If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Despite myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) affecting millions of people worldwide, many clinicians lack the knowledge to appropriately diagnose or manage ME/CFS. Unfortunately, clinical guidance has been scarce, obsolete, or potentially harmful. Consequently, up to 91% of patients in the United States remain undiagnosed, and those diagnosed often receive inappropriate treatment. These problems are of increasing importance because after acute COVID-19, a significant percentage of people remain ill for many months with an illness similar to ME/CFS. In 2015, the US National Academy of Medicine published new evidence-based clinical diagnostic criteria that have been adopted by the US Centers for Disease Control and Prevention. Furthermore, the United States and other governments as well as major health care organizations have recently withdrawn graded exercise and cognitive-behavioral therapy as the treatment of choice for patients with ME/CFS. Recently, 21 clinicians specializing in ME/CFS convened to discuss best clinical practices for adults affected by ME/CFS. This article summarizes their top recommendations for generalist and specialist health care providers based on recent scientific progress and decades of clinical experience. There are many steps that clinicians can take to improve the health, function, and quality of life of those with ME/CFS, including those in whom ME/CFS develops after COVID-19. Patients with a lingering illness that follows acute COVID-19 who do not fully meet criteria for ME/CFS may also benefit from these approaches.
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, multi-system disease affecting millions of people worldwide. Despite its high prevalence and disabling nature, medical education programs rarely cover ME/CFS and guidance for practicing clinicians is often outdated and inappropriate.
US Institute of Medicine Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Washington, DC: The National Academies Press; 2015.
US Institute of Medicine Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Washington, DC: The National Academies Press; 2015.
US Institute of Medicine Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Washington, DC: The National Academies Press; 2015.
To obtain a diagnosis, patients frequently have had to see multiple clinicians over a number of years. Even after diagnosis, patients struggle to obtain appropriate care and have often been prescribed treatments, such as cognitive-behavioral therapy (CBT) and graded exercise therapy (GET), that could worsen their condition.
US Institute of Medicine Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Washington, DC: The National Academies Press; 2015.
Myalgic encephalomyelitis/chronic fatigue syndrome patients’ reports of symptom changes following cognitive behavioural therapy, graded exercise therapy and pacing treatments: analysis of a primary survey compared with secondary surveys.
In 2015, the US National Academy of Medicine (NAM, previously the Institute of Medicine) created new ME/CFS clinical diagnostic criteria that required the hallmark symptom of post-exertional malaise (PEM).
US Institute of Medicine Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Washington, DC: The National Academies Press; 2015.
The US Centers for Disease Control and Prevention have adopted these new criteria, have removed recommendations for CBT and GET, and have begun to incorporate the best clinical practices of ME/CFS experts. These steps will help improve the speed and accuracy of diagnosis and the quality of clinical care.
Lingering symptoms including fatigue follow various types of infectious illnesses.
US Institute of Medicine Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Washington, DC: The National Academies Press; 2015.
US Institute of Medicine Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Washington, DC: The National Academies Press; 2015.
Chronic COVID-19 syndrome and chronic fatigue syndrome (ME/CFS) following the first pandemic wave in Germany—a first analysis of a prospective observational study. medRxiv. Preprint posted online February 8, 2021.
EUROPEAN ME NETWORK (EUROMENE) expert consensus on the diagnosis, service provision and care of people with ME/CFS in Europe. Preprints. Preprint posted online October 16.
Accurately and expeditiously diagnosing ME/CFS is important. There are many steps a clinician can take to improve the health, function, and quality of life of these patients. Even if they do not go on to develop ME/CFS, some patients with post-COVID conditions may also benefit from approaches such as pacing.
Epidemiology
Myalgic encephalomyelitis/chronic fatigue syndrome affects between 836,000 and 2.5 million Americans of all ages, ethnicities, genders, and socioeconomic backgrounds.
US Institute of Medicine Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Washington, DC: The National Academies Press; 2015.
US Institute of Medicine Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Washington, DC: The National Academies Press; 2015.
US Institute of Medicine Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Washington, DC: The National Academies Press; 2015.
US Institute of Medicine Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Washington, DC: The National Academies Press; 2015.
Historically, premorbid mood disorders, personality issues, and childhood adversity have been linked to the development of ME/CFS. However, study limitations, such as use of overly broad criteria that included people with depression but not ME/CFS, could confound those findings.
US Institute of Medicine Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Washington, DC: The National Academies Press; 2015.
Functional status and well-being in people with myalgic encephalomyelitis/chronic fatigue syndrome compared with people with multiple sclerosis and healthy controls.
Myalgic encephalomyelitis/chronic fatigue syndrome substantially impairs occupational, educational, social, and personal activities. The degree of impairment can exceed that of rheumatoid arthritis, multiple sclerosis, depression, heart disease, cancer, and lung disease.
Functional status and well-being in people with myalgic encephalomyelitis/chronic fatigue syndrome compared with people with multiple sclerosis and healthy controls.
