A 38-year-old teacher presents with severe fatigue, poor sleep, aching muscles, memory loss, and inability to exercise. She and her sister became ill after a viral infection 3 years ago. A workup by her primary care physician was unrevealing and treatment with antidepressants and supplements was not beneficial. She and her primary care physician are considering initiating medical leave because she is making simple mistakes in spelling and arithmetic. Although she denies any past psychiatric problems and does not feel depressed now, her primary care physician has referred her to a psychiatrist for consultation. How should this patient be evaluated and treated?
The Clinical Problem
Unexplained, persistent, and debilitating fatigue is the hallmark of chronic fatigue syndrome (CFS), an illness of unknown etiology. In a large community-based study in the United States, the prevalence of CFS was estimated to be 0.42%, with the highest rates among women, minority groups, and people with lower levels of education and occupational status.1 Rates up to 2.6%, however, have been reported in some primary care populations.2
CFS occurs in people of all ages and socioeconomic groups, and among all races and ethnicities.3 The condition often co-exists with fibromyalgia, irritable bowel syndrome, and major depression.4,5
CFS has been intensively studied, yet little progress has been made in identifying its cause or causes. Investigations have documented diverse abnormalities but none are reproducibly present in the majority of patients with CFS in well-controlled investigations.6 Additionally, CFS is associated with substantially impaired function. Fewer than 10% of patients return to pre-morbid levels of functioning, even though 11% to 64% report global or overall improvement.7,8
No demographic or initial illness features consistently influence prognosis.9 In some studies, psychiatric disorders, a strong belief in a physical cause of illness, and long illness duration have been associated with a poor outcome.7,8 Given the heterogeneity of the condition, it is possible that the severity and effect of CFS may differ depending on the etiology of symptoms.10
Clinical Evaluation and Diagnosis
The diagnosis of CFS is made using a clinical case definition. The 1994 consensus-based criteria developed by the Centers for Disease Control and Prevention (CDC) are the most widely used (Sidebar 1, see page 352).11 This symptom-based case definition incorporates a basic distinction between unexplained fatigue and fatigue attributable to medical and psychiatric causes. A notable feature of the CDC definition is that psychotic and eating disorders are exclusionary for the diagnosis of CFS, but many other psychiatric disorders can co-exist with CFS. Recently, a careful review of the CDC case definition clarified ambiguities regarding exclusionary and co-existing conditions.12 In addition, there have been suggestions to refine the case definition based on empirical findings, as well as recommendations to identify subgroups based on primary symptoms.12–14
Centers for Disease Control and Prevention Diagnostic Criteria for Chronic Fatigue Syndrome11
Clinically evaluated, unexplained, persistent or relapsing fatigue that:
- Is of new or definite onset
- Is not due to ongoing exertion
- Is not substantially relieved by rest
- Results in a substantial reduction in previous levels of occupational, educational, social, or personal activities
Concurrent occurrence of four or more of the following symptoms, all of which must have persisted or recurred for at least 6 months:
- Impaired short-term memory or concentration severe enough to cause substantial reduction in previous levels of activity
- Sore throat
- Tender cervical or axillary lymph nodes
- Muscle pain
- Multijoint pain without joint swelling or redness
- Headaches of a new type or severity
- Unrefreshing sleep
- Post-exertional malaise lasting more than 24 hours
Body mass index greater than or equal to 45
Active medical condition that may explain the chronic fatigue, such as untreated hypothyroidism
Previously diagnosed medical conditions that have not fully resolved, such as previously treated malignancies or unresolved cases of hepatitis B or C virus infection
Any past or current psychiatric disorder with psychotic or melancholic features, including bipolar or affective disorders, schizophrenia, delusional disorders, as well as dementias, anorexia nervosa, and bulimia nervosa
Alcohol or other substance abuse within 2 years before the onset of chronic fatigue and at any time afterwards
The clinical evaluation of patients presenting with fatigue is aimed at assessing complaints and degree of impairment and detecting underlying medical or psychiatric causes of fatigue.11 The CDC diagnostic criteria require that fatigued patients be assessed with a battery of standard laboratory tests (eg, complete blood count with differential, erythrocyte sedimentation rate, chemical analysis, liver tests, thyroid stimulating hormone, antinuclear antibodies, urinalysis) and a thorough history and physical examination.11,15 In most cases, microbiological investigations are not indicated, even in patients with a post-infectious onset.
