Additions and corrections
We know that our community continues to wrestle over the appropriate diagnostic criteria for myalgic encephalomyelitis to the point that it has can cause contention and consternation in our interactions and discussions. Concern around the legitimacy of the several diagnostic criteria in use is a natural outgrowth of the disbelief and stigma around ME.
The purpose of this article is to provide a source of neutral disambiguation to which people with ME, providers, and researchers can refer — to inform rather than convince. Over the course of the article, we can and must address some prominent misconceptions in search of better clarity. However, there are no conclusions drawn here. That is up to the reader.[pullquote align=”full” cite=”” link=”” color=”” class=”” size=”14″]The article proceeds as though these three premises are a given: a criteria that is useful as a diagnostic tool must include an accurate description of symptoms that are either unique on their own, or unique in combination. For purposes of education, a diagnostic criteria is useful if it provides an accurate picture of how the disease might present in clinic. Finally, a criteria is useful for treatment that includes the greatest number of people who suffer from the disease, without including those who do not.[/pullquote]
We will discuss the following criteria and disease definitions: Oxford, Ramsay, Fukuda, the Canadian Consensus Criteria (CCC), the International Consensus Criteria (ICC), and the National Academies of Medicine Criteria (IOM or NAM). Inclusion ought not be considered equivalent to recommendation or endorsement.
Because the diagnostic criteria has been such a point of contention, quotes about the disease and criteria have been taken out of context in order to support interlocutors’ favored arguments. To mitigate this issue, each section will link back to the original document, allowing readers to see where the information originated and to explore the context as necessary for clarification.
This is a long article! Please feel free to bookmark and return.
Misconceptions about diagnostic criteria
- ME has no single biomarker that may be used in diagnosis. This is not to say that there are no abnormalities in people with ME. Some of these include decreased natural killer cell function (or number), and other immunological abnormalities; metabolic changes; and white matter hyperintensities on MRI. However, none of these are unique to ME. Shifts in natural killer cell function and metabolic shifts such as we see in ME are also seen after other significant biological trauma, including sepsis, physical trauma, or severe burns. White matter hyperintensities can be seen in several different diseases and disorders, including migraine. While a clinician has tools that will show signs of illness in people with ME, there’s no way to identify someone with the disease through such testing alone.The use of symptom-based criteria doesn’t make ME any less real than the many other complex chronic diseases and disorders for which there is no biomedical test and which must also be diagnosed the same way. That includes hEDS, autism, MCAS, POTS, and many, many others.Without a unique biomarker, there is no way to ‘prove’ a criteria identifies patients with the same illness. However, we can argue a criteria to be more or less useful than others.
- The criteria that captures the fewest patients must be correct. A researcher could create a diagnostic criteria that states that on top of meeting Fukuda, the patient must have one blue eye and one brown. That would create the smallest criteria for ME or CFS in existence, but this would not make it more likely to be an accurate or useful criteria for people with ME. The number of patients captured is unrelated to a diagnostic criteria’s accuracy or usefulness, when divorced from other considerations.
- Not explicitly listing exclusions means diagnosis without checking for other illness. Diagnosis of all disease requires ruling out other, similar conditions, even where biomarkers are present. This is implicit in the diagnostic process.
- If clinicians and researchers we know participated, the criteria is probably good. Clinicians and researchers we know participated in all the criteria currently in use to greater and lesser degrees, with significant overlap in who worked on which criteria. The criteria must stand on its own merits.
- We can apply a diagnostic criteria to previously-investigated populations. Determining whether or not a patient meets all the requirements of a diagnostic criteria is often not possible without a clinical examination. At the very least, targeted questions about intensity, duration, and nature of required symptoms must be elicited. For this reason, it is often not possible to retrospectively determine whether a population examined for one criteria meets others.
- Every diagnostic criteria must serve the same purpose.In medicine, the goal is to provide appropriate interventions as swiftly as possible in order to address symptoms of disease. In research, the goal is to have as well-characterized a population as possible to investigate aspects of the disease-process or determine effective treatments. These differing goals may mean that some criteria are more appropriate for research and some are more appropriate for clinical practice.
The Oxford Criteria
The Oxford Criteria only requires long-term fatigue.
There are two subsets of the Oxford Criteria; one requires infectious or post-infectious onset.
