Myalgic Encephalomyelitis: International Consensus Criteria, Journal of Internal Medicine, 20 July 2011
by Tony Britton on July 22, 2011
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Myalgic Encephalomyelitis: International Consensus Criteria
Bruce M Carruthers, MD, CM, FRCP(C) (coeditor); Independent, Vancouver, B.C., Canada
Marjorie I van de Sande, BEd, GradDip Ed (coeditor); Independent, Calgary, AB, Canada
Kenny L De Meirleir, MD, PhD; Department of Physiology and Medicine, Vrije University of Brussels, Himmunitas Foundation, Brussels, Belgium.
Nancy G Klimas, MD; Department of Medicine
,University of Miami Miller School of Medicine and Miami Veterans
Affairs Medical Center, Miami, FL, USA
Gordon Broderick, PhD; Department of Medicine, University of Alberta, Edmonton, AB, Canada
Terry Mitchell, MA, MD, FRCPath; Honorary Consultant for NHS at Peterborough/Cambridge, Lowestoft, Suffolk, United Kingdom.
Don Staines, MBBS, MPH, FAFPHM, FAFOEM; Gold Coast
Public Health Unit, Southport, Queensland; Health Sciences and Medicine,
Bond University, Robina, Queensland, Australia AC
Peter Powles, MRACP, FRACP, FRCP(C), ABSM; Faculty
of Health Sciences, McMaster University and St. Joseph’s Healthcare
Hamilton, Hamilton, ON, Canada.
Nigel Speight, MA, MB, BChir, FRCP, FRCPCH, DCH; Independent, Durham, United Kingdom
Rosamund Vallings, MNZM, MB, BS, MRCS, LRCP; Howick Health and Medical Centre, Howick, New Zealand.
Lucinda Bateman, MS, MD; Fatigue Consultation
Clinic, Salt Lake Regional Medical Center: adjunct faculty – Internal
Medicine, Family Practice, University of Utah, Salt Lake City, UT, USA.
Barbara Baumgarten-Austrheim, MD; ME/CFS Center,
Oslo University Hospital HF, Norway. David S Bell, MD, FAAP; Department
of Paediatrics, State University of New York, Buffalo, NY.
Nicoletta Carlo-Stella, MD, PhD; Independent, Pavia, Italy
John Chia, MD; Harbor-UCLA Medical Center, University of California, Los Angeles; EV Med Research, Lomita, CA, USA
Austin Darragh, MA, MD, FFSEM. (RCPI, RCSI), FRSHFI Biol I (Hon); University of Limerick, Limerick, Ireland
Daehyun Jo, MD, PhD; Pain Clinic, Konyang University Hospital, Daejeon, Korea
Don Lewis, MD; Donvale Specialist Medical Centre, Donvale, Victoria, Australia
Alan R Light, PhD; Depts or Anesthesiology, Neurobiology and Anatomy,University of Utah, Salt Lake City, Utah, USA.
Sonya Marshall-Gradisbik, PhD; Health Sciences and Medicine, Bond University, Robina, Queensland, Australia.
Ismael Mena, MD; Depart. Medicina Nuclear, Clinica Las Condes, Santiago, Chile
Judy A Mikovits, PhD; Whittemore Peterson Institute, University of Nevada, Reno, NV USA
Kunihisa Miwa, MD, PhD; Miwa Naika Clinic, Toyama, Japan
Modra Murovska, MD, PhD; A. Kirchenstein Institute of Microbiology and Virology, Riga Stradins University, Riga, Latvia,
Martin L Pall, PhD; Department of Biochemistry & Basic Medical Sciences, Washington State University, Portland, OR, USA
Staci Stevens, MA; Department of Sports Sciences, University of the Pacific, Stockton, CA USA.
This is an Accepted Article that has been peer-reviewed and approved for publication in the Journal of Internal Medicine,
but has yet to undergo copy-editing and proof correction. Please cite
this article as an “Accepted Article”; doi: 10.1111/j.1365-
2796.2011.02428.x
Running Title: ME: Intl. Consensus Criteria
Abstract
The label “chronic fatigue syndrome” (CFS) has persisted for many
years because of lack of knowledge of the etiological agents and of the
disease process. In view of more recent research and clinical experience
that strongly point to widespread inflammation and multisystemic
neuropathology, it is more appropriate and correct to use the term
“myalgic encephalomyelitis”(ME) because it indicates an underlying
pathophysiology. It is also consistent with the neurological
classification of ME in the World Health Organization’s International
Classification of Diseases (ICD G93.3). Consequently, an International
Consensus Panel consisting of clinicians, researchers, teaching faculty
and an independent patient advocate was formed with the purpose of
developing criteria based on current knowledge. Thirteen countries and a
wide range of specialties were represented. Collectively, members have
approximately 400 years of both clinical and teaching experience,
authored hundreds of peer reviewed publications, diagnosed or treated
approximately 50,000 ME patients, and several members coauthored
previous criteria. The expertise and experience of the panel members as
well as PubMed and other medical sources were utilized in a progression
of suggestions/drafts/reviews/revisions. The authors, free of any
sponsoring organization, achieved 100% consensus through a Delphi type
process.
