Content uploaded by Frank N.M. Twisk
Author content
All content in this area was uploaded by Frank N.M. Twisk on Mar 20, 2016
Content may be subject to copyright.
Available via license: CC BY 4.0
Content may be subject to copyright.
diagnostics
Discussion
Replacing Myalgic Encephalomyelitis and Chronic
Fatigue Syndrome with Systemic Exercise Intolerance
Disease Is Not the Way forward
Frank N.M. Twisk
ME-de-patiënten Foundation, Zonnedauw 15, 1906 HB Limmen, The Netherlands; frank.twisk@hetnet.nl;
Tel.: +31-72-505-4775
Academic Editor: Andreas Kjaer
Received: 31 December 2015; Accepted: 1 February 2016; Published: 5 February 2016
Abstract:
Myalgic encephalomyelitis (ME), described in the medical literature since 1938, is
characterized by distinctive muscular symptoms, neurological symptoms, and signs of circulatory
impairment. The only mandatory feature of chronic fatigue syndrome (CFS), introduced in 1988
and redefined in 1994, is chronic fatigue, which should be accompanied by at least four or more out
of eight “additional” symptoms. The use of the abstract, polythetic criteria of CFS, which define
a heterogeneous patient population, and self-report has hampered both scientific progress and
accurate diagnosis. To resolve the “diagnostic impasse” the Institute of Medicine proposes that a new
clinical entity, systemic exercise intolerance disease (SEID), should replace the clinical entities ME
and CFS. However, adopting SEID and its defining symptoms, does not resolve methodological and
diagnostic issues. Firstly, a new diagnostic entity cannot replace two distinct, partially overlapping,
clinical entities such as ME and CFS. Secondly, due to the nature of the diagnostic criteria, the
employment of self-report, and the lack of criteria to exclude patients with other conditions, the SEID
criteria seem to select an even more heterogeneous patient population, causing additional diagnostic
confusion. This article discusses methodological and diagnostic issues related to SEID and proposes
a methodological solution for the current “diagnostic impasse”.
Keywords:
myalgic encephalomyelitis; chronic fatigue syndrome; systemic exercise intolerance
disease; diagnosis; assessment
1. Introduction
In 1938 a detailed analysis of an outbreak of “atypical poliomyelitis” among the personnel of
the Los Angeles County General Hospital during the summer of 1934 was published [
1
]. Since then,
myalgic encephalomyelitis (ME) has been described under various names, mainly on account of
outbreaks [
2
,
3
], and in 1956 ME was identified as a new clinical entity [
4
] in response to an outbreak in
the Royal Free Hospital in London in 1955 [
5
] and earlier outbreaks all over the world. Based upon
an analysis of the literature until then, the clinical picture of ME was described by
Ramsay et al.
[
5
,
6
]
in the late 1980s. ME is primarily defined by distinctive neuro-muscular symptoms: prolonged
muscle weakness after minor exertion, neurological symptoms indicative of cerebral dysfunction,
and circulatory impairment, and a chronic relapsing course. Much of the confusion with regard
to ME originates from the introduction of the diagnostic entity chronic fatigue syndrome (CFS) [
7
]
by the US Centers for Disease Control and Prevention (CDC) in 1988 [
8
]. CFS was redefined in
1994 [
9
]. The only mandatory symptom of CFS is chronic fatigue, which should be accompanied
by four out of eight “additional” symptoms,” e.g., unrefreshing sleep and headaches. Since then
the focus of research shifted from ME to CFS. This introduced two major methodological problems.
Firstly, the diagnostic criteria for ME and CFS define two distinct, partially overlapping, clinical
Diagnostics 2016, 6, 10; doi:10.3390/diagnostics6010010 www.mdpi.com/journal/diagnostics
Diagnostics 2016, 6, 10 2 of 13
entities (see Figure 1). For example, fatigue is not required for the diagnosis ME, while post-exertional
muscle weakness and typical neurological symptoms are not required to meet the diagnosis CFS.
Secondly, due to its polythetic nature, the CFS [
9
] criteria define a heterogeneous group of people with
chronic fatigue [
10
–
12
]. Not surprisingly, research into CFS has often yielded contradictory results or
abnormalities present in subgroups of patients [13].
Diagnostics2016,6,10 2of13
diagnostic criteria for ME and CFS define two distinct, partially overlapping, clinical entities (see
Figure1). Forexample,fatigue is not required forthe diagnosisME, whilepost‐exertionalmuscle
weaknessandtypicalneurologicalsymptomsarenotrequiredtomeetthediagnosisCFS.Secondly,
duetoitspolytheticnature,the
CFS[9]criteriadefineaheterogeneousgroupofpeoplewithchronic
fatigue [10–12]. Not surprisingly, research into CFS has often yielded contradictory results or
abnormalitiespresentinsubgroupsofpatients[13].
Figure 1. Myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS): two distinct,
partiallyoverlapping diagnoses.Thesizesof theshapesdo not reflecttheabsolutesizesofvarious
patient(sub)populations.
In order to resolve the diagnostic confusion, partly due to the introduction of CFS in the
1980s/1990s [8,9], the Institute of Medicine (IOM) was asked “to define diagnostic criteria for
myalgic encephalomyelitis/chronic fatigue syndrome, to propose a process forthe reevaluation of
thesecriteriainthefuture,andtoconsiderwhether
anewnameforthisdiseaseiswarranted”[14]
(p. xv). In response tothat request,the IOMproposed thata newclinicalentity, systemicexercise
intolerancedisease(SEID),definedbynewdiagnosticcriteria,shouldreplacetheclinicalentitiesME
andCFS.ThisclinicalentitySEIDhasalreadybeenembraced
bysomeresearchers[15].Thisarticle
discusses the shortcomings of the method by which SEID was developed and its outcome, the
diagnostic criteria of SEID, and proposes a methodological solution for the current diagnostic
impasseregardingMEandCFS.
2.MethodologicalShortcomingsoftheDevelopmentProcedureofSystemicExerciseIntolerance
Disease
(SEID)
Thisparagraphdiscussesimplicationsofthestartingpointsofthedevelopmentprocess,which
significantlyaffectedtheoutcome,whichwillbediscussedinthenextparagraph.
2.1.ThePre‐AssumptionthatMyalgicEncephalomyelitis(ME)andChronicFatigueSyndrome(CFS)Denote
“SimilarConditions”IsInvalid
TheIOMconsiderMEandCFS
tobe“conditionswithsimilarsymptoms”[14](p.1).According
to the IOM, “Many patients prefer ‘myalgic encephalomyelitis’”, because “they believe it better
reflectsthemedicalnatureoftheillness”[14](pp.30–31).AstheIOM[14]reportnotes:“[T]hereare
patients and researchers who maintain that ME and CFS are
two different illnesses and oppose
simplychangingthenameofCFStoME[13].”[14](p.31).However,thepositionthatMEandCFS
aredistinct,partiallyoverlappingconditions,isnotamatter ofopinion,butamatterof definition.
As can be seen in List 1, typical neuro‐muscular
symptoms define ME [5,6], while the only
mandatoryfeatureofCFS[9]is[unexplained]chronicfatigue(List2).Despiteoverlap,muscularand
neurological features typical for ME are not required to fulfill the case criteria for CFS, while
Figure 1.
Myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS): two distinct,
partially overlapping diagnoses. The sizes of the shapes do not reflect the absolute sizes of various
patient (sub)populations.
