LIMITATIONS OF THE RESEARCH BASE

One of the most significant challenges to achieving a better understanding of ME/CFS results from the methodological limitations of the current research base. Issues related to external and internal validity and to reliability frequently have led to inconsistent results across studies, as well as other shortcomings. Despite these limitations, however, the committee was able to glean evidence of symptoms, signs, and objective measures for ME/CFS. The evidence with respect to major symptoms and manifestations is presented in this chapter, while that related to other symptoms and manifestations and to pediatric ME/CFS is reviewed in Chapters 5 and 6, respectively. This review of the evidence serves as the basis for the committee's proposed diagnostic criteria for ME/CFS, which are presented in Chapter 7.

FATIGUE AND ITS IMPACT ON FUNCTION

The dictionary definition of fatigue as a noun is “weariness from bodily or mental exertion.” Fatigue is not typically considered a disease but is commonly used in medicine to represent a broad spectrum of tiredness, from the physical, cognitive, or emotional feeling at the end of a long day to the emotional or physical toll of acute, chronic, or terminal illness (Gambert, 2005).

Fatigue is one of the most common and nonspecific presenting complaints in primary care. Unfortunately, the word “fatigue” does not convey information about the cause, severity, or chronicity of fatigue or its impact on functionality. Although fatigue is a common experience, it has no unique physiological explanations or objective markers. A broad range of physical, medical, and mental health conditions and stressors may result in the complaint of fatigue (Matthews et al., 1991). Aging alone is associated with a gradual increase in fatigue and reduction in functional capacity for a variety of reasons (National Institute on Aging, 2007). Although overlap exists, fatigue usually can be distinguished from somnolence (also called drowsiness or sleepiness), which often is attributed to deprivation of sleep, primary sleep disorders, or sedating medications (Hossain et al., 2005). Thus, clinicians are challenged to integrate the subjective and objective evidence that can help identify the neurologic, malignant, infectious, inflammatory, cardiopulmonary, metabolic, endocrinologic, physical deconditioning, pharmacologic, or mental health factors that may underlie the presenting complaint of fatigue. (Note that a complete discussion of the differential diagnosis of fatigue is beyond the scope of this report.)

Impact of Fatigue on Function

Fatigue may be most relevant when assessed relative to its impact on function. However, disability caused by fatigue may not reflect the levels of fatigue a patient is experiencing. For instance, despite feeling extremely fatigued, a person may continue working to survive economically and stop only when functionally impaired (Jason and Brown, 2013). Appendix C provides additional examples and rates of functional impairment due to ME/CFS symptoms. In general, patients with ME/CFS experience a marked decrease in function across an array of domains, frequently attributed, at least in part, to their fatigue (Komaroff et al., 1996a).

Efforts have been made to assess the impact of the disease on patients' function, but most such efforts have been research based. One of the more commonly used tools in medical research as well as in ME/CFS studies is the Short Form 36-Item Questionnaire (SF-36) of the Medical Outcomes Study (MOS) (McHorney et al., 1993; Ware, 2002), a standardized and validated 36-item patient-report questionnaire with eight principal components or subscales used to determine the impact of illness on functionality. Early studies used this tool to distinguish ME/CFS from major depression, multiple sclerosis, acute infectious mononucleosis, hypertension, congestive heart failure, type II diabetes mellitus, acute myocardial infarction, unexplained chronic fatigue, and healthy controls (Buchwald et al., 1996; Komaroff et al., 1996a).

The VT (vitality) subscale of the MOS SF-36, for example, a questionnaire used to assess function, is thought to reflect both mental and physical function (McHorney et al., 1993) and includes the sum of four questions about having a lot of energy, being full of life/pep, feeling worn out, or feeling tired, with higher scores reflecting greater vitality (Ware, 2002). VT scores are consistently much lower in ME/CFS patients with and without comorbidities than in healthy controls and patients with other chronic illnesses, including fibromyalgia. Examples of mean VT scores on the MOS SF-36 from various published studies for the general population and those with ME/CFS and other chronic fatiguing illnesses are summarized in Table 4-1 to demonstrate the profoundly low scores for ME/CFS compared with the other conditions. Several of the studies in the table do not specify the scoring algorithm (raw versus normalized t score) for the MOS SF-36, so that bias may exist in comparing VT scores across the studies. However, this bias is unlikely to explain the clear differences seen between the ME/CFS and non-ME/CFS groups in Table 4-1.

TABLE 4-1

Mean VT Score on the MOS SF-36 for ME/CFS Versus Other Fatigue Conditions.

While Jason and Brown (2013) demonstrated that the VT scores of ME/CFS patients ranged from 15 to 25 depending on subtyping strategies, other domains often are affected as well. Nacul and colleagues (2011a) found that scores on the role-physical (RP)¹ subscale of the SF-36 were even more affected than scores on the VT subscale (version 2) but that all domains were impaired, with mental health being the best preserved. Jason and colleagues (2011c) found that impairments in VT, social functioning, and RP had the greatest sensitivity and specificity in identifying patients who met the Fukuda definition of ME/CFS. In one early study, all eight subscores of the SF-36 were lower in ME/CFS patients than in the general population and other disease comparison controls, with the exception of the mental health and role-emotional subscales in the controls with major depression (Komaroff et al., 1996a).

It should be noted that, while widely used in research, the SF-36 may not be well suited to general clinical use because of user fees and the general process of having to submit test results to the sponsor for scoring. The RAND-36 is an alternative version that is freely accessible, but it has a complex scoring algorithm (RAND, 1984).

POST-EXERTIONAL MALAISE (PEM)

Prevalence of PEM in ME/CFS Patients

The prevalence of PEM among ME/CFS patients as diagnosed by existing criteria varies from 69 to 100 percent (Chu et al., 2013; De Becker et al., 2001; Jason et al., 2011b; Kerr et al., 2010; Nacul et al., 2011b; Vermeulen and Scholte, 2003; Zhang et al., 2010). In a longitudinal study that followed a random, community-based sample for 10 years, 100 percent of participants fulfilling the Fukuda definition reported PEM as a symptom at some point during their illness (Jason et al., 2011b), even though the Fukuda definition does not require PEM for diagnosis. Prevalence estimates of PEM vary for two major reasons: (1) some studies use ME/CFS case definitions that require PEM, while others list it as an optional symptom; and (2) the way PEM is defined, operationalized, or queried for can affect how patients interpret the concept of PEM and whether they endorse it (Jason et al., 1999, 2004, 2014).

The prevalence of PEM in healthy control subjects is considerably lower than in ME/CFS patients, ranging from 4 to 8 percent (Hawk et al., 2006b; Jason et al., 2011b; Kerr et al., 2010; Komaroff et al., 1996b; Zhang et al., 2010). Jason and colleagues (2013b) found that a greater percentage of ME/CFS patients than healthy controls experienced PEM symptoms (see Figure 4-1). After moderate thresholds for frequency and severity were applied, the percentage of controls who endorsed PEM decreased further, from 7 to 19 percent to 2 to 7 percent.⁵ Thus, applying increased severity or frequency thresholds for PEM may assist in identifying patients with ME/CFS (Hawk et al., 2006b).

FIGURE 4-1

Percentage of ME/CFS patients and healthy controls reporting PEM symptoms of at least moderate severity that occurred at least half of the time during the past 6 months. NOTE: All patients fulfilled the Fukuda definition for CFS. SOURCE: Jason et al., 2013b. (more...)

A few studies that compared ME/CFS with other diseases found that, although PEM was experienced by 19 to 20 percent of subjects with major depressive disorder (Hawk et al., 2006a; Komaroff et al., 1996b) and 52 percent of patients with multiple sclerosis (Komaroff et al., 1996b), it was still much more common in ME/CFS patients than in comparison groups. One study found that 64 percent of patients with major depressive disorder experienced PEM, but the authors did not describe how PEM was assessed (Zhang et al., 2010). As mentioned earlier, these prevalence estimates may vary depending on how PEM was defined and queried for, and thus they need to be interpreted with caution.

SLEEP-RELATED SYMPTOMS

Description of Sleep-Related Symptoms in ME/CFS

Patients with ME/CFS frequently experience sleep-related problems such as insomnia, sleep disturbances, unrefreshing sleep, and nonrestorative sleep (FDA, 2013; Fossey et al., 2004). These symptoms are included in all existing ME/CFS case definitions and diagnostic criteria (see Chapter 3). Unrefreshing sleep, or feeling as tired upon waking as before going to bed, is among the most common symptoms reported by ME/CFS patients, and only a small percentage of patients diagnosed with ME/CFS fail to report some type of sleep dysfunction (Carruthers et al., 2003; IACFS/ME, 2014; Jason et al., 2013b). This section summarizes the evidence on sleep-related signs and symptoms in ME/CFS reviewed by the committee to determine whether such symptoms should be a component of its recommended diagnostic criteria for ME/CFS.

ME/CFS patients are more likely than healthy controls to experience sleep-related symptoms occurring at least half of the time and of at least moderate severity (see Figure 4-2) (Jason et al., 2013b). Although sleep-related symptoms also are reported by healthy persons and by chronically fatigued persons who do not fulfill ME/CFS criteria, a greater percentage of people fulfilling ME/CFS criteria report unrefreshing sleep, sleep disturbances, and difficulties falling asleep or waking up early in the morning (Komaroff et al., 1996a; Krupp et al., 1993; Nisenbaum et al., 2004) relative to these other groups.

FIGURE 4-2

Percentage of ME/CFS patients and healthy controls reporting sleep-related symptoms of at least moderate severity that occurred at least half of the time during the past 6 months. NOTE: All patients fulfilled the Fukuda definition for CFS. SOURCE: Jason (more...)

Sleep-related complaints may change throughout the course of the illness. For example, one study found that in the first few months of the illness, ME/CFS patients complain of hypersomnia, but as the disease progresses, they have trouble staying asleep (Morriss et al., 1997). A cross-sectional study of randomly selected patients found that sleep-related symptoms may become less frequent over the course of the illness (Nisenbaum et al., 2003); however, this may be due to behavioral adaptation or changes in sleep medication.

Sleep-related symptoms are listed differently in the various diagnostic criteria for ME/CFS (see Box 4-1), and there is conflicting evidence on whether ME/CFS patients fulfilling different diagnostic criteria experience sleep-related symptoms differently. Those fulfilling the CCC reported significantly worse (in terms of frequency and severity, p < 0.05) unrefreshing sleep (Jason et al., 2012a, 2013a) and more difficulty falling asleep (Jason et al., 2012a) relative to those fulfilling the Fukuda definition. Similarly, another study found that patients fulfilling the International Consensus Criteria for ME (ME-ICC) reported significantly worse symptom scores for unrefreshing sleep, need to nap during each day, difficulty falling asleep, and difficulty staying asleep relative to those fulfilling the Fukuda definition (Brown et al., 2013). In contrast to these results, however, are those from two other studies. One study found that more patients fulfilling the Fukuda definition reported greater difficulty staying asleep than those fulfilling the CCC (Jason et al., 2004), while a second study reported no significant differences in sleep-related symptom scores between patients fulfilling the Fukuda definition and those fulfilling the ME-ICC (Jason et al., 2014). Regardless, it is clear that all the major diagnostic criteria include sleep-related symptoms.

BOX 4-1

Sleep-Related Symptoms in Case Definitions and Diagnostic Criteria for ME/CFS. Unrefreshing sleep is a minor criterion (not required). Sleep apnea and narcolepsy are exclusionary conditions (as they are conditions that explain chronic fatigue).

Chronic fatigue may be caused by sleep disorders; thus, most diagnostic criteria for ME/CFS require ruling out primary or treatable sleep disorders before a diagnosis of ME/CFS can be made (see Box 4-1). Sleep apnea—whether obstructive, central, or undefined—is an exclusionary condition in several criteria, but there is less consistency regarding whether other sleep disorders, such as narcolepsy or the spectrum of obstructive or central sleep disorders, truly exclude ME/CFS (Carruthers et al., 2003; Fukuda et al., 1994; Jason et al., 2010b; NICE, 2007). Some researchers have noted that the inclusion of unrefreshing or nonrestorative sleep as a case-defining symptom, combined with listing sleep disorders as exclusionary conditions, may confuse the diagnosis and management of ME/CFS (Mariman et al., 2012; Unger et al., 2004).

NEUROCOGNITIVE MANIFESTATIONS

Prevalence of Neurocognitive Manifestations in ME/CFS Patients

Estimates of the prevalence of neurocognitive manifestations in ME/CFS patients vary as a result of the different definitions used in research and the assessment of these manifestations using patient reports. The 2003 CCC, 2010 Revised CCC, and 2011 ME-ICC require the presence of neurological/cognitive manifestations for a diagnosis of ME/CFS, while the 1994 Fukuda definition and 2007 British National Institute for Health and Clinical Excellence (NICE) Clinical Guidelines do not. Moreover, these various case definitions and diagnostic criteria are inconsistent in the manifestations or symptoms listed for this category. For instance, the Fukuda definition includes only “impaired memory or concentration” as one optional criterion, while the CCC requires the presence of two or more difficulties from a more extensive list of cognitive (confusion, impairment of concentration and short-term memory consolidation, disorientation, difficulty with information processing) or neurologic (perceptual and sensory disturbances, ataxia, muscle weakness, and fasciculations) manifestations.

A study conducted in Belgium in a population of patients with chronic fatigue found a prevalence of 93 percent for attention deficit, 85.6 percent for memory disturbance, and 75.5 percent for difficulties with words for those fulfilling the Fukuda definition (De Becker et al., 2001). When applying frequency and severity scores of at least 2, Jason and colleagues (2013b) found that a greater percentage of ME/CFS patients than healthy controls reported neurocognitive symptoms of at least moderate severity that occurred at least half of the time (see Figure 4-3).

FIGURE 4-3

Percentage of ME/CFS patients and healthy controls reporting neurocognitive manifestations of at least moderate severity that occurred at least half of the time during the past 6 months. NOTE: All patients fulfilled the Fukuda definition for CFS. SOURCE: (more...)

ORTHOSTATIC INTOLERANCE AND AUTONOMIC DYSFUNCTION

Assessment of Orthostatic Intolerance and Autonomic Dysfunction in ME/CFS

Clinical History

When querying for orthostatic intolerance, clinicians should pose questions about the frequency and severity of lightheadedness, near-fainting (presyncope), syncope, sweating, palpitations, chest pain, orthostatic dyspnea, and related symptoms when individuals are sitting or standing for prolonged periods of time. Chronic fatigue, difficulty concentrating, exercise intolerance, nausea, and tremulousness are common across a variety of forms of orthostatic intolerance. Not all individuals report lightheadedness; some simply report feeling unwell when upright and they avoid these situations. Questions with a high yield include asking how individuals feel in the following circumstances: while waiting in line, at receptions, in choir, while shopping or at the mall, while sitting still for long periods, and when exposed to warm/stressful circumstances (e.g., summer weather; after hot showers, baths, and saunas; after episodes of fear, pain, or exposure to blood) (Grubb, 2005; Raj, 2013; Thieben et al., 2007).

