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Chronic fatigue syndrome, myalgic encephalomyelitis, a primer for clinical practitioners

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Rev Environ Health 2015; 30(4): 223–249
*Corresponding author: Dr. Alison C. Bested, 107-1265 Morningside
Ave, Toronto, Ontario, Canada, E-mail: acbes@bell.net; and
Department of Medicine, University of British Columbia, Vancouver,
BC, Canada
Lynn M. Marshall: Department of Family and Community Medicine,
University of Toronto, Toronto, ON, Canada
Alison C. Bested* and Lynn M. Marshall
Review of Myalgic Encephalomyelitis/Chronic
Fatigue Syndrome: an evidence-based approach
to diagnosis and management by clinicians
DOI 10.1515/reveh-2015-0026
Received August 17, 2015; accepted November 2, 2015
Abstract: This review was written from the viewpoint of
the treating clinician to educate health care professionals
and the public about Myalgic Encephalomyelitis/Chronic
Fatigue Syndrome (ME/CFS). It includes: the clinical
definition of ME/CFS with emphasis on how to diagnose
ME/CFS; the etiology, pathophysiology, management
approach, long-term prognosis and economic cost of ME/
CFS. After reading this review, you will be better able to
diagnose and treat your patients with ME/CFS using the
tools and information provided. Myalgic encephalomy-
elitis/chronic fatigue syndrome (ME/CFS) is a complex,
chronic medical condition characterized by symptom clus-
ters that include: pathological fatigue and malaise that
is worse after exertion, cognitive dysfunction, immune
dysfunction, unrefreshing sleep, pain, autonomic dys-
function, neuroendocrine and immune symptoms. ME/
CFS is common, often severely disabling and costly. The
Institute of Medicine (IOM) reviewed the ME/CFS lit-
erature and estimates that between 836,000 and 2.5 mil-
lion Americans have ME/CFS at a cost of between 17 and
24billion dollars annually in the US. The IOM suggested
a new name for ME/CFS and called it Systemic Exertion
Intolerance Disease (SEID). SEID’s diagnostic criteria are
less specific and do not exclude psychiatric disorders in
the criteria. The 2010 Canadian Community Health Survey
discovered that 29% of patients with ME/CFS had unmet
health care needs and 20% had food insecurity – lack of
access to sufficient healthy foods. ME/CFS can be severely
disabling and cause patients to be bedridden. Yet most
patients (80%) struggle to get a diagnosis because doc-
tors have not been taught how to diagnose or treat ME/
CFS in medical schools or in their post-graduate educa-
tional training. Consequently, the patients with ME/CFS
suffer. They are not diagnosed with ME/CFS and are not
treated accordingly. Instead of compassionate care from
their doctors, they are often ridiculed by the very people
from whom they seek help. The precise etiology of ME/CFS
remains unknown, but recent advances and research dis-
coveries are beginning to shed light on the enigma of this
disease including the following contributors: infectious,
genetic, immune, cognitive including sleep, metabolic
and biochemical abnormalities. Management of patients
with ME/CFS is supportive symptomatic treatment with a
patient centered care approach that begins with the symp-
toms that are most troublesome for the patient. Pacing of
activities with strategic rest periods is, in our opinion,
the most important coping strategy patients can learn to
better manage their illness and stop their post-exertional
fatigue and malaise. Pacing allows patients to regain the
ability to plan activities and begin to make slow incremen-
tal improvements in functionality.
Keywords: case definition; chronic fatigue syndrome;
myalgic encephalomyelitis; pathophysiology and treat-
ment; SEID.
Case study: CL
CL was a 54 year old woman who was referred for investi-
gation of her severe fatigue that had been present for the
past 2 years. Before she was sick she worked full time as a
kindergarten teacher. She loved her job. She was happily
married with two sons who were at university. Before her
illness, she went to advanced Pilates classes 3 to 4 X a week
and enjoyed entertaining family and friends on weekends.
Her illness started 2years ago when she was at a Christ-
mas party. Everyone at the party got the flu. They all got
better but she never recovered. She could not go back to
teaching after the Christmas holidays because she was so ill.
She was unable to work since that time. At the time of pres-
entation she had the following symptoms: severe fatigue
and malaise, so much that she could barely stand long
enough to make a meal most days. She had equal numbers
of good days and bad days. Her energy on a good day was
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224 Bested and Marshall: Review of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
5out of 10. Her energy on a bad day was 3 out of 10 and she
was in bed. Her premorbid energy on the Functional Capac-
ity Scale was 9 to 10/10 (See Appendix 1). She pushed herself
to get things done on a good day. For example, she would
go to the bank; but after she stood in line for a few minutes
she felt very exhausted and felt like she was going to faint.
One time she was so embarrassed because she had to sit on
the floor to recover enough to go home. She had recurrent
sore throats and swollen glands, which were worse after
she pushed herself. She had unrefreshing sleep, woke up
repeatedly throughout the night and woke up exhausted
every morning no matter what time she went to bed. On good
days she could be on the computer to do emails for half an
hour, but she had to stop because she could not concentrate
or focus. She called it “brain fog”. Most days she could not
read anything but a few paragraphs because she could not
remember the story line. Previously she was an avid reader.
She had muscle pain that moved around her body and new
headaches she had never had before and which were worse
when a storm was coming in.
She had been tried on various antidepressants
because her physician thought she was depressed but she
did not tolerate them. She had no history of depression
and did not think she was depressed; she just did not have
the energy to get things done the way she used to. She
pushed herself to do things when she had more energy
on a good day – but she ended up “crashed” in bed for
2days afterward with immobilizing post exertional physi-
cal and/or mental fatigue. She was sad that she could no
longer work at the job she loved and exercise as she had
in the past. She was frustrated and angry that after seeing
10 doctors she did not have a diagnosis and no one could
help her. She just wanted to get better.
Introduction
Myalgic encephalomyelitis/chronic fatigue syndrome
(ME/CFS) is known as a very complex chronic clinical con-
dition plagued by having no diagnostic blood test or inves-
tigation. Funding for research has been sparse (1). There
are 20 consensus research and clinical definitions of ME/
CFS in the literature (2) including: Canadian Consensus
Criteria (3), Fukuda (4), Holmes (5), International Criteria
(6), Oxford (7), etc. with an inability to separate ME and
CFS. The United States Institute of Medicine appointed a
committee in 2015, which wrote new ME/CFS criteria and
renamed it Systemic Exertion Intolerance Disease (SEID).
With inconsistent ME/CFS criteria, it has been difficult to
carry out definitive studies on patients with ME/CFS that
would lead to new understanding of pathophysiology,
new diagnostic tests, and treatment methods.
As a result of not having diagnostic blood tests or
investigative tools plus the variety of case criteria having
different selection and exclusion criteria, many clini-
cians have been skeptical that ME/CFS was legitimate. As
a result, patients with ME/CFS have been maligned and
told they did not have a real physical illness and that it
was “all in their head”. The IOM acknowledged this in the
report Beyond Myalgic Encephalomyelitis/Chronic Fatigue
Syndrome: Redefining an Illness and described it as “a
disease characterized by profound fatigue, cognitive dys-
function, sleep abnormalities, autonomic manifestations,
pain, and other symptoms that are made worse by exer-
tion of any sort. ME/CFS can severely impair patients’
ability to conduct their normal lives.” (8).
ME/CFS case definitions are assessed in terms of sen-
sitivity (ability to identify ME/CFS patients correctly) and
specificity (ability to exclude patients that do not have
ME/CFS). It is essential to identify ME/CFS patient popu-
lations correctly. If patient samples include participants
with different conditions, it is impossible to determine
what are the core domains or symptoms.
The new SEID criteria were not assessed with patient
data sets and controls. Analysis of 796 CFS patients
BioBank samples found that the new SEID criteria selected
more patients who had less impairment and fewer symp-
toms than several other criteria. It excluded symptoms of
pain and immune system dysfunction. Also, SEID does
not exclude “individuals from major depressive disorder
illness groups as well as other medical illnesses” (9, 10).
The SEID criteria is similar to the 1994 Fukuda CFS crite-
ria and the 1991 Oxford CFS criteria which include other
patient populations including major psychiatric illnesses
in their criteria. There are “detrimental consequences for
research in the interpretation of epidemiological, etiologi-
cal and treatment” for patients with ME/CFS (11).
The purpose of this article, as long-standing clini-
cians with considerable experience re ME/CFS, is to
inform other clinicians about how to assess and manage
patients with ME/CFS as research proceeds, because
there remains a severe gap in diagnosis and appropriate
management using the available evidence. As a result of
its better specificity, by the exclusion of other treatable
illnesses (including psychiatric illnesses), and its well
defined clinical criteria, we will continue to use the Cana-
dian Consensus Criteria (CCC) when diagnosing patients
with ME/CFS. Jason et al. validated the CCC symptoms
by using the DePaul Symptom Questionnaire (12) in
several patient samples, and assessed function by using
the Short Form 36-Item Questionnaire (SF-36) (13). (Both
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Bested and Marshall: Review of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome225
questionnaires and scoring systems are available online)
A symptom must be present with moderate severity about
half of the time to meet criteria for a symptom category,
and a patient must score below a certain maximum score
on at least two of the three scales of the SF-36 to meet cri-
teria for a substantial reduction in functioning. This vali-
dation and development of the Revised Canadian myalgic
encephalomyelitis chronic fatigue syndrome case defini-
tion (14) was to operationalize the CCC, make it more relia-
ble as a diagnostic tool and allow its use in future research
studies. The CCC is best able to differentiate between ME/
CFS and another common cause of fatigue: depression.
This makes it very useful for primary care clinicians. The
recently published 2014 “ME/CFS: Primer for Clinical
Practitioners” published by the International Association
for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis
(IACFS/ME) used the CCC (15).
In order to diagnose ME/CFS using the Canadian Con-
sensus Criteria (CCC) (3), exclusion criteria must first be
applied; then the patient must have the following criteria:
pathological fatigue, post-exertional fatigue and malaise,
sleep dysfunction, pain, cognitive dysfunction, and two
symptoms from the following categories: autonomic,
neuroendocrine or immune. The patient needs to have
had the illness for a minimum of 6months if an adult and
3months if a child. See Appendix 2 for the ME/CFS Clini-
cal Diagnostic Criteria Worksheet. Despite the symptom
complexity of ME/CFS, doctors can use the same skills to
manage ME/CFS that they utilize successfully in patients
with other complex conditions.
Prevalence of ME/CFS
Adults
Middle aged women comprise 70% of ME/CFS patients.
Women are twice as likely to have ME/CFS as men (16–18).
ME/CFS is found in people of all ages and races. A
case as young as 4years old has been reported. It is more
common in adolescents than children. Cases can occur in
clusters or sporadically (19).
The prevalence of ME/CFS has been estimated to be
between 0.004%–0.0087% (20), 0.42% (16) and 2.54%
(21). The large discrepancy in the prevalence statistics is
as a result of using different definitions of ME/CFS. The
more specific the exclusion criteria in the definition the
smaller the number of patients diagnosed with ME/CFS.
This translates into between 836,000 and 2.5 million
Americans having ME/CFS according to theIOM.
Children
In children and adolescents the prevalence estimates
range from 24 to 116 per 100,000 (22). Up until now, exist-
ing studies of ME/CFS in youth have conflicting numbers
and have lacked the ability to rigorously estimate the
overall prevalence of pediatric ME/CFS or examine risk
factors for the illness. Weaknesses of the studies were
recruiting strategies: only doctors were reporting the
patients ill with ME/CFS or the studies involved uncon-
firmed phone surveys. Jason etal. have published a pedi-
atric case criteria (22). See Appendix 3.
Prognosis
Adults
The prognosis of ME/CFS is variable. Patients may show
some improvement over the first five years of the illness
and usually plateau at a level below their pre-illness func-
tioning level. Most patients never regain their premorbid
level of health or functioning (23, 24).
A review of 14 studies found on average that 5% of
patients recovered (range 0%–31%); 40% of patients
improved during follow-up (range 8%–63%); 8%–30%
returned to work; 5%–20% of patients reported worsening
of symptoms (25, 26).
The patients may be functionally impaired mildly
(can work with accommodation of hours that are usually
reduced or work from home), or moderately or severely
(bedridden) (27). During the course of the illness patients
commonly have good (remission) and bad (relapse) days
with bad days being called crash days (28).
Patients who do recover often need more rest than
their contemporaries. Some patients may slowly get
worse.
Risk factors for severity (29–32) of the illness are:
The severity of the illness at the time of onset
The standard of early management of the illness (e.g.
late diagnosis or overexertion in the early stages of the
illness are likely to lead to deterioration)
Having a mother with the illness
Comorbid diagnosis of fibromyalgia
Death certificates, in patients with ME/CFS, are usually
documented as the patient’s death being caused by
another co-existing illness since the cause of death on
the death certificate is not listed as ME/CFS. Therefore,
the mortality rate is difficult to determine from reviewing
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226 Bested and Marshall: Review of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
death certificates of patients with ME/CFS. Preliminary
data from one study found suicide, heart disease and
cancer to be the leading causes of death in patients with
ME/CFS and the mean ages of death from these causes
were well below national averages. Another study found
that all-cause mortality rates of individuals with ME/CFS
were not significantly different from standardized mortal-
ity rates (33, 34).
Children
The long term prognosis in children is generally better
than in adults even in those with severe disease. Even
those who report being in remission do not perform as
well as controls. Children with ME/CFS may have been ill
for such a long time that they do not remember what it
was like to be well and normal (35–38).
Economic costs of ME/CFS
ME/CFS is a severely debilitating chronic disease. As a
result there is a tremendous burden for patients and their
caregivers, as well as the health care system. Unemploy-
ment rates among those with the disorder ranged from
35% to 69%. One study found that as a result of ME/CFS,
individual income losses of approximately $20,000 annu-
ally occurred in households (39, 40).
There is a huge economic cost for the individual, their
family and for society. The annual direct medical costs per
ME/CFS patients ranges from $2342 in a community-based
sample (previously undiagnosed) to $8675 in a tertiary
sample (already diagnosed).
The Canadian Community Health Survey of 2005
and 2010 documented that patients with ME/CFS are sig-
nificantly impaired compared with Canadians with other
chronic conditions such as cancer and heart disease.
Patients with ME/CFS reported high levels of permanent
inability to work, needing help with activities of daily living
and high number of consultations with doctors (10+ per
year). They reported high rates of unmet health care and
home care needs and high levels of moderate or severe food
insecurity. A sizeable proportion report income and pro-
ductivity loss of $20,000 per patient, and many report an
annual household income  < $15,000 (18, 32, 41).
The direct and indirect economic costs of ME/CFS
to society are estimated to be in the billions: somewhere
between $18 and $24 billion annually in the US (41).
Why do doctors have difficulty
making the diagnosis of ME/CFS
intheir patients?
Insufficient training: Most medical schools do not
teach about ME/CFS to their medical students.
Medical textbooks are not up to date in this area
of medicine. Doctors, both general practitioners
and specialists, have not been taught about ME/
CFS in a formal systematic fashion as was done
in the past with emerging diseases such as HIV/
AIDS. As a result of poor practitioner training
about ME/CFS,it takes patients many years to get a
diagnosis,but this problem can be solved with edu-
cation. It is estimated that only 20% of the people
sufferingwith ME/CFS have been actually diagnosed
(42,43).
Fatigue: as a symptom comprises 25% of primary care
physicians’ appointments (4, 44).
Multiple Clinical and Research Definitions (2, 42).
How to make the diagnosis of ME/
CFS using the Canadian consensus
criteria
Exclusion of treatable diseases
The first step is to rule out all of the treatable active dis-
eases that cause: fatigue, sleep disturbance, cognitive
dysfunction and pain (see Table 1). If the symptoms of
ME/CFS are the result of another treatable condition the
diagnosis of ME/CFS should be deferred until the treat-
ment is attempted. Sometimes it turns out that treat-
ment of the other conditions e.g. sleep apnea causes
a partial improvement but the symptom cluster and
severity of ME/CFS remains and the diagnosis can still
be made.
Laboratory tests and investigations used to rule out
the treatable chronic diseases include the following (see
Tables 2 and 3).
The purpose of testing is to rule out other conditions
which may account for any of the symptoms of ME/CFS.
Routine testing cannot rule in ME/CFS however, there are
specialty tests available through research centres which
can be very helpful.
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Table 1:Exclusion of treatable active disease with laboratory tests or investigations.
Endocrine disorders Rheumatological diseases: Systemic Lupus,
Rheumatoid Arthritis, Polymyalgia Rheumatica
Anemia: Iron deficiency, other treatable forms
Addison’s disease Infectious Diseases: HIV, Lyme Disease, TB,
Chronic Hepatitis,
Iron Overload
Cushing’s syndrome Substance Abuse Severe obesity (BMI>)
Diabetes Neurologic Disorders: MS, Parkinson’s
Disease, Myasthenia Gravis, B deficiency
Cancer
Hypothyroidism hyperthyroidismPrimary Psychiatric Disorders Treatable Sleep Disorders: Apnea, Narcolepsy
Table 2:Investigation of ME/CFS: routine laboratory testing.
