Practice Essentials
Chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis (ME) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), is a complex and debilitating condition characterized by unexplained severe fatigue that is not relieved by rest, cognitive dysfunction, and impaired daily functioning. It affects people of all ages and can have significant personal, social, and economic consequences. [1, 2]
Diagnostic criteria
According to the National Academy of Medicine, diagnosis of ME/CFS requires the presence of the following 3 symptoms for more than 6 months, and the intensity of the symptoms should be moderate or severe for at least 50% of the time [3, 4] :
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Fatigue: A noticeable decrease or impairment in the ability of a patient to engage in activities that they enjoyed before the onset of the illness, with this impairment continuing for more than 6 months and associated with new-onset severe fatigue, unrelated to exertion, and not relieved by rest.
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Post-exertional malaise (PEM): Patients experience worsening symptoms and function after exposure to physical or cognitive stressors that were previously well tolerated.
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Unrefreshing sleep: Patients feel tired after a night's sleep.
Criterion fulfillment for diagnosis requires all 3 of the symptoms above, along with one of the symptoms below [2] :
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Cognitive impairment - Problems with the thought or executive function, worsened by exertion, effort, or stress or time pressure.
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Orthostatic intolerance - Worsening of symptoms upon assuming and maintaining an upright posture. Symptoms are improved,, although not necessarily eliminated, by lying back down or elevating the feet.
Etiology
Many viruses have been studied as potential causes of ME/CFS ; however, no definitive causal relation has been determined. Historically, human herpesvirus type 6, enterovirus, rubella virus, Candida albicans, bornavirus, Mycoplasma, Chlamydia pneumoniae, retroviruses, coxsackie B virus, cytomegalovirus, and xenotropic murine leukemia virus-related virus have been studied and have not been found to cause CFS. [5, 6, 7, 8, 9, 10, 11, 12] Some people infected with Epstein-Barr virus, Ross River virus, Coxiella burnetii, or Giardia have developed criteria for ME/CFS , but not all individuals with ME/CFS have had these infections. [13] Other studies have observed alterations in the functioning of natural killer (NK) cells and a decreased response of T cells to certain specific antigens. [14, 15, 16]
Environmental factors also have been suspected as a trigger for ME/CFS; however, no specific factors have been identified.
Testing
Laboratory findings are normal in ME/CFS. Tests are used to assess for other underlying causes of fatigue, as follows:
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Complete blood cell count
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Chemistries including electrolytes, renal, and liver function tests
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Thyroid function tests
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C-reactive protein
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Erythrocyte sedimentation rate
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Creatine kinase
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Cultures, viral titers, cerebrospinal fluid studies (upon high suspicion for infection)
Other tests may include the following:
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Polysomnography
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Electrocardiography (ECG)
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Cardiopulmonary exercise test separated by 24 hours
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Tilt-table testing
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Computed tomography (CT) or magnetic resonance imaging (MRI) of the brain is useful for ruling out central nervous system (CNS) disorders in patients with otherwise unexplained CNS symptoms. Results of CT scanning and MRI may be normal in patients with ME/CFS. Findings of CNS imaging studies are not specific for ME/CFS and thus are used to rule out alternative explanations rather than to diagnose CFS.
According to a systematic review by Shan et al, consistent observation of sluggish functional MRI (fMRI) signal response suggests abnormal neurovascular coupling in ME/CFS. [17] Almutairi et al, in another systematic review, found that fMRI studies demonstrated both increases and decreases in activation patterns in patients with ME/CFS but noted that this may have been related to task demand. They also noted that fMRI signal cannot differentiate between neural excitation and inhibition or function-specific neural processing. [18]
Treatment
Treatment is largely supportive and focuses on symptom relief. Large randomized, controlled trials such as the pacing, graded activity, and cognitive behaviour therapy: a randomised evaluation (PACE) trial and reviews have recommended cognitive behavioral therapy (CBT) as an effective method for treating ME/CFS in adults. [19, 20] However, the surveillance report from the National Institute for Health and Care Excellence (NICE) recommends against CBT. [21] The Centers for Disease Control and Prevention (CDC) and the Agency for Healthcare Research and Quality (AHRQ) both have removed CBT as a recommended treatment for ME/CFS because of insufficient evidence. [22]
Exercise is not a cure for ME/CFS. A review evaluated exercise therapy for patients with ME/CFS. The study found that patients felt less fatigued following exercise therapy and felt improved in terms of sleep, physical function, and general health. However, the authors could not conclude that exercise therapy improved the outcomes of pain, quality of life, anxiety, and/or depression. [23]
The PACE trial found that graded exercise therapy (GET) effectively improved measures of fatigue and physical functioning. [19] However, updates from the NICE guideline surveillance report recommend against GET. [19, 20, 21, 22]
Prognosis
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has no cure, its symptoms can persist for years, and its clinical course is punctuated by remissions and relapses. One prospective study suggests that approximately 50% of patients with ME/CFS can return to part-time or full-time work. [24] Longer duration of illness, severe fatigue, comorbid depression, and anxiety are factors associated with a poorer prognosis. [25] Good outcomes are associated with less fatigue severity at baseline, a sense of control over symptoms, and no attribution of the illness to a physical cause. [26] Despite the considerable burden of morbidity associated with ME/CFS, there is no evidence of an increased risk for mortality.