Formal Questionnaires

Several questionnaires are validated for use in adults with autonomic dysfunction or orthostatic intolerance syndromes, but they have not been evaluated specifically among those with ME/CFS. They include the Orthostatic Grading Scale (OGS) (Schrezenmaier et al., 2005); the Orthostatic Hypotension Questionnaire (OHQ) (Kaufmann et al., 2012); and a series of questionnaires developed at the Mayo Clinic, beginning with the 169-item Autonomic Symptom Profile (ASP) (Suarez et al., 1999), followed by the 84-question COMPASS. The COMPASS has been further abbreviated to a 31-item questionnaire (COMPASS 31) (Sletten et al., 2012).

Objective Measures

Orthostatic vital signs—measured by taking heart rate and blood pressure in supine, sitting, and standing positions—often are measured within 2 minutes or less, and thus are insufficient to identify most forms of chronic orthostatic intolerance. Prolonged testing of at least 10 minutes usually is needed for a sufficient orthostatic challenge. Two forms of prolonged orthostatic testing (standing test and upright tilt test) are commonly employed (see Box 4-2). The recommended duration of upright posture for detecting POTS is 10 minutes (Raj, 2013). Although neurally mediated hypotension can occur within the first 10 minutes of upright posture, an orthostatic stress of more than 10 minutes of upright posture more commonly is required (Benditt et al., 1991). The median time to develop hypotension among adults with ME/CFS is 30 minutes in some studies (Bou-Holaigah et al., 1995). Among those with ME/CFS, orthostatic symptoms during tilt testing emerge within minutes, long before hemodynamic changes are documented (Razumovsky et al., 2003).

BOX 4-2

Prolonged Orthostatic Testing. This test can be performed in any clinic. The individual lies supine for 5 minutes to yield a steady baseline, then stands quietly, leaning against a wall, for 10 minutes. The individual is instructed to avoid moving, shifting (more...)

Some investigators prefer to simulate orthostatic stress using lower-body negative pressure (LBNP), but these methods are used mainly in research settings (Wyller et al., 2008). Other methods used to capture physiological changes during upright tilt include transcranial Doppler ultrasound to measure cerebral blood flow velocity, capnography to measure expired CO₂, and near infrared spectroscopy to measure changes in cerebral tissue oxygenation (Naschitz et al., 2000; Ocon et al., 2012; Tanaka et al., 2002).

Clinicians who evaluate those with orthostatic intolerance recognize that individuals with ME/CFS can develop an exacerbation of their typical symptoms not just during the head-up tilt test but for several days afterward. The committee's literature search did not identify any publications describing this observation more formally, although administration of 1 liter of normal saline following the tilt test to reverse the post-tilt test exacerbation in symptoms is part of the tilt testing protocol in some centers (Rowe et al., 2001). Intravenous saline has been shown to improve orthostatic tolerance and to modify autonomic tone in those with neurally mediated syncope (Burklow et al., 1999) and after experimental prolonged bed rest (Takenaka et al., 2002).

Evidence for Orthostatic Intolerance and Autonomic Abnormalities in ME/CFS

This section examines the evidence for orthostatic intolerance and autonomic abnormalities in adults with ME/CFS. The methodology used for the committee's literature review is described in Chapter 1. A full search for all forms of autonomic dysfunction (e.g., bladder dysfunction, gastrointestinal motility disorders) was not conducted. Instead, the committee elected to focus on circulatory abnormalities, as these are the most frequently reported autonomic abnormalities in ME/CFS. The most common forms of orthostatic intolerance are described in Box 4-3. Several studies reviewed were conducted by the same group of investigators. When it was not possible to ascertain from the description of the study methods whether the data were for independent study populations or some of the same patients on more than one occasion, the committee chose to select the most representative (or largest) of the studies for each group.

BOX 4-3

Common Orthostatic Intolerance Syndromes. POTS is defined by a heart rate increase between the supine position and 10 minutes of standing of more than 30 beats per minute (bpm) for adults or 40 bpm for adolescents, or a heart rate that reaches 120 bpm (more...)

The studies reviewed vary widely on several methodological variables, notably in the following categories:

• patient characteristics (age, duration of ME/CFS, severity of ME/CFS, the ME/CFS case definition used, whether subjects were selected based on autonomic symptoms, referral biases, whether the testing was performed on patients seeking clinical care or those participating in a research study);
• preparation for the test (medications allowed, prior sodium intake, duration of pretest fast);
• the type of orthostatic testing (active standing, standing while leaning against a wall, head-up tilt table) and, with tilt testing, the protocol used (e.g., angle of the tilt table, time of day for the study, ambient room temperature, degree of movement permitted);
• duration of the orthostatic stress; and
• criteria for abnormal response to orthostatic stress (earlier studies tended to report only rates of NMH, without reporting rates of POTS, and studies employing less than 10 minutes of orthostatic stress reported rates of POTS, as these tests were not sufficiently prolonged to be able to exclude NMH).

These methodological factors contributed to the variability in rates of orthostatic intolerance reported in the various studies.

Orthostatic Testing

Prolonged orthostatic testing (> 10 minutes)

The literature search identified 14 studies of prolonged orthostatic testing in which adults with ME/CFS were compared with healthy controls (Bou-Holaigah et al., 1995; De Lorenzo et al., 1997; Duprez et al., 1998; Hollingsworth et al., 2010; Jones et al., 2005; LaManca et al., 1999a; Naschitz et al., 2000, 2002; Poole et al., 2000; Razumovsky et al., 2003; Schondorf et al., 1999; Streeten et al., 2000; Timmers et al., 2002; Yataco et al., 1997), as well as three studies of subjects with ME/CFS without controls (Freeman and Komaroff, 1997; Reynolds et al., 2013; Rowe et al., 2001). None of the studies with controls and only one of the three studies without controls (Freeman and Komaroff, 1997) recruited participants based on the presence of autonomic symptoms.

Of the 14 studies with healthy controls in which orthostatic testing lasted longer than 10 minutes, only 2 did not report a higher prevalence of either POTS or NMH among those with ME/CFS compared with controls (Duprez et al., 1998; Jones et al., 2005). The rates of reported abnormalities ranged from 0 percent (Duprez et al., 1998) to 96 percent (Bou-Holaigah et al., 1995). The median proportion with hemodynamic abnormalities during the first 30-45 minutes upright in these studies was 37 percent in ME/CFS versus 7.5 percent in controls. In the three additional studies without controls, the reported rates of orthostatic intolerance ranged from 11 to 66 percent of adults with ME/CFS. This number needs to be interpreted with caution given the varying durations of orthostatic stress (ranging from 20 to 60 minutes) and other methodological differences in testing.

Brief orthostatic testing (< 10 minutes)

The literature search identified seven studies with brief durations of orthostatic stress (2-10 minutes) (De Becker et al., 1998; Freeman and Komaroff, 1997; Hoad et al., 2008; Miwa, 2014; Natelson et al., 2007; Soetekouw et al., 1999; Winkler et al., 2004). The samples sizes ranged from 20 to 62 subjects with ME/CFS (median N = 37). Two studies used head-up tilt testing and five active standing as the orthostatic stressor. The prevalence of orthostatic intolerance was not documented in two studies in which the main focus was formal autonomic testing (De Becker et al., 1998; Soetekouw et al., 1999). In all of the remaining studies, the prevalence of POTS was numerically higher in adults with ME/CFS than in controls (Freeman and Komaroff, 1997; Hoad et al., 2008; Miwa, 2014; Natelson et al., 2007; Winkler et al., 2004). Combining the data from these studies, the overall prevalence of POTS was 27 percent in adults with ME/CFS and 4.2 percent in healthy controls. The range of overall orthostatic abnormalities (including POTS, hypotension, and hypocapnia) in these studies with brief orthostatic testing varied widely—from 14 to 67 percent—in individual studies, reflecting differences in study measures, subject selection, and duration of orthostatic stress.

Symptoms reported during orthostatic testing

The literature review identified five studies reporting orthostatic or ME/CFS symptoms following standing or tilt table testing. Upright posture was associated with provocation of fatigue symptoms and higher rates of lightheadedness, nausea, and warmth in 55-100 percent of subjects with ME/CFS (Bou-Holaigah et al., 1995; Hollingsworth et al., 2010; Naschitz et al., 2000; Streeten et al., 2000). For example, during the first 45 minutes of head-up tilt, 100 percent of 23 ME/CFS participants reported worse fatigue, 91 percent lightheadedness, 91 percent increased warmth, 73 percent nausea, and 18 percent diaphoresis. Controls made no reports of similar symptoms (Bou-Holaigah et al., 1995). One small study found a normalization of heart rate and blood pressure changes and improvement in ME/CFS symptoms after the acute application of a 45-mm Hg external compression device while subjects continued to stand (Streeten et al., 2000). In a study of 64 British adults with ME/CFS, 6 participants were unable to tolerate head-up tilt because of weakness. Of the remaining 58 with ME/CFS, 32 (55 percent) were symptomatic during the test, compared with 17/64 (27 percent) healthy controls. The types of symptoms were not specified (Hollingsworth et al., 2010). Research also has shown that the severity of orthostatic symptoms may predict the functional status of those with ME/CFS (Costigan et al., 2010).

Treatment of orthostatic intolerance

Open (nonblinded) treatment studies of ME/CFS subjects found improvement in function after increased sodium intake or pharmacological treatment of orthostatic intolerance (Bou-Holaigah et al., 1995; De Lorenzo et al., 1997; Kawamura et al., 2003; Naschitz et al., 2004). However, randomized trials of fludrocortisone failed to confirm the efficacy of this treatment in adults as monotherapy or combined with hydrocortisone (Blockmans et al., 2003; Peterson et al., 1998; Rowe et al., 2001).

Autonomic Testing

More formal autonomic testing—using such measures as the cold pressor test, heart rate responses to deep breathing, handgrip tests, the Valsalva maneuver, and quantitative sudomotor axon reflex tests—has not been conducted as extensively as have tests of the heart rate and blood pressure response to orthostatic stress. The majority of studies reporting the Valsalva ratio found no differences between ME/CFS and control groups (De Becker et al., 1998; Schondorf et al., 1999; Soetekouw et al., 1999; Winkler et al., 2004). Measures of heart rate variability have been used to examine the effects of autonomic tone on the heart noninvasively. ME/CFS is associated with enhanced sympathetic nervous system tone and reduced parasympathetic tone at baseline (Freeman and Komaroff, 1997; Frith et al., 2012; Sisto et al., 1995), in response to cognitive and orthostatic challenges (Beaumont et al., 2012; Yamamoto et al., 2003; Yataco et al., 1997), after walking (Cordero et al., 1996), and during sleep (Boneva et al., 2007; Rahman et al., 2011; Togo and Natelson, 2013; Yamaguti et al., 2013).

Ambulatory blood pressure measurements in subjects with ME/CFS have had conflicting results. One study found significantly lower systolic, diastolic, and mean arterial pressure in ME/CFS patients compared with controls, and a second found nighttime hypotension in ME/CFS patients (Newton et al., 2009; Van de Luit et al., 1998). Duprez and colleagues (1998), however, found no differences in daytime or nighttime blood pressure in ME/CFS patients. Of interest, although blood pressure did not differ in that study, there were significant differences in heart rate between ME/CFS cases and healthy controls throughout the 24-hour period.

Blood Volume and Cardiac Function Testing

Studies measuring blood volume have found lower values in ME/CFS subjects than in controls. Hurwitz and colleagues (2010) found a total blood volume deficit of 15.1 percent in ME/CFS patients compared with controls. Streeten and Bell (1998) identified low red blood cell mass in 16 of 19 patients with ME/CFS and an overall total lower blood volume in 63 percent of ME/CFS patients. Okamoto and colleagues (2012b) identified a 10.4 percent lower total blood volume in subjects with ME/CFS and POTS compared with controls studied at the same center.

Hurwitz and colleagues (2010) confirmed a lower cardiac index in ME/CFS patients (due to a 10.2 percent lower stroke index compared with sedentary and nonsedentary controls) and a cardiac contractility deficit of 25.1 percent. In a series of studies possibly involving some of the same patients, a high prevalence of orthostatic intolerance, associated with smaller heart on cardiothoracic ratios, was found in ME/CFS patients (Miwa, 2014; Miwa and Fujita, 2008, 2009, 2011). Hollingsworth and colleagues (2010) found a greater left ventricular work index with standing in ME/CFS patients compared with controls, suggesting that when the patients were standing, their hearts were working harder. These findings were associated with the presentation of symptoms with standing in 95 percent of ME/CFS patients.

Orthostatic Hypocapnia

Three studies examined orthostatic hypocapnia in subjects with CFS. Naschitz and colleagues (2000) found that end-tidal CO₂ was similar for ME/CFS patients and controls when supine, consistent with the absence of hyperventilation at baseline, but end-tidal CO₂ was lower for the ME/CFS subjects during upright tilt testing. These results were confirmed by Razumovsky and colleagues (2003) during prolonged head-up tilt testing and by Natelson and colleagues (2007) during 8 minutes of active standing.

Microcirculatory Flow

Three studies examined abnormalities in peripheral blood flow in ME/CFS patients using different physiologic or pharmacologic challenges. ME/CFS patients had abnormally prolonged vasodilation in response to transdermally applied acetylcholine (Khan et al., 2003), reduced oxygen delivery to muscles after exercise and after cuff ischemia (McCully and Natelson, 1999), and a strikingly increased venous contractile sensitivity to infused epinephrine (Streeten, 2001). These studies have yet to be replicated.

Overlap of ME/CFS with Other Conditions Associated with Orthostatic Intolerance

A small number of studies have examined the prevalence of ME/CFS symptoms in those diagnosed with POTS (Okamoto et al., 2012b) or vasovagal syncope (Kenny and Graham, 2001; Legge et al., 2008). Okamoto and colleagues (2012b) examined the prevalence of the ME/CFS symptoms of the Fukuda definition among those with POTS who did not satisfy the criteria for ME/CFS, comparing this group with those who had POTS together with ME/CFS. Those with POTS alone often reported an elevated prevalence of severe fatigue, unrefreshing sleep, impaired memory or concentration, muscle pain, and post-exertional fatigue, although they did not have a sufficient number of symptoms to satisfy the Fukuda definition. By definition, the prevalence of Fukuda symptoms was higher in ME/CFS subjects who also had POTS than in those with POTS alone, but the pattern of symptoms was similar between the two groups (Okamoto et al., 2012b).

A high prevalence of hypotension and tachycardia is seen in FM, which, as noted earlier, is a clinical condition often comorbid with ME/CFS. Sympathetic predominance of heart rate variability also is seen in FM studies (Martinez-Lavin, 2007; Martinez-Martinez et al., 2014).

The prevalence of Ehlers-Danlos syndrome and joint hypermobility is higher in ME/CFS patients than in healthy controls (Barron et al., 2002; Rowe et al., 1999). Studies also confirm high rates of fatigue as well as orthostatic and autonomic symptoms in those with hypermobility (Gazit et al., 2003) and the hypermobile form of Ehlers-Danlos syndrome (De Wandele et al., 2014a,b).

