Myalgic Encephalomyelitis/Chronic Fatigue Syndrome


Chronic Fatigue Syndrome(CFS) is a life-altering condition that involves multiple and complex systems.[1] CFS over the years has been known by various names such as chronic fatigue and immune dysfunction syndrome, chronic Epstein-Barr virus, myalgic encephalomyelitis, neuromyasthenia, as well as the “yuppie flu”.[2] CFS is characterized by overlapping symptoms (about 70%) with Fibromyalgia that have some biologic denominator.[3]

Defining the Chronic Fatigue Syndrome is difficult because of the variation in the symptoms, unavailability of the specific diagnostic test, and overlap of symptoms with other disease conditions. [1]The Centers for Disease Control and Prevention (CDC) performed detailed research on CFS after lots of outbreaks and in 1988, CDC defined CFS and set the diagnostic criteria for CFS. Later, in 1994, a more specified definition was established and was called the Fukuda definition. The Fukuda definition created more chances of misdiagnosis and CFS misrepresented the severity of illness. Hence, the Canadian Consensus Criteria (CCC) defined CFS as Myalgic Encephalomyopathy(ME)/CFS in 2003. This definition incorporated the cognitive issues, sensory-motor dysfunction, and involvement of endocrine systems as well. Further in 2011, International Consensus Criteria changed the definition by removing the fatigue as a required symptom and it resembled the definition of ME. ICC focused more to distinguish the features from other chronic illnesses. After lots of research over decades, the Institute of Medicine in 2015 defined the name of the disease as  Systemic Exertion Intolerance Disease (SEID). The criteria to be diagnosed with SEID is there should be new-onset with the substantial functional impairment and symptoms should persist for more than 6 months.[4] The symptoms for the diagnosis of SEID are[4]:

  • Fatigue
  • Either cognitive problem or orthostatic intolerance
  • Sleep disturbances
  • Post-Exertional Malaise


The aetiology and pathophysiology remain unknown. [2][6][7] Several attempts in research have been made to investigate the aetiology, causes, and pathogenesis of Chronic Fatigue Syndrome (CFS). Earlier theories focused on the prominence of symptoms that suggested an acute viral illness or a psychiatric disorder. Other theories have documented abnormalities including brain structure and function, neuroendocrine responses, sleep architecture, immune function, virological studies, exercise capacity, and psychological profiles. [2] CFS involves complex interactions between regulating systems and seems to involve both the central and peripheral nervous systems, the immune system, and the hormonal regulation system. The aetiology and pathogenesis are believed to be multifactorial[2]. High rates are seen recent infection (cold, flulike illness) after a fever and Lyme disease [2]

Infectious Theory

Epstein Barr virusCandida albicans, Borrelia burgdorferi, Enterovirus, Cytomegalovirus, Human Herpesvirus, Espumavirus, Retrovirus, Borna virus, Coxsackie B virus, and hepatitis C virus (HCV) have been associated to CFS, but their pathogenic relationship with the syndrome has not been demonstrated.[8]

Immunological Theory

Although different disorders have been found in the immune system or its function, currently there is no scientific evidence to attribute the cause of this syndrome to a primary disorder of the immune system. There are a large number of studies on immune disorders in the CFS assessing identical parameters, but they frequently yield contradictory results[8]

Neuroendocrinological Theory

Several disorders in the hypothalamic-pituitary-adrenal axis (HPA) and in the production of related hormones have been found in CFS, as well as a disorder of the regulating mechanisms of the autonomic nervous system. It is currently known that the relationships between the different parts of the nervous system are mediated by neurotransmitters and that their disorders lead to unbalanced functioning of certain structures and to the development of well-known diseases. Many of the clinical features in patients with CFS are similar to those found in patients with fibromyalgia, and it can, therefore, be postulated that the physiopathological mechanisms are probably similar in both conditions[8]. In patients with fibromyalgia, the research on neurotransmitter disorders has started to yield positive findings, and it is known that different clinical manifestations will appear according to the type and the site of action of affected neurotransmitters

Biopsychosocial Theory

CFS is often associated with depression, which has led many physicians to believe that CFS is a purely somatic illness. Evidence supporting this conclusion is lacking. Strong evidence suggests that childhood trauma increases the risk of CFS by as much as sixfold. Some persons may assume that childhood trauma decreases resiliency, but there is evidence to suggest that it may also play an organic role by increasing the risk of adrenal system dysfunction. It is important to note that social support systems for persons with CFS tend to be less reliable than for those who are healthy. Treatment for CFS is less likely to succeed in persons with poor social adjustment.[9]

Sleep and Nutrition

There is an association between delayed dim light melatonin onset and CFS, suggesting that delayed circadian rhythm could contribute to CFS. Although melatonin is available over the counter for delayed dim light melatonin onset in the United States, there is no evidence for improvement in CFS with melatonin.

