Elsevier

Psychiatry Research

Volume 200, Issues 2–3, 30 December 2012, Pages 754-760
Psychiatry Research

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

https://doi.org/10.1016/j.psychres.2012.03.031Get rights and content

Abstract

There is much debate on the diagnostic classification of Myalgic Encephalomyelitis (ME), Chronic Fatigue Syndrome (CFS) and chronic fatigue (CF). Post-exertional malaise (PEM) is stressed as a key feature. This study examines whether CF and CFS, with and without PEM, are distinct diagnostic categories.

Fukuda's criteria were used to diagnose 144 patients with chronic fatigue and identify patients with CFS and CF, i.e. those not fulfilling the Fukuda's criteria. PEM was rated by means of a scale with defined scale steps between 0 and 6. CFS patients were divided into those with PEM lasting more than 24 h (labeled: ME) and without PEM (labeled: CFS). The 12-item Fibromyalgia and Chronic Fatigue Syndrome (FF) Rating Scale was used to measure severity of illness. Plasma interleukin-1 (IL-1), tumor necrosis factor (TNF)α, and lysozyme, and serum neopterin were employed as external validating criteria.

Using fatigue, a subjective feeling of infection and PEM we found that ME, CFS, and CF were distinct categories. Patients with ME had significantly higher scores on concentration difficulties and a subjective experience of infection, and higher levels of IL-1, TNFα, and neopterin than patients with CFS. These biomarkers were significantly higher in ME and CFS than in CF patients. PEM loaded highly on the first two factors subtracted from the data set, i.e. “malaise-sickness” and “malaise-hyperalgesia”.

Fukuda's criteria are adequate to make a distinction between ME/CFS and CF, but ME/CFS patients should be subdivided into ME (with PEM) and CFS (without PEM).

Introduction

What's in a name: Myalgic Encephalomyelitis (ME), Chronic Fatigue Syndrome (CFS), chronic fatigue (CF)? Those three diagnostic labels refer to a syndrome characterized by chronic fatigue and a number of related symptoms, e.g. neurocognitive disorders, muscle pain, gastrointestinal symptoms, autonomic symptoms, etc. Since 1934, in many cases on account of sudden outbreaks, ME has been described under various terms, e.g. atypical poliomyelitis and epidemic neuromyasthenia (Gilliam, 1938, Crowley et al., 1957, Strickland et al., 2001, Acheson, 1959). The label ME was first defined by Acheson (1956), i.e. muscle pain with paresis and cramps, signs of damage to the brain and spinal cord, and emotional disturbances. In 1969, ME has been acknowledged by the WHO as a neurological disorder (WHO, 1967). In 1978, researchers at a symposium organized by the Royal Society of Medicine concluded that ME should be considered a separate nosologic entity (Anon, 1978). In the eighties, the phenomenology of ME was refined by Ramsay et al. (1988). These authors described three symptom clusters: (a) muscle symptoms; (b) cerebral dysfunctions; and (c) circular impairments. In 1990, Dowsett et al. (1994) proposed a definition of ME known as the “London criteria”, i.e. muscular fatigue following minimal exertion with a prolonged recovery time; impairment of short-term memory and loss of powers of concentration, usually coupled with other neurological and psychological disturbances, such as emotional lability, nominal dysphasia, disturbed sleep patterns, disequilibrium or tinnitus; and in addition autonomic and immunological symptoms. All abovementioned descriptions pointed towards the protracted course of ME with relapses and the tendency towards chronicity and the fluctuation of symptoms, often precipitated by exercise.

In 1988, Holmes et al. (1988) introduced the term CFS. In 1994, the Centers for Disease Control and Prevention (CDC) criteria for CFS were published by Fukuda et al. (1994). These consist of (a) a self–reported severe chronic fatigue lasting six months or longer with all other medical conditions being excluded; and (b) four or more of the following symptoms: substantial impairment in short–term memory or concentration; sore throat; tender cervical and axillary lymph nodes; muscle pain; multi–joint pain without selling or redness; headache of new type; unrefreshing sleep; and post-exertional malaise lasting more than 24 h. In contrast with the different connotations, CFS is considered to be an equivalent for and post-viral fatigue syndrome by the WHO since 1993 (WHO, 1992).

