American Journal of Biochemistry and Biotechnology 6 (2): 120-135, 2010
ISSN 1553-3468© 2010 Science Publications

The Development of a Revised Canadian Myalgic Encephalomyelitis
Chronic Fatigue Syndrome Case Definition
1
1

Leonard A. Jason, 1Meredyth Evans, 1Nicole Porter, 1Molly Brown,
Abigail Brown, 1Jessica Hunnell, 1Valerie Anderson, 1Athena Lerch,
2
Kenny De Meirleir and 3Fred Friedberg
1
Department of Psychology, DePaul University,
Center for Community Research, Chicago, Il, 60614, USA
2
Department of Physical Education and Physical Therapy,
Vrije Universiteit Brussel, Belgium
3
Department of Psychiatry and Behavioral Science,State University of New York at Stony Brook, USA

Abstract: Problem statement: Several investigators have indicated that case definitions for Chronic
Fatigue Syndrome (CFS) are characterized by vaguely worded criteria that lack operational definitions
and guidelines. The most widely used CFS case definition is the Fukuda et al. criteria, which uses
polythetic criteria (i.e., patients are only required to have four out of a possible eight symptoms). Yet
two of these eight symptoms (post-exertional malaise and memory/concentration problems) are an
essential feature of this illness and the Fukuda et al. criteria do not require that these symptoms bepresent among all patients. Significant methodological problems could occur if investigators in
different settings recruit samples with different percentages of these core symptoms. In contrast, theCanadian clinical case definition does require specific ME/CFS symptoms such as post-exertionalmalaise and memory/concentration problems. The provision of operationally explicit, objective criteria
on specific key symptoms might reduce criterion variance as a source of unreliability. In addition, theuse of structured interview schedules will ensure that symptoms are assessed in a consistent way
across settings. Conclusion/Recommendations: In this article, we specified explicit rules fordetermining whether critical symptoms meet ME/CFS criteria using a revised Canadian case definition
and a questionnaire has been developed to assess core symptoms. It is hoped that these developments
will lead to increased reliability of this revised Canadian case definition as well as more frequent useof these criteria by investigators.
Key words: Myalgic encephalomyelitis, chronic fatigue syndrome, chronic fatigue, post-exertionalmalaise, illnessand (1994) and recently revised by Goudsmit et al.
(2009) in an effort to distinguish the ME criteria fromthat of CFS. These ME case definitions recognize thefollowing four cardinal features: (1) physical or mental
fatigue or muscle weakness after minimal
exertion which may persist long after exertion ends;(2) circulatory impairment (e.g., feeling hot when it’scold, postural hypotension); (3) one or more symptoms
indicating the involvement of the central nervous
system such as impairment of memory andconcentration and disturbed sleep patterns and (4) themarked fluctuation of symptoms. Other symptoms
emphasized included: Pain and autonomic and

INTRODUCTION
Efforts to develop a CFS case definition can betraced back to the 1950s. In 1955, there was an
outbreak of a CFS-like illness at the Royal Free
Hospital and Ramsay (1981; 1988), the medical
consultant in charge, published a number ofdescriptions of this disease, which subsequently
became known as Myalgic Encephalomyelitis (ME)
(Hyde et al., 1992) (Ramsay used a different term in his
early research, but he changed after Acheson (1959)
came up with ME). Based on Ramsay’s concept,
research criteria were developed by Dowsett et al. (1990)

Corresponding Author: Leonard A. Jason, Department of Psychology, DePaul University, Center for Community Research,
Chicago, Il, 60614, USA Tel: 773-325-2018 Fax: 773-325-4923

120

Am. J. Biochem. & Biotech., 6 (2): 120-135, 2010
In 1994, with sponsorship from the Centers for
Disease Control and prevention (CDC) in the US, arevised case definition for CFS (Fukuda et al., 1994)
was developed and it is now used throughout the world.
This CFS case definition requires a person toexperience six or more months of chronic fatigue of
new or definite onset, that is not substantially alleviatedby rest, not the result of ongoing exertion and that
results in substantial reductions in occupational, socialand personal activities. To be diagnosed with CFS,
individuals also need to have the concurrent occurrenceof four or more of eight symptoms that do not predate
the fatigue and persists for six or more months since theonset (e.g., sore throat, lymph node pain, muscle pain,
joint pain, post-exertional malaise, headaches of a newor different type, memory and concentration difficulties
and unrefreshing sleep). Although the first CFS criteria
published by Holmes et al. (1988) (as specified by the
Schluederberg et al. (1992) revision), excluded
individuals with the presence of anxiety disorders,somatoform
disordersandnonpsychoticor
nonmelancholic depression prior to CFS onset, these
conditions were no longer exclusionary under the
Fukuda et al. case definition. Jason et al. (2001)
compared the Fukuda et al. (1994) and Holmes et al.
(1988) criteria and found that the Holmes et al. (1988)
criteria selected a group of patients with higher
symptomatology and functional impairment.
Unfortunately, the current US case definition for
CFS (Fukuda et al., 1994) is characterized by vaguely
worded criteria that are lacking operational definitions
and guidelines to assist health care professionals in theirinterpretation and application of the diagnostic tool
(Jason et al., 1999a; Reeves et al., 2003). In order toprovide more guidelines and specific criteria for thiscase definition, the CDC developed an empiric casedefinition for CFS that involves assessment ofsymptoms, disability and fatigue (Reeves et al., 2005).
The CDC empiric case definition assesses disability
using the Medical Outcomes Study Short Form-36
Health Survey (SF-36) (Ware et al., 2000); symptoms
using the Symptom Inventory (Wagner et al., 2005) andfatigue using the Multidimensional Fatigue Inventory(Smets et al., 1995). However, using these new empiric
criteria, the estimated prevalence rates of CFS haveincreased to 2.54% (Reeves et al., 2007), rates that areabout ten times higher than prior CDC estimates(Reyes et al., 2003) and prevalence estimates ofother investigators (Jason et al., 1999b) using the
Fukuda et al. criteria. It is possible that the increase in
CFS prevalence in the United States is due to abroadening of the Fukuda et al. case definition in an
attempt to operationalize the criteria. Further, theimmunological abnormalities and physicians werealertedtoinappropriate
nightor
daytimesweating, gastro-intestinal disturbances, dizziness orvertigo,hyperacusis,
blurredvision, sorethroat, headaches and intolerance to alcohol. When
Jason et al. (2003) attempted to operationalize some ofthese ME criteria by selecting individuals with postexertional malaise, memory and concentration
impairment and fluctuation of symptoms and thencompared these patients to those meeting the current
US definition of CFS (Fukuda et al., 1994), the ME
criteria selected a more symptomatic group of patients.
In 1998, Holmes et al. (1988) constructed the first
US working case definition of CFS. According to thiscase definition, individuals needed to report six or moremonths of persistent or relapsing, debilitating fatigue
that does not resolve with bedrest to meet criteria. Also,
participants were required to report at least 8 of 11 minor
symptoms (fever or chills, sore throat, lymph node pain,
muscle weakness, muscle pain, post-exertional malaise,headaches of a new or different type, migratory
arthralgia, neuropsychiatric complaints, sleep disturbanceand a sudden onset of symptoms). Participants were also
required to report at least a 50% impairment of dailyfunctioning, as compared to premorbid levels. As theHolmes et al. (1988) criteria were utilized in researchand practice, it became evident that there werenumerous inconsistencies in interpretation andclassification. For example, Katon et al. (1991) foundthat patients with CFS were indistinguishable from thosewith chronic fatigue not meeting the (Holmes et al.,1988) CDC criteria. Another major concern was thatthe requirement of eight or more minor symptoms could
inadvertently select for individuals with psychiatricproblems (Katon and Russo, 1992).
A few years later, another set of more broadly
defined CFS criteria were developed by British
researchers (Sharpe et al., 1991). To qualify for adiagnosis of CFS using the British CFS criteria, thefollowing features needed to be present: (1) fatigue
must be the principal symptom; (2) the syndrome must
be definite in onset and not lifelong; (3) the syndrome
must be severe, disabling and have an effect on physicaland mental (cognitive) functioning; (4) the syndrome
must have been present for six months or more than
50% of the time and (5) other symptoms may bepresent, particularly myalgias, mood and sleep
disturbance. These criteria were not frequently used byinvestigators, as they were considered considerably
broader than the Holmes et al. (1988) criteria and a few
years later, international consensus developed a new
CFS case definition (Fukuda et al., 1994).
121

