Fatigue in Multiple Sclerosis (MS)

Definition, mechanisms and modern approaches to management

Fatigue is one of the most prevalent and disabling symptoms in multiple sclerosis (MS), affecting up to 80% of patients and often reported as the single most troubling symptom, regardless of the level of physical disability. It interferes with daily activities, work, family life and social participation, and is strongly associated with reduced quality of life.

MS-related fatigue is not the same as “normal tiredness” after exertion or lack of sleep. It is often described by patients as an overwhelming lack of physical and mental energy that appears out of proportion to activity, may be present from the morning, worsens throughout the day and is not fully relieved by rest or sleep.

What is MS-related fatigue?

In clinical practice, MS-related fatigue is defined as a subjective lack of physical and/or mental energy, perceived by the patient or caregiver, that interferes with usual and desired activities. It can be:

• Physical fatigue – feeling of heaviness and weakness in the limbs, reduced endurance, difficulty walking or climbing stairs.
• Cognitive fatigue – rapid mental exhaustion, difficulty concentrating, slower thinking, problems with multitasking.
• Mixed fatigue – combination of physical and cognitive components, which is especially common in MS.

Fatigue is often more pronounced in the afternoon and may be triggered or worsened by physical exertion, emotional stress, infection, lack of sleep or elevated body temperature.

How common is fatigue in MS and how does it affect daily life?

Up to 80% of people with MS experience clinically significant fatigue at some point during the disease course, and about half report it as one of the most disabling symptoms. Fatigue can be present even in patients with minimal neurological disability and relatively preserved mobility.

The impact of fatigue is multidimensional:

• reduced ability to work or study full time;
• limitation of physical activity and daily chores;
• decreased participation in family and social life;
• worsening of mood, increased risk of anxiety and depression;
• negative effect on adherence to disease-modifying therapy and rehabilitation.

Because of this, it is important to recognise fatigue not as an inevitable consequence of MS, but as a treatable symptom that deserves a structured and proactive approach.

Causes and mechanisms of fatigue in MS

The pathophysiology of MS-related fatigue is multifactorial and includes both primary mechanisms directly related to MS and secondary factors that may aggravate fatigue.

Primary (central) mechanisms

• Inflammatory and neurodegenerative changes in cortical and subcortical networks involved in motor control, motivation and attention.
• Widespread demyelination and impaired conduction, leading to increased “energy cost” of neural activity.
• Altered functional connectivity in monoaminergic circuits (dopamine, serotonin, noradrenaline) associated with motivation, reward and effort.
• Neuroendocrine changes, including dysregulation of the hypothalamic–pituitary–adrenal axis.

Peripheral and secondary factors

• Physical deconditioning and muscle fatigue due to reduced activity.
• Sleep disorders (insomnia, restless legs syndrome, sleep apnea, nocturia).
• Depression, anxiety and other mood disorders.
• Thyroid dysfunction, anemia and other medical comorbidities.
• Adverse effects of medications (sedating antihistamines, some antiepileptic drugs, benzodiazepines, high-dose baclofen, etc.).
• Heat sensitivity and impaired thermoregulation, which further worsen conduction in demyelinated pathways.

In each individual patient, several mechanisms usually coexist. Therefore, management should start with a careful evaluation of potential contributing factors rather than with an empirical prescription of stimulants.

Assessment and differential diagnosis

Evaluation of MS-related fatigue includes a detailed clinical interview, neurological examination and, when needed, additional laboratory and instrumental tests. The goals are to:

• characterise the type of fatigue (physical, cognitive, mixed);
• assess severity and impact on daily life;
• identify treatable secondary factors;
• distinguish fatigue from depression, apathy and sleepiness.

Standardised questionnaires, such as the Fatigue Severity Scale (FSS) or the Modified Fatigue Impact Scale (MFIS), help to quantify fatigue and to monitor response to interventions. Cognitive fatigue can be further assessed using neuropsychological tests with prolonged or repetitive tasks.

It is also important to rule out other conditions that may mimic or aggravate fatigue: anemia, thyroid disease, vitamin B12 deficiency, uncontrolled pain, chronic infections, poorly controlled diabetes and others.

Non-pharmacological management: the foundation of treatment

Current evidence and international guidelines emphasise that the first-line management of MS-related fatigue should be non-pharmacological. Several approaches have demonstrated benefit in randomised trials and meta-analyses.

1. Exercise and physical rehabilitation

Individually tailored exercise programmes (aerobic training, resistance exercises, balance and flexibility training) can reduce both subjective and objective fatigue, improve mobility and enhance mood. Importantly, in MS patients the correct dose of physical activity does not “exhaust” the nervous system but, on the contrary, contributes to better energy management and overall fitness.