One study has shown that persons with CFS have lower ratios of omega-3 to omega-6 unsaturated fatty acids and lower zinc levels than healthy patients. However, studies of nutritional supplementation in those with CFS have shown no benefit[9].

Characteristics/Clinical Presentation

Commonly Reported Symptoms

  • Fatigue [10] prolonged (lasting more than 6 months), overwhelming fatigue commonly exacerbated by minimal physical activity. [2]
  • Exertional Malaise [10]
  • Sleep Disturbance [10]
  • Cognitive Impairment
  • Decreased Concentration
  • Impaired short term memory [10]
  • Myalgia [10]
  • Frequent or recurring sore throat [2][6]
  • Fever (common at onset) [2]
  • Muscle Pain [2][6] (common at onset)
  • Muscle Weakness (common at onset)
  • Multiple Joint Pain [6] without swelling or redness [2]
  • Neurally mediated hypotension (NMH) (May experience lightheadedness, lower blood pressure and pulse, visual dimming, slow response to verbal stimuli) [2]
  • Tender lymph nodes in neck or armpit [2][6]


  • CFS will vary from person to person but will often follow a course, alternating between periods of illness and relative well-being. Some people may experience partial or complete remission of symptoms; however, they often reoccur. [2]
  • Recovery rates can be unclear, depending on the study, improvement rates vary from 8% to 63% with a median of 40% of people improving during follow up. [2]
  • Full recovery may be rare, with an average of only 5-10% sustaining total remission. [2]

Associated Co-morbidities

  • Neurally mediated hypotension (NMH) is a common finding in individuals with CFS. Individuals with NMH have low blood pressure and heart rate; thus, they can experience syncope, visual dimming, or a slow response to verbal stimuli. [2]
  • Anxiety [11][7]
  • Depression [11][7][12] Connection between immuno-inflammatory and TRYCAT pathways and physio-somatic symptoms. [7]
  • Fibromyalgia [2][7][13]
  • Irritable Bowel Syndrome [7][12]
  • Myofascial pain syndrome [7]
  • Temporomandibular joint syndrome [7]
  • Interstitial cystitis [7]
  • Raynaud's phenomenon [7]
  • Prolapsed mitral valve [7]
  • Migraine [7]
  • Allergies [7]
  • Multiple chemical sensitivities [7]
  • Sicca syndrome [7]
  • Obstructive or central sleep apnea [7]

Diagnostic Criteria

ME / CFS) is diagnosed after ruling out all other diseases that may explain the symptoms presented. There are various symtoms of ME/CFS and the symptoms vary according to the type of diagnostic criteria used. There are various criteria for the diagnosis and some are:[14]

  • Centers for Disease Control and Prevention (CDC) Holmes 1988
  • Centers for Disease Control and Prevention (CDC) Fukuda 1994
  • Canadian Consensus Criteria (CCC) 2003
  • International Consensus Criteria (ICC) 2011
  • Institute of Medicine (IOM), 2015

According to the recent criteria, that is IOM 2015, the new name was given for the disease and was Systemic Exertion Intolerance Disease (SEID). The criteria are:

  • New or definite onset fatigue
  • Substantial functional impairment
  • Symptoms lasting for minimum of 6 months
  • The patient should have persistent fatigue, sleep disturbances, post-exertional malaise, and should have either a cognitive problem or orthostatic intolerance.

