Clinical manifestations

Presentation and course

The reported symptoms vary according to source. A Centers for Disease Control study indicates that sore throat, fever, tender lymph nodes, general weakness, and muscle pain are the most frequent symptoms (55), whereas another source reported unrefreshing sleep, muscle pain, post-exertion fatigue, thinking or memory impairment, and joint pain as the five most prevalent symptoms (47). A third study suggests (in decreasing frequency) fatigue after exercise, poor concentration, forgetfulness, muscle pain, stiff joints, light sensitivity, upset stomach, headaches, sore throats, and breathlessness are the most frequent symptoms (43). Despite the grouping of common symptoms, a definite lack of symptom homogeneity exists, and almost every patient has a unique and even fluctuating constellation of symptoms.

Chronic fatigue syndrome strikes sufferers both gradually and suddenly, though results are mixed as to which onset occurs more frequently (59; 46; 54). However, sufferers with gradual onset, because of “recruitment bias,” are traditionally underrepresented in clinical trials and, thus, represent a larger proportion of the population than previously thought (64). Further, the course may be affected by the type of onset, as those with acute onset have more frequent and severe symptoms (55), though psychiatric symptoms are generally greater among those with gradual onset (59).

The standard criteria for diagnosis are based on the 1994 Centers for Disease Control definition (29):

(1) Clinically evaluated, unexplained, persistent or relapsing chronic fatigue that is of new or definite onset, is not the result of ongoing exertion, is not substantially alleviated by rest, and results in a substantial reduction in previous levels of occupational, educational, social, or personal activities.
(2) Four or more of the following symptoms, all of which must have occurred during at least 6 months of the illness and must not have predated the fatigue:
	• self-reported impairment in memory and concentration (“brain fog”) • sore throat • tender cervical or axillary lymph nodes • muscle pain • multi-joint pain • headaches of a new pattern or severity • unrefreshing sleep • postexertional malaise lasting more than 24 hours

Post-exertional malaise is defined as severe fatigue after minimal physical, mental, or cognitive exertion.

The 2003 Canadian ME/CFS case criteria specified:

(1) Post-exertional malaise must occur with rapid muscle or cognitive fatigability, taking 24 hours or longer to recover.

(2) Unrefreshing sleep, myalgia, and arthralgia must be reported.

(3) Two or more neurologic or cognitive manifestations must be present.

(4) At least one of the autonomic, neuroendocrine, or immune manifestations must be present.

In 2015, the National Academy of Medicine published diagnostic criteria for ME/CFS in adults and children (14). It stated that three symptoms and at least one of two additional manifestations are required for the diagnosis.

The three symptoms required are:

(1) A substantial reduction or impairment in the ability to engage in pre-illness levels of activity (occupational, educational, social, or personal life) that:
	(a) lasts more than 6 months (b) is accompanied by fatigue that is
		(i) often profound (ii) of new onset (not lifelong) (iii) not the result of ongoing or unusual excessive exertion (iv) not substantially alleviated by rest.
(2) Post-exertional malaise, which is a worsening of symptoms after physical, mental, or emotional exertion that would not have caused a problem before the illness. The symptoms typically worsen 12 to 48 hours after the activity or exposure and can last days or even weeks.
(3) Unrefreshing sleep.

At least one of the following two additional manifestations must be present:

(1) Patients with cognitive impairment have problems with thinking, memory, executive function, and information processing as well as attention deficit and impaired psychomotor functions.

(2) Patients with orthostatic intolerance develop worsening symptoms on assuming and maintaining upright posture as measured by objective heart rate and blood pressure. Orthostatic symptoms include lightheadedness, fainting, increased fatigue, cognitive worsening, headaches, or nausea (14).

Autonomic dysfunction, such as orthostatic hypotension, sweating abnormalities, urinary and sexual alterations, and neuroendocrine manifestations (most commonly anxiety, panic attack, or recurrent feelings of feverishness) are part of the clinical presentation.

One of the most common comorbidities found in this syndrome is postural orthostatic tachycardia syndrome.

The fatigue in patients suffering from ME/CFS is more intense than usual tiredness related to physical exercise, it combines cognitive and physical exhaustion, weakness, heaviness, general malaise, lightheadedness, and sleepiness.

The most prevalent cognitive deficits are lower processing speed, worse verbal attention, and lower sustained attention. The inability to concentrate and thought slowness has been defined as “brain fog.”

