Treatment of myalgic encephalomyelitis/chronic fatigue syndrome

INTRODUCTION — 

Chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), is a complicated disease characterized by unexplained, persistent, and relapsing fatigue. There is evidence of underlying abnormalities in the nervous system, the immune system, and metabolic function in affected patients. However, diagnosis can be difficult due to the lack of a test with adequate sensitivity and specificity. The treatment of ME/CFS will be reviewed here. The clinical features and diagnosis of this disorder and the approach to the patient with fatigue are discussed separately. (See "Clinical features and diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome" and "Approach to the adult patient with fatigue".)

MANAGEMENT OVERVIEW — 

Management should focus on treating common symptoms and comorbid conditions, such as sleep disorders, pain, depression and anxiety, memory and concentration difficulties, and dizziness and lightheadedness. (See 'Approach to common symptoms/comorbidities' below.)

When caring for a patient with ME/CFS, the clinician should establish a rapport with the patient to provide support and reassurance. Clinicians should:

●Explain to the patient that the severity is variable but can be completely incapacitating, and that the symptoms are valid. Tell the patient that authoritative institutions, such as the Institute of Medicine (IOM) of the National Academy of Sciences, have concluded that CFS is a real illness; the symptoms are not imaginary or due to malingering [1,2]. Patients and their family members often find it helpful to read the IOM document to underscore the validity of the patient's disease.

●Explain that, although there is no diagnostic test currently available, studies have identified underlying abnormalities in the nervous system, the immune system, and metabolic function in patients with ME/CFS [3].

●Promise to be honest. Patients may be mistrustful because of prior negative experiences, and regaining trust may take a great deal of time.

●Explain to the patient that this is not a new disease, explain that it has been described in the medical literature for several centuries, and emphasize that research over the past 30 years has improved our knowledge about ME/CFS.

When necessary, we discuss the possibility of work modifications with patients and their employers so that they can continue to work; examples of such modifications include working part-time, working from home, or taking a nap or break. Some patients need to go on either short- or long-term disability. (See "Disability assessment and determination in the United States".)

Many controversies remain about the optimal management of ME/CFS. Furthermore, clinical trial results are often complicated by different case definitions, the inclusion of patients who may not actually have ME/CFS, and waxing and waning symptoms being inherent to the disease process itself [4]. Clinicians and patients should be cautious about the use of unproven interventions that are potentially dangerous and often expensive. In addition, the benefit of counseling and exercise therapies (eg, cognitive-behavioral therapy and graded exercise therapy), which can produce meaningful benefits in some patients, may be of limited value or cause post-exertional fatigue in others. (See 'Exercise and activity management for all patients' below and 'Interventions of unclear or no benefit' below.)

EXERCISE AND ACTIVITY MANAGEMENT FOR ALL PATIENTS — 

Remaining physically active may improve fatigue and other symptoms in patients who have the capacity to do so. However, the physical activity must be individualized since exercise can exacerbate postexertional malaise (PEM), which is a worsening of symptoms following physical or mental exertion [5]. Symptoms of PEM typically present 12 to 48 hours after activity and may last for days. In a retrospective study of 150 patients with ME/CFS, physical and cognitive exertion most commonly triggered fatigue; cognitive difficulties, sleep disturbances, headaches, muscle pain, and flu-like feelings were also described [6].

To minimize PEM, clinicians and patients must determine the degree of activity that can be tolerated by each individual patient. For those interested in increasing activity, activity management first includes the establishment of a baseline of achievable patient-specific exercise or physical activity, usually determined by or in mutual decision with the patient. This can then be followed by a gradual, incremental increase in the duration of time spent physically active as directed by the patient. We also emphasize that they should not try to do too much, even if they happen to have much more energy one day. The objective is not an immediate return to pre-illness functioning, but rather maintenance of a slowly progressive level of activity. Overall, the type and amount of exercise should be discussed and individualized with each patient.