Mild: mobile and self-caring; may continue working but will have reduced other activities
•
Moderate: reduced mobility, restricted in instrumental activities of daily living, needs frequent periods of rest; usually not working
•
Severe: mostly housebound; limited to minimal activities of daily living (eg, face washing, showering); severe cognitive difficulties; may be wheelchair dependent
•
Very severe: mostly bedridden; unable to independently carry out most activities of daily living; often experience extreme sensitivity to light, sound, and other sensory input
Up to 75% are unable to work, and an estimated 25% are consistently housebound or bedbound.
Multi-site clinical assessment of myalgic encephalomyelitis/chronic fatigue syndrome (MCAM): design and implementation of a prospective/retrospective rolling cohort study [erratum appears in Am J Epidemiol. 2017;186(1):129].
US Food and Drug Administration The voice of the patient. A series of reports from the U.S. Food and Drug Administration’s (FDA’s) patient-focused drug development initiative. September 2013.
Although it is known that patients can be ill for years or even decades, no definitive study of prognosis exists. Studies are limited by small sample sizes, high dropout rates, short follow-up times, inclusion of patients with other conditions, and inappropriate definitions of recovery.
One ME/CFS-focused clinical practice estimated that 50% of its patients were still ill after 2 decades whereas a second estimated 93% (oral communication, US ME/CFS Clinician Coalition, March 2019). Temporary remission is reported, but relapses often occur. Patients most commonly report a fluctuating illness pattern in which symptoms wax and wane but are always present.
Specialty clinics for ME/CFS reported that 84% of 960 patients observed long term developed at least 1 comorbid condition. Additional comorbidities were associated with worsened health.
In 2015, the NAM published updated criteria. The new criteria require substantial impairment in function accompanied by fatigue, PEM, unrefreshing sleep, and either cognitive impairment or orthostatic intolerance (Figure). Symptoms should be of at least moderate intensity and present at least 50% of the time during a 6-month period. Other important factors include perionset infection, widespread pain, and impaired natural killer cell activity. Additional symptoms include influenza-like symptoms (eg, sore throat, tender lymph nodes); hypersensitivity to external stimuli (eg, food, smells, light, sound, touch, chemicals); susceptibility to infections; visual disturbances; gastrointestinal or genitourinary symptoms; respiratory issues, such as air hunger; and thermoregulatory issues.
FigureThe 2015 National Academy of Medicine diagnostic criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
The NAM criteria enable a proactive diagnosis based on these core symptoms. In addition, disease experts often use the 2003 Canadian Consensus Criteria or the 2011 ME International Consensus Criteria to confirm a diagnosis of ME/CFS.
The hallmark symptom of PEM is an exacerbation of some or all of a patient’s symptoms and a further reduction in functioning after physical, cognitive, orthostatic, emotional, or sensory challenges that were previously tolerated. PEM is characterized by the following:
•
Immediate or delayed onset. Onset may be immediate or delayed by hours to days after the challenge.
•
Prolonged duration. Days, weeks, or months may pass before patients return to their previous baseline.
•
Disproportionate intensity. The intensity and duration of PEM are unexpectedly disproportionate to the magnitude of the PEM trigger. For the mildly ill, working a few hours or a day can trigger PEM, whereas for the most severely ill, even basic activities of daily living will be sufficient.
Notably, although postexercise fatigue and musculoskeletal pain are common in healthy people and other medical conditions (eg, osteoarthritis), the postexertional worsening of function and the constellation of symptoms (such as sleep, memory, concentration, influenza-like feelings [eg, sore throat], and mood) seen in ME/CFS are distinctive.
were commonly used to diagnose ME/CFS. The Fukuda definition was a diagnosis of exclusion and required only medically unexplained, chronic fatigue but not PEM or other important symptoms of ME/CFS. Clinicians believed that they had to eliminate every possible cause of fatigue, leading to delays in or avoidance of diagnosing ME/CFS. As noted by the NAM, not all patients diagnosed by the Fukuda criteria will meet ME/CFS criteria and will need to be reevaluated.
Etiology and Pathophysiology
While the exact etiology of ME/CFS is uncertain, studies show neurologic, immunologic, autonomic, and energy metabolism impairments.
US Institute of Medicine Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Washington, DC: The National Academies Press; 2015.
US Institute of Medicine Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Washington, DC: The National Academies Press; 2015.
In contrast, patients with ME/CFS experience PEM, a distinctive exacerbation of the patient’s set of symptoms and a further reduction in functioning after previously tolerated physical, cognitive, orthostatic, emotional, or sensory stressors. Multiple studies using both patient-reported and physiologic outcome measures have confirmed these accounts.
US Institute of Medicine Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Washington, DC: The National Academies Press; 2015.
In the past, some physicians and scientists speculated that these exertional limitations were due to physical deconditioning or an irrational fear of activity.
While chronically inactive people are likely to be deconditioned, deconditioning does not explain the symptoms of ME/CFS. Instead, evidence suggests that problems generating and using the main energy molecule, adenosine triphosphate (ATP), may be a fundamental driver of ME/CFS.
For example, when sedentary but healthy people or people affected by a number of other chronic illnesses are asked to exercise to their maximal ability on 2 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 the same on repeated testing.