In order to resolve the diagnostic confusion, partly due to the introduction of CFS in the
1980s/1990s [
8
,
9
], the Institute of Medicine (IOM) was asked “to define diagnostic criteria for myalgic
encephalomyelitis/chronic fatigue syndrome, to propose a process for the reevaluation of these
criteria in the future, and to consider whether a new name for this disease is warranted” [
14
] (p. xv).
In response to that request, the IOM proposed that a new clinical entity, systemic exercise intolerance
disease (SEID), defined by new diagnostic criteria, should replace the clinical entities ME and CFS.
This clinical entity SEID has already been embraced by some researchers [
15
]. This article discusses
the shortcomings of the method by which SEID was developed and its outcome, the diagnostic criteria
of SEID, and proposes a methodological solution for the current diagnostic impasse regarding ME
and CFS.
2. Methodological Shortcomings of the Development Procedure of Systemic Exercise Intolerance
Disease (SEID)
This paragraph discusses implications of the starting points of the development process, which
significantly affected the outcome, which will be discussed in the next paragraph.
2.1. The Pre-Assumption that Myalgic Encephalomyelitis (ME) and Chronic Fatigue Syndrome (CFS) Denote
“Similar Conditions” Is Invalid
The IOM consider ME and CFS to be “conditions with similar symptoms” [
14
] (p. 1). According to
the IOM, “Many patients prefer ‘myalgic encephalomyelitis’”, because “they believe it better reflects
the medical nature of the illness” [
14
] (pp. 30–31). As the IOM [
14
] report notes: “[T]here are patients
and researchers who maintain that ME and CFS are two different illnesses and oppose simply changing
the name of CFS to ME [
13
].” [
14
] (p. 31). However, the position that ME and CFS are distinct, partially
overlapping conditions, is not a matter of opinion, but a matter of definition. As can be seen in List
1, typical neuro-muscular symptoms define ME [
5
,
6
], while the only mandatory feature of CFS [
9
] is
[unexplained] chronic fatigue (List 2). Despite overlap, muscular and neurological features typical for
ME are not required to fulfill the case criteria for CFS, while “fatigue” is not essential for ME. List 3
Diagnostics 2016, 6, 10 3 of 13
illustrates a patient fulfilling the diagnosis CFS with no characteristic ME symptom at all, while List 4
depicts the clinical picture of an ME patient not meeting the diagnosis CFS.
List 1. The original diagnostic criteria of ME [5,6].
Distinct features of ME are:
‚
A unique form of muscle fatiguability: prolonged muscle weakness (and myalgia), lasting for
days, even after a minor degree of physical effort (*
1
).
‚
Circulatory impairment, implicated by cold extremities and hypersensitivity to climatic change,
but above all an ashen-grey facial pallor approximately 20 or 30 min before the patient complains
of feeling ill.
‚
Cerebral dysfunction: impairment of memory and concentration and emotional lability, alterations
of sleep rhythm (*
2
), vivid dreams (*
2
), episodic sweating and orthostatic tachycardia as cardinal
features (the latter two not always present).
‚ Variability and fluctuation of both symptoms and physical findings over the day.
‚ A tendency to become chronic.
(*
1
) While post-exertional “malaise” (PEM), defined as an exacerbation of symptoms after physical
or cognitive exertion or orthostatic stress, is an element of the diagnostic criteria of CFS, the ME criteria
specifically require prolonged post-exertional muscle weakness (and muscle pain) after a minor
physical effort. (*
2
) Although both ME and CFS symptoms relate to sleep, reversal of sleep rhythm and
unrefreshing sleep are different types of symptoms.
List 2. The diagnostic criteria of CFS [9].
‚
Severe chronic_fatigue for 6 or more consecutive months, that is not due to ongoing exertion or
other medical conditions associated with fatigue and significantly interferes with daily activities
and work,
‚ Accompanied by at least 4 or more of the following 8 symptoms:
‚ post-exertional malaise lasting more than 24 h (*
1
);
‚ unrefreshing sleep (*
2
);
‚ significant impairment of short-term memory or concentration;
‚ muscle pain;
‚ joint pain without swelling or redness;
‚ headaches of a new type, pattern, or severity;
‚ tender lymph nodes in the neck or armpit; and
‚ a sore throat that is frequent or recurring.
(*
1
) While post-exertional “malaise” (PEM), defined as an exacerbation of symptoms after physical
or cognitive exertion or orthostatic stress, is an element of the diagnostic criteria of CFS, the ME criteria
specifically require prolonged post-exertional muscle weakness (and muscle pain) after a minor
physical effort. (*
2
) Although both ME and CFS symptoms relate to sleep, reversal of sleep rhythm and
unrefreshing sleep are different types of symptoms.
List 3. Example of a patient with CFS [9] not fulfilling the diagnosis ME [5,6].
Clinical picture of a patient fulfilling the diagnosis CFS:
‚ chronic fatigue for 6 or more consecutive months;
‚ unrefreshing sleep;
‚ significant impairment of short-term memory or concentration;
Diagnostics 2016, 6, 10 4 of 13
‚ headaches of a new type, pattern, or severity; and
‚ a sore throat that is frequent or recurring.
List 4.
Example of a patient with distinctive ME [
5
,
6
] symptoms not meeting the diagnosis CFS.
Clinical picture of a patient fulfilling the diagnosis criteria of ME:
‚ prolonged muscle weakness and muscle pain after minimal exertion;
‚
circulatory impairment, e.g., indicated by cold extremities, disturbed thermoregulation, low body
temperature, and orthostatic tachycardia; and
‚ cognitive impairment and other symptoms indicating neurological dysfunction.
2.2. The Literature Analyzed by the Medicine (IOM) Committee Largely Relates to CFS Research
Scientific literature from 1938 [
1
] until the late 1980s relate to findings in ME, as defined in
1988 [
5
,
6
], while almost all research studies in the last decades relate to symptoms and abnormalities
in CFS, defined in 1988 [
8
] and redefined in 1994 [
9
]. Research into CFS, thoroughly analyzed research
by the IOM [
14
], is not applicable to ME, since only a part of the patient population potentially meets
the diagnostic criteria for ME, while not all ME patients qualify as CFS patients. Likewise, research
into ME, which got far less attention in the analysis, cannot be generalized to CFS.
2.3. Consensus on “an Unclear Picture of the Symptoms” in a Heterogeneous Patient Group Does Not
Guarantee a Good Solution
The IOM performed a comprehensive review of studies of (a) fatigue; and (b) notions related to the
“minor” symptoms of CFS [
9
]: post-exertional “malaise” (an exacerbation of symptoms after physical
or cognitive exertion), neurocognitive manifestations (relating to impairment of short-term memory or
concentration), sleep (relating to unrefreshing sleep), pain (relating to muscle pain, multi-joint pain
and headaches: three “minor” symptoms of CFS), and immune manifestations (relating to tender
lymph nodes and sore throat); and/or (c) findings associated with autonomic and neuroendocrine
manifestations and infections in ME and/or CFS. Articles, citations of the articles and “grey” literature
were evaluated by two to five committee members assigned to each topic using a modified “GRADE
grid” [
16
,
17
], after which a recommendation was made based upon consensus in the committee.