REFERENCES

• Armitage R. The effects of nefazodone on sleep in depressed patients and healthy controls. International Journal of Psychiatry in Clinical Practice. 1999;3(2):73–79. [PubMed: 24941089]
• Armitage R, Landis C, Hoffmann R, Lentz M, Watson NF, Goldberg J, Buchwald D. The impact of a 4-hour sleep delay on slow wave activity in twins discordant for chronic fatigue syndrome. Sleep. 2007;30(5):657–662. [PubMed: 17552382]
• Armitage R, Landis C, Hoffmann R, Lentz M, Watson N, Goldberg J, Buchwald D. Power spectral analysis of sleep EEG in twins discordant for chronic fatigue syndrome. Journal of Psychosomatic Research. 2009;66(1):51–57. [PMC free article: PMC2634600] [PubMed: 19073294]
• Arroll MA, Attree EA, O'Leary JM, Dancey CP. The delayed fatigue effect in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Fatigue: Biomedicine, Health & Behavior. 2014;2(2):57–63.
• Attree EA, Dancey CP, Pope AL. An assessment of prospective memory retrieval in women with chronic fatigue syndrome using a virtual-reality environment: An initial study. Cyberpsychology and Behavior. 2009;12(4):379–385. [PubMed: 19591619]
• Attree EA, Arroll MA, Dancey CP, Griffith C, Bansal AS. Psychosocial factors involved in memory and cognitive failures in people with myalgic encephalomyelitis/ chronic fatigue syndrome. Psychology Research and Behavior Management. 2014;7:67–76. [PMC free article: PMC3940708] [PubMed: 24596470]
• Bailes S, Libman E, Baltzan M, Amsel R, Schondorf R, Fichten CS. Brief and distinct empirical sleepiness and fatigue scales. Journal of Psychosomatic Research. 2006;60(6):605–613. [PubMed: 16731235]
• Balady GJ, Arena R, Sietsema K, Myers J, Coke L, Fletcher GF, Forman D, Franklin B, Guazzi M, Gulati M, Keteyian SJ, Lavie CJ, Macko R, Mancini D, Milani RV. Clinician's guide to cardiopulmonary exercise testing in adults: A scientific statement from the American Heart Association. Circulation. 2010;122(2):191–225. [PubMed: 20585013]
• Ball N, Buchwald DS, Schmidt D, Goldberg J, Ashton S, Armitage R. Mono-zygotic twins discordant for chronic fatigue syndrome: Objective measures of sleep. Journal of Psychosomatic Research. 2004;56(2):207–212. [PubMed: 15016580]
• Baraniuk JN, Adewuyi O, Merck SJ, Ali M, Ravindran MK, Timbol CR, Ray-Han R, Zheng Y, Le U, Esteitie R, Petrie KN. A chronic fatigue syndrome (CFS) severity score based on case designation criteria. American Journal of Translational Research. 2013;5(1):53–68. [PMC free article: PMC3560481] [PubMed: 23390566]
• Barnden LR, Crouch B, Kwiatek R, Burnet R, Mernone A, Chryssidis S, Scroop G, del Fante P. A brain MRI study of chronic fatigue syndrome: Evidence of brainstem dysfunction and altered homeostasis. NMR in Biomedicine. 2011;24(10):1302–1312. [PMC free article: PMC4369126] [PubMed: 21560176]
• Barron DF, Cohen BA, Geraghty MT, Violand R, Rowe PC. Joint hypermobility is more common in children with chronic fatigue syndrome than in healthy controls. Journal of Pediatrics. 2002;141(3):421–425. [PubMed: 12219066]
• Bazelmans E, Bleijenberg G, Voeten MJM, van der Meer JWM, Folgering H. Impact of a maximal exercise test on symptoms and activity in chronic fatigue syndrome. Journal of Psychosomatic Research. 2005;59(4):201–208. [PubMed: 16223622]
• Beaumont A, Burton AR, Lemon J, Bennett BK, Lloyd A, Vollmer-Conna U. Reduced cardiac vagal modulation impacts on cognitive performance in chronic fatigue syndrome. PLoS ONE. 2012;7(11):e49518. [PMC free article: PMC3498107] [PubMed: 23166694]
• Benarroch EE. Postural tachycardia syndrome: A heterogeneous and multifactorial disorder. Mayo Clinic Proceedings. 2012;87(12):1214–1225. [PMC free article: PMC3547546] [PubMed: 23122672]
• Benditt DG, Remole S, Bailin S, Dunnigan ANN, Asso A, Milstein S. Tilt table testing for evaluation of neurally-mediated (cardioneurogenic) syncope: Rationale and proposed protocols. PACE Pacing and Clinical Electrophysiology. 1991;14(10):1528–1537. [PubMed: 1721135]
• Black CD, McCully KK. Time course of exercise induced alterations in daily activity in chronic fatigue syndrome. Dynamic Medicine. 2005;4(10) [PMC free article: PMC1280928] [PubMed: 16255779]
• Black CD, O'Connor PJ, McCully KK. Increased daily physical activity and fatigue symptoms in chronic fatigue syndrome. Dynamic Medicine. 2005;4(3) [PMC free article: PMC555551] [PubMed: 15745455]
• Blackman A, McGregor C, Dales R, Driver HS, Dumov I, Fleming J, Fraser K, George C, Khullar A, Mink J, Moffat M, Sullivan GE, Fleetham JA, Ayas N, Bradley TD, Fitzpatrick M, Kimoff J, Morrison D, Ryan F, Skomro R, Series F, Tsai W. Canadian Sleep Society/Canadian Thoracic Society position paper on the use of portable monitoring for the diagnosis of obstructive sleep apnea/hypopnea in adults. Canadian Respiratory Journal. 2010;17(5):229–232. [PMC free article: PMC2975504] [PubMed: 21037998]
• Blackwood SK, MacHale SM, Power MJ, Goodwin GM, Lawrie SM. Effects of exercise on cognitive and motor function in chronic fatigue syndrome and depression. Journal of Neurology Neurosurgery and Psychiatry. 1998;65(4):541–546. [PMC free article: PMC2170292] [PubMed: 9771781]
• Blockmans D, Persoons P, Van Houdenhove B, Lejeune M, Bobbaers H. Combination therapy with hydrocortisone and fludrocortisone does not improve symptoms in chronic fatigue syndrome: A randomized, placebo-controlled, double-blind, crossover study. American Journal of Medicine. 2003;114(9):736–741. [PubMed: 12829200]
• Boneva RS, Decker MJ, Maloney EM, Lin JM, Jones JF, Helgason HG, Heim CM, Rye DB, Reeves WC. Higher heart rate and reduced heart rate variability persist during sleep in chronic fatigue syndrome: A population-based study. Autonomic Neuroscience: Basic and Clinical. 2007;137(1-2):94–101. [PubMed: 17851136]
• Bou-Holaigah I, Rowe PC, Kan J, Calkins H. The relationship between neurally mediated hypotension and the chronic fatigue syndrome. Journal of the American Medical Association. 1995;274(12):961–967. [PubMed: 7674527]
• Brown AA, Jason LA, Evans MA, Flores S. Contrasting case definitions: The ME international consensus criteria vs. the Fukuda et al. CFS criteria. North American Journal of Psychology. 2013;15(1):103–120. [PMC free article: PMC4215640] [PubMed: 25364305]
• Brown MM, Jason LA. Functioning in individuals with chronic fatigue syndrome: Increased impairment with co-occurring multiple chemical sensitivity and fibromyalgia. Dynamic Medicine. 2007;6(6) [PMC free article: PMC1890280] [PubMed: 17540028]
• Bruce RA, Kusumi F, Hosmer D. Maximal oxygen intake and nomographic assessment of functional aerobic impairment in cardiovascular disease. American Heart Journal. 1973;85(4):546–562. [PubMed: 4632004]
• Buchwald D, Pearlman T, Umali J, Schmaling K, Katon W. Functional status in patients with chronic fatigue syndrome, other fatiguing illnesses, and healthy individuals. American Journal of Medicine. 1996;101(4):364–370. [PubMed: 8873506]
• Burklow TR, Moak JP, Bailey JJ, Makhlouf FT. Neurally mediated cardiac syncope: Autonomic modulation after normal saline infusion. Journal of the American College of Cardiology. 1999;33(7):2059–2066. [PubMed: 10362214]
• Bush VE, Wight VL, Brown CM, Hainsworth R. Vascular responses to orthostatic stress in patients with Postural Orthostatic Tachycardia Syndrome (POTS), in patients with low orthostatic tolerance, and in asymptomatic controls. Clinical Autonomic Research. 2000;10(5):279–284. [PubMed: 11198483]
• Busichio K, Tiersky LA, DeLuca J, Natelson BH. Neuropsychological deficits in patients with chronic fatigue syndrome. Journal of the International Neuropsychological Society. 2004;10(2):278–285. [PubMed: 15012848]
• Buysse DJ, Reynolds CF III, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: A new instrument for psychiatric practice and research. Psychiatry Research. 1989;28(2):193–213. [PubMed: 2748771]
• Calkins H, Seifert M, Morady F. Clinical presentation and long-term followup of athletes with exercise-induced vasodepressor syncope. American Heart Journal. 1995;129(6):1159–1164. [PubMed: 7754948]
• Capuron L, Welberg L, Heim C, Wagner D, Solomon L, Papanicolaou DA, Craddock RC, Miller AH, Reeves WC. Cognitive dysfunction relates to subjective report of mental fatigue in patients with chronic fatigue syndrome. Neuropsychopharmacology. 2006;31(8):1777–1784. [PubMed: 16395303]
• Carruthers BM, Jain AK, De Meirleir KL, Peterson DL, Klimas NG, Lemer AM, Bested AC, Flor-Henry P, Joshi P, Powles ACP, Sherkey JA, van de Sande MI. Myalgic encephalomyelitis/chronic fatigue syndrome: Clinical working case definition, diagnostic and treatment protocols (Canadian case definition). Journal of Chronic Fatigue Syndrome. 2003;11(1):7–115.
• Carruthers BM, van de Sande MI, De Meirleir KL, Klimas NG, Broderick G, Mitchell T, Staines D, Powles ACP, Speight N, Vallings R, Bateman L, Baumgarten-Austrheim B, Bell DS, Carlo-Stella N, Chia J, Darragh A, Jo D, Lewis D, Light AR, Marshall-Gradisbik S, Mena I, Mikovits JA, Miwa K, Murovska M, Pall ML, Stevens S. Myalgic encephalomyelitis: International consensus criteria. Journal of Internal Medicine. 2011;270(4):327–338. [PMC free article: PMC3427890] [PubMed: 21777306]
• Caseras X, Mataix-Cols D, Giampietro V, Rimes KA, Brammer M, Zelaya F, Chalder T, Godfrey EL. Probing the working memory system in chronic fatigue syndrome: A functional magnetic resonance imaging study using the n-back task. Psychosomatic Medicine. 2006;68(6):947–955. [PubMed: 17079703]
• Caseras X, Mataix-Cols D, Rimes KA, Giampietro V, Brammer M, Zelaya F, Chalder T, Godfrey E. The neural correlates of fatigue: An exploratory imaginal fatigue provocation study in chronic fatigue syndrome. Psychological Medicine. 2008;38(7):941–951. [PubMed: 18447963]
• CDC (Centers for Disease Control and Prevention). CDC symptom inventory. 2005. [January 12, 2015]. http://www​.institutferran​.org/documentos​/cdc_full_symptom_inventory.pdf .
• Chalder T, Berelowitz G, Pawlikowska T, Watts L, Wessely S, Wright D, Wallace EP. Development of a fatigue scale. Journal of Psychosomatic Research. 1993;37(2):147–153. [PubMed: 8463991]
• Chu L, Sunnquist M, So S, Jason LA. Patient survey results for FDA drug development meeting for ME and CFS. Apr 25-26, 2013. [August 19, 2014]. http://www​.iacfsme.org/LinkClick​.aspx?fileticket=E8i8MVWh​%2bX0​%3d&tabid=119 .
• Ciccone DS, Natelson BH. Comorbid illness in women with chronic fatigue syndrome: A test of the single syndrome hypothesis. Psychosomatic Medicine. 2003;65(2):268–275. [PubMed: 12651994]
• Claypoole K, Mahurin R, Fischer ME, Goldberg J, Schmaling KB, Schoene RB, Ashton S, Buchwald D. Cognitive compromise following exercise in monozygotic twins discordant for chronic fatigue syndrome: Fact or artifact. Applied Neuropsychology. 2001;8(1):31–40. [PubMed: 11388121]
• Claypoole KH, Noonan C, Mahurin RK, Goldberg J, Erickson T, Buchwald D. A twin study of cognitive function in chronic fatigue syndrome: The effects of sudden illness onset. Neuropsychology. 2007;21(4):507–513. [PubMed: 17605583]
• Cockshell SJ, Mathias JL. Cognitive functioning in chronic fatigue syndrome: A meta-analysis. Psychological Medicine. 2010;40(8):1253–1267. [PubMed: 20047703]
• Cockshell SJ, Mathias JL. Test effort in persons with chronic fatigue syndrome when assessed using the validity indicator profile. Journal of Clinical and Experimental Neuropsychology. 2012;34(7):679–687. [PubMed: 22440059]
• Cockshell SJ, Mathias JL. Cognitive deficits in chronic fatigue syndrome and their relationship to psychological status, symptomatology, and everyday functioning. Neuropsychology. 2013;27(2):230–242. [PubMed: 23527651]
• Cockshell SJ, Mathias JL. Cognitive functioning in people with chronic fatigue syndrome: A comparison between subjective and objective measures. Neuropsychology. 2014;28(3):394–405. [PubMed: 24364389]
• Constant EL, Adam S, Gillain B, Lambert M, Masquelier E, Seron X. Cognitive deficits in patients with chronic fatigue syndrome compared to those with major depressive disorder and healthy controls. Clinical Neurology & Neurosurgery. 2011;113(4):295–302. [PubMed: 21255911]
• Cook DB, Nagelkirk PR, Peckerman A, Poluri A, Mores J, Natelson BH. Exercise and cognitive performance in chronic fatigue syndrome. Medicine & Science in Sports & Exercise. 2005;37(9):1460–1467. [PubMed: 16177595]
• Cook DB, O'Connor PJ, Lange G, Steffener J. Functional neuroimaging correlates of mental fatigue induced by cognition among chronic fatigue syndrome patients and controls. Neuroimage. 2007;36(1):108–122. [PubMed: 17408973]
• Cook DB, Stegner AJ, Nagelkirk PR, Meyer JD, Togo F, Natelson BH. Responses to exercise differ for chronic fatigue syndrome patients with fibromyalgia. Medicine and Science in Sports and Exercise. 2012;44(6):1186–1193. [PMC free article: PMC3319493] [PubMed: 22157881]
