Myalgic Encephalomyelitis: International Consensus Criteria

Abstract

The label 'chronic fatigue syndrome' (CFS) has persisted for many years because of the lack of knowledge of the aetiological agents and 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 patients with ME, 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 healthcare providers, improve the consistency of diagnoses in adult and paediatric patients internationally and facilitate clearer identification of patients for research studies.

Full text

doi: 10.1111/j.1365-2796.2011.02428.x
Myalgic encephalomyelitis: International Consensus Criteria
B. M. Carruthers
1
, M. I. van de Sande
2
,K.L.DeMeirleir
3
, N. G. Klimas
4
,G.Broderick
5
, T. Mitchell
6
,D.Staines
7,8
,
A. C. P. Powles
9
,N.Speight
10
,R.Vallings
11
,L.Bateman
12,13
, B. Baumgarten-Austrheim
14
,D.S.Bell
15
, N. Carlo-Stella
16
,
J. Chia
17,18
,A.Darragh
19
,D.Jo
20
,D.Lewis
21
,A.R.Light
22
, S. Marshall-Gradisbik
8
,I.Mena
23
,J.A.Mikovits
24
, K. Miwa
25
,
M. Murovska
26
,M.L.Pall
27
&S.Stevens
28
From the
1
Independent, Vancouver, BC, Canada;
2
Independent, Calgary,AB, Canada;
3
Departmentof Physiologyand Medicine,Vrije Universityof
Brussels,HimmunitasFoundation,Brussels, Belgium;
4
Departmentof Medicine,Universityof Miami Miller Schoolof Medicine and MiamiVeterans
AffairsMedical Center,Miami, FL, USA;
5
Departmentof Medicine,Universityof Alberta, Edmonton, AB, Canada;
6
HonoraryConsultantfor NHS at
Peterborou gh ⁄Cambridge,Lowestoft, Suffolk, UK;
7
Gold CoastPublic HealthUnit, Southport,Queensland;
8
HealthSciences and Medicine,Bond
University, Robina,Queensland,Australia;
9
Facultyof Health Sciences,McMaster University and St. Joseph’sHealthcareHamilton, Hamilton,ON,
Canada;
10
Independent, Durham,UK;
11
HowickHealth and MedicalCentre, Howick,New Zealand;
12
FatigueConsultationClinic, Salt Lake
RegionalMedical Center;
13
InternalMedicine,Family Practice,University ofUtah, Salt Lake City,UT, USA;
14
ME ⁄CFS Center,Oslo University
HospitalHF, Norway;
15
Departmentof Paediatrics,State University of New York,Buffalo, NY, USA;
16
Independent, Pavia,Italy;
17
Harbor-UCLA
MedicalCenter, University of California,Los Angeles,CA;
18
EV Med Research, Lomita,CA, USA;
19
Universityof Limerick,Limerick,Ireland;
20
Pain
Clinic,Konyang University Hospital,Daejeon,Korea;
21
DonvaleSpecialistMedical Centre,Donvale, Victoria,Australia;
22
Departments of
Anesthesiology,Neurobiologyand Anatomy, University of Utah,Salt Lake City,UT, USA;
23
Departmentof MedicinaNuclear, ClinicaLas Condes,
Santiago,Chile;
24
WhittemorePetersonInstitute, University of Nevada,Reno, NV, USA;
25
Miwa NaikaClinic, Toyama,Japan;
26
A. Kirchenstein
Instituteof Microbiology and Virology,Riga StradinsUniversity,Riga, Latvia;
27
Departmentof Biochemistry& Basic MedicalSciences, Washington
StateUniversity, Portland, OR; and
28
Departmentof SportsSciences, University of thePacific, Stockton,CA USA
Abstract. Carruthers BM, van de Sande MI, De
Meirleir KL, Klimas NG, Broderick G, Mitchell T,
Staines D, Powles ACP, Speight N, Vallings R, Bat-
eman L, Baumgarten-Austrheim B, Bell DS, Carlo-
Stella N, Chia J, Darragh A, Jo D, Lewis D, Light
AR, Marshall-Gradisbik S, Mena I, Mikovits JA,
Murovska M, Pall ML, Stevens S (Independent,
Vancouver, BC, Canada; Independent, Calgary, AB,
Canada; Department of Physiology and Medicine,
Vrije University of Brussels, Himmunitas Founda-
tion, Brussels, Belgium; Department of Medi-
cine,University of Miami Miller School of Medicine
and Miami Veterans Affairs Medical Center, Miami,
FL, USA; Department of Medicine, University of
Alberta, Edmonton, AB, Canada; Honorary Consul-
tant for NHS at Peterborough⁄Cambridge, Lowest-
oft, Suffolk, UK; Gold Coast Public Health Unit,
Southport, Queensland; Health Sciences and Medi-
cine, Bond University, Robina, Queensland,
Australia; Faculty of Health Sciences, McMaster
University and St Joseph’s Healthcare Hamilton,
Hamilton, ON, Canada; Independent, Durham, UK;
Howick Health and Medical Centre, Howick, New
Zealand; Fatigue Consultation Clinic, Salt Lake
Regional Medical Center; Internal Medicine, Family
Practice, University of Utah, Salt Lake City, UT,
USA; ME ⁄CFS Center, Oslo University Hospital HF,
Norway; Department of Paediatrics, State Univer-
sity of New York, Buffalo, NY; Independent, Pavia,
Italy; Harbor-UCLA Medical Center, University of
California, Los Angeles, CA; EV Med Research,
Lomita, CA, USA; University of Limerick, Limerick,
Ireland; Pain Clinic, Konyang University Hospital,
Daejeon, Korea; Donvale Specialist Medical Centre,
Donvale, Victoria, Australia; Departments or
Anesthesiology, Neurobiology and Anatomy, Uni-
versity of Utah, Salt Lake City, Utah, USA; Health
Sciences and Medicine, Bond University, Robina,
Queensland, Australia; Department of Medicina
Nuclear, Clinica Las Condes, Santiago, Chile; Whit-
temore Peterson Institute, University of Nevada,
Reno, NV, USA; Miwa Naika Clinic, Toyama, Japan;
A. Kirchenstein Institute of Microbiology and Virol-
ogy, Riga Stradins University, Riga, Latvia; Depart-
ment of Biochemistry & Basic Medical Sciences,
Washington State University, Portland, OR; Depart-
ment of Sports Sciences, University of the Pacific,
Stockton, CA USA). Myalgic encephalomyelitis:
International Consensus Criteria (Review). J Intern
Med 2011; 270:327–338.
The label ‘chronic fatigue syndrome’ (CFS) has per-
sisted for many years because of the lack of knowl-
edge of the aetiological agents and the disease pro-
cess. In view of more recent research and clinical
experience that strongly point to widespread inflam-
mation 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 Interna-
tional Consensus Panel consisting of clinicians,
researchers, teaching faculty and an independent
Re-use of this article is permitted in accordance with the Terms
and Conditions set out at http://wileyonlinelibrary.com/online
open#OnlineOpen_Terms
ª2011The Associationfor the Publicationof the Journalof Internal Medicine 327
Review |