Am. J. Biochem. & Biotech., 6 (2): 120-135, 2010degree of arthralgia and/or myalgia (there are a small
number of patients with no pain or sleep dysfunction
and a diagnosis can only be given when these
individuals have a classical case with an infectious
illness onset). Finally, there needs to be at least one
symptom from two of the following categories:
autonomic
manifestations(neurally
mediated
hypotension, light headedness), neuroendocrine
manifestations (e.g., recurrent feelings of feverishness
and cold extremities) and immune manifestations (e.g.,recurrent sore throats). Jason et al. (2004) comparedpersons meeting the Canadian clinical case definition(Carruthers et al., 2003), the Fukuda et al. criteria andpeople experiencing chronic fatigue explained bypsychiatric reasons. The Canadian criteria, in contrast
to the Fukuda et al. criteria, selected cases with lesspsychiatric comorbidity, more physical functional
impairment,
morefatigue/weakness
andneuropsychiatric and neurology symptoms. Moreover,those meeting the Canadian criteria were more
symptomatically different from the psychiatricallycaused chronic fatigue group than those meeting the
Fukuda et al. (1994) criteria.
Jason et al. (2006) later used the Canadian casedefinition model to develop a pediatric case definition
for ME/CFS. To meet criteria, youth needed to meet thefollowing six classic categories including fatigue, postexertional malaise; unrefreshing sleep, or disturbance ofsleep quantity or rhythm; myofascial pain, joint pain,
abdominal and/or head pain; two or moreneurological/cognitive manifestations and at least one
symptom from two of three subcategories including
autonomic
manifestations,
neuroendocrine
manifestations, or immune manifestations. In order tooperationalize these symptoms, a questionnaire wasdeveloped with specific questions relating to each of thecategories above. Jason et al. (2010a) found that the
Fukuda et al. (1994) criteria was less sensitive than thePediatric ME/CFS criteria in identifying pediatric
ME/CFS cases. Jason et al. (2010a) developed aseparate classification for those who met almost all
criteria termed the Moderate ME/CFS clinical criteria.
The group that meets full criteria might be mostappropriately used for research criteria, whereas thosewith more moderate features are less impaired and moreheterogeneous and thus, they might fall under a moreclinical case definition.
More restrictive or more liberal criteria clearly
have an effect on who is classified as having CFS but
these different definitions also pose difficulties ininterpreting results of related studies (Komaroff et al.,1996). To deal with these problems, there have been
efforts to use statistical methods to classify symptoms

empiric case definition has potential for inclusion ofcases with primary psychiatric conditions. In support ofthis thesis, Jason et al. (2009a) found that 38% of thosewith a diagnosis of a Major Depressive Disorder weremisclassified as having CFS using the new CDC
empiric case definition.
The Fukuda et al. (1994) case definition uses
polythetic criteria, that is, a set of symptoms in which
not all need to be present to make a diagnosis. The useof polythetic criteria derived by expert committees (asis the case with CFS) may not be methodologicallysound (Jason and Choi, 2008). For example, use ofpolythetic criteria may result in the comparison of two
different groups of patients within the same diagnostic
category or similar groups in different diagnostic
categories. Because the Fukuda et al. (1994) criteria
only require four symptoms out of a possible eight,
critical CFS symptoms such as post-exertional malaise
and memory and concentration problems are notrequired of all patients and this might further
complicate identification of comparable samples. In
contrast, a CFS case definition developed in Australia
by Lloyd et al. (1990) stipulated that post-exertionalmalaise, as well as memory and concentrationdifficulties were central for a diagnosis (this definition
has not been frequently used, as is true with the British
criteria). As mentioned above, the earlier ME definition
involves two primary symptoms: post-exertionalmalaise and impairment of memory and concentration(Dowsett et al., 1994).
A clinical case definition for ME/CFS that is called
the Canadian criteria also specified the these two core
symptoms as well as several other symptoms(Carruthers et al., 2003). (The acronym ME/CFS refers
to Myalgic Encephalomyelitis and Chronic Fatigue
Syndrome, according to the Canadian Case Definition.
The patient community has felt that the term chronic
fatigue syndrome trivializes the seriousness of thisillness, as the illness is typified by many severe
symptoms in addition to fatigue and fatigue is generally
regarded as a common symptom experienced by manyotherwise healthy individuals in the general population.
The term Myalgic Encephalomyelitis had been usedprior to the use of the term chronic fatigue syndrome(Acheson, 1959). The Canadian clinical case definition
specifies that post-exertional malaise must occur with aloss of physical or mental stamina, rapid muscle orcognitive fatigability, usually taking 24 hours or longer
to recover. In addition, there need to be two or moreneurological/cognitive manifestations (e.g., confusion,
impairment of concentration and short term-memory).
There also needs to be unrefreshing sleep or poor sleep
quantity or rhythm disturbance, as well as a significant
122Am. J. Biochem. & Biotech., 6 (2): 120-135, 2010of individuals with severe fatigue (Janal et al., 2006;
Nisenbaum et al., 1998; 2004; Sullivan et al., 2005).
For example, Friedberg et al. (2000) found three
symptom factors (cognitive problems, flu-like
symptoms and neurological symptoms) in a sample ofpatients with CFS. Also using factor analysis withpatients diagnosed with CFS, Ray et al. (1992) found
the following factors: Emotional distress, fatigue,
somatic symptoms and cognitive difficulty. Rowe andRowe (2002) confirmatory factor analysis with apediatric sample found muscle pain and fatigue,
neurological/cognitive symptoms, abdominal, head andchest pain and both neurophysiological andimmunological factors.
Some of the theoretical benefits of using these typesof statistical approaches to better understand symptoms
can be demonstrated from a study by Jason et al. (2002a).
They used factor analysis to provide support for the
existence of four distinct components of chronic fatigue:
Lack of Energy (fatigue intensity), Physical Exertion(fatigue exacerbated by physical exertion), Cognitive
Problems (difficulties with short-term memory,concentration and information processing) and Fatigue
and Rest (rest or sleep is not restorative). Two of the
primary dimensions of fatigue that emerged in a sample
meeting the Fukuda et al. (1994) criteria for CFS basedon self-report (“CFS-like”) were post-exertional fatigue
and cognitive problems. Using cluster analysis, Jason andTaylor (2002) found that a majority of individuals with
CFS with moderate to severe symptoms could be
accurately classified into two clusters both with severe
post-exertional fatigue but different levels of
improvement after rest. This study also found more
severe cognitive problems in the clusters of patients
having CFS. These finding support the designation of
post-exertional fatigue and cognitive problems as core
symptoms, similar to what has been recommended in
the ME criteria (Dowsett et al., 1994), the Australiancase definition (Lloyd et al., 1990) and the Canadianclinical case definition for ME/CFS (Carruthers et al.,2003).
Finally, Jason et al. (2007) provided individuals
with CFS a theoretically driven questionnaire thatfeatured neuropsychiatric, vascular, inflammatory,
muscle/joint, infectious and other symptoms. Whenthese theoretically derived symptoms were factor
analyzed, a more interpretable factor structure was
identified than when factor analysis was applied to theeight Fukuda et al. (1994) symptoms. The findings
from this study provide empirical support for
identifying the following six types of symptoms among