• Cordero DL, Sisto SA, Tapp WN, LaManca JJ, Pareja JG, Natelson BH. Decreased vagal power during treadmill walking in patients with chronic fatigue syndrome. Clinical Autonomic Research. 1996;6(6):329–333. [PubMed: 8985621]
• Corral-Penafiel J, Pepin JL, Barbe F. Ambulatory monitoring in the diagnosis and management of obstructive sleep apnoea syndrome. European Respiratory Review. 2013;22(129):312–324. [PMC free article: PMC9487363] [PubMed: 23997059]
• Costigan A, Elliott C, McDonald C, Newton JL. Orthostatic symptoms predict functional capacity in chronic fatigue syndrome: Implications for management. QJM: Monthly Journal of the Association of Physicians. 2010;103(8):589–595. [PubMed: 20534655]
• Cowan DC, Allardice G, Macfarlane D, Ramsay D, Ambler H, Banham S, Livingston E, Carlin C. Predicting sleep disordered breathing in outpatients with suspected OSA. BMJ Open. 2014;4(4):e004519. [PMC free article: PMC4010842] [PubMed: 24736037]
• Creti L, Libman E, Baltzan M, Rizzo D, Bailes S, Fichten CS. Impaired sleep in chronic fatigue syndrome: How is it best measured. Journal of Health Psychology. 2010;15(4):596–607. [PubMed: 20460416]
• Davenport TE, Stevens SR, Baroni K, Van Ness JM, Snell CR. Reliability and validity of Short Form 36 version 2 to measure health perceptions in a sub-group of individuals with fatigue. Disability & Rehabilitation. 2011a;33(25-26):2596–2604. [PubMed: 21682669]
• Davenport TE, Stevens SR, Baroni K, Van Ness M, Snell CR. Diagnostic accuracy of symptoms characterising chronic fatigue syndrome. Disability & Rehabilitation. 2011b;33(19-20):1768–1775. [PubMed: 21208154]
• Davey NJ, Puri BK, Nowicky AV, Main J, Zaman R. Voluntary motor function in patients with chronic fatigue syndrome. Journal of Psychosomatic Research. 2001;50(1):17–20. [PubMed: 11259796]
• Davis JM, Claypoole KH. Neuropsychological functioning in a pre-screened sample of chronic fatigue syndrome patients. Archives of Clinical Neuropsychology. 1997;12(4):306.
• De Becker P, Dendale P, De Meirleir M, Campine I, Vandenborne K, Hagers Y. Autonomic testing in patients with chronic fatigue syndrome. American Journal of Medicine. 1998;105(3A):22S–26S. [PubMed: 9790478]
• De Becker P, Roeykens J, Reynders M, McGregor N, De Meirleir K. Exercise capacity in chronic fatigue syndrome. Archives of Internal Medicine. 2000;160(21):3270–3277. [PubMed: 11088089]
• De Becker P, McGregor N, De Meirleir K. A definition-based analysis of symptoms in a large cohort of patients with chronic fatigue syndrome. Journal of Internal Medicine. 2001;250(3):234–240. [PubMed: 11555128]
• De Lange FP, Kalkman JS, Bleijenberg G, Hagoort P, van der Meer JWM, Toni I. Gray matter volume reduction in the chronic fatigue syndrome. Neuroimage. 2005;26(3):777–781. [PubMed: 15955487]
• De Lange FP, Koers A, Kalkman JS, Bleijenberg G, Hagoort P, van der Meer JWM, Toni I. Increase in prefrontal cortical volume following cognitive behavioural therapy in patients with chronic fatigue syndrome. Brain. 2008;131(8):2172–2180. [PubMed: 18587150]
• De Lorenzo F, Hargreaves J, Kakkar VV. Pathogenesis and management of delayed orthostatic hypotension in patients with chronic fatigue syndrome. Clinical Autonomic Research. 1997;7(4):185–190. [PubMed: 9292244]
• De Wandele I, Calders P, Peersman W, Rimbaut S, De Backer T, Malfait F, De Paepe A, Rombaut L. Autonomic symptom burden in the hypermobility type of Ehlers-Danlos syndrome: A comparative study with two other EDS types, fibromyalgia, and healthy controls. Seminars in Arthritis and Rheumatism. 2014a;44(3):353–361. [PubMed: 24968706]
• De Wandele I, Rombaut L, Leybaert L, Van de Borne P, De Backer T, Malfait F, De Paepe A, Calders P. Dysautonomia and its underlying mechanisms in the hypermobility type of Ehlers-Danlos syndrome. Seminars in Arthritis and Rheumatism. 2014b;44(1):93–100. [PubMed: 24507822]
• DeLuca J, Kalmar JH. Information processing speed in clinical populations. New York: Taylor & Francis; 2008.
• DeLuca J, Johnson SK, Beldowicz D, Natelson BH. Neuropsychological impairments in chronic fatigue syndrome, multiple sclerosis, and depression. Journal of Neurology, Neurosurgery & Psychiatry. 1995;58(1):38–43. [PMC free article: PMC1073266] [PubMed: 7823065]
• DeLuca J, Christodoulou C, Diamond BJ, Rosenstein ED, Kramer N, Natelson BH. Working memory deficits in chronic fatigue syndrome: Differentiating between speed and accuracy of information processing. Journal of the International Neuropsychological Society. 2004a;10(1):101–109. [PubMed: 14751012]
• DeLuca J, Christodoulou C, Diamond BJ, Rosenstein ED, Kramer N, Ricker JH, Natelson BH. The nature of memory impairment in chronic fatigue syndrome. Rehabilitation Psychology. 2004b;49(1):62–70.
• Den Eede FV, Moorkens G, Hulstijn W, Maas Y, Schrijvers D, Stevens SR, Cosyns P, Claes SJ, Sabbe BGC. Psychomotor function and response inhibition in chronic fatigue syndrome. Psychiatry Research. 2011;186(2-3):367–372. [PubMed: 20797797]
• DePaul Research Team. Depaul symptom questionnaire. 2010. [August 20, 2014]. http://condor​.depaul​.edu/ljason/cfs/measures.html .
• Diamond E. Developing a cardiopulmonary exercise testing laboratory. Chest. 2007;132(6):2000–2007. [PubMed: 18079235]
• Dickson A, Toft A, O'Carroll RE. Neuropsychological functioning, illness perception, mood and quality of life in chronic fatigue syndrome, autoimmune thyroid disease and healthy participants. Psychological Medicine. 2009;39(9):1567–1576. [PubMed: 19144216]
• Duffy FH, McAnulty GB, McCreary MC, Cuchural GJ, Komaroff AL. EEG spectral coherence data distinguish chronic fatigue syndrome patients from healthy controls and depressed patients: A case control study. BMC Neurology. 2011;11 [PMC free article: PMC3146818] [PubMed: 21722376]
• Duprez DA, De Buyzere ML, Drieghe B, Vanhaverbeke F, Taes Y, Michielsen W, Clement DL. Long- and short-term blood pressure and RR-interval variability and psychosomatic distress in chronic fatigue syndrome. Clinical Science. 1998;94(1):57–63. [PubMed: 9505867]
• Edinger JD, Wohlgemuth WK, Krystal AD, Rice JR. Behavioral insomnia therapy for fibromyalgia patients: A randomized clinical trial. Archives of Internal Medicine. 2005;165(21):2527–2535. [PubMed: 16314551]
• Farquhar WB, Hunt BE, Taylor JA, Darling SE, Freeman R. Blood volume and its relation to peak O(2) consumption and physical activity in patients with chronic fatigue. American Journal of Physiology. Heart and Circulatory Physiology. 2002;282(1):H66–H71. [PubMed: 11748048]
• FDA (Food and Drug Administration). The voice of the patient: Chronic fatigue syndrome and myalgic encephalomyelitis. Bethesda, MD: Center for Drug Evaluation and Research (CDER), FDA; 2013.
• Fischler B, LeBon O, Hoffmann G, Cluydts R, Kaufman L, DeMeirleir K. Sleep anomalies in the chronic fatigue syndrome: A comorbidity study. Neuropsychobiology. 1997;35(3):115–122. [PubMed: 9170115]
• Fishbain DA, Cole B, Lewis JE, Gao J. What is the evidence for chronic pain being etiologically associated with the DSM-IV category of sleep disorder due to a general medical condition? A structured evidence-based review. Pain Medicine. 2010;11:158–179. [PubMed: 19788712]
• Fjell AM, Walhovd KB, Brown TT, Kuperman JM, Chung Y, Hagler DJ Jr, Venkatraman V, Roddey JC, Erhart M, McCabe C, Akshoomoff N, Amaral DG, Bloss CS, Libiger O, Darst BF, Schork NJ, Casey BJ, Chang L, Ernst TM, Gruen JR, Kaufmann WE, Kenet T, Frazier J, Murray SS, Sowell ER, van Zijl P, Mostofsky S, Jernigan TL, Dale AM. Multimodal imaging of the self-regulating developing brain. Proceedings of the National Academy of Sciences of the United States of America. 2012;109(48):19620–19625. [PMC free article: PMC3511748] [PubMed: 23150548]
• Foral P, Knezevich J, Dewan N, Malesker M. Medication-induced sleep disturbances. The Consultant Pharmacist. 2011;26(6):414–425. [PubMed: 21628140]
• Fossey M, Libman E, Bailes S, Baltzan M, Schondorf R, Amsel R, Fichten CS. Sleep quality and psychological adjustment in chronic fatigue syndrome. Journal of Behavioral Medicine. 2004;27(6):581–605. [PubMed: 15669445]
• Foster GR, Goldin RD, Thomas HC. Chronic hepatitis C virus infection causes a significant reduction in quality of life in the absence of cirrhosis. Hepatology. 1998;27(1):209–212. [PubMed: 9425939]
• Freeman R, Komaroff AL. Does the chronic fatigue syndrome involve the autonomic nervous system. American Journal of Medicine. 1997;102(4):357–364. [PubMed: 9217617]
• Freeman R, Wieling W, Axelrod FB, Benditt DG, Benarroch E, Biaggioni I, Cheshire WP, Chelimsky T, Cortelli P, Gibbons CH, Goldstein DS, Hainsworth R, Hilz MJ, Jacob G, Kaufmann H, Jordan J, Lipsitz LA, Levine BD, Low PA, Mathias C, Raj SR, Robertson D, Sandroni P, Schatz IJ, Schondorf R, Stewart JM, van Dijk JG. Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome. Autonomic Neuroscience. 2011;161(1-2):46–48. [PubMed: 21393070]
• Frith J, Zalewski P, Klawe JJ, Pairman J, Bitner A, Tafil-Klawe M, Newton JL. Impaired blood pressure variability in chronic fatigue syndrome: A potential biomarker. QJM: Monthly Journal of the Association of Physicians. 2012;105(9):831–838. [PubMed: 22670061]
• Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A, Schluederberg A, Jones JF, Lloyd AR, Wessely S, Gantz NM, Holmes GP, Buchwald D, Abbey S, Rest J, Levy JA, Jolson H, Peterson DL, Vercoulen J, Tirelli U, Evengård B, Natelson BH, Steele L, Reyes M, Reeves WC. The chronic fatigue syndrome: A comprehensive approach to its definition and study. Annals of Internal Medicine. 1994;121(12):953–959. [PubMed: 7978722]
• Furst G. Measuring fatigue in chronic fatigue syndrome why and how. Journal of Chronic Fatigue Syndrome. 1999;5(3-4):55–59.
• Gambert SR. Fatigue: Finding the cause of a common complaint. Clinical Geriatrics. 2005;13(10):6–8.
• Gazit Y, Nahir AM, Grahame R, Jacob G. Dysautonomia in the joint hypermobility syndrome. American Journal of Medicine. 2003;115(1):33–40. [PubMed: 12867232]
• Gerrity TR, Bates J, Bell DS, Chrousos G, Furst G, Hedrick T, Hurwitz B, Kula RW, Levine SM, Moore RC, Schondorf R. Chronic fatigue syndrome: What role does the autonomic nervous system play in the pathophysiology of this complex illness. Neuroimmunomodulation. 2002;10(3):134–141. [PubMed: 12481153]
• Gibson H, Carroll N, Clague JE, Edwards RH. Exercise performance and fatiguability in patients with chronic fatigue syndrome. Journal of Neurology, Neurosurgery & Psychiatry. 1993;56(9):993–998. [PMC free article: PMC489735] [PubMed: 8410041]
• Gotts ZM, Deary V, Newton J, Van der Dussen D, De Roy P, Ellis JG. Are there sleep-specific phenotypes in patients with chronic fatigue syndrome? A cross-sectional polysomnography analysis. BMJ Open. 2013;3(6):e002999. [PMC free article: PMC3669720] [PubMed: 23794547]
• Grubb BP. Clinical practice. Neurocardiogenic syncope. New England Journal of Medicine. 2005;352(10):1004–1010. [PubMed: 15758011]
• Harel D, Thombs BD, Hudson M, Baron M, Steele R. Measuring fatigue in SSC: A comparison of the Short Form-36 Vitality Subscale and Functional Assessment of Chronic Illness Therapy-Fatigue Scale. Rheumatology (Oxford). 2012;51(12):2177–2185. [PubMed: 22923749]
• Hawk C, Jason LA, Torres-Harding S. Differential diagnosis of chronic fatigue syndrome and major depressive disorder. International Journal of Behavioral Medicine. 2006a;13(3):244–251. [PubMed: 17078775]
• Hawk C, Jason LA, Torres-Harding S. Reliability of a chronic fatigue syndrome questionnaire. Journal of Chronic Fatigue Syndrome. 2006b;13(4):41–66.
• Hoad A, Spickett G, Elliott J, Newton J. Postural orthostatic tachycardia syndrome is an under-recognized condition in chronic fatigue syndrome. QJM: Monthly Journal of the Association of Physicians. 2008;101(12):961–965. [PubMed: 18805903]
• Hollingsworth KG, Jones DE, Taylor R, Blamire AM, Newton JL. Impaired cardiovascular response to standing in chronic fatigue syndrome. European Journal of Clinical Investigation. 2010;40(7):608–615. [PubMed: 20497461]
• Hossain JL, Ahmad P, Reinish LW, Kayumov L, Hossain NK, Shapiro CM. Subjective fatigue and subjective sleepiness: Two independent consequences of sleep disorders. Journal of Sleep Research. 2005;14(3):245–253. [PubMed: 16120099]
• Hou R, Moss-Morris R, Bradley B, Peveler R, Mogg K. Attentional bias towards health-threat information in chronic fatigue syndrome. European Neuropsychopharmacology. 2008;18(Suppl. 4):S278. [PubMed: 18582611]
• Hou R, Moss-Morris R, Risdale A, Lynch J, Jeevaratnam P, Bradley BP, Mogg K. Attention processes in chronic fatigue syndrome: Attentional bias for health-related threat and the role of attentional control. Behaviour Research and Therapy. 2014;52:9–16. [PubMed: 24262484]
• Hurwitz BE, Coryell VT, Parker M, Martin P, Laperriere A, Klimas NG, Sfakianakis GN, Bilsker MS. Chronic fatigue syndrome: Illness severity, sedentary lifestyle, blood volume and evidence of diminished cardiac function. Clinical Science. 2010;118(2):125–135. [PubMed: 19469714]