The purpose of the physical and laboratory evaluation is to rule out other causes of fatigue, as no single test or combination of tests is sufficiently sensitive or specific to aid in diagnosing CFS, and the physical examination in CFS is generally unremarkable.16 The most common abnormality on physical examination is the presence of musculoskeletal tenderness at certain points on the body, which are used to define fibromyalgia and also occur in 25% to 70% of patients with CFS.17 A tender-point examination is indicated in all patients because of the overlap of CFS and fibromyalgia.1
It is also important to distinguish fatigue from sleepiness and drowsiness, and muscle pain from frank weakness, as these symptoms suggest other conditions, such as primary sleep disorders and neuromuscular disease. Polysomnography should be considered if daytime sleepiness, drowsiness, or hypersomnia are present. Consistent muscle cramping following exertion or the presence of fasciculations indicate the need to obtain muscle enzymes and electromyography.
Finally, patients should be evaluated for psychiatric illness so disorders exclusionary for the diagnosis of CFS can be identified and co-existing conditions can be effectively treated.11 Because psychosocial factors have been shown to play a role in the severity and effects of CFS, coping styles, personality features, and other psychosocial factors should be assessed routinely as part of the clinical evaluation. Assessing the social support system is helpful in understanding the patient's family and life environment, and involving the partner and other family members may facilitate the treatment plan. Neuropsychological testing should be considered when cognitive deficits seem to interfere with the ability to perform a job. Demonstrating objective deficits can direct rehabilitation strategies for improving memory and attention, such as the use of a day-planner or handheld personal data assistant or job site modifications.
Primary care providers and psychiatrists should be able to diagnose most cases of CFS. The CDC criteria guide the initial evaluation of patients in clinical settings, although they were developed primarily for research purposes.11 Nonetheless, even physicians with expertise in CFS may have difficulty selecting tests to rule in or out a particular disorder or determine if fatigue is due to CFS or a co-existing condition. For example, a positive Western blot test for Borrelia burgdorferii could be more difficult to interpret in a patient with apparent CFS than in a patient with frank manifestations of Lyme disease. In addition, the proportion of patients diagnosed with CFS who will eventually develop a well-recognized fatiguing disorder, such as multiple sclerosis, is uncertain. Thus, an appropriate work-up for CFS is one that includes an assessment for the common causes of fatigue but is also individualized. Specialists should be consulted to evaluate atypical symptoms or those that do not resolve with treatment.
Differential Diagnosis: Implications for Pathogenesis
The pathogenesis of CFS remains elusive. CFS has been attributed to viral infections, immune and neuroendocrine dysfunction, abnormalities in the nervous system and muscle, disturbed sleep, psychological disorders, and genetic factors.5,6 Investigations have addressed all of these domains, but abnormalities, when present, generally are subtle, are difficult to reproduce when well-matched controls are used, and have little diagnostic value for the individual patient. Recent research supports a familial predisposition to chronic fatigue and CFS, but no genetic loci have been identified, and routine genetic testing is unavailable.18–20
Infections and the Immune System
Many investigations have sought infectious and immunological etiologies because several CFS symptoms resemble those of an acute infection, and the majority of patients recall their illness started with a flu-like episode.5 Although no consistent evidence exists that CFS is caused by a specific pathogen, infections (eg, Epstein Barr virus infection) may precipitate some cases of CFS.21
Recently, a 2′,5′-oligoadenylate-dependent 37-kDa form of RNase in extracts of peripheral blood mononuclear cells has been reported as a diagnostic test for CFS, but other studies indicate the need for further validation.22,23 Of the many immunological abnormalities described, the most consistently reported are depressed natural killer cell function and increased expression of T-lymphocyte activation markers.24 Nonetheless, because the results of immunological tests bear little relationship to the severity of CFS symptoms, they are not recommended outside the research setting.25
Abnormalities in hypothalamic-pituitary-adrenal axis function and serotonin neurotransmission are among the most reproducible findings in patients with CFS. Relative hypocortisolism and upregulation of the serotonergic system have been described, but it is unclear whether these abnormalities explain the symptoms of CFS.26 An assessment of the hypothalamic-pituitary-adrenal axis usually is not fruitful in guiding therapy unless frank hypofunction is suspected clinically.
Central Nervous System
The basis for the cognitive complaints in CFS has been evaluated by structural and functional neuroimaging and neuropsychological evaluation. Central nervous system lesions and perfusion abnormalities have been found on magnetic resonance imaging and SPECT scans in some studies, although no specific anatomic pattern has emerged.27–29 Therefore, imaging studies are not routinely indicated.
