Fatigue

Definition

Fatigue in a medical context is used to cover experiences of low energy that are not caused by normal life.

A 2021 review proposed a definition for fatigue as a starting point for discussion: "A multi-dimensional phenomenon in which the biophysiological, cognitive, motivational and emotional state of the body is affected resulting in significant impairment of the individual's ability to function in their normal capacity".

Another definition is that fatigue is "a significant subjective sensation of weariness, increasing sense of effort, mismatch between effort expended and actual performance, or exhaustion independent from medications, chronic pain, physical deconditioning, anaemia, respiratory dysfunction, depression, and sleep disorders".

Terminology

The use of the term fatigue in medical contexts may carry inaccurate connotations from the more general usage of the same word. More accurate terminology may also be needed for variants within the umbrella term of fatigue.

Comparison with other terms

Tiredness

Tiredness which is a normal result of work, mental stress, anxiety, overstimulation and understimulation, jet lag, active recreation, boredom, or lack of sleep is not considered medical fatigue. This is the tiredness described in MeSH Descriptor Data.

Exhaustion

Exhaustion is a state of extreme tiredness.

Sleepiness

Sleepiness refers to a tendency to fall asleep, whereas fatigue refers to an overwhelming sense of tiredness, lack of energy, and a feeling of exhaustion. Sleepiness and fatigue often coexist as a consequence of sleep deprivation. However sleepiness and fatigue may not correlate. Fatigue is generally considered a longer-term condition than sleepiness (somnolence).

Classification

ICD-11

"Fatigue" is categorised as ICD-11 code MG22.

Presentation

Common features

Distinguishing features of medical fatigue include:

• unpredictability,
• variability in severity,
• fatigue being relatively profound/overwhelming, and having extensive impact on daily living,
• lack of improvement with rest,
• where an underlying disease is present, the amount of fatigue is often not commensurate with the severity of the underlying disease.

Differentiating features

Differentiating characteristics of fatigue that may help identify the possible cause of fatigue include:

• Post-exertional malaise; a common feature of ME/CFS, and experienced by a significant proportion of people with Long Covid, but not a feature of other fatigues.
• Increased by heat or cold; MS fatigue is in many cases affected in this way.
• Flare-ups and Remissions; Some fatigue diseases have flareups of a few weeks (lupus, fibromyalgia). Other fatigue diseases may have longer patterns of activity and remission, or no remissions at all (MS).
• Variability within a day; Some fatigues (rheumatoid arthritis (RA), cancer-related fatigue) seem to often be continual (24/7), whilst others (MS, Sjögren's, lupus, brain injury) often vary in intensity at different times within a day. A 2010 study found that Sjögren's patients reported fatigue after rising, an improvement in mid-morning, and worsening later in the day, whereas lupus (SLE) patients reported lower fatigue after rising followed by increasing fatigue through the day. ME/CFS symptoms can be continual, or can fluctuate during the day, from day to day, and over longer periods. Fibromyalgia fatigue can be continual or variable.
• The pace of onset may be a related differentiating factor; MS fatigue can have abrupt onset.
• Feeling of weight; some fatigues, including that caused by MS, create a sense of weight or gravity; "I feel like I have lead weights attached to my limbs ... or I am being pulled down by gravity."

Some people may have multiple causes of fatigue.

Causes

Fatigue is complex and can be driven and maintained by a potentially wide range of biopsychosocial factors. Tiredness is a common medically unexplained symptom. In up to a third of fatigue primary care cases, no medical or psychiatric diagnosis is found.

Adverse life events

Adverse life events have been associated with fatigue.

Drug use

A 2021 study in a Korean city found that alcohol consumption was the variable with the most correlation with overall fatigue. A 2020 Norway study found that 69% of substance use disorder patients had severe fatigue symptoms, and particularly those with extensive use of benzodiazepines. Causality, as opposed to correlation, were not proven in these studies.

Digital screen use

The protracted use of digital screens—such as those associated with computers, laptops and smartphones—can cause eye fatigue, and induce a general state of mental and physical exhaustion. Specific symptoms may include sore eyes, blurred vision, headaches and associated orthopedic issues such as a sore neck and back. These symptoms collectively are known as computer vision syndrome (CVS) or in colloquial parlance as screen fatigue.

Sleep disturbance

Fatigue can often be traced to poor sleep habits. Sleep deprivation and disruption is associated with subsequent fatigue. Sleep disturbances due to disease may impact fatigue. Caffeine and alcohol can disrupt sleep, causing fatigue.

Medications

Fatigue may be a side effect of certain medications (e.g., lithium salts, ciprofloxacin); beta blockers, which can induce exercise intolerance, medicines used to treat allergies or coughs, and many cancer treatments, particularly chemotherapy and radiotherapy. Use of benzodiazepines has been found to correlate with higher fatigue.

Association with diseases and illnesses

Fatigue is often associated with diseases and conditions. Some major categories of conditions that often list fatigue as a symptom include physical diseases, substance use illness, mental illnesses, and other diseases and conditions.

Physical diseases

Before you add your "favorite", please make sure that it's not already in the list!

Categories (like "autoimmune diseases") are far more important than isolated examples (like "multiple sclerosis"). We DO not want hundreds of individual diseases listed here.

Thanks for your help, and happy editing!

