Fatigue in Multiple Sclerosis: Causes, Evaluation and Treatment
Pathological fatigue is one of the most common and underestimated symptoms of multiple sclerosis. It can be severe even with relatively little motor disability and can affect work, thinking, physical activity, family life and social functioning.
In a 2024 meta-analysis including 69 studies from 27 countries, fatigue was present in approximately 59% of people with MS. Estimates varied substantially depending on the scale used, age, disability and disease phenotype.
What is pathological fatigue in multiple sclerosis?
Fatigue is a subjective sense of insufficient physical or mental energy that interferes with desired and necessary activities.
Disproportionate to effort
Exhaustion may occur after minimal activity or even without an obvious trigger.
Not always relieved by sleep
Unlike ordinary tiredness, a good night's sleep may reduce the symptom but does not necessarily eliminate it.
It affects function
Fatigue becomes clinically important when it limits work, education, physical activity, self-care or social life.
Pooled global prevalence in a 2024 meta-analysis.
Estimated prevalence in the SPMS subgroup in the same analysis.
Estimated prevalence in relapsing-remitting MS.
Fatigue, fatigability, weakness and sleepiness are different phenomena
| Phenomenon | What it means | Example |
|---|---|---|
| Fatigue | Subjective sense of exhaustion or insufficient physical or cognitive energy. | “I feel as if my energy has run out even though I have barely done anything.” |
| Fatigability | Measurable deterioration in task performance during sustained effort. | Walking speed or cognitive-task accuracy decreases as the task continues. |
| Muscle weakness | Reduced strength due to impairment of the motor system. | Inability to maintain force against resistance during a neurological examination. |
| Sleepiness | Tendency to fall asleep, often related to sleep deprivation, sleep apnea or sedating medications. | Falling asleep while reading, watching television or riding in a vehicle. |
Why this is not merely an academic distinction
A 2026 meta-analysis found that subjective fatigue and objectively measured cognitive fatigability were only weakly related, with a pooled correlation of approximately r = 0.19. A normal short cognitive test therefore does not mean that a patient “cannot be fatigued”, and severe subjective fatigue does not necessarily produce a rapid decline in objective performance.
Why does fatigue occur in multiple sclerosis?
There is no single mechanism of fatigue. It usually reflects a combination of primary changes related to MS itself and secondary factors that can often be modified.
Central mechanisms
- reduced efficiency of neural networks after demyelination and axonal injury;
- changes in functional connectivity between motor, cognitive and motivational networks;
- involvement of thalamo-cortical, basal ganglia and cerebellar circuits;
- changes in monoaminergic regulation;
- possible contributions from inflammatory and neuroendocrine mechanisms.
The functional “cost” of movement and thinking
After CNS injury, the brain may need to recruit more resources to perform a familiar task. The person may still complete the activity, but its energetic and cognitive “cost” becomes greater.
This is one reason why fatigue can occur even with a relatively low EDSS.
Before prescribing a “fatigue medication”, look for factors that make fatigue worse
Sleep
Sleep deprivation, insomnia, obstructive sleep apnea, restless legs syndrome, pain, spasticity or frequent nocturnal urination.
Mood
Depression and anxiety can worsen fatigue, but fatigue should not automatically be attributed to a psychological cause.
Medications
Sedatives, some antiseizure drugs, muscle relaxants and other medications can increase daytime exhaustion or sleepiness.
Medical causes
Anemia, iron or B12 deficiency, thyroid disease and other metabolic disorders are assessed when clinically indicated.
Other MS symptoms
Pain, spasticity, gait impairment and the constant need to compensate for weakness increase the energy cost of activity.
Infection and heat
Even a small rise in body temperature can temporarily worsen conduction in demyelinated fibers and increase fatigue and other old symptoms.
How fatigue is assessed in clinical practice
Fatigue cannot be confirmed by a single blood test or MRI. Evaluation is built around the symptom itself, its effect on daily life and the search for modifiable causes.
Clinical profile
When fatigue begins, how it changes during the day and whether it is related to heat, sleep, exertion, work, infections or medications.
Scales
Commonly used instruments include the FSS, Modified Fatigue Impact Scale (MFIS) and Fatigue Scale for Motor and Cognitive Functions (FSMC). They measure different aspects of fatigue and are not interchangeable.
Sleep and mood
When appropriate, daytime sleepiness, sleep apnea, insomnia, depression and anxiety are assessed.
Blood tests are not a “fatigue panel”
Depending on the situation, a complete blood count, ferritin, B12, TSH and other tests may be appropriate. The extent of testing is guided by the history and symptoms.
Treating fatigue: sequence matters more than a list of drugs
Physical activity can genuinely reduce fatigue
In 2026, a large umbrella review combining 46 systematic reviews with meta-analyses found that structured exercise had the most consistent effect among interventions studied for MS-related fatigue.
