ME: Chronic Fatigue Syndrome or a distinct clinical entity

Ellen Goudsmit, formerly University of East London, Charles Shepherd ME Association, Christine Dancey, formerly University of East London, Sandra Howes, Croydon

Originally published in Health Psychology Update, 2009, 18, 1, 26-33.  Footnote was added October 2012 by EM Goudsmit.

Ellen Goudsmit, PhD, FBPsS, is a psychologist who has long studied ME (myalgic encephalomyelitis) and CFS (chronic fatigue syndrome). She believes that the diagnostic confusion between what are two quite separate conditions is unhelpful both for sufferers and for the understanding of both conditions.

FoodsMatter carries three of her articles on the subject: Classic ME: the basics which defines ME; ME or CFS, that is the question which explores the differences between the two conditions, and this one, ME: Chronic Fatigue Syndrome or a distinct clinical entity, a fully referenced academic paper from which the two articles are drawn.

The term chronic fatigue syndrome (CFS) was introduced in 1988 as a result of a number of factors. Following four outbreaks in the USA during the mid-eighties, a committee dominated by individuals who had not read or recalled the older literature and  didn’t  believe that ME was the cause of the illness, was asked to advise the CDC, the government agency that investigates epidemics and new diseases. The views of the two ME specialists who attended that meeting warned that the emphasis on fatigue would result in confusion and as history has shown, they were right.  

Myalgic encephalomyelitis (ME) is a disabling condition characterised by profound fatigue following minimal exertion and a delay in recovery after exertion ends. In 1988, when  specialists introduced the concept of  chronic fatigue syndrome (CFS), it was assumed that the illness in question was identical to ME but the lack of research criteria for the latter has prevented the testing of this assumption. 
            In this article, we propose criteria and guidelines which can be used to study ME and determine whether it is a synonym for CFS or one of several subgroups contained within the CFS construct. If  clinically meaningful differences are identified, the criteria may help to increase diagnostic precision and facilitate further research into the cause, course and treatment of ME.    

Chronic fatigue syndrome (CFS) is a disabling condition characterised by profound fatigue of new or definite onset, plus  four or more co-existing symptoms, including  sore throat, muscle and joint  pain, post-exertional malaise, headaches, unrefreshing sleep and impaired memory or concentration (Fukuda et al., 1994).  The term was  introduced in 1988 to replace a number of different names for the same symptom complex, including  post-viral fatigue syndrome, epidemic neuromyasthenia,  myalgic encephalomyelitis (ME), Royal Free Disease and Icelandic Disease (Ramsay, 1988; Spracklen, 1988). A working case definition for the new construct was devised  by consensus in order to provide more diagnostic consistency, and improve  the comparability and reproducibility of clinical research (Holmes et al., 1988). However, a meeting in 1993 concluded that the criteria did not effectively distinguish CFS from other types of unexplained fatigue, and the case definition was revised (Centers for Disease Control and Prevention, 2006; Fukuda et al., 1994). The new diagnostic algorithm quickly became the gold standard,  both in research and clinical practice (Jason et al., 2005) but in recent years, there has been growing concern about the sensitivity, specificity, and reliability of the revised criteria (King & Jason, 2005).  For example, two studies found that people who met the 1988 case definition reported a larger number and more severe symptoms than those who fulfilled the 1994 revision (De Becker et al., 2001; Jason et al., 2001).  There also appear to be marked differences within the samples selected using the 1994 guidelines.  Kennedy et al. (2004) assessed three groups of patients who all met the 1994 criteria but whose symptoms had a different mode of onset. The people who had become ill after service in the first Gulf War had significantly more physical symptoms (fatigue and pain) and significantly reduced muscle power in the lower limbs than those who had developed CFS following exposure to organophosphate insecticides, and the group with other aetiologies. An additional flaw was identified by King and Jason (2005) who compared patients with CFS and major depressive disorder and were not able to differentiate between the two based on the prevalence of seven out of the eight minor criteria. These findings not only demonstrate the heterogeneity of the population with CFS as currently defined, but also indicate a strong potential for individuals with another disorder to be misclassified as having CFS. Likewise, it raises the question to what extent CFS can still be compared to conditions such as ME and post-viral fatigue and whether interventions developed for the former are appropriate and equally effective for the latter (Friedberg & Sohl, 2009; Jason et al., 2005; Price et al., 2008).