those
with
CFS:
neurocognitive,
vascular,
inflammation, muscle/joint pain, infectious andsleep/post-exertional malaise. Several studies haveprovided empirical support for examining thesedifferent types of symptoms among patients with CFS
including post-exertional malaise (Jason et al., 2002a;
Jason and Taylor, 2002), neuropsychological or
cognitive problems (Ray et al., 1992; Rowe and Rowe,
2002; Jason et al., 2002a), infectious symptoms(Nisenbaum et al., 1998; Friedberg et al., 2000;
Rowe and Rowe, 2002), muscle/joint difficulties(Nisenbaum et al., 2004; Rowe and Rowe, 2002),
vascular issues (Rowe and Rowe, 2002; Jason et al.,
2002b), inflammatory problems (Corradi et al., 2006)
and unrefreshing sleep (Nisenbaum et al., 2004;
Jason et al., 2002a). It is interesting that the Canadianclinical case definition (Carruthers et al., 2003) requires
all six areas to be assessed, whereas vascular andinflammatory processes are not assessed by the
Fukuda et al. CFS criteria. These findings suggest that a
broader group of symptoms, ones which aretheoretically derived, might be needed to moreaccurately identify critical symptoms of those with thisillness.
The Canadian case definition requires specific
ME/CFS symptoms. However, the provision ofoperationally explicit, objective criteria is not enough toensure that scientists can elicit the necessary
information to permit them to gather reliable
information. There is also a need to construct structured
interview schedules that ensure that questions are asked
in a consistent way and this increases the chance thatdata collected in different settings are comparable. This
report specifies explicit rules for determining ME/CFS
status using a revised Canadian case definition and aquestionnaire to assess symptoms (for a copy, write thefirst author).
The revised Canadian ME/CFS criteria: The
definition presented in Table 1 has elements of the
Fukuda et al. (1994) case definition, along with someof the recommendations of Reeves et al. (2003). We
have also incorporated the structure of the Canadianclinical case definition for ME/CFS developed by
Carruthers et al. (2003). We believe that requiring
specific symptoms does capture the critical symptoms
for a person with ME/CFS. However, we have tried tolimit the types of symptoms within each of theCanadian criteria categories to allow investigators tomore reliably categorize adult patients.
123Am. J. Biochem. & Biotech., 6 (2): 120-135, 2010
Table 1: Criteria for the revised Canadian ME/CFS criteria
Definition of Research ME/CFS criteria
I.
Over the past 6 months, persistent or recurring chronic fatigue that is not lifelong and results in substantial reductions in previous levels ofoccupational, educational, social and personal activities. The concurrent occurrence of the following classic ME/CFS symptoms (See II
through VI), which must have persisted or recurred during the past six months of illness (symptoms may predate the reported onset of
fatigue).
II. Post-exertional malaise and/ or post-exertional fatigue. With activity (it need not be strenuous and may include walking up a flight of stairs,
using a computer, or reading a book), there must be a loss of physical or mental stamina, rapid/sudden muscle or cognitive fatigability, postexertional malaise and/or fatigue and a tendency for other associated symptoms within the patient’s cluster of symptoms to worsen. The
recovery is slow, often taking 2-24 hours or longer.
III. Unrefreshing sleep or disturbance of sleep quantity or rhythm disturbance. May include unrefreshing sleep, prolonged sleep (including
frequent naps), disturbed sleep (e.g., inability to fall asleep or early awakening) and/or day/night reversal.
IV. Pain (or discomfort) that is often widespread and migratory in nature. At least one symptom from any of the following:
Myofascial and/or joint pain. Myofascial pain can include deep pain, abdomen/stomach pain, or achy and sore muscles. Pain,
stiffness, or tenderness may occur in any joint but must be present in more than one joint and lacking edema or other signs ofinflammation.

V.

Abdominal and/or head pain. May experience stomach pain or chest pain. Headaches often described as localized behind the eyes or in
the back of the head. May include headaches localized elsewhere, including migraines. Headaches would need to be more frequent
than they were before, which would indicate new pattern, of a new type as compared to headaches previously experienced (i.e.,
location of pain has changed, nature of pain has changed), or different in severity type as compared to headaches previously
experienced by the patient.
Two or more neurological/cognitive manifestations:••

Impaired memory (self-reported or observable disturbance in ability to recall information or events on a short-term basis)
Difficulty focusing vision and attention (disturbed concentration may impair ability to remain on task, to screen out extraneous/excessive
stimuli)
Loss of depth perception•
Difficulty finding the right word•
Frequently forget what wanted to say•
Absent mindedness•
Slowness of thought•
Difficulty recalling information•
Need to focus on one thing at a time•
Trouble expressing thought•
Difficulty comprehending information•
Frequently lose train of thought•
Sensitivity to bright lights or noise•
Muscle weakness/muscle twitches
VI. At least one symptom from two of the following three categories:
1.
2.
3.

Autonomic manifestations: Neurally mediated hypotension, postural orthostatic tachycardia, delayed postural hypotension, palpitations withor without cardiac arrhythmias, dizziness or fainting, feeling unsteady on the feet--disturbed balance, shortness of breath, nausea, bladderdysfunction, or irritable bowel syndrome.
Neuroendocrine manifestations Recurrent feelings of feverishness and cold extremities, subnormal body temperature and marked diurnal
fluctuations, sweating episodes, intolerance of extremes of heat and cold, marked weight change-loss of appetite or abnormal appetite.
Immune manifestations: Recurrent flu-like symptoms, non-exudative sore or scratchy throat, repeated fevers and sweats, lymph nodes
tender to palpitation--generally minimal swelling noted, new sensitivities to food, odors, or chemicals.