– complete blood count and differential
– erythrocyte sedimentation rate and C-reactive protein
– iron studies: serum iron, iron-binding capacity, ferritin
– vitamin B and serum folate
– electrolytes: sodium, potassium, calcium, phosphate, magnesium
– fasting glucose
liver function: bilirubin, alkaline phosphatase (ALP), gamma
glutamyl transaminase (GGT), alanine transaminase (ALT),
aspartate transaminase (AST) (probably GGT is a good single
screening test)
renal function: creatinine clearance, urea, glomerular filtration
rate (eGFR), albumin/globulin ratio
thyroid function: thyroid stimulating hormone (TSH), free
thyroxine (T), free thyroxine
– creatine phosphokinase (CPK)
– -hydroxy-cholcalciferol (Vitamin D)
– urinalysis
infectious disease screen HIV, hepatitis, Lyme disease, Q fever,
etc.
– Microbiology: stools, throat, urine, sputum, genital
– am and pm cortisol
– renin/aldosterone ratio
– ACTH
– prolactin
– testosterone
– rheumatoid factor
– serum amylase
– urine drug screen for substance abuse
– MRI if multiple sclerosis suspected
– tilt table test for autonomic function – if available
Table 3:Investigation of ME/CFS: additional tests to be considered depending on symptoms.
– Cardiac: chest x-ray, electrocardiogram (EKG/ECG), tilt table test for autonomic function
– Endocrine/Metabolic: short ACTH challenge test or cortisol stimulation test, parathyroid hormone, estradiol, follicle-stimulating hormone,
– Gastrointestinal: endoscopy: gastroscopy, colonoscopy; gastric emptying study, gliadin and endomysial antibodies
Infectious Diseases: screen for HIV, hepatitis, Lyme disease, Q fever and microbiology of stools, throat, urine, sputum, genital as
appropriate
– Immunology/Autoimmunity: antinuclear antibodies, total and subclass immunoglobulins, functional antibodies and lymphocyte subsets
– Neurological: MRI if multiple sclerosis suspected
– Pulmonary: overnight polysomnogram and possibly multiple sleep latency test
– Urinary: cystoscopy
Co-morbid conditions
A number of co-morbid (non-exclusionary) conditions
may co-exist with ME/CFS. These conditions include:
fibromyalgia, multiple chemical sensitivity, orthostatic
intolerance, irritable bowel syndrome, irritable bladder
syndrome, interstitial cystitis, sicca syndrome, temporo-
mandibular joint syndrome, migraine headache, aller-
gies, thyroiditis, Raynaud’s phenomenon and prolapsed
mitral valve. These conditions should be investigated in
their own right and treated appropriately (45).
ME/CFS clinical diagnostic canadian
consensus criteria (3)
In order to make the diagnosis of ME/CFS the patient must
have the following criteria:
Fatigue
Post-Exertional Fatigue and Malaise
Sleep Dysfunction
Pain
Cognitive Dysfunction
At least one Symptom from Two of the Following
Categories:
Automatic Nervous System Dysfunction
Neuroendocrine Dysfunction
Immune Dysfunction
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228 Bested and Marshall: Review of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Illness length is chronic:
Adults 6 months
Children 3 months
See Appendix 2 for the CCC ME/CFS diagnostic criteria
worksheet that can be used in your office. The pediatric
definition worksheet is Appendix 3.
Fatigue
In ME/CFS the fatigue is “pathological” or abnormal,
more intense and different from normal tiredness. It may
combine cognitive and physical exhaustion, weakness,
heaviness, general malaise, lightheadedness and sleepi-
ness. It can also include the symptom “wired fatigue” in
which adrenaline is pumping in the presence of severe
fatigue. It is of new onset, not explained by another diag-
nosis, persistent, has both physical and mental compo-
nents. The patient’s activity level is reduced by 50% or
more. There are ranges of fatigue that patients describe,
most often from severe to completely bedridden. The
attached validated Functional Capacity Scale in Appen-
dix 1 assists you and your patient to communicate about
fatigue and other symptom severity.
The vitality (VT) subscale of the Medical Outcomes
Study (MOS)-Short Form-36 (SF-36) questionnaire is used
to assess function including mental and physical func-
tion (30, 32). The SF-36 includes four questions concern-
ing energy; being full of life/pep, feeling worn out, or
feeling tired. The higher scores indicate greater vitality
(46). VT scores are consistently much lower in ME/CFS
patients with and without comorbidities than in healthy
controls and patients with other chronic illnesses. While
Jason and Brown demonstrated that the VT scores of ME/
CFS patients ranged from 15 to 25 depending on subtyp-
ing strategies, other domains often are affected as well
and were reliable reflections of fatigue in patients with
ME/CFS (47). The RAND-36 is an alternative version of the
SF-36 and is freely accessible with a complex scoring algo-
rithm that is available online (13).
Post–exertional fatigue and malaise (PEM)
This symptom, PEM, is considered one of the distinguish-
ing symptom of ME/CFS. It helps differentiate ME/CFS
from other conditions in which patients feel better after
exertion such as depression. PEM refers to severe physical
or mental/cognitive post-exertional fatigue. This means
that there are worsening of symptoms after minimal phys-
ical or mental/cognitive exertion. For example, the patient
does not recover after normal activities of daily living such
as: brushing their teeth, taking a shower or doing emails
on the computer for 15 min. The mental fatigue or cogni-
tive dysfunction – what patients describe as “brain fog”
– includes: poor concentration, groping for words and
poor short-term memory. The fatigue may also include
malaise or flu-like feelings and/or pain and worsening of
the patient’s other associated symptoms. There is a patho-
logically slow recovery period that lasts anywhere from
24h to weeks. The patient may become bedridden during
this “crash” period. A “crash” is an episode of immobiliz-
ing post-exertional physical and/or mental fatigue and
malaise.
Sleep dysfunction
The patient’s sleep is unrefreshing. This may be due to dif-
ficulty falling asleep, multiple interruptions while trying
to sleep or the sleep rhythm is chaotic and sometimes
reversed. There may be daytime hypersomnia (exces-
sive sleep) especially early in the illness and in younger
patients. Sleep problems are chronic and the dysfunction
worsens during a “crash” period. A subset of as many as
20% of patients have sleep apnea, upper airway resistance
syndrome, restless leg syndrome or other treatable sleep
disorders. An overnight sleep study may help to discern
specific problems.
Pain
There is a significant degree of myalgia and joint pain that
is often migratory. The pain is chronic and may range from
mild to severe and often meets the criteria for Fibromyal-
gia. There may be significant headaches that are a new
type, pattern or severity.
Neurological/cognitive dysfunction
Cognitive function worsens with fatigue. To qualify for
this criteria, two or more of the following symptoms must
be present: confusion, impaired concentration, poor
attention, slowed processing of information, poor short-
term memory, disorientation to place, difficulty with
categorizing and impaired word retrieval. This cognitive
dysfunction is often described by patients as “brain fog”.
Neurocognitive impairment involving concentration and
memory are cited as some of the most disruptive and func-
tionally disabling symptoms of ME/CFS.
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Ataxia, muscle weakness and fasciculations are
common. Patients have difficulty with inaccurate body
boundaries. This may result in patients having clumsi-
ness and walking into doorjambs while walking through
a doorway or losing their balance while walking down
stairs. Difficulty with depth perception and focusing of
their vision can make it difficult to walk, for example, on
uneven/rough surfaces.
There may be overload phenomena, where patients
with ME/CFS are hypersensitive to sensory stimulation
including: bright lights, noise, odors and temperature
extremes. This makes it difficult for patients to attend
social functions and go into public places. Some patients
with ME/CFS lose the ability to screen out and ignore
extraneous stimuli similar to a deaf person at a party with
a hearing aid that cannot screen out the background noise.
The additional stimulation causes mental exhaustion and
patients “crash” as a result. Patients can also become
emotionally overloaded which can lead to anxiety.
At least one symptom from two of the following categories
Autonomic dysfunction manifestations
Autonomic dysfunction is an umbrella term for various
conditions in which the autonomic nervous system (ANS)
malfunctions.
The autonomic nervous system (ANS) provides the
unconscious control by the brain of the basic bodily func-
tions including: heart rate, body temperature, breathing
rate, digestion, bladder and sexual function and other
systems. The ANS is composed of two opposing subsys-
tems: the sympathetic autonomic nervous system (SANS)
and the parasympathetic autonomic nervous system
(PANS). Most organs have nerves from both the sympa-
thetic and parasympathetic systems.
The SANS usually stimulates organs: it increases heart
rate and blood pressure when necessary. It causes the
fight or flight reaction when in danger. The PANS usually
dampens down bodily processes and is often referred to as
the relaxation response. For example, it reduces heart rate
and blood pressure. It provides rest and digest reactions,
and stimulates urination.
Symptoms of Autonomic Dysfunction:
Dizziness and fainting upon standing up (orthostatic
hypotension, POTS)
Inability to alter heart rate with exercise (exercise
intolerance)
Sweating abnormalities, which could alternately be
too much sweat or insufficient sweat
Digestion difficulties due to slow digestion. Resulting
symptoms could include loss of appetite, bloating,
diarrhea or constipation, and difficulty swallowing.
Urinary problems. These can include difficulty start-
ing urination, incontinence, and incomplete empty-
ing of the bladder
Sexual problems. In men, this could be difficulty
with ejaculation and/or maintaining an erection. In
women, this could be vaginal dryness and/or diffi-
culty with orgasm
Vision problems. This could be blurry vision, or
the failure of the pupils to react quickly enough to
changes in light.
Any or all of these symptoms may be present in patients
with ME/CFS and range from mild to severe.
Chronic Orthostatic Intolerance: is the inability to
sustain upright activity including: sitting, standing or
walking. The most symptoms in ME/CFS include: over-
whelming exhaustion, an urgency to lie down, feeling
faint, mental confusion, malaise and the worsening of
other symptoms. The symptoms are relieved when reclin-
ing. Patients, like Case CL, often develop these symptoms
when standing waiting in line e.g. at the bank.
Documentation of Orthostatic Intolerance: can be done
in the office setting by first setting a baseline blood pressure
by measuring the BP after the patient lies supine for 5 min.
Next the patient stands still for 10min and does not move
their legs. BP and heart rate are taken every 2min for 10
min. Symptoms such as fatigue, lightheadedness, nausea,
warmth, shortness of breath, headache, pain, reduced con-
centration/brain fog are recorded on a 0–10 scale when the
patient is supine and then every few minutes when stand-
ing still. The patient must be monitored at all times due to
the possibility of syncope and falling injuries. A positive
test documents a drop in blood pressure, increase in heart
rate, color or volume changes in the lower legs or the pres-
ence of symptoms of orthostatic intolerance.
Subtypes of Chronic Orthostatic Intolerance:
a. Neurally mediated hypotension (NMH) is an abnor-
mality in the regulation of blood pressure during upright
posture. There is a drop in systolic BP of 20–25mm Hg
(compared to the BP measured when the person is lying
flat) when standing still. Symptoms may include light-
headedness, dizziness, pressure-like chest pain over
the left chest, visual changes, weakness, slowed verbal
response, pallor, an urgency to lie down and syncope.
b. Postural orthostatic tachycardia syndrome (POTS)
is present when the heart rate increases by 30 beats per
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230 Bested and Marshall: Review of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
minute (bpm) for adults, or 40 bpm for adolescents, or
if it reaches 120 bpm or higher over the first 10min of
standing. Symptoms may include: lightheadedness,
dizziness, nausea, fatigue, tremor, irregular breath-
ing, headaches, visual changes, sweating, and rarely
syncope. POTS is an abnormality in the autonomic
regulation of heart rate; the heart itself is usually nor-
mal. The increased heart rate may be accompanied by
a fall in blood pressure, neurally mediated hypoten-
sion, while standing. The two conditions, POTS and
NMH, often are found together and can cause chronic,
daily, orthostatic symptoms.
c. Delayed postural hypotension happens when there
is a delayed drop in blood pressure 10 min or more
after the patient stands.
Neuroendocrine manifestations
Hypothalamic-pituitary-adrenal axis dysfunction is asso-
ciated with dysfunction of the autonomic and immune
system. This results in loss of thermostatic stability with
marked intolerance to heat or cold. There may be marked
diurnal fluctuation, sweating episodes and recurrent
feeling of feverishness and cold extremities. Patients often
experience worsening of their symptoms during changes
of the weather (when storms are coming) and are often
worse in the winter months when the weather systems
change more frequently. There may be marked weight
change with some patients experiencing a loss of appetite
(anorexia) and others having an increased appetite.
Patients with ME/CFS have loss of adaptability and
tolerance for stress. Things they could easily handle before
their illness become stressful. Stress builds with physical,
mental or emotional exertion beyond their available enve-
lope of energy. Stress may cause symptom relapses and
anxiety/panic attacks or may be part of the overload phe-
nomenon. Recovery is slower than normal.
Immune manifestations
Some patients have symptoms from immune system acti-
vation and these include general malaise or flu-like feel-
ings and feeling feverish. It is more prominent at the outset
and may decrease over time. Flu-like symptoms often recur
during times of post exertional malaise. Tender lymphad-
enopathy in the cervical axillary, inguinal or other areas
may be present. Patients may have recurrent sore throats
with non-exudative pharyngitis with bilateral crimson
(red) crescents visible in the anterior pillars (palatoglos-
sal arches) of the soft palate. The erythema may extend
and include the uvula.
There may be new sensitivities to food, medications
and/or chemicals. Much smaller doses of medications are
needed in some patients. Some patients develop environ-
mental sensitivities/multiple chemical sensitivity (ES/
MCS) and react adversely to multiple unrelated chemicals
in their environment with a range of symptoms. These
reactions cause patients to withdraw from social and
public events in an effort to avoid becoming unwell. This
leads to social isolation.
The illness persists for at least 6months in adults
It usually has a distinct onset, although it may be gradual.
Preliminary diagnosis may be possible earlier. Three
months is appropriate for children and adolescents.
Suggestive physical signs and symptoms
The following signs are suggestive of ME/CFS but are not
specific for it. Physical signs are more prominent at the
beginning of the illness before patients have had a chance
to learn how to accommodate their life to the illness and
stay within their energy envelope. Patients look tired.
They have drooped postures and slouch with rounded
shoulders when sitting in a chair. Some patients need
to lie down on the examination table while they wait to
be seen. Others come in wheelchairs. The totally bedrid-
den patients cannot come for office visits and need to be
seen at their home. Some patients have periorbital shiners
indicating allergies and puffy eyes indicating fatigue or
edema. They may have a sore throat and examination of
their throat shows crimson or red crescents. These are seen
during a crash and viral vesicles can also sometimes be
seen indicating viral reactivation. This may be accompa-
nied by tender lymphadenopathy in the cervical, axillary
and inguinal areas. Examination of the pupils may show
oscillation of the pupils or diminished pupillary accom-
modation. The imbalance of the central sympathetic and
parasympathetic nervous system in may be the underly-
ing mechanism (48).
Measurement of the blood pressure may show a drop
when changing from a lying to standing position when
orthostatic hypotension is present. There may be other
features of automatic dysfunction including an increase
in pulse indicating Postural Orthostatic Tachycardia Syn-
drome (POTS). There may be abdominal bloating and
tenderness as part of the irritable bowel symptoms. Exam-
ination of the central nervous system may show hyper-
sensitivity to vibration sense, a positive Romberg test
and a positive Tandem test. Cognitive dysfunction can be
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Bested and Marshall: Review of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome231
validated by the use of standardized neurocognitive tests
where available. These findings help to confirm the diag-
nosis of ME/CFS.
Some patients also have Fibromyalgia in addition to
ME/CFS and have positive tender points on examination.
Etiology and pathophysiology
ofME/CFS
A specific cause of ME/CFS has not been found and
there is no clinically available diagnostic test. Prior to
having ME/CFS, most patients were healthy, fully func-
tional and had active social lives. 50%–80% of patients
with ME/CFS started suddenly with a flu-like illness,
from which the patient never recovered. ME/CFS is com-
monly found after an infection by a virus, bacteria or
parasite.
The pathophysiological consequences of ME/CFS are
multi-systemic. Below is a brief overview of the informa-
tion available to date. See the 2015 IOM report for a more
extensive summary (8).
Genetic predisposition
Female gender is a predisposing factor in adults. In
children there is no gender differential. Genealogy
data from three generations of people entered in
the Utah Population Data Base shows an increased
relative risk among first degree relatives 2.70, second
degree relatives 2.34, and third degree relatives 1.93
(49, 50).
Twin studies show a higher concordance in monozy-
gotic (55%) compared to dizygotic (19%) twins (51–54).
A study of gene expression was done that identifies
differential expression of 88 human genes in patients
with ME/CFS. Clustering of quantitative PCR data
from patients with ME/CFS reveals seven distinct sub-
types with distinct differences in Medical Outcomes
Survey Short Form-36 scores, clinical phenotypes and
severity (55).
