Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Clinical Working Case
Definition, Diagnostic and Treatment Protocols

J of Chronic Fatigue Syndrome, Vol. 11(1) 2003, pp. 7-115

Bruce M. Carruthers, MD, CM, FRCP(C); Anil Kumar Jain, BSc, MD;
Kenny L. De Meirleir, MD, PhD; Daniel L. Peterson, MD; Nancy G. Klimas, MD;
A. Martin Lerner, MD, PC, MACP; Alison C. Bested, MD, FRCP(C); Pierre
Flor-Henry, MB, ChB, MD, Acad DPM, FRC, CSPQ; Pradip Joshi, BM, MD,
FRCP(C); A. C. Peter Powles, MRACP, FRACP, FRCP(C), ABSM; Jeffrey A.
Sherkey, MD, CCFP(C); Marjorie I. van de Sande, BEd, Grad Dip Ed

Correspondence to: Dr. Bruce M. Carruthers, C58, Site 25, RR I,
Galiano, BC VON lPO, Canada (E-mail: mailto:carruthers@gulfislands.com ).


ABSTRACT.
Recent years have brought growing recognition of the need for clinical
criteria for myalgic encephalomyelitis (ME), which is also called chronic
fatigue syndrome (CFS). An Expert Subcommittee of Health Canada established
the Terms of Reference, and selected an Expert Medical Consensus Panel
representing treating physicians, teaching faculty and researchers. 

A Consensus Workshop was held on March 30 - April 1, 2001 to culminate the
review process and establish consensus for a clinical working case
definition, diagnostic protocols and treatment protocols. We present a
systematic clinical working case definition that encourages a diagnosis
based on characteristic patterns of symptom clusters, which reflect
specific areas of pathogenesis. Diagnostic and treatment protocols, and a
short overview of research are given to facilitate a comprehensive and
integrated approach to this illness. Throughout this paper, "myalgic
encephalomyelitis" and "chronic fatigue syndrome" are used interchangeably
and this illness is referred to as "ME/CFS."


KEYWORDS. Clinical case definition, myalgic encephalomyelitis, chronic
fatigue syndrome, ME, CFS, diagnostic protocol, treatment protocol


INTRODUCTION

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe
systemic, acquired illness that can be debilitating. It manifests symptoms
predominantly based on neurological, immunological and endocrinological
dysfunction. While the pathogenesis is suggested to be multi-factorial, the
hypothesis of initiation by a viral infection has been prominent. A wide
range of viruses and other infectious agents, such as Epstein-Barr Virus
(1,2,3,4,5), Human Herpesvirus-6 and 7 (6,7,8,9,10), Enterovirus (11,12),
Cytomegalovirus (13,14,15), Lentivirus (16), Chlamydia (17), and Mycoplasma
(18,19), have been investigated but findings are mixed and there is no
conclusive support for anyone pathogen. As antibody titers in standard
laboratory tests usually employ a whole viral preparation or a single viral
polypeptide, an incomplete or mutated pathogen replication could go
undetected. It is unclear whether the pathogens play a direct causal role,
accompany an underlying infection, trigger reactivation/replication of
latent pathogens, represent reactivated latent pathogens, activate a neural
response or modulate the immune system to induce ME/CFS (20). Possibly a
new microbe will be identified. Viral involvement is supported by an
infectious initiating trigger in at least half of the patients (21), and by
confirmed findings of biochemical dysregulation of the 2-5A
synthetase/ribonuclease L (RNase L) antiviral defense pathway in monocytes
(22,23,24,25,26), a pathway which is activated in viral disorders (27).

Before acquiring the illness most patients were healthy, leading full and
active lifestyles. ME/CFS most frequently follows an acute prodromal
infection, varying from upper respiratory infections, bronchitis or
sinusitis, or gastroenteritis, or an acute "flu-like" illness. Other
prodromal events that may stress the neuroimmunoendocrine regulatory system
include immunization, anesthetics, and exposure to environmental pollutants
(28), chemicals, and heavy metals (29). Physical trauma such as a motor
vehicle accident, a fall, or surgery may also trigger ME/CFS. In rare
occasions, ME/CFS has developed following a blood transfusion. Within days
or weeks of the initiating event, patients show a progressive decline in
health and develop a cascade of symptoms. The subset of patients that have
a gradual onset are less likely to show discrete triggering events.