The scope of this paper is limited to criteria of ME and their
application. Accordingly, the criteria reflect the complex
symptomatology. Operational notes enhance clarity and specificity by
providing guidance in the expression and interpretation of symptoms.
Clinical and research application guidelines promote optimal recognition
of ME by primary physicians and other health care providers, improve
consistency of diagnoses in adult and paediatric patients
internationally, and facilitate clearer identification of patients for
research studies.
Introduction
Myalgic encephalomyelitis (ME), also referred to in the literature as
chronic fatigue syndrome (CFS), is a complex disease involving profound
dysregulation of the central nervous system (CNS) [1-3] and immune
system [4-8], dysfunction of cellular energy metabolism and ion
transport [9-11], and cardiovascular abnormalities [12-14]. The
underlying pathophysiology produces measurable abnormalities in physical
and cognitive function and provides a basis for understanding the
symptomology. Thus, the development of International Consensus Criteria
that incorporate current knowledge should advance the understanding of
ME by health practitioners, and benefit both the physician and patient
in the clinical setting as well as clinical researchers.
The problem with broadly inclusive criteria [15, 16] is that they do
not select homogeneous sets of patients. The Centers for Disease Control
prevalence estimates increased tenfold from 0.24% using the Fukuda
criteria [17] to 2.54% using the Reeves empirical criteria [16]. Jason
et al. [18] suggest there are flaws in Reeves’ methodology because it is
possible to meet the empirical criteria for ME without having any
physical symptoms and it does not discriminate ME/CFS patients from
those with Major Depressive Disorder. Patient sets that include people
who do not have the disease lead to biased research findings,
inappropriate treatments, and waste scarce research funds [19].
Some symptoms of the Fukuda criteria overlap with depression whereas
the Canadian Consensus Criteria [20] differentiate ME patients from
those who are depressed and identify patients who are more physically
debilitated and have greater physical and cognitive functional
impairments [21].
International Consensus Criteria
The Canadian Consensus Criteria were used as a starting point, but
significant changes were made. The six-month waiting period before
diagnosis is no longer required. No other disease criteria require that
diagnoses be withheld until after the patient has suffered with the
affliction for six months. Notwithstanding periods of clinical
investigation will vary and may be prolonged, diagnosis should be made
when the clinician is satisfied that the patient has ME rather than
having the diagnosis restricted by a specified time factor. Early
diagnoses may elicit new insights into the early stages of pathogenesis;
prompt treatment may lessen the severity and impact.
Using “fatigue” as a name of a disease gives it exclusive emphasis
and has been the most confusing and misused criterion. No other
fatiguing disease has “chronic fatigue” attached to its name – e.g.
cancer/chronic fatigue, multiple sclerosis/chronic fatigue – except
ME/CFS. Fatigue in other conditions is usually proportional to effort or
duration with a quick recovery, and will recur to the same extent with
the same effort or duration that same or next day. The pathological low
threshold of fatigability of ME described in the following criteria
often occurs with minimal physical or mental exertion, and with reduced
ability to undertake the same activity within the same or several days.
The International Consensus Criteria (Table 1) identify the unique
and distinctive characteristic patterns of symptom clusters of ME. The
broad spectrum of symptoms alerts medical practitioners to areas of
pathology and may identify critical symptoms more accurately [18-20].
Operational notes following each criterion provide guidance in symptom
expression and contextual interpretation. This will assist the primary
clinician in identifying and treating ME patients in the primary care
setting.
Table 1
MYALGIC ENCEPHALOMYELITIS: INTERNATIONAL CONSENSUS CRITERIA
Adult and Pediatric ● Clinical and Research
Myalgic encephalomyelitis is an acquired neurological disease with
complex global dysfunctions. Pathological dysregulation of the nervous,
immune and endocrine systems, with impaired cellular energy metabolism
and ion transport are prominent features. Although signs and symptoms
are dynamically interactive and causally connected, the criteria are
grouped by regions of pathophysiology to provide general focus.
A patient will meet the criteria for post-exertional neuroimmune
exhaustion (A), at least one symptom from three neurological impairment
categories (B), at least one symptom from
three immune/gastro-intestinal/genitourinary impairment categories (C),
and at least one symptom from energy metabolism/transport impairments
(D).
