Fatigue – Prof G's MS Blog Archive

Gratitude

Barts-MS rose-tinted-odometer: ★★★★★

A problem in modern medical practice is the assumption that there is a pill for everything. The one eye-opener for me after my recent trauma has been how easy it is for medics to reach for the prescription pad. When I was first discharged from hospital I was on 14 different medications. About half of the medications were prescribed to manage or prevent the side effects of the primary medications. It is easy to rationalise the use of each of the 14 medications, but were they all necessary? It is quite astounding how we have ‘pharmaceuticalised medicine’.

Initially, when my head was muzzled by morphine and gabapentin, I had an elaborate system in place to make sure I didn’t miss or forget any of my medications. This experience has given me a profound appreciation for how difficult it must be for some of my own patients, particularly those with cognitive impairment, to manage their own polypharmacy. The other question, which is the elephant in the room, is are all these medications really necessary.

A good example in MS is the management of MS-related fatigue. MS neurologists prescribe a large number of different medications for MS fatigue when in reality none, yes zero, of these medications has been shown to make a difference in randomised controlled trials. A recent study from the US shows that amantadine, modafinil and methylphenidate make no difference. In comparison, mindfulness therapy has been shown to work in several MS fatigue trials. So why don’t neurologists prescribe mindfulness to more of their patients? There is also an expanding evidence-base that mindfulness therapy helps depression, anxiety and insomnia.

Maybe 2021 should be the year when the medical profession questions and challenges the ‘pharmaceutical-model of medicine’ and helps lobby the NHS so that all of our patients have access to mindfulness therapy.

If you have a moment can I suggest you watch Gratitude, on the ‘Mindfulness 360 – Center For Mindfulness’ channel on YouTube. Are you surprised that this is better than a tablet?

I would be very interested if you could share your thoughts on this blog post and your own experiences with tablets versus mindfulness therapy for managing your symptoms. There are a lot of cynical HCPs out there who question the benefits of mindfulness, which is just one of the main barriers that prevent the wide adoption of this complementary therapy into routine MS practice.

Nourbakhsh et al. Safety and efficacy of amantadine, modafinil, and methylphenidate for fatigue in multiple sclerosis: a randomised, placebo-controlled, crossover, double-blind trial. Lancet Neurol. 2021 Jan;20(1):38-48.

Background: Methylphenidate, modafinil, and amantadine are commonly prescribed medications for alleviating fatigue in multiple sclerosis; however, the evidence supporting their efficacy is sparse and conflicting. Our goal was to compare the efficacy of these three medications with each other and placebo in patients with multiple sclerosis fatigue.

Methods: In this randomised, placebo-controlled, four-sequence, four-period, crossover, double-blind trial, patients with multiple sclerosis who reported fatigue and had a Modified Fatigue Impact Scale (MFIS) score of more than 33 were recruited at two academic multiple sclerosis centres in the USA. Participants received oral amantadine (up to 100 mg twice daily), modafinil (up to 100 mg twice daily), methylphenidate (up to 10 mg twice daily), or placebo, each given for up to 6 weeks. All patients were intended to receive all four study medications, in turn, in one of four different sequences with 2-week washout periods between medications. A biostatistician prepared a concealed allocation schedule, stratified by site, randomly assigning a sequence of medications in approximately a 1:1:1:1 ratio, in blocks of eight, to a consecutive series of numbers. The statistician and pharmacists had no role in assessing the participants or collecting data, and the participants, caregivers, and assessors were masked to allocation. The primary outcome measure was the MFIS measured while taking the highest tolerated dose at week 5 of each medication period, analysed by use of a linear mixed-effect regression model. This trial is registered with ClinicalTrials.gov, NCT03185065 and is closed.

