What is ME?
Part 1: Nomenclature: a disease of many names
Part 2: Defining ME/CFS: diagnostic criteria
Part 3: Research-based definitions and recommendations
Part 4: Epidemiology: estimating disease prevalence
Part 5: Co-morbidity and overlap with other conditions
Part 6: Mortality in people with ME/CFS
In the video above, Dr Charles Shepherd, Hon. Medical Adviser to the ME Association, provides a summary overview of ME/CFS – symptoms, diagnosis, management, prognosis etc.
The video was produced by NHS Choices.
The information below has been taken from the comprehensive: ME/CFS/PVFS An Exploration of Key Clinical Issues (2018).
It’s undergone a thorough, 6,000-word revision, is up to date, fully-referenced, and contains 147, A4-size pages. It features all relevant published research and contains far more information than we could possibly include on our website.
Written by Dr Charles Shepherd, Hon. Medical Adviser to the ME Association, and Dr Abhijit Chaudhuri, Consultant Neurologist, Essex Centre for Neurosciences, Clinical Issues is reviewed and revised on an annual basis.
You can purchase a copy from our online shop or by contacting head office on 01280 818964 (Monday-Friday, 9.30am to 3.00pm).
Free copy available for medical professionals!
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Most doctors now accept that ME/CFS and PVFS (myalgic encephalomyelitis/chronic fatigue syndrome and post-viral fatigue syndrome) are genuine and disabling illnesses.
The World Health Organisation (2016) classifies ME (and PVFS) as a disease of the central nervous system (G93.3). And, although CFS is not classified as a distinct clinical entity, it is indexed to G93.3.
- The Department of Health officially recognises ME/CFS to be a ‘debilitating and distressing condition’ and more recently ‘recognises CFS/ME as a neurological condition of unknown origin’.
The 2002 report to the Chief Medical Officer (CFS/ME Working Group 2002; section 12) reinforced the serious and debilitating nature of ME/CFS.
- An academic study carried out at Sheffield Hallam University and published in 1996, estimated that the annual economic cost of ME/CFS to the nation in relation to lost income, benefits and health costs was around £3.5 billion (Bibby and Kershaw 1996).
- A 2017 analysis of the economic cost of ME/CFS, carried out by 2020 Health, has produced a very similar figure.
Even the National Institute of Health and Care Excellence (NICE) in the clinical guideline for ME/CFS, state:
|‘The physical symptoms can be as disabling as multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, congestive heart failure and other chronic conditions.’
‘CFS/ME places a substantial burden on people with the condition, their families and carers, and hence on society.’
In America, an influential 2015 report from the Institute of Medicine (IOM) also reinforced the seriousness of the condition:
‘Misconceptions or dismissive attitudes on the part of healthcare providers make the path to diagnosis long and frustrating for many patients.’
‘The committee stresses that healthcare providers should acknowledge ME/CFS as a serious illness that requires timely diagnosis and appropriate care.’
The IOM report concluded:
‘It is clear from the evidence compiled by the committee that ME/CFS is a serious, chronic, complex, and multisystem disease that frequently and dramatically limits the activities of affected patients’.
However, disagreements and uncertainties remain – especially over nomenclature, definition, causation and the most appropriate forms of management.
Therapeutic nihilism (scepticism) is no longer an option as there is a great deal that can be done to improve the quality of life for people with ME/CFS.
Additional support from the ME Association:
Nomenclature: a disease of many names
M.E. (Myalgic Encephalomyelitis) is a name that was originally introduced in a Lancet editorial (The Lancet 1956) to describe people with the illness who had been admitted to London’s Royal Free Hospital back in 1955.
Clinically, myalgic was used to refer to the characteristic muscle symptoms, encephalomyelitis to the brain symptoms. Pathologically, encephalomyelitis indicates inflammation within the brain and spinal cord – a description for which there is currently no sound scientific evidence.
C.F.S. (Chronic Fatigue Syndrome) is the name currently favoured by the UK medical profession because it makes no firm assumption about cause. However, the term CFS is widely disliked and viewed as inappropriate by the patient community.
CFS perpetuates misunderstandings about causation and management of the disease and results in dismissive attitudes from both healthcare providers and the general public. This is a view that the the ME Association shares. It is rather like describing dementia as a ‘chronic forgetfulness syndrome’.
