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Review of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: An evidence-based approach to diagnosis and management by clinicians

  • Environmental Health Clinic, Women's College Hospital


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.
Appendices Found Online Only:
Appendices: Tools for Clinicians:
1. Functional Capacity Scale
2. ME/CFS Clinical Diagnostic Criteria Worksheet
3. Definition of ME/CFS for Children
4. Activity Log
Appendix 1 : Functional Capacity Scale
Write (using ink) in each hourly time slot
1. your activity using one word (e.g. dressed, made bed, nap) and
2. an energy scale number from the Functional Capacity Scale below as you are doing it throughout the day.
Rest is defined as lying down, eyes shut, meditating or sleeping.
You may change the times on the left hand side of the log to suit your usual daily schedule.
Complete it every day and keep it in a handy place
Take your completed logs to your doctor/other health care provider at follow-up visits.
Your logs assist your doctor/other health care provider to adjust your treatment plan as needed.
Completed logs may reassure your insurance company of your active ongoing participation in your treatment.
The Functional Capacity Scale incorporates energy rating, symptom severity, and activity level. The description after
each scale number should help you to rate your functional capacity every hour of each day.
Energy Number:
0 = No energy, severe symptoms including very poor concentration; bed ridden all day; cannot do self-care (e.g.
need bed bath to be given).
1 = Severe symptoms at rest, including very poor concentration; in bed most of the day; need assistance with self-
care activities (bathing).
2 = Severe symptoms at rest, including poor concentration; frequent rests or naps; need some assistance with
limited self-care activities.
3 = Moderate symptoms at rest, including poor concentration; need frequent rests or naps; can do independent
self-care but have severe post exertion fatigue.
4 = Moderate symptoms at rest, including some difficulty concentrating; need frequent rests throughout the day;
can do independent self-care and limited activities of daily living (e.g. light housework, laundry); can walk for a
few minutes per day.
5 = Mild symptoms at rest with fairly good concentration for short periods (15 minutes); need a.m. and p.m. rest;
can do independent self-care and moderate activities of daily living, but have slight post exertion fatigue; can
walk 10-20 minutes per day.
6 = Mild or no symptoms at rest with fairly good concentration for up to 45 minutes, cannot multitask; need
afternoon rest; can do most activities of daily living except vacuuming; can walk 20-30 minutes per day; can do
volunteer work maximum total time 4 hours per week, with flexible hours.
7 = Mild or no symptoms at arrest with good concentration for up to ½ day; can do more intense activities of daily
living (e.g. grocery shopping, vacuuming) but may get post exertion fatigue if ‘overdo’: can walk 30 minutes per
day; can work limited hours, less than 25 hours per week; no or minimal social life.
8 = Mild intermittent symptoms with good concentration; can do full self-care, work 40 hours per week, enjoy a
social life, do moderate vigorous exercise three times per week.
9 = No symptoms with very good concentration, full work and social life; can do vigorous exercise three to five
times a week.
10 = No symptoms, excellent concentration, over achiever (sometimes may require less sleep than average
NUMBER OF USABLE HOURS / DAY = Number of hours NOT asleep or resting/meditating with eyes closed.
Dr. Alison Bested © Please use this with your patients.
Dr. Lynn Marshall
Appendix 2 : ME/CFS CCC Clinical Diagnostic Criteria Worksheet*
Name____________________________ Patient ID___________________ Date _______________
To diagnose ME/CFS, the patient must have the following clinical symptom criteria:
Pathological fatigue, post-exertional malaise, sleep problems, pain, two neurocognitive symptoms, and
at least one symptom from two of the following categories: autonomic, neuroendocrine, immune
The fatigue and the other symptoms must persist, or be relapsing for at least six months in adults,
or three months in children and adolescents. A provisional diagnosis may be possible earlier
The symptoms cannot be explained by another illness.
Improved diagnostic accuracy can be obtained by measuring the severity and frequency of the listed
Clinical Criteria Present
Description of Symptoms
Pathological fatigue [ ]
A significant degree of new onset, unexplained, persistent or recurrent
physical and/or mental fatigue that substantially reduces activity levels and
which is not the result of ongoing exertion and is not relieved by rest
Post-exertional malaise & [ ]
worsening of symptoms
Mild exertion or even normal activity is followed by malaise, the loss of
physical and mental stamina and/or worsening of other symptoms.