patient advocate was formed with the purpose of
developing criteria basedon current knowledge.Thir-
teen countries and a wide range of specialties were
represented. Collectively, members have approxi-
mately 400 years of both clinicaland teaching experi-
ence, authored hundreds of peer-reviewed publica-
tions, diagnosed or treated approximately 50 000
patients with ME, and several members coauthored
previous criteria. The expertise andexperience of the
panel members as well as PubMed and other medical
sources were utilized in a progression of sugges-
tions ⁄drafts ⁄reviews ⁄revisions. The authors, free of
any sponsoring organization, achieved100% consen-
sus through a Delphi-type process. The scope of this
paper is limitedto criteria of ME and their application.
Accordingly, the criteria reflect the complex symp-
tomatology. Operational notes enhance clarity and
specificity by providing guidance in the expression
and interpretation of symptoms. Clinical and re-
search application guidelines promote optimal recog-
nition of ME by primary physicians and other health-
care providers, improve the consistency of diagnoses
in adult and paediatric patients internationally and
facilitate clearer identificationof patients for research
studies.
Keywords: chronic fatigue syndrome, criteria, defini-
tion, diagnosis, myalgicencephalomyelitis.
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 metabo-
lism and ion transport [9–11] and cardiovascular
abnormalities [12–14]. The underlying pathophysiol-
ogy produces measurable abnormalities in physical
and cognitive function and provides a basis for
understanding the symptomatology. Thus, the devel-
opment 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
settingas well as clinical researchers.
The problem with broadly inclusive criteria [15, 16] is
that they donot select homogeneous sets of patients.
The Centers for DiseaseControl prevalenceestimates
increased tenfold from 0.24% usingthe Fukuda crite-
ria [17] to 2.54% using the Reeves empirical criteria
[16]. Jason et al. [18] suggest that 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 pa-
tients with ME ⁄CFS 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 Crite-
ria [20] differentiate patients with ME from those who
are depressed and identify patients who are more
physically debilitated and have greater physical and
cognitive functionalimpairments [21].
Internat ional Consensus Cr iteria
The Canadian Consensus Criteria were used as a
starting point, but significant changes were made.
The 6-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 6 months. Notwith-
standing 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 im-
pact.
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. can-
cer ⁄chronic fatigue, multiple sclerosis⁄chronic fati-
gue – except ME ⁄CFS. Fatigue in other conditions is
usually proportionalto 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 de-
scribedin the following criteria oftenoccurs with min-
imal physical or mental exertion and with reduced
ability toundertake the same activity withinthe same
or severaldays.
The International Consensus Criteria (Table 1) iden-
tify the uniqueand 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
B. M. Carruthers et al. |Review: ME: Intl. Consensus Criteria
328 ª2011 TheAssociation forthe Publicationof the Journal ofInternal MedicineJournal of InternalMedicine270; 327–338

Table 1 Myalgic encephalomyelitis: international consensus criteria
Adultand paediatric •clinical and research
Myalgic encephalomyelitis is an acquired neurological disease with complex global dysfunctions. Pathological dysregulation of
the nervous, immuneand endocrine systems, withimpaired cellular energymetabolism and iontransport are prominent features.
Although signs and symptoms are dynamicallyinteractive and causally connected, the criteria are grouped by regions of patho-
physiology to providegeneral focus.
A patient will meet the criteria for postexertional 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), andat least one symptomfrom energy metabolism ⁄transport impairments (D).
A. Postexertionalneuroimmuneexhaustion(PENE pen’-e):Compulsory
This cardinal feature is a pathological inability to produce sufficient energyon demand with prominent symptoms primarily in
the neuroimmuneregions. Characteristicsare as follows:
1. Marked, rapid physical and ⁄or cognitivefatigability in response to exertion, which may be minimal such as activities
of dailyliving or simplemental tasks,can be debilitating and causea relapse.
2. Postexertional symptom exacerbation: e.g.acute flu-likesymptoms, painand worseningof other symptoms.
3. Postexertional exhaustion may occur immediately afteractivity or be delayed by hoursor days.
4. Recoveryperiod is prolonged, usuallytaking 24 h or longer. A relapsecan last days,weeks or longer.
5. Low threshold of physical and mental fatigability (lack of stamina) results in a substantial reduction in pre-illness
activitylevel.
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 fromreading for ½ hour, it will takemuch longer torecover from grocery shoppingfor ½ 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 athletecould have a 50%reduction in his ⁄herpre-illnessactivity leveland is still more activethan a sedentaryperson.
B. Neurologicalimpairments
At leastone symptom fromthree of the following four symptom categories
1. Neurocognitiveimpairments
a. Difficulty processing information: slowed thought, impaired concentration e.g. confusion, disorientation, cognitive
overload, difficulty with making dec isions,slowed speech,acquired or exertionaldyslexia
b. Short-term memory loss: e.g.difficulty remembering what one wanted to say, what one was saying, retrieving words,
recalling information,poorworking memory
2. Pain
a. Headaches: e.g. chronic, generalizedheadaches often involve aching of the eyes,behind the eyes or back of the head that
may be associatedwith cervicalmuscle tension;migraine; tension headaches
b. Significant pain can be experiencedin muscles, muscle-tendonjunctions, joints, abdomenor chest. It is noninflamma-
tory in nature and often migrates. e.g. generalized hyperalgesia,widespread pain (may meet fibromyalgia criteria), myo-
fascialor radiating pain
3. Sleepdisturbance
a. Disturbedsleep patterns: e.g. insomnia, prolonged sleep including naps,sleeping most of the dayand being awake most
of the night, frequentawakenings,awaking muchearlier than before illnessonset, vividdreams ⁄nightmares
b. Unrefreshed sleep:e.g. awaken feeling exhausted regardless of duration of sleep,day-time sleepiness
B. M. Carruthers et al. |Review: ME: Intl. Consensus Criteria
ª2011 TheAssociation forthe Publicationof the Journal of InternalMedicine Journalof InternalMedicine 270; 327–338 329

Table 1
Continued
Adultand paediatric •clinical andresearch
4. Neurosensory, perceptual and motordisturbances
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, poorcoordination,feeling unsteady on feet,ataxia
Notes:Neurocognitive impairments, reported or observed, becomemore pronounced with fatigue. Overload phenomena may
be evident when two tasks are performed simultaneously. Abnormal accommodation responses of the pupils are common.
Sleep disturbances are typically expressed by prolonged sleep, sometimes extreme, in the acute phase and often evolve into
marked sleep reversal in thechronic stage. Motordisturbances may not be evident in mild or moderate cases but abnormal tan-
dem gait and positive Romberg test may be observed in severe cases.
C. Immune,gastro-intestinal andgenitourinaryImpairments
At least onesymptom from threeof the followingfive symptom categories
1. Flu-likesymptoms may be recurrent or chronic and typically activateor worsen with exertion. e.g. sore throat, sinu-
sitis, cervical an d ⁄oraxillary lymphnodes may enlargeor be tender on palpitation
2. Susceptibility toviral infectionswith prolongedrecovery periods
3. Gastro-intestinaltract: e.g. nausea, abdominal pain,bloating, irritable bowelsyndrome
4. Genitourinary: e. g. urinary urgency or frequency,nocturia
5. Sensitivities tofood,medications,odoursorchemicals
Notes: Sore throat, tender lymph nodes, and flu-like symptoms obviouslyare not specific to ME but their activation in reaction to
exertion is abnormal. The throat may feel sore, dry and scratchy. Faucial inject iona nd crimson crescents may be seen in the tonsil-
lar fossae, whichare an indicationof immune activation.
D. Energy production ⁄transportation impairments: At least one symptom
1. Cardiovascular: e.g. inability to tolerate an upright position - orthostatic intolerance, neurally mediated hypotension, pos-
turalorthostatic tachycardia syndrome,palpitationswith or without cardiac arrhythmias, light-headedness⁄dizziness
2. Respiratory: e.g. airhunger, labouredbreathing,fatigue of chest wallmuscles
3. Loss of thermostatic stability: e.g. subnormal body temperature, marked diurnal fluctuations; sweating episodes, recur-
rent feelings of feverishness with or without low grade fever, cold extremities
4. Intolerance of extremesof temperature
Notes:Orthostaticintolerance maybe delayed by several minutes. Patients who haveorthostatic intolerancemay exhibit mottling
of extremities, extreme palloror Raynaud’sPhenomenon.In the chronic phase, moonsof finger nails mayrecede.
Paediatric considerations
Symptoms may progress more slowly in children than in teenagers or adults. In addition to postexertional neuroimmune exhaus-
tion,the most prominentsymptoms tendto be neurological: headaches, cognitive impairments,and sleep disturbances.
1. Headaches: Severe or chronicheadaches areoften debilitating. Migraine may be accompaniedby a rapid drop in tempera-
ture, shaking, vomiting, diarrhoea and severe weakness.
2. Neurocognitive impairments: Difficulty focusing eyes and reading are common. Children may become dyslexic, which
may only beevident when fatigued. Slowprocessing of informationmakes it difficultto follow auditoryinstructionsor take
notes. All cognitive impairments worsen with physical or mental exertion. Young people will not be able to maintain a full
school programme.
3. Pain may seemerratic and migratequickly. Jointhypermobilityis common.
Notes: Fluctuation and severity hierarchy of numerous prominent symptoms tend to vary more rapidly and dramatically than in
adults.
B. M. Carruthers et al. |Review: ME: Intl. Consensus Criteria
330 ª2011 TheAssociation forthe Publicationof the Journal ofInternal MedicineJournal of InternalMedicine270; 327–338

