Clinic Speak: fatigue trial

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MS-related fatigue is more complex than you realise. Is your fatigue being managed correctly? #ClinicSpeak #MSBlog #MSResearch

“This small study shows that in RRMSers fatigue is more likely to respond to amantadine than modafanil and acetyl-l-carnitine. This study will need to be replicated, but the results are not surprising to me.”


“Fatigue is one of the most disabling symptoms MSers suffer from and in over 50% of MSers it is the one symptom they would like to get rid of most. MS-related fatigue is complex and has several underlying mechanisms. Firstly, inflammation in the brain causes fatigue. This is due to inflammatory mediators (IL-1 and TNF-alpha) triggering sickness behaviour. The latter is a behavioral response we have to inflammation, which forces us to rest and sleep, so that the body can recover. This is what happens to you when you get a viral infection; in fact many of the MSers 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 MSers who go onto highly-effective DMTs comeback saying ‘I feel so much better, my fatigue and/or brain fog has cleared’.”


“Another cause of fatigue is exercise related conduction block. This is when MSers 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. These types of fatigue are treated by rest, cooling and possibly drugs such as fampridine that improve conduction.”


“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 brain power to complete the same task that normal people do. This type of fatigue usually manifests as mental fatigue and is why MSers have difficulty concentrating for prolonged periods of time. At present we have no specific treatment for 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 that need to be looked for include:
  1. Infection; we all get tired when we  have infections; it triggers sickness behaviour
  2. An underactive thyroid gland or hypothyroidism; this is commoner in MSers
  3. Poor sleep hygiene and/or sleep disorders; if you are not sleeping well you feel tired in the morning
  4. Obesity; being overweight takes more energy to perform physical tasks
  5. Depression and anxiety; fatigue is a common symptom of depression
  6. Side effects of drugs; in particular drugs that cause sedation and from DMTs (e.g. as part of the flu-like side effects from interferon-beta)
  7. 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 reduces fatigue 
  8. Poor nutrition; some MSers 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 MSers with this problem. 

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 of the consultation room. Like other MS-related problems a holistic approach is needed to manage and treat MS-related fatigue correctly.”


“If you have time it would be helpful if you could complete the survey below. The survey will allow us to take this discussion forward over the next few weeks. Engaging with this issue should help you self-manage your fatigue.”




Ledinek et al. Evaluating the effects of amantadin, modafinil and acetyl-l-carnitine on fatigue in multiple sclerosis- result of a pilot randomized, blind study. Clin Neurol Neurosurg. 2013;115 Suppl 1:S86-9


OBJECTIVE: Fatigue affects more than 60% of  MSers and is one of the most troublesome symptoms of the disease. Current treatment options for MS fatigue include amantadine, modafinil and acetyl-l-carnitine (ALCAR). The aim of our study was to compare efficacy of amantadine, modafinil and ALCAR with placebo in MSers.



METHODS: MSers with a disability level ≤5.5 on the Kurtzke Expanded Disability Status Scale (EDSS) and fatigue were included in the study. MSers were assigned to a one month treatment with either amantadine 200mg, ALCAR 2g, modafinil 200mg or placebo. Efficacy of the treatment was evaluated by using the modified fatigue impact scale (MFIS).


RESULTS: Sixty MSers were included in the study (39 females). The mean age of MSers was 38±6.7 years and the mean disease duration was 6.6±1.2 years. Contrast analysis showed significantly lower mean MFIS score after one month in MSers on amantadine compared to placebo (mean difference=17.3, p=0.001). There was also a trend of a lower MFIS score in ALCAR group in comparison to placebo (mean difference=12.4, p=0.05, with Keppel-corrected alpha of 0.046). The quality of life measured as SF 36 – PCS and SF 36 – MCS proved to be significantly influenced by treatment.


CONCLUSION: One month treatment with amantadine improved fatigue in MSers with relapsing-remitting MS as evaluated by MFIS. No or only a trend of improvement was seen in patients treated with modafinil or ALCAR, respectively.
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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.

11 comments

  • Prof G,

    I know that a lot of people on Tysabri feel that it improves their fatigue – is this improvement described with any other DMT?

    Does this suggest that fatigue is due to some sort of ongoing slow burn inflammation not immediately detectable clinically or on imaging? (as in a slow burn that causes atrophy only detectable over months or years)

    Is the increased IL-1/TNF-alpha measureable clinically or does it just happen in the CNS?

