Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a relatively common illness, yet despite considerable investigation, current treatments have modest benefits, and the prognosis remains poor. Because CFS/ME is a heterogeneous disorder with diverse etiological factors and pathological features, a patient-centered integrative framework based on modifiable physiological and environmental factors may offer hope for more effective management and better clinical outcomes. An individualized approach may also help target interventions for subgroups most likely to respond to specific treatments. This review summarizes a number of avenues for integrative management, including dietary modification, functional nutritional deficiencies, physical fitness, psychological and physical stress, environmental toxicity, gastrointestinal disturbances, immunological aberrations, inflammation, oxidative stress, and mitochondrial dysfunction. A personalized, integrative approach to CFS/ME deserves further consideration as a template for patient management and future research. (Altern Ther Health Med. 2014;20(1):29-40.)
Benjamin I. Brown, ND, is a lecturer at the UK College of Nutrition and Health (BCNH) in London, England.
Corresponding author: Benjamin I. Brown, ND
Chronic unexplained fatigue is a very common clinical complaint. In primary care settings, an estimated 24% of patients report fatigue as a significant problem, and population estimates for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) range from 1.85% to 11.3%.1 Despite the high prevalence of CFS/ME and considerable research on the disease, the amount of time required to diagnose it remains long, and its prognosis continues to be poor. Diagnosis takes an average of 5 years from initiation of symptoms to identification of the syndrome, with total recovery rates between 0% and 37% and rates of improvement between 6% and 63%.2 The poor prognosis for CFS/ME in part may be due to its heterogeneous nature, and like many chronic diseases, it has a number of etiological and functional disturbances that contribute to the disease’s course and symptoms.
Although the exact cause of CFS/ME is unknown, several underlying and sometimes characteristic states of physiological dysfunction have been identified; in particular, abnormalities of the immune and central nervous systems have been found.3 These finding have led some researchers to suggest that looking for the cause of CFS/ME is a self-defeating exercise; they suggest that focusing on rehabilitation and improvement of functional status is more important.4 This notion leads to the possibility of creating an integrative management approach that is grounded in the hypothesis that CFS/ME is the manifestation of a complex state of physiological dysfunction unique to an individual.5
Integrative medicine involves the application of a patient-centered, individualized approach to disease management that incorporates the best available treatment options, including conventional and evidence-based complementary and alternative medicine.6 To this end, the practitioner may evaluate physiological function during assessment, while treatments typically may incorporate environmental, lifestyle, mind-body, dietary, and nutraceutical interventions. The aim of this review is to explore modifiable environmental and physiological factors that may play a role in CFS/ME and to discuss the current evidence for corresponding treatments from an integrative perspective.
CLINICAL ASSESSMENT AND DEFINITION
The current method of diagnosis of CFS/ME is based on exclusion of alternative explanations for fatigue, and no accepted, standard investigative tests exist that can confirm or refute a diagnosis.7 The most commonly accepted symptom criterion is the 1994 case definition for CFS/ME from the Centers for Disease Control and Prevention (CDC).8
According to this definition, an individual must satisfy 2 criteria to be diagnosed with CFS. The individual (1) must have self-reported, persistent or relapsing fatigue for at least 6 consecutive months, and other medical conditions for which manifestation includes fatigue must be excluded by clinical diagnosis and (2) must have 4 or more of the following symptoms concurrently: postexertional malaise, impaired memory or concentration, unrefreshing sleep, muscle pain, multijoint pain without redness or swelling, tender cervical or axillary lymph nodes, sore throat, or headache—that must have persisted or recurred during 6 or more consecutive months of illness and must not have predated the fatigue.
Scientists have also noted that children may differ in presentation from adults with CFS/ME, displaying symptoms such as sadness, hyperactivity (initial phase), episodic tension headaches, abdominal pain, tachycardia, and orthostatic hypotension. Notably CFS/ME in children may be mistaken for laziness or school phobia.9
Routine clinical investigations are recommended by the UK National Institute of Clinical Excellence to exclude medical causes of chronic fatigue, and additional serology should be done to exclude bacterial and/or viral involvement if the individual’s history suggests the possibility of a recent infection.10
Individuals with CFS/ME should also be evaluated for psychiatric illnesses, as symptoms of depression and psychological stress are commonly associated with the condition.11 Although depressive disorder may be an important diagnostic exclusion, a number of important features can indicate a concomitant presentation of CFS/ME with depression.
Differential symptoms of CFS/ME with depression compared to primary depression include the following: (1) individuals with CFS/ME lack feelings of anhedonia (inability to experience pleasure, guilt, and decreased motivation that is classically seen in individuals with depression); (2) individuals experience several CFS/ME symptoms, including prolonged fatigue after physical exertion, night sweats, sore throats, and swollen lymph nodes, which are not commonly found in depression; (3) fatigue is the principal feature of CFS/ME but does not assume equal prominence in depression; and (4) illness onset with CFS/ME is often sudden, occurring over a few hours or days, whereas primary depression generally shows a more gradual onset.12,13
Most important, CFS/ME shares many symptomatic features with other functional somatic syndromes, including irritable bowel syndrome (IBS), fibromyalgia (FM), multiple chemical sensitivity, headaches, and temporomandibular joint dysfunction.14 Overlap between CFS/ME and FM is particularly common, with approximately 20% to 75% of individuals with CFS/ME meeting the criteria for FM.15-17
Currently recommended treatments for CFS/ME include cognitive behavior therapy (CBT) and graded exercise therapy (GET), and no suggested pharmacological therapies are available.18 Clinical improvements, however, are modest, with some 40% to 50% of patients reporting improvements in fatigue after treatment with CBT or GET versus 20% to 30% in usual care. Furthermore, the generalizability of findings from randomized, controlled trials to real-world clinical settings is contentious, and long-term treatment outcomes are uncertain.19
The effects of GET and CBT on disability and quality of life are discouraging. At 12 months, health-related quality of life was not shown to improve with CBT and GET versus usual care; in fact, physical function and scores for bodily pain were worse in the intervention group.20 One study examined the impact of interventions, including GET and CBT, on disability, as indicated primarily by the ability to work.21 It concluded that no currently available intervention was able to restore functional status (ie, the ability to work).
The apparent limitations of current treatments, coupled with the diverse etiopathogenesis of CFS/ME, has led some investigators to suggest that an individually tailored approach to treatment, which takes into account a patient’s unique pathological features and employs corresponding evidence-based treatments, may be a more rational approach to patient management.19
A number of modifiable physiological and environmental factors have been investigated as contributors to CFS/ME. These factors include dietary and nutritional factors, physical fitness, psychological and physical stress, various environmental pollutants, gastrointestinal disturbances, chronic infection, inflammation and oxidative stress, and mitochondrial dysfunction (Figure 1).
In this review, the author explores each of these categories sequentially, briefly discussing supportive evidence for their contribution to CFS/ME and then investigating potential treatments, including behavioral, mind-body, dietary, lifestyle, and nutraceutical interventions.
DIETARY AND GENERAL NUTRITIONAL CONSIDERATIONS
Although diet is known to be a potent modifier of several chronic diseases, investigations of diet in CFS/ME are lacking. One investigation found no relationship between current dietary habits—including intake of alcohol, fat, fibers, fruit, and vegetables—and fatigue severity or functional impairments in individuals with CFS/ME.22 Although individuals with CFS/ME tended to lead healthier lifestyles compared to the general population, in one study, 70% had unhealthy fat, fruit, and vegetable intake, and 95% had unhealthy fiber intake.22
It is plausible to suggest that dietary intervention could improve functional status in CFS/ME, considering that a healthy dietary pattern such as a traditional Mediterranean-style diet could counter functional impairments, such as low-grade inflammation and oxidative stress, and improve mental vigor, mood, and physical fitness.23-27 Some evidence that supports this hypothesis comes from a dietary intervention with high-polyphenol dark chocolate. In this study, eating dark chocolate for 8 weeks—15 grams, 3 times per day—significantly reduced fatigue, increased physical activity, and reduced anxiety and depression in CFS/ME sufferers.28 Phytonutrient-dense, polyphenol-rich foods are thought to be a major reason for the beneficial effects of a traditional Mediterranean-style diet.29
Food sensitivities may play a role in chronic unexplained fatigue. One investigation reportedly found that the elimination of wheat, milk, benzoates, nitrites, nitrates, food additives, and food colorings resulted in a significant improvement in CFS/ME symptoms of fatigue, recurrent fever, sore throat, muscle pain, headache, joint pain, cognitive dysfunction, and IBS.30 In addition, celiac disease is commonly associated with fatigue, which improves on a gluten-free diet; however the possibility of a relationship between CFS/ME and gluten sensitivity has not been investigated.31
Functional Nutritional Deficiencies
Functional nutrition is a paradigm grounded in the notion that unique imbalances in nutritional status can give rise to changes in physiological function that may ultimately influence the expression of disease.32 The functional-nutrition model is a patient-centered approach that is concerned with identifying nutritional imbalances unique to an individual and correcting them through diet and/or nutritional supplementation to restore healthy physiological function. A number of functional nutritional deficiencies have been identified in CFS/ME. While nutrient interventions are likely to have small effect sizes and considerable variations in treatment response in studies, it is important to consider that they may still offer benefit to the individual, and they have an excellent safety profile.33
Vitamin D. A retrospective survey of serum levels of 25-hydroxyvitamin D (25[OH]D) in individuals with CFS/ME found that vitamin D levels were significantly lower compared to the general population, with a mean of 44.4 nmol/L (optimal levels > 75 nmol/L).34 Researchers have hypothesized that vitamin D deficiency may contribute to CFS/ME though association with increased oxidative stress, inflammation, and subsequent generation of fatigue symptoms.35 In a series of case reports, the treatment of CFS/ME with vitamin D was reported to result in a modest clinical improvement in some individuals.36 No controlled clinical trials of vitamin D in CFS/ME have occurred.
