Chronic Fatigue Syndrome: Case Definitions,Possible Causes,and Therapies

Abstract

Chronic fatigue syndrome (CFS) is a complex disorder of uncertain etiology, and there is no definitive diagnostic test or cure. This article provides a summary of case definitions and diagnostic guidelines for CFS, theories about possible causes, evidence-based therapies, and complementary and alternative medicine (CAM) clinical approaches to treatment.

Historical Background and Epidemiology

Symptoms that resembled CFS were described as far back as the mid-eighteenth century.¹ Outbreaks of CFS-like illnesses were reported in 1934 at the Los Angeles County Hospital, in California, and, in 1955, at the Royal Free Hospital in London. In the California outbreak, the illness was referred to as atypical poliomyelitis because of CFS' resemblance to polio. In the British case, the illness was named benign myalgic encephalomyelitis (ME); benign ME was included in the International Classification of Diseases in 1969 as a disease of the nervous system. The term chronic fatigue syndrome was proposed in the medical literature in 1988 as an alternative to chronic Epstein-Barr virus (EBV) to describe symptoms similar to those caused by EBV—which causes mononucleosis—because a causal link between EBV and CFS was not established.² International researchers and the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, later developed case definitions of the disorder for research and clinical purposes.

CFS—also known as chronic fatigue immune dysfunction syndrome (CFIDS)—is a complex disorder characterized by chronic, profound, debilitating, and unexplained fatigue that interferes significantly with daily activities.³ In addition to severe fatigue after physical activity or mental exertion, other hallmarks of CFS include: unrefreshing sleep; muscle and joint pain; headaches; and impairment of concentration and short-term memory. Although the condition is commonly referred to in the literature as CFS/ME (e.g., by the International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis [IACFS/ME]; see Resources), some researchers regard CFS and ME as distinct diagnoses with different etiologic factors and biomarkers.⁴

According to the Institute of Medicine (IOM) of the National Academies of Science (in Washington, D.C.), CFS/ME affects between 836,000 and 2.5 million Americans, and an estimated 84–91% of people with the disorder have not yet been diagnosed.⁵ Women are more often affected than men, and although the average age of onset is 33,⁵ CFS also affects between 0.2% and 2.3% of children and adolescents.⁶

The lack of a standardized definition for CFS, the lack of a definitive etiology and diagnostic test, and symptoms that overlap those of fibromyalgia (FM) and other “functional” pain syndromes and various types of infections, makes estimating the prevalence of CFS a challenge. Estimating the overall prevalence of CFS has been likened to “hitting a moving target,” which depends on the sample being studied and case definition being applied.⁷ A major issue in the development of prevalence studies is differing case definitions with respect to inclusion criteria for comorbid and psychiatric conditions such as depression. A meta-analysis of 14 studies found the pooled prevalence of CFS to be 3.28% for patient self-report and 0.76% for clinical assessment, with the latter deemed more reliable.⁸

Case Definitions for CFS

The 1994 CDC Case Definition

A systematic review of 38 validation studies showed that the 1994 CDC/Fukuda et al. case definition⁹ was most frequently used.¹⁰ This case definition requires a patient to meet the following criteria that include the presence of:

(1) Severe chronic fatigue for 6 or more consecutive months unrelieved by bed rest, that is not caused by ongoing exertion or another medical condition associated with fatigue;

(2) Fatigue that interferes significantly with daily activities and work; and

(3) Four or more of the following symptoms concurrently:

• Postexertion malaise lasting for more than 24 hours

• Unrefreshing sleep

• Significant impairment of short-term memory or concentration

• Pain in the joints without swelling or redness

• Headaches of a new type, pattern, or severity

• Tender lymph nodes in the neck or armpits

• A sore throat that is frequent or recurrent.

Proposed New Case Definition and Diagnostic Guidelines

In February 2015, the IOM issued a report with recommendations and suggested clinician tools to facilitate evidence-based diagnosis of CFS. The goal of the IOM was to enable better understanding of and treatment for disorder that is still regarded with skepticism by some health care practitioners although at least one-fourth of patients have been homebound or bedridden at some point as a result of this condition (See Proposed New Diagnostic Criteria for ME/CFS).¹¹

Among the IOM report's recommendations is changing the name of the disorder to systemic exertion intolerance disease (SEID), to reflect the central characteristic of the disorder more accurately, as the majority of patients have reported at least moderately severe physical, cognitive, or emotional exhaustion at least half of the time during the past 6 months. Another rationale for the name change is that the term CFS has been shown to trivialize the seriousness of the disorder, thereby affecting the perceptions of patients, health care practitioners, and others associated with the illness.