A. Post-Exertional Neuroimmune Exhaustion (PENE pen׳-e) Compulsory This
cardinal feature is a pathological inability to produce sufficient
energy on demand with prominent symptoms primarily in the neuroimmune
regions. Characteristics are:
1. Marked, rapid physical and/or cognitive fatigability in response
to exertion, which may be minimal such as activities of daily living or
simple mental tasks, can be debilitating and cause a relapse.
2. Post-exertional symptom exacerbation: e.g. acute flu-like symptoms, pain and worsening of other symptoms
3. Post-exertional exhaustion may occur immediately after activity or
be delayed by hours or days. 4. Recovery period is prolonged, usually
taking 24 hours or longer. A relapse can last days, weeks or longer. 5.
Low threshold of physical and mental fatigability (lack of stamina)
results in a substantial reduction in pre-illness activity level.
Operational Notes: For a diagnosis of ME, symptom severity must
result in a significant reduction of a patient’s premorbid activity
level. Mild (an approximate 50% reduction in pre-illness activity
level), moderate (mostly housebound), severe (mostly bedridden), or very
severe (totally bedridden and need help with basic functions). There
may be marked fluctuation of symptom severity and hierarchy from day to
day or hour to hour. Consider activity, context and interactive effects.
Recovery time: e.g. Regardless of a patient’s recovery time from
reading for 1⁄2 hour, it will take much longer to recover from grocery
shopping for 1⁄2 hour and even longer if repeated the next day – if
able. Those who rest before an activity or have adjusted their activity
level to their limited energy may have shorter recovery periods than
those who do not pace their activities adequately. Impact: e.g. An
outstanding athlete could have a 50% reduction in his/her pre-illness
activity level and is still more active than a sedentary person.
B. Neurological Impairments At least One Symptom from three of the following four symptom categories
1. Neurocognitive Impairments
a. Difficulty processing information: slowed thought, impaired
concentration e.g. confusion, disorientation, cognitive overload,
difficulty with making decisions, slowed speech, acquired or exertional
dyslexia
b. Short-term memory loss: e.g. difficulty remembering what one
wanted to say, what one was saying, retrieving words, recalling
information, poor working memory
2. Pain
a. Headaches: e.g. chronic, generalized headaches often involve
aching of the eyes, behind the eyes or back of the head that may be
associated with cervical muscle tension; migraine; tension headaches
b. Significant pain can be experienced in muscles, muscle-tendon
junctions, joints, abdomen or chest. It is non-inflammatory in nature
and often migrates. e.g. generalized hyperalgesia, widespread pain (may
meet fibromyalgia criteria), myofascial or radiating pain
3. Sleep Disturbance
a. Disturbed sleep patterns: e.g. insomnia,
prolonged sleep including naps, sleeping most of the day and being awake
most of the night, frequent awakenings, awaking much earlier
than before illness onset, vivid dreams/nightmares
b. Unrefreshed sleep: e.g. awaken feeling exhausted regardless of duration of sleep, day-time sleepiness
4. Neurosensory, Perceptual and Motor Disturbances
a. Neurosensory and perceptual: e.g. inability to focus vision,
sensitivity to light, noise, vibration, odour, taste and touch; impaired
depth perception
b. Motor: e.g. muscle weakness, twitching, poor coordination, feeling unsteady on feet, ataxia
Notes: Neurocognitive impairments, reported or observed, become more pronounced with fatigue.
Overload phenomena may be evident when two tasks are performed
simultaneously. Abnormal reaction to light – fluctuation or reduced
accommodation responses of the pupils with retention of reaction. Sleep
disturbances are typically expressed by prolonged sleep, sometimes
extreme, in the acute phase and often evolve into marked sleep reversal
in the chronic stage. Motor disturbances may not be evident in mild or
moderate cases but abnormal tandem gait and positive Romberg test may be
observed in severe cases.
C. Immune, Gastro-intestinal & Genitourinary Impairments
At least One Symptom from three of the following five symptom categories
1. Flu-like symptoms may be recurrent or chronic and typically activate or worsen with exertion.
e.g. sore throat, sinusitis, cervical and/or axillary lymph nodes may enlarge or be tender on palpitation
2. Susceptibility to viral infections with prolonged recovery periods
3. Gastro-intestinal tract: e.g. nausea, abdominal pain, bloating, irritable bowel syndrome
4. Genitourinary:e.g.urinaryurgencyorfrequency,nocturia
5. Sensitivities to food, medications, odours or chemicals
Notes: Sore throat, tender lymph nodes, and flu-like symptoms
obviously are not specific to ME but their activation in reaction to
exertion is abnormal. The throat may feel sore, dry and scratchy.
Faucial injection and crimson crescents may be seen in the tonsillar
fossae, which are an indication of immuneactivation.