In addition to the National Academy of Medicine criteria, disease experts often use the 2003 Canadian Consensus Criteria or the 2011 Myalgic Encephalomyelitis International Consensus Criteria to confirm a diagnosis of ME/CFS.

Prognosis and complications

The clinical course of chronic fatigue syndrome is as varied as its presentation of symptoms. The most frequently reported symptoms at the onset are sore throat, fever, muscle pain, and muscle weakness. During progression, reports of muscle pain and forgetfulness increase, and reports of depression decrease. Chronic fatigue syndrome often follows a cyclic course, oscillating between periods of illness and well-being (10).

Studies indicate that a complete recovery is rare. The reported improvement rates vary from 17% to 64%. A full recovery only happened in 5% of patients.

However, after 2 years, approximately 80% of patients experience some improvement; partial recovery is believed to be due to attenuation of symptom severity over time and adaptation to the altered lifestyle. These patients may experience exacerbations during periods of increased stress or illness. A significant minority of chronic fatigue syndrome sufferers experience progressive worsening of symptoms. Suicidal thoughts or feelings often occur in patients with the most severe symptoms of chronic fatigue syndrome (28). Patients may recover to the point of resuming normal work and activities but experience symptoms periodically.

Old age and comorbidities may be associated with poorer outcomes. There is mixed evidence for a worse prognosis in patients with comorbid fibromyalgia (31; 39).

The presence of psychiatric comorbidities could be a predictor for poorer prognosis. Life stressors, female gender, and lower socioeconomic status were also reported as being predictors of outcome (31).

The Centers for Disease Control four-city survey (discussed in the Epidemiology section) found that 50% of patients reported “recovery,” most within 5 years after the onset of symptoms (10). Further, recovery is more probable in individuals whose complaints are less severe, loss in total number, and of a short duration (73; 47).

ME/CFS has not been associated with an increased mortality rate.

Biological basis

Etiology and pathogenesis

It is important to note that chronic fatigue syndrome should be differentiated between primary, secondary, and comorbid fatigue. Primary fatigue can occur independently or be part of a disease process. For instance, fatigue in multiple sclerosis can be considered primary fatigue because tissue destruction of cortical and subcortical networks can lead to impairment of anatomical or function connections responsible for energy regulation (24). In the case of multiple sclerosis, cytokine release can also mediate symptoms of fatigue (34). Secondary fatigue results from the presence of factors associated with certain diseases, such as thyroid disease, mood disorders, sleep disorders, and chronic anemia. Comorbid fatigue occurs in the context of a primary disease but is not causally related to it (51).

The cause of chronic fatigue syndrome is unknown. The development of chronic fatigue syndrome may be attributable to a single causal factor or multiple precipitating causes. Suggested etiologies include infectious (bacterial, viral), psychiatric, stress and trauma, immunologic, toxic-metabolic, and nutritional (10). Such broad etiologic categories imply a lack of consensus and adequate understanding. However, chronic fatigue syndrome may represent a heterogeneous condition with different causes inciting the condition in different populations.

Because no definitive etiology has been established for chronic fatigue syndrome, pathogenetic mechanisms are unclear. Lack of illness-defining gross or histopathologic findings further obscures pathophysiology. Because fatigue is the prominent feature of the condition, many studies focused on this complaint. Analysis of muscle biopsies was inconclusive (20). Electrical studies by single-fiber EMG failed to demonstrate overt abnormalities involving the neuromuscular junction (20). Both anatomic and functional studies of the brain have been unrevealing. Detailed magnetic resonance imaging of the brain failed to distinguish patients with chronic fatigue syndrome from normal controls (62). Electroencephalograms show mild, nonspecific changes during sleep that are of dubious value (42). Studies of SPECT scans are controversial (21). Thus far, attempts to determine the physiologic basis for the symptoms, anatomic signature, and functional correlates of the disease have all been unsuccessful.

Role of inflammation and immunity. Chronic fatigue syndrome has also been linked to a variety of infectious agents, including Epstein-Barr virus, human herpes virus 6, retroviruses, cytomegalovirus, enteroviruses, stealth virus, Borna virus, and the Ross River virus (18). A proposed mechanism of the viral etiology involves Levy’s proposed “hit and run” effect, whereby an acute viral infection leads to chronic fatigue syndrome, the virus causes immune abnormalities, the virus is cleared, and the immune system remains in the activated state (38). Some suggest the presence of active, low-grade viral infection drives the condition. Several inflammatory cytokines have been invoked, but there are no conclusive results. A study has found that leptin mediates daily cytokine fluctuations that lead to chronic fatigue syndrome (66).