and contextual interpretation. This willassist the pri-
mary clinician in identifying and treating patients
with ME in theprimary care setting.
Criteriaare supported by research
Criterial symptoms are supported by a study of more
than 2500 patients thatdetermined which symptoms
had the greatest efficacy to identify patients with ME
[22]. Investigations into 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 signal-
ling [29, 30] and altered oestrogen receptor expres-
sion [31]. In addition, evidence supporting a genetic
predisposition to ME points to modifications in sero-
tonin transporter genes [32, 33], the glucocorticoid
receptor gene [34], as well as HLA class II involvement
[35]. Thepotential combinatorial effects of thesemod-
ifications have received limited attention [33, 36].
Some early broad-based studies show a lack of objec-
tive findings such as no association with HLA geno-
type [37]. A study of patients from a twin registry sug-
gested that environmental factors may outweigh any
genetic predisposition in broader patientpopulations
[38].
Underlying problems of inconsistent findings in re-
search studies have been identified [39, 40] and in-
clude a need for studies to be based on larger sample
sizes witha more clearly definedphenotype, in partic-
ular one that recognizes the likely existence of signifi-
cant subgroups within the patient population. In a
study of the Reeves empirical criteria[16], Jason et al.
[18] reported that 38% of patients diagnosed with
major depressive disorder were misclassified as hav-
ing CFS and only 10% of patients identified as having
CFS actually had ME. Accordingly, the primary goal
of this consensus report is to establish a more selec-
tive set of clinical criteria that would identify patients
who have neuroimmune exhaustion with a pathologi-
cal low threshold of fatigability and symptom flare in
response to exertion. This will enable patients to be
diagnosed and enrolled in research studies interna-
tionally under a case definition that is acceptable to
physicians and researchers around the world.
Postexertional neuroimmune exhaustion (PENEpen¢-e)
‘Malaise’ – a vague feeling of discomfort or fatigue [41]
– is an inaccurate andinadequate word for the patho-
logical low-threshold fatigability and postexertional
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. Postexertional 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 endo-
crine systems, and cellular metabolism and ion
transport [42–46]. The normal acti vity ⁄rest cycle,
which involves performing an activity, becoming fati-
gued and taking a rest whereby energy is restored,
becomesdysfunctional.
Numerous papers document abnormal biological re-
sponses to exertion, such as loss of the invigorating
effects of exercise [20], decreased pain threshold
[47–49], decreased cerebral oxygen and blood vol-
ume ⁄flow [50–53], decreased maximum heart rate
Table 1
Continued
Adultand paediatric •clinical andresearch
Classification
——— Myalgic encephalomyelitis
——— Atypical myalgic encephalomyelitis: meets criteria for postexertional neuroimmune exhaustion but has a limit of two
less thanrequired of theremaining criterial symptoms. Painor sleep disturbance maybe absent in rarecases.
Exclusions: As in alldiagnoses, exclusion ofalternate explanatory diagnoses is achieved bythe patient’s history, physical exam-
ination, and laboratory ⁄biomarker testing as indicated. It is possibleto 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. Pae-
diatric: ‘primary’school phobia.
Comorbid entities: Fibromyalgia, myofascial pain syndrome, temporomandibular joint syndrome, irritable bowel syndrome,
interstitial cystitis, Raynaud’s phenomenon,prolapsed mitralvalve, migraines, allergies, multiple chemical sensitivities,Hashi-
moto’sthyroiditis,Sicca syndrome, reactivedepression.Migraine andirritable bowelsyndrome mayprecede ME butthen become
associated with it. Fibromyalgiaoverlaps.
B. M. Carruthers et al. |Review: ME: Intl. Consensus Criteria
ª2011 TheAssociation forthe Publicationof the Journal of InternalMedicine Journalof InternalMedicine 270; 327–338 331