The Oxford Criteria presents the disease as psychiatric.
Severe psychiatric illness is exclusionary in Oxford. Suggested comparison groups include people with neuromuscular disorders (such as MS or ALS) and other conditions that may cause debility. Oxford also suggests depressive disorder as a comparison group, making it clear that the original conception of the disease was not as a kind of vegetative depression. However, the less stringent version of the Oxford Criteria is frequently and almost exclusively used by biopsychosocial theorists, who often conceptualize the disease as a psychosomatic syndrome.
The Oxford Criteria is often used in biopsychosocial (BPS) research in the UK. It has been included here so that readers can understand the implications of using this diagnostic criteria for studies of people with ME.
The Oxford criteria requires that severe, disabling fatigue of new origin be present. The fatigue must have both cognitive and physical effects and not be due to any other fatiguing disease or disorder, such as anemia. The fatigue must be present for at least six months and must have been present for at least 50% of the time. Like Fukuda, Oxford explicitly excludes severe mental illness such as schizophrenia or bipolar disorder.
Myalgias (muscle pain), mood disturbances, and sleep disturbances may be present, but these are not required for diagnosis.
Oxford, post-infectious (Post-Infectious Fatigue Syndrome):
In addition to meeting the Oxford criteria above, the disease must be proved to have initiated during or in the wake of an infection, with confirmation from clinician and/or laboratory of the infectious state. The disease must persist at least six months after the infection has cleared.
Click here to read the Oxford Criteria on pubmed or click on the popout below.
The Ramsay definition
Note: There are a great number of misconceptions floating around about Ramsay’s definition. This may be because the definition is represented in A. Melvin Ramsay’s book Myalgic Encephalomyelitis and Postviral Fatigue States, subtitled The saga of Royal Free disease. It is not a published paper, and is not available online in its entirety.
Ramsay’s criteria says…
Ramsay’s book outlines a disease definition rather than a diagnostic criteria. A diagnostic criteria is written such that clinicians can diagnose the disease by determining whether certain symptoms or biomarkers are present. Ramsay’s book outlines a narrative description of disease etiology and presentation without stating which symptoms (or how many) must be present for diagnosis save ‘muscle fatiguability’ of which Ramsay says, “Without it, I would be unwilling to diagnose a patient with ME”; and low-grade fever in the acute stages. Ramsay did not attempt a diagnostic criteria, and his disease definition should not be labeled as one. For the same reason, Ramsay’s definition is not suitable as an inclusion criteria for research. Despite that it is not a diagnostic criteria, it remains a valuable tool for clinicians.
Ramsay’s definition specifies that only Virus X causes ME.
Ramsay references more than one type of infection that may precede ME onset in his accounts of historical epidemics, including poliomyelitis and Coxsackie B. Ramsay also states “…it [ME] may be sudden and without apparent cause, as in cases where the first intimation of illness is an alarming attack of acute vertigo, but usually there is a history of infection of the upper respiratory tract or, occasionally, the gastrointestinal tract with nausea and/or vomiting.” Ramsay says, then, that infection “usually” precedes onset, but sometimes there is no apparent infection; and that when there is not, it is often heralded instead by what appears to be autonomic symptoms. Ramsay acknowledges some cases of ME do not appear to be post-infectious.
Ramsay’s definition describes acute onset only.
Ramsay describes both acute and ‘insidious’ cases when he describes the history of the disease, stating, “…the onset of the disease was acute in four cases, and insidious in fifteen” in regards to one outbreak (pp. 16, New York outbreak, 1950). In a medical context, refers to a more gradual onset.
Myalgic encephalomyelitis and postviral fatigue states has one of the most complete accounts of the history and presentation of the disease — in part because it is a book rather than a research paper or consensus criteria (see ‘misconceptions’). The book details symptoms not described elsewhere; and in part because it is the only definition or diagnostic criteria to distinguish the symptoms of early onset from the symptoms of the chronic disease.
Acute symptoms/peri-onset symptoms (pp. 29)
According to Ramsay, peri-onset symptoms include persistent and profound fatigue and a “medley” of potential other symptoms, such as headache; giddiness; muscle pain, cramps, or twitching; muscle tenderness or weakness; parasthesia (unusual sensations, typically in extremities); frequent urination and difficulty with fluid balance; and sensory disturbances such as tinnitus, deafness alternating with hyperacusis, or blurred vision; and malaise, a general feeling of being ill or unwell. Ramsay also points out that hypoglycemia is common around onset, and mentions that in some cases it is extreme enough to warrant hospitalization. Finally, he states that “all cases” will run a low-grade fever seldom exceeding 100F (28C).