Physiological measures in participants with chronic fatigue syndrome, multiple sclerosis and healthy controls following repeated exercise: a pilot study.
Physiological measures in participants with chronic fatigue syndrome, multiple sclerosis and healthy controls following repeated exercise: a pilot study.
Ventricular cerebrospinal fluid lactate is increased in chronic fatigue syndrome compared with generalized anxiety disorder: an in vivo 3.0 T 1H MRS imaging study.
in the blood, cerebrospinal fluid, and muscles. This could be due to increased production or decreased elimination. If aerobic metabolism is impaired, cells switch to anaerobic metabolic pathways instead, which produce more lactic acid but 18 times less ATP per glucose molecule.
These changes may explain why patients have difficulty with tasks they tolerated before illness and with sustaining activities. Damage to more than 1 energy generation system may account for why severely affected patients are often so limited. Tomas and Newton
Myalgic encephalomyelitis (ME), chronic fatigue syndrome (CFS), and chronic fatigue (CF) are distinguished accurately: results of supervised learning techniques applied on clinical and inflammatory data.
revealed increased complement split products, oxidative stress, and gene expression of interleukin-10. Increased levels of immune system molecules in the brain, such as interleukin-1 and interleukin-10, can cause symptoms such as fatigue, pain, influenza-like feelings, and cognitive impairment. These objective changes correspond with and may contribute to the patient experiences of PEM.
Unrefreshing Sleep
Patients experience various sleep disturbances, such as problems in falling or staying asleep. However, even when these problems are treated, most patients remain tired or sick on awakening. Reduced heart rate variability, controlled by the autonomic nervous system, is linked to unrefreshing sleep in ME/CFS and other conditions.
Furthermore, studies have reported that nocturnal parasympathetic activity is decreased relative to sympathetic activity in ME/CFS, the inverse of what should be occurring during rest.
US Institute of Medicine Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Washington, DC: The National Academies Press; 2015.
Motor speed, verbal abilities, and global reasoning remain intact.
Brain studies have found brain inflammation and reductions in white matter and possibly in gray matter. Neuroinflammation is correlated with cognitive impairment and impaired connectivity across various regions of the brain.
US Institute of Medicine Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Washington, DC: The National Academies Press; 2015.
In up to 95% of those with ME/CFS, an immobile, upright position (eg, prolonged standing or sitting) will cause or worsen symptoms such as lightheadedness, nausea, fatigue, palpitations, and cognitive impairment.
US Institute of Medicine Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Washington, DC: The National Academies Press; 2015.
Assumption of a sitting or supine position can alleviate symptoms. This phenomenon is called orthostatic intolerance and includes orthostatic hypotension, postural orthostatic tachycardia syndrome, and neurally mediated hypotension.
Objective physiologic abnormalities include the following:
•
Abnormal heart rate and blood pressure changes after passive standing and tilt table tests
Cerebral blood flow is reduced in ME/CFS during head-up tilt testing even in the absence of hypotension or tachycardia: a quantitative, controlled study using Doppler echography.
Decreases in stroke volume index and cardiac index that are not correlated with activity levels, contradicting theories that deconditioning explains ME/CFS
The abnormal cardiac index and stroke volume index changes during a normal tilt table test in ME/CFS patients compared to healthy volunteers, are not related to deconditioning.
US Institute of Medicine Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Washington, DC: The National Academies Press; 2015.
Cerebral blood flow is reduced in ME/CFS during head-up tilt testing even in the absence of hypotension or tachycardia: a quantitative, controlled study using Doppler echography.
US Institute of Medicine Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Washington, DC: The National Academies Press; 2015.
It is unknown whether this finding is a cause, consequence, or epiphenomenon of ME/CFS. Although patients with ME/CFS do not present with symptomatic, opportunistic infections (eg, cryptosporidiosis, tuberculosis), some do experience recurrent herpes infections.
US Food and Drug Administration The voice of the patient. A series of reports from the U.S. Food and Drug Administration’s (FDA’s) patient-focused drug development initiative. September 2013.
Some are susceptible to colds and may take longer to recover from infections, whereas others experience less frequent common infections (oral communication, US ME/CFS Clinician Coalition, May 2021).
US Food and Drug Administration The voice of the patient. A series of reports from the U.S. Food and Drug Administration’s (FDA’s) patient-focused drug development initiative. September 2013.
US Institute of Medicine Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Washington, DC: The National Academies Press; 2015.
but the specific microorganism is often not identified because the illness initially appeared to be self-limited. Other times, ME/CFS follows a well-documented infectious illness, such as Epstein-Barr virus infectious mononucleosis or Giardia-caused diarrhea.
US Institute of Medicine Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Washington, DC: The National Academies Press; 2015.
The purpose of initial evaluations is to determine whether alternative conditions may account for all of the patient’s symptoms, to confirm ME/CFS through recognition of characteristic symptoms and signs, and to identify comorbid conditions. Because there are no definitive diagnostic tests, diagnosis relies on medical history and physical examination and may require multiple visits. Tests and referrals to specialists are used primarily to identify alternative diagnoses and comorbidities.