[54], impaired oxygen delivery to muscles [55], ele-
vated levels of nitric oxide metabolites [56] and wors-
ening of other symptoms [57]. Patients reach the
anaerobic threshold and maximal exercise at a
much lower oxygen consumption level [58]. Re-
ported prolonged effects of exertion include elevated
sensory signalling to the brain [59] that is inter-
preted as pain and fatigue [29], elevated cytokine
activity [60], delay in symptom activation [61] and a
recovery period of at least 48 h [57]. When an exer-
cise 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 [62].
Both submaximal and self-paced physiologically
limited exercise resulted in postexertional malaise
[48].
Neurolog ical impairments
Some viruses and bacteria can infect immune and
neural cells and cause chronic inflammation. Struc-
tural and functional pathological abnormalities [3]
within the brain and spinal cord suggest dysregula-
tion of the CNS control system and communication
network [62], which play crucial roles in cognitive
impairment and neurological symptoms [20]. Neuro-
inflammation of the dorsal root ganglia, gatekeepers
of peripheral sensory information travelling to the
brain, has been observed in spinal autopsies (Chau-
dhuri A. Royal Society of Medicine Meeting 2009).
Identified cerebrospinal fluid proteomes distinguish
patients from healthy controls and post-treatment
Lyme disease [63]. Neuroimaging studies report irre-
versible punctuate lesions [64], an approximate 10%
reduction in grey matter volume [65, 66], hypoperfu-
sion [50, 67–71] and brain stem hypometabolism [1].
Elevated levels of lateral ventricular lactate are con-
sistent with decreased cortical blood flow, mitochon-
drial dysfunction and oxidative stress [72]. Research
suggests that dysregulation of the CNS and auto-
nomic nervous system alters the processing of pain
and sensory input [29, 47, 73, 74]. Patients’ percep-
tion that simple mental tasks require substantial ef-
fort 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 [75–77]. Poor attentional
capacity and working memory are prominent dis-
abling symptoms [20, 75, 78].
Immune impairments
Most patients have an acute infectious onset withflu-
like and ⁄or respiratory symptoms. A wide range of
infectious agents have been reported in the subsets of
patients, including xenotropic murine leukaemia
virus-related virus (XMRV) [79] and othermurine leu-
kaemia virus (MLV)-related viruses [80], enterovirus
[81–83],Epstein–Barr virus [84], human herpes virus
6 and 7 [85–87], Chlamydia [88], cytomegalovirus
[89], parvovirus B19 [90] and Coxiella burnetti [84].
Chronic enterovirus infection of the stomach and al-
tered levels of D Lactic acid-producing bacteria in the
gastrointestinal tract have been investigated [82, 91].
Possibly, the initial infection damages part of the CNS
and immune system causing profound deregulation
and abnormal responses to infections [4]. Publica-
tions describe decreased natural killer cell signalling
and function, abnormal growth factor profiles, de-
creased neutrophil respiratory bursts and Th1, with
a shift towardsa Th2 profile [4–8, 92, 93]. Chronic im-
mune activation [27], increases in inflammatory cyto-
kines, pro-inflammatory alleles [4–8, 94–96], chemo-
kines and T lymphocytes and dysregulation of the
antiviral ribonuclease L (RNase L) pathway [62, 97–
100] may play a role in causing flu-like symptoms,
which aberrantly flare in response to exertion [5,92].
Energy production ⁄transport impairments
The consistent clinical picture of profound energy
impairment suggests dysregulation of the mito-
chondria and cellular energy metabolism and ion
transport and channelopathy [9–11, 100, 101]. 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 [102–104], inflammatory cytokine elevation
[94–96] and mitochondrial dysfunction [105–108]
and result in reduced blood flow and vasculopathy
[106, 107].
Findings of ‘small heart’ with small left ventricular
chamber and poor cardiac performance in patient
subsets [109, 110] support previous reports of car-
diac and left ventricular dysfunction [13, 111, 112],
which predispose to orthostatic intolerance [14, 113].
Low blood pressure and exaggerated diurnal varia-
tion may be due to abnormal blood pressure regula-
tion [114]. Altered control and reduced cortisol pro-
duction during and following exercise may be
involved. Orthostatic intolerance is associated with
functional impairment and symptom severity [115].
Measurable vascular abnormalities suggest that the
brain is not receiving sufficient circulating blood vol-
ume in an upright position [12, 113], which is intensi-
fied when standing in one place such as a grocery
B. M. Carruthers et al. |Review: ME: Intl. Consensus Criteria
332 ª2011 TheAssociation forthe Publicationof the Journal ofInternal MedicineJournal of InternalMedicine270; 327–338

store check-out line. Significant reduction in heart
rate variability during sleep is associated with poor
sleep quality and suggests a pervasive state of noctur-
nal sympathetic hypervigilance [116].
Application of criteria
Diagnostic criteria serve two necessary but divergent
functions – the first is diagnosing individuals ina clin-
ical setting and the second is identifying patient sets
for research studies.
Clinicalapplication
Generalconsiderations
1Determine whether symptom cluster patterns are
congruent with those expected from dysfunction of an
underlying causal system.
2Symptoms 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 symp-
tom patternsand severity of their impact.
3Symptom severity impact must result in a 50% or
greater reduction in 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 physicalfunctions.
4Symptom severity hierarchy should be determined
periodically to help orientand monitor treatment.
5Criterial subgroups: Postexertional neuroimmune
exhaustion is the hallmark feature. It may be helpful
to subgroup according to which of the other diagnos-
tic criterial patterns best representa patient’s cluster
of most severe symptoms: neurological, immune,
energy metabolism ⁄transport or eclectic (symptoms
widely distributed amongst subgroups).
6Separate primary symptoms from secondary symp-
toms and aggravators. Distinguish primary symptom
complexes formed by a disease process from second-
ary effects of coping with the disease, such as anxiety
about finances. Determine the effects and burden of
aggravators and stressenhancers such as fast paced
environments and exposure to toxins.
7Determine total illness burden by assessing symp-
tom severity, interaction and overall impact. Consider
all aspects of the patient’s life – physical, occupa-
tional, educational, social and personal activities of
daily living. Patients who prioritize their activities
may be able to do one important activity by eliminat-
ing or severely reducing activities in other aspects of
their life.
8The International Symptom Scale should not be
part of the initial clinical interview becauseit may dis-
turb the weighting and significance of results ob-
tained for an individual patient. When used periodi-
cally, it can help position the patient within the
group, orient the treatment programme and monitor
its effectiveness.
Paediatric considerations
1If possible, interviewa young person with bothpar-
ents because each may remember different symp-
toms or interactive events that may help determine
onset and when the illness began to interfere with
daily function.
2Children 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.
3Children may appear irritable when they are asked
to do something when they feel exhausted. On the
other hand, they are often able to accommodate fati-
gue by resting, which may be inappropriately inter-
preted as being lazy.
4School Phobia: Young patients spend most of
their out-of-school hours resting, whereas children
with school phobia will be socializing and partici-
pating in activities. However, it is possible that
school phobia may become a secondary symptom
because of bullying or academic difficulties owing
to having ME.
5Natural Course: Children can be very severely af-
flicted but those whose symptoms are of mild to mod-
erate severity generally are more likely to have them
go into remission than adults. Prognosis cannot be
predictedwith certainty.
Researchapplication
A clinical diagnosis must be confirmed before a
patient can provide useful general knowledge about
the disease. The data obtained from patients allow
controlled and meaningful observations and suggest
hypotheses to be tested and confirmed or refuted.
B. M. Carruthers et al. |Review: ME: Intl. Consensus Criteria
ª2011 TheAssociation forthe Publicationof the Journal of InternalMedicine Journalof InternalMedicine 270; 327–338 333

General c onsiderations
1Patients should meet the full criteria for epidemio-
logical studies. If specific subgroups or atypical ME
are included in a research study, that should be
clearly indicat ed.
2Specificity: Because critical symptoms are compul-
sory, it ensuresproper selectionof patients. Keyoper-
ational guidelines enhance clarity and specificity.
Ranking the hierarchy of the most troublesome
symptomsmay be helpful in somestudies.
3Reliability: Symptoms must not be viewed as a
nominal checklist. The International Consensus Cri-
teria focus on symptom patterns, which increase reli-
ability. The International Symptom Scale ensures
consistency in the way questions are asked and fur-
ther increases the reliability of data collected in differ-
ent locations. Patients should complete the Interna-
tional Symptom Scale prior to entering a research
study.
Optionalconsiderations
Classifying patients bysubgroups to enable the com-
parison of patients within the diagnosis of ME may be
helpfulin some studies.
1Onset: acute infectious or gradual.
2Onset severity may be a good predictor of severity
in the chronicphase.
3Symptom severity: mild, moderate, severe, very
severe.
4Criterial subgroups: neurological, immune, energy
metabolism ⁄transpor t or eclectic.
(See clinical application for symptom severity and cri-
terial subgroups.)
Conclusions
The International Consensus Criteria provide a
framework for the diagnosis of ME that is consis-
tent with the patterns of pathophysiological dys-
function emerging from published research find-
ings 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 com-
mon factor or principal component analyses to
identify symptom constructs [117, 118]. Others
have extended the use of such methods to guide
the analysis of gene expression profiles [28] and to
delineate patient subgroups [119]. Consistent with
this approach, the panel is developing an Interna-
tional 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 specifica-
tion of measurable factors that are most relevant to
the illness. Establishing such criteria was the pri-
mary 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’ Guide-
lines, which will include diagnostic protocol based
on the International Consensus Criteria and treat-
ment 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 guide-
lines are designed specifically for use by the primary
care physician in the hope of improving rapid diag-
nosis and treatment by first-line medical care pro-
viders. 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 the consis-
tency of diagnoses internationally. The compulsory
critical criteria allow comparable data to be col-
lected in various locations and may assist in devel-
oping consistent biomarkers and further insights
into the mechanism and aetiology of myalgic
encephalomyelitis.
Funding
This Consensus paper is free of sponsorship. All
authors contributed theirtime and expertise on a vol-
unteer basis and no one received any payments or
honorariums.
Conflictofintereststatement
All authorshave disclosed potential conflicts of inter-
est, and all members declare that they have no com-
peting interests.
B. M. Carruthers et al. |Review: ME: Intl. Consensus Criteria
334 ª2011 TheAssociation forthe Publicationof the Journal ofInternal MedicineJournal of InternalMedicine270; 327–338