--

• autoimmune diseases, such as celiac disease, lupus, multiple sclerosis, myasthenia gravis, NMOSD, Sjögren's syndrome, rheumatoid arthritis, spondyloarthropathy and UCTD; this population's primary concern is fatigue;
• blood disorders, such as anemia and hemochromatosis;
• brain injury;
• cancer, in which case it is called cancer fatigue;
• COVID-19 and long COVID;
• endocrine diseases or metabolic disorders: diabetes mellitus, hypothyroidism and Addison's disease;
• fibromyalgia;
• heart failure and heart attack;
• HIV
• inborn errors of metabolism such as fructose malabsorption;
• infectious diseases such as infectious mononucleosis or tuberculosis;
• irritable bowel syndrome;
• kidney diseases, e.g., acute renal failure, chronic renal failure;
• leukemia or lymphoma;
• liver failure or liver diseases, e.g., hepatitis;
• Low blood pressure
• Lyme disease;
• neurological disorders such as narcolepsy, Parkinson's disease, postural orthostatic tachycardia syndrome (POTS) and post-concussion syndrome;
• nutritional deficiencies, such as, sodium, iron, vitamin B12, and folate deficiencies
• physical trauma and other pain-causing conditions, such as arthritis;
• sleep deprivation or sleep disorders, e.g. sleep apnea;
• stroke
• thyroid disease such as hypothyroidism;
• sarcoidosis
• mast cell activation syndrome

Mental illnesses

• anxiety disorders, such as generalized anxiety disorder;
• developmental disorders such as autism spectrum disorder;
• depression;
• eating disorders, which can produce fatigue due to inadequate nutrition;

Other

• myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)
• idiopathic chronic fatigue, a term used to describe chronic fatigue which does not have symptoms of ME/CFS. However ICF does not have a dedicated diagnostic code in the World Health Organization's ICD-11 classification. This includes a category MG22 Fatigue (typically fatigue following exertion but sometimes may occur in the absence of such exertion as a symptom of health conditions), and many other categories where fatigue is mentioned as a secondary result of other factors.
• 8E49 Postviral fatigue syndrome
• QE84 Acute stress reaction, Combat fatigue
• 6A70-6A7Z Depressive disorders
• 07 Sleep-wake disorders
• FB32.5 Muscle strain or sprain, causing muscular fatigue
• NF01.3 Heat fatigue, transient
• MA82.Y Voice disturbances, causing voice fatigue
• BD1Z Heart failure, unspecified, causing myocardial fatigue
• JA65.Y Conditions predominantly related to pregnancy, causing fatigue which complicates pregnancy
• SD91 Fatigue consumption disorder, causing coughing, fever, diarrhea, chest pain etc.
• MG2A Ageing associated decline in intrinsic capacity, causing senile fatigue
• NF07.2 Exhaustion due to exposure
• NF01 Heat exhaustion
• 6C20 Bodily distress disorder.
• Gulf War syndrome;

Primary vs. secondary

In some areas, it has been proposed that fatigue be separated into

• primary fatigue, caused directly by a disease process, and
• ordinary or secondary fatigue, caused by a range of causes including exertion and also secondary impacts on a person of having a disease (such as disrupted sleep). The ICD-11 MG22 definition of fatigue captures both types of fatigue; it includes fatigue that "occur[s] in the absence of... exertion... as a symptom of health conditions."

Obesity

Obesity correlates with higher fatigue levels and incidence.

Somatic symptom disorder

In somatic symptom disorder the patient is overfocused on a physical symptom, such as fatigue, that may or may not be explained by a medical condition.

Scientifically unsupported causes

The concept of adrenal fatigue is often raised in media but no scientific basis has been found for it.

Mechanisms

The mechanisms that cause fatigue are not well understood. Several mechanisms may be in operation within a patient, with the relative contribution of each mechanism differing over time.

Proposed fatigue explanations due to permanent changes in the brain may have difficulty in explaining the "unpredictability" and "variability" (i.e. appearing intermittently during the day, and not on all days) of the fatigue associated with inflammatory rheumatic diseases and autoimmune diseases (such as multiple sclerosis).

Inflammation

Inflammation distorts neural chemistry, brain function and functional connectivity across a broad range of brain networks, and has been linked to many types of fatigue. Findings implicate neuroinflammation in the etiology of fatigue in autoimmune and related disorders. Low-grade inflammation may cause an imbalance between energy availability and expenditure.

Cytokines are small protein molecules that modulate immune responses and inflammation (as well as other functions) and may have causal roles in fatigue. However a 2019 review was inconclusive as to whether cytokines play any definitive role in ME/CFS.

Reduced brain connectivity

Fatigue has been correlated with reductions in structural and functional connectivity in the brain. This has included in post-stroke, MS, NMOSD and MOG, and ME/CFS. This was also found for fatigue after brain injury, including a significant linear correlation between self-reported fatigue and brain functional connectivity.

Areas of the brain for which there is evidence of relation to fatigue are the thalamus and middle frontal cortex, fronto-parietal and cingulo-opercular, and default mode network, salience network, and thalamocortical loop areas.

A 2024 review found that structural connectivity changes may underlie fatigue in pwRRMS but that the overall results were inconclusive, possibly explained by heterogeneity and limited number of studies.

A small 2023 study found that infratentorial lesion volume (cerebellar and brainstem) was a relatively good predictor of RRMS fatigue severity.

Damage to brain white matter

Studies have found MS fatigue correlates with damage to NAWM (normal appearing white matter) (which will not show on normal MRI but will show on DTI (diffusion tensor imaging)). The correlation becomes unreliable in patients aged over 65 due to damage due to ageing.

Heat shock proteins

A small 2016 study found that primary Sjögren's syndrome patients with high fatigue, when compared with those with low fatigue, had significantly higher plasma concentrations of HSP90α, and a tendency to higher concentrations of HSP72. A small 2020 study of Crohn's disease patients found that higher fatigue visual analogue scale (fVAS) scores correlated with higher HSP90α levels. A related small 2012 trial investigating if application of an IL-1 receptor antagonist (anakinra) would reduce fatigue in primary Sjögren's syndrome patients was inconclusive.

Measurement

Fatigue is currently measured by many different self-measurement surveys. Examples are the Fatigue Symptom Inventory (FSI) and the Fatigue Severity Scale. There is no consensus on best practice, and the existing surveys do not capture the intermittent nature of some forms of fatigue. Heart rate variability cannot currently distinguish between physical fatigue and mental fatigue. Many studies have shown that salivary cortisol can measure mental fatigue.

