Rethinking Treatment and Measurements of Fatigue in Multiple Sclerosis

John DeLuca, PhD

One of the most prevalent symptoms patients with multiple sclerosis (MS) experience is fatigue, a hot topic of conversation and research in the field. Despite the increasing amount of literature on different types of approaches of studying fatigue, there is one theory of observation that has emerged from the research. In a previous research review on fatigue in MS, studies showed that interaction between the striatum and prefrontal cortex were reliant on dopamine.¹ Thus, the results from the neuroimaging studies suggest that fatigue is caused from the interruption of communication between the areas of the brain, supporting the dopamine imbalance hypothesis.

Recently, John DeLuca, PhD, senior vice president for Research and Training at Kessler Foundation, chaired a session on current topics trending in MS rehabilitation at the 2023 Consortium of Multiple Sclerosis Centers (CMSC) Annual Meeting, held May 31 to June 3, in Aurora, Colorado. The session focused on understanding fatigue and its management in clinical practice. DeLuca presented on the definition of fatigue as well as measuring it in patients with MS.²

At the meeting, DeLuca sat down in an interview with NeurologyLive® to provide an overview of his presentation on fatigue, how it is being treated currently in practice, and his recommendations for clinicians. He discussed how functional neuroimaging can help to contribute to a better understanding of fatigue in MS. He also spoke about the limitations of medication-based treatments for fatigue in patients with MS according to the latest research. In addition, he reviewed how patient preferences and reward activities could be incorporated into the treatment of fatigue in MS.

Can you provide an overview of your presentation on fatigue at CMSC 2023?

John DeLuca, PhD: My presentation covered “What do we know about fatigue and what we don't know. Do we understand what fatigue is? Can we measure it? What's going on in the brain and can we treat it?” Fatigue is the most significant symptom that patients with MS talk about that affects their lives and affects them in a variety of different ways. Do we understand what fatigue is by what the patients are telling us? We have fatigue instruments that we use, but part of the issue is that these fatigue instruments actually don't measure fatigue alone. The results are contaminated by a number of other factors, such as sleep disturbance, depression, deconditioning or differentiating weakness from true muscle weakness, and hormonal changes. The question has been, do we understand what fatigue is? The answer is, we really don't. Our instruments don't really provide the facts of fatigue. Self-reported fatigue by the patient uses these instruments, which are called traits of fatigue.

There's also fatigue in the moment, called “state” fatigue, which a lot of studies look at. But “state” fatigue and “trait” fatigue don’t correlate or correlate poorly, so do we really know what fatigue is? That's a real problem, and highlights that we need to have a better way to conceptualize fatigue.

One way is to distinguish between primary and secondary fatigue. Primary fatigue is what MS is doing in the brain that's causing fatigue. Secondary fatigue refers to elements that perpetuate or influence primary fatigue. For example, deconditioning, medication effects, and sleep effects are all considered factors of secondary fatigue. So, can primary fatigue be measured? Well, we discussed in this symposium on how by using functional neuroimaging, we've been able to come up with a fatigue network, essentially a biomarker of fatigue. What we do is cognitively test fatigue in patients within the scanner for half an hour. Before and after each cognitive test we give them, between six or seven tests, we ask patients to rate their fatigue on a scale from none to very high. We find that their increase in “state” fatigue correlates with changes in a fatigue network in the brain. We think that such a fatigue network can be the biomarker that can be used to examine how we treat fatigue.

What are clinicians in MS doing currently to treat fatigue in their patients?

It's interesting when we talk about treating fatigue because if we can't define it or measure it, how do we treat it? We have to treat it, but we really need a new paradigm to understand fatigue. One of the things we've known for over 100 years is that self-reported fatigue does not correlate well with performance, or what some call “fatigability” today. The number one issue of what patients describe to us may not be the sole cause of what's going on in their lives. We as experts have to figure that out. With that all said, how do we treat fatigue? What mostly happens is people are treated with medications such as modafinil, methylphenidate, and amantadine, but in reality, the data shows that those medications don't work.

The latest paper published in Lancet Neurology from 2021 explicitly stated that the results of these data are because of a placebo effect and the problem with these drugs is their serious adverse effects. So that's a real issue. We end up asking the question, should we have our patients on these medications if we know they don't work? But then what does work?

The two areas that say the data is fairly good are cognitive behavioral therapy and mindfulness treatments. Why those things work is because they're designed to have the patients change their thinking or change their behavior. It helps them to understand fatigue, how it influences them, and how they could change their thinking or behavior about how their fatigue affects them. The important thing is that the data is pretty good for cognitive behavioral therapy, and mindfulness treatment can be incorporated into cognitive behavioral therapy.

While it's easy to prescribe a medication, I think it's our job as clinicians to find out the best way to treat our patients. If we know that the data are showing cognitive behavioral therapy and mindfulness therapy are better for them, let's provide that to the patient. I urge clinicians to look in their communities and find out where they can get this treatment for their patients. They might find a combination of medication and cognitive behavioral therapy could be an approach that better helps the patient. Let's go with the evidence. That's what evidence-based medicine really is about.

What are the next steps that clinicians in MS should take in helping their patients with fatigue?

We found that when we look at fatigue in the brain, this fatigue network is really based around the striatum. Theories exist now for 20 years on how the striatum is involved with fatigue, and have resulted in good data to show that the striatum is the major region of this fatigue network. But what's interesting is that the striatum is also the major area of the reward system of the brain. We've found in our research that when patients are involved in rewarding activity, fatigue decreases. This decrease is associated with changes in the fatigue network. We have observed this in cognitive interventions, and we have preliminary data on exercise. But the idea here is, if we can use what the patients themselves find rewarding, can that be used to reduce fatigue? Why don't we ask our patients something like, “What is it that you would love to do that you don't do so much anymore because of your MS?”

For instance, a patient reports that they loved to read books and now they can't because they don't remember what has been read and get frustrated. One approach may be to have the patient join a reading group, which not only increases socialization, but helps with issues such as reading comprehension. If this action is rewarding for the patient, the data shows that fatigue should decrease.

I believe we need a new approach to studying fatigue and we should include a major focus measuring primary fatigue. I believe we can do that through more research on understanding the brain network of fatigue. In addition, I think our treatment for fatigue should be what is rewarding to the patient, because the data are showing that this can reduce fatigue, be used to increase socialization, and increase the patient's understanding of their fatigue and its impact on their everyday life. When I speak to physical therapists, they say, “That's how exercise works because the patients find it rewarding.” The key ingredient here is reward because of the overlap in the brain between the reward and fatigue networks.

Transcript edited for clarity. Click here for more coverage of CMSC 2023.

REFERENCES
1. Dobryakova E, Genova HM, DeLuca J, Wylie GR. The dopamine imbalance hypothesis of fatigue in multiple sclerosis and other neurological disorders. Front Neurol. 2015;6:52. Published 2015 Mar 12. doi:10.3389/fneur.2015.00052
2. DeLuca, J. What is Fatigue and Can We Measure It?. Part 1: Understanding Fatigue and its Clinical Management. Presented at: 2023 CMSC Annual Meeting; May 31 to June 3; Aurora, CO.