However, compared with controls subjects, patients with CFS often score lower, but still in the normal range, on tests of information processing, working memory, and information acquisition.30 Neuropsychological testing may help document cognitive impairment in selected patients even though comparative data obtained before illness onset are rarely available.
Autonomic Nervous System
The role of autonomic dysfunction in CFS, demonstrated by tilt-table testing and manifested by hypotension with bradycardia or hypotension with tachycardia on vertical tilting, remains controversial.31 Several studies in adults have observed abnormalities; however, two recent controlled studies could not reproduce these earlier findings.32,33 Because the frequency and severity of autonomic dysfunction in CFS is unclear, such studies should be reserved for patients with CFS who have suggestive symptoms such as true syncope, pre-syncope with standing, or clear postural symptoms.
Many patients with CFS complain of exercise intolerance, with even minor physical activity leading to worsening symptoms. However, tests of muscle strength, endurance, and function typically are normal.34 Reductions in muscle oxidative capacity and metabolism, as well as histological and anatomic abnormalities, have been reported but are far from universal.35 Physical fitness levels do not appear to differ from appropriate healthy controls.36
Some patients with fatigue have evidence of a treatable sleep disorder, such as obstructive sleep apnea, on polysomnography.37 Sleep disorders are the most commonly overlooked medical diagnosis among patients with presumptive CFS, underscoring the importance of distinguishing fatigue from sleepiness and drowsiness.38
The presence of a clearly diagnosed severe sleep disorder excludes the diagnosis of CFS. However, although systematic trials have not been conducted, treatment of mild sleep disorders does not appear to fully reverse the overall illness of patients who otherwise meet criteria for CFS.
CFS also has been postulated to be an atypical psychiatric disorder, even though the majority of patients with CFS do not have evidence of current psychiatric disorders.6 However, high rates of lifetime mood disorders, generalized anxiety disorder, and somatoform disorders have been observed in patients with CFS.6,39 Psychosocial factors such as avoidance coping strategies, poor social support, low self-esteem, stressful life events, premorbid psychological problems, and personality disorders may perpetuate the symptoms of CFS or exacerbate the associated impairment.40–45 Structured psychiatric or clinical interviews may be needed to assess co-existing psychiatric illness and psychosocial functioning.
Major depression has received particular attention as a possible cause of CFS. Overall, 50% to 75% of patients with CFS have a lifetime history of major depression, and 25% have a concurrent episode of depression at the time of CFS diagnosis.39 The high rate of depression in CFS could be an artifact of shared symptoms contributing to both diagnoses or may be due to an emotional response to disabling fatigue. Likewise, patients may be depressed or frustrated by physicians' inability to identify a cause, suggesting that there is no “real” illness, or inaccurately diagnosing depression as the cause of CFS.46
Several lines of research, outlined in a recent review of CFS, provide evidence that CFS and major depression are different conditions.6 First, patients with CFS generally do not endorse the anhedonia, guilt, and lack of motivation typical of depression. Second, severe major depression may be associated with a central upregulation of the hypothalamic-pituitary-adrenal axis, whereas in CFS, downregulation is observed. Third, therapeutic doses of antidepressants have not been effective in treating the symptoms of CFS. Fourth, patients with CFS do not all have lifetime evidence of major depression. Finally, in genetic studies, fatigue and depression appear to be distinguishable traits.19
There is some evidence, however, that unexplained fatigue and depression may act as independent risk factors for each other.47 For example, some data suggest patients with CFS and other coexisting conditions such as fibromyalgia appear to be at greater risk for major depression.48 Although it is important to identify and treat co-existing depression and anxiety, it is unlikely that psychiatric disorders per se will prove to be the primary or exclusive cause of CFS.6
A fundamental tenet of management of CFS is the establishment of a good patient-physician relationship, which involves illness validation, reassurance, and a mutually acceptable view of illness and the treatment plan. The physician should acknowledge the patient's symptoms and suffering as real. Physicians who manage patients with CFS must be comfortable with slow and deliberate progress and frequent setbacks while maintaining a positive attitude.5
The physician should provide reassurance that CFS is not associated with excess mortality, that symptoms often improve with time, and that some therapeutic options provide benefit.49 Long-term studies have shown that, with treatment, up to two-thirds of patients may have improvement in their symptoms.6 Patients need to establish realistic goals for managing their lives and restructuring activities.