Clinical aspects of ME
ME is a condition which was first described in the literature in the 1930s (Gilliam, 1938).  However, it first came to prominence after a series of outbreaks, the most famous of which closed the Royal Free Hospital for three months in 1955 (Ramsay, 1988). For many years, the illness was thought to be caused by an enterovirus (Innes, 1970, Lane et al., 2003; McGarry et al., 1994; Yousef et al., 1988) but to date, research has not been able to differentiate between ME and other post-infective fatigue syndromes (e.g. Goudsmit, 1996; Hickie et al., 2006).  
            The illness tends to start as an unremarkable viral infection, which may be accompanied by myalgia, lymphadenopathy, or a gastro-intestinal upset (Shepherd, 1992).  However, instead of recovering, patients begin to experience profound fatigue following activities which were previously completed without difficulty.  Also typical is a prolonged delay in the restoration of muscle power (Paul et al., 1999; Ramsay, 1983).  This is sometimes described as post-exertional fatigue and while this is a minor criterion for the diagnosis of  CFS, it is considered a cardinal feature of ME (Ramsay, 1988; Dowsett & Welsby, 1992).   
            As in CFS, patients report a variety of other symptoms. Prominent are a flu-like malaise and neurological symptoms such as disequilibrium and vertigo (Dowsett et al., 1990; Murdoch, 1987; Shepherd, 1992).  Patients may also experience sensory disturbances such as paraesthesiae, tinnitus and hyperacusis as well as visual abnormalities such as photophobia (Potaznick & Kozol, 1992) and/or increased sensitivity to certain patterns (Smith, 1991).  Neuropsychological symptoms associated with ME include cognitive problems such as loss of short-term memory, an inability to concentrate and difficulties with word finding i.e. anomia and dysnomia (Fleming, 1994).  The deficits are often severe and a major source of disability (Goudsmit, 1996). For instance, the performance of 20 patients on a selection of tests revealed scores which fell between those of  patients with mild and moderate Alzheimer's Disease (Scholey et al., 1999).
            As well as the fatigue, muscle weakness and evidence of  central nervous system dysfunction, there may also be symptoms associated with impaired circulation. This manifests itself in cold extremities, perceived low temperatures and a sudden facial pallor (Ramsay, 1983). Also typical is the disturbance in thermoregulatory control e.g. feeling weak after a hot bath (Macintyre, 1992, Ramsay, 1988, Shepherd, 1992), and intolerance to alcohol (Shepherd, 1992). All these symptoms show a marked diurnal and cyclical variability in their intensity, and although it is not always possible to identify a specific cause for the exacerbations, reports suggest that the condition often worsens as a result of over-exertion, concurrent infections, and in some cases, 'stress' (Dowsett et al., 1990; Goudsmit, 1996).
            Studies on the symptoms reported by patients indicate that ME and CFS cannot be differentiated in terms of the prevalence or severity of fatigue (e.g. Goudsmit et al., 2008a).  Moreover, there appears to be no significant difference in the percentage of  individuals with myalgia, headaches, sleep disturbance, gastro-intestinal symptoms, or emotional distress (De Becker et al., 2001, Dowsett et al., 1990; Jason et al., 2002).  There are no data for multi-joint pain to allow a meaningful comparison, but there is evidence suggesting that people with ME experience a greater number and more severe neurological and cognitive symptoms (Jason et al., 2003, Scholey et al., 1999). In contrast, research has indicated that post-exertional fatigue, a characteristic symptom of ME, is not as common or as disabling in patients with CFS (Jason et al., 2002; Jason et al., 2003; Sisto et al., 1998).
            Aside from the subtle differences in the symptom complex, there are other considerations which challenge the assumption of equivalence. For instance, ME/post viral fatigue is much less common than CFS: 1 per 1000 versus 10-26 per 1000 in the UK, respectively (Ho-Yen & McNamara, 1991; Wessely et al, 1997). The epidemics of ME provide strong evidence of an infectious aetiology (Ramsay, 1988), whereas research into CFS has identified disturbances in the hypothalamic-pituitary-adrenal axis consistent with reports of  childhood trauma, over-active lifestyles and chronic stress (Heim et al., 2009; Jason et al., 2005; van Houdenhove et al., 2006). Of course, it is possible that traumatic events and a failure to cope with recurring stressors may make individuals more vulnerable to infection. Moreover, the neuroendocrine abnormalities associated with psychological distress may undermine or delay recovery (Heim et al., 2009). However, research has not identified a higher incidence of ME or post-viral fatigue in countries  with a history of long term conflict (e.g. Israel), or in populations with a higher prevalence of  trauma-related disorders, e.g. the children of Holocaust survivors (Glassman, personal communication). More significantly, research on CFS has not yet replicated the finding of the delayed recovery of muscle strength after minimal exertion (Paul et al., 1999).* To summarise, the evidence suggests that infection and immune dysfunction play a greater role in the aetiology of ME (Vollmer-Conna et al., 2008) while many cases of CFS may be attributed to the physiological effects of  chronic stress and other psycho-social factors (Heim et al., 2009; Hempel et al., 2008).
The psychosocial aspects of ME
There have been numerous papers on the psychosocial aspects of CFS (e.g. Powell et al.,  1990; Saltzstein et al., 1998; van Geelen et al., 2007) and latterly, CFS/ME (Arroll & Senior, 2008; Hempel et al., 2008).  Given the assumption of equivalence, there has been less interest in ME as defined by Ramsay (1988) and Dowsett and Welsby (1992). The studies described below were conducted by researchers with a special interest in ME.
            For example, Goudsmit conducted a number of studies assessing the psychosocial aspects of ME using a clinical case definition which required the presence of the main features described above, notably the muscle fatiguability following minimal exertion, the involvement of the central nervous system and the marked diurnal variability.  In the first of these studies, 53 people recruited from the ME Association were sent questionnaires asking about their symptoms, views on aetiology, coping strategies and the effects of their condition on various life domains (Goudsmit, 1996, p. 97-156).  Data were also collected from interviews with 17 patients recruited from local surgeries. Both groups had been diagnosed by a qualified medical practitioner. The results revealed that many patients attributed their illness to an infection combined with taking too little rest during the initial stages.  Although some speculated that hassles and a 'busy lifestyle' may have reduced their resistance, most rejected the view that their illness was a result of a single psychological factor, or the result of inactivity. 
            Over 80% related that their condition had a significant impact on their relationships and over 70% admitted to experiencing emotional distress.  The most commonly cited  coping strategies were rest and relaxation, pacing of activities, dietary changes and the taking of nutritional supplements. There was no evidence of ‘total rest’ or phobic avoidance behaviour, strategies commonly associated with CFS in the British literature (Deary, 2008; Wessely et al., 1998).
A further study by Goudsmit (1996, p.157-230) examined the relationship between symptoms, uncertainty and outcome on the one hand, and anxiety and depression, on the other. The sample comprised 58 patients attending a microbiology clinic who met the definitions of ME described in Dowsett and Welsby (1992) and Ramsay (1988). The uncertainty surrounding the illness was a significant predictor of both anxiety and depression. Based on her findings, she proposed that the uncertainty concerning the diagnosis, symptoms and prognosis may undermine adjustment and that this aspect of the condition needs to be considered when formulating management programmes for people with ME (Goudsmit, 1996).
More recently, Goudsmit et al (2008b) compared the degree of neuroticism in 48 patients with ME, 50 with multiple sclerosis (MS) and 48 healthy controls.  The mean neuroticism scores of the two patient groups were higher than those of the controls but there was no significant difference between the patient groups. In a fourth study, Goudsmit et al., (2009) examined the impact of ME on 13 life domains using the Illness Intrusiveness Rating Scale (Devins et al., 1983). The mean score of the patients was extremely high: 66 from a possible range of 7 – 91. This exceeded the reported scores for patients with MS, rheumatoid arthritis and various forms of cancer, but was identical to the mean of a group of people with CFS (Dancey & Friend, 2008).

