Abstract

Chronic fatigue syndrome (CFS) and fibromyalgia (FM) are medically unexplained syndromes that can and often do co-occur. For this reason, some have posited that the two are part of the same somatic syndrome—examples of symptom amplification. This hypothesis would suggest that few differences exist between the two syndromes. To evaluate this interpretation, we have searched the literature for articles comparing CFS to FM, reviewing only those articles which report differences between the two. This review presents data showing differences across a number of parameters—implying that the underlying pathophysiology in CFS may differ from that of FM. We hope that our review encourages other groups to look for additional differences between CFS and FM. By continuing to preserve the unique illness definitions of the two syndromes, clinicians will be able to better identify, understand and provide treatment for these individuals.

Introduction

Chronic fatigue syndrome (CFS) and fibromyalgia (FM) are medically unexplained illnesses, predominantly of women, characterized by disabling fatigue and by widespread pain with tenderness, respectively. In contrast to FM which has no exclusionary diagnostic criteria, CFS should not be diagnosed unless medical and psychiatric causes of fatigue have been ruled out; thus, the prevalence of FM is ∼10-fold higher than that of CFS (31 vs. 0.3%2). Of 313 patients diagnosed with CFS at our CFS Cooperative Research Center through 2003, 76% were women and 34% had co-morbid FM. The peak age at which each syndrome occurs is not the same, however. CFS peaks in the mid 40’s and then drops off,2 while the prevalence of FM increases monotonically over the decades, peaking at the 55–64 age range.1

Since these two illnesses can and often do co-occur, some researchers3 have argued that the ‘similarities between them outweigh the differences’ and proposed abandoning discrete case definitions for a more general diagnosis of ‘functional somatic syndromes’; this position may be labeled the single syndrome hypothesis. Other researchers have extended this line of thinking by suggesting that the problem common to both syndromes is the psychogenic process of symptom amplification—a common psychological tendency to somatize or misconstrue the significance of normal physical sensations.4 This point of view leads to a testable hypothesis. If CFS and FM are the same, then there should be few differences among the possible groups of CFS alone, CFS and FM, or FM alone. To evaluate this hypothesis, we reviewed our own data, research articles and our literature collection. We also searched the literature using PubMed and Google Scholar for articles comparing CFS to FM, reviewing only those articles that reported differences between the two syndromes. In doing so, we used two search strategies. The first strategy looked across specific systems thought to be involved in the pathophysiology of these illnesses—e.g. neuroendocrine or hypothalamo–pituitary axis and FM or CFS; it produced four references. A more inclusive second search was then conducted whereby the search term ‘cfs fm differences’ yielded 29 results on PubMed; five of these results were applicable. Using the same search term on Google scholar yielded 11 applicable results out of 7890. In completing these searches, we did not review those articles that reported similarities, and focused on those which noted differences between the two illness groups or between only one of the groups and the controls.

Differences could be quantitative as evidenced by their being significantly different on some measure, or they could be qualitative. An example of what we mean by ‘qualitative’ relates to spinal fluid substance P, reported to be elevated in FM by four labs (see Reference 55 as one of these) but found to be in the normal range in CFS.6 Operationally, we will label a difference as qualitative if it differs significantly from values found in ‘both’ the other disease group and controls or, as in the case with substance P, if it is found only in one disease group. Qualitative differences would provide stronger evidence for the conclusion that the two illnesses were not the same than would be the case if we were to find only quantitative differences. In this way, our work seeks to look for differences as suggested by Peter White’s test of whether an illness differs from another illness with which it overlaps based on illness phenotypes and associations between risk markers.7

Our own studies have compared those with CFS alone to those with CFS + FM and have revealed the following results: (i) Those in the former but not the latter group showed neuropsychological dysfunction and an elevated brain serotonergic response to tryptophan infusion relative to controls.8,9 (ii) Those with CFS + FM but not CFS alone showed an altered physiological response to a standardized sub-maximal exercise test through reduced blood pressure and an increased stroke index.10 (iii) Transitions among the different stages of sleep showed dramatic differences in the pattern of sleep when the two groups were compared to controls: CFS only patients showed sleep disruption in rapid eye movements (REM) sleep, while CFS + FM patients showed sleep disruption in slow wave sleep and evidence of increased sleep pressure.11 (iv) Concerning post-traumatic stress disorder (PTSD), CFS only patients had community rates of PTSD on diagnostic psychiatric interview—i.e. 1.5%, while those with CFS + FM were substantially and significantly higher—8.5% (Natelson, unpublished data). Another group has reported this same general finding.12 (v) Finally, our group has identified 124 patients (M:F = 84:40) diagnosed with obstructive sleep apnea based on their fulfilling diagnostic criteria of having apnea–hypopnea indices of 5 or higher during overnight polysomnography. None of these patients had FM alone, while 3 had CFS + FM (4%) and 11 had CFS only (Natelson and Vgontzas, unpublished data). These findings indicate discordance in rates of FM and CFS; rates of FM occurred at approximately those expected in community samples compared with substantially higher rates for CFS.