It may be helpful for the provider and patient to agree on a model of illness; ours focuses on factors that predispose, precipitate, predict outcome, and perpetuate illness. Although comprehensive evaluation and differential diagnosis are essential, care should be taken to avoid unnecessary, potentially costly, and harmful treatments. Patient education and sources of reliable information should be provided early in the course of treatment and an understanding established that treatment is directed primarily toward relieving symptoms and improving function. It also is important for providers to encourage open and honest communication because many patients seek alternative therapies despite lack of evidence for their effectiveness.49–51
Due to the unclear etiology of CFS, specific treatments are directed empirically at relieving target symptoms and improving functioning.6 An array of pharmacologic and nonpharmacologic therapies with varying dosages and treatment durations have been evaluated in randomized, controlled trials (Sidebar 2, see page 356). These trials, however, have used different case definitions, populations, exclusion criteria, and outcome measures. A recent systematic review of 44 controlled treatment trials revealed most therapies were ineffective.49 Notably, none of the five placebo-controlled trials of antidepressants (eg, phenelzine, selegiline, moclobemide, fluoxetine) showed clinically important improvements in fatigue.49 The response of depressive symptoms to fluoxetine also was minimal, possibly because of the serotonergic hypersensitivity demonstrated in CFS.25 As with other chronic conditions, detection and treatment of co-existing mood and anxiety disorders is part of the management of CFS. Consultation is appropriate for patients with treatment-resistant comorbid psychiatric disorders.
Treatments for Chronic Fatigue Syndrome Used in Randomized Controlled Trials
Unlikely To Be Beneficial
Liver extract containing B12 and folic acid (intramuscular)
Evening primrose oil
Immunoglobulin preparations (intravenous)
Serotonin reuptake inhibitors
Treatments for Chronic Fatigue Syndrome Used in Randomized Controlled Trials
Treatments for Chronic Fatigue Syndrome Used in Randomized Controlled Trials
Treatments for Chronic Fatigue Syndrome Used in Randomized Controlled Trials
Nonpharmacologic treatments — specifically, graded exercise programs and cognitive-behavior therapy — have shown promise in improving the outcome of CFS.49 Despite mixed results in earlier studies, more than 70% of patients who received 13 to 16 sessions of cognitive-behavior therapy in recent well-controlled trials improved in physical and other functioning, compared with 20% to 27% who received relaxation or usual medical care.52–54 Similarly, randomized controlled trials of graded aerobic exercise have reported significant improvements in fatigue, functional status, and fitness.49
Although functional improvement is common in most cases of CFS, complete resolution of the illness is unusual, regardless of the therapeutic approach.49 Of note, improvements resulting from behavioral approaches appear to be sustained for 5 years of follow-up.53 Although cognitive and behavioral factors can play a role in perpetuating the symptoms of CFS, the success of behavioral approaches does not imply that CFS has a psychiatric etiology. Regardless of the therapy used, it is important to intervene before behaviors associated with chronicity are well established or iatrogenic harm has occurred.
The greatest economic effect of CFS results from income lost by working less or not at all. In one study of 402 patients at a university-based chronic fatigue clinic, 37% of patients with CFS were unable to work at all, and 23% of those still employed reported decreased performance at work.55 These rates are similar to those among patients with rheumatoid arthritis or severe osteoarthritis, and much higher than the 5% of the general population who are unable to work.56 Patients with CFS also are substantially more impaired across multiple domains than both healthy adults and people with congestive heart failure, diabetes, acute mononucleosis, depression and cancer survivors especially in role and social functioning.57,58 These findings are consistent and have been substantiated in a multinational study.59
No standardized measures can quantify work disability in patients with CFS. The value of physical capacity testing as a correlate for occupational performance remains to be evaluated. Often, specialists who may only interact with the patient on a limited basis for a diagnostic evaluation are asked to conduct disability examinations. However, a physician who has a long-term relationship with the patient, even pre-dating illness onset, is best suited to assess disability through personal and laboratory information gathered over time.
