Chronic Fatigue Syndrome (Myalgic Encephalomyelitis)

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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] :

Criterion fulfillment for diagnosis requires all 3 of the symptoms above, along with one of the symptoms below[2] :

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:

Other tests may include the following:

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:

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]

History

Patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) typically report postexertional fatigue and feeling excessively tired after relatively normal tasks that they did for years before ME/CFS without any particular problem. Patients also report fatigue even after prolonged periods of rest or sleep. At least one quarter of patients with ME/CFS are bed- or house-bound at some point in their illness. Patients with CFS often report a history of antecedent flulike infection that precipitated the prolonged state of fatigue and followed the initial illness.

Patients with ME/CFS typically report problems with short-term memory but not with long-term memory. They may also report verbal dyslexia that manifests as the inability to find or say a particular word during normal speech. This typically disturbs patients with ME/CFS and may interfere with their occupation.

The National Academy of Medicine notes 5 main symptoms of CFS[3, 4] :

Physical Examination

Physical examination often reveals no abnormalities. Some patients may have positive orthostatic vital signs.

Many patients with or without myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) have small, moveable, painless lymph nodes that most commonly involve the neck, axillary region, or inguinal region. A single lymph node that is very large, tender, or immobile suggests a diagnosis other than CFS. Similarly, generalized adenopathy suggests a diagnosis other than CFS.

In the oropharynx, purple or crimson crescent discoloration of both anterior tonsillar pillars in the absence of pharyngitis is a frequent marker in patients with CFS. The cause of crimson crescents is unknown, but they are common in patients with CFS. Nonetheless, crimson crescents are not specific for CFS.

Trigger points, which suggest fibromyalgia, are absent in patients with CFS. Fibromyalgia and CFS rarely coexist in the same patient.

Approach Considerations

A proposed approach to diagnosing myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) involves assessing patients presenting with impaired function, fatigue, post-exertional malaise, unrefreshing sleep, cognitive impairment, and/or orthostatic intolerance. Healthcare providers conduct a thorough medical history, physical and mental health exams, and laboratory tests to rule out other conditions. If symptoms persist for six months or longer, ME/CFS is diagnosed, and patients should be periodically re-evaluated and have routine health monitoring. Symptoms and comorbidities should be addressed and managed to improve quality of life. Healthcare providers should also remain vigilant for illnesses with similar symptoms.[4]

The CDC advises conducting an initial evaluation for patients with ME/CFS that includes urinalysis, complete blood count, comprehensive metabolic panel, and assessments of phosphorus, thyroid-stimulating hormone, and C-reactive protein. Screening for celiac disease using immunoglobulin A endomysial antibodies is also recommended by NICE, along with urine drug screening, rheumatoid factor testing, and antinuclear antibody testing if warranted by the patient's history or physical examination. Viral titers are generally not recommended unless there are specific indications of an infectious process, as they may not conclusively confirm or rule out a diagnosis of ME/CFS.[1]

Laboratory Studies

Most individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) have normal routine laboratory test results despite experiencing significant debilitation.[36] Additional testing may be required based on the individual's medical history and physical examination findings to rule out other potential illnesses.

For example, if autoimmune disease is suspected, healthcare providers may recommend further tests like antinuclear antibodies. However, excessive testing without clinical suspicion should be avoided due to the risk of false-positive results.

If abnormal laboratory results are identified, additional evaluation is necessary. For instance, if anemia is detected, further investigations are often recommended to determine the cause and provide appropriate treatment. These tests may include assessments for B12 and folate deficiencies, as anemia can be a symptom of conditions like celiac disease.

Some healthcare providers specialized in ME/CFS may include vitamin level tests, such as B12, folate, and vitamin D, as part of the initial assessment. Assessing B12 and folate levels can be particularly beneficial for individuals with cognitive issues to identify underlying conditions.

Assessing ME/CFS involves examining the patient's symptoms, medical history, physical examination results, recent laboratory tests, and clinical assessment.

Like with any medical condition, healthcare professionals usually decide on the sequence and importance of laboratory tests based on the specific presentation of each patient.