A study was done using single-nucleotide polymor-
phism (SNP) analysis to identify subtypes of ME/CFS
with distinct clinical phenotypes. Twenty one SNPs
were significantly associated with ME/CFS compared
with depressed and normal groups. One hundred and
forty eight SNP alleles had a significant association
with one or more ME/CFS subtypes (56).
Infection
ME/CFS can be triggered by viral, bacterial or para-
sitic infections.
Prospective studies found ME/CFS in 11% of people
with severe infections following: Epstein Barr virus
(EBV), non-EBV associated glandular fever, Ross River
virus, Giardia lamblia, parvovirus B19, and Q fever
infections.
Prodromal infections included sinusitis, bronchi-
tis, gastroenteritis, flu-like illness or parasites e.g.
giardiasis (57–60).
Immune system dysfunction
The pathological fatigue that is present in ME/CFS is multi-
factorial and based on several dysfunctional body systems
that contribute to the patient’s overall feeling and level of
fatigue. These dysfunctional body systems include the
following: immune, cognitive, sleep, autonomic nervous
system, mitochondrial dysfunction and biochemistry.
“Malaise” is a general body discomfort or weakness,
often marking the onset of an of infection/flu-like illness or
other disease. Fatigue and flu-like symptoms are linked to
activation of the immune system and research scientists are
in the process of unraveling these mechanisms in ME/CFS.
Immune system changes in ME/CFS
The immune system abnormalities in patients with ME/
CFS are diverse and tend to wax and wane over the course
of the illness and with the severity of the symptoms.
Some abnormalities are present at the onset but decrease
over time and are reinitiated during symptom flares or
“crashes”. The immune findings are not specific to ME/
CFS and are found in other diseases.
There is strong evidence of immune dysfunction in
ME/CFS. Fatigue and flu-like symptoms may be linked to
elevated levels of various cytokines, including interferons
and interleukins. In addition lower cognitive function is
significantly related to low NK cell function. The dysreg-
ulation of the RNase L pathway supports the hypothesis
that viral infection may play a role in the pathogenesis of
the illness. The IOM’s 2015 Report concluded that there
was “sufficient evidence to support the finding of immune
dysfunction in ME/CFS” (61, 62).
T helper cells (Th cells) trigger and direct immune
cells as part of the body’s immune system. They can dif-
ferentiate into two sub-types: Th1 and Th2 cells. Th1 cells
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232 Bested and Marshall: Review of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
are involved in producing the body’s cellular immunity.
Th2 cells are instrumental in humoral immunity (produc-
tion of antibodies), mucosal immunity and the allergy
response (63–65).
T-helper 2 shift in Cellular Immunity: Dominance
of humoral over cell-mediated immunity. Patients are
more prone to the development of new allergies to
medications, food and environmental chemicals and
multiple chemical sensitivity (66, 67).
Low natural killer (NK) cell cytotoxicity: NK cells
are part of the innate immune system and provide
surveillance against tumor cells and infections and
host rejection of bone marrow transplants. Patients
with ME/CFS have poorly functioning NK cells. The
poor NK function correlates with the severity of ill-
ness and disturbed cognitive function in patients
with ME/CFS (68–72). Low NK cytotoxicity is also
found in rheumatoid arthritis, cancer, HIV, MS,
SLE, smokers, major depressive disorder and sleep
deprivation.
Activation of Cytokines: There is imbalance in the
regulation of immune function as illustrated by the
study of cytokine networks by Broderick etal. These
cytokine networks were significantly different in geo-
metrical arrangement, more than expected by chance.
The ME/CFS network is more hub-like in configura-
tion compared to healthy controls (HC). The cytokine
changes in ME/CFS are subtle and not shown by
measuring individual cytokine levels. The distinction
between the ME/CFS patients and healthy controls is
displayed by the hub-like configuration showing dif-
ferences in the relationships between the cytokines in
patients with ME/CFS. “These observations are con-
sistent with several processes active in latent viral
infection and would not have been uncovered by
assessing individual marker expression alone” (73).
See Figure 1.
CFS patients who experienced significant symptom
flare post-exercise showed increased cytokines at the
8h post-exercise (74).
Daily fatigue severity was significantly correlated
with inflammation in a study of adipokine lep-
tin in women with CFS and not in the controls. A
machine learning algorithm differentiated high
from lowfatigue days in the CFS group with 78.3%
accu racy (75).
Hub
Figure 1:Cytokine co-expression networks were constructed from the pair-wise mutual information (MI) patterns found within each subject
group. Networks for HC and CFS had visibly different topologies (geometric arrangements). A weighted spring-electrical embedding struc-
turally reveals the subject-subject (inset) and cytokine-cytokine associations based on measurements in 59 healthy control subjects (A) and
40 CFS patients (B). All edge weights are significant at p0.01. Separation of subjects was consistent with their assignment to diagnos-
tic groups supporting the use of within-group variation in the estimation of mutual information for cytokine-cytokine associations (73).
Diagram used with permission.
Broderick G, Fuite J, Kreitz A, Vernonb SD, Klimas N, Fletcherd MA. A Formal Analysis of Cytokine Networks in Chronic Fatigue Syndrome.
Brain Behav Immun 2010;24(7): 1209–1217. doi:10.1016/j.bbi.2010.04.012.
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Bested and Marshall: Review of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome233
Another case control study showed that early ME/CFS
cases had a prominent activation of both pro- and
anti-inflammatory cytokines as well as dissociation of
intercytokine regulatory networks. The newer ME/CFS
cases had stronger cytokine variation compared to the
patients who were ill longer. These findings suggest
that the immunopathology of ME/CFS changes with
time (62).
A positron emission tomography study measured a
translocator protein expressed by activated microglia
or astrocytes. This ligand was elevated in patients
with ME/CFS demonstrating that neuroinflammation
Figure 2:Pathways associated with secondary fatigue. Prolonged
and or excessive stimulation of membrane bound Toll-like receptors
(TLRs) results in the production of pro-inflammatory cytokines (PICs)
and reactive oxygen and nitrogen species (O&NS) at sufficiently
high concentrations to cause macromolecule damage leading to the
production of redox-derived damage-associated molecular patterns
(DAMPs). The presence of such DAMPs leads to chronic engagement
of TLRs and a spiraling, self-amplifying pattern of increasing ROS/
RNS and PICs in a TLR radical cycle. Increasing levels of ROS/RNS
damage mitochondrial lipids and proteins leading to dissipation of
the mitochondrial membrane potential and inhibition of the electron
transport chain. This leads to compromised oxidative phosphoryla-
tion and the production of ROS making another major contribution
to the inflammatory milieu and another element in the develop-
ment of a vicious spiral of bioenergetics decline. Elevated levels of
PICs in the periphery activate microglia and astrocytes in the brain
leading to the production of elevated PICs and ROS/RNS causing
mitochondrial and metabolic dysfunction (77). Diagram is used with
permission.
Morris G, Berk M, Walder K, Maes M. Central pathways causing
fatigue in neuroinflammatory and autoimmune illnesses BMC Medi-
cine (2015) 13:28. DOI 10.1186/s12916-014-0259-2.
was present in widespread brain areas in CFS/ME
patients versus healthy controls (76).
Figure 2 illustrates the possible interactions of periph-
eral inflammation and immune activation, together
with the subsequent activation of glial cells and
mitochondrial damage. Together these findings may
account for the severe levels of intractable fatigue and
disability seen in many patients with a diagnosis of
ME/Chronic Fatigue Syndrome.
Dysregulation of antiviral defense pathway ribonuclease
L/2–5A synthetase (RNase L)
An abnormally low molecular weight (small size) 37
kilo Dalton (kDa) RNase L is produced
the purpose of normal RNase L is to kill RNA in cells,
both cellular and virus
it is not turned off in the normal negative feedback
loop
RNase L continually destroys cell membranes includ-
ing mitochondrial membranes causing leaks which
lead to cellular damage and dysfunction (78).
Antibodies in ME/CFS
ME/CFS has been reported to be associated with auto-
immune disorders: hypothyroidism and Sjogren’s
syndrome.
Antibodies found include: antinuclear antibodies,
rheumatoid factor, and thyroid antibodies. The sig-
nificance of this is unknown.
Antibodies are also found to viruses: Epstein Barr,
Cytomegalovirus, Human Herpes Virus 6, Parvovirus,
etc. The viruses may become reactivated with elevated
antibodies due to impaired immune surveillance (79).
Post exertional malaise/fatigue (PEM)
Post Exertional Malaise (PEM) Definition: PEM is the
exacerbation of a patient’s symptoms and deterioration in
function after physical or cognitive effort that was easily
tolerated premorbidly. The cardiopulmonary exercise
test (CPET) is used to assess exercise capacity (maximal
oxygen consumption or VO2 max) and provides objective
and reproducible indices of functional capacity for cardio-
vascular and pulmonary disease.
“Energy for physical activities is produced through
two physiological systems: 1) Anaerobic metabolism is
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234 Bested and Marshall: Review of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
thepredominant metabolic pathway during the first 90s
of exercise; 2) The aerobic/oxidative system is the primary
source of energy during physical activities lasting longer
than 90 s. Because most daily physical activities exceed
90 s, the aerobic system is typically utilized to produce
the energy-releasing nucleotide adenosine triphosphate
(ATP), at a steady rate in order to perform activities of
daily living. In patients with ME/CFS, aerobic metabolism
may be impaired. Thus, any physical exertion exceeding
90 s may utilize a dysfunctional aerobic system, which
leads to increased reliance on anaerobic metabolism. This
imbalance may be linked to the prolonged symptoms and
functional deficits associated with PEM” (80).
Research studies showed that whereas patients with
other conditions including severe cardiac and pulmonary
disease are able to replicate their performance on a CPET
on two consecutive days, patients with ME/CFS showed
decreased functional capacity on the second testing day
despite maximal effort both days. Second day decrements
found in ME/CFS included: VO2max, VO2 at ventilatory
threshold and maximal workload or workload at ventila-
tory threshold. VO2max measured during repeated CPETs
was shown to be reliable with the test-retest showing a dif-
ference of  < 7%. The 2 day CPET testing provided objective
evidence that corroborated ME/CFS patients’ subjective
reports of impaired functionality with PEM, impaired cog-
nitive function, and validated the severity and duration of
their PEM.
It is hoped by the authors that this test will move
from research studies into clinical use. Further testing is
required to identify which patients with ME/CFS show this
unique finding. If found to be diagnostic, the creation of
a certified training program for personnel with standard-
ized ME/CFS 2 day CPET protocol and with built in quality
assurance measures (to standardize the CPET reliability of
the 2 day testing) is needed. This test is not suitable for
bedridden patients who would not be able to tolerate the
testing. Perhaps in the future a modification of the test
will be created (81–84).
The role of impaired aerobic metabolism in produc-
ing pathological fatigue, post-exertional malaise and a
prolonged recovery time is still being evaluated. Several
mechanisms may be involved and patients may have a
variety of abnormalities.
Mitochondrial/energy production
abnormalities
Several studies have shown evidence of impairment
of oxidative phosphorylation including decreased ATP
production by the mitochondria resulting in reduced
aerobic energy production. This may be due to lack of
essential substrates and interference in mitochondria
function by inflammatory molecules (85–88).
The patients’ physical and mental exertions can
exceed patients’ anaerobic threshold; but patients have
faulty aerobic metabolism. As a result the anaerobic meta-
bolic pathways are used by these patients. The anaero-
bic pathways are produce less energy and also cause the
production of lactic acid and a disturbance of ATP/ADP
metabolic cycling (86, 89, 90). Evidence for mitochon-
drial abnormalities includes: mitochondrial myopathy,
impaired oxygen consumption during exercise; activation
of anaerobic metabolic pathways in the early stages of
exercise and raised brain ventricular lactate levels (91–95).
In other patients with ME/CFS low mitochondrial ATP
levels may be present with normally functioning mito-
chondria. This may result from the brain’s autonomic
dysfunction causing decreased circulating blood volume
resulting in decreased transportation of oxygen to the cells
and mitochondria in patients with ME/CFS and resulting
fatigue (85).
Cognitive dysfunction
Cognitive dysfunction is present in the vast majority of
patients with ME/CFS. Reported symptoms include slowed
information processing, memory impairment, attention
deficits, and impaired psychomotor function as measured
by a range of neuropsychological tests (see Figure 3). This
cognitive dysfunction can be severe enough to impair or
prevent ability to work.
An electroencephalogram (EEG) study was done on
50 CFS patients and age matched controls. The EEG data
and exact low-resolution electromagnetic tomography
(eLORETA) results showed widespread cortical hypoacti-
vation in CFS patients as demonstrated by increased delta
and decreased beta2 frequency bands. These findings pro-
vided objective quantification of central nervous system
dysregulation in CFS patients (99).
Quantitative electroencephalogram (QEEG) is another
tool (in addition to neuropsychological tests) that shows
abnormalities in patients with ME/CFS. The same research
group did a pilot study using quantitative EEG (qEEG) and
peak alpha frequency in CFS patients to look at the cogni-
tive impairment known as “brain fog” in 50 CFS patients
and 50 age matched healthy controls. The alpha fre-
quency is associated with cognitive and memory perfor-
mance. The results found decreased peak alpha frequency
(PAF) in 58% of the cortex in CFS patients compared to
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Bested and Marshall: Review of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome235
controls. qEEG and PAF measurements of cognitive fog
and fatigue may have prognostic value in evaluating CFS
patients(100).
Sleep dysfunction
Unrefreshing sleep, or feeling just as tired when waking up
as when going to bed, is among the most common symp-
toms reported by ME/CFS patients. Overnight sleep studies
(polysomnographic studies) show that patients with ME/
CFS have decreased sleep efficiency, decreased total sleep
time and reduced time spent in deep restorative– delta
wave sleep. Sleep can also be disturbed as a result of mul-
tiple arousals with alpha (awake EEG rhythm) wave intru-
sions during sleep on the overnight sleep study (101104).
Prob
lems remembering
Difficulty expressing thoughts
Difficulty paying attention
Difficulty understanding
Absent-mindedness
Slowness of thought
80%
Memory and concentration problems
73%
69%
66% 68%
55%
7% 7%
5%
2% 2% 2%
Figure 3:is used with permission (96). The percentage of CFS
patients and controls who reported frequency and severity scores
of neurocognitive manifestations of at least moderate severity that
occur at least half of the time for symptoms specified by the Fukuda
etal. criteria (96–98).
Jason LA, Sunnquist M, Brown A, Evans M, Vernon S, Furst J, Simonis
V. Examining case definition criteria for chronic fatigue syndrome
and myalgic encephalomyelitis. Fatigue: Biomedicine, Health &
Behavior 2013;2(1)40–56.
Stage shifts and dynamic stage transitions have
been shown to discriminate between ME/CFS patients
and healthy controls. The emergence of new, more sensi-
tive techniques that examine the microstructure of sleep
are showing promise for detecting differences in sleep
between patients and healthy individuals. There is prelim-
inary evidence that alterations in sleep stage transitions
and sleep instability may be evident (105).
A recent polysomnographic study of CFS patients
showed that they mainly differ in sleep fragmentation and
slow wave sleep (SWS) durations. They found lower pro-
portions of very slow oscillations during SWS in Primary
Insomnia and CFS. They found normal or increased SWS
durations but lower proportions of ultra slow power. Their
findings suggest a possible quantitative compensation of
altered homeostatic regulation in CFS (106).
The diagnosis of a primary sleep disorder does not
rule out a diagnosis of ME/CFS as both can be present in
the same patient. As many as 20% of patients with ME/
CFS have a primary sleep disorder. However, even when
optimally treated, they continue to have symptoms of ME/
CFS. In these cases both diagnoses should be made.
Pain
The majority of patients with ME/CFS have pain of varying
types and severity. See Figure 4.
Pain is often part of an ME/CFS patient’s symptom
cluster that is triggered by physical and/or mental activity
and part of the post-exertional malaise (PEM). The types
of pain and severity of the pain vary. It could be disabling.
The most common pain is described as muscle aches and
pains, joint pain, and headaches. Less common are tender
lymph nodes, sore throats, abdominal pain, eye and chest
pain (96, 107–109).
Autonomic dysfunction
Autonomic dysfunction is thought to be centrally medi-
ated as part of the brain dysfunction found in ME/CFS and
can be seriously disabling (110–112).
Documented studies of autonomic dysfunction in ME/
CFS have included:
Tilt table testing – available in large centres to sub-
type orthostatic intolerance (113). The severity of
orthostatic symptoms predicts the functional status
of patients with ME/CFS (114) and may cause relapse
of symptoms. Patients with low energy,   3/10 on the
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236 Bested and Marshall: Review of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
functional capacity scale are not suitable for this type
of testing.
Heart rate variability (available at specialist centers)
is abnormal in patients with ME/CFS with increased
sympathetic nervous system tone and decreased par-
asympathetic tone (114, 115).