Infectious triggers, along with mitochondrial dysfunction and the presence of underlying genetic predisposition, are driving forces in developing ME/CFS.

The autoimmune pathogenesis of molecular mimicry is like that proposed for multiple sclerosis, in which the antigenic determinant recognized by the immune system closely resembles a normal cellular component. This results in cross-reaction, where the immune system is directed against a normal constituent of the cell. Evidence for autoimmunity includes the reaction of chronic fatigue syndrome sera with nuclear envelope antigens, immunoprecipitation of the nuclear envelope protein lamin B1, and a high frequency of autoantibodies to insoluble cellular antigens (50). However, the presence of autoantibodies in healthy individuals warrants caution in interpreting these studies.

Reduced natural killer function and cytotoxicity and reduced expression of transient receptor potential channels were found in patients with ME/CFS compared to healthy controls (48).

A chronically high level of cytokines may interfere with the stress response and could partially explain chronic fatigue and flu-like symptoms in many patients with ME/CFS (19).

There are suggested steps in the initiation and maintenance of chronic fatigue syndrome. The immune response after infection triggers B cells/plasma cells and autoantibodies in the underlying pathology. The vascular system is a potential target for autoantibodies that affect endothelium or neurovascular and autonomic small nerve fibers.

Autoantibodies could be pathogenic IgGs or functional autoantibodies that normally occur after infection but persist and fail to resolve over time. The consequences are endothelial dysfunction in large and small arteries, impaired venous return and preload failure, arteriovenous shunting (presumed to impair autoregulation of blood flow), and tissue hypoxia on exertion.

In a study evaluating 250 patients with ME/CFS, C1q expression was increased. As the first component in the classical complement pathway, C1q defends against invading pathogens and promotes clearing of dead cell debris. This finding in patients with ME/CFS indicates a state of active efferocytosis toward fighting a subjacent infection or while clearing damaged tissue.

Mitochondrial hypotheses. It seems that patients with ME/CFS suffer from increased oxidative stress faster and for longer than healthy controls, and their antioxidant response is delayed and reduced (19).

Impaired activity of the pyruvate dehydrogenase enzyme activity may increase the risk for the development of ME/CFS. Early conversion to less efficient anaerobic metabolism could explain the characteristic post-exertional malaise.

In both healthy and sick patients, physical exercise improves fatigue, sleep, pain, cognition, and mood. In contrast, patients with ME/CFS experience post-exertional malaise, a distinctive exacerbation of the patient’s symptoms, and a further reduction in functioning after previously tolerated physical, cognitive, orthostatic, emotional, or sensory stressors.

When sedentary but healthy people or people affected by other chronic illnesses are asked to exercise to their maximal ability on two consecutive days, energy test results do not change significantly from one day to the next. They may not use oxygen as efficiently as healthy, physically fit people, but their energy efficiency remains unchanged on repeated testing. In contrast, in patients with ME/CFS, the ability to generate energy deteriorates on a repeated test on the second day.

High levels of lactate and increased acidosis in blood, CSF, and muscles were reported. Post-exertional malaise was reported to be associated with increased levels in the brain of interleukin-1 and interleukin-10 (05).

Neuropsychiatric disease. Chronic fatigue syndrome has been suspected to be a neuropsychiatric disorder or a type of depression. Although depression is frequent in chronic fatigue syndrome, most patients do not exhibit the characteristic self-reproach or biological features of endogenous depression. The depression in chronic fatigue syndrome appears to be reactive and associated with frustration. Although organic factors may precipitate chronic fatigue syndrome, cognitive behavioral factors may perpetuate the illness. The avoidance of mental and physical activities due to symptom exacerbation can lead to loss of control, demoralization, possible depression, and anxiety (39).

Patients with ME/CFS experience various sleep disturbances, such as problems in falling or staying asleep. Reduced heart rate variability is linked to unrefreshing sleep in ME/CFS. Nocturnal parasympathetic activity decreases relative to sympathetic activity in patients with ME/CFS.