Recovery is delayed, taking more than 24 hours
Sleep problems [ ]
Sleep is un-refreshing:
disturbed quantity - daytime hypersomnia or nighttime insomnia
and/or disturbed rhythm - day/night reversal
Rarely, there is no sleep problem
Pain [ ]
Pain is widespread, migratory or localized:
myalgia; arthralgia (without signs of inflammation); and/or
headache - a new type, pattern or severity
Rarely, there is no pain
2 Cognitive symptoms [ ]
Impaired concentration, short term memory or word retrieval;
hypersensitivity to light, noise or emotional overload;
confusion; disorientation; slowness of thought; muscle weakness; ataxia
At least 1 symptom from
2 of these categories:
(a) Autonomic [ ]
(b) Neuroendocrine [ ]
(c) Immune [ ]
(a) Autonomic:
Orthostatic intolerance; neurally mediated hypotension (NMH);
postural orthostatic tachycardia (POTS); light-headedness;
extreme pallor; palpitations; exertional dyspnea;
urinary frequency; irritable bowel syndrome (IBS); nausea
(b) Neuroendocrine:
Low body temperature; cold extremities; sweating;
intolerance to heat or cold; reduced tolerance for stress; other symptoms
worsen with stress; weight change; abnormal appetite
(c) Immune:
Recurrent flu-like symptoms; sore throats; tender lymph nodes;
fevers; new sensitivities to food, medicines, odors or chemicals
ME/CFS Clinical Diagnostic Criteria Worksheet (continued)
Symptom Characteristics:
A sudden onset is most common, but the onset may be gradual
Symptoms may vary from day to day or during the day
Relapses and remissions are frequent
Post-exertional symptom flare-ups may occur immediately or they can be delayed 24 hours or more
If pain and/or sleep disorder are absent, ME/CFS can be diagnosed if the illness has an abrupt onset
Exclusionary illnesses:
Many other illnesses have symptoms that mimic ME/CFS symptoms. Active disease processes that could explain the
major symptoms of fatigue, sleep disturbance, pain, and neurocognitive dysfunction must be ruled out by history,
physical examination and medical testing. The following lists some more common, exclusionary conditions:
Autoimmune diseases such as rheumatoid arthritis, lupus
Cardiac disease
Endocrine disorders such as diabetes, Addison’s disease, thyroid disease, menopause
Infectious diseases such as tuberculosis, HIV/AIDS, chronic hepatitis, Lyme disease
Intestinal diseases such as celiac or Crohn’s disease
Neurological disorders such as multiple sclerosis, Parkinson's disease, myasthenia gravis
Primary psychiatric disorders and substance abuse (but not clinical depression)
Significant pulmonary disease
Primary sleep disorders such as sleep apnea.
Non-exclusionary conditions:
Some co-morbid entities commonly occur in association with ME/CFS. They include: allergies,
fibromyalgia (FM), irritable bowel syndrome (IBS) and multiple chemical sensitivities (MCS)
Any medical condition that has been adequately treated and is under control
Any isolated physical abnormality or laboratory test that is insufficient to diagnose an exclusionary
ME/CFS and FM are often closely associated and should be considered to be overlapping syndromes.
A co-morbid condition may precede the onset of ME/CFS by many years, but then become associated with it.
If the patient has unexplained, prolonged fatigue but has an insufficient number of symptoms to meet the criteria
for ME/CFS, the illness should be classified as idiopathic chronic fatigue.
_________ Patient meets the criteria for ME/CFS
_________ Full criteria not met but patient should be monitored
__________________________________ _______________
Provider’s Signature Date
Carruthers BM, et al. ME/CFS: Clinical Working Case Definition, Diagnostic and Treatment Protocols. J CFS 2003;11(1):7-115.
Jason LA, et al. The development of a revised Canadian Myalgic Encephalomyelitis-Chronic Fatigue Syndrome case
definition. American J Biochemistry Biotechnology 2010;6(2): 120-135.
Appendix 3 : Definition of ME/CFS for Children
Jason LA Barker K Brown A. Pediatric Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Rev Health Care.
I. Clinically evaluated, unexplained, persistent or relapsing chronic fatigue over the past 3 months that:
A. Is not the result of ongoing exertion
B. Is not substantially alleviated by rest
C. Results in substantial reduction in previous levels of educational, social and personal activities
D. Must persist or reoccur for at least three months
II. The concurrent occurrence of the following classic ME/CFS symptoms, which must have
persisted or recurred during the past three months of illness (symptoms may predate the
reported onset of fatigue).
A. Post-exertional malaise and/or post-exertional fatigue.
With activity (it need not be strenuous and may include walking up a flight of
stairs, using a computer, or reading a book), there must be a loss of physical or
mental stamina, rapid/sudden muscle or cognitive fatigability, post-exertional
malaise and/or fatigue and a tendency for other associated symptoms within
the patient’s cluster of symptoms to worsen. The recovery is slow, often taking
24 hours or longer.
B. Unrefreshing sleep or disturbance of sleep quantity or rhythm disturbance.
May include prolonged sleep (including frequent naps), disturbed sleep (e.g.,
inability to fall asleep or early awakening), and/or day/night reversal.
C. Pain (or discomfort) that is often widespread and migratory in nature. At least one
symptom from any of the following:
Myofascial and/or joint pain (Myofascial pain can include deep pain, muscle
twitches, or achy and sore muscles. Pain, stiffness, or tenderness may occur
in any joint but must be present in more than one joint and lacking edema or
other signs of inflammation.)
Abdominal and/or head pain (May experience eye pain/sensitivity to bright
light, stomach pain, nausea, vomiting, or chest pain. Headaches often described
as localized behind the eyes or in the back of the head. May include
headaches localized elsewhere, including migraines.)