The following tests are regularly employed by healthcare providers with specialized knowledge in ME/CFS for patient evaluation. The primary objective is to identify and exclude other potential illnesses. It may not be necessary to conduct all of the listed tests initially or simultaneously:

 

Other Tests

Further examinations such as imaging studies and physiological evaluations may be necessary to identify potential underlying conditions. These assessments could encompass[36] :

Patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may have comorbid conditions that contribute to fatigue and other symptoms such as blood pressure abnormalities, which should be managed accordingly. However, extensive testing and frequent healthcare visits can worsen ME/CFS symptoms, so careful scheduling of follow-up appointments is essential. It is important to recognize that some individuals with ME/CFS may not appear visibly ill during office visits, and those with severe symptoms may have difficulty attending all appointments.

Cognitive testing

Testing can help evaluate cognitive functions in patients with ME/CFS, as the condition can impact concentration, memory, and processing speed. These assessments can pinpoint areas where specific tools or strategies may be beneficial.

For children and adolescents with ME/CFS, cognitive assessments and interventions can be especially valuable. Given the importance of academic performance for these individuals, addressing their unique educational requirements is crucial.[36]

Imaging Studies

MRI or other neuroimaging procedures may be necessary.[36]

Activity

Post-Exertional Malaise (PEM)

Post-Exertional Malaise (PEM) in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a hallmark symptom characterized by a exacerbation of symptoms following physical or mental exertion that would have been tolerated previously. This delayed response typically occurs 12-48 hours after the activity and can last for an extended period, often days or even weeks. Managing PEM involves carefully balancing activity and rest to prevent symptom flare-ups and relapse. Patients are advised to identify their individual limits for mental and physical activity, known as their "energy envelope", to avoid exceeding their capacities and triggering PEM.[37]  

Researchers Wormgoor and Rodenburg conducted a study focusing on the importance and effects of addressing PEM in rehabilitation stays, consultations, and hospital interventions. Their analysis, based on data from patient surveys, revealed varying rates of addressing PEM in different healthcare settings. Patients who received tailored PEM-focused care reported higher satisfaction and beneficial outcomes. Addressing PEM was associated with positive perceptions about healthcare providers' knowledge and understanding of ME/CFS, symptom acknowledgment, and treatment approaches. This emphasizes the importance of considering PEM in managing ME/CFS within healthcare settings.[38]

Activity planning

It is crucial to tailor any activity or exercise plan for individuals with ME/CFS based on their unique condition and preferences, incorporating their input.[37] Consulting with a rehabilitation specialist may be beneficial, as daily tasks can be challenging for some patients and may require breaking them down into more manageable segments.

While vigorous aerobic exercise is beneficial for many chronic illnesses, it can be harmful to ME/CFS patients who cannot tolerate such routines. Patients should focus on maintaining activities they can handle to avoid deconditioning, with some needing treatment for orthostatic intolerance before considering any additional activity.

For patients capable of handling their current activity level and in tune with their body's signals, a gradual increase in exercise might be helpful in improving physical fitness and preventing deconditioning. Healthcare providers knowledgeable about ME/CFS may recommend working with an exercise physiologist specializing in the condition to develop an individualized and adaptable approach to increasing activity levels.

Activity planning for children

Managing ME/CFS in pediatric patients involves addressing the impact of activities of daily living, education, and social engagement, which can trigger post-exertional malaise (PEM) in some cases.[37]  Although some young patients may require careful planning to accommodate these activities, others may navigate them with ease.

Ensuring continuity in schooling and social connections is vital in managing the condition in children. Healthcare providers can collaborate with young patients and school authorities, potentially implementing study plans or Individualized Educational Plans (IEP) to support their educational needs. Healthcare professionals play a crucial role in advocating for adequate support in academic settings from the outset of ME/CFS evaluation.

Children experiencing severe fatigue and cognitive challenges may benefit from accommodations such as part-time schooling, home tutoring, or temporary withdrawal from school until symptom management improves. For more guidance on this subject, resources like the Pediatric ME/CFS Fact Sheet for Healthcare Professionals offer valuable insights and recommendations.

Gaunt et al conducted a pragmatic parallel groups randomized controlled trial that compared graded exercise therapy (GET) with activity management (AM) in children aged 8-17 years with mild/moderate ME/CFS who sought care at a National Health Service (NHS) specialist pediatric service in Great Britain. They found no proof that graded exercise therapy (GET) was more beneficial or cost-effective compared with activity management (AM), and the children in both groups had very limited improvement at 6 and 12 months.[38]

Orthostatic intolerance

Many individuals with ME/CFS also endure symptoms that worsen when standing upright, a condition called orthostatic intolerance.[37] Common symptoms include dizziness, lightheadedness, palpitations, and feeling faint, with adolescents being especially vulnerable. Patients may not always recognize this issue, making it important to inquire about specific experiences related to standing and posture.