Autonomic nervous system dysfunction. An additional area of research involves chronic activation of the sympathetic nervous system. A process known as “tuning” is believed to result in increased sympathetic tone. According to this proposed mechanism, the sympathetic nervous system is activated by either a high-intensity stimulus or chronic low-intensity stimulation until it reaches a heightened state of arousal. This heightened sympathetic state leads to heightened sensitivity of the limbic system. In turn, the limbic system develops greater excitatory capacity with a decreased inhibitory state, causing the brain to become hypersensitive to stress. The hypersensitive sympathetic nervous system, therefore, causes increased neuronal firing to the point of neurotoxicity and neuronal death (28). This theory is interesting but requires the development of an adequate model for testing.

Secondary compensatory efforts include autonomic adaptations, such as increased sympathetic tone, as well as metabolic adaptations to restore energy supply (27).

Autonomic nervous system dysfunction is widely described as a chronic fatigue syndrome pathomechanism. Autonomic nervous system function can be measured noninvasively using heart rate variability to differentiate between healthy and diseased states.

Chronic sympathetic overactivity might lead to the downregulation of autonomic nervous system receptors and, therefore, may suppress maximum heart rate and other functions. The heart rate response to head-up tilt testing was higher in patients with chronic fatigue syndrome compared to healthy controls.

Reduced parasympathetic reactivation during exercise recovery was observed in patients with ME/CFS. The parasympathetic tone may reflect an individual’s functional capacity for exercise. Patients with ME/CFS demonstrate a reduced functional capacity for exercise. Physical training increases the parasympathetic tone and could be beneficial for patients with ME/CFS (72).

Hormonal imbalance. In recent years reports have indicated that hypothalamic hypofunction could be seen in chronic fatigue states. Relative hypocortisolism was reported in many patients with chronic fatigue syndrome but could be seen in other chronic idiopathic disorders, including fibromyalgia, inflammatory disorders, and posttraumatic stress disorder.

A loss of morning peak ACTH (adrenocorticotropic hormone) and decreased responsiveness to pharmacological challenge are reported in chronic fatigue syndrome compared to controls.

A case-control study demonstrated that patients with chronic fatigue syndrome exhibited lower free T3 (triiodothyronine), TT3 (total triiodothyronine), decreased peripheral conversion of T4 (thyroxine) to T3, normal/high-normal TT4 (total thyroxine) level, and lower protein binding of thyroid hormones (58).

Hydrocortisone (5 mg/day) and fludrocortisone (0.1 to 0.2 mg) were tested in placebo double-blind controlled studies, and no benefit was noticed (52; 08).

Other mechanisms. Several papers raised the possibility of alteration in gut microbiome composition and involvement of dysbiosis in disease pathogenesis. Dysbiosis is a well-known cause of increased gut permeability. This phenomenon, known as leaky gut, allows bacterial translocation into the bloodstream, increasing inflammation. Therapeutic interventions, such as a leaky gut repair diet and the use of anti-inflammatory and anti-oxidative substances aimed to re-establish eubiosis and reduce intestinal permeability, may be helpful in patients with chronic fatigue syndrome.

Noncoding RNAs (ncRNA) control various levels of gene expression, chromatin architecture, epigenetic memory, transcription, RNA splicing, editing, and translation. One specific type of ncRNA, microRNA (miRNA), alters and modulates developmental, physiological, and pathophysiological processes. This modulation can be achieved by silencing genes, initiating the cleavage of their respective target mRNA, or by inhibiting gene translation. The altered protein expression characterizes chronic pain and contributes to developing long-term hyperexcitability of nociceptive neurons in the periphery. The central nervous system is characterized by expressional changes of signaling molecules, transmitters, ion channels, or structural proteins.

Most of the miRNA differentially expressed in patients with chronic fatigue syndrome is involved in immune response regulation. miRNAs have the potential to be utilized as biomarkers for disease diagnosis and prognosis.

Although chronic fatigue syndrome pathogenesis is still unknown, several studies suggest the possibility of genetic predisposition. Mothers and children diagnosed with chronic fatigue syndrome share similar symptoms. Being a multifactorial disease, a varied genetic contribution is more likely to explain predisposition and heredity than a single variation.

Besides classical genetics, epigenetics are also linked to chronic fatigue syndrome and can potentially explain the major pathways involved in the disease (19).