Background
Chronic fatigue syndrome (myalgic encephalomyelitis; ME/CFS) is a prevalent condition affecting over 2 million Americans, many of whom remain undiagnosed. Women more commonly are affected than men, with higher prevalence in individuals older than 40 years. Chronic fatigue syndrome (ME/CFS) does not show a specific racial or educational inclination. It can have significant mental and emotional effects, leading to a higher unemployment rate compared to those with chronic fatigue without meeting ME/CFS criteria. The substantial economic impact of ME/CFS is evidenced by the estimated annual cost of lost productivity, amounting to $9.1 billion in the United States back in 2002. Additionally, individuals with ME/CFS are more likely to report subjective functional impairment compared to those with chronic fatigue. [1]
Research groups and clinicians currently use three main definitions for diagnosing CFS or ME: the Fukuda criteria (CDC's 1988 criteria), [27] the Canadian Consensus Criteria of 2003, and criteria suggested by the IOM committee. The Fukuda criteria are considered somewhat outdated, lacking a requirement for core symptoms. The 2015 IOM Committee criteria include impaired ability to engage in pre-illness activity levels lasting more than 6 months, increased symptoms following exertion (post-exertional malaise), unrefreshing sleep, and either cognitive impairment or orthostatic intolerance for diagnosis. [2]
The exact cause of ME/CFS is not known, but it is believed to be a biological illness rather than a psychological disorder. Various factors have been implicated in its development, including immune dysfunction, hormonal irregularities, metabolic issues, and abnormal responses to oxidative stress. Research has shown abnormalities in natural killer cells and T-cells, elevated levels of cytokines, and the presence of autoantibodies in individuals with ME/CFS. [13, 28]
Diagnosing ME/CFS can be challenging due to the lack of specific diagnostic tests and the absence of a universally accepted definition. This can lead to delays in diagnosis and under-recognition of the condition by healthcare professionals. Different treatment approaches have been recommended for ME/CF, such as cognitive behavioral therapy and graded exercise therapy, although there is controversy and disagreement about their effectiveness among patients and healthcare providers. [1]
Access to specialist services for ME/CFS varies across different regions, with some areas reporting limited availability of specialized care. Addressing these disparities in access to care is important to ensure better support and management of individuals with ME/CFS.
Infections such as Epstein-Barr, Ross River, Coxiella burnetii, herpesviruses, enterovirus, and others, including SARS-CoV-2, have been linked to an ME/CFS-like illness. Individuals with severe symptoms during these infections are more likely to develop ME/CFS later on, with up to 80% of patients reporting ME/CFS following a viral-like illness. Although no single infectious agent has been pinpointed as the definitive cause of ME/CFS, immune system alterations may contribute to its development in some cases. [15]
Patients with ME/CFS present to the emergency department with a complex list of symptoms, including orthostatic intolerance, fatigue, postexertional malaise (PEM), and diarrhea. [29]
Between 836,000 and 3.3 million individuals in the United States are affected by ME/CFS, and more than 90% of those with ME/CFS have not received a formal diagnosis from a medical professional. [3] An estimated 84-91% of individuals with the condition have not been diagnosed; therefore, the true prevalence is unknown. Overall, ME/CFS is more common in females than in males and occurs most commonly in young to middle-aged adults. [30] The average age of onset is 33 years, although cases have been reported in patients younger than 10 years and older than 70 years.
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) originally was termed myalgic encephalomyelitis (ME) because British clinicians noted a skeletal muscle component manifesting as chronic fatigue and an encephalitic component manifesting as cognitive difficulties. However, this term is considered inaccurate by some experts because there is a lack of encephalomyelitis in laboratory and imaging studies, and myalgia is not a core symptom of the disease. [3]
The National Academy of Medicine (formerly The Institute of Medicine) proposed that the condition be called systemic exertion intolerance disease (SEID) to better reflect the condition's hallmark defining symptom, postexertional malaise. [31]
The cause of ME/CFS is unknown, and there are no direct tests to diagnose ME/CFS. If the source of the fatigue can be explained, the patient probably does not have ME/CFS. The diagnosis is one of exclusion that meets the clinical criteria below.
Pathophysiology
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a challenging condition characterized by a range of symptoms impacting multiple physiological systems. Postinfectious fatigue syndromes, such as ME/CFS, are believed to be triggered by infections that lead to complex physiological changes and disruptions. These disruptions can include issues such as autoimmunity, hypovolemia, vascular leakage, endothelial damage, and cardiovascular and respiratory stress, which can contribute to an increased sympathetic stress response.