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: BM Carruthers, MI van de Sande. Initial
suggestions and subsequent critical reviews: KL De
Meirleir, NG Klimas, G Broderick, T Mitchell,
D Staines, ACP Powles, N Speight, R Vallings, L
Bateman, B Baumgarten-Austrheim, DS Bell, N Car-
lo-Stella, J Chia, A Darragh, D Jo, D Lewis, AR Light,
S Marshall-Gradisbik, I Mena, JA Mikovits, K Miwa,
M Murovska,ML Pall, S Stevens.
Final approval and consensus
There was 100% consensus by the authors on the
final consensus paper. BM Carruthers, MI van de
Sande, KL De Meirleir, NG Klimas, G Broderick,
T Mitchell, D Staines, ACP Powles, N Speight, R
Vallings, L Bateman, B Baumgarten-Austrheim, DS
Bell, N Carlo-Stella, J Chia, A Darragh,D Jo, D Lewis,
AR Light, S Marshall-Gradisbik, I Mena, JAMikovits,
K Miwa, M Murovska, ML Pall, S Stevens.
Consensu s coordinator
M van de Sande.
References
1 Tirelli U, Chierichetti F, Tavio M et al. Brain positron emission
tomography (PET) in chronic fatigue syndrome: preliminary
data.Am J Med 1998; 105: 54S–8S.
2 Cook DB, Lange G, DeLuca J, Natelson BH. Relationship of
brain MRI abnormalities and physical functional status in
chronicfatigue syndrome.Int J Neurosci2001; 107: 1–6.
3ChenR,LiangFX,MoriyaJet al. Chronic fatigue syndromeand
the centralnervous system.JIntMedRes2008; 36: 867–74.
4 Broderick G, Fuite J, Kreitz A, Vernon SD, Klimas N, Fletcher
MA. A formal analysis of cytokine networks in chronic fatigue
syndrome.Brain BehavImmun 2010; 24:1209–17.
5 Lorusso L, Mikhaylova SW, Capelli E, Ferrari D, Ngonga GK,
RicevutiG. Immunological aspectsof chronicfatigue syndrome.
AutoimmunRev 2009; 8:287–91.
6 Fletcher MA, ZengXR, Maher K et al. Biomarkersin chronic fati-
gue syndrome:evaluationof natural killercell function and dip-
eptidyl pep tidase IV. PLoS ONE 2010; 5:e10817.
7 Mihaylova I, DeRuyter M, Rummens JL, Basmans E, Maes M.
Decreased expression of CD69 in chronic fatigue syndrome in
relationto inflammatorymarkers:evidence for a severe disorder
in the early activation of T lymphocytes and natural killer cells.
NeuroEndocrinol Lett2007; 28: 477–83.
8 Klimas NG, Salvato FR, Morgan R, Fletcher MA. Immunologic
abnormalities in chronic fatigue syndrome. J Clin Microbiol
1990;28: 1403–10.
9 Myhill S, Booth NE, McLaren-Howard J. Chronic fatigue syn-
drome and mitochondrialdysfunction. Int J ClinExp Med 2009;
2: 1–16.
10 Pieczenik SR, Neustadt J. Mitochondrial dysfunction and
molecular pathways of disease. Exp Mol Pathol 2007; 83:
84–92.
11 Behan WM, More IA, Behan PO. Mitochondrial abnormalities
in the postviral fatigue syndrome. Acta Neuropathol 1991; 83:
61–5.
12 Streeten DH, Thomas D, Bell DS. The roles of orthostatic hypo-
tension, orthostatic tachycardia and subnormal erythrocyte
volumein the pathogenesisof the chronicfatigue syndrome.Am
JMed2000; 320: 1–8.
13 Peckerman A, LaManca JJ, Dahl KA, Chemitiganti R, Qureishi
B, Natelson BH. Abnormal impedance cardiography predicts
symptom severity in Chronic Fatigue Syndrome. Am J Med Sci
2003;326: 55–60.
14 HollingsworthKG, Jones DE, TaylorR, Blamire AM, NewtonJL.
Impaired cardiovascular response to standing in chronic fati-
gue syndrome. Eur J Clin Invest2010; 40: 608–15.
15 Sharpe MC, Archard LC, Banatvala JE et al. A report – chronic
fatigue syndrome: guidelines for research. JRSocMed1991;
84: 118–21.
16 Reeves WC, Wagner D, Nisenbaum R et al. Chronic fatigue syn-
drome – a clinically empirical approach to its definition and
study. BMC Med 2005;3: 19.
17 Fukuda K, Straus SE, HickieI et al. Chronic FatigueSyndrome:
a comprehensive approach to its definition and study. Ann
InternMed 1994; 121: 953–9.
18 Jason LA, Najar N, Porter N, Reh C. Evaluating the Centers for
DiseaseControl’s empirical chronicfatigue syndromecase defi-
nition. J Disabil Pol Studies 2009; 20: 91–100. doi:10.1177/
1044207308325995.Accessed on 10 February2011 at http://
dps.sagepub.com/content/20/2.toc.
19 Jason LA, Choi M. Dimensions and assessment of fatigue. In:
WatanabeY, Evengard B, NatelsonBH, Jason LA, KuratsuneH,
eds. Fatigue Science Human Health. Tokyo: Springer, 2008;
1–16.
20 Carruthers BM, Jain AK, De Meirleir KL et al. Myalgic encepha-
lomyelitis ⁄chronic fatiguesyndrome:clinical workingcase defi-
nition, diagnostic and treatment protocols. J. Chronic Fatigue
Syndr. 2003; 11: 7–116.Accessed on 20 March 2011at http://
www.mefmaction.com/images/stories/Medical/ME-CFS-
Consensus-Document.pdf.
21 Jason LA, Torres-Harding SR, JurgensA, HelgersonJ. Compar-
ing the Fuku da et al. Criteria and the Canadian case definition
for chronic fatigue syndrome. J. Chronic Fatigue Syndr. 2004;
12: 37–52. Accessed on 10 February 2011 at http://www.
cfids-cab.org/cfs-inform/CFS.case.def/jason.etal04.pdf.
22 De Becker P, McGregor N, De Meirleir K. A definition-based
analysis of symptoms in a large cohort of patients with chronic
fatiguesyndrome. JInternMed2001; 250: 234–40.
23 Rowe KS, Rowe KJ. Symptom patterns of children and adoles-
cents with chronic fatigue syndrome. In: Singh NN, Ollendick
TH, Singh AN,eds. Intern Perspective Child Adolescence Mental
Health.Oxford: ElsevierScience Ltd,2002; 2.
B. M. Carruthers et al. |Review: ME: Intl. Consensus Criteria
ª2011 TheAssociation forthe Publicationof the Journal of InternalMedicine Journalof InternalMedicine 270; 327–338 335