Findings: Between Oct 4, 2017, and Feb 27, 2019, of 169 patients screened, 141 patients were enrolled and randomly assigned to one of four medication administration sequences: 35 (25%) patients to the amantadine, placebo, modafinil, and methylphenidate sequence; 34 (24%) patients to the placebo, methylphenidate, amantadine, and modafinil sequence; 35 (25%) patients to the modafinil, amantadine, methylphenidate, and placebo sequence; and 37 (26%) patients to the methylphenidate, modafinil, placebo, and amantadine sequence. Data from 136 participants were available for the intention-to-treat analysis of the primary outcome. The estimated mean values of MFIS total scores at baseline and the maximal tolerated dose were as follows: 51·3 (95% CI 49·0-53·6) at baseline, 40·6 (38·2-43·1) with placebo, 41·3 (38·8-43·7) with amantadine, 39·0 (36·6-41·4) with modafinil, and 38·6 (36·2-41·0) with methylphenidate (p=0·20 for the overall medication effect in the linear mixed-effect regression model). As compared with placebo (38 [31%] of 124 patients), higher proportions of participants reported adverse events while taking amantadine (49 [39%] of 127 patients), modafinil (50 [40%] of 125 patients), and methylphenidate (51 [40%] of 129 patients). Three serious adverse events occurred during the study (pulmonary embolism and myocarditis while taking amantadine, and a multiple sclerosis exacerbation requiring hospital admission while taking modafinil).

Interpretation: Amantadine, modafinil, and methylphenidate were not superior to placebo in improving multiple sclerosis fatigue and caused more frequent adverse events. The results of this study do not support an indiscriminate use of amantadine, modafinil, or methylphenidate for the treatment of fatigue in multiple sclerosis.

Ulrichsen et al. Clinical Utility of Mindfulness Training in the Treatment of Fatigue After Stroke, Traumatic Brain Injury and Multiple Sclerosis: A Systematic Literature Review and Meta-analysis. Front Psychol. 2016 Jun 23;7:912. doi: 10.3389/fpsyg.2016.00912. eCollection 2016.

Background: Fatigue is a common symptom following neurological illnesses and injuries, and is rated as one of the most debilitating sequela in conditions such as stroke, traumatic brain injury (TBI), and multiple sclerosis (MS). Yet effective treatments are lacking, suggesting a pressing need for a better understanding of its etiology and mechanisms that may alleviate the symptoms. Recently mindfulness-based interventions have demonstrated promising results for fatigue symptom relief.

Objective: Investigate the efficacy of mindfulness-based interventions for fatigue across neurological conditions and acquired brain injuries.

Materials and methods: Systematic literature searches were conducted in PubMed, Medline, Web of Science, and PsycINFO. We included randomized controlled trials applying mindfulness-based interventions in patients with neurological conditions or acquired brain injuries. Four studies (N = 257) were retained for meta-analysis. The studies included patients diagnosed with MS, TBI, and stroke.

Results: The estimated effect size for the total sample was -0.37 (95% CI: -0.58, -0.17).

Conclusion: The results indicate that mindfulness-based interventions may relieve fatigue in neurological conditions such as stroke, TBI, and MS. However, the effect size is moderate, and further research is needed in order to determine the effect and improve our understanding of how mindfulness-based interventions affect fatigue symptom perception in patients with neurological conditions.

Simpson et al. Effects of Mindfulness-based interventions on physical symptoms in people with multiple sclerosis – a systematic review and meta-analysis. Mult Scler Relat Disord. 2020 Feb;38:101493.

Background: Physical wellbeing is commonly impaired in people with multiple sclerosis (PwMS). This study aims to update our previous systematic review (2014) and conduct a meta-analysis on the efficacy of Mindfulness-based interventions (MBIs) for improving physical symptoms in PwMS.

Methods: In November 2017 we carried out systematic searches for eligible randomised controlled trials (RCTs) in seven major databases, updating our search in July 2018. We used medical subject headings and key words. Two independent reviewers used pre-defined criteria to screen, data extract, quality appraise, and analyse studies. The Cochrane Collaboration risk of bias tool was used to determine study quality. Physical wellbeing was the main outcome of interest. We used the random effects model for meta-analysis, reporting effect sizes as Standardised Mean Difference (SMD). This study is registered with PROSPERO: CRD42018093171.