VII. Exclusionary versus Non-Exclusionary conditions:A.

Exclusionary conditions:1.

Any active medical condition that may explain the presence of chronic fatigue, such as:

i.
ii.
iii.
iv.
v.
vi.
vii.
viii.
ix.
x.
xi.
xii.
xiii.

Untreated hypothyroidism
Sleep apnea
Narcolepsy
Malignancies
Leukemia
Unresolved hepatitis
Multiple Sclerosis
Juvenile rheumatoid arthritis
Lupus erythematosus
HIV/AIDS
Severe obesity (BMI greater than 40; but if weight gain follows onset of ME/CFS, the patient could meet the Clinical Criteria)
Celiac disease
Lyme disease124

Am. J. Biochem. & Biotech., 6 (2): 120-135, 2010
Table 1: Continued
2. Some active psychiatric conditions that may explain the presence of chronic fatigue, such as:
i.
ii.
iii.

v.

Schizophrenia or psychotic disorders
Bipolar disorder
Active alcohol or substance abuse-except as below:a.
Alcohol or substance abuse that has been successfully treated and resolved should not be considered exclusionary.
Active anorexia nervosa or bulimia nervosa-except as below:
b. Eating disorders that have been treated and resolved should not be considered exclusionary.
Depressive disorders with melancholic or psychotic features

B.

Not necessarily exclusionary3.

May have presence of concomitant disorders that do not adequately explain fatigue and are, therefore, not necessarily exclusionary.

i.

Psychiatric diagnoses such as:a. Anxiety disorders
b. Somatoform disorders
c. Depressive disorders
Other conditions defined primarily by symptoms that cannot be confirmed by diagnostic laboratory tests, such as:a. Multiple food and/or chemical sensitivity
b. Fibromyalgia
Any condition under specific treatment sufficient to alleviate all symptoms related to that condition and for which the adequacy oftreatment has been documented.
Any condition that was treated with definitive therapy before development of chronic symptomatic sequelae.
Any isolated and unexplained physical examination, laboratory or imaging test abnormality that is insufficient to strongly suggest theexistence of an exclusionary condition.

iv.

ii.

iii.
iv.
v.

The Canadian ME/CFS clinical case definition(Carruthers et al., 2003), states that “The patient musthave a significant degree of new onset, unexplained,
persistent, or recurrent physical and mental fatigue that
substantially reduces activity level” (p.6) and “thefatigue should be severe enough to substantially reduce
the patient’s activity level, usually by approximately
50%” (p.14). Finally, the authors indicate that theillness usually has a distinct onset (although it may be
gradual) and it persists for at least 6 months.

that the survey item should specify that these symptoms
should be assessed over the last 6 months in order todetermine a current ME/CFS diagnosis. It is also
unclear what is meant by “persisted or recurred.” Thisphrase has generally referred to a symptom that has
been ongoing and constant, but sometimes there aregood periods and bad periods. We now operationalize
this phrase by assessing how often the person has
experienced the symptom (fatigue or other symptoms)
over the past 6 months using the following scale: 0 =none of the time, 1 = a little of the time, 2 = about
half the time, 3 = most of the time, 4 = all of the time.
To be counted as “persisted or recurred,” the individual
would have to indicate a score of 2 or higher. In
addition, it is important that fatigue and the other core
symptoms should be either moderate or severe;
however this “severity index” has not been well definedin previous criteria. We now specify that existing
symptoms be rated on the following scale: 0 = symptom
not present, 1 = mild, 2 = moderate, 3= severe, 4 = very
severe. Symptoms need to be rated at moderate (i.e., 2)or worse to meet criteria. Therefore, to meet criteria for
a given symptom, specific frequency and severity
ratings must be met over the past 6 months.
The threshold number of 4 out of 8 Fukuda et al.
(1994) core symptoms has been changed and we now
adopt a similar system to that used with the Canadian
ME/CFS criteria (Carruthers et al., 2003). The DePaul
Symptom Questionnaire provides a structured way togather standardized information that can be used to aid

The Fukuda et al. (1994) case definition states thefollowing: A case of the chronic fatigue syndrome isdefined by the presence of the following: (1) clinicallyevaluated, unexplained, persistent or relapsing chronic
fatigue that is of new or definite onset (has not been
lifelong); is not the result of ongoing exertion; is notsubstantially alleviated by rest and results in substantial
reduction in previous levels of occupational,
educational, social, or personal activities and (2) the
concurrent occurrence of four or more of the following
symptoms, all of which must have persisted or recurred
during 6 or more consecutive months of illness andmust not have predated the fatigue (p.956).
Given that some language used in the Fukuda et al.
criteria is vague, we have created operational
definitions to improve diagnostic reliability.
According to the Fukuda et al. (1994) criteria, a 6month period could have been over the last 6 months,
or during a 6 month period a few years ago. We believe125

Am. J. Biochem. & Biotech., 6 (2): 120-135, 2010
think I do very little in a day,” they would meetcriterion for fatigue on this scale. Clearly, almost allindividuals with depressive disorders would meet thisreduced activity criterion. Jason et al. (2010b) also foundthat Reeves et al. (2005) cutoff scores for the MFI had
inadequate sensitivity and specificity when attempting
to differentiate ME/CFS cases from controls.
In order to avoid the potential pitfalls associatedwith previous approaches of operationalizing fatigue
and to maintain consistency with the Fukuda et al.
(1994) and Carruthers et al. (2003) case definitions, the
ME/CFS fatigue criterion is met if a person indicatesthat their fatigue/extreme tiredness has persisted orrecurred over the past 6 months at frequency andseverity ratings of 2 or higher. A person must also meetthe criteria for substantial reductions described below.
Some patients with CFS are not chronically fatigued,
but they have a problem of endurance or stamina andneed lengthy times to recover following minimal
degrees of activity (Hyde, 1999). A person with
ME/CFS who participates in very little activity(possibly to minimize ME/CFS symptoms) whencompared to his or her same-age peers, could become
exhausted upon minimal exertion. While normal fatigue
is not activity limiting, the fatigue present in ME/CFS
limits the individual’s activity to varying degrees.
Therefore, in addition to assessing whether or not a
person has persistent or recurring chronic fatigue overthe past 6 months, we have added questions that
identify those individuals who have low stamina andendurance, but currently have less fatigue/energy
problems because they are severely limiting their daily
activities. Individuals who do not meet the fatigue
criterion may still obtain a Clinical ME/CFS diagnosis
if they meet the other five criteria.