D. Two or more neurocognitive manifestations:
Impaired memory (self-reported or observable disturbance in ability to recall
information or events on a short-term basis)
Difficulty focusing (disturbed concentration may impair ability to remain on
task, to screen out extraneous/excessive stimuli in a classroom, or to
focus on reading, computer/work activity, or television programs)
Difficulty finding the right word
Frequently forget what wanted to say
Absent mindedness
Slowness of thought
Difficulty recalling information
Need to focus on one thing at a time
Trouble expressing thought
Difficulty comprehending information
Frequently lose train of thought
New trouble with math or other educational subjects
E. At least one symptom from two of the following three categories:
1. Autonomic manifestations: Neurally mediated hypotension, postural orthostatic
tachycardia, delayed postural hypotension, palpitations with or without
cardiac arrhythmias, dizziness, feeling unsteady on the feetdisturbed balance,
shortness of breath.
2. Neuroendocrine manifestations: Recurrent feelings of feverishness and
cold extremities, subnormal body temperature and marked diurnal fluctuations,
sweating episodes, intolerance of extremes of heat and cold, marked
weight change-loss of appetite or abnormal appetite, worsening of symptoms
with stress.
3. Immune manifestations: Recurrent flu-like symptoms, non-exudative sore
or scratchy throat, repeated fevers and sweats, lymph nodes tender to palpitation
generally minimal swelling noted, new sensitivities to food, odors, or
III. Exclusionary conditions:
A. Any active medical condition that may explain the presence of chronic fatigue, such as:
1. Untreated hypothyroidism
2. Sleep apnea
3. Narcolepsy
4. Malignancies
5. Leukemia
6. Unresolved hepatitis
7. Multiple Sclerosis
8. Juvenile rheumatoid arthritis
9. Lupus erythematosus
11. Severe obesity (BMI greater than 40)
12. Celiac disease
13. Lyme disease
B. Some active psychiatric conditions that may explain the presence of chronic
fatigue, such as:
1. Childhood schizophrenia or psychotic disorders
2. Bipolar disorder
3. Active alcohol or substance abuseexcept as below:
a) Alcohol or substance abuse that has been successfully treated and
resolved should not be considered exclusionary.
4. Active anorexia nervosa or bulimia nervosaexcept as below:
a) Eating disorders that have been treated and resolved should not be
considered exclusionary.
5. Depressive disorders
IV. May have presence of concomitant disorders that do not adequately explain fatigue, and
are, therefore, not necessarily exclusionary.
1. Psychiatric diagnoses such as:
a) School phobia
b) Separation anxiety
c) Anxiety disorders
d) Somatoform disorders
e) Depressive disorders
2. Other conditions defined primarily by symptoms that cannot be confirmed by
diagnostic laboratory tests, such as:
a) Multiple food and/or chemical sensitivity
b) Fibromyalgia
3. Any condition under specific treatment sufficient to alleviate all symptoms
related to that condition and for which the adequacy of treatment has been
4. Any condition, that was treated with definitive therapy before development of
chronic symptomatic sequelae.
5. Any isolated and unexplained physical examination, laboratory or imaging test
abnormality that is insufficient to strongly suggest the existence of an
exclusionary condition.
Appendix 4 : Activity Log
Name: ______________________________ Date Commencing: _______________________
SLEEP: Write number of hours slept and quality 1 = very poor 2 = poor 3 = fair 4 = good 5 = very good
Functional Capacity Scale: Record your activity and energy rating every hour using the scale 1-10/10
Activities: (please specify)
6 a.m.
7 a.m.
8 a.m.
9 a.m.
10 a.m.
11 a.m.
12 p.m.
1 p.m.
2 p.m.
3 p.m.
4 p.m.
5 p.m.
6 p.m.
7 p.m.
8 p.m.
9 p.m.
10 p.m.
11 p.m.
# of minutes
# of usable
hours / day
Dr. Alison Bested © We encourage you to copy this log for use with your patients.
Dr. Rosemary Underhill
... Ідентичність вивчалась багатьма авторами (Г.Андреєва, Е. Еріксон, Б.Іванененко, В.Кириченко, Л.Кривобородтко, С.Ревенко, Л. Шнейдер). Значна увага приділялась вивченню особистісної ідентичності старшокласника та їх соціометричного статусу в групі [3,4,6,7,8]. Вивченню ідентичності як показника психічного здоров'я присвячені роботи таких вчених як: (Е. ...
... Список інформаційних джерел: [3][4][5][6][7]. Нагадаємо, що прокрастинація це свідоме відкладання, відтермінування суб'єктом намічених дій, завдань, незважаючи на негативні наслідки такої поведінки; це своєрідна емоційна реакція особистості на планові або необхідні справи, схильність людини до відкладання своїх справ "на потім", "на завтра", "на майбутнє". ...
... При цьому вікові закономірності розвитку наповнюються реальним змістом, коли розглядаються в нерозривній єдності з індивідуальними особливостями особистості, що розвивається. У ході проведеного нами дослідження встановлено, що розвиток рухових та інтелектуальних здібностей порізному співвідноситься у юнаків у процесі дорослішання, має зв'язки з нейро, та психодинамічними рівнями індивідуальності та є проявом індивідуальних особливостей вікового розвитку [5,6,7,8]. ...