Treatment Guidelines and Informational Resources
In addition to consensus guidelines for the diagnosis of CFS,11,60,61 management recommendations have been issued by the CDC, the Royal College of Physicians, and the Royal Australasian College of Physicians (Sidebar 3, see page 357). Several organizations also provide fact sheets and Web sites for public information. Particularly useful are those supported by the CDC, the National Institutes of Health, the Chronic Fatigue Immune Dysfunction Syndrome Association, and the American College of Physicians. Although hundreds of internet sites offer information of varying quality and accuracy, careful review, scrutiny and informed discussion of CFS websites are recommended for patients and physicians alike.62,63
Treatment Guidelines and Informational Resources for Chronic Fatigue SyndromeTreatment Guidelines
Centers for Disease Control and Prevention http://www.cdc.gov/ncidod/diseases/cfs/publications/management.htm
Royal College of Physicians http://www.rcpsych.ac.uk/publications/cr/cr54.htm
Royal Australasian College of Physicians http://www.mja.com.au/public/guides/cfs/cfs1.htmlInformational Resources
Centers for Disease Control and Prevention http://www.cdc.gov/ncidod/diseases/cfs
National Institutes of Health http://www.niaid.nih.gov/factsheets/cfs.htm
American College of Physicians http://pier.acponline.org/index.html
Chronic Fatigue Immune Dysfunction Syndrome Association http://www.cfids.org
CFS is a syndrome characterized by a profound sense of fatigue along with cognitive, musculoskeletal, and sleep symptoms that lead to significant functional impairment. Although complaints of fatigue are common and nonspecific in clinical practice, recent research has served to sharpen the focus on the complexity and importance of this symptom. Significant advances have been made in nosologic understanding and management of CFS. The fundamental goal of clinical practice is differential diagnosis, distinguishing CFS from other underlying causes of fatigue due to medical or psychiatric illnesses.
As with other somatic syndromes, CFS is associated with frequent comorbidity, and it derives from multiple physical and psychological factors that may predispose an individual, and precipitate or perpetuate the syndrome. Specific treatments are symptom-based, with cognitive-behavior therapies and exercise programs showing particular promise.
- Jason LA, Richman JA, Rademaker AW, et al. A community-based study of chronic fatigue syndrome. Arch Intern Med. 1999;159(18): 2129–2137. doi:10.1001/archinte.159.18.2129 [CrossRef]10527290
- Wessely S, Chalder T, Hirsch S, Wallace P, Wright D. The prevalence and morbidity of chronic fatigue and chronic fatigue syndrome: a prospective primary care study. Am J Public Health. 1997;87(9):1449–1455. doi:10.2105/AJPH.87.9.1449 [CrossRef]9314795
- Jason LA, Taylor RR, Kennedy CL, et al. Chronic fatigue syndrome: sociodemographic subtypes in a community-based sample. Eval Health Prof. 2000; 23(3):243–263. doi:10.1177/01632780022034598 [CrossRef]11067190
- Aaron LA, Buchwald D. A review of the evidence for overlap among unexplained clinical conditions. Ann Intern Med. 2001;134(9 Pt 2):868–881. doi:10.7326/0003-4819-134-9_Part_2-200105011-00011 [CrossRef]11346323
- Wessely S, Hotopf M, Sharpe M. Chronic Fatigue and its Syndromes. Oxford, England: Oxford University Press; 1998.
- Afari N, Buchwald DS. Chronic fatigue syndrome: a review. Am J Psychiatry. 2003; 160(2):221–236. doi:10.1176/appi.ajp.160.2.221 [CrossRef]12562565
- Joyce J, Hotopf M, Wessely S. The prognosis of chronic fatigue and chronic fatigue syndrome: a systematic review. QJM. 1997; 90(3):223–233. doi:10.1093/qjmed/90.3.223 [CrossRef]9093600
- Schmaling KB, Fiedelak JI, Katon WJ, Bader JO, Buchwald DS. Prospective study of the prognosis of unexplained chronic fatigue in a clinic-based cohort. Psychosom Med. 2003; 65(6):1047–1054. doi:10.1097/01.PSY.0000088587.29901.69 [CrossRef]14645784