Etiologic Factors

A single cause for CFS/ME has not been identified, and some investigators consider CFS and ME to be distinct diagnostic categories with different biomarkers and etiologic triggers.⁴ Hypothesized precipitating triggers are discussed in the sections below.

Infections

Infections such as EBV (in the herpes group of viruses), Borrelia burgdorferi (Lyme disease, a bacterial disease transmitted by a tick-borne parasite), and Candida yeast infection have been implicated in CFS/ME. In pediatric patients, CFS is especially likely to develop after an acute flu-like or mononucleosis-like illness.¹² A retrospective evaluation of data on children increasingly being referred for fatigue symptoms from 2002 to 2011 showed that 27 of the 37 children who had been diagnosed with CFS tested positive for previous infection with EBV, Lyme disease, or cytomegalovirus (related to viruses that cause mononucleosis and chickenpox).

Considerable controversy has been generated regarding whether or not retroviruses—pathogens that overtake cells' normal genetic processes to spread infections—are a contributing factor in the pathogenesis of CFS. A newly discovered retrovirus, xenotropic murine leukemia-related virus (XMRV), was detected in the blood cells of 68 of 101 patients with CFS (67%), compared to 8 of 218 (3.7%) healthy controls.¹³ However, in subsequent studies, researchers were unable to replicate these findings; contamination of human DNA samples with similar mouse DNA was detected only in samples obtained from patients with CFS.¹⁴ Another analysis found no evidence of XMRV in the peripheral blood leukocytes (PBLs) DNA of 150 patients with ME/CFS and 30 healthy controls, or in the PBLs or brain tissue of 61 individuals with or without unspecified encephalopathy.¹⁵ Despite such negative findings, some researchers continue to believe that a retrovirus is implicated in CFS.¹⁶

Neuroimmune Dysfunction

In a systematic review of 196 case-control studies, researchers found that the majority (65%) involved sympathetic nervous system responses to chronic stress as the common underlying pathogenesis of CFS, FM, irritable bowel syndrome, and interstitial cystitis.¹⁷ Methods most often used to assess sympathetic functionality were heart rate (HR) variability analysis, sympathetic skin response, tilt table testing, and genetic studies.

A neuroimmune model has been proposed to account for the wide range of neurologic and immunologic abnormalities reported in patients with CFS/ME and other autoimmune and neuroinflammatory disorders associated with incapacitating fatigue.¹⁸ These abnormalities include raised levels of oxidative and nitrosative stress, and proinflammatory cytokines (e.g., interleukin[IL]-1, tumor necrosis factor–α); mitochondrial dysfunctions; autonomic disturbances; brain pathology; reduced levels of antioxidants; and buildups of toxic metabolites.¹⁹ According to this model, initial infection and immune activation, caused by a number of possible pathogens, lead to a state of chronic peripheral immune activation sustained after the precipitating infection has been cleared. Subsequent responses by the central nervous system to chronic immune activation are responsible for the fatigue and remitting–relapsing nature of CFS/ME.¹⁸

In a systematic review of 23 case-control studies, researchers examined if patients with CFS, compared to controls, had a different immune response to exercise.²⁰ The researchers found evidence for a different postexertional immune response in the patients who had CFS.²⁰ This included a more pronounced response in the oxidative stress system and an alteration in immune cells' gene-expression profile (i.e., increases in IL-10 and gene expression of certain microbial-sensing proteins known as toll-like receptors).

Unlike previous research that compared heterogeneous populations with CFS to controls, a recent analysis of responses to a mild stressor found distinct plasma immune signatures in CFS/ME present in the course of the disease in patients with CFS for 3 or fewer years (n=52) that were not present in patients with a longer duration of illness (i.e., >3 years; n=246), relative to healthy controls (n=348).²¹ Early CFS/ME was more highly correlated with activation of both pro- and anti-inflammatory cytokines than cases of longer duration. The researchers commented that this difference in biomarkers in distinct disease stages is consistent with the concept of a viral trigger or disrupted homeostasis of immune regulatory networks underlying CFS/ME. Lead author Mady Hornig, MD—a professor of epidemiology at Columbia University, in New York City, and director of transactional research at the Center for Infection and Immunity—said that this finding has important implications for early diagnosis and treatment and added:

It appears that ME/CFS patients are flush with cytokines until around the 3-year mark, at which point, the immune system shows signs of exhaustion and cytokine levels drop. Early diagnosis may provide unique opportunities for treatment that likely differ from those that would be appropriate in later phases of the illness.