Data to support the use of individualized pacing are based upon observational studies [7-9]. Clinical trial data had supported the use of a more formal graded exercise therapy (GET) program; however, the data from these trials have subsequently been reviewed, and several limitations were identified. GET is no longer recommended in ME/CFS. (See 'Behavioral therapies' below.)

APPROACH TO COMMON SYMPTOMS/COMORBIDITIES — 

Common symptoms and comorbid conditions associated with ME/CFS include sleep disorders, pain, depression and anxiety, memory and concentration difficulties, and dizziness and lightheadedness. In general, treatment must be individualized, addressing the most disruptive symptoms first. Our approach to the management of these symptoms is described below. The United States Centers for Disease Control and Prevention offers additional patient advice on the management of each of these conditions [10].

Sleep disorders — The most characteristic sleep problems seen in patients with ME/CFS are difficulty falling asleep, frequent awakenings during the night (difficulty staying asleep), and awakening unrested nearly every morning. Some patients also report extreme sleepiness, intense and vivid dreaming, restless legs, or nighttime muscle spasms.

Sleep hygiene measures should be discussed with patients with insomnia. If that does not result in improvement, evaluation for other sleep disorders should be pursued. If ME/CFS is the only identified cause of the sleep disturbance, pharmacologic therapies, such as over-the-counter products or tricyclic agents, can be tried. Clinicians experienced with ME/CFS report that patients treated with low-dose tricyclics (eg, amitriptyline or nortriptyline 10 mg one hour before bedtime) describe having more hours of uninterrupted sleep, although no large, randomized trials have been conducted. Even though this is a very small dose, some patients still may feel groggy upon awakening; this usually passes after about a week. If this low dose does not reduce frequent nocturnal awakenings, gradual escalation of the dose is warranted. Improved sleep is usually seen within 48 hours.

Additional information on the management of sleep disorders can be found in separate topic reviews. (See "Overview of the treatment of insomnia in adults" and "Approach to the patient with excessive daytime sleepiness" and "Management of restless legs syndrome and periodic limb movement disorder in adults" and "Nocturnal muscle cramps".)

Pain — Tension headaches, myalgias/arthralgias, and sensitive skin are common with ME/CFS and can be managed symptomatically with a nonsteroidal anti-inflammatory drug or acetaminophen. Nonpharmacologic interventions may also be helpful. (See "Tension-type headache in adults: Acute treatment" and "Approach to the patient with myalgia" and "Approach to the management of chronic non-cancer pain in adults".)

If these interventions do not work, we often initiate therapy with a tricyclic agent. Several randomized trials have shown that low-dose tricyclic therapy is beneficial in fibromyalgia (see "Fibromyalgia: Treatment in adults", section on 'Amitriptyline and related tricyclic antidepressants'), and given the similarity in epidemiology and symptoms, some clinicians consider ME/CFS and fibromyalgia to be part of a spectrum of disorders. However, no large trials have been conducted in patients with CFS.

When used for fibromyalgia or ME/CFS, tricyclics do not seem to work via an antidepressant effect; when patients respond, the response is immediate (24 to 48 hours), not after a two- to three-week delay as would be expected with depression. In addition, doses much lower (10 to 20 mg at bedtime) than prescribed for depression typically are used; and in patients with coexisting mood disorders, those disorders do not seem to respond to such low-dose tricyclics.

Depression and anxiety — Depression and anxiety may occur as a consequence of ME/CFS, and screening for depression is advised (calculator 1). Patients diagnosed with either condition should be offered appropriate pharmacologic therapy and/or psychotherapy. (See "Major depressive disorder in adults: Approach to initial management" and "Generalized anxiety disorder in adults: Management".)