Results: We identified 10 RCTs as eligible for inclusion in the systematic review (including 678 PwMS), whilst seven RCTs (555 PwMS) had data that could be used in our meta-analyses. In general, comorbidity, disability, ethnicity and socio-economic status were poorly reported. MBIs included manualised and tailored interventions, treatment duration 6-9 weeks, delivered face-to-face and online in groups and also individually. For fatigue, against any comparator SMD was 0.24 (0.08 – 0.41), I2=0%; against active comparators only, SMD was 0.10 (-0.14 – 0.34), I2=0%. For pain SMD was 0.16 (-0.46 – 0.79), I2=77%. Three adverse events occurred across all studies.

Conclusions: MBIs appear to be an effective treatment for fatigue in PwMS. The optimal MBI in this context remains unclear. Further research into MBI optimisation, cost- and comparative-effectiveness is required.

Crowdfunding: Are you a supporter of Prof G’s ‘Bed-to-5km Challenge’ in support of MS research?

CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211

Wiped-out and you?

Do you relate to this list of facts in relation to MS-fatigue?

The most common spontaneously reported symptom for pwMS is fatigue.
PwMS use the words “tired,” “exhausted,” “wiped out,” and having “little or no energy” to describe their fatigue.
More patients rated fatigue as their “most troubling symptom” compared with other MS-related symptoms.
Half of the people living with MS report feeling constantly fatigued and more than 90% reported experiencing fatigue at least daily.
The top three most frequently reported negative impacts of fatigue were social functioning, emotional well-being, and cognitive functioning.
PwMS describe themselves as “homebodies,” as fatigue limited their social interactions with friends and family and impacted the types of activities they could participate in.
PwMS attribute their inability to think clearly or focus for long periods of time to their fatigue.
PwMS report experiencing depression and anxiety because of their fatigue, which would often have further negative effects on their relationships with friends and family.

Although this list comes from a new qualitative study on MS-related fatigue (see below) they are not new insights.

As fatigue is a reasonably well-defined problem in MS we should be asking ourselves why haven’t we cracked it and have effective treatments to manage it?

I think we can crack-it but we have to acknowledge that MS fatigue relates to (1) active inflammation and (2) the consequences of the damage that inflammation causes. If we acknowledge this then we are half-way towards treating and preventing MS-related fatigue, i.e. treating MS early (before too much damage occurs) and effectively (NEDA and beyond).

The following is what we know about MS-related fatigue.

Inflammation in the brain causes fatigue. This is due to inflammatory mediators or cytokines, in particular, interleukin-1 (IL-1) and TNF-alpha, which trigger sickness behaviour. Sickness behaviour is the behavioural response we have to inflammation, which forces us to rest and sleep so that our body can recover. This is what happens to you when you get a viral infection; in fact many of the pwMS I look after describe their fatigue as being similar to the fatigue they experience when they get flu. Sickness behaviour from an evolutionary perspective is well conserved and occurs in most animals. This type of fatigue needs to be managed by switching off ongoing inflammation in the brain. This is why so many pwMS who go onto highly-effective DMTs come back saying ‘I feel so much better, my fatigue and/or brain fog has cleared’. Do you relate to this? This is why recent-onset fatigue that can’t be explained by other factors (see below) may indicate MS disease activity. At present fatigue on its own does not constitute a relapse, but there are some of us who would disagree; particularly if we investigate more deeply we often find subclinical/MRI or biomarker (neurofilament) evidence of relapse in these patients.

Another cause of fatigue is the exercise-related conduction block. This is when pwMS notice their legs getting weaker with exercise. We think this is due to demyelinated, or remyelinated axons, failing to conduct electrical impulses when they become exhausted. Exercise-induced fatigue is probably the same as temperature-related fatigue; a rise in body temperature also causes vulnerable axons to block and stop conducting. To deal with this type of fatigue we need therapies to promote remyelination and to increase conduction. These types of fatigue are treated by rest, cooling and possibly drugs such as fampridine that improve conduction. At the heart of this type of fatigue is localised energy failure.

The other cause of fatigue is neural plasticity. When the brain is damaged by MS other areas are co-opted to help take over, or supplement, the function of the damaged area. In other words, it takes more brainpower to complete the same task that normal people do. This type of fatigue usually manifests as mental fatigue and is why pwMS have difficulty concentrating for prolonged periods of time. At present we have no specific treatment for this type of fatigue except to prevent it by treating MS early and effectively. Some patients find amantadine and modafinil helpful. In short, preventing the loss of brainpower, or damage, in the first place should prevent this type of fatigue.