Proposed New Diagnostic Criteria for ME/CFS ¹¹

Diagnosis requires that the patient have the following 3 symptoms:

1. A substantial reduction or impairment in the ability to engage in pre-illness levels of occupational, educational, social, or personal activities that persists for more than 6 months and is accompanied by fatigue, which is often profound, is of new or definite onset (not lifelong), is not the result of ongoing excessive exertion, and is not substantially alleviated by rest, and

2. Post-exertional malaise

3. Unrefreshing sleep.

At least one of the following manifestations is also required:

• Cognitive impairment

• Orthostatic intolerance.

In a study of patients with CFS/ME (n=9) and healthy controls (n=10) who underwent functional positron emission tomography (PET) imaging, neuroinflammation was found to be present in widespread brain areas in the patients with CFS/ME and was associated with severity of neuropsychologic symptoms as assessed by a questionnaire.²² A measure of inflammation in the amygdala, thalamus, and midbrain was positively associated with the cognitive impairment score; in the cingulate cortex and thalamus with pain scores; and in the hippocampus with depression scores.

Patients with CFS are frequently also diagnosed with postural orthostatic tachycardia syndrome (POTS), which suggests a shared pathogenesis.²³ Such concurrence was observed in 11% (33/306) of patients seen at a clinic between 2009 and 2012, particularly in younger patients with a shorter duration of illness. POTS was diagnosed by noting an orthostatic increase in HR>30 beats per minute in a 20-minute standing task. Patients with concurrent CFS and POTS had significantly higher HR and lower pulse pressures, and were significantly less likely to complete the task. The researchers concluded that patients with comorbid CFS and POTS may represent a distinct subgroup of patients with CFS, and that these findings support the utility of screening younger patients with fatigue for POTS. A systematic literature review of 27 case-control studies on autonomic nervous system (ANS) functioning in patients with CFS, examining HR responses to head-tilt lift and other autonomic response testing also showed that patients with CFS had an increased prevalence of POTS, compared to controls, suggesting that such responses may be useful diagnostically.²⁴

Psychosocial and Physical Stressors

Early psychiatric theories attributed CFS to hysteria or hypochondria, and led many researchers and clinicians to doubt the legitimacy of the syndrome. However, physical and/or psychosocial stressors are well-known modulating factors in inflammatory and autoimmune disorders and pain. In a study using measures, including the CFS/ME Symptom Questionnaire, 27 patients with CFS/ME presented with significantly more post-traumatic stress disorder symptoms and fewer coping strategies for addressing pain than 27 healthy controls.²⁵

No specific metabolic alterations have been identified in patients with CFS. Researchers tested the hypothesis that patients with CFS have sensitized fatigue pathways in peripheral tissues that become activated during exercise and produce increased fatigue and pain.²⁶ In assessing mechanical and heat hyperalgesia by a visual analogue scale (VAS) following a 5-minute handgrip exercise (involving forearm occlusion) and a nonocclusion state in 39 patients with CFS, compared to 29 controls, qualitative sensory testing provided evidence supporting this hypothesis.

Genetic Polymorphisms

Genetic polymorphisms have been suggested as influences in functional pain syndromes such as CFS, FM, irritable bowel syndrome, temporomandibular disorder, and interstitial cystitis.²⁷

Nutritional Deficiencies

See the section below on Integrative Clinical Approaches, where nutritional deficiencies are discussed along with strategies for addressing these deficiencies.

Nonpharmacologic Treatment Options

Exercise

For a meta-analysis of 8 randomized clinical trials (RCTs; total N=1518) researchers reviewed the effects of exercise therapy for patients diagnosed with CFS, compared with other active interventions or a control condition.²⁸ Seven of the RCTs focused on aerobic exercise—such as walking, swimming, cycling, or dancing—at various levels of intensity, ranging from very low to rigorous. Control groups consisted of treatment as usual, relaxation, cognitive behavioral therapy, supportive listening, pacing, pharmacologic, and combination treatment. Therapy duration ranged from 12 to 26 weeks. Positive effects of exercise were found with respect to sleep, physical function, and self-perceived general health, but no conclusion could be drawn for the outcomes of pain, quality of life (QoL), anxiety, depression, dropout rate, and health service resources. None of the studies suggested that exercise therapy would worsen outcomes.