However, antidepressants are not a direct treatment for ME/CFS, and the results of small, controlled studies of antidepressant medications have yielded conflicting results. As an example, a randomized, placebo-controlled trial of fluoxetine in 96 patients, 45 percent of whom were depressed, showed no benefit of therapy at eight weeks [11]. By contrast, a study of the monoamine oxidase inhibitor phenelzine noted significant improvement in the treatment group compared with placebo [12]. Nevertheless, certain antidepressant agents may have utility in treating associated depression, insomnia, or myalgia [13]. (See 'Sleep disorders' above and 'Pain' above.)

Cognitive difficulties — We refer patients with substantial cognitive problems for neurocognitive evaluation. Deficits in attention, complex information processing, and initial acquisition of new information have been documented in patients with ME/CFS. These deficiencies are not explained by coexisting psychiatric disorders, although patients who also suffer from depression may incur additional cognitive problems.

Dizziness and lightheadedness — Patients with ME/CFS with persistent dizziness and lightheadedness may benefit from fludrocortisone, midodrine, or beta blockers [14,15]. These treatments are extrapolated from their use in postural tachycardia syndrome (also termed postural orthostatic tachycardia syndrome, or POTS). Studies suggest that patients with ME/CFS can benefit from POTS treatments with or without a confirmed diagnosis of POTS. In one report, 23 subjects with ME/CFS underwent tilt-table testing; 22 were found to have an abnormal test compared with 4 of 14 unmatched controls [14]. Those patients with a positive test were treated with escalating doses of fludrocortisone, atenolol, and disopyramide; almost all reported complete or partial resolution of symptoms. However, several small blinded studies have not confirmed the effectiveness of mineralocorticoid therapy [16-18].

Tilt-table testing may be expensive and difficult to access. As an alternative for clinicians and patients looking to better characterize persistent dizziness and lightheadedness, a National Aeronautics and Space Administration lean test may be helpful [19]. For patients amenable to a therapy trial, we start with low doses and increase slowly over several weeks [14]. Initial drug choice is guided by the presence of the following signs or symptoms:

●Fludrocortisone for orthostatic hypotension or other signs of hypovolemia – Orthostatic hypotension, urinary frequency, and/or electrolyte imbalances suggest relative hypovolemia. For symptomatic patients with systolic blood pressure <110 mmHg, we use fludrocortisone at a starting dose of 0.05 or 0.1 mg daily. If there is no benefit in two weeks, we increase the dose to a maximum of 0.2 mg daily.

●Midodrine if leg swelling or other signs of venous pooling are present – Midodrine supports improved blood flow in patients with venous pooling. We use 2.5 to 10 mg every four hours as needed before upright activity. We avoid dosing midodrine within four hours of bedtime to avoid evening supine hypertension.

●Beta blockers if heart rate is elevated – We prioritize beta blockers for patients whose heart rates frequently exceed 100 beats per minute (BPM). For patients with baseline heart rates <60 BPM, we use beta blockers cautiously at low initial doses (eg, propranolol 10 mg or atenolol 25 mg) dosed 30 minutes before activity. We titrate the dose slowly based on symptoms, heart rate, and blood pressure.

Fludrocortisone, midodrine, or beta blockers may be combined as tolerated if symptoms persist with monotherapy.

POTS diagnosis and management are discussed in further detail separately. (See "Postural tachycardia syndrome".)

INTERVENTIONS OF UNCLEAR OR NO BENEFIT — 

A number of medication, dietary, and behavioral interventions have been evaluated for the treatment of ME/CFS. Many interventions have been found to be of no benefit. However, the benefit of others is unclear, and they should be considered on a case-by-case basis.

Medications and diet — A number of medications and special diets have been evaluated in patients with ME/CFS, and most have not proven successful [20-22]. Only some of these approaches have been tested in controlled trials. A major problem with evaluating the effect of therapy in ME/CFS is that the symptoms fluctuate over time and may remit spontaneously. While placebo treatment can lead to subjective improvement, as with other conditions [20], the placebo response does not appear to be particularly robust in CFS [23].

Examples of therapies that we do not typically administer include:

●Acyclovir – A controlled trial of intravenous and oral acyclovir was based upon the unsupported but possible association with Epstein-Barr virus infection [24]. However, the outcome showed no benefit over placebo. In addition, studies have failed to note any association with active EBV infection.