Fatigue can also be related to so-called co-morbidities, or other diseases, that are related to MS. The big co-morbidities that cause fatigue, which need to be screened for are:

Infection – we all get tired when we have infections; it triggers sickness behaviour
An underactive thyroid gland or hypothyroidism – hypothyroidism is commoner in pwMS
Poor sleep hygiene and/or sleep disorders – if you are not sleeping well you feel tired in the morning
Obesity – when you are overweight it takes more energy to perform physical tasks
Depression and anxiety; fatigue is a common symptom of depression and anxiety and unless this is screened for and treated in persists.
Side effects of drugs; in particular drugs that cause sedation and from DMTs. Anticholinergics and anti-spasticity drugs are sedating and blunt cognition and may worsen MS-related fatigue. Specific side effects, for example, the flu-like side effects from interferon-beta may make fatigue worse.
Excessive alcohol consumption; although classified as drug alcohol causes and exacerbates MS-related fatigue in several ways, most notably by causing poor sleep hygiene and exacerbating depression.
Deconditioning; deconditioning is simply the term we use for being unfit. If you are unfit, performing a demanding physical task makes you tired. Deconditioning is treated with exercise, which paradoxically can reduce fatigue.
Poor nutrition; some pwMS are anorexic and eat very poorly and hence have little energy as a result of this. Although this is quite rare I look after a few pwMS with this problem. Similarly, overnutrition may have the same effect. Some of the hormones your gut produce cause you to feel tired and want to sleep; i.e. the so-called siesta effect. Reducing the size of your meals and changing your eating behaviour may improve post-prandial (after eating fatigue). I have a few patients who avoid eating lunch for this reason. Too much fast-sugar (high-glycaemic index) raises insulin levels that cause post-prandial insomnia or food coma. Going onto a low carbohydrate diet helps this type of fatigue.

It is apparent from this discussion that fatigue in MS is more complex than you realise and needs a systematic approach to be treated and managed correctly. So be careful, or at least wary, when your neurologist simply wants to reach for the prescription pad to get you out of the consultation room as quickly as possible. Like other MS-related problems, an holistic and systematic approach is needed to manage and treat MS-related fatigue correctly.

On a positive note, you should also be able to use the information in this post to help formulate a fatigue self-management plan and prepare yourself to ask the really challenging questions when you next see your MS team.

I would be interested to know if any of you have any stories to relate with us about your attempts to self-manage your fatigue, particularly during lock-down.

Penner et al. Exploring the Impact of Fatigue in Progressive Multiple Sclerosis: A Mixed-Methods Analysis. Mult Scler Relat Disord 2020 May 27;43:102207.

Background: Patient-focused literature on fatigue in progressive forms of multiple sclerosis (MS) is sparse. This study aimed to explore progressive MS patients’ experiences of fatigue.

Methods: Adult patients in the United States with primary progressive MS (n=21) and secondary progressive MS (n=23), recruited from research panels, completed the following PRO measures: Patient Global Impression of Severity (Fatigue) (PGI-F); Fatigue Scale of Motor and Cognitive Functions (FSMC); Modified Fatigue Impact Scale (MFIS); Patient Health Questionnaire, two-item version (PHQ-2); and Patient Determined Disease Steps (PDDS). Patients subsequently participated in a 45-minute semistructured telephone interview and were asked to describe their MS symptoms and to comment on how MS affected their day-to-day lives. More detailed questions followed on the nature of their fatigue, including symptoms, impacts, frequency, and bothersomeness.