Ramsay also mentions swollen lymph nodes and post-exertional malaise (though he doesn’t label it as such) in his description of peri-onset symptoms, stating, “if muscle power is found to be satisfactory [in minor/moderate-presenting patients], a re-examination should be made after exercise”.
Symptoms of the chronic condition (pp. 29)
Ramsay divides symptoms of the chronic condition into three main categories: issues with the muscular, circulatory, and central and autonomic nervous systems.
Muscular system (pp 30)
Muscle fatigability, in which it may take days for normal function to return, must be present in all cases, although minor or moderate cases may only show this post-exertionally. In severe cases, muscular spasm/twitching is “a prominent feature”, along with swollen bands in the muscle. In less severe cases, tender points in the trapezius (neck and upper back) or gastrocnemius (back of the lower leg) muscles may be found. Ramsay also mentions issues with fine motor control.
Circulatory system (pp 30)
Ramsay mentions cold extremities and hypersensitivity to cold, along with an ashen-grey pallor preceding worsened symptoms.
Central and autonomic nervous system (pp 31)
Problems with memory and concentration are central, along with emotional lability (mood swings, sometimes dramatic; Ramsay gives “bouts of weeping” as an example).
Ramsay goes on to detail a number of issues with cognition, including difficulty with reading comprehension, choosing the wrong word when speaking (paraphasia, dysphasia), difficulty with word-finding (anomia, anomic dysphagia), alterations in sleep rhythm and/or vivid dreams.
Finally, Ramsay mentions symptoms with likely autonomic origins, such as sensory sensitivity, increased frequency of urination, episodic sweating, and orthostatic tachycardia (POTS).
Onset and recovery
Onset is described as being post-infectious, typically in the upper respiratory tract or digestive tract, but with some cases arising in the absence of clear signs of infection; Ramsay states that the first troubling symptom in these cases is often “an alarming attack of vertigo” (see ‘misconceptions’).
Ramsay states that “most cases” make a complete recovery and that only 25% of people with ME will have the disease ten years or longer. However, the numbers Ramsay uses arise from polls of local support groups, and it is unclear how they tracked recovery.
Ramsay suggests absolute rest in the early stages of the disease, and that relapses can be caused by “excessive physical or mental stress, or both”, or new infection (pp 32). Ramsay speaks of relative remissions lasting years before the disease relapses, and calls this one form of the disease. The other he identifies as a form in which “no remission occurs”. Ramsay paints this form of the disease as more severe.
The Fukuda Criteria
The Fukuda criteria does not list post-exertional malaise as a symptom.
The Fukuda criteria includes but does not require post-exertional malaise. It is one of eight symptoms of which four are required for diagnosis. That means a patient may be diagnosed using Fukuda even if they don’t experience PEM. However, PEM would count as evidence for diagnosis of CFS.
The Fukuda Criteria fatigue that is “unexplained, persistent or relapsing”, “of new or definite onset, [and] is not the result of ongoing exertion; is not substantially alleviated by rest; and results in substantial reduction in previous levels of occupational, educational, social, or personal activities.”
In addition to this fatigue, at least four of the following eight symptoms must be present (or relapsing-remitting) for at least six months. These other symptoms cannot have preceded the onset of the fatigue described above, and include: substantial impairment in short-term memory or concentration; sore throat; tender lymph nodes; muscle pain; multi-joint pain without swelling or redness; headaches of a new type, pattern, or severity; unrefreshing sleep; and post-exertional malaise lasting more than 24 hours. Click on the pop-out below to check out the Fukuda criteria.
Click here to see The Fukuda Criteria.
A criteria that requires a certain number of symptoms out of a list of potential symptoms is called a polythetic criteria. All the criteria discussed here have polythetic elements, save the two Oxford criteria. Polythetic criteria can mean that people with varying symptoms may have the same diagnosis. For example, there are 163 different possible combinations of symptoms that would still qualify to meet Fukuda criteria. If we consider issues with short-term memory and issues with concentration two potential items rather than one, this number of combinations increases.
