Fatigue

This article is about the medical term. For other uses, see Fatigue (disambiguation).

Not to be confused with Muscle weakness or Lethargy.

Fatigue describes a state of tiredness (which is not sleepiness) or exhaustion.^[1] In general usage, fatigue often follows prolonged physical or mental activity. When fatigue occurs independently of physical or mental exertion, or does not resolve after rest or sleep, it may have other causes, such as a medical condition.^[2]

Fatigue
Other names	Exhaustion, weariness, tiredness, lethargy, listlessness
Specialty	Internal medicine and most other specialities
Treatment	Avoid known stressors, avoid unhealthy habits such as: drug use, excessive alcohol consumption, smoking; healthy diet, exercise regularly, medication, staying hydrated, and vitamins

Fatigue (in a medical context) is complex and its cause is often unknown.^[3] Fatigue is associated with a wide variety of conditions including autoimmune disease, organ failure, chronic pain conditions, mood disorders, heart disease, infectious diseases, and post-infectious-disease states.^[4]

Fatigue (in the general usage sense of normal tiredness) can include both physical and mental fatigue. Physical fatigue results from muscle fatigue brought about by intense physical activity.^[5][6][7] Mental fatigue results from prolonged periods of cognitive activity which impairs cognitive ability. Mental fatigue can manifest as sleepiness, lethargy, or directed attention fatigue.^[8] Mental fatigue can also impair physical performance.^[9]

Definition

Fatigue in a medical context is used to cover experiences of low energy that are not caused by normal life.^[10][11]

Distinguishing features of such fatigue include

• not linking fatigue to an obvious cause,
• lack of improvement with rest,
• variability in severity,
• unpredictability, and
• fatigue being more profound/overwhelming, and having extensive impact on daily living.^[12]

Correlation of the quantum of fatigue with the severity of an underlying disease is often not present.^[12]

Fatigue is multi-faceted and broadly defined, which makes understanding the cause of its manifestations especially difficult in conditions with diverse pathology including autoimmune diseases.^[13]

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".^[12]

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.".^[14]

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 to cover variants within the umbrella term of fatigue.^[15]

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.^[16]

Sleepiness

Fatigue is generally considered a longer-term condition than sleepiness (somnolence).^[17] Although sleepiness can be a symptom of a medical condition, it usually results from lack of restful sleep, or lack of stimulation.^[18] Fatigue is often described as an uncomfortable tiredness, whereas sleepiness can be comfortable and inviting.

Classification

See also: Central nervous system fatigue and Muscle fatigue

By type

Uni- or multi-dimensional

It is disputed whether there are different dimensions of fatigue, such as peripheral (muscle) and central (mental) fatigue, or whether fatigue is a uni-dimensional phenomenon that influences different aspects of human life.^[19][20]

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.^[12]

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.^[21] 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.^[22] The central component of fatigue is triggered by an increase of the level of serotonin in the central nervous system.^[23] During motor activity, serotonin released in synapses that contact motor neurons promotes muscle contraction.^[24] 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.^[25]

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.^[26]

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.^[8] 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.^[27]

Decreased attention can also be described as a more or less decreased level of consciousness.^[28] 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.^{[citation needed]}

The perception of mental fatigue is believed to be modulated by the brain's reticular activating system (RAS).^{[citation needed]}

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%.^[29]

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".^[30][31]

People with autoimmune diseases including inflammatory rheumatic diseases such as rheumatoid arthritis, psoriatic arthritis and primary Sjögren's syndrome, experience similar fatigue.^[32][33][34]

By timescale

Acute

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.^[35]

Other common causes of acute fatigue include depression and chemical causes, such as dehydration, poisoning, low blood sugar, or mineral or vitamin deficiencies.

Prolonged

Prolonged fatigue is a self-reported, persistent (constant) fatigue lasting at least one month.^{[medical citation needed]}

Chronic

Chronic fatigue is a self-reported fatigue lasting at least 6 consecutive months. Chronic fatigue may be either persistent or relapsing.^[36] 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.^[37][38] 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, chronic fatigue syndrome, and rheumatoid arthritis.^[12]

Fatigue that dissociates by quantum with disease activity represents a large health economic burden and unmet need to patients and to society.^[12]

Measurement

Fatigue is currently measured by many different self-measurement surveys.^[39] There is no consensus on best practice,^[40] and the existing surveys do not capture the intermittent nature of some forms of fatigue.