• Hutchinson CV, Badham SP. Patterns of abnormal visual attention in myalgic encephalomyelitis. Optometry and Vision Science. 2013;90(6):607–614. [PubMed: 23689679]
• IACFS/ME (International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis). ME/CFS: Primer for clinical practitioners. Chicago, IL: IACFS/ME; 2014.
• Inbar O, Dlin R, Rotstein A, Whipp BJ. Physiological responses to incremental exercise in patients with chronic fatigue syndrome. Medicine & Science in Sports & Exercise. 2001;33(9):1463–1470. [PubMed: 11528333]
• Jackson ML, Bruck D. Sleep abnormalities in chronic fatigue syndrome/myalgic encephalomyelitis: A review. Journal of Clinical Sleep Medicine. 2012;8(6):719–728. [PMC free article: PMC3501671] [PubMed: 23243408]
• Jason LA, Brown MM. Sub-typing daily fatigue progression in chronic fatigue syndrome. Journal of Mental Health. 2013;22(1):4–11. [PMC free article: PMC3889482] [PubMed: 22548385]
• Jason LA, Taylor RR. Applying cluster analysis to define a typology of chronic fatigue syndrome in a medically-evaluated, random community sample. Psychology and Health. 2002;17(3):323–337.
• Jason LA, Ropacki MT, Santoro NB, Richman JA, Heatherly W, Taylor R, Ferrari JR, Haney-Davis TM, Rademaker A, Dupuis J, Golding J, Plioplys AV, Plioplys S. A screening instrument for chronic fatigue syndrome: Reliability and validity. Journal of Chronic Fatigue Syndrome. 1997;3(1):39–59.
• Jason LA, King CP, Frankenberry EL, Jordan KM, Tryon WW, Rademaker F, Huang CF. Chronic fatigue syndrome: Assessing symptoms and activity level. Journal of Clinical Psychology. 1999;55(4):411–424. [PubMed: 10348404]
• Jason LA, Taylor RR, Kennedy CL, Jordan K, Huang CF, Torres-Harding S, Song S, Johnson D. A factor analysis of chronic fatigue symptoms in a community-based sample. Social Psychiatry & Psychiatric Epidemiology. 2002a;37(4):183–189. [PubMed: 12027245]
• Jason LA, Torres-Harding SR, Carrico AW, Taylor RR. Symptom occurrence in persons with chronic fatigue syndrome. Biological Psychology. 2002b;59(1):15–27. [PubMed: 11790441]
• Jason LA, Torres-Harding SR, Jurgens A, Helgerson J. Comparing the Fukuda et al. criteria and the Canadian case definition for chronic fatigue syndrome. Journal of Chronic Fatigue Syndrome. 2004;12(1):37–52.
• Jason LA, Jessen T, Porter N, Boulton A, Njoku MG, Friedberg G. Examining types of fatigue among individuals with ME/CFS. Disability Studies Quaterly. 2009;29(3)
• Jason LA, Boulton A, Porter NS, Jessen T, Njoku MG, Friedberg F. Classification of myalgic encephalomyelitis/chronic fatigue syndrome by types of fatigue. Behavioral Medicine. 2010a;36(1):24–31. [PMC free article: PMC4852700] [PubMed: 20185398]
• Jason LA, Evans M, Porter N, Brown M, Brown A, Hunnell J, Anderson V, Lerch A, De Meirleir K, Friedberg F. The development of a revised Canadian myalgic encephalomyelitis chronic fatigue syndrome case definition. American Journal of Biochemistry and Biotechnology. 2010b;6(2):120–135.
• Jason LA, Evans M, Brown M, Porter N, Brown A, Hunnell J, Anderson V, Lerch A. Fatigue scales and chronic fatigue syndrome: Issues of sensitivity and specificity. Disability Studies Quarterly: DSQ. 2011a;31(1) [PMC free article: PMC3181109] [PubMed: 21966179]
• Jason LA, Porter N, Hunnell J, Brown A, Rademaker A, Richman JA. A natural history study of chronic fatigue syndrome. Rehabilitation Psychology. 2011b;56(1):32–42. [PMC free article: PMC3171164] [PubMed: 21401284]
• Jason LA, Brown M, Evans M, Anderson V, Lerch A, Brown A, Hunnell J, Porter N. Measuring substantial reductions in functioning in patients with chronic fatigue syndrome. Disability and Rehabilitation. 2011c;33(7):589–598. [PMC free article: PMC3170036] [PubMed: 20617920]
• Jason LA, Brown A, Clyne E, Bartgis L, Evans M, Brown M. Contrasting case definitions for chronic fatigue syndrome, myalgic encephalomyelitis/chronic fatigue syndrome and myalgic encephalomyelitis. Evaluation and the Health Professions. 2012a;35(3):280–304. [PMC free article: PMC3658447] [PubMed: 22158691]
• Jason LA, Unger ER, Dimitrakoff JD, Fagin AP, Houghton M, Cook DB, Marshall GD, Klimas N, Snell C. Minimum data elements for research reports on CFS. Brain, Behavior, and Immunity. 2012b;26(3):401–406. [PMC free article: PMC4643273] [PubMed: 22306456]
• Jason LA, Brown A, Evans M, Sunnquist M, Newton JL. Contrasting chronic fatigue syndrome versus myalgic encephalomyelitis/chronic fatigue syndrome. Fatigue. 2013a;1(3):168–183. [PMC free article: PMC3728084] [PubMed: 23914329]
• Jason LA, Sunnquist M, Brown A, Evans M, Vernon S, Furst J, Simonis V. Examining case definition criteria for chronic fatigue syndrome and myalgic encephalomyelitis. Fatigue: Biomedicine, Health & Behavior. 2013b;2(1) [PMC free article: PMC3912876] [PubMed: 24511456]
• Jason LA, Sunnquist M, Brown A, Evans M, Newton JL. Journal of Health Psychology. 2014. Are myalgic encephalomyelitis and chronic fatigue syndrome different illnesses? A preliminary analysis. [Epub ahead of print] [PMC free article: PMC4125561] [PubMed: 24510231]
• Jason L, Evans M, So S, Scott J, Brown. A. Journal of Prevention and Intervention in the Community. In press. Problems in defining postexertional malaise. [PMC free article: PMC4295644] [PubMed: 25584525]
• Johns MW. Sensitivity and specificity of the multiple sleep latency test (MSLT), the maintenance of wakefulness test and the epworth sleepiness scale: Failure of the MSLT as a gold standard. Journal of Sleep Research. 2000;9(1):5–11. [PubMed: 10733683]
• Jones DE, Hollingsworth KG, Taylor R, Blamire AM, Newton JL. Abnormalities in ph handling by peripheral muscle and potential regulation by the autonomic nervous system in chronic fatigue syndrome. Journal of Internal Medicine. 2010;267(4):394–401. [PubMed: 20433583]
• Jones DE, Hollingsworth KG, Jakovljevic DG, Fattakhova G, Pairman J, Blamire AM, Trenell MI, Newton JL. Loss of capacity to recover from acidosis on repeat exercise in chronic fatigue syndrome: A case-control study. European Journal of Clinical Investigation. 2012;42(2):186–194. [PubMed: 21749371]
• Jones JF, Nicholson A, Nisenbaum R, Papanicolaou DA, Solomon L, Boneva R, Heim C, Reeves WC. Orthostatic instability in a population-based study of chronic fatigue syndrome. American Journal of Medicine. 2005;118(12):1415. [PubMed: 16378795]
• Juenger J, Schellberg D, Kraemer S, Haunstetter A, Zugck C, Herzog W, Haass M. Health related quality of life in patients with congestive heart failure: Comparison with other chronic diseases and relation to functional variables. Heart. 2002;87(3):235–241. [PMC free article: PMC1767036] [PubMed: 11847161]
• Kanjwal K, Karabin B, Kanjwal Y, Grubb BP. Postural orthostatic tachycardia syndrome following Lyme disease. Cardiology Journal. 2011;18(1):63–66. [PubMed: 21305487]
• Kanjwal Y, Kosinski DAN, Grubb BP. The postural orthostatic tachycardia syndrome. Pacing and Clinical Electrophysiology. 2003;26(8):1747–1757. [PubMed: 12877710]
• Kasper DL, Braunwalkd E, Fauci AS, Hauser SL, Longo DL, Jameson JL, editors. Harrison's principles of internal medicine. 16th. Vol. 2. New York: McGraw-Hill; 2005.
• Katch VL, Sady SS, Freedson P. Biological variability in maximum aerobic power. Medicine & Science in Sports & Exercise. 1982;14(1):21–25. [PubMed: 7070252]
• Kaufmann H, Malamut R, Norcliffe-Kaufmann L, Rosa K, Freeman R. The Orthostatic Hypotension Questionnaire (OHQ): Validation of a novel symptom assessment scale. Clinical Autonomic Research. 2012;22(2):79–90. [PubMed: 22045363]
• Kawamura Y, Kihara M, Nishimoto K, Taki M. Efficacy of a half dose of oral pyridostigmine in the treatment of chronic fatigue syndrome: Three case reports. Patho physiology. 2003;9(3):189–194. [PubMed: 14567934]
• Keller BA, Pryor JL, Giloteaux L. Inability of myalgic encephalomyelitis/ chronic fatigue syndrome patients to reproduce VO₂ peak indicates functional impairment. Journal of Translational Medicine. 2014;12(1):104. [PMC free article: PMC4004422] [PubMed: 24755065]
• Kenny RA, Graham LA. Chronic fatigue syndrome symptoms common in patients with vasovagal syncope. American Journal of Medicine. 2001;110(3):242–243. [PubMed: 11221638]
• Kerr JR, Gough J, Richards SC, Main J, Enlander D, McCreary M, Komaroff AL, Chia JK. Antibody to parvovirus B19 nonstructural protein is associated with chronic arthralgia in patients with chronic fatigue syndrome/myalgic encephalomyelitis. Journal of General Virology. 2010;91(Pt. 4):893–897. [PubMed: 20007355]
• Khan F, Spence V, Kennedy G, Belch JJ. Prolonged acetylcholine-induced vasodilatation in the peripheral microcirculation of patients with chronic fatigue syndrome. Clinical Physiology & Functional Imaging. 2003;23(5):282–285. [PubMed: 12950326]
• Kierlin L, Littner MR. Parasomnias and antidepressant therapy: A review of the literature. Front Psychiatry. 2011;2:71. [PMC free article: PMC3235766] [PubMed: 22180745]
• Kishi A, Struzik ZR, Natelson BH, Togo F, Yamamoto Y. Dynamics of sleep stage transitions in healthy humans and patients with chronic fatigue syndrome. American Journal of Physiology—Regulatory Integrative & Comparative Physiology. 2008;294(6):R1980–R1987. [PMC free article: PMC9741833] [PubMed: 18417644]
• Kishi A, Natelson BH, Togo F, Struzik ZR, Rapoport DM, Yamamoto Y. Sleep-stage dynamics in patients with chronic fatigue syndrome with or without fibromyalgia. Sleep. 2011;34(11):1551–1560. [PMC free article: PMC3198210] [PubMed: 22043126]
• Kishi A, Togo F, Cook DB, Klapholz M, Yamamoto Y, Rapoport DM, Natelson BH. The effects of exercise on dynamic sleep morphology in healthy controls and patients with chronic fatigue syndrome. Physiological Reports. 2013;1(6):e00152. [PMC free article: PMC3871467] [PubMed: 24400154]
• Knoop H, Prins JB, Stulemeijer M, van der Meer JWM, Bleijenberg G. The effect of cognitive behaviour therapy for chronic fatigue syndrome on self-reported cognitive impairments and neuropsychological test performance. Journal of Neurology, Neurosurgery & Psychiatry. 2007;78(4):434–436. [PMC free article: PMC2077788] [PubMed: 17369597]
• Komaroff AL, Buchwald D. Symptoms and signs of chronic fatigue syndrome. Reviews of Infectious Diseases. 1991;13(Suppl. 1):S8–S11. [PubMed: 2020806]
• Komaroff AL, Fagioli LR, Doolittle TH, Gandek B, Gleit MA, Guerriero RT, Kornish IRJ, Ware NC, Ware JE Jr, Bates DW. Health status in patients with chronic fatigue syndrome and in general population and disease comparison groups. American Journal of Medicine. 1996a;101(3):281–290. [PubMed: 8873490]
• Komaroff AL, Fagioli LR, Geiger AM, Doolittle TH, Lee J, Kornish J, Gleit MA, Guerriero RT. An examination of the working case definition of chronic fatigue syndrome. American Journal of Medicine. 1996b;100(1):56–64. [PubMed: 8579088]
• Komaroff AL, Fagioli LR, Doolittle TH, Gandek B, Gleit MA, Guerriero RT, Kornish RJ II, Ware NC, Ware JE Jr, Bates DW. Chronic fatigue syndrome questionnaire. In Health status in patients with chronic fatigue syndrome and in general population and disease comparison groups. American Journal of Medicine. 1996c;101(3):281–290. [PubMed: 8873490]
• Krupp LB, LaRocca NG, Muir-Nash J, Steinberg AD. The fatigue severity scale. Application to patients with multiple sclerosis and systemic lupus erythematosus. Archives of Neurology. 1989;46(10):1121–1123. [PubMed: 2803071]
• Krupp LB, Jandorf L, Coyle PK, Mendelson WB. Sleep disturbance in chronic fatigue syndrome. Journal of Psychosomatic Research. 1993;37(4):325–331. [PubMed: 8510058]
• Kushida CA, Littner MR, Morgenthaler T, Alessi CA, Bailey D, Coleman J Jr, Friedman L, Hirshkowitz M, Kapen S, Kramer M, Lee-Chiong T, Loube DL, Owens J, Pancer JP, Wise M. Practice parameters for the indications for polysomnography and related procedures: An update for 2005. Sleep. 2005;28(4):499–521. [PubMed: 16171294]
• LaManca JJ, Sisto SA, DeLuca J, Johnson SK, Lange G, Pareja J, Cook S, Natelson BH. Influence of exhaustive treadmill exercise on cognitive functioning in chronic fatigue syndrome. American Journal of Medicine. 1998;105(3A):59S–65S. [PubMed: 9790484]
• LaManca JJ, Peckerman A, Walker J, Kesil W, Cook S, Taylor A, Natelson BH. Cardiovascular response during head-up tilt in chronic fatigue syndrome. Clinical Physiology. 1999a;19(2):111–120. [PubMed: 10200892]
• LaManca JJ, Sisto SA, Zhou X, Ottenweller JE, Cook S, Peckerman A, Zhang QW, Denny TN, Gause WC, Natelson BH. Immunological response in chronic fatigue syndrome following a graded exercise test to exhaustion. Journal of Clinical Immunology. 1999b;19(2):135–142. [PubMed: 10226888]
• LaManca JJ, Peckerman A, Sisto SA, DeLuca J, Cook S, Natelson BH. Cardiovascular responses of women with chronic fatigue syndrome to stressful cognitive testing before and after strenuous exercise. Psychosomatic Medicine. 2001;63(5):756–764. [PubMed: 11573024]