Two further criticisms of CFS as a name are that it:
- fails to reflect the diverse symptomatology and severity of the illness, and,
- that it has become a convenient label for anyone with persistent unexplained fatigue.
It should also be noted that CFS is designed to select homogeneous (very similar) groups of patients for research purposes. The definition is not intended for the diagnostic assessment of what is likely to be a very heterogeneous (diverse) group of clinical presentations.
P.V.F.S. (Post-Viral Fatigue Syndrome) is the term introduced during the 1980s as a description for patients who could clearly trace the onset of their illness back to a viral infection. PVFS is a helpful description to use when an extended period of ill health follows an acute infection and a diagnosis of ME/CFS is not yet appropriate.
Dr Charles Shepherd, Hon. Medical Adviser to the ME Association, talks about the issues relating to nomenclature and the differences between M.E. and CFS, in a short video that was made by ME/CVS Vereniging.
The current situation regarding nomenclature
M.E. (Myalgic Encephalopathy)
The term ‘encephalomyelitis’ is not a pathologically proven explanation for what may be happening within the nervous system in ME/CFS.
Consequently, it often causes dissent among doctors. The ME Association therefore proposed the term encephalopathy as an alternative, meaning a significant disorder of brain function.
We believe that encephalopathy may be a more appropriate way of describing the various abnormalities in hypothalamic, autonomic and cognitive functions and in cerebral perfusion that have been reported in the research literature.
Some psychiatrists regard ME/CFS to be part of a wider spectrum of non-organic (functional) disorders where multiple, medically unexplained symptoms (or functional somatic symptoms) are assumed to be a result of unresolved psychological distress occurring in the absence of any organic disease.
We believe the fundamental flaw in this assumption is that common symptoms do not necessarily suggest that a common pathogenesis of disorders underlies these symptoms.
The international debate about nomenclature and definition is on-going. For more information, see commentaries:
- Nacul et al (2017a) Differing case definitions point to the need for an accurate diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome, and,
- Nacul et al (2017b) How have selection bias and disease misclassification undermined the validity of myalgic encephalomyelitis/chronic fatigue syndrome studies?
Defining ME/CFS: diagnostic criteria
The situation regarding diagnostic criteria has become increasingly complicated, and there are now over 20 different diagnostic criteria for ME, CFS, PVFS or ME/CFS.
Most of these diagnostic criteria have been produced for research purposes, but some are designed for clinical purposes or for both research and clinical purposes. At present, there is no world-wide agreement on which set of criteria should be used for either research or clinical purposes.
Most of the recent research into ME/CFS has been carried out using patients who meet the 1994 Centres for Disease Control and Prevention (CDC) criteria for CFS, also known as the Fukuda criteria, although some research groups are now making use of the 2003 Canadian criteria (below).
Many clinicians take a pragmatic approach and rely on their clinical judgement when making a diagnosis of ME/CFS rather than strictly adhering to any particular set of diagnostic criteria.
The main diagnostic criteria for ME/CFS:
Canadian clinical criteria (2003)
The ME Association has endorsed the Canadian clinical criteria – detailed diagnostic guidance produced by a multidisciplinary group of doctors (Carruthers et al 2003). This guidance is intended to provide a clinical definition that places a much greater emphasis on a disease that equates with neuroimmune dysfunction. However, the content validity of the Canadian criteria has been challenged (Asprusten et al 2015).
London criteria for ME (1994)
In the UK, proposals were published for a revised definition of ME – the London criteria – that are very closely based on Dr Melvin Ramsay’s original description of the illness. The London criteria were modified in 2009 by members of the original group (Goudsmit et al 2009), including Dr Charles Shepherd, Hon. Medical Adviser to the ME Association.
International Consensus Criteria (2011)
Another proposed set of diagnostic criteria comes in the form of the International Consensus Criteria (ICC; Carruthers et al 2011).
In these criteria, the key symptom is post-exertional neuroimmune exhaustion – i.e. low stamina, rapid fatigability, symptom exacerbation – with prolonged recovery. This is accompanied by neurological, immune/gastrointestinal/genitourinary symptoms, plus energy metabolism/transport impairment and at least a 50% reduction in activity.
A study by Jason et al (2016), which analysed two discrete data sets and compared people meeting the ICC with people meeting the Fukuda K et al 1994 (CDC, see Table 2 on p.13) CFS criteria, found that the ICC case definition identified patients with more functional impairments and worse symptoms than those meeting the Fukuda criteria.