Nintendo announced plans for a device to possibly quantitatively measure fatigue in 2014,^[41] but the project was stopped in 2016.^[42]

Causes

Undiagnosed

The cause of fatigue is often undiagnosed.^[43]

Idiopathic chronic fatigue

Main article: Idiopathic chronic fatigue

Idiopathic chronic fatigue is chronic fatigue not caused by a known proximate cause such as a discrete medical condition, drug or alcohol use.

Medications

Fatigue may be a side effect of certain medications (e.g., lithium salts, ciprofloxacin); beta blockers, which can induce exercise intolerance; and many cancer treatments, particularly chemotherapy and radiotherapy.

Drug use

Caffeine and alcohol can cause fatigue.^[44]

Sleep deprivation

Sleep deprivation and disruption is associated with subsequent fatigue. ^[45][46]

Obesity

Obesity appears to correlate with greater fatigue incidence.^[47]

Psychological stress and conditions

Depression and adverse life events have been associated with fatigue.^[32]

Association with diseases

Fatigue is often associated with diseases and conditions. Some major categories of conditions that often list fatigue as a symptom include:

• Autoimmune diseases,^[48][49] such as celiac disease, lupus, multiple sclerosis,^[50] myasthenia gravis, NMOSD, Sjögren's syndrome, spondyloarthropathy and UCTD.^[51][52] This population's primary concern is fatigue.^[33][53]
• Anxiety disorders, such as generalized anxiety disorder^{[medical citation needed]}
• Blood disorders, such as anemia and hemochromatosis^{[medical citation needed]}
• Brain injury^[54]
• Cancer, in which case it is called cancer fatigue^[55]
• Covid-19; long Covid.^[56]
• Substance use disorders including alcohol use disorder^[57]
• Depression and other mental disorders that feature depressed mood^{[medical citation needed]}
• Developmental disorders such as autism spectrum disorder^[58]
• Eating disorders, which can produce fatigue due to inadequate nutrition
• Endocrine diseases or metabolic disorders: diabetes mellitus, hypothyroidism and Addison's disease^[59]
• Fibromyalgia
• Gulf War syndrome
• Heart failure
• HIV
• Inborn errors of metabolism such as fructose malabsorption.^[60][61]
• Infectious diseases such as infectious mononucleosis or tuberculosis^[59]
• Irritable bowel syndrome
• Kidney diseases e.g. acute renal failure, chronic renal failure^[59]
• Leukemia or lymphoma
• Liver failure or liver diseases e.g. Hepatitis^[59]
• Lyme disease
• Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)^[57]
• Neurological disorders such as narcolepsy, Parkinson's disease, Postural Orthostatic Tachycardia Syndrome and post-concussion syndrome
• Physical trauma and other pain-causing conditions, such as arthritis
• Sleep deprivation or sleep disorders, e.g. sleep apnea^[59]
• Stroke
• Thyroid disease such as hypothyroidism

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).^{[62][63][64][65][66]} The ICD definition of fatigue ^[67] captures both types of fatigue; it includes fatigue that "occur[s] in the absence of... exertion... as a symptom of health conditions."

Mechanisms

The mechanisms that cause fatigue are not well understood.^[13] Several mechanisms may be in operation within a patient,^[68] with the relative contribution of each mechanism differing over time.^[12]

Inflammation

Inflammation distorts neural chemistry, brain function and functional connectivity across a broad range of brain networks,^[69] and has been linked to many types of fatigue.^[48][70] Findings implicate neuroinflammation in the etiology of fatigue in autoimmune and related disorders.^[32][48] Low-grade inflammation may cause an imbalance between energy availability and expenditure.^[71] Cytokines are small protein molecules that modulate immune responses and inflammation (as well as other functions) and may have causal roles in fatigue.^[72][73] The inflammation model 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).^[32]

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.^[74]

Reduced brain connectivity

Fatigue has been correlated with reductions in structural and functional connectivity in the brain.^[75] This has included in post-stroke,^[76] MS,^[77] NMOSD and MOG,^[14] and ME/CFS.^[78] This was also found for fatigue after brain injury,^[79] including a significant linear correlation between self-reported fatigue and brain functional connectivity.^[80] (Areas of the brain for which there is evidence of relation to fatigue are the thalamus and middle frontal cortex,^[80] fronto-parietal and cingulo-opercular,^[79] and default mode network, salience network, and thalamocortical loop areas.^[75][81])