24 h Holter monitoring may reveal benign car-
diac rhythm disturbances and non-specific T wave
changes, repetitive oscillating T-wave inversions and/
or flat T-waves. On the EKG requisition, clinicians
must ask the technician to document the presence
of oscillating T-wave inversions or T-wave flattening
in the report or they will be reported as non-specific
Twave changes (116).
Low blood volume has also been found in patients
with ME/CFS by between 10% and 15% compared to
controls (117, 118). This is likely related to the orthos-
tatic symptoms.
Ehlers-Danlos syndrome and joint hypermobility is
higher in ME/CFS patients than in healthy controls
and is associated with orthostatic intolerance (119).
Neuroendocrine dysregulation
One or more of the following neuroendocrine abnormali-
ties has been found in studies of patients with ME/CFS:
Reduced function of the HPA axis, which can affect
adrenal, gonad, and thyroid function (93, 120).
Raised levels of neuropeptide Y (released in the brain
and sympathetic nervous system following stress),
possibly linked to the dysfunction of the HPA axis.
Neuropeptide Y levels in plasma have been correlated
with symptom severity (121).
Mild hypocortisolism and attenuated diurnal varia-
tion of cortisol (122).
Blunted DHEA response to ACTH injection despite
normal basal levels (123).
Low IGF1 (somatomedin) levels and an exaggerated
growth hormone response to pyridostigmine (124).
Increased prolactin response to buspirone (125).
A disturbance of fluid metabolism as evidenced by
low baseline levels of arginine vasopressin (126).
Relatively lower levels of aldosterone in patients com-
pared with controls (127).
The presence of increased HR and reduced Heart Rate
Variability in ME/CFS during sleep coupled with higher
norepinephrine levels and lower plasma aldoster-
one suggest a state of sympathetic autonomic nervous
system predominance possibly from defective serotoner-
gic signaling in the brain and resulting neuroendocrine
alterations.
Approach to treatment
This section draws heavily from the recommendations
found in ME/CFS: A Primer for Clinical Practitioners
2014 (15, pages 17–27). This is Level V evidence based on
expert clinician opinion. There is no specific treatment
for ME/CFS to date. Therefore we recommend providing
patient-centred, supportive, symptomatic care.
Goals of treatment
Improvement of current symptoms, functioning and
quality of life.
Prevention of worsening symptoms.
Help patients cope with the emotional impact and
grieve the losses that have resulted from having a
chronic, complex, debilitating illness.
10%
aches
Joint pain
Sore
throat
Lymph node
problems
44%
31%
50%
73%
64%
Headaches
7% 1% 0%
12%
Headaches
Joint pain
Sore throat
Tender lymph nodes
Figure 4:Used with permission. The percentage of CFS patients
and controls who reported frequency and severity scores of pain
symptoms of at least moderate severity that occur at least half of
the time for symptoms specified by the Fukuda etal. criteria (96).
Jason LA, Sunnquist M, Brown A, Evans M, Vernon S, Furst J, Simonis
V. Examining case definition criteria for chronic fatigue syndrome
and myalgic encephalomyelitis. Fatigue: Biomedicine, Health &
Behavior 2013;2(1)40–56.
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Bested and Marshall: Review of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome237
Prevention of the development of depression and
potential suicide by managing the physical and emo-
tional issues resulting from ME/CFS.
Prevention of new environmentally-associated ill-
nesses with worsening of the condition, such as mul-
tiple chemical sensitivity.
Treatment/management begins with validation of the
patient’s experience and acknowledging that the patient’s
illness is a real physical disease – ME/CFS. Having a diag-
nosis is the beginning of healing for many patients who
have been told “it’s all in your head” for many years. It is
estimated that only 20% of individuals with ME/CFS have
been diagnosed and even fewer have access to expert
management advice.
Management strategies
Establish supportive therapeutic relationship with
the patient
Educate patient and family about the condition
Collaborate with patient to develop an individualized
treatment program
Empower the patient to trust his/her own experiences
and use his/her symptoms as early warning devices to
avoid PEM relapse/crash
Symptomatic treatment begins with helping patients
cope with their most debilitating symptoms.
Easier office visits
To improve the efficiency of an office visit and clinical
management, we suggest the following:
Request the patient write down their medical history
before the first visit. Patients often forget parts of
their history during an office visit because of physical
fatigue and cognitive dysfunction.
Ask patients to bring a support person (family mem-
ber or friend) with them at each visit to make notes
of what medical advice occurred during the visit for
the patient to review later. Offer to record sessions to
serve as a memory aid.
Give the patient your recommendations in writing
at the end of the visit. They may not remember oral
instructions.
At each follow-up visit have patients write out on a
form you provide the following headings for them to
complete before their next visit:
Improvements from the last visit. Patients may
forget to tell you what has improved unless you
ask. Celebrate their incremental progress with
them. This encourages patients and empowers
them to cope with their chronic illness.
Top 3 most troublesome symptoms. Limit the
number of symptoms dealt with at a visit in order
to avoid overloading the patient and to deal with
the reality of time constraints of an office visit.
All medications and supplements with doses.
Patients do not remember changes.
Begin new medications at a low dose (1/4 the recom-
mended dose) for a few days and increase slowly to a
therapeutic level since patients have increased reac-
tions/sensitivities to new medications.
Schedule ongoing visits on a regular basis. Preferably,
the patient will choose the interval and may alter it as
required.
If new symptoms not in their cluster of symptoms
appear, these should be treated as a newly developing
illness and investigated accordingly.
Schedule an annual follow-up assessment to review
symptoms and severity, a physical exam, a functional
capacity evaluation, routine screening blood tests, and
a review of the patient’s management/treatment plan.
Ensure that all new symptoms are not blamed on
ME/CFS. When new symptoms arise that are not in
the patient’s symptom constellation they should be
investigated.
Complete the private or public insurance forms to
ensure that patients have access to food, shelter
and transportation. Understand the meanings of the
terms “disabled” in these contracts and document the
patient’s degree of disability: partial or total. The long
term prognosis is dependent on the severity of ME/
CFS and the length of time that the patient has had
ME/CFS (30–32).
Management of symptoms
Symptomatic treatment begins with helping patients
cope with their most debilitating symptoms. Assist each
patient to make a symptom list and then prioritize which
are most problematic. Start at the top of the list and work
down. As patients experience benefits they will become
more confident and motivated towards self- management.
Not all patients will improve, but there is potential
for modest to a great degree of improvement for most
individuals.
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238 Bested and Marshall: Review of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Fatigue and Post-exertional Malaise
Patients with ME/CFS experience pathological fatigue and
post-exertional malaise (PEM). When they “overexert” all
their symptoms worsen. The sleep disturbance during a
crash is usually described as “tired but wired”. The body
is physically exhausted, but the brain cannot turn off to
fall asleep due to increased sympathetic nervous system
stimulation (128).
Energy conservation exercise
Many patients were athletic before they became ill and
felt good when they exercised. When patients with ME/
CFS push themselves to exercise they will develop PEM
if they go beyond their body’s available energy enve-
lope. PEM has been documented in patients with ME/
CFS on 2-day bicycle ergometry testing (129). Their faulty
muscle aerobic metabolism does not produce the energy
needed for aerobic exercise. Therefore, patients should
stop if symptoms become worse. Increases in exercise
are advised only when patients feel they are coping with
current activity levels. In ME/CFS any exercise program
must be tailored to the individual patient. In the more
severely ill patients doing activities of daily living, such as
taking a shower, is their exercise (130,131).
Graded exercise therapy
The Oxford criteria for chronic fatigue syndrome were
used to assess graded exercise therapy (GET) and also for
the Cochrane analysis (132). The Oxford CFS criteria do not
exclude patients with psychiatric disorders: depressive
illness, anxiety disorders and hyper-ventilation syn-
drome. It is known that depressed patients improve with
activity. ME/CFS is a physical illness with post-exertional
malaise. As a result of including patients with depression
in the Oxford studies, the studies erroneously concluded
that CFS patients improve with GET. Patients with ME/CFS
have documented PEM on 2 day bicycle ergometry testing.
Therefore GET is contraindicated and can be harmful for
patients with ME/CFS using the CCC criteria (82, 84–86,
129, 133, 134).
Pacing
Pacing is physical energy conservation. Learning to pace
by taking breaks or rests in between activities helps to
prevent relapsing and spending the next few days to a
week in bed recuperating. In this context “rest” means
lying down meditating or sleeping in order to minimize
postural hypotension symptoms. Pacing is described as
staying within the “energy envelope”; staying as active
as possible but avoiding overexertion and crashing.
Pacing is the most effective tool patients have to help
them manage their symptoms. Research shows that those
who stay within their energy envelope have significant
improvements in physical functioning and fatigue sever-
ity compared to those who exceed their envelope (133)
(see Figure 5).
It helps patients learn how to pace to reframe how to
approach getting their daily activities done. When they
were well and wanted to do something e.g. go shopping,
it was simple. They grabbed their wallet and drove to the
mall and shopped for as long as they liked because they
had normal energy. Now their energy is limited and it is
6.4
6.2
6.0
5.8
5.6
5.2
Baseline
Outside envelope
Within envelope
Fatigue severity declines when patients stay within energy envelop
Fatigue severity score
Post-treatment 6-month follow-up
Time
12-month follow-up
5.4
Figure 5:Diagram used with permission (133).
Jason LA, Benton M. The impact of energy modulation on physical functioning and fatigue and severity among patients with ME/CFS. Patient
Education Couns. 2009;77(2):237–241. doi:10.1016/j.pec.2009.02.015.
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much more limited than when they were well. In order to
improve they need to discover their new physical bound-
ary of energy to avoid relapsing. The easiest way to do this
is for them to be aware of their body’s needs by taking a
moment before they go shopping and check in with their
body. Patients can close their eyes and say, “Body, in this
moment do I have the energy to go shopping?” If their
body says “Yes” then they need to figure out their body’s
limits in the present time because this will fluctuate with
good and bad days. Patients can close their eyes and ask
themselves, “For how many minutes can I go shopping?”
Patients can then scroll through the ten times table until
they get a number that is comfortable for their body– for
example 30 min. In order to stay within the energy enve-
lope or physical boundary patients need an external alarm
because as part of their cognitive dysfunction many have
lost their sense of time passing or linear time sense. Ask
them to set the alarm on their cell phone to let them know
when to stop. This takes practice and self discipline. It
allows patients to begin to accomplish more because they
lose less time in bed recovering from a relapse/crash (113,
135). Pacing is not popular with patients. They think they
will never get anything done with this approach. Explain
that accomplishing a small number of tasks consistently is
more productive than accomplishing a lot 1 day and then
taking many days to recover and accomplishing nothing.
This is a huge paradigm shift: thinking of themselves and
putting their needs and their bodies’ needs first.
Using an activity log and recording their daily rou-
tines as they are doing them helps give patients knowl-
edge as to what is working for them. See Activity Log in
Appendix 4 (136).
This is an example of pacing when shopping. Break
shopping into multiple steps: 1) rest at home before
driving the car to the store, 2) drive to the store, 3) rest,
lying down in the car after driving to the store, 4) shop for
30min in the store, 5) rest lying down in the car before
going home, 6) drive home and 7) rest at home.
Pacing can also be applied to cooking and housework.
Functional capacity scale (FCS) ratings from 0 to 10
Fatigue is an imprecise term which is difficult to opera-
tionalize. We wrote the Functional Capacity Scale to better
understand what patients are able to do on a given day.
Before using this scale, when patients said they “felt
better”, they were sent back to work. Much to our dismay
3 months later they had crashed and were much worse
than before. How had this happened? The functional
capacity scale operationalizes what patients can do phys-
ically and mentally on a scale of 0–10 in a given day. It
can distinguish between patients’ good and bad days and
shows their progress over time. See Appendix 1 for the
Functional Capacity Scale.
At the first office visit we introduce the FCS (with a
range of 0–10) to the patient and pick out a higher number
on the scale for a good day and a lower number on the
scale for a bad day. We also determine how many days a
week are good or bad days. Normal energy is 9–10/10. The
level 0 represents a patient in the ICU requiring total bed
care.
Severely ill patients: functional capacity energy
rating 0–3. At this severely low level of energy the
scale ranges from describing patients who are bed-
ridden – 0/10 to patients who can do independent
self-care (washing at the sink) for a few minutes–
3/10. At this level “exercise” consists of exercises to
maintain muscle and mobility and include: range of
motion exercises, stretching and increasing mobil-
ity as tolerated. Patients are bed or house bound.
These activities may be done passively with a few
repetitions to start for the patient by their caregiver
with rest periods before and after as tolerated by the
patient and under the guidance of a professional
who understands ME/CFS so that symptoms are not
triggered by the activity.
Less severely ill patients: functional capacity rat-
ing 4–5. At this low level of energy the scale ranges
from describing patients who are able to do light
housework or walk for a few minutes to patients
who can walk 10–20 min a day. These activities
include range of motion exercises and stretching to
begin with and can be done by the patient in inter-
vals of 90s or less to keep the patient using mainly
their anaerobic metabolism. Patients need to rest
between intervals and avoid PEM and further exer-
cise until completely recovered. If orthostatic hypo-
tension is present these may be done lying down
as opposed to sitting or standing to avoid trigger-
ing symptoms. As stamina improves the addition
of leisurely walking can be added, initially inside
the house from room to room or walking halls in
the apartment. Resistance training using resistance
bands or light (1 to 2) pound weights can be added.
Again this needs to be done in intervals of time to
keep the metabolism working mainly anaerobically.
This is the opposite of the aerobic workouts that
patients did in the past when they pushed to the
maximum and the goal was to getthe heart pump-
ing and beating faster.
Moderately ill patients: functional capacity rating
6–8. At this moderately low level of energy the scale
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240 Bested and Marshall: Review of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
ranges from describing patients who are able to walk
20–30min a day to being able to work out vigorously
three times a week. Exercise can begin with leisurely
walking or riding an exercise bike. Riding a bicycle on
the street is not recommended because of patients’
difficulty with balance. Tai Chi and supportive yoga
may also be helpful. Again patients must be mind-
ful of staying within their energy envelope to avoid
crashing. A patient has to be functioning consistently
at 6/10 to consider part time, flexible work and 7/10
or above for full time work. Ability to work outside
the home also depends on responsibilities inside the
home.
Medications for fatigue
Due to limited effectiveness, medications for fatigue are
not generally recommended. Very rarely they may be used
to help patients manage at exceptional and potentially
exhausting events in the patient’s life (e.g. attending a
funeral or wedding). Patients should avoid using medica-
tion to do more than their body can handle – causing PEM
symptoms. Examples of stimulants that can be used on
a occasional basis include: caffeine, Dexamphetamine,
Methylphenidate and Modafinil.
Sleep
Sleep hygiene
Patients with non-restorative sleep wake up feeling unre-
freshed and as tired as they were before they went to bed.
The following sleep hygiene suggestions may be helpful to
patients (137).
Establish a nighttime routine so patients go to sleep
when their body is winding down. Going to bed
for example at 10:00 p.m. and waking 710 h later
(depending on the body’s needs) helps maintain
healthy circadian rhythms.
Wake at the same time every day to retrain the circa-
dian rhythm.
Pace activities during the day to avoid aggravating
symptoms that interfere with sleep. If patients do not
pace during the daytime they will get a second wind,
or an adrenaline rush. Patients describe this as going
to bed “tired and wired”. The following day patients
are “crashed” and wake up exhausted.
Avoid watching TV or using computer devices before
bed. These images are stimulating and include blue
light which turns off melatonin production. Blue light
blocking glasses can help.
Table 4:List of medications helpful for sleep.
Dimenhydrinate – mg Trazodone .– mg
Melatonin – mg Cyclobenzaprine – mg
Tryptophan  mg– g Mirtazapine .– mg
Zopiclone/Imovane – mg Zolpidem .– mg
Clonazepam .– mg Gabapentin – mg
Doxepin/Sinequan – mg Pregabalin – mg
Amitriptyline, Nortriptyline – mgQuetiapine .– mg
Ropinirole or Pramipexole
.–. mg
Meditate, relax and wind down before bedtime for
20 min to an hour. This helps to increase the para-
sympathetic tone. increase relaxation, reduce active
thinking by the brain and reduce pain levels by
increasing the body’s endorphins.
Darken the bedroom with blackout curtains or use a
sleep mask at night. This helps the brain to produce
the melatonin needed for sleep. In the morning expo-
sure with bright natural light or a seasonal affective
disorder (SAD) light is helpful (138).
Use earplugs or soundproofing for noise, or sleep in
a different bedroom from (a snoring) partner or ram-
bunctious pet.
Make sure the bed is comfortable so that it cushions
the body and prevents the worsening of pain. Most
people prefer a moderate to firm support with a pil-
low top or eggshell foam on top.
If unable to sleep use meditation tapes to help the
brain to turn off and relax the body or try light reading.
Take calcium, magnesium, remedies, and medica-
tions if needed. Drink non-caffeinated herbal teas e.g.
chamomile or peppermint to help the body to relax.
