Chronic fatigue syndrome (CFS) is characterized by a sudden or gradual onset of persistent disabling fatigue, postexertional malaise (PEM, exertional exhaustion), unrefreshing sleep, cognitive and autonomic dysfunction, myalgia, arthralgia, headache, and sore throat and lymph nodes, with symptoms lasting at least 6 months.
Exertional exhaustion is the critical aspect that distinguishes myalgic encephalomyelitis/CFS from other nociceptive, interoceptive, and fatiguing illnesses.
The lack of energy may be caused by autoimmune and metabolomic dysfunction that reduces mitochondrial ATP production.
The primary goals of management are to provide a supportive healthcare environment with a team of occupational, physical, and other appropriate therapists who will manage symptoms and improve functional capacity.
The chronic but fluctuating disabilities require substantial lifestyle changes to plan each day's activities carefully, conserve energy resources for the most important tasks, schedule rest periods to avoid individuals overtaxing themselves, and to improve the quality of sleep.
Medications are not curative. Pharmacotherapy is indicated to treat pain, migraine, sleep disturbance, and comorbid conditions such as irritable bowel syndrome, anxiety, or depression.
Definitions of chronic fatigue syndrome (CFS) have evolved from a focus on fatigue and impairment as described in the Centers for Disease Control (CDC) criteria,  to postexertional malaise (PEM)/exertional exhaustion in myalgic encephalomyelitis (ME)/CFS as defined by the Canadian Consensus Criteria,   and systemic exertion intolerance disease (SEID) introduced by the US Institute of Medicine.   These 3 definitions have compatible criteria that focus on PEM, disability, sleep, pain, and cognition.  
Exertional exhaustion is the critical aspect that distinguishes ME/CFS from other nociceptive, interoceptive, and fatiguing illnesses. This means people with CFS must make significant lifestyle changes to conserve their physical resources and mental concentration to stay competent in normal occupational, educational, and social settings. They are often limited to a few hours per day of productive endeavors, with the remainder of the time spent resting with slow and partial recovery from the disorganized thoughts, total body pain, malaise, and other features of their chronic fatigue state. Consideration of “fatigue” as mental or physical tiredness is too simplistic to encompass the scope of impairment in CFS, and belies the inadequacy of the vocabulary of fatigue. There is a strong bias to the vocabulary of acute viral illness, such as influenza and poliomyelitis, because these were considered historical precedents of CFS.
CFS is characterized by a sudden or gradual onset of persistent disabling fatigue, postexertional malaise (PEM, exertional exhaustion), unrefreshing sleep, cognitive and autonomic dysfunction, myalgia, arthralgia, headaches, and sore throat and lymph nodes, with symptoms lasting at least 6 months.  PEM is the hallmark of CFS. The fatigue is not related to other medical conditions, and symptoms do not improve with sleep or rest.
Systemic exertion intolerance disease (SEID) was defined by the US Institute of Medicine (IOM). Diagnosis of SEID requires disabling fatigue, PEM, unrefreshing sleep, and cognitive and autonomic dysfunction that is persisting, moderate or severe, and present at least 50% of the time in order to denote the unique symptom spectrum. 
It is inappropriate to use the 1991 Oxford criteria of fatigue as an alternative for CFS because the Oxford criteria are based on “mild fatigue", do not require postexertional malaise, and allow inclusion of chronic idiopathic fatigue, depression, and other fatiguing conditions.  Up to 30.5% of the population have chronic fatigue  and would meet Oxford criteria for study inclusion. Studies that used the Oxford criteria are not representative of the more severe and restricted definitions of CFS that the CDC, Canadian Consensus, or SEID criteria define. Exercise and cognitive behavioral therapy studies that used the Oxford criteria for study inclusion are biased and misleading because people with true CFS are underrepresented, with excessive recruitment of people with chronic idiopathic fatigue and depression who are known to respond well to these modalities. 
Metabolomics dysfunction   and beneficial effects of rituximab provide new insights into the pathophysiological mechanisms of CFS. These studies of biological dysfunction suggest that CFS does not overlap with chronic idiopathic fatigue or depression.
Division of Rheumatology, Immunology, and Allergy
JNB is an author of a number of references cited in this monograph.
Dr James N. Baraniuk would like to gratefully acknowledge Dr Craig N. Sawchuk and Dr Dedra Buchwald, the previous contributors to this monograph. CNS declares that he has no competing interests. DB is an author of a number of references cited in this monograph.
Howick Health and Medical Centre
RV declares that she has no competing interests.
Consultant Neurologist and Clinical Director of Neurosciences
Department of Neurology
AC has received honoraria, speaker fee, and sponsorship from the following pharmaceutical companies: TEVA, Novartis, Biogen, Bayer Schering, Terumo BCT, and Genzyme.
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