Conference Paper
Full-text available
Матеріали четвертого міжнародного симпозіуму «Освіта і здоров’я підростаючого покоління»: Зб. наук. Праць / За ред. Страшка С.В. – Вип. 4. – К.: Алатон, 2022. – 141 с.
... Myalgic encephalomyelitis/chronic fatigue syndrome (ME / CFS) is a chronic acquired disease characterized by pathological fatigue, with worsening of fatigue and other symptoms after physical or mental exertion, which often lasts more than 24 hours (socalled post-exertional malaise), unrefreshing sleep, cognitive impairment, pain syndromes, neuroendocrine and immune dysfunctions of and the disorder of autonomic nervous regulation (dysautonomia) [1]. The prevalence of ME/CFS according to the recent systemic review is 0.89%, and the disorder is characterized by an approximately 1.5fold predominance of women [2]. ...
... Seven of these symptoms belonged to the "post-expression malaise" domain, which is one of the key manifestations of ME / CFS [1]. 4 symptoms belonged to the domain of "immune dysfunction", 4 symptoms -to the domain of "sleep disorders", 2 symptoms to the domain "neurological sensory / motor disorders", 2 symptoms to the domain "dysfunction of the autonomic nervous system", and 1 to the domain of "pain syndromes" . ...
A Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating chronic disease of unknown aetiology under growing interest now in view of the increasingly recognized post-COVID syndrome as a new entity with similar clinical presentation. We performed the first cross-sectional study of ME/CFS in community population in Russia and then described and compared some clinical and pathophysiological characteristics of ME/CFS and post-COVID syndrome as neuroimmune disorders. Of the cohort of 76 individuals who suggested themselves suffering from ME/CFS 56 subsequently were confirmed as having CFS/ME according to ≥1 of the 4 most commonly used case definition. Of the cohort of 14 individuals with post-COVID-19 syndrome 14 met diagnostic criteria for ME/CFS. The prevalence of clinically expressed and subclinical anxiety and depression in ME / CFS and post-COVID ME/CFS did not differ significantly from that in healthy individuals. Severity of anxiety / depressive symptoms did not correlate with the severity of fatigue neigther in ME / CFS nor in post-COVID ME/CFS, but the positive correlation was found between the severity of fatigue and 20 other symptoms of ME / CFS related to the domains of “post-exertional exhaustion”, “immune dysfunction”, “sleep disturbances”, "dysfunction of the autonomic nervous system", "neurological sensory / motor disorders" and "pain syndromes". Immunological abnormalities were identified in 12/12 patients with ME / CFS according to the results of laboratory testing. The prevalence of postural orthostatic tachycardia assessed by the active standing test was 37.5% in ME / CFS and 75.0% in post-COVID ME/CFS (the latter was higher than in healthy controls, p = 0.02) There was a more pronounced increase in heart rate starting from the 6th minute of the test in post-COVID ME/CFS compared with the control group. Assessment of the functional characteristics of microcirculation by laser doppler flowmetry revealed obvious and very similar changes in ME/CFS and post-COVID ME/CFS compared to the healthy controls. The identified pattern corresponded to the hyperemic form of microcirculation disorders, usually observed in acute inflammatory processes or in deficiency of systemic vasoconstriction influences.
... However, this study is one of the various attempts to manage chronic fatigue syndrome due to COVID-19. Several authors have agreed that possible treatments of this condition must differentiate possible organic and functional causes [23]. Although a clear and unambiguous pathogenesis has not yet been identified, there is agreement on the roles of other viral infections. ...
Full-text available
Introduction: Although the understanding of several aspects of long COVID-19 syndrome is increasing, there is limited literature regarding the treatment of these signs and symptoms. The aim of our systematic review was to understand which therapies have proved effective against the symptoms of long COVID-19. Methods: A systematic search for randomized controlled or clinical trials in several databases was conducted through 15 May 2022. Specific inclusion criteria included: (1) intervention studies, either randomized controlled (RCTs) or clinical trials; (2) diagnosis of long COVID-19, according to the World Health Organization criteria; (3) presence of long COVID-19 for at least 12 weeks after SARS-CoV-2 infection. Results: We initially found 1638 articles to screen. After removing 1602 works based on their title/abstract, we considered 35 full texts, and among them, two intervention studies were finally included. The first RCT focused on the greater improvement of treatment combining olfactory rehabilitation with oral supplementation with Palmitoylethanolamide and Luteolin in patients with olfactory dysfunction after COVID-19. The second study evaluated the positive impact of aromatherapy vs. standard care in adult females affected by fatigue. Conclusion: Our systematic review found only two intervention studies focused on patients affected by long COVID-19. More intervention studies are needed to investigate potentially positive interventions for long COVID-19 symptoms.
... Inefficient of ATP synthesis as well as dysregulation in fatty acid and amino acid metabolism have been suggested to be also implicated in CFS pathogenesis [19] The anti-inflammatory properties of mitochondrial nutrients (MNs) are well documented in the literature [20,21]. The dietary implementation of MNs seems to prevent the uncontrolled production of mitochondrial reactive oxygen species (mtROS), responsible of mitochondrial damage and mitochondrial dysfunction. ...