Pace with rests as required throughout the day but
avoid napping past 3 pm because it interferes with
nighttime sleep.
Reduce or eliminate caffeine-containing beverages
and food.
Medications (see Table 4)
The medications listed below are a mixture of over the
counter and prescription drugs. A list like this emphasizes
that one size does not fit all. The list is not all inclusive.
Remember that ME/CFS is a chronic, usually lifelong con-
dition. Most patients will require some type of sleep aid
ongoing, not just for 2 weeks as the drug monographs state.
Sometimes rotating medications is helpful to decrease
the development of tolerance. These medications can be
started at 1/4 of the normal dose until the effective dose or
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Bested and Marshall: Review of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome241
maximum recommended dose is reached. These medica-
tions must be individualized and based on the best match
between the patient’s symptoms and the medication
available. Sleep medications need to be reviewed with the
patient’s entire group of other medications and supple-
ments to ensure there are no contraindications. To help
with this, is it is best if the patient uses one pharmacy.
Pain
Pain in ME/CFS is often migratory in muscles and joints.
It may be mild, moderate or severe. New headaches occur
and are often migraines. Fibromyalgia is a co-morbid con-
dition with ME/CFS and needs to be considered if pain is
present.
Pain needs to be treated and treatment varies with
the severity of the pain and what modalities most help the
individual patient. Useful modalities for some patients
include: meditation/relaxation response, warm baths,
massage, stretches, acupuncture, hydrotherapy, chiro-
practic, yoga, Tai Chi, TENS (transcutaneous electrical
nerve stimulation), physiotherapy and nerve blocks (help
migraines).
The pain medications range from over the counter
anti-inflammatories and pain medications, muscle relax-
ants, to prescribed central desensitizers and narcotic
analgesics in extreme cases (see Table 5).
Start with 1/4 doses in more medication-sensitive
patients.
Establish clear goals with the patient for a trial, as
well as start and assessment times. Stop the medica-
tion if not effective.
Use the functional capacity scale and activity logs and
pain scales to measure the effectiveness of medication.
Table 5:Medications helpful for pain.
Anti-inflammatories Antidepressants
Acetaminophen –mg q
h/prn
Aspirin –mg q – h/prn
Diclofenac –mg daily
Naproxen –mg daily
Duloxetine –mg daily
Milnacipran –mg bid
Anticonvulsants Analgesics
Gabapentin –mg daily Narcotics
Available in long and short
acting formulations.
Tramadol
Codeine phosphate
Oxycodone
Morphine
Pregabalin –mg daily
Valproate –mg daily
Topirimate –mg daily
Use patient contracts if narcotic medication is used.
CAGE questionnaire to screen for appropriate patients
if using narcotics- a mnemonic for attempts to cut
back on drinking, being Annoyed at criticisms about
drinking, feeling guilty about drinking, and using
alcohol as an eye opener.
Use long-acting narcotics if effective.
Work with a pain consultant if possible to manage the
more complex cases.
Cognitive dysfunction
Patients have poor concentration, difficulty focusing and
reading, grope for words, get lost in familiar places, have
lost their sense of time and have difficulty with short term
memory. They think and process more slowly and think-
ing takes more effort. They need the same treatment as
brain injured patients to cope with cognitive dysfunction.
What helps patients to stay organized and in control?
Write it down. Patients need a place to write down
what they need to remember either on their cell phone
or in a “memory book”. They need written instruc-
tions for any treatments you prescribe. It helps if the
same person can come with them to appointments as
their designated “memory person”.
Promote habits to simply their life e.g. key hook to
hang their keys on each time they use the car.
Pace activities that use mental energy e.g. time
spent doing emails on the computer. Mental tasks
need to be treated like physical activities and have
a limit set before started. If they do not stop in time,
they will crash/have symptom relapse just as they
would from physical activities.
There are no specific medications that have been helpful
for cognitive dysfunction to date. Stimulants have not
been effective.
Managing depression, anxiety and distress
Education, support and coping skills
To differentiate between symptoms of depression and
anxiety secondary to ME/CFS and psychiatric disorders,
ask the patient what they will do the next time they have
a “good day”. A patient with ME/CFS will have a long list
of ideas whereas a patient with major depressive disor-
der will say they can not think of anything they enjoy any
more. Patients with an anxiety disorder will have a list of
reasons why they won’t be able to do or enjoy the activities.
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242 Bested and Marshall: Review of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Whereas patients with psychiatric disorders generally feel
better after exertion, Patients with ME/CFS feel worse after
exertion or exercise. Patients with ME/CFS are human
and get frustrated and angry when they crash and on bad
energy days, but it improves on their good energy days.
Patients with ME/CFS need to grieve the loss of their lives:
their health, jobs, finances, friends, and sometimes family.
The hospital anxiety and depression scale (HADS) and the
beck anxiety or depression inventories are useful to evalu-
ate anxiety and depression in patients with physical health
conditions as they do not assume that all physical symp-
toms are caused by the psychiatric disorder (139, 140).
Patients with major depressive disorder (MDD) have
difficulty initiating activities. They usually have a very
low mood, may have suicidal thoughts, loss of interest or
desire to do things, lack enjoyment, have a sense of worth-
lessness or guilt, and feel better after exercise.
In comparison patients with ME/CFS are highly moti-
vated. They want to and try accomplish things that they
have not been able to do as a result of their low energy on
their bad days.
Patients find hope by getting a diagnosis, a medical
plan and by getting their medical, home care and social
needs met. If depression does occur with ME/CFS it may
develop into MDD and needs to be immediately treated.
If suicidal thoughts are present, referral plus hospitaliza-
tion for the patient’s safety may be necessary.
Anxiety about health and life circumstances can be
secondary to ME/CFS. Generalized anxiety disorder (GAD)
is characterized by excessive worry about a wide variety
of things; whereas people with ME/CFS can distract them-
selves from anxiety and still enjoy some things in life.
People with GAD are anxious all the time.
Helpful interventions
Start an educational and support group for the mobile
patients and families in your practice so that they can
improve their coping skills. The group setting with
others who “get it” can be immensely reassuring, as
well as decreasing isolation (141, 142).
Explore meaningful fun low level activities patients
can do by themselves or with family to find their joy
in life (143, 144).
Patients need time and safety to grieve their losses
and to vent their frustration at being ill and losing
their jobs and their life. If you cannot offer this sup-
port refer to a mental health professional.
Patients benefit from a good ME/CFS support group
where they learn about their illness and are sur-
rounded with supportive people. Avoid groups where
the biggest event is “who is the sickest”, as they dis-
courage patients and they feel worse after attending.
Psychotropic medications
Patients who develop a psychiatric disorder should be
treated with medications as any other patients with
anxiety, depression, obsessive compulsive disorder, etc.
Due to their sensitivity, medications should be started at
a low dose and increased slowly as tolerated over weeks.
Cognitive behavioral therapy (CBT)
CBT is a counseling strategy that helps patients evalu-
ate the accuracy of their thoughts and assumptions. CBT
coping skills reduce worry, sadness and anger which
consequently reduces the emotional drain of negative
emotions.
Historically in the literature CBT was inappropriately
touted as a cure for patients with ME/CFS if they changed
their “belief system”. ME/CFS is a physical illness and not
a psychological illness, therefore CBT cannot cure ME/
CFS. What CBT can do is to help patients cope with being
chronically ill and manage their emotional reactions better
so that they do not waste valuable energy on worrying or
feeling guilty about things that they cannot control. We
like to think of CBT as “emotional energy conservation”.
Management of Orthostatic intolerance (OI) and
cardiovascular symptoms
Many patients have symptoms suggestive of OI such as
feeling light-headed, dizzy, faint or having heart palpita-
tions. Changing positions slowly from lying to sitting and
then standing is essential to manage symptoms. Pumping
their calves to push the blood back to their core is helpful.
Prolonged standing is to be avoided. Pressure stockings
(knee highs or full pantyhose) and elevating the legs while
sitting helps to manage OI.
It often helps to increase patients’ blood volume for
fewer OI symptoms. This can be done by increasing salt
and electrolyte intake with fluids. Start with a pinch
of salt and increase to a total of 1 tsp of salt to be taken
throughout the day. Increasing salty foods is also helpful.
This may reduce symptoms of postural hypotension and
tachycardia.
Fludrocortisone 0.1–0.2mg/day or Midodrine 10mg
up to four times daily help some patients. Tachycardia
or palpitations from postural hypotension can be treated
with low dose beta-blockers, such as Atenolol 25–50mg or
Propranolol 10–20 mg.
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Bested and Marshall: Review of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome243
Management of gastrointestinal and genitourinary
problems
Diet
A well balanced diet is essential for healing. Providing
food to eat is a problem for many patients due to lack of
money to buy food, lack of energy to shop for and prepare
food, and finally lack of energy to chew and swallow food.
Income assistance may be needed to buy the food. Home-
care services may be needed to cook the food. If patients
cannot chew they may benefit from mashed meals in a
shake form. Bedbound patients may need to be fed.
Ideally avoid refined sugars, caffeine, alcohol and
deep fried foods. To keep energy maximal, eating small
meals and snacks helps many patients. To facilitate this,
some patients find it handy to have a small refrigerator
in their room so that they can have easy access to pre-
cooked prepared food and avoid navigating the stairs to
the kitchen.
Patients may have GI symptoms that include irritable
bowel, reflux, nausea, and pain. Slow gastric emptying
and poor bowel peristalsis can be present. Evidence based
treatment of IBS with the Low FODMAP (Fermentable
Oligo-Di-Monosaccharides and Polyols) diet helps some
patients. Some patients have small bowel dysbiosis/leaky
gut and have developed new food sensitivities. In these
patients, reducing and avoiding sensitive foods which
worsen symptoms is helpful (145). Ideally, patients could
rotate their foods every 4–5days so they avoid developing
more food sensitivities.
If intestinal dysbiosis is present patients may improve
their symptoms taking L-glutamine or butyrate (145) or by
using evidence based probiotics.
Specific nutrients
Vitamins: Because patients with ME/CFS eat often so
poorly they may benefit from a multivitamin/multi-
mineral. Use of supplements should ideally be super-
vised by a knowledgeable person.
Vitamin D3 Levels should be checked as a baseline
for this patient population as they are at risk for oste-
oporosis due to lack of weight bearing exercise and
poor absorption (146).
Vitamin B12 and B-Complex Patients with ME/CFS
have been found to have low levels of B12 in their
cerebrospinal fluid (147). A trial of B12, methylcobal-
amin, 1000 μg IM weekly for 6 weeks may be help-
ful. Fatigue symptoms and cognitive symptoms may
improve. There have been no reports of side effects,
despite the high blood levels.
Essential Fatty Acids Some patients symptoms
improve on supplementation with eicosapenta-
noic acid, an essential fatty acid that is found in
omega-3 fish oil (148, 149). Also vitamin and min-
eral cofactors including vitamin C, biotin, niacin,
folic acid, selenium, zinc, and magnesium, may be
supportive in conjunction with essential fatty acids
supplementation.
Zinc deficiency may contribute to decreased function
of natural killer cells and cell-mediated immune dys-
function (150). Zinc supplements must be balanced
with copper in the correct ratio.
CoQ10 Plasma CoQ10 is significantly lower in a sub-
stantial number of ME/CFS patients compared to
healthy controls. Some patients may show improve-
ment with CoQ10 100–400 mg daily. If effective, to
maintain improvement CoQ10 needs to be taken long
term (151, 152).
Urinary symptoms
Patients with ME/CFS may have symptoms of frequency,
dysuria and bladder pain. Low grade bacterial infection
should be ruled out. Interstitial cystitis, detruser instabil-
ity, urethral syndrome and endometriosis also may occur
and may require specialist referral.
Managing Infections and immunological factors
In patients in whom viral, bacterial or parasitic infections
have been found (e.g. herpes viruses, enteroviruses, Bor-
relia burgdorferi, mycoplasma, Giardia lamblia) long-term
antibiotics, anti-parasitic or antiviral therapy may be
helpful (153).
Isoprinosine (Imunovir) is an immune modulator that
may be helpful in selected patients. Specialist advice may
be in order if clinical experience is limited.
Based on two randomized trials, the experimental
drug Rintatolimod (Ampligen®) has been shown to benefit
patients in the first three years of the illness who are more
disabled (154, 155). The drug was not FDA approved but is
available for fees to recover costs.
Allergies and environmental sensitivities/multiple
chemical sensitivity
Allergies
Many patients with ME/CFS suffer from allergies to natural
inhalants (such as grasses, trees, pollens, etc.) that may
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244 Bested and Marshall: Review of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
worsen symptoms during relapse. Treatment with nasal
sprays, inhalers or topical skin applications may be ade-
quate, but many will need to use an oral antihistamine.
A non-sedating antihistamine (24h Claritin/Loratadine or
Reactine/Cetirizine HCl) can be used in the daytime and
a sedating antihistamine (Benadryl/Diphenhydramine) at
night.
Environmental sensitivities/multiple chemical
sensitivity (MCS)
Rather than an allergic response, patients become sensi-
tive to low levels of specific odors or chemicals, or elec-
tromagnetic radiation. On exposure to their sensitizing
substances, an exacerbation of symptoms is provoked. For
example, perfumes, cigarette smoke, cleaning products,
paint, glue and many other odors, as well as excess use
of cell phones, may trigger symptoms. These patients may
need advice on how to avoid these environmental factors.
Patients with multiple food sensitivities who avoid
sensitive foods may need dietary counseling to rotate their
foods to avoid malnutrition (156, 157).
Alternative and complementary approaches
The use of acupuncture, massage therapy, meditation
and chiropractic treatments have been helpful in some
patients. The research of CAM therapies and methods is
not well documented in the literature. Patients often try
costly therapies hoping for a cure. More detailed informa-
tion may be found in the reviews (158, 159).
Summary: myalgic encephalomyelitis/
chronic fatigue syndrome: what’s in
a name?
The above collection of data has shown that ME/CFS is a
complex condition that affects every organ system in the
body. There is evidence of inflammation at the cellular
and biochemical levels: in the muscles, brain and spinal
cord in patients with ME/CFS. The name for this illness
has had a huge impact on the medical, scientific and
patient communities – how it is viewed and how patients
are treated by the medical community (160). We are now
at the descriptive stage of ME/CFS, delineating symp-
toms and symptom clusters and reporting on pathologi-
cal cellular and biochemical observations. Myalgic means
muscle pain. Encephalomyelitis means inflammation of
the brain and spinal cord. The term myalgic encephalo-
myelitis is recognizable as a descriptive term for this con-
dition with its host of symptoms. It is listed in the World
Health Organization’s classification system of diagnoses
under neurology. Research is not yet clear enough about
which symptoms are characteristic for ME and which for
CFS. For now, let us continue to use ME/CFS in the CCC.
It is well recognized in the literature and is currently able
to describe this illness with its constellation of symptoms
and exclude other illnesses.
When we are able to find a definitive cause that will
satisfy the strictest definition of the word “disease” and
with consultation from all interested groups; clinicians,
scientists and patients; let us convene for a new name then.
The IOM recommended reconvening in 5 years after
testing the new SEID criteria in clinical trials. Jason’s
research group did test the SEID definition against the
CCC definition in different patient data bases and found,
that as a result of including the psychiatric disorders and
other comorbid conditions, the SEID definition’s specific-
ity was worse and as a result the prevalence rate of ME/
CFS was higher (96, 161). It would be prudent to have feed-
back given now from all concerned groups to the Secretary
of US Department of Health and Human Services to ensure
that money and effort is not wasted in research and clini-
cal trials that will not be meaningful.
The Canadian Consensus Criteria Definition for ME/
CFS has acceptable sensitivity and specificity. It includes
essential exclusion criteria and inclusion criteria. We rec-
ommend using this definition for your patients.
References
1. Parlor M. Canadian Institutes of Health Research funding for
research into chronic conditions, Quest 101, National ME/FM
Action Network, Winter 2014:3.
2. Brurberg KG, Fonhus MS, Larun L, Flottorp S. Case definitions for
chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME):
a systematic review. BMJ Open 2014;4:e003973.
3. Carruthers BM, Jain AK, De Meirleir KL, Peterson D, Klimas NG,
etal. Myalgic encephalomyelitis/chronic fatigue syndrome: clini-
cal working case definition, diagnostic and treatments protocols.
J Chronic Fatigue Synd 2003;11(1):7–115.
4. Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, etal. The
chronic fatigue syndrome: A comprehensive approach to its
definition and study. Ann Int Med 1994;121(12):953–9.
5. Holmes GP, Kaplan JE, Gantz NM, Komaroff AL, Schonberger LB,
etal. Chronic fatigue syndrome: a working case definition. Ann
Intern Med 1988;108:387–9.
6. Carruthers BM, van de Sande MI, De Meirleir KL, Klimas NG,
Broderick G, etal. Myalgic encephalomyelitis: international
consensus criteria. J Int Med 2011;270:327–38.