    Many thanks as always

  • An excellent post; very helpful. Thanks for taking the time to write these kinds of posts. I would appreciate more of them.

  • Do you consider adderall a fatigue treatment? It helps mine as I feel fatigue far more readily on days when I don't take it.

  • Agree with above – excellent post. While I don't suffer from fatigue or depression, I get "tired" of knowing I'm ill for the rest of my life and will get worse and worse in the future.

    I like your tube map, but would also graphic showing likely timescales for new treatments arriving, possible breakthroughs. MSers need hope and I'd hate to think that if I called it a day in 5 years time, that there was a treatment which really boosted some repair 3 years later.

  • Are there anti inflammatory treatments available or in the pipeline for progressive MSers, that would possibly address this and improve the situation?

  • is it me or is every aspect of MS grim? The fatigue issues outlined above are a disease in themselves, but we are then dumped with a box full of other symptoms which in themselves all look like serious diseases e.g. depression, bladder problems, paralysis etc etc. We deal with multiple diseases which can never be irradicated and get worse and worse. But at the core of these mulitple diseases is a process which is destroying the brain / spinal cord and the cause of all these dreadful diseases. Yet the research world focuses on individual symptoms or a mouse model of the diesease and steers away from addressing the core disease process! If the process could be stopped and the damage repaired I'd be me again. But I'm coming to a conclusion that in my lifetime this won't be a reality. The blog gave me hope when I started following it c.3 years ago, but now I feel it is jsut telling me what I know – the symptoms are really bad and treatments ineffective, a cure is unlikely in the near future i.e. a treatment to shut down the disease, and repair is science fiction i.e. come back in 2114. When the neuros and researchers go to bed to bed at night they should thank their gods that they don't have this vile disease.

  • A while back Prokarin (histamine +caffeine) was touted as a treatment for MS. Although it did not alter disease progression it seems logical that caffeine would have a beneficial effect on fatigue. Millions consume caffeinated beverages every day for this exact purpose. Do any MSers find moderate caffeine intake beneficial for managing fatigue?

  • Twelve years ago I suffered dreadful fatigue following a virus. I was given Amantadine that made no difference. Eventually, I was diagnosed with Kidney cancer, had surgery and my fatigue returned to it was previously. I could recover after sleeping. Two years later I felt the same overwhelming fatigue, I was checked for cancer and was told I was okay. My Neurologist ignored this and sent me for a scan and I had Breast cancer. The difference is that following sleep and waking up exhausted is not necessarily MS. When I swim I can hardly walk when I leave the pool, but recover after rest. My GP knows I can tell if something is wrong and I am not handed drugs without blood tests etc.

  • Most annoying for me is the activity induced fatigue. Cleaning my home will shut my body down after 15 min. I can walk with a cane 2-4 blocks then that's it I am unable to stand and must rest. I have significant spasticity and at night when I initiate movement – changing positions, my body will contract, I will awaken and this can last for hours. I take vyvanse on days I am needing to be in the world. It helps me but I must take it early in the morn. I used to be a second degree black belt woman. My innate fortitude is of some help. Love to u all. I now must get up finish dressing( shower wore me out) and carry on ��

  • I used to be a very active person – gardening, painting, renovating, furniture restoration etc etc. But now – my fatigue just about rules my life – or more accurately – has just about deleted so many activities from my life – can’t work full time any more (even at a desk job), can’t do gardening, can’t do housework, can’t “do” shopping. When combined with legs that don’t want to work properly, fatigue has me caught up in a vicious cycle where I have so little energy that I can’t do the basic exercises the physio has given me, which would build strength, and thus hopefully help with fatigue. Trying to do even a few minutes of exercise leaves me exhausted. Walking 150 metres leaves me needing to rest, and standing up for any length of time beyond 10 minutes is not achievable. There are many things I don’t even start now because I know I won’t be able to finish them.

    I use all of the fatigue management strategies and “tricks”, but if there ain’t enough petrol in the tank………

    However, I have learnt one trick that might give some of you a laugh – if you have a vacuum cleaner where the steel pipe is one of those extending ones that “collapses” for storage – you can actually do the vacuuming while kneeling down! I need to wear cushioned kneepads to do this, but it saves on the leg power needed to get the job done – and certainly gives any visitors a good laugh.

By Prof G

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