D. Energy Production/Transportation Impairments: At least One Symptom
1. Cardiovascular: e.g. inability to tolerate an upright position –
orthostatic intolerance, neurally mediated hypotension, postural
orthostatic tachycardia syndrome, palpitations with or without cardiac
arrhythmias, light-headedness/dizziness
2. Respiratory: e.g. air hunger, laboured breathing, fatigue of chest wall muscles
3. Loss of thermostatic stability: e.g. subnormal body temperature,
marked diurnal fluctuations; sweating episodes, recurrent feelings of
feverishness with or without low grade fever, cold extremities
4. Intolerance of extremes of temperature
Notes: Orthostatic intolerance may be delayed by several minutes.
Patients who have orthostatic intolerance may exhibit mottling of
extremities, extreme pallor or Raynaud’s Phenomenon. In the chronic
phase, moons of finger nails may recede.
Paediatric Considerations
Symptoms may progress more slowly in children than in teenagers or
adults. In addition to post- exertional neuroimmune exhaustion, the most
prominent symptoms tend to be neurological: headaches, cognitive
impairments, and sleep disturbances.
1. Headaches: Severe or chronic headaches are often debilitating.
Migraine may be accompanied by a rapid drop in temperature, shaking,
vomiting, diarrhoea and severe weakness.
2. Neurocognitive Impairments: 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. 3. Pain may seem erratic and migrate
quickly. Joint hyper-mobility is common.
Notes: Fluctuation and severity hierarchy of numerous prominent
symptoms tend to vary more rapidly and dramatically than in adults.
Classification ____ Myalgic Encephalomyelitis ____ Atypical Myalgic
Encephalomyelitis: meets criteria for post-exertional neuroimmune
exhaustion but has two or less than required of the remaining criterial
symptoms. Pain or sleep disturbance may be absent in rare cases.
Exclusions: As in all diagnoses, exclusion of alternate explanatory
diagnoses is achieved by the patient’s history, physical examination,
and laboratory/biomarker testing as indicated. It is possible to have
more than one disease but it is important that each one is identified
and treated. Primary psychiatric disorders, somatoform disorder and
substance abuse are excluded.
Paediatric: ‘primary’ school phobia.
Co-morbid Entities: Fibromyalgia, Myofascial Pain Syndrome,
Temporomandibular Joint Syndrome, Irritable Bowel Syndrome, Interstitial
Cystitis, Raynaud’s Phenomenon, Prolapsed Mitral Valve, Migraines,
Allergies, Multiple Chemical Sensitivities, Hashimoto’s Thyroiditis,
Sicca Syndrome, Reactive Depression. Migraine and irritable bowel
syndrome may precede ME but then become associated with it. Fibromyalgia
overlaps.
Criteria Are Supported by Research
Criterial symptoms are supported by a study of more than 2,500
patients that determined which symptoms had the greatest efficacy to
identify ME patients [22]. Investigations of gene expression [23-27] and
structure further support the criteria at a molecular level including
anomalies of increased oxidative stress [4, 28], altered immune and
adrenergic signalling [29, 30], and altered oestrogen receptor
expression [31]. In addition, evidence supporting a genetic
predisposition to ME points to modifications in serotonin transporter
genes [32, 33], the glucocorticoid receptor gene [34], as well as HLA
class II involvement [35]. The potential combinatorial effects of these
modifications have received limited attention [36, 37]. Some early broad
based studies show a lack of objective findings such as no association
with HLA genotype [38]. A study of patients from a twin registry
suggested that environmental factors may outweigh any genetic
predisposition in broad based patient populations [39].
Underlying problems of inconsistent findings in research studies have
been identified [40, 41] and include a need for studies to be based on
larger sample sizes with a more clearly defined phenotype; in particular
one that recognizes the likely existence of significant subgroups
within the patient population. In a study of the Reeves empirical
criteria [16], Jason et al [18] reported that thirty-eight percent (38%)
of patients diagnosed with Major Depressive Disorder were misclassified
as having CFS and only ten percent (10%) of patients identified as
having CFS actually had ME. Accordingly, the primary goal of this
consensus report is to establish a more selective set of clinical
criteria that would identify patients who have neuroimmune exhaustion
with a pathological low-threshold of fatigability and symptom flare in
response to exertion. This will enable like patients to be diagnosed and
enrolled in research studies internationally under a case definition
that is acceptable to physicians and researchers around the world. A.
Post-Exertional Neuroimmune Exhaustion (PENE pen׳-e)
“Malaise – a vague feeling of discomfort or fatigue” [42] is an
inaccurate and inadequate word for the pathological low-threshold
fatigability and post-exertional symptom flare. Pain and fatigue are
crucial bioalarm signals that instruct patients to modify what they are
doing in order to protect the body and prevent further damage.