In 2003 a Canadian Expert Consensus Panel introduced a case definition for ME/CFS in which post-exertional malaise, neurological, neuro-cognitive, neuroendocrine, autonomic, circulatory, and immune manifestations are compulsory (Carruthers et al., 2003). Recently, new diagnostic criteria for ME were published, i.e. the International Consensus criteria (ICC), in which post-exertional neuro-immune exhaustion is a compulsory criterion (Carruthers et al., 2011). The authors propose to abolish the chronic fatigue criterion and the CFS label definitely, because, according to the authors, in view of recent research and clinical experience, it is much more appropriate to use the name ME, since this name refers to the underlying pathophysiology: widespread inflammation and multi-systemic neuropathology, and not to symptoms.

There is, however, evidence that the CFS criteria according to Fukuda et al. (1994) define a heterogeneous population of individuals with chronic fatigue (Wessely, 1996, Lane et al., 1998) of which ME patients are a subset. This is because post-exertional malaise and cognitive impairment are compulsory for the diagnosis ME, but not mandatory for the classification CFS. Based upon the results of Nacul et al. (2011) and Peckerman et al. (2003) it is estimated that 40–60% of individuals with CFS fulfill the more strict criteria for ME, including post-exertional malaise and cognitive complaints. All in all, some authors advocate to use the less strict definitions of “CFS” (2005), while others propose to adopt more strict criteria based on post-exertional malaise (Carruthers et al., 2003, Carruthers et al., 2011). In our research we employed the Fukuda criteria to delineate CFS (although we labeled it ME/CFS) and to define patients with chronic fatigue who did not fulfill all CDC criteria as CF (Maes et al., 2006, Maes et al., 2007, Maes et al., 2011). Those studies showed that patients with ME/CFS are more severely ill and suffer from more severe immune aberrations than those with CF.

The abovementioned case definitions were made on the basis of clinical insights or a consensus between researchers and clinicians. Surprisingly, none of these studies employed multivariate statistical analyses, such as supervised learning techniques or pattern recognition methods to validate the classifications or to find new structures in the clinical data sets (Maes, 2009, Maes et al., 1990a, Maes et al., 1990b, Maes et al., 1990c, Maes et al., 1998). Phrased differently, not one of these classifications has passed the external validation criterion and thus none of the proposed classification systems is validated.

The aim of the present study was to examine whether CF; CFS according to Fukuda's criteria without post-exertional malaise; and CFS with post-exertional malaise, labeled as ME, are three qualitatively distinct subgroups with respect to external validating criteria including severity of ME/CFS symptoms and immune biomarkers, e.g. plasma interleukin-1 (IL-1) and tumor necrosis factor (TNF)α, and serum lysozyme and neopterin. IL-1 and TNFα are two pro-inflammatory cytokines; lysozyme is a hydrolase with antibacterial properties and a marker of monocyte/macrophage activation; and neopterin is a marker of cell mediated immunity. These 4 biomarkers are significantly higher in ME/CFS according to the Fukuda et al. (1994) criteria than in patients with CF and normal volunteers, indicating inflammation (increased IL-1, TNFα and lysozyme) and cell mediated immune (CMI) activation (Maes et al., 2011). These and other immune disorders are described in the inflammatory theory of ME/CFS (Maes, 2009, Maes and Twisk, 2010).

Section snippets

Subjects

One hundred and forty-four subjects participated in this study. All were admitted to the Maes Clinic, Antwerp, Belgium. All participants belong to the Benelux higher middle class. The diagnosis ME/CFS was made using the CDC criteria (1994). We excluded patients with a life time diagnosis of axis-I DSM IV-TR diagnoses; and patients who were treated with psychotropic drugs the two years before inclusion in this study. 107 subjects fulfilled the ME/CFS criteria according to Fukuda, while 37

Differences between ME, CFS and CF

Table 1 shows the clinical and biological differences between ME, CFS and CF. There were no significant differences in age or gender ratio between the three subgroups. ANOVAs showed significant differences in the total FF score and all FF items. Dunn–Sheffe test performed at p=0.0166 after p-correction for three comparisons showed that the total FF score was higher in CFS (t=7.10, p<0.001) and ME (t=9.33, p<0.001) than in CF, and higher in ME than in CFS (t=2.77, p=0.006). Dunn–Sheffe test

Discussion

The first major finding of this study is that ME, CFS and CF are three different categories with regard to clinical symptoms and the biomarkers as well. Thus, ME patients show more severe clinical symptoms and immune aberrations as compared with CFS patients, while both ME and CFS show more severe symptoms and immune disorders than patients with CF. These findings show that ME/CFS as defined by the CDC criteria is indeed a heterogeneous group (Wessely, 1996, Lane et al., 1998, Nacul et al., 2011

Funding

There was no specific funding for this specific study.