A standing test, like the NASA lean test, can provide direct assessment of orthostatic intolerance, with additional formal tilt table tests potentially considered. Abnormal responses may include increased heart rate (postural orthostatic tachycardia syndrome) or low/high blood pressure (orthostatic hypo-/hypertension), necessitating evaluation by a cardiologist or neurologist.

Strategies to manage orthostatic issues involve avoiding triggers like heat or prolonged standing, utilizing postural maneuvers, compression garments, or increased salt/fluid intake where appropriate. If non-pharmacological methods prove ineffective, medications tailored for conditions like POTS and neurally mediated hypotension may be necessary, along with support stockings to alleviate symptoms.

Natelson et al assessed the physiologic response of patients with ME/CFS to a standardized orthostatic challenge.[39] They administered a 10-minute passive vertical lean test as an orthostatic challenge-OC and recorded changes in vital signs and end tidal CO2 63 patients assessed from one to three times during several years. The most frequent abnormality was hypocapnia, either resting or caused by OC, and the second most frequent was postural orthostatic tachycardia.

Difficulty sleeping

Patients with ME/CFS often experience non-restorative sleep, waking up feeling less refreshed than before the onset of illness.[37] Common sleep issues in ME/CFS include frequent awakening, vivid dreaming, restless legs, nocturnal myoclonus, and difficulty falling asleep or hypersomnia. While good sleep hygiene practices are recommended, patients may still wake unrefreshed, prompting consideration of sleep medication, starting with over-the-counter options.

In cases where standard interventions do not improve sleep quality, healthcare providers may prescribe sleep medication cautiously, using the lowest effective dose for the shortest duration. If unrefreshing sleep persists despite treatment, consultation with a sleep specialist for further evaluation, including a possible sleep study, is crucial. Addressing primary sleep disorders like sleep apnea or narcolepsy can benefit individuals, but ME/CFS symptoms may persist even after sleep disorder treatment.

For some severely affected ME/CFS patients, standard sleep recommendations may not be sufficient or may have limited effectiveness.

Pain

People with ME/CFS commonly experience muscle and joint pain, along with headaches and skin sensitivity. Initial management options include over-the-counter pain medications like acetaminophen, aspirin, or ibuprofen, with a pain specialist consultation recommended if these remedies are insufficient.[37] Counseling for pain management techniques is often beneficial for chronic pain.

Non-pharmacological methods, such as stretching, manual therapy, massage, heat therapy, toning exercises, and hydrotherapy, may also aid in managing pain for patients with ME/CFS. These approaches should be carefully tailored to prevent post-exertional malaise. Acupuncture, administered by a licensed practitioner, is another potential option for pain relief in some individuals.

Memory and Concentration Problems

Memory issues in patients with ME/CFS can be managed using memory aids such as organizers, notebooks, smartphones, and tablets for tasks, appointments, and reminders. Careful planning and monitoring of cognitive activities are essential to prevent mental overexertion and post-exertional malaise, as rest periods should follow mental activities to prevent symptom exacerbation.

When addressing cognitive problems, caution is advised when considering stimulant medications. Mild stimulants can be beneficial for some patients, but stronger stimulants may lead to a cycle of overactivity followed by crashes, known as the "push-crash cycle." Monitoring for potential adverse effects like insomnia and weight loss is crucial, as many stimulants carry the risk of habit formation and tolerance with daily use. Regular follow-up is necessary to manage these medications effectively.

Depression and Anxiety

Patients with chronic illnesses sometimes develop depression and/or anxiety as a co-morbid condition with their chronic illnesses. Some might have these conditions preceding, but not causative of, their chronic illnesses.

As many as half of patients with ME/CFS develop depression at some time during their illness. Brief psychiatric screening tools can be given and scored in the primary care setting.

When the assessments suggest possible depression or other psychiatric diagnoses, that condition should be managed. Referrals to mental health professionals may be warranted either alone or in combination with medication.

Although treating these comorbid conditions can be helpful, treatment for such conditions does not cure ME/CFS.

Some patients with ME/CFS who are clinically depressed may benefit from antidepressants. However, healthcare providers should use caution in prescribing these medications. Some drugs to treat depression might worsen other ME/CFS symptoms and cause side effects, particularly sedation and orthostatic hypotension. If prescribed, medication for depression should start at a low dose with careful monitoring for side effects. As for all patients starting anti-depressants, improvement might not occur for several weeks.

