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Myalgic Encephalomyelitis (ME), also known as chronic fatigue syndrome (CFS), is a disease process that is characterized by excessive fatigue, cognitive dysfunction, autonomic disruptions, pain and a variety of less common features. The symptoms are exacerbated by physical, emotional, and autonomic stressors and can significantly impair a patient’s day-to-day function.1-3  

According to National Academy of Medicine 2015 diagnostic and treatment guidelines, the diagnostics Criteria are as follows: 

Patients must have three core symptoms

  • Impaired function and fatigue that has persisted for > 6 months 
  • Moderate-severe post-exertional malaise (PEM) that is present more than 50% of the time 
  • Moderate-severe unrefreshing sleep that is present more than 50% of the time 

Patients must have at least one of the following manifestations

  • Moderate-severe cognitive impairment that is present more than 50% of the time 
  • Orthostatic intolerance 


The cause of ME/CFS is unknown, however, in most cases, the disease process has been found to be preceded by a triggering challenge to the immune system such as an infection. ME/CFS patients have been shown to have abnormal functioning NK cells of the immune system.4,5 Other proposed mechanisms include immune system changes, stress affecting body chemistry, changes in energy production and a possible genetic link.4

Epidemiology including risk factors and primary prevention 

ME/CFS is thought to be up to three times more common in women. Although most patients diagnosed with ME/CFS are Caucasian, several studies suggest it may be more common in minority populations such as Latino and African American communities in addition to rural populations.2,6-7 It is estimated that there are around 1.7 to 3.8 million patients diagnosed with ME/CFS in the US based on 2017 estimate.8 Post COVID it is estimated that his number has risen significantly to about 5 to 9 million.9 The age of onset for ME/CFS is thought to have two peaks, one at ages 11-19 years in pediatric/adolescent populations and another peak at ages 30-39 years of age.2 However, due to general lack of understanding of the disease process or definition and varying clinical guidance in the medical community, many cases of ME/CFS are not diagnosed. Additionally, because  the cause of ME/CFS is unknown, there are no targeted strategies for preventing the development of the disease.


The underlying pathophysiology of the various processes involved in ME/CFS has not been elucidated. Studies suggest a complex dysregulation of a combination of the immune system, central nervous system, cellular energy and ion transport systems are all involved. One study suggests presence of gene expression changes to adrenergic and sensory receptors following moderate exercise in CE/MFS patients.10,11 It has also been suggested that muscle cells in CE/MFS have impaired ability to extract oxygen during physical activity.12

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time) 

ME/CFS begins suddenly with an infectious-like syndrome preceding the disease process. Symptoms cause a decline in function with up to a quarter of patients becoming bed or housebound and three quarters of patients with impaired participation in normal work or school activities.1,2 The symptoms can persist for years, and most patients are unable to return to pre-illness activities. Treatment of the condition and other co-morbid conditions may improve quality of life.  

Patients have intermittent “relapses” or “crashes” during which time a stressor leads to acute worsening of their symptoms and overall function. These crashes have been termed “Post-Exertional Malaise” (PEM). The stressors can be physical, emotional, or even autonomic triggers. Studies have shown that patients with PEM have impaired response to exercise compared to healthy, but deconditioned, controls.2,12

The crashes can vary in severity and time of onset, ranging from hours to days until patients experience the peak decline in function or worsening of their specific ME/CFS symptoms. The specific types of exertion that cause the crashes will vary from patient to patient, sometimes even simple activities of daily living can trigger a crash. These are often activities that were previously tolerated. When the crash resolves, the patients return to their prior level of function and typical ME/CFS symptom burden. The return to prior to crash baseline can take hours to weeks, but the disease process itself is not progressive.13 Over time, patients can develop an understanding of their own triggering activities to minimize crashes. Other patients may get stuck in a cycle of over-exertion followed by crashes if they have not been educated on PEM which can appear to patients as progressive decline in function.  