Because symptoms of severe vitamin D deficiency may include fatigue, depression, weakness, and muscle pain, people with vitamin D deficiency may often be misdiagnosed as having FM or CFS.37 In one report, 93% of adults and children presenting with nonspecific muscle pain were vitamin D deficient.38 Another study found that 58% of participants with musculoskeletal pain, headache, and fatigue were vitamin D deficient.39 Individuals with nonspecific skeletomuscular pain should have their serum 25(OH)D assessed because of the wide-ranging health benefits of treating vitamin D deficiency.40
Long-chain Polyunsaturated Fatty Acids. It has been hypothesized that a functional impairment of fatty-acid metabolism may in part explain functional changes in the central nervous system as well as clinical symptoms for individuals with CFS/ME. Central to this hypothesis is the notion that viral infection associated with CFS/ME may impair the biosynthetic pathway for long-chain polyunsaturated fatty acids (PUFAs) that in turn could have important consequences for the structure and function of the central nervous system.41
The findings of a randomized, controlled clinical trial lend support to this hypothesis.42 The researchers observed that treatment with the fatty acids γ-linolenic acid (GLA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) improved the symptoms of CFS/ME. A second clinical trial, however, failed to confirm these results.43
In a series of case reports, treatment with high potency EPA and GLA resulted in clinical improvement for CFS/ME sufferers.44 And in a separate case report, high-resolution, structural scans using magnetic resonance imaging (MRI) revealed that treatment was accompanied by improvements in brain structure—a reduction in lateral ventricular volume.45
B Vitamins. Functional deficiencies of the vitamins pyridoxine, riboflavin, and thiamine in individuals with CFS/ME have been reported.46 And evidence of low levels of serum folate and elevated levels of homocysteine in cerebrospinal fluid—a functional marker of folate or vitamin B12 deficiency—have also been documented.47,48
Studies of clinical interventions with B vitamins have been mixed. Two randomized, controlled trials have compared treatment with nicotinamide adenine dinucleotide (NADH), the active form of niacin, to treatment with a placebo or to psychological therapy. One randomized clinical trial showed statistically significant effects for NADH (10 mg) on symptom scores after 1 month of treatment, when compared with a placebo.49 A second clinical trial also reported significant positive effects for NADH (5-10 mg) in the first month of treatment and a continued but modest trend toward improvement after 3 months.50 Treatment with a multivitamin and minerals was found to improve symptoms of functional fatigue while another study of a multivitamin in CFS/ME sufferers demonstrated no benefit.51,52 A study of a folate and vitamin B12 also reported no evidence of benefit.53
Magnesium. Low magnesium status has been described in CFS/ME and FM sufferers in some but not all studies, and the contribution of low magnesium status to the pathogenesis of chronic fatigue remains controversial.54,55 It has been suggested, however, that subclinical magnesium deficiency could be difficult to detect and could be linked to the development of CFS/ME via contribution to a pro-oxidant, low-grade inflammatory state.56
Some empirical evidence suggests that magnesium supplementation may be helpful to individuals with CFS/ME. In a case control study, intravenous treatment with magnesium was found to improve energy levels and emotional state and to reduce pain.57 And an isolated case report described an individual with severe CFS/ME who experienced significant clinical improvement after intravenous magnesium therapy.58
Amino Acids. Based on the hypothesis that a functional deficiency in various amino acids required for neurotransmitter synthesis and production of adenosine triphosphate (ATP) might contribute to CFS/ME, an exploratory open label study was conducted.59 CFS/ME participants had their fasting levels of plasma amino acid measured and were then prescribed 15-gram mixtures of free-form amino acids based on their test results. The treatment duration was 3 months. Of the 20 participants who completed the study, 90% experienced at least a 25% improvement in symptoms, with 75% having reported a 50% to 100% improvement. This promising study suggests a need for further research on the potential of personalized amino acid therapy.
Carnitine. The amino acid carnitine plays a crucial role in mitochondrial energy production, and both functional deficiencies and the effects of dietary supplementation have been investigated. In one study, the plasma carnitine status of participants with CFS/ME was found to be 30% to 40% lower in certain forms of carnitine than controls, with a significant correlation between carnitine concentrations and clinical symptoms.60
A randomized, controlled trial of carnitine (3000 mg/d) in individuals with CFS/ME demonstrated a significant clinical improvement in symptoms, especially between the fourth and eighth week of treatment.61 Comparing acetyl-L-carnitine (2000 mg/d), propionyl-L-carnitine (2000/d), or a combined treatment (2000 mg of each/d), an open label study found beneficial effects on symptoms such as fatigue, pain, and cognitive function from all treatments.62
Zinc. Serum zinc has been found to be significantly lower in individuals with CFS/ME versus healthy controls, and low levels of zinc have been associated with an increase in symptom severity and measures of immunological dysfunction.63 Based on the correlation between low serum zinc and increased clinical symptom severity, the study’s investigators suggested that some participants with CFS/ME should be considered for treatment with zinc supplements. Although no clinical trials of zinc in CSF/ME have occurred, clinical evidence suggests that zinc supplementation may influence fatigue, immune function, mood, inflammation, and oxidative stress.64-67
A characteristic feature of CFS/ME is worsening of symptoms after increased daily physical activity or modest amounts of exercise.68,69 Individuals with CFS/ME are also known to have a lower, peak, isometric muscle strength and perform less physical activity during daily life.70 Compared to healthy controls, individuals with CFS/ME tend to have a relatively lengthened and accentuated, oxidative stress response to physical activity that is linked to the development of postexertional symptom exacerbation.71 Elevations in the proinflammatory, cytokine tumor necrosis factor-α (TNF-α) at 2 time points—3 hours and 3 days after exercise—have also been observed.72
To improve physical fitness gradually and reduce symptoms, GET has been proposed as a treatment for CFS/ME and appears to be moderately effective when delivered by highly experienced therapists. A systematic review of GET suggested that some individuals might benefit from exercise therapy.73 A more recent review of GET, which examined 12 studies, concluded that consistent evidence of benefit exists, although the level of benefit was not quantifiable.74 Nevertheless the role of GET has been criticized based on marginal benefits versus usual care, and opponents suggest that exercise may exacerbate an underlying pathological state of inflammatory and oxidative stress, resulting in symptom exacerbation and patients’ dissatisfaction.75
Overall, the effects of GET appear to be modest and may have adverse effects.76 Therefore, GET may not always be appropriate, and the underlying inflammation and oxidative stress may need to be addressed first. If commencing exercise therapy, a self-paced approach may minimize risk of adverse effects (ie, advise patients not to increase physical activity if they are well and to reduce or stop exercise if unwell).77
PSYCHOLOGICAL AND PHYSICAL STRESS
The role of stress and the functional dynamics of the hypothalamic-pituitary-adrenal (HPA) axis in the development, maintenance, and treatment of CFS/ME have attracted considerable research. Dysfunction of the HPA axis is one of the most consistent findings in CFS/ME, with evidence suggesting an influence on functional status and treatment response.78
A review of the current evidence concluded that the most generalizable characteristic of the HPA axis dysfunction across CFS/ME sufferers is a modest reduction in cortisol levels in some individuals.79 Underlying, low cortisol levels are changes in HPA axis dynamics, including an attenuated, diurnal variation of cortisol; enhanced negative feedback to the HPA axis; and blunted HPA axis responsiveness.
