerosis

HOLLY ATKINSON, MD: Hello and welcome to today's conversation on MS. I'm your host, Dr. Holly Atkinson. Today's conversation is going to focus on the management of fatigue and cognitive dysfunction associated with multiple sclerosis. Joining me are Dr. Heidi Crayton, Dr. Peter Riskind and Dr. Rock Heyman.

Dr. Heidi Crayton is assistant professor of neurology and director of the MS Center at the Georgetown University Medical Center in Washington, DC. It's nice to have you here, Heidi.

HEIDI CRAYTON, MD: Thank you.

HOLLY ATKINSON, MD: Dr. Peter Riskind is professor of clinical neurology and director of the Multiple Sclerosis Clinic at the University of Massachusetts Medical School and UMass Memorial Health Center.And Dr. Rock Heyman is assistant professor of neurology and director of the MS Center at the University of Pittsburgh School of Medicine. Thanks for joining us. Heidi, we're going to concentrate on talking today about fatigue and cognitive dysfunction, as I said. Let's start with fatigue. What's the prevalence of this symptom in MS? Obviously very high.

HEIDI CRAYTON, MD: Pretty high. Most patients actually list fatigue as at least one of their top three symptoms, even if they're not very physically disabled. Eighty to ninety percent, certainly, in the MS population at large, and I think it's really quite disabling.

HOLLY ATKINSON, MD: I was just going to follow up with that: what about the quality of life? Do you find that this is one of the most disturbing of the symptoms to patients?

HEIDI CRAYTON, MD: Most definitely. Most definitely. I think it's almost more difficult to deal with than a physical disability like gait difficulties or visual difficulties. It's really, I think, the reason that people have more problems with their work environment, their relationships at home.

HOLLY ATKINSON, MD: Yeah, it affects everything globally.

HEIDI CRAYTON, MD: You bet.

HOLLY ATKINSON, MD: Peter, what do we know about the pathophysiology of fatigue in MS?

PETER RISKIND, MD: Well, we don't really understand it very well at all. So we don't really know what's causing it. We don't really understand exactly what part of the brain, if there's a specific part of the brain that's not working to cause fatigue. There's a little bit of data from positron emission tomography studies that suggest some of the front part of the brain: the frontal cortex, prefrontal cortex, basil ganglia might be involved. But really that's a small study. Those patients were also depressed. MRI studies really don't help in terms of showing specific localization of lesions that correspond to fatigue.

HOLLY ATKINSON, MD: What's the theory that you buy into?

PETER RISKIND, MD: I think it's a dysfunction of the relationship between the hypothalamus and prefrontal cortex. That would fit with the PET study, actually. I think that remains to be proven.

HOLLY ATKINSON, MD: Rock, start the conversation for us on how you approach a patient with fatigue. And obviously, there are other symptoms that come in here, such as depression, which complicates the picture. But what's your initial approach to the patient with fatigue?

ROCK HEYMAN, MD: Certainly a comprehensive history is needed. When a patient comes in complaining of fatigue, it can many things besides multiple sclerosis -- depression being very common in MS, but certainly other conditions besides multiple sclerosis can cause fatigue. People with MS are at higher risk for thyroid disease, for instance. Diabetes even. So a metabolic evaluation or at least a comprehensive medical evaluation. Looking at their sleep quality and sleep quantity. Looking at their mood. Consider checking a vitamin B12 if it's never been done. But there are many different factors and one of the struggles we have in the MS clinic is trying to decide who has pure MS fatigue versus what is acquired due to other factors.

HOLLY ATKINSON, MD: Heidi, you're shaking your head "yes" here.

HEIDI CRAYTON, MD: Definitely. I think that fatigue is so interrelated with other symptomatology from MS, and one of the first areas that I address is sleep and sleep difficulties, because if sleep hygiene is not in order, then people are going to be fatigued as a result of that. So I think that that's one of the first places to start.

HOLLY ATKINSON, MD: Peter?

PETER RISKIND, MD: I agree that sleep is often a big problem in our MS patients and sometimes a big contributor to fatigue. We've even had a few instances of patients that are fatigued because the spouse has sleep apnea. So I definitely think that sleep is one thing that needs to be paid a lot of attention to.

HOLLY ATKINSON, MD: Well, if you have pure MS fatigue, how do you start -- assuming that you've gone through these differentials and you've made sure that there are not other contributing factors -- what's your first-line approach to nonpharmacologic therapy, Heidi?

HEIDI CRAYTON, MD: Energy conservation techniques. Keeping oneself cool, especially in the summertime when fatigue is at its all-time high because of the heat. Keeping cool. Pacing themselves, and if it's at all possible, to try to take planned breaks and naps throughout the day, and I oftentimes write notes to try to facilitate that in somebody's workplace.

PETER RISKIND, MD: Right. Although, paradoxically, aerobic exercise is sometimes very helpful.

HEIDI CRAYTON, MD: Yes. Most definitely.

PETER RISKIND, MD: So in patients that are heat-sensitive, I often recommend walking in water up to the waist in a swimming pool that's cool. And that's a good way to exercise and not get overheated.