Typical Presentation: Important Elements of the History
Patients typically experience a proven or nonspecific infection but fail to recover as expected and continue to be ill weeks to months later. Some patients may identify a noninfectious trigger (eg, surgery, pregnancy, vaccination) or no precipitant at all. Chronologic patterns can vary. In some patients, all of the ME/CFS symptoms develop within hours or days of the instigating event, whereas others report symptoms appearing more gradually over weeks and months. Patients often describe a waxing and waning pattern or sometimes remission to normal health followed by relapse.
Patients may initially complain of persistent influenza-like symptoms, sleep disturbances, problems in thinking, profound fatigue, problems in being upright, and difficulty in keeping up with normal activities. They may struggle with school, work, family responsibilities, exercise, socializing, or personal care. They may complain of pain and hypersensitivities to light, sound, fragrances, food, and medications. Patients may be susceptible to mold or other environmental toxins. They may experience other symptoms but not link them to their illness or have difficulty describing them. Consequently, it is important for clinicians to ask explicitly about the symptoms composing the criteria for ME/CFS. Examples of questions to ask are listed in Table 1. Family members may need to respond for the most severely ill.
All questions should explore frequency and severity. To fulfill 2015 National Academy of Medicine diagnostic criteria, symptoms must be of at least moderate severity and present at least 50% of the time.
Impairment in function with profound fatigue
•
“Flu-like fatigue/exhaustion”
•
“I feel like a battery that is never able to be recharged fully despite resting a lot and limiting my activities to only the bare essentials needed to get by.”
•
“Thinking takes a lot more work than it used to.”
•
“My arms, legs, body feel heavy and harder to move.”
•
Severe limitations in personal and household management
•
Loss of job, medical insurance, and career
•
Being predominantly housebound
•
Decreased social interaction and increased isolation
Clinicians should ask additional questions to understand the nature of fatigue; for instance, “What do you mean by fatigued?” and “On a scale of 0 (no energy) to 10 (full energy), how fatigued are you?”.
•
What helps your fatigue the most (resting, lying down, quiet situations, not exercising or avoiding exercise)? What makes the fatigue worse?
•
What are you able to do now?
•
How does it compare with what you were able to do before?
•
Think back to what you were able to do before you became sick. How much has this illness affected: (a) your ability to work? (b) your ability to take care of yourself/your family and to do chores?
•
What happens when you try to push through the fatigue?
Post-exertional malaise
•
“Crash,” “relapse,” “collapse”
•
Mentally tired after the slightest effort
•
Physically drained or sick after mild activity
•
The more demanding, prolonged, or repeated the activity, the more severe and prolonged the payback
•
What happens to you as you engage in normal physical or mental exertion? or after?
•
How much activity does it take you to feel ill?
•
What symptoms develop from standing or exertion?
•
How long does it take to recover from physical or mental effort?
•
If you go beyond your limits, what are the consequences?
•
What types of activities do you avoid because of what will happen if you do them?
Unrefreshing sleep
•
“Feeling like I never slept”
•
“Cannot fall asleep or stay asleep”
•
“After long or normal hours of sleep, I still don’t feel good in the morning.”
•
Do you have any problems getting to sleep or staying asleep?
•
Do you feel rested in the morning or after you have slept?
•
Tell me about the quality of your sleep.
•
Do you need too much sleep?
•
Do you need to take more naps than other people? (There may be other sleep disruptors as well.)
Cognitive impairments
•
“Brain fog”
•
“Confusion”
•
“Disorientation”
•
“Hard to concentrate, can’t focus”
•
“Inability to process information”
•
“Can’t find the right words”
•
“Inability to multitask”
•
“Problems with decision-making”
•
“Absent-minded/forgetful”
•
Do you have problems doing the following activities: driving, watching a movie, reading a book/magazine, completing complex tasks under time constraints, following/participating in conversation, doing more than 1 thing at a time?
•
Compared with before your illness, how is your performance at work or school now?
Orthostatic intolerance
•
Lightheadedness
•
Dizziness
•
Spatial disorientation or imbalance
•
Fainting
•
Feeling unwell, dizzy, or lightheaded when sitting up or standing still for extended periods (note “extended” can mean a few minutes for the severely affected)
•
How do you feel when you have been standing still for more than a few minutes?
•
What happens to you after you get up rapidly after lying down or sitting for a long time?
•
How long can you stand before feeling ill? For example, can you do the dishes? Can you stand in line for a bus or movie? Are you able to grocery shop or go to a mall?
•
How does hot weather affect you?
•
Do you study or work lying down, in bed or a recliner? Why?
•
Do you prefer to sit with knees to your chest or legs under you?
Adapted from the National Academy of Medicine Report Guide for Clinicians,
US Institute of Medicine Beyond myalgic encephalomyelitis/chronic fatigue syndrome: redefining an illness. Report guide for clinicians. The National Academies Press. February 2015.
with permission of the National Academy of Sciences.
a All questions should explore frequency and severity. To fulfill 2015 National Academy of Medicine diagnostic criteria, symptoms must be of at least moderate severity and present at least 50% of the time.
b Clinicians should ask additional questions to understand the nature of fatigue; for instance, “What do you mean by fatigued?” and “On a scale of 0 (no energy) to 10 (full energy), how fatigued are you?”.