Diagnosis

Diagnosis guidance

A 2023 guidance indicates the following

• in the primary care setting, a medical or psychiatric diagnosis is found in at least two-thirds of patients;
• the most common diagnoses are viral illness, upper respiratory infection, iron-deficiency anaemia, acute bronchitis, adverse effects of a medical agent in the proper dose, and depression or other mental disorder, such as panic disorder, and somatisation disorder;
• the origin of fatigue may be central, brain-derived, or peripheral, usually of a neuromuscular origin—it may be attributed to physical illness, psychological (e.g., psychiatric disorder), social (e.g., family problems), and physiological factors (e.g., old age), occupational illness (e.g., workplace stress);
• when unexplained, clinically evaluated chronic fatigue can be separated into ME/CFS and idiopathic chronic fatigue.

A 2016 German review found that

• about 20% of people complaining of tiredness to a GP (general practitioner) suffered from a depressive disorder.
• anaemia, malignancies and other serious somatic diseases were only very rarely found in fatigued primary care patients, with prevalence rates hardly differing from non-fatigued patients.
• if fatigue occurred in primary care patients as an isolated symptom without additional abnormalities in the medical history and in the clinical examination, then extensive diagnostic testing rarely helped detect serious diseases. Such testing might also lead to false-positive tests.

A 2014 Australian review recommended that a period of watchful waiting may be appropriate if there are no major warning signs.

A 2009 study found that about 50% of people who had fatigue received a diagnosis that could explain the fatigue after a year with the condition. In those people who had a possible diagnosis, musculoskeletal (19.4%) and psychological problems (16.5%) were the most common. Definitive physical conditions were only found in 8.2% of cases.

Classification

By type

Uni- or multi-dimensional

Fatigue can be seen as a uni-dimensional phenomenon that influences different aspects of human life. It can be multi-faceted and broadly defined, making understanding the causes of its manifestations especially difficult in conditions with diverse pathology including autoimmune diseases.

A 2021 review considered that different "types/subsets" of fatigue may exist and that patients normally present with more than one such "type/subset". These different "types/subsets" of fatigue may be different dimensions of the same symptom, and the relative manifestations of each may depend on the relative contribution of different mechanisms. Inflammation may be the root causal mechanism in many cases.

Physical

Physical fatigue, or muscle fatigue, is the temporary physical inability of muscles to perform optimally. The onset of muscle fatigue during physical activity is gradual, and depends upon an individual's level of physical fitness – other factors include sleep deprivation and overall health. Physical fatigue can be caused by a lack of energy in the muscle, by a decrease of the efficiency of the neuromuscular junction or by a reduction of the drive originating from the central nervous system, and can be reversed by rest. The central component of fatigue is triggered by an increase of the level of serotonin in the central nervous system. During motor activity, serotonin released in synapses that contact motor neurons promotes muscle contraction. During high level of motor activity, the amount of serotonin released increases and a spillover occurs. Serotonin binds to extrasynaptic receptors located on the axonal initial segment of motor neurons with the result that nerve impulse initiation and thereby muscle contraction are inhibited.

Muscle strength testing can be used to determine the presence of a neuromuscular disease, but cannot determine its cause. Additional testing, such as electromyography, can provide diagnostic information, but information gained from muscle strength testing alone is not enough to diagnose most neuromuscular disorders.

Mental=====

Mental fatigue is a temporary inability to maintain optimal cognitive performance. The onset of mental fatigue during any cognitive activity is gradual, and depends upon an individual's cognitive ability, and also upon other factors, such as sleep deprivation and overall health.

Mental fatigue has also been shown to decrease physical performance. It can manifest as somnolence, lethargy, directed attention fatigue, or disengagement. Research also suggests that mental fatigue is closely linked to the concept of ego depletion, though the validity of the concept is disputed. For example, one pre-registered study of 686 participants found that after exerting mental effort, people are likely to disengage and become less interested in exerting further effort.

Decreased attention can also be described as a more or less decreased level of consciousness. In any case, this can be dangerous when performing tasks that require constant concentration, such as operating large vehicles. For instance, a person who is sufficiently somnolent may experience microsleep. However, objective cognitive testing can be used to differentiate the neurocognitive deficits of brain disease from those attributable to tiredness.

The perception of mental fatigue is believed to be modulated by the brain's reticular activating system (RAS).

Fatigue impacts a driver's reaction time, awareness of hazards around them and their attention. Drowsy drivers are three times more likely to be involved in a car crash, and being awake over 20 hours is the equivalent of driving with a blood-alcohol concentration level of 0.08%.

Neurological fatigue

People with multiple sclerosis experience a form of overwhelming tiredness that can occur at any time of the day, for any duration, and that does not necessarily recur in a recognizable pattern for any given patient, referred to as "neurological fatigue", and often as "multiple sclerosis fatigue" or "lassitude". People with autoimmune diseases including inflammatory rheumatic diseases such as rheumatoid arthritis, psoriatic arthritis and primary Sjögren's syndrome, experience similar fatigue. Attempts have been made to isolate causes of central nervous system fatigue.

By timescale

; :Acute fatigue is that which is temporary and self-limited. Acute fatigue is most often caused by an infection such as the common cold and can be cognized as one part of the sickness behavior response occurring when the immune system fights an infection. Other common causes of acute fatigue include depression and chemical causes, such as dehydration, poisoning, low blood sugar, or mineral or vitamin deficiencies. ; :Prolonged fatigue is a self-reported, persistent (constant) fatigue lasting at least one month. ; :Chronic fatigue is a self-reported fatigue lasting at least 6 consecutive months. Chronic fatigue may be either persistent or relapsing. Chronic fatigue is a symptom of many chronic illnesses and of idiopathic chronic fatigue.

By effect

Fatigue can have significant negative impacts on quality of life. Profound and debilitating fatigue is the most common complaint reported among individuals with autoimmune disease, such as systemic lupus erythematosus, multiple sclerosis, type 1 diabetes, celiac disease, Myalgic Encephalomyelitis/chronic fatigue syndrome, and rheumatoid arthritis. Fatigue has been described by sufferers as 'incomprehensible' due to its unpredictable occurrence, lack of relationship to physical effort and different character as compared to tiredness.

WHO classification

The World Health Organization's ICD-11 classification includes a category MG22 Fatigue (typically fatigue following exertion but sometimes may occur in the absence of such exertion as a symptom of health conditions), and many other categories where fatigue is mentioned as a secondary result of other factors.

