Chronic Fatigue Syndrome
- 1 Definition/Description
- 2 Aetiology/Causes
- 3 Characteristics/Clinical Presentation
- 4 Diagnostic Tests
- 5 Differential Diagnosis
- 6 Management
- 7 Resources
- 8 References
Chronic Fatigue Syndrome (CFS) is a debilitating and complex disorder that is not a single disease but the result of a combination of factors and is a subset of chronic fatigue. This is characterized by intense fatigue that is not improved by bed rest and that may be worsened by physical activity or mental exertion. This unexplained fatigue must last at least 6 consecutive months, must significantly interfere with daily activities/work, and the individual must concurrently demonstrate 4 or more of 8 specific symptoms. There has been some difficulty in exactly defining CFS due to its very nature, and there have been multiple studies attempt to develop and finalize diagnostic criteria for CFS.
It is a disease that causes central nervous system (CNS) and immune system disturbances, cell energy metabolisms and ion transport dysfunction, as well as cardiovascular problems, gastrointestinal dysfunction, cognitive impairment, myalgia, arthralgia, orthostatic intolerance, inflammation and innate immunity disturbances and the main clinical sign is persisting chronic fatigue, which is not relieved by rest and lasts for more than 6 months. A large group of patients remains wheelchair-dependent and many remain housebound or even bed bound. A Cochrane Review done in 2016 described CFS as an illness characterized by persistent, medically unexplained fatigue [with] symptoms that include severe, disabling fatigue, as well as musculoskeletal pain, sleep disturbance, headaches, and impaired concentration and short-term memory.
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”. CFS is characterized by overlapping symptoms (about 70%) with Fibromyalgia that have some biologic denominator.
The aetiology and pathophysiology remain unknown.  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.  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. High rates are seen recent infection (cold, flulike illness) after a fever and Lyme disease 
Epstein Barr virus, Candida 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.
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
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. 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
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.
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.
Commonly reported symptoms:
- Fatigue  prolonged (lasting more than 6 months), overwhelming fatigue commonly exacerbated by minimal physical activity. 
- Exertional Malaise 
- Sleep Disturbance 
- Cognitive Impairment
- Decreased Concentration
- Impaired short term memory 
- Myalgia 
- Frequent or recurring sore throat 
- Fever (common at onset) 
- Muscle Pain  (common at onset)
- Muscle Weakness (common at onset)
- Multiple Joint Pain  without swelling or redness 
- Neurally mediated hypotension (NMH) (May experience lightheadedness, lower blood pressure and pulse, visual dimming, slow response to verbal stimuli) 
- Tender lymph nodes in neck or armpit 
- 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. 
- 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. 
- Full recovery may be rare, with an average of only 5-10% sustaining total remission. 
- 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. 
- Anxiety 
- Depression  Connection between immuno-inflammatory and TRYCAT pathways and physio-somatic symptoms. 
- Fibromyalgia 
- Irritable Bowel Syndrome 
- Myofascial pain syndrome 
- Temporomandibular joint syndrome 
- Interstitial cystitis 
- Raynaud's phenomenon 
- Prolapsed mitral valve 
- Migraine 
- Allergies 
- Multiple chemical sensitivities 
- Sicca syndrome 
- Obstructive or central sleep apnea 
Currently, there are no specific tests available that identify CFS. Recently scientists have developed a test for chronic fatigue syndrome. A new study reported that the researchers at the Stanford University School of Medicine have developed a blood test that can accurately detect ME/CFS that detects the reaction of the immune cells and blood plasma to stress. The findings may also help screen effective drugs for the condition. Goodman suggests that physicians rule out other diagnoses (from the list below: Differential Diagnosis) and make use of the CDC’s criteria to determine if an individual has CFS.  The CDC’s criteria are: 
1. Clinically evaluated, unexplained persistent or relapsing chronic fatigue that is any of the following:
- New or definite onset
- Not the result of ongoing exertion
- Not substantially alleviated by rest
- Results in a substantial reduction in previous levels of occupational, educational, social, or personal activities
2. The concurrent occurrence of 4 or more of the following symptoms:
- Substantial impairment in short-term memory or concentration
- Sore throat
- Tender lymph nodes
- Muscle pain
- Multiple arthralgias (joint pain) without swelling or redness
- Headaches of a new type, pattern, or severity
- Unrefreshing sleep
- Post-exertional malaise lasting more than 24 hours
The symptoms must have persisted or recurred during 6 or more consecutive months of illness and must not have predated the fatigue. 
Sixteen gene abnormalities have been found in individuals with CFS, some related to immunity and defense; however, further research is needed to determine just how gene expression might effect those with CFS. 