●Antibiotics – There is often a great temptation to give patients empiric treatment with antibiotics, especially if the patient happens to have a positive Lyme serology. It is important to appreciate, however, that a positive Lyme serology does not diagnose Lyme disease, which is a clinical diagnosis. A true positive Lyme serology merely confirms past exposure to Borrelia burgdorferi but not active infection with that organism. Clinical trials have failed to demonstrate a benefit of prolonged antimicrobial therapy in persons with fatigue and a positive Lyme serology. (See "Diagnosis of Lyme disease" and "Treatment of Lyme disease", section on 'Persistent symptoms after treatment'.)

Concern about misdiagnosis and the treatment of fibromyalgia as Lyme disease led the American College of Rheumatology, in collaboration with the Infectious Diseases Society of America, to perform a cost-benefit analysis of antibiotic treatment for such patients [25]. The incidence of false-positive serologic results in patients from endemic areas with nonspecific myalgia or fatigue was four times that of true-positive results. Treatment of such antibody-positive patients with parenteral antibiotics caused an additional 29 cases of drug toxicity and costs USD $86,221 for each true-positive patient treated.

●Cytokine inhibitors – Proinflammatory cytokines, such as interleukin (IL) 1, may be involved in the pathogenesis of CFS. The efficacy of the IL-1 receptor antagonist anakinra was evaluated in a randomized trial of 50 women who met United States Centers for Disease Control and Prevention (CDC) criteria for ME/CFS and had severe fatigue and functional impairment (assessed using standardized scales) [26]. Patients received anakinra (100 mg subcutaneously daily) for four weeks or placebo. There was no significant difference in fatigue between the groups at the end of treatment or after an additional 20 weeks of follow-up. In addition, there were more injection site reactions in those that received anakinra (68 versus 4 percent). There is no available information on the effectiveness of other cytokine inhibitors.

●Galantamine – Galantamine is a centrally acting acetylcholinesterase inhibitor that has been used to treat Alzheimer's disease. In the largest and best-designed randomized, double-blind, controlled trial that has been performed for the treatment of ME/CFS, 434 patients at multiple centers were randomly assigned to one of four doses of galantamine or placebo [27]. At 16 weeks, there was no benefit from galantamine in the primary endpoint (improvement in the Clinical Global Impression Scale) or in any secondary endpoints.

●Glucocorticoids – The results of studies evaluating glucocorticoids have been inconsistent. A double-blind, randomized, placebo-controlled trial of 25 to 35 mg/day of oral hydrocortisone for 12 weeks in 70 patients showed modest benefit at the expense of adrenal suppression [28]. By comparison, in a randomized crossover trial, clinical improvement was observed in response to 5 to 10 mg/day of hydrocortisone among 32 patients with chronic fatigue but without a comorbid psychiatric disorder [29]. No adrenal suppression was observed, but the duration of therapy was only one month.

●Immune globulin – Randomized trials of intravenous immune globulin have yielded mixed results, with a high incidence of adverse effects [30-33]. In open trials and case series, immunoglobulin therapy (subcutaneous, intramuscular, or intravenous) was associated with symptom improvement; however, these were small, unblinded studies [34-36].

●Methylphenidate – A double-blind, randomized, placebo-controlled crossover study of 60 patients who fulfilled the CDC criteria for ME/CFS evaluated treatment with methylphenidate (10 mg twice daily) compared with placebo [37]. Methylphenidate compared with placebo had a clinically significant effect on fatigue in 17 percent of patients and on concentration in 22 percent of patients. However, this potential benefit must be weighed against potential adverse effects of the drug, its contraindication in patients with certain conditions (eg, glaucoma), and its addictive potential.