In addition to the fact that the IOM committee largely based their opinion of “ME/CFS” on research
into CFS, this working method introduces three additional issues: (1) the current definition of CFS [
9
] is
leading, therefore typical ME symptoms, e.g., prolonged post-exertional muscle weakness, circulatory
impairment, and specific symptoms related to cerebral dysfunction, were not taken into consideration;
(2) some candidate symptoms were included in the analysis arbitrarily, e.g., autonomic dysfunction,
while other possible symptoms, e.g., visual symptoms, were not analyzed; and (3) for a number of
reasons, e.g., expert panel composition [
18
] and low interrater reliability [
19
], consensus on “an unclear
picture of the symptoms and signs” [
14
] (p. 72) in heterogeneous patient samples may lead to arbitrary
decisions. This latter issue is exemplified by the important role of orthostatic intolerance in the
diagnosis SEID, a less common symptom in CFS [
20
], while more prevalent symptoms of CFS [
20
], e.g.,
muscle pain and flu-like symptoms, are arbitrarily not included in the definitional criteria of SEID [
14
].
3. Diagnostic Shortcomings of the New Definition for “ME/CFS”: SEID
According to the IOM [
14
], a diagnosis of SEID should be made if three symptoms are present
and if the patient reports at least one of two facultative symptoms (List 5).
Looking at the definition of SEID three important observations can be made. Firstly, although
ill-defined, post-exertional “malaise” is mandatory for the diagnosis SEID. Secondly, chronic fatigue,
a vague and ambiguous concept that has created much confusion, still has a central role in the
diagnostic criteria. Lastly, all core symptoms are abstract and should be assessed using questionnaires
and patient self-report.
Diagnostics 2016, 6, 10 5 of 13
List 5. Proposed diagnostic criteria for SEID [14] (p. 6).
The diagnosis (SEID) requires that the patient have the following three symptoms:
‚
a substantial reduction or impairment in the ability to engage in pre-illness levels of occupational,
educational, social, or personal activities, that persists for more than 6 months and is accompanied
by fatigue, which is often profound, is of new or definite onset (not lifelong), is not the result of
ongoing excessive exertion, and is not substantially alleviated by rest;
‚ post-exertional malaise (*
1
); and
‚ unrefreshing sleep (*
1
)
At least one of the two following manifestations is also required:
‚ cognitive impairment (*
1
); or
‚ orthostatic intolerance
(*
1
) Frequency and severity of symptoms should be assessed. The diagnosis (SEID) should be
questioned if patients do not have these symptoms at least half of the time with moderate, substantial,
or severe intensity.
3.1. Neither ME nor CFS Is Covered by the Diagnostic Criteria of SEID
Both ME and CFS are not covered by the proposed diagnostic criteria for SEID [
14
]. Firstly, the
clinical entity SEID does not capture the essence of ME (List 1). Hallmark symptoms of ME, long-lasting
post-exertional muscle weakness, neurological dysfunction, e.g., implicated by cognitive impairment and
hyperacusis, and symptoms related to circulatory impairment, are not required to meet the diagnostic
criteria of SEID. The huge discrepancy between SEID and ME is largely due to two methodological
shortcomings discussed in the previous section: The premise that ME and CFS are similar conditions
is invalid and the development process was almost solely based upon research into CFS patient
populations. Secondly, although fatigue is also a principle feature of SEID, SEID does not include
facultative symptoms of CFS [
9
], often present in patients, e.g., muscle pain and flu-like feelings [
20
],
while orthostatic intolerance not incorporated in the diagnosis criteria for CFS [
9
] has been given
a prominent role in the diagnosis [
14
]. While a few studies observed high prevalence rates for orthostatic
intolerance in CFS [
21
], several studies have found much lower prevalence rates of orthostatic intolerance
in CFS [
22
–
24
]. Looking at the high prevalence of symptoms left out of the diagnostic criteria, e.g., muscle
pain, including this symptom seems odd. Since subgroups of patients with orthostatic intolerance also
report fatigue, unrefreshing sleep and exercise intolerance, these patients could also meet the diagnosis
SEID. All in all, SEID cannot adequately replace the diagnostic entities ME and CFS. The position of
SEID [14] in relation to ME [5,6] and CFS [9] is illustrated by Figure 2.
Diagnostics2016,6,10 5of13
a substantial reduction or impairment in the ability to engage in pre‐illness levels of
occupational,educational,social,orpersonalactivities,thatpersistsformorethan6months
and is accompanied by fatigue, which is often profound, is of new or definite onset (not
lifelong),isnottheresult
ofongoingexcessiveexertion,andisnotsubstantiallyalleviatedby
rest;
post‐exertionalmalaise(*
1
);and
unrefreshingsleep(*
1
)
Atleastoneofthetwofollowingmanifestationsisalsorequired:
cognitiveimpairment(*
1
);or
orthostaticintolerance
(*
1
)Frequencyandseverity of symptoms shouldbe assessed.The diagnosis (SEID)shouldbe
questioned if patients do not have these symptoms at least half of the time with moderate,
substantial,orsevereintensity.
3.1.NeitherMEnorCFSIsCoveredbytheDiagnosticCriteriaofSEID
BothMEandCFS
arenotcoveredbytheproposeddiagnosticcriteriaforSEID[14].Firstly,the
clinical entity SEID does not capture the essence of ME (List 1). Hallmark symptoms of ME,
long‐lasting post‐exertional muscle weakness, neurological dysfunction, e.g., implicated by
cognitive impairment and hyperacusis, and symptoms related to circulatory impairment,
are not
required to meet the diagnostic criteria of SEID. The huge discrepancy between SEID and ME is
largelyduetotwomethodologicalshortcomingsdiscussedintheprevioussection:Thepremisethat
MEandCFSaresimilarconditionsisinvalidandthedevelopmentprocesswasalmostsolelybased
uponresearchinto
CFSpatientpopulations.Secondly,althoughfatigueisalsoaprinciplefeatureof
SEID,SEIDdoesnotincludefacultativesymptomsofCFS[9],oftenpresentinpatients,e.g.,muscle
painandflu‐likefeelings[20],whileorthostaticintolerancenotincorporatedinthediagnosiscriteria
forCFS[9]hasbeengivena
prominentroleinthediagnosis[14].Whileafewstudiesobservedhigh
prevalence rates for orthostatic intolerance in CFS [21], several studies have found much lower
prevalence rates of orthostatic intolerance in CFS [22–24]. Looking at the high prevalence of
symptomsleftout of the diagnosticcriteria,e.g.,muscle pain, including
thissymptomseemsodd.
Sincesubgroups ofpatientswithorthostaticintolerancealsoreportfatigue,unrefreshingsleepand
exercise intolerance, these patients could also meet the diagnosis SEID. All in all, SEID cannot
adequatelyreplacethediagnosticentitiesMEandCFS. Theposition ofSEID[14]inrelationtoME
[5,6]
andCFS[9]isillustratedbyFigure2.
Figure 2.
SEID is neither covering ME nor CFS. The sizes of the shapes do not reflect the absolute sizes
of various patient (sub)populations.
Diagnostics 2016, 6, 10 6 of 13
3.2. The Abstract and Ill-Defined Symptoms of SEID Cannot Be Assessed by Self-Report
ME and CFS are clinical entities defined by their symptoms. However, characteristic symptoms of
ME, e.g., post-exertional muscle weakness, and CFS, e.g., fatigue and unrefreshing sleep, are subjective
and can neither be measured nor compared. For example, Jason et al. [
25
] found that “fatigue” in
ME/CFS has at least five dimensions (post-exertional exhaustion, wired: over-stimulated when very
tired, brain fog: cognitive impairment, complete lack of energy, and flu-like fatigue/feelings) and that
fatigue in ME/CFS is not the “fatigue” as experienced by the general population. Research in and
diagnosis of ME and CFS is often based upon questionnaires and self-report of typical symptoms, e.g.,
using a visual analogue scale. However, reliability and validity, criteria to substantiate the legitimacy
of a subjective outcome, do not ensure an adequate measure [
26
]. Even more, symptoms reported
by patients, e.g., fatigue, do not have to correlate with objective measures of disability in ME/CFS.