Systemic review of studies

The following studies are arranged systematically in bullet format, divided into the following groups.

Hormone dynamics

  • There seems to be an abnormality in the growth hormone system in FM which does not exist in CFS. Several research groups,13,14 but not all,15,16 have reported reduced levels of insulin-like growth factor I, also known as somatomedin, in FM with additional evidence supporting dysfunction in growth hormone secretion itself.17 By contrast, one study in CFS reported frank increases in somatomedin relative to controls.18 Also, a double blind, placebo-controlled treatment trial of FM patients with growth hormone reported patient self-assessed improvement as well as a reduction in tender point scores.19

  • Levels of nocturnal plasma melatonin in premenopausal women were found to be significantly higher in FM patients than in either CFS patients or healthy controls.20

  • Crofford and colleagues21 have sampled blood for adrenocorticotrophic hormone (ACTH) and cortisol every 10 min for a 24-h period from 14 patients with CFS, 11 patients with CFS and FM, 12 patients with FM only and from healthy controls matched by age, gender and menstrual status. The group found elevated quiescent cortisol levels in patients with FM only that were not seen in those with CFS only and not as prominent as those observed in patients with CFS and FM; of interest was the fact that the majority of FM patients showed no evidence of cessation of hormonal secretion—quiescent period—which was not the case for CFS. In addition, the researchers reported differences in early morning cortisol levels: decreased levels were present in the CFS only group but not in the FM only group; and intermediary levels were present in patients with FM and CFS. Based on this information, the authors concluded that there were differences in the basal circadian architecture of those with CFS alone and FM alone, while patients with both CFS and FM had cortisol levels which fell between the two groups.

Genetics/molecular biology

  • One hypothesis as to the cause of CFS is viral infection due to dysregulated antiviral processes. To test this idea, a number of studies have focused on the 2-5 A synthetase/ribonuclease L pathway because it is central to the antiviral activity of interferon. Earlier work had reported an unidentified low molecular weight form of ribonuclease L hypothesized to act as an inhibitor of interferon-induced antiviral activity. DeMeirleir and colleagues22 have studied the distribution of the 2-5 A binding proteins from the blood mononuclear cells of 57 CFS patients of whom 53 reported having an ‘acute or subacute viral onset’, 11 FM patients and 28 healthy controls. Graphical results were presented for the 37 kDa, the 40 kDa and the 80 kDa binding proteins, and the former two appeared to show substantially higher values for CFS than for FM. Statistical data were reported only for the 37 kDa binding protein: It was found in 88% of CFS patients compared with 38% of FM patients (Fisher’s test <0.001) and 32% of controls. The group believes that the 39 kDa protein is the low molecular weight ribonuclease L that was previously found.

  • Despite their overlapping symptomatology, recent studies have suggested that CFS and FM have different genetic profiles. In 2008, a group of Spanish researchers collected blood samples from large numbers of patients with either CFS or FM and found 15 single-nucleotide polymorphisms that differentiated the two illnesses. They were able to replicate this finding with a second independent sample of blood from other CFS and FM patients.23 Light et al.24 expanded on these findings in a study on the effects of sub-maximal exercise by looking for differences in gene expression between patients with CFS alone vs. those with FM alone. The group reported that patients with CFS alone and CFS + FM responded to the exercise with similar upregulated gene expression of certain sensory ion channel and adrenergic genes as well as for the anti-inflammatory cytokine, IL-10 compared with controls. On the other hand, FM only patients did not show these results following exercise but instead had significantly higher baseline levels of two sensory ion channels and IL-10.24