Full-text available
Chronic COVID syndrome is characterized by chronic fatigue, myalgia, depression and sleep disturbances, similar to chronic fatigue syndrome (CFS) and fibromyalgia syndrome. Implementations of mitochondrial nutrients (MNs) with diet are important for the clinical effects antioxidant. We examined if use of an association of coenzyme Q10 and alpha lipoic acid (Requpero®) could reduce chronic covid symptoms. The Requpero study is a prospective observational study in which 174 patients, who had developed chronic-covid syndrome, were divided in two groups: The first one (116 patients) received coenzyme Q10 + alpha lipoic acid, and the second one (58 patients) did not receive any treatment. Primary outcome was reduction in Fatigue Severity Scale (FSS) in treatment group compared with control group. complete FSS response was reached most frequently in treatment group than in control group. A FSS complete response was reached in 62 (53.5%) patients in treatment group and in two (3.5%) patients in control group. A reduction in FSS core < 20% from baseline at T1 (non-response) was observed in 11 patients in the treatment group (9.5%) and in 15 patients in the control group (25.9%) (p < 0.0001). To date, this is the first study that tests the efficacy of coenzyme Q10 and alpha lipoic acid in chronic Covid syndrome. Primary and secondary outcomes were met. These results have to be confirmed through a double blind placebo controlled trial of longer duration.
... It has been estimated that the frequency of CFS/ME is around 0.2% -0.8% of the population with between 836,000 to 2.5 million Americans suffering from the condition. The annual health care cost is estimated to be between US$17-24 billion [2]. ...
Full-text available
Citation: Gregory Russell-Jones.(2022). Functional Vitamin B12 deficiency in Chronic Fatigue Syndrome. Int J Psychiatry 7(3): 153-158. Abstract Chronic Fatigue Syndrome/Myalgic encephalomyelitis (CFS/ME) is a complex chronic condition, characterized by periods of extreme fatigue, for which an underlying medical condition has previously not been identified. Many of the symptoms of CFS/ME, are, though, similar to those with vitamin B12 deficiency. In contrast to nutritional vitamin B12 deficiency, the majority of individuals with CFS have been shown to have functional vitamin B12 deficiency as well as functional vitamin B2 deficiency. This functional B12 deficiency occurred despite elevated serum B12 being found, and hence presents as Paradoxical vitamin B12 deficiency. As such, CFS due to functional B2 deficiency presents as Paradoxical B12 deficiency. Maintenance of vitamin B12 functional activity is critically dependent upon functional B2 sufficiency, and hence resolution of CFS there must first be resolution of functional B2 deficiency before treatment with vitamin B12 can be effective.
... The VN stimulates the hypothalamic-pituitary-adrenal (HPA) axis regulating glucocorticoid hormone production in the adrenal glands and regulating cholinergic anti-inflammatory pathways via an inflammatory reflex [54]. Dysfunction of the HPA is also associated with autonomic and immune system dysfunction and an inability to tolerate changes in temperature [55]. Endogenic glucocorticoids play vital roles in biological processes such as metabolism, growth, and inflammation, where they have immunosuppressive activity [56]. ...
Full-text available
Functional somatic syndromes are increasingly diagnosed in chronically ill patients presenting with an array of symptoms not attributed to physical ailments. Conditions such as chronic fatigue syndrome, fibromyalgia syndrome, or irritable bowel syndrome are common disorders that belong in this broad category. Such syndromes are characterised by the presence of one or multiple chronic symptoms including widespread musculoskeletal pain, fatigue, sleep disorders, and abdominal pain, amongst other issues. Symptoms are believed to relate to a complex interaction of biological and psychosocial factors, where a definite aetiology has not been established. Theories suggest causative pathways between the immune and nervous systems of affected individuals with several risk factors identified in patients presenting with one or more functional syndromes. Risk factors including stress and childhood trauma are now recognised as important contributors to chronic pain conditions. Emotional, physical, and sexual abuse during childhood is considered a severe stressor having a high prevalence in functional somatic syndrome suffers. Such trauma permanently alters the biological stress response of the suffers leading to neuroexcitatory and other nerve issues associated with chronic pain in adults. Traumatic and chronic stress results in epigenetic changes in stress response genes, which ultimately leads to dysregulation of the hypothalamic-pituitary axis, the autonomic nervous system, and the immune system manifesting in a broad array of symptoms. Importantly, these systems are known to be dysregulated in patients suffering from functional somatic syndrome. Functional somatic syndromes are also highly prevalent co-morbidities of psychiatric conditions, mood disorders, and anxiety. Consequently, this review aims to provide insight into the role of the nervous system and immune system in chronic pain disorders associated with the musculoskeletal system, and central and peripheral nervous systems.