• Lange G, Steffener J, Cook DB, Bly BM, Christodoulou C, Liu WC, DeLuca J, Natelson BH. Objective evidence of cognitive complaints in chronic fatigue syndrome: A BOLD fMRI study of verbal working memory. Neuroimage. 2005;26(2):513–524. [PubMed: 15907308]
• Larun L, Malterud K. Identity and coping experiences in chronic fatigue syndrome: A synthesis of qualitative studies. Patient Education and Counseling. 2007;69(1-3):20–28. [PubMed: 17698311]
• Lawrie SM, MacHale SM, Cavanagh JTO, O'Carroll RE, Goodwin GM. The difference in patterns of motor and cognitive function in chronic fatigue syndrome and severe depressive illness. Psychological Medicine. 2000;30(2):433–442. [PubMed: 10824663]
• Le Bon O, Fischler B, Hoffmann G, Murphy JR, De Meirleir K, Cluydts R, Pelc I. How significant are primary sleep disorders and sleepiness in the chronic fatigue syndrome. Sleep Research Online. 2000;3(2):43–48. [PubMed: 11382899]
• Le Bon O, Neu D, Valente F, Linkowski P. Paradoxical nrems distribution in “pure” chronic fatigue patients a comparison with sleep apnea-hypopnea patients and healthy control subjects. Journal of Chronic Fatigue Syndrome. 2007;14(2):45–59.
• Le Bon O, Neu D, Berquin Y, Lanquart J-P, Hoffmann R, Mairesse O, Armitage R. Ultra-slow delta power in chronic fatigue syndrome. Psychiatry Research. 2012;200(2-3):742–747. [PubMed: 22771174]
• Legge H, Norton M, Newton J. Fatigue is significant in vasovagal syncope and is associated with autonomic symptoms. Europace. 2008;10(9):1095–1101. [PubMed: 18550509]
• Lewis I, Pairman J, Spickett G, Newton JL. Clinical characteristics of a novel subgroup of chronic fatigue syndrome patients with postural orthostatic tachycardia syndrome. Journal of Internal Medicine. 2013;273(5):501–510. [PubMed: 23206180]
• Libman E, Creti L, Baltzan M, Rizzo D, Fichten CS, Bailes S. Sleep apnea and psychological functioning in chronic fatigue syndrome. Journal of Health Psychology. 2009;14(8):1251–1267. [PubMed: 19858344]
• Light AR, White AT, Hughen RW, Light KC. Moderate exercise increases expression for sensory, adrenergic, and immune genes in chronic fatigue syndrome patients but not in normal subjects. The Journal of Pain. 2009;10(10):1099–1112. [PMC free article: PMC2757484] [PubMed: 19647494]
• Light AR, Bateman L, Jo D, Hughen RW, Vanhaitsma TA, White AT, Light KC. Gene expression alterations at baseline and following moderate exercise in patients with chronic fatigue syndrome and fibromyalgia syndrome. Journal of Internal Medicine. 2012;271(1):64–81. [PMC free article: PMC3175315] [PubMed: 21615807]
• Low PA, Sandroni P, Joyner M, Shen W. Postural tachycardia syndrome. Journal of Cardiovascular Electrophysiology. 2009;20(3):352–358. [PMC free article: PMC3904426] [PubMed: 19207771]
• MacLean A, Allen E, Magath T. Orthostatic tachycardia and orthostatic hypotension: Defects in the return of venous blood to the heart. American Heart Journal. 1944;27(2):145–163.
• Maes M, Twisk FNM, Johnson C. Myalgic encephalomyelitis (ME), chronic fatigue syndrome (CFS), and chronic fatigue (CF) are distinguished accurately: Results of supervised learning techniques applied on clinical and inflammatory data. Psychiatry Research. 2012;200(2-3):754–760. [PubMed: 22521895]
• Mahurin RK, Goldberg JH, Claypoole KH, Arguelles L, Ashton S, Buchwald D. Cognitive processing in monozygotic twins discordant for chronic fatigue syndrome. Neuropsychology. 2004;18(2):232–239. [PubMed: 15099145]
• Majer M, Jones JF, Unger ER, Youngblood LS, Decker MJ, Gurbaxani B, Heim C, Reeves WC. Perception versus polysomnographic assessment of sleep in CFS and non-fatigued control subjects: Results from a population-based study. BMC Neurology. 2007;7 [PMC free article: PMC2231384] [PubMed: 18053240]
• Majer M, Welberg LAM, Capuron L, Miller AH, Pagnoni G, Reeves WC. Neuropsychological performance in persons with chronic fatigue syndrome: Results from a population-based study. Psychosomatic Medicine. 2008;70(7):829–836. [PubMed: 18606722]
• Mariman A, Vogelaers D, Hanoulle I, Delesie L, Pevernagie D. Subjective sleep quality and daytime sleepiness in a large sample of patients with chronic fatigue syndrome (CFS). Acta Clinica Belgica. 2012;67(1):19–24. [PubMed: 22480034]
• Marino M, Li Y, Rueschman MN, Winkelman JW, Ellenbogen JM, Solet JM, Dulin H, Berkman LF, Buxton OM. Measuring sleep: Accuracy, sensitivity, and specificity of wrist actigraphy compared to polysomnography. Sleep. 2013;36(11):1747–1755. [PMC free article: PMC3792393] [PubMed: 24179309]
• Marshall PS, Forstot M, Callies A, Peterson PK, Schenck CH. Cognitive slowing and working memory difficulties in chronic fatigue syndrome. Psychosomatic Medicine. 1997;59(1):58–66. [PubMed: 9021867]
• Martin M, Alexeeva I. Mood volatility with rumination but neither attentional nor interpretation biases in chronic fatigue syndrome. British Journal of Health Psychology. 2010;15(4):779–796. [PubMed: 20100398]
• Martinez-Lavin M. Biology and therapy of fibromyalgia. Stress, the stress response system, and fibromyalgia. Arthritis Research & Therapy. 2007;9(4):216. [PMC free article: PMC2206360] [PubMed: 17626613]
• Martinez-Martinez LA, Mora T, Vargas A, Fuentes-Iniestra M, Martinez-Lavin M. Sympathetic nervous system dysfunction in fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, and interstitial cystitis: A review of case-control studies. Journal of Clinical Rheumatology. 2014;20(3):146–150. [PubMed: 24662556]
• Matthews DA, Manu P, Lane TJ. Evaluation and management of patients with chronic fatigue. American Journal of the Medical Sciences. 1991;302(5):269–277. [PubMed: 1750445]
• McCully KK, Natelson BH. Impaired oxygen delivery to muscle in chronic fatigue syndrome. Clinical Science. 1999;97(5):603–608. discussion 611-613. [PubMed: 10545311]
• McHorney CA, Ware JE Jr, Raczek AE. The MOS 36-item Short-Form Health Survey (SF-36): II. Psychometric and clinical tests of validity in measuring physical and mental health constructs. Medical Care. 1993;31(3):247–263. [PubMed: 8450681]
• Meeus M, Hermans L, Ickmans K, Struyf F, Van Cauwenbergh D, Bronckaerts L, De Clerck LS, Moorken G, Hans G, Grosemans S, Nijs J. Pain Practice. 2014. [January 14, 2015]. Endogenous pain modulation in response to exercise in patients with rheumatoid arthritis, patients with chronic fatigue syndrome and comorbid fibromyalgia, and healthy controls: A double-blind randomized controlled trial. http:​//onlinelibrary​.wiley.com/doi/10.1111/papr.12181/pdf . [PubMed: 24528544]
• Merkus MP, Jager KJ, Dekker FW, Boeschoten EW, Stevens P, Krediet RT. Quality of life in patients on chronic dialysis: Self-assessment 3 months after the start of treatment. The Necosad Study Group. American Journal of Kidney Diseases. 1997;29(4):584–592. [PubMed: 9100049]
• Meyer JD, Light AR, Shukla SK, Clevidence D, Yale S, Stegner AJ, Cook DB. Post-exertion malaise in chronic fatigue syndrome: Symptoms and gene expression. Fatigue: Biomedicine, Health & Behavior. 2013;1(4):190–209.
• Michiels V, Cluydts R. Neuropsychological functioning in chronic fatigue syndrome: A review. Acta Psychiatrica Scandinavica. 2001;103(2):84–93. [PubMed: 11167310]
• Michiels V, Cluydts R, Fischler B, Hoffmann G, Le Bon O, De Meirleir K. Cognitive functioning in patients with chronic fatigue syndrome. Journal of Clinical & Experimental Neuropsychology: Official Journal of the International Neuropsychological Society. 1996;18(5):666–677. [PubMed: 8941852]
• Miwa K. Cardiac dysfunction and orthostatic intolerance in patients with myalgic encephalomyelitis and a small left ventricle. Heart Vessels. 2014:1–6. [PubMed: 24736946]
• Miwa K, Fujita M. Small heart syndrome in patients with chronic fatigue syndrome. Clinical Cardiology. 2008;31(7):328–333. [PMC free article: PMC6653127] [PubMed: 18636530]
• Miwa K, Fujita M. Cardiovascular dysfunction with low cardiac output due to a small heart in patients with chronic fatigue syndrome. Internal Medicine. 2009;48(21):1849–1854. [PubMed: 19881233]
• Miwa K, Fujita M. Small heart with low cardiac output for orthostatic intolerance in patients with chronic fatigue syndrome. Clinical Cardiology. 2011;34(12):782–786. [PMC free article: PMC6652296] [PubMed: 22120591]
• Moffoot AP, O'Carroll RE, Bennie J, Carroll S, Dick H, Ebmeier KP, Goodwin GM. Diurnal variation of mood and neuropsychological function in major depression with melancholia. Journal of Affective Disorders. 1994;32(4):257–269. [PubMed: 7897090]
• Morgenthaler T, Alessi C, Friedman L, Owens J, Kapur V, Boehlecke B, Brown T, Chesson A Jr, Coleman J, Lee-Chiong T, Pancer J, Swick TJ. Practice parameters for the use of actigraphy in the assessment of sleep and sleep disorders: An update for 2007. Sleep. 2007;30(4):519–529. [PubMed: 17520797]
• Morriss R, Sharpe M, Sharpley AL, Cown PJ, Hawton K, Morris J. Abnormalities of sleep in patients with the chronic fatigue syndrome. British Medical Journal. 1993;306(6886):1161–1164. [PMC free article: PMC1677618] [PubMed: 8499816]
• Morriss RK, Wearden AJ, Battersby L. The relation of sleep difficulties to fatigue, mood and disability in chronic fatigue syndrome. Journal of Psychosomatic Research. 1997;42(6):597–605. [PubMed: 9226607]
• Moya A, Sutton R, Ammirati F, Blanc JJ, Brignole M, Dahm JB, Deharo JC, Gajek J, Gjesdal K, Krahn A, Massin M, Pepi M, Pezawas T, Ruiz Granell R, Sarasin F, Ungar A, van Dijk JG, Walma EP, Wieling W. Guidelines for the diagnosis and management of syncope (version 2009). European Heart Journal. 2009;30(21):2631–2671. [PMC free article: PMC3295536] [PubMed: 19713422]
• Murrough JW, Mao X, Collins KA, Kelly C, Andrade G, Nestadt P, Levine SM, Mathew SJ, Shungu DC. Increased ventricular lactate in chronic fatigue syndrome measured by 1H MRS imaging at 3.0 T. II: Comparison with major depressive disorder. NMR in Biomedicine. 2010;23(6):643–650. [PubMed: 20661876]
• Nacul LC, Lacerda EM, Campion P, Pheby D, Drachler MD, Leite JC, Poland F, Howe A, Fayyaz S, Molokhia M. The functional status and well being of people with myalgic encephalomyelitis/chronic fatigue syndrome and their carers. BMC Public Health. 2011a;11 [PMC free article: PMC3123211] [PubMed: 21619607]
• Nacul LC, Lacerda EM, Pheby D, Campion P, Molokhia M, Fayyaz S, Leite JC, Poland F, Howe A, Drachler ML. Prevalence of myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS) in three regions of England: A repeated cross-sectional study in primary care. BMC Medicine. 2011b;9:91. [PMC free article: PMC3170215] [PubMed: 21794183]
• Nakamura T, Schwander SK, Donnelly R, Ortega F, Togo F, Broderick G, Yamamoto Y, Cherniack NS, Rapoport D, Natelson BH. Cytokines across the night in chronic fatigue syndrome with and without fibromyalgia. Clinical and Vaccine Immunology. 2010a;17(4):582–587. [PMC free article: PMC2849324] [PubMed: 20181767]
• Nakamura T, Togo F, Cherniack NS, Rapoport D, Natelson BH. A subgroup of patients with chronic fatigue syndrome may have a disorder of arousal. The Open Sleep Journal. 2010b;3:6–11.
• Nakatomi Y, Mizuno K, Ishii A, Wada Y, Tanaka M, Tazawa S, Onoe K, Fukuda S, Kawabe J, Takahashi K, Kataoka Y, Shiomi S, Yamaguti K, Inaba M, Kuratsune H, Watanabe Y. Neuroinflammation in patients with chronic fatigue syndrome/ myalgic encephalomyelitis: An 11C-(R)-PK11195 PET study. Journal of Nuclear Medicine. 2014;55(6):945–950. [PubMed: 24665088]
• Naschitz JE, Rosner I, Rozenbaum M, Gaitini L, Bistritzki I, Zuckerman E, Sabo E, Yeshurun D. The capnography head-up tilt test for evaluation of chronic fatigue syndrome. Seminars in Arthritis & Rheumatism. 2000;30(2):79–86. [PubMed: 11071579]
• Naschitz JE, Sabo E, Naschitz S, Rosner I, Rozenbaum M, Fields M, Isseroff H, Priselac RM, Gaitini L, Eldar S, Zukerman E, Yeshurun D. Hemodynamics instability score in chronic fatigue syndrome and in non-chronic fatigue syndrome. Seminars in Arthritis & Rheumatism. 2002;32(3):141–148. [PubMed: 12528078]
• Naschitz J, Dreyfuss D, Yeshurun D, Rosner I. Midodrine treatment for chronic fatigue syndrome. Postgraduate Medical Journal. 2004;80(942):230–232. [PMC free article: PMC1742969] [PubMed: 15082846]
• Natelson BH, Intriligator R, Cherniack NS, Chandler HK, Stewart JM. Hypocapnia is a biological marker for orthostatic intolerance in some patients with chronic fatigue syndrome. Dynamic Medicine. 2007;6 [PMC free article: PMC1796865] [PubMed: 17263876]
• National Institute on Aging. Unexplained fatigue in the elderly—workshop summary. 2007. [January 12, 2015]. http://www​.nia.nih.gov​/print/about/events​/2011/unexplained-fatigue-elderly .
• Neu D, Mairesse O, Hoffmann G, Dris A, Lambrecht LJ, Linkowski P, Verbanck P, Olivier LB. Sleep quality perception in the chronic fatigue syndrome: Correlations with sleep efficiency, affective symptoms and intensity of fatigue. Neuropsychobiology. 2007;56(1):40–46. [PubMed: 17986836]