In some cases, the development of CFS/ME may be preceded by adverse life events and neuroendocrine dysfunction.80 However, it seems that HPA axis dysfunction typically develops after the onset of CFS/ME, at which point it plays an important role in the maintenance of symptoms and in the disease’s course.79 It has been proposed that the cause of HPA axis dysfunction is multifactorial and involves a variety of factors, including physical inactivity, diet, sleep disturbance, chronic psychological stress, mental health, and the phase of the CFS/ME itself.81
Cognitive Behavioral Therapy
One intervention that may improve some individuals’ ability to cope with the illness and modestly improve clinical symptoms is cognitive behavioral therapy (CBT).82 A clinical trial of CBT found a 16% increase in total cortisol output after 6 months of therapy, making it one of the few interventions shown to improve cortisol levels in individuals with CFS/ME.83 It is worth noting, however, that some individuals with CFS/ME report feeling worse after CBT, which may be due in part to deficits in clinical administration or to side effects from graded exercise usually incorporated in CBT treatment.84
Mind-body therapies may help reduce stress and improve HPA axis function. Three meditation interventions for CFS/ME have found a reduction in symptoms and/or an increase in physical functioning.85 And fatigue symptoms and mental functioning improved compared to controls in a randomized, controlled trial of qigong exercise.86
Because low cortisol is a common feature of CFS/ME, some studies have explored the effects of low-dose hydrocortisone administration, although this treatment is not recommended.87 While low-dose hydrocortisone is generally well-tolerated and can reduce fatigue in the short term, studies of clinical interventions have suggested that treatment suppresses adrenal glucocorticoid responsiveness, which limits the usefulness of this therapy.88,89
Herbal medicines with evidence for improving physiological adaption to stress are referred to as adaptogens.90 An isolated case report suggested that treatment with the herbal medicine licorice (Glycyrrhiza glabra) could improve symptoms of CFS/ME.91 The researcher hypothesized that this effect was due to the ability of glycyrrhetic acid, an active metabolite in licorice, to inhibit the enzymatic breakdown of cortisol. Evidence suggests that licorice can increase cortisol availability; however, it has not been studied in individuals with CFS/ME.92
The herbal medicine Rhodiola rosea has demonstrated an antifatigue effect in a number of clinical studies.93 In individuals with stress-related burnout, R rosea was found to improve mood, fatigue, and HPA axis function, although investigations related to CFS/ME are lacking.94
A clinical study of Siberian ginseng (Eleutherococcus senticosus) failed to find overall evidence of benefit in participants with chronic fatigue; however, a subgroup analysis did suggest a modest benefit in participants with less-severe fatigue.95
A number of reports have linked toxins—including pesticides and insecticides, mercury, lead, nickel, and ciguatera poisoning—to CFS/ME or chronic, fatigue-like symptoms.96 Cadmium and tobacco smoke have also been hypothesized to play a role.97,98 Because these reports are limited by several factors, such as variable exposure and outcome measurements, small sample sizes, and unreliable CFS/ME definitions, they provide only weak evidence of an association; however, further research in this area appears warranted.
In an illustrative study, serum organophosphates in CFS/ME participants were found to be higher than in control participants and comparable CFS/ME participants with a known chemical exposure.99 This finding suggests a possible role for low-level bioaccumulation of persistent organic pollutants in the development of CFS/ME. Another report found that a small group of individuals who had developed CFS/ME after toxic exposure (ciguatera poisoning or exposure to solvents) had disturbances of hypothalamic function similar to matched CFS/ME controls. Moreover, the group with toxic exposure had more severe dysfunction of the immune system.100
Various methods are available to enhance detoxification. A number of foods and nutrients have been shown to reduce absorption and/or enhance the excretion of various toxicants, while avoidance of environmental and food sources of toxins may minimize exposure.101 Nutritional detoxification incorporates dietary change and the use of nutrients to support endogenous detoxification pathways and has been shown to enhance hepatic metabolism and improve subjective symptoms of fatigue.102-105
A detoxification program using ascorbic acid and choline for individuals with CFS/ME reported that symptoms improved as blood levels of pesticides decreased.106 And a group of individuals with mercury toxicity and severe fatigue, but not established CFS/ME, reportedly experienced excellent improvements after specialized dental-amalgam removal (a source of mercury exposure) and a detoxification program incorporating oral dimercapto-succinic acid (DMSA), chlorella, and additional nutrient and antioxidant support.107 Interestingly, infrared sauna therapy, which might support diaphoretic elimination of persistent organic pollutants, may also benefit CFS/ME.108,109
Gastrointestinal dysfunction is very common in CFS/ME and may contribute to the pathogenesis of the disease.110 A number of changes in gastrointestinal function have been identified in CFS/ME, including alterations in the gut microbiota (dysbiosis), increased gastrointestinal permeability, and altered mucosal immunity. The gastrointestinal system has also been considered a source of systemic, low-grade inflammation and oxidative stress in CFS/ME.111
In particular, dysbiosis, increased intestinal permeability, and subsequent low-grade metabolic endotoxemia, or leaky gut, have been suggested to play a role in CFS/ME pathogenesis.112,113 Low levels of Bifidobacterium, high levels of Enterococcus and Streptococcus, and small intestinal bacterial overgrowth (SIBO) have been identified and may influence systemic CFS/ME pathology.114,115 And compared to healthy controls, the prevalence and median values for serum antibodies against the lipopolysaccharide (endotoxin) were found to be significantly greater in participants with CFS/ME and were significantly correlated to symptom severity.116
Nutritional Management of Leaky Gut
Circulating endotoxin has been shown to be highly responsive to dietary change, with a healthy dietary pattern able to reduce circulating endotoxin by 31% within 1 month.117 One study examined the effects of a clinical intervention aimed at reducing intestinal permeability and circulating endotoxin in CFS/ME. Dietary change and treatment with anti-inflammatory and antioxidative nutrients—such as glutamine, N-acetylcysteine, and zinc—over 10 to 14 months significantly reduced antibody responses to endotoxin, with over 50% of participants showing significant clinical improvement or remission.118
Experimental evidence suggests that administration of probiotic bacteria may attenuate the underlying pathology of CFS/ME, namely systemic inflammation and oxidative stress.119 Probiotic bacteria have also been demonstrated to influence HPA-axis function and mood in humans, which may be of particular relevance to CFS/ME sufferers.120
A clinical intervention with a strain of Lactobacillus casei Shirota in participants with CFS/ME was found to increase gut Lactobacillus and Bifidobacterium and to decrease anxiety symptoms significantly after 8 weeks of treatment, as compared to controls.121 And another clinical trial of a probiotic (Lactobacillus paracasei sp. paracasei F19, Lactobacillus acidophilus NCFB 1748, and Bifidobacterium lactis Bb12) in
CFS/ME found a significant improvement in neurocognitive function and a trend toward improvement in general symptoms and quality of life in some individuals.122
The development of CFS/ME is frequently reported to occur after infectious-like illness characterized by symptoms such as myalgia, fever, adenopathy, and respiratory issues, and/or gastrointestinal disturbances. Several viruses and some bacteria have been implicated, although the evidence for a specific infectious cause of CFS/ME is mixed. Immune dysfunction has also been reported; in particular, impaired T- and B-cell memory and altered natural killer (NK) cell activity may decrease resistance to viral pathogens. It is likely that an interplay between decreased immunological resistance and chronic viral infection plays a role in maintaining CFS/ME symptoms.123
Many of the pathogens linked to CFS/ME are able to produce a persistent, often lifelong, infection and, therefore, may be a cause of continued immunological involvement. Several have also been shown to be neuropathogens directly or indirectly affecting the central nervous system, which may in part explain the pathological features and clinical symptoms of CFS/ME.124 Further, experimental evidence suggests that viral infection may be exacerbated by chronic stress.125
A number of immunological therapies have been explored, with mixed evidence of benefit. For example, intravenous immunoglobulin therapy was found to be ineffective, while α-interferon treatment improved quality of life only in individuals with low NK cell function.126,127 In contrast, long-term treatment with the antiviral drug valacyclovir led to decreased serum antibodies to Epstein-Barr virus (EBV) and a significant clinical improvement in a subgroup of individuals with CFS/ME with persistent EBV infection.128
Immunonutrition and Herbal Medicine
Nutritional interventions—for example, vitamin C, zinc, and essential fatty acids—have been proposed to play a role in CFS/ME management due to their potential to improve immunological function and/or act as antiviral agents; however, human clinical investigations are lacking.56 Of particular note, low PUFAs and zinc status have been observed in individuals with CFS/ME and correlated with decreased immune function.129,130 Both zinc and PUFAs have well documented immunomodulatory activity.131,132
An exploratory study of the herbal medicines Echinacea and Panax ginseng found that they were able to stimulate cellular immune function in the isolated serum of participants with CFS/ME.133 Considering the well-established immune modulating and antiviral effects of Echinacea, investigation in CFS/ME sufferers with evidence of chronic viral infection appears warranted.134
INFLAMMATION AND OXIDATIVE STRESS
Inflammation and oxidative stress have been proposed as fundamental pathological features of CFS/ME, and several independent investigations have found evidence of distinct elevations in chronic, low-grade inflammation and oxidative stress in CFS/ME sufferers compared to healthy controls.135-137