The rationale for the new criteria for ME
The heterogeneity of the population with CFS  was acknowledged by the International Study Group advising the Centers of Disease Control and Prevention as far back as 1993 and led them to recommend the stratification of samples and comparison of subsets  (Fukuda et al., 1994). As a result, there has been a resurgence of interest in post-infectious conditions and other illnesses resembling ME (Cameron et al., 2006; Jason et al., 2003; Kerr & Tyrrell, 2003; Vernon et al., 2006, Vollmer-Conna et al., 2008).   
            One factor which has limited research into ME is the lack of  published consensus criteria. To explore whether ME is a discrete disorder or subgroup of CFS and to answer many other questions relating to this condition, we formulated criteria and guidelines based on what are generally regarded as the most accurate descriptions of  the illness (e.g. Dowsett & Welsby, 1992; Ramsay, 1988). They are consistent with the London criteria which were devised for two national patient groups in the 1990s and used in a number of  studies on ME (e.g. Costa et al., 1995; McCue et al., 2003; Perrin, 1998). The proposed criteria focus on the core symptoms of  the condition. This may help to avoid the problems associated with the existing polythetic case definitions, i.e., the inclusion of  patients on the basis that they experience a certain number of listed symptoms, which in the case of CFS tend to be non-specific and may not allow researchers to differentiate between CFS and disorders such as depression (Goudsmit, 1996; Jason et al., 2005; King & Jason, 2005).  
The criteria for research into ME
All patients should fulfil the following five criteria:

  • A new onset of significantly abnormal levels of muscle fatiguability and/or muscle weakness, precipitated by relatively minor levels of activity. Symptoms typically worsen during the next 24-48 hours.
  • The presence of symptoms indicating the involvement of the brain and central nervous system (e.g. impaired short-term memory and concentration, disturbed sleep patterns, balance problems).
  • Periods of impaired circulation compatible with autonomic dysfunction (e.g. facial pallor, disturbances in thermoregulation including inappropriate sweating and sensitivity to both heat and cold; postural hypotension and/or orthostatic intolerance).
  • Fluctuation of symptoms, from hour to hour and day to day.
  • These symptoms must have been present during the past three months (to exclude patients with the debility which often follows illnesses such as influenza).