Epidemiology

Initial reports indicated that chronic fatigue syndrome was a rare illness. However, methodological problems with the studies led to great underestimation and underrepresentation of the afflicted populations. The Centers for Disease Control conducted an epidemiological survey in four United States cities between 1989 and 1993 of a physician-referred population of patients with possible chronic fatigue syndrome (10). This study estimated that between 4.0 and 8.7 per 100,000 people ages 18 years and older who were receiving medical care had chronic fatigue syndrome.

Chronic fatigue syndrome affects between 836,000 and 3.3 million Americans of all ages, ethnicities, genders, and socioeconomic backgrounds. The Institute of Medicine in 2015 estimated that 84% to 91% of people with chronic fatigue syndrome have not been diagnosed, making measurement of prevalence difficult (35). Due to loss of productivity and high medical costs, there is an estimated economic burden of $18 billion to $51 billion annually in United States (71).

This disorder affects approximately 1% of the population, 17 to 24 million people worldwide.

Women are three times more affected than men. Onset often occurs between the ages 10 to 19 years and 30 to 39 years but can affect people older than 77 years and as young as 2 years.

Blacks and Latinos may be affected at a higher rate and severity.

An infectious episode near the onset is reported by 80% of the patients (05).

More than 80% of the population in the Centers for Disease Control study had advanced education with one third of the sample population coming from higher-income families (10). Furthermore, chronic fatigue syndrome sample populations tend to be highly educated and higher achievers. It has been hypothesized that assertive higher achievers would be less likely to accept that nothing is medically wrong based on normal laboratory test results (28).

A CDC study published in December 2023 showed that white non-Hispanic (1.5%) adults were more likely to have ME/CFS compared with Asian non-Hispanic (0.7%) and Hispanic (0.8%) adults. Adults with a family income less than 100% of the federal poverty level (2%) were more likely to have ME/CFS, followed by those at 100% to 199% (1.7%) and those above 200% (1.1%). The percentage of adults who had Me/CFS increased with the increasing rurality of their place of residence (71).

Approximately 0.1% to 2% of adolescents are affected by ME/CFS. Approximately 12% of young people accessing pediatric ME/CFS services are younger than 12 years of age.

Prevention

Contagious diseases usually occur in well-defined clusters as outbreaks or epidemics. Although fatiguing illnesses have been reported in outbreak clusters, none of the patients in the outbreaks present symptoms that fit the description of chronic fatigue syndrome. The Centers for Disease Control has yet to confirm a cluster of chronic fatigue syndrome outbreaks. Evidence does not indicate that chronic fatigue syndrome is a contagious disease transmitted from person to person (10).

Although there is still controversy regarding distinct predisposing factors, certain trends tend to recur in the medical histories of patients with chronic fatigue syndrome. Predisposing factors for chronic fatigue syndrome include an overactive lifestyle lacking adequate time for rest and reflection, long periods of stress, and a history of depression.

Early diagnosis of chronic fatigue syndrome would have an impact on disease management, even in the absence of any specific treatment. When the diagnosis is possible, recommendations to reduce activity levels, avoid further stressors, and treat infection are to be considered. Identifying the energy threshold and adjusting activity accordingly is important to avoid exacerbation. Strong support from educational institutions and workplaces in accommodating the need for adequate recovery is paramount (49).

Differential diagnosis

Confusing conditions

Fatigue is a common complaint in daily life associated with a range of medical problems. Most of the people with ongoing fatigue do not have ME/CFS but have symptoms that are caused by other conditions, emotional well-being, or lifestyle factors. The presence of post-exertional malaise raises the level of suspicion, as this is quite typical, though not specific for ME/CFS.

Fatigue should be differentiated from muscle weakness, which suggests a neuromuscular disorder, and anhedonia should be differentiated from major depression.

Hypersomnolence and sleep disorder suggest a need to exclude obstructive sleep apnea.

Chronic fatigue syndrome shares features with numerous other chronic illnesses. Table 1 lists the illnesses commonly confused with chronic fatigue syndrome (16). Some features in fibromyalgia, Gulf War syndrome, major depressive disorder, and temporomandibular disorder closely resemble those in chronic fatigue syndrome (01; 33). In addition, fibromyalgia, multiple chemical sensitivity, irritable bowel syndrome, chronic tension-type headache, and interstitial cystitis are frequent comorbid conditions.