This is exemplified by the observation that patients with “chronic, but stable CFS” have a significantly
decreased aerobic capacity, which is correlated with self-reported physical activity, but is not correlated
with self-reported fatigue [
27
] and the finding that a reduction of “fatigue” is not reflected by increased
physical activity levels [
28
]. The five symptoms defining the clinical entity SEID are ambiguous and
subjective. For that reason assessing symptoms by questionnaires and scores based on self-report is
insufficient. Introducing thresholds for frequency (at least half of the time) and severity (moderate,
substantial, or very severe), as proposed by the IOM, does not resolve the issue of false negatives and
false positives. Jason et al. [
20
], for example, observed that even when these thresholds are applied,
4.7% of the healthy controls still met the diagnostic criteria for CFS [
9
] and at least 4% of the patients
would not meet the diagnosis of CFS, since their “fatigue” would be insufficient.
Considering the controversy [
29
], there is an ambiguity of subjective measures and there are
opposing views on the nature of the symptoms: With, on the one hand, “unhelpful cognitions
and behavior perpetuating the symptoms” [
30
,
31
] versus, on the other hand, distinctive biological
abnormalities explaining a multisystem illness [
32
,
33
], it is essential that symptoms are assessed
objectively wherever possible, and not by subjective measures from self-report only. As the IOM
report [
14
] states: “(Twisk) asserts that (
. . .
) objective assessment must address the unique symptoms
in accordance with the diagnosis, whether it be ME or CFS” [
34
]. Various symptoms of ME and CFS can
be assessed objectively, e.g., cognitive impairment, (post-exertional) muscle weakness, post-exertional
“malaise” (long-lasting negative impact of exertion on symptoms) and orthostatic intolerance [35].
3.3. The SEID Criteria Do Not Seem Reduce the Heterogeneity of the CFS Patient Population
There is ample evidence that the diagnostic criteria for CFS define a heterogeneous population
of people with chronic fatigue [
10
–
12
]. Introducing a new diagnostic entity, SEID, should have
helped to resolve this issue. However, Jason et al. [
36
] recently found that the SEID criteria [
14
] are not
substantially more restrictive than the CFS criteria [
9
] in a selective group of people with a self-reported
diagnosis of ME and/or CFS. While 92% of the patients fulfilled the diagnosis of CFS [
9
], 88% met the
SEID criteria. Therefore, the new criteria do not seem to reduce the diversity of the patient population.
Even more, reducing the number of symptoms required and leaving out very common CFS symptoms,
(e.g., muscle pain and flu-like feeling), will most likely increase the heterogeneity. It is not known
how many people would meet the diagnosis SEID [
14
] without fulfilling the CFS criteria [
10
] in
a non-selective group of people from the general population.
3.4. The Definition of SEID Includes People with Other Conditions
Contrary to the CFS definition [
9
], the SEID definition [
14
] does not exclude other disorders, so
people with other medical and psychiatric conditions could meet the diagnosis SEID. As explained
in the literature [
37
], people with other conditions also experience the symptoms, i.e., fatigue,
exercise intolerance, unrefreshing sleep, and orthostatic intolerance or cognitive impairment, essential
to meet the diagnosis of SEID. Patients with any of the following conditions will all meet the
Diagnostics 2016, 6, 10 7 of 13
criteria for a diagnosis of SEID: postural orthostatic tachycardia syndrome, chronic heart failure,
chronic obstructive pulmonary disease, mitochondrial diseases, Addison’s disease, fibromyalgia and
depression. Depression and medical conditions that may explain chronic fatigue are exclusionary
criteria for the diagnosis CFS [
9
]. Not surprisingly, a recent study [
38
] found that substantial subgroups
of patients with multiple sclerosis, lupus, and chronic fatigue who did not meet the diagnosis criteria of
CFS [
9
] and had major depressive disorder fulfilled the diagnostic criteria for SEID [
14
]. The situation
regarding the inclusion of other conditions is illustrated in Figure 3.
Diagnostics2016,6,10 7of13
intheliterature[37],peoplewithotherconditionsalsoexperiencethesymptoms,i.e.fatigue,exercise
intolerance, unrefreshing sleep, and orthostatic intolerance or cognitive impairment, essential to
meetthediagnosisofSEID.Patientswithanyofthefollowingconditionswillallmeetthecriteriafor
a diagnosis of SEID: postural orthostatic
tachycardia syndrome, chronic heart failure, chronic
obstructive pulmonary disease, mitochondrial diseases, Addison’s disease, fibromyalgia and
depression. Depression and medical conditions that may explain chronic fatigue are exclusionary
criteria for the diagnosis CFS [9]. Not surprisingly, a recent study [38] found that substantial
subgroups of patients with multiple sclerosis, lupus, and chronic
fatigue who did not meet the
diagnosis criteria of CFS[9] andhad major depressive disorder fulfilledthe diagnostic criteria for
SEID[14].ThesituationregardingtheinclusionofotherconditionsisillustratedinFigure3.
Figure3.SEIDoverlapswithother(medicalandpsychiatric)conditions.Thesizesoftheshapesdo
notreflecttheabsolutesizesofvariouspatient(sub)populations.
4.ProposalforaMethodologicalSolutionfortheCurrent“DiagnosticImpasse”
To resolve the “diagnostic impasse,” which for an essential part originates from the
introductionoftheill‐definedentityCFS[9],andtoavoidadditionalconfusionbyintroducinganew,
only partially overlapping,clinical entity, SEID,it is crucialto
develop empiricdefinitionsfor ME
and conditions currently covered by the CFS “waste basket” diagnosis based upon the following
methodological principles: (1) the original diagnostic criteria of ME [5,6] and criteria for CFS [9]
define two, partially overlapping, conditions and should not be merged into a “hybrid”; (2)
symptoms should
be assessed by objective measures, not by self‐report (only); (3) confounding
variables, for example mode of onset, phase, duration of illness, gender, age and comorbidities,
shouldbetakenintoaccount;(4)patternrecognitionmethodsshouldbeusedinsteadofconsensus;
and(5)diagnosticlabelsshouldpreferablyreflecttheclinicalpicture.
4.1.MakeaClearDistinctionbetweenPatientsMeetingtheDiagnosisofMEorCFS
Ascan be seen in Figure1, ME[5,6]/CFS[9]isa“hybrid”not onediagnosticentity. It should
alsobenotedthatthediagnosticcriteriaofCFSdefineadiffusesyndrome,notadisease.To
resolve
theissue,patientsmeetingthe(original)criteria[5,6]forME,adistinctclinicalentity[2],shouldbe
exploredindetail,whilethe(remaining)patientsfulfillingthediagnosticcriteriaforCFS[9]should
also be analyzed in depth. Considering the heterogeneity of the CFS patient population, the
(remaining)CFSpatientsmost
likelysufferfromvariousdisorders.Lumpingpatients(MEpatients
and CFS patients with various disorders)will not improve anaccurate diagnosis. This is not only
importantforresearchpurposes,butalsofortheclinicalpractice.
4.2.SymptomsShouldBeAssessedObjectivelyIfFeasible,NotOnlybySelf‐Report
Figure 3.