Specific secondary or associated conditions and complications

ME/CFS is associated with a variety of comorbid conditions. Table 1 lists common co-morbid conditions but is not an all-inclusive list.2 It is also important to note that there are many other illnesses that present with similar symptoms of ME/CFS. The difference in these illnesses, however, is that treatment of the specific condition may resolve the patient’s symptoms. Table 2 lists important illnesses to keep on one’s differential, but it is not an all-inclusive list.2

Common Comorbid Conditions Associated with ME/CFS

Table 1. List of common comorbid conditions seen in patients with ME/CFS. This is not an exhaustive list. 

Body System Condition 
Autonomic • Postural Orthostatic Tachycardia Syndrome (POTS)
• Orthostatic Hypotension (OH)
Neurologic • Fibromyalgia
• Migraines
• Neuropathy
Immune • Immunodeficiencies
Gastrointestinal • Celiacs
• Irritable Bowel Syndrome
Sleep • Sleep Apnea
• Restless Leg Syndrome
Endocrine • Hypothyroidism
Psychiatric • Anxiety
• Depression
Gynecologic • Endometriosis
• Vulvodynia

Table 2. List of differential diagnoses to consider in patients that present with ME/CFS symptoms. This is not an exhaustive list.

Body System Condition 
Rheumatologic• Systemic Lupus Erythematous
• Rheumatoid Arthritis
• Polymyalgia Rheumatica
Neurologic • Multiple Sclerosis
• Parkinson’s Disease
• Myasthenia Gravis
• Traumatic Brain Injury
Hematologic/Oncologic• Cancer
• Anemia
Gastrointestinal • Celiacs
• Irritable Bowel Syndrome
• Small Intestinal Bacterial Overgrowth
Sleep • Sleep Apnea
• Narcolepsy
Endocrine • Hypothyroidism
• Adrenal Insufficiency
Psychiatric • Anxiety
• Depression
Infectious• HIV
• Hepatitis B/Hepatitis C

Essentials of Assessment 


A thorough history is important in assessing patients for ME/CFS. Clinicians should ask patients about any infectious or flu-like symptoms that preceded the changes to their health. Information should be obtained about changes in their quality of sleep, cognition, level of energy, and the effects of exertion on their ability to function. 

Physical examination

Physical examination depends on the presentation. By far, most of the patients get diagnosed after the acute illness or preceding event has surpassed. A detailed neurological and musculoskeletal examination is prudent along with a systemic examination to look for abnormalities. Other symptoms that can be elicited through physical exams include light sensitivity, detection of visual disturbances on testing of visual acuity and fields. Furthermore, physical examination may reveal signs of other co-morbid conditions such as neuropathies, inflammatory joint changes, or movement abnormalities. Formal Neuropsychologic testing can assist in identifying cognitive impairment especially if it is affecting function, vocation and quality of life but is often expensive and time consuming. Orthostatic intolerance can be tested with tilt-table testing.1

Functional assessment

A decline in function is a core part of the ME/CFS. As a part of the hallmark PEM described above, small amounts of exertion can lead to even further functional decline.  Clinicians can estimate functional impairments by asking about hours of upright activity in 24-hr period.14 Additionally, there are multiple self-reported questionnaires that can measure fatigue. Modified Fatigue Impact Scale, Chalder Fatigue Scale or Fatigue Severity Scale are some examples which are commonly used. Objective measures like 30 sec sit-to-stand, 6-minute walk test and time up and go test can also be used to assess endurance and sometimes aerobic capacity.

