Should we call it catamenial or menstruation-related fatigue?

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Somebody was ‘surprised that only one person’ added menstruation as a cause of fatigue on our fatigue survey. I am surprised too. Why?




The study below is in line with some of my own anecdotal observations in pwMS and has implications for all pwMS. In short higher body temperature is associated with worse fatigue.

Why would pwMS have a higher body temperature? They have MS lesions in the area of the brain that controls body temperature; this area is called the hypothalamus. This is unlikely as this problem would be greater on pwMS who have more advanced MS who tend to have a higher lesion load and are therefore more likely to have lesions in the hypothalamus. In this study pwMS with SPMS did not have a raised body temperature. In fact, hypothermia or low body temperature occurs in pwMS from lesions in the brain’s temperature control centre. I have only ever seen this rarely and all my patients had very advanced MS (bed-bound). 


I suspect the most likely explanation for the raised body temperature in pwMS is ongoing active inflammation in the brain. Inflammatory MS lesions produce chemical signals called cytokines that may explain the raised body temperature. Again, interleukin-1 (IL-1) and TNF-alpha are the main cytokine culprits when it comes to raising your body temperature. These cytokines bind to nerve cells in the hypothalamus and stimulate sickness behaviour, which includes fatigue, hypersomnolence (tiredness), a rise in body temperature and a change in your metabolism to conserve energy. If this is the case then pwMS could use their body temperature as a way to monitor if their MS is active or not? A corollary to this would be if that if you went on to a highly-effective DMT that shut down inflammation in the brain it should lower your body temperature. I have previously proposed that this would be an interesting study to do. Is there anyone up for doing this study?

Several of my clinical anecdotes are congruent with the results of the study below are: 

(1) I have several patients who take antipyretics (medication to lower your temperature) as a means of treating their fatigue. Some use paracetamol or acetaminophen and others ibuprofen; they swear by it. 

(2) Women with MS often complain of worse fatigue during menstruation; a period in their menstrual cycle associated with slightly higher body temperature. 

(3) Flu-like symptoms associated with interferon-beta therapy, which cause mild pyrexia, exacerbate fatigue. 

(4) Warm environments, exercise and infections all of which raise body temperature exacerbate fatigue.

(5) Despite the poor evidence-base, a large number of pwMS swear that cooling improves their fatigue. One of my patients has had a walk-in butchers fridge installed in her home. The fridge is large enough to take her wheelchair. She spends 4 to 5 half-hour sessions in the fridge every day; she claims this is the only way she can cope with her fatigue.

There are some small trials supporting these observations; i.e. that aspirin, a widely used anti-pyretic helps MS-related fatigue. Could the latter be due to the effect of aspirin on core body temperature?

A raised body temperature would cause fatigue, via a similar mechanism to Uhthoff’s phenomenon. In a small survey, we did on this blog back in 2014 approximately a third of respondents noticed an improvement in their fatigue levels with antipyretics. This is something you may want to explore with your neurologist.



Study 1

Sumowski & Leavitt Body temperature is elevated and linked to fatigue in relapsing-remitting multiple sclerosis, even without heat exposure. Arch Phys Med Rehabil. 2014 Feb. pii: S0003-9993(14)00126-9.

OBJECTIVE: To investigate whether resting body temperature is elevated and linked to fatigue in RRMSer.

DESIGN: Cross-sectional study investigating (a) differences in resting body temperature across RRMS, SPMS, and healthy groups, and (b) the relationship between body temperature and fatigue in RRMSers.

SETTING: Climate-controlled laboratory (∼22°C) within a non-profit medical rehabilitation research center.

PARTICIPANTS: Fifty RRMSers, 40 matched healthy controls, and 22 SPMSers.

INTERVENTION: None.

MAIN OUTCOME MEASURE(S): Body temperature was measured with an aural infrared thermometer (normal body temperature for this thermometer is 36.75°C), and differences were compared across RRMS, SPMS, and healthy persons. RRMSers completed measures of general fatigue (Fatigue Severity Scale; FSS), as well as physical and cognitive fatigue (Modified Fatigue Impact Scale; MFIS).