Results: Patients’ mean age was 52.5 years, mean time since diagnosis was 14.7 years, and 81.8% were female. 79.5% of patients were unemployed and/or receiving disability benefits. Of all spontaneously reported MS symptoms, fatigue was the most common (n=38, 86.4%), followed by ambulation problems (n=31, 70.5%) and muscle weakness (n=25, 56.8%). Patients used the words “tired,” “exhausted,” “wiped out,” and having “little or no energy” to describe their fatigue. More patients rated fatigue as their “most troubling symptom” (n=17, 38.6%) compared with other MS-related symptoms. Half of patients reported feeling constantly fatigued, and more than 90% reported experiencing fatigue at least daily. The top three most frequently reported negative impacts of fatigue were social functioning, emotional well-being, and cognitive functioning (all >80%). Patients described themselves as “homebodies,” as fatigue limited their social interactions with friends and family and impacted the types of activities they could participate in. Patients attributed their inability to think clearly or focus for long periods of time to their fatigue. Patients also reported experiencing depression and anxiety because of their fatigue, which would often have further negative effects on their relationships with friends and family. On the fatigue PRO measures, mean (standard deviation) scores were 75.2 (14.7) on the FSMC and 55.0 (15.2) on the MFIS. Most participants scored in the “high” fatigue category on the FSMC (84.1%) and above the clinically significant fatigue threshold (86.4%). MFIS and FSMC total scores correlated with PGI-F (polyserial correlations r=0.74 and r=0.62, both p<0.01) and PHQ-2 (r=0.56 and r=0.57, both p<0.01), but not with PDDS (r=0.09 and r=0.02, both p>0.05).

Conclusions: Fatigue is a common, troublesome, and disabling symptom which has a profound impact on patients’ daily lives, as evidenced by qualitative analyses and high scores on established fatigue measures observed in this sample. These findings provide insights into the burden of fatigue and can inform its measurement in both clinical and research settings. Treatments that improve the symptoms of fatigue or prevent exacerbations are needed for patients with progressive MS.

CoI: multiple

Temperature Sensitivity

Are you temperature sensitive?

In my experience the vast majority of pwMS are affected by changes in temperature; typically it is hot or cold temperature that triggers changes in central nerve conduction velocity that brings on old symptoms. One of my patients reports becoming paralysed if sits outdoors in the sunshine for as little as 30 minutes in the middle of summer. Other report worsening of their cognitive fatigue with relatively minor changes in temperature. Women post-ovulation raise their body temperatures by about 0.5C; in some woman this enough to incapacitate them. I call this catamenial temperature-related fatigue and it often responds to non-steroidal anti-inflammatories and maybe the reason why aspirin has been shown to improve MS-related fatigue.

This Korean study below is fascinating. They show that short-term exposure to wide diurnal temperature ranges (DTRs), which have become increasingly common as a result of climate change, is associated with an increased risk of visits to A&E (emergency departments). The was an ~9% change in the odds ratio per 1 °C increase in the diurnal temperature range. If this data is reproduced then it will have a major impact on how we manage patients with MS as global warming ramps up. I suspect the many exacerbations triggered by hot weather may prove to be pseudo-relapses. I suspect this may be the ideal use of serum neurofilament levels; to differentiate relapses from pseudorelapses. Sorting out this old problem may prevent unnecessary MRI scans and more importantly reduce the use of corticosteroids use for possible relapse.

Please be aware that it is not only the ambient temperature that is important, fever can also result in worsening of symptoms. With the COVID-10 pandemic in full swing, I suspect many more pwMS will be monitoring their temperatures as an indicator of infection. I wonder how many of you are doing this? And if yes was it advised by any HCP?

Byun et al. Association between diurnal temperature range and emergency department visits for multiple sclerosis: A time-stratified case-crossover study. Sci Total Environ. 2020 Feb 25;720:137565. doi: 10.1016/j.scitotenv.2020.137565.