For example, one study found significantly increased levels of C-reactive protein (CRP) and 8-iso-prostaglandin F2α isoprostanes in participants with CFS/ME versus healthy participants.138 In another investigation, peroxide concentrations were significantly higher in participants with CFS/ME and distinctly differentiated participants with CFS/ME from healthy controls.139 And some evidence suggests that elevations in oxidative stress correlate directly with symptom severity.140
The elevation in inflammation and oxidative stress underlying CFS/ME has been proposed to place individuals at risk for other chronic diseases associated with these pathological sequelae; in particular, heart disease may be a risk.141 Cardiovascular risk factors are higher in CFS/ME sufferers, and a lower life expectancy has been reported in individuals with CFS/ME, with heart failure a major cause of mortality.142,143
Antioxidant and Anti-inflammatory Nutrition
Because oxidative stress may play an important role in disease pathogenesis and can be reduced by dietary change and nutritional supplementation, such interventions have been proposed for the management of CFS/ME but so far are not well-investigated.144 Additionally the interpretation of nutritional antioxidant interventions is limited by the fact that an antioxidative function is typically only one of many diverse and unique biological effects of various nutritional substances. Nonetheless some experimental evidence in models of CFS/ME has indicated that certain natural antioxidants may result in reductions in oxidative stress that correlate with symptom improvement.145 For example, both green tea extract and curcumin have been shown to reduce oxidative stress and fatigue.146,147
The dietary supplement coenzyme Q10 (CoQ10) is an essential cofactor in mitochondrial energy metabolism and a strong antioxidant with indications of potential benefit in CFS/ME. CoQ10 is produced endogenously; however, a number of studies have indicated a functional deficiency of CoQ10 in individuals with CFS/ME and FM that may be related to clinical symptoms, increased oxidative stress, and compromised mitochondrial energy metabolism.148-151 Although CoQ10 supplementation has not yet been studied in CFS/ME, a number of clinical reports concerning individuals with FM have suggested CoQ10 treatment can improve symptoms, such as muscle pain, sleep, alertness, headache, and fatigue while decreasing oxidative stress and increasing the formation of new mitochondria (mitochondrial biogenesis).152-154
Inflammation can also be mitigated by nutrition. For example, the traditional Mediterranean dietary pattern has been shown to reduce chronic, low-grade inflammation and may hypothetically be of benefit in CFS/ME.155 A number of dietary supplements have demonstrated anti-inflammatory effects in human clinical studies, including PUFAs and magnesium, which, as previously discussed, may have particular relevance to CFS/ME sufferers.156,157
A number of independent investigators have suggested that mitochondrial dysfunction may be central to the pathology of CFS/ME.158-161 Using a test that measures the availability of ATP and the efficiency of oxidative phosphorylation in mitochondria, it was found that all tested individuals with CFS/ME had evidence of mitochondrial dysfunction, as compared to controls, and this dysfunction was correlated with the severity of the illness.162 This finding is supported by other studies indicating the involvement of mitochondrial dysfunction.163-166
Evidence of CoQ10 deficiency in CFS/ME provides further support for mitochondrial involvement, as CoQ10 status has been proposed as a measure of mitochondrial function.167 CoQ10 deficiency has been shown to decrease expression of proteins involved in mitochondrial energy metabolism, reduce mitochondrial membrane potential, increase production of reactive oxygen species, and result in the degradation of dysfunctional CoQ10-deficient mitochondria.168
Mitochondrial nutrients have been defined as nutritional compounds that (1) enter the cells and mitochondria following exogenous administration, (2) protect the mitochondria from oxidative damage, and (3) improve mitochondrial function.169 A number of important effects have been ascribed to various mitochondrial nutrients, including the ability to reduce oxidative stress, enhance energy metabolism, and increase mitochondrial biogenesis.170
The clinical effects of a number of nutrients discussed above may be due in part to improvements in mitochondrial function. For example, high doses of B vitamins can stimulate defective coenzymes; magnesium is a cofactor in ATP metabolism; and acetyl-L-carnitine is responsible for the transport of acetyl-CoA into the mitochondria during fatty acid oxidation.184-186 An open-label study with D-ribose, a structural component of intermediate metabolites required for mitochondrial energy metabolism, found significant improvements in energy, well-being, sleep, and mental clarity and decreased pain in a group of participants with CFS/ME and FM after 3 weeks.187 And investigation of a nutritional formulation designed to support mitochondrial function—containing vitamins, minerals, amino acids, plant extracts, phospholipids, and fatty acids—reported a 43% reduction in fatigue in individuals with CFS/ME and FM after 8 weeks of treatment.188
Preliminary findings from a clinical audit of CFS/ME individuals who showed evidence of mitochondrial dysfunction and who had received an integrative treatment plan, suggested that this approach may result in important improvements in clinical symptoms and mitochondrial function.189 This plan frequently included the mitochondrial nutrients D-ribose, magnesium, acetyl-L-carnitine, and CoQ10.
The possible causes, disordered physiology, and clinical presentations of CFS/ME vary between individuals. For example not all individuals may have vitamin D deficiency, low diurnal cortisol, or active EBV infection. An integrative management approach could help identify an individual’s unique state of dysfunction and personalize treatment. Clinical assessment might therefore use investigative methods that help delineate functional status (ie, functional pathology); see Table 1.
The assessment of the unique functional status of an individual may help identify treatments that are more likely to elicit a clinical response. Personalization of treatments may be particularly relevant to nutritional interventions where background nutritional status may influence therapeutic effect. This comprehensive approach could be very useful in the clinical practice to get symptom relief for one unique individual at a time.
Relevant to future CFS/ME research, this approach is evidently different from clinical trials that evaluate single interventions across broad groups of participants. Methodology would need to be developed that takes into account subgroups of participants, individualized assessments, and tailored treatment plans.
Finally, an integrative management model may increase the cost and commitment to treatment; however, it is likely to produce better outcomes by addressing the fundamental pathological features as well as environmental, lifestyle, and behavioral factors that contribute to the maintenance of the disease.
Currently accepted treatments for CFS/ME have modest clinical benefits and for most patients the disease prognosis remains poor. Because CFS/ME is a heterogeneous disorder with diverse etiological factors and pathological features, a patient-centered integrative framework based on modifiable physiological and environmental factors may offer hope for more effective management and better clinical outcomes. An individualized approach to patient management may also help identify patient subgroups that are more likely to respond favorably to specific treatments. A personalized, integrative approach to CFS/ME deserves further consideration as a template for patient management and future research.
The author received no grants or other financial support for this review.
- Jason LA, Evans M, Brown M, Porter N. What is fatigue? Pathological and nonpathological fatigue. PM R. 2010;2(5):327-331.
- Cairns R, Hotopf M. A systematic review describing the prognosis of chronic fatigue syndrome. Occup Med (Lond). 2005;55(1):20-31.
- Nijs J, Meeus M, Van Oosterwijck J, et al. In the mind or in the brain? Scientific evidence for central sensitisation in chronic fatigue syndrome. Eur J Clin Invest. 2012;42(2):203-212.
- Holgate ST, Komaroff AL, Mangan D, Wessely S. Chronic fatigue syndrome: understanding a complex illness. Nat Rev Neurosci. 2011;12(9):539-544.
- Ulvestad E. Chronic fatigue syndrome defies the mind-body-schism of medicine: new perspectives on a multiple realisable developmental systems disorder. Med Health Care Philos. 2008;11(3):285-292
- Kotsirilos V, Vitetta L, Sali A. A Guide to Evidence-based Integrative and Complementary Medicine. Chatswood, Australia: Churchill Livingstone; 2011.
- Harvey SB, Wessely S. Chronic fatigue syndrome: identifying zebras amongst the horses. BMC Med. Oct 2009;7:58.
- CFS case definition. Centers for Disease Control and Prevention Web site. http://www.cdc.gov/cfs/case-definition/index.html. Revised May 14, 2012. Accessed January 9, 2013.
- Avellaneda Fernández A, Pérez Martín A, Izquierdo Martinez M, et al. Chronic fatigue syndrome: aetiology, diagnosis and treatment. BMC Psychiatry. 2009;9(suppl 1):S1.
- Chronic Fatigue Syndrome/Myalgic Encephalomylitis (or Encephalopathy): Diagnosis and Management of CFS/ME in Adults and Children. London, UK: National Institute for Health and Clinical Excellence; 2007.
- Jones JF, Lin JM, Maloney EM, et al. An evaluation of exclusionary medical/psychiatric conditions in the definition of chronic fatigue syndrome. BMC Med. Oct 2009;7:57.
- Craig T, Kakumanu S. Chronic fatigue syndrome: evaluation and treatment. Am Fam Physician. 2002;65(6):1083-1090.
- Jason LA, Corradi K, Torres-Harding S, Taylor RR, King C. Chronic fatigue syndrome: the need for subtypes. Neuropsychol Rev. 2005;15(1):29-58.
- Clauw DJ. Perspectives on fatigue from the study of chronic fatigue syndrome and related conditions. PM R. 2010;2(5):414-430.
- Buchwald D, Garrity D. Comparison of patients with chronic fatigue syndrome, fibromyalgia, and multiple chemical sensitivities. Arch Intern Med. 1994;154(18):2049-2053.
- Jason LA, Taylor RR, Kennedy CL. Chronic fatigue syndrome, fibromyalgia, and multiple chemical sensitivities in a community-based sample of persons with chronic fatigue syndrome-like symptoms. Psychosom Med. 2000;62(5):655-663.
- Aaron LA, Burke MM, Buchwald D. Overlapping conditions among patients with chronic fatigue syndrome, fibromyalgia, and temporomandibular disorder. Arch Intern Med. 2000;160(2):221-227.
- Yancey JR, Thomas SM. Chronic fatigue syndrome: diagnosis and treatment. Am Fam Physician. 2012;86(8):741-746.