in the diagnosis of ME/CFS. For meeting full criteria of
ME/CFS, the following six classic ME/CFS symptom
categories must occur. A scoring sheet for determining
if a person meets ME/CFS criteria and how to score theSF-36 scales can also be obtained by writing the firstauthor.
Fatigue: Our first criterion involves persistent orrecurring chronic fatigue over the past six months thatis not lifelong and results in substantial reductions inprevious levels of occupational, educational, social andpersonal activities. The Fukuda et al. (1994) casedefinition requires that the fatigue not be lifelong andthat it be of a new and definite onset. In a revision of
the Fukuda et al. (1994) criteria, Reeves et al. (2003)
stated that only participants who recount having always
felt severely fatigued should be excluded as having“lifelong” fatigue. We also decided to use this criterion
in formulating the diagnostic criteria. A person would
not meet this ME/CFS criterion if they answered yes tothe following question: “Have you always had
persistent or recurring fatigue/energy problems, evenback to your earliest memories as a child? By persistingor recurring, we mean that the fatigue/energy problems
are usually ongoing and constant, but sometimes there
are good periods and bad periods. The original
Canadian criteria mentioned a “distinct onset” butallowed for gradual onset. We agree with this guideline,
but also note that onset often occurs quickly (withindays/weeks), especially following an infectious
epsiode/surgery/pregnancy. This is not always when
patients get all the symptoms but they notice a distinct
difference in their health.
In terms of fatigue severity ratings, a number offatigue scales have been used, but Stouten (2005) has
warned that many fatigue scales do not accurately
represent the severe fatigue that is characteristics of
ME/CFS. Deciding on which subscales and cut off
scores to use has also been problematic. For example,
with the CDC empiric case definition, Reeves et al.
(2005) used the Multidimensional Fatigue Inventory(MFI) (Smets et al., 1995) to assess severe fatigue. The
MFI scales range from 4-20 and Reeves et al. (2005)
defined severe fatigue as a score of greater than orequal to 13 on the MFI general fatigue scale or greaterthan or equal to 10 on the reduced activity scale. In one
study of three groups with CFS, the mean MFI generalfatigue scores were 18.3-18.8 (Tiersky et al., 2003) andthese scores are clearly higher than the Reeves et al.
(2005) cutoff of 13. In addition, reduced activity items
refer to issues that a person with depression might
easily endorse. If a person indicated that the following
two items were entirely true: “I get little done,” and “I

Substantial reduction in functioning: According to
the Fukuda et al. (1994) criteria, fatigue is associatedwith substantial reductions in “previous levels ofoccupational, educational, social, or personal activities”(p.956). Therefore, we have included an assessment of
substantial reductions under the fatigue criterion. An
instrument that has been frequently used to assess thisdisability construct is the Medical Outcomes Study
Short Form-36 Health Survey (SF-36) (Ware andSherbourne, 1992). This instrument is a 36 item, broadlybased, self report measure of functional status related tophysical and social functioning, physical role functioning,
emotional role functioning, bodily pain, general health,vitality, mental health and health transition. Higher scoreson this scale indicate higher functioning.
Reeves et al. (2005) empiric CFS case definition
selected four of the eight SF-36 subscales to measure126

Am. J. Biochem. & Biotech., 6 (2): 120-135, 2010
computer, reading a book or other activities of dailyliving such as dressing, bathing, eating, cooking, or
shopping), there must be a loss of physical or mental
stamina, rapid/sudden muscle or cognitive fatigability,
post-exertional malaise and/or post-exertional fatigue
and a tendency for other associated symptoms within
the patient’s cluster of symptoms to worsen. The
recovery is slow, often taking 2-24 hours or longer.
Although a person with ME/CFS may feel better
after rest, he or she may get sick again quickly upon
minimal activity or exertion. In this case, the rest does
not completely eliminate the syndrome but it may
provide some relief; therefore, this symptom patternshould not exclude a ME/CFS diagnosis. In the case ofan adult who is active (e.g., participates inextracurricular activities, sports, outings with friends)
but exhausted, yet also recovers quickly when activity
is decreased, the fatigue would be considered the resultof ongoing exertion or activity and thus, would be
excluded from a diagnosis of ME/CFS. However, aperson who participates in very little activity (possibly
to minimize ME/CFS symptoms) when compared to his
or her same-age peers and who also becomes exhausted
upon minimal exertion, would meet the post-exertionalmalaise criterion. In summary, normal fatigue is not
activity limiting, whereas the fatigue/energy problems
present in ME/CFS limits the individual’s activity tovarying degrees. A person experiences post-exertionalmalaise when recovery does not occur quickly after
exhausting activity or when activities have to be
restricted to avoid experiencing fatigue/energy
problems, or when increased fatigue and/or worseningof symptoms are experienced after exercise.
Within a group of individuals diagnosed with CFS,
Jason et al. (1999a) found that post-exertional fatigue
or malaise for individuals with CFS ranged from 93.840.6% depending on how the question was asked. Thereis certainly a need to standardize the questions used toreduce this source of unreliability. In addition, length ofthe period of post-exertional malaise may vary from
activity to activity or by time period within the person.
It would be more useful to subgroup patients into thefollowing groups rather than to discount the complaintsof patients who do not report experiencing this symptom
for 24 hours or longer: Post-exertional malaise lasting for
1-6 hours; post-exertional malaise lasting for 7-23 hours;
post-exertional malaise lasting for 24 hours or longer,
with exact length specified by patient.
Recently, Jason et al. (2009b) developed the
ME/CFS Fatigue Types Questionnaire (MFTQ), a 22
item scale designed to measure the duration, severity
and frequency of different fatigue-related sensations
and symptoms. The MFTQ appears to be a reliable anddisability/substantial reductions.
According toReeves et al. (2005) empiric case definition, thedisability criterion was met by scoring below the 25th
percentile on at least one of the following four SF-36
sub-scales: Physical Functioning (less than or equal to70), Role-Physical (less than or equal to 50), Social
Functioning (less than or equal to 75), or RoleEmotional (less than or equal to 66.7). Based on thissystem, a person could meet the disability CFS criteria
without any reductions in key areas of physicalfunctioning and only have impairment in the roleemotional area (e.g., problems with work or other daily
activities as a result of emotional problems). Jason et al.
(2009a) have challenged the inclusion of the RoleEmotional subscale as not being appropriate because it
assesses change in function as a result of any emotional
problems. Ware et al. (2000) found that the mean forRole-Emotional for a clinical depression group was
38.9, indicating that almost all those with clinicaldepression would meet the CFS disability criterion, as
they would be within the lower 25th percentile on thissubscale.
Jason et al. (2010c) found that Role-Emotional had
the lowest threshold for both identifying individuals
with CFS and identifying others who did not have thisillness. However, Vitality, Social Functioning andRole-Physical have the highest threshold. In a literature
review, the Vitality, Social Functioning and RolePhysical subscales best discriminated those with CFSfrom controls (Jason et al., 2010c). The Vitality scalemeasures items that assess feeling full of pep andenergy, as well as those that focus on feeling worn out
or tired. Social functioning is assessed by items thatinvolve interference with your normal social activities
with family, friends, neighbors or groups. The RolePhysical subscale focuses on items assessing the needto cut down or limit one’s work, social, or otheractivities, as well as accomplishing less than one might
like. In other words, these three subscales capture
significant limitations in the person’s ability to haveenergy and accomplish activities in life. To meet thesubstantial reduction criteria, we now stipulate that at aminimum, a person needs to meet criteria on two of thethree designated subscales: Score less than or equal to
35 for Vitality, less than or equal to 62.5 for Social
Functioning, or less than or equal to 50 for RolePhysical. The substantial reduction criteria must be met
in order for the fatigue criterion of the Revised
Canadian ME/CFS case definition to be met.
Post-exertional malaise and/or post-exertional
fatigue: With activity (it need not be strenuous andmay include walking up a flight of stairs, using a127

