Fatigue

Fatigue is generally considered a more long-term condition than sleepiness (somnolence).[14] Although sleepiness can be a symptom of a medical condition, it usually results from lack of restful sleep, or a lack of stimulation.[15] Fatigue is often described as an uncomfortable tiredness, whereas sleepiness can be comfortable and inviting.

Fatigue can have significant negative impacts on quality of life.[16][17] 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]

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.[18]

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.[19] 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.[20] The central component of fatigue is triggered by an increase of the level of serotonin in the central nervous system.[21] During motor activity, serotonin released in synapses that contact motor neurons promotes muscle contraction.[22] 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.[23]

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.[24]

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.[25]

Decreased attention can also be described as a more or less decreased level of consciousness.[26] 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%.[27]

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".[28][29]

People with inflammatory rheumatic diseases, including rheumatoid arthritis, psoriatic arthritis and primary Sjogren's Syndrome, experience similar fatigue.[30]

Patients very often present with many types or subsets of fatigue.[30]

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.[31]

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.[32] Chronic fatigue is a symptom of many chronic illnesses and of idiopathic chronic fatigue.

The mechanisms that cause fatigue are not well understood.[12]

Inflammation distorts neural chemistry, brain function and functional connectivity across a broad range of brain networks,[33] and has been linked to many types of fatigue.[34][35] Findings implicate neuroinflammation in the etiology of fatigue in autoimmune and related disorders.[34][30] Low-grade inflammation may cause an imbalance between energy availability and expenditure.[36] Cytokines are small protein molecules that modulate immune responses and inflammation (as well as other functions) and may have causal roles in fatigue.[37]

However 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).[30]

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.[38]

The cause of fatigue is often undiagnosed.[39]

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

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.

Caffeine and alcohol can cause fatigue.[40]

Obesity appears to correlate with greater fatigue incidence.[41]

Depression and adverse life events have been associated with fatigue.[30]

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

• Autoimmune diseases,[34][42] such as celiac disease, lupus, multiple sclerosis,[43] myasthenia gravis, Sjögren's syndrome, and spondyloarthropathy
• Anxiety disorders, such as generalized anxiety disorder
• Blood disorders, such as anemia and hemochromatosis
• Brain injury[44]
• Cancer, in which case it is called cancer fatigue[45]
• Chronic fatigue syndrome (CFS)[46]
• Covid-19; long covid.[47]
• Substance use disorders including alcohol use disorder[46]
• Depression and other mental disorders that feature depressed mood
• Developmental disorders such as autism spectrum disorder[48]
• Eating disorders, which can produce fatigue due to inadequate nutrition
• Endocrine diseases or metabolic disorders: diabetes mellitus, hypothyroidism and Addison’s disease[49]
• Fibromyalgia
• Gulf War syndrome
• Heart failure
• HIV
• Inborn errors of metabolism such as fructose malabsorption.[50][51]
• Infectious diseases such as infectious mononucleosis or tuberculosis[49]
• Irritable bowel syndrome
• Kidney diseases e.g. acute renal failure, chronic renal failure[49]
• Leukemia or lymphoma
• Liver failure or liver diseases e.g. Hepatitis[49]
• Lyme disease
• 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[49]
• Stroke
• Thyroid disease such as hypothyroidism

In some areas it has been proposed that fatigue be separated into primary fatigue, caused directly by a disease process, and secondary fatigue, caused by more general impacts on the person of having a disease (such as disrupted sleep).[52][53][54][55]

Fatigue is sometimes used to describe the tiredness which is a normal result of work, mental stress, anxiety, overstimulation and understimulation, jet lag, active recreation, boredom, or lack of sleep. This is not considered medical fatigue.[40]

Medications may be evaluated for side effects that contribute to fatigue[62][63] and the interactions of medications are complex.[64]

Reductions in obesity and in caffeine and alcohol intake may reduce fatigue.[65]

The UK NICE recommends consideration of amantadine, modafinil and SSRIs for MS fatigue.[66] Psychostimulants such as methylphenidate, amphetamines, and modafinil have been used in the treatment of fatigue related to depression,[67][68][69][70] and medical illness such as chronic fatigue syndrome[71][72] and cancer.[73][68][74][75][76][77][78] They have also been used to counteract fatigue in sleep loss[79] and in aviation.[80]