- Luyten P, Van Houdenhove B, Pae CU, Kempke S, Van Wambeke P. Treatment of chronic fatigue syndrome: findings, principles and strategies. Psychiatry Investig. 2008;5(4):209-212.
- Núñez M, Fernández-Solà J, Nuñez E, Fernandez-Huerta JM, Godas-Sieso T, Gomez-Gil E. Health-related quality of life in patients with chronic fatigue syndrome: group cognitive behavioral therapy and graded exercise versus usual treatment: a randomized controlled trial with 1 year of follow-up. Clin Rheumatol. 2011;30(3):381-389.
- Ross SD, Estok RP, Frame D, Stone LR, Ludensky V, Levine CB. Disability and chronic fatigue syndrome: a focus on function. Arch Intern Med. 2004;164(10):1098-1107.
- Goedendorp MM, Knoop H, Schippers GM, Bleijenberg G. The lifestyle of patients with chronic fatigue syndrome and the effect on fatigue and functional impairments. J Hum Nutr Diet. 2009;22(3):226-231.
- Galland L. Diet and inflammation. Nutr Clin Pract. 2010;25(6):634-640.
- Bulló M, Lamuela-Raventós R, Salas-Salvadó J. Mediterranean diet and oxidation: nuts and olive oil as important sources of fat and antioxidants. Curr Top Med Chem. 2011;11(14):1797-1810.
- McMillan L, Owen L, Kras M, Scholey A. Behavioral effects of a 10-day Mediterranean diet: results from a pilot study evaluating mood and cognitive performance. Appetite. 2011;56(1):143-147.
- Jacka FN, Pasco JA, Mykletun A, et al. Association of Western and traditional diets with depression and anxiety in women. Am J Psychiatry. 2010;167(3):305-311.
- Fernández JM, Rosado-Álvarez D, Da Silva Grigoletto ME, et al. Moderate-to-high-intensity training and a hypocaloric Mediterranean diet enhance endothelial progenitor cells and fitness in subjects with the metabolic syndrome. Clin Sci (Lond). 2012;123(6):361-373.
- Sathyapalan T, Beckett S, Rigby AS, Mellor DD, Atkin SL. High cocoa polyphenol rich chocolate may reduce the burden of the symptoms in chronic fatigue syndrome. Nutr J. Nov 2010;9:55.
- Ortega R. Importance of functional foods in the Mediterranean diet. Public Health Nutr. 2006;9(8A):1136-1140.
- Logan AC, Wong C. Chronic fatigue syndrome: oxidative stress and dietary modifications. Altern Med Rev. 2001;6(5):450-459.
- Siniscalchi M, Iovino P, Tortora R, et al. Fatigue in adult coeliac disease. Aliment Pharmacol Ther. 2005;22(5):489-494.
- Bland JS, Levin B, Costarella L, et al, eds. Clinical Nutrition: A Functional Approach. 2nd ed. Federal Way, WA: Institute for Functional Medicine; 2004.
- Blumberg J, Heaney RP, Huncharek M, et al. Evidence-based criteria in the nutritional context. Nutr Rev. 2010;68(8):478-484.
- Berkovitz S, Ambler G, Jenkins M, Thurgood S. Serum 25-hydroxy vitamin D levels in chronic fatigue syndrome: a retrospective survey. Int J Vitam Nutr Res. 2009;79(4):250-254.
- Hoeck AD, Pall ML. Will vitamin D supplementation ameliorate diseases characterized by chronic inflammation and fatigue? Med Hypotheses. 2011;76(2):208-213.
- Höck AD. Divalent cations, hormones, psyche and soma. J Chronic Fatigue Syndr. 2000;6(3-4):117-131.
- Shinchuk LM, Holick MF. Vitamin D and rehabilitation: improving functional outcomes. Nutr Clin Pract. 2007;22(3):297-304.
- Plotnikoff GA, Quigley JM. Prevalence of severe hypovitaminosis D in patients with persistent, nonspecific musculoskeletal pain. Mayo Clin Proc. 2003;78(12):1463–1470.
- Knutsen KV, Brekke M, Gjelstad S, Lagerlov P. Vitamin D status in patients with musculoskeletal pain, fatigue and headache: a cross-sectional descriptive study in a multi-ethnic general practice in Norway. Scand J Prim Health Care. 2010;28(3):166-171.
- Holick MF. Vitamin D deficiency: what a pain it is. Mayo Clin Proc. 2003;78(12):1457-1459.
- Puri BK. Long-chain polyunsaturated fatty acids and the pathophysiology of myalgic encephalomyelitis (chronic fatigue syndrome). J Clin Pathol. 2007;60(2):122-124.
- Behan PO, Behan WM, Horrobin D. Effect of high doses of essential fatty acids on the postviral fatigue syndrome. Acta Neurol Scand. 1990;82(3):209–216.
- Warren G, McKendrick M, Peet M. The role of essential fatty acids in chronic fatigue syndrome: a case-controlled study of red-cell membrane essential fatty acids (EFA) and a placebo-controlled treatment study with high dose of EFA. Acta Neurol Scand. 1999;99(2):112-116.
- Puri BK. The use of eicosapentaenoic acid in the treatment of chronic fatigue syndrome. Prostaglandins Leukot Essent Fatty Acids. 2004;70(4):399-401.
- Puri BK, Holmes J, Hamilton G. Eicosapentaenoic acid-rich essential fatty acid supplementation in chronic fatigue syndrome associated with symptom remission and structural brain changes. Int J Clin Pract. 2004;58(3):297-299.
- Heap LC, Peters TJ, Wessely S. Vitamin B status in patients with chronic fatigue syndrome. J R Soc Med. 1999;92(4):183-185.
- Jacobson W, Saich T, Borysiewicz LK, Behan WM, Behan PO, Wreghitt TG. Serum folate and chronic fatigue syndrome. Neurology. 1993;43(12):2645-2647.
- Regland B, Andersson M, Abrahamsson L, Bagby J, Dyrehag LE, Gottfries CG. Increased concentrations of homocysteine in the cerebrospinal fluid in patients with fibromyalgia and chronic fatigue syndrome. Scand J Rheumatol. 1997;26(4):301-307.
- Forsyth LM, Preuss HG, MacDowell AL, Chiazze L Jr, Birkmayer GD, Bellanti JA. Therapeutic effects of oral NADH on the symptoms of patients with chronic fatigue syndrome. Ann Allergy Asthma Immunol. 1999;82(2):185-191.
- Santaella ML, Font I, Disdier OM. Comparison of oral nicotinamide adenine dinucleotide (NADH) versus conventional therapy for chronic fatigue syndrome. P R Health Sci J. 2004;23(2):89-93.
- Le Gal M, Cathebras P, Struby K. Pharmaton capsules in the treatment of functional fatigue: a double-blind study versus placebo evaluated by a new methodology. Phytother Res. 1996;10(1):49-53.
- Kaslow JE, Rucker L, Onishi R. Liver extract-folic acid-cyanocobalamin vs placebo for chronic fatigue syndrome. Arch Intern Med. 1989;149(11):2501-2503.
- Martin RWY, Ogston SA, Evans JR. Effects of vitamin and mineral supplementation on symptoms associated with chronic fatigue syndrome with Coxsackie B antibodies. J Nutr Environ Med. 1994;4(1):11-23.
- Seelig M. Review and hypothesis: might patients with the Chronic Fatigue Syndrome have latent tetany of magnesium deficiency. J Chronic Fatigue Syndr. 1998;4(2):77-108.
- Werbach MR. Nutritional strategies for treating chronic fatigue syndrome. Altern Med Rev. 2000;5(2):93-108.
- Manuel y Keenoy B, Moorkens G, Vertommen J, Noe M, Neve J, De Leeuw I. Magnesium status and parameters of the oxidant-antioxidant balance in patients with chronic fatigue: effects of supplementation with magnesium. J Am Coll Nutr. 2000;19(3):374-382.
- Cox IM, Campbell MJ, Dowson D. Red blood cell magnesium and chronic fatigue syndrome. Lancet. 1991;337(8744):757-760.
- Takahashi H, Imai K, Katanuma A, et al. A case of chronic fatigue syndrome who showed a beneficial effect by intravenous administration of magnesium sulphate [in Japanese]. Arerugi. 1992;41(11):1605-1610.
- Bralley JA, Lord RS. Treatment of chronic fatigue syndrome with specific amino acid supplementation. J Appl Nutr. 1994;46(3):74-78.
- Reuter SE, Evans AM. Long-chain acylcarnitine deficiency in patients with chronic fatigue syndrome: potential involvement of altered carnitine palmitoyltransferase-I activity. J Intern Med. 2011;270(1):76-84.
- Plioplys AV, Plioplys S. Amantadine and L-carnitine treatment of Chronic Fatigue Syndrome. Neuropsychobiology. 1997;35(1):16-23.
- Vermeulen RC, Scholte HR. Exploratory open label, randomized study of acetyl- and propionylcarnitine in chronic fatigue syndrome. Psychosom Med. 2004;66(2):276-282.