Post-exertional neuroimmune exhaustion is part of the body’s global
protection response and is associated with dysfunction in the regulatory
balance within and between the nervous, immune and endocrine systems,
and cellular metabolism and ion transport [43-47]. The normal
activity/rest cycle, which involves performing an activity, becoming
fatigued, and taking a rest whereby energy is restored, becomes
dysfunctional.
Numerous papers document abnormal biological responses to exertion,
such as loss of the invigorating effects of exercise [20], decreased
pain threshold [48-50], decreased cerebral oxygen and blood volume/flow
[51-54], decreased maximum heart rate [55], impaired oxygen delivery to
muscles [56], elevated levels of nitric oxide metabolites [57], and
worsening of other symptoms [58]. Patients reach the anaerobic threshold
and maximal exercise at a much lower oxygen consumption level [59].
Reported prolonged effects of exertion include elevated sensory
signalling to the brain [60] that is interpreted as pain and fatigue
[61], elevated cytokine activity [62], delay in symptom activation [63]
and a recovery period of at least 48 hours [58]. When an exercise test
was given on two consecutive days, some patients experienced up to a 50%
drop in their ability to produce energy on the second evaluation [64].
Both submaximal and self-paced physiologically limited exercise resulted
in post-exertional malaise [49].
B. Neurological Impairments
Some viruses and bacteria can infect immune and neural cells and
cause chronic inflammation. Structural and functional pathological
abnormalities [3] within the brain and spinal cord suggest dysregulation
of the CNS control system and communication network [64], which play
crucial roles in cognitive impairment and neurological symptoms [20].
Neuroinflammation of the dorsal root ganglia, gatekeepers of peripheral
sensory information traveling to the brain, has been observed in spinal
autopsies. (Chaudhuri A. Royal Society of Medicine Meeting 2009)
Identified cerebrospinal fluid proteomes distinguish patients from
healthy controls and post-treatment Lyme disease [65].
Neuroimaging studies report irreversible punctuate lesions [66], an
approximate 10% reduction in gray matter volume [67, 68], hypoperfusion
[69-74] and brain stem hypometabolism [1]. Elevated levels of lateral
ventricular lactate are consistent with
decreasedcorticalbloodflow,mitochondrialdysfunctionandoxidativestress[75].
Research suggests that dysregulation of the CNS and autonomic nervous
system alters processing of pain and sensory input [48, 61, 76, 77].
Patients’ perception that simple mental tasks require substantial effort
is supported by brain scan studies that indicate greater source
activity and more regions of the brain are utilized when processing
auditory and spatial cognitive information [78-80]. Poor attentional
capacity and working memory are prominent disabling symptoms [20, 78,
81].
C. Immune Impairments
Most patients have an acute infectious onset with flu-like and/or
respiratory symptoms. A wide range of infectious agents have been
reported in subsets of patients including Xenotropic murine leukemia
virus-related virus (XMRV) [82] and other murine leukemia virus
(MLV)-related viruses [83], enterovirus [84-86], Epstein Barr virus
[87], human herpes virus 6 and 7 [88-90], Chlamydia [91],
cytomegalovirus [92], parvovirus B19 [93] and Coxiella burnetti [87].
Chronic enterovirus infection of the stomach and altered levels of D
Lactic acid producing bacteria in the gastrointestinal tract have been
investigated [85, 94]. Possibly the initial infection damages part of
the CNS and immune system causing profound deregulation and abnormal
responses to infections [4]. Publications describe decreased natural
killer cell signalling and function, abnormal growth factor profiles,
decreased neutrophil respiratory bursts and Th1, with a shift towards a
Th2 profile [4-8, 95, 96]. Chronic immune activation [27], increases in
inflammatory cytokines, pro-inflammatory alleles [4-8, 97-99],
chemokines and T lymphocytes, and dysregulation of the antiviral
riboneuclease L (RNase L) pathway [64, 100-103] may play a role in
causing flu-like symptoms, which aberrantly flare in response to
exertion [5, 95].
D. Energy Production/Transport Impairments
The consistent clinical picture of profound energy impairment
suggests dysregulation of the mitochondria and cellular energy
metabolism and ion transport, and channelopathy [9- 11, 103, 104]. A
biochemical positive feedback cycle called the ‘NO/ONOO- cycle’ may play
a role in maintaining the chronic nature of ME, the presence of
oxidative stress [105-107], inflammatory cytokine elevation [97-99] and
mitochondrial dysfunction [108-111], and result in reduced blood flow
and vasculopathy [109, 110].