SEID overlaps with other (medical and psychiatric) conditions. The sizes of the shapes do
not reflect the absolute sizes of various patient (sub)populations.
4. Proposal for a Methodological Solution for the Current “Diagnostic Impasse”
To resolve the “diagnostic impasse,” which for an essential part originates from the introduction
of the ill-defined entity CFS [
9
], and to avoid additional confusion by introducing a new, only partially
overlapping, clinical entity, SEID, it is crucial to develop empiric definitions for ME and conditions
currently covered by the CFS “waste basket” diagnosis based upon the following methodological
principles: (1) the original diagnostic criteria of ME [
5
,
6
] and criteria for CFS [
9
] define two, partially
overlapping, conditions and should not be merged into a “hybrid”; (2) symptoms should be assessed
by objective measures, not by self-report (only); (3) confounding variables, for example mode of onset,
phase, duration of illness, gender, age and comorbidities, should be taken into account; (4) pattern
recognition methods should be used instead of consensus; and (5) diagnostic labels should preferably
reflect the clinical picture.
4.1. Make a Clear Distinction between Patients Meeting the Diagnosis of ME or CFS
As can be seen in Figure 1, ME [
5
,
6
]/CFS [
9
] is a “hybrid” not one diagnostic entity. It should
also be noted that the diagnostic criteria of CFS define a diffuse syndrome, not a disease. To resolve
the issue, patients meeting the (original) criteria [
5
,
6
] for ME, a distinct clinical entity [
2
], should be
explored in detail, while the (remaining) patients fulfilling the diagnostic criteria for CFS [
9
] should also
be analyzed in depth. Considering the heterogeneity of the CFS patient population, the (remaining)
CFS patients most likely suffer from various disorders. Lumping patients (ME patients and CFS
patients with various disorders) will not improve an accurate diagnosis. This is not only important for
research purposes, but also for the clinical practice.
4.2. Symptoms Should Be Assessed Objectively If Feasible, Not Only by Self-Report
Considering the controversy with regard to the etiology and psychophysiology of ME and
CFS [
29
,
39
] and the abstract and subjective nature of typical symptoms of ME and CFS, a diagnosis
Diagnostics 2016, 6, 10 8 of 13
based upon self-reported measures is not adequate. As far is possible, objective methods should
be employed to assess the symptoms and disability [
35
]. Characteristic symptoms, e.g., “fatigue,”
long-lasting post-exertional weakness, cognitive impairment, post-exertional malaise (the negative
effect of exercise on cognitive and physical performance levels) and visual problems can be “objectified”
by using well-accepted methods, e.g., (repeated) cardiopulmonary exercise tests, neuropsychological
tests (before and after an exercise test), (repeated) muscle power strength and endurance tests, tilt-table
tests, and visual field tests. The status and disability of a patient should also be expressed in objective
measures, e.g., activity levels, employment status and health care usage, as much as possible.
4.3. Take into Account Confounding Factors
Several findings show that the mode of onset, phase, duration of illness, gender, age and
comorbidities, e.g., gastro-intestinal symptoms and (secondary) depression, can have an important
influence on the clinical status and abnormalities in ME/CFS. The impact of these factors is illustrated
by a study [
40
] that found clear gender differences in symptomology and a study [
41
] that established
that sudden vs. gradual onset of CFS differentiates patients on cognitive and psychiatric measures.
The influence of these variables on abnormalities is exemplified by a study [
42
] that found that patients
with short-duration illness (
ď
3 years) exhibited pronounced activation of pro- and anti-inflammatory
cytokines and dysregulation of intercytokine regulatory networks, while patients with long-duration
illness showed an inverse picture, possibly due to “immune exhaustion” and a study [
43
] which
observed elevated interleukin (IL)-8 levels in the spinal fluid of patients with sudden (viral-like) onset
compared to patients with gradual onset and healthy controls.
4.4. Use Pattern Recognition Methods to Develop Empiric Definitions for ME, CFS-1 etc.
Based on the mandatory symptoms of ME (prolonged post-exertional muscle weakness, signs
indicating cerebral dysfunction and symptoms reflecting circulatory deficits), pattern recognition
methods could be employed to objectively establish optional symptoms of ME [
5
,
6
] and their
prevalence rates, taken into account confounding factors. All symptoms should be assessed objectively
wherever possible. Biomarkers should be investigated to validate the diagnosis ME biomarkers.
Pattern recognition algorithms should also be used to subdivide the remaining population of patients
fulfilling the current CFS [
9
] criteria and not meeting the ME criteria [
5
,
6
] in distinct CFS “symptom
clusters” based upon mandatory symptoms and to establish optional symptoms in these symptom
clusters” (CFS-1, CFS-2, etc.). Some researchers suggest that CFS patients with postural orthostatic
tachycardia syndrome reflect a distinct patient subgroup of the CFS [
9
] population [
22
] with specific
phenotypic features [
23
]. Pattern recognition methods could be used to reject or validate this position
and to reveal other distinct patient populations. Interestingly, research has uncovered at least seven
gene expression subtypes in CFS patients [
44
,
45
] with distinct differences in clinical phenotypes
and severity.
4.5. Diagnostic Labels Should Preferably Reflect the Clinical Picture
Preferably diagnostic labels reflect the etiology, multiple sclerosis, or instigating agent, brucellosis.
Although the name ME, especially the encephalomyelitis part of the name, is contested [
29
,
46
], some
studies have found direct or indirect evidence of neuro-inflammation. Using recently proposed new
criteria for ME [
47
], a recent study [
48
] observed neuro-inflammation in widespread brain areas in ME
patients. Findings of a recent study into CFS [
49
] indicate “a markedly disturbed immune signature in
the cerebrospinal fluid [...] consistent with immune activation in the central nervous system, and a shift
toward an allergic or T helper type-2 pattern associated with autoimmunity.” Another study [
43
] found
an increase in protein levels and number of white blood cells in 30% of the CFS [
9
] patients, found
elevated IL-10 levels in patients with abnormal spinal fluids compared to patients with normal fluid or
controls, and found higher levels of IL-8 in CFS patients with sudden, influenza-like onset. Therefore,
there are indications of neuro-inflammation in CFS patients or subgroups. How many of these patients
Diagnostics 2016, 6, 10 9 of 13
fulfilled the original criteria of ME [
5
,
6
] is unknown. Systemic exercise intolerance disease (SEID) does
not reflect the clinical picture of ME. This abstract label captures the central symptom of the diagnostic
criteria of SEID. Rather than choosing a new name, preserving the term ME would be sensible, since
all “old” studies relate to ME, and the WHO has acknowledged ME as a neurological disease since
1969 [
50
]. If one would argue that neuro-inflammation is not (sufficiently) proven in ME yet, the
eponymous Ramsay’s disease would by far be the most sensible alternative. As mentioned, the CFS [
9
]
criteria define a heterogeneous group of people with chronic fatigue [
10
–
12
]. The polythetic nature
of the definition of CFS (List 2) allows for 163 different combinations of symptoms. As mentioned,
pattern analysis should be used to reveal symptom clusters/diseases currently classified as CFS. The
“symptoms clusters” under the CFS “umbrella diagnosis” (“CFS-1,” “CFS-2,” etc.) should be named
after the mandatory symptom(s) in each disorder until the exact etiology of that disorder is unraveled
by future research (Figure 4).