ME/CFS is primarily an endemic disorder (30,31) but occurs in both epidemic
(2,32), and sporadic forms. It affects all racial/ethnic groups, is seen in
all socioeconomic strata (33,34,25). Epidemiological studies have indicated
a wide range of prevalence, from 75 to 2,600 per 100,000
(36,37,38,39,40,41) in different care settings; however, in a large sample
of over 28,000 adults, 422 per 100,000 or 0.42% suffered from ME/CFS (36).
It is more prevalent in females (522 per 100,000), as is arthritis and
rheumatism. When comparing the ME/CFS prevalence figures for women with
those for other illnesses, such as AIDS (12 per 100,000), breast cancer (26
per 100,000) (36), lung cancer (33 per 100,000) and diabetes (900 per
100,000), one realizes the need for a clinical definition and research for
ME/CFS.

In response to cluster outbreaks of this illness, a working case definition
for CFS was published under the aegis of the Centers for Disease Control
(CDC), U.S.A. in 1988 (42). Their 1994 revised definition (43) has been
used as the standard in Canada. These definitions, along-with the 1988 and
1990 Australian definitions (30,38), and the 1991 Oxford, U.K. definition
(44) have provided a basis for inter-subjective agreement and have played
an essential role in orienting clinical research.

As the CDC definition was primarily created to standardize research, it may
not be appropriate to use for clinical diagnoses, a purpose for which it
was never intended. There has been a growing demand within the medical
community for a clinical case definition for ME/CFS for the benefit of the
family physician and other treating clinicians. The CDC definition, by
singling out severe, prolonged fatigue as the sole major (compulsory)
criterion, de-emphasized the importance of other cardinal symptoms,
including post-exertional malaise, pain, sleep disturbances, and cognitive
dysfunction. This makes it more difficult for the clinician to distinguish
the pathological fatigue of ME/CFS from ordinary fatigue or other fatiguing
illnesses.

Based on the consensus panel's collective extensive clinical experience
diagnosing and/or treating more than twenty thousand (20,000) ME/CFS
patients, a working clinical case definition, that encompassed the pattern
of positive signs and symptoms of ME/CFS, was developed. The objective was
to provide a flexible conceptual framework for clinical diagnoses that
would be inclusive enough to be useful to clinicians who are dealing with
the unique symptomatic expression of individual patients and the unique
context within which their illness arises. The panel felt there was a need
for the criteria to encompass more symptoms in order to reflect ME/CFS as a
distinct entity and distinguish it from other clinical entities that have
overlapping symptoms. As fatigue is an integral part of many illnesses, the
panel concurred that more of the prominent symptoms should be compulsory.

Our strategy was to group symptoms together which share a common region of
pathogenesis, thus enhancing clarity and providing a focus to the clinical
encounter. The inclusion of more of the potential spectrum of
symptomatology in the clinical definition should allow a more adequate
expression of the actual symptoms of any given patient's pathogenesis. We
hope that the clinical working case definition will encourage a
consideration of the ongoing interrelationships of each patient's symptoms
and their coherence into a syndrome of related symptoms sharing a complex
pathogenesis rather than presenting a "laundry list" of seemingly unrelated
symptoms. We believe this will sharpen the distinction between ME/CFS and
other medical conditions that may be confused with it in the absence of a
definite laboratory test for ME/CFS.

Since the development of our clinical criteria, we have had an opportunity
to review the analysis of symptoms in over 2,500 patients by De Becker et
al. (45). They found that the Holmes definition (42) of fatigue,
swollen/tender lymph nodes, sore throat, muscle weakness, recurrent
flu-like symptoms, post-exertional fatigue, myalgia, memory disturbance,
nonrestorative sleep and replacing low-grade fever with hot flashes; and
the addition of ten other symptoms (attention deficit, paralysis, new
sensitivities to food/drugs, cold extremities, difficulties with words,
urinary frequency, muscle fasciculations, lightheadedness, exertional
dyspnea and gastrointestinal disturbance) strengthen the ability to select
ME/CFS patients. Based on this study, we added exertional dyspnea and
muscle fasciculations to our clinical definition. All the symptoms which
the De Becker et al. study (45) recommended adding to strengthen the
ability to select ME/CFS patients are in our definition except paralysis,
which the panel did not consider prevalent enough for inclusion in a
clinical definition. The clinical definition has additional symptoms, such
as orthostatic intolerance, which we feel are important in a clinical setting.


© 2003 by The Haworth Press, Inc. All rights reserved.