Why am I so fatigued?

Fatigue is one of the most disabling and poorly managed MS symptoms. In this Newsletter I try and explain why people with MS get fatigued and how to investigate and manage it.

Aug 09, 2021

Summary

Fatigue in MS is common and most people with MS (pwMS) who complain of fatigue rarely get it investigated or managed properly. This Newsletter highlights how complex MS-related fatigue is and how it needs to be investigated and managed holistically.

Case Study

“A 28-year old woman with early relapsing-remitting MS, on glatiramer acetate, and little overt neurological impairment suffers from severe fatigue, which is worse during the latter half of her menstrual cycle. She has recently split up with her long-term partner, because of the impact her symptoms have had on her relationship. She has also had to stop working as a bank clerk because of her fatigue.”

Does this sound familiar to you? How should I approach diagnosing the cause(s) of her fatigue and manage it?

Fatigue is one of the most disabling symptoms pwMS suffer from. In over 50% of pwMS fatigue is the one symptom they would like to get rid of most. MS-related fatigue has several underlying mechanisms.

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; I would disagree particularly if I find subclinical/MRI or biomarker (neurofilament) evidence of a relapse.

This is why this patient needs to be examined and will need an MRI and a lumbar puncture to measure her spinal fluid neurofilament levels. If she has EIDA (evident inflammatory disease activity) she will need her DMT switched.

Exercise-related conduction block

This is when pwMS notice their legs getting weaker or another neurological symptom getting worse 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.

Temperature-related conduction block

Many pwMS are temperature sensitive. Typically high temperatures make fatigue worse, but some patients notice it with low temperatures as well. Many people with MS manipulate their behaviour to avoid hot or cold environments. Some pwMS find using cooling suits helpful. However, these are costly and are not covered by the NHS. Cold or ice baths, swimming and air conditioning are things that can help with temperature-related fatigue. One of my patients has had a walking Butchers fridge installed in her house and she literally spends 30 mins four to five times a day in the fridge to manage her fatigue. She is a wheelchair user and she sits in her wheelchair in the fridge.

Catamenial and menopausal fatigue

This is a form of temperature-related fatigue that occurs in women during the second half of their menstrual cycle when their body temperature increases. I have written a separate newsletter on this (That time of the Month). Catamenial fatigue, however, does respond to nonsteroidal antiinflammatories (NSAIDs) such as ibuprofen and naproxen, and paracetamol.

Fatigue is a common symptom of menopause. This is another reason why women with MS who are menopausal and have fatigue find HRT (hormone replacement therapy) helpful. The cause of fatigue is not necessarily temperature-related although some women describe it getting much worse when they experience hot fushes. Hot flushes are not only due to a rise in body temperature but also vascular flushing of the face.

Whether or not men go through menopause is a moot point. Most endocrinologists I have spoken to don’t recognise male menopause. Despite this, testosterone levels do drop with age and I have had some male patients who have found HRT (testosterone replacement therapy) has helped their MS-related fatigue. The problem in the NHS is that indications for testosterone replacement therapy (TRT) are very well-defined and quite narrow; hence most pwMS who want a trial of TRT have to get this prescribed privately.

Please note this patient suffers from catamenial fatigue and would do well on naproxen, which is longer acting than ibuprofen and paracetamol. The naproxen only needs to be taken during the second half of her cycle.

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 and multitasking. At present we have no specific treatment for this type of fatigue, but some patients find amantadine and modafinil helpful. There is also some emerging evidence that fampridine may also help with cognitive fatigue. In short, preventing the loss of brainpower, or damage, in the first place should prevent this type of fatigue.

Yes, the patient above complains of this type of fatigue and despite not having much physical disability she has a high brain MS lesion load and obvious brain volume loss. One option would be for her to have a formal neuropsychological assessment to establish if she has a cognitive impairment; knowing this will allow us to refer her to a cognitive rehabilitation programme, which can target specific areas to help her cope with her cognitive deficits.

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Co-morbidities and or other diseases

Co-morbidities and other diseases that may be related to MS can cause fatigue and should be screened for. This includes infection; we all get tired when we have infections. Infections trigger sickness behaviour. In people with more advanced MS, this is usually the urinary tract, but other sites include the sinuses, teeth, lungs and bowel.

Fatigue is common with thyroid disease. Both an underactive thyroid gland or hypothyroidism and an overactive gland with thyrotoxicosis cause fatigue. Diabetes, other endocrine problems, anaemia and cardiac, renal, liver and lung diseases cause fatigue.

This is why this patient needs a full medical assessment to exclude comorbidities.

Poor sleep hygiene and/or sleep disorders

If you are not sleeping well you feel tired in the morning. Most pwMS have poor sleep hygiene and almost half of pwMS have a sleep disorder. A clue to this is how you feel in the morning and whether or not you have excessive daytime sleepiness. If you wake up in the morning and don’t feel refreshed and/or you fall asleep frequently during the day then you need a proper sleep assessment done. You can complete the Epworth Sleep Scale online to see if you have a problem. I will do a separate MS-Selfie Newsletter on sleep to cover this topic in more detail.

This patient was screened for poor sleep hygiene and she did volunteer intermittent early morning waking due to bladder problems and anxiety. Both of these would need to be addressed as part of her fatigue management programme.

Obesity

When you are overweight it takes more energy to perform physical tasks and obesity itself causes fatigue. Recently an association has been found between obesity and depression. Obesity also predisposes you to sleep disorders; obese pwMS are more likely to have obstructive sleep apnoea. This is why you have to engage with lifestyle and wellness programmes to manage fatigue.

Fortunately, this patient was not obese.

Depression and anxiety

Fatigue is a common symptom of depression and anxiety. There are many online screening tools for depression and anxiety. The one that is probably the best to use if you have MS is the hospital anxiety and depression scale or the HADS.

It was clear that this patient had both depression and anxiety, which were related to the impact MS had had on her occupational and social functioning. This will need to be managed with cognitive behavioural therapy (CBT), mindfulness and an exercise programme and this was not helpful the judicious use of an antidepressant may be required. Failing this a referral to a psychiatrist and/or psychologist may be necessary.

Side-effects of drugs

Fatigue is a common side effect of many medications, in particular drugs that cause sedation and it is common with some 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.

So if you have fatigue it is important to review your medications. MS is associated with polypharmacy and often some of the medications that cause or exacerbate fatigue can be weaned.

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. Most patients claim that they can’t exercise because it makes their fatigue worse. Yes, it does happen but if you persevere and get yourself fit your fatigue will usually improve. The important thing is to start a graded exercise programme and build up slowly.

Exercise does some incredible things to the brain, many of which explain why it is effective at treating not only fatigue but depression and anxiety as well. Exercise is also a disease-modifying therapy and hence everyone with MS should be participating in an exercise programme.

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 produces cause you to feel tired and want to sleep; i.e. the so-called siesta effect or food coma. Reducing the size of your meals and changing your eating behaviour may improve postprandial hypersomnolence (after eating fatigue). For more information on food coma please read my MS-Selfie Newsletter from the 12th of July.

Conclusion

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 HCP 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, a holistic and systematic approach is needed to manage and treat MS-related fatigue correctly.

The case study above illustrates the complexity of MS-related fatigue. If you have any personal anecdotes to share with us please do. There is nothing better than learning from each other.

MS-Selfie