Laboratory studies

Currently, there is no single validated lab test utilized for diagnosing ME/CFS. Poor NK cell cytotoxicity has been correlated to ME/CFS disease severity.1,4 There have been attempts to find genetic testing especially single nucleotide polymorphism that can predict, but at this time no such conclusive evidence exists.15,16

A variety of diagnostic tests can assist in identifying common comorbid conditions and assist in ruling out other illnesses that could be causing similar symptoms. The initial standard lab workup includes CBC, CMP, Thyroid studies, ANA, Rheumatoid Factor, ESR/CRP, Cortisol studies, and Vitamin levels. Depending on the presenting symptoms, additional labs can be obtained in search for infections (HIV antibodies, Hepatitis panels, syphilis), myositis (creatine kinase), or cancer.17


There is no imaging study that will diagnose ME/CFS as it is a syndrome of a variety of symptoms. Diagnostic tests such as nerve conduction studies, electromyography, biopsy, or autonomic testing may assist in diagnosing and guiding treatment of co-morbid conditions such as neuropathies and orthostatic hypotension.

Supplemental assessment tools

A commonly utilized supplemental assessment tool is a symptom diary that patients are asked to maintain. The symptom diary assists with understanding the chronicity of symptoms, any exacerbating or alleviating factors and may inform response to current treatments. Activity tracking should be maintained in diaries which can help corelate activities with crashes. Various assessment questionnaires can be used to assess the severity of symptoms in specific domains such as mood, cognition, energy, quality of life, and level of function. 

Early predictions of outcomes

Overall, many patients with ME/CFS continue to have functional impairments chronically. Predictors of outcomes has been a topic of debate with studies showing variable results. The relationship between age of onset, illness duration, and ultimate improvement in symptoms has not been clearly defined. A delay in diagnosis has been shown to predict poorer outcomes.18  


Several environmental factors may come into play in the care of ME/CFS patients. Some patients may have light, sound, and odor hypersensitivity as a part of their disease process.1,13 Changes in weather may also trigger PEM. Additionally, a common comorbid condition includes chemical sensitivities and the presence of new or worsened allergies. Patients and clinicians should be mindful of environmental triggers. 

Social role and social support system

Patients will need a strong social support system as they manage their disease process given its chronicity, the presence of intermittent crashes, and overall decline in function. They may need additional assistance at home, accommodation at work or school, and emotional support. Family education and support is essential for functional improvement of patients as the impact of daily life is significant.

Professional issues

By the time patients are diagnosed with ME/CFS, most of them have been to numerous different medical specialists to address their symptoms. It is not uncommon for patients to have felt unsupported by the healthcare community. Thus, it is important to understand how much this disease process affects their quality of life and to validate the patient’s experiences and symptoms. Healthcare provider awareness and education is needed as this diagnosis continues to be ignored and poorly managed due to chronicity of symptoms and lack of definitive treatment.  

Rehabilitation Management and Treatments 

Available or current treatment guidelines

The general treatment for ME/CFS requires a thorough, well-rounded approach. A variety of aspects of care need to be addressed. 

  • Validation of patient’s illness and experience 
  • Symptom management and treatment. There is no specific treatment approved specifically for ME/CFS. However, multiple pharmacologic and non-pharmacologic interventions can be initiated to improve symptoms related to cognition changes, pain, autonomic dysfunction, sleep, and other associated conditions.  
  • Sleep and other mental health issues like stress, anxiety and depression should be adequately addressed with non-pharmacologic and pharmacological interventions as needed.
  • Education on PEM and utilization of pacing (individualized activity planning for energy conservation). Clinicians can utilize tools such as symptom or activity logs, as well as heartrate or pulse-ox monitors to assist in creating pacing strategies for patients. The goal is to strike a balance between rest and activity to prevent and speed up recovery from PEM.13 4P’s are usually recommended when managing ME/CFS- Plan, Pace, Prioritize, and Prevent.
  • Treatment of co-morbid conditions 
  • Address impaired ADLs and mobility: assist with DME, home health assistance 

At different disease stages

  • New onset/acute- (time of infection, acute development of new symptoms) 
    • Treatment of acute triggering infectious process if indicated.
    • Testing for commonly co-morbid conditions given presenting symptoms. 
    • Symptom relief.
    • Education on disease process if diagnosis can be made at the time.
  • Chronic/stable 
    • Includes rehabilitation strategies geared towards pacing and energy conservation for prevention of PEM.
    • Regular assessment of DME and need for additional assistive devices. 
    • Patient and family education.
  • PEM crashes
    • Functional assessment.
    • Assist in treating/addressing causing factors.
    • Adjustments to pacing and energy conservation strategies.

