Robert Zivadinov, MD, PhD, Director, Buffalo Neuroimaging Analysis Center, Director, Center for Biomedical Imaging at the Clinical Translational Science Institute, Professor of Neurology, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, talks about the prevalence of fatigue in patients with multiple sclerosis (MS).

DocWire News: How common is fatigue among patients with MS?

Dr. Zivadinov: Fatigue among patients with MS is very frequent. More than 80% of the patients have fatigue within one year of diagnosis of MS, but the fact is also that fatigue may be really a broader symptom of MS, because there have been studies that found that more than 50% to 60% of the patients have already fatigue as a first sign of their disease even before the first demyelinating events occur. So the real frequency or prevalence of fatigue, it’s clearly unknown. But it’s definitely one of the first incident symptoms of MS and definitely within one year, more than 80% of the patients have some kind of fatigue. And over time the prevalence of these symptoms is also increasing, especially among patients who are moving from relapsing to progressive disease stages.

DocWire News: What causes fatigue in patients with MS?

Dr. Zivadinov: So, that’s really an important question. First of all, I think we need to say that the exact mechanism of MS fatigue is not fully understood. There are a number of theories. And probably, the fatigue can be divided in two related pathophysiologies: one is the primary fatigue, and the secondary fatigue. The primary fatigue is probably the result of the pathophysiology of MS, and I will dedicate a little bit more time on these type of fatigue. But … the secondary fatigue is related to more MS complications, [of which] other symptoms may coexist with fatigue in those patients.

For example, when we talk about secondary fatigue, clearly different pathos may contribute to this, including a lack of sleep, depression, medication-related side effects, or even pain, physical deterioration, and weakness. These are all secondary symptoms that contribute to the fatigue, per se. When it comes to the primary fatigue, that’s really a little bit [of] a different story, because there are probably three or four different areas from where these fatigues comes. First it has been now vastly shown in research studies that damage in the gray and white matter in terms of lesions as well as brain atrophy are the most important contributors to the fatigue.

When I say lesions, I mean about inflammatory processes, because the lesions are forming in a certain part of the brain. In the white matter, they are much more inflammatory than they are in the gray matter. And so the exact mechanism by which these lesions contribute to fatigue is unknown, but probably they create disconnectivity. When you have tracts from one side of the brain to the other side of the brain or the spinal cord connecting different parts, and when the lesion forms in the middle of the track, it creates disconnectivity. This leads to a creation of so-called maladaptive network, because the different halves of the brain are not efficiently functioning and communicating between each other.

This disconnectivity between different parts of the brain is probably one of the biggest drivers of fatigue. One particular region has been really linked to incidence of fatigue, and that is [the] thalamus. [The] thalamus is really a central relay of different functions related to sleep, cognition, motor, sensory, and other functions. And because [the] thalamus is so early involved in MS, that’s probably why also fatigue is seen so early in the disease. There have been really many studies between fatigue and [the] thalamus, particularly on some structures or subnuclei of the thalamus. They may be more important for development of fatigue symptoms than the others.

Also, there have been studies showing that in particular in some regions of the brain, for example inferior temporal gyrus, inferior frontal gyrus, nucleus accumbens—these are also important structures for fatigue. This is a very rich area of research and has been really a lot published. But I would say that it’s really a multifactorial reason why these patients have fatigue, and it’s related to the combination of the development of brain atrophy and location of the lesions in particular parts of the brain with disconnection between different areas. These can be studied in two major ways. One is through doing functional, and the other through doing structural, MRI. Functional MRI studies have shown that really decrease of efficiency in some of these, where the full neural network is really one of the primary drivers of the fatigue in MS.