Viral infections, such as those seen in Covid-19, have the potential to impact various bodily systems, leading to sympathetic vasoconstriction and triggering conditions like ME/CFS. Specifically, Covid-19 can affect the endothelium, leading to cardiovascular complications and respiratory stress, which may contribute to the development of ME/CFS following severe viral infections.
The pathophysiology of ME/CFS involves disruptions in energy production, gut health, autonomic function, and immune regulation. Metabolic and mitochondrial dysfunction can lead to issues like inefficient respiration and metabolic shifts, while immune cell dysfunction, chronic inflammation, and oxidative stress can further impact overall health. Understanding these interconnections and disruptions is essential for developing targeted and effective treatment strategies for individuals with ME/CFS. [32]
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is recognized as a biological illness and not a psychological disorder or malingering for secondary gain. Patients experience diverse pathophysiological changes affecting various organ systems, though no single diagnostic marker is currently sensitive or specific enough for diagnosis. Changes observed in ME/CFS include:
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Immune System: Impaired natural killer cell and T cell function, chronic inflammation, and the presence of specific autoantibodies.
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Energy Metabolism: Inefficient energy production or utilization from normal cellular sources such as oxygen, glucose, and amino acids, as well as studies showing impaired oxygen consumption.
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Neuroendocrine System: Dysregulation of the hypothalamic-pituitary-adrenal axis and flattened cortisol profiles in some patients.
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Autonomic Nervous System: Orthostatic intolerance, manifesting as neurally-mediated hypotension (NMH) and postural orthostatic tachycardia syndrome (POTS), along with symptoms such as difficulty regulating body temperature and sweating abnormalities.
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Gastrointestinal System: Conditions such as irritable bowel syndrome, leaky gut, and changes in intestinal microbiomes are reported.
Other notable symptoms observed in ME/CFS include musculoskeletal pain, endometriosis, early menopause, and menstrual irregularities being more prevalent in women with ME/CFS compared to those without the condition.
Etiology
The exact cause of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) remains a mystery, but it increasingly is being recognized as a chronic illness linked to infections. This is due to the high occurrence of infections in ME/CFS patients and the similarities in symptoms between ME/CFS and post-infection illnesses. There may be other factors that also play a role in the development of ME/CFS. [33]
Infection
Illness resembling ME/CFS has been reported following infections with various diseases such as Epstein-Barr, Ross River, Coxiella burnetii (Q fever), herpesviruses, enterovirus, rubella, Candida albicans, bornaviruses, mycoplasma, retroviruses, and SARS-CoV-2 (COVID-19). Individuals who experienced severe symptoms with these infections are more likely to develop ME/CFS-like symptoms later on. While no single infectious agent has been identified as the definitive cause of ME/CFS, up to 80% of patients develop ME/CFS following an acute viral-like illness, with the specific cause often unknown. It is hypothesized that some individuals may experience immune system changes post-infection that contribute to the development of ME/CFS. [33, 34]
Stressors
Certain patients mention that they have encountered an accident, trauma, immobilization, surgical procedure, or notable physical or emotional stress before the emergence of ME/CFS symptoms. [33]
Genetics
Myalgic enceophalomyelitis/chronic fatigue syndrome (ME/CFS) has been observed within some families. This suggests either a possible genetic link or a common environmental exposure (infectious or toxic). Twin studies show higher rates of ME/CFS in identical twins than in fraternal twins. However, specific genetic associations have not been established. [33]
Environmental Factors
Although exposure to mold or toxins has been considered a potential catalyst for ME/CFS, direct links between specific environmental factors and the condition have yet to be confirmed. [33]
Epidemiology
It is estimated that there are between 836,000 and 3.3 million individuals in the United States affected by myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). More than 90% of those with ME/CFS have not received a formal diagnosis from a medical professional. The economic impact of ME/CFS amounts to approximately $18 to $51 billion each year in the United States, encompassing medical expenses and income loss. [3]
Prognosis
Recovery rates for patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are not well-documented, but early diagnosis and appropriate management may be influential. Some patients recover fully, whereas others show improvement but do not return to their pre-illness levels of function. Some individuals continue modified activities to sustain improvement or symptom-free status. Remissions can happen, but relapses may follow. Certain symptoms may persist or worsen over time. Further research is essential, however it generally is believed that children and teenagers have a higher likelihood of achieving full or partial recovery from ME/CFS compared to adults.
Individuals with ME/CFS have a poor prognosis with low rates of recovery or improvement. Ghali et al conducted a retrospective medical record review that included adult with ME/CFS, aged 18 years and older, diagnosed according to the international consensus criteria (ICC 2011), who visited an outpatient clinic in France from October 2011 to December 2019 and were followed up until December 2020. Data collection was conducted by reviewing their medical records retrospectively.
The study revealed that ME/CFS patients have a poor prognosis with low rates of recovery or improvement. It found that older patients with ME/CFS have better outcomes compared to younger patients. Diagnostic delays were linked to a poorer prognosis, underscoring the importance of early diagnosis and management. Increased awareness among healthcare providers about ME/CFS is crucial for enhancing patient outcomes. [35]