24 Kaushik N, Fear D, Richards SC et al. Gene expression in
peripheral blood mononuclear cells from patients with chronic
fatiguesyndrome. J ClinPathol 2005; 58:826–32.
25 Kerr JR, Burke B, Petty R et al. Seven genomic subtypes of
chronic f atigue syndrome ⁄myalgic encephalomyelitis; a de-
tailed analysis of gene network and clinical phenotypes. JClin
Pathol2008; 61: 730–9.
26 Kerr JR, Petty R, Burke B et al. Geneexpression subtypesin pa-
tients withchronic fatigue syndrome ⁄myalgic encephalomyeli-
tis. JInfectDis2008; 197: 1171–84.
27 Aspler AL, Bolshin C, Vernon SD, Broderick G. Evidence of
inflammatory immune signalling in chronic fatigue syndrome:
a pilotstudy of gene expressionin peripheralblood. Behav Brain
Funct2008; 4: 44. doi :10.1186/1744-9081 -4-44.
28 Broderick G, Craddock RC, Whistler T, Taylor R, Klimas N,
Unger ER. Identifying illness parameters in fatiguing syn-
dromesusing classical projection methods.Pharmacogenomics
2006;7: 407–19.
29 Light AR, White AT, Hughen RW, Light KC. Moderate exercise
increases expression for sensory, adrenergic, and immune
genes in chronic fatigue syndrome patients but not in normal
subjects. JPain2009; 10: 1099–112.
30 Light AR, Bateman L, Jo D et al. Gene expression alterations at
baseline and following moderate exercise in patients with
Chronic Fatigue Syndrome, and Fibromyalgia Syndrome.
J Intern Med 2011; ???: ???. May 26. doi: 10.1111/j.1365-
2796.2011.02405.x.[Epub aheadof print].
31 Gra
¨ns H, Nilsson M, Dahlman-Wright K, Evenga
˚rd B. Reduced
levelsof oestrogen receptor beta mRNAin Swedish patients with
chronicfatigue syndrome.JClinPathol2007; 60: 195–8.
32 Narita M, NishigamiN, Narita N et al. Association bet ween sero-
tonin transporter gene polymorphism and chronic fatigue syn-
drome.Biochem BiophysRes Commun 2003; 311:264–6.
33 Falkenberg VR, Gurbaxani BM, UngerER, Rajeevan MS. Func-
tionalgenomics of serotoninreceptor 2A (HTR2A):interactionof
polymorphism, methylation, expression and disease associa-
tion. Neuromolecular Med 2011;13: 66–76.
34 Rajeevan MS, Smith AK, Dimulescu I et al. Glucocorticoid
receptor polymorphisms and haplotypes associated with
chronicfatigue syndrome.Genes BrainBehav 2007; 6: 167–76.
35 Carlo-Stella N, BozziniS, De Silvestri A et al. Molecularstudy of
receptorfor advanced glycation endproduct gene promoter and
identification of specific HLA haplotypes possibly involved in
chronicfatigue syndrome.Int J Immunopathol Pharmacol 2009;
22: 745–54.
36 Goertzel BN, Pennachin C, de SouzaCoelho L, Gurbaxani B,
MaloneyEM, Jones JF. Combinations of single nucleotidepoly-
morphisms in neuroendocrine effector and receptor genes
predict chronic fatigue syndrome. Pharmacogenomics 2006; 7:
475–83.
37 Underhill JA, Mahalingam M, Peakman M, Wessely S. Lack of
association between HLA genotype and chronic fatigue syn-
drome.Eur J Immunogenet2001; 28: 425–8.
38 Sullivan PF, Evenga
˚rd B, Jacks A, Pedersen NL. Twin analyses
of chronic fatigue in a Swedish national sample. Psychol Med
2005;35: 1327–36.
39 Landmark-HøyvikH, Reinertsen KV, LogeJH et al. The genetics
and epigenetics of fatigue.PM R 2010; 2: 456–65.
40 Maher K, Klimas NG, Fletcher MA. Immunology. In: Jason LA,
Fennell PA, Taylor RR, eds. Handbook of Chronic Fatigues.
Hoboken, New Jersey & Canada: John Wiley & Sons, 2003;
124–51.
41 W.B. Saunders Company. Dorland’s Illustrated Medical Dictio-
nary, 29th edn. Philadelphia: W.B. Saunders Company; 2000:
1049.
42 Jason LA, Helgerson J, Torres-Harding SR, Carrico AW, Taylor
RR. Variability in diagnostic criteria for chronic fatigue syn-
drome may result in substantial differences in patterns of
symptomsand disability.Eval Health Prof2003; 26: 3–22.
43 Jason LA, Taylor RR, Kennedy CL et al. Afactoranalysisof
chronic fatigue symptoms in a community-based sample. Soc
Psychiatry Psyc hiatr Epidemiol 2002; 37: 183–9.
44 Dowsett EG, Ramsay AM, McCartney RA, Bell EJ. Myalgic
encephalomyelitis– a persistententeroviral infection? Postgrad
Med J 1990;66: 526–30.
45 Lloyd AR, Hickie I,Boughton CF, SpencerO, Wakefield D. Prev-
alenceof chronic fatiguesyndrome in anAustralian population.
Med J Aust1990; 153: 522–8.
46 Nijs J, Meeus M, McGregor NR et al. Chronic fatigue syndrome:
exercise performance related to immune dysfunction. Med Sci
SportsExerc 2005; 37:1647–54.
47 Meeus M, Roussel NA, TruijenS, Nijs J. Reduced pressurepain
thresholds in response toexercise in chronic fatigue syndrome
butnot in chronic low backpain: an experimentalstudy.JReha-
bil Med 2010; 42: 884–90.
48 Van Oosterwijck J, Nijs J, Meeus M et al. Pain inhibition and
postexertional malaise in myalgic encephalomyelitis ⁄chronic
fatigue syndrome; an experimental study. JInternMed2010;
268:265–78.
49 Whiteside A, Hansen S, Chaudhuri A. Exercise lowers pain
threshold in chronicfatigue syndrome.Pain 2004; 109:497–9.
50 Yoshiuchi K, Farkas I, Natelson BH. Patients with chronic fati-
gue syndrome have reduced absolute cortical blood flow. Clin
PhysiolFunct Imaging2006; 26: 83–6.
51 Goldstein JA. Chronic Fatigue Syndrome: The Limbic Hypothe-
sis. Binghampton,New York: Haworth Medical Press,1993: 19,
116.
52 Streeten DH. Roleof impaired lower-limb venous innervation in
the pathogenesis of thechronic fatigue syndrome. Am J Med Sci
2001;321: 163–7.
53 Neary PJ, Roberts AD, Leavins N, Harrison MF, Croll JC, Sex-
smith JR. Prefrontal cortex oxygenation during incremental
exercise in chronic fatigue syndrome. Clin Physiol Funct Imag-
ing 2008;28: 364–72.
54 VanNess JM, Snell CR, Dempsey WL, Strayer DR, Stevens SR.
Subclassifyingchronic fatiguesyndrome usingexercise testing.
Med SciSports Exerc 2003; 35:908–13.
55 De Becker P, Roeykens J, ReyndersM, McGregor N, De Meirleir
K. Exercise capacity in chronic fatigue syndrome. Arch Intern
Med 2000;170: 3270–7.
56 Sua´ rez A, Guillamo´E,RoigTet al. Nitric oxide metabolite
production during exercise in chronic fatigue syndrome: a
case-control study. J Womens Health (Larchmt) 2010; 19:
1073–7.
57 VanNess JM, Stevens SR,Bateman L, Stiles TL, Snell CR. Post-
exertional malaise in women with chronic fatigue syndrome.
JWomensHealth(Larchmt)2010; 19: 239–44.
58 Vermeulen RCW, Kurk RM, Visser FC, Sluiter W, Scholte HR.
Patients with chronic fatigue syndrome performed worse than
controls in a controlled repeated exercise study despite a nor-
mal oxidative phosphorylation capacity. JTranslMed2010; 8:
93. doi:10.1186/1479-5876-8-93.
59 Demitrack MA, Crofford LJ. Evidence for and pathophysiologic
implication of hypothalamic-pituitary-adrenal axis dysregula-
B. M. Carruthers et al. |Review: ME: Intl. Consensus Criteria
336 ª2011 TheAssociation forthe Publicationof the Journal ofInternal MedicineJournal of InternalMedicine270; 327–338