• 8E49 Postviral fatigue syndrome
• QE84 Acute stress reaction, Combat fatigue
• 6A70-6A7Z Depressive disorders
• 07 Sleep-wake disorders
• FB32.5 Muscle strain or sprain, causing muscular fatigue
• NF01.3 Heat fatigue, transient
• MA82.Y Voice disturbances, causing voice fatigue
• BD1Z Heart failure, unspecified, causing myocardial fatigue
• JA65.Y Conditions predominantly related to pregnancy, causing fatigue which complicates pregnancy
• SD91 Fatigue consumption disorder, causing coughing, fever, diarrhea, chest pain etc.
• MG2A Ageing associated decline in intrinsic capacity, causing senile fatigue
• NF07.2 Exhaustion due to exposure
• NF01 Heat exhaustion
• 6C20 Bodily distress disorder. ICD-11 It does not include any fatigue-based psychiatric illness (unless it is accompanied by related psychiatric symptoms).

DSM-5 lists 'fatigue or loss of energy nearly every day' as one factor in diagnosing depression.

Treatment and management

Management may include review of factors and methods as explained below.

Cessation of medications causing fatigue

Taking of medications with side effects of contributing to fatigue may be ceased.

Medications to treat fatigue

The UK NICE recommends consideration of amantadine, modafinil, and selective serotonin reuptake inhibitors (SSRIs) for MS fatigue. A PCORI review, however, found amantadine, methylphenidate, and modafinil no more effective than placebo in reducing fatigue, with side effects reported. Psychostimulants such as methylphenidate, amphetamines, and modafinil have been used in the treatment of fatigue related to depression, and medical illness such as chronic fatigue syndrome and cancer. They have also been used to counteract fatigue in sleep loss and in aviation.

Mental health tools

CBT can be useful for fatigue, including ME/CFS but is not included in NICE guidelines for ME/CFS treatment.

Other approaches

Avoidance of body heat

Fatigue in MS often correlates with relatively high endogenous body temperature.

Improved sleep

Improving sleep has been associated with reduced fatigue but only in small studies.

Intermittent fasting

A very small 2022 study found 40% reductions in fatigue categorisations after three months of 16:8 intermittent fasting.

Vagus nerve stimulation

A very small 2023 study of Sjogren's patients showed reductions in self-reported fatigue after 56 days of vagus nerve stimulation.

Qigong and Tai Chi

Qigong and Tai chi have been postulated as helpful to reduce fatigue, but the evidence is of low quality.

Approaches to managing fatigue

Some health systems help people manage their fatigue better through attitude changes and skills transference.

Prevalence

2023 guidance stated fatigue prevalence is between 4.3% and 21.9%. Prevalence is higher in women than men.

A 2021 German study found that fatigue was the main or secondary reason for 10–20% of all consultations with a primary care physician.

A large study based on the 2004 Health and Retirement Study (HRS), a biennial longitudinal survey of US adults aged 51 and above, with mean age 65, found that 33% of women and 29% of men self-reported fatigue.

Fatigue represents a large health economic burden and unmet need to patients and to society.

Possible purposes of fatigue

Body resource management purposes

Fatigue has been posited as a bio-psycho-physiological state reflecting the body's overall strategy in resource (energy) management. Fatigue may occur when the body wants to limit resource utilisation ("rationing") in order to use resources for healing (part of sickness behaviour) or conserve energy for a particular current or future anticipated need, including a threat.

Evolutionary purposes

It has been posited that fatigue had evolutionary benefits in making more of the body's resources available for healing processes, such as immune responses, and in limiting disease spread by tending to reduce social interactions.