HOLLY ATKINSON, MD: Do you find, Rock, that most patients are able to really incorporate this advice into their daily life? How are they, in terms of education when it comes to fatigue?

ROCK HEYMAN, MD: It's variable. Certainly they need education. Many patients may feel guilty because they're not carrying as much of a load at home or as much of a load at work, and therefore they're actually -- we find they're working through their lunch hour -- staying at their desk and not getting the breaks that we'd like them to have. Having them develop their support system if they haven't had it is a very difficult thing to do. But every employer's different. Every patient's different. But the individual variables are important for success when we come to treating.

HOLLY ATKINSON, MD: Let's talk about pharmacologic treatment now. When would you go to pharmacologic treatment?

HEIDI CRAYTON, MD: If those nonpharmacological methods don't work and are really not successful, then I think that it's time to start pharmacological intervention, and . . .

HOLLY ATKINSON, MD: How long would you give the nonpharmacologic ones?

HEIDI CRAYTON, MD: A week. A couple of weeks, really. I have a very low threshold. I don't have -- I don't wait for people to feel better for a long period of time. If those -- if those techniques -- those conservative techniques, I jump right into pharmacological therapy.

HOLLY ATKINSON, MD: Peter?

PETER RISKIND, MD: We are usually attempting the nonpharmacologic therapies at the same time as we're waiting for the results for thyroid testing and so forth, or maybe a sleep study. So by the time those come back (and they're often negative), then we're ready to jump in with some treatment with medication.

HOLLY ATKINSON, MD: Rock, what do you start with?

ROCK HEYMAN, MD: I usually start with amantadine. It's been around longer and it's much less expensive then modafinil. However, I think modafinil's data may be somewhat better. I explain to the patients that they're going to feel an effect early on. Usually they'll notice it within a day or two or three, so it's not a medicine they need to try for a month. I start with one pill a morning. In two or three days, if they're no better, either go to two pills in the morning or one morning and one midday.

HOLLY ATKINSON, MD: Biggest side effects?

ROCK HEYMAN, MD: Biggest side effect probably would be nausea and occasionally insomnia. But there are other side effects, including livedo reticularis, a mottling or blotching of the skin which, while not dangerous, I don't like my patients to have and would encourage them to try another drug if they have it.

HOLLY ATKINSON, MD: Peter?

PETER RISKIND, MD: A common mistake is to give the second dose in the evening. I see this all the time, and then the patient doesn't sleep all night and their fatigue is worse. So I never give the second dose any later than noon to one o'clock in the afternoon.

HOLLY ATKINSON, MD: Yeah, that's a very important tip. Heidi, do you start the same way?

HEIDI CRAYTON, MD: Yes, I do. I do amantadine first line, and if I fail with amantadine then I move on to modafinil.

HOLLY ATKINSON, MD: Any final thoughts for the practicing physician in terms of fatigue? What do you think is the most important take-home point?

HEIDI CRAYTON, MD: Be aggressive about treating it.

HOLLY ATKINSON, MD: Peter?

PETER RISKIND, MD: I think that's definitely a big part of it, and persist in trying different things and looking for the cause, because our experience is that it can take months sometimes before we finally do get the, "Ah-ha. That's why they're so tired." And, there may be some stress that they didn't mention at the time when we were first seeing them, or you finally figure out that they're hypothyroid or whatever. It may take a little time.

HOLLY ATKINSON, MD: So keep looking. Be diligent.

PETER RISKIND, MD: Keeping concerned about it.

HOLLY ATKINSON, MD: Rock?

ROCK HEYMAN, MD: And also watch for depression. I think fatigue can lead to depression, just like depression can cause fatigue. So if a patient does have persisting difficultly with fatigue, you have to really watch for depression.

HOLLY ATKINSON, MD: Any particular antidepressant that you may start with?

ROCK HEYMAN, MD: There are so many different options and I base it on an individual basis, but many of them can be activating and improve energy.

HOLLY ATKINSON, MD: Let's turn to cognitive dysfunction. Prevalence of that, Heidi?

HEIDI CRAYTON, MD: Pretty high, once again, and hand-in-hand with fatigue. I think that most -- for most patients, that's their biggest fear. Probably a larger concern that gait difficulties or visual difficulties is cognitive difficulties, and I think it is really pretty prevalent.

HOLLY ATKINSON, MD: Peter, what do you usually see in terms of its manifestation? Obviously there are some cognitive functions that you will notice and lose initially.

PETER RISKIND, MD: Right. I think one of the big problems that patients are aware of is that they're having problems with what they call multitasking, and so they're having trouble doing more than one thing at a time, they're having to keep lists (which, of course, many people do anyway, but that's even more important for them), and they're having some minor memory problems, often as an early manifestation. An important thing to note is they almost never have language problem. That can happen as a neuropsychological manifestation of sort of more truly dementing illnesses. That's fairly unusual.

HOLLY ATKINSON, MD: Rock, at times the cognitive dysfunction can be fairly difficult to diagnose. How do you think your way through that when you do have a difficult situation?