tion in fibromyalgia and chronic fatigue syndrome. Ann NY
Acad Sci1998; 840: 684–97.
60 White AT, Light AR, Hughen RWet al. Severity of symptom flare
after moderate exercise is linked to cytokine activity in chronic
fatiguesyndrome. Psychophysiol2010; 47: 615–24.
61 Yoshiuchi K, CookDB, Ohashi K et al. A real- time assessm ent of
the effect of exercise in c hronic fatigue syndrome. Physiol Behav
2007;92: 963–8.
62 Snell CF, VanNess JM, Stayer DF, Stevens SR. Exercisecapac-
ity and immune function in male and female patients with
chronicfatigue syndrome(CFS). In Vivo2005; 19: 387–90.
63 Schutzer SE, Angel TE, Liu T et al. Distinct cerebrospinal fluid
proteomes differentiate post-treatment Lyme disease from
chronicfatigue syndrome.PLoS ONE 2011;6: e1 7287.
64 Lange G, Wang S, DeLuca J, Natelson BH. Neuroimaging in
chronicfatigue syndrome.Am J Med 1998; 105:50S–3S.
65 de Lange FP, Kalkman JS, Bleijenberg G, Hagoort P, van der
Meer JW, Toni I. Gray matter volume reduction in the chronic
fatiguesyndrome. Neuroimage 2005;26: 777–81.
66 Okada T, Tanaka M, Kuratsune H, Watanabe Y, Sadato N.
Mechanisms underlying fatigue: a voxel-based morphometric
studyof chronic fatigue syndrome. BMC Neurol2004; 4: 14.
67 Costa DC, Tannock C, Brostoff J. Brainstem perfusion is im-
pairedin chronic fatiguesyndrome.QIM 1995; 88: 767–73.
68 Mena I, Villanueva-Meyer J. Study of cerebralperfusion by Neu-
roSPECT in patients with chronic fatigue syndrome. In: Hyde
BM, Goldstein J, Levine P,eds. The Clinical and Scientific Basis
of Myalgic Encephalomyelitis, Chronic Fatigue Syndrome.
Ottawa, Ontario & Ogdensburg, New York State: The Nightin-
gale Research Foundation, 1992; 432–8.
69 Goldberg MJ, Mena I, Darcourt J. NeuroSPECT findings in
children with chronic fatigue syndrome. J. Chronic Fatigue
Syndr. 1997; 3: 61–6. Accessed on 22 March 2011 at http://
bubl.
ac.uk/archive/journals/jcfs/v03n0197.htm#5neurospect.
70 Ichise M, Salit I, Abbey S et al. Assessment of regional cerebral
perfusionby Tc-HMPAO SPECT in Chronic Fatigue Syndrome.
Nucl MedCommun 1995; 13: 767–72.
71 Biswal B, Kunwar P, Natelson BH. Cerebral blood flow is re-
duced in chronic fatigue syndrome as assessed by arterial spin
labeling. JNeurolSci2001;301: 9–11.
72 Mathew SJ, Mao X, Keegan KA et al. Ventricular cerebrospinal
fluid lactate is increased in chronicfatigue syndromecompared
with generalized anxiety disorder: an in vivo 3.0 T (q)H MRS
imaging study. NMR Biomed 2009; 22:251–8.
73 Meeus M, Nijs J, HuybrechtsS, Truijen S. Evidence for general-
ized hyperalgesia in chronic fatigue syndrome: case control
study. Clin Rheumatol2010; 29: 393–8.
74 Siemionow V, Fang Y, Calabrese L, Sahgal V, Yue GH. Altered
central nervous system signal during motor performance in
chronic fatigue syndrome. Clin Neurophysiol 2004; 115:2372–
81.
75 Lange G, Steffner J, Cook DB et al. Objective evidence of
cognitive complaints in chronic fatigue syndrome: a BOLD
fMRI study of verbal working memory. Neuroimage 2005; 26:
513–4.
76 Flor-Henry P,Lind JC, Koles ZJ. EEGsource analysisof chronic
fatiguesyndrome. Psychiatry Res2010; 181: 155–65.
77 Cook DB, O’Connor PJ, Lange G, Steffener J. Functional neu-
roimaging correlates of mental fatigue induced by cognition
among fatigue syndrome patients and controls. Neuroimage
2007;36: 108–22.
78 Michiels V, CluydtsR, Fischler B. Attention and verballearning
in patients with chronic fatigue syndrome. J Int Neuropsychol
Soc 1998; 4:456–66.
79 Lombardi VC, Ruscetti FW, Das Gupa J et al. Detection of an
infectious retrovirus, XMRV, in blood cells of patients with
chronicfatigue syndrome. Science 2009; 326: 585–9.
80 Lo SC, Pripuzova N, Li B et al. Detection of MLV-related virus
gene sequences in blood of patients with chronic fatigue syn-
drome and healthy blood donors. Proc Natl Acad Sci USA 2010;
107: 15874–9.
81 Chia J, Chia A, Voeller M, Lee T, Chang R. Acute enterovirus
infection followed by myalgia encephalomyelitis ⁄chronic fati-
gue syndrome and viral persistence. J Clin Pathol 2010; 63:
163–8.
82 Chia J, Chia A. Chronic fatigue syndrome is associated with
chronic enterovirus infection of the stomach. JClinPathol
2008;61: 43–8.
83 Chia JK. The role of enterovirus in chronic fatigue syndrome.
J Clin Pathol2005; 58: 1126–32.
84 Zang L, Gough J, ChristmasD et al. Microbial infections in eight
genomicsubtypes of chronicfatigue syndromemyalgic enceph-
alomyelitis. J ClinPathol 2010; 63: 156–64.
85 Ablashi DV, EastmanHB, Owen CB. FrequentHHV-6 antibody
and HHV-6 reactivation in multiple sclerosis (MS) and chronic
fatiguesyndrome (CFS)patients. J Clin Virol2000; 16: 179–91.
86 Chapenko S, Krumina A, Koziereva S et al. Activation of human
herpesviruses 6 and 7 in patients with chronic fatigue syn-
drome.JClinVirol2006; 37(Suppl1): S47–51.
87 Nicolson GL, Gan R, Haiser J. Multiple co-infections (Myco-
plasma, Chlamydia, human herpes virus-6) in blood of chronic
fatigue syndrome patients: association with signs and symp-
toms. APMIS 2003;111: 557–66.
88 Chia JK, Chia LY. Chronic Chlamydia pneumonia infection: a
treatable cause of chronic fatigue syndrome. Clin Infect Dis
1999;29: 452–3.
89 Beqaj SH, Lerner AM, Fitzgerald JD. Immunoassay with cyto-
megalovirus early antigens from gene products P52 and CM 2
(UL44 and UL 57) detects active infection in patients with
chronicfatigue syndrome. J Clin Pathol2008; 61: 623–6.
90 Kerr JR, Cunniffe VS, Kelleher P, BernsteinRM, Bruce IN. Suc-
cessful intravenous immunoglobulin therapy in 3 cases of par-
vovirus B19-associated chronic fatigue syndrome. Clin Infect
Dis 2003;36: e100–6.
91 Sheedy JR, Richards EH, Wettenhall REH et al. Increased D-
lactic acid intestinal bacteria in patients with Chronic Fatigue
Syndrome.In Vivo 2009; 23:621–8.
92 Brenu EW, Staines DR, Baskurt OK et al. Immune and hemo-
rheological changes in chronic fatigue syndrome. JTranslMed
2010;8: 1.
93 Klimas NG, Koneru AO. Chronic fatigue syndrome: inflamma-
tion, immune function, and neuroendocrine interactions. Curr
RheumatolRep 2007; 9: 483–7.
94 Fletcher MA, Zeng XR, Barnes Z, Levis S, Klimas NG. Plasma
cytokines in women with chronic fatigue syndrome. JTransl
Med 2009;7: 96.
95 Cameron B, Hirschberg DL, Rosenberg-Hassan Y, Ablashi D,
Lloyd AR. Serum cytokine levels in postinfective fatigue syn-
drome.Clin Infect Dis 2010;50: 278–9.
96 Carlo-Stella N, Badulli C, De Sivestri A et al. The first study of
cytokine genomic polymorphisms in CFS: positive association
of TNF-857and IFNgamma874 rare alleles.Clin Exp Rheumatol
2006;24: 179–82.
B. M. Carruthers et al. |Review: ME: Intl. Consensus Criteria
ª2011 TheAssociation forthe Publicationof the Journal of InternalMedicine Journalof InternalMedicine 270; 327–338 337

