Original article
Chronic fatigue syndrome: Is it one discrete syndrome or many? Implications for the “one vs. many” functional somatic syndromes debate

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Abstract

There is a current debate as to whether “functional somatic syndromes” (FSSs) are more similar to or different from each other. While at the same time, there is evidence of heterogeneity within single syndromes. So, it could be that these syndromes are all part of one big process/illness, are discrete in their own right, or that they are heterogeneous collections of different illnesses lumped together by common symptoms but separated by uncommon pathophysiologies. The example of chronic fatigue syndrome (CFS) is instructive. There is evidence to support all three models of understanding. Three recent large studies have suggested that FSSs are both similar and dissimilar at the same time. The solution to the debate is that we need to both “lump” and “split.” We need to study both the similarities between syndromes and their dissimilarities to better understand what we currently call the FSSs.

Introduction

In order to understand the cause or pathophysiology of an illness or disease the usual first step is to define the phenotype of that illness and then seek associations with putative risk markers. Without doing that, no amount of markers will be shown to be consistently associated with one distinct illness or disorder. The example of one particular “functional somatic syndrome” (FSS), namely, chronic fatigue syndrome (CFS), provides insights into the difficulties of trying to define the phenotype in the absence of the biomarkers that usually help us to define a disease phenotype in the first place, The literature about CFS also provides the possible solution to this problem for both CFS and for all FSSs in general.

Section snippets

Does a phenotype of CFS exist?

There are several operationalized criteria used for defining CFS [1], [2], [3]. These criteria provide reliability across different studies [4], but the tests of validity suggest that they do not “cleave nature at the joint” [5], omitting more patients that have chronic unexplained disabling fatigue than they include. At the same time, large empirical studies suggest that there is a more broadly defined phenotype of chronic unexplained fatigue with associated symptoms (thus a CFS) with good

Is CFS homogeneous or heterogeneous?

There have been several attempts to test the heterogeneity of CFS, using symptoms and demographic data to define the phenotypes [5], [6], [11], [12], [13], [14], [15]. Some studies used principal components or other factor analyses to define the syndromes themselves, whereas others used latent class analysis to seek clusters of patients. The early studies found a broad phenotype in the majority and a separate polysymptomatic phenotype in the minority, labeled as a somatization disorder [11],

Is CFS part of another FSS?

A related but seemingly paradoxical issue is the need to explain the clinical associations between the FSSs. Why is CFS strongly associated with both chronic widespread pain (”fibromyalgia”) and irritable bowel syndrome (IBS) [13], [26], [27], [28]? Could it be that there is only one general functional somatic disorder [29], [30]? One way to answer these questions was attempted in a primary care prospective case-control study of risk markers of patients with fatigue syndromes (postinfectious

Are the risks for FSSs biological or psychosocial?

The Swedish twin study mentioned in the previous section suggested that risks were both genetic and environmental. Environmental risks can be biological and psychosocial [34], [35]. What are the psychosocial risks for CFS in particular and FSS in general, and are they specific for each FSS? The Swedish twin registry helps us out again in answering these questions. Kato et al. [34] used the registry to examine childhood risks for CFS and found that perceived stress and “emotional instability”

How might we seek further knowledge about how FSSs are both similar but different?

It may be possible that not all endophenotypes underlying specific or associated syndromes share the same generic risks for all FSSs, such as early life adversity. The next tranche of studies needs to test this possibility, as well as to test the validity and reliability of these potential endophenotypes in men and to seek etiological risks in a longitudinal study of endophenotypes, such as altered stress response related to early life adversity and its genetic associations. Longitudinal and

Conclusions

Chronic fatigue syndrome can be considered as a discrete FSS, made up of different subphenotypes, which we are beginning to understand by their underlying endophenotypes. At the same time, CFS shares common risk markers with other FSSs, which are both genetic and environmental. The environmental risks are both psychosocial and biological with interactions between them. This “both separate and combined” approach applies to all FSSs. In order to better understand and treat patients with complex

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