Although multiple sclerosis (MS) has been the leading cause of neurologically-induced disability in young adults, risk factors for the relapse and acute aggravation of MS remain unclear. A few studies have suggested a possible role of temperature changes on the relapse and acute aggravation of MS. We investigated the association between short-term exposure to wide diurnal temperature ranges (DTRs) and acute exacerbation of MS requiring an emergency department (ED) visit. A total of 1265 patients visited EDs for acute aggravation of MS as the primary disease in Seoul between 2008 and 2014 from the national emergency database. We conducted a conditional logistic regression analysis of the time-stratified case-crossover design to compare DTRs on the ED visit days for MS and those on control days matched according to the day of the week, month, and year. We examined possible associations with other temperature-related variables (ambient temperature, between-day temperature change, and sunlight hours). Short-term exposure to wide DTRs immediately increased the risk of ED visits for MS. Especially, 2-day average (lag0-1) DTR levels on the day of and one day prior to ED visits exhibited the strongest association (an 8.81% [95% CI: 3.46%-14.44%] change in the odds ratio per 1 °C increase in the DTR). Other temperature-related variables were not associated with MS aggravation. Our results suggest that exposure to wider DTR may increase the risk of acute exacerbation of MS. Given the increasing societal burden of MS and the increasing temperature variability due to climate change, further studies are required.

CoI: multiple

Genius

My #ECTRIMS2019 highlight #3 is the elevation of fatigue to be the first secondary outcome measure in a clinical trial. Was this genius or a marketing coup? I would have loved to be a fly on the wall when the steering committee of the OPTIMUM study made the decision to bump fatigue to the top of the secondary outcomes.

If you have MS you know that the most troubling symptom the majority of MSers complain about is fatigue. Therefore for a DMT to be able to claim it reduces fatigue is a big deal. I suspect MSers will find the promise of fatigue reduction a very compelling reason to choose one DMT over another.

The Oral Ponesimod Versus Teriflunomide In Relapsing MUltiple Sclerosis (OPTIMUM) study was positive. Compared to teriflunomide ponesimod reduced the relative annualised relapse rate (ARR) by 30.5% (P<0.0003) and 3-month CDP (confirmed disability progression) by 17% (not significant).

If you recall this study was one of the studies we asked the Crowd to predict the results of. In fact, they were almost spot-on; they predicted that ponesimod would reduce the ARR and CDP compared to teriflunomide by 33.8% (interquartile range=24.5-44.3%) and 21.2% (interquartile range=10.0-25.0%), respectively. My interpretation is that the Crowd did very well; well done!

Please note that I will be contacting the winners of the #ECTRIMS competition very soon. There will two awards one for the OPTIMUM study and a second award for the ASCLEPIOS I & II studies.

When it comes to the S1P wars ponesimod is setting itself up very nicely to go head-2-head with newer entrants, i.e. siponimod and ozanimod. In my opinion, the safety profile of ponesimod is reasonably good, the lack of need for 1st-dose monitoring will put it alongside ozanimod in the S1P Me-Too wars. The question everyone is now asking ‘Will fatigue be the trump card?’. What do you think?

CoI: multiple

Heat

My thoughts are for our readers with MS who are having to live through and cope with the latest heatwave. The BBC has just reported that this is the hottest late August bank holiday on record; “Temperatures had reached 33.2C (91.8F) at Heathrow by 14:16 BST, the Met Office said, beating the previous record of 28.2C set two years ago. On Sunday, the record for the hottest late August Bank Holiday weekend was broken, with a high of 33.3C”.

How are you tolerating the heat? I suspect many of you with heat sensitivity will be experiencing worsening fatigue, pseudo-relapses (heat-induced intermittent symptoms) and difficulty sleeping. Are you coping? Do you have any advice for your fellow MSers?

Please note that the main consequences of a raised body temperature in demyelinated, or remyelinated, pathways is slowed conduction. The commonest example is exercise-induced fatigue, but this summer’s heatwave will be causing symptoms without the need for exercise. Some of you will find difficulty walking difficult; your legs will begin to drag minutes into walking rather than after 20-30 minutes. Others will notice blurring of vision mid-morning when in the past this would only happen in the late afternoon. The reason for this is that the demyelinated segments in the nerve stop conducting due to conduction block induced by a slight rise in temperature affecting the functioning of the sodium channels. The latter are the molecules in the membranes of nerve cells that transmit the electrical signal down a nerve fibre, which require energy to work. These sodium channels are ion pumps, which are optimised to function at a certain temperature and explains why MSers are heat sensitive.

Most of you will have heard of Uhthoff’s phenomenon. Wilhelm Uhthoff (1853-1927) was a famous German Professor of ophthalmology who described temporary visual loss associated with optic neuritis linked to physical exercise. This was later found to be caused by a rise in body temperature. This phenomenon is now known to affect other neurological systems as well; for example, the motor system when walking, balance and sensory pathways and even the cognitive centres.