Coordination of care

Given the variety of systems involved in ME/CFS syndrome, in addition to the numerous co-morbid conditions that patients can develop, coordination of care between multiple sub-specialty providers is key to adequately caring for these patients. Prior to ME/CFS diagnosis, many patients have already seen multiple specialty providers for their symptoms individually. Primary care and rehabilitation specialists are specialties that need to play a central role in coordinating care for such patients as redundant investigations and futile treatment options are commonly tried.

Patient & family education

Education on the disease process and PEM phenomenon are important aspects of helping patients not only feel validated in their experience but also assist in improving quality of life and preventing acute exacerbations. Patient self-management guides and handouts are available to download freely and such use should be encouraged.1,4

Measurement of treatment outcomes

Treatment outcomes can be measured by following level of functional impairment and any changes over time in activity. Clinicians may monitor conditions such as orthostatic intolerance assessing for increased tolerance over time. They can also assess for improvements in cognition after pharmacologic and non-pharmacologic interventions through a variety of assessment tools. Physical measures of function that are mentioned earlier can be followed over time to see progress.

Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

  • Understand the ME/CFS is a disease process that exists separately from common co-morbid conditions and can involve a variety of body systems. 
  • There is no single biomarker or test for diagnosis of ME/CFS, though patients have been shown to have lower functioning NK cells and thus have an impaired immune system response. 
  • It is important for clinicians to recognize the symptoms of ME/CFS and provide education and support to patients and their families regarding the disease process 
  • Mainstay of treatment includes symptom management, treatment of comorbid conditions, and assessment of functional status with assistance on pacing strategies 
  • With a subset of patients with Long COVID developing ME/CFS like picture the estimated prevalence has risen significantly. It is important to educate providers and healthcare teams to identify and manage such symptoms.

Cutting Edge/ Emerging and Unique Concepts and Practice 

Despite the identification of multiple molecular pathway alterations in ME/CFS patients, no single biomarker test has been identified as a method of diagnosing ME/CFS. Multiple studies have identified a variety of molecular changes that occur in the seeing of PEM episodes.5,10,19 One group has found that ME/CFS blood cells have specific changes that occur under hyperosmotic stress and have created a nanoelectric assay that measures real time molecular events to capture these changes.19 The goal of this assay is to establish utilization of a blood-based diagnostic biomarker for future research and in clinical practice. 

Gaps in the Evidence-Based Knowledge 

A subset of patients who have been acutely infected with COVID-19 can develop a collection of symptoms termed Long-COVID. Long-COVID symptoms include cognitive dysfunction, fatigue, and a whole list of other symptoms. Surveying of Long-COVID patients has suggested overlap in symptoms and the presence of PEM-like experiences in Long-COVID patients, with a group of Long-COVID patients meeting diagnostic criteria for ME/CFS.13,20 With the COVID-19 pandemic, there is an increased drive to research the associated long-term effects. It is hoped that in elucidating the processes behind the post-viral fatigue and changes in Long-COVID patients, more light will be shed on treating patients with ME/CFS. Genetic testing to identify individuals that are pre-disposed to such conditions would help manage such patients proactively.


