Clinical evaluation of persons with a fatiguing illness requires a thorough history that assesses physical and psychological symptoms, social factors, and medications and supplements that could contribute to fatigue; a thorough physical examination, a mental status examination; and, a minimum battery of laboratory tests. The presence of a medical or psychiatric condition that may explain the chronic fatigue state excludes the classification as CFS in research studies because overlapping pathophysiology may confound findings specific to CFS. The concept of "exclusionary conditions" makes sense only in research settings in which such distinction is required for clarity. In clinical settings, exclusionary conditions provide a list of differential or comorbid diagnoses that should be considered in patients with debilitating fatigue. This is important because appropriate intervention for these disorders could improve quality of life. In the clinical setting, patients with exclusionary conditions may be diagnosed and managed as having CFS on the basis of the physician's medical opinion as to whether the exclusionary condition is likely to be a major contributor to the patient's fatigue.
For the research definition of CFS, some exclusionary medical diagnoses may be considered permanent if no intervention will adequately resolve the condition. By contrast, some medical conditions will resolve or are adequately managed with treatment and should therefore be considered temporary exclusions. Research studies should stratify those individuals with apparently resolved medical conditions that otherwise meet the CFS case definition.
The 1994 case definition excluded psychiatric conditions that prevent a subject from accurately reporting symptoms and those with fatigue as a reasonably anticipated symptom. Consistent application of these exclusionary criteria has proven difficult because there was no recommendation as to how these conditions should be accurately and rapidly detected. In addition, opinions have evolved as to the best way to approach psychiatric diagnoses that may arise as result of, or co-morbid with, CFS. The following guidelines include recommendations for exclusionary psychiatric conditions and for stratification of study subjects.
The 1994 CFS case definition stipulates that patients have the following: 1) clinically evaluated, unexplained, persistent or relapsing chronic fatigue (of least 6 months duration) that is of new or definite onset (i.e., has not been lifelong), 2) is not the result of ongoing exertion; 3) is not substantially alleviated by rest; and 4) results in substantial reduction in previous levels of occupational, educational, social, or personal activities . These descriptors of fatigue are difficult to apply in practice . The stipulation that the fatigue is "of new or definite onset" (i.e., has not been life long) was intended to exclude subjects with personality or somatization disorders that are characterized by a "lifelong pattern of presentations to medical attention with unexplained symptoms" . We recommend that somatization disorder be identified and serve as a stratification diagnosis. Only subjects who recount having always felt fatigued should be excluded as having "lifelong" fatigue.
The stipulation that the fatigue be unrelated to ongoing exertion was intended to distinguish the unexplained fatigue in persons with CFS from that due to ongoing physical demands. However, CFS patients have an exaggerated fatigue response to previously well-tolerated activities and many report their fatigue is unusually sensitive to physical or mental exertion. Indeed, post-exertional malaise lasting more than 24 hours is one of the accompanying symptoms that define CFS. Therefore, this requirement should be interpreted as referring to exhaustion unrelated to an excessively demanding schedule that would induce fatigue in an otherwise healthy adult.
The requirement that rest should not substantially alleviate the fatigue is also unclear. It was intended to exclude the type of fatigue associated with overwork that resolves when the excessive demands end. Most persons with CFS experience some alleviation of fatigue and accompanying symptoms if they rest, but this relief does not allow for recovery of pre-illness physical and mental stamina. Some CFS patients use resting as a strategy to avoid over-exertion and the attendant exacerbation of symptoms. Therapeutic use of rest or a partial response to rest should not exclude a subject's illness from classification as CFS.
Finally, reliance on an affirmation that the fatigue substantially limits performance of daily activities is insufficient because "substantial" limitation is undefined, and independent confirmation of the reported level of disability is rarely sought. Fatigue is highly subjective, multidimensional, and variable during the course of disease. Ambiguities in the nature and severity of fatigue could be reduced by assessing fatigue and associated symptoms in a standardized manner. Measures of fatigue should encompass both its intensity and associated disability .
The 1994 case definition defines CFS by the presence of debilitating fatigue accompanied by at least four of eight designated symptoms. These symptoms are non-specific and variable in both nature and severity over time. They were selected on the basis of consensus clinical opinion and were not identified empirically. Accompanying symptoms must have persisted or recurred during six or more consecutive months of illness and cannot have predated the fatigue. Designated accompanying symptoms include the following: post-exertional malaise lasting more than 24 hours; unrefreshing sleep; impaired short-term memory or concentration severe enough to cause substantial reduction in previous levels of occupational, educational, social, or personal activities; headaches of a new type, pattern, or severity; muscle pain; multi-joint pain without swelling or redness; sore throat; and tender cervical/axillary lymph nodes. It is important to stress that these are symptoms not signs. Signs such as inflamed tonsils or swollen lymph nodes should prompt the search for alternative diagnoses.
Most CFS patients report unrefreshing sleep. However, narcolepsy and clinically significant obstructive sleep apnea are considered exclusionary diagnoses. It is unclear whether as yet-undefined sleep pathologies should be considered as co-morbid features of CFS or as common pathogenic pathways. Unrefreshing sleep accompanies a variety of sleep disorders and may explain some fatiguing illnesses . Thus, assessment of sleep must detect treatable primary sleep disorders and evaluate sleep-related symptoms that may be part of CFS.
CFS patients typically complain of difficulties with concentration, memory, and thinking, yet neuropsychological testing does not generally confirm the reported cognitive dysfunction [49, 50]. The available data point to a more global, but non-specific performance deficit possibly related to impaired attention and slowed processing speed . Investigators should use the report of cognitive impairment by the individual or a reliable informant as an initial screening tool. Measurement of cognitive function is complex, time consuming, and cannot be currently recommended for use in classifying CFS in research studies. However, studies exploring the cognitive dimension of CFS should be high priority.
Five of the eight CFS-defining symptoms reflect pain (headaches of a new type, pattern, or severity, muscle pain, and multi-joint pain without swelling or redness, sore throat, tender cervical/axillary lymph nodes). Pain may be a result of, responsible for, or associated with, both fatigue and sleep disturbances. Assessment of chronic pain (such as that reported by patients with CFS) includes a clinical history, physical examination, and psychiatric screening, all of which are discussed above. The SPHERE records sufficient information on the frequency and extent of chronic pain for most CFS research studies. However, pain may be the primary determinant of disability for some CFS patients. Chronic widespread pain may be a stratifying factor in the analyses.