RESULTS: There was a large effect of group (p<.001, ηp2=.132) whereby body temperature was higher in RRMSers (37.04°C±0.27) relative to healthy controls (36.83 ± 0.33; p = .009) and SPMSers (36.75°C±0.39; p=.001). Warmer body temperature in RRMSer was associated with worse general fatigue (FSS; rp=.315, p=.028) and physical fatigue (pMFIS; rp=.318, p=.026), but not cognitive fatigue (cMIFS; rp=-.017, p=.909).

CONCLUSIONS: These are the first-ever demonstrations that body temperature is elevated endogenously in RRMSers and linked to worse fatigue. We discuss these findings in the context of failed treatments for fatigue in RRMS, including several failed randomized controlled trials (RCTs) of stimulants (modafinil). In contrast, our findings may help explain how RCTs of cooling garments and antipyretics (aspirin) have effectively reduced MS fatigue, and encourage further research on cooling/antipyretic treatments of fatigue in RRMS.


Study 2

Leavitt et al. Aspirin is an effective pretreatment for exercise in multiple sclerosis: A double-blind randomized controlled pilot trial. Mult Scler. 2018 Oct;24(11):1511-1513.

Exercise benefits multiple sclerosis (MS) patients, but exercise-induced overheating is a deterrent for many. We conducted a double-blind crossover-design placebo-controlled pilot of aspirin to increase time-to-exhaustion (TTE) and reduce exercise-induced body temperature increase. A total of 12 patients participated. At enrollment, 8 of 12 reported heat sensitivity during exercise. After 650 mg of aspirin or placebo, participants performed lower body cycle ergometer exercise test. TTE increased after aspirin compared to placebo: t(11) = 2.405, p = 0.035 (Cohen’s d = 1.45). Body temperature increase after exercise with acetylsalicylic acid (ASA) was reduced by 56% in heat-sensitive patients, although limited power precluded statistical significance. Aspirin may represent an effective pretreatment for exercise in MS.


Study 3

Shaygannejad et al. Comparison of the effect of aspirin and amantadine for the treatment of fatigue in multiple sclerosis: a randomized, blinded, crossover study. Neurol Res. 2012 Nov;34(9):854-8.


OBJECTIVES: The purpose of this study was to compare the relative efficacy of acetylsalicylic acid (ASA) and amantadine for the treatment of fatigue in multiple sclerosis (MS).

METHODS: A 10-week, randomized double-blind crossover clinical trial conducted from October 2009 to September 2010. Fifty-two patients with MS presenting fatigue at 21 to 53 years of age were randomly allocated to the two treatment groups. The first group received amantadine (100 mg twice daily) for a total of 4 weeks. The second group received ASA (500 mg once daily) for four weeks. After a 2-week washout period, they crossed over to the alternative treatment for 4 weeks. Patients were rated at baseline and the end of each phase with the Fatigue Severity Scale (FSS).

RESULTS: ASA appeared to be equivalent in efficacy and safety to amantadine. A significant decrease in FSS occurred in both groups. Of the 26 patients treated with amantadine, the mean (SD) of FSS decreased from 4·8 (1·4) to 4·0 (1·4) (P<0·001). In the 26 patients treated with ASA, the mean (SD) of FSS decreased from 4·6 (1·4) to 3·5 (1·5) (P<0·001).

DISCUSSION: This study demonstrates that both ASA and amantadine significantly reduce MS-related fatigue. Both ASA and amantadine have previously been shown to reduce fatigue, and we postulate that treatment with ASA and amantadine may have similar benefits.

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

6 comments

  • Prof G it is good to have you back and engaged with the blog. The blog has not been the same without these sorts of posts. Thank you.

  • My fatigue definitely gets worse in the second half of my menstrual cycle. I find 15mg of meloxicam very helpful. If I don't take the dispersable tablet I feel like I am walking in treacle.

    • Not surprising. Meloxicam is a NSAID and will reduce body temperature It is also generic and therefore quite cheap I don't use it and typically prescribe Ibuprofen, naproxen or indomethacin.

  • Thank you for the post Prof G.
    I've noticed that when I take plant yohimbe(stimulant,alpha adrenergic antagonist,SERT and DAT inhibitor) I have energy despite walking and sunbathing in the hot summer day. Yohimbe is a bit harsh plant and I don't use it often,but it was obvious to me that even if my body temperature is high,there are no signs of fatigue if my catecholamines levels are up.
    So Unthoff's phenomenon is relative,it shows only if sympathetic outflow is low. (at least for me)

    Regards
    Marko

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