Patients with less severe ME/CFS may benefit from non-medication techniques that reduce stress and anxiety and promote a sense of well-being. Examples of such techniques include deep breathing and muscle relaxation, massage, and movement therapies (such as stretching, yoga, and tai chi).

Healthcare providers should be mindful that initiating or resuming these or other movement therapies requires careful consideration to avoid post-exertional malaise.

Exercise Therapy

Smakowski et al examined the effectiveness of graded exercise therapy provided to patients with chronic fatigue syndrome/myalgic encephalomyelitis (ME/CFS) in a specialist clinic by collecting patient-reported outcome data at multiple time points during therapy.[40] Benchmarking analyses were used to compare the results with those from randomized controlled trials.

Fatigue scores were significantly reduced by session 4 (-5.18) and at follow-up (-4.73). Work and social adjustment and physical functioning progressively improved over the course of therapy, reaching significance at discharge (–5.42) and maintained at follow-up (WSAS, -4.97; SF-36, 10.75). Physical functioning were improved at discharge (9.63) and maintained at follow-up (10.75). Depression scores decreased significantly over time (F  = 3.19, p = .047), but paired t-tests revealed there were no differences between pre-treatment and discharge (–1.52) or follow-up (–0.92).

 

 

Guidelines Summary

Guidelines on Myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome: diagnosis and management by National Institute for Health and Care Excellence (NICE) are highlighted below.[1] Please see the complete guideline for more information.

The CDC recommends the following laboratory tests in patients with suspected ME/CFS[36] :

The following tests are regularly employed by healthcare providers with specialized knowledge in ME/CFS for patient evaluation. The primary objective is to identify and exclude other potential illnesses. It may not be necessary to conduct all of the listed tests initially or simultaneously:

Testing Recommendations for Suspected ME/CFS by the US ME/CFS Clinician Coalition provide recommendations for a set of tests to identify alternative and comorbid diagnoses in ME/CFS patients. The recommendations suggest a limited set of tests for all suspected cases, with additional tests based on individual patient presentations. These recommendations are general guidance for a diagnostic process that may involve multiple office visits and referrals to specialists, requiring the clinician's clinical judgment. The guidance also includes recommendations for tests to support disability claims and guide treatment decisions.

 

 

Medication Summary

No drugs are FDA approved for the treatment of ME/CFS. Clinical trials have found that antiviral agents are ineffective in relieving the symptoms of CFS.[41] Various medications have been shown to be ineffective, including antibiotics, glucocorticoids, liver extract, chelating agents, intravenous (IV) vitamins, vitamin B-12, and IV or oral vitamin or mineral supplements. Antidepressants have no major role in the treatment of CFS.

A randomized placebo-controlled double-blind trial to evaluate the effect of cytokine inhibition with anakinra, a recombinant human interleukin-1 (IL-1) receptor antagonist, was conducted and did not show any improvement in fatigue severity both in the short term (4 weeks) or the long term (6 months).[42] Future studies may evaluate inhibition of other cytokines such as IL-6, tumor necrosis factor, and/or interferons.

To date, no evidence-based interventions are available for the treatment of ME/CFS.

What is chronic fatigue syndrome (CFS)?What are the diagnostic criteria for chronic fatigue syndrome (CFS)?What is the pathophysiology of chronic fatigue syndrome (CFS)?What causes chronic fatigue syndrome (CFS)?What is the prevalence of chronic fatigue syndrome (CFS)?What is the prognosis of chronic fatigue syndrome (CFS)?Which clinical history findings are characteristic of chronic fatigue syndrome (CFS)?What are the signs and symptoms of chronic fatigue syndrome (CFS)?Which physical findings are characteristic of chronic fatigue syndrome (CFS)?How is chronic fatigue syndrome (CFS) differentiated from other fatigue-producing disorders?What are the differential diagnoses for Chronic Fatigue Syndrome (Myalgic Encephalomyelitis)?What is the role of lab studies is the workup of chronic fatigue syndrome (CFS)?Which tests may be performed in the diagnosis evaluation of chronic fatigue syndrome (CFS)?What is the role of the imaging studies in the workup of chronic fatigue syndrome (CFS)?How is chronic fatigue syndrome (CFS) treated?Which dietary modifications are used in the treatment of chronic fatigue syndrome (CFS)?What is the role of exercise therapy in the treatment of chronic fatigue syndrome (CFS)?What is the role of medications in the treatment of chronic fatigue syndrome (CFS)?