Fibromyalgia is similar in presentation and a frequent comorbid condition. Estimates show that 20% to 80% of patients with fibromyalgia have chronic fatigue syndrome and that about 35% to 75% of patients with chronic fatigue syndrome also have fibromyalgia (36; 01). Sore throat, mild fever, or chills are the most discriminating factors between fibromyalgia and chronic fatigue syndrome. In addition, chronic fatigue syndrome and major depressive disorder were best discriminated by features of postexertional malaise, impaired memory, and unrefreshing sleep in chronic fatigue syndrome (33). The severity of symptoms also appears to distinguish chronic fatigue syndrome from some similar fatigue conditions, although symptoms can be severe in fibromyalgia and multiple chemical sensitivity (36; 33).

It is estimated that up to 90% of people with ME/CFS are yet undiagnosed, and 29% of patients waited 5 years for a diagnosis.

Although patients with ME/CFS have abnormalities in MRI and SPECT, the significance of those findings is unclear, and routine neuroimaging is not recommended (62).

Routine cardiac assessment is also not recommended.

Table 1. Differential Diagnoses for Chronic Fatigue Syndrome

Category	Condition
Infectious	Chronic Epstein-Barr virus Influenza HIV infection Other viral infections (HHV-6, retroviruses, enteroviruses) Tuberculosis Lyme disease
Neuroendocrine	Hypothyroidism Hyperthyroidism Addison disease Adrenal insufficiency Cushing disease Diabetes
Psychiatric	Bipolar affective disorder Schizophrenia Delusional disorders Major depressive disorder Dementia Anorexia nervosa Bulimia nervosa
Neuropsychologic	Obstructive sleep syndromes (sleep apnea, narcolepsy) Multiple sclerosis Parkinsonism
Hematologic	Anemia Lymphoma Occult malignancy
Rheumatologic	Fibromyalgia Sjögren syndrome Polymyalgia rheumatica Giant cell arteritis Polymyositis Dermatomyositis
Other	Nasal obstruction from allergies, sinusitis, anatomic obstruction Chronic illness (congestive heart failure, renal, hepatic, pulmonary disease, autoimmune) Pharmacologic side effects (eg, beta blockers, antihistamines) Alcohol or substance abuse Heavy metal exposure and toxicity (eg, lead) Body weight fluctuation (severe obesity or marked weight loss)

Associated or underlying disorders

Some conditions are often present concomitantly to ME/CFS, such as fibromyalgia, restless legs syndrome, periodic limb disorder, postural orthostatic tachycardia syndrome, irritable bowel syndrome, hypermobility Ehlers Danlos syndrome, small fiber neuropathy, interstitial cystitis, chronic pelvic pain, migraine, mast cell activation disorder, and eosinophilic esophagitis (45).

Diagnostic workup

Because there is no single test to establish the diagnosis of chronic fatigue syndrome, a diagnostic workup is performed to exclude other possible conditions. Once chronic fatigue syndrome is considered a possibility, a complete patient history and thorough examination should first be obtained to rule out contributing factors and comorbid conditions known to cause fatigue. Patient history should focus on identifying psychiatric illnesses, substance history, chronic disorders of family members that might produce fatigue, recent viral or bacterial infections, stressful lifestyle, and any other information contributing to fatigue.

The physical examination should look for the presence of pallor, cardiac arrhythmia, fever or other indication of infection, weight loss, lymphadenopathy, evidence of inflammatory arthritis, occult blood loss, organomegaly, or abdominal masses, neurologic signs of impaired coordination, hypertension, edema, obesity, peripheral neuropathy, goiter, dry hair or skin, hemoptysis, or pregnancy (69).

Suggested laboratory tests include:

• Complete blood count • Comprehensive metabolic panel • Thyroid function studies • Erythrocyte sedimentation rate, CRP – as a general indicator of inflammation • Screening blood tests for gluten sensitivity • Vitamin B12, Vitamin D, folate • Serum ferritin • Urinalysis • Antinuclear antibody, rheumatoid factor. • Overnight oximetry (04; 25)

Symptom-specific tests are in Table 2.

Table 2. Symptom Tests for Chronic Fatigue Syndrome

Category	Tests
Infectious	Serology, only if history of infections
Neuroendocrine	hormone and stimulation or suppression tests (eg, T3 suppression test, ACTH, Cortrosyn stimulation, dexamethasone suppression, urinary free cortisol)
Psychiatric	Mental status examination
Neuropsychologic	mental status testing and imaging studies
Hematologic	peripheral blood smears
Rheumatologic	muscle biopsy
Other	allergy testing and toxicology screens

Head-up tilt test, auditory brainstem responses, and electrodermal conductivity are not recommended because there is not enough evidence for routine use in the diagnosis of ME/CFS.