Resources

Organizations

International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (IACFS/ME)

9650 Rockville Pike

Bethesda, MD 20814

Phone: (301) 634-7701

Fax: (301) 634-7099

Website: www.iacfsme.org

E-mail: membership@iacfsme.org

The IACFS/ME promotes research and education related to the care of patients with CFS/ME. This nonprofit organization sponsors the peer-reviewed journal Fatigue: Biomedicine, Health and Behavior.

Bateman Horne Center

1002 E. South Temple, Suite 408

Salt Lake City, UT 84102

Website: www.batemanhornecenter.org

E-mail: support@batemanhornecenter.org

Phone: (801) 359-7400

Bateman Horne Center's mission is to improve resources and advocate for patients with CFS, ME, and FMS; to educate health care providers, patients, and the general public about these illnesses; and to promote research on their causes, diagnosis, and treatment.

Recommended Reading

The Fatigue and Fibromyalgia Solution:

The Essential Guide to Overcoming Chronic Fatigue and Fibromyalgia, Made Easy!

By Jacob Teitelbaum, MD

New York: Avery/Penguin Group, 2013

Treating and Beating Fibromyalgia and Chronic Fatigue Syndrome:

You Can Feel Good Again, 5th ed.

By Rodger H. Murphree, DC, CNS

Birmingham, AL: Harrison Hampton, 2013

Diagnosing and Treating Chronic Fatigue Syndrome:

It's Mitochondria, Not Hypochondria

By Sarah Myhill, MB, BS

London: Hammersmith Health Books, 2014

An RCT was conducted to investigate the feasibility and efficacy of isometric yoga* in patients with CFS whose conditions were resistant to conventional treatments (e.g., pharmacotherapy, cognitive–behavioral therapy, and/or graded exercise therapy).²⁹ Patients were assigned to a group treated with standard pharmacologic therapy (n=15) or to conventional therapy plus isometric yoga practice (n=15), which consisted of 20-minute private sessions with an instructor and at-home practice with the aid of a digital video disc and booklet for ∼2 months.

Based on assessments of mood, fatigue, and health-related QoL administered immediately before and after the final yoga session and based on patients' diaries, the researchers concluded that isometric yoga was a successful adjunct therapy for this patient population.²⁹ They suggested that yoga's beneficial effects were the result of altering presumed mechanisms of action, such as predominance of the ANS over the parasympathetic nervous system, dysfunction of the hypothalamic–pituitary–adrenal axis, disruption of circadian rhythms, elevated serum levels of cortisol, and expression of proinflammatory cytokines.

To evaluate the effectiveness of Chinese qigong exercise on the symptoms of fatigue, sleep disruption, anxiety, and depression in CFS, 150 participants with a CFS-like illness were randomly assigned to either 16 1-hour qigong lessons and self-practice over 9 consecutive weeks or a wait-list.³⁰ As assessed at baseline, immediately post-treatment, and 3-months' follow-up, qigong exercise significantly improved subjective sleep quality, and scores on measures of anxiety and depression.

Dietary Supplements

Multivitamin–mineral supplements— Before and after 2 months of taking a multivitamin–mineral supplement, 38 women (ages 18–50) who were diagnosed with CFS had their antioxidant status assessed according to superoxide dismutase (SOD) activity in pre- and postplasma samples, and self-assessed improvement on several measures.³¹ There were significant improvements in SOD activity, and significant decreases in fatigue, sleep disorders, ANS symptoms, intensity of headaches, and subjective feelings of having infections. The researchers concluded that treatment with a multivitamin–mineral supplement could be a safe, easy way to reduce symptoms and QoL of patients with CFS.

d-ribose— d-Ribose, a carbohydrate that occurs naturally in the body, has been shown to increase cellular energy synthesis in heart and skeletal muscle. An open-label, uncontrolled pilot study evaluated if d-ribose could also improve energy synthesis in patients with CFS and/or FM (N=41).³² Patients were given a twice-daily dose of 5 g of d-ribose for a total of 280 g over a 28-day period. d-Ribose produced significant improvement in ∼ 60% of patients according to pre- and post administration of VAS categories of energy, sleep, mental clarity, pain intensity, and well-being, as well as having an average improvement of 30% in global assessment scoring. d-Ribose was well-tolerated.