Authenticated | acbes@bell.net author's copy
Download Date | 11/28/15 2:31 PM
Bested and Marshall: Review of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome245
7. Sharpe MC, Archard LC, Banatvala JE, Borysiewicz LK, ClareAW,
etal. A report – chronic fatigue syndrome: guidelines for
research. J Royal Society Med 1991;84:118–21.
8. IOM (Institute of Medicine). Beyond Myalgic Encephalomyelitis/
Chronic Fatigue Syndrome: Redefining an Illness. Washington,
DC: The National Academies, 2015:282pp.
9. Jason LA, Sunnquist M, Kot B, Brown A. Unintended
consequences of not specifying exclusionary illnesses
for systemic Exertion Intolerance Disease. Diagnostics
2015;5:272–86.
10. Jason LA, Sunnquist M, Brown A, Newton JL, Strand EB, etal.
Chronic fatigue syndrome versus systemic exertion intolerance
disease. Fatigue 2015;3:127–41.
11. Jason L, Sunnquist M, Brown A, McManimen S, Furst J. Reflec-
tions on the IOM’s systemic exertion intolerance disease. Pol
Arch Med Wewn 2015;576–80. pii: AOP_15_067.
12. Brown AA, Jason LA. Validating a measure of myalgic encepha-
lomyelitis/chronic fatigue syndrome symptomatology. Fatigue
Biomed Health Behav 2014;2:132–52.
13. McHorney CA, Ware JE, Raczek AE. The MOS 36-item Short-Form
Health Survey (SF-36): II. Psychometric and clinical tests of
validity in measuring physical and mental health constructs.
Medical Care 1993;31(3):247–63.
14. Jason, LA, Evans M, Porter N, Brown M, Brown A, etal. The
development of a revised Canadian myalgic encephalomyelitis
chronic fatigue syndrome case definition. Am J Biochem Biotech
2010;6(2):120–35.
15. Friedberg F, Bateman L, Bested A, Davenport T, Friedman K,
etal. International Association for Chronic Fatigue Syndrome/
Myalgic Encephalomyelitis ME/CFS: primer for clinical practi-
tioners. Chicago, IL: IACFS/ME. 2014:50pp.
16. Jason LA, Richman JA, Rademaker AW, Jordan KM, Plioplys AV,
etal. A community-based study of chronic fatigue syndrome.
Arch Int Med 1999;159(18):2129–37.
17. Bierl C, Nisenbaum R, Hoaglin DC, Randall B, Jones AB, etal.
Regional distribution of fatiguing illnesses in the United States:
a pilot study. Popul Health Metr 2004;2(1):1.
18. Halapy E, Parlor, M. The Quantitative Data: Environmental Sen-
sitivities/Multiple Chemical Sensitivity (ES/MCS), Fibromyalgia
(FM), Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome
(ME/CFS), October 2013. http://www.meao.ca/files/Quantita-
tive_Data_Report.pdf.
19. Levine PH. Epidemic neuromyasthenia and chronic fatigue syn-
drome: epidemiological importance of a cluster definition. Clin
Infect Dis 1994;18 Suppl 1:S16–20.
20. Reyes M, Gary HE Jr, Dobbins JG, Randall B, Steele L, etal.
Descriptive epidemiology of chronic fatigue syndrome:
CDC surveillance in four US cities, September 1989 through
August1993. Morbid Mortal Week Report Surveil Sum
1997;46(SS–2):1–13.
21. Reeves WC, Jones JF, Maloney E, Heim C, Hoaglin DC, etal.
Prevalence of chronic fatigue syndrome in metropolitan, urban,
and rural Georgia. Popul Health Metr 2007;5:5.
22. Jason LA, Barker K, Brown A. Pediatric myalgic encephalomyeli-
tis/chronic fatigue syndrome. Rev Health Care 2012;3(4):257–70.
23. Nisenbaum R, Jones A, Jones J, Reeves W. Longitudinal analysis
of symptoms reported by patients with chronic fatigue syn-
drome. Ann Epi 2000;10(7):458.
24. Reynolds KJ, Vernon SD, Bouchery E, Reeves WC. The economic
impact of chronic fatigue syndrome. Cost Effect Res Alloc 2004;2:4.
25. Cairns RH. Systematic review describing the prognosis of
chronic fatigue syndrome. Occup Med (Oxford, England)
2005;55(1):20–31.
26. March D. The Natural Course of Chronic Fatigue Syndrome: Evi-
dence from a Multi-Site Clinical Epidemiology Study. Presenta-
tion IACFS San Francisco Conference 2014.
27. Brown MM, Bell DS, Jason LA, Christos C, Bell DE. Understand-
ing long-term outcomes of chronic fatigue syndrome. J Clin
Psychol 2012;68(9):1028–35.
28. Joyce J, Hotopf M, Wessely S. The prognosis of chronic fatigue
and chronic fatigue syndrome: a systematic review. Q J Med
1997;90(3):223–33.
29. Ciccone DS, Chandler HK, Natelson BH. Illness trajectories in
the chronic fatigue syndrome: a longitudinal study of improvers
versus non-improvers. J Nerv Ment Dis 2010;198(7):486–93.
30. Pheby D, Saffron L. Risk factors for severe ME/CFS. Biol Med
2009;1(4):50–74.
31. Bell DS. Twenty-five year follow-up in chronic fatigue syndrome:
Rising Incapacity. Mass CFIDS Assoc. Continuing Education
Lecture April 16, 2011.
32. Rusu C, Gee ME, Lagacé C, Parlor M. Chronic fatigue syndrome
and fibromyalgia in Canada: prevalence and associations with
six health status indicators. Health Prom Chron Dis Prev Can
2015;35(1):3–11.
33. Jason L, Corradi K, Gress S, Williams S, Torres-Harding S.
Causes of death among patients with chronic fatigue syndrome.
Health Care for Wom Int 2006;27(7):615–26.
34. Smith WR, Noonan C, Buchwald D. Mortality in a cohort of
chronically fatigued patients. Psych Med 2006;36(9):1301–6.
35. Jason LA, Barker K, Brown A. Pediatric myalgic encephalomyeli-
tis/chronic fatigue syndrome. Rev Health Care 2012;3(4):257–70.
36. Jason LA, Katz BZ, Shiraishi Y, Mears C, Im Y, etal. Predictors of
post-infectious chronic fatigue syndrome in adolescents. Heal
Psych Behav Med 2014;2(1):41–51.
37. Bell DS, Jordan K, Robinson M. Thirteen-year follow-up of chil-
dren and adolescents with chronic fatigue syndrome. Pediatrics
2001;107(5):994–8.
38. Rowe KSKJ. Symptom patterns in children and adolescents with
chronic fatigue syndrome. In: Singh NN, Ollendick TH, SinghAN,
editors. International Perspectives on Child and Adolescent
Mental Health: Selected Proceedings of the Second Interna-
tional Conference on Child & Adolescent Mental Health, Kuala
Lumpur, Malaysia, June 2000;2:395–422.
39. Taylor RR, Kielhofner GW. Work-related impairment and employ-
ment-focused rehabilitation options for individuals with chronic
fatigue syndrome: A review. J Mental Health 2005;14(3):253–267.
40. Crawley EM, Emond AM, Sterne JAC. Unidentified chronic fatigue
syndrome/myalgic encephalomyelitis (CFS/ME) is a major cause
of school absence: surveillance outcomes from school-based
clinics. BMJ Open 2011;1(2):e000252.
41. Jason LA, Benton MC, Valentine L, Johnson A, Torres-Harding S.
The economic impact of ME/CFS: Individual and societal costs.
Dynamic Med 2008;7:6.
42. Jason L, Torres-Harding S, Njok M. The face of CFS in the U.S.
CFIDS Chronicle 2006;16–21. http://www.researchgate.net/
profile/Leonard_Jason/publication/236995875.
43. Solomon L, Reeves WC. Factors influencing the diagnosis of
chronic fatigue syndrome. Arch Int Med 2004;164(20):2241–5.
44. Hickie IB, Hooker AW, Hadzi-Pavlovic D, Bennett BK,
WilsonAJ, etal. Fatigue in selected primary care settings:
Authenticated | acbes@bell.net author's copy
Download Date | 11/28/15 2:31 PM
246 Bested and Marshall: Review of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Sociodemographic and psychiatric correlates. Med J Australia
1996;164:585–8.
45. Friedberg F, Bateman L, Bested A, Davenport T, Friedman K,
etal. International Association for Chronic Fatigue Syndrome/
Myalgic Encephalomyelitis ME/CFS: Primer for clinical practi-
tioners. Chicago, IL: IACFS/ME, 2014:16pp.
46. Ware JE. SF-36 Health Survey. In Chronic fatigue and chronic
fatigue syndrome: A co-twin control study of functional status.
Qual Life Res 2002;11:463–71.
47. Jason LA, Brown MM. Sub-typing daily fatigue progression in
chronic fatigue syndrome. J Mental Health 2013;22(1):4–11.
48. Lowenstein O, Feinberg R, Loewenfeld IE. Pupillary movements
during acute and chronic fatigue. Invest Ophthal Visual Sci
1963;(2):138–57.
49. Albright F, Light K, Light A, Bateman L, Cannon-Albright LA.
Evidence for a heritable predisposition to Chronic Fatigue Syn-
drome. BMC Neurology 2011;11:62.
50. Underhill R, O’Gorman R. The prevalence of Chronic Fatigue
Syndrome and chronic fatigue among family members of CFS
patients. J CFS 2006;13(1):3–13.
51. Buchwald D, Buchwald D, Hererell R, Ashton BS, BelcourtM,
etal. A twin study of chronic fatigue. Psychosomatic Med
2001;63:936–43.
52. Schur E, Afari N, Goldberg J, Dedra B, Sullivan PF. Twin analyses
of fatigue. Twin Res Hum Genet 2007;10(5):729–33.
53. Hickie IB, Bansal AS, Kirk KM, Lloyd AR, Martin, NG. A twin study
of the etiology of prolonged fatigue and immune activation.
Twin Res 2001;4(2):94–102.
54. Kaiser J, Biomedicine. Genes and chronic fatigue: how strong is
the evidence? Science 2006;312(5774):669–71.
55. Kerr JR, Burke B, Petty R, Gough J, Fear D, etal. Seven genomic
subtypes of chronic fatigue syndrome/myalgic encephalomyeli-
tis: a detailed analysis of gene networks and clinical pheno-
types. J Clin Pathol 2008;61(6):730–9.
56. Shimosako N, Kerr JR. Use of single-nucleotide polymorphisms
(SNPs) to distinguish gene expression subtypes of chronic
fatigue syndrome/myalgic encephalomyelitis (CFS/ME). J Clin
Pathol 2014;67(12):1078–83.
57. Hickie I, Davenport T, Wakefield D, Vollmer-Conna U, CameronB,
etal. Infection Outcomes Study. Post-infective and chronic
fatigue syndromes precipitated by viral and non-viral patho-
gens: prospective cohort study. Br Med J 2006;333(7568):575.
58. Naess H, Nyland M, Hausken T, Follestad I, Nyland H. Chronic
fatigue syndrome after giardia enteritis: Clinical charac-
teristics, disability and long-term sickness absence. BMC
Gastroenterology 2012;12:13.
59. Mørch K, Hanevik K, Rivenes AC, Bødtker JE, Næss H, etal.
Chronic fatigue syndrome 5years after giardiasis: differential
diagnoses, characteristics and natural course. BMC Gastroen-
terology 2013;13(28):1–8.
60. Katz BZ, Shiraishi Y, Mears CJ, Binns HJ, Taylor R. Chronic fatigue
syndrome following infectious mononucleosis in adolescents.
Pediatrics 2009;124(1):189–93.
61. Siegel SD, Antoni MH, Fletcher MA, Maher K, Segota MC, etal.
Impaired natural immunity, cognitive dysfunction, and physical
symptoms in patients with chronic fatigue syndrome: Preliminary
evidence for a subgroup? J Psychosom Res 2006;60(6):559–66.
62. Hornig M, MOntoya JG, Klimas NG, Levine S, Felsenstein D, etal.
Distinct plasma immune signatures in ME/CFS are present early
in the course of illness. Sci Adv 2015;1:e1400121.
63. Bonecchi R, Bianchi G, Bordignon PP, D’Ambrosio D, LangR,
etal. Differential expression of chemokine receptors and
chemotactic responsiveness of type 1 T helper cells (Th1’s) and
Th2’s. J. Exp. Med 1998;187:129–34.
64. Arestides RS, He H, Westlake RM, Chen AI, Sharpe AH, etal.
Costimulatory molecule OX40L is critical for both Th1 and Th2
responses in allergic inflammation. Eur J Immunol 2002;32:
2874–80.
65. Simpson CR, Anderson WJ, Helms PJ, Taylor MM, Watson L, etal.
Coincidence of immune-mediated disease driver by Th1 and
Th2 subsets suggests a common aetiology. A population based
study using computerized general practice data. Clin Exp All: J
Br Soc Allergy Clin Immunol 2002;32(1):37–42.
66. Torres-Harding S, Matthew Sorenson M, Jason LA, Kevin Maher K,
Fletcher MA. Evidence for T-helper 2 shift and association with
illness parameters in chronic fatigue syndrome (CFS). Bull IACFS
ME 2008;16(3):19–33.
67. Chris R, De Meirleir K. Self-test monitoring of the Th1/Th2 bal-
ance in health and disease with special emphasis on chronic
fatigue syndrome/myalgic encephalomyelitis. J Med Lab Diagn
2012;3(1):1–6.
68. Fletcher MA, Zeng XR, Barnes Z, Leivs S, Klimas NG. Plasma
cytokines in women with chronic fatigue syndrome. J Transl Med
2009;7:96.
69. Fletcher MA, Zeng XR, Maher K, Levis S, Hurwitz B, etal.
Biomarkers in chronic fatigue syndrome: Evaluation of natural
killer cell function and dipeptidyl peptidase IV/CD26. PLoS ONE
2010;5(5):e10817.
70. Klimas NG, Salvato FR, Morgan R, Fletcher MA. Immunologic
abnormalities in chronic fatigue syndrome. J Clin Microbiol
1990;28(6):1403–10.
71. Brenu EW, Huth TK, Hardcastle SL, Fuller K, Kaur M, etal. Role of
adaptive and innate immune cells in chronic fatigue syndrome/
myalgic encephalomyelitis. Int Immun 2014;26(4):233–42.
72. Hardcastle SL, Brenu EW, Johnston S, Nguyen T, Huth T, etal.
Characterisation of cell functions and receptors in Chronic
Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). BMC
Immunology 2015;16:35.
73. Broderick G, Fuite J, Kreitz A, Vernonb SD, Klimas N, etal. A for-
mal analysis of cytokine networks in chronic fatigue syndrome.
Brain Behav Immun 2010;24(7):1209–17.
74. White AT, Light AR, Hughen RW, Bateman L, Thomas B, etal.
Severity of symptom flare after moderate exercise is linked to
cytokine activity in chronic fatigue syndrome. Psychophysiology
2010;47(4):615–24.
75. Stringer EA, Baker KS, Carroll IR, Montoya JG, Chu L, etal. Daily
cytokine fluctuations, driven by leptin, are associated with
fatigue severity in chronic fatigue syndrome: evidence of inflam-
matory pathology. J Translat Med 2013;11:93.
76. Nakatomi Y, Mizuno K, Ishii A, Wada Y, Tanaka M, etal. Neuroin-
flammation in patients with chronic fatigue syndrome/myalgic
encephalomyelitis: an 11C-(R)-PK11195 PET study. J Nucl Med
2014;55:945–50.
77. Morris G, Berk M, Walder K, Maes M. Central pathways causing
fatigue in neuroinflammatory and autoimmune illnesses BMC
Med 2015;13:28.
78. Suhadolnik RJ, Peterson DL, O’Brien K, Cheney PR, Herst CV,
etal. Biochemical evidence for a novel low molecular weight
2–5A dependent RNase L in chronic fatigue syndrome. J Inter-
feron Cytokine Res 1997;17:377–85.
Authenticated | acbes@bell.net author's copy
Download Date | 11/28/15 2:31 PM
Bested and Marshall: Review of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome247
79. Gaber T, Oo WW. Prevalence of hypothyroidism in chronic
fatigue syndrome patients. J Neuro 2013;260:S98–9.
80. Friedberg F, Bateman L, Bested A, Davenport T, Friedman K,
etal. International Association for Chronic Fatigue Syndrome/
Myalgic Encephalomyelitis ME/CFS: Primer for clinical practi-
tioners. Chicago, IL: IACFS/ME, 2014:22pp.
81. Keller BA, Pryor JL, Giloteaux L. Inability of myalgic encepha-
lomyelitis/chronic fatigue syndrome patients to reproduce
VO2 peak indicates functional impairment. J Translat Med
2014;12(1):104.
82. Davenport TE, Stevens SR, Baroni K, Van Ness M, Snell CR.
Diagnostic accuracy of symptoms characterizing chronic fatigue
syndrome. Dis Rehab 2011;33(19–20):1768–75.