US Institute of Medicine criteria for SEID (2015)
The US Institute of Medicine report (2015) recommended that CFS and ME should be replaced by a new name – systemic exertion intolerance disease (SEID) – to better reflect the key symptoms associated with this disease.
The report also recommended that ME/CFS should no longer be a diagnosis of exclusion and that there should be a new clinical definition in relation to SEID.
These report proposals received a generally positive response in the medical journals (Clayton 2015; The Lancet 2015). However, a more critical analysis has been prepared by Jason et al (2015). Public reaction here in the UK to changing the name to SEID has been mixed, with the majority rejecting the new name in a ME Association website poll.
The Institute of Medicine recommendations now form a key part of the revised and updated CDC website for ME/CFS (as at June 2018).
US Institute of Medicine: proposed diagnostic criteria for SEID
Diagnosis requires that the patient have the following three symptoms:
1. A substantial reduction or impairment in the ability to engage in pre-illness levels of occupational, educational, social, or personal activities that persists for more than 6 months and is accompanied by fatigue, which is often profound, is of new or definite onset (not lifelong), is not the result of ongoing excessive exertion, and is not substantially alleviated by rest,
2. Post-exertional malaise* and
3. Unrefreshing sleep*
At least one of the two following manifestations is also required:
1. Cognitive impairment* or
2. Orthostatic intolerance.
Symptoms must be present at least half of the time and have moderate, substantial, or severe intensity
*Frequency and severity of symptoms should be assessed. The diagnosis of ME/CFS should be questioned if patients do not have these symptoms at least half of the time with moderate, substantial, or severe intensity.
Research-based definitions and recommendations
The CDC (Fukuda) definition
A number of consensus-driven, symptom-based definitions for CFS have been published. The definition produced by the US Centers for Disease Control and Prevention ( Fukuda K et al 1994) is widely used for research purposes, but it has a number of defects (e.g. the requirement for symptoms to be present for six months before a diagnosis can be made) that limit its use in clinical practice.
The NIH Pathways to Prevention Report
In 2014, an unbiased, independent panel developed a report of the NIH Pathways to Prevention Workshop: Advancing the Research on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, which summarised the findings of a two-day influential workshop and identified future research priorities.
The workshop had extensively reviewed thousands of published research studies on ME/CFS and heard from top experts in the field. The report was published in Annals of Internal Medicine in June 2015 and urged innovative biomedical research to improve the diagnosis and treatment of ME/CFS.
|“ME/CFS exists, and despite the absence of a clear definition, an estimated one million Americans are affected by it,” said Dr. Green, Panel chair, University of Michigan Schools of Medicine and Public Health.
“In order to develop primary prevention strategies and effective drug treatments, there needs to be a clear understanding of its causes and the populations it affects.”
The National Institutes of Health (NIH) report also made a number of important conclusions and recommendations regarding current and future research strategy into ME/CFS. These included:
- The research and health care community has frustrated its constituents by not appropriately assessing and treating the disease and by allowing patients to be stigmatised.
- The lack of a universally accepted case definition makes determining incidence and prevalence difficult and leads to variability in such estimates. A team of stakeholders (such as patients, clinicians, researchers and federal agencies) should be assembled to reach a consensus on the definition and variables of CFS.
- Some instruments used to evaluate ME/CFS are not validated, are inappropriate and may be misleading.
- The lack of a specific and sensitive diagnostic test and clearly defined diagnostic criteria has hampered research on pathogenesis, treatment and conceptualisation of ME/CFS as a disease entity.
- Most (clinical trial) studies have significant methodological limitations and take place primarily in speciality clinics in relatively homogeneous populations. These trials often use subjective, unclear and poorly defined end points (which may not be meaningful to patients) and do not provide information explaining the high withdrawal rates.
The Oxford definition
The NIH Pathways to Prevention report also concluded that continuing use of the Oxford research definition for chronic fatigue syndrome (Sharpe et al 1991) may impair progress and cause harm and should therefore be retired from further use.
The ME Association agrees that the Oxford definition of chronic fatigue syndrome should no longer be used due to the way in which it can result in the recruitment into research studies of people with milder idiopathic fatigue and affective disorders.
Baraniuk (2017a) compared the selectivity of Oxford and Centers for Disease Control (Fukuda) criteria in a US population and concluded that the prevalence of CFS is grossly overestimated by using Oxford criteria when compared to CDC criteria. Baraniuk also found that Oxford criteria inappropriately selected healthy subjects with mild fatigue and chronic idiopathic fatigue and mislabelled them as having CFS.