Measures such as the Profile of Fatigue-Related Symptoms  (PFRS) developed by Ray et al. (1992) may help support the diagnosis and we recommend that all patients should record a score of at least 2 out of 6 on the two items relating to the presence of muscle weakness following exertion.  This is a core symptom and the score provides additional evidence of its presence and severity.


Many symptoms experienced by people with ME are also reported by people with other disorders.  The most prevalent of these include pain – which can be muscular, arthritic or neuropathic in character; hyperacusis and tinnitus; photophobia and blurred vision; frequency of micturition and hypersensitivity to chemicals and drugs.  Also common are symptoms suggestive of immune system dysfunction and/or persisting infection,  such as episodes of low-grade fever (not exceeding an oral temperature of 38.6C) combined with feeling feverish; sore throat which may be persistent or recurrent, and arthralgia.
While the presence of these symptoms are not discriminative, the marked diurnal fluctuations in severity are typical of ME.  Exacerbations are frequently triggered by physical or mental exertion and this association should always be sought whilst taking the history (Ramsay, 1988).
Characteristic physical signs are sometimes seen in ME and in combination  with the symptoms above also contribute to the validity of the diagnosis. Nevertheless their absence does not exclude the condition. They are as follows:
1.    Pharyngitis.
2.    Tenderness and possible enlargement of lymph nodes.
3.    A positive Romberg test or Fukuda test.

Although ME often follows an infection, usually a viral illness (which may be sub-clinical), it may also be triggered by other factors such as immunizations, trauma and exposure to chemicals. Furthermore, in a minority of patients, ME has a gradual onset with no apparent triggering factor. For these reasons, and in line with the criteria for CFS, evidence of a preceding viral illness is not a prerequisite for diagnosis or inclusion in a study group.

Assessment, investigation and diagnosis
Because it is vital that the samples used in research are as 'pure' as possible, the presence of  certain co-morbid disorders would be grounds for disqualification. Some of the more common alternative diagnoses to be borne in mind before selecting a participant for a study on ME are listed in Shepherd and Chaudhuri (2008, p. 15).

Other reasons for exclusion from research into ME
It is of particular importance to identify cases of chronic fatigue which can be largely explained by psychological factors. For example, if there are signs of persistent anhedonia, apathy, low self-esteem, feelings of worthlessness and guilt, the possibility of primary depressive illness should be considered and, if there is any doubt, the participant should be excluded from the study. Similarly, if the patient has had any other illness or undertaken any treatments - orthodox, complementary or nutritional - in the previous three months, their inclusion may introduce additional variables which could confound the results.

These new criteria were devised to increase diagnostic precision and allow researchers to compare and contrast ME and CFS. They will not only enable scientists to test the assumption that the two conditions are identical, but they should also help to clarify whether interventions which have been shown to be effective in one can be safely used to treat the other.  Finally, if evidence indicates that ME is a distinct subgroup, the criteria may not only prove to be of value in research, but also in clinical practice.      


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*Footnote 2012  (EMG)
In a recently published study, Jason et al. (2012) compared patients selected using the 2009 criteria for ME, the Canadian criteria for ME/CFS (Carruthers et al., 2003), and the CDC case definition for CFS (Fukuda et al., 1994).  They reported that on the Short-Form 36, the ME group “had directionally worse scores  when compared to the ME/CFS criteria” and also performed less well on certain cognitive tests. Moreover, a greater percentage of patients with ME had a sudden onset of their illness, and linked it to a virus. In their discussion, Jason et al suggested that the criteria for ME and ME/CFS appeared to select a group of patients with more physical and cognitive symptoms as well as more severe functional impairments  than individuals with CFS.  A surprising finding was that the ME group seemed to have fewer mental health issues than the people with ME/CFS. The results are consistent with those of Jason et al. (2003) and add to the evidence challenging the assumption of equivalence. 

Carruthers, BM., Jain, AK., De Meirleir, KL., Peterson, DL., Klimas, NG., Lerner, AM et al. (2003). Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Clinical Working Case Definition, Diagnostic and Treatment Protocols. Journal of Chronic Fatigue Syndrome, 11,` 1, 7-116.

Jason, LA., Brown, A., Clyne, E., Bartgis, L., Evans, M & Brown, M. (2012). Contrasting case definitions for chronic fatigue syndrome, myalgic encephalomyelitis/chronic fatigue syndrome and myalgic encephalomyelitis.  Evaluation & the Health Professions, 35, 280-304.

C. EM Goudsmit 2012.

First Published in 2012

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