Fatigue in MS Linked to Elevated Body Temperature
This cross-sectional study has revealed that elevated body temperature is associated with fatigue in relapsing-remitting multiple sclerosis, even in the absence of heat exposure
Elevated body temperature is associated with fatigue in patients with relapsing-remitting multiple sclerosis (RRMS), even without exposure to external sources of heat, according to a cross-sectional study published online February 19 in the Archives of Physical Medicine and Rehabilitation (Sumowski and Leavitt, 2014).
James F. Sumowski, Ph.D., from Neuropsychology and Neuroscience, Kessler Foundation, West Orange, New Jersey, and the Department of Physical Medicine and Rehabilitation, Rutgers, New Jersey Medical School, Newark, and Victoria M. Leavitt, Ph.D., from the Manhattan Memory Center, New York City, note that exposure to external sources of heat has long been known to increase fatigue in patients with MS. However, no one has investigated whether body temperature is increased endogenously (i.e., without exposure to heat) and whether such increases might be linked to fatigue in RRMS.
These investigators studied 112 subjects: 50 patients with RRMS, 22 patients with secondary-progressive MS (SPMS), and 40 healthy control patients.
Pairwise comparisons showed significantly higher body temperatures among patients with RRMS (mean ± standard deviation, 37.04°C ± 0.27°C) relative to healthy control patients (36.83°C ± 0.33°C; P = 0.009) and patients with SPMS (36.75°C ± 0.39°C; P = 0.001). There was no statistically significant difference in temperatures between healthy control participants and patients with SPMS, the authors note.
Patients with RRMS were mostly women who had neither experienced an exacerbation during the previous 6 weeks nor were taking corticosteroids or antipyretics. Patients in the SPMS group met the same inclusion criteria.
Participants in the RRMS and control groups were in their mid-40s, with mean disease duration of 12.8 ± 8.0 years. The mean age of the participants in the SPMS group was 53.8 ± 7.4 years; disease duration was 17.6 ± 7.4 years.
The investigators recorded participants' core body temperatures, and in the patients with RRMS, they used both the Fatigue Severity Scale (FSS) and the Modified Fatigue Impact Scale (MFIS) to assess fatigue.
Patients with RRMS reported higher levels of general fatigue on the FSS as well as elevated levels of physical fatigue and cognitive fatigue on the MFIS. Warmer body temperatures among patients with RRMS were associated with higher self-reported general fatigue on the FSS and physical fatigue on the MFIS, but not cognitive fatigue on the MFIS.
The researchers said this is the first time it has been demonstrated that body temperature is elevated in patients with RRMS relative to healthy control patients and to patients with SPMS. It is also the first time elevated body temperatures have been positively linked to increased fatigue in patients with RRMS, they said.
They added that their findings might help explain why cooling garments and antipyretics tend to reduce fatigue in patients with MS.
Key open questions
- In patients with RRMS, could inflammation alone be sufficient to elevate body temperature, or are other factors likely to contribute?
- Might variations in age, menstrual cycles, and food and/or alcohol intake have been responsible for at least some of the increases in body temperature observed in this study?
- Given that in the RRMS group a link was observed between increased temperature and general and physical fatigue, why was no correlation seen with cognitive function?
Funding for this project was provided in part by the National Institutes of Health and the Kessler Foundation Research Center. Neither of the authors has reported conflicts of interest.
This article makes 2 fascinating conclusions. First, that patients with relapsing-remitting multiple sclerosis (RRMS) have elevated resting body temperature compared with healthy control patients and with patients with secondary-progressive multiple sclerosis (SPMS). And second, that elevated body temperature in RRMS is associated with increased general and physical fatigue.
The occurrence of increased symptoms in patients with MS related to elevated body temperature is known as Uhthoff's phenomenon, after the German ophthalmologist who observed a link between body exercise and worsening vision more than 100 years ago (Fraser et al.). However, it has not been previously demonstrated that patients with MS have elevated resting body temperature or that elevated resting body temperature correlates with fatigue.
These findings are potentially very important from both clinical and pathophysiological perspectives. We know that fatigue is a common debilitating symptom in people with MS. Its etiology is unknown, and treatment is difficult. If patients with RRMS really have elevated resting body temperature, lowering body temperature may be an effective form of symptomatic treatment. The authors report that cooling garments and antipyretics have successfully reduced MS fatigue in other studies. In addition, if elevated resting body temperature correlates with fatigue, it might prove useful in the diagnosis of RRMS as well as serve as a biomarker regarding the effectiveness of disease-modifying therapy.
In this study, patients with SPMS, who have less cerebral inflammation than patients with RRMS, did not have different temperatures than controls, supporting the authors' contention that ongoing cerebral inflammation may be responsible for the elevated body temperature of patients with RRMS. It is also conceivable that active MS lesions in RRMS may interfere directly with the centers for cerebral temperature regulation, but this seems less likely.
Although this is an important study, it has a number of important limitations that undermine the strength of its conclusions.
The results of this study are provocative and potentially important but cannot be taken on face value, given the article's significant methodological limitations. The study needs to be replicated with larger sample sizes matched for age and sex. Food and alcohol intake also need to be standardized.
The conclusions would be much more convincing if there were multiple temperature measurements at specific times throughout the day and on different days for each subject. Menstrual cycles also need to be recorded and plotted against temperature.
In addition, the clinical status of the patients with RRMS needs to be defined regarding the length of time since diagnosis, extent of disability, and current disease activity. Disease activity should be assessed by neurologic examination and magnetic resonance imaging. The presence of gadolinium-enhancing lesions, for example, would suggest active central nervous system inflammation, which, using the authors' hypothesis, should lead to elevated resting body temperature.
Another group that would be worth testing would be patients with clinically isolated syndrome. It would be interesting to observe whether body temperature is elevated at this early stage of disease or whether this phenomenon only occurs when patients evolve to RRMS.
One also wonders whether body temperature is elevated in other conditions in which fatigue is prominent, such as chronic pain, depression, and fibromyalgia. Participants in these diverse groups could be compared with healthy controls to further explore the intriguing hypothesis that there is a relationship between resting body temperature and fatigue.
PMID: 24561056 Sumowski JF, Leavitt VM. Body temperature is elevated and linked to fatigue in relapsing-remitting multiple sclerosis, even without heat exposure. Arch Phys Med Rehabil. 2014. [Epub ahead of print]
PMID: 22146611 Fraser CL, Davagnanam I, Radon M, Plant GT. The time course and phenotype of Uhthoff phenomenon following optic neuritis. Mult Scler. 2012;18(7):1042-1044.