  1. ME/CFS Bateman Horne Center: Bateman Horne Center;  [Available from: https://batemanhornecenter.org/education/me-cfs/.
  2. Coalition USMCC. Diagnosing And Treating Myalgic Encephalomyelitis/Chronic Fatigue Syndrome – U.S. ME/CFS Clinician Coalition. 2020.
  3. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. The National Academies Collection: Reports funded by National Institutes of Health. Washington (DC)2015.
  4. Prevention CfDCa. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Center for Disease Control and Prevention; 2022 [Available from: https://www.cdc.gov/me-cfs/index.html.
  5. Eaton-Fitch N, du Preez S, Cabanas H, Staines D, Marshall-Gradisnik S. A systematic review of natural killer cells profile and cytotoxic function in myalgic encephalomyelitis/chronic fatigue syndrome. Syst Rev. 2019;8(1):279.
  6. Lim EJ, Ahn YC, Jang ES, Lee SW, Lee SH, Son CG. Systematic review and meta-analysis of the prevalence of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). J Transl Med. 2020;18(1):100.
  7. Jason LA, Richman JA, Rademaker AW, Jordan KM, Plioplys AV, Taylor RR, et al. A community-based study of chronic fatigue syndrome. Arch Intern Med. 1999;159(18):2129-37.
  8. Valdez AR, Hancock EE, Adebayo S, Kiernicki DJ, Proskauer D, Attewell JR, et al. Estimating Prevalence, Demographics, and Costs of ME/CFS Using Large Scale Medical Claims Data and Machine Learning. Front Pediatr. 2018;6:412.
  9. Mirin AA, Dimmock ME, Jason LA. Updated ME/CFS prevalence estimates reflecting post-COVID increases and associated economic costs and funding implications. Fatigue: Biomedicine, Health & Behavior. 2022;10(2).
  10. Light AR, Bateman L, Jo D, Hughen RW, Vanhaitsma TA, White AT, et al. Gene expression alterations at baseline and following moderate exercise in patients with Chronic Fatigue Syndrome and Fibromyalgia Syndrome. J Intern Med. 2012;271(1):64-81.
  11. Komaroff AL. Advances in Understanding the Pathophysiology of Chronic Fatigue Syndrome. JAMA. 2019;322(6):499-500.
  12. Vermeulen RC, Vermeulen van Eck IW. Decreased oxygen extraction during cardiopulmonary exercise test in patients with chronic fatigue syndrome. J Transl Med. 2014;12:20.
  13. Organization MA. Pacing and Management Guide for ME/CFS and Long COVID: Me Action Organization;  [Available from: https://www.meaction.net/wp-content/uploads/2023/02/Pacing-Guide-Clincians.FINAL2_.pdf.
  14. Lucinda Bateman M. Upright Activity and Exercise Intolerance: Critical Concepts in the Evaluation of Chronic Fatigue: Bateman Horne Center; 2019.
  15. Goertzel BN, Pennachin C, de Souza Coelho L, Gurbaxani B, Maloney EM, Jones JF. Combinations of single nucleotide polymorphisms in neuroendocrine effector and receptor genes predict chronic fatigue syndrome. Pharmacogenomics. 2006;7(3):475-83.
  16. Wang T, Yin J, Millder AH, Xiap C. A systematic review of the association between fatigue and genetic polymorphisms. Brain, Behavior, and Immunity. 2017;62(May 2017):230-44.
  17. Coalition USMCC. Testing Recommendations For Suspected ME/CFS – U.S. ME/CFS Clinician Coalition 2020.
  18. Ghali A, Lacout C, Fortrat JO, Depres K, Ghali M, Lavigne C. Factors Influencing the Prognosis of Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Diagnostics (Basel). 2022;12(10).
  19. Esfandyarpour R, Kashi A, Nemat-Gorgani M, Wilhelmy J, Davis RW. A nanoelectronics-blood-based diagnostic biomarker for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Proc Natl Acad Sci U S A. 2019;116(21):10250-7.
  20. Davis HE, Assaf GS, McCorkell L, Wei H, Low RJ, Re’em Y, et al. Characterizing long COVID in an international cohort: 7 months of symptoms and their impact. EClinicalMedicine. 2021;38:101019.

Author Disclosure

Surendra Barshikar, MD, MBA
Nothing to Disclose

Jasmina Solankee, MD
Nothing to Disclose