83. Cockshell SJ, Mathias JL. Cognitive functioning in people with
chronic fatigue syndrome: A comparison between subjective
and objective measures. Neuropsychology 2014;28(3):394–405.
84. VanNess JM, Stevens SR, Bateman L, Stiles TL, Snell CR. Pos-
texertional malaise in women with chronic fatigue syndrome.
JWom Health 2010;19(2):239–44.
85. Vermeulen RC, Kurk RM, Visser FC, Sluiter W, Scholte HR.
Patients with chronic fatigue syndrome performed worse than
controls in a controlled repeated exercise study despite a normal
oxidative phosphorylation capacity. J Transl Med 2010;11:8:93.
86. Myhill S, Booth NE, McLaren-Howard J. Chronic fatigue
syndrome and mitochondrial dysfunction. Int J Clin Exp Med
2009;2(1):1–16.
87. Whistler T, Toni Whistler T, James F, Jones JF, Elizabeth R, etal.
Exercise responsive genes measured in peripheral blood of
women with chronic fatigue syndrome and matched control
subjects. BMC Physiol 2005;24;5(1):5.
88. Morris G, Maes M. Mitochondrial dysfunctions in myalgic
encephalomyelitis/chronic fatigue syndrome explained by acti-
vated immuno-inflammatory, oxidative and nitrosative stress
pathways. Metab Brain Dis 2014;29(1):19–36.
89. Wong R, Lopaschuk G, Zhu G, Walker F, Catellier F, etal. Skeletal
muscle metabolism in the chronic fatigue syndrome. In vivo
assessment by 31P nuclear magnetic resonance spectroscopy.
Chest 1992;102(6):1716–22.
90. Booth NE, Myhill S, McLaren-Howard J. Mitochondrial dysfunc-
tion and the pathophysiology of Myalgic Encephalomyelitis/
Chronic Fatigue Syndrome. Int J Clin Exp Med 2012;5(3):208–20.
91. Behan WMH, More IAR, Behan PO. Mitochondrial abnor-
malities in the postviral fatigue syndrome. Acta Neuropathol
1991;83(1):61–5.
92. Jones DE, Hollingsworth KG, Jakovljevic DG, Fattakhova G,
Pairman J, etal. Loss of capacity to recover from acidosis on
repeat exercise in chronic fatigue syndrome: a case-control
study. Eur J Clin Invest 2012;42(2):186–94.
93. Mathew SJ, Mao X, Keegan KA, Levine SM, Smith ELP, etal.
Ventricular cerebrospinal fluid lactate is increased in chronic
fatigue syndrome compared with generalized anxiety disor-
der: an in vivo 3.0 T (1)H MRS imaging study. NMR Biomed
2009;22(3):251–8.
94. Shungu DC, Weiduschat N, Murrough JW, Mao X, Pillemer S,
etal. Increased ventricular lactate in chronic fatigue syndrome.
III. Relationships to cortical glutathione and clinical symptoms
implicate oxidative stress in disorder pathophysiology. NMR
Biomed 2012;25(9):1073–87.
95. Murrough JW, Mao X, Collins KA, Kelly C, Andrade G, etal.
Increased ventricular lactate in chronic fatigue syndrome
measured by 1H MRS imaging at 3.0 T. II: comparison with
major depressive disorder. NMR Biomed 2010;23(6):643–50.
96. Jason LA, Sunnquist M, Brown A, Evans M, Vernon S, etal.
Examining case definition criteria for chronic fatigue syndrome
and myalgic encephalomyelitis. Fatigue 2013;2(1)40–56.
97. Togo F, Lange G, Natelson BH, Quigley KS. Attention network
test: Assessment of cognitive function in chronic fatigue syn-
drome. J Neuropsych 2015;9:1–9.
98. Claypoole KH, Claypoole KH, Noonan C, Mahurin RK, Goldberg
J, etal. A twin study of cognitive function in chronic fatigue
syndrome: The effects of sudden illness onset. Neuropsychol-
ogy 2007;21(4):507–13.
99. Zinn ML, Zinn MA, Maldonado J, Norris J, Valencia I, etal. Cortical
hypoactivation during resting state EEG suggests central nervous
system pathology in patients with Chronic Fatigue Syndrome.
Presentation: IACFS/ME, 11th Biennial Conference, March 2014,
page 43. http://iacfsme.org/PDFS/2014Syllabus25.aspx.
100. Zinn ML, Zinn MA, Maldonado J, Norris J, Valencia I, etal.
EEG peak alpha frequency is associated with chronic fatigue
syndrome: a case-control observational study. Presentation:
IACFS/ME, 11th Biennial Conference, March 2014, page 42.
http://iacfsme.org/PDFS/2014Syllabus25.aspx.
101. Kishi AZ, Struzik ZR, Natelson BH, Togo F, Yamamoto Y.
Dynamics of sleep stage transitions in healthy humans and
patients with chronic fatigue syndrome. Am J Physiol – Reg I
2008;294(6):R1980–7.
102. Neu D, Mairesse O, Verbanck P, Linkowski P, Le Bon O. Non-
REM sleep EEG power distribution in fatigue and sleepiness.
JPsychosom Res 2014;76(4):286–91.
103. Van Hoof E, De Becker P, Lapp C, Cluydts R, De MeirleirK.
Defining the occurrence and influence of alpha-delta
sleepin chronic fatigue syndrome. Am J Med Sci
2007;333(2):78–84.
104. Togo F, Natelson BH, Cherniack NS, FitzGibbons J, GarconC,
etal. Sleep structure and sleepiness in chronic fatigue syn-
drome with or without coexisting bromyalgia. Arthritis Res
Ther. 2008;10(3):R56.
105. Jackson ML, Bruck D. Sleep abnormalities in chronic fatigue
syndrome/myalgic encephalomyelitis: a review. J Clin Sleep
Med 2012;8(6):719–28.
106. Neu D, Mairesse O, Verbanck P, Le Bon O. Slow wave sleep in
the chronically fatigued: power spectra distribution patterns
in chronic fatigue syndrome and primary insomnia. Clin
Neurophysiol 2015;126(10):1926–33.
107. Unger, E. Measures of CFS in a multi-site clinical study. Paper
read at FDA Scientic Drug Development Workshop, April 26,
2013, Washington, DC.
108. Food and Drug Administration. The voice of the patient:
Chronic fatigue syndrome and myalgic encephalomyelitis.
Bethesda, MD: Center for Drug Evaluation and Research,
FDA,2013.
109. Ickmans K, Meeus M, Kos D, Clarys P, Meersdom G, etal. Cog-
nitive performance is of clinical importance, but is unrelated
to pain severity in women with chronic fatigue syndrome. Clin
Rheumy 2013;32(10):1475–85.
110. Rowe PC, Calkins H. Neurally mediated hypotension and
chronic fatigue syndrome. A J Med 1998;105(3A):15S–21.
111. Rowe PC, Bou-Holaigah I, Kan JS, Calkins H. Is neurally medi-
ated hypotension an unrecognized cause of chronic fatigue?
Lancet 1995;345(8950):623–4.
Authenticated | acbes@bell.net author's copy
Download Date | 11/28/15 2:31 PM
248 Bested and Marshall: Review of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
112. Bou-Holaigah I, Rowe PC, Kan J, Calkins H. The relationship
between neurally mediated hypotension and the chronic
fatigue syndrome. J Am Med Ass 1995;274(12):961–7.
113. Hollingsworth KG, Jones DE, Taylor R, Blamire AM, NewtonJL.
Impaired cardiovascular response to standing in chronic
fatigue syndrome. Eur J Clin Invest 2010;40(7):608–15.
114. Costigan A, Elliott C, McDonald C, Newton JL. Orthostatic
symptoms predict functional capacity in chronic fatigue
syndrome: implications for management. QMJ: J Ass Phy
2010;103(8):589–95.
115. Freeman R, Komaro AL. Does the chronic fatigue syn-
drome involve the autonomic nervous system? Am Med
1997;102(4):357–64.
116. Lerner AM, Lawrie C, Dworkin HS. Repetitively negative chang-
ing T waves at 24-h electrocardiographic monitors in patients
with the chronic fatigue syndrome. Le ventricular dysfunction
in a cohort. Chest 1993;104(5):1417–21.
117. Streeten DH, Thomas D, Bell DS. The roles of orthostatic hypo-
tension, orthostatic tachycardia and subnormal erythrocyte
volume in the pathogenesis of the chronic fatigue syndrome.
Am J Med 2000;320:1–8.
118. Hurwitz BE, Coryell VT, Parker M, Martin P, Laperriere A, etal.
Chronic fatigue syndrome: Illness severity, sedentary lifestyle,
blood volume and evidence of diminished cardiac function.
Clin Sci 2010;118(2):125–35.
119. Rowe PC, Barron DF, Calkins H, Maumenee IH, TongPY,
etal. Orthostatic intolerance and chronic fatigue
syndrome associated with Ehlers-Danlos syndrome. J Ped
1999;135(4):494–9.
120. Fuite J, Vernon SD, Broderick G. Neuroendocrine and immune
network re-modeling in chronic fatigue syndrome: an explora-
tory analysis. Genomics 2008;92(6):393–9.
121. Fletcher MA, Rosenthal M, Antoni M, Ironson G, Zeng XR, etal.
Plasma neuropeptide Y: a biomarker for symptom severity in
chronic syndrome. Behav Brain Funct 2010;6:76.
122. Papadopoulos AS, Cleare AJ. Hypothalamic-pituitary-adrenal
axis dysfunction in chronic fatigue syndrome. Nat Rev Endo-
crinol 2011 Sep;8(1):22–32.
123. De Becker P, De Meirleir K, Joos E, Campine I, Van SteenbergeE,
etal. Dehydroepiandrosterone (DHEA) response to i.v. ACTH
in patients with chronic fatigue syndrome. Horm Metab Res
1999;31(1):18–21.
124. Allain TJ, Bearn JA, Coskeran P, Jones J, Checkley A, etal.
Changes in growth hormone, insulin, insulin like growth
factors (IGFs), and IGF-binding protein-1 in chronic fatigue
syndrome. Biol Psychiatry 1997 41(5):567–73.
125. Sharpe M, Clements A, Hawton K, Young AH, Sargent P, etal.
Increased prolactin response to Buspirone in chronic fatigue
syndrome. J Aect Disord 1996;41(1):71–6.
126. Bakheit AM, Behan PO, Watson WS, Morton JJ. Abnormal
arginine-vasopressin secretion and water metabolism in
patients with postviral fatigue syndrome. Acta Neurol Scand
1993;87(3):234–8.
127. Boneva RS, Decker MJ, Maloney EM, Lin JM, Jones JF, etal.
Higher heart rate and reduced heart rate variability persist
during sleep in chronic fatigue syndrome: a population-based
study. Auton Neurosci 2007;137(1–2):94–101.
128. Jason LA, Boulton A, Porter NS, Jessen T, Njoku MG, etal.
Classication of myalgic encephalomyelitis/chronic fatigue
syndrome by types of fatigue. Behav Med 2010;36(1):24–31.
129. Jones DE, Hollingsworth KG, Jakovljevic DG, Fattakhova G,
Pairman J, etal. Loss of capacity to recover from acidosis on
repeat exercise in chronic fatigue syndrome: a case-control
study. Eur J Clin Invest 2012;42(2):186–94.
130. Davenport TE, Stevens SR, VanNess MJ, Snell CR, Little T. Con-
ceptual model for physical therapist management of chronic
fatigue syndrome/myalgic encephalomyelitis. Phys Ther
2010;90(4):602–14.
131. Stevens SR, Davenport TE. Functional outcomes of anaerobic
rehabilitation in an individual with chronic fatigue syndrome:
case report with 1-year follow-up. Bulletin of the International
Association for Chronic Fatigue Syndrome/Myalgic Encephalo-
myelitis 2010;18(3). http://iacfsme.org/ME-CFS-Primer-Educa-
tion/Bulletins/Volume-18,-Issue-3-Fall-2010.aspx.
132. Larun L, Brurberg KG, Odgaard-Jensen J, Price JR. Exercise
therapy for chronic fatigue syndrome. Cochrane Database
SystRev 2015. DOI: 10.1002/14651858.CD003200.pub3.
133. Jason LA, Benton M. The impact of energy modulation
onphysical functioning and fatigue and severity
amongpatients with ME/CFS. Patient Educ Couns
2009;77(2):237–41.
134. Whistler T, Jones JF, Unger ER, Vernon SD. Exercise responsive
genes measured in peripheral blood of women with chronic
fatigue syndrome and matched control subjects. BMC Physiol.
2005;5(1):5.
135. Jason L, Benton M, Torres-Harding S, Muldowney K. The impact
of energy modulation on physical functioning and fatigue
severity among patients with ME/CFS. Patient Educ Couns
2009;77:237–41.
136. Bested AC, Logan AC, Howe R. Hope and Help for Chronic
Fatigue Syndrome and Fibromyalgia, 2nd ed. Nashville:
Cumberland House, 2008:267pp.
137. Taylor DJ, Roane BM. Treatment of insomnia in adults and chil-
dren: a practice-friendly review of research. J Clinical Psychol-
ogy 2010;66(11):1137–47.
138. Carrier J, Dumont M. Sleep propensity and sleep architecture
aer bright light exposure at three dierent times of day.
JSleep Res 1995;4(4):202–11.
139. Morriss RK, Wearden AJ. Screening instruments for psychi-
atric morbidity in chronic fatigue syndrome. J R Soc Med
1998;91(7):365–8.
140. Zigmond AS, Snaith RP. The hospital anxiety and depression
scale. Acta Psychiat Scand 1983;67(6):361–70.
141. Friedberg F, Jason LA. Understanding chronic fatigue syn-
drome: An empirical guide to assessment and treatment.
Washington, D.C.: American Psychological Association, 1998.
Chapter 7: Dierential diagnosis in CFS; p. 99–118.
142. Friedberg F. Fibromyalgia and chronic fatigue syndrome: Seven
proven steps to less pain and more energy. Oakland, CA: New
Harbinger, 2006.
143. Ray C, Jeeries S, Weir WR. Life-events and the course of
chronic fatigue syndrome. Brit J Med Psychol 1995;68:323–31.
144. Friedberg F. Chronic fatigue syndrome, bromyalgia, and
related illnesses: a clinical model of assessment and interven-
tion. J Clinical Psychology 2010;6:641–65.
145. Maes M, Leunis JC. Normalization of leaky gut in chronic
fatigue syndrome (CFS) is accompanied by a clinical improve-
ment: eects of age, duration of illness and the translocation
of LPS from gram-negative bacteria. Neuro Endocrinol Lett
2008;29(6):902–10.
Authenticated | acbes@bell.net author's copy
Download Date | 11/28/15 2:31 PM
Bested and Marshall: Review of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome249
146. Berkovitz S, Ambler G, Jenkins M, Thurgood S. Serum
25-hydroxy vitamin D levels in chronic fatigue syndrome: a
retrospective survey. Int J Vitam Nutr Res 2009;79(4):250–4.
147. Regland B, Andersson M, Abrahamsson L, Bagby J, Dyrehag LE,
etal. Increased concentrations of homocysteine in the cerebro-
spinal fluid in patients with bromyalgia and chronic fatigue
syndrome. Scand J Rheumatol 1997;26(4):301–7.
148. Puri BK. The use of eicosapentaenoic acid in the treatment of
chronic fatigue syndrome. Prostaglandins Leukot Essent Fatty
Acids 2004;70(4):399–401.
149. Puri BK. Long-chain polyunsaturated fatty acids and the
pathophysiology of myalgic encephalomyelitis (chronic fatigue
syndrome). J Clin Pathol 2007;60:122–4.
150. Prasad AS. Zinc: mechanisms of host defense. J Nutr
2007;137(5):1345–9.
151. Maes M. Coenzyme Q10 deciency in myalgic encephalomy-
elitis/chronic fatigue syndrome (ME/CFS) is related to fatigue,
autonomic and neurocognitive symptoms and is another risk
factor explaining the early mortality in ME/CFS due to cardio-
vascular disorder. Neuro Endocrinol Lett 2009;30(4):470–6.
152. Morris G, Anderson G, Berk M, Maes M. Coenzyme Q10 Deple-
tion in Medical and Neuropsychiatric Disorders: Potential
Repercussions and Therapeutic Implications. Mol Neurobiol
201348(3):883–903.
153. Bansal AS, Bradley AS, Bishop KN, Kiani-Alikhan S, Ford B.
Chronic fatigue syndrome, the immune system and viral infec-
tion. [Rev] Brain Beh Imm 2012;26(1):24–31.
154. Strayer DR, Carter WA, Brodsky I, Cheney P, Peterson D, etal. A
controlled clinical trial with a specically congured RNA drug,
poly(I).poly(C12U), in chronic fatigue syndrome. Clin Infect Dis
1994;18 Suppl 1:S88–95.