Isoflavones— In an experimental study, a diet high in the isoflavone daidzein plus genistein inhibited the gene expression of serum, brain, and skin inflammatory mediators on stress tasks in mice.³³ The investigators noted that this finding is relevant to patients with CFS, in whom corticotropin-releasing hormone and neurotensin secreted under stress activate mast cells, which trigger inflammatory mediators that contribute to CFS symptoms.

Robuvit®— In a pilot study of 48 subjects with CFS, compared to a control group (n=43), Robuvit (Horphag Research (USA) Inc., Hoboken, New Jersey), a proprietary extract of Quercus robur (French oak), significantly reduced symptoms of extreme exhaustion, muscle pain, poor concentration and memory, and oxidative stress.³⁴ Overall mood also improved in the group who received the supplement. For this study, the intervention group subjects received 200 mg per day of the extract in capsule form for at least 6 months. All subjects in the study were evaluated with a CFS questionnaire and the Brief Mood Introspection Scale at baseline, and at 3 and 6 months. No side-effects were observed. The reduction in oxidative stress appears to be a prime mechanism of action of Robuvit in patients with CFS.

Other Supplements— A systematic review of 70 RCTs of CAM interventions for CFS identified l-carnitine, magnesium, and S-adenosylmethionine (SAMe) as supplements warranting further research.³⁵ A systematic review of 17 studies that tested supplements for CFS found evidence of the beneficial effects of magnesium and nicotinamide adenine dinucleotide+hydrogen.³⁶

Traditional Chinese Medicine

A systematic review of 23 RCTs (total N=1776) of Traditional Chinese Medicine (TCM) approaches for treating CFS concluded that Chinese herbal medicine, acupuncture, and qigong are potentially effective for patients with CFS, although further studies are needed.³⁷ Myelophil—an extract mixture of Astragali Radix (astragalus; Astragalus spp.) and Salviae Miltiorrhizae Radix (salvia root; Salvia miltiorrhiza Bge.)—is a TCM used for the treatment of chronic fatigue–associated disorders.³⁸

In an RCT, subjects (n=13) who complained of chronic fatigue received a low dose (3 mg) (n=11) or a high dose (6 mg) (n=12) of Myelophil for 4 weeks. The low dose significantly reduced subjective fatigue severity scores, compared with the controls.³⁹ The low dose group showed a significantly greater decrease compared to the high dose group in severity scores.

Integrative Clinical Approaches

Jacob E. Teitelbaum, MD—the owner and medical director of the Fatigue and Fibromyalgia Network in Kona, Hawaii—developed a holistic approach for treating patients with CFS and fibromyalgia.⁴⁰ Dr. Teitelbaum's S.H.I.N.E.^® protocol refers to 5 key areas that need to be addressed in order to overcome the symptoms of what he calls the modern “energy crisis” of mitochondrial dysfunction:

(1) Sleep that is disordered and needs to be addressed

(2) Hormonal support for adrenal insufficiency

(3) Immune support for the rising number of autoimmune symptoms

(4) Nutritional support to counter the deleterious effects of the typical Western diet

(5) Exercise.

While not denying the utility of as-needed use of prescription aids for addressing poor sleep associated with stress or hypothalamic dysfunction, Dr. Teitelbaum prefers natural sleep remedies for patients to take at bedtime, including theanine (50–200 mg), an amino acid derived from green tea (Camellia sinensis); wild lettuce (Lactuca virosa L.; 30–120 mg); Jamaican dogwood (Piscidia erythrina or Piscidia piscipula; 12–48 mg); hops (Humulus lupulus L.; 30–120 mg); passionflower (Passiflora incarnata; 90–360 mg); and valerian (Valeriana officinalis; 200–800 mg). Extracts of these botanicals and amino acids are found in Revitalizing Sleep Formula,^® which Dr. Teitelbaum helped develop for Enzymatic Therapy, LLC (Green Bay, Wisconsin).^{40
†} According to his study (discussed above in the Dietary Supplements section), he has found d-ribose to benefit his patients.³²

Hormonal support entails testing for and optimizing adrenal, thyroid, testosterone, and estrogen functions. Dr. Teitelbaum considers standard tests (unspecified) to be inadequate for the diagnosis of low hormone levels. Nutritional support for adrenal insufficiency includes adrenal glandulars, bioidentical cortisol (under 15 mg/day), and dehydroepiandrosterone (DHEA). The doses are: for women, 5–10 mg/day; for men, 25–50 mg/day. Underactive thyroid is treated by individually adjusted doses of synthetic T₄ (thyroxine), pure T₃ (triiodothyronine), or sustained-release T_3.