- Maes M, Mihaylova I, De Ruyter M. Lower serum zinc in Chronic Fatigue Syndrome (CFS): relationships to immune dysfunctions and relevance for the oxidative stress status in CFS. J Affect Disord. 2006;90(2-3):141-147.
- Kilic M. Effect of fatiguing bicycle exercise on thyroid hormone and testosterone levels in sedentary males supplemented with oral zinc. Neuro Endocrinol Lett. 2007;28(5):681-685.
- Mariani E, Neri S, Cattini L, et al. Effect of zinc supplementation on plasma IL-6 and MCP-1 production and NK cell function in healthy elderly: interactive influence of +647 MT1a and -174 IL-6 polymorphic alleles. Exp Gerontol. 2008;43(5):462-471.
- Siwek M, Dudek D, Paul IA, et al. Zinc supplementation augments efficacy of imipramine in treatment resistant patients: a double blind, placebo-controlled study. J Affect Disord. 2009;118(1-3):187-195.
- Bao B, Prasad AS, Beck FW, et al. Zinc decreases C-reactive protein, lipid peroxidation, and inflammatory cytokines in elderly subjects: a potential implication of zinc as an atheroprotective agent. Am J Clin Nutr. 2010;91(6):1634-1641.
- Clapp LL, Richardson MT, Smith JF, Wang M, Clapp AJ, Pieroni RE. Acute effects of thirty minutes of light-intensity, intermittent exercise on patients with chronic fatigue syndrome. Phys Ther. 1999;79(8):749-756.
- Black CD, O’Conner PJ, McCully KK. Increased daily physical activity and fatigue symptoms in chronic fatigue syndrome. Dyn Med. 2005;4(1):3.
- Nijs J, Aelbrecht S, Meeus M, Van Oosterwijck J, Zinzen E, Clarys P. Tired of being inactive: a systematic literature review of physical activity, physiological exercise capacity and muscle strength in patients with chronic fatigue syndrome. Disabil Rehabil. 2011;33(17-18):1493-1500.
- Jammes Y, Steinberg JG, Mambrini O, Bregeon F, Delliaux S. Chronic fatigue syndrome: assessment of increased oxidative stress and altered muscle excitability in response to incremental exercise. J Intern Med. 2005;257(3):299-310.
- White PD, Nye KE, Pinching AJ, et al. Immunological changes after both exercise and activity in chronic fatigue syndrome: a pilot study. J Chronic Fatigue Syndr. 2004;12(2):51–66.
- Edmonds M, McGuire H, Price J. Exercise therapy for chronic fatigue syndrome. Cochrane Database Syst Rev. 2004;(3):CD003200.
- Van Cauwenbergh D, De Kooning M, Ickmans K, Nijs J. How to exercise people with chronic fatigue syndrome: evidence-based practice guidelines. Eur J Clin Invest. 2012;42(10):1136-1144.
- Twisk FN, Maes M. A review on cognitive behavioral therapy (CBT) and graded exercise therapy (GET) in myalgic encephalomyelitis (ME) / chronic fatigue syndrome (CFS): CBT/GET is not only ineffective and not evidence-based, but also potentially harmful for many patients with ME/CFS. Neuro Endocrinol Lett. 2009;30(3):284-299.
- Kindlon T, Goudsmit EM. Graded exercise for chronic fatigue syndrome: too soon to dismiss reports of adverse reactions. J Rehabil Med. 2010;42(2):184.
- Nijs J, Paul L, Wallman K. Chronic fatigue syndrome: an approach combining self-management with graded exercise to avoid exacerbations. J Rehabil Med. 2008;40(4):241-247.
- Van Den Eede F, Moorkens G, Van Houdenhove B, Cosyns P, Claes SJ. Hypothalamic-pituitary-adrenal axis function in chronic fatigue syndrome. Neuropsychobiology. 2007;55(2):112-120.
- Papadopoulos AS, Cleare AJ. Hypothalamic-pituitary-adrenal axis dysfunction in chronic fatigue syndrome. Nat Rev Endocrinol. 2011;8(1):22-32.
- Heim C, Nater UM, Maloney E, Boneva R, Jones JF, Reeves WC. Childhood trauma and risk for chronic fatigue syndrome: association with neuroendocrine dysfunction. Arch Gen Psychiatry. 2009;66(1):72-80.
- Cleare AJ. The HPA axis and the genesis of chronic fatigue syndrome. Trends Endocrinol Metab. 2004;15(2):55-59.
- Price JR, Mitchell E, Tidy E, Hunot V. Cognitive behavior therapy for chronic fatigue syndrome in adults. Cochrane Database Syst Rev. July 2008;(3):CD001027.
- Roberts AD, Papadopoulos AS, Wessely S, Chalder T, Cleare AJ. Salivary cortisol output before and after cognitive behavioral therapy for chronic fatigue syndrome. J Affect Disord. 2009;115(1-2):280-286.
- White PD, Sharpe MC, Chalder T, DeCesare JC, Walwyn R; PACE trial group. Protocol for the PACE trial: a randomized controlled trial of adaptive pacing, cognitive behavior therapy, and graded exercise, as supplements to standardised specialist medical care versus standardised specialist medical care alone for patients with the chronic fatigue syndrome/myalgic encephalomyelitis or encephalopathy. BMC Neurol. March 2007;7:6.
- Porter NS, Jason LA, Boulton A, Bothne N, Coleman B. Alternative medical interventions used in the treatment and management of myalgic encephalomyelitis/chronic fatigue syndrome and fibromyalgia. J Altern Complement Med. 2010;16(3):235-249.
- Ho RT, Chan JS, Wang CW, et al. A randomized controlled trial of qigong exercise on fatigue symptoms, functioning, and telomerase activity in persons with chronic fatigue or chronic fatigue syndrome. Ann Behav Med. 2012;44(2):160-170.
- Reid SF, Chalder T, Cleare A, Hotopf M, Wessely S. Chronic fatigue syndrome. Clin Evid (Online). Aug 2008;2008. pii:1101.
- Cleare AJ, Heap E, Malhi GS, Wessely S, O’Keane V, Miell J. Low-dose hydrocortisone in chronic fatigue syndrome: a randomized crossover trial. Lancet. 1999;353(9151):455-458.
- McKenzie R, O’Fallon A, Dale J, et al. Low-dose hydrocortisone for treatment of chronic fatigue syndrome: a randomized controlled trial. JAMA. 1998;280(12):1061-1066.
- Panossian A, Wikman G. Evidence-based efficacy of adaptogens in fatigue, and molecular mechanisms related to their stress-protective activity. Curr Clin Pharmacol. 2009;4(3):198-219.
- Baschetti R. Chronic fatigue syndrome and licorice [letter]. N Z Med J. 1995;108:156-157.
- Methlie P, Husebye EE, Hustad S, Lien EA, Lovas K. Grapefruit juice and licorice increase cortisol availability in patients with Addison’s disease. Eur J Endocrinol. 2011;165(5):761-769. doi:10.1530/EJE-11-0518.
- Panossian A, Wikman G, Sarris J. Rosenroot (Rhodiola rosea): traditional use, chemical composition, pharmacology and clinical efficacy. Phytomedicine. 2010;17(7):481-493.
- Olsson EM, von Schéele B, Panossian AG. A randomized, double-blind, placebo-controlled, parallel-group study of the standardised extract shr-5 of the roots of Rhodiola rosea in the treatment of subjects with stress-related fatigue. Planta Med. 2009;75(2):105-112.
- Hartz AJ, Bentler S, Noyes R, et al. Randomized controlled trial of Siberian ginseng for chronic fatigue. Psychol Med. 2004;34(1):51-61.
- Nacul LC, Lacerda EM, Sakellariou D. Is there an association between exposure to chemicals and chronic fatigue syndrome? Review of the evidence. Bull IACFS ME. 2009;17(1):3-15.
- Pacini S, Fiore MG, Magherini S, et al. Could cadmium be responsible for some of the neurological signs and symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Med Hypotheses. 2012;79(3):403-407.
- Jay SJ. Tobacco use and chronic fatigue syndrome, fibromyalgia, and temporomandibular disorder. Arch Intern Med. 2000;160(15):2398, 2401.
- Dunstan RH, Donohoe M, Taylor W, et al. A preliminary investigation of chlorinated hydrocarbons and chronic fatigue syndrome. Med J Aust. 1995;163(6):294-297.
- Racciatti D, Vecchiet J, Ceccomancini A, Ricci F, Pizzigalo E. Chronic fatigue syndrome following a toxic exposure. Sci Total Environ. 2001;270(1-3):27-31.
- Sears ME, Genuis SJ. Environmental determinants of chronic disease and medical approaches: recognition, avoidance, supportive therapy, and detoxification. J Environ Public Health. 2012;2012:356798. doi:10.1155/2012/356798.
- Bland JS, Bralley JA. Nutritional upregulation of hepatic detoxification enzymes. J Appl Nutr. 1992;44:2-15.
- Bland JS, Barrager E, Reedy RG, Bland K. A medical food-supplemented detoxification program in the management of chronic health problems. Altern Ther Health Med. 1995;1(5):62-71.
- MacIntosh A, Ball K. The effects of a short program of detoxification in disease-free individuals. Altern Ther Health Med. 2000;6(4);70-76.