Am. J. Biochem. & Biotech., 6 (2): 120-135, 2010
and/or day/night reversal. We have included items in
the DePaul Symptom Questionnaire that assess several
symptom indicators of sleep dysfunction and one
symptom needs to meet the frequency and severity
ratings of 2 or higher to meet the sleep criterion.

valid measure of fatigue types in individuals with
ME/CFS. When factor analyzed, several fatigue factors
emerged for individuals with CFS (Post-Exertional,
Wired, Brain Fog, Energy and Flu-Like fatigue) but thehealthy control group only experienced one overallfactor involving generalized fatigue. Jason et al.
(2010d) found that the post-exertional factor had
adequate sensitivity and specificity (it was able toidentify individuals who had ME/CFS and also exclude
individuals who did not have this illness). Five items
from the MFTQ with the highest loadings on the postexertional factor included: Dead, heavy feeling that
occurs quickly after starting to exercise; next day
soreness or fatigue after non-strenuous, everyday
activities; mentally tired after the slightest effort;
physically drained or sick after mild activity andminimum exercise makes you physically tired(Jason et al. 2009b). We included these five items on
the DePaul Symptom Questionnaire to measure postexertional malaise. To meet criteria for post-exertionalmalaise or post-exertional fatigue, one of these items
need to be endorsed at sufficient frequency and severity(2 or greater on a scale of 0-4). This number of items
was confirmed as having the best sensitivity andspecificity (Jason et al., 2010d).

Myofascial pain, joint pain, abdominal and/or head
pain: The fourth symptom category requires that theperson exhibit myofascial pain, joint pain, abdominal
and/or head pain. Myofascial pain can include deep
pain, abdomen/stomach pain, or achy and sore muscles.
Pain, stiffness, or tenderness may occur in any joint but
must be present in more than one joint and lacking
edema or other signs of inflammation. The pain
criterion is met if a person meets the frequency andseverity ratings of 2 or higher for one pain symptom.
Pain is among the most frequently cited reasons forseeking medical attention. However, the assessment ofpain is particularly difficult given that the experience of
this complaint is highly subjective. For example, pain isdifficult to describe and different descriptions may be
used by two different individuals to describe the same
phenomenon (Turk and Melzack, 1992). Furthermore,
the association between physical abnormalities andpatients report of pain is often ambiguous and weakly
correlated. Physical pathology also has not been foundto be predictive of disability (Cats-Baril and Frymoyer,1991). In fact, there are no isomorphic relationships
between reports of pain, disability and tissue pathology.
Given the inherent subjectivity of pain and the frequent
absence of objective findings to account for thissymptom, pain can only be assessed indirectly (Turkand Melzack, 1992). It is recommended that complaintsof joint pain and muscle pain be carefully distinguishedto ensure accurate reporting of symptoms. Complaintsof muscle pain should be described as sensations ofpain or aching experienced in the muscles and theyshould be distinguished from feelings of weakness or
pain experienced in other areas such as the joints(Sharpe et al., 1991).
Headaches can occur in a variety of different forms
and are typically classified into the following
categories: vascular headaches (e.g., migraine, cluster,
hypertensive), muscle contraction headaches (e.g.,chronic myositis, cervical osteoarthritis, depressive
equivalents and conversion reactions) and traction andinflammatory headaches (e.g., mass lesions,
temporomandibular joint, occlusive vascular disease). It
is not sufficient to simply ask whether the patient has
had a previous or lifelong problem with headaches.
Such a question is likely to result in inaccurate
information because it is not specific enough.
Assessment includes whether the headaches the patient

Sleep: The third symptom category is unrefreshing
sleep, or disturbance of sleep quantity or rhythm. As
discussed above, many of the symptom criteria lackclear guidelines for clinicians to follow when
conducting an assessment. For example, there are no
guidelines for how the term “unrefreshing sleep” should
be defined and evaluated. Research findings indicatethat tiredness is associated with any disturbance in sleep
such as too much sleep, sleep at the wrong time andfragmented sleep. Patients with ME/CFS often reportunrefreshing, disturbed, or poor quality sleep; however,the Fukuda et al. (1994) case definition does notadequately define “nonrestorative sleep” or specify how
this complaint should be assessed. It is unclear whether
this symptom would be counted for individuals whoreport nonrestorative sleep for most but not all nights.
Additionally, it is not specifically stated if someone
would meet this criterion if he or she has restorative
sleep but other sleep problems such as difficulties
falling asleep, maintaining sleep, or waking up early.
Komaroff et al. (1996) found that 98% of a chronicallyfatigued group had sleep disturbances, but only 89%
reported awakening unrefreshed. To assess sleep
difficulties, it is important to assess for dysfunction inareas beyond just nonrestorative sleep and include
prolonged sleep (including frequent naps), disturbed
sleep (e.g., inability to fall asleep or early awakening)128

Am. J. Biochem. & Biotech., 6 (2): 120-135, 2010
feverishness and cold extremities, subnormal bodytemperature and marked diurnal fluctuations, sweating
episodes, intolerance of extremes of heat and cold,
marked weight change-loss of appetite or abnormal
appetite and worsening of symptoms with stress.

is reporting are (1) more frequent than they were
before, which would indicate new pattern, (2) of a new
type as compared to headaches previously experienced(i.e., location of pain has changed, nature of pain haschanged) and (3) different in severity type as comparedto headaches previously experienced by the patient. If apatient endorses these three criteria and indicates theirheadaches meet the frequency and severity cutoffs, thenthis report of headaches would be counted toward
fulfilling the pain criterion.

Immune manifestations: Immune manifestations
include recurrent flu-like symptoms, non-exudative soreor scratchy throat, repeated fevers and sweats, lymph
nodes tender to palpitation--generally minimal swelling
noted and new sensitivities to food, odors, or chemicals.
Sore throat is one immune manifestation that is often
difficult to assess because of its subjective nature.
While physical findings are sometimes present and canprovide objective evidence of this symptom, often times
such findings are not present. According to a study
conducted by Gerber et al. (1984), sore throat is thethird most common reason for patient visits to primarycare practitioners. Sore throat is most commonly
associated with pharyngitis, the inflammation of thepharynx and surrounding lymphoid tissue. There are
numerous other conditions, however, that may also
produce sore throat. These conditions range from local
disorders (e.g., ear, throat, nose infections) to systemic
disorders (e.g., CFS, rheumatoid arthritis, viral
hepatitis) and include infectious and non-infectious
etiologies (Muhrer, 1991).