Autonomic function

  • Naschitz et al.25 have published data, which indicates that FM and CFS differ in their mechanisms of autonomic dysfunction. The group developed a ‘hemodynamic instability score’ (HIS) using computerized image analysis to track blood pressure and heart rate over time during the postural challenge of a 30-min head-up tilt. FM patients had higher blood pressures both basally and at the end of tilt than either controls or CFS patients. The computed HIS scores differentiated the two patient groups with CFS differing significantly from both FM and healthy controls.25 The group replicated this finding in a follow-up study using a new set of patients and showed that the method discriminated well between the two patient groups.26 Finally, in their most recent study, this group reported that FM patients had QTc intervals on their electrocardiograms that were in the normal range compared with significantly lower intervals in CFS patients—a finding they reported as being 81% specific for differentiating the groups.27

Biomarkers

  • Two preliminary studies have suggested differences between CFS only patients and those with CFS + FM. The first study used an electrophoretic analysis of urine to find potential biomarkers differentiating the two illnesses.28 Its strength lay in its ability to present and compare data from individual patients between illness groups and healthy controls. For a peak to be considered significant, it had to come from multiple patients—thus representing a true peak rather than an outlier due to data from a single patient. Statistically significant electrophoretic peaks differentiated CFS alone from CFS + FM, and both patient groups from controls. The second study looked at the muscle biochemistry of the vastus lateralis via biopsy and was completed in six CFS patients and three FM patients compared to six healthy controls. The study was done to see if evidence of muscle damage could be found as a possible consequence of impairment of the oxidant/antioxidant system.29 Significant differences between CFS and FM and between each of the illness groups and the controls were found in the fatty acid composition and in the membrane fluidity of the muscle with FM patients showing the most marked changes. Sample size is an obvious issue in this report.

See Table 1 for a summary of differences between CFS and FM.

Table 1

Summary of differences found between CFS and FM in the literature and from the Natelson Lab

Topic Study Conclusions 

 
General White et al. (1999)1 Prevalence of FM increases monotonically and peaks at the 55–64 years of age range 
 Jason et al. (1999)2 CFS peaks during the age range of the mid 40’s and drops off 
Hormones and neurotransmitters Bennett et al. (1992)13 Reduced levels of somatomedin in FM 
Ferraccioli et al. (1994)14  
 Buchwald et al. (1996)15 Disruption of somatomedin is not evident in CFS, FM or CFS + FM 
 McCall-Hosenfeld et al. (2003)16 Concentrations of somatomedin similar in FM and controls 
 Cuatrecasas et al. (2010)17 Dysfunction of growth hormone secretion in FM 
 Bennett et al. (1997)18 Increases in somatomedin in CFS compared to controls 
 Bennett et al. (1998)19 Improvements in symptoms and tender point scores in women with FM and low somatomedin 
 Korszun et al. (1999)20 Nocturnal plasma melatonin higher in FM than CFS and healthy controls 
 Crofford et al. (2004)21 Differences in basal circadian architecture of CFS alone and FM alone with intermediate cortisol levels for CFS + FM 
 Russell et al. (1994)5 Spinal fluid substance P elevated in FM 
 Evengard et al. (1998)6 Spinal fluid substance P in normal range in CFS 
 Cook et al. (2005)8 Neuropsychological dysfunction in CFS compared to controls but not CFS+FM compared to controls 
 Weaver et al. (2010)9 Elevated brain serotonergic response to tryptophan infusion for CFS alone compared to controls but not for CFS+FM compared to controls 
Genetics/molecular biology DeMeirleir et al. (2000)22 Higher distribution values of 37 and 40 kDa binding proteins in CFS compared to FM 
Garcia-Fructuoso et al. (2008)23 Fifteen single-nucleotide polymorphisms differentiate CFS and FM 
 Light et al. (2012)24 Upregulated gene expression of sensory ion channel and adrenergic genes and IL-10 in CFS and CFS+FM after exercise when compared to controls; vs. higher baseline levels of two sensory ion channels and IL-10 in FM 
Autonomic function Naschitz et al. (2001)25 Significantly different HIS scores in CFS when compared to FM and healthy controls 
 Naschitz et al. (2003)26 Further evidence differentiating the two patient groups 
 Naschitz et al. (2008)27 Normal range QTc intervals on electrocardiograms of those with FM compared to significantly lower intervals for those with CFS 
 Cook et al. (2012)10 Reduced blood pressure and increased stroke index response to standardized maximal exercise test in CFS + FM, but not in CFS 
Biomarkers Casado et al. (2005)28 Significant urinary electrophoretic peaks differentiated CFS from CFS + FM, and both of these groups from controls 
 Fulle et al. (2000)29 Significantly different fatty acid composition and membrane fluidity in vastus lateralis biopsies of CFS and FM and between each group and controls 
Sleep Kishi et al. (2011)11 Sleep disruption in REM sleep in CFS compared to sleep disruption in slow wave sleep and increased sleep pressure in CFS + FM, when comparing both to controls 
 Natelson and Vgontzas (unpublished data) Community rates of FM and higher rates of CFS in patients with obstructive sleep apnea 
Co-morbidities Natelson (unpublished data) Community rates of PTSD on diagnostic interview in those with CFS compared to higher rates in those with CFS + FM 
 Roy-Byrne et al. (2004)12  
Topic Study Conclusions 