- Lamb JJ, Konda VR, Quig DW, et al. A program consisting of a phytonutrient-rich medical food and an elimination diet ameliorated fibromyalgia symptoms and promoted toxic-element detoxification in a pilot trial. Altern Ther Health Med. 2011;17(2):36-44.
- Richardson J. Four cases of pesticide poisoning, presenting as “ME,” treated with choline and ascorbic acid mixture. J Chronic Fatigue Syndr. 2000;6(2):11-21.
- Wojcik DP, Godfrey ME, Christie D, Haley BE. Mercury toxicity presenting as chronic fatigue, memory impairment and depression: diagnosis, treatment, susceptibility, and outcomes in a New Zealand general practice setting (1994-2006). Neuro Endocrinol Lett. 2006;27(4):415-423.
- Masuda A, Kihara T, Fukudome T, Shinsato T, Minagoe S, Tei C. The effects of repeated thermal therapy for two patients with chronic fatigue syndrome. J Psychosom Res. 2005;58(4):383-387.
- Crinnion WJ. Sauna as a valuable clinical tool for cardiovascular, autoimmune, toxicant- induced and other chronic health problems. Altern Med Rev. 2011;16(3):215-225.
- Sperber AD, Dekel R. Irritable bowel syndrome and co-morbid gastrointestinal and extra-gastrointestinal functional syndromes. J Neurogastroenterol Motil. 2010;16(2):113-119.
- Lakhan SE, Kirchgessner A. Gut inflammation in chronic fatigue syndrome. Nutr Metab (Lond). Oct 2010;7:79.
- Evengård B, Gräns H, Wahlund E, et al. Increased number of Candida albicans in the faecal microflora of chronic fatigue syndrome patients during the acute phase of illness. Scand J Gastroenterol. 2007;42(12):1514-1515.
- Maes M, Twisk FN, Kubera M, Ringel K, Leunis JC, Geffard M. Increased IgA responses to the LPS of commensal bacteria is associated with inflammation and activation of cell-mediated immunity in chronic fatigue syndrome. J Affect Disord. 2012;136(3):909-917.
- Logan AC, Venket Rao A, Irani D. Chronic fatigue syndrome: lactic acid bacteria may be of therapeutic value. Med Hypotheses. 2003;60(6):915-923.
- Sheedy JR, Wettenhall RE, Scanlon D, et al. Increased d-lactic acid intestinal bacteria in patients with chronic fatigue syndrome. In Vivo. 2009;23(4):621-628.
- Maes M, Mihaylova I, Leunis JC. Increased serum IgA and IgM against LPS of enterobacteria in chronic fatigue syndrome (CFS): indication for the involvement of gram-negative enterobacteria in the etiology of CFS and for the presence of an increased gut-intestinal permeability. J Affect Disord. 2007;99(1-3):237-240.
- Pendyala S, Walker JM, Holt PR. A high-fat diet is associated with endotoxemia that originates from the gut. Gastroenterology. 2012;142(5):1100-1101.e2.
- Maes M, Leunis JC. Normalization of leaky gut in chronic fatigue syndrome (CFS) is accompanied by a clinical improvement: effects of age, duration of illness and the translocation of LPS from gram-negative bacteria. Neuro Endocrinol Lett. 2008;29(6):902-910.
- Singh PK, Chopra K, Kuhad A, Kaur IP. Role of Lactobacillus acidophilus loaded floating beads in chronic fatigue syndrome: behavioral and biochemical evidences. Neurogastroenterol Motil. 2012;24(4):366-e170.
- Messaoudi M, Lalonde R, Violle N, et al. Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects. Br J Nutr. 2011;105(5):755-764.
- Rao AV, Bested AC, Beaulne TM, et al. A randomized, double-blind, placebo-controlled pilot study of a probiotic in emotional symptoms of chronic fatigue syndrome. Gut Pathog. 2009;1(1):6. doi:10.1186/1757-4749-1-6.
- Sullivan A, Nord CE, Evengård B. Effect of supplement with lactic-acid producing bacteria on fatigue and physical activity in patients with chronic fatigue syndrome. Nutr J. Jan 2009;8:4. doi:10.1186/1475-2891-8-4.
- Bansal AS, Bradley AS, Bishop KN, Kiani-Alikhan S, Ford B. Chronic fatigue syndrome, the immune system and viral infection. Brain Behav Immun. 2012;26(1):24-31.
- Komaroff AL, Cho TA. Role of infection and neurologic dysfunction in chronic fatigue syndrome. Semin Neurol. 2011;31(3):325-337.
- Glaser R, Padgett DA, Litsky ML, et al. Stress-associated changes in the steady-state expression of latent Epstein-Barr virus: implications for chronic fatigue syndrome and cancer. Brain Behav Immun. 2005;19(2):91-103.
- Vollmer-Conna U, Hickie I, Hadzi-Pavlovic D, et al. Intravenous immunoglobulin is ineffective in the treatment of patients with chronic fatigue syndrome. Am J Med. 1997;103(1):38-43.
- See DM, Tilles JG. alpha-Interferon treatment of patients with chronic fatigue syndrome. Immunol Invest. 1996;25(1-2):153-164.
- Lerner AM, Beqaj SH, Deeter RG, Fitzgerald JT. Valacyclovir treatment in Epstein-Barr virus subset chronic fatigue syndrome: thirty-six months follow-up. In Vivo. 2007;21(5):707-713.
- Maes M, Mihaylova I, De Ruyter M. Lower serum zinc in Chronic Fatigue Syndrome (CFS): relationships to immune dysfunctions and relevance for the oxidative stress status in CFS. J Affect Disord. 2006;90(2-3):141-147.
- Maes M, Mihaylova I, Leunis JC. In chronic fatigue syndrome, the decreased levels of omega-3 poly-unsaturated fatty acids are related to lowered serum zinc and defects in T cell activation. Neuro Endocrinol Lett. 2005;26(6):745-751.
- Prasad AS. Zinc: role in immunity, oxidative stress and chronic inflammation. Curr Opin Clin Nutr Metab Care. 2009;12(6):646-652.
- Sijben JW, Calder PC. Differential immunomodulation with long-chain n-3 PUFA in health and chronic disease. Proc Nutr Soc. 2007;66(2):237-259.
- See DM, Broumand N, Sahl L, Tilles JG. In vitro effects of echinacea and ginseng on natural killer and antibody-dependent cell cytotoxicity in healthy subjects and chronic fatigue syndrome or acquired immunodeficiency syndrome patients. Immunopharmacology. 1997;35(3):229-235.
- Hudson JB. Applications of the phytomedicine Echinacea purpurea (Purple Coneflower) in infectious diseases. J Biomed Biotechnol. 2012;2012:769896. doi:10.1155/2012/769896.
- Pall ML, Satterlee JD. Elevated nitric oxide/peroxynitrite mechanism for the common etiology of multiple chemical sensitivity, chronic fatigue syndrome, and posttraumatic stress disorder. Ann N Y Acad Sci. March 2001;933:323-329.
- Maes M. Inflammatory and oxidative and nitrosative stress pathways underpinning chronic fatigue, somatization and psychosomatic symptoms. Curr Opin Psychiatry. 2009;22(1):75-83.
- Klimas NG, Broderick G, Fletcher MA. Biomarkers for chronic fatigue. Brain Behav Immun. 2012;26(8):1202-1210.
- Spence VA, Kennedy G, Belch JJ, Hill A, Khan F. Low-grade inflammation and arterial wave reflection in patients with chronic fatigue syndrome. Clin Sci (Lond). 2008;114(8):561-566.
- Maes M, Kubera M, Uytterhoeven M, Vrydags N, Bosmans E. Increased plasma peroxides as a marker of oxidative stress in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Med Sci Monit. 2011;17(4):SC11-SC15.
- Kennedy G, Spence VA, McLaren M, Hill A, Underwood C, Belch JJ. Oxidative stress levels are raised in chronic fatigue syndrome and are associated with clinical symptoms. Free Radic Biol Med. 2005;39(5):584-589.
- Maes M, Twisk FN. Why myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may kill you: disorders in the inflammatory and oxidative and nitrosative stress (IO&NS) pathways may explain cardiovascular disorders in ME/CFS. Neuro Endocrinol Lett. 2009;30(6):677-693.
- Maloney EM, Boneva RS, Lin JM, Reeves WC. Chronic fatigue syndrome is associated with metabolic syndrome: results from a case-control study in Georgia. Metabolism. 2010;59(9):1351-1357.
- Jason LA, Corradi K, Gress S, Williams S, Torres-Harding S. Causes of death among patients with chronic fatigue syndrome. Health Care Women Int. 2006;27(7):615-626.
- Logan AC, Wong C. Chronic fatigue syndrome: oxidative stress and dietary modifications. Altern Med Rev. 2001;6(5):450-459.
- Singh A, Naidu PS, Gupta S, Kulkarni SK. Effect of natural and synthetic antioxidants in a mouse model of chronic fatigue syndrome. J Med Food. 2002;5(4):211-220.