References

References

1. "Fatigue".
2. "Cancer terms".
3. (August 2014). "Fatigue in healthy and diseased individuals". Am J Hosp Palliat Care.
4. (19 October 2017). "Medically unexplained symptoms".
5. (September 2019). "Anti-Inflammatory Diets and Fatigue". Nutrients.
6. (February 1992). "Some central and peripheral factors affecting human motoneuronal output in neuromuscular fatigue". Sports Medicine.
7. (July 1981). "Muscular endurance and surface electromyogram in isometric and dynamic exercise". Journal of Applied Physiology.
8. (June 1997). "Fatigue revisited". Journal of Sports Sciences.
9. (March 2009). "Mental fatigue impairs physical performance in humans". Journal of Applied Physiology.
10. (September 2018). "Mental Fatigue Impairs Endurance Performance: A Physiological Explanation". Sports Med.
11. (2 May 2023). "Shared imaging markers of fatigue across multiple sclerosis, aquaporin-4 antibody neuromyelitis optica spectrum disorder and MOG antibody disease". Brain Communications.
12. (2020). "What's in a name? That which we call Multiple Sclerosis Fatigue". Multiple Sclerosis.
13. "MeSH Browser".
14. "Exhaustion".
15. Rogers, Ann E.. (April 11, 2008). "Patient Safety and Quality: An Evidence-Based Handbook for Nurses". Agency for Healthcare Research and Quality (US).
16. (August 11, 1997). "Fatigue and sleep disorders". Behaviour Research and Therapy.
17. (February 2006). "Distinguishing sleepiness and fatigue: focus on definition and measurement". Sleep Medicine Reviews.
18. https://icd.who.int/browse/2025-01/mms/en#1109546957
19. (November 2021). "Fatigue in inflammatory rheumatic diseases: current knowledge and areas for future research". Nature Reviews Rheumatology.
20. (25 October 2021). "Fatigue in patients with chronic disease: results from the population-based Lifelines Cohort Study". Scientific Reports.
21. (2006). "Fatigue in Liver Disease: Pathophysiology and Clinical Management". Canadian Journal of Gastroenterology.
22. (May 2020). "Management of Fatigue in Rheumatoid Arthritis". RMD Open.
23. "Myalgische Enzephalomyelitis / Chronic Fatigue Syndrome (ME/CFS) – Aktueller Kenntnisstand".
24. Fleming, Russell. (April 19, 2024). "Neurology Today: Are ME/CFS and Long Covid part of the same disorder?".
25. Trust, M. S.. "Temperature sensitivity | MS Trust".
26. "MS and heat fatigue: does it come down to sweating?".
27. (October 24, 2017). "Lupus".
28. "Manage Your Lupus | Lupus UK".
29. "Fibromyalgia: Symptoms, Diagnosis & Treatment".
30. "Fatigue in Patients With Multiple Sclerosis".
31. "Relapsing remitting MS (RRMS)". MS Society.
32. (November 19, 2019). "Presentation and Clinical Course of ME/CFS | Information for Healthcare Providers | Myalgic Encephalomyelitis/Chronic Fatigue Syndrome ME/CFS | CDC".
33. (June 2020). "A Qualitative Metasynthesis of the Experience of Fatigue Across Five Chronic Conditions". Journal of Pain and Symptom Management.
34. "What is cancer fatigue?".
35. (February 4, 2010). "Fatigue After Brain Injury: BrainLine Talks With Dr. Nathan Zasler | BrainLine".
36. (18 August 2016). "The daily struggle of living with extreme fatigue".
37. (May 2010). "Primary Sjogren's syndrome: too dry and too tired". Rheumatology.
38. (April 20, 2018). "Pain and Fatigue Variability Patterns Distinguish Subgroups of Fibromyalgia Patients". The Journal of Pain.
39. "Fatigue | MS Trust".
40. (8 September 2023). "Dee feels like a prisoner in her own body and wants more people to know the truth about her illness". ABC News.
41. Dures, Emma. (2024). "2023 EULAR recommendations for the management of fatigue in people with inflammatory rheumatic and musculoskeletal diseases". Elsevier BV.
42. (15 December 2023). "Factors affecting physical and mental fatigue in adults from South Korea: A cross-sectional study". Medicine.
43. (2020). "Impact of clinical and sociodemographic factors on fatigue among patients with substance use disorder: a cohort study from Norway for the period 2016–2020 - PMC". Substance Abuse Treatment, Prevention, and Policy.
44. (2023). "Promising Pedagogies for Teacher Inquiry and Practice: Teaching Outloud". Teachers College Press.
45. "Ophthalmology: Computer-Related Eye Fatigue".
46. (12 August 2016). "Commercial Motor Vehicle Driver Fatigue, Long-Term Health, and Highway Safety: Research Needs". National Academies Press (US).
47. (February 25, 2022). "Predicting and mitigating fatigue effects due to sleep deprivation: A review". Frontiers in Neuroscience.
48. (12 February 2015). "Fatigue in Multiple Sclerosis: A Look at the Role of Poor Sleep". Frontiers in Neurology.
49. (1993). "SLEEP DISTURBANCES IN PATIENTS WITH PRIMARY SJÖGREN'S SYNDROME". Rheumatology.
50. (26 April 2018). "Tiredness and fatigue".
51. "Fatigue Causes".
52. (July 2010). "Physical and psychosocial correlates of severe fatigue in rheumatoid arthritis". Rheumatology.
53. (January 26, 2021). "Fatigue in Systemic Lupus Erythematosus and Rheumatoid Arthritis: A Comparison of Mechanisms, Measures and Management". Journal of Clinical Medicine.
54. (November 2019). "A biopsychosocial network model of fatigue in rheumatoid arthritis: a systematic review". Rheumatology.
55. (2019). "Fatigue severity in anti-nuclear antibody-positive individuals does not correlate with pro-inflammatory cytokine levels or predict imminent progression to symptomatic disease". Arthritis Research & Therapy.
56. (23 March 2015). "Fatigue Survey Results Released". Autoimmune Association.
57. Cleveland Clinic medical professional. (2022-12-07). "Blood Disorders: Types, Symptoms & Treatments".
58. Hamilton, James Peter Adam. (2022-09-06). "Hemochromatosis".
59. "Fatigue after brain injury".
60. (18 August 2016). "The daily struggle of living with extreme fatigue".
61. "What is cancer fatigue? | Coping physically | Cancer Research UK".
62. (7 January 2021). "Long-term effects of coronavirus (Long COVID)".
63. (2001). "Problem-oriented Medical Diagnosis". Lippincott Williams & Wilkins.
64. (2013). "Beyond pain in fibromyalgia: insights into the symptom of fatigue". Arthritis Research & Therapy.
65. (August 2010). "Fatigue after myocardial infarction: Relationships with indices of emotional distress, and sociodemographic and clinical variables". International Journal of Nursing Practice.
66. (April 2017). "Fatigue Symptom Management in People Living With Human Immunodeficiency Virus". Journal of Hospice & Palliative Nursing.