Differential Diagnosis

The following are possible differential diagnoses: [2][7]

  • Fibromyalgia: Patients with Fibromyalgia usually present with increased pain, while patients with CFS experience greater fatigue.
  • Mononucleosis
  • Lyme Disease
  • Thyroid conditions
  • Diabetes
  • Multiple Sclerosis 
  • Various Cancers
  • Depression
  • Bipolar disorder


There is no known cure for CFS, therefore the focus is aimed at symptom relief and improved function. A combination of drug and nondrug therapies is recommended. However, no single therapy has proven to help all individuals with CFS. [2]


While studies have investigated the use of various medications, none have been found to have consistent results. The following drugs are used to address and manage symptoms:

  • Medications to reduce pain, discomfort, and fever
  • Medications to treat anxiety
  • Medications to treat sleep disturbance (amitryptyline, nefazodone [2])
  • Modafinil [10]
  • Medications to treat joint pain (amytryptyline [2])
  • Medications to treat depression (sertralin, paroxetine, nefazodone [2])
  • Anti-inflammatory drugs (aspirin, acetaminophen [2])
  • NSAIDS to address headache relief [2]
  • Rintatolimod improved measures of exercise performance compared with placebo (low strength of evidence) [3]
  • Dehydroepiandrosterone (DHEA) was found in a pilot study to significantly reduce the pain, helplessness, anxiety, thinking, memory, and activities of daily living difficulties associated with CFS; however, further research is necessary. [2]
  • Based on current evidence corticosteroids cannot be recommended for CFS due to complications of long-term use. Mineralocorticoids and Intravenous Immunoglobulin are not recommended either and need further research. [2]

Physical Therapy Management


Physical therapy begins by assessing the patient’s current health status to see if signs of deconditioning exist. There are various physiotherapy intervention strategies for CFS.Few of them can be listed as:

  • Resistance exercise[16]
  • Flexibility training[17]
  • Relaxation therapy[17]
  • Graded Exercise Therapy (GET)[16][18]
  • Cognitive Behavioral Therapy (CBT)[16][18]
  • Multidisciplinary Rehabilitation Treatment (MRT)[16]
  • Guided graded exercise self-help [19]
  • Pain relief techniques [6]

Physical therapy exercise session for CFS is focused on progressing from minimal activity to 30 minutes of continuous exercise during periods of remission, [2]always focusing on gentle, graded, flexible exercise that is monitored continuously [6] Goodman suggests monitoring vital signs and assessing fatigue levels using a 5-point scale during exercise and activities. [2] Education about the syndrome, the importance of exercise, and how to pace oneself in everyday activities to avoid fatigue and relapse is a key component in the management of CFS. [2]

Recent Evidences

  • Graded exercise therapy (GET) has been shown to be a more effective treatment option than stretching and relaxation exercises for individuals with CFS, while all the above options are important aspects of care for the individual. [2] GET, along with counselling and behavioural therapies, has shown improvements in measures of fatigue, function, global improvement, and work impairment. [6] GET, when combined with CBT, had greater success in reducing fatigue and improving physical function than did adaptive pacing therapy (APT) or specialist medical care (SMC) alone. While APT encourages adaptation to illness, CBT and GET encourage gradual increases in activity with the aim of ameliorating the illness. [11] GET results are still variable (see chart below [6]) and will benefit from further research to determine effects on individuals with CFS. [6] 
  • According to the European Journal of Clinical Investigation in regards to Exercise Guidelines for Patients with CFS, there are four subgroups of the parameters considered in the GET and CBT interventions. These include time- or symptom-contingency, exercise frequency, exercise modality, and home exercises. A time-contingent approach to exercise therapy for patients with CFS is superior over the symptom-contingent approach. As for exercise frequency, available studies point towards the treatment of 10-11 sessions of 4-5 months. Exercise modalities that are most appropriate for people with CFS are aerobic in nature. This might include activities such as swimming, biking, and especially walking. Strength, balance, and stretching activities could be added to aerobic exercise, however, as a stand-alone-treatment, these interventions are ineffective. Home exercise should be based on the evidence, consist of 5 exercise bouts, starting for a duration between 5 and 15 minutes, gradually increasing to 30 minutes. See chart below for a visual depiction of the current evidence. [7]
A Chart summarizing the clinical messages: exercise therapy for people with chronic fatigue syndrome.
  • Recent studies suggest that CBT and GET both are ineffective as well as harmful treatment options for many people with ME/CFS. The exercise session has shown to increase the post-exertional malaise and it affects the physical capacity and fatigue level of the patient. The post exertional fatigue may again precipitate the condition. Hence, CBT and GET aren't the gold standard option for every patient with CFS.[18]
  • A recent blog by David Tuller gives an idea about the flaws of the PACE trial of CFS. The author summarizes that there was an unreliable baseline score for the proper outcome of the study. Anyone can be in the category of recovered without getting any intervention. The blog also mentioned that the PACE protocol was modified according to the feasibility of the researcher.[20]
  • According to the recent systematic review published in 2018, resistance exercises are also equally effective as GET and MRT have shown more effective in reducing long-term fatigue severity compared to CBT and CFS. But due to limited study and sample numbers, it is difficult to conclude the generalized treatment option.[16]
  • Guided graded exercise self-help can be used as a treatment for managing fatigue in chronic fatigue syndrome and when it is impossible to provide face to face therapy sessions. [19]
  • One study states that due to the necessary and unique components of helping individuals manage chronic fatigue, physical therapists need to be trained on how to both deliver pain management and exercise programs to these individuals. [6]