Management

No standard therapy is available to alleviate symptoms of the disease effectively.

Treatment of chronic fatigue syndrome is focused on the management of symptoms, particularly comorbidities such as depression, sleep, and cognitive impairment. Suggested treatment strategies include behavioral, pharmacological, immunological, nutritional, and alternative.

Symptomatic management. For post-exertional malaise pacing and rest, stimulus reduction and tracking devices or symptom diaries are useful.

Fatigue is treated using pacing, low-dose naltrexone, low-dose aripiprazole, anti-inflammatory diets, supplements, and correction of vitamin deficiency.

Melatonin, trazodone, suvorexant, doxepin, tricyclic antidepressants, gabapentin, and pregabalin may help with sleep issues.

Cognitive dysfunction could be addressed by using journals, memory aids, occupational therapy, low-dose naltrexone, low-dose aripiprazole, and careful use of stimulants.

For orthostatic intolerance, the recommended measures are fluids, electrolyte supplementation, compression stockings, fludrocortisone, midodrine, propranolol, pyridostigmine, and guanfacine.

Dizziness is a frequent chronic complaint (persistent postural-perceptual dizziness). It could be treated with vestibular therapy and low-dose selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors.

Muscle or joint pain should be managed by stretching, duloxetine, milnacipran, pregabalin, gabapentin, tricyclic antidepressant, and low-dose naltrexone (3 to 4.5mg) (09).

For neuropathy, the best agents are pregabalin, gabapentin, and tricyclic antidepressants.

Sensory amplification is treated using noise-cancellation headphones, tinted glasses, and crowd exposure reduction.

Anti-inflammatory diets, small meals, pro/symbiotic, antidiarrheals or antihistamines, and fiber and motility agents may improve gastrointestinal problems (32).

Cognitive behavioral therapy and graded exercise. Behavioral modification is a popular approach. This typically involves instituting forms of graded exercise therapy or cognitive-behavioral therapy. Graded exercise therapy has shown lasting improvements in functional capacity and overall fatigue, and some evidence even suggests improvement in mood and sleep (30; 53; 44). Similarly, cognitive-behavioral therapy has reportedly led to sustained reductions in functional impairment and fatigue severity as well as pain reduction and mood improvement (17; 37). A randomized study found that graded exercise therapy and cognitive-behavioral therapy moderately improved outcomes from chronic fatigue syndrome (75). Cognitive-behavioral therapy for chronic fatigue syndrome has been studied in adolescents with positive results (67). Graded exercise therapy has also been studied in a self-administered form and was found to be effective (75). Multidisciplinary rehabilitation therapy, which is a combination of cognitive-behavioral therapy and other interventions, was found to be more effective than cognitive-behavioral therapy alone (74).

Immunological treatment. Immunological treatments have shown some promise, but data are often inconclusive and limited. Rintatolimod, a double-stranded RNA immunomodulatory agent that is attributed to be an agonist Toll-like receptor-3 (TLR-3), although dsRNA analogues typically bind TLR-7 and 8, is said to improve both cognitive and physical deficits (65). A U.S. Food and Drug Administration panel voted 8 to 5 against its use. Immunoglobulin infusions reportedly improve general functioning in some patients (40; 57). Self-administered s.c. immunoglobulins were reported feasible in a small cohort of patients with chronic fatigue syndrome and improved symptoms and physical functioning (61).

Improvement after staphylococcus toxoid injections has been reported, but further studies are needed (76). An IL-1 inhibitor did not show any benefit in improving symptoms of chronic fatigue syndrome as it did not differ from placebo (56).

A trial examined whether rituximab, an anti-CD20 monoclonal antibody, would lead to improvement in measurements of fatigue (26). The primary endpoint, which was defined as the effect on self-reported fatigue score 3 months after intervention, was negative. However, using a self-reported fatigue scale, there was a major or moderate overall response in 11 of 15 patients (67%) in the rituximab group and only 2 of 15 patients (13%) in the placebo group.

Fatty acid, acetylcarnitine and propionylcarnitine, and magnesium supplementation studies are inconclusive. In a trial of 434 patients, galantamine did not show any benefit (07).