2. Cognitive-behavioural therapy and psychoeducation

Cognitive-behavioural therapy (CBT), individually or in groups, helps patients to better understand the mechanisms of fatigue, modify unhelpful beliefs (“I must do everything as before or I am failing”), and develop adaptive coping strategies. Psychoeducational programmes that explain the nature of fatigue, the role of sleep, stress and activity scheduling are an important component of multidisciplinary care.

3. Energy conservation and activity management

Occupational therapists teach patients how to distribute activity throughout the day, alternate tasks with rest breaks, prioritise what is truly important, and avoid “energy traps” (for example, long queues, heavy shopping, long walks in the heat).

4. Optimising sleep and treating comorbidities

Addressing insomnia, nocturia, restless legs syndrome or sleep apnea, as well as correcting endocrine and metabolic disorders, is essential for successful fatigue management. Sometimes normalising sleep and treating depression or anxiety leads to a marked reduction in fatigue without the need for specific stimulants.

Pharmacological treatment of MS-related fatigue

No medication is currently specifically approved by regulatory agencies for MS-related fatigue. However, several agents are used off-label, with modest but clinically meaningful efficacy in some patients.

• Amantadine (usually 100 mg twice daily) is one of the most commonly used drugs. It may reduce perceived fatigue in a subset of patients and is generally well tolerated, although it can cause insomnia, nausea, ankle oedema or livedo reticularis.
• Modafinil (100–200 mg in the morning, with an optional second dose at noon) is a wakefulness promoting agent originally developed for narcolepsy. It may be helpful particularly in patients with coexisting excessive daytime sleepiness, but cardiovascular and psychiatric comorbidities must be taken into account.
• Methylphenidate has been studied in several small trials, but the evidence for its benefit in MS fatigue is limited and conflicting, while the risk of side effects is higher. It is usually reserved for selected cases.

Recently, a large randomised crossover trial compared amantadine, modafinil and methylphenidate with placebo and showed modest effects and a relatively high rate of adverse events. Therefore, pharmacological treatment should be considered only after optimisation of non-pharmacological strategies, with careful individual risk–benefit analysis.

Cooling strategies and temperature management

In many people with MS, fatigue is clearly aggravated by heat and improved by cooling. This can be related both to increased conduction block in demyelinated pathways and to systemic effects of elevated body temperature.

Cooling garments (cooling vests, neck and head coolers, cooling suits) have been evaluated in several clinical studies. They can:

• reduce perceived physical fatigue and heat sensitivity;
• increase walking distance and exercise tolerance;
• improve comfort and participation in outdoor activities during warm seasons.

Not all patients experience the same degree of benefit, and long-term effects require further research. However, for individuals with pronounced heat sensitivity, cooling garments can be a valuable adjunct to other treatments.

Simple everyday strategies are also important: choosing breathable clothing, avoiding direct sun, using air conditioning or fans, taking lukewarm (not hot) showers, and planning outdoor activity during cooler hours of the day.

Practical tips for patients with MS-related fatigue

• Discuss fatigue openly with your neurologist – it is a legitimate and treatable symptom, not “laziness”.
• Try to identify and, when possible, modify factors that worsen fatigue (heat, infections, lack of sleep, stress).
• Structure the day: plan the most important tasks for the time when you usually feel better.
• Alternate activity and rest; short regular breaks are more effective than one long rest at the end of the day.
• Incorporate regular, moderate exercise approved by your neurologist or physiotherapist.
• Pay attention to sleep hygiene: regular schedule, comfortable environment, avoiding screens and heavy meals before bedtime.
• Seek psychological support if fatigue is accompanied by low mood, anxiety or loss of interest.
• Ask your neurologist whether specific medications for fatigue are appropriate in your situation.

FAQ about fatigue in MS

Is fatigue always related to MS activity?

Not necessarily. Fatigue can be present in all stages of MS, including stable phases, and does not always correlate with MRI activity or relapse rate. However, sudden worsening of fatigue, especially if accompanied by other neurological symptoms, should prompt medical evaluation.

Is it worth doing sports if I feel exhausted?

In the absence of contraindications, regular, properly dosed physical activity is one of the most effective non-pharmacological treatments for fatigue. The programme should be tailored to your abilities and adjusted gradually, ideally under the supervision of a physiotherapist familiar with MS.

Can diet supplements cure fatigue?

There is currently no convincing evidence that vitamins or dietary supplements alone can “cure” MS-related fatigue. Correction of documented deficiencies (for example, vitamin D, B12 or iron) is important, but should be part of a broader management plan that includes lifestyle measures, rehabilitation and, when appropriate, medications.

Key references

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