Diagnostics2016,6,10 9of13
fluids compared to patients with normal fluid or controls, and found higher levels of IL‐8 in CFS
patientswithsudden,influenza‐likeonset.Therefore,thereareindicationsofneuro‐inflammationin
CFSpatientsorsubgroups. How manyof thesepatientsfulfilled theoriginalcriteriaof ME[5,6]is
unknown.
Systemic exercise intolerancedisease (SEID) does not reflect the clinical picture of ME.
This abstract label captures the central symptom of the diagnostic criteria of SEID. Rather than
choosinganewname,preservingthetermMEwouldbesensible,sinceall“old”studiesrelatetoME,
andtheWHOhasacknowledged
MEasa neurologicaldiseasesince1969[50].Ifonewouldargue
that neuro‐inflammation is not (sufficiently) proven in ME yet, the eponymous Ramsay’s disease
would by far be the most sensible alternative. As mentioned, the CFS [9] criteria define a
heterogeneousgroupofpeoplewithchronicfatigue[10–12].
Thepolytheticnatureofthedefinition
ofCFS (List2)allowsfor163different combinationsof symptoms.Asmentioned, patternanalysis
should be used to reveal symptom clusters/diseases currently classified as CFS. The “symptoms
clusters” under the CFS “umbrella diagnosis” (“CFS‐1,” “CFS‐2,” etc.) should be named after the
mandatory symptom(s) in each disorder until the exact etiology of that disorder is unraveled by
futureresearch(Figure4).
Figure4.Proposedsolutiontoresolvethediagnosticimpasse.Thesizesoftheshapesdonotreflect
theabsolutesizesofvariouspatient(sub)populations.
5.Discussion
Due to the abstract and subjective nature of characteristic symptoms and the lack of clear
etiologicexplanations,MEandCFSarestillsurroundedbycontroversy.Itisgoodtonoteachange
of direction in the attitude towards ME/CFS. Indeed, “ME/CFS is a serious, chronic, complex
systemicdiseasethat
oftencanprofoundlyaffectthelivesofpatients”[14]withclearimmunological,
neurological,endocrine,autonomicandmetabolicabnormalities[51,52].ME/CFSis“amedical—not
apsychiatricorpsychological—illness”[52].Greenandcolleagues[51]takeafirmstandbyposing
that “both society and the medical profession have contributed to the disrespect
and rejection
experienced by patients with ME/CFS.” In order to improve the situation for patients, the IOM
proposestoreplaceMEandCFSwithSEID[14],withakeyrolefor“exerciseintolerance,”ahighly
characteristicfeatureofMEandCFS.
However,despitegoodintentions,introducinganewclinicalentitySEID
[14]doesnotresolve
the most important methodological and diagnostic issues. Firstly, a new clinical entity cannot
replace two distinct, partially overlapping, clinicalentities. ME/CFS is a “hybrid diagnosis”: Only
part of the CFS [9] patient population meet the more strict criteria for ME [5,6], while ME [5,6]
patients not
reporting fatigue or at least four of the “additional” symptoms do not meet the
diagnosisCFS[9].Secondly,duetotheirabstractandill‐definednatureofthediagnosticcriteriaof
SEID, the proposal to employ self‐report, instead of an objective assessment of typical symptoms,
andthelackofexclusion
criteriatoprecludepatientswithothermedicalandpsychiatricconditions,
Figure 4.
Proposed solution to resolve the diagnostic impasse. The sizes of the shapes do not reflect the
absolute sizes of various patient (sub)populations.
5. Discussion
Due to the abstract and subjective nature of characteristic symptoms and the lack of clear etiologic
explanations, ME and CFS are still surrounded by controversy. It is good to note a change of direction
in the attitude towards ME/CFS. Indeed, “ME/CFS is a serious, chronic, complex systemic disease
that often can profoundly affect the lives of patients” [
14
] with clear immunological, neurological,
endocrine, autonomic and metabolic abnormalities [51,52]. ME/CFS is “a medical—not a psychiatric
or psychological—illness” [
52
]. Green and colleagues [
51
] take a firm stand by posing that “both
society and the medical profession have contributed to the disrespect and rejection experienced by
patients with ME/CFS.” In order to improve the situation for patients, the IOM proposes to replace
ME and CFS with SEID [
14
], with a key role for “exercise intolerance,” a highly characteristic feature
of ME and CFS.
However, despite good intentions, introducing a new clinical entity SEID [
14
] does not resolve
the most important methodological and diagnostic issues. Firstly, a new clinical entity cannot replace
two distinct, partially overlapping, clinical entities. ME/CFS is a “hybrid diagnosis”: Only part of
the CFS [
9
] patient population meet the more strict criteria for ME [
5
,
6
], while ME [
5
,
6
] patients not
reporting fatigue or at least four of the “additional” symptoms do not meet the diagnosis CFS [
9
].
Secondly, due to their abstract and ill-defined nature of the diagnostic criteria of SEID, the proposal to
employ self-report, instead of an objective assessment of typical symptoms, and the lack of exclusion
criteria to preclude patients with other medical and psychiatric conditions, the diagnostic criteria of
SEID seem to select an even more heterogeneous patient population of patients with chronic fatigue,
Diagnostics 2016, 6, 10 10 of 13
thereby causing further scientific and diagnostic confusion, not reducing confusion. The position
that “the new IOM case definition and algorithm [
14
] provide a starting place for future studies of
diagnostic testing” [15] for ME and CFS is seriously open to question for the arguments given.
6. Conclusions
Replacing ME [
5
,
6
] and CFS [
9
] by a third clinical entity does not resolve the diagnostic and
scientific impasse. SEID is based upon the invalid premise that ME and CFS are similar conditions,
a thorough analysis of scientific literature that mainly relates to CFS, and consensus. As a logical
consequence, SEID [
14
] does not capture the essence of ME [
5
,
6
]. Moreover the diagnostic criteria of
SEID are not more restrictive than the CFS criteria [
9
] and also apply to people with other medical and
psychological conditions. Self-report and subjective measures, as proposed by the IOM [
14
], are not
adequate for diagnosis and assessment of the clinical status of patients in research.
To resolve the diagnostic impasse and to improve the quality of research, (a) the scientific
community should acknowledge that much of the confusion originates from merging two clinical
entities, ME and CFS, into a “hybrid diagnosis” (ME/CFS); (b) symptoms should be assessed by
objective measures, not by self-report only; (c) pattern recognition methods should be used to establish
the optional symptoms of ME [
5
,
6
], and to reveal “symptom clusters”/disorders covered by the
“umbrella diagnosis” CFS, taking into account confounding variables, like onset, and duration of
illness; and (d) diagnostic labels should preferably reflect the clinical picture.
Acknowledgments:
This article is dedicated to Melvin Ramsay, who investigated myalgic encephalomyelitis with
great determination for decades, and to many others, including Elizabeth Dowsett, Donald Acheson, Byron Hyde,
David Bell, Paul Cheney and Daniel Peterson.
Author Contributions: The author designed and wrote the manuscript.
Conflicts of Interest: The author declares no conflict of interest.
References
1.
Gilliam, A.G. Epidemiological Study on an Epidemic, Diagnosed as Poliomyelitis, Occurring among the Personnel
of Los Angeles County General Hospital during the Summer of 1934; Public Health Bulletin 240; United States
Treasury Department Public Health Service: Washington, DC, USA, 1938; pp. 1–90.
2.
Acheson, E.D. The clinical syndrome variously called benign myalgic encephalomyelitis, Iceland disease
and epidemic neuromyasthenia. Am. J. Med. 1959, 26, 569–595. [CrossRef]
3.