- Cairns R, Hotopf M. A systematic review describing the prognosis of chronic fatigue syndrome. Occup Med. 2005;55(1):20–31. doi:10.1093/occmed/kqi013 [CrossRef]
- Kennedy G, Abbot NC, Spence V, Underwood C, Belch JJ. The specificity of the CDC-1994 criteria for chronic fatigue syndrome: comparison of health status in three groups of patients who fulfill the criteria. Ann Epidemiol. 2004;14(2):95–100. doi:10.1016/j.annepidem.2003.10.004 [CrossRef]15018881
- Fukuda K, Straus SE, Hickie I, et al. The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med. 1994;121(12):953–959. doi:10.7326/0003-4819-121-12-199412150-00009 [CrossRef]7978722
- Reeves WC, Lloyd A, Vernon SD, et al. Identification of ambiguities in the 1994 chronic fatigue syndrome research case definition and recommendations for resolution. BMC Health Serv Res. 2003;3(1):25. doi:10.1186/1472-6963-3-25 [CrossRef]
- Nisenbaum R, Reyes M, Unger ER, Reeves WC. Factor analysis of symptoms among subjects with unexplained chronic fatigue: what can we learn about chronic fatigue syndrome?J Psychosom Res. 2004;56(2):171–178. doi:10.1016/S0022-3999(03)00039-4 [CrossRef]15016574
- Tan EM, Sugiura K, Gupta S. The case definition of chronic fatigue syndrome. J Clin Immunol. 2002;22(1):8–12. doi:10.1023/A:1014248301721 [CrossRef]11958593
- Schluederberg A, Straus SE, Peterson P, et al. NIH conference. Chronic fatigue syndrome research. Definition and medical outcome assessment. Ann Intern Med. 1992;117(4): 325–331. doi:10.7326/0003-4819-117-4-325 [CrossRef]1322076
- Lane T, Matthews D, Manu P. The low yield of physical examinations and laboratory investigations of patients with chronic fatigue. Am J Med Sci. 1990;299(5):313–318. doi:10.1097/00000441-199005000-00005 [CrossRef]2337122
- Komaroff AL, Buchwald D. Symptoms and signs of chronic fatigue syndrome. Rev Infect Dis. 1991;13Suppl 1:S8–11. doi:10.1093/clinids/13.Supplement_1.S8 [CrossRef]2020806
- Hickie I, Bennett B, Lloyd A, Heath A, Martin N. Complex genetic and environmental relationships between psychological distress, fatigue and immune functioning: a twin study. Psychol Med. 1999;29(2):269–277. doi:10.1017/S0033291798007922 [CrossRef]10218918
- Hickie I, Kirk K, Martin N. Unique genetic and environmental determinants of prolonged fatigue: a twin study. Psychol Med. 1999; 29(2):259–268. doi:10.1017/S0033291798007934 [CrossRef]10218917
- Buchwald D, Herrell R, Ashton S, et al. A twin study of chronic fatigue. Psychosom Med. 2001;63(6):936–943. doi:10.1097/00006842-200111000-00012 [CrossRef]11719632
- Salit IE. Precipitating factors for the chronic fatigue syndrome. J Psychiatr Res. 1997; 31(1):59–65. doi:10.1016/S0022-3956(96)00050-7 [CrossRef]9201648
- De Meirleir K, Bisbal C, Campine I, et al. A 37 kDa 2–5A binding protein as a potential biochemical marker for chronic fatigue syndrome. Am J Med. 2000;108(2):99–105. doi:10.1016/S0002-9343(99)00300-9 [CrossRef]11126321
- Gow JW, Simpson K, Behan PO, et al. Antiviral pathway activation in patients with chronic fatigue syndrome and acute infection. Clin Infect Dis. 2001;33(12):2080–2081. doi:10.1086/324357 [CrossRef]11698994
- Barker E, Fujimura SF, Fadem MB, Landay AL, Levy JA. Immunologic abnormalities associated with chronic fatigue syndrome. Clin Inf Dis. 1994;18Suppl 1:S136–141. doi:10.1093/clinids/18.Supplement_1.S136 [CrossRef]
- Swanink CM, Vercoulen JH, Galama JM, et al. Lymphocyte subsets, apoptosis, and cytokines in patients with chronic fatigue syndrome. J Infect Dis. 1996;173(2):460–463. doi:10.1093/infdis/173.2.460 [CrossRef]8568312
- Cleare AJ. The HPA axis and the genesis of chronic fatigue syndrome. Trends Endocrin Metab. 2004;15(2):55–59. doi:10.1016/j.tem.2003.12.002 [CrossRef]
- Schwartz RB, Komaroff AL, Garada BM, et al. SPECT imaging of the brain: comparison of findings in patients with chronic fatigue syndrome, AIDS dementia complex, and major unipolar depression. AJR Am J Roentgenol. 1994;162(4):943–951. doi:10.2214/ajr.162.4.8141022 [CrossRef]8141022