Immune support involves testing for and treating infections, such as Candida overgrowth, viral infections (primarily human herpesvirus-6, EBV, and cytomegalovirus), and small-intestine bacterial overgrowth (SIBO). Some evidence suggests that patients with CFS have abnormalities in microbial flora, including SIBO.⁴¹ Natural antivirals recommended by Dr. Teitelbaum are thymic protein A and lauricidin. The use of filtered water is advised for eliminating parasites. In a case series, ∼5% of 1262 patients developed CFS following giardiasis enteritis infection.⁴² Patients are advised to exercise to the extent that their symptoms are not exacerbated. Nutritional support includes d-ribose, a sugar found naturally in the body that cells need to make adenosine triphosphate (ATP), to accelerate the recovery of energy.³²

Sarah Myhill, MB, BS—a British physician in private practice in Upper Weston, United Kingdom—regards mitochondrial failure as the central cause of CFS. In a clinical audit of 138 patients with CFS/ME, all of the patients had mitochondrial dysfunction, as measured by an ATP Profile test.⁴³ She recommends a treatment plan based on the following: a Paleolithic diet including low glycemic foods; nutritional supplements including a multimineral mix, vitamins C, D, and B₁₂, and omega-3; adequate sleep; and pacing (a balance between work and rest). All of the patients who followed this treatment regimen reportedly had improvement in mitochondrial function by a factor of 4.

Rodger H. Murphree, DC, CNS—a chiropractic physician and certified nutrition specialist who practices functional and orthomolecular medicine in Homewood, Alabama—offers a proprietary package of nutrients to address the core issues of CFS (as well as FM).⁴⁴ The “4 pillars” of this Jump-Start^® program are the following:

(1) 5-Hydroxytryptophan (5-HTP) to build serotonin and promote restorative sleep, the lack of which is central in both CFS and FM

(2) Adrenal Cortex (500 mg daily, divided into 2 doses) to address adrenalin insufficiency, depression, and stress issues

(3) Pancreatic digestive enzymes or betaine hydrochloride with pepsin enzyme with each meal to heal intestinal permeability (“leaky gut”) and prevent further nutritional deficiencies

(4) A daily multivitamin–mineral formula in doses that promote optimal health rather than merely the minimum recommended daily allowance required to prevent deficiencies.

Dr. Murphree also tests for and treats thyroid function, chronic inflammation, food allergies, Candida infection, parasites, and other conditions that may contribute to CFS.

Conclusion

Whether this condition is called CFS, ME/CFS, CFIDS, or SEID, and whatever case definition is used to determine its prevalence, this complex disorder impacts QoL greatly for many patients and poses a clinical challenge. An individualized approach should be created for each patient, taking into account the fact that patients frequently complain of persistent fatigue after such conventional therapies as pharmacologic drugs, cognitive–behavioral therapy, or graded exercise.

Recent findings support the concept of CFS as a distinct disease entity with specific biomarkers. Further research needs to be conducted to learn more about the causes and the course of the disease, refine the case definition, identify subsets of patients, and corroborate evidence-based therapies. Lucinda Bateman, MD—the founder of the Fatigue Consultation Clinic in Salt Lake City, Utah, and the Organization for Fatigue & Fibromyalgia Education and Research (see Resources)—has aptly expressed the need for holistic support of patients, saying: “I hope we leave name change deliberations in the dust and focus on the people who are ill.”⁴⁵ ■

Footnotes

References

Mandal

. Chronic Fatigue Syndrome History. Online document at: www.news-medical.net/health/Chronic-Fatigue-Syndrome-History.aspx Accessed March 16, 2015 .

Holmes

, Kaplan

, Gantz

, et al. Chronic fatigue syndrome: A working case definition. Ann Intern Med, 1988; 108:387–389.

Centers for Disease Control and Prevention. Chronic Fatigue Syndrome (CFS): General Information. Online document at: www.cdc.gov/cfs/general/index.html Accessed March 5, 2015 .

Maes

. Inflammatory and oxidative and nitrosative stress cascades as new drug targets in myalgic encephalomyelitis and chronic fatigue syndrome. Mod Trends Pharmacopsychiatri, 2013; 28:162–174.

Institute of Medicine of the National Academies. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Key Facts. Online document at: www.iom.edu/∼/media/Files/Report%20Files/2015/MECFS/MECFS_KeyFacts.pdf Accessed March 14, 2015 .