Findings of “small heart” with small left ventricular chamber and
poor cardiac performance in patient subsets [112, 113] support previous
reports of cardiac and left ventricular dysfunction [114-116], which
predispose to orthostatic intolerance [14, 117]. Low blood pressure and
exaggerated diurnal variation may be due to abnormal blood pressure
regulation [118]. Altered control and reduced cortisol production during
and following exercise may be involved. Orthostatic intolerance is
associated with functional impairment and symptom severity [119].
Measurable vascular abnormalities suggest that the brain is not
receiving sufficient circulating blood volume in an upright position
[12, 117], which is intensified when standing in one place such as a
grocery store check-out line.
Significant reduction in heart rate variability during sleep is
associated with poor sleep quality and suggests a pervasive state of
nocturnal sympathetic hypervigilance [120].
Application of Criteria
Diagnostic criteria serve two necessary but divergent functions – the
first is diagnosing individuals in a clinical setting and the second is
identifying patient sets for research studies.
A. Clinical Application 1. General Considerations
a. Determine whether symptom cluster patterns are congruent with those expected from dysfunction of an underlying causal system.
b. Symptoms interact dynamically within a stable cluster because they
share the same deep causal roots. Patients’ contextual observations are
essential in determining the expression of interaction of symptom
patterns and severity of their impact.
c. Symptom severity impact must result in a 50% or greater reduction
of a patient’s premorbid activity level for a diagnosis of ME. Mild:
approximately 50% reduction in activity, moderate: mostly housebound,
severe: mostly bedbound, and very severe: bedbound and dependent on help
for physical functions.
d. Symptom severity hierarchy should be determined periodically to help orient and monitor treatment.
e. Criterial subgroups: Post-exertional neuroimmune exhaustion is the
hallmark feature. It may be helpful to subgroup according to which of
the other diagnostic criterial patterns best represent a patient’s
cluster of most severe symptoms: neurological, immune, energy
metabolism/transport, or eclectic (symptoms widely distributed among
subgroups).
f. Separate primary symptoms from secondary symptoms and aggravators.
Distinguish primary symptom complexes formed by a disease process from
secondary effects of coping with the disease, such as anxiety about
finances. Determine the effects and burden of aggravators and stress
enhancers such as fast paced environments and exposure to toxins.
g. Determine total illness burden by assessing symptom severity,
interaction and overall impact. Consider all aspects of the patient’s
life – physical, occupational, educational, social and personal
activities of daily living. Patients who prioritize their activities may
be able to do one important activity by eliminating or severely
reducing activities in other aspects of their life.
h. The International Symptom Scale should not be part of the initial
clinical interview because it may disturb the weighting and significance
of results obtained for an individual patient. When used periodically,
it can help position the patient within the group, orient the treatment
program and monitor its effectiveness.
2. Paediatric Considerations
a. If possible, interview a young person with both parents because
each may remember different symptoms or interactive events that may help
determine onset and when the illness began to interfere with daily
function.
b. Children cannot be expected to judge pre-illness function with
current function. Assess impact by comparing hobbies, educational,
social and sport activities the child participated in before illness
with present activity level.
c. Children may appear irritable when they are asked to do something
when they feel exhausted. On the other hand, they are often able to
accommodate fatigue by resting, which may be inappropriately interpreted
as being lazy.
d. School Phobia: Young patients spend most of their out-of-school
hours resting whereas children with school phobia will be socializing
and participating in activities. However, it is possible that school
phobia may become a secondary symptom because of bullying or academic
difficulties due to having ME.
e. Natural Course: Children can be very severely afflicted but those
whose symptoms are of mild to moderate severity generally are more
likely to have them go into remission than adults. Prognosis cannot be
predicted with certainty.
B. Research Application
A clinical diagnosis must be confirmed before a patient can provide
useful general knowledge about the disease. The data obtained from
patients allows controlled and meaningful observations and suggests
hypotheses to be tested and confirmed or refuted.
1. General Considerations a. Patients should meet the full criteria for epidemiological studies. If specific subgroups or atypical ME are included in a research study, that should be
clearly indicated. b. Specificity: Because critical symptoms are
compulsory, it ensures proper selection of patients. Key operational
guidelines enhance clarity and specificity. Ranking the hierarchy of the
most troublesome symptoms may be helpful in some studies. c.
Reliability: Symptoms must not be viewed as a nominal checklist. The
International Consensus Criteria focus on symptom patterns, which
increase reliability. The International Symptom Scale ensures
consistency in the way questions are asked and further increases
reliability of data collected in different locations. Patients
should complete the International Symptom Scale prior to entering a
research study.
2. Optional Considerations
Classifying patients by subgroups to enable comparison of patients within the diagnosis of ME may be helpful in some studies.
a. Onset: acute infectious or gradual
b. Onset severity may be a good predictor of severity in the chronic phase.
c. Symptom severity: mild, moderate, severe, very severe d. Criterial
subgroups: neurological, immune, energy metabolism/transport, or
eclectic
(See clinical application for symptom severity and criterial subgroups.)