Psychological Management

Cognitive Behavior Therapy (CBT) has emerged as a treatment option for those with CFS. General improvements have been reported in fatigue, pain, and social adjustment. [6][2][13] CBT involves enabling individuals to develop a consistent approach to activity, gradually increase activity, develop healthy sleep patterns, and identify and challenge unhelpful cognitions. [13]

 CBT is one of the few non-pharmacological management techniques recommended for individuals with CFS [6]; however, it too, has had mixed results. If an individual is experiencing high levels of pain, Marshall suggests other treatment strategies be used in combination because CBT is aimed more specifically at managing fatigue levels. [6] 

CBT is an individualized, proactive approach on the patient’s part, involving self-reflection and monitoring in the hopes of discovering what kinds of behaviours or thoughts are causing the CFS symptoms. [2][13] CBT also involves learning coping strategies and initiating a daily schedule of rest and activity in order to address fatigue levels and optimize function.[2] According to Stahl, Rimes, and Chalder, there should be a greater emphasis placed on behavoural change in the early stages of treatment, which may result in greater subsequent cognitive change and superior treatment outcomes. [13]

Due to some of the limitations of CBT as an effective treatment option for patients with Chronic Fatigue Syndrome, researchers looked to evaluate the effectiveness of CBT versus a multidisciplinary rehabilitation treatment. It has been noted that patient with CFS who reported a higher frequency of weight fluctuations, physical shaking and pain, who were more symptom-focused and anxious had a poor CBT outcome compared to other patients. [2] Therefore, other treatment options must be considered to aid in the rehabilitation of this population.

Multidisciplinary rehabilitation treatment might include CBT and other different strategies such as gradual reactivation, pacing, mindfulness, body awareness therapy, normalization of sleep/wake rhythm, and social reintegration. [2] Vos Vromans et al found that multidisciplinary rehabilitation treatment is more effective in sustaining the decrease in fatigue severity and that patients are more satisfied with the results at 52 weeks compared to CBT. [2]

Self Management

Marshall [6] stated that in their study, individuals with CFS reported trying to self-manage their symptoms in addition to physical therapy or alternative techniques. Self-pacing, stretches, breathing exercises, and yoga were among the kinds of activities reported; with stretches and breathing exercises managing pain levels the best (see chart below). [6]
Different management strategies for CFS

Isometric yoga is another possible treatment method for those with CFS. It along with conventional therapy was more effective in relieving fatigue than was conventional therapy alone in patients with CFS who did not respond adequately to conventional therapy. The results of this study suggested that an isometric yoga program is both feasible and acceptable for patients with CFS. The results also indicated that isometric yoga can significantly improve fatigue, enhance vigour, reduce pain, and improve quality of life. [12]

Lifestyle Management[2]

Lifestyle management includes :

  • Prevention of overexertion
  • Reduction in stress
  • Dietary restrictions
  • Nutritional supplementation


Physical Therapist’s Guide to Chronic Fatigue Syndrome
Treating Chronic Fatigue Syndrome (ME/CFS): The IACFS/ME Conference Overviews Part V
Chronic fatigue syndrome/myalgic encephalomyelitis. A primer for clinical practitioners