• Neu D, Hoffmann G, Moutrier R, Verbanck P, Linkowski P, Le Bon O. Are patients with chronic fatigue syndrome just “tired” or also “sleepy” Journal of Sleep Research. 2008;17(4):427–431. [PubMed: 19021860]
• Neu D, Kajosch H, Peigneux P, Verbanck P, Linkowski P, Le Bon O. Cognitive impairment in fatigue and sleepiness associated conditions. Psychiatry Research. 2011;189(1):128–134. [PubMed: 21196050]
• Newton JL, Okonkwo O, Sutcliffe K, Seth A, Shin J, Jones DEJ. Symptoms of autonomic dysfunction in chronic fatigue syndrome. QJM: Monthly Journal of the Association of Physicians. 2007;100(8):519–526. [PubMed: 17617647]
• Newton JL, Sheth A, Shin J, Pairman J, Wilton K, Burt JA, Jones DE. Lower ambulatory blood pressure in chronic fatigue syndrome. Psychosomatic Medicine. 2009;71(3):361–365. [PubMed: 19297309]
• NICE (National Institute for Health and Clinical Excellence). Chronic fatigue syndrome/ myalgic encephalomyelitis (or encephalopathy): Diagnosis and management of CFS/ME in adults and children. London, UK: NICE; 2007.
• Nijs J, Van Oosterwijck J, Meeus M, Lambrecht L, Metzger K, Fremont M, Paul L. Unravelling the nature of postexertional malaise in myalgic encephalomyelitis/ chronic fatigue syndrome: The role of elastase, complement C4a and interleukin-1beta. Journal of Internal Medicine. 2010;267(4):418–435. [PubMed: 20433584]
• Nijs J, Nees A, Paul L, De Kooning M, Ickmans K, Meeus M, Van Oosterwijck J. Altered immune response to exercise in patients with chronic fatigue syndrome/ myalgic encephalomyelitis: A systematic literature review. Exercise Immunology Review. 2014;20:94–116. [PubMed: 24974723]
• Nisenbaum R, Reyes M, Mawle AC, Reeves WC. Factor analysis of unexplained severe fatigue and interrelated symptoms: Overlap with criteria for chronic fatigue syndrome. American Journal of Epidemiology. 1998;148(1):72–77. [PubMed: 9663406]
• Nisenbaum R, Jones JF, Unger ER, Reyes M, Reeves WC. A population-based study of the clinical course of chronic fatigue syndrome. Health & Quality of Life Outcomes. 2003;1:49. [PMC free article: PMC269990] [PubMed: 14613572]
• Nisenbaum R, Reyes M, Unger ER, Reeves WC. Factor analysis of symptoms among subjects with unexplained chronic fatigue: What can we learn about chronic fatigue syndrome. Journal of Psychosomatic Research. 2004;56(2):171–178. [PubMed: 15016574]
• Ocon AJ, Messer ZR, Medow MS, Stewart JM. Increasing orthostatic stress impairs neurocognitive functioning in chronic fatigue syndrome with postural tachycardia syndrome. Clinical Science. 2012;122(5):227–238. [PMC free article: PMC3368269] [PubMed: 21919887]
• Okamoto LE, Raj SR, Biaggioni I. Chronic fatigue syndrome and the autonomic nervous system. Primer on the Autonomic Nervous System. 3rd. Robertson D, Biaggioni I, Burnstock G, Low PA, Paton JFR, editors. Oxford: Academic Press; 2012a. pp. 531–534.
• Okamoto LE, Raj SR, Peltier A, Gamboa A, Shibao C, Diedrich A, Black BK, Robertson D, Biaggioni I. Neurohumoral and haemodynamic profile in postural tachycardia and chronic fatigue syndromes. Clinical Science. 2012b;122(4):183–192. [PMC free article: PMC3203411] [PubMed: 21906029]
• Oliveira MG, Garbuio S, Treptow EC, Polese JF, Tufik S, Nery LE, Bittencourt L. The use of portable monitoring for sleep apnea diagnosis in adults. Expert Review of Respiratory Medicine. 2014;8(1):123–132. [PubMed: 24308652]
• Owen AM, McMillan KM, Laird AR, Bullmore E. N-back working memory paradigm: A meta-analysis of normative functional neuroimaging studies. Human Brain Mapping. 2005;25(1):46–59. [PMC free article: PMC6871745] [PubMed: 15846822]
• Parsaik A, Allison TG, Singer W, Sletten DM, Joyner MJ, Benarroch EE, Low PA, Sandroni P. Deconditioning in patients with orthostatic intolerance. Neurology. 2012;79(14):1435–1439. [PMC free article: PMC3525293] [PubMed: 22993288]
• Paul L, Wood L, Behan WMH, Maclaren WM. Demonstration of delayed recovery from fatiguing exercise in chronic fatigue syndrome. European Journal of Neurology. 1999;6(1):63–69. [PubMed: 10209352]
• Peterson PK, Sirr SA, Grammith FC, Schenck CH, Pheley AM, Hu S, Chao CC. Effects of mild exercise on cytokines and cerebral blood flow in chronic fatigue syndrome patients. Clinical and Diagnostic Laboratory Immunology. 1994;1(2):222–226. [PMC free article: PMC368231] [PubMed: 7496949]
• Peterson PK, Pheley A, Schroeppel J, Schenck C, Marshall P, Kind A, Haugland JM, Lambrecht LJ, Swan S, Goldsmith S. A preliminary placebo-controlled crossover trial of fludrocortisone for chronic fatigue syndrome. Archives of Internal Medicine. 1998;158(8):908–914. [PubMed: 9570178]
• Picavet HS, Hoeymans N. Health related quality of life in multiple musculoskeletal diseases: SF-36 and EQ-5d in the DMC₃ study. Annals of the Rheumatic Diseases. 2004;63(6):723–729. [PMC free article: PMC1755044] [PubMed: 15140781]
• Plash WB, Diedrich A, Biaggioni I, Garland EM, Paranjape SY, Black BK, Dupont WD, Raj SR. Diagnosing postural tachycardia syndrome: Comparison of tilt testing compared with standing haemodynamics. Clinical Science (London). 2013;124(2):109–114. [PMC free article: PMC3478101] [PubMed: 22931296]
• Poole J, Herrell R, Ashton S, Goldberg J, Buchwald D. Results of isoproterenol tilt table testing in monozygotic twins discordant for chronic fatigue syndrome. Archives of Internal Medicine. 2000;160(22):3461–3468. [PubMed: 11112240]
• Puri BK, Jakeman PM, Agour M, Gunatilake KD, Fernando KA, Gurusinghe AI, Treasaden IH, Waldman AD, Gishen P. Regional grey and white matter volumetric changes in myalgic encephalomyelitis (chronic fatigue syndrome): A voxelbased morphometry 3 T MRI study. British Journal of Radiology. 2012;85(1015):e270–e273. [PMC free article: PMC3474083] [PubMed: 22128128]
• Qanneta R. Obstructive sleep apnea syndrome manifested as a subset of chronic fatigue syndrome: A comorbidity or an exclusion criterion. Rheumatology International. 2013:1–2. [PubMed: 23595569]
• Qanneta R. Obstructive sleep apnea syndrome manifested as a subset of chronic fatigue syndrome: A comorbidity or an exclusion criterion. Rheumatology International. 2014;34(3):441–442. [PubMed: 23595569]
• Rahman K, Burton A, Galbraith S, Lloyd A, Vollmer-Conna U. Sleep-wake behavior in chronic fatigue syndrome. Sleep: Journal of Sleep and Sleep Disorders Research. 2011;34(5):671–678. [PMC free article: PMC3079947] [PubMed: 21532961]
• Raj SR. Postural Orthostatic Tachycardia Syndrome (POTS). Circulation. 2013;127(23):2336–2342. [PMC free article: PMC3756553] [PubMed: 23753844]
• RAND. RAND 36-Item Health Survey. 1984. [January 14, 2015]. http://www​.rand.org/health​/surveys_tools​/mos/mos_core_36item_survey.html .
• Ray C, Weir WRC, Phillips S, Cullen S. Development of a measure of symptoms in chronic fatigue syndrome: The Profile of Fatigue-Related Symptoms (PFRS). Psychology & Health. 1992;7(1):27–43.
• Razumovsky AY, DeBusk K, Calkins H, Snader S, Lucas KE, Vyas P, Hanley DF, Rowe PC. Cerebral and systemic hemodynamics changes during upright tilt in chronic fatigue syndrome. Journal of Neuroimaging. 2003;13(1):57–67. [PubMed: 12593133]
• Reeves WC, Heim C, Maloney EM, Youngblood LS, Unger ER, Decker MJ, Jones JF, Rye DB. Sleep characteristics of persons with chronic fatigue syndrome and non-fatigued controls: Results from a population-based study. BMC Neurology. 2006;6 [PMC free article: PMC1660569] [PubMed: 17109739]
• Reynolds GK, Lewis DP, Richardson AM, Lidbury BA. Comorbidity of postural orthostatic tachycardia syndrome and chronic fatigue syndrome in an Australian cohort. Journal of Internal Medicine. 2013;275(4):409–417. [PubMed: 24206536]
• Rosen CL, Auckley D, Benca R, Foldvary-Schaefer N, Iber C, Kapur V, Rueschman M, Zee P, Redline S. A multisite randomized trial of portable sleep studies and positive airway pressure autotitration versus laboratory-based polysomnography for the diagnosis and treatment of obstructive sleep apnea: The homepap study. Sleep. 2012;35(6):757–767. [PMC free article: PMC3353048] [PubMed: 22654195]
• Rowe PC, Calkins H. Neurally mediated hypotension and chronic fatigue syndrome. American Journal of Medicine. 1998;105(3A):15S–21S. [PubMed: 9790477]
• Rowe PC, Bou-Holaigah I, Kan JS, Calkins H. Is neurally mediated hypotension an unrecognised cause of chronic fatigue. Lancet. 1995;345(8950):623–624. [PubMed: 7898182]
• Rowe PC, Barron DF, Calkins H, Maumenee IH, Tong PY, Geraghty MT. Orthostatic intolerance and chronic fatigue syndrome associated with Ehlers-Danlos syndrome. Journal of Pediatrics. 1999;135(4):494–499. [PubMed: 10518084]
• Rowe PC, Calkins H, DeBusk K, McKenzie R, Anand R, Sharma G, Cuccherini BA, Soto N, Hohman P, Snader S, Lucas KE, Wolff M, Straus SE. Fludrocortisone acetate to treat neurally mediated hypotension in chronic fatigue syndrome: A randomized controlled trial. Journal of the American Medical Association. 2001;285(1):52–59. [PubMed: 11150109]
• Salaffi F, Sarzi-Puttini P, Girolimetti R, Atzeni F, Gasparini S, Grassi W. Health-related quality of life in fibromyalgia patients: A comparison with rheumatoid arthritis patients and the general population using the SF-36 Health Survey. Clinical and Experimental Rheumatology. 2009;27(5, Suppl. 56):S67–S74. [PubMed: 20074443]
• Sargent C, Scroop GC, Nemeth PM, Burnet RB, Buckley JD. Maximal oxygen uptake and lactate metabolism are normal in chronic fatigue syndrome. Medicine & Science in Sports & Exercise. 2002;34(1):51–56. [PubMed: 11782647]
• Schmaling KB, Lewis DH, Fiedelak JI, Mahurin R, Buchwald DS. Single-photon emission computerized tomography and neurocognitive function in patients with chronic fatigue syndrome. Psychosomatic Medicine. 2003;65(1):129–136. [PubMed: 12554824]
• Schondorf R, Benoit J, Wein T, Phaneuf D. Orthostatic intolerance in the chronic fatigue syndrome. Journal of the Autonomic Nervous System. 1999;75(2-3):192–201. [PubMed: 10189122]
• Schrezenmaier C, Gehrking JA, Hines SM, Low PA, Benrud-Larson LM, Sandroni P. Evaluation of orthostatic hypotension: Relationship of a new self-report instrument to laboratory-based measures. Mayo Clinic Proceedings. 2005;80(3):330–334. [PubMed: 15757013]
• Schrijvers D, Van Den Eede F, Maas Y, Cosyns P, Hulstijn W, Sabbe BGC. Psychomotor functioning in chronic fatigue syndrome and major depressive disorder: A comparative study. Journal of Affective Disorders. 2009;115(1-2):46–53. [PubMed: 18817977]
• Sharpley A, Clements A, Hawton K, Sharpe M. Do patients with “pure” chronic fatigue syndrome (neurasthenia) have abnormal sleep. Psychosomatic Medicine. 1997;59(6):592–596. [PubMed: 9407577]
• Short K, McCabe M, Tooley G. Cognitive functioning in chronic fatigue syndrome and the role of depression, anxiety, and fatigue. Journal of Psychosomatic Research. 2002;52(6):475–483. [PubMed: 12069872]
• Shungu DC, Weiduschat N, Murrough JW, Mao X, Pillemer S, Dyke JP, Medow MS, Natelson BH, Stewart JM, Mathew SJ. Increased ventricular lactate in chronic fatigue syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology. NMR in Biomedicine. 2012;25(9):1073–1087. [PMC free article: PMC3896084] [PubMed: 22281935]
• Sisto SA, Tapp W, Drastal S, Bergen M, DeMasi I, Cordero D, Natelson B. Vagal tone is reduced during paced breathing in patients with the chronic fatigue syndrome. Clinical Autonomic Research. 1995;5(3):139–143. [PubMed: 7549414]
• Sletten DM, Suarez GA, Low PA, Mandrekar J, Singer W. COMPASS 31: A refined and abbreviated Composite Autonomic Symptom Score. Mayo Clinic Proceedings. 2012;87(12):1196–1201. [PMC free article: PMC3541923] [PubMed: 23218087]
• Smets EM, Garssen B, Bonke B, De Haes JC. The Multidimensional Fatigue Inventory (MFI) psychometric qualities of an instrument to assess fatigue. Journal of Psychosomatic Research. 1995;39(3):315–325. [PubMed: 7636775]
• Smith AP, Borysiewicz L, Pollock J, Thomas M, Perry K, Llewelyn M. Acute fatigue in chronic fatigue syndrome patients. Psychological Medicine. 1999;29(2):283–290. [PubMed: 10218920]
• Smith GA, Carew M. Decision time unmasked: Individuals adopt different strategies. Australian Journal of Psychology. 1987;39(3):339–351.
• Snell CR, Stevens SR, Davenport TE, Van Ness JM. Discriminative validity of metabolic and workload measurements for identifying people with chronic fatigue syndrome. Physical Therapy. 2013;93(11):1484–1492. [PubMed: 23813081]
• Soetekouw P, Lenders JWM, Bleijenberg G, Thien T, van der Meer JWM. Autonomic function in patients with chronic fatigue syndrome. Clinical Autonomic Research. 1999;9(6):334–340. [PubMed: 10638807]
• Sorensen B, Streib JE, Strand M, Make B, Giclas PC, Fleshner M, Jones JF. Complement activation in a model of chronic fatigue syndrome. Journal of Allergy & Clinical Immunology. 2003;112(2):397–403. [PubMed: 12897748]
• Spitzer AR, Broadman M. A retrospective review of the sleep characteristics in patients with chronic fatigue syndrome and fibromyalgia. Pain Practice. 2010a;10(4):294–300. [PubMed: 20230458]