The key symptom of PEM is often not mentioned spontaneously as patients may not be familiar with the concept. The nature and severity of PEM symptoms, the degree of reduction in function, and PEM’s time course can vary from episode to episode and with the type of activity. If the patient is unable to clearly answer the PEM questions suggested in Table 1, ask the patient to keep a journal for 1 or 2 weeks detailing activities and symptoms (type, intensity, frequency, duration). The patient may be in a constant state of PEM, making it difficult to recognize the impact of overexertion. During the next visit, clinicians should review this journal with the patient to identify the distinctive features of PEM: odd symptoms that would not normally follow exertion (eg, sore throat, problems in thinking), intensity or duration of symptoms out of proportion to preceding activities (eg, having to lie down for an hour after a few hours of sedentary work), a further reduction of function after activity, and typically delayed onset of symptoms (eg, a few hours or a day later).
Unrefreshing sleep can be manifested as feeling unrested and unwell on awakening, regardless of how long the patient slept uninterrupted. Some patients need an hour or more on awakening to start feeling better, with late evenings being their best time of day. Patients may also experience trouble in falling asleep, staying asleep, waking up early, or staying awake during the day. They may experience a shifted sleep cycle.
Orthostatic intolerance commonly is manifested as lightheadedness, palpitations, or syncope. However, patients with ME/CFS often experience subtler symptoms, such as feeling sick, nauseous, tired, or confused during periods of sitting or standing still.
Inquiring about symptoms during aggravating (eg, long lines, hot weather) and alleviating situations (eg, lying, sitting down) is helpful. Patients may have been diagnosed with anxiety as some symptoms (eg, lightheadedness, a “racing heart”) are shared by both conditions. Accurate identification of orthostatic intolerance avoids misdiagnosis with a psychiatric disorder and ensures its appropriate management, which is different from that of anxiety.
Some patients are so affected by cognitive dysfunction that they cannot converse, read a book, follow directions, or remember what was just said. Other patients function reasonably well for brief periods but suffer from cognitive fatigue or reduced or slowed abilities under time or other pressures. Many patients stop or restrict driving because of these issues.
The most severely ill patients are bedbound and unlikely to be seen in the clinician’s office but may be seen in emergency departments and hospitals during a crisis.
Whether in the hospital or at home, the very severely ill require individualized care that accounts for their severe energy limitations and sensory sensitivities. The recent expansion of telemedicine may facilitate the provision of care for all ME/CFS patients. Management of the severely ill is further described by Kingdon et al
Myalgic encephalomyelitis/chronic fatigue syndrome is also seen in pediatric patients and appears to have a better prognosis than in adults. The epidemiology, diagnosis, and management of ME/CFS in children and adolescents is further elaborated by Rowe et al.
Abnormal physical findings may be absent, particularly if the patient has rested extensively before the office visit. Some nonspecific abnormal physical examination findings may exist and may worsen during the course of an office visit (Supplemental Table 1, available online at http://www.mayoclinicproceedings.org). Whereas the absence of these signs does not exclude ME/CFS, their presence may support an ME/CFS diagnosis.
The physical examination may help identify alternative diagnoses and comorbidities. The neurologic examination, in particular, may eliminate neurologic disorders. Abnormal physical findings beyond those associated with ME/CFS should be followed up as potential indications of other conditions (Supplemental Table 1).
Diagnostic Testing
There is no validated diagnostic test. Basic tests recommended for all patients (Table 2) or tests for a particular presentation (Supplemental Table 2, available online at http://www.mayoclinicproceedings.org) may be used to identify alternative conditions and comorbidities.
The Chem20 panel is a set of common laboratory tests ordered by health care professionals in the United States. It consists of 20 tests that provide information on the patient’s chemical balance and metabolism. For more information, see https://www.ucsfhealth.org/medical-tests/003468.
Four-point salivary cortisol (eg, wakening, at noon, 4:00 pm, and bedtime), am cortisol
Antinuclear antibody
Thyroid-stimulating hormone, free thyroxine
C-reactive protein
Vitamin B12
Erythrocyte sedimentation rate
Vitamin D, 25-dihydroxy
Ferritin
Urinalysis
Adapted from Testing Recommendations for Suspected ME/CFS,
with permission of the US ME/CFS Clinician Coalition.
a The Chem20 panel is a set of common laboratory tests ordered by health care professionals in the United States. It consists of 20 tests that provide information on the patient’s chemical balance and metabolism. For more information, see https://www.ucsfhealth.org/medical-tests/003468.
A 4-point salivary cortisol test can help identify the abnormal diurnal cortisol patterns seen in ME/CFS (oral communication, US ME/CFS Clinician Coalition, March 2019).