Fukuda has an extensive list of exclusionary conditions, including drug and alcohol abuse, depression with psychotic features, side effects of medication, and eating disorders. Fukuda also lists severe obesity as exclusionary (BMI > 45).
The Canadian Consensus Criteria
Misconception: CCC doesn’t really require PEM.
Clarification: The Canadian Consensus Criteria refers to “Post-Exertional Malaise and/or Fatigue”. Grammatically, this may be taken as “post-exertional malaise (symptom 1) or fatigue (symptom 2)”; or “post-exertional malaise and/or post-exertional fatigue”. The latter is the only possible interpretation for two reasons.
First and most obviously, the first symptom required for CCC diagnosis is fatigue on its own. Why would that also be the second required symptom? That is not a sensible interpretation.
Second, the paragraph directly below the heading further explores the symptom. The text describes the second required symptom as “post exertional malaise and/or fatigue and/or pain and a tendency for other associated symptoms within the patient’s cluster of symptoms to worsen. There is a pathologically slow recovery period – usually 24 hours or longer” making it clear that each of these symptoms is worse post-exertionally with slowed recovery (from exertion) rather than meant to be considered separate from exertion.
Finally, if any doubt remains, pain is also listed as its own, separate required symptom. If #2 did not mean “post-exertional pain” then pain is another symptom that would be required twice over.
The Canadian Consensus Criteria was written by an international panel, despite the name.
The criteria requires that four symptoms be present:
The first is fatigue of new onset, unexplained by other conditions, either persistent or recurring, with physical and mental dimensions, that substantially reduces activity level.
The second required symptom is post-exertional malaise and/or post-exertional fatigue, and/or post-exertional pain, described as “…an inappropriate loss of physical and mental stamina, rapid muscular and cognitive fatigability, post exertional malaise and/or fatigue and/or pain and a tendency for other associated symptoms within the patient’s cluster of symptoms to worsen. There is a pathologically slow recovery period – usually 24 hours or longer.” (See misconceptions for issues with this point.)
The third required symptom is sleep issues. The Canadian Consensus Criteria states that “There is unrefreshed sleep or sleep quantity or rhythm disturbances such as reversed or chaotic diurnal sleep rhythms.” We can summarize this symptom by stating that the patient must have unrefreshing sleep; insomnia and/or hypersomnia; and/or an inverted sleep cycle.
The fourth required symptom is pain; the CCC points out that this includes headaches of a new type, pattern or severity; muscle pain; and/or joint pain. They also emphasize that the pain may be bothersome in different places at different times (“migratory in nature”).
The CCC requires that the symptoms be present for at least 6 months in adults and at least 3 months in children. Like Ramsay, it acknowledges that there is gradual onset in some, while most experience acute/sudden onset of symptoms.
Beyond these four required symptoms, CCC further requires at least two neurological or cognitive symptoms; and at least one symptom from two of the following three categories: autonomic, neuroendocrine, and immune.
Potential neurological symptoms (of which the patient must have at least two) include: trouble concentrating; confusion; disorientation; difficulty with information processing, categorizing and word retrieval; perceptual and sensory disturbances, such as spatial instability, disorientation, and inability to focus vision; ataxia, muscle weakness, and fasciculations; and sensory sensitivities such as photophobia, hyperacusis (sound sensitivity), potentially leaning to emotional overload and/or anxiety. There are some places here where it is unclear whether a line contains one potential symptom or counts as more — ataxia, muscle weakness, and fasciculations, for example, appear to go together as one consideration but may constitute three.
The patient must have at least one symptom from at least two of the following categories: (1) autonomic: orthostatic intolerance; light-headedness; extreme pallor; nausea and irritable bowel syndrome; urinary frequency and bladder dysfunction; palpitations with or without cardiac arrhythmias; exertional dyspnea (shortness of breath). (2) neuroendocrine: loss of thermostatic stability; intolerance of extremes of heat and cold; marked weight change; loss of adaptability and worsening of symptoms with stress (3) immune: tender lymph nodes, recurrent sore throat, recurrent flulike symptoms, general malaise, and/or new sensitivities to food, medications and/or chemicals.