 
General White et al. (1999)1 Prevalence of FM increases monotonically and peaks at the 55–64 years of age range 
 Jason et al. (1999)2 CFS peaks during the age range of the mid 40’s and drops off 
Hormones and neurotransmitters Bennett et al. (1992)13 Reduced levels of somatomedin in FM 
Ferraccioli et al. (1994)14  
 Buchwald et al. (1996)15 Disruption of somatomedin is not evident in CFS, FM or CFS + FM 
 McCall-Hosenfeld et al. (2003)16 Concentrations of somatomedin similar in FM and controls 
 Cuatrecasas et al. (2010)17 Dysfunction of growth hormone secretion in FM 
 Bennett et al. (1997)18 Increases in somatomedin in CFS compared to controls 
 Bennett et al. (1998)19 Improvements in symptoms and tender point scores in women with FM and low somatomedin 
 Korszun et al. (1999)20 Nocturnal plasma melatonin higher in FM than CFS and healthy controls 
 Crofford et al. (2004)21 Differences in basal circadian architecture of CFS alone and FM alone with intermediate cortisol levels for CFS + FM 
 Russell et al. (1994)5 Spinal fluid substance P elevated in FM 
 Evengard et al. (1998)6 Spinal fluid substance P in normal range in CFS 
 Cook et al. (2005)8 Neuropsychological dysfunction in CFS compared to controls but not CFS+FM compared to controls 
 Weaver et al. (2010)9 Elevated brain serotonergic response to tryptophan infusion for CFS alone compared to controls but not for CFS+FM compared to controls 
Genetics/molecular biology DeMeirleir et al. (2000)22 Higher distribution values of 37 and 40 kDa binding proteins in CFS compared to FM 
Garcia-Fructuoso et al. (2008)23 Fifteen single-nucleotide polymorphisms differentiate CFS and FM 
 Light et al. (2012)24 Upregulated gene expression of sensory ion channel and adrenergic genes and IL-10 in CFS and CFS+FM after exercise when compared to controls; vs. higher baseline levels of two sensory ion channels and IL-10 in FM 
Autonomic function Naschitz et al. (2001)25 Significantly different HIS scores in CFS when compared to FM and healthy controls 
 Naschitz et al. (2003)26 Further evidence differentiating the two patient groups 
 Naschitz et al. (2008)27 Normal range QTc intervals on electrocardiograms of those with FM compared to significantly lower intervals for those with CFS 
 Cook et al. (2012)10 Reduced blood pressure and increased stroke index response to standardized maximal exercise test in CFS + FM, but not in CFS 
Biomarkers Casado et al. (2005)28 Significant urinary electrophoretic peaks differentiated CFS from CFS + FM, and both of these groups from controls 
 Fulle et al. (2000)29 Significantly different fatty acid composition and membrane fluidity in vastus lateralis biopsies of CFS and FM and between each group and controls 
Sleep Kishi et al. (2011)11 Sleep disruption in REM sleep in CFS compared to sleep disruption in slow wave sleep and increased sleep pressure in CFS + FM, when comparing both to controls 
 Natelson and Vgontzas (unpublished data) Community rates of FM and higher rates of CFS in patients with obstructive sleep apnea 
Co-morbidities Natelson (unpublished data) Community rates of PTSD on diagnostic interview in those with CFS compared to higher rates in those with CFS + FM 
 Roy-Byrne et al. (2004)12  

Critique, synthesis and discussion

Perhaps related to referral patterns in America where patients with widespread pain were sent to rheumatologists and patients with severe fatigue to infectious disease specialists, research on CFS and FM has tended to follow separate tracks. However, the overlap in symptomatology between the two syndromes and the fact that both remain medically unexplained despite decades of research has led some to consider them common illnesses, indicative of somatic amplification, differing from one another only in degree. While such an explanation may explain some number or percentage of patients with these disorders, this review provides evidence that it cannot explain all cases in that the data we have reviewed suggest that, at least in some cases, the illnesses may be different. Across a number of systems, patients with CFS alone differ from those either with CFS + FM or from those with FM alone with the bulk of these studies showing clear qualitative differences differentiating CFS from FM.