Testing can also guide treatment decisions and objectively document disability. For instance, ME/CFS experts may use microbial panels and natural killer cell activity,
US Institute of Medicine Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Washington, DC: The National Academies Press; 2015.
a measure of immune functioning, to help guide treatment decisions. Neuropsychological testing can demonstrate cognitive impairment and repeated cardiopulmonary exercise testing an inability to repeat or to sustain physical activities. However, these tests involve a challenge that may induce severe or long-lasting PEM. This risk may be warranted for disability evaluations,
At the same time, patients can have both ME/CFS and other diseases. History, physical examination, screening instruments, and diagnostic tests can help distinguish other conditions from ME/CFS. For example, fatigue and a reduction in activities can be seen in both ME/CFS and depression or anxiety; but PEM and orthostatic intolerance are not characteristic of mood disorders, whereas feelings of worthlessness are typically absent in ME/CFS.
In general, PEM is a distinctive feature that can help differentiate ME/CFS from other diseases. Therapeutic trials may also help; if treatment for the alternative diagnosis completely eliminates a patient’s symptoms, ME/CFS is not the correct diagnosis.
Table 3Medical Conditions That Present Similarly to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Endocrine/metabolic disorders
Rheumatologic disorders
Neurologic disorders
Primary adrenal insufficiency, hypercortisolism, hyperthyroidism or hypothyroidism, diabetes, hypercalcemia
Human immunodeficiency virus infection, Lyme and other tick-borne diseases, hepatitis B/C, tuberculosis, giardiasis, West Nile virus, Q fever, coccidioidomycosis, syphilis, Epstein-Barr virus infection,
The NAM criteria require that symptoms exist for 6 months because acute medical conditions or lifestyle issues should resolve within that time. During these 6 months, the provider should observe patients closely to detect other causes for their symptoms while also beginning treatment as discussed later.
Diagnosis of Comorbidities
Myalgic encephalomyelitis/chronic fatigue syndrome is often associated with various comorbidities that can contribute substantially to the patient’s symptom burden (Supplemental Table 3, available online at http://www.mayoclinicproceedings.org).
For example, fibromyalgia is common and may increase the muscle pain of ME/CFS. As with alternative conditions, history, physical examination, tests, and therapeutic trials can help diagnose these comorbidities. Treating these conditions will not cure ME/CFS but can reduce symptom burden and improve quality of life. Documenting these conditions may also promote appropriate reimbursement by insurance groups and may support a disability claim and access to other needed resources.
Outdated Standard of Care
In the past, CBT and GET were studied and recommended for ME/CFS on the basis of the disease theory that “the symptoms and disability of CFS/ME are perpetuated predominantly by unhelpful illness beliefs (fears) and coping behaviors (avoidance [of activity]),” leading to considerable deconditioning.
However, GET and CBT studies have been widely criticized for their methodology, inadequate tracking of harms, and a disease theory that conflicts with the evidence of multisystem biologic impairment.
Myalgic encephalomyelitis/chronic fatigue syndrome patients’ reports of symptom changes following cognitive behavioural therapy, graded exercise therapy and pacing treatments: analysis of a primary survey compared with secondary surveys.
The largest of these studies is the 2011 PACE (Pacing, graded Activity, and Cognitive behavior therapy; a randomised Evaluation) trial. PACE reported that these therapies were safe and resulted in recovery for 22% of participants and improvement for 60% to 61%.
Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial.
When the data were reanalyzed with the original protocol, improvement decreased by a factor of 3 and recovery rates decreased to 7% for CBT and 4% for GET, not significantly different from controls.
The US Agency for Healthcare Research and Quality reported that many of these studies used definitions that could have included participants with other conditions and found little or no evidence of efficacy once these studies were excluded from the analysis.
US Agency for Healthcare Research and Quality Diagnosis and treatment of myalgic encephalomyelitis/chronic fatigue syndrome. Evidence Report/Technology Assessment No. 219. AHRQ Pub. No. 15-E001-EF. December 2014. Addendum July 2016.
Myalgic encephalomyelitis/chronic fatigue syndrome patients’ reports of symptom changes following cognitive behavioural therapy, graded exercise therapy and pacing treatments: analysis of a primary survey compared with secondary surveys.
Because of these concerns, the US Centers for Disease Control and Prevention and health agencies in some countries have since removed recommendations for CBT and GET.
UK National Institute for Health and Care Excellence NICE draft guidance addresses the continuing debate about the best approach to the diagnosis and management of ME/CFS. November 10, 2020.
Despite the lack of ME/CFS-specific US Food and Drug Administration–approved treatments, health care professionals can greatly reduce a patient’s burden of disease and improve their quality of life. Basic principles of care are outlined below.
Validate the Patient’s Experience
Validate the patient’s illness experience and educate patients, family members, and others (eg, employers, schools). Frequently, patients’ concerns have been dismissed, downplayed, misdiagnosed as depression or anxiety, or labeled as hypochondriasis. Almost all patients consider obtaining an ME/CFS diagnosis to be a turning point in their illness, allowing them to better understand, explain, cope with, and find support for their situation.
Patients often need help acquiring handicap placards, work or school accommodations, housing, adequate nutrition, disability benefits, and other necessary resources. Conduct a careful assessment of the patient’s needs and provide information, documentation, referrals, equipment, and accommodations to address these needs. Documenting how symptoms affect function during every appointment can save time in documenting disability later. Patients should assist by documenting such information before the visit. Referrals to specialists or allied health professionals, such as occupational therapists and physical therapists, may be helpful in securing the needed documentation and support. Addressing these issues can help maximize patients’ function and quality of life.
are available. Patient websites and community support groups may have information about local programs.