●Modafinil – In a small, double-blind, placebo-controlled crossover study that included 14 patients with ME/CFS, modafinil, a selective wakefulness-promoting agent, had a mixed effect on cognition; had no effect on fatigue, quality of life, or mood; and had a negative effect on mental flexibility and motor speed [38].

●Rintatolimod – Rintatolimod is an intravenously administered investigational immune modulator and antiviral drug that has been approved for the treatment of CFS in Canada and Europe [39]. It improved measures of exercise performance in two randomized trials; however, the clinical implications were unclear. Treatment with this drug should be considered experimental until more studies have been done.

●Rituximab – Rituximab is an anti-CD20 monoclonal antibody, which leads to depletion of B cells. The results of a small double-blind, placebo-controlled trial, in which 30 patients with CFS received rituximab (500 mg/m²) or saline, suggested there may be some benefit to this therapy, as improvement in self-reported fatigue was seen during the 12-month follow-up period in 10 of 15 patients (67 percent) who received rituximab versus 2 of 15 patients (13 percent) who received placebo [40]. However, in a larger study that included 151 patients, there was no difference in fatigue scores in patients who did or did not receive rituximab over 24 months [41]; in addition, more patients in the rituximab group had serious adverse events (26 versus 19 percent), as well as adverse events possibly or probably related to the study drug (34 versus 16 percent).

Other modalities that have been tried but have not been successful include amantadine, cimetidine, interferon, magnesium, vitamin B12, bovine or porcine liver extract, dialyzable leukocyte extract, essential fatty acids, evening primrose oil, Biobran MGN-3 (a natural killer cell stimulant), exclusion diets, and removal of dental fillings.

Behavioral therapies — Counseling therapies (eg, cognitive-behavioral therapy [CBT]) and graded exercise therapy (GET) may produce meaningful benefits in some patients, but for others, these structured interventions can worsen postexertional malaise (PEM) and other symptoms.

●CBT – This approach typically involves a series of one-hour sessions designed to alter beliefs and behaviors that could exacerbate symptoms. It is important to note that endorsement of CBT does not reflect a belief that the illness is purely psychological; a number of chronic medical conditions benefit from CBT. (See "Overview of psychotherapies", section on 'Cognitive and behavioral therapies'.)

Several studies suggest that CBT can improve fatigue symptoms and function in patients with ME/CFS [42-49]. CBT can also be beneficial for common symptoms, such as sleep disturbances and pain. However, it remains unclear if and how to integrate CBT into the care of patients with ME/CFS since there are several limitations of the available studies that show benefit, as described below.

●GET – In a structured program such as GET, patients aim for a goal of 30 minutes of light exercise five times per week, after which the intensity and aerobic nature of the exercise can be gradually increased. A target heart rate range should be set to avoid overexertion, generally <100 beats per minute, and GET should be supervised by a physical or exercise therapist.

The use of GET had initially been recommended by many providers based upon data from clinical trials that found exercise therapy (eg, walking, swimming, cycling, dancing) of 12 to 26 weeks' duration was associated with reduced fatigue compared with other management strategies [50]. Although remaining active is important for patients with ME/CFS, the use of GET has now been questioned since there are concerns that this structured type of approach may be associated with worsening of PEM. In addition, there are several limitations to the key studies that supported the use of GET [45,51-56], including those in the highly publicized PACE trial [45], which are described below. The PACE trial was a large randomized trial that included 641 patients with CFS that found GET resulted in lower fatigue scores (3.2 points lower on a 33-point scale, 95% CI 1.8 to 5.0) and higher physical function scores (9.4 points higher on a 100-point scale, 95% CI 2.0 to 12.1) compared with medical care alone [45].

●Limitations of behavioral studies – The use of behavioral interventions such as CBT and GET was initially supported based upon findings in randomized trials [42-59]; however, several limitations of these studies have subsequently been identified [60-63].