- Fibromyalgia: Patients with Fibromyalgia usually present with increased pain, while patients with CFS experience greater fatigue.
- Lyme Disease
- Thyroid conditions
- Multiple Sclerosis
- Various Cancers
- 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. 
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 )
- Modafinil 
- Medications to treat joint pain (amytryptyline )
- Medications to treat depression (sertralin, paroxetine, nefazodone )
- Anti-inflammatory drugs (aspirin, acetaminophen )
- NSAIDS to address headache relief 
- Rintatolimod improved measures of exercise performance compared with placebo (low strength of evidence) 
- 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. 
- 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. 
Physical Therapy Management
Physical therapy begins by assessing the patient’s current health status to see if signs of deconditioning exist. If so, Goodman suggests starting with a strengthening program and then progressing to activities that test the cardiovascular system.  Physical therapy management of CFS is focused on progressing from minimal activity to 30 minutes of continuous exercise during periods of remission, always focusing on gentle, graded, flexible exercise that is monitored continuously  Goodman suggests monitoring vital signs and assessing fatigue levels using a 5-point scale during exercise and activities.  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. 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. 
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.  GET, along with counselling and behavioural therapies, has shown improvements in measures of fatigue, function, global improvement, and work impairment.  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.  GET results are still variable (see chart below ) and will benefit from further research to determine effects on individuals with CFS. 
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. 
A Chart summarizing the clinical messages: exercise therapy for people with chronic fatigue syndrome. 
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. 
Psychological ManagementCognitive Behavior Therapy (CBT) has emerged as a treatment option for those with CFS. General improvements have been reported in fatigue, pain, and social adjustment.  CBT involves enabling individuals to develop a consistent approach to activity, gradually increase activity, develop healthy sleep patterns, and identify and challenge unhelpful cognitions.  CBT is one of the few non-pharmacological management techniques recommended for individuals with CFS ; 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.  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.  CBT also involves learning coping strategies and initiating a daily schedule of rest and activity in order to address fatigue levels and optimize function. According to Stahl, Rimes, and Chalder, there should be a greater emphasis placed on behavioural change in the early stages of treatment, which may result in greater subsequent cognitive change and superior treatment outcomes.  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.  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.  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. 
See Physical Therapy Management for information regarding the combination of GET and CBT.
Marshall  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). 
For more information on the benefits of yoga for individuals with CFS, see Physical Therapy Management.
Systematic Reviews have shown effectiveness and benefits with cognitive behaviour therapy and graded exercise therapy.
- 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
- Goodman CC., Fuller KS. Pathology: implications for the physical therapist. 4th ed. St. Louis: Saunders; 2015.
- 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.
- Rasa S, Nora-Krukle Z, Henning N, Eliassen E, Shikova E, Harrer T, Scheibenbogen C, Murovska M, Prusty BK. Chronic viral infections in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Journal of translational medicine. 2018 Dec;16(1):268.
- Larun, L. et al. Exercise therapy for chronic fatigue syndrome (Review). Cochrane Database of Systematic Reviews. 2016:(12). DOI:10.1002/14651858.CD003200.pub6
- Goodman C, Snyder T. Differential Diagnosis for Physical Therapists Screening for Referral. 5th ed. St. Louis, MO: Elsevier Inc; 2013.
- The Mighty Chronic Fatigue Vs. Tiredness Available from: https://www.youtube.com/watch?v=CEcd0KxfVOM
- 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.
- 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.
- 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.
- Yancey JR, Thomas SM. Chronic fatigue syndrome: diagnosis and treatment. Am Fam Physician. 2012 Oct 15;86(8):741-6.
- 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
- Anderson, G. et al. Biological phenotypes underpin the physio-somatic symptoms of somatization, depression, and chronic fatigue syndrome. Aeta Psychiatrica Scandinavica. 2014:83-97.
- 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.
- Accessed on 03/05/19 https://www.prohealth.com/library/groundbreaking-blood-test-identify-chronic-fatigue-syndrome-90986
- Accessed from http://med.stanford.edu/news/all-news/2019/04/biomarker-for-chronic-fatigue-syndrome-identified.html on 03/05/2019
- Patrick Yoder PT Management of Chronic Fatigue Syndrome Available from https://www.youtube.com/watch?time_continue=4&v=K7qCgyu3mMA
- Dr. Josh Axe5 Steps to Overcome Chronic Fatigue Available from https://www.youtube.com/watch?time_continue=3&v=zSycAMGkqM4
- TED What happens when you have a disease doctors can't diagnose | Jennifer Brea. Available from https://www.youtube.com/watch?time_continue=3&v=Fb3yp4uJhq0