Aerobic exercise
Produces a small but reasonably consistent average effect. Options may include walking, cycling, an elliptical trainer, swimming or another form of tolerated aerobic activity.
Resistance training
Recent meta-analyses also show benefit. The program should progress gradually, particularly in the presence of weakness, spasticity or balance impairment.
Mind-body and combined programs
Yoga, balance exercises and combined programs may be helpful, although effect sizes vary considerably across studies.
The main principle is not to “train through exhaustion”
The goal is to increase tolerated activity gradually without provoking prolonged worsening. With gait impairment, spasticity, marked heat sensitivity or greater disability, the program is best adapted together with a physiotherapist.
Cognitive behavioral therapy and energy management
CBT for fatigue is not an attempt to persuade a patient that the symptom is “psychological”. The goal is to modify patterns of behavior, sleep, activity and responses to symptoms that can sustain the cycle of exhaustion.
CBT
A 2024 meta-analysis confirmed that cognitive behavioral therapy reduces fatigue in MS. The effect may be especially relevant when fatigue is accompanied by sleep disturbance, anxiety, catastrophizing or irregular patterns of activity.
Energy management
The patient learns to distribute tasks, schedule the most demanding activities for periods of higher energy, use short recovery periods and reduce unnecessary energy expenditure.
Why heat worsens fatigue and when cooling may help
In some people, even a small rise in body temperature temporarily impairs impulse conduction in demyelinated nerve fibers. This is one mechanism of Uhthoff's phenomenon.
Ambient temperature
Heat and poorly ventilated rooms can worsen not only fatigue but also old visual, motor or sensory symptoms.
Exercise
Exercise itself is beneficial, but with marked heat sensitivity the room temperature, ventilation and recovery schedule matter.
Cooling
A cool pool, air conditioning, cooling vests and other devices may provide temporary functional improvement in heat-sensitive patients.
Medications for fatigue: why the evidence is conflicting
There is no medication with consistently reproducible benefit for most people with MS-related fatigue. Drug treatment is therefore considered individually, after secondary causes and non-drug approaches have been addressed.
| Drug / approach | What is known | Practical meaning |
|---|---|---|
| Amantadine | Earlier small studies suggested modest benefit, but in the large placebo-controlled crossover TRIUMPHANT-MS trial amantadine was not superior to placebo. | It is sometimes tried off-label after individual assessment, but should not automatically be prescribed to every patient with fatigue. |
| Modafinil | In TRIUMPHANT-MS it was not superior to placebo. In COMBO-MS 2024, modafinil, CBT and their combination were associated with similar clinically meaningful improvement, but that study had no placebo group. | It may be discussed individually, especially when prominent daytime sleepiness is present, but the evidence does not support universal effectiveness. |
| Methylphenidate | It was also no better than placebo in TRIUMPHANT-MS, while adverse events were more frequent than with placebo. | It is not part of routine standard treatment for MS-related fatigue. |
| Antidepressants | They may reduce fatigue when depression makes a major contribution. Some guidance allows individualized off-label discussion of selected drugs. | The main target is coexisting depression; antidepressants are not automatically used as a “fatigue medication”. |
What should not be considered proven treatment for fatigue
A “special diet for fatigue”
There is no convincing evidence that a specific diet specifically reduces MS-related fatigue. Healthy nutrition is important for general health, but that is a different question.
Vitamin B12 without deficiency
B12 deficiency should be corrected. But B12 injections are not a treatment for fatigue in a patient whose vitamin level is normal.
Caffeine as therapy
Caffeine can temporarily increase alertness, but it is not a proven treatment for pathological fatigue in MS and can worsen sleep.
Experimental neuromodulation
tDCS and other methods are being studied and some meta-analyses show a short-term efficacy signal, but they are not yet standard treatment for fatigue.
Work, family and planning the day
For many people, the main problem with fatigue is not the score on a scale, but the inability to predict how much energy will remain by the middle or end of the day.
Schedule demanding tasks
Place difficult activities at times when energy is usually higher, leaving less important tasks for periods of lower performance.
Short recovery instead of prolonged inactivity
Alternating activity with short breaks is often more useful than withdrawing completely from physical and social activity.
Workplace adaptation
Flexible hours, remote work, seated work, air conditioning and reducing unnecessary movement can substantially improve functional outcome.
A change in fatigue is a reason to look for the cause, not automatically to change DMT
More typical of a secondary cause
- abrupt worsening after several nights of poor sleep;
- heat or fever;
- infection;
- a new sedating medication;
- worsening pain or spasticity.
Neurological reassessment is needed
- fatigue is accompanied by new focal symptoms;
- persistent functional worsening has appeared;
- the disease course has changed;
- there is doubt about control of MS activity or progression.