Centers for Disease Control and Prevention. Chronic Fatigue Syndrome (CFS) in Children and Adolescents. Online document at: www.cdc.gov/cfs/pediatric/index.html Accessed March 9, 2015 .

Phoenix Rising. Hitting a Moving Target I: Defining and Quantifying CFS. The New Prevalence Estimates. Online document at: http://phoenixrising.me/research-2/defining-chronic-fatigue-syndrome-mecfs/hitting-a-moving-target-i-defining-and-quantifying-cfs-the-new-prevalence-estimates Accessed March 10, 2015 .

Johnstone

, Brenu

, Staines

, Marshall-Gradisnik

. The prevalence of chronic fatigue syndrome/myalgic encephalomyelitis: A meta-analysis. Clin Epidemiol, 2013; 5:105–110.

Fukuda

, Straus

, Hickie

, et al. The chronic fatigue syndrome: A comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med, 1994; 121:953–959.

10.

Brurberg

, Fønhus

, Larun

, et al. Case definitions for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME): A systematic review. BMJ Open, 2014; 4:e003973.

11.

Institute of Medicine. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Online document at: www.iom.edu/∼/media/Files/Report%20Files/2015/MECFS/MECFS_ReportBrief.pdf Accessed March 17, 2015 .

12.

Elgen

, Hikmat

, Aspevik

, Hagen

. CFS in children and adolescent [sic]: Ten years of retrospective clinical evaluation. Int J Pediatr, 2013; 2013:270373.

13.

Lombardi

, Ruscetti

, Das Gupta

, et al. Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. Science, 2009; 326:585–589.

14.

Oakes

, Tai

, Cingöz

, et al. Contamination of human DNA samples with mouse DNA can lead to false detection of XMRV-like sequences. Retrovirology, 2010; 7:109.

15.

Rasa

, Nora-Kruckle

, Chapenko

, et al. No evidence of XMRV provirus sequences in patients with myalgic encephalomyelitis/chronic fatigue syndrome and individuals with unspecified encephalopathy. New Microbiol, 2014; 37:17–24.

16.

Johnston

. Chasing the Shadow Virus: Chronic Fatigue Syndrome and XMRV. Discover, March 17, 2013. Online document at: http://discovermagazine.com/2013/march/17-shadow-virus Accessed March 18, 2015 .

17.

Martinez-Martinez

, Mora

, Vargas

, et al. Sympathetic nervous system dysfunction in fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, and interstitial cystitis: A review of case-control studies. J Clin Rheumatol, 2014; 20:146–150.

18.

Morris

, Maes

. A neuro-immune model of myalgic encephalomyelitis/chronic fatigue syndrome. Metab Brain Dis, 2013; 28:523–540.

19.

Morris

, Berk

, Galecki

, et al. The neuro-immune pathophysiology of central and peripheral fatigue in systemic immune-inflammatory and neuro-immune diseases. Mol Neurobiol, 2015; January 20:e-pub ahead of print.

20.

Nijs

, Nees

, Paul

, et al. Altered immune response to exercise in patients with chronic fatigue syndrome/myalgic encephalomyelitis: A systematic literature review. Exerc Immunol Rev, 2014; 20:94–116.

21.

Hornig

, Montoya

, Klimas

, et al. Distinct plasma immune signatures in ME/CFS are present early in the course of illness. Sci Adv, 2015; 1:e1400121.

22.

Nakatomi

, Mizuno

, Ishii

, et al. Neuroinflammation in patients with chronic fatigue syndrome/myalgic encephalomyelitis: An 11C-(R)-PK11195 PET study. J Nucl Med, 2014:55:945–950.

23.

Reynolds

, Lewis

, Richardson

, Lidbury

. Comorbidity of postural orthostatic tachycardia syndrome and chronic fatigue syndrome in an Australian cohort. J Intern Med, 2014; 275:409–417.

24.

Van Cauwembergh

, Nijs

, Kos

, et al. Malfunctioning of the autonomic nervous system in patients with chronic fatigue syndrome: A systematic literature review. Eur J Clin Invest, 2014; 44:516–526.

25.

Krzeczkowska

, Karatzias

, Dickson

. Pain in people with chronic fatigue syndrome: The role of traumatic stress and coping strategies. Psychol Health Med, 2015; 20:210–216.

26.

Staud

, Mokthech

, Price

, Robinson

. Evidence for sensitized fatigue pathways in patients with chronic fatigue syndrome. Pain, 2015; 156:750–759.

