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>>>>> Help ME Circle <<<<
>>>> 4 August 2011 <<<<
Editorship : j.van.roijen@chello.nl
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Below you will find the Abstract, the Introduction-, and
Discussion-sections, and (for private members) an
attachment as pdf of the accepted preprint format of
*The International Consensus Criteria* - Carruthers,
B.M. et al.
In Help ME Circle, 28 July 2011: *ME Intern. Consensus
Criteria -Announcement*, the Co-editors Bruce
Carruthers and Marj van de Sande said that the criteria
will be available free online when it is assigned an issue.
But I had to pay 40+$ for the preprint format (WILEY).
List members can find this version at:
http://www.megaupload.com/?d=3DHCO0MNDI
~jan van Roijen
````
JOURNAL OF INTERNAL MEDICINE
International Consensus Criteria
doi: 10.1111/j.1365-2796.2011.02428.x
Accepted manuscript online: 20 JUL 2011,
Article type : Review
Myalgic Encephalomyelitis: International
Consensus Criteria
Abstract
The label =93chronic fatigue syndrome=94 (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 =93myalgic encephalomyelitis=94(ME)
because it indicates an underlying pathophysiology.
It is also consistent with the neurological classification of
ME in the World Health Organization=92s 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 =93fatigue=94 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=94 attached
to its name =96 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.
(Please insert Table 1 here.)
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=94 [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=92s 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 decreased cortical blood flow,
mitochondrial dysfunction and oxidative stress [75].
Research suggests that dysregulation of the CNS and
autonomic nervous system alters processing of pain and
sensory input [48, 61, 76, 77].
Patients=92 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=92 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 =93small heart=94 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 =96 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=92s 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=92s 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=92s life =96 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
~~~~ =20
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