ME/CFS is inherently difficult to study because there is no international consensus on the case definition. Patients' symptoms can also vary over time, and outcome measures are usually subjective in the absence of an accurate objective marker of disease severity. As an example, upon reanalyzing data from studies that used a stricter case definition, CBT decreased fatigue (low strength of evidence) but did not affect quality of life (also low strength of evidence), and there was insufficient evidence on impact on function, employment, and global improvement [63].

Other methodologic questions have also been raised. The PACE trial, which is described above [45], has been criticized on several counts. In addition to using inclusion criteria that were too broad for CFS, limitations include: using thresholds of improvement that deviated from the published trial protocol and may have inflated outcomes; telling study participants during the course of the study that CBT and GET were beneficial, thereby possibly biasing patients' assessment of their response; and lacking objective outcome measures [60-62].

Guidance from national organizations regarding these interventions is somewhat mixed. The United States CDC removed discussion of CBT and GET from its patient information website, and it suggests avoiding "push and crash" cycles [10]. In the United Kingdom, the National Institute for Health and Care Excellence (NICE) guidelines from 2007 endorsed CBT and GET and noted insufficient evidence to suggest pacing; these are undergoing review [64]. Guidance from a major physicians' organization in Alberta, Canada presents both GET and pacing as evidence-based strategies and acknowledges the debate about the relative merits [65].

PROGNOSIS — 

The short-term prognosis for recovery of function is generally poor in chronic fatigue syndrome (CFS). The long-term prognosis appears to be better, although studies have been conflicting. In one report of 144 patients followed by questionnaire, for example, the proportion of patients with functional impairment was 73 percent at six weeks to six months and only 33 percent at two to four years [66]. However, other studies noted a poorer outcome. A prospective study found that only 4 of 27 patients achieved sustained remission during a three-year observation period [24], and a retrospective evaluation of 495 patients with CFS or idiopathic chronic fatigue (unexplained debilitating fatigue lasting more than six months that does not fulfill criteria for CFS) reported symptomatic improvement in 64 percent at 1.5 years but complete resolution in only 2 percent [67]. In the latter series, patients with CFS had a greater symptom severity and a lower level of functioning at follow-up than those with idiopathic chronic fatigue. Regardless of the long-term prognosis, neither CFS nor chronic fatigue results in organ failure. CFS has not been associated with an increased risk of all-cause mortality but may be associated with an increased risk for suicide [68]. (See "Approach to the adult patient with fatigue".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Myalgic encephalomyelitis/chronic fatigue syndrome (The Basics)")

●Beyond the Basics topic (see "Patient education: Myalgic encephalomyelitis/chronic fatigue syndrome (Beyond the Basics)")

Additional information for patients with CFS and those caring for them can be obtained from the United States Centers for Disease Control and Prevention:

Centers for Disease Control and Prevention (CDC)

US Department of Health and Human Services

1600 Clifton Rd

Atlanta, GA 30329-4027

Telephone: 800-232-4636

www.cdc.gov/me-cfs/about/index.html

SUMMARY AND RECOMMENDATIONS

●Definition – Chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), is a complicated disease characterized by unexplained, persistent, and relapsing fatigue. There is evidence of underlying abnormalities in the nervous system, the immune system, and metabolic function in affected patients. (See 'Introduction' above.)

●Exercise and activity management – Remaining physically active may improve fatigue and other symptoms in patients who have the capacity to do so. However, the physical activity must be individualized since exercise may exacerbate postexertional malaise (PEM), which is a worsening of symptoms following physical or mental exertion. To minimize PEM, clinicians and patients must determine the degree of activity that can be tolerated by each individual patient before creating a graded activity plan. (See 'Exercise and activity management for all patients' above.)

●Symptom management – Management should focus on treating common symptoms and comorbid conditions, such as sleep disorders, pain, depression and anxiety, memory and concentration difficulties, and dizziness and lightheadedness. (See 'Approach to common symptoms/comorbidities' above.)

●Prognosis – The short-term prognosis for recovery of function is generally poor in CFS. The long-term prognosis appears to be better, although studies have been conflicting. (See 'Prognosis' above.)