27.

Furquim

, Flamengui

, Conti

. TMD and chronic pain: A current view. Dental Press J Orthod, 2015; 20:127–133.

28.

Larun

, Brurberg

, Odgaard-Jensen

, Price

. Exercise therapy for chronic fatigue syndrome. Cochrane Database Syst Rev, 2015; 2:CD003200.

29.

Oka

, Tanahashi

, Chijiwa

, et al. Isometric yoga improves the fatigue and pain of patients with chronic fatigue syndrome who are resistant to conventional therapy: A randomized, controlled trial. Biopsychosoc Med, 2014; 8:27.

30.

Chan

, Ho

, Chung

, et al. Qigong exercise alleviates fatigue, anxiety, and depressive symptoms, improves sleep quality, and shortens sleep latency in persons with chronic fatigue syndrome-like illness. Evid Based Complement Alternat Med, 2014; 2014:106048.

31.

Maric

, Brkic

, Tomic

, et al. Multivitamin mineral supplementation in patients with chronic fatigue syndrome. Med Sci Monit, 2014; 20:47–53.

32.

Teitelbaum

, Johnson

, St Cyr

. The use of d-ribose in chronic fatigue syndrome and fibromyalgia: A pilot study. J Altern Complement Med, 2006; 12:857–862.

33.

Vasiadi

, Newman

, Theoharides

. Isoflavones inhibit poly(I:C)-induced serum, brain, and skin inflammatory mediators—relevance to chronic fatigue syndrome. J Neuroinflammation, 2014; 11:168.

34.

Belcaro

, Cornelli

, Luzzi

, et al. Improved management of primary chronic fatigue syndrome with the supplement French oak wood extract (Robuvit®): A pilot, registry evaluation. Panminerva Med, 2014; 56:63–72.

35.

Porter

, Jason

, Boulton

, et al. Alternative medical interventions used in the treatment and management of myalgic encephalomyelitis/chronic fatigue syndrome and fibromyalgia. J Altern Complement Med, 2010; 16:235–249.

36.

Alraek

, Lee

, Choi

, et al. Complementary and alternative medicine for patients with chronic fatigue syndrome: A systematic review. BMC Complement Altern Med, 2011; 11:87.

37.

Wang

, Li

, Liu

, et al. Traditional Chinese Medicine for chronic fatigue syndrome: A systematic review of randomized clinical trials. Complement Ther Med, 2014; 22:826–833.

38.

Lee

J-S

, Kim

H-G

, Han

J-M

, et al. Ethanol extract of Astragali Radix and Salviae Miltiorrhizae Radix, Myelophil, exerts anti-amnesic effect in a mouse model of scopolamine-induced memory deficits. J Ethnopharmacol, 2014; 153:782–792.

39.

Cho

, Cho

, Shin

, et al. Myelophil, an extract mix of Astragali Radix and Salviae Radix, ameliorates chronic fatigue: A randomised, double-blind, controlled pilot study. Complement Ther Med, 2009; 17:141–146.

40.

Teitelbaum

. The Fatigue and Fibromyalgia Solution: The Essential Guide to Overcoming Chronic Fatigue and Fibromyalgia, Made Easy!. New York: Avery/Penguin Group, 2013.

41.

Logan

, Venket

, Irani

. Chronic fatigue syndrome: Lactic acid bacteria may be of therapeutic value. Med Hypotheses, 2003; 60:915–923.

42.

Naess

, Nyland

, Hausken

, et al. Chronic fatigue syndrome after Giardia enteritis: Clinical characteristics, disability and long-term sickness absence. BMC Gastroenterol, 2012; 12:13.

43.

Myhill

, Booth

, McLaren-Howard

. Targeting mitochondrial dysfunction in the treatment of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)—a clinical audit. Int J Clin Exp Med, 2013; 6:1–15.

44.

Murphree

. Treating and Beating Fibromyalgia and Chronic Fatigue Syndrome: You Can Feel Good Again, 5th ed. Birmingham, AL: Harrison Hampton, 2013.

45.

Solve ME/CFS Initiative: Guest Blog: Dr. Lucinda Bateman on the Discussion Surrounding the IOM Report. Online document at: http://solvecfs.org/dr-bateman-discussion-post-iom-report/#at_pco+smlwn-1.0&at_si=54f8d50fe&at_ab=per-2&at_pos=0&at_tot=1 Accessed March 28, 2015 .