Teach Pacing
Pacing is an individualized approach to energy conservation and management used to minimize the frequency, duration, and severity of PEM. Because PEM is associated with poor energy production and can be instigated by a variety of stimuli (eg, physical/cognitive exertion; emotional, orthostatic, and sensory stressors),
US Institute of Medicine Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Washington, DC: The National Academies Press; 2015.
US Food and Drug Administration The voice of the patient. A series of reports from the U.S. Food and Drug Administration’s (FDA’s) patient-focused drug development initiative. September 2013.
patients must carefully plan where and how to spend their limited energy. Typically, patients must decrease the total amount of their activities and restrict their exposures to PEM-inducing stimuli as much as possible. Reducing PEM can help alleviate fatigue, cognitive defects, sleep disturbances, pain, and other symptoms while helping to avoid repeated post-exertional relapses that can have a long-term impact.
and use of energy-saving/monitoring devices (eg, shower chairs, motorized scooters, pedometers, heart rate monitors) are often beneficial, as are diaries to help patients identify when they are exceeding their limits. Even with such aids, pacing is challenging and some setbacks are inevitable, especially because tolerance for activity can vary from day to day.
Once patients are effectively pacing without triggering PEM, some patients may be able to engage in very short periods of activity to increase their stamina. This must be individualized for the patient’s level of severity and specific triggers of PEM and must be done in such a way that it does not provoke PEM. Even for those patients who can tolerate such activity, the expected level of improvement may be small and is not seen in all patients.
Treat the Symptoms of ME/CFS
Although there are no approved treatments specific to ME/CFS, clinicians can reduce the severity of symptoms with standard pharmacologic and nonpharmacologic treatments.
Nonpharmacological approaches (Table 4) for orthostatic intolerance include salt and fluid loading and compression stockings, whereas memory aids (notebooks, calendars) may help with cognitive issues. Patients may also be helped by ear plugs, eye masks, and sunglasses to minimize light and noise intrusion; sleep hygiene measures (tailored as needed for patients who are bedbound or have orthostatic intolerance); and avoidance of certain foods to decrease gastrointestinal disturbances.
These are general recommendations. The treating physician should use these after careful consideration of the needs of the individual patient along with up-to-date drug product information. For more information on dosing and use of the pharmacologic therapies, see the referenced document.
Postexertional malaise
Nonpharmacologic approaches to conserve energy and to minimize postexertional malaise
• Assistive devices, such as motorized scooters, handicap parking stickers, shower chairs to conserve energy
• Home health aides for those who are more severely ill
• Ear plugs, eye masks, perfume-free environments to decrease sensory stimulation; may need to maintain low sensory environment for the most severely ill
• School or work accommodations, such as flexible hours, shortened days
Pharmacologic approaches
• No specific recommendations
Orthostatic intolerance
Nonpharmacologic approaches
• Salt and fluid loading, electrolyte drinks
• Compression stockings
• Positional changes; avoid prolonged sitting or standing
• Consistent, tailored exercise as long as the patient can perform them without triggering postexertional malaise; may need to exercise lying down, seated, or in water
• Treat comorbidities that may contribute to orthostatic intolerance
• Sleep hygiene practices are a part of treatment but may be marginally effective in most patients; need to be tailored for severely ill and those with orthostatic intolerance
• Healthy, varied diet low in processed food. Some patients may be able to minimize gastrointestinal symptoms by eliminating certain foods (eg, 1 or more of caffeine, alcohol, spicy foods, aspartame, sugar, possibly dairy or gluten).
Pharmacologic approaches
• If small intestinal bacterial overgrowth—rifaximin, oral vancomycin, metronidazole
with permission of the US ME/CFS Clinician Coalition.
a These are general recommendations. The treating physician should use these after careful consideration of the needs of the individual patient along with up-to-date drug product information. For more information on dosing and use of the pharmacologic therapies, see the referenced document.
Sleep may be improved with medications, such as trazodone, clonazepam, tricyclic antidepressants, and suvorexant. Methylphenidate, modafinil, or dextroamphetamine can occasionally help with cognitive issues, but there is a risk of addiction with methylphenidate and dextroamphetamine. Patients with ME/CFS and clinicians report improvement from therapies such as fludrocortisone and fluid expansion.
On occasion, patients may require intravenous administration of fluids for severe orthostatic intolerance episodes. Medications such as gabapentin, pregabalin, low-dose naltrexone, and duloxetine may be used to treat pain.
Medications should be initiated at lower dosages and slowly titrated up to avoid triggering drug sensitivities common in ME/CFS. To reduce polypharmacy, medications that treat more than 1 symptom should be favored. Clinicians should also be aware of sensitivities to anesthesia and medication ingredients considered to be inactive (eg, fillers, vehicles, preservatives).