Given the sheer number of listed symptoms, it might seem like the number of permutations of patient presentation increases. It does! However, it’s important to keep in mind that all people who meet CCC must have had four symptoms for six months: fatigue; post-exertional issues; sleep disturbances; and pain. This means we are already working with a more specific population by the time polythetic criteria questions come into play. Finally, CCC mentions “overload phenomena”, which is not a standard medical term so far as we can determine, and requires more explanation than given.
International Consensus Criteria
The International Consensus Criteria (ICC) is the successor to the CCC with a good deal of overlap in the working groups that produced them.
It has one, required symptom: post-exertional neuroimmune exhaustion, defined as the inability to “produce sufficient energy on demand”, with symptoms “primarily in the neuroimmune regions”, and points out that the response may be immediately after activity or delayed. This includes physical and/or cognitive fatigability in response to what may be minimal activity with post-exertional exacerbation of symptoms that may take days, weeks, or longer from which to recover. As a result, there is a substantial reduction in pre-illness activity levels. Due to PENE, symptom presentation may vary a great deal in the same patient over time. Finally, damage from PENE may be cumulative and resting before activity may reduce PENE (see PENE description in the pop-out below or click here)
ICC requires at least one symptom in at least three categories of four. The four categories are neurocognitive; pain; sleep disturbances; and neurosensory.
Neurocognitive complaints include: difficulty with information-processing, including slowed thought, or impaired concentration — for example, confusion, disorientation, cognitive overload, difficulty with decision-making, slowed speech, and acquired or exertional dyslexia. Short-term memory loss, e.g. difficulty with word-retrieval, difficulty remembering what one wanted to say, or what one was saying; difficulty recalling information or poor working memory are also within the neurocognitive category.
The pain category includes headaches, often involving aching behind the eyes or back of the head, associated with cervical muscle tension; migraine; or tension headaches. It also includes muscular, tendon, or joint pain, as well as pain in the chest or abdomen. It is non-inflammatory and often migratory in nature. Patients may meet fibromyalgia criteria (myofascial) and may radiate.
The sleep disturbance category includes disturbed sleep patterns such as insomnia, hypersomnia, inverted sleep cycle, frequent awakenings, awakening much earlier than before onset, and vivid dreams and nightmares. The patient may also experience unrefreshing sleep (awakening feeling exhausted), and daytime sleepiness.
The neurosensory, perceptual and motor disturbances category includes the inability to focus vision, sensory sensitivities, and impaired depth perception; muscle weakness, twitching, poor coordination, feeling unsteady on one’s feet, and ataxia.
As with CCC, it is sometimes challenging to determine which descriptive terms represent one required symptom and which represent several. For example, certainly poor coordination and feeling unsteady are very similar symptoms and cluster around descriptively similar symptoms (ataxia). This is less concerning here, however, since ICC only requires that the patient have one symptom in any given category.
The criteria notes that neurological symptoms may become more pronounced with fatigue, and adds that abnormal pupillary responses are sometimes seen, though these are not part of the diagnostic algorithm. Like CCC, ICC mentions “overload phenomena” — this needs more description than is included in either criteria.
ICC requires at least three of the following five symptoms or symptom-categories be present: flu-like symptoms that are recurrent or chronic and activate or worsen with exertion, such as sore throat, sinusitis, and tender or enlarged lymph nodes; susceptibility to viral infections with prolonged recovery periods; GI symptoms such as nausea, abdominal pain, bloating, irritable bowel syndrome (IBS); genitourinary symptoms such as urinary urgency or frequency or needing to get up at night to urinate; and sensitivities to food, medications, odors or chemicals.
In addition, ICC requires one of the following be present: (1) cardiovascular symptoms such as orthostatic intolerance, which may be delayed; palpitations with/without arrhythmias, or dizziness; (2) respiratory symptoms such as air hunger, labored breathing, or fatigue of chest wall muscles; (3) loss of thermostatic ability (lower than normal body temperature, marked differences in nighttime vs daytime temperatures; sweating episodes; recurrent feelings of feverishness with or without low-grade fever; or cold extremities; and (4) intolerance of extremes of temperature.