ROCK HEYMAN, MD: It is difficult to diagnose and you need to consider other issues, just as we did with fatigue. Someone may come in complaining of cognitive dysfunction when really there are other issues going on, and a patient's complain of cognitive dysfunction does not necessarily mean that they have cognitive dysfunction. If a caregiver complains -- a family member, or they're having worker employment issues, then we found it very useful to ask, "How was your last job evaluation doing?" But if somebody is having symptoms and it's not obvious, we don't have any easy screens. The Mini-Mental Status Exam that neurologists use often for dementia of the Alzheimer's type is not useful for detecting subtle or mild cognitive dysfunction. Formal testing may be necessary.

HOLLY ATKINSON, MD: Heidi, what do we know about the pathophysiology of cognitive dysfunction?

HEIDI CRAYTON, MD: We really don't know a lot about the pathophysiology, just like with fatigue, but I think that, again, this is a little difficult to sift out a times because it's so related -- so interrelated with fatigue and depression. And if fatigue and depression are on board, you are very, very likely to see cognitive dysfunction, so it's a little bit difficult to even sift out which is the primary issue.

HOLLY ATKINSON, MD: Nonpharmacological treatment. What's the first approach you take, Peter?

PETER RISKIND, MD: Well, again, trying to simplify people's lives is one thing. There's such a thing as what's called cognitive rehab, which is what I was sort of alluding to earlier, which is keeping lists or using other approaches to compensate for problems that people may have. Minimizing the demands on people sometimes helps, or maybe changing jobs in some cases is necessary.

HOLLY ATKINSON, MD: How do you go about determining that?

PETER RISKIND, MD: Well, I do have a detailed neuropsychological evaluation done, I have a very good neuropsychologist who works with me that helps me work on that particular issue.

HOLLY ATKINSON, MD: Rock, pharmacologic treatment.

ROCK HEYMAN, MD: When it comes to cognitive rehabilitation, I think physicians should be aware there are different individuals who may be helpful. Some people have good neuropsychologists who do cognitive rehab or retraining. Other people use occupational therapists or speech pathologists. Different backgrounds, and I think neurologists need to know who does that type of rehabilitation in their area. Often if there's not someone around who does a lot of this, they might want to say, "Well, who does head injury rehabilitation?" who would be the most similar person to look at.

HOLLY ATKINSON, MD: That's a very good point.

ROCK HEYMAN, MD: And I think those kind of accommodations and planning are more necessary than trying medications, because we do not yet have any proven medicines that are going to affect cognitive dysfunction once it occurs. We really like to prevent it, and we really like to get people started on a disease modifying drug before they have this.

PETER RISKIND, MD: I'd just add that there are certainly times when fatigue is actually a major contributor to cognitive dysfunction, so sometimes treating the fatigue with amantadine or modafinil might actually have, as an outcome, an improved cognitive function.

HOLLY ATKINSON, MD: Heidi, what about ongoing clinical trials and what is coming down the pike?

HEIDI CRAYTON, MD: In terms of fatigue management and cognitive rehab or treatment, there are several trials looking at, typically, Alzheimer's-types of medications -- anticholinesterases. Small studies but they look interesting and promising, and some of us actually do use Alzheimer's-types of drugs to treat cognitive deficits in MS.

HOLLY ATKINSON, MD: If there's a pitfall here, Peter in treating cognitive dysfunctions, what is it?

PETER RISKIND, MD: I think it's in the patient that, in their overall physical appearance looks good and perhaps has been stable, overlooking the possibility that they're actually losing cognitive function. So it's not a rarity for us to have someone who's gradually losing cognitive function, but the rest of the exam and their balance and so forth is all fine, and so if one isn't paying careful attention to the fact that they're actually progressing along this very important parameter, one will just totally miss it.

HOLLY ATKINSON, MD: We have just a few minutes left, so what I'd like to do is have you give us some final thoughts here for your colleagues. If you want them to remember certain pearls, what would they be?

ROCK HEYMAN, MD: Well, I think when it comes to cognitive dysfunction, it can also be multifactorial, and do not overlook depression and anxiety as aggravating factors. No one is going to function as well cognitively when those factors are ongoing, and whether they have difficultly or not underneath it, you need to make sure that the general person is well.

HOLLY ATKINSON, MD: Peter?

PETER RISKIND, MD: Well, we've had a number of patients that were fatigued and had severe memory problems with MS, and I would say, bear in mind the possibility of obstructive sleep apnea, because we've fixed a bunch of people by making that diagnosis.

HOLLY ATKINSON, MD: Heidi?

HEIDI CRAYTON, MD: And make sure that sleep hygiene is intact. Make sure that fatigue and cognitive deficits are not a result of poor sleep hygiene because of nocturia or restless leg syndrome or spasticity.

HOLLY ATKINSON, MD: So it's really a multifactorial approach here where you have to be considering all these symptoms simultaneously and addressing them on a number of different levels.

HEIDI CRAYTON, MD: You bet.

HOLLY ATKINSON, MD: And thank you for joining us.