- Lewis D, Mayberg H, Fischer M, et al. Monozygotic twins discordant for chronic fatigue syndrome: regional cerebral blood flow SPECT. Radiology. 2001;219(3):766–773. doi:10.1148/radiology.219.3.r01jn18766 [CrossRef]11376266
- Greco A, Tannock C, Brostoff J, Costa DC. Brain MR in chronic fatigue syndrome. Am J Neuroradiol. 1997;18(7):1265–1269.9282853
- Michiels V, Cluydts R. Neuropsychological functioning in chronic fatigue syndrome: a review. Acta Psychiatr Scand. 2001;103(2): 84–93. doi:10.1034/j.1600-0447.2001.00017.x [CrossRef]11167310
- Bou-Holaigah I, Rowe PC, Kan J, Calkins H. The relationship between neurally mediated hypotension and the chronic fatigue syndrome. JAMA. 1995;274(12):961–967. doi:10.1001/jama.1995.03530120053041 [CrossRef]7674527
- Poole J, Herrell R, Ashton S, Goldberg J, Buchwald D. Results of isoproterenol tilt table testing in monozygotic twins discordant for chronic fatigue syndrome. Arch Intern Med. 2000;160(22):3461–3468. doi:10.1001/archinte.160.22.3461 [CrossRef]11112240
- Timmers HJ, Wieling W, Soetekouw PM, et al. Hemodynamic and neurohumoral responses to head-up tilt in patients with chronic fatigue syndrome. Clin Auton Res. 2002; 12(4):273–280. doi:10.1007/s10286-002-0014-1 [CrossRef]12357281
- Grau JM, Casademont J, Pedrol E, et al. Chronic fatigue syndrome: studies on skeletal muscle. Clin Neuropathol. 1992;11(6):329–332.1473316
- Gibson H, Carroll N, Clague JE, Edwards RH. Exercise performance and fatiguability in patients with chronic fatigue syndrome. J Neurol Neurosurg Psych. 1993;56(9):993–998 doi:10.1136/jnnp.56.9.993 [CrossRef]
- Bazelmans E, Bleijenberg G, Van der Meer JW, Folgering H. Is physical deconditioning a perpetuating factor in chronic fatigue syndrome? A controlled study on maximal exercise performance and relations with fatigue, impairment and physical activity. Psychol Med. 2001;31(1):107–114. doi:10.1017/S0033291799003189 [CrossRef]11200949
- Buchwald D, Pascualy R, Bombardier C, Kith P. Sleep disorders in patients with chronic fatigue. Clin Infect Dis. 1994;18Suppl 1: S68–72. doi:10.1093/clinids/18.Supplement_1.S68 [CrossRef]8148456
- Manu P, Lane TJ, Mathews DA, Castriotta RJ, Watson RK, Abeles M. Alpha-delta sleep patterns in patients with chief complaint of chronic fatigue. South Med J. 1994; 87(4):465–470. doi:10.1097/00007611-199404000-00008 [CrossRef]8153772
- Johnson SK, DeLuca J, Natelson BH. Chronic fatigue syndrome: reviewing the research findings. Ann Behav Med. 1999;21(3):258–271. doi:10.1007/BF02884843 [CrossRef]
- Afari N, Schmaling K, Herrell R, et al. Coping strategies in twins with chronic fatigue and chronic fatigue syndrome. J Psychosom Res. 2000;48(6):547–554. doi:10.1016/S0022-3999(00)00093-3 [CrossRef]11033373
- Prins JB, Bos E, Huibers MJ, et al. Social support and the persistence of complaints in chronic fatigue syndrome. Psychother Psychosom. 2004;73(3):174–182. doi:10.1159/000076455 [CrossRef]15031590
- Creswell C, Chalder T. Underlying self-esteem in chronic fatigue syndrome. J Psychosom Res. 2002;53(3):755–761. doi:10.1016/S0022-3999(02)00329-X [CrossRef]12217449
- Hatcher S, House A. Life events, difficulties and dilemmas in the onset of chronic fatigue syndrome: a case-control study. Psychol Med. 2003;33(7):1185–1192. doi:10.1017/S0033291703008274 [CrossRef]14580073
- Tiersky LA, Matheis RJ, DeLuca J, Lange G, Natelson BH. Functional status, neuropsychological functioning, and mood in chronic fatigue syndrome (CFS): relationship to psychiatric disorder. J Nervous Mental Dis. 2003;191(5):324–331. doi:10.1097/01.NMD.0000066155.65473.26 [CrossRef]
- Henderson M, Tannock C. Objective assessment of personality disorder in chronic fatigue syndrome. J Psychosom Res. 2004; 56(2):251–254. doi:10.1016/S0022-3999(03)00571-3 [CrossRef]15016586