A separate category for pediatric ME is included, which states that, “in addition to post-exertional neuroimmune exhaustion”, childhood symptoms “tend to be neurological”, including headaches, cognitive impairments, and sleep disturbances. “Migraine may be accompanied by a rapid drop in temperature, shaking, vomiting, diarrhoea and severe weakness. Difficulty focusing eyes and reading are common. Children may become dyslexic, which may only be evident when fatigued. Slow processing of information makes it difficult to follow auditory instructions or take notes. All cognitive impairments worsen with physical or mental exertion. Young people will not be able to maintain a full school program. Pain may seem erratic and migrate quickly. Joint hypermobility is common.”
National Academy of Medicine (Institute of Medicine) criteria
The NAM or IOM criteria was conceptualized as a way of enabling general practitioners in the US to more swiftly identify people with ME to refer to specialist care. The IOM report stated that the 2015 criteria was “streamlined for practical use in the clinical setting.”
The NAM criteria, or IOM criteria requires the following three symptoms: fatigue that is persistent and profound, of new and definite onset, that is not the result of ongoing exertion and not alleviated by rest that impairs the ability to engage in pre-illness activity; post-exertional malaise, an “exacerbation of some or all of an individual’s ME/CFS symptoms after physical or cognitive exertion, or orthostatic stress that leads to a reduction in functional ability”; and unrefreshing sleep.
In addition to these required symptoms, people diagnosed with the NAM criteria must present with either cognitive impairment or orthostatic intolerance.
All of the patient’s symptoms must experience these symptoms at least half the time and the intensity of the symptom must be substantial —moderate or severe — and last six months or more. See a pop-out here, and turn to page 210.
NAM adds, “clinical features that may be seen in patients with this disorder are a history of certain infections known to act as triggers for ME/CFS that preceded the onset of symptoms and many types of pain, including headaches, arthralgia, and myalgia. Other complaints, such as gastrointestinal and genitourinary problems, sore throat, tender axillary/cervical lymph nodes, and sensitivity to external stimuli, are reported less frequently (Buchwald and Garrity, 1994; Jason et al., 2013; McGregor et al., 1996). These features, when present, can support the diagnosis of ME/CFS.” However, these are not required for diagnosis.
This is a lot! Let’s talk about some similarities and differences in the criteria. Remember:
- A criteria is useful for diagnosis if the symptoms on their own or in combination are unique enough to separate it from others;
- A criteria is useful for treatment if it includes as many people with the disease as possible while still excluding those who do not;
- A criteria is useful for medical education if its symptoms accurately convey how the disease may present in a clinical setting.
Let’s discuss a few important ways in which the criteria differ.
1. Number of required symptoms
Oxford requires the fewest symptoms: just one. CCC and ICC are tied for the greatest number of required symptoms: eight. However, in CCC four of those are required symptoms and four are polythetic. In ICC one of those symptoms is required, and seven are polythetic.
2. Time to diagnosis
Most of the diagnostic criteria that mention a timeframe require six months of symptoms before diagnosis (Oxford, Fukuda, CCC, and NAM). ICC is the exception to the rule, as it may be diagnosed immediately. CCC suggests 3 months for pediatric ME.
3. Requiring post-exertional malaise
Many of the diagnostic criteria require PEM or an equivalent, but some do not. The diagnostic criteria that require it include the Canadian Consensus Criteria, the International Consensus Criteria, and the National Academy of Medicine Criteria. Arguably, the Ramsay definition requires PEM, given that its definition of muscle fatigability discusses worsened weakness post-exertionally with extended recovery periods. Oxford does not include post-exertional malaise, and Fukuda does not require it.
There is some anecdotal evidence that some people with other complex chronic illnesses experience post-exertional malaise. Though they may not use the term, narrative descriptions make it clear that the symptom is best identified as PEM. While it may be easy to say that they have then been misdiagnosed and ‘actually’ have ME, without a biomarker it should become clear on a moment’s reflection the circularity of this argument.
Criteria comparison chart
Click the pop-out below to see a comparison chart between all of the diagnostic criteria for ME, CFS, or ME/CFS.
When we undertake these important decisions as a community, the most important thing is that we be informed about our choices.
#MEAction launched its six-month Values & Policy Initiative at the beginning of October to bring the community together to discuss our core values, tactics and positions so that we are more unified in our work as a large, diverse community. This initiative will ultimately culminate in a statement of principles and values as well as a formal policy platform, which the community will ratify with an up-or-down vote.
Visit our Values & Policy Initiative webpage to read the editorials we have published around these topics, and see the timeline for upcoming conversations!