Author

Jefferson R Roberts, MD, Chief of Rheumatology Service, Tripler Army Medical Center; Assistant Clinical Professor of Medicine, Uniformed Services University of the Health Sciences

Disclosure: Nothing to disclose.

Coauthor(s)

Mary L Lan, MD, MPH, Resident Physician, Department of Medicine, Tripler Army Medical Center

Disclosure: Nothing to disclose.

Michael W Price, MD, Chief, Medical Specialty Clinic #1, Tripler Army Medical Center; Instructor in Medicine, Uniformed Services University of the Health Sciences, F Edward Herbert School of Medicine

Disclosure: Nothing to disclose.

Specialty Editors

Michael A Kaliner, MD, Clinical Professor of Medicine, George Washington University School of Medicine; Medical Director, Institute for Asthma and Allergy

Disclosure: Nothing to disclose.

Chief Editor

Michael Stuart Bronze, MD, David Ross Boyd Professor and Chairman, Department of Medicine, Stewart G Wolf Endowed Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Center; Master of the American College of Physicians; Fellow, Infectious Diseases Society of America; Fellow of the Royal College of Physicians, London

Disclosure: Nothing to disclose.

Additional Contributors

Burke A Cunha, MD, Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital

Disclosure: Nothing to disclose.

Acknowledgements

Bryan D Carter, PhD Professor of Child Psychology in Psychiatry and Behavioral Sciences, Chief Psychologist in Division of Child and Adolescent Psychiatry, Director of Predoctoral Internship in Clinical Child/Pediatric Psychology, Director of Postdoctoral Fellowship Program in Pediatric Psychology, Director of Pediatric Consultation-Liaison Service to Kosair Children's Hospital, University of Louisville School of Medicine

Bryan D Carter, PhD is a member of the following medical societies: American Psychological Association

Disclosure: Nothing to disclose.

Thomas M Kerkering, MD Chief of Infectious Diseases, Virginia Tech Carilion School of Medicine

Thomas M Kerkering, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Public Health Association, American Society for Microbiology, American Society of Tropical Medicine and Hygiene, Infectious Diseases Society of America, Medical Society of Virginia, and Wilderness Medical Society

Disclosure: Nothing to disclose.

Leonard R Krilov, MD Chief of Pediatric Infectious Diseases and International Adoption, Vice Chair, Department of Pediatrics, Professor of Pediatrics, Winthrop University Hospital

Leonard R Krilov, MD is a member of the following medical societies: American Academy of Pediatrics, American Pediatric Society, Infectious Diseases Society of America, Pediatric Infectious Diseases Society, and Society for Pediatric Research

Disclosure: Medimmune Grant/research funds Cliinical trials; Medimmune Honoraria Speaking and teaching; Medimmune Consulting fee Consulting

Mark R Schleiss, MD American Legion Chair of Pediatrics, Professor of Pediatrics, Division Director, Division of Infectious Diseases and Immunology, Department of Pediatrics, University of Minnesota Medical School

Mark R Schleiss, MD is a member of the following medical societies: American Pediatric Society, Infectious Diseases Society of America, Pediatric Infectious Diseases Society, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Russell W Steele, MD Head, Division of Pediatric Infectious Diseases, Ochsner Children's Health Center; Clinical Professor, Department of Pediatrics, Tulane University School of Medicine

Russell W Steele, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Immunologists, American Pediatric Society, American Society for Microbiology, Infectious Diseases Society of America, Louisiana State Medical Society, Pediatric Infectious Diseases Society, Society for Pediatric Research, and Southern Medical Association

Disclosure: Nothing to disclose.

Julian M Stewart, MD, PhD Associate Chairman of Pediatrics, Director, Center for Hypotension, Westchester Medical Center; Professor of Pediatrics and Physiology, New York Medical College

Julian M Stewart, MD, PhD is a member of the following medical societies: American Academy of Pediatrics

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Robert W Tolan Jr, MD Chief, Division of Allergy, Immunology and Infectious Diseases, The Children's Hospital at Saint Peter's University Hospital; Clinical Associate Professor of Pediatrics, Drexel University College of Medicine

Robert W Tolan Jr, MD is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, American Society for Microbiology, American Society of Tropical Medicine and Hygiene, Infectious Diseases Society of America, Pediatric Infectious Diseases Society, Phi Beta Kappa, and Physicians for Social Responsibility

Disclosure: Novartis Honoraria Speaking and teaching

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

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