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Objectives: This meta-analysis aimed to assess the effectiveness and safety of Chinese herbal medicine (CHM) in treating chronic fatigue syndrome (CFS). Methods: Nine electronic databases were searched from inception to May 2022. Two reviewers screened studies, extracted the data, and assessed the risk of bias independently. The meta-analysis was performed using the Stata 12.0 software. Results: Eighty-four RCTs that explored the efficacy of 69 kinds of Chinese herbal formulas with various dosage forms (decoction, granule, oral liquid, pill, ointment, capsule, and herbal porridge), involving 6,944 participants were identified. This meta-analysis showed that the application of CHM for CFS can decrease Fatigue Scale scores (WMD: –1.77; 95%CI: –1.96 to –1.57; p < 0.001), Fatigue Assessment Instrument scores (WMD: –15.75; 95%CI: –26.89 to –4.61; p < 0.01), Self-Rating Scale of mental state scores (WMD: –9.72; 95%CI:–12.26 to –7.18; p < 0.001), Self-Rating Anxiety Scale scores (WMD: –7.07; 95%CI: –9.96 to –4.19; p < 0.001), Self-Rating Depression Scale scores (WMD: –5.45; 95%CI: –6.82 to –4.08; p < 0.001), and clinical symptom scores (WMD: –5.37; 95%CI: –6.13 to –4.60; p < 0.001) and improve IGA (WMD: 0.30; 95%CI: 0.20–0.41; p < 0.001), IGG (WMD: 1.74; 95%CI: 0.87–2.62; p < 0.001), IGM (WMD: 0.21; 95%CI: 0.14–0.29; p < 0.001), and the effective rate (RR = 1.41; 95%CI: 1.33–1.49; p < 0.001). However, natural killer cell levels did not change significantly. The included studies did not report any serious adverse events. In addition, the methodology quality of the included RCTs was generally not high. Conclusion: Our study showed that CHM seems to be effective and safe in the treatment of CFS. However, given the poor quality of reports from these studies, the results should be interpreted cautiously. More international multi-centered, double-blinded, well-designed, randomized controlled trials are needed in future research. Systematic Review Registration : [ ], identifier [CRD42022319680].
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease with an unclear etiology and pathogenesis. Both an involvement of the immune system and gut microbiota dysbiosis have been implicated in its pathophysiology. However, potential interactions between adaptive immune responses and the microbiota in ME/CFS have been incompletely characterized. Here, we profiled antibody responses of patients with severe ME/CFS and healthy controls against microbiota and viral antigens represented as a phage-displayed 244,000 variant library. Patients with severe ME/CFS exhibited distinct serum antibody epitope repertoires against flagellins of Lachnospiraceae bacteria. Training machine learning algorithms on this antibody-binding data demonstrated that immune responses against gut microbiota represent a unique layer of information beyond standard blood tests, providing improved molecular diagnostics for ME/CFS. Together, our results point toward an involvement of the microbiota-immune axis in ME/CFS and lay the foundation for comparative studies with inflammatory bowel diseases and illnesses characterized by long-term fatigue symptoms, including post–COVID-19 syndrome.
Introduction Persistent debilitating fatigue is a frequent complaint in patients with systemic autoimmune rheumatic diseases (SARDs). Fatigue is, however, frequently overlooked in the clinic, and patients who successfully achieve remission of their disease, often still have a lowered quality of life due to its persistence. How similar is this fatigue to Myalgic encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), what is this fatigue associated with, and what tools/approaches (if any), have resulted in the improvement of fatigue in these patients is poorly defined. Areas covered Similarities between the pathophysiology of ME/CFS, systemic sclerosis (SSc) and primary systemic vasculitides (PSV) are discussed, followed by an in-depth review of the prevalence and correlates of fatigue in these diseases. The authors reviewed literature from MEDLINE, APA PsycInfo, Embase, and CINAHL. Expert opinion Persistent fatigue is a prominent feature in SARDs and may not be associated with components commonly associated with disease activity and/or progression. Immune and metabolic commonalities exist between ME/CFS, SSc, and PSVs – suggesting that common pathways inherent to the diseases and fatigue may be present. We suggest that patients with features of ME/CFS need to be identified by treating physicians, as they may require alternative approaches to therapy to improve their quality of life.
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Background: Research into acupuncture and moxibustion and their application for chronic fatigue syndrome (CFS) has been growing, but the findings have been inconsistent. Objective: To evaluate the existing randomized clinical trials (RCTs), compare the efficacy of acupuncture, moxibustion and other traditional Chinese medicine (TCM) treatments. Data sources: Three English-language databases (PubMed, Embase, Web of Science, and The Cochrane Library) and 4 Chinese-language biomedical databases (Chinese Biomedical Literature Database, VIP Database for Chinese Technical Periodicals, China National Knowledge Infrastructure, and Wanfang) were searched for RCTs published from database inception through August 2021. Study selection: RCTs include acupuncture, moxibustion, traditional Chinese herbal medicine, western medicine and no control. Data extraction and synthesis: Data were screened and extracted independently using predesigned forms. The quality of RCTs was appraised with the Cochrane Collaboration risk of bias tool. We conducted a random-effects network meta-analysis within a frequentist framework. We assessed the certainty of evidence contributing to network estimates of the main outcomes with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. Main outcomes and measures: The primary outcomes were the overall response rate and FS-14 scale. Results: A total of 51 randomized controlled trials involving 3473 patients with CFS were included in this review. Forty one studies indicate low risk or unknown risk, and the GRADE scores of the combined results show low levels. Among the main indicators, traditional Chinese medicine therapies have excellent performance. However, the overall response rate is slightly different from the results obtained from the Fatigue Scale-14 total score. Moxibustion and traditional Chinese medicine (Odds ratios 48, 95% CrI 15-150) perform better in the total effective rate, while moxibustion plus acupuncture (MD 4.5, 95% CrI 3.0-5.9) is better in the FS-14 total score. Conclusions: The effect of acupuncture and moxibustion in the treatment of CFS was significantly higher than that of other treatments. Traditional Chinese medicine should be used more widely in the treatment of CFS.