Neurological/cognitive manifestations: The fifth
symptom category is the occurrence of two or moreneurological/cognitive manifestations at frequency andseverity ratings of 2 or higher. People with CFS
typically complain that fatigue affects their physicaland mental functioning. Generally, patients reportproblems with concentration and absent mindedness,
impaired memory, difficulty making decisions,difficulties taking in written or spoken material andexecuting familiar sequences of events, such as grocery
shopping (Wearden and Appleby, 1997). In addition,
many patients with CFS complain that performing
mental work is aversive for them, to the degree thatthey either stop doing it or start to experience
symptoms (Wood et al., 1994). Aside from cognitive
manifestations, many people experience neurologicalsymptoms such as perceptual disturbances (e.g.,inability to focus vision and attention), motor
disturbances (e.g., muscle weakness and twitches) andoverload phenomenon (e.g., sensitivity to light orsound) (Carruthers et al., 2003). As a result, many
people with CFS describe their neurological/cognitivedifficulties as one of the more disabling and troubling
symptoms of their illness.

Medical and psychiatric evaluation: It is critical to doa medical evaluation in order to identify exclusionary
medical diagnoses that would explain the fatigue andsymptoms (Fukuda et al., 1994). Medical diagnoses thathave been adequately treated (e.g., Lyme disease) orthat are not likely to cause fatigue should not be
considered exclusionary. Table 1 lists exclusionary
medical conditions as well as those that should notnecessarily be considered exclusionary and may present
comorbidly with ME/CFS.
Psychiatric evaluation is essential to rule out
psychiatric diagnoses that may be the cause of fatigue
and preclude a diagnosis of CFS. The Structured ClinicalInterview for the DSM-IV (SCID) (Spitzer et al., 1995),
a semi-structured psychiatric interview, should be used
for psychiatric evaluation. Test-retest reliability wasassessed for the SCID yielding good Kappa scores(Williams et al., 1992). The professionally administered
SCID allows for clinical judgment in the assignment ofsymptoms to psychiatric or medical categories, a crucial
distinction in the assessment of symptoms that overlap
between CFS and psychiatric disorders, e.g., fatigue,
concentration difficulty and sleep disturbance. A
psychodiagnostic study (Taylor and Jason, 1998) validated
the use of the SCID in a sample of CFS patients.

Autonomic,
neuroendocrine,or
immunemanifestations: Finally, the sixth symptom category
requires at least one symptom at frequency and severity
ratings of 2 or higher from two of the following threesubcategories: (1) Autonomic manifestations, (2)Neuroendocrine manifestations and (3) Immune
manifestations.
Autonomic manifestations: Autonomic manifestations
include neurally mediated hypotension, postural
orthostatic tachycardia, delayed postural hypotension,
palpitations with or without cardiac arrhythmias,dizziness, feeling unsteady on the feet, disturbed
balance, shortness of breath, nausea, bladderdysfunction and irritable bowel syndrome.
Neuroendocrine manifestations: Neuroendocrine
manifestations
includerecurrent
feelingsof129

Am. J. Biochem. & Biotech., 6 (2): 120-135, 2010
Meeting research versus clinical criteria: Table 1
provides all the symptoms as specified in the Revised
Canadian ME/CFS case definition. Some meet fullcriteria whereas others who are very symptomatic do
not meet full criteria. We argue as we did with thePediatric case definition (Jason et al., 2006) that thosethat meet full criteria are more homogenous and might
be best used for research purposes and we now classify
these individuals as meeting the Research ME/CFS
criteria. Still, others might have the illness but not meet
one of the required criteria. We classified suchindividual as meeting Clinical ME/CFS criteria. These
individuals needed to have six or more months offatigue and needed to report symptoms in five out of thesix ME/CFS symptom categories (one of which has to bepost exertional malaise, as it is critical to this casedefinition). In addition, for autonomic, neuroendocrine
and immune manifestations, adults must have at least one
symptom in any of these three categories, as opposed to
one symptom from two of the three categories. We also
have a category called Atypical ME/CFS, which isdefined as six or more months of fatigue, but having two
to four ME/CFS symptoms. There is also a category
called ME/CFS-Like, which involves exhibiting all
criteria categories but for a duration of fewer than 6months. Further, a person could be classified as having
ME/CFS in remission if the person had previously been
diagnosed with CFS by a physician but was not currently
meeting the Research ME/CFS Criteria, Clinical
ME/CFS criteria, or Atypical ME/CFS criteria and musthave 0 or 1 classic ME/CFS symptoms.

Exclusionary psychiatric conditions are noted inTable 1. Major Depressive Disorder with melancholicor psychotic features are considered exclusionary
conditions in our criteria, primarily due to the findingsthat melancholic and psychotic processes represent
distinct biological or endocrinological processes andmay respond well to antidepressant or antipsychotic
medications (Robbins et al., 1989; Schulkin, 1994).
Reeves et al. (2003) has recommended that Major
Depressive Disorder with melancholic features,anorexia nervosa, or bulimia, not be considered
exclusionary if these conditions have been resolved formore than 5 years before the onset of the current illness.
However, for our ME/CFS case definition, eating
disorders (i.e., anorexia nervosa and bulimia nervosa)and substance abuse are exclusionary only if thediagnosis is current. A diagnosis of melancholic
depression, substance abuse or eating disorder that has
been appropriately treated and resolved should not be
considered exclusionary. We believe that psychotic
disorders of any variety continue to be exclusionary.
Predating criteria: The provision that the symptoms
such as sore throat or memory impairment not predate
the fatigue has also been modified. Some individuals
who develop ME/CFS experience a prodromal phase, inwhich symptoms begin to appear in the year prior to theonset of fatigue. Jason et al. (1999a) compared twogroups of patients, those with CFS and those withchronic fatigue due to psychiatric reasons. Using thetwo Fukuda et al. (1994) criteria of having six or moremonths of fatigue and the symptom not predating theillness, only one of eight Fukuda symptoms weresignificantly different between the two groups.
However, if one did not count whether a symptom
predated the illness and used both the 6 month criteria
as well as only counting moderate to serious
manifestations of the illness (as recommended in ourcurrent case definition), then four out of the eight
symptoms were significantly differentiated between thetwo groups. There were significantly higher symptoms
for the CFS group versus the psychiatric fatigued groupfor muscle pain (46.9% versus 24.2%), headaches(50.0% versus 21.2%), impaired memory/concentration(65.6% versus 30.3%) and unrefreshing sleep (78.1%
versus 39.4%). Therefore, it is not whether a symptom
occurred before the illness, but the issue of severity ofsymptoms that is the best discriminator of those with
CFS versus those who have a psychiatric reason for
their fatigue. In our revised case definition, we count all
symptoms even if they occurred prior to the onset of thefatigue.