Prevalence

 

Minor dark circles, in addition to a hint of eye bags, a combination which is suggestive of sleep deprivation and/or mental fatigue

2023 guidance stated fatigue prevalence is between 4.3% and 21.9%. Prevalence is higher in women than men.^[82]

2021 German study found that fatigue was the main or secondary reason for 10–20% of all consultations with a primary care physician.^[83]

Diagnosis

The overall goal in diagnosis is to identify and rule out any treatable conditions. This is done by considering

• the person's medical history, any other symptoms present.
• evaluation of the qualities of the fatigue itself. Identifiable patterns to the fatigue can include being more tired at certain times of day, whether fatigue increases throughout the day, and whether fatigue is reduced after taking a nap.
• sleep patterns. These can be examined by enquiring about quality of sleep, the emotional state of the person, sleep pattern, and stress level. The amount of sleep, the hours that are set aside for sleep, and the number of times that a person awakens during the night are important. A sleep study may be ordered to rule out a sleep disorder.
• depression and other psychological conditions.
• substance use disorders, and use of caffeine and alcohol.
• poor diet.
• lack of physical exercise (which paradoxically increases fatigue).

Further tests may include

• blood tests to check for infection or anemia.
• urinalysis to look for signs of liver disease or diabetes mellitus.
• other tests to check for kidney and liver function, such as a comprehensive metabolic panel.^[84] Other tests may be chosen depending on the patient's social history, such as an HIV test or pregnancy test.

A 2009 study concluded about 50% of people who have fatigue receive a diagnosis that could explain the fatigue after a year with the condition. In those people who have a possible diagnosis, musculoskeletal (19.4%) and psychological problems (16.5%) are the most common. Definitive physical conditions were only found in 8.2% of cases.^[85]

2023 guidance stated

• 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 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.^[82]

Treatment and Management

Management may include the following;

Review of existing medications

Medications may be evaluated for side effects that contribute to fatigue^{[86][87][better source needed]} and the interactions of medications are complex.^{[non-primary source needed][88]}

Lifestyle changes

Fatigue may be reduced by reducing obesity, caffeine and alcohol intake,^[89] pain and sleep disturbance, and by improving mental well-being.^[90][12]

Medications used to treat fatigue

The UK NICE recommends consideration of amantadine, modafinil and SSRIs for MS fatigue.^[91] Psychostimulants such as methylphenidate, amphetamines, and modafinil have been used in the treatment of fatigue related to depression,^{[92][93][94][95]} and medical illness such as chronic fatigue syndrome^[96][97] and cancer.^{[93][98][99][100][101][102][103]} They have also been used to counteract fatigue in sleep loss^[104] and in aviation.^[105]

Vagus nerve stimulation

A small study showed possible efficacy of vagus nerve stimulation for fatigue reduction in Sjogren's patients.^[106]

Mental health tools

CBT has been found useful.^[107]

Possible purposes of fatigue

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.^[68]

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 conserve energy for a particular need, including a threat. This need may be a current or future anticipated need.^[12]

See also

• Acquiescence
• Affect
• Cancer-related fatigue
• Central governor
• Chronic stress
• Clouding of consciousness
• Combat stress reaction
• Directed attention fatigue
• Effects of fatigue on safety
• Feeling
• Gaucher's disease
• Heat illness
• Malaise
• Microsleep
• Museum fatigue
• Presenteeism
• Sleep-deprived driving
• Pacing (activity management)
• Zoom fatigue

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Further reading

• Byung-Chul Han: Müdigkeitsgesellschaft. Matthes & Seitz, Berlin 2010, ISBN 978-3-88221-616-5. (Philosophical essay about fatigue as a sociological problem and symptom).
  • Danish edition: Træthedssamfundet. Møller, 2012, ISBN 978-87-994043-7-7.
  • Dutch edition: De vermoeide samenleving. van gennep, 2012, ISBN 978-94-6164-071-0.
  • Italian editions: La società della stanchezza. nottetempo, 2012, ISBN 978-88-7452-345-0.
  • Korean edition: 한병철 지음 | 김태환 옮김. Moonji, 2011, ISBN 978-89-320-2396-0.
  • Spanish edition: La sociedad del cansancio. Herder Editorial, 2012, ISBN 978-84-254-2868-5.

External links

 

Wikiquote has quotations related to Fatigue.

 

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• Fatigue – Information for Patients, U.S. National Cancer Institute