155. Strayer DR, Carter WA, Stouch BC, Stevens SR, Bateman L,
etal. Chronic Fatigue Syndrome AMP-516 Study Group, Mitchell
WM. A double-blind, placebo-controlled, randomized, clini-
cal trial of the TLR-3 agonist rintatolimod in severe cases of
chronic fatigue syndrome. PLoS ONE 2012;7(3):e31334.
156. Magill MK, Suruda A. Multiple chemical sensitivity syndrome.
Am Fam Phys 1998;58(3):721–8.
157. Marshall L, Bested AJM, Kerr K, Bray R. Environmental
Sensitivities-Multiple Chemical Sensitivities Status Report.
Toronto, Canada, 2011. http://www.womenshealthmatters.
ca/assets/legacy/wch/pdfs/ESMCSStatusReportJune22011.
pdf.
158. Alraek T, Lee MS, Choi TY, Cao H, Liu J. Complementary and
alternative medicine for patients with chronic fatigue syn-
drome: a systematic review. BMC Compl Alt Med 2011;11:87.
159. Porter NS, Jason LA, Boulton A, Bothne N, Coleman B. Alterna-
tive medical interventions used in the treatment and manage-
ment of myalgic encephalomyelitis/chronic fatigue syndrome
and bromyalgia. J Alt Compl Med 2010;16(3):235–49.
160. Jason LA, Richman JA. How science can stigmatize: The
case of chronic fatigue syndrome. J Chronic Fatigue Synd
2008;14(4):85–103.
161. Jason L, Sunnquist M, Brown A, McManimen S, Furst J. Reflec-
tions on the IOM’s systemic exertion intolerance disease. Pol
Arch Med Wewn 2015 pii: AOP_15_067.
Supplemental Material: The online version of this article
(DOI:10.1515/reveh-2015-0026) offers supplementary material,
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... An abrupt onset with a viral-like syndrome occurred in most patients in outbreaks [2,40] and in many patients with sporadic ME/CFS [45]. Symptoms and signs included: fatigue, malaise, drowsiness, headache, low grade fever, myalgia, stiff neck, photophobia, dizziness or vertigo, and upper respiratory symptoms with cervical lymphadenopathy or a gastro-intestinal upset. ...
... In outbreak cases the initial flu-like symptoms appear to be prodromal symptoms of ME/CFS, but in sporadic cases, it is unclear as to whether the initial flu-like, upper respiratory or gastrointestinal symptoms are prodromal symptoms of ME/CFS or are due to another infectious illness which triggers its onset. A small minority of patients in outbreaks [39,47] and some sporadic patients [45] report an insidious onset. ...
... There is also a large variation in symptomatology among patients with sporadic ME/CFS and many patients suffer from remissions and relapses. Mild cases are able to go to work, while severe cases may be wheelchair dependent, housebound or bedbound [45]. Outbreak patients appear to have a better prognosis than sporadic patients. ...
Article
Full-text available
The etiology of myalgic encephalomyelitis also known as chronic fatigue syndrome or ME/CFS has not been established. Controversies exist over whether it is an organic disease or a psychological disorder and even the existence of ME/CFS as a disease entity is sometimes denied. Suggested causal hypotheses have included psychosomatic disorders, infectious agents, immune dysfunctions, autoimmunity, metabolic disturbances, toxins and inherited genetic factors. Clinical, immunological and epidemiological evidence supports the hypothesis that: ME/CFS is an infectious disease; the causal pathogen persists in patients; the pathogen can be transmitted by casual contact; host factors determine susceptibility to the illness; and there is a population of healthy carriers, who may be able to shed the pathogen. ME/CFS is endemic globally as sporadic cases and occasional cluster outbreaks (epidemics). Cluster outbreaks imply an infectious agent. An abrupt flu-like onset resembling an infectious illness occurs in outbreak patients and many sporadic patients. Immune responses in sporadic patients resemble immune responses in other infectious diseases. Contagion is shown by finding secondary cases in outbreaks, and suggested by a higher prevalence of ME/CFS in sporadic patients’ genetically unrelated close contacts (spouses/partners) than the community. Abortive cases, sub-clinical cases, and carrier state individuals were found in outbreaks. The chronic phase of ME/CFS does not appear to be particularly infective. Some healthy patient-contacts show immune responses similar to patients’ immune responses, suggesting exposure to the same antigen (a pathogen). The chronicity of symptoms and of immune system changes and the occurrence of secondary cases suggest persistence of a causal pathogen. Risk factors which predispose to developing ME/CFS are: a close family member with ME/CFS; inherited genetic factors; female gender; age; rest/activity; previous exposure to stress or toxins; various infectious diseases preceding the onset of ME/CFS; and occupational exposure of health care professionals. The hypothesis implies that ME/CFS patients should not donate blood or tissue and usual precautions should be taken when handling patients’ blood and tissue. No known pathogen has been shown to cause ME/CFS. Confirmation of the hypothesis requires identification of a causal pathogen. Research should focus on a search for unknown and known pathogens. Finding a causal pathogen could assist with diagnosis; help find a biomarker; enable the development of anti-microbial treatments; suggest preventive measures; explain pathophysiological findings; and reassure patients about the validity of their symptoms.
... Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Gulf War Illness (GWI) share features of post-exertional malaise (exertional exhaustion), fatigue that is not relieved by rest, unrefreshing and non-restorative sleep, total body pain, systemic hyperalgesia, interoceptive and functional disorders of viscera and disability with severely impaired quality of life (Fukuda et al., 1994;Carruthers et al., 2003;Friedberg et al., 2014). This broad range of symptoms has been difficult to explain by any traditional single medical or psychiatric system of disease. ...
... ME/CFS has been considered to be a chronic consequence following flu-like epidemics (Daugherty et al., 1991) but has a heterogeneous presentation and unknown aetiology. Prevalence is 0.2-2% (Friedberg et al., 2014;Baraniuk, 2019). The 1984 Center for Disease Control ('Fukuda') criteria require moderate to severe unremitting fatigue of new onset that persists longer than 6 months and has no explanation despite appropriate medical investigations (Fukuda et al., 1994). ...
Article
Full-text available
Gulf War Illness affects 25–30% of American veterans deployed to the 1990–91 Persian Gulf War and is characterized by cognitive post-exertional malaise following physical effort. Gulf War Illness remains controversial since cognitive post-exertional malaise is also present in the more common Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. An objective dissociation between neural substrates for cognitive post-exertional malaise in Gulf War Illness and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome would represent a biological basis for diagnostically distinguishing these two illnesses. Here, we used functional magnetic resonance imaging to measure neural activity in healthy controls and patients with Gulf War Illness and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome during an N-back working memory task both before and after exercise. Whole brain activation during working memory (2-Back > 0-Back) was equal between groups prior to exercise. Exercise had no effect on neural activity in healthy controls yet caused deactivation within dorsal midbrain and cerebellar vermis in Gulf War Illness relative to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients. Further, exercise caused increased activation among Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients within the dorsal midbrain, left operculo-insular cortex (Rolandic operculum) and right middle insula. These regions-of-interest underlie threat assessment, pain, interoception, negative emotion and vigilant attention. As they only emerge post-exercise, these regional differences likely represent neural substrates of cognitive post-exertional malaise useful for developing distinct diagnostic criteria for Gulf War Illness and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.
... As expected, there were more females in ME/CFS because of the known female predominance [6] and more male veterans with GWI from assault divisions deployed to the Persian Gulf (Table 1). PTSD was more common in GWI. ...
Preprint
Background: Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS), Gulf War Ill-ness (GWI) and control subjects had fMRI during difficult cognitive tests performed before and after submaximal exercise provocation (Washington 2020). Exercise caused increased activation in ME/CFS but decreased activation for GWI in the dorsal midbrain, left Rolandic operculum and right middle insula. Midbrain and isthmus nuclei participate in threat assessment, attention, cognition, mood, pain, sleep, and autonomic dysfunction Methods: Activated midbrain nuclei were inferred by re-analysis of data from 31 control, 36 ME/CFS and 78 GWI subjects using a seed region approach and the Harvard Ascending Arousal Network. Results: Before exercise, control and GWI had greater activation during cognition than ME/CFS in left pedunculotegmental nucleus. Postexercise ME/CFS had greater activation than GWI for midline periaqueductal gray, dorsal and median raphe, and right midbrain reticular formation, parabrachial complex and locus coeruleus. The change between days (delta) was positive for ME/CFS but negative for GWI indicating reciprocal patterns of activation. Controls had no changes. Conclusions: Exercise caused opposite effects with increased activation in ME/CFS but decreased activation in GWI indicating different pathophysiological responses to exertion and mechanisms of disease. Midbrain and isthmus nuclei contribute to postexertional malaise in ME/CFS and GWI.
... To redress the confusion created by so many case definitions, a clinical guideline IACFS/ME primer for General Health Practitioners (GPs) was developed in 2012 by a panel of experts from the International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (IACFS/ME) [21]. This included commonly used clinical guidelines, but showed considerable variation in symptoms and co-morbidities from those based on individual case definitions [25]. ...
Article
Full-text available
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe fatigue illness that occurs most commonly following a viral infection, but other physiological triggers are also implicated. It has a profound long-term impact on the life of the affected person. ME/CFS is diagnosed primarily by the exclusion of other fatigue illnesses, but the availability of multiple case definitions for ME/CFS has complicated diagnosis for clinicians. There has been ongoing controversy over the nature of ME/CFS, but a recent detailed report from the Institute of Medicine (Academy of Sciences, USA) concluded that ME/CFS is a medical, not psychiatric illness. Importantly, aspects of the biological basis of the ongoing disease have been revealed over the last 2–3 years that promise new leads towards an effective clinical diagnostic test that may have a general application. Our detailed molecular studies with a preclinical study of ME/CFS patients, along with the complementary research of others, have reported an elevation of inflammatory and immune processes, ongoing neuro-inflammation, and decreases in general metabolism and mitochondrial function for energy production in ME/CFS, which contribute to the ongoing remitting/relapsing etiology of the illness. These biological changes have generated potential molecular biomarkers for use in diagnostic ME/CFS testing.
... The International Association for CFS/ME (IACFS/ME*) Primer for Clinical Practitioners [21] approximates this more individualized approach to behavioral management with the patient and avoids the use of the CBT term given its negative connotations. With this more enlightened approach, we can do a better job of educating physicians and other practitioners on how to most effectively help CFS patients, rather than alienate them. ...
... This makes it very useful for primary care clinicians. The recently published 2014 "ME/CFS: Primer for Clinical Practitioners" published by the International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (IACFS/ME) used the CCC (15). In order to diagnose ME/CFS using the Canadian Consensus Criteria (CCC) (3), exclusion criteria must first be applied; then the patient must have the following criteria: pathological fatigue, post-exertional fatigue and malaise, sleep dysfunction, pain, cognitive dysfunction, and two symptoms from the following categories: autonomic, neuroendocrine or immune. ...
Article
Full-text available
This review was written from the viewpoint of the treating clinician to educate health care professionals and the public about Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). It includes: the clinical definition of ME/CFS with emphasis on how to diagnose ME/CFS; the etiology, pathophysiology, management approach, long-term prognosis and economic cost of ME/CFS. After reading this review, you will be better able to diagnose and treat your patients with ME/CFS using the tools and information provided. Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, chronic medical condition characterized by symptom clusters that include: pathological fatigue and malaise that is worse after exertion, cognitive dysfunction, immune dysfunction, unrefreshing sleep, pain, autonomic dysfunction, neuroendocrine and immune symptoms. ME/CFS is common, often severely disabling and costly. The Institute of Medicine (IOM) reviewed the ME/CFS literature and estimates that between 836,000 and 2.5 million Americans have ME/CFS at a cost of between 17 and 24 billion dollars annually in the US. The IOM suggested a new name for ME/CFS and called it Systemic Exertion Intolerance Disease (SEID). SEID's diagnostic criteria are less specific and do not exclude psychiatric disorders in the criteria. The 2010 Canadian Community Health Survey discovered that 29% of patients with ME/CFS had unmet health care needs and 20% had food insecurity - lack of access to sufficient healthy foods. ME/CFS can be severely disabling and cause patients to be bedridden. Yet most patients (80%) struggle to get a diagnosis because doctors have not been taught how to diagnose or treat ME/CFS in medical schools or in their post-graduate educational training. Consequently, the patients with ME/CFS suffer. They are not diagnosed with ME/CFS and are not treated accordingly. Instead of compassionate care from their doctors, they are often ridiculed by the very people from whom they seek help. The precise etiology of ME/CFS remains unknown, but recent advances and research discoveries are beginning to shed light on the enigma of this disease including the following contributors: infectious, genetic, immune, cognitive including sleep, metabolic and biochemical abnormalities. Management of patients with ME/CFS is supportive symptomatic treatment with a patient centered care approach that begins with the symptoms that are most troublesome for the patient. Pacing of activities with strategic rest periods is, in our opinion, the most important coping strategy patients can learn to better manage their illness and stop their post-exertional fatigue and malaise. Pacing allows patients to regain the ability to plan activities and begin to make slow incremental improvements in functionality.
... Recently the International Consensus Panel developed criteria and suggested also using the term "myalgic encephalomyelitis" (ME), due to widespread inflammation and the multisystem-ic neuropathology of the disease (Carruthers et al., 2011). The primer for clinical practitioners, published in 2012, gives advice on how to diagnose ME/CFS and which therapies can be used (Friedberg, 2012). According to population-based studies, already reported 15 years ago, the estimated worldwide prevalence of ME/CFS is from 0.2 up to 2.6%. ...
Article
Full-text available
Xenotropic murine leukemia virus-related virus (XMRV) has been considered a possible trigger of myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS) and could also be linked with unspecified encephalopathy. The aim of this study was to analyse the frequency of XMRV proviral sequences in peripheral blood leukocyte (PBL) DNA from 150 patients with ME/CFS and 30 apparently healthy individuals, as well as in PBL and brain tissue DNA from 61 individuals with/without unspecified encephalopathy. Targeting the XMRV proviral gag gene sequence by nested polymerase chain reaction (nPCR) with previously reported primer sets, provirus was not detected either in DNA from patients with ME/CFS and individuals with unspecified encephalopathy, or in apparently healthy individuals. Only the positive control gave the amplimer of 410 base pairs (bp) after the second round that corresponds to the expected XMRV gag gene fragment. In addition, DNA was found to be negative in nPCR assays, targeting XMRV specific env gene sequence, using previously described primer sets. Also only positive control gave the amplimer of 218 bp after the second round, corresponding to the expected XMRV env gene fragment. Using nPCR we found no evidence of XMRV infection either in apparently healthy individuals or in patients with ME/CFS and individuals with unspecified encephalopathy.
Article
Full-text available
The Institute of Medicine recently proposed a new case definition for chronic fatigue syndrome (CFS), as well as a new name, Systemic Exertion Intolerance Disease (SEID). Contrary to the Fukuda et al.'s CFS case definition, there are few exclusionary illnesses specified for this new SEID case definition. The current study explored this decision regarding exclusionary illnesses using the SEID criteria with four distinct data sets involving patients who had been identified as having CFS, as well as healthy controls, community controls, and other illness groups. The findings indicate that many individuals from major depressive disorder illness groups as well as other medical illnesses were categorized as having SEID. The past CFS Fukuda et al. prevalence rate in a community based sample of 0.42 increased by 2.8 times with the new SEID criteria. The consequences for this broadening of the case definition are discussed.
Article
Full-text available
ME/CFS is a serious illness affecting several hundred thousand British people. Some 25% of people with ME/CFS may be severely ill (housebound or bedbound), sometimes for decades. This observational, questionnaire-based study was designed to identify risk factors for severe disease. Exposure to potential risk factors, including familial risks, personality, and early management of the illness, was compared in 124 people with severe disease and 619 mildly ill controls. Severity was determined by self-report and the Barthel (activities of daily living) Index. Premorbid personality was assessed using the Neuroticism and Conscientiousness domains of the IPIP scale. Analysis was by tests of association and logistic regression. Early management of the illness appeared the most important determinant of severity. Having a mother with ME/CFS was also important. Smoking and personality were not risk factors, neurotic traits being more frequent among the less severely ill. Conscientiousness overall was not related to severity.
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The Institute of Medicine (IOM) in the US has recently proposed that the term Systemic Exertion Intolerance Disease (SEID) replace Chronic Fatigue Syndrome (CFS). In addition, the IOM proposed a new case definition for SEID, which includes substantial reductions or impairments in the ability to engage in pre-illness activities, unrefreshing sleep, post-exertional malaise, and either cognitive impairment or orthostatic intolerance. Unfortunately, these recommendations for a name change were not vetted with patient and professional audiences, and the new criteria were not evaluated with data sets of patients and controls. A recent poll suggests that the majority of patients reject this new name. In addition, studies have found that that prevalence rates will dramatically increase with the new criteria, particularly due to the ambiguity revolving around exclusionary illnesses. Findings suggest that the new criteria select more patients who have less impairment and fewer symptoms than several other criteria. The implications of these findings are discussed.
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