67. (April 2002). "Systematic review of the comorbidity of irritable bowel syndrome with other disorders: What are the causes and implications?". Gastroenterology.
68. (February 2007). "Review article: fructose malabsorption and the bigger picture". Alimentary Pharmacology & Therapeutics.
69. (February 2021). "Fatigue in irritable bowel syndrome is associated with plasma levels of TNF-α and mesocorticolimbic connectivity". Brain, Behavior, and Immunity.
70. (2020-11-27). "Diagnosis, Classification and Management of Mast Cell Activation Syndromes (MCAS) in the Era of Personalized Medicine". International Journal of Molecular Sciences.
71. (2017). "Characterization of Mast Cell Activation Syndrome". The American Journal of the Medical Science.
72. (2024-06-09). "Mast cell activation syndrome: An up-to-date review of literature". World J Clin Pediatr.
73. (2013). "Diagnostic and statistical manual of mental disorders 5th edition: [[DSM-5]]". American Psychiatric Association.
74. (April 2022). "Current and lifetime somatic symptom burden among transition-aged autistic young adults". Autism Research.
75. "ICD-11 for Mortality and Morbidity Statistics".
76. (November 2021). "Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Essentials of Diagnosis and Management". Mayo Clinic Proceedings.
77. (June 2019). "Differential diagnosis between "chronic fatigue" and "chronic fatigue syndrome"". Integrative Medicine Research.
78. (5 June 2021). "Comparing Idiopathic Chronic Fatigue and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) in Males: Response to Two-Day Cardiopulmonary Exercise Testing Protocol". Healthcare.
79. (December 2014). "Gulf War Syndrome: a review of current knowledge and understanding". Journal of the Royal Naval Medical Service.
80. (2018). "Fatigue in Patients With Multiple Sclerosis". Practical Neurology.
81. (2015). "Fatigue in Multiple Sclerosis: Neural Correlates and the Role of Non-Invasive Brain Stimulation". Frontiers in Cellular Neuroscience.
82. (July 2019). "Importance of fatigue and its measurement in chronic liver disease". World Journal of Gastroenterology.
83. (June 2013). "Fatigue". European Journal of Hospital Pharmacy.
84. (3 July 2016). "Central fatigue in multiple sclerosis: a review of the literature". The Journal of Spinal Cord Medicine.
85. (27 July 2022). "The pathophysiology of motor fatigue and fatigability in multiple sclerosis". Frontiers in Neurology.
86. "ICD-11 for Mortality and Morbidity Statistics".
87. (15 April 2006). "Cross-Sectional Relationship of Reported Fatigue to Obesity, Diet, and Physical Activity: Results From the Third National Health and Nutrition Examination Survey". Journal of Clinical Sleep Medicine.
88. (25 April 2005). "The Association of Obesity, Cytokine Levels, and Depressive Symptoms With Diverse Measures of Fatigue in Healthy Subjects". Archives of Internal Medicine.
89. (November 23, 2017). "Obesity".
90. "Evaluation of fatigue — Differential diagnosis of symptoms | BMJ Best Practice US".
91. (2024). "StatPearls". StatPearls Publishing.
92. "Evaluation of fatigue — Differential diagnosis of symptoms | BMJ Best Practice US".
93. "Somatic symptom disorder — Symptoms and causes".
94. (December 2016). "Adrenal fatigue does not exist: a systematic review". BMC Endocrine Disorders.
95. Whitbourne, Kathryn. (February 7, 2021). "Adrenal Fatigue: Is It Real?". Metcalf, Eric.
96. (May 2012). "Chapter 29: Unproved and controversial methods and theories in allergy-immunology". Allergy and Asthma Proceedings.
97. (November 15, 2019). "Fatigue in inflammatory rheumatic disorders: pathophysiological mechanisms". Rheumatology.
98. (November 2019). "Fatigue in inflammatory rheumatic disorders: pathophysiological mechanisms". Rheumatology.
99. (June 2020). "The biological basis of chronic fatigue: neuroinflammation and innate immunity". Current Opinion in Neurology.
100. (2018). "The High Costs of Low-Grade Inflammation: Persistent Fatigue as a Consequence of Reduced Cellular-Energy Availability and Non-adaptive Energy Expenditure". Frontiers in Behavioral Neuroscience.
101. (2017). "Role of Inflammation in Human Fatigue: Relevance of Multidimensional Assessments and Potential Neuronal Mechanisms". Frontiers in Immunology.
102. (August 24, 2019). "A systematic review of cytokines in chronic fatigue syndrome/myalgic encephalomyelitis/systemic exertion intolerance disease (CFS/ME/SEID)". BMC Neurology.
103. (April 1, 2019). "Neural Mechanisms of Mental Fatigue Revisited: New Insights from the Brain Connectome". Engineering.
104. (February 28, 2023). "Disruptions in Structural and Functional Connectivity Relate to Poststroke Fatigue". Brain Connectivity.
105. (October 22, 2013). "Regional Brain Atrophy and Functional Connectivity Changes Related to Fatigue in Multiple Sclerosis". PLOS ONE.
106. (February 1, 2016). "Abnormal Resting-State Functional Connectivity in Patients with Chronic Fatigue Syndrome: Results of Seed and Data-Driven Analyses". Brain Connectivity.
107. (January 30, 2021). "Cingulo-Opercular and Frontoparietal Network Control of Effort and Fatigue in Mild Traumatic Brain Injury". Frontiers in Human Neuroscience.
108. (February 16, 2016). "Post mTBI fatigue is associated with abnormal brain functional connectivity". Scientific Reports.
109. (September 2022). "Fatigue Leads to Dynamic Shift in Fronto-parietal Sustained Attention Network". Proceedings of the Human Factors and Ergonomics Society Annual Meeting.
110. (2024). "Brain connectivity changes underlying depression and fatigue in relapsing-remitting multiple sclerosis: A systematic review". PLOS ONE.
111. (2023). "EDSS and infratentorial white matter lesion volume are considered predictors of fatigue severity in RRMS". Scientific Reports.
112. (June 2020). "Brain anatomical correlates of fatigue in multiple sclerosis". Multiple Sclerosis Journal.
113. (March 2023). "Structural and functional magnetic resonance imaging correlates of fatigue and dual-task performance in progressive multiple sclerosis". Journal of Neurology.
114. (December 2018). "The neural basis of fatigue in multiple sclerosis: A multimodal MRI approach". Neurology Clinical Practice.
115. (November 2016). "Fatigue in multiple sclerosis: The contribution of occult white matter damage". Multiple Sclerosis Journal.
116. (November 2014). "Regional but Not Global Brain Damage Contributes to Fatigue in Multiple Sclerosis". Radiology.