  1. 1.0 1.1 Open medicine foundation, what is ME/CFS?. Available from: date: 2020/08/10)
  2. 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 2.15 2.16 2.17 2.18 2.19 2.20 2.21 2.22 2.23 2.24 2.25 2.26 2.27 2.28 2.29 2.30 2.31 2.32 2.33 2.34 2.35 2.36 Goodman CC., Fuller KS. Pathology: implications for the physical therapist. 4th ed. St. Louis: Saunders; 2015.
  3. 3.0 3.1 Goodman C, Snyder T. Differential Diagnosis for Physical Therapists Screening for Referral. 5th ed. St. Louis, MO: Elsevier Inc; 2013.
  4. 4.0 4.1 Open Medicine Foundation.History of ME/CFS. Available from date: 2020/09/10)
  5. The Mighty Chronic Fatigue Vs. Tiredness Available from:
  6. 6.00 6.01 6.02 6.03 6.04 6.05 6.06 6.07 6.08 6.09 6.10 6.11 6.12 6.13 6.14 6.15 Marshall, R BSc (HONS), Paul, L PhD, Wood, L PhD. The search for pain relief in people with chronic fatigue syndrome: a descriptive study. Physiotherapy Theory and Practice. 2011:27(5);373-383. Available from: PubMed.
  7. 7.00 7.01 7.02 7.03 7.04 7.05 7.06 7.07 7.08 7.09 7.10 7.11 7.12 7.13 7.14 7.15 7.16 7.17 Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; Board on the Health of Select Populations; Institute of Medicine. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome:Redefining an Illness Washington,DC: National Academies Press (US); 2015 Feb 10.
  8. 8.0 8.1 8.2 Fernández AA, Martín ÁP, Martínez MI, Bustillo MA, Hernández FJ, de la Cruz Labrado J, Peñas RD, Rivas EG, Delgado CP, Redondo JR, Giménez JR. Chronic fatigue syndrome: aetiology, diagnosis and treatment. BMC psychiatry. 2009 Oct;9(1):S1.
  9. 9.0 9.1 Yancey JR, Thomas SM. Chronic fatigue syndrome: diagnosis and treatment. Am Fam Physician. 2012 Oct 15;86(8):741-6.
  10. 10.0 10.1 10.2 10.3 10.4 10.5 Haney, E. et al. Diagnostic Methods for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Systematic Review for a National Institutes of Health Pathways to Prevention Workshop. Annals of Internal Medicine. June 2015:162(12), 834-841.
  11. 11.0 11.1 11.2 Cella, M., White, PD., Sharp, M., Chalder. T. Cognitions, behaviours and co-morid psychiatric diagnosies in patients with chronic fatigue syndrome. Psychological Medicine. 2013 (43). 370-380. DOI 10.1017/S0033291712000979
  12. 12.0 12.1 12.2 Anderson, G. et al. Biological phenotypes underpin the physio-somatic symptoms of somatization, depression, and chronic fatigue syndrome. Aeta Psychiatrica Scandinavica. 2014:83-97.
  13. 13.0 13.1 13.2 13.3 13.4 Snell, C. R. et al. Discriminative Validity of Metabolic and Workload Measurements for Identifying People with Chronic Fatigue Syndrome. Physical Therapy Journal. November 2013:93, 1484-1492.
  14. Open Medicine Foundation.Diagnosis of ME/CFS. available from: (accessed date: 2020/09/10)
  15. Patrick Yoder PT Management of Chronic Fatigue Syndrome Available from
  16. 16.0 16.1 16.2 16.3 16.4 Galeoto G, Sansoni J, Valenti D, Mollica R, Valente D, Parente M, Servadio A. The effect of physiotherapy on fatigue and physical functioning in chronic fatigue syndrome patients: a systematic review. La Clinica Terapeutica. 2018 Jul 10;169(4):e184-8. available from:
  17. 17.0 17.1 Fulcher KY, White PD. Randomised controlled trial of graded exercise in patients with the chronic fatigue syndrome. Bmj. 1997 Jun 7;314(7095):1647. available from:
  18. 18.0 18.1 18.2 Twisk FN, Arnoldus RJ, Maes M, Anderson G, Morris G, Berk M, Jason LA, Evans M, Brown M, Maes M, Twisk FN. A review on cognitive behavioral therapy (CBT) and graded exercise therapy (GET) in myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS): CBT/GET is not only ineffective and not evidence-based, but also potentially harmful for many patients. Expert Opinion on Medical Diagnostics. 2013 Jul 1;7(4):413-5.
  19. 19.0 19.1 Clauw DJ. Guided graded exercise self-help as a treatment of fatigue in chronic fatigue syndrome. The Lancet. 2017 Jul 22;390(10092):335-6. Available from:
  20. Tulle David. TRIAL BY ERROR: The Troubling Case of the PACE Chronic Fatigue Syndrome Study. Virology blog. Weblog. [Online] Available from: [Accessed 31 October 2020].
  21. Dr. Josh Axe5 Steps to Overcome Chronic Fatigue Available from
  22. TED What happens when you have a disease doctors can't diagnose | Jennifer Brea. Available from