CONCLUSION
In this study, we present the Revised Canadian
ME/CFS case definition, which provides greater
specification to the work of Carruthers et al. (2003).
The scientific enterprise depends on reliable and valid
ways of classifying patients into diagnostic categories
and this critical research activity can enable
investigators
tobetterunderstandetiology,
pathophysiology and treatment approaches for CFS andother disorders (King and Jason, 2005). Whendiagnostic categories lack reliability and accuracy, thequality of treatment and clinical research can besignificantly compromised. A misdiagnosis may lead to
improper treatment and in cases of severe illness, thematter of an incorrect diagnosis can have serious
consequences. In other words, the validity (i.e.,
usefulness) of a diagnostic category is inherently
limited by its reliability. Therefore, to the extent towhich a diagnostic category is unreliable, a limit isplaced on its validity for any clinical research
130Am. J. Biochem. & Biotech., 6 (2): 120-135, 2010
joint pain, muscle pain, impairment in concentration).
Consequently, it is possible that some patients with a
primary mood disorder could be misdiagnosed ashaving ME/CFS. Yet, these are distinct illnesses, as
several ME/CFS symptoms are not commonly found in
depression, including prolonged fatigue after physicalexertion, night sweats, sore throats and swollen lymph
nodes. Illness onset with ME/CFS often occurs over a
few hours or days, whereas primary depression generallyshows a more gradual onset. Biological findings also
differentiate the two conditions (Jason et al., 2005). The
inclusion of the latter type of patients in the current
ME/CFS case definition could confound theinterpretation of epidemiologic and treatment studies;
therefore, complicating efforts to identify biologicalmarkers for this illness.
The DePaul Symptom Questionnaire is a usefulscreening tool to assess for ME/CFS according to the
Revised Canadian ME/CFS case definition, but it does
not provide the full picture of a patient’s
symptomatology. Thus, for research purposes, we
propose some additional measures that could be
administered to obtain more comprehensive data on
symptomatology. For fatigue, the Fatigue Severity
Scale (FSS) (Krupp et al., 1989) is a measure of the
behavioral consequences of fatigue. In a study by
Jason et al. (2010e), the FSS was found to have a better
ability to detect cases and non-cases than the MFI(Smets et al., 1995), the Fatigue Scale (Chalder et al.,1993) and the Profile of Fatigue-Related Symptoms(Ray et al., 1992). For sleep disturbances, we suggest
the Pittsburgh Sleep Quality Index (Buysse, 1989) for
measuring sleep disruptions and sleep quality. Finally,
pain symptoms can be assessed with the McGill Pain
Questionnaire, a well-validated measure (Melzack,1975).
Fukuda et al. (1994) recommended subgrouping
adult CFS patients and while not the focus of thisarticle, similar efforts suggest this would be appropriate
in the study of ME/CFS (Jason et al., 2005). Cancer andheart disease are comprised of many subtypes and thismay also be the case with ME/CFS. Although ME/CFS
has also been referred to as unexplained fatigue, this isalso changing with scientific discoveries. For research
purposes, each of the six domains that are assessed with
the Revised Canadian criteria may be operationalized in
more objective and precise ways in the future. For thefatigue criterion, efforts are ongoing to measure actual
behavioral abnormalities among ME/CFS patients using
actigraphs (Tryon et al., 2004). Post-exertional fatigue
and pain can be measured by increases in theexpression for sensory, adrenergic and immune genes
following moderate exercise (Light et al., 2009).

(Spitzer et al., 1975). The poor understanding of thepathophysiology of ME/CFS may be due casedefinitions lacking reliabiltiy and validity andimproving the case definition may prevent
complications in identifying biological markers in thisillness. Issues concerning reliability of clinicaldiagnosis are therefore complex and have importantresearch and practical implications (Jason et al., 2005).
One of the greatest sources of diagnostic
unreliability is criterion variance, which is differencesin the formal inclusion and exclusion criteria used byclinicians to classify patients into diagnostic categories(Spitzer et al., 1975). Cantwell (1996) purports that
diagnostic criteria should specify which diagnostic
instrument to use, what informants to use and how torate for presence and severity of the criteria. For
example, one might specify that a certain number andtype of symptoms should be present in order to make aparticular diagnosis. In addition to the importance ofthe number and type of symptoms, definitions offatigue should also include specific guidelines
pertaining to the importance of symptom severity in the
diagnostic procedure. Given the high variability insymptom severity among persons with fatigue,
standardized procedures need to be employed for
determining whether or not a particular symptom issevere enough to qualify for the diagnosis of fatigue.
Although brief periods of fatigue (i.e., less than 1month duration) occur in approximately 15-25% of the
population, chronic fatigue occurs in about 4-5% of the
population (Jason et al., 2010b). In a community-based
epidemiologic study of fatigue (Jason et al., 1999b), of
those identified with six or more months of fatigue,
54% had chronic fatigue explained by medical or
psychiatric reasons, including cancer, multiple sclerosis
and melancholic depression. If about 5% of the
population has six or more months of fatigue and about
half of this is due to clear medical or psychiatricreasons, then the critical question is how many of theremaining 2.5% have ME/CFS? The empiric CFS casedefinition (Reeves et al., 2005) estimates that 2.54% dohave this illness, so that research group would suggestthat almost all would fall within the CFS category.
However, Jason et al. (2009b) believe that within this
2.54% are mood disorders, which are one of the mostprevalent psychiatric disorders (1 month prevalence rateof major depressive episode is 2.2%) (Regier et al.,1988). As an example, Major Depressive Disorder(MDD) can be confused with ME/CFS because it has
some overlapping symptoms with the illness. It is
possible that some patients with MDD also havechronic fatigue and four Fukuda et al. (1994) symptoms
that can occur with depression (e.g., unrefreshing sleep,
131Am. J. Biochem. & Biotech., 6 (2): 120-135, 2010
Unrefreshing sleep or disturbance of sleep quantity or
rhythmdisturbancewillbemeasuredbypolysomnography(Shaver,
2003).
Neurological/cognitive manifestations could bemeasured by objective evidence using functional
Magnetic Resonance Imaging (fMRI) (Lange et al.,2005). Autonomic manifestations could be assessedby ejection fraction decreases, suggesting left
ventricular dysfunction in the heart (Peckerman et al.,2003). Neuroendocrine manifestations can bemeasured by abnormal levels of circulating cortisol(Torres-Harding et al., 2008). Finally, immune
manifestations could be measured by elevations in
CD5+CD19+ subset and decreased natural killer cell
cytotoxicity (Maher et al., 2003).
In conclusion, studies examining sources ofdiagnostic unreliability have shown that criterion
variance, differences in the formal inclusion andexclusion criteria used by clinicians to classify patients’
data into diagnostic categories, accounts for the largest
source of diagnostic unreliability (Spitzer et al., 1975).
Moreover, research has demonstrated that criterion
variance is most likely to occur when operationally
explicit criteria do not exist for diagnostic categories(Spitzer et al., 1978). The provision of either astructured or semi-structured standardized instrument
designed to elicit the required information (formal
inclusion and exclusion criteria) would greatly reduce
this source of variance and improve the diagnostic
reliability of CFS. If ME/CFS is to be diagnosed
reliably across health care professionals, we believe that
it is imperative to provide specific thresholds andscoring rules for the symptom criteria. Without suchstandardization, symptom variability will be a functionof the assessment procedure and etiological factors. In
other words, by determining specific thresholds andscoring rules for the symptom criteria, variability islikely to result in increased diagnostic reliability.

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