However, this interpretation must be tempered with caution for several reasons. The first is that relatively little attention has been paid to the possibility that the physiology and/or biochemistry of the two syndromes may differ and so much of the research on each of these syndromes has not considered the existence of the other; as seen by the studies on spinal fluid substance P. A parallel problem is obvious from our own studies. For much of our work, we had National Institutes of Health (NIH) funding establishing a CFS Cooperative Research Center which allowed us to study CFS alone and CFS + FM—but not FM alone. Being able to study all three patient groups will thus be critical to further explore the differences between CFS and FM. The work from Kathy and Alan Light in Utah provides the blueprint for further studies designed to address this issue.

The second set of issues has to do with those studies reporting quantitative differences between the two syndromes—i.e. in terms of the magnitude of differences found and the statistical methods used to describe those differences. For example, in the hormone pattern studies reviewed above, differences in pattern between CFS and FM were noted but, overall, the two patterns are quite similar; thus the biological significance of these differences may not be great. Moreover in these studies, as well as in the last two reviewed, many t-tests were done without considering how that might influence the meaningfulness of the findings reported. In contrast to these articles reporting quantitative differences between the two syndromes, many of the remaining articles cited report qualitative differences with data from one syndrome being significantly different from both the other syndrome and healthy controls.

Despite these shortcomings, this review certainly does suggest that the underlying pathophysiology in CFS can differ from that in FM. This interpretation needs to be considered in evaluating a proposal from a group of rheumatologists to change the case definition for diagnosing FM without providing empiric evidence for the need for such a change.30 One reason for doing this was their belief that the original case definition had set such a ‘high bar for diagnosis that there was little variation in symptoms’ among patients. They suggested dropping the tender point requirement and adding categorical scales to capture cognitive symptoms, unrefreshing sleep, fatigue and several other somatic symptoms. Our concern was that doing this would have two effects: first, it would remove much of the difference between FM and CFS, which might lead to the disappearance of CFS as a unique entity and, second, it would greatly expand the number of people receiving the diagnosis of FM. There are some data available on the first of these concerns. The De Paul group applied both case definitions for diagnosing FM to 112 CFS patients.31 Thirty one percent fulfilled the 1990 criteria for the diagnosis of FM while 54% fulfilled the newly suggested 2010 criteria. We interpret the data reviewed here as suggesting that reducing the differences between CFS and FM by altering case definitions should not be done without stronger empiric reason to support such a change.

Moreover, we hope the result of this review will be to encourage further studies seeking to identify differences between CFS alone, CFS and FM, and FM alone. Finding such differences will point to disparities in the underlying pathophysiological processes responsible for each syndrome and will end arguments about illness definitions. Most importantly, this knowledge will shift the focus of researchers towards identifying, understanding and then being able to treat these processes. This is particularly important to the individual patient with medically unexplained symptoms. Such a patient often falls between the cracks of classical medicine. When such a patient presents to her physician, and diagnostic tests are normal, the doctor’s response often is: ‘There is nothing wrong; perhaps you should see a psychiatrist’.

When the patient does go to the psychiatrist, often the only diagnosis rendered is somatization disorder—the psychiatric diagnosis for medically unexplained illnesses and thought to reflect the individual’s over-reacting to her own visceral sensations—thus a psychogenic condition. Some years ago, we assessed rates of somatization disorder in patients with CFS. We found that this diagnosis depended very much on how somatic symptoms were coded. When coded as physical, the diagnosis was rare, but when coded as psychiatric, the rate approached 100%.32 Data such as those reviewed here indicate that grouping CFS and FM together as the same illness process is probably inappropriate and may in fact be stigmatizing.33 Finding differences between these two syndromes should serve to shift the focus of discussion from CFS and FM being psychogenic processes to a hunt for the biological cause(s) of each. Such a shift may lead the doctor to hesitate before telling the patient that nothing is wrong and thus lead to better patient care.

Funding

Dr Natelson's time in preparing this paper was supported in part by NIH grant #NS-075653.

Conflict of interest: None declared.

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