Conclusions
The International Consensus Criteria provide a framework for the
diagnosis of ME that is consistent with the patterns of
pathophysiological dysfunction emerging from published research findings
and clinical experience. Symptom patterns interact dynamically because
they are causally connected. This has been formally addressed by some
investigators who have used well-established multivariate statistical
techniques, such as common factor or principal component analyses to
identify symptom constructs [121, 122]. Others have extended the use of
such methods to guide the analysis of gene expression profiles [28] and
to delineate patient sub-groups [123]. Consistent with this approach,
the panel is developing an International Consensus Symptom Scale (ICSS)
that will build on these underlying interactions. However a necessary
first step in establishing a quantitative score for any diagnostic
instrument is the specification of measurable factors that are most
relevant to the illness. Establishing such criteria was the primary
objective of this work and we believe the International Consensus
Criteria will help clarify the unique signature of ME.
It is important to note that the current emphasis must primarily
remain a clinical assessment, with selection of research subjects coming
later. For this reason the panel is developing Physicians’ Guidelines,
which will include diagnostic protocol based on the International
Consensus Criteria and treatment guidelines that reflect current
knowledge. Individuals meeting the International Consensus Criteria have
myalgic encephalomyelitis and should be removed from the Reeves
empirical criteria and the National Institute for Clinical Excellence
(NICE) criteria for chronic fatigue syndrome. These guidelines are
designed specifically for use by the primary care physician in the hope
of improving rapid diagnosis and treatment by first-line medical care
providers. This may result in the development of an additional short
form version that would build on the relationships linking symptoms to
formulate an abbreviated screening protocol. For the first time
clinical, paediatric and research applications are provided, which will
advance the understanding of myalgic encephalomyelitis and enhance
consistency of diagnoses internationally. The compulsory critical
criteria allow comparable data to be collected in various locations and
may assist in developing consistent biomarkers and further insights into
the mechanism and etiology of myalgic encephalomyelitis.
KEY WORDS: myalgic encephalomyelitis, chronic
fatigue syndrome, criteria, definition, diagnosis. Funding This
Consensus paper is free of sponsorship. All authors contributed their
time and expertise on a volunteer basis and no one received any payments
or honorariums.
Conflict of Interest Statement.
All authors have disclosed potential conflicts of interest and all
members declare that they have no competing interests. Acknowledgements
The panel would like to gratefully acknowledge the participation and
support of the patients and their families in the research described
herein and upon which these guidelines are based.
Author Contributions Coeditors – conception, drafting of paper and revisions: B.M. Carruthers, M.I. van de Sande.
Initial suggestions and subsequent critical reviews: K.L. De
Meirleir, N.G. Klimas, G. Broderick, T. Mitchell, D. Staines, A.C.P.
Powles, N. Speight, R. Vallings, L. Bateman, B. Baumgarten- Austrheim,
D.S. Bell, N. Carlo-Stella, J. Chia, A. Darragh, D. Jo, D. Lewis, A.R.
Light, S. Marshall- Gradisbik, I. Mena, J.A. Mikovits, K. Miwa, M.
Murovska, M.L. Pall, S. Stevens.
Final approval and consensus: There was 100% consensus by the authors
on the final consensus paper. B. M. Carruthers, M. I. van de Sande,
K.L. De Meirleir, N.G. Klimas, G. Broderick, T. Mitchell, D. Staines ,
A.C.P. Powles, N. Speight, R. Vallings, L. Bateman, B.
Baumgarten-Austrheim, D.S. Bell, N. Carlo-Stella, J. Chia, A. Darragh,
D. Jo, D. Lewis, A.R. Light, S. Marshall-Gradisbik, I. Mena, J.A.
Mikovits, K. Miwa, M. Murovska, M.L. Pall, S. Stevens.
Consensus Coordinator: M. van de Sande
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Correspondence address.
Corresponding author: Dr. Bruce Carruthers, 4607 Blenheim St., Vancouver, British Columbia V6L 3A3, Canada. bcarruth@telus.net
Correspondingauthor for submission of document:
Dr.GordonBroderick,Divisionof Pulmonary Medicine, Department of
Medicine, University of Alberta, WMC 2E4.41 WC Mackenzie Health Sciences
Bldg, 8440 – 112 Street, Edmonton AB T6G 2R7, Canada.
gordon.broderick@ualberta.ca
Requests for Single Reprints: Ms. Marj van de Sande, 151 Arbour Ridge
Circle NW, Calgary, Alberta T3G 3V9, Canada. mvandes@shaw.ca
Current Author Addresses
Dr. Carruthers: 4607 Blenheim St., Vancouver, BC, V6L 3A3, Canada. bcarruth@telus.net
Ms. van de Sande: 151 Arbour Ridge Circle NW, Calgary, AB T3G 3V9, Canada. mvandes@shaw.ca
Dr. De Meirleir: Department of Physiology, Vrije University of
Brussels, Himmunitas Foundation, Brussels, 1120, Belgium.