- Singal A, Kaur S, Tirkey N, Chopra K. Green tea extract and catechin ameliorate chronic fatigue-induced oxidative stress in mice. J Med Food. 2005;8(1):47-52.
- Gupta A, Vij G, Sharma S, Tirkey N, Rishi P, Chopra K. Curcumin, a polyphenolic antioxidant, attenuates chronic fatigue syndrome in murine water immersion stress model. Immunobiology. 2009;214(1):33-39.
- Maes M, Mihaylova I, Kubera M, Uytterhoeven M, Vrydags N, Bosmans E. Coenzyme Q10 deficiency in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is related to fatigue, autonomic and neurocognitive symptoms and is another risk factor explaining the early mortality in ME/CFS due to cardiovascular disorder. Neuro Endocrinol Lett. 2009;30(4):470-476.
- Maes M, Mihaylova I, Kubera M, Uytterhoeven M, Vrydags N, Bosmans E. Lower plasma Coenzyme Q10 in depression: a marker for treatment resistance and chronic fatigue in depression and a risk factor to cardiovascular disorder in that illness. Neuro Endocrinol Lett. 2009;30(4):462-469.
- Cordero MD, Moreno-Fernández AM, deMiguel M, et al. Coenzyme Q10 distribution in blood is altered in patients with fibromyalgia. Clin Biochem. 2009;42(7-8):732-735.
- Cordero MD, De Miguel M, Moreno Fernández AM, et al. Mitochondrial dysfunction and mitophagy activation in blood mononuclear cells of fibromyalgia patients: implications in the pathogenesis of the disease. Arthritis Res Ther. 2010;12(1):R17.
- Cordero MD, Cano-García FJ, Alcocer-Gómez E, De Miguel M, Sanchez-Alcazar JA. Oxidative stress correlates with headache symptoms in fibromyalgia: coenzyme Q10 effect on clinical improvement. PLoS One. 2012;7(4):e35677.
- Cordero MD, Alcocer-Gómez E, de Miguel M, et al. Coenzyme Q(10): a novel therapeutic approach for Fibromyalgia? case series with 5 patients. Mitochondrion. 2011;11(4):623-625.
- Cordero MD, Santos-García R, Bermejo-Jover D, Sanchez-Dominguez B, Jaramillo-Santos MR, Bullon P. Coenzyme Q10 in salivary cells correlate with blood cells in fibromyalgia: improvement in clinical and biochemical parameter after oral treatment. Clin Biochem. 2012;45(6):509-511.
- Galland L. Diet and inflammation. Nutr Clin Pract. 2010;25(6):634-640.
- Calder PC. Omega-3 fatty acids and inflammatory processes. Nutrients. 2010;2(3):355-374.
- Almoznino-Sarafian D, Berman S, Mor A, et al. Magnesium and C-reactive protein in heart failure: an anti-inflammatory effect of magnesium administration? Eur J Nutr. 2007;46(4):230-237.
- Pieczenik SR, Neustadt J. Mitochondrial dysfunction and molecular pathways of disease. Exp Mol Pathol. 2007;83(1):84-92.
- Bains W. Treating Chronic Fatigue states as a disease of the regulation of energy metabolism. Med Hypotheses. 2008;71(4):481-488.
- Myhill S, Booth NE, McLaren-Howard J. Chronic fatigue syndrome and mitochondrial dysfunction. Int J Clin Exp Med. 2009;2(1):1-16.
- Maes M. An intriguing and hitherto unexplained co-occurrence: depression and chronic fatigue syndrome are manifestations of shared inflammatory, oxidative and nitrosative (IO&NS) pathways. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35(3):784-794.
- Booth NE, Myhill S, McLaren-Howard J. Mitochondrial dysfunction and the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Int J Clin Exp Med. 2012;5(3):208-220.
- Behan WM, More IA, Behan PO. Mitochondrial abnormalities in the postviral fatigue syndrome. Acta Neuropathol. 1991;83(1):61-65.
- Lane RJ, Barrett MC, Woodrow D, Moss J, Fletcher R, Archard LC. Muscle fibre characteristics and lactate responses to exercise in chronic fatigue syndrome. J Neurol Neurosurg Psychiatry. 1998;64(3):362-367.
- Vermeulen RC, Kurk RM, Visser FC, Sluiter W, Scholte HR. Patients with chronic fatigue syndrome performed worse than controls in a controlled repeated exercise study despite a normal oxidative phosphorylation capacity. J Transl Med. Oct 2010;8:93.
- Smits B, van den Heuvel L, Knoop H, et al. Mitochondrial enzymes discriminate between mitochondrial disorders and chronic fatigue syndrome. Mitochondrion. 2011;11(5):735-738.
- Mitochondrial Medicine Society’s Committee on Diagnosis; Haas RH, Parikh S, Falk MJ, et al. The in-depth evaluation of suspected mitochondrial disease. Mol Genet Metab. 2008;94(1):16-37.
- Rodríguez-Hernández A, Cordero MD, Salviati L, et al. Coenzyme Q deficiency triggers mitochondria degradation by mitophagy. Autophagy. 2009;5(1):19-32.
- Liu J, Ames BN. Reducing mitochondrial decay with mitochondrial nutrients to delay and treat cognitive dysfunction, Alzheimer’s disease, and Parkinson’s disease. Nutr Neurosci. 2005;8(2):67-89.
- Liu J, Shen W, Zhao B, et al. Targeting mitochondrial biogenesis for preventing and treating insulin resistance in diabetes and obesity: hope from natural mitochondrial nutrients. Adv Drug Deliv Rev. 2009;61(14):1343-1352.
- Fasano A, Catassi C. Clinical practice: celiac disease. N Engl J Med. 2012;367(25):2419-2426.
- Mullin GE, Swift KM, Lipski L, Turnbull LK, Rampertab SD. Testing for food reactions: the good, the bad, and the ugly. Nutr Clin Pract. 2010;25(2):192-198.
- Gozansky WS, Lynn JS, Laudenslager ML, Kohrt WM. Salivary cortisol determined by enzyme immunoassay is preferable to serum total cortisol for assessment of dynamic hypothalamic–pituitary–adrenal axis activity. Clin Endocrinol (Oxf). 2005;63(3):336-341.
- Jerjes WK, Cleare AJ, Wessely S, Wood PJ, Taylor NF. Diurnal patterns of salivary cortisol and cortisone output in chronic fatigue syndrome. J Affect Disord. 2005;87(2-3):299-304.
- Nater UM, Maloney E, Boneva RS, et al. Attenuated morning salivary cortisol concentrations in a population-based study of persons with chronic fatigue syndrome and well controls. J Clin Endocrinol Metab. 2008;93(3):703-709.
- Crinnion WJ. The benefits of pre- and post-challenge urine heavy metal testing, I. Altern Med Rev. 2009;14(1):3-8.
- Crinnion WJ. Polychlorinated biphenyls: persistent pollutants with immunological, neurological, and endocrinological consequences. Altern Med Rev. 2011;16(1):5-13.
- Flores R, Shi J, Gail MH, Gajer P, Ravel J, Goedert JJ. Assessment of the human faecal microbiota, II: reproducibility and associations of 16S rRNA pyrosequences. Eur J Clin Invest. 2012;42(8):855-863.
- Bures J, Cyrany J, Kohoutova D, et al. Small intestinal bacterial overgrowth syndrome. World J Gastroenterol. 2010;16(24):2978-2990.
- Vojdani A. For the assessment of intestinal permeability, size matters. Altern Ther Health Med. 2013;19(1):12-24.
- Basu S. F2-isoprostanes in human health and diseases: from molecular mechanisms to clinical implications. Antioxid Redox Signal. 2008;10(8):1405-1434.
- Musunuru K, Kral BG, Blumenthal RS, et al. The use of high-sensitivity assays for C-reactive protein in clinical practice. Nat Clin Pract Cardiovasc Med. 2008;5(10):621-635.
- Pieczenik SR, Neustadt J. Mitochondrial dysfunction and molecular pathways of disease. Exp Mol Pathol. 2007;83(1):84-92.
- Ames BN, Elson-Schwab I, Silver EA. High-dose vitamin therapy stimulates variant enzymes with decreased coenzyme binding affinity (increased K(m)): relevance to genetic disease and polymorphisms. Am J Clin Nutr. 2002;75(4):616-658.
- McCully KK, Malucelli E, Iotti S. Increase of free Mg2+ in the skeletal muscle of chronic fatigue syndrome patients. Dyn Med. Jan 2006;5:1.
- No authors listed. Acetyl-L-carnitine: monograph. Altern Med Rev. 2010;15(1):76-83.
- Teitelbaum J, Jandrain J, McGrew R. Treatment of chronic fatigue syndrome and fibromyalgia with D-ribose: an open-label, multicenter study. Open Pain J. 2012;5:32-37.
- Nicolson GL, Ellithorpe R. Lipid replacement and antioxidant nutritional therapy for restoring mitochondrial function and reducing fatigue in chronic fatigue syndrome and other fatiguing illnesses. J Chronic Fatigue Syndr. 2006;13(1):57-68.
- Myhill S, Booth NE, McLaren-Howard J. 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):1-15.