Acknowledgement

All authors contributed equally to the work presented in this paper.

References (40)

  • O. Zachrisson et al.

    A rating scale for fibromyalgia and chronic fatigue syndrome (the FibroFatigue scale)

    Journal of Psychosomatic Research

    (2002)
  • E.D. Acheson

    A new clinical entity?

    Lancet

    (1956)
  • M.S. Aldenderfer et al.

    Validation Techniques

    Cluster Analysis

    (1986)
  • B.M. Carruthers et al.

    Myalgic encephalomyelitis/chronic fatigue syndrome: clinical working case definition, diagnostic and treatment guidelines: a consensus document

    Journal of Chronic Fatigue Syndrome

    (2003)
  • B.M. Carruthers et al.

    Myalgic encephalomyelitis: international consensus criteria

    Journal of Internal Medicine

    (2011)
  • G. Cavadini et al.

    TNF-alpha suppresses the expression of clock genes by interfering with E-box-mediated transcription

    Proceedings of the National Academy of Sciences in the USA

    (2007)
  • S.J. Cockshell et al.

    Cognitive functioning in chronic fatigue syndrome: a meta-analysis

    Psychological Medicine

    (2010)
  • N. Crowley et al.

    Epidemiological aspects of an outbreak of encephalomyelitis at the Royal Free Hospital, London, in the summer of 1955

    The Journal of Hygiene (London)

    (1957)
  • M.P. Derde et al.

    Extraction of information from large data sets by pattern recognition. Fresenius Z

    Analytical Chemistry

    (1982)
  • Dowsett, E.G., Goudsmit, E., Macintyre, A., Shepherd, C.B., 1994. London criteria for M.E. Report from The National...
  • Cited by (75)

    • Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Essentials of Diagnosis and Management

      2021, Mayo Clinic Proceedings
      Citation Excerpt :

      Using functional magnetic resonance imaging, Cook et al51 found that altered brain activity accompanied post-exertional symptom exacerbation and impaired cognitive function. Maes et al71 found that PEM is associated with increased levels of interleukin-1, and Nijs et al72 revealed increased complement split products, oxidative stress, and gene expression of interleukin-10. Increased levels of immune system molecules in the brain, such as interleukin-1 and interleukin-10, can cause symptoms such as fatigue, pain, influenza-like feelings, and cognitive impairment.

    • Post-exertional malaise is associated with greater symptom burden and psychological distress in patients diagnosed with Chronic Fatigue Syndrome

      2020, Journal of Psychosomatic Research
      Citation Excerpt :

      After correcting for comparisons between three groups, patients with PEM had significantly higher scores on subjective experience of infection and concentration difficulties, as well as higher levels of inflammatory markers; patients who experienced chronic fatigue but did not meet Fukuda criteria also differed from patients with and without PEM. The authors concluded that these three groups are distinct diagnostic categories and speculated that immune activation is a predisposing factor for the development of PEM [24]. It appears that some of the heterogeneity of the CFS patient population is related to the presence or absence of PEM, which has demonstrated associations with symptom burden and inflammatory biomarkers.

    • Inflammatory proteins are altered in chronic fatigue syndrome—A systematic review and meta-analysis

      2019, Neuroscience and Biobehavioral Reviews
      Citation Excerpt :

      TNFα (k = 30) was elevated in the CFS group (ES = 0.274, 95% CI [0.126, 0.422], p < 0.001), and this effect was not affected by sensitivity analysis, although removal of potentially incomparable studies reduced heterogeneity (from 71.2 to 64.8). A single outlier (Maes et al., 2012, 2013) was removed post-hoc as it clearly and substantially contributed to remaining significant heterogeneity; after its removal, statistical significance was maintained (k = 29, ES = 0.202, 95% CI [0.077, 0.328], p = 0.002) while reducing heterogeneity (I2 = 57.5%). Results are displayed in Fig. 2.

    View all citing articles on Scopus
    View full text