Apart from cooling, we do not had a treatment for Uhthoff’s phenomenon. The drug Fampridine has been licensed to improve walking speed in MSers. Interestingly, several MSers have said to me in the past that their heat sensitivity has improved since taking Fampridine.

CoI: Multiple

Exercise, exercise, exercise ….

If you live in London it is impossible not to have gotten caught up in London-Marathon fever over the weekend.

Eliud Kipchoge won the London marathon in the second fastest recorded time (two hours two minutes 38 seconds). Interestingly, Kipchoge wears an electric blue band on his wrist, where four simple words are written: “No human is limited”. He has obviously not met someone with advanced MS who is disabled.

In the study below people with progressive MS used up to 2.81x times more energy on average, for simple mobility tasks, compared to control subjects. The progressive MSers in this study accumulated an oxygen deficit and experienced fatigue and exertion when repeating simple motor tasks such as rolling over in bed, moving from a lying to a sitting or a sitting to standing position, walking and climbing steps. Reasons for why MSers use more energy is complex but part of it is due to deconditioning, i.e. simply being unfit.

We don’t know how the brain perceives fatigue but a higher oxygen cost during physical activity is measured by the body and results in a greater perception of fatigue. The reason why Eliud Kipchoge can run mile after mile at a pace no man or woman has done before is that he is conditioned to do so and has trained his brain to not feel fatigue.

“The mind is what drives a human being, If you have that belief – pure belief in your heart – that you want to be successful then you can talk to your mind and your mind will control you to be successful. My mind is always free. My mind is flexible. That is why I wear this band on my wrist. I want to show the world that you can go beyond your thoughts, you can break more than you think you can break.” Eliud Kipchoge.

Lessons from elite marathon runners and the findings from this study suggest that rehabilitation interventions that increase endurance during physical tasks will help reduce fatigue in people with progressive MS. The question now is to get NHS resources allocated to setting-up a National exercise and training programme for MS-related fatigue and to get MSers to buy into the benefits of regular exercise no matter how disabled they are. I know this is easier said than done, but that is no excuse not to get it done; it needs to be done.

Please note, it is also not only about exercise, but how you live your life.

Kipchoge’s believes that “living simply sets you free”. For nearly 300 days a year, he lives and trains at a simple training centre in Kaptagat, a tiny village in the Kenyan highlands. He is known as the “boss man” by his training partners but that doesn’t stop him cleaning the toilets or doing his share of the daily chores. If you are interested in being inspired please watch ‘Breaking2’ a Nike sponsored project to see if the 2-hour barrier for the marathon could be broken. It is not that Kipchoge came so close to breaking the two-hour barrier, missing it by a mere 25 seconds, but his philosophy on how to live that is so inspiring. I am in awe!

Devasahayam et al. Oxygen cost during mobility tasks and its relationship to fatigue in progressive Multiple Sclerosis. Arch Phys Med Rehabil. 2019 Apr 23. pii: S0003-9993(19)30257-6.

OBJECTIVE: To compare the oxygen costs of mobility tasks between individuals with progressive MS using walking aids and matched controls and to determine whether oxygen cost predicted fatigue.

DESIGN: Cross-sectional descriptive.

SETTING: A rehabilitation research laboratory.

PARTICIPANTS: 14 adults with progressive MS (54.07+8.46 years of mean age) using walking aids and 8 age/sex-matched controls without MS.

INTERVENTIONS: Participants performed five mobility tasks (rolling in bed, lying to sitting, sitting to standing, walking and climbing steps) wearing a portable metabolic cart.

OUTCOME MEASURE(S): Oxygen consumption (V̇O2) during mobility tasks, maximal V̇O2 during graded maximal exercise test, perceived exertion and task-induced fatigue measured on a visual analogue scale before and after mobility tasks.