What can currently be considered the most reasonable strategy?
1. Do not treat fatigue as an “inevitable part of MS” that simply has to be tolerated.
2. Do not start by searching for the “strongest drug”. First define the symptom phenotype and look for secondary causes.
3. Use structured physical activity and behavioral approaches as the foundation of treatment, adapting them to the individual level of disability and heat sensitivity.
4. Consider pharmacotherapy individually and assess it not by the subjective impression of the first few days but against a predefined functional goal.
5. If the character of fatigue changes, reassess sleep, medications, general medical causes and the status of MS itself.
When fatigue requires a separate clinical assessment
Fatigue interferes with work or usual life
It is important to understand which mechanism is responsible for the loss of energy and function.
Rest does not help
This is a reason to assess sleep-related causes, depression, medications, deconditioning and primary MS-related fatigue.
Fatigue medications do not work
Sometimes the problem is not the choice of drug, but an incorrectly identified mechanism of the symptom.
Fatigue has changed noticeably
New persistent worsening requires reassessment of contributing causes and the course of MS.
Consultation with Dr. Lidiia Prakhova
With marked fatigue in the setting of multiple sclerosis, it is possible to assess the contribution of the disease itself, sleep, mood, medications, pain, spasticity, gait impairment, heat sensitivity and general medical factors.
The aim is to create an individualized plan in which fatigue treatment is linked to the patient's real function, rather than only to a questionnaire score.
Frequently asked questions about fatigue in MS
Is fatigue in MS simply weakness?
Does worsening fatigue always mean an MS relapse?
Does exercise help?
Does modafinil help?
Should I rest more?
Does cooling help?
Dr. Lidiia Prakhova
Neurologist, Doctor of Medical Sciences. Main areas of clinical work include neuroimmunology, multiple sclerosis, movement disorders, migraine, spasticity and botulinum toxin therapy.
ORCID: 0000-0002-4776-2999
The information on this page is educational and does not replace an individual medical consultation.
Key scientific references
- Yi X, Zhang Y, Du Q, et al. Global prevalence of fatigue in patients with multiple sclerosis: a systematic review and meta-analysis. Front Neurol. 2024;15:1457788. doi:10.3389/fneur.2024.1457788
- Fleischmann HH, Derusha AE, Kiselica AM, Correia S, Sweet LH. The Relationship Between Subjective and Objective Fatigue Assessment Approaches in Multiple Sclerosis: A Meta-Analysis. Neuropsychol Rev. 2026. doi:10.1007/s11065-026-09696-8
- Hawas Y, Abdelmageed A, Abouzid M, et al. Measurements and management of multiple sclerosis-related fatigue: an umbrella review and meta-analysis. Disabil Rehabil. 2026. doi:10.1080/09638288.2026.2711882
- Vo HLT, Elias S, Hardy TA. Cognitive behavioural therapy for fatigue in patients with multiple sclerosis: A systematic review and meta-analysis. Mult Scler Relat Disord. 2024;91:105908. doi:10.1016/j.msard.2024.105908
- Yang J, Li H, Zhang Y, Hu S, Yu Z. Effects of exercise on fatigue and quality of life in multiple sclerosis: a network meta-analysis and systematic review. J Neurol. 2025;272(9):621. doi:10.1007/s00415-025-13368-7
- Nourbakhsh B, Revirajan N, Morris B, 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;20(1):38–48. doi:10.1016/S1474-4422(20)30354-9
- Braley TJ, Ehde DM, Alschuler KN, et al. Comparative effectiveness of cognitive behavioural therapy, modafinil, and their combination for treating fatigue in multiple sclerosis (COMBO-MS). Lancet Neurol. 2024;23(11):1108–1118. doi:10.1016/S1474-4422(24)00354-5
- Patejdl R, Zettl UK. The Pathophysiology of Motor Fatigue and Fatigability in Multiple Sclerosis. Front Neurol. 2022;13:891415. doi:10.3389/fneur.2022.891415
- Margoni M, Valsasina P, Bacchetti A, et al. Resting State Functional Connectivity Modifications in Monoaminergic Circuits Underpin Fatigue Development in Patients With Multiple Sclerosis. Mol Psychiatry. 2024;29(9):2647–2656. doi:10.1038/s41380-024-02532-6
- Schwid SR, Petrie MD, Murray R, et al. A randomized controlled study of the acute and chronic effects of cooling therapy for MS. Neurology. 2003;60(12):1955–1960. doi:10.1212/01.WNL.0000070183.30517.2F
- National Institute for Health and Care Excellence. Multiple sclerosis in adults: management. NICE guideline NG220. Updated recommendations on fatigue management, 2022. NICE NG220
Material updated September 2026.