• Spitzer AR, Broadman M. Treatment of the narcoleptiform sleep disorder in chronic fatigue syndrome and fibromyalgia with sodium oxybate. Pain Practice. 2010b;10(1):54–59. [PubMed: 20629967]
• Spotila J. Post-exertional malaise in chronic fatigue syndrome. Charlotte, NC: CFIDS Association of America; 2010.
• Stewart JM, Gewitz MH, Weldon A, Munoz J. Patterns of orthostatic intolerance: The orthostatic tachycardia syndrome and adolescent chronic fatigue. Journal of Pediatrics. 1999;135(2, Pt. 1):218–225. [PubMed: 10431117]
• Stewart JM, Medow MS, Messer ZR, Baugham IL, Terilli C, Ocon AJ. Postural neurocognitive and neuronal activated cerebral blood flow deficits in young chronic fatigue syndrome patients with postural tachycardia syndrome. American Journal of Physiology—Heart & Circulatory Physiology. 2012;302(5):H1185–H1194. [PMC free article: PMC3311460] [PubMed: 22180650]
• Streeten DHP. Role of impaired lower-limb venous innervation in the pathogenesis of the chronic fatigue syndrome. American Journal of the Medical Sciences. 2001;321(3):163–167. [PubMed: 11269790]
• Streeten DH, Anderson GH Jr. Delayed orthostatic intolerance. Archives of Internal Medicine. 1992;152(5):1066–1072. [PubMed: 1580710]
• Streeten DHP, Bell DS. Circulating blood volume in chronic fatigue syndrome. Journal of Chronic Fatigue Syndrome. 1998;4(1):3–11.
• Streeten DHP, Thomas D, Bell DS. The roles of orthostatic hypotension, orthostatic tachycardia, and subnormal erythrocyte volume in the pathogenesis of the chronic fatigue syndrome. American Journal of the Medical Sciences. 2000;320(1):1–8. [PubMed: 10910366]
• Suarez GA, Opfer-Gehrking TL, Offord KP, Atkinson EJ, O'Brien PC, Low PA. The autonomic symptom profile: A new instrument to assess autonomic symptoms. Neurology. 1999;52(3):523–528. [PubMed: 10025781]
• Takenaka K, Suzuki Y, Uno K, Sato M, Komuro T, Haruna Y, Kobayashi H, Kawakubo K, Sonoda M, Asakawa M, Nakahara K, Gunji A. Effects of rapid saline infusion on orthostatic intolerance and autonomic tone after 20 days bed rest. American Journal of Cardiology. 2002;89(5):557–561. [PubMed: 11867041]
• Tanaka H, Matsushima R, Tamai H, Kajimoto Y. Impaired postural cerebral hemodynamics in young patients with chronic fatigue with and without orthostatic intolerance. Journal of Pediatrics. 2002;140(4):412–417. [PubMed: 12006954]
• Taylor HL, Buskirk E, Henschel A. Maximal oxygen intake as an objective measure of cardio-respiratory performance. Journal of Applied Physiology. 1955;8(1):73–80. [PubMed: 13242493]
• Taylor RR, Jason LA, Curie CJ. Prognosis of chronic fatigue in a community-based sample. Psychosomatic Medicine. 2002;64(2):319–327. [PubMed: 11914449]
• Thieben MJ, Sandroni P, Sletten DM, Benrud-Larson LM, Fealey RD, Vernino S, Lennon VA, Shen WK, Low PA. Postural orthostatic tachycardia syndrome: The Mayo Clinic experience. Mayo Clinic Proceedings. 2007;82(3):308–313. [PubMed: 17352367]
• Thorpy MJ. The clinical use of the multiple sleep latency test. The standards of practice committee of the American sleep disorders association. Sleep. 1992;15(3):268–276. [PubMed: 1621030]
• Tiersky LA, Johnson SK, Lange G, Natelson BH, DeLuca J. Neuropsychology of chronic fatigue syndrome: A critical review. Journal of Clinical and Experimental Neuropsychology. 1997;19(4):560–586. [PubMed: 9342690]
• Tiersky LA, Matheis RJ, DeLuca J, Lange G, Natelson BH. Functional status, neuropsychological functioning, and mood in chronic fatigue syndrome (CFS): Relationship to psychiatric disorder. Journal of Nervous and Mental Disease. 2003;191(5):324–331. [PubMed: 12819552]
• Timmers HJ, Wieling W, Soetekouw PM, Bleijenberg G, van der Meer JW, Lenders JW. Hemodynamic and neurohumoral responses to head-up tilt in patients with chronic fatigue syndrome. Clinical Autonomic Research. 2002;12(4):273–280. [PubMed: 12357281]
• Togo F, Natelson BH. Heart rate variability during sleep and subsequent sleepiness in patients with chronic fatigue syndrome. Autonomic Neuroscience: Basic and Clinical. 2013;176(1-2):85–90. [PMC free article: PMC4100066] [PubMed: 23499514]
• Togo F, Natelson BH, Cherniack NS, FitzGibbons J, Garcon C, Rapoport DM. Sleep structure and sleepiness in chronic fatigue syndrome with or without coexisting fibromyalgia. Arthritis Research & Therapy. 2008;10(3):R56. [PMC free article: PMC2483445] [PubMed: 18474105]
• Togo F, Natelson BH, Cherniack NS, Klapholz M, Rapoport DM, Cook DB. Sleep is not disrupted by exercise in patients with chronic fatigue syndromes. Medicine & Science in Sports & Exercise. 2010;42(1):16–22. [PMC free article: PMC2796587] [PubMed: 20010134]
• Togo F, Lange G, Natelson BH, Quigley KS. Journal of Neuropsychology. 2013. [January 14, 2015]. Attention network test: Assessment of cognitive function in chronic fatigue syndrome. http:​//onlinelibrary​.wiley.com/doi/10.1111/jnp.12030/pdf . [PMC free article: PMC4159443] [PubMed: 24112872]
• Tomfohr LM, Ancoli-Israel S, Loredo JS, Dimsdale JE. Effects of continuous positive airway pressure on fatigue and sleepiness in patients with obstructive sleep apnea: Data from a randomized controlled trial. Sleep. 2011;34(1):121–126. [PMC free article: PMC3001790] [PubMed: 21203367]
• Trivedi MH, Rush AJ, Armitage R, Gullion CM, Grannemann BD, Orsulak PJ, Roffwarg HP. Effects of fluoxetine on the polysomnogram in outpatients with major depression. Neuropsychopharmacology. 1999;20(5):447–459. [PubMed: 10192825]
• Unger ER, Nisenbaum R, Moldofsky H, Cesta A, Sammut C, Reyes M, Reeves WC. Sleep assessment in a population-based study of chronic fatigue syndrome. BMC Neurology. 2004;4 [PMC free article: PMC419502] [PubMed: 15096280]
• Unger ER, Miller AH, Jones JF, Drake DF, Tian H, Pagnoni G. Decreased basal ganglia activation in chronic fatigue syndrome subjects is associated with increased fatigue. The FASEB Journal. 2012;26
• Van de Luit L, Van der Meulen J, Cleophas TJM, Zwinderman AH. Amplified amplitudes of circadian rhythms and night time hypotension in patients with chronic fatigue syndrome; improvement by inopamil but not by melatonin. European Journal of Internal Medicine. 1998;9(2):99–103. [PubMed: 9822046]
• Van Den Eede F, Moorkens G, Hulstijn W, Maas Y, Schrijvers D, Stevens SR, Cosyns P, Claes SJ, Sabbe BGC. Psychomotor function and response inhibition in chronic fatigue syndrome. Psychiatry Research. 2011;186(2-3):367–372. [PubMed: 20797797]
• Van Oosterwijck J, Nijs J, Meeus M, Lefever I, Huybrechts L, Lambrecht L, Paul L. Pain inhibition and postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: An experimental study. Journal of Internal Medicine. 2010;268(3):265–278. [PubMed: 20412374]
• VanNess JM, Snell CR, Stevens SR. Diminished cardiopulmonary capacity during post-exertional malaise. Journal of Chronic Fatigue Syndrome. 2007;14:77–85.
• VanNess JM, Stevens SR, Bateman L, Stiles TL, Snell CR. Postexertional malaise in women with chronic fatigue syndrome. Journal of Women's Health. 2010;19(2):239–244. [PubMed: 20095909]
• Vercoulen JHMM, Bazelmans E, Swanink CMA, Galama JMD, Fennis JFM, van der Meer JWM, Bleijenberg G. Evaluating neuropsychological impairment in chronic fatigue syndrome. Journal of Clinical and Experimental Neuropsychology. 1998;20(2):144–156. [PubMed: 9777468]
• Vermeulen RC, Scholte HR. Rupture of silicone gel breast implants and symptoms of pain and fatigue. Journal of Rheumatology. 2003;30(10):2263–2267. [PubMed: 14528527]
• Vermeulen RCW, 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. Journal of Translational Medicine. 2010;8(93) [PMC free article: PMC2964609] [PubMed: 20937116]
• Wagner D, Nisenbaum R, Heim C, Jones JF, Unger ER, Reeves WC. Psychometric properties of the CDC symptom inventory for assessment of chronic fatigue syndrome. Population Health Metrics. 2005;3:8. [PMC free article: PMC1183246] [PubMed: 16042777]
• Ware JE. SF-36 Health Survey. In Chronic fatigue and chronic fatigue syndrome: A co-twin control study of functional status. Quality of Life Research. 2002;11:463–471. [PubMed: 12113393]
• Watson NF, Kapur V, Arguelles LM, Goldberg J, Schmidt DF, Armitage R, Buchwald D. Comparison of subjective and objective measures of insomnia in monozygotic twins discordant for chronic fatigue syndrome. Sleep. 2003;26(3):324–328. [PubMed: 12749553]
• Watson NF, Jacobsen C, Goldberg J, Kapur V, Buchwald D. Subjective and objective sleepiness in monozygotic twins discordant for chronic fatigue syndrome. Sleep. 2004;27(5):973–977. [PubMed: 15453557]
• Weltman A, Snead D, Stein P, Seip R, Schurrer R, Rutt R, Weltman J. Reliability and validity of a continuous incremental treadmill protocol for the determination of lactate threshold, fixed blood lactate concentrations, and VO₂max. International Journal of Sports Medicine. 1990;11(1):26–32. [PubMed: 2318561]
• Whelton CL, Salit I, Moldofsky H. Sleep, Epstein-Barr virus infection, musculoskeletal pain, and depressive symptoms in chronic fatigue syndrome. Journal of Rheumatology. 1992;19(6):939–943. [PubMed: 1328633]
• White AT, Light AR, Hughen RW, Bateman L, Martins TB, Hill HR, Light KC. Severity of symptom flare after moderate exercise is linked to cytokine activity in chronic fatigue syndrome. Psychophysiology. 2010;47(4):615–624. [PMC free article: PMC4378647] [PubMed: 20230500]
• White AT, Light AR, Hughen RW, VanHaitsma TA, Light KC. Differences in metabolite-detecting, adrenergic, and immune gene expression after moderate exercise in patients with chronic fatigue syndrome, patients with multiple sclerosis, and healthy controls. Psychosomatic Medicine. 2012;74(1):46–54. [PMC free article: PMC3256093] [PubMed: 22210239]
• Whitehead L. The measurement of fatigue in chronic illness: A systematic review of unidimensional and multidimensional fatigue measures. Journal of Pain and Symptom Management. 2009;37(1):107–128. [PubMed: 19111779]
• Wiborg JF, van der Werf S, Prins JB, Bleijenberg G. Being homebound with chronic fatigue syndrome: A multidimensional comparison with outpatients. Psychiatry Research. 2010;177(1-2):246–249. [PubMed: 20207012]
• Wilson A, Hickie I, Lloyd A, Hadzi-Pavlovic D, Boughton C, Dwyer J, Wakefield D. Longitudinal study of outcome of chronic fatigue syndrome. British Medical Journal. 1994;308(6931):756–759. [PMC free article: PMC2539669] [PubMed: 8142830]
• Winkler AS, Blair D, Marsden JT, Peters TJ, Wessely S, Cleare AJ. Autonomic function and serum erythropoietin levels in chronic fatigue syndrome. Journal of Psychosomatic Research. 2004;56(2):179–183. [PubMed: 15016575]
• Wyller VB, Barbieri R, Thaulow E, Saul JP. Enhanced vagal withdrawal during mild orthostatic stress in adolescents with chronic fatigue. Annals of Noninvasive Electrocardiology. 2008;13(1):67–73. [PMC free article: PMC6932180] [PubMed: 18234008]
• Yamaguti K, Tajima S, Kuratsune H. Autonomic dysfunction in chronic fatigue syndrome. Advances in Neuroimmune Biology. 2013;4(4):281–289.
• Yamamoto Y, LaManca JJ, Natelson BH. A measure of heart rate variability is sensitive to orthostatic challenge in women with chronic fatigue syndrome. Experimental Biology & Medicine. 2003;228(2):167–174. [PubMed: 12563023]
• Yataco A, Talo H, Rowe P, Kass DA, Berger RD, Calkin H. Comparison of heart rate variability in patients with chronic fatigue syndrome and controls. Clinical Autonomic Research. 1997;7(6):293–297. [PubMed: 9430800]
• Yoshiuchi K, Cook DB, Ohashi K, Kumano H, Kuboki T, Yamamoto Y, Natelson BH. A real-time assessment of the effect of exercise in chronic fatigue syndrome. Physiology & Behavior. 2007;92(5):963–968. [PMC free article: PMC2170105] [PubMed: 17655887]
• Zhang L, Gough J, Christmas D, Mattey DL, Richards SC, Main J, Enlander D, Honeybourne D, Ayres JG, Nutt DJ, Kerr JR. Microbial infections in eight genomic subtypes of chronic fatigue syndrome/myalgic encephalomyelitis. Journal of Clinical Pathology. 2010;63(2):156–164. [PMC free article: PMC2921262] [PubMed: 19955554]

Footnotes

1

The RP subscale combines the scores of four questions related to physical activity.

2

Personal communication; public comments submitted to the IOM Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome for meeting 1, 2014.

3

Personal communication; public comments submitted to the IOM Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome for meeting 3, 2014.

4

Ibid.

5

Jason and colleagues (2013b) compared 236 ME/CFS patients with 86 healthy controls who completed the DePaul Symptom Questionnaire, rating the frequency and severity of 54 symptoms. Patient data were obtained from the SolveCFS BioBank, which includes patients diagnosed by a licensed physician using either the Fukuda definition or the CCC.

6

Fischler and colleagues (1997) did not exclude sleep disorders.

7

Personal communication; public comments submitted to the IOM Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome for meeting 3, 2014.