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Risk factors to prolonged fatigue syndromes (PFS) are controversial. Pre-morbid and/or current psychiatric disturbance, and/or disturbed cell-mediated immunity (CMI), have been proposed as etiologic factors. Self-report measures of fatigue and psychologic distress and three in vitro measures of CMI were collected from 124 twin pairs. Crosstwincrosstrait correlations were estimated for the complete monozygotic (MZ; 79 pairs) and dizygotic (DZ; 45 pairs) twin groups. Multivariate genetic and environmental models were fitted to explore the patterns of covariation between etiologic factors. For fatigue, the MZ correlation was more than double the DZ correlation (0.49 versus 0.16) indicating strong genetic control of familial aggregation. By contrast, for in vitro immune activation measures MZ and DZ correlations were similar (0.49–0.69 versus 0.42–0.53) indicating the etiologic role of shared environments. As small univariate associations were noted between prolonged fatigue and the in vitro immune measures (r = −0.07 to −0.12), multivariate models were fitted. Relevant etiologic factors included: a common genetic factor accounting for 48% of the variance in fatigue which also accounted for 4%, 6% and 8% reductions in immune activation; specific genetic factors for each of the in vitro immune measures; a shared environment factor influencing the three immune activation measures; and, most interestingly, unique environmental influences which increased fatigue but also increased markers of immune activation. PFS that are associated with in vitro measures of immune activation are most likely to be the consequence of current environmental rather than genetic factors. Such environmental factors could include physical agents such as infection and/or psychologic stress.
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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.
Research on pediatric Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is reviewed in this article. Many recent articles in this area highlight the existence of key differences between the adult and pediatric forms of the illness. This review article provides an overview of pediatric ME/ CFS, including epidemiology, diagnostic criteria, treatment, and prognosis. Challenges to the field are identified with the hope that in the future pediatric cases of ME/CFS can be more accurately diagnosed and successfully managed.
Background: Chronic fatigue syndrome (CFS) is characterised by persistent, medically unexplained fatigue, as well as symptoms such as musculoskeletal pain, sleep disturbance, headaches and impaired concentration and short-term memory. CFS presents as a common, debilitating and serious health problem. Treatment may include physical interventions, such as exercise therapy, which was last reviewed in 2004. Objectives: The objective of this review was to determine the effects of exercise therapy (ET) for patients with CFS as compared with any other intervention or control.• Exercise therapy versus 'passive control' (e.g. treatment as usual, waiting-list control, relaxation, flexibility).• Exercise therapy versus other active treatment (e.g. cognitive-behavioural therapy (CBT), cognitive treatment, supportive therapy, pacing, pharmacological therapy such as antidepressants).• Exercise therapy in combination with other specified treatment strategies versus other specified treatment strategies (e.g. exercise combined with pharmacological treatment vs pharmacological treatment alone). Search methods: We searched The Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register (CCDANCTR), the Cochrane Central Register of Controlled Trials (CENTRAL) and SPORTDiscus up to May 2014 using a comprehensive list of free-text terms for CFS and exercise. We located unpublished or ongoing trials through the World Health Organization (WHO) International Clinical Trials Registry Platform (to May 2014). We screened reference lists of retrieved articles and contacted experts in the field for additional studies SELECTION CRITERIA: Randomised controlled trials involving adults with a primary diagnosis of CFS who were able to participate in exercise therapy. Studies had to compare exercise therapy with passive control, psychological therapies, adaptive pacing therapy or pharmacological therapy. Data collection and analysis: Two review authors independently performed study selection, risk of bias assessments and data extraction. We combined continuous measures of outcomes using mean differences (MDs) and standardised mean differences (SMDs). We combined serious adverse reactions and drop-outs using risk ratios (RRs). We calculated an overall effect size with 95% confidence intervals (CIs) for each outcome. Main results: We have included eight randomised controlled studies and have reported data from 1518 participants in this review. Three studies diagnosed individuals with CFS using the 1994 criteria of the Centers for Disease Control and Prevention (CDC); five used the Oxford criteria. Exercise therapy lasted from 12 to 26 weeks. Seven studies used variations of aerobic exercise therapy such as walking, swimming, cycling or dancing provided at mixed levels in terms of intensity of the aerobic exercise from very low to quite rigorous, whilst one study used anaerobic exercise. Control groups consisted of passive control (eight studies; e.g. treatment as usual, relaxation, flexibility) or CBT (two studies), cognitive therapy (one study), supportive listening (one study), pacing (one