Parish, J.G. Early outbreaks of “epidemic neuromyasthenia”. Postgrad. Med. J.
1978
, 54, 711–717. [CrossRef]
[PubMed]
4. Acheson, E.D. A new clinical entity? Lancet 1956, 267, 789–790.
5.
Ramsay, A.M. Myalgic Encephalomyelitis and Postviral Fatigue States: The Saga of Royal Free Disease, 2nd ed.;
Gower Publishing Corporation: London, UK, 1988.
6.
Ramsay, A.M. The clinical identity of the Myalgic Encephalomyelitis syndrome. ME Assoc. 1988. Available
online: http://web.onetel.com/~kickback/THE%20CLINICAL%20IDENTITY%20OF%20ME.html
(accessed on 3 February 2016).
7. Dowsett, E.G. Myalgic encephalomyelitis, or what? Lancet 1988, 332, 101. [CrossRef]
8.
Holmes, G.P.; Kaplan, J.E.; Gantz, N.M.; Komaroff, A.L.; Schonberger, L.B.; Straus, S.E.; Jones, J.F.;
Dubois, R.E.; Cunningham-Rundles, C.; Pahwa, S.; et al. Chronic fatigue syndrome: A working case
definition. Ann. Intern. Med. 1988, 108, 387–389. [CrossRef] [PubMed]
9.
Fukuda, K.; Straus, S.E.; Hickie, I.; Sharpe, M.; Dobbins, J.G.; Komaroff, A.L. The chronic fatigue syndrome:
A comprehensive approach to its definition and study. Ann. Intern. Med.
1994
, 121, 953–959. [CrossRef]
[PubMed]
10.
Fischer, D.B.; William, A.H.; Strauss, A.C.; Unger, E.R.; Jason, L.; Marshall, G.D.J.; Dimitrakoff, J.D. Chronic
fatigue syndrome: The current status and future potentials of emerging biomarkers. Fatigue
2014
, 2, 93–109.
[CrossRef] [PubMed]
Diagnostics 2016, 6, 10 11 of 13
11.
Wilson, A.; Hickie, I.; Hadzi-Pavlovic, D.; Wakefield, D.; Parker, G.; Straus, S.E.; Dale, J.; McCluskey, D.;
Hinds, G.; Brickman, A.; et al. What is chronic fatigue syndrome? Heterogeneity within an international
multicentre study. Aust. N. Z. J. Psychiatry 2001, 35, 520–527. [CrossRef] [PubMed]
12.
May, M.; Emond, A.; Crawley, E. Phenotypes of chronic fatigue syndrome in children and young people.
Arch. Dis. Child. 2010, 95, 245–249. [CrossRef] [PubMed]
13.
Twisk, F.N.M. The status of and future research into Myalgic Encephalomyelitis and chronic fatigue
syndrome: The need of accurate diagnosis, objective assessment, and acknowledging biological and clinical
subgroups. Front. Physiol. 2014, 5, 109. [CrossRef] [PubMed]
14.
IOM (Institute of Medicine). Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness;
The National Academies Press: Washington, DC, USA, 2015.
15.
Haney, E.; Smith, M.E.; McDonagh, M.; Pappas, M.; Daeges, M.; Wasson, N.; Nelson, H.D. Diagnostic
methods for Myalgic Encephalomyelitis/chronic fatigue syndrome: A systematic review for a national
institutes of health pathways to prevention workshop. Ann. Intern. Med.
2015
, 162, 834–840. [CrossRef]
[PubMed]
16.
Jaeschke, R.; Guyatt, G.H.; Dellinger, P.; Schünemann, H.; Levy, M.M.; Kunz, R.; Norris, S.; Bion, J.;
GRADE-Working-Group. Use of GRADE grid to reach decisions on clinical practice guidelines when
consensus is elusive. BMJ 2008, 337, a744. [CrossRef] [PubMed]
17.
Guyatt, G.H.; Oxman, A.D.; Vist, G.E.; Kunz, R.; Falck-Ytter, Y.; Alonso-Coello, P.; Schünemann, H.J.;
Group, G.W. GRADE: An emerging consensus on rating quality of evidence and strength of
recommendations. BMJ 2008, 336, 924–946. [CrossRef] [PubMed]
18.
Nair, R.; Aggarwal, R.; Khanna, D. Methods of formal consensus in classification/diagnostic criteria and
guideline development. Semin. Arthritis Rheum. 2011, 41, 95–105. [CrossRef] [PubMed]
19.
Hartling, L.; Hamm, M.P.; Milne, A.; Vandermeer, B.; Santaguida, P.L.; Ansari, M.; Tsertsvadze, A.; Hempel, S.;
Shekelle, P.; Dryden, D.M. Testing the risk of bias tool showed low reliability between individual reviewers
and across consensus assessments of reviewer pairs. J. Clin. Epidemiol.
2013
, 66, 973–981. [CrossRef]
[PubMed]
20.
Jason, L.A.; Sunnquist, M.; Brown, A.; Evans, M.; Vernon, S.D.; Furst, J.D.; Simonis, V. Examining case
definition criteria for chronic fatigue syndrome and myalgic encephalomyelitis. Fatigue
2014
, 2, 40–56.
[CrossRef] [PubMed]
21. Bou-Holaigah, I.; Rowe, P.C.; Kan, J.; Calkins, H. The relationship between neurally mediated hypotension
and the chronic fatigue syndrome. JAMA 1995, 274, 961–967. [CrossRef] [PubMed]
22.
Reynolds, G.K.; Lewis, D.P.; Richardson, A.M.; Lidbury, B.A. Comorbidity of postural orthostatic tachycardia
syndrome and chronic fatigue syndrome in an Australian cohort. J. Intern. Med.
2014
, 275, 409–417.
[CrossRef] [PubMed]
23.
Lewis, I.; Pairman, J.; Spickett, G.; Newton, J.L. Clinical characteristics of a novel subgroup of chronic fatigue
syndrome patients with postural orthostatic tachycardia syndrome. J. Intern. Med.
2013
, 273, 501–510.
[CrossRef] [PubMed]
24.
Hoad, A.; Spickett, G.; Elliott, J.; Newton, J. Postural orthostatic tachycardia syndrome is an under-recognized
condition in chronic fatigue syndrome. QJM 2008, 101, 961–965. [CrossRef] [PubMed]
25.
Jason, L.A.; Jessen, T.; Porter, N.; Boulton, A.; Gloria-Njoku, M.; Friedberg, F. Examining Types of Fatigue
among Individuals with ME/CFS. Available online: http://dsq-sds.org/article/view/938/1113 (accessed
on 3 February 2016).
26.
Elasy, T.A.; Gaddy, G. Measuring subjective outcomes: Rethinking reliability and validity. J. Gen. Intern. Med.
1998, 13, 757–761. [CrossRef] [PubMed]
27.
Weinstein, A.A.; Drinkard, B.M.; Diao, G.; Furst, G.; Dale, J.K.; Straus, S.E.; Gerber, L.H. Exploratory analysis
of the relationships between aerobic capacity and self-reported fatigue in patients with rheumatoid arthritis,
polymyositis, and chronic fatigue syndrome. PM R 2009, 1, 620–628. [CrossRef] [PubMed]
28.
Wiborg, J.F.; Knoop, H.; Stulemeijer, M.; Prins, J.B.; Bleijenberg, G. How does cognitive behaviour therapy
reduce fatigue in patients with chronic fatigue syndrome? The role of physical activity. Psychol. Med.
2010
, 40,
1281–1287. [PubMed]
29.