117. (February 2017). "Integrity of normal-appearing white matter: Influence of age, visible lesion burden and hypertension in patients with small-vessel disease". Journal of Cerebral Blood Flow & Metabolism.
118. (2016). "Heat shock proteins and chronic fatigue in primary Sjögren's syndrome". Innate Immunity.
119. (February 2020). "Heat-shock protein 90 α in plasma reflects severity of fatigue in patients with Crohn's disease". Innate Immunity.
120. (10 January 2012). "Interleukin-1 Inhibition and Fatigue in Primary Sjögren's Syndrome – A Double Blind, Randomised Clinical Trial". PLOS ONE.
121. (September 2005). "The effect of interleukin-1 blockade on fatigue in rheumatoid arthritis—a pilot study". Rheumatology International.
122. (June 2022). "Fatigue and expression of heat-shock protein genes in plaque psoriasis". Clinical and Experimental Dermatology.
123. (September 2021). "Measuring fatigue: a meta-review". International Journal of Dermatology.
124. (July 23, 2022). "Comparative responsiveness and minimally important difference of Fatigue Symptom Inventory (FSI) scales and the FSI-3 in trials with cancer survivors". Journal of Patient-Reported Outcomes.
125. "INFORMATION ABOUT THE FATIGUE SYMPTOM INVENTORY (FSI) AND THE MULTIDIMENSIONAL FATIGUE SYMPTOM INVENTORY (MFSI)".
126. (December 2022). "Comparative responsiveness and minimally important difference of Fatigue Symptom Inventory (FSI) scales and the FSI-3 in trials with cancer survivors". Journal of Patient-Reported Outcomes.
127. "Fatigue Severity Scale (FSS)".
128. (November 2008). "Validation of the Fatigue Severity Scale in a Swiss Cohort". Sleep.
129. "Fatigue Severity Scale (FSS)".
130. (23 March 2015). "Fatigue Survey Results Released".
131. (2023). "Understanding mental fatigue and its detection: a comparative analysis of assessments and tools". [[PeerJ]].
132. (October 20, 2016). "The differential diagnosis of tiredness: a systematic review". BMC Family Practice.
133. Practitioners, The Royal Australian College of general. "Fatigue – a rational approach to investigation".
134. (November 2009). "Diagnoses during follow-up of patients presenting with fatigue in primary care". CMAJ.
135. (July 2021). "Pain and fatigue in primary Sjögren's syndrome". Rheumatology.
136. (July 28, 2019). "Importance of fatigue and its measurement in chronic liver disease". World Journal of Gastroenterology.
137. (2019). "Fatigue, Sleep, and Autoimmune and Related Disorders". Frontiers in Immunology.
138. "Weakness and fatigue". Healthwise Inc..
139. (October 2001). "Spinal and supraspinal factors in human muscle fatigue". Physiological Reviews.
140. (August 2000). "Serotonin and central nervous system fatigue: nutritional considerations". The American Journal of Clinical Nutrition.
141. (August 2005). "Synaptic release of serotonin induced by stimulation of the raphe nucleus promotes plateau potentials in spinal motoneurons of the adult turtle". The Journal of Neuroscience.
142. (March 2013). "Serotonin spillover onto the axon initial segment of motoneurons induces central fatigue by inhibiting action potential initiation". Proceedings of the National Academy of Sciences of the United States of America.
143. (January 2008). "Muscle fatigue: what, why and how it influences muscle function". The Journal of Physiology.
144. (May 2020). "Strong Effort Manipulations Reduce Response Caution: A Preregistered Reinvention of the Ego-Depletion Paradigm". Psychological Science.
145. (1991). "Difficult Diagnosis 2". W.B. Saunders Co..
146. (January 2018). "The Brain Health Assessment for Detecting and Diagnosing Neurocognitive Disorders". J Am Geriatr Soc.
147. (June 2021). "A systematic review of the association between fatigue and cognition in chronic noncommunicable diseases". Chronic Illn.
148. (2023). "Efficient assessment of brain fog and fatigue: Development of the Fatigue and Altered Cognition Scale (FACs)". PLOS ONE.
149. (2014). "Neural mechanisms of mental fatigue". Rev Neurosci.
150. (2016). "Arousal and the control of perception and movement". Curr Trends Neurol.
151. (January 2020). "Arousal and sleep circuits". Neuropsychopharmacology.
152. (April 2023). "The reticular activating system: a narrative review of discovery, evolving understanding, and relevance to current formulations of brain death". Can J Anaesth.
153. (2024). "StatPearls". StatPearls Publishing.
154. "Drowsy Driving is Impaired Driving".
155. (June 2021). "What's in a name? That which we call ''Multiple Sclerosis Fatigue''". Multiple Sclerosis.
156. (February 2010). "Development of a patient reported outcome scale for fatigue in multiple sclerosis: The Neurological Fatigue Index (NFI-MS)". Health and Quality of Life Outcomes.
157. "TikTok — Make Your Day".
158. (May 2012). "Genetic associations of fatigue and other symptom domains of the acute sickness response to infection". Brain, Behavior, and Immunity.
159. (August 2021). "Dissecting the fatigue experience: A scoping review of fatigue definitions, dimensions, and measures in non-oncologic medical conditions". Brain Behav Immun Health.
160. (2008). "A systematic review of chronic fatigue syndrome: don't assume it's depression". Prim Care Companion J Clin Psychiatry.
161. (December 1994). "The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group". Annals of Internal Medicine.
162. (16 August 2016). "Idiopathic chronic fatigue in older adults is linked to impaired mitochondrial content and biogenesis signaling in skeletal muscle". Oncotarget.
163. (25 June 2021). "Understanding Fatigue in Sjögren's Syndrome: Outcome Measures, Biomarkers and Possible Interventions". Frontiers in Immunology.
164. (January 2013). "I've lost the person I used to be— Experiences of the consequences of fatigue following myocardial infarction". International Journal of Qualitative Studies on Health and Well-being.
165. (2019). "ICD-11 - Mortality and Morbidity Statistics {{!}} MG22 Fatigue".
166. (2018). "Nosological journey of somatoform disorders: From briquet's syndrome to bodily distress disorder". Indian Journal of Social Psychiatry.
167. (September 2020). "Evolution of bodily distress disorders". Current Opinion in Psychiatry.
168. (August 26, 2022). "Depression Definition and DSM-5 Diagnostic Criteria".
169. (October 2013). "A review on antiepileptic drugs-dependent fatigue: pathophysiological mechanisms and incidence". European Journal of Pharmacology.