Some disease experts have selectively used antivirals and immune modulators off-label in some patients and have observed favorable responses (oral communication, US ME/CFS Clinician Coalition, March 2018 to March 2021). A specialty consultation may be helpful in developing a treatment plan and in managing those aspects of the disease with which the referring physician is unfamiliar.
Treat Comorbidities
Treatment of comorbidities can positively affect a patient’s quality of life and severity of symptoms. Common comorbidities (Supplemental Table 3) include fibromyalgia, mast cell activation syndrome, postural orthostatic tachycardia syndrome, Ehlers-Danlos syndrome, sleep apnea, irritable bowel syndrome, and secondary depression/anxiety.
Ensure that treatments for comorbidities are also appropriate for ME/CFS. For example, whereas exercise may help patients with fibromyalgia, it can make patients with ME/CFS worse.
Schedule Regular Follow-up Visits
Ask patients to report any new or worsening symptoms and confirm that these are not caused by another condition. Instruct patients to report any new drugs, supplements, or complementary approaches and review for potential adverse effects and treatment interactions. This is especially important in older patients because of the higher risk of medication-related adverse effects.
The 2019 American Geriatrics Society Beers Criteria Update Expert Panel American Geriatrics Society 2019 updated AGS Beers Criteria for potentially inappropriate medication use in older adults.
Patients will have questions about their long-term prognosis. Be honest but also reassure patients that there are steps that can be taken to help manage their symptoms, maximize their functioning, and improve their quality of life to the greatest extent possible.
For many decades, care of patients affected by ME/CFS has been negatively impacted by lack of accurate, up-to-date knowledge among health care providers. Even when health care professionals are sympathetic, they are often uncertain about how to assess patients and what can be done after diagnosis. This need is more urgent than ever, given the risk for development of ME/CFS in some patients with COVID-19. Hopefully, this article has answered some questions surrounding this enigmatic condition and outlined a clear path forward for clinicians. As with many chronic medical conditions, although there is not yet a cure for ME/CFS, health care providers are in a unique position to have a positive impact on patients’ lives. For more information, visit the US ME/CFS Clinician Coalition website.
Peter C. Rowe, MD, Director, Children's Center Chronic Fatigue Clinic, and Professor of Pediatrics at the Johns Hopkins University School of Medicine, provided helpful insights on sections related to orthostatic intolerance.
Bateman Horne Center provided valuable support for the annual US ME/CFS Clinician Coalition meetings, during which the information in this article was discussed.
Myalgic encephalomyelitis/chronic fatigue syndrome patients’ reports of symptom changes following cognitive behavioural therapy, graded exercise therapy and pacing treatments: analysis of a primary survey compared with secondary surveys.
Chronic COVID-19 syndrome and chronic fatigue syndrome (ME/CFS) following the first pandemic wave in Germany—a first analysis of a prospective observational study. medRxiv. Preprint posted online February 8, 2021.
EUROPEAN ME NETWORK (EUROMENE) expert consensus on the diagnosis, service provision and care of people with ME/CFS in Europe. Preprints. Preprint posted online October 16.
Functional status and well-being in people with myalgic encephalomyelitis/chronic fatigue syndrome compared with people with multiple sclerosis and healthy controls.
Multi-site clinical assessment of myalgic encephalomyelitis/chronic fatigue syndrome (MCAM): design and implementation of a prospective/retrospective rolling cohort study [erratum appears in Am J Epidemiol. 2017;186(1):129].
The voice of the patient. A series of reports from the U.S. Food and Drug Administration’s (FDA’s) patient-focused drug development initiative. September 2013.
Physiological measures in participants with chronic fatigue syndrome, multiple sclerosis and healthy controls following repeated exercise: a pilot study.
Ventricular cerebrospinal fluid lactate is increased in chronic fatigue syndrome compared with generalized anxiety disorder: an in vivo 3.0 T 1H MRS imaging study.
Myalgic encephalomyelitis (ME), chronic fatigue syndrome (CFS), and chronic fatigue (CF) are distinguished accurately: results of supervised learning techniques applied on clinical and inflammatory data.
Cerebral blood flow is reduced in ME/CFS during head-up tilt testing even in the absence of hypotension or tachycardia: a quantitative, controlled study using Doppler echography.
The abnormal cardiac index and stroke volume index changes during a normal tilt table test in ME/CFS patients compared to healthy volunteers, are not related to deconditioning.
Beyond myalgic encephalomyelitis/chronic fatigue syndrome: redefining an illness. Report guide for clinicians. The National Academies Press. February 2015.
Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial.
Grant Support: This project was supported by funding from Open Medicine Foundation for travel and hotel costs for the 2018 and 2019 meetings of the ME/CFS Clinician Coalition.
Potential Competing Interests: Dr Felsenstein reports personal fees from Once Here Foundation, during the conduct of the study. Dr Lapp reports personal fees from AIM Immunotech, personal fees from Pfizer, and personal fees from Eli Lilly, outside the submitted work. Dr Komaroff reports personal fees from Serimmune, Inc., outside the submitted work. Dr Peterson reports a grant from AIM Immunotech, outside the submitted work.
00513-9&id=gr1.jpg){kind=link}