Results from epidemiologic studies, which have attempted to estimate the prevalence of ME/CFS, vary according to the population being studied, the survey methodology used and the criteria used to establish the diagnosis.
From the information currently available, and the consensus reached in the report to the Chief Medical Officer on ME/CFS (CFS/ME Working Group 2002), we make the following conclusions:
- A prevalence rate of at least two per 1,000 of the adult population – although the actual figure is probably closer to four per 1,000 (Jason et al 1999), i.e. 0.2-0.4%. This means that somewhere between 150,000 and 250,000 people in the UK have ME/CFS. A general practice with 10,000 patients could have up to 40 cases of ME/CFS.
- All age groups and social classes are affected – although it is rare for patients below the age of seven and above the age of 60 to have a new diagnosis of ME/CFS. The most common age of onset is between 13 and 15 in children and between early twenties and mid-forties in adults.
- Older people with ME/CFS demonstrate a disease phenotype very different from younger people. The combination of differing underlying pathogenic mechanisms and the physiological aspects of ageing result in a greater disease impact on those in the older age group (Lewis et al 2013b).
- Female:male predominance (around 2:1).
- ME/CFS has been reported worldwide and across ethnicities (Jason et al 1999; Njoku et al 2007).
- No specific personality profile predisposes to the risk of developing ME/CFS.
- Higher rates have been found in first degree relatives (Walsh et al 2001), and a study of female twin pairs found concordance rates of 38% and 11% among monozygotic and dizygotic pairs (Buchwald et al 2001).
The most relevant UK study (Nacul et al 2011b) involved a sample of 143,000 individuals aged 18 to 64 years covered by three primary care services in three regions of England.
The study estimated a 0.2% minimum prevalence rate of ME/CFS meeting any of the study case definitions (CDC or Canadian), with a prevalence of 0.19% for the CDC definition and 0.11% for the Canadian definition. The estimated minimal yearly incidence was 0.015%.
A more recent study from America, which looked at CFS in Olmsted County, Minnesota, found an overall prevalence and incidence of 71.34 per 100,000 persons and 13.16 per 100,000 person-years (Vincent et al 2012).
Chronic fatigue, or being ‘tired all the time’, is a very common clinical presentation in primary care. The explanation is often multifactorial, and the majority of these patients will not meet the criteria for ME/CFS.
Comorbidity and overlap with other conditions
A number of conditions appear to be more common in people with ME/CFS. In particular:
- fibromyalgic-type pain;
- atypical facial pain;
- gynaecological conditions, pelvic pain unrelated to menstruation, endometriosis (Sinaii et al 2002) and periods of amenorrhoea (Boneva et al 2011);
- hypermobility syndromes (Nijs et al 2006);
- interstitial cystitis/bladder pain syndrome (Clauw et al 1997);
- irritable bowel syndrome (Hanevik et al 2014); and
- migraine type headaches (Ravindran et al 2011).
What is more relevant to research is the way in which some of the key clinical features of ME/CFS, especially autonomic dysfunction, central (brain) fatigue and cognitive dysfunction, are also prominent in other conditions with a neurological and/or immunological component – as in primary biliary cirrhosis or Sjögren’s syndrome.
There is growing evidence to demonstrate that autonomic dysfunction, and the effect it has on peripheral blood flow, plays a role in cognitive dysfunction, central fatigue and possibly even peripheral (muscle) fatigue (He et al 2013).
It has been suggested that chronic immune activation and/or reactivated viral infection may play a role in increasing the risk of malignancy. There is very little sound research to support such an association. However, a population-based case-control study among the US elderly found a higher risk of non-Hodgkin lymphoma (Chang et al 2012).
Mortality in people with ME/CFS
There is very little research examining mortality in ME/CFS. Anecdotal information, as well as some research studies, indicates that there is an increased risk of suicide.
McManimen et al (2016) have examined whether people with ME/CFS are dying earlier than the overall population from the same cause. This was done through analysing data on cause and age of death from 56 people with ME/CFS.
The findings from this very small study suggest that there is a significantly increased risk of earlier all-cause and cardiovascular related mortality along with a lower age of suicide and cancer. As the authors point out, this is a small study with over-representation of people with severe ME/CFS. So, these findings cannot be regarded as conclusive evidence.
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