170. (8 March 2016). "What to do when medication makes you sleepy".
171. (May 2013). "Drug-drug interactions that should be non-interruptive in order to reduce alert fatigue in electronic health records". Journal of the American Medical Informatics Association.
172. (June 22, 2022). "Recommendations | Multiple sclerosis in adults: management | Guidance | NICE".
173. (2023-09-01). "Comparing Treatments for Multiple Sclerosis-Related Fatigue - Evidence Update for Clinicians".
174. (April 2008). "Psychostimulants for depression". Cochrane Database Syst Rev.
175. (February 2009). "Methylphenidate for the treatment of depressive symptoms, including fatigue and apathy, in medically ill older adults and terminally ill adults". Am J Geriatr Pharmacother.
176. (March 2016). "Stimulants for depression: On the up and up?". Aust N Z J Psychiatry.
177. (September 2021). "Comparative efficacy and safety of stimulant-type medications for depression: A systematic review and network meta-analysis". J Affect Disord.
178. (February 2010). "Chronic fatigue syndrome: is there a role for non-antidepressant pharmacotherapy?". Expert Opin Pharmacother.
179. (June 2008). "Diagnostic and treatment challenges of chronic fatigue syndrome: role of immediate-release methylphenidate". Expert Rev Neurother.
180. (September 1996). "Use of stimulants in the medically ill". Psychiatr Clin North Am.
181. (August 2010). "Psychostimulants for cancer-related fatigue". J Natl Compr Canc Netw.
182. (April 2011). "Psychostimulants for the management of cancer-related fatigue: a systematic review and meta-analysis". J Pain Symptom Manage.
183. (2014). "Effect of methylphenidate in patients with cancer-related fatigue: a systematic review and meta-analysis". PLOS ONE.
184. (2014). "Review of clinical trials of pharmacologic interventions for cancer-related fatigue: focus on psychostimulants and steroids". Cancer J.
185. (2015). "The dopamine imbalance hypothesis of fatigue in multiple sclerosis and other neurological disorders". Front Neurol.
186. (September 2005). "The use of stimulants to modify performance during sleep loss: a review by the sleep deprivation and Stimulant Task Force of the American Academy of Sleep Medicine". Sleep.
187. (March 2021). "Stimulant Use as a Fatigue Countermeasure in Aviation". Aerosp Med Hum Perform.
188. (September 2013). "The process of cognitive behaviour therapy for chronic fatigue syndrome: Which changes in perpetuating cognitions and behaviour are related to a reduction in fatigue?". Journal of Psychosomatic Research.
189. (January 27, 2022). "Self-help tips to fight tiredness".
190. (February 28, 2024). "Does the effect of cognitive behavior therapy for chronic fatigue syndrome (ME/CFS) vary by patient characteristics? A systematic review and individual patient data meta-analysis". Psychological Medicine.
191. (October 2020). "Cognitive behavioural therapy for chronic fatigue and chronic fatigue syndrome: outcomes from a specialist clinic in the UK". Journal of the Royal Society of Medicine.
192. (October 29, 2021). "Recommendations | Myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome: diagnosis and management | Guidance | NICE".
193. Jefferies, Emma. (November 6, 2023). "The ME Association raises concerns about new research promoting CBT as a treatment for ME/CFS".
194. "Heat Sensitivity".
195. (August 11, 2014). "Higher Body Temperature in RRMS Patients Could Cause Increased Fatigue".
196. (July 15, 2014). "Body temperature is elevated and linked to fatigue in relapsing-remitting multiple sclerosis, even without heat exposure". Archives of Physical Medicine and Rehabilitation.
197. (November 2015). "Elevated body temperature is linked to fatigue in an Italian sample of relapsing–remitting multiple sclerosis patients". Journal of Neurology.
198. (June 2019). "Pathophysiological and cognitive mechanisms of fatigue in multiple sclerosis". Journal of Neurology, Neurosurgery, and Psychiatry.
199. (September 2022). "Neurostructural and Neurophysiological Correlates of Multiple Sclerosis Physical Fatigue: Systematic Review and Meta-Analysis of Cross-Sectional Studies". Neuropsychology Review.
200. (2016). "Central fatigue in multiple sclerosis: A review of the literature". The Journal of Spinal Cord Medicine.
201. (November 2022). "Heat and cold sensitivity in multiple sclerosis: A patient-centred perspective on triggers, symptoms, and thermal resilience practices". Multiple Sclerosis and Related Disorders.
202. (November 15, 2010). "Thermoregulation in multiple sclerosis". Journal of Applied Physiology.
203. (2018). "Thermoregulation: From Basic Neuroscience to Clinical Neurology, Part II". Elsevier.
204. (October 2012). "Improvement in pain, fatigue, and subjective sleep quality through sleep hygiene tips in patients with fibromyalgia". Revista Brasileira de Reumatologia.
205. (June 2022). "Sleep quality in relation to trait energy and fatigue: an exploratory study of healthy young adults". Sleep Science.
206. (October 10, 2022). "Intermittent Fasting—Short- and Long-Term Quality of Life, Fatigue, and Safety in Healthy Volunteers: A Prospective, Clinical Trial". Nutrients.
207. (April 2023). "The Effects of Noninvasive Vagus Nerve Stimulation on Fatigue in Participants With Primary Sjögren's Syndrome". Neuromodulation: Technology at the Neural Interface.
208. (5 April 2017). "Does Tai Chi relieve fatigue? A systematic review and meta-analysis of randomized controlled trials". PLOS ONE.
209. (22 June 2021). "Efficacy of Qigong Exercise for Treatment of Fatigue: A Systematic Review and Meta-Analysis". Frontiers in Medicine.
210. (2019). "Exercise on Brain Health". Academic Press.
211. Trust, Royal United Hospitals Bath NHS Foundation. "Royal United Hospitals Bath NHS Foundation Trust".
212. (April 12, 2023). "Energy & Fatigue".
213. "Managing MS Fatigue - Help & Support | MS Society".
214. "Fatigue".
215. "Cancer fatigue: Why it occurs and how to cope".
216. "Evaluation of fatigue — Differential diagnosis of symptoms".
217. (July 1998). "Fatigue in the general norwegian population". Journal of Psychosomatic Research.
218. (August 30, 2021). "Fatigue as the Chief Complaint". Deutsches Ärzteblatt International.
219. (October 2010). "Prevalence and Predictors of Fatigue in Middle-Aged and Older Adults: Evidence from the Health and Retirement Study". Journal of the American Geriatrics Society.