Holgate, S.T.; Komaroff, A.L.; Mangan, D.; Wessely, S. Chronic fatigue syndrome: Understanding a complex
illness. Nat. Rev. Neurosci. 2011, 12, 539–544. [CrossRef] [PubMed]
Diagnostics 2016, 6, 10 12 of 13
30.
Sharpe, M. Cognitive behavior therapy for chronic fatigue syndrome: efficacy and implications. Am. J. Med.
1998, 105, 104S–109S. [CrossRef]
31.
Vercoulen, J.H.; Swanink, C.M.; Galama, J.M.; Fennis, J.F.; Jongen, P.J.; Hommes, O.R.; van der Meer, J.W.;
Bleijenberg, G. The persistence of fatigue in chronic fatigue syndrome and multiple sclerosis: Development
of a model. J. Psychosom. Res. 1998, 45, 507–517. [CrossRef]
32.
Hooper, M. Myalgic encephalomyelitis: A review with emphasis on key findings in biomedical research.
J. Clin. Pathol. 2007, 60, 466–471. [CrossRef] [PubMed]
33.
Twisk, F.N.M. The 4I hypothesis: A neuro-immunological explanation for characteristic symptoms of Myalgic
Encephalomyelitis/chronic fatigue syndrome. Int. J. Neurol. Res. 2015, 1, 20–38. [CrossRef]
34. Twisk, F.N.M. A definition of recovery in myalgic encephalomyelitis and chronic fatigue syndrome should
be based upon objective measures. Qual. Life Res. 2014, 23, 2417–2418. [CrossRef] [PubMed]
35.
Twisk, F.N.M. Accurate diagnosis of Myalgic Encephalomyelitis and chronic fatigue syndrome based upon
objective test methods for characteristic symptoms. World J. Methodol. 2015, 5, 68–87. [PubMed]
36.
Jason, L.A.; Sunnquist, M.; Brown, A.; Newton, J.L.; Strand, E.B.; Vernon, S.D. Chronic fatigue syndrome
versus systemic exertion intolerance disease. Fatigue Biomed. Health Behav. 2015, 3. [CrossRef] [PubMed]
37.
Twisk, F.N.M. A critical analysis of the proposal of the Institute of Medicine to replace myalgic
encephalomyelitis and chronic fatigue syndrome by a new diagnostic entity called systemic exertion
intolerance disease. Curr. Med. Res. Opin. 2015, 31, 1333–1347. [CrossRef] [PubMed]
38.
Jason, L.A.; Sunnquist, M.; Kot, B.; Brown, A.; Reed, J. Unintended consequences of not specifying
exclusionary illnesses with systemic exertion intolerance disease. Diagnostics 2015, 5, 272–286. [CrossRef]
39.
Maes, M.; Twisk, F.N.M. Chronic fatigue syndrome: Harvey and Wessely’s (bio)psychosocial model versus
a bio(psychosocial) model based on inflammatory and oxidative and nitrosative stress pathways. BMC Med.
2010, 8, 35. [CrossRef] [PubMed]
40.
Faro, M.; Sàez-Francás, N.; Castro-Marrero, J.; Aliste, L.; Fernández-de-Sevilla, T.; Alegre, J. Gender
differences in chronic fatigue syndrome. Reumatol Clin. 2015. [CrossRef]
41.
DeLuca, J.; Johnson, S.K.; Ellis, S.P.; Natelson, B.H. Sudden vs. gradual onset of chronic fatigue syndrome
differentiates individuals on cognitive and psychiatric measures. J. Psychiatr. Res.
1997
, 31, 83–90. [CrossRef]
42.
Hornig, M.; Montoya, J.G.; Klimas, N.G.; Levine, S.; Felsenstein, D.; Bateman, L.; Peterson, D.L.;
Gottschalk, C.G.; Schultz, A.F.; Che, X.; et al. Distinct plasma immune signatures in ME/CFS are present
early in the course of illness. Sci. Adv. 2015, 1, e1400121. [CrossRef] [PubMed]
43.
Natelson, B.H.; Weaver, S.A.; Tseng, C.L.; Ottenweller, J.E. Spinal fluid abnormalities in patients with chronic
fatigue syndrome. Clin. Diagn. Lab. Immunol. 2005, 12, 52–55. [CrossRef] [PubMed]
44.
Kerr, J.R.; Petty, R.; Burke, B.; Gough, J.; Fear, D.; Sinclair, L.I.; Mattey, D.L.; Richards, S.C.; Montgomery, J.;
Baldwin, D.A.; et al. Gene expression subtypes in patients with chronic fatigue syndrome/myalgic
encephalomyelitis. J. Infect. Dis. 2008, 197, 1171–1184. [CrossRef] [PubMed]
45.
Kerr, J.R.; Burke, B.; Petty, R.; Gough, J.; Fear, D.; Mattey, D.L.; Axford, J.S.; Dalgleish, A.G.; Nutt, D.J. Seven
genomic subtypes of chronic fatigue syndrome/myalgic encephalomyelitis: A detailed analysis of gene
networks and clinical phenotypes. J. Clin. Pathol. 2008, 61, 730–739. [CrossRef] [PubMed]
46.
Van der Meer, J.W.M.; Lloyd, A.R. A controversial consensus—Comment on article by Broderick et al.
J. Intern. Med. 2012, 271, 29–31. [CrossRef] [PubMed]
47.
Carruthers, B.M.; van de Sande, M.I.; de Meirleir, K.L.; Klimas, N.G.; Broderick, G.; Mitchell, T.; Staines, D.;
Powles, A.C.P.; Speight, N.; Vallings, R.; et al. Myalgic encephalomyelitis: International consensus criteria.
J. Intern. Med. 2011, 270, 327–338. [CrossRef] [PubMed]
48.
Nakatomi, Y.; Mizuno, K.; Ishii, A.; Wada, Y.; Tanaka, M.; Tazawa, S.; Onoe, K.; Fukuda, S.;
Kawabe, J.; Takahashi, K.; et al. Neuroinflammation in patients with chronic fatigue syndrome/Myalgic
Encephalomyelitis: An 11C-(R)-PK11195 PET study. J. Nucl. Med. 2014, 55, 945–950. [CrossRef] [PubMed]
49.
Hornig, M.; Gottschalk, G.; Peterson, D.L.; Knox, K.K.; Schultz, A.F.; Eddy, M.L.; Che, X.; Lipkin, W.I.
Cytokine network analysis of cerebrospinal fluid in myalgic encephalomyelitis/chronic fatigue syndrome.
Mol. Psychiatry 2015. [CrossRef] [PubMed]
50.
World Health Organization. International Classification of Diseases, 8th Revision ed.; (ICD-8); Code 323; WHO:
Geneva, Switzerland, 1967; p. 158.
Diagnostics 2016, 6, 10 13 of 13
51.
Green, C.R.; Cowan, P.; Elk, R.; O’Neil, K.M.; Rasmussen, A.L. National Institutes of Health pathways to
prevention workshop: Advancing the research on Myalgic Encephalomyelitis/chronic fatigue syndrome.
Ann. Intern. Med. 2015, 162, 860–865. [CrossRef] [PubMed]
52.
Komaroff, A.L. Myalgic Encephalomyelitis/chronic fatigue syndrome: A real illness. Ann. Intern. Med.
2015, 162, 871–872. [CrossRef] [PubMed]
©
2016 by the author; licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons by Attribution
(CC-BY) license (http://creativecommons.org/licenses/by/4.0/).