Multivitamin-mineral supplements, adequate lipid replacement, and antioxidant therapy have benefits in reducing the severity of symptoms in patients with chronic fatigue syndrome (06).

Coenzyme Q10 plus NADH as a nutritional supplement in ME/CFS reduced cognitive fatigue, sleep, and overall fatigue expression, improving quality of life (11; 12).

Alternative therapeutic approaches such as acupuncture, massage therapy, herbal therapy, Chinese qigong therapy, and thermal therapy are advocated by certain groups, but in the absence of a carefully designed trial, are difficult to assess (23; 41; 63).

Special considerations

Pregnancy

The frequency of spontaneous abortion was nearly four-fold in those whose onset occurred after pregnancy (60). Some women have a significant amelioration of their symptoms and experience a relatively better year while pregnant. It seems that almost 30% of women have no changes, 30% show improvement, and 30% will get worse (68).

Pediatric age group

Chronic fatigue syndrome has a prevalence of 0.2% to 2.4%. It negatively impacts the quality of life for children. Sore throat, joint and muscle pain, nausea, sleep dysfunction, and cognitive and psychosocial symptoms appear in children.

Children are diagnosed after 3 months of symptoms, whereas adults need 6 months.

Dietary changes, exercise, and psychosocial factors can reduce the symptoms and improve quality of life. Adolescents with ME/CFS have a higher incidence of lactose intolerance. There is a positive association between low socioeconomic status and poor recovery outcomes.

Adding coenzyme q10, evening primrose oil, magnesium, and fluoride to the diet showed improved symptoms after 6 months.

Cardiovascular exercise and resistance training improve fatigue severity and symptoms of depression in adolescents with ME/CFS.

Multifaceted treatment strategies consist of graded activities and exercise programs, cognitive behavioral therapy, nutritional advice, and, in some cases, family sessions. This treatment strategy reduced the severity of the illness, improved school attendance, and raised school test scores (13).

COVID-19 and chronic fatigue syndrome

Coronavirus disease 2019 (COVID-19), a highly contagious respiratory disease caused by the severe acute respiratory syndrome coronavirus-2 (SARS-COV-2) was declared a pandemic by the World Health Organization in March 2020. Although there was significant public concern and research centered around the acute course, the chronic sequelae of this disease are becoming more prevalent and are now a continuous subject of academic and public interest.

Long COVID, long-haul COVID-19, post-COVID syndrome, chronic COVID syndrome, and post-acute sequelae of SARS-CoV-2 infection (PASC) are terms for persistent symptoms lasting more than 2 months after infection. The characteristics and mysterious nature of long COVID connected this disease with ME/CFS. Aside from similarities in clinical features, long COVID and ME/CFS have commonalities in their pathophysiology, such as immune system dysregulation, hyperinflammatory state, and excessive oxidative stress.

High physical fatigue, exhaustion when initiating exercise, post-exertional malaise, difficulty sleeping, myalgia, muscle weakness, and cold limbs were the most common noncognitive symptoms seen in patients with post-COVID syndrome and patients with ME/CFS.

Cognitive symptoms, such as lack of concentration, sustained attention problems, mental fatigue, slowness of thought, and forgetfulness, were the most prevalent seen in the patients with post-COVID syndrome and those with ME/CFS. Regarding the neuropsychiatric status, patients with ME/CFS showed greater anxiety, depressive symptoms, suicidal ideation, and a generally worse perception of their health compared to those with post-COVID syndrome. The level of functionality in patients with post-COVID syndrome is mainly related to more physical than neuropsychiatric impairment. Pain and reduced physical activity are most important in patients with post-COVID-19 syndrome (03).

The genetic association in cohort studies indicates these two complex diseases share only a few common genes, ACE, HLA-A, HLA-C, HLA-DQA1, HLA-DRB1, and TYK2, which appear to be involved in the regulation of immune processes (70).

Autonomic dysfunction is more often reported in patients with ME/CFS compared to those with post-COVID syndrome. The prevalence of postural orthostatic tachycardia syndrome is around 0.2% to 1% in the general population, 31% in patients with ME/CFS, and 13.8% in the post-Covid condition (02).

Treatment consists of supplements, relaxing modalities such as yoga, meditation, and, if tolerated, graded exercises as well as symptomatic treatment.