97 De Meirleir K, Bisbal C, CampineI et al. A 37 kDa 2-5A binding
protein as a potential biochemical marker for chronic fatigue
syndrome.Am J Med 2000; 108:99–105.
98 Sudolnik RJ, Peterson DL, O’Brien K et al.. Biochemical evi-
dencefor a novel low molecularweight 2-5A-dependentRNase L
in chronic fatigue syndrome. J Interferon Cytokine Res 1997;
17: 377–85.
99 Nijs J, Fre´mont M. Intracellular immunedysfunctionin myalgic
encephalomyelitis ⁄chronic fatigue syndrome: state of the art
and therapeutic implications. Expert Opin Ther Targets 2008;
12: 281–9.
100 Nijs J, De Meirleir K, Meeus M, McGregor Nr, Englebienne P.
Chronic fatigue syndrome: intracellular immune deregulations
as a possible etiology for abnormal exercise response. Med
Hypotheses 2004;62: 759–65.
101 Wong R, Lopaschuk G, ZhuG et al. Skeletalmuscle metabolism
in the chronic fatigue syndrome. In vivoassessment by 31P nu-
clear magnetic resonance spectroscopy. Chest 1992; 102:
1716–22.
102 Jammes Y, Steinberg JG, Mambrini O, Bre´geon F, Delliaux S.
Chronic fatigue syndrome: assessment of increased oxidative
stress and altered muscle excitability in response toincremen-
tal exercise. JInternMed2005; 257: 299–310.
103 Miwa K, Fujita M.Fluctuationof serum vitamin E(alphatocoph-
erol) concentrationsduring exacerbationand remissionphases
in patients with chronicfatigue syndrome.Heart Vessels 2010;
25: 319–23.
104 Richards RS, Wang L, Jelinek H. Erythrocyte oxidative
damage in chronic fatigue syndrome. Arch Med Res 2007; 38:
94–8.
105 Pall ML, SatterleeJD. Elevated nitric oxide ⁄peroxynitrite mech-
anism for the common etiology of multiple chemicalsensitivity,
chronic fatigue syndrome, and posttraumatic stress disorder.
Ann NY AcadSci 2001; 933: 323–9.
106 Kurup RK, Kurup PA.Hypothalamic digoxin, cerebralchemical
dominanceand myalgicencephalomyelitis.Int J Neurosci2003;
113:683–701.
107 Pall ML. Explaining ‘‘UnexplainedIllnesses’’: Disease Paradigm
for Chronic Fatigue Syndrome, Multiple Chemical Sensitivity,
Fibromyalgia, Post-Traumatic Stress Disorder, Gulf War Syn-
dromeand Others. Binghamton, NY: Harrington Park(Haworth)
Press,2007.
108 Chaudhuri A, Watson WS, Pearn J, Behan PO. The symptoms
of chronicfatigue syndrome are relatedto abnormalion channel
function.Med Hypotheses2000; 54: 59–63.
109 Miwa K, Fujita M. Cardiacfunction fluctuatesduring exacerba-
tion and remission in young adults with chronic fatigue syn-
dromeand ‘‘small heart’’.JCardiol2009; 54: 29–35.
110 Miwa K, Fujita M. Small heart syndrome in patients with
chronicfatigue syndrome.Clin Cardiol2008; 31: 328–33.
111 Peckerman A, LaMancaJJ, Qureishi B et al. Baroreceptor reflex
and integrative stress responses in chronic fatigue syndrome.
Psychosom Med 2003; 65:889–95.
112 Lerner AM, Lawrie C, DworkinHS. Repetitively negative chang-
ing T waves at 24-h electrocardiographic monitors in patients
with the chronic fatigue syndrome. Left ventricular dysfunction
in a cohort. Chest 1993;104: 1417–21.
113 Rowe PC, Calkins H. Neurally mediated hypotension and
chronicfatigue syndrome.Am J Med 1998; 105:15S–21S.
114 Newton JL, Sheth A, Shin J et al. Lower ambulatory blood pres-
sure in chronic fatigue syndrome. Psychosom Med 2009; 71:
361–5.
115 Costigan A, Elliott C, McDonald C, Newton JL. Orthostatic
symptoms predict functional capacity in chronic fatigue syn-
drome:implicationsfor management.QJM 2010; 103:589–95.
116 Burton AR, Rahman K, Kadota Y, Lloyd A, Vollmer-Conna U.
Reduced heart rate variability predicts poor sleep quality in
case-control study of chronic fatigue syndrome. Exp Brain Res
2010;204: 71–8.
117 Nisenbaum R, Reyes M,Mawle AC, Reeves WC. Factor analysis
of unexplained severe fatigue and interrelated symptoms: over-
lap with criteria for chronic fatigue syndrome. Am J Epidemiol
1998;148: 72–7.
118 Priebe S, Fakhoury WK, Henningsen P. Functional incapacity
and physical and psychological symptoms: how they intercon-
nect in chronic fatigue syndrome. Psychopathology 2008; 41:
339–45.
119 Carmel L, Efroni S, White PD, Aslakson E, Vollmer-Conna U,
Rajeevan MS. Gene expression profile of empirically delineated
classes of unexplained chronic fatigue. Pharmacogenomics
2006;7: 375–86.
Correspondence: Dr Bruce Carruthers, 4607 Blenheim St., Vancou-
ver,British ColumbiaV6L 3A3, Canada.
(fax:+1 604 263 9059; e-mail:bcarruth@telus.net);and
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.
(fax:+1 780 407 6384; e-mail:gordon.broderick@ualberta.ca).
B. M. Carruthers et al. |Review: ME: Intl. Consensus Criteria
338 ª2011 TheAssociation forthe Publicationof the Journal ofInternal MedicineJournal of InternalMedicine270; 327–338