- Deale A, Wessely S. Diagnosis of psychiatric disorder in clinical evaluation of chronic fatigue syndrome. J R Soc Med. 2000; 93(6)s:310–312. doi:10.1177/014107680009300608 [CrossRef]10911826
- Skapinakis P, Lewis G, Mavreas V. Temporal relations between unexplained fatigue and depression: longitudinal data from an international study in primary care. Psychosom Med. 2004;66(3):330–335. doi:10.1097/01.psy.0000124757.10167.b1 [CrossRef]15184691
- Ciccone DS, Natelson BH. Comorbid illness in women with chronic fatigue syndrome: a test of the single syndrome hypothesis. Psychosom Med. 2003;65(2):268–275. doi:10.1097/01.PSY.0000033125.08272.A9 [CrossRef]12651994
- Whiting P, Bagnall A, Sowden AJ, et al. Interventions for the treatment and management of chronic fatigue syndrome: a systematic review. JAMA. 2001;286(11):1360–1368. doi:10.1001/jama.286.11.1360 [CrossRef]11560542
- Afari N, Eisenberg DM, Herrell R, et al. Use of alternative treatments by chronic fatigue syndrome discordant twins. Integr Med. 2000;2(2):97–103. doi:10.1016/S1096-2190(99)00017-7 [CrossRef]10882883
- Brouwers FM, Van Der Werf S, Bleijenberg G, Van Der Zee L, Van Der Meer JW. The effect of a polynutrient supplement on fatigue and physical activity of patients with chronic fatigue syndrome: a double-blind randomized controlled trial. QJM. 2002;95(10):677–683. doi:10.1093/qjmed/95.10.677 [CrossRef]12324640
- Prins JB, Bleijenberg G, Bazelmans E, et al. Cognitive behaviour therapy for chronic fatigue syndrome: a multicentre randomized controlled trial. Lancet. 2001;357(9259): 841–847. doi:10.1016/S0140-6736(00)04198-2 [CrossRef]11265953
- Deale A, Husain K, Chalder T, Wessely S. Long-term outcome of cognitive behavior therapy versus relaxation therapy for chronic fatigue syndrome: a 5-year follow-up study. Am J Psychiatry. 2001;158(12):2038–2042 doi:10.1176/appi.ajp.158.12.2038 [CrossRef]11729022
- Deale A, Chalder T, Marks IM, Wessely S. Cognitive behaviour therapy for chronic fatigue syndrome: a randomized controlled trial. Am J Psychiatry. 1997;154(3):408–414. doi:10.1176/ajp.154.3.408 [CrossRef]9054791
- Bombardier CH, Buchwald D. Chronic fatigue, chronic fatigue syndrome, and fibromyalgia. Disability and healthcare use. Med Care. 1996;34(9):924–930. doi:10.1097/00005650-199609000-00005 [CrossRef]8792781
- Sokka T, Kautiainen H, Mottonen T, Hannonen P. Work disability in rheumatoid arthritis 10 years after the diagnosis. J Rheumatol. 1999;26(8):1681–1685.10451062
- Buchwald D, Pearlman T, Umali J, Schmaling K, Katon W. Functional status in patients with chronic fatigue syndrome, other fatiguing illnesses, and healthy individuals. Am J Med. 1996;101(4):364–370. doi:10.1016/S0002-9343(96)00234-3 [CrossRef]8873506
- Servaes P, Prins J, Verhagen C, Bleijenberg G. Fatigue after breast cancer and in chronic fatigue syndrome: similarities and differences. J Psychsom Res. 2002;52(6):453–459. doi:10.1016/S0022-3999(02)00300-8 [CrossRef]
- Hardt J, Buchwald D, Wilks D, et al. Health-related quality of life in patients with chronic fatigue syndrome: an international study. J Psychosom Res. 2001;51(2):431–434. doi:10.1016/S0022-3999(01)00220-3 [CrossRef]11516765
- Sharpe M, Archard LC, Banatvala JE, et al. A report – chronic fatigue syndrome: guidelines for research. J R Soc Med. 1991;84(2): 118–121. doi:10.1177/014107689108400224 [CrossRef]1999813
- Working group of the Royal Australasian College of Physicians. Chronic fatigue syndrome. Clinical practice guidelines – 2002. Med J Aust. 2002;176Suppl:S23–56.
- Gantz NM, Coldsmith EE. Chronic fatigue syndrome and fibromyalgia resources on the world wide web: a descriptive journey. Clin Infect Dis. 2001;32(6):938–948. doi:10.1086/319362 [CrossRef]11247716
- Kisely S. Treatments for chronic fatigue syndrome and the Internet: a systematic survey of what your patients are reading. Australian N Z J Psychiatry. 2002;36(2):240–245. doi:10.1046/j.1440-1614.2002.01017.x [CrossRef]