RESULTS: People with progressive MS had significantly higher oxygen cost in all tasks compared to controls (p<0.05): climbing steps (3.60 times more in MS), rolling in bed (3.53), walking (3.10), lying to sitting (2.50), and sitting to standing (1.82). There was a strong, positive correlation between task-induced fatigue and oxygen cost of walking, (rs(13)=0.626, p=0.022).

CONCLUSIONS: People with progressive MS used 2.81 times more energy on average for mobility tasks compared to controls. People with progressive MS experienced accumulation of oxygen cost, fatigue and exertion when repeating tasks and higher oxygen cost during walking was related to greater perception of fatigue. Our findings suggest that rehabilitation interventions that increase endurance during functional tasks could help reduce fatigue in people with progressive MS who use walking aids.

Food coma: does it affect you?

This post explains why eating may exacerbate MS-related fatigue and what you can do to counteract it.

Do you suffer from food coma or excessive sleepiness and fatigue after eating a meal?

For ‘normal people’, we call this phenomenon postprandial somnolence or the siesta syndrome. Others refer to it as the ‘food coma’. It is my anecdotal experience that people with MS, in particular, people with more advanced MS, are particularly sensitive to postprandial sleepiness and fatigue. Why?

Postprandial somnolence (PPS) is a normal state of drowsiness or lassitude following a meal. PPS is a real phenomenon and has two components: (1) a state of perceived low energy related to activation of the parasympathetic nervous system in response to expansion of the stomach and duodenum from a meal. In general, the parasympathetic system slows everything down. (2) A specific state of sleepiness, which is triggered by the hormone cholecystokinin (CCK) that is released in response to eating and changes in the firing and activation of specific brain regions. The reflexes responsible for PPS are referred to as neurohormonal modulation of sleep through the coupling of digestion and the brain. The signals from the gut to the brain travel via the vagus nerve.

My index patient is so affected by PPS that she now only eats one meal a day; her evening meal. She does this quite late so that she can crash and sleep about an hour after eating. She is a professional and needs to be functional during the day and finds if she eats anything substantial in the day she simply can’t work because of her overwhelming desire to sleep. We have tried caffeine, modafinil and amantadine to counteract PPS, but they only had a small effect in counteracting her PPS and allowing her to work productivel. Other patients reporting this have noticed some benefit from stimulants. Interestingly, my index patient, like a few others, finds carbohydrate-rich foods particularly potent at inducing ‘food coma’

Physiologists think that not all foodstuffs are made equal when it comes to causing PPS and it appears that glucose, or sugar, induced insulin is one of the drivers of this behavioural response. I suspect this why people who fast or eat very low carbohydrate or ketogenic diets describe heightened alertness and an ability to concentrate for much longer periods of time.

The reason for doing this post is to find out how common PPS is in the MS population and to give you some simple advice to counteract it. If you suffer from PPS can I suggest you review your diet and see if you identify ways to modify your eating habits and/or diets to coounteract PPS?

You could adopt the above extreme solution and only eat one meal per day. Clearly, this not for everyone and is very difficult to implement. I say this, but many of my Muslim patients report feeling so much better during Ramadan when they essentially practice this type of eating pattern.
You could reduce your meal size and cut out any carbohydrates from your daytime meals. You may find this difficult because it takes time for your metabolism to become optimised for ketosis. If any of you are interested in the science of ketosis I have written a Medium post on ketogenic and low-carbohydrate diets.
Some of my patients find micro-meals helpful, i.e. instead of large meals you eat multiple small snacks during the day.
The judicious use of stimulants. I tend to recommend caffeine, followed by modafinil and them amantadine. Please note you should probably not take stimulants later than about 3-4 pm as they have a long half-life and can cause insomnia.
Some of my patients have also reported that exercise has helped them deal with PPS. I am not sure how exercise works except by possibly lowering glucose and insulin levels and improving insulin sensitivity. The latter will reduce hyperinsulinaemia that will not only cause PPS, but is an impotant driver and component of the metabolic syndrome.

Please note that PPS will be worse if you suffer from a sleep disorder and suffer from daytime sleepiness. Most pwMS have a sleep disorder so there is little point in focusing on PPS and ignoring the elephant in the room.

If you have a few minutes to spare can you please complete this survey and let us know if you come across any other effective treatments to manage your PPS.