DE.MEIRLEIR@telenet.be
Dr. Klimas: Department of Medicine, University of Miami, 1201 NW 16 St., Miami, FL 33125, USA. nkdoc123@aol.com
Dr. Broderick: Division of Pulmonary Medicine, Department of
Medicine, University of Alberta, WMC 2E4.41 WC Mackenzie Health Sciences
Bldg, 8440 – 112 Street, Edmonton, Alberta, T6G 2R7, Canada.
gordon.broderick@ualberta.ca
Dr. Mitchell: Lowestoft, Suffolk, NR32 5HD, United Kingdom. terry@gerken.org.uk
Dr. Staines: Public Health Medicine and Neuroimmunology, Queensland
Health, Gold Coast Public Health Unit, Southport, Queensland 4215;
Faculty of Health Sciences and Medicine, Bond University, Robina,
Queensland 4229; Australia. Don_Staines@health.qld.gov.au Dr. Powles:
Faculty of Health Sciences, McMaster University and St. Joseph’s
Healthcare Hamilton, 50 Charlton Ave E., Hamilton, Ontario L0R 1H2,
Canada. ppowles@stjosham.on.ca
Dr. Speight: Southlands Gilesgate, Durham, DH1 1QN, United Kingdom. speight@doctors.org.uk
Dr. Vallings: Howick Health and Medical Centre, 108 Ridge Road, Howick, New Zealand. vallings@xtra.co.nz
Dr. Bateman: Fatigue Consultation Clinic , 1002 East South Temple,
Suite 408, Salt Lake City, Utah 84102, USA. fcclinic@xmission.com
Dr. Baumgarten-Austrheim: ME/CFS Center, Oslo University Hospital HF, Pb 4956 Nydalen, N- 0424 Oslo, Norway. uxbaba@ous-hf.no
Dr. Bell: 77 South Main Street, Lydonville NY 14098, NY, USA. dsbellmd@yahoo.com
Dr. Carlo-Stella: Menocchio 10, I-27100, Pavia, Italy. nickics@libero.it
Dr. Chia: Harbor-UCLA Medical Center, University of California, Los Angeles, CA 90024; EV Med
Research, 25332 Narbonne Ave. #170, Lomita, CA 90717, USA. evmed@sbcglobal.net
Dr. Darragh: ‘Tarabeag’, Hill of Tara, Tara, Co Meath, Ireland ;
Chemical & Environmental Science Department, University of Limerick,
Limerick, Ireland. daratara@eircom.net
Dr. Jo: Pain Clinic, Konyang University Hospital, Daejeon, Korea. pandjo@paran.com
Dr. Lewis: CFS Discovery, Donvale Specialist Medical Centre, Suite 8,
90 Mitcham Road, Donvale, Victoria 3111, Australia.
dplewis@cfsdiscovery.oc.au
Dr. Light: Depts. of Anesthesiology, Neurobiology and Anatomy, 3C 444
SOM, University of Utah, 30N 1900E, Salt Lake City, Utah 84132, USA.
alan.light@hsc.utah.edu
Dr. Marshall-Gradisnik: Faculty of Health Sciences and Medicine, Bond
University, Robina, Queensland 4229, Australia. smarshal@bond.edu.au
Dr. Mena: Depart. Medicina Nuclear, Clinica Las Condes, Santiago, Chile. imenamd@gmail.com
Dr. Mikovits: Whittemore Peterson Institute for Neuro-Immune Disease,
Applied Research Facility, Rm. 401/MS199, 1664 North Virginia St.,
University of Nevada, Reno, NA 89557, USA. judym@wpinstitute.org
Dr. Miwa: Miwa Naika Clinic, Shintomicho 1-4-3, Toyama 930-0002, Japan. k-3wa@pm.ctt.ne.jp
Dr. Murovska: A. Kirchenstein Institute of Microbiology and Virology,
Riga Stradins University, Ratsupites St. 5, Riga, Latvia, LV-1067.
modra@latnet.lv
Dr. Pall: Dept. of Biochemistry and Basic Medical Sciences,
Washington State University, 638 NE 41st Ave., Portland, OR 97232 USA.
martin_pall@wsu.edu
Ms. Stevens: Pacific Fatigue Laboratory, Department of Sport
Sciences, University of the Pacific, 3601 Pacific Avenue, Stockton, CA
95211, USA. sstevens@pacific.edu
With thanks to the M.E. Association