study), pharmacological treatment (one study) and combination treatment (one study). Risk of bias varied across studies, but within each study, little variation was found in the risk of bias across our primary and secondary outcome measures.Investigators compared exercise therapy with 'passive' control in eight trials, which enrolled 971 participants. Seven studies consistently showed a reduction in fatigue following exercise therapy at end of treatment, even though the fatigue scales used different scoring systems: an 11-item scale with a scoring system of 0 to 11 points (MD -6.06, 95% CI -6.95 to -5.17; one study, 148 participants; low-quality evidence); the same 11-item scale with a scoring system of 0 to 33 points (MD -2.82, 95% CI -4.07 to -1.57; three studies, 540 participants; moderate-quality evidence); and a 14-item scale with a scoring system of 0 to 42 points (MD -6.80, 95% CI -10.31 to -3.28; three studies, 152 participants; moderate-quality evidence). Serious adverse reactions were rare in both groups (RR 0.99, 95% CI 0.14 to 6.97; one study, 319 participants; moderate-quality evidence), but sparse data made it impossible for review authors to draw conclusions. Study authors reported a positive effect of exercise therapy at end of treatment with respect to sleep (MD -1.49, 95% CI -2.95 to -0.02; two studies, 323 participants), physical functioning (MD 13.10, 95% CI 1.98 to 24.22; five studies, 725 participants) and self-perceived changes in overall health (RR 1.83, 95% CI 1.39 to 2.40; four studies, 489 participants). It was not possible for review authors to draw conclusions regarding the remaining outcomes.Investigators compared exercise therapy with CBT in two trials (351 participants). One trial (298 participants) reported little or no difference in fatigue at end of treatment between the two groups using an 11-item scale with a scoring system of 0 to 33 points (MD 0.20, 95% CI -1.49 to 1.89). Both studies measured differences in fatigue at follow-up, but neither found differences between the two groups using an 11-item fatigue scale with a scoring system of 0 to 33 points (MD 0.30, 95% CI -1.45 to 2.05) and a nine-item Fatigue Severity Scale with a scoring system of 1 to 7 points (MD 0.40, 95% CI -0.34 to 1.14). Serious adverse reactions were rare in both groups (RR 0.67, 95% CI 0.11 to 3.96). We observed little or no difference in physical functioning, depression, anxiety and sleep, and we were not able to draw any conclusions with regard to pain, self-perceived changes in overall health, use of health service resources and drop-out rate.With regard to other comparisons, one study (320 participants) suggested a general benefit of exercise over adaptive pacing, and another study (183 participants) a benefit of exercise over supportive listening. The available evidence was too sparse to draw conclusions about the effect of pharmaceutical interventions. Authors' conclusions: Patients with CFS may generally benefit and feel less fatigued following exercise therapy, and no evidence suggests that exercise therapy may worsen outcomes. A positive effect with respect to sleep, physical function and self-perceived general health has been observed, but no conclusions for the outcomes of pain, quality of life, anxiety, depression, drop-out rate and health service resources were possible. The effectiveness of exercise therapy seems greater than that of pacing but similar to that of CBT. Randomised trials with low risk of bias are needed to investigate the type, duration and intensity of the most beneficial exercise intervention.
Conference Paper
Patients with chronic fatigue syndrome (CFS) are known to have chronic cognitive impairment known as brain fog accompanied by persistent fatigue. To gain insight into how cognitive impairment is produced, EEG was recorded from 19 scalp locations with link-ear reference during a 3-minute, eyes-closed task in 50 patients with CFS and 50 healthy control subjects, matched for age (range 28 to 74 years), gender, and educational level. The Multidimensional Fatigue Inventory (MFI-20) and the Fatigue Severity Scale (FSS) were likewise administered to the same group of patients. Using the EEG data, current densities were localized and computed from 1-30 Hz with exact low-resolution electromagnetic tomography (eLORETA). Non-parametric statistical mapping (SnPM) and linear regression analyses were used to evaluate the differences in current densities in each Brodmann area grouping of cortical grey matter voxels. Results: Frontal, temporal, parietal, limbic and sub-lobar regions of interest (ROI’s) demonstrated significantly different current densities in CFS patients when compared to healthy controls (HC). Statistically significant differences were found in the delta (1-3 Hz) and in the beta-2 (19-21 Hz) frequency bands in both the left and right hemisphere. Delta sources were found predominately in the frontal and limbic regions of interest (ROI) with beta-2 sources found predominately in central and superior parietal ROIs. Linear regression models, predicting current density from the MFI-20 reduced motivation subscale, found increased delta in the left frontal, temporal, parietal, limbic and sub-lobar ROIs. eLORETA was able to detect evidence of widespread cortical hypoactivation in CFS patients as demonstrated by increased delta and decreased beta-2 sources. Taken together, our findings provide objective quantification of central nervous system dysregulation in